Accelerated in vitro release testing methods for extended release parenteral dosage forms

PubMed Central

Shen, Jie; Burgess, Diane J.

2012-01-01

Objectives This review highlights current methods and strategies for accelerated in vitro drug release testing of extended release parenteral dosage forms such as polymeric microparticulate systems, lipid microparticulate systems, in situ depot-forming systems, and implants. Key findings Extended release parenteral dosage forms are typically designed to maintain the effective drug concentration over periods of weeks, months or even years. Consequently, “real-time” in vitro release tests for these dosage forms are often run over a long time period. Accelerated in vitro release methods can provide rapid evaluation and therefore are desirable for quality control purposes. To this end, different accelerated in vitro release methods using United States Pharmacopoeia (USP) apparatus have been developed. Different mechanisms of accelerating drug release from extended release parenteral dosage forms, along with the accelerated in vitro release testing methods currently employed are discussed. Conclusions Accelerated in vitro release testing methods with good discriminatory ability are critical for quality control of extended release parenteral products. Methods that can be used in the development of in vitro-in vivo correlation (IVIVC) are desirable, however for complex parenteral products this may not always be achievable. PMID:22686344

Formulation characteristics and in vitro release testing of cyclosporine ophthalmic ointments.

PubMed

Dong, Yixuan; Qu, Haiou; Pavurala, Naresh; Wang, Jiang; Sekar, Vasanthakumar; Martinez, Marilyn N; Fahmy, Raafat; Ashraf, Muhammad; Cruz, Celia N; Xu, Xiaoming

2018-06-10

The aim of the present study was to investigate the relationship between formulation/process variables versus the critical quality attributes (CQAs) of cyclosporine ophthalmic ointments and to explore the feasibility of using an in vitro approach to assess product sameness. A definitive screening design (DSD) was used to evaluate the impact of formulation and process variables. The formulation variables included drug percentage, percentage of corn oil and lanolin alcohol. The process variables studied were mixing temperature, mixing time and the method of mixing. The quality and performance attributes examined included drug assay, content uniformity, image analysis, rheology (storage modulus, shear viscosity) and in vitro drug release. Of the formulation variables evaluated, the percentage of the drug substance and the percentage of corn oil in the matrix were the most influential factors with respect to in vitro drug release. Conversely, the process parameters tested were observed to have minimal impact. An evaluation of the release mechanism of cyclosporine from the ointment revealed an interplay between formulation (e.g. physicochemical properties of the drug and ointment matrix type) and the release medium. These data provide a scientific basis to guide method development for in vitro drug release testing of ointment dosage forms. These results demonstrate that the in vitro methods used in this investigation were fit-for-purpose for detecting formulation and process changes and therefore amenable to assessment of product sameness. Published by Elsevier B.V.

Assessment of Aprotinin Loaded Microemulsion Formulations for Parenteral Drug Delivery: Preparation, Characterization, in vitro Release and Cytotoxicity Studies.

PubMed

Okur, Neslihan Üstündağ; Özdemir, Derya İlem; Kahyaoğlu, Şennur Görgülü; Şenyiğit, Zeynep Ay; Aşıkoğlu, Makbule; Genç, Lütfi; Karasulu, H Yeşim

2015-01-01

The object of the current study was to prepare novel microemulsion formulations of aprotinin for parenteral delivery and to compare in vitro characteristics and release behaviour of different Technetium-99m ((99m)Tc)-Aprotinin loaded microemulsion formulations. In addition, cytotoxicity of microemulsion formulation was evaluated with cell culture studies on human immortalized pancreatic duct epithelial-like cells. For this aim, firstly, pseudo-ternary phase diagrams were plotted to detect the formulation region and optimal microemulsions were characterized for their thermodynamic stability, conductivity, particle size, zeta potential, viscosity, pH and in vitro release properties. For in vitro release studies aprotinin was labelled with (99m)Tc and labelling efficiency, radiochemical purity and stability of the radiolabeled complex were determined by several chromatography techniques. Radiolabeling efficiency of (99m)Tc-Aprotinin was found over than 90% without any significant changes up to 6 hours after labelling at room temperature. After that, in vitro release studies of (99m)Tc-Aprotinin loaded microemulsions were performed with two different methods; dissolution from diffusion cells and dialysis bags. Both methods showed that release rate of (99m)Tc- Aprotinin from microemulsion could be controlled by microemulsion formulations. Drug release from the optimized microemulsion formulations was found lower compared to drug solution at the end of six hours. According to stability studies, the optimized formulation was found to be stable over a period of 12 months. Also, human immortalized pancreatic duct epithelial-like cells were used to evaluate the cytotoxicity of optimum formulation. Developed microemulsion did not reveal cytotoxicity. In conclusion the present study indicated that the M1-APT microemulsion is appropriate for intravenous application of aprotinin.

[Preparation of hydrophilic matrix sustained release tablets of total lactones from Andrographis paniculata and study on its in vitro release mechanism].

PubMed

Xu, Fang-Fang; Shi, Wei; Zhang, Hui; Guo, Qing-Ming; Wang Zhen-Zhong; Bi, Yu-An; Wang, Zhi-Min; Xiao, Wei

2015-01-01

In this study, hydrophilic matrix sustained release tablets of total lactones from Andrographis paniculata were prepared and the in vitro release behavior were also evaluated. The optimal prescription was achieved by studying the main factor of the type and amount of hydroxypropyl methylcellulose (HPMC) using single factor test and evaluating through cumulative release of three lactones. No burst drug release from the obtained matrix tablets was observed. Drug release sustained to 14 h. The release mechanism of three lactones from A. paniculata was accessed by zero-order, first-order, Higuchi and Peppas equation. The release behavior of total lactones from A. paniculata was better agreed with Higuchi model and the drug release from the tablets was controlled by degradation of the matrix. The preparation of hydrophilic matrix sustained release tablets of total lactones from A. paniculata with good performance of drug release was simple.

Preparation and in vitro evaluation of xanthan gum facilitated superabsorbent polymeric microspheres.

PubMed

Bhattacharya, Shiv Sankar; Mazahir, Farhan; Banerjee, Subham; Verma, Anurag; Ghosh, Amitava

2013-10-15

Interpenetrating polymer network (IPN) hydrogel microspheres of xanthan gum (XG) based superabsorbent polymer (SAP) and poly(vinyl alcohol) (PVA) were prepared by water-in-oil (w/o) emulsion crosslinking method for sustained release of ciprofloxacin hydrochloride (CIPRO). The microspheres were prepared with various ratios of hydrolyzed SAP to PVA and extent of crosslinking density. The prepared microspheres with loose and rigid surfaces were evidenced by scanning electron microscope (SEM). Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis confirmed the IPN formation. Differential scanning calorimetry (DSC) study was performed to understand the dispersion nature of drug after encapsulation. The in vitro drug release study was extensively evaluated depending on the process variables in both acidic and alkaline media. All the formulations exhibited satisfactory physicochemical and in vitro release characteristics. Release data indicated a non-Fickian trend of drug release from the formulations. Based on the results, this study suggest that CIPRO loaded IPN microspheres were suitable for sustained release application. Copyright © 2013 Elsevier Ltd. All rights reserved.

Local Anesthetic Microcapsulation.

DTIC Science & Technology

1982-06-14

viscosities as disparate as R. S. V. 4.~O~6dl/g. ’ Microencapsulation of lidocaine (base) yielded 212-300 micron microcapsules with 50% in vitro drug...release in 6 hours; 150-212 micron microcapsules released 3-0% i7n-2 hours. Etidocaing and bupivacaine vo> 41’. were microencapsulated in a more...Etidocaine Microencapsulation 9 c. Bupivacaine Microencapsulation 12 3. In Vitro Drug Release from Microcapsules 15 a. Lidocaine (base) Release Studies

Controlled delivery of basal insulin from phase-sensitive polymeric systems after subcutaneous administration: in vitro release, stability, biocompatibility, in vivo absorption, and bioactivity of insulin.

PubMed

Al-Tahami, Khaled; Oak, Mayura; Singh, Jagdish

2011-06-01

The purpose of this study was to investigate the phase-sensitive delivery systems (D,L-polylactide in triacetin) for controlled delivery of insulin at basal level. The effect of varying concentration of zinc, polymer, and insulin on the in vitro release of insulin was evaluated. Stability of released insulin was investigated by differential scanning calorimetry, circular dichroism, and matrix-assisted laser desorption/ionization time of flight mass spectrometry. In Vivo insulin absorption and bioactivity were studied in diabetic rats. In vitro and In Vivo biocompatibility of delivery systems were evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and skin histology, respectively. Extended release profiles of insulin for 2, 4, and 8 weeks from delivery systems containing 20%, 30%, and 40% (w/v) polymer concentration was observed. A ratio of 1:5 insulin hexamer to zinc was shown to be optimum. Physical and chemical stability of released insulin was greatly conserved. In Vivo studies demonstrated controlled release of insulin with reduction in blood glucose for approximately 1 month. In vitro and In Vivo studies demonstrated that the delivery system was biocompatible and controlled the delivery of insulin for longer durations after single subcutaneous injection. Copyright © 2010 Wiley-Liss, Inc.

Effect of medium-chain triglycerides on the release behavior of Endostar encapsulated PLGA microspheres.

PubMed

Meng, Boyu; Li, Ling; Hua, Su; Wang, Qingsong; Liu, Chunhui; Xu, Xiangyang; Yin, Xiaojin

2010-09-15

The incomplete release of Endostar from PLGA microspheres was observed in our previous study. In the present study, we focused on the effect of medium-chain triglycerides (MCT) on the in vitro/in vivo release behavior of Endostar encapsulated PLGA microspheres, which were prepared by a water-in-oil-in-water (W/O/W) double-emulsion method with or without MCT. The in vitro accumulated release of Endostar from microspheres co-encapsulated with 30% MCT was found to be 79.04% after a 30-day incubation period in PBS (pH 7.4) at 37 degrees C. However, the accumulated release of Endostar from MCT-free microspheres was found to be only 32.22%. Pouches containing Endostar encapsulated PLGA microspheres were implanted subcutaneously in rats. The effect of MCT on the in vivo release showed a similar trend to the in vitro release. After 30 days, only 9.87% of the total encapsulated Endostar was retained in microspheres co-encapsulated with 30% MCT, while 42.25% of Endostar was retained in MCT-free microspheres. The co-encapsulation of MCT provided the microspheres with a porous surface, which significantly improved the in vitro/in vivo release of Endostar from PLGA microspheres. In addition, in vitro experiments showed that MCT co-encapsulated PLGA microspheres had more inter-connected pores, faster degradation of PLGA, and faster swelling of microspheres, which helped to explain the mechanism of the effect of MCT on improving the release of Endostar from PLGA microspheres. Copyright 2010 Elsevier B.V. All rights reserved.

In vitro effect of. Delta. sup 9 -tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E sub 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rettori, V.; Aguila, M.C.; McCann, S.M.

Previous in vivo studies have shown that {Delta}{sup 9}-tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were deigned to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or nonrepinephrine on LHRH release.more » The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E{sub 2} (PGE{sub 2}) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE{sub 2} suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE{sub 2} synthesis and release. The authors speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release.« less

A level A in vitro/in vivo correlation in fasted and fed states using different methods: applied to solid immediate release oral dosage form.

PubMed

Souliman, Sabah; Blanquet, Stéphanie; Beyssac, Eric; Cardot, Jean-Michel

2006-01-01

The first purpose of this study was to simulate the impact of food intake on drug release and absorption in vivo using a novel in vitro system which mimics the gastro-intestinal (GI) tract in man. The drug studied was acetaminophen in the form of immediate release (IR) tablets. The second purpose was to establish a level A in vitro/in vivo correlation that could predict the bioavailability of a drug instead of using difficult, time-consuming and expensive in vivo bioequivalence studies. The artificial digestive system was used to estimate the availability of acetaminophen IR tablets for absorption in fasted and fed states. The same study was performed in vivo under similar conditions. A comparison study was carried out between the classical and the novel methods to estimate the efficacy of the new in vitro system to simulate the influence of food on drug release and absorption in vivo. A level A in vitro/in vivo correlation was established with a correlation coefficient of 0.9128 and 0.9984 in the fasted and fed states, respectively. Compared to USP II method, the novel in vitro model demonstrated a high level of efficacy in mimicking the behaviour of acetaminophen IR tablets in vivo in fasted and fed states.

Liquid crystalline systems for transdermal delivery of celecoxib: in vitro drug release and skin permeation studies.

PubMed

Estracanholli, Eder André; Praça, Fabíola Silva Garcia; Cintra, Ana Beatriz; Pierre, Maria Bernadete Riemma; Lara, Marilisa Guimarães

2014-12-01

Liquid crystalline systems of monoolein/water could be a promising approach for the delivery of celecoxib (CXB) to the skin because these systems can sustain drug release, improve drug penetration into the skin layers and minimize side effects. This study evaluated the potential of these systems for the delivery of CXB into the skin based on in vitro drug release and skin permeation studies. The amount of CXB that permeated into and/or was retained in the skin was assayed using an HPLC method. Polarizing light microscopy studies showed that liquid crystalline systems of monoolein/water were formed in the presence of CXB, without any changes in the mesophases. The liquid crystalline systems decreased drug release when compared to control solution. Drug release was independent of the initial water content of the systems and CXB was released from cubic phase systems, irrespective of the initial water content. The systems released the CXB following zero-order release kinetics. In vitro drug permeation studies showed that cubic phase systems allowed drug permeation and retention in the skin layers. Cubic phase systems of monoolein/water may be promising vehicles for the delivery of CXB in/through the skin because it improved CXB skin permeation compared with the control solution.

Influence of the test method on in vitro drug release from intravitreal model implants containing dexamethasone or fluorescein sodium in poly (d,l-lactide-co-glycolide) or polycaprolactone.

PubMed

Stein, Sandra; Auel, Tobias; Kempin, Wiebke; Bogdahn, Malte; Weitschies, Werner; Seidlitz, Anne

2018-06-01

Sustained intravitreal dexamethasone (DX) administration with the FDA and EMA approved Ozurdex® implant is indicated for the treatment of macular edema and non-infectious uveitis. Since drug release after intravitreal application cannot be determined in vivo in human eyes, the characterization of drug release in vitro in addition to animal models is of great importance. The aim of this study was to provide information about the influence of the test method on the in vitro drug release from intravitreal model implants. The following test methods were used: a shaking incubator experiment in reagent tubes, the small volume USP apparatus 7, the Vitreous Model (VM) and a system simulating the impact of movement on the VM (Eye Movement System, EyeMoS). Cylindrical model implants composed of DX and PLGA (poly (d,l-lactide-co-glycolide)) and additional polycaprolactone (PCL) implants containing fluorescein sodium (FS) as a model substance were produced by hot melt extrusion and were cut to a length of approximately 6 mm. Drug release was studied in ringer buffer pH 7.4 and in a modified polyacrylamide gel (PAAG) as vitreous substitute. In combination with the VM, the shape, the gel structure and a partial liquefaction (50%) were simulated in vitro. Swelling, disintegration, fragmentation, surface enlargement and changes in shape of the PLGA model implants were observed during the drug release study. We experienced that not each of the test methods and media were suitable for drug release studies of the PLGA implants. Marked differences in the release profiles were observed depending on the employed test method. These results emphasize the necessity to understand the underlying in vivo processes and to transfer the knowledge about the release determining factors into reliable in vitro test systems. Copyright © 2018 Elsevier B.V. All rights reserved.

In vitro and in vivo evaluation of sanguinarine liposomes prepared by a remote loading method with three different ammonium salts.

PubMed

Ke, X; Bei, J H; Zhang, Y; Li, J

2011-04-01

Sanguinarine liposomes were prepared by a remote loading method using three different ammonium salts. A series of studies, including in vitro release, in vitro and in vivo anti-tumor effects and pharmacokinetics in rats, were conducted. The three liposomes showed pH-sensitive release characteristics in vitro, but there were obvious variations in their release profiles. Among the three liposomes, the liposomes made using ammonium citrate and phosphate possessed better anti-tumor activity in vitro and in vivo, compared with the liposome using ammonium sulfate. Pharmacokinetics test results in rats indicated that sanguinarine liposomes have notably elevated AUC (P<0.05) and markedly lower CL (P<0.05) compared with the solution, but there were no obvious differences between the three liposomes. The present study may be useful for better understanding and better choice of a suitable ammonium salt for the remote loading method.

Formulation and in vitro evaluation of xanthan gum or carbopol 934-based mucoadhesive patches, loaded with nicotine.

PubMed

Abu-Huwaij, Rana; Obaidat, Rana M; Sweidan, Kamal; Al-Hiari, Yusuf

2011-03-01

Bilayer nicotine mucoadhesive patches were prepared and evaluated to determine the feasibility of the formulation as a nicotine replacement product to aid in smoking cessation. Nicotine patches were prepared using xanthan gum or carbopol 934 as a mucoadhesive polymers and ethyl cellulose as a backing layer. The patches were evaluated for their thickness, weight and content uniformity, swelling behavior, drug-polymers interaction, adhesive properties, and drug release. The physicochemical interactions between nicotine and the polymers were investigated by Fourier transform infrared (FTIR) spectroscopy. Mucoadhesion was assessed using two-arm balance method, and the in vitro release was studied using the Franz cell. FTIR revealed that there was an acid base interaction between nicotine and carbopol as well as nicotine and xanthan. Interestingly, the mucoadhesion and in vitro release studies indicated that this interaction was strong between the drug and carbopol whereas it was weak between the drug and xanthan. Loading nicotine concentration to non-medicated patches showed a significant decrease in the mucoadhesion strength of carbopol patches and no significant effect on the mucoadhesion strength of xanthan patches. In vitro release studies of the xanthan patches showed a reasonable fast initial release profile followed by controlled drug release over a 10-h period. © 2010 American Association of Pharmaceutical Scientists

Controlled release hydrophilic matrix tablet formulations of isoniazid: design and in vitro studies.

PubMed

Hiremath, Praveen S; Saha, Ranendra N

2008-01-01

The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer-Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f (2) metric values. The release profiles found to follow Higuchi's square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.

Extended release dosage form of glipizide: development and validation of a level A in vitro-in vivo correlation.

PubMed

Ghosh, Animesh; Bhaumik, Uttam Kumar; Bose, Anirbandeep; Mandal, Uttam; Gowda, Veeran; Chatterjee, Bappaditya; Chakrabarty, Uday Sankar; Pal, Tapan Kumar

2008-10-01

Defining a quantitative and reliable relationship between in vitro drug release and in vivo absorption is highly desired for rational development, optimization, and evaluation of controlled-release dosage forms and manufacturing process. During the development of once daily extended-release (ER) tablet of glipizide, a predictive in vitro drug release method was designed and statistically evaluated using three formulations with varying release rates. In order to establish internally and externally validated level A in vitro-in vivo correlation (IVIVC), a total of three different ER formulations of glipizide were used to evaluate a linear IVIVC model based on the in vitro test method. For internal validation, a single-dose four-way cross over study (n=6) was performed using fast-, moderate-, and slow-releasing ER formulations and an immediate-release (IR) of glipizide as reference. In vitro release rate data were obtained for each formulation using the United States Pharmacopeia (USP) apparatus II, paddle stirrer at 50 and 100 rev. min(-1) in 0.1 M hydrochloric acid (HCl) and pH 6.8 phosphate buffer. The f(2) metric (similarity factor) was used to analyze the dissolution data. The formulations were compared using area under the plasma concentration-time curve, AUC(0-infinity), time to reach peak plasma concentration, T(max), and peak plasma concentration, C(max), while correlation was determined between in vitro release and in vivo absorption. A linear correlation model was developed using percent absorbed data versus percent dissolved from the three formulations. Predicted glipizide concentrations were obtained by convolution of the in vivo absorption rates. Prediction errors were estimated for C(max) and AUC(0-infinity) to determine the validity of the correlation. Apparatus II, pH 6.8 at 100 rev. min(-1) was found to be the most discriminating dissolution method. Linear regression analysis of the mean percentage of dose absorbed versus the mean percentage of in vitro release resulted in a significant correlation (r(2)>or=0.9) for the three formulations.

Drug release and swelling kinetics of directly compressed glipizide sustained-release matrices: establishment of level A IVIVC.

PubMed

Sankalia, Jolly M; Sankalia, Mayur G; Mashru, Rajashree C

2008-07-02

The purpose of this study was to examine a level A in vitro-in vivo correlation (IVIVC) for glipizide hydrophilic sustained-release matrices, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. The effect of polymeric blends of ethylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, xanthan gum, guar gum, Starch 1500, and lactose on in vitro release profiles was studied and fitted to various release kinetics models. Water uptake kinetics with scanning electron microscopy (SEM) was carried out to support the drug release mechanism. An IVIVC was established by comparing the pharmacokinetic parameters of optimized (M-24) and marketed (Glytop-2.5 SR) formulations after single oral dose studies on white albino rabbits. The matrix M-19 (xanthan:MCC PH301 at 70:40) and M-24 (xanthan:HPMC K4M:Starch 1500 at 70:25:15) showed the glipizide release within the predetermined constraints at all time points with Korsmeyer-Peppas' and zero-order release mechanism, respectively. Kopcha model revealed that the xanthan gum is the major excipient responsible for the diffusional release profile and was further supported by SEM and swelling studies. A significant level A IVIVC with acceptable limits of prediction errors (below 15%) enables the prediction of in vivo performance from their in vitro release profile. It was concluded that proper selection of rate-controlling polymers with release rate modifier excipients will determine overall release profile, duration and mechanism from directly compressed matrices.

In vitro-in vivo correlation for nevirapine extended release tablets.

PubMed

Macha, Sreeraj; Yong, Chan-Loi; Darrington, Todd; Davis, Mark S; MacGregor, Thomas R; Castles, Mark; Krill, Steven L

2009-12-01

An in vitro-in vivo correlation (IVIVC) for four nevirapine extended release tablets with varying polymer contents was developed. The pharmacokinetics of extended release formulations were assessed in a parallel group study with healthy volunteers and compared with corresponding in vitro dissolution data obtained using a USP apparatus type 1. In vitro samples were analysed using HPLC with UV detection and in vivo samples were analysed using a HPLC-MS/MS assay; the IVIVC analyses comparing the two results were performed using WinNonlin. A Double Weibull model optimally fits the in vitro data. A unit impulse response (UIR) was assessed using the fastest ER formulation as a reference. The deconvolution of the in vivo concentration time data was performed using the UIR to estimate an in vivo drug release profile. A linear model with a time-scaling factor clarified the relationship between in vitro and in vivo data. The predictability of the final model was consistent based on internal validation. Average percent prediction errors for pharmacokinetic parameters were <10% and individual values for all formulations were <15%. Therefore, a Level A IVIVC was developed and validated for nevirapine extended release formulations providing robust predictions of in vivo profiles based on in vitro dissolution profiles. Copyright 2009 John Wiley & Sons, Ltd.

Bilayer tablets of Paliperidone for Extended release osmotic drug delivery

NASA Astrophysics Data System (ADS)

Chowdary, K. Sunil; Napoleon, A. A.

2017-11-01

The purpose of this study is to develop and optimize the formulation of paliperidone bilayer tablet core and coating which should meet in vitro performance of trilayered Innovator sample Invega. Optimization of core formulations prepared by different ratio of polyox grades and optimization of coating of (i) sub-coating build-up with hydroxy ethyl cellulose (HEC) and (ii).enteric coating build-up with cellulose acetate (CA). Some important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated. The optimization of formulation and process was conducted by comparing different in vitro release behaviours of Paliperidone. In vitro dissolution studies of Innovator sample (Invega) with formulations of different release rate which ever close release pattern during the whole 24 h test is finalized.

The study on the entrapment efficiency and in vitro release of puerarin submicron emulsion.

PubMed

Yue, Peng-Fei; Lu, Xiu-Yun; Zhang, Zeng-Zhu; Yuan, Hai-Long; Zhu, Wei-Feng; Zheng, Qin; Yang, Ming

2009-01-01

The entrapment efficiency (EE) and release in vitro are very important physicochemical characteristics of puerarin submicron emulsion (SME). In this paper, the performance of ultrafiltration (UF), ultracentrifugation (UC), and microdialysis (MD) for determining the EE of SME were evaluated, respectively. The release study in vitro of puerarin from SME was studied by using MD and pressure UF technology. The EE of SME was 86.5%, 72.8%, and 55.8% as determined by MD, UF, and UC, respectively. MD was not suitable for EE measurements of puerarin submicron oil droplet, which could only determine the total EE of submicron oil droplet and liposomes micelles, but it could be applied to determine the amount of free drug in SMEs. Although UC was the fastest and simplest to use, its results were the least reliable. UF was still the relatively accurate method for EE determination of puerarin SME. The release of puerarin SME could be evaluated by using MD and pressure UF, but MD seemed to be more suitable for the release study of puerarin emulsion. The drug release from puerarin SME at three drug concentrations was initially rapid, but reached a plateau value within 30 min. Drug release of puerarin from the SME occurred via burst release.

Formulation and in vitro evaluation of xanthan gum-based bilayered mucoadhesive buccal patches of zolmitriptan.

PubMed

Shiledar, Rewathi R; Tagalpallewar, Amol A; Kokare, Chandrakant R

2014-01-30

A novel bilayered mucoadhesive buccal patch of zolmitriptan was prepared using xanthan gum (XG) as mucoadhesive polymer. Hydroxypropyl methylcellulose E-15 was used as film-former and polyvinyl alcohol (PVA) was incorporated, to increase the tensile strength of the patches. To study the effect of independent variables viz. concentrations of XG and PVA, on various dependent variables like in vitro drug release, ex vivo mucoadhesive strength and swelling index, 3(2) factorial design was employed. In vitro drug release studies of optimized formulation showed initially, rapid drug release; 43.15% within 15 min, followed by sustained release profile over 5h. Incorporation of 4% dimethyl sulfoxide enhanced drug permeability by 3.29 folds, transported 29.10% of drug after 5h and showed no buccal mucosal damage after histopathological studies. In conclusion, XG can be used as a potential drug release modifier and mucoadhesive polymer for successful formulation of zolmitriptan buccal patches. Copyright © 2013 Elsevier Ltd. All rights reserved.

In vitro evaluation of electrospun PLGA/PLLA/PDLLA blend fibers loaded with naringin for guided bone regeneration.

PubMed

Guo, Zhenzhao; Wu, Shuai; Li, Hong; Li, Qiyan; Wu, Gang; Zhou, Changren

2018-03-30

The present study was to evaluate fiber mesh loaded with naringin via electrospinning to guide bone regeneration in vitro. The naringin-loaded fiber mesh was prepared via elctrospinning of PLGA, PLLA, PDLLA blending solution with naringin. SEM showed that naringin decreased the fiber's diameter according to the concentration of naringin. After 20 days' degradation in PBS, the drug-loaded fiber meshes still kept their stability with about 10% decrease in tensile strength. In vitro release experiments showed a sustained and steady naringin releasing profile with little initial burst releasing. Compared to the mats without naringin, the fiber mats loaded with naringin showed the most pronounced enhancement of cell growth when MC3T3-E1 cells were cultured on the fiber mats. The blend fiber loaded with naringin has optimized physical properties and sustained release profile in vitro. The study presents a promising fibrous mesh material for guided bone regeneration therapy.

In Vitro and In Vivo Sustained Zero-Order Delivery of Rapamycin (Sirolimus) From a Biodegradable Intraocular Device.

PubMed

Lance, Kevin D; Good, Samuel D; Mendes, Thaís S; Ishikiriyama, Mynna; Chew, Patrick; Estes, Laurel S; Yamada, Kazuhito; Mudumba, Sri; Bhisitkul, Robert B; Desai, Tejal A

2015-11-01

We created implantable intraocular devices capable of constant and continuous rapamycin release on the scale of months to years. Polycaprolactone (PCL) thin films were used to encapsulate rapamycin to create implantable and biodegradable intraocular devices. Different film devices were studied by modifying the size, thickness, and porosity of the PCL films. In vitro release of rapamycin was observed to be constant (zero-order) through 14 weeks of study. Release rates were tunable by altering PCL film porosity and thickness. In vivo release of rapamycin was observed out through 16 weeks with concentrations in the retina-choroid in the therapeutic range. Rapamycin concentration in the blood was below the lower limit of quantification. The drug remaining in the device was chemically stable in vitro and in vivo, and was sufficient to last for upwards of 2 years of total release. The mechanism of release is related to the dissolution kinetics of crystalline rapamycin. Microporous PCL thin film devices demonstrate good ocular compatibility and the ability to release rapamycin locally to the eye over the course of many weeks.

Formulation development and release studies of indomethacin suppositories.

PubMed

Sah, M L; Saini, T R

2008-01-01

Indomethacin suppositories were prepared by using water-soluble and oil soluble suppository bases, and evaluated for in vitro release by USP I and modified continuous flow through bead bed apparatus. Effect of the Tween 80 (1% and 5%) was further studied on in vitro release of the medicament. Release rate was good in water-soluble suppositories bases in comparison to oil soluble suppositories bases. Release was found to be greater in modified continuous flow through bead bed apparatus. When surfactant was used in low concentration then release rate was much greater, as compared to high concentration. When stability studies were performed on the prepared indomethacin suppositories it was found that suppositories made by water-soluble base had no significant changes while suppositories prepared by oil soluble bases, had some signs of instability.

An Accelerated Release Method of Risperidone Loaded PLGA Microspheres with Good IVIVC.

PubMed

Hu, Xiaoqin; Zhang, Jianwei; Tang, Xuemei; Li, Mingyuan; Ma, Siyu; Liu, Cheng; Gao, Yue; Zhang, Yue; Liu, Yan; Yu, Fanglin; Yang, Yang; Guo, Jia; Li, Zhiping; Mei, Xingguo

2018-01-01

A long release period lasting several days or several weeks is always needed and thereby it is tedious and time consuming to screen formulations of such microspheres with so long release period and evaluate their release profiles in vitro with conventional long-term or "real-time" release method. So, an accelerated release testing of such system is necessary for formulation design as well as quality control purpose. The purpose of this study is to obtain an accelerated release method of risperidone loaded poly(lactic-co-glycolic acid) (PLGA) microspheres with good in vitro/in vivo correlation (IVIVC). Two formulations of risperidone loaded PLGA microspheres used for evaluating IVIVC were prepared by O/W method. The accelerated release condition was optimized by investigating the effect of pH, osmotic pressure, temperature and ethanol concentration on the release of risperidone from microspheres and the in vitro accelerated release profiles of risperidone from PLGA microspheres were obtained under this optimized accelerated release condition. The plasma concentration of risperidone were also detected after subcutaneous injection of risperidone loaded microspheres to rats. The in vivo cumulative absorption profiles were then calculated using Wagner-Nelson model, Loo- Riegelman model and numerical convolution model, respectively. The correlation between in vitro accelerated release and in vivo cumulative absorption were finally evaluated with Least Square Method. It was shown that temperature and ethanol concentration significantly affected the release of risperidone from the microspheres while pH and osmotic pressure of release media slightly affected the release behavior of risperidone. The in vitro release of risperidone from microspheres were finally undergone in PBS (pH7.0, 300mosm) with 20% (V/V) ethanol at 45°C. The sustained and complete release of risperidone was observed in both formulations under the accelerated release condition although these two release profiles were dissimilar. The correlation coefficients (R2) of IVIVC were all above 0.95 and the slopes were all between 0.9564 and 1.1868 in spite of fitted model and microsphere formulation. An in vitro accelerated release method of risperidone microspheres with good IVIVC was established in this paper and this accelerated release method was supposed to have great potential in both in vivo performance prediction and quality control for risperidone loaded PLGA microspheres. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect.

PubMed

Sonvico, Fabio; Conti, Chiara; Colombo, Gaia; Buttini, Francesca; Colombo, Paolo; Bettini, Ruggero; Barchielli, Marco; Leoni, Barbara; Loprete, Luca; Rossi, Alessandra

2017-09-28

In this work, a fixed-dose combination of gabapentin and flurbiprofen formulated as multilayer tablets has been designed, developed and studied in vitro and in vivo. The aim was to construct a single dosage form of the two drugs, able to perform a therapeutic program involving three release kinetics and two delivery sites, i.e., immediate release of gabapentin, intra-gastric prolonged release of gabapentin and intestinal (delayed) release of flurbiprofen. An oblong three-layer tablet was manufactured having as top layer a floating hydrophilic polymeric matrix for gastric release of gabapentin, as middle layer a disintegrating formulation for immediate release of a gabapentin loading dose and as bottom layer, an uncoated hydrophilic polymeric matrix, swellable but insoluble in gastric fluids, for delayed and prolonged release of flurbiprofen in intestinal environment. The formulations were studied in vitro and in vivo in healthy volunteers. The in vitro release rate assessment confirmed the programmed delivery design. A significant higher bioavailability of gabapentin administered 30min after meal, compared to fasting conditions or to dose administration 10min before meal, argued in favor of the gastro-retention of gabapentin prolonged release layer. The two drugs were delivered at different anatomical sites, since the food presence prolonged the gastric absorption of gabapentin from the floating layer and delayed the flurbiprofen absorption. The attainment of a successful delayed release of flurbiprofen was realized by a matrix based on a polymers' combination. The combined use of three hydrophilic polymers with different pH sensitivity provided the dosage form layer containing flurbiprofen with gastro-resistant characteristics without the use of film coating. Copyright © 2017 Elsevier B.V. All rights reserved.

[Study on sustained release preparations of Epimedium component].

PubMed

Yan, Hong-mei; Ding, Dong-mei; Zhang, Zhen-hai; Sun, E; Song, Jie; Jia, Xiao-bin

2015-04-01

The formulation for sustained release tablet of Epinedium component was selected and the evaluation equation of in vitro release was established. The liquidity of component was improved with the help of colloidal silica aided by spray drying, which would be the main drug in the sustained release tablets. Dissolution was selected as an evaluation index to investigate skeletal material type, fillers, impact porogen, lubricants and other materials on the quality of sustained release tablet. The sustained release tablets were prepared by dry compression. Formulation of sustained release preparations was main drug 35%, HPMC K(4M) 20% and HPMC K(15M) 10% as skeleton material, MCC 31% as filler, PEG6000 2% as porogen and magnesium stearate 2% as lubricant. The sustained release tablets released up to 80% in 8 h. The zero order equation, primary equation and Higuchi equation could simulate the release characteristics of sustained release tablets in vitro, the correlation coefficients r were larger than 0.96. The primary equation was most similar in vitro release characteristics and its correlation coefficient r was 0.9950. The preparation method is simple and the results of formulation selection are reliable. It can be used to guide the production of Epimedium component sustained release preparations.

Preparation and characterization of cefditoren pivoxil-loaded liposomes for controlled in vitro and in vivo drug release

PubMed Central

Venugopalarao, Gojjala; Lakshmipathy, Rajasekhar; Sarada, Nallani Chakravarthula

2015-01-01

Background The application of antibiotics has been limited due to weak biodistribution and pharmacokinetics. Encapsulation of these drugs in lipid vesicles might be a good solution for obtaining the required properties. Liposomes are one of the most suitable drug-delivery systems to deliver the drug to the target organ and minimize the distribution of the drug to non-target tissues. Objective The study reported here aimed to develop cefditoren pivoxil liposomes by thin-film hydration, characterize them in terms of physical interactions, and undertake in vitro and in vivo release studies. Methodology The pre-formulation studies were carried out using Fourier-transform infrared spectroscopy and differential scanning calorimetry. Cefditoren pivoxil liposomal formulations were formulated by thin-film hydration using biomaterials ie, soya lecithin and cholesterol in different molar ratios. The best molar ratio was determined by in vitro studies such as entrapment efficacy, particle size distribution, and diffusion. Results From the in vitro release studies, it was found that the formulation that contained soya lecithin and cholesterol in a 1.0:0.6 molar ratio gave good entrapment of 72.33% and drug release of 92.5% at 36 hours. Further, the formulation’s zeta potential and surface morphology were examined and stability and in vivo studies were undertaken evaluating the pharmacokinetic parameters, which showed promising results. Conclusion Formulation CPL VI showed the maximum drug-loading capacity of 72.3% with good controlled release and acceptable stability when compared with the other formulations. In vivo studies in rabbits showed that the drug release from the liposomes was successfully retarded with good controlled release behavior which can be used to treat many bacterial infections with a minimal dose. PMID:26491316

Design and in vivo evaluation of carvedilol buccal mucoadhesive patches.

PubMed

Thimmasetty, J; Pandey, G S; Babu, P R Sathesh

2008-07-01

The buccal region offers an attractive route of administration for systemic drug delivery. Carvedilol (dose, 3.125-25 mg) is beta-adrenergic antagonist. Its oral bioavailability is 25-35% because of first pass metabolism. Buccal absorption studies of a carvedilol solution in human volunteers showed 32.86% drug absorption. FTIR and UV spectroscopic methods revealed that there was no interaction between carvedilol and polymers. Carvedilol patches were prepared using HPMC, carbopol 934, eudragit RS 100, and ethylcellulose. The patches were evaluated for their thickness uniformity, folding endurance, weight uniformity, content uniformity, swelling behaviour, tensile strength, and surface pH. In vitro release studies were conducted for carvedilol-loaded patches in phosphate buffer (pH, 6.6) solution. Patches exhibited drug release in the range of 86.26 to 98.32% in 90 min. Data of in vitro release from patches were fit to different equations and kinetic models to explain release profiles. Kinetic models used were zero and first-order equations, Hixon-Crowell, Higuchi, and Korsmeyer-Peppas models. In vivo drug release studies in rabbits showed 90.85% of drug release from HPMC-carbopol patch while it was 74.63 to 88.02% within 90 min in human volunteers. Good correlation among in vitro release and in vivo release of carvedilol was observed.

Tamoxifen citrate loaded chitosan-gellan nanocapsules for breast cancer therapy: development, characterisation and in-vitro cell viability study.

PubMed

Kathle, Pankaj Kumar; Gautam, Nivedita; Kesavan, Karthikeyan

2018-06-08

The objective of this study was to evaluate the potential of chitosan-gellan nanocapsules (CGNCs) for encapsulation and sustained release of Tamoxifen citrate (TMC) for breast cancer therapy. Polyelectrolyte complex coacervation method was used for production of CGNCs. Interaction studies were conducted by Fourier-transform infra-red (FT-IR), differential scanning colorimetric (DSC), and X-ray diffraction (XRD) to investigate any interaction between drug and excipients. Physicochemical parameters, in vitro drug release and release kinetic were studied. In vitro cell viability study using Michigan Cancer Foundation-7 (MCF-7) breast cancer cells was also investigated. CGNCs had a smooth surface and nanosize range with a positive surface charge and exhibited sustained drug release. Further, TMC loaded CGNCs were found to be more cytotoxic than the free drug in MCF-7. Thus CGNCs may be suitable for breast cancer treatment due to delivering the drug at the site of action for a prolonged period of time.

A reproducible accelerated in vitro release testing method for PLGA microspheres.

PubMed

Shen, Jie; Lee, Kyulim; Choi, Stephanie; Qu, Wen; Wang, Yan; Burgess, Diane J

2016-02-10

The objective of the present study was to develop a discriminatory and reproducible accelerated in vitro release method for long-acting PLGA microspheres with inner structure/porosity differences. Risperidone was chosen as a model drug. Qualitatively and quantitatively equivalent PLGA microspheres with different inner structure/porosity were obtained using different manufacturing processes. Physicochemical properties as well as degradation profiles of the prepared microspheres were investigated. Furthermore, in vitro release testing of the prepared risperidone microspheres was performed using the most common in vitro release methods (i.e., sample-and-separate and flow through) for this type of product. The obtained compositionally equivalent risperidone microspheres had similar drug loading but different inner structure/porosity. When microsphere particle size appeared similar, porous risperidone microspheres showed faster microsphere degradation and drug release compared with less porous microspheres. Both in vitro release methods investigated were able to differentiate risperidone microsphere formulations with differences in porosity under real-time (37 °C) and accelerated (45 °C) testing conditions. Notably, only the accelerated USP apparatus 4 method showed good reproducibility for highly porous risperidone microspheres. These results indicated that the accelerated USP apparatus 4 method is an appropriate fast quality control tool for long-acting PLGA microspheres (even with porous structures). Copyright © 2015 Elsevier B.V. All rights reserved.

STUDIES ON TUBERCULIN FEVER. 3. MECHANISMS INVOLVED IN THE RELEASE OF ENDOGENOUS PYROGEN IN VITRO.

PubMed

ATKINS, E; HEIJN, C

1965-08-01

In a search for the source of the circulating endogenous pyrogen (EP) that mediates tuberculin-induced fever, tuberculin was incubated in vitro with various tissues of rabbits sensitized by intravenous infection with BCG. Evidence was obtained that tuberculin specifically stimulates cells in the blood of sensitized rabbits to generate pyrogen in vitro, whereas both lymph node and spleen cells from the same donors were inactive. Since normal blood cells, incubated in plasma of sensitized donors, were similarly activated, it is postulated that circulating antibodies play a role in sensitizing cells (presumably granulocytes) to release pyrogen on contact with tuberculin) both in vitro and in vivo. Release of endogenous pyrogen in vitro may be a sensitive means of detecting immunologic reactions between antigen and specifically sensitized blood cells-in other allergic states accompanied by fever.

Preparation and in vitro/in vivo evaluation of gestodene (GEST) intravaginal ring.

PubMed

Li, Chunxiao; Ning, Meiying; Yao, Xiaodong; Wang, Yankun; Liu, Ying

2016-09-01

Preparation and in vitro/in vivo evaluation of gestodene (GEST) intravaginal ring (IVR) formulations which can release a constant dose of GEST during 3 weeks were investigated. In present study a reservoir gestodene intravaginal ring, including a gestodene silicone elastomer core and the non-active silicone layer, was reported, which was manufactured by reaction injection moulding at 80°C for 20 min. The raw materials compatibility experiments showed that the silicone elastomer core carrier wouldn't interact with drugs. In vitro release samples were determined by HPLC and the experiment was performed under sink conditions. The equation of cumulative release verse time was Y=64.76χ+5.44 (r=0.9998), performing zero-order release at about the target dose of 60 µg/day over 21 days. Drug release increased with temperature elevating from 45 to 55°C, which could be attributed to optimizing the prescription. In addition, the pharmacokinetic and safety studies of gestodene intravaginal ring were evaluated in female New Zealand White rabbits. The GEST in plasma was analyzed by LC-MS/MS and the results proved that the correlation between in vitro and in vivo was relatively well.

Control-release microcapsule of famotidine loaded biomimetic synthesized mesoporous silica nanoparticles: Controlled release effect and enhanced stomach adhesion in vitro.

PubMed

Li, Jing; Wang, Hongyu; Yang, Baixue; Xu, Lu; Zheng, Nan; Chen, Hongtao; Li, Sanming

2016-01-01

In the present work, control-release microcapsule of famotidine (FMT) loaded biomimetic synthesized mesoporous silica nanoparticles (B-MSNs) was developed, and controlled release effect and stomach adhesion of this formulation in vitro were mainly investigated. B-MSN was previously synthesized and it was amorphous mesoporous nanoparticles with helical channels. Cytotoxicity of B-MSN was studied using human breast cancer cells (MCF-7) and the result indicated that cytotoxicity of B-MSN can be neglected. After loading FMT into B-MSN, specific surface area, pore volume and pore diameter of B-MSN were obviously reduced. In vitro dissolution test showed that B-MSN had the ability to slow down FMT release for 15 min. In order to prolong controlled release effect and remained the advantage of B-MSN (improve drug stability due to its rigid silica framework), the combined application of control-release microcapsule (using cellulose and hydroxypropyl methylcellulose K15M as excipients) with B-MSN was designed. It was obvious that newly designed formulation significantly controlled FMT release with Fickian diffusion mechanism and showed enhanced stomach adhesion in vitro, which has significant value in widening the application of B-MSN in formulation design. Copyright © 2015 Elsevier B.V. All rights reserved.

Development of a novel drug delivery system, time-controlled explosion system (TES). IV. In vivo drug release behavior.

PubMed

Ueda, S; Ibuki, R; Kawamura, A; Murata, S; Takahashi, T; Kimura, S; Hata, T

1994-01-01

Time-Controlled Explosion System (TES) has the time-controlled drug release property with a pre-designed lag time. The drug release from the system is initiated by destruction of the membrane. In this study, metoprolol tartrate was used as a model drug. After five types of TES with different in vitro lag times were orally administrated to dogs, plasma metoprolol concentration was monitored. There existed a good correlation between in vitro and in vivo lag time, while the extent of absorbed metoprolol decreased with prolongation of lag time. Next, the in vivo drug release behavior was directly investigated using five different colored TES with a lag time of two hours. Each TES was consecutively administrated to the fasted dogs at predetermined intervals. The amount of metoprolol released was monitored by recovering the administered TES from the gastrointestinal trace. The in vivo release profile corresponded with the in vitro one. It is demonstrated that TES can release the drug in in vivo conditions similarly to in vitro. Based on these results, the decrease of the absorption is suggested to be caused by increased hepatic first-pass metabolism of the drug due to the retarded release rate with longer lag time.

Accelerated in vitro release testing method for naltrexone loaded PLGA microspheres.

PubMed

Andhariya, Janki V; Choi, Stephanie; Wang, Yan; Zou, Yuan; Burgess, Diane J; Shen, Jie

2017-03-30

The objective of the present study was to develop a discriminatory and reproducible accelerated release testing method for naltrexone loaded parenteral polymeric microspheres. The commercially available naltrexone microsphere product (Vivitrol ® ) was used as the testing formulation in the in vitro release method development, and both sample-and-separate and USP apparatus 4 methods were investigated. Following an in vitro drug stability study, frequent media replacement and addition of anti-oxidant in the release medium were used to prevent degradation of naltrexone during release testing at "real-time" (37°C) and "accelerated" (45°C), respectively. The USP apparatus 4 method was more reproducible than the sample-and-separate method. In addition, the accelerated release profile obtained using USP apparatus 4 had a shortened release duration (within seven days), and good correlation with the "real-time" release profile. Lastly, the discriminatory ability of the developed accelerated release method was assessed using compositionally equivalent naltrexone microspheres with different release characteristics. The developed accelerated USP apparatus 4 release method was able to detect differences in the release characteristics of the prepared naltrexone microspheres. Moreover, a linear correlation was observed between the "real-time" and accelerated release profiles of all the formulations investigated, suggesting that the release mechanism(s) may be similar under both conditions. These results indicate that the developed accelerated USP apparatus 4 method has the potential to be an appropriate fast quality control tool for long-acting naltrexone PLGA microspheres. Copyright © 2017 Elsevier B.V. All rights reserved.

In vitro controlled release of clove essential oil in self-assembly of amphiphilic polyethylene glycol-block-polycaprolactone.

PubMed

Thonggoom, O; Punrattanasin, N; Srisawang, N; Promawan, N; Thonggoom, R

2016-05-01

In this study, a micellar delivery system with an amphiphilic diblock copolymer of poly (ethylene glycol) and poly (ɛ-caprolactone) was synthesised and used to incorporate hydrophobic clove essential oil (CEO). To determine an optimal delivery system, the effects of the copolymer's hydrophobic block length and the CEO-loading content on the encapsulation of CEO were investigated. Percentages of entrapment efficiency (%EE), CEO loading (%CEO), and in vitro release profiles were determined. The size, size distribution, zeta potential, and morphology of the obtained micelles were determined by DLS, FE-SEM, and TEM. The %EE, %CEO, and in vitro release profiles of CEO incorporated in micelles were analysed by HPLC. The study revealed a sustained release profile of CEO from CEO-loaded micelles. The results indicate the successful formulation of CEO-loaded PEG-b-PCL micelle nanoparticles. It is suggested that this micelle system has considerably potential applications in the sustained release of CEO in intravascular drug delivery.

Preparation and Physicochemical Evaluation of Controlled-release Carbon Source Tablet for Groundwater in situ Denitrification

NASA Astrophysics Data System (ADS)

Kim, Y.; Kang, J. H.; Yeum, Y.; Han, K. J.; Kim, D. W.; Park, C. W.

2015-12-01

Nitric nitrogen could be the one of typical pollution source such asNO3-through domestic sewage, livestock and agricultural wastewater. Resident microflorain aquifer has known to remove the nitric nitrogen spontaneously following the denitration process with the carbon source (CS) as reactant. However, it could be reacted very slowly with the rack of CS and there have been some studies for controlled addition of CS (Ref #1-3). The aim of this study was to prepare the controlled-release carbon source (CR-CS) tablet and to evaluate in vitro release profile for groundwater in situ denitrification. CR-CS tablet could be manufactured by direct compression method using hydraulic laboratory press (Caver® 3850) with 8 mm rounded concave punch/ die.Seven kinds of CR-CS tablet were prepared to determine the nature of the additives and their ratio such as sodium silicate, dicalcium phosphate, bentonite and sand#8.For each formulation, the LOD% and flowability of pre-mixed powders and the hardness of compressed tablets were analyzed. In vitro release study was performed to confirm the dissolution profiles following the USP Apparatus 2 method with Distilled water of 900mL, 20 °C. As a result, for each lubricated powders, they were compared in terms of ability to give an acceptable dry pre-mixed powder for tableting process. The hardness of the compressed tablets is acceptable whatever the formulations tested. After in vitro release study, it could confirm that the different formulations of CR-CS tablet have a various release rate patterns, which could release 100% at 3 hrs, 6 hrs and 12 hrs. The in vitro dissolution profiles were in good correlation of Higuchi release kinetic model. In conclusion, this study could be used as a background for development and evaluation of the controlled-release carbon source (CR-CS) tablet for the purification of groundwater following the in situ denitrification.

Preparation and evaluation of sustained release loxoprofen loaded microspheres.

PubMed

Venkatesan, P; Manavalan, R; Valliappan, K

2011-06-01

The aim of present study was to formulate and evaluate the loxoprofen loaded Sustained release microspheres by emulsion solvent evaporation technique. Ethylcellulose, a biocompatible polymer is used as the retardant material. The effects of process conditions such as drug loading, polymer type and solvent type on the characteristics of microspheres were investigated. The prepared microspheres were characterized for their particle size and drug loading and drug release. The in-vitro release studies were carried out in phosphate buffer at pH 7.4. The prepared microspheres were white, free flowing and spherical in shape. The drug-loaded microspheres showed 71.2% of entrapment and the in-vitro release studies showed that Loxoprofen microspheres of 1:3 ratios showed better sustained effect over a period of 8 hours.

Preparation and evaluation of sustained release loxoprofen loaded microspheres

PubMed Central

Venkatesan, P.; Manavalan, R.; Valliappan, K.

2011-01-01

The aim of present study was to formulate and evaluate the loxoprofen loaded Sustained release microspheres by emulsion solvent evaporation technique. Ethylcellulose, a biocompatible polymer is used as the retardant material. The effects of process conditions such as drug loading, polymer type and solvent type on the characteristics of microspheres were investigated. The prepared microspheres were characterized for their particle size and drug loading and drug release. The in-vitro release studies were carried out in phosphate buffer at pH 7.4. The prepared microspheres were white, free flowing and spherical in shape. The drug-loaded microspheres showed 71.2% of entrapment and the in-vitro release studies showed that Loxoprofen microspheres of 1:3 ratios showed better sustained effect over a period of 8 hours PMID:24826017

Formulation and Evaluation of Tramadol hydrochloride Rectal Suppositories.

PubMed

Saleem, M A; Taher, M; Sanaullah, S; Najmuddin, M; Ali, Javed; Humaira, S; Roshan, S

2008-09-01

Rectal suppositories of tramadol hydrochloride were prepared using different bases and polymers like PEG, cocoa butter, agar and the effect of different additives on in vitro release of tramadol hydrochloride was studied. The agar-based suppositories were non-disintegrating/non-dissolving, whereas PEGs were disintegrating/dissolving and cocoa butter were melting suppositories. All the prepared suppositories were evaluated for various physical parameters like weight variation, drug content and hardness. The PEG and cocoa butter suppositories were evaluated for macromelting range, disintegration and liquefaction time. In vitro release study was performed by USP type I apparatus. The prepared suppositories were within the permissible range of all physical parameters. In vitro drug release was in the order of PEG>Agar>cocoa butter. Addition of PVP, HPMC in agar suppositories retards the release. The mechanism of drug release was diffusion controlled and follows first order kinetics. The results suggested that blends of PEG of low molecular weight (1000) with high molecular weight (4000 and 6000) in different percentage and agar in 10% w/w as base used to formulate rapid release suppositories. The sustained release suppositories can be prepared by addition of PVP, HPMC in agar-based suppositories and by use of cocoa butter as base.

In Vitro and In Vivo Sustained Zero-Order Delivery of Rapamycin (Sirolimus) From a Biodegradable Intraocular Device

PubMed Central

Lance, Kevin D.; Good, Samuel D.; Mendes, Thaís S.; Ishikiriyama, Mynna; Chew, Patrick; Estes, Laurel S.; Yamada, Kazuhito; Mudumba, Sri; Bhisitkul, Robert B.; Desai, Tejal A.

2015-01-01

Purpose We created implantable intraocular devices capable of constant and continuous rapamycin release on the scale of months to years. Methods Polycaprolactone (PCL) thin films were used to encapsulate rapamycin to create implantable and biodegradable intraocular devices. Different film devices were studied by modifying the size, thickness, and porosity of the PCL films. Results In vitro release of rapamycin was observed to be constant (zero-order) through 14 weeks of study. Release rates were tunable by altering PCL film porosity and thickness. In vivo release of rapamycin was observed out through 16 weeks with concentrations in the retina–choroid in the therapeutic range. Rapamycin concentration in the blood was below the lower limit of quantification. The drug remaining in the device was chemically stable in vitro and in vivo, and was sufficient to last for upwards of 2 years of total release. The mechanism of release is related to the dissolution kinetics of crystalline rapamycin. Conclusions Microporous PCL thin film devices demonstrate good ocular compatibility and the ability to release rapamycin locally to the eye over the course of many weeks. PMID:26559479

Influence of Drug Properties and Formulation on In Vitro Drug Release and Biowaiver Regulation of Oral Extended Release Dosage Forms.

PubMed

Lin, Zhongqiang; Zhou, Deliang; Hoag, Stephen; Qiu, Yihong

2016-03-01

Bioequivalence (BE) studies are often required to ensure therapeutic equivalence for major product and manufacturing changes. Waiver of a BE study (biowaiver) is highly desired for such changes. Current regulatory guidelines allow for biowaiver of proportionally similar lower strengths of an extended release (ER) product provided it exhibits similar dissolution to the higher strength in multimedia. The objective of this study is to demonstrate that (1) proportionally similar strengths of ER tablets exhibiting similar in vitro dissolution profiles do not always assure BE and (2) different strengths that do not meet the criteria for dissolution profile similarity may still be bioequivalent. Four marketed ER tablets were used as model drug products. Higher and lower (half) strength tablets were prepared or obtained from commercial source. In vitro drug release was compared using multi-pH media (pH 1.2, 4.5, 6.8) per regulatory guidance. In vivo performance was assessed based on the available in vivo BE data or established in vitro-in vivo relationships. This study demonstrated that the relationship between in vitro dissolution and in vivo performance is complex and dependent on the characteristics of specific drug molecules, product design, and in vitro test conditions. As a result, proportionally similar strengths of ER dosage forms that meet biowaiver requirements per current regulatory guidelines cannot ensure bioequivalence in all cases. Thus, without an established relationship between in vitro and in vivo performance, granting biowaiver based on passing in vitro tests may result in the approval of certain bioinequivalent products, presenting risks to patients. To justify any biowaiver using in vitro test, it is essential to understand the effects of drug properties, formulation design, product characteristics, test method, and its in vivo relevance. Therefore, biowaiver requirements of different strengths of ER dosage forms specified in the current regulatory guidance should be reevaluated to assure consistent safety and efficacy among different strengths.

Novel catalase loaded nanocores for the treatment of inflammatory bowel diseases.

PubMed

Parihar, Arun K S; Srivastava, Shikha; Patel, Satish; Singh, Manju R; Singh, Deependra

2017-08-01

Inflammatory bowel disease (IBD) is an inflammatory disorder of the digestive tract reported to be primarily caused by oxidative stress. In this study, alginate encapsulated nanoceramic carriers were designed to deliver acid labile antioxidant enzyme catalase orally. Complete system was characterized for size, loading efficiency, in vitro antioxidant assay and in vitro release. The prepared nanoceramic system was found to be spherical with diameter of 925 ± 6.81 nm. The in vitro release data followed the Higuchi model in acidic buffer whereas in alkaline pH sustained and almost first order release of enzyme was observed up to 6 h.

Preclinical and clinical in vitro in vivo correlation of an hGH dextran microsphere formulation.

PubMed

Vlugt-Wensink, K D F; de Vrueh, R; Gresnigt, M G; Hoogerbrugge, C M; van Buul-Offers, S C; de Leede, L G J; Sterkman, L G W; Crommelin, D J A; Hennink, W E; Verrijk, R

2007-12-01

To investigate the in vitro in vivo correlation of a sustained release formulation for human growth hormone (hGH) based on hydroxyethyl methacrylated dextran (dex-HEMA) microspheres in Pit-1 deficient Snell dwarf mice and in healthy human volunteers. A hGH-loaded microsphere formulation was developed and tested in Snell dwarf mice (pharmacodynamic study) and in healthy human volunteers (pharmacokinetic study). Single subcutaneous administration of the microspheres in mice resulted in a good correlation between hGH released in vitro and in vivo effects for the hGH-loaded microsphere formulation similar to daily injected hGH indicating a retained bioactivity. Testing the microspheres in healthy volunteers showed an increase (over 7-8 days) in hGH serum concentrations (peak concentrations: 1-2.5 ng/ml). A good in vitro in vivo correlation was obtained between the measured and calculated (from in vitro release data) hGH serum concentrations. Moreover, an increased serum concentration of biomarkers (insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) was found again indicating that bioactive hGH was released from the microspheres. Good in vitro in vivo correlations were obtained for hGH-loaded dex-HEMA microspheres, which is an important advantage in predicting the effect of the controlled drug delivery product in a clinical situations.

Preclinical and Clinical In Vitro In Vivo Correlation of an hGH Dextran Microsphere Formulation

PubMed Central

de Vrueh, R.; Gresnigt, M. G.; Hoogerbrugge, C. M.; van Buul-Offers, S. C.; de Leede, L. G. J.; Sterkman, L. G. W.; Crommelin, D. J. A.; Hennink, W. E.; Verrijk, R.

2007-01-01

Purpose To investigate the in vitro in vivo correlation of a sustained release formulation for human growth hormone (hGH) based on hydroxyethyl methacrylated dextran (dex-HEMA) microspheres in Pit-1 deficient Snell dwarf mice and in healthy human volunteers. Materials and Methods A hGH-loaded microsphere formulation was developed and tested in Snell dwarf mice (pharmacodynamic study) and in healthy human volunteers (pharmacokinetic study). Results Single subcutaneous administration of the microspheres in mice resulted in a good correlation between hGH released in vitro and in vivo effects for the hGH-loaded microsphere formulation similar to daily injected hGH indicating a retained bioactivity. Testing the microspheres in healthy volunteers showed an increase (over 7–8 days) in hGH serum concentrations (peak concentrations: 1–2.5 ng/ml). A good in vitro in vivo correlation was obtained between the measured and calculated (from in vitro release data) hGH serum concentrations. Moreover, an increased serum concentration of biomarkers (insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) was found again indicating that bioactive hGH was released from the microspheres. Conclusions Good in vitro in vivo correlations were obtained for hGH-loaded dex-HEMA microspheres, which is an important advantage in predicting the effect of the controlled drug delivery product in a clinical situations. PMID:17929148

A novel glycyrrhetinic acid-modified oxaliplatin liposome for liver-targeting and in vitro/vivo evaluation

PubMed Central

Chen, Jingde; Jiang, Hong; Wu, Yin; Li, Yandong; Gao, Yong

2015-01-01

In this study, oxaliplatin (OX) liposomes surface-modified with glycyrrhetinic acid (GA) were developed by the film-dispersion method. Their morphology, physical and chemical properties, and in vitro release performance were investigated. The transmission electron microscope (TEM) image showed that most liposomes were spherical particles with similar size and uniform dispersion. Both OX-liposomes and GA-OX-liposomes had an average size of 90 nm. They were negatively charged, with zeta potentials of −20.6 and −21.3 mV, respectively, and the entrapment efficiency values of both were higher than 94%. In vitro data showed that the application of liposomes could prolong the OX release. The relatively high correlation coefficient values obtained from analyzing the amount of drug released versus the square root of time depicted that release followed the Weibull model. No significant changes were observed after the addition of GA to the liposomes. In vivo, the relatively long time to reach the maximum plasma concentration of OX-liposomes suggested a sustained-release profile of liposomes, which was consistent with the results of the in vitro release study. The increased area under the curve and maximum plasma concentration of OX-liposomes and GA-OX-liposomes demonstrated an increased absorption. The drug concentration in tissues indicated that the GA-modified liposomes delivered OX mainly to liver after intravenous administration. In addition, no severe signs, such as appearance of epithelial necrosis or sloughing of epithelial cells, were detected in histology studies. PMID:25945038

Polymeric nanoparticles containing diazepam: preparation, optimization, characterization, in-vitro drug release and release kinetic study

NASA Astrophysics Data System (ADS)

Bohrey, Sarvesh; Chourasiya, Vibha; Pandey, Archna

2016-03-01

Nanoparticles formulated from biodegradable polymers like poly(lactic-co-glycolic acid) (PLGA) are being extensively investigated as drug delivery systems due to their two important properties such as biocompatibility and controlled drug release characteristics. The aim of this work to formulated diazepam loaded PLGA nanoparticles by using emulsion solvent evaporation technique. Polyvinyl alcohol (PVA) is used as stabilizing agent. Diazepam is a benzodiazepine derivative drug, and widely used as an anticonvulsant in the treatment of various types of epilepsy, insomnia and anxiety. This work investigates the effects of some preparation variables on the size and shape of nanoparticles prepared by emulsion solvent evaporation method. These nanoparticles were characterized by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM). Zeta potential study was also performed to understand the surface charge of nanoparticles. The drug release from drug loaded nanoparticles was studied by dialysis bag method and the in vitro drug release data was also studied by various kinetic models. The results show that sonication time, polymer content, surfactant concentration, ratio of organic to aqueous phase volume, and the amount of drug have an important effect on the size of nanoparticles. Hopefully we produced spherical shape Diazepam loaded PLGA nanoparticles with a size range under 250 nm with zeta potential -23.3 mV. The in vitro drug release analysis shows sustained release of drug from nanoparticles and follow Korsmeyer-Peppas model.

Controlled release of paclitaxel from a self-assembling peptide hydrogel formed in situ and antitumor study in vitro

PubMed Central

Liu, Jingping; Zhang, Lanlan; Yang, Zehong; Zhao, Xiaojun

2011-01-01

Background A nanoscale injectable in situ-forming hydrogel drug delivery system was developed in this study. The system was based on a self-assembling peptide RADA16 solution, which can spontaneously form a hydrogel rapidly under physiological conditions. We used the RADA16 hydrogel for the controlled release of paclitaxel (PTX), a hydrophobic antitumor drug. Methods The RADA16-PTX suspension was prepared simply by magnetic stirring, followed by atomic force microscopy, circular dichroism analysis, dynamic light scattering, rheological analysis, an in vitro release assay, and a cell viability test. Results The results indicated that RADA16 and PTX can interact with each other and that the amphiphilic peptide was able to stabilize hydrophobic drugs in aqueous solution. The particle size of PTX was markedly decreased in the RADA16 solution compared with its size in water. The RADA16-PTX suspension could form a hydrogel in culture medium, and the elasticity of the hydrogel showed a positive correlation with peptide concentration. In vitro release measurements indicated that hydrogels with a higher peptide concentration had a longer half-release time. The RADA16-PTX hydrogel could effectively inhibit the growth of the breast cancer cell line, MDA-MB-435S, in vitro, and hydrogels with higher peptide concentrations were more effective at inhibiting tumor cell proliferation. The RADA16-PTX hydrogel was effective at controlling the release of PTX and inhibiting tumor cell growth in vitro. Conclusion Self-assembling peptide hydrogels may work well as a system for drug delivery. PMID:22114478

Sustained Release of Green Tea Polyphenols from Liposomal Nanoparticles; Release Kinetics and Mathematical Modelling.

PubMed

Prakash Upputuri, Ravi Theaj; Azad Mandal, Abul Kalam

2017-01-01

Background: Green tea polyphenols (GTP) are known to have several health benefits. In spite of these benefits, its application as a therapeutic agent is limited due to some of its limitations such as stability, bioavailability, and biotransformation. To overcome these limitations, liposomal nanoparticles have been used as a carrier of the GTP. Objective: Encapsulation of GTP to the liposomal nanoparticles in order to achieve a sustained release of the GTP and to determine the drug release kinetics and the mechanism of the release. Materials and Methods: GTP encapsulated liposomal nanoparticles were prepared using phosphatidyl choline and cholesterol. The synthesized particles were characterized for their particle size and morphology. In vitro release studies were carried out, followed by drug release kinetics, and determining the mechanism of release. In vitro , antioxidant assay was determined following 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. Results: Atomic force microscope (AFM) and high resolution scanning electron microscope (HR SEM) images showed spherical particles of the size of 64.5 and 252 nm. An encapsulation efficiency as high as 77.7% was observed with GTP concentration of 5 mg.mL -1 . In vitro release studies showed that the loading concentrations of GTP were independent to the cumulative percentage of the drug release. GTP release by varying the pH and temperature showed a direct correlation between the release parameter and the percentage of drug release. The higher the pH and temperature, the higher was the percentage of the drug release. The release data showed a good correlation with Zero order kinetics and the mechanism of the release being anomalous mode. Radical scavenging activity of the released GTP showed a potent scavenging activity. Conclusion: GTP encapsulated liposomal nanoparticles could be used as a delivery vehicle for achieving a sustained release.

[Study on self-microemulsifying membrane controlled-release drop pill of hawthorn leaves flavonoids].

PubMed

Wang, Jin-Xuan; Huang, Hong-Zhang; Li, Ning; Gao, Chong-Kai

2014-03-01

To prepare the hawthorn leaves flavonoids self-microemulsifying membrane controlled-release coated drop pill, and to study its release rate in vitro and pharmacokinetics study in vivo. In order to improve the dissolution of hawthorn leaves flavonoids, self-microemulsifying technology was used to prepare the hawthorn leaves flavonoids self-microemulsion. Hawthorn leaves flavonoids self-microemulsifying drop pill was prepared with the PEG 6000. Studies were made on the in vitro release of flavonoids from hawthorn leaves self-micro-emulsifying membrane-moderated coated drop pills and the in vivo pharmacokinetic in rats. The prescription of flavonoids from hawthorn leaves self-micro-emulsifying drop pills was 0.25 g of flavonoids from hawthorn leaves, 0.25 g of iodophenyl maleimide, 0.375 g of polyethylene glycol 400, 0.375 g of cremophor RH 40 and 2 g of polyethylene glycol 6000. The optimized prescription was 4 g of ethyl cellulose 20, 0.64 g of polyethylene glycol 400, 1.8 g of diethyl phthalate, and the weight of coating materials increased by 3.5%. Flavonoids from hawthorn leaves self-micro-emulsifying membrane-moderated coated drop pills complied with the design of sustained-release in 12 h in terms of in vitro release and in vivo pharmacokinetic parameters in rats, and its bioavailability was 2.47 times of quick-release drop pills. Slightly soluble flavonoids from hawthorn leaves could be made into sustained-release preparations by the self-micro-emulsifying and coating technology.

A simple and rapid approach to evaluate the in vitro in vivo role of release controlling agent ethyl cellulose ether derivative polymer.

PubMed

Akhlaq, Muhammad; Khan, Gul Majid; Jan, Syed Umer; Wahab, Abdul; Hussain, Abid; Nawaz, Asif; Abdelkader, Hamdy

2014-11-01

Diclofenac sodium (DCL-Na) conventional oral tablets exhibit serious side effects when given for a longer period leading to noncompliance. Controlled release matrix tablets of diclofenac sodium were formulated using simple blending (F-1), solvent evaporation (F-2) and co-precipitation techniques (F-3). Ethocel® Standard 7 FP Premium Polymer (15%) was used as a release controlling agent. Drug release study was conducted in 7.4 pH phosphate buffer solutions as dissolution medium in vitro. Pharmacokinetic parameters were evaluated using albino rabbits. Solvent evaporation technique was found to be the best release controlling technique thereby prolonging the release rate up to 24 hours. Accelerated stability studies of the optimized test formulation (F-2) did not show any significant change (p<0.05) in the physicochemical characteristics and release rate when stored for six months. A simple and rapid method was developed for DCL-Na active moiety using HPLC-UV at 276nm. The optimized test tablets (F-2) significantly (p<0.05) exhibited peaks plasma concentration (cmax=237.66±1.98) and extended the peak time (tmax=4.63±0.24). Good in-vitro in vivo correlation was found (R(2)=0.9883) against drug absorption and drug release. The study showed that once-daily controlled release matrix tablets of DCL-Na were successfully developed using Ethocel® Standard 7 FP Premium.

Formulation and In Vitro, In Vivo Evaluation of Effervescent Floating Sustained-Release Imatinib Mesylate Tablet

PubMed Central

Kadivar, Ali; Kamalidehghan, Behnam; Javar, Hamid Akbari; Davoudi, Ehsan Taghizadeh; Zaharuddin, Nurul Dhania; Sabeti, Bahareh; Chung, Lip Yong; Noordin, Mohamed Ibrahim

2015-01-01

Introduction Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT). Conventional imatinib mesylate (Gleevec) tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets. Methodology Floating sustained-release Imatinib mesylate tablets were prepared using the wet granulation method. Tablets were formulated using Hydroxypropyl Methylcellulose (HPMC K4M), with Sodium alginate (SA) and Carbomer 934P (CP) as release-retarding polymers, sodium bicarbonate (NaHCO3) as the effervescent agent and lactose as a filler. Floating behavior, in vitro drug release, and swelling index studies were conducted. Initial and total drug release duration was compared with a commercial tablet (Gleevec) in 0.1 N HCl (pH 1.2) at 37 ± 0.5°C for 24 hours. Tablets were then evaluated for various physical parameters, including weight variation, thickness, hardness, friability, and drug content. Consequently, 6 months of physical stability studies and in vitro gastro-retentive studies were conducted. Results and Discussion Statistical data analysis revealed that tablets containing a composition of 14.67% w/w HPMC K4M, 10.67%, w/w Na alginate, 1.33%, w/w Carbomer 934P and 9.33%, w/w NaHCO3 produced the most favorable formulation to develop 24-hour sustained-release tablets with optimum floating behavior and satisfactory physicochemical characteristics. Furthermore, in vitro release study revealed that the formulated SR tablet had significantly lower Cmax and higher Tmax compared to the conventional tablet (Gleevec). Thus, formulated SR tablets preserved persistent concentration of plasma up to 24 hours. Conclusion In conclusion, in order to suggest a better drug delivery system with constant favorable release, resulting in optimized absorption and less side effects, formulated CP-HPMC-SA based imatinib mesylate floating sustained-release tablets can be a promising candidate for cancer chemotherapy. PMID:26035710

Vorinostat-eluting poly(DL-lactide-co-glycolide) nanofiber-coated stent for inhibition of cholangiocarcinoma cells

PubMed Central

Song, Yeon Hui; Kim, Chan; Kim, Jungsoo; Seo, Sol-Ji; Jeong, Young-Il; Kang, Dae Hwan

2017-01-01

Purpose The aim of this study was to fabricate a vorinostat (Zolinza™)-eluting nanofiber membrane-coated gastrointestinal (GI) stent and to study its antitumor activity against cholangiocarcinoma (CCA) cells in vitro and in vivo. Methods Vorinostat and poly(DL-lactide-co-glycolide) dissolved in an organic solvent was sprayed onto a GI stent to make a nanofiber-coated stent using an electro-spinning machine. Intact vorinostat and vorinostat released from nanofibers was used to assess anticancer activity in vitro against various CCA cells. The antitumor activity of the vorinostat-eluting nanofiber membrane-coated stent was evaluated using HuCC-T1 bearing mice. Results A vorinostat-incorporated polymer nanofiber membrane was formed on the surface of the GI stent. Vorinostat was continuously released from the nanofiber membrane over 10 days, and its release rate was higher in cell culture media than in phosphate-buffered saline. Released vorinostat showed similar anticancer activity against various CCA cells in vitro compared to that of vorinostat. Like vorinostat, vorinostat released from nanofibers induced acetylation of histone H4 and inhibited histone deacetylases 1⋅3⋅4/5/7 expression in vitro and in vivo. Furthermore, vorinostat nanofibers showed a higher tumor growth inhibition rate in HuCC-T1 bearing mice than vorinostat injections. Conclusion Vorinostat-eluting nanofiber membranes showed significant antitumor activity against CCA cells in vitro and in vivo. We suggest the vorinostat nanofiber-coated stent may be a promising candidate for CCA treatment. PMID:29089762

Formulation and Optimization of Polymeric Nanoparticles for Intranasal Delivery of Lorazepam Using Box-Behnken Design: In Vitro and In Vivo Evaluation

PubMed Central

Sharma, Deepak; Maheshwari, Dipika; Rana, Ravish; Bhatia, Shanu; Singh, Manisha; Gabrani, Reema; Sharma, Sanjeev K.; Ali, Javed; Sharma, Rakesh Kumar; Dang, Shweta

2014-01-01

The aim of the present study was to optimize lorazepam loaded PLGA nanoparticles (Lzp-PLGA-NPs) by investigating the effect of process variables on the response using Box-Behnken design. Effect of four independent factors, that is, polymer, surfactant, drug, and aqueous/organic ratio, was studied on two dependent responses, that is, z-average and % drug entrapment. Lzp-PLGA-NPs were successfully developed by nanoprecipitation method using PLGA as polymer, poloxamer as surfactant and acetone as organic phase. NPs were characterized for particle size, zeta potential, % drug entrapment, drug release behavior, TEM, and cell viability. Lzp-PLGA-NPs were characterized for drug polymer interaction using FTIR. The developed NPs showed nearly spherical shape with z-average 167–318 d·nm, PDI below 0.441, and −18.4 mV zeta potential with maximum % drug entrapment of 90.1%. In vitro drug release behavior followed Korsmeyer-Peppas model and showed initial burst release of 21.7 ± 1.3% with prolonged drug release of 69.5 ± 0.8% from optimized NPs up to 24 h. In vitro drug release data was found in agreement with ex vivo permeation data through sheep nasal mucosa. In vitro cell viability study on Vero cell line confirmed the safety of optimized NPs. Optimized Lzp-PLGA-NPs were radiolabelled with Technitium-99m for scintigraphy imaging and biodistribution studies in Sprague-Dawley rats to establish nose-to-brain pathway. PMID:25126544

Sustained Release of Lidocaine from Solvent-Free Biodegradable Poly[(d,l)-Lactide-co-Glycolide] (PLGA): In Vitro and In Vivo Study.

PubMed

Kau, Yi-Chuan; Liao, Chia-Chih; Chen, Ying-Chi; Liu, Shih-Jung

2014-09-16

Local anesthetics are commonly used for pain relief by regional nerve blocking. In this study, we fabricated solvent-free biodegradable pellets to extend the duration of lidocaine release without any significant local or systemic toxicity levels. To manufacture the pellets, poly[(d,l)-lactide-co-glycolide] (PLGA) was first pre-mixed with lidocaine powder into different ratios. The powder mixture was then compressed with a mold (diameter of 1, 5, 8 or 10 mm) and sintered at 65 °C to form pellets. The in vitro release study showed that the lidocaine/PLGA pellets exhibited a tri-phase release behavior (a burst, a diffusion-controlled release and a degradation-dominated release) and reached completion around day 28. Scanning electron microscope (SEM) photos show that small channels could be found on the surfaces of the pellets on day 2. Furthermore, the polymer matrix swelled and fell apart on day 7, while the pellets became viscous after 10 days of in vitro elution. Perineural administration of the lidocaine/PLGA pellets produced anti-hypersensitivity effects lasting for at least 24 h in rats, significant when compared to the control group (a pure PLGA was pellet administered). In addition, no inflammation was detected within the nerve and in the neighboring muscle by histopathology.

Preparation, In Vitro Characterization, and In Vivo Pharmacokinetic Evaluation of Respirable Porous Microparticles Containing Rifampicin

PubMed Central

Kundawala, Aliasgar; Patel, Vishnu; Patel, Harsha; Choudhary, Dhaglaram

2014-01-01

Abstract This study aimed to prepare and evaluate rifampicin microparticles for the lung delivery of rifampicin as respirable powder. The microparticles were prepared using chitosan by the spray-drying method and evaluated for aerodynamic properties and pulmonary drug absorption. To control the drug release, tripoly-phosphate in different concentrations 0.6, 0.9, 1.2, and 1.5 was employed to get a sustained drug release profile. The microparticles were evaluated for drug loading, % entrapment efficiency, tapped density, morphological characteristics, and in vitro drug release studies. Aerosol properties were determined using the Andersen cascade impactor. Porous microparticles with particle sizes (d0.5) less than 10 μm were obtained. The entrapment of rifampicin in microparticles was up to 72%. In vitro drug release suggested that the crosslinked microparticles showed sustained release for more than 12 hrs. The drug release rate was found to be decreased as the TPP concentration was increased. The microparticles showed a fine particle fraction in the range of 55–63% with mass median aerodynamic diameter (MMAD) values below 3 μm. The in vivo pulmonary absorption of the chitosan microparticles suggested a sustained drug release profile up to 72 hrs with an elimination rate of 0.010 per hr. The studies revealed that the spray-dried porous microparticles have suitable properties to be used as respirable powder in rifampicin delivery to the lungs. PMID:25853075

Formulation and evaluation of controlled release matrix mucoadhesive tablets of domperidone using Salvia plebeian gum

PubMed Central

Arora, Gurpreet; Malik, Karan; Singh, Inderbir; Arora, Sandeep; Rana, Vikas

2011-01-01

The aim of study was to prepare controlled release matrix mucoadhesive tablets of domperidone using Salvia plebeian gum as natural polymer. Tablets were formulated by direct compression technology employing the natural polymer in different concentrations (5, 10, 15 and 20% w/w). The prepared batches were evaluated for drug assay, diameter, thickness, hardness and tensile strength, swelling index, mucoadhesive strength (using texture analyzer) and subjected to in vitro drug release studies. Real-time stability studies were also conducted on prepared batches. In vitro drug release data were fitted in various release kinetic models for studying the mechanism of drug release. Tensile strength was found to increase from 0.808 ± 0.098 to 1.527 ± 0.10 mN/cm2 and mucoadhesive strength increased from 13.673 ± 1.542 to 40.378 ± 2.345 N, with an increase in the polymer concentration from 5 to 20% (A1 to A4). Swelling index was reported to increase with both increase in the concentration of gum and the time duration. The in vitro drug release decreased from 97.76 to 83.4% (A1 to A4) with the increase in polymer concentration. The drug release from the matrix tablets was found to follow zero-order and Higuchi models, indicating the matrix-forming potential of natural polymer. The value of n was found to be between 0.5221 and 0.8992, indicating the involvement of more than one drug release mechanism from the formulation and possibly the combination of both diffusion and erosion. These research findings clearly indicate the potential of S. plebeian gum to be used as binder, release retardant and mucoadhesive natural material in tablet formulations. PMID:22171313

Bisphenol A release from orthodontic adhesives measured in vitro and in vivo with gas chromatography.

PubMed

Moreira, Marília Rodrigues; Matos, Leonardo Gontijo; de Souza, Israel Donizeti; Brigante, Tamires Amabile Valim; Queiroz, Maria Eugênia Costa; Romano, Fábio Lourenço; Nelson-Filho, Paulo; Matsumoto, Mírian Aiko Nakane

2017-03-01

The objectives of this study were to quantify in vitro the Bisphenol A (BPA) release from 5 orthodontic composites and to assess in vivo the BPA level in patients' saliva and urine after bracket bonding with an orthodontic adhesive system. For the in-vitro portion of this study, 5 orthodontic composites were evaluated: Eagle Spectrum (American Orthodontics, Sheboygan, Wis), Enlight (Ormco, Orange, Calif), Light Bond (Reliance Orthodontic Products, Itasca, Ill), Mono Lok II (Rocky Mountain Orthodontics, Denver, Colo), and Transbond XT (3M Unitek, Monrovia, Calif). Simulating intraoral conditions, the specimens were immersed in a water/ethanol solution, and the BPA (ng.g -1 ) liberation was measured after 30 minutes, 24 hours, 1 day, 1 week, and 1 month by the gas chromatography system coupled with mass spectrometry. Twenty patients indicated for fixed orthodontic treatment participated in the in-vivo study. Saliva samples were collected before bracket bonding and then 30 minutes, 24 hours, 1 day, 1 week, and 1 month after bonding the brackets. Urine samples were collected before bonding and then at 1 day, 1 week, and 1 month after bonding. The results were analyzed statistically using analysis of variance and Tukey posttest, with a significance level of 5%. All composites evaluated in vitro released small amounts of BPA. Enlight composite showed the greatest release, at 1 month. Regarding the in-vivo study, the mean BPA level in saliva increased significantly only at 30 minutes after bonding in comparison with measurements recorded before bonding. All orthodontic composites released BPA in vitro. Enlight and Light Bond had, respectively, the highest and lowest BPA releases in vitro. The in-vivo experiment showed that bracket bonding with the Transbond XT orthodontic adhesive system resulted in increased BPA levels in saliva and urine. The levels were significant but still lower than the reference dose for daily ingestion. Copyright © 2016 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

Mechanistic investigation of drug release from asymmetric membrane tablets: effect of media gradients (osmotic pressure and concentration), and potential coating failures on in vitro release.

PubMed

Am Ende, Mary Tanya; Miller, Lee A

2007-02-01

An asymmetric membrane (AM) tablet was developed for a soluble model compound to study the in vitro drug release mechanisms in challenge conditions, including osmotic gradients, concentration gradients, and under potential coating failure modes. Porous, semipermable membrane integrity may be compromised by a high fat meal or by the presence of a defect in the coating that could cause a safety concern about dose-dumping. The osmotic and diffusional release mechanisms of the AM tablet were independently shut down such that their individual contribution to the overall drug release was measured. Shut off of osmotic and diffusional release was accomplished by performing dissolution studies into receptor solutions with osmotic pressure above the internal core osmotic pressure and into receptor solutions saturated with drug, respectively. The effect of coating failure modes on in vitro drug release from the AM tablet was assessed through a simulated high-fat meal and by intentionally compromising the coating integrity. The predominant drug release mechanism for the AM tablet was osmotic and accounted for approximately 90-95% of the total release. Osmotic release was shutoff when the receptor media osmotic pressure exceeded 76 atm. Diffusional release of the soluble drug amounted to 5-10% of the total release mechanism. The observed negative in vitro food effect was attributed to the increased osmotic pressure from the high fat meal when compared to the predicted release rates in sucrose media with the same osmotic pressure. This suppression in drug release rate due to a high fat meal is not anticipated to affect in vivo performance of the dosage form, as the rise in pressure is short-lived. Drug release from the AM system studied was determined to be robust to varying and extreme challenge conditions. The conditions investigated included varying pH, agitation rate, media osmotic pressure, media saturated with drug to eliminate the concentration gradient, simulated high fat meal, and intentionally placed film coating defects. Osmotic and diffusional shut off experiments suggest that the mechanism governing drug release is a combination of osmotic and diffusional at approximately 90-95% and 5-10%, respectively. In addition, the coating failure mode studies revealed this formulation and design is not significantly affected by a high fat meal or by an intentionally placed defect in the film coating, and more specifically, did not result in a burst of drug release.

Formulation and evaluation of controlled release antibiotic biodegradable implants for post operative site delivery.

PubMed

Mathur, Vijay; Mudnaik, Rajesh; Barde, Laxmikant; Roy, Arghya; Shivhare, Umesh; Bhusari, Kishore

2010-03-01

Biodegradable implants of ciprofloxacin hydrochloride for post operative site delivery were prepared using glyceryl monostearate and different concentrations of polyethylene glycol (PEG 6000), glycerol and Tween 80 as erosion enhancers by compression and molding technique. Formulations were subjected to in vitro drug release by the USP dissolution method, while promising formulations were subjected to in vitro drug release by the agar gel method and also to stability studies. It was observed that glyceryl monostearate formed hydrophobic matrix and delayed the drug delivery. Antibiotic release profile was controlled by using different combinations of erosion enhancers. The formulation prepared by the compression method showed more delayed release compared to formulations prepared by the molding method.

An investigation into the characteristics and drug release properties of multiple W/O/W emulsion systems containing low concentration of lipophilic polymeric emulsifier.

PubMed

Vasiljevic, Dragana; Parojcic, Jelena; Primorac, Marija; Vuleta, Gordana

2006-02-17

Multiple W/O/W emulsions with high content of inner phase (Phi1=Phi2=0.8) were prepared using relatively low concentrations of lipophilic polymeric primary emulsifier, PEG 30-dipolyhydroxystearate, and diclofenac diethylamine (DDA) as a model drug. The investigated formulations were characterized and their stability over the time was evaluated by dynamic and oscillatory rheological measurements, microscopic analysis and in vitro drug release study. In vitro release profiles of the selected model drug were evaluated in terms of the effective diffusion coefficients and flux of the released drug. The multiple emulsion samples exhibited good stability during the ageing time. Concentration of the lipophilic primary emulsifier markedly affected rheological behaviour as well as the droplet size and in vitro drug release kinetics of the investigated systems. The multiple emulsion systems with highest concentration (2.4%, w/w) of the primary emulsifier had the lowest droplet size and the highest apparent viscosity and highest elastic characteristics. Drug release data indicated predominately diffusional drug release mechanism with sustained and prolonged drug release accomplished with 2.4% (w/w) of lipophilic emulsifier employed.

Optimization, in vitro release and bioavailability of gamma-oryzanol-loaded calcium pectinate microparticles reinforced with chitosan.

PubMed

Kim, Jong Soo; Lee, Ji-Soo; Chang, Pahn-Shick; Lee, Hyeon Gyu

2010-09-30

Response surface methodology was used to optimize coating conditions, including chitosan concentration (X(1)) and coating time (X(2)), for sustained release of chitosan-coated Ca-pectinate (CP) microparticles containing oryzanol (OZ). The optimized values of X(1) and X(2) were found to be 1.48% and 69.92 min, respectively. These optimized values agreed favorably with the predicted results, indicating the utility of predictive models for the release of OZ in simulated intestinal fluid. In vitro release studies revealed that the chitosan-coated CP microparticles were quite stable under acidic conditions, but swell and disintegrate under alkaline conditions. In vivo release study of OZ, physically entrapped within chitosan-coated CP microcapsules, demonstrated the sustained release of OZ and could be used to improve the bioavailability of OZ following oral administration. Copyright 2010 Elsevier B.V. All rights reserved.

Release of an endogenous pyrogen in vitro from rabbit mononuclear cells.

PubMed

Atkins, E; Bodel, P; Francis, L

1967-08-01

The capacity of rabbit mononuclear cells to release an endogenous pyrogen (EP) in vitro has been studied. After incubation with tuberculin, preparations of predominantly monocytic cells, derived from the respiratory passages of the lungs of rabbits sensitized with BCG, were activated to release EP. Pyrogen production occurred more slowly with lung monocytes than with blood leukocytes of similarly sensitized rabbits and 9 to 10 hr incubation in a fully supportive medium was required to produce clear-cut results. As previously reported with blood leukocytes, mononuclear cells from the lungs of normal animals were also activated by tuberculin but to a lesser degree than were those from specifically sensitized rabbits. Under a variety of conditions, mononuclear cells from either spleen or lymph nodes of the same sensitized rabbits failed to release detectable amounts of pyrogen when incubated with tuberculin in vitro but were activated in a majority of instances when phagocytosis of heat-killed staphylococci was used as the stimulus. Release of pyrogen from lung monocytes appears to be an active process that is both temperature-dependent and requires protein synthesis. Neither serum antibody nor complement appears to play a role in this process. Evidence is presented that the granulocyte is the main source of pyrogen evolved by blood leukocytes incubated in vitro with OT or heat-killed staphylococci, whereas the lung macrophage and/or monocyte is responsible for most of the pyrogen released from the lung cell preparations. From these studies, it is concluded that mononuclear cells can be activated in vitro by several microbial stimuli and must be considered an additional cellular source of EP. The clinical implications of these findings for the pathogenesis of fever in granulomatous diseases where the monocyte is the predominant cell are discussed.

Pharmacokinetics and correlation between in vitro release and in vivo absorption of bio-adhesive pellets of panax notoginseng saponins.

PubMed

Li, Ying; Zhang, Yun; Zhu, Chun-Yan

2017-02-01

The present study was designed to prepare and compare bio-adhesive pellets of panax notoginseng saponins (PNS) with hydroxy propyl methyl cellulose (HPMC), chitosan, and chitosan : carbomer, explore the influence of different bio-adhesive materials on pharmacokinetics behaviors of PNSbio-adhesive pellets, and evaluate the correlation between in vivo absorption and in vitro release (IVIVC). In order to predict the in vivo concentration-time profile by the in vitro release data of bio-adhesive pellets, the release experiment was performed using the rotating basket method in pH 6.8 phosphate buffer. The PNS concentrations in rat plasma were analyzed by HPLC-MS-MS method and the relative bioavailability and other pharmacokinetic parameters were estimated using Kinetica4.4 pharmacokinetic software. Numerical deconvolution method was used to evaluate IVIVC. Our results indicated that, compared with ordinary pellets, PNS bio-adhesive pellets showed increased oral bioavailability by 1.45 to 3.20 times, increased C max , and extended MRT. What's more, the release behavior of drug in HPMC pellets was shown to follow a Fickian diffusion mechanism, a synergetic function of diffusion and skeleton corrosion. The in vitro release and the in vivo biological activity had a good correlation, demonstrating that the PNS bio-adhesive pellets had a better sustained release. Numerical deconvolution technique showed the advantage in evaluation of IVIVC for self-designed bio-adhesive pellets with HPMC. In conclusion, the in vitro release data of bio-adhesive pellets with HPMC can predict its concentration-time profile in vivo. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Phytantriol based liquid crystal provide sustained release of anticancer drug as a novel embolic agent.

PubMed

Qin, Lingzhen; Mei, Liling; Shan, Ziyun; Huang, Ying; Pan, Xin; Li, Ge; Gu, Yukun; Wu, Chuanbin

2016-01-01

Phytantriol has received increasing amount of attention in drug delivery system, however, the ability of the phytantriol based liquid crystal as a novel embolic agent to provide a sustained release delivery system is yet to be comprehensively demonstrated. The purpose of this study was to prepare a phytantriol-based cubic phase precursor solution loaded with anticancer drug hydroxycamptothecine (HCPT) and evaluate its embolization properties, in vitro drug release and cytotoxicity. Phase behavior of the phytantriol-solvent-water system was investigated by visual inspection and polarized light microscopy, and no phase transition was observed in the presence of HCPT within the studied dose range. Water uptake by the phytantriol matrices was determined gravimetrically, suggesting that the swelling complied with the second order kinetics. In vitro evaluation of embolic efficacy indicated that the isotropic solution displayed a satisfactory embolization effect. In vitro drug release results showed a sustained-release up to 30 days and the release behavior was affected by the initial composition and drug loading. Moreover, the in vitro cytotoxicity and anticancer activity were evaluated by MTT assay. No appreciable mortality was observed for NIH 3T3 cells after 48 h exposure to blank formulations, and the anticancer activity of HCPT-loaded formulations to HepG2 and SMMC7721 cells was strongly dependent on the drug loading and treatment time. Taken together, these results indicate that phytantriol-based cubic phase embolic gelling solution is a promising potential carrier for HCPT delivery to achieve a sustained drug release by vascular embolization, and this technology may be potential for clinical applications.

Formulation of unidirectional release buccal patches of carbamazepine and study of permeation through porcine buccal mucosa

PubMed Central

Govindasamy, Parthasarathy; Kesavan, Bhaskar Reddy; Narasimha, Jayaveera Korlakunta

2013-01-01

Objective To achieve transbuccal release of carbamazepine by loading in unidirectional release mucoadhesive buccal patches. Methods Buccal patches of carbamazepine with unidirectional drug release were prepared using hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and ethyl cellulose by solvent casting method. Water impermeable backing layer (Pidilite® Biaxially-oriented polypropylene film) of patches provided unidirectional drug release. They were evaluated for thickness, mass uniformity, surface pH and folding endurance. Six formulations FA2, FA8, FA10, FB1, FB14 and FB16 (folding endurance above 250) were evaluated further for swelling studies, ex vivo mucoadhesive strength, ex vivo mucoadhesion time, in vitro drug release, ex vivo permeation, accelerated stability studies and FTIR and XRD spectral studies. Results The ex vivo mucoadhesion time of patches ranged between 109 min (FA10) to 126 min (FB14). The ex vivo mucoadhesive force was in the range of 0.278 to 0.479 kg/m/s. The in vitro drug release studies revealed that formulation FA8 released 84% and FB16 released 99.01% of drug in 140 min. Conclusions The prepared unidirectional buccal patches of carbamazepine provided a maximum drug release within specified mucoadhesion period and it indicates a potential alternative drug delivery system for systemic delivery of carbamazepine. PMID:24093793

Application of Box-Behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: Optimization, in vitro release, ocular tolerance, and antibacterial activity.

PubMed

Baig, Mirza Salman; Ahad, Abdul; Aslam, Mohammed; Imam, Syed Sarim; Aqil, Mohd; Ali, Asgar

2016-04-01

The aim of the present study was to develop and optimize levofloxacin loaded solid lipid nanoparticles for the treatment of conjunctivitis. Box-Behnken experimental design was applied for optimization of solid lipid nanoparticles. The independent variables were stearic acid as lipid (X1), Tween 80 as surfactant (X2) and sodium deoxycholate as co-surfactant (X3) while particle size (Y1) and entrapment efficiency (Y2) were the dependent variables. Further in vitro release and antibacterial activity in vitro were also performed. The optimized formulation of levofloxacin provides particle size of 237.82 nm and showed 78.71% entrapment efficiency and achieved flux 0.2,493 μg/cm(2)/h across excised goat cornea. In vitro release study showed prolonged drug release from the optimized formulation following Korsmeyer-Peppas model. Antimicrobial study revealed that the developed formulation possesses antibacterial activity against Staphylococcus aureus, and Escherichia coli equivalent to marketed eye drops. HET-CAM test demonstrated that optimized formulation was found to be non-irritant and safe for topical ophthalmic use. Our results concluded that solid lipid nanoparticles are an efficient carrier for ocular delivery of levofloxacin and other drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Investigation of factors affecting in vitro doxorubicin release from PEGylated liposomal doxorubicin for the development of in vitro release testing conditions.

PubMed

Shibata, Hiroko; Izutsu, Ken-Ichi; Yomota, Chikako; Okuda, Haruhiro; Goda, Yukihiro

2015-01-01

Establishing appropriate drug release testing methods of liposomal products for assuring quality and performance requires the determination of factors affecting in vitro drug release. In this study, we investigated the effects of test conditions (human plasma lot, pH/salt concentration in the test media, dilution factor, temperature, ultrasound irradiation, etc.), and liposomal preparation conditions (pH/concentration of ammonium sulfate solution), on doxorubicin (DXR) release from PEGylated liposomal DXR. Higher temperature and lower pH significantly increased DXR release. The evaluation of DXR solubility indicated that the high DXR release induced by low pH may be attributed to the high solubility of DXR at low pH. Ultrasound irradiation induced rapid DXR release in an amplitude-dependent manner. The salt concentration in the test solution, human plasma lot, and dilution factor had a limited impact on DXR-release. Variations in the ammonium sulfate concentration used in solutions for the formation/hydration of liposomes significantly affected DXR release behavior, whereas differences in pH did not. In addition, heating condition in phosphate-buffered saline at lower pH (<6.5) exhibited higher discriminative ability for the release profiles from various liposomes with different concentrations of ammonium sulfate than did ultrasound irradiation. These results are expected to be helpful in the process of establishing appropriate drug release testing methods for PEGylated liposomal DXR.

Release of EPA and DHA from salmon oil - a comparison of in vitro digestion with human and porcine gastrointestinal enzymes.

PubMed

Aarak, K E; Kirkhus, B; Holm, H; Vogt, G; Jacobsen, M; Vegarud, G E

2013-10-01

In the present study, we hypothesised whether in vitro digestion of salmon oil would release different amounts of PUFA depending on the origin of the lipolytic enzymes used. For this purpose, in vitro digestion of salmon oil (SO) was performed using human duodenal juice (HDJ) or a commercial enzyme preparation consisting of porcine pancreatin and bile (PB). The lipolytic effect was determined by measuring the release of fatty acids (FA) using solid-phase extraction and GC-flame ionisation detection, withdrawing samples every 20 min during digestion. The amount of FA released indicated that a plateau was reached after 80 min with approximately similar amounts of FA detected using both HDJ and PB (379 (sd 18) and 352 (sd 23) mg/g SO, respectively). However, the release of 18 : 2, EPA (20 : 5) and DHA (22 : 6) was significantly different during in vitro digestion. At 80 min, HDJ and PB released 43 and 33% of 18 : 2, 14 and 9% of EPA and 11 and 9% of DHA, respectively. Both enzyme preparations released approximately the same amounts of the other FA analysed. The effect of the addition of bile salts (BS) was significantly different in the two enzyme systems, where porcine pancreatin highly responded to the increase in BS concentration, in contrast to HDJ.

Determination of diffusion coefficient for released nanoparticles from developed gelatin/chitosan bilayered buccal films.

PubMed

Mahdizadeh Barzoki, Zahra; Emam-Djomeh, Zahra; Mortazavian, Elaheh; Rafiee-Tehrani, Niyousha; Behmadi, Homa; Rafiee-Tehrani, Morteza; Moosavi-Movahedi, Ali Akbar

2018-06-01

This study aims at the mathematical optimization by Box-Behnken statistical design, fabrication by ionic gelation technique and in vitro characterization of insulin nanoparticles containing thiolated N- dimethyl ethyl chitosan (DMEC-Cys) conjugate. Then Optimized insulin nanoparticles were loaded into the buccal film, and in-vitro drug release from films was investigated, and diffusion coefficient was predicted. The optimized nanoparticles were shown to have mean particle size diameter of 148nm, zeta potential of 15.5mV, PdI of 0.26 and AE of 97.56%. Cell viability after incubation with optimized nanoparticles and films were assessed using an MTT biochemical assay. In vitro release study, FTIR and cytotoxicity also indicated that nanoparticles made of this thiolated polymer are suitable candidates for oral insulin delivery. Copyright © 2018 Elsevier B.V. All rights reserved.

Development, evaluation and pharmacokinetics of time-dependent ketorolac tromethamine tablets.

PubMed

Vemula, Sateesh Kumar; Veerareddy, Prabhakar Reddy

2013-01-01

The present study was intended to develop a time-dependent colon-targeted compression-coated tablets of ketorolac tromethamine (KTM) using hydroxypropyl methylcellulose (HPMC) that release the drug slowly but completely in the colonic region by retarding the drug releases in stomach and small intestine. KTM core tablets were prepared by direct compression method and were compression coated with HPMC. The formulation is optimized based on the in vitro drug release studies and further evaluated by X-ray imaging technique in healthy humans to ensure the colonic delivery. To prove these results, in vivo pharmacokinetic studies in human volunteers were designed to study the in vitro-in vivo correlation. From the in vitro dissolution study, optimized formulation F3 showed negligible drug release (6.75 ± 0.49%) in the initial lag period followed by slow release (97.47 ± 0.93%) for 24 h which clearly indicates that the drug is delivered to the colon. The X-ray imaging studies showed that the tablets reached the colon without disintegrating in upper gastrointestinal system. From the pharmacokinetic evaluation, the immediate-release tablets producing peak plasma concentration (C(max)) was 4482.74 ng/ml at 2 h T(max) and colon-targeted tablets showed C(max) = 3562.67 ng/ml at 10 h T(max). The area under the curve for the immediate-release and compression-coated tablets was 10595.14 and 18796.70 ng h/ml and the mean resident time was 3.82 and 10.75 h, respectively. Thus, the compression-coated tablets based on time-dependent approach were preferred for colon-targeted delivery of ketorolac.

Development of in vitro-in vivo correlation of parenteral naltrexone loaded polymeric microspheres.

PubMed

Andhariya, Janki V; Shen, Jie; Choi, Stephanie; Wang, Yan; Zou, Yuan; Burgess, Diane J

2017-06-10

Establishment of in vitro-in vivo correlations (IVIVCs) for parenteral polymeric microspheres has been very challenging, due to their complex multiphase release characteristics (which is affected by the nature of the drug) as well as the lack of compendial in vitro release testing methods. Previously, a Level A correlation has been established and validated for polymeric microspheres containing risperidone (a practically water insoluble small molecule drug). The objectives of the present study were: 1) to investigate whether a Level A IVIVC can be established for polymeric microspheres containing another small molecule drug with different solubility profiles compared to risperidone; and 2) to determine whether release characteristic differences (bi-phasic vs tri-phasic) between microspheres can affect the development and predictability of IVIVCs. Naltrexone was chosen as the model drug. Three compositionally equivalent formulations of naltrexone microspheres with different release characteristics were prepared using different manufacturing processes. The critical physicochemical properties (such as drug loading, particle size, porosity, and morphology) as well as the in vitro release characteristics of the prepared naltrexone microspheres and the reference-listed drug (Vivitrol®) were determined. The pharmacokinetics of the naltrexone microspheres were investigated using a rabbit model. The obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method, and compared with the in vitro release profiles of the naltrexone microspheres obtained using USP apparatus 4. Level A IVIVCs were established and validated for predictability. The results demonstrated that the developed USP 4 method was capable of detecting manufacturing process related performance changes, and most importantly, predicting the in vivo performance of naltrexone microspheres in the investigated animal model. A critical difference between naltrexone and risperidone loaded microspheres is their respective bi-phasic and tri-phasic release profiles with varying burst release and lag phase. These variations in release profiles affect the development of IVIVCs. Nevertheless, IVIVCs have been established and validated for polymeric microspheres with different release characteristics. Copyright © 2017. Published by Elsevier B.V.

Bovine Serum Albumin Nanoparticles Containing Amphotericin B: Characterization, Cytotoxicity and In Vitro Antifungal Evaluation.

PubMed

Casa, Diani Meza; Karam, Thaysa Ksiaskiewcz; Alves, Aline de Cristo Soares; Zgoda, Aline Aparecida; Khalil, Najeh Maissar; Mainardes, Rubiana Mara

2015-12-01

In this study, nanoparticles based on bovine serum albumin (BSA) containing amphotericin B (AmB) were obtained by the desolvation method and characterized with respect to size, size distribution, AmB encapsulation efficiency, AmB state of aggregation, and AmB in vitro release profile. After, the effect of nanoparticles on the cytotoxicity of human erythrocytes in vitro and efficacy over strains of Candida spp. were evaluated. The mean particle size was 156 nm and the AmB encapsulation efficiency was over 82%. The in vitro release profile revealed a sustained release of approximately 48% of AmB over 5 days. AmB is present in BSA nanoparticles as monomer. AmB-loaded nanoparticles showed very low index of hemolysis (less than 8%) in 72 h of assay compared to free AmB, which presented 100% of hemolysis in 2 h of incubation. The AmB-loaded BSA nanoparticles were as effective as free AmB against Candida albicans and Candida tropicalis, considering their sustained release profile. Thus, BSA nanoparticles are potential carriers for AmB, reducing its molecular aggregation and prolonging its release, resulting in lower cytotoxicity while maintaining its antifungal activity.

Development of a multilayered association polymer system for sequential drug delivery

NASA Astrophysics Data System (ADS)

Chinnakavanam Sundararaj, Sharath kumar

As all the physiological processes in our body are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the primary objective of this research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. This particular device was designed aimed at the treatment of periodontitis, a highly prevalent oral inflammatory disease that affects 90% of the world population. This condition is caused by bacterial biofilm on the teeth, resulting in a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The polymers used for the fabrication of this multilayered device consists of cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion property of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. After the initial characterization of the CAPP system, the device was specifically modified to achieve sequential release of drugs aimed at the treatment of periodontitis. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. To obtain different erosion times and achieve appropriate release profiles specific to the disease condition, the device was modified by increasing the number of layers or by inclusion of a slower eroding polymer layer. In all the cases, the device was able to release the four different drugs in the designed temporal sequence. Analysis of antibiotic and antiinflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. Following extensive studies on the in vitro sequential drug release from these devices, the in vivo drug release profiles were investigated. The CAPP devices with different release rates and dosage formulations were implanted in a rat calvarial onlay model, and the in vivo drug release and erosion was compared with in vitro results. In vivo studies showed sequential release of drugs comparable to those measured in vitro, with some difference in drug release rates observed. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule. KEYWORDS: Multiple drug delivery, Periodontitis, Cellulose acetate phthalate, Pluronic F-127, Sequential drug release, in vitro drug release, in vivo drug release.

Investigating the in-vitro and in-vivo flavour release from 21 fresh-cut apples.

PubMed

Ting, Valentina J L; Romano, Andrea; Soukoulis, Christos; Silcock, Patrick; Bremer, Phil J; Cappellin, Luca; Biasioli, Franco

2016-12-01

In-vitro and in-vivo flavour release from 21 different apple cultivars was studied using proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS) with a focus on the relationship between texture and volatile organic compound (VOC) emission. Generally, firm-juicy cultivars had a shorter time to first swallow (Tswal) and a higher number of swallows (Nswal), while softer-mealy cultivars had a longer Tswal and a lower Nswal. Firm-juicy cultivars containing high VOC concentrations had a short time to maximum intensity (Tmax) owing to a shorter Tswal and a higher Nswal as juice was released during mastication. Swallowing increased VOC flow through the nasal cavity. These results differ from previous flavour release studies with gel/gel-like model systems as juiciness/release of fluids is not a factor in such matrices. The current study, therefore, highlights the benefits of using in-vivo analysis to gain a better understanding of flavour release in real food products. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmaceutical suspension containing both immediate/sustained-release amoxicillin-loaded gelatin nanoparticles: preparation and in vitro characterization.

PubMed

Harsha, Sree

2013-01-01

Pharmaceutical suspension containing oral dosage forms delivering both immediate-release and sustained-release amoxicillin was developed as a new dosage form to eradicate Helicobacter pylori. Amoxicillin-loaded gelatin nanoparticles are able to bind with the mucosal membrane after delivery to the stomach and could escalate the effectiveness of a drug, providing dual release. The objective of this study was to develop amoxicillin nanoparticles using innovative new technology--the Büchi Nano Spray Dryer B-90 - and investigate such features as drug content, particle morphology, yield, in vitro release, flow properties, and stability. The nanoparticles had an average particle size of 571 nm. The drug content and percentage yield was 89.2% ± 0.5% and 93.3% ± 0.6%, respectively. Angle of repose of nanoparticle suspension was 26.3° and bulk density was 0.59 g/cm(3). In vitro drug release of formulations was best fitted by first-order and Peppas models with R (2) of 0.9841 and 0.9837 respectively; release profile was 15.9%, while; for the original drug, amoxicillin, under the same conditions, 90% was released in the first 30 minutes. The nanoparticles used in this study enabled sustained release of amoxicillin over an extended period of time, up to 12 hours, and were stable for 12 months under accelerated storage conditions of 25 °C ± 2 °C and 60% ± 5% relative humidity.

Formation of nanoparticles of a hydrophilic drug using supercritical carbon dioxide and microencapsulation for sustained release.

PubMed

Thote, Amol J; Gupta, Ram B

2005-03-01

Our purpose was to produce nanoparticles of a hydrophilic drug with use of supercritical carbon dioxide (CO2), encapsulate the obtained nanoparticles into polymer microparticles with use of an anhydrous method and study their sustained in vitro drug release. The hydrophilic drug, dexamethasone phosphate, is dissolved in methanol and injected in supercritical CO2 with an ultrasonic field for enhanced molecular mixing (supercritical antisolvent technique with enhanced mass transfer [SAS-EM]). Supercritical CO2 rapidly extracts methanol leading to instantaneous precipitation of drug nanoparticles. The nanoparticles are then encapsulated in poly(lactide-co-glycolide) (PLGA) polymer by use of the anhydrous solid-oil-oil-oil technique. This results in a well-dispersed encapsulation of drug nanoparticles in polymer microspheres. In vitro drug release from these microparticles is studied. With supercritical CO2 used as an antisolvent, nanoparticles of dexamethasone phosphate were obtained in the range of 150 to 200 nm. On encapsulation in polylactide coglycolide, composite microspheres of approximately 70 microm were obtained. The in vitro drug release of these nanoparticles/microparticles composites shows sustained release of dexamethasone phosphate over a period of 700 hours with almost no initial burst release. Nanoparticles of dexamethasone phosphate can be produced with the SAS-EM technique. When microencapsulated, these particles can provide sustained drug release without initial burst release. Because the complete process is anhydrous, it can be easily extended to produce sustained release formulations of other hydrophilic drugs.

Development and Characterization of Novel Floating-Mucoadhesive Tablets Bearing Venlafaxine Hydrochloride.

PubMed

Misra, Raghvendra; Bhardwaj, Peeyush

2016-01-01

The present investigation is concerned about the development of floating bioadhesive drug delivery system of venlafaxine hydrochloride which after oral administration exhibits a unique combination of floating and bioadhesion to prolong gastric residence time and increase drug bioavailability within the stomach. The floating bioadhesive tablets were prepared by the wet granulation method using different ratios of hydroxypropyl methyl cellulose (HPMC K4MCR) and Carbopol 934PNF as polymers. Sodium bicarbonate (NaHCO3) and citric acid were used as gas (CO2) generating agents. Tablets were characterized for floating properties, in vitro drug release, detachment force, and swelling index. The concentration of hydroxypropyl methyl cellulose and Carbopol 934PNF significantly affects the in vitro drug release, floating properties, detachment force, and swelling properties of the tablets. The optimized formulation showed the floating lag time 72 ± 2.49 seconds and duration of floating 24.50 ± 0.74 hr. The in vitro release studies and floating behavior were studied in simulated gastric fluid (SGF) at pH 1.2. Different drug release kinetics models were also applied. The in vitro drug release from tablets was sufficiently sustained (more than 18 hr) and the Fickian transports of the drug from the tablets were confirmed. The radiological evidence suggests that the tablets remained buoyant and altered position in the stomach of albino rabbit and mean gastric residence time was prolonged (more than > 6 hr).

Modulation of venlafaxine hydrochloride release from press coated matrix tablet.

PubMed

Gohel, M C; Soni, C D; Nagori, S A; Sarvaiya, K G

2008-01-01

The aim of present study was to prepare novel modified release press coated tablets of venlafaxine hydrochloride. Hydroxypropylmethylcellulose K4M and hydroxypropylmethylcellulose K100M were used as release modifier in core and coat, respectively. A 3(2) full factorial design was adopted in the optimization study. The drug to polymer ratio in core and coat were chosen as independent variables. The drug release in the first hour and drug release rate between 1 and 12 h were chosen as dependent variables. The tablets were characterized for dimension analysis, crushing strength, friability and in vitro drug release. A check point batch, containing 1:2.6 and 1:5.4 drug to polymer in core and coat respectively, was prepared. The tablets of check point batch were subjected to in vitro drug release in dissolution media with pH 5, 7.2 and distilled water. The kinetics of drug release was best explained by Korsmeyer and Peppas model (anomalous non-Fickian diffusion). The systematic formulation approach enabled us to develop modified release venlafaxine hydrochloride tablets.

Preformulation experiences and in vitro model studies with spironolactone-containing suppositories.

PubMed

Regdon, G; Deák, D; Regdon, G; Muskó, Z; Erös, I

2001-01-01

The optimal suppository base for the formulation of rectal suppositories containing diuretic spironolactone was selected experimentally. Model studies were carried out about the effect of solubility-increasing additives on the release of the drug from the suppositories. During the in vitro examinations acceptor phases of different pH values were used, and both diffusion time and the number of samplings were changed. Among the lipophilic and hydrophilic suppository bases studied the hydrophilic Macrogolum 1540 was found to be optimal. The release and diffusion of spironolactone was the most favourable from these suppositories. During storage these suppositories remained stable and the values of release did not decrease significantly (p < 0.05).

Antibacterial, anti-inflammatory, and bone-regenerative dual-drug-loaded calcium phosphate nanocarriers-in vitro and in vivo studies.

PubMed

Madhumathi, K; Rubaiya, Y; Doble, Mukesh; Venkateswari, R; Sampath Kumar, T S

2018-05-01

A dual local drug delivery system (DDS) composed of calcium phosphate bioceramic nanocarriers aimed at treating the antibacterial, anti-inflammatory, and bone-regenerative aspects of periodontitis has been developed. Calcium-deficient hydroxyapatite (CDHA, Ca/P = 1.61) and tricalcium phosphate (β-TCP) were prepared by microwave-accelerated wet chemical synthesis method. The phase purity of the nanocarriers was confirmed by x-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR), while the transmission electron microscopy (TEM) confirmed their nanosized morphology. CDHA was selected as carrier for the antibiotic (tetracycline) while TCP was chosen as the anti-inflammatory drug (ibuprofen) carrier. Combined drug release profile was studied in vitro from CDHA/TCP (CTP) system and compared with a HA/TCP (BCP) biphasic system. The tetracycline and ibuprofen release rate was 71 and 23% from CTP system as compared to 63 and 20% from BCP system. CTP system also showed a more controlled drug release profile compared to BCP system. Modeling of drug release kinetics from CTP system indicated that the release follows Higuchi model with a non-typical Fickian diffusion profile. In vitro biological studies showed the CTP system to be biocompatible with significant antibacterial and anti-inflammatory activity. In vivo implantation studies on rat cranial defects showed greater bone healing and new bone formation in the drug-loaded CTP system compared to control (no carrier) at the end of 12 weeks. The in vitro and in vivo results suggest that the combined drug delivery platform can provide a comprehensive management for all bone infections requiring multi-drug therapy.

Paclitaxel-loaded polymeric microparticles: Quantitative relationships between in vitro drug release rate and in vivo pharmacodynamics

PubMed Central

Tsai, Max; Lu, Ze; Wientjes, M. Guillaume; Au, Jessie L.-S.

2013-01-01

Intraperitoneal therapy (IP) has demonstrated survival advantages in patients with peritoneal cancers, but has not become a widely practiced standard-of-care in part due to local toxicity and sub-optimal drug delivery. Paclitaxel-loaded, polymeric microparticles were developed to overcome these limitations. The present study evaluated the effects of microparticle properties on paclitaxel release (extent and rate) and in vivo pharmacodynamics. In vitro paclitaxel release from microparticles with varying physical characteristics (i.e., particle size, copolymer viscosity and composition) was evaluated. A method was developed to simulate the dosing rate and cumulative dose released in the peritoneal cavity based on the in vitro release data. The relationship between the simulated drug delivery and treatment outcomes of seven microparticle compositions was studied in mice bearing IP human pancreatic tumors, and compared to that of the intravenous Cremophor micellar paclitaxel solution used off-label in previous IP studies. Paclitaxel release from polymeric microparticles in vitro was multi-phasic; release was greater and more rapid from microparticles with lower polymer viscosities and smaller diameters (e.g., viscosity of 0.17 vs. 0.67 dl/g and diameter of 5–6 vs. 50–60 μm). The simulated drug release in the peritoneal cavity linearly correlated with treatment efficacy in mice (r2>0.8, p<0.001). The smaller microparticles, which distribute more evenly in the peritoneal cavity compared to the large microparticles, showed greater dose efficiency. For single treatment, the microparticles demonstrated up to 2-times longer survival extension and 4-times higher dose efficiency, relative to the paclitaxel/Cremophor micellar solution. Upon repeated dosing, the paclitaxel/Cremophor micellar solution showed cumulative toxicity whereas the microparticle that yielded 2-times longer survival did not display cumulative toxicity. The efficacy of IP therapy depended on both temporal and spatial factors that were determined by the characteristics of the drug delivery system. A combination of fast- and slow-releasing microparticles with 5–6 μm diameter provided favorable spatial distribution and optimal drug release for IP therapy. PMID:24056144

In vivo predictive release methods for medicated chewing gums.

PubMed

Gajendran, Jayachandar; Kraemer, Johannes; Langguth, Peter

2012-10-01

Understanding the performance of a drug product in vivo plays a key role in the development of meaningful in vitro drug release methodology. In case of functional chewing gums, the mode and the mechanism of release and the site of application differ significantly from other conventional solid oral dosage forms and require a special consideration to extract meaningful information from clinical studies. In the current study, suitable drug release methodology was developed to predict the in vivo performance of an investigated chewing gum product. Different parameters of the drug release testing apparatus described in the Ph. Eur. and Pharmeuropa were evaluated. Drug release data indicate that the parameters, chewing distance, chewing frequency and twisting motion, affect the drug release. Higher drug release was observed when the frequency was changed from 40 chews/min to 60 chews/min for apparatus A and B, as was the case for the twisting motion when changed from 20º to 40º for apparatus B. As far as the chewing distance is concerned, the release rate was in the following order; apparatus A: 0.3 mm > 0.5 mm > 0.7 mm; apparatus B: 1.4 mm > 1.6 mm > 1.8 mm. A suitable apparatus set-up for in vitro release testing was identified. The method will be useful for the establishment of in vitro in vivo correlations (IVIVC) for medicated chewing gums. Interchangeability of the apparatus for a product is not generally recommended without prior knowledge of the performance of the product, as the construction and principle of operation for the apparatus differ considerably. Copyright © 2012 John Wiley & Sons, Ltd.

Improved oral bioavailability of valsartan using proliposomes: design, characterization and in vivo pharmacokinetics.

PubMed

Nekkanti, Vijaykumar; Venkatesan, Natarajan; Wang, Zhijun; Betageri, Guru V

2015-01-01

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6 ± 2.9% with a vesicle size of 364.1 ± 14.9 nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12 h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.

9 CFR 113.8 - In vitro tests for serial release.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false In vitro tests for serial release. 113... REQUIREMENTS Applicability § 113.8 In vitro tests for serial release. (a) Master Seed which has been established as pure, safe, and immunogenic shall be used for preparing seed for production as specified in the...

Multiple emulsions as effective platforms for controlled anti-cancer drug delivery.

PubMed

Dluska, Ewa; Markowska-Radomska, Agnieszka; Metera, Agata; Tudek, Barbara; Kosicki, Konrad

2017-09-01

Developing pH-responsive multiple emulsion platforms for effective glioblastoma multiforme therapy with reduced toxicity, a drug release study and modeling. Cancer cell line: U87 MG, multiple emulsions with pH-responsive biopolymer and encapsulated doxorubicin (DOX); preparation of multiple emulsions in a Couette-Taylor flow biocontactor, in vitro release study of DOX (fluorescence intensity analysis), in vitro cytotoxicity study (alamarBlue cell viability assay) and numerical simulation of DOX release rates. The multiple emulsions offered a high DOX encapsulation efficiency (97.4 ± 1%) and pH modulated release rates of a drug. Multiple emulsions with a low concentration of DOX (0.02 μM) exhibited broadly advanced cell (U87 MG) cytotoxicity than free DOX solution used at the same concentration. Emulsion platforms could be explored for potential delivery of chemotherapeutics in glioblastoma multiforme therapy.

A short term quality control tool for biodegradable microspheres.

PubMed

D'Souza, Susan; Faraj, Jabar A; Dorati, Rossella; DeLuca, Patrick P

2014-06-01

Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C.

Development, characterization, and in vivo assessment of mucoadhesive nanoparticles containing fluconazole for the local treatment of oral candidiasis.

PubMed

Rençber, Seda; Karavana, Sinem Yaprak; Yılmaz, Fethiye Ferda; Eraç, Bayri; Nenni, Merve; Özbal, Seda; Pekçetin, Çetin; Gurer-Orhan, Hande; Hoşgör-Limoncu, Mine; Güneri, Pelin; Ertan, Gökhan

2016-01-01

This study aimed to develop a suitable buccal mucoadhesive nanoparticle (NP) formulation containing fluconazole for the local treatment of oral candidiasis. The suitability of the prepared formulations was assessed by means of particle size (PS), polydispersity index, and zeta potential measurements, morphology analysis, mucoadhesion studies, drug entrapment efficiency (EE), in vitro drug release, and stability studies. Based on the optimum NP formulation, ex vivo drug diffusion and in vitro cytotoxicity studies were performed. Besides, evaluation of the antifungal effect of the optimum formulation was evaluated using agar diffusion method, fungicidal activity-related in vitro release study, and time-dependent fungicidal activity. The effect of the optimum NP formulation on the healing of oral candidiasis was investigated in an animal model, which was employed for the first time in this study. The zeta potential, mucoadhesion, and in vitro drug release studies of various NP formulations revealed that chitosan-coated NP formulation containing EUDRAGIT(®) RS 2.5% had superior properties than other formulations. Concerning the stability study of the selected formulation, the formulation was found to be stable for 6 months. During the ex vivo drug diffusion study, no drug was found in receptor phase, and this is an indication of local effect. The in vitro antifungal activity studies showed the in vitro efficacy of the NP against Candida albicans for an extended period. Also, the formulation had no cytotoxic effect at the tested concentration. For the in vivo experiments, infected rabbits were successfully treated with local administration of the optimum NP formulation once a day. This study has shown that the mucoadhesive NP formulation containing fluconazole is a promising candidate with once-a-day application for the local treatment of oral candidiasis.

Colon targeted curcumin delivery using guar gum.

PubMed

Elias, Edwin J; Anil, Singhal; Ahmad, Showkat; Daud, Anwar

2010-06-01

Curcumin is used in the treatment of colon cancer, but its very poor absorption in the upper part of the GIT is a major concern. As a site for drug delivery, the colon offers a near neutral pH, reduced digestive enzymatic activity, a long transit time and an increased responsiveness to absorption enhancers. The aim of the present study was to identify a suitable polymer (guar gum) based matrix tablet for curcumin with sufficient mechanical strength and promising in vitro mouth-to-colon release profile. Three formulations of curcumin were prepared using varying concentrations of guar gum containing 50 mg curcumin by the wet granulation method. Tablets were subjected to evaluation by studying parameter like hardness, friability, drug content uniformity, and in-vitro drug release. In vitro drug release was evaluated using simulated stomach, intestinal and colonic fluids. The susceptibility of guar gum to colonic bacteria was also assessed by a drug release study with rat caecal contents. The 40% guar gum containing formulation (F-1) showed better drug release (91.1%) after 24 hours in the presence of rat caecal contents in comparison with the 50% guar gum containing formulation (F-2) (82.1%). Curcumin could, thus, be positively delivered to the colon for effective colon cancer treatment using guar gum.

Effect of glycerol on sustained insulin release from PVA hydrogels and its application in diabetes therapy

PubMed Central

Cai, Yunpeng; Che, Junyi; Yuan, Minglu; Shi, Xiaohong; Chen, Wei; Yuan, Wei-En

2016-01-01

The present study aimed to investigate the effects of glycerol on the physical properties and release of an insulin-loaded polyvinyl alcohol (PVA) hydrogel film. The insulin-loaded hydrogel composite film was produced using the freeze-thawing method, after which the in vitro swelling ratio, transmittance and insulin release, and the in vivo pharmacodynamics, of hydrogels containing various volumes of glycerol were investigated. The results demonstrated that the addition of glycerol reduced the swelling ratio and increased the softness of the PVA hydrogel film. An analysis of insulin release in vitro and of the hypoglycemic effects in rats demonstrated that the PVA hydrogel film had a sustained release of insulin and long-acting effect over 10 days. The results of the present study suggested that, as a hydrophilic plasticizer, glycerol was able to enhance the release of insulin in the early stage of release profile by enhancing the formation of water channels, although the total swelling ratio was decreased. Therefore, the insulin-loaded glycerol/PVA hydrogel film may be a promising sustained-release preparation for the treatment of diabetes. PMID:27698690

A modified SILCS contraceptive diaphragm for long-term controlled release of the HIV microbicide dapivirine.

PubMed

Major, Ian; Boyd, Peter; Kilbourne-Brook, Maggie; Saxon, Gene; Cohen, Jessica; Malcolm, R Karl

2013-07-01

There is considerable interest in developing new multipurpose prevention technologies to address women's reproductive health needs. This study describes an innovative barrier contraceptive device--based on the SILCS diaphragm--that also provides long-term controlled release of the lead candidate anti-HIV microbicide dapivirine. Diaphragm devices comprising various dapivirine-loaded polymer spring cores overmolded with a nonmedicated silicone elastomer sheath were fabricated by injection molding processes. In vitro release testing, thermal analysis and mechanical characterization were performed on the devices. A diaphragm device containing a polyoxymethylene spring core loaded with 10% w/w dapivirine provided continuous and controlled release of dapivirine over a 6-month period, with a mean in vitro daily release rate of 174 mcg/day. The mechanical properties of the new diaphragm were closely matched to the SILCS diaphragm. The study demonstrates proof of concept for a dapivirine-releasing diaphragm with daily release quantities potentially capable of preventing HIV transmission. In discontinuous clinical use, release of dapivirine may be readily extended over 1 or more years. Copyright © 2013 Elsevier Inc. All rights reserved.

Sustained release vancomycin-coated titanium alloy using a novel electrostatic dry powder coating technique may be a potential strategy to reduce implant-related infection.

PubMed

Han, Jing; Yang, Yi; Lu, Junren; Wang, Chenzhong; Xie, Youtao; Zheng, Xuebin; Yao, Zhenjun; Zhang, Chi

2017-07-24

In order to tackle the implant-related infection, a novel way was developed in this study to coat vancomycin particles mixed with controlled release coating materials onto the surface of titanium alloy by using an electrostatic dry powder coating technique. To characterize this sustained release antibacterial coating, surface morphology, in vitro and in vivo drug release were sequentially evaluated. In vitro cytotoxicity was tested by Cell Counting Kit-8 (CCK-8) assay and cytological changes were observed by inverted microscope. The antibacterial properties against MRSA, including a bacterial growth inhibition assay and a colony-counting test by spread plate method were performed. Results indicated that the vancomycin-coated sample was biocompatible for Human osteoblast cell line MG-63 and displayed effective antibacterial ability against MRSA. The coating film was revealed uniform by scanning electron microscopy. Both the in vitro and in vivo drug release kinetics showed an initially high release rate, followed by an extended period of sustained drug release over 7 days. These results suggest that with good biocompatibility and antibacterial ability, the sustained release antibacterial coating of titanium alloy using our novel electrostatic dry powder coating process may provide a promising candidate for the treatment of orthopedic implant-related infection.

In Vitro and In Vivo Investigation of the Potential of Amorphous Microporous Silica as a Protein Delivery Vehicle

PubMed Central

Vanmellaert, Lieve; Vermaelen, Peter; Deroose, Christophe M.; Naert, Ignace; Cardoso, Marcio Vivan; Martens, Johan A.

2013-01-01

Delivering growth factors (GFs) at bone/implant interface needs to be optimized to achieve faster osseointegration. Amorphous microporous silica (AMS) has a potential to be used as a carrier and delivery platform for GFs. In this work, adsorption (loading) and release (delivery) mechanism of a model protein, bovine serum albumin (BSA), from AMS was investigated in vitro as well as in vivo. In general, strong BSA adsorption to AMS was observed. The interaction was stronger at lower pH owing to favorable electrostatic interaction. In vitro evaluation of BSA release revealed a peculiar release profile, involving a burst release followed by a 6 h period without appreciable BSA release and a further slower release later. Experimental data supporting this observation are discussed. Apart from understanding protein/biomaterial (BSA/AMS) interaction, determination of in vivo protein release is an essential aspect of the evaluation of a protein delivery system. In this regard micropositron emission tomography (μ-PET) was used in an exploratory experiment to determine in vivo BSA release profile from AMS. Results suggest stronger in vivo retention of BSA when adsorbed on AMS. This study highlights the possible use of AMS as a controlled protein delivery platform which may facilitate osseointegration. PMID:23991413

Pinosylvin-Based Polymers: Biodegradable Poly(Anhydride-Esters) for Extended Release of Antibacterial Pinosylvin.

PubMed

Bien-Aime, Stephan; Yu, Weiling; Uhrich, Kathryn E

2016-07-01

Pinosylvin is a natural stilbenoid known to exhibit antibacterial bioactivity against foodborne bacteria. In this work, pinosylvin is chemically incorporated into a poly(anhydride-ester) (PAE) backbone via melt-condensation polymerization, and characterized with respect to its physicochemical and thermal properties. In vitro release studies demonstrate that pinosylvin-based PAEs hydrolytically degrade over 40 d to release pinosylvin. Pseudo-first order kinetic experiments on model compounds, butyric anhydride and 3-butylstilbene ester, indicate that the anhydride linkages hydrolyze first, followed by the ester bonds to ultimately release pinosylvin. An antibacterial assay shows that the released pinosylvin exhibit bioactivity, while in vitro cytocompatibility studies demonstrate that the polymer is noncytotoxic toward fibroblasts. These preliminary findings suggest that the pinosylvin-based PAEs can serve as food preservatives in food packaging materials by safely providing antibacterial bioactivity over extended time periods. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development of albumin-based nanoparticles for the delivery of abacavir.

PubMed

Wilson, Barnabas; Paladugu, Latishkumar; Priyadarshini, S R Brahmani; Jenita, J Josephine Leno

2015-11-01

The study was designed to prepare and evaluate albumin nanoparticles containing antiviral drug abacavir sulphate. Various batches of albumin nanoparticles containing abacavir sulphate were prepared by desolvation method. The abacavir loaded particles were characterized for their yield, percentage of drug loading, surface morphology, particle size, surface charge, pattern of in vitro drug release and release mechanism studies. Drug loading ranged from 1.2 to 5.9%w/w. The mean particle size and the surface charge were 418.2nm and -40.8mV respectively. The in vitro drug release varied between 38.73 and 51.36%w/w for 24h. The n value for Korsmeyer-Peppas was 0.425 indicating Fickian type drug release. The preliminary findings indicated that albumin nanoparticles of abacavir can be prepared by desolvation method with good yield, high drug loading and sustained release. Copyright © 2015 Elsevier B.V. All rights reserved.

Development of sustained release capsules containing "coated matrix granules of metoprolol tartrate".

PubMed

Siddique, Sabahuddin; Khanam, Jasmina; Bigoniya, Papiya

2010-09-01

The objective of this investigation was to prepare sustained release capsule containing coated matrix granules of metoprolol tartrate and to study its in vitro release and in vivo absorption. The design of dosage form was performed by choosing hydrophilic hydroxypropyl methyl cellulose (HPMC K100M) and hydrophobic ethyl cellulose (EC) polymers as matrix builders and Eudragit® RL/RS as coating polymers. Granules were prepared by composing drug with HPMC K100M, EC, dicalcium phosphate by wet granulation method with subsequent coating. Optimized formulation of metoprolol tartrate was formed by using 30% HPMC K100M, 20% EC, and ratio of Eudragit® RS/RL as 97.5:2.5 at 25% coating level. Capsules were filled with free flowing optimized granules of uniform drug content. This extended the release period upto 12 h in vitro study. Similarity factor and mean dissolution time were also reported to compare various dissolution profiles. The network formed by HPMC and EC had been coupled satisfactorily with the controlled resistance offered by Eudragit® RS. The release mechanism of capsules followed Korsemeyer-Peppas model that indicated significant contribution of erosion effect of hydrophilic polymer. Biopharmaceutical study of this optimized dosage form in rabbit model showed 10 h prolonged drug release in vivo. A close correlation (R(2) = 0.9434) was established between the in vitro release and the in vivo absorption of drug. The results suggested that wet granulation with subsequent coating by fluidized bed technique, is a suitable method to formulate sustained release capsules of metoprolol tartrate and it can perform therapeutically better than conventional immediate release dosage form.

Porous polystyrene beads as carriers for self-emulsifying system containing loratadine.

PubMed

Patil, Pradeep; Paradkar, Anant

2006-03-01

The aim of this study was to formulate a self-emulsifying system (SES) containing a lipophilic drug, loratadine, and to explore the potential of preformed porous polystyrene beads (PPB) to act as carriers for such SES. Isotropic SES was formulated, which comprised Captex 200 (63% wt/wt), Cremophore EL (16% wt/wt), Capmul MCM (16% wt/wt), and loratadine (5% wt/wt). SES was evaluated for droplet size, drug content, and in vitro drug release. SES was loaded into preformed and characterized PPB using solvent evaporation method. SES-loaded PPB were evaluated using scanning electron microscopy (SEM) for density, specific surface area (S BET ), loading efficiency, drug content, and in vitro drug release. After SES loading, specific surface area reduced drastically, indicating filling of PPB micropores with SES. Loading efficiency was least for small size (SS) and comparable for medium size (MS) and large size (LS) PPB fractions. In vitro drug release was rapid in case of SS beads due to the presence of SES near to surface. LS fraction showed inadequate drug release owing to presence of deeper micropores that resisted outward diffusion of entrapped SES. Leaching of SES from micropores was the rate-limiting step for drug release. Geometrical features such as bead size and pore architecture of PPB were found to govern the loading efficiency and in vitro drug release from SES-loaded PPB.

Porous polystyrene beads as carriers for self-emulsifying system containing loratadine.

PubMed

Patil, Pradeep; Paradkar, Anant

2006-03-24

The aim of this study was to formulate a self-emulsifying system (SES) containing a lipophilic drug, loratadine, and to explore the potential of preformed porous polystyrene beads (PPB) to act as carriers for such SES. Isotropic SES was formulated, which comprised Captex 200 (63% wt/wt), Cremophore EL (16% wt/wt), Capmul MCM (16% wt/wt), and loratadine (5% wt/wt). SES was evaluated for droplet size, drug content, and in vitro drug release. SES was loaded into preformed and characterized PPB using solvent evaporation method. SES-loaded PPB were evaluated using scanning electron microscopy (SEM) for density, specific surface area (S(BET)), loading efficiency, drug content, and in vitro drug release. After SES loading, specific surface area reduced drastically, indicating filling of PPB micropores with SES. Loading efficiency was least for small size (SS) and comparable for medium size (MS) and large size (LS) PPB fractions. In vitro drug release was rapid in case of SS beads due to the presence of SES near to surface. LS fraction showed inadequate drug release owing to presence of deeper micropores that resisted outward diffusion of entrapped SES. Leaching of SES from micropores was the rate-limiting step for drug release. Geometrical features such as bead size and pore architecture of PPB were found to govern the loading efficiency and in vitro drug release from SES-loaded PPB.

Pirfenidone-loaded liposomes for lung targeting: preparation and in vitro/in vivo evaluation

PubMed Central

Meng, Hui; Xu, Yong

2015-01-01

Background The purpose of this study was to develop novel pirfenidone (PFD)-loaded liposomes for targeting to the lung. Methods The liposomes were prepared by the film hydration method, and their in vitro/vivo characteristics were evaluated. Results The PFD liposomes appeared visually as green to yellowish suspensions and were spherical in shape. The particle size was 582.3±21.6 nm and the entrapment efficiency was relatively high (87.2%±5.7%). The liposomes showed typical sustained and prolonged drug-release behavior in vitro and fitted well with the Weibull distribution equation. The relatively slower time taken to reach a minimal plasma PFD concentration in vivo suggests that PFD liposomes have a sustained-release profile, which is consistent with the results of the in vitro release study. The PFD liposomes showed the largest area under the curve for the lung. The high distribution of PFD achieved in the lungs using this liposomal formulation may be explained by physical entrapment of the liposomes in the vascular network of the lung. Histopathological results indicated that liposomal PFD could alleviate pathological injury in lung tissue. Conclusion This liposomal formulation can enable sustained release of PFD and increase targeting to the lung. PMID:26185416

Recent advances in testing of microsphere drug delivery systems.

PubMed

Andhariya, Janki V; Burgess, Diane J

2016-01-01

This review discusses advances in the field of microsphere testing. In vitro release-testing methods such as sample and separate, dialysis membrane sacs and USP apparatus IV have been used for microspheres. Based on comparisons of these methods, USP apparatus IV is currently the method of choice. Accelerated in vitro release tests have been developed to shorten the testing time for quality control purposes. In vitro-in vivo correlations using real-time and accelerated release data have been developed, to minimize the need to conduct in vivo performance evaluation. Storage stability studies have been conducted to investigate the influence of various environmental factors on microsphere quality throughout the product shelf life. New tests such as the floating test and the in vitro wash-off test have been developed along with advancement in characterization techniques for other physico-chemical parameters such as particle size, drug content, and thermal properties. Although significant developments have been made in microsphere release testing, there is still a lack of guidance in this area. Microsphere storage stability studies should be extended to include microspheres containing large molecules. An agreement needs to be reached on the use of particle sizing techniques to avoid inconsistent data. An approach needs to be developed to determine total moisture content of microspheres.

Effect of bioadhesion on initial in vitro buoyancy of effervescent floating matrix tablets of ciprofloxacin HCL

PubMed Central

Negi, Jeetendra Singh; Trivedi, Abhinav; Khanduri, Praveen; Negi, Vandana; Kasliwal, Nikhil

2011-01-01

The purpose of this study was to investigate effect of bioadhesion on the initial in vitro buoyancy behaviour of effervescent matrix tablets of ciprofloxacin HCl (CIPRO). Tablets were prepared by direct compression using HPMC K4M and Carbopol 971P as hydrophilic-controlled release polymers, sodium bicarbonate (NaHCO3) as gas-generating agent, polyplasdone XL, Explotab and Ac-Di-Sol as swelling agents. Tablets were evaluated for normal and modified initial in vitro floating behavior, floating duration, swelling behavior and in vitro drug release studies. A modified buoyancy lag time for tablets was determined in order to include the effect of bioadhesion on initial buoyancy. The initial buoyancy was found depended on bioadhesion ability of tablets. The lowest modified buoyancy lag time of 20 seconds was obtained for Formulation F7 having both NaHCO3 and polyplasdone XL. The floating duration was also found dependent on concentration of NaHCO3 and swelling agents. The drug release of F7 was also sustained up to 12-hr duration with anomalous drug transport mechanism. PMID:22171304

Comparative assessment of in vitro release kinetics of calcitonin polypeptide from biodegradable microspheres.

PubMed

Prabhu, Sunil; Sullivan, Jennifer L; Betageri, Guru V

2002-01-01

The objective of our study was to compare the in vitro release kinetics of a sustained-release injectable microsphere formulation of the polypeptide drug, calcitonin (CT), to optimize the characteristics of drug release from poly-(lactide-co-glycolide) (PLGA) copolymer biodegradable microspheres. A modified solvent evaporation and double emulsion technique was used to prepare the microspheres. Release kinetic studies were carried out in silanized tubes and dialysis bags, whereby microspheres were suspended and incubated in phosphate buffered saline, sampled at fixed intervals, and analyzed for drug content using a modified Lowry protein assay procedure. An initial burst was observed whereby about 50% of the total dose of the drug was released from the microspheres within 24 hr and 75% within 3 days. This was followed by a period of slow release over a period of 3 weeks in which another 10-15% of drug was released. Drug release from the dialysis bags was more gradual, and 50% CT was released only after 4 days and 75% after 12 days of release. Scanning electron micrographs revealed spherical particles with channel-like structures and a porous surface after being suspended in an aqueous solution for 5 days. Differential scanning calorimetric studies revealed that CT was present as a mix of amorphous and crystalline forms within the microspheres. Overall, these studies demonstrated that sustained release of CT from PLGA microspheres over a 3-week period is feasible and that release of drug from dialysis bags was more predictable than from tubes.

In-vitro trials to ascertain sustained release efficacy of assembly pheromone micro particles for the control of brown dog tick, Rhipicephalus sanguineus.

PubMed

Bhoopathy, Dhivya; Bhaskaran Ravi, Latha

2017-12-01

Sustained release micro particles were prepared incorporating assembly pheromone and deltamethrin. Two natural polymers, namely, chitosan and calcium alginate and a synthetic polymer, poly-ε-caprolactone were used for encapsulating the assembly pheromone-acaricide combination. The micro particles were subjected to in vitro evaluation freshly after preparation and then at monthly intervals to assess their sustained release efficacy. The response of the unfed stages of dog tick, Rhipicephalus sanguineus to fresh and aged micro particles was assessed and results were recorded. The micro particles were found to release assembly pheromone in a sustained manner up to 2 months of study period.

Formulation, in vitro evaluation and kinetic analysis of chitosan-gelatin bilayer muco-adhesive buccal patches of insulin nanoparticles.

PubMed

Mahdizadeh Barzoki, Zahra; Emam-Djomeh, Zahra; Mortazavian, Elaheh; Akbar Moosavi-Movahedi, Ali; Rafiee Tehrani, M

2016-11-01

The present study was performed to optimise the formulation of a muco-adhesive buccal patch for insulin nanoparticles (NPs) delivery. Insulin NPs were synthesised by an ionic gelation technique using N-di methyl ethyl chitosan cysteine (DMEC-Cys) as permeation enhancer biopolymer, tripolyphosphate (TPP) and insulin. Buccal patches were developed by solvent-casting technique using chitosan and gelatine as muco-adhesive polymers. Optimised patches were embedded with 3 mg of insulin-loaded NPs with a homogeneous distribution of NPs in the muco-adhesive matrix, which displayed adequate physico-mechanical properties. The drug release characteristics, release mechanism and kinetics were investigated. Data fitting to Peppas equation with a correlation coefficient indicated that the mechanism of drug release followed an anomalous transport that means drug release was afforded through drug diffusion along with polymer erosion. In vitro drug release, release kinetics, physical and mechanical studies for all patch formulations reflected the ideal characteristics of this buccal patch for the delivery of insulin NPs.

Development of a discriminative biphasic in vitro dissolution test and correlation with in vivo pharmacokinetic studies for differently formulated racecadotril granules.

PubMed

Deng, Jia; Staufenbiel, Sven; Hao, Shilei; Wang, Bochu; Dashevskiy, Andriy; Bodmeier, Roland

2017-06-10

The purpose of this study was to discriminate the release behavior from three differently formulated racecadotril (BCS II) granules and to establish an in vitro-in vivo correlation. Three granule formulations of the lipophilic drug were prepared with equivalent composition but prepared with different manufacturing processes (dry granulation, wet granulation with or without binder). In vitro release of the three granules was investigated using a biphasic dissolution system (phosphate buffer pH6.8 and octanol) and compared to the conventional single phase USP II dissolution test performed under sink and non-sink conditions. In vivo studies with each granule formulation were performed in rats. Interestingly, the granule formulations exhibited pronouncedly different behavior in the different dissolution systems depending on different wetting and dissolution conditions. Single phase USP II dissolution tests lacked discrimination. In contrast, remarkable discrimination between the granule formulations was observed in the octanol phase of biphasic dissolution system with a rank order of release from granules prepared by wet granulation with binder>wet granulation without binder>dry granulation. This release order correlated well with the wettability of these granules. An excellent correlation was also established between in vitro release in the octanol phase of the biphasic test and in vivo data (R 2 =0.999). Compared to conventional dissolution methods, the biphasic method provides great potential to discriminate between only minor formulation and process changes within the same dosage form for poorly soluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Aqueous Polymer Dispersion Coating Used for Osmotic Pump Tablets: Membrane Property Investigation and IVIVC Evaluation.

PubMed

Cheng, Lizhen; Gai, Xiumei; Wen, Haoyang; Liu, Dandan; Tang, Xin; Wang, Yanyan; Wang, Tuanjie; Pan, Weisan; Yang, Xinggang

2018-01-01

The objective of this study was to investigate the fundamental properties of propranolol hydrochloride osmotic pump tablets coated by aqueous polymer dispersion, simultaneously exploring the in vitro and in vivo correlation of the tablet. The physicochemical properties and parameters of aqueous polymer dispersion membranes (SEM, water uptake, and water vapor transmission coefficient) were investigated. In addition, the release behavior and the in vitro release and in vivo absorption profiles of the tablets coated by aqueous polymer dispersion were investigated by comparing with propranolol hydrochloride osmotic pump tablets coated by an organic solvent. Results showed that the similarity factor (f 2 ) between cellulose acetate-coated tablet and Eudragit-coated tablet was 78.1, and f 2 between cellulose acetate-coated tablet and Kollicoat-coated tablet was 77.6. The linear IVIVC of Eudragit-coated and Kollicoat-coated osmotic pump tablets was determined, which confirmed excellent correlation between the absorption in vivo and the drug release in vitro. Consequently, the membrane coated by aqueous polymer dispersion or organic solvent has similar in vitro release rates of controlled release. Also, compared with organic solvent coating, aqueous polymer dispersion has numerous advantages, such as reduced toxicity and no environmental damage. Therefore, the aqueous polymer dispersion technology has enormous potential as a replacement of organic solvent coating.

Bioavailability and in vivo release behavior of controlled-release multiple-unit theophylline dosage forms in beagle dogs, cynomolgus monkeys, and göttingen minipigs.

PubMed

Ikegami, Kengo; Tagawa, Kozo; Osawa, Takashi

2006-09-01

To determine the usefulness of monkey as an animal model, bioavailability and in vivo release behaviors of theophylline (TP) after oral administration of controlled-release beads in dogs, monkeys, and minipigs were evaluated. Controlled-release beads were prepared using a centrifugal-fluid type granulator, that is, CF-granulator, and Ethylcellulose (EC) was used as controlled-release coating agent. Aqueous solution and EC-coated beads, which contained TP were orally administered to animals after at least 1-week intervals. In dogs and minipigs, their relative bioavailabilities of EC-coated beads were 33.1% and 47.0%, respectively, and in vivo TP release from EC-coated beads in the gastrointestinal tract of dogs and minipigs were not reflected in vitro data. In monkeys, relative bioavailability of EC-coated beads was 80.0% and the highest among the three species, and release amount of TP from EC-coated beads at 24 h after oral administration was 82.8% and 92.4%, which was almost correlated to in vitro data. Therefore, the discrepancy of the relative bioavailability in three species is considered to be due to the difference of in vivo release behavior of TP. The monkey may be useful animal model for bioavailability studies of controlled-release dosage forms of TP from the viewpoint of in vitro-in vivo release correlation. (c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association.

An understanding of modified release matrix tablets behavior during drug dissolution as the key for prediction of pharmaceutical product performance - case study of multimodal characterization of quetiapine fumarate tablets.

PubMed

Kulinowski, Piotr; Woyna-Orlewicz, Krzysztof; Rappen, Gerd-Martin; Haznar-Garbacz, Dorota; Węglarz, Władysław P; Dorożyński, Przemysław P

2015-04-30

Motivation for the study was the lack of dedicated and effective research and development (R&D) in vitro methods for oral, generic, modified release formulations. The purpose of the research was to assess multimodal in vitro methodology for further bioequivalence study risk minimization. Principal results of the study are as follows: (i) Pharmaceutically equivalent quetiapine fumarate extended release dosage form of Seroquel XR was developed using a quality by design/design of experiment (QbD/DoE) paradigm. (ii) The developed formulation was then compared with originator using X-ray microtomography, magnetic resonance imaging and texture analysis. Despite similarity in terms of compendial dissolution test, developed and original dosage forms differed in micro/meso structure and consequently in mechanical properties. (iii) These differences were found to be the key factors of failure of biorelevant dissolution test using the stress dissolution apparatus. Major conclusions are as follows: (i) Imaging methods allow to assess internal features of the hydrating extended release matrix and together with the stress dissolution test allow to rationalize the design of generic formulations at the in vitro level. (ii) Technological impact on formulation properties e.g., on pore formation in hydrating matrices cannot be overlooked when designing modified release dosage forms. Copyright © 2015 Elsevier B.V. All rights reserved.

Accelerated in vitro release testing of implantable PLGA microsphere/PVA hydrogel composite coatings

PubMed Central

Shen, Jie; Burgess, Diane J.

2011-01-01

Dexamethasone loaded poly(lactic-co-glycolic acid) (PLGA) microsphere/PVA hydrogel composites have been investigated as an outer drug-eluting coating for implantable devices such as glucose sensors to counter negative tissue responses to implants. The objective of this study was to develop a discriminatory, accelerated in vitro release testing method for this drug-eluting coating using United States Pharmacopeia (USP) apparatus 4. Polymer degradation and drug release kinetics were investigated under “real-time” and accelerated conditions (i.e. extreme pH, hydro-alcoholic solutions and elevated temperatures). Compared to “real-time” conditions, the initial burst and lag phases were similar using hydro-alcoholic solutions and extreme pH conditions, while the secondary apparent zero-order release phase was slightly accelerated. Elevated temperatures resulted in a significant acceleration of dexamethasone release. The accelerated release data were able to predict “real-time” release when applying the Arrhenius equation. Microsphere batches with faster and slower release profiles were investigated under “real-time” and elevated temperature (60°C) conditions to determine the discriminatory ability of the method. The results demonstrated both the feasibility and the discriminatory ability of this USP apparatus 4 method for in vitro release testing of drug loaded PLGA microsphere/PVA hydrogel composites. This method may be appropriate for similar drug/device combination products and drug delivery systems. PMID:22016033

Accelerated in vitro release testing of implantable PLGA microsphere/PVA hydrogel composite coatings.

PubMed

Shen, Jie; Burgess, Diane J

2012-01-17

Dexamethasone loaded poly(lactic-co-glycolic acid) (PLGA) microsphere/PVA hydrogel composites have been investigated as an outer drug-eluting coating for implantable devices such as glucose sensors to counter negative tissue responses to implants. The objective of this study was to develop a discriminatory, accelerated in vitro release testing method for this drug-eluting coating using United States Pharmacopeia (USP) apparatus 4. Polymer degradation and drug release kinetics were investigated under "real-time" and accelerated conditions (i.e. extreme pH, hydro-alcoholic solutions and elevated temperatures). Compared to "real-time" conditions, the initial burst and lag phases were similar using hydro-alcoholic solutions and extreme pH conditions, while the secondary apparent zero-order release phase was slightly accelerated. Elevated temperatures resulted in a significant acceleration of dexamethasone release. The accelerated release data were able to predict "real-time" release when applying the Arrhenius equation. Microsphere batches with faster and slower release profiles were investigated under "real-time" and elevated temperature (60°C) conditions to determine the discriminatory ability of the method. The results demonstrated both the feasibility and the discriminatory ability of this USP apparatus 4 method for in vitro release testing of drug loaded PLGA microsphere/PVA hydrogel composites. This method may be appropriate for similar drug/device combination products and drug delivery systems. Copyright © 2011 Elsevier B.V. All rights reserved.

Development and effect of different bioactive silicate glass scaffolds: in vitro evaluation for use as a bone drug delivery system.

PubMed

Soundrapandian, Chidambaram; Mahato, Arnab; Kundu, Biswanath; Datta, Someswar; Sa, Biswanath; Basu, Debebrata

2014-12-01

Local drug delivery systems to bone have attracted appreciable attention due to their efficacy to improve drug delivery, healing and regeneration. In this paper, development and characterization of new formulations of bioactive glass into a porous scaffold has been reported for its suitability to act as a drug delivery system in the management of bone infections, in vitro. Two new glass compositions based on SiO2-Na2O-ZnO-CaO-MgO-P2O5 system (BGZ and MBG) have been developed which after thorough chemical and phase evaluation, studied for acellular static in vitro bioactivity in SBF. Porous scaffolds made of these glasses have been fabricated and characterized thoroughly for bioactivity study, SEM, XRD, in vitro cytotoxicity, MTT assay and wound healing assay using human osteocarcoma cells. Finally, gatifloxacin was loaded into the porous scaffold by vacuum infiltration method and in vitro drug release kinetics have been studied with varying parameters including dissolution medium (PBS and SBF) and with/without impregnation chitosan. Suitable model has also been proposed for the kinetics. 63-66% porous and 5-50μm almost unimodal porous MBG and BGZ bioactive glass scaffolds were capable of releasing drugs successfully for 43 days at concentrations to treat orthopedic infections. In addition, it was also observed that the release of drug followed Peppas-Korsmeyer release pattern based on Fickian diffusion, while 0.5-1% chitosan coating on the scaffolds decreased the burst release and overall release of drug. The results also indicated that MBG based scaffolds were bioactive, biocompatible, noncytotoxic and exhibited excellent wound healing potential while BGZ was mildly cytotoxic with moderate wound healing potential. These results strongly suggest that MBG scaffolds appear to be a suitable bone drug delivery system in orthopedic infections treatment and as bone void fillers, but BGZ should be handled with caution or studied elaborately in detail further to ascertain and confirm the cytotoxic nature and wound healing potential of this glass. Copyright © 2014 Elsevier Ltd. All rights reserved.

An investigation into the influence of experimental conditions on in vitro drug release from immediate-release tablets of levothyroxine sodium and its relation to oral bioavailability.

PubMed

Kocic, Ivana; Homsek, Irena; Dacevic, Mirjana; Parojcic, Jelena; Miljkovic, Branislava

2011-09-01

The aim of this study was to investigate the influence of experimental conditions on levothyroxine sodium release from two immediate-release tablet formulations which narrowly passed the standard requirements for bioequivalence studies. The in vivo study was conducted as randomised, single-dose, two-way cross-over pharmacokinetic study in 24 healthy subjects. The in vitro study was performed using various dissolution media, and obtained dissolution profiles were compared using the similarity factor value. Drug solubility in different media was also determined. The in vivo results showed narrowly passing bioequivalence. Considering that levothyroxine sodium is classified as Class III drug according to the Biopharmaceutics Classification System, drug bioavailability will be less sensitive to the variation in its dissolution characteristics and it can be assumed that the differences observed in vitro in some of investigated media probably do not have significant influence on the absorption process, as long as rapid and complete dissolution exists. The study results indicate that the current regulatory criteria for the value of similarity factor in comparative dissolution testing, as well as request for very rapid dissolution (more than 85% of drug dissolved in 15 min), are very restricted for immediate-release dosage forms containing highly soluble drug substance and need further investigation. The obtained results also add to the existing debate on the appropriateness of the current bioequivalence standards for levothyroxine sodium products.

In vitro biorelevant models for evaluating modified release mesalamine products to forecast the effect of formulation and meal intake on drug release.

PubMed

Andreas, Cord J; Chen, Ying-Chen; Markopoulos, Constantinos; Reppas, Christos; Dressman, Jennifer

2015-11-01

Postprandial administration of solid oral dosage forms greatly changes the dissolution environment compared to fasted state administration. The aims of this study were to investigate and forecast the effect of co-administration of a meal on drug release for delayed and/or extended release mesalamine formulations as well as design of in vitro tests to distinguish among formulations in a biorelevant way. Five different mesalamine formulations (Asacol® 400 mg, Mezavant® 1200 mg, Pentasa® 500 mg and Salofalk® in the 250 mg and 500 mg strengths) were investigated with biorelevant dissolution methods using the USP apparatus III and USP apparatus IV (open loop mode) under both fasted and fed state conditions, as well as with the dissolution methods described in pharmacopeia for delayed and extended release mesalamine products. Using the biorelevant experimental conditions proposed in this study, changes in release in the proximal gut due to meal intake are forecast to be minimal for Asacol®, Mezavant®, Pentasa® and Salofalk® 500 mg, while for Salofalk® 250 mg release was predicted to occur much earlier under fed state conditions. The USP apparatus III generally tended to result in faster dissolution rates and forecast more pronounced food effects for Salofalk® 250 mg than the USP apparatus IV. The biorelevant dissolution gradients were also able to reflect the in vivo behavior of the formulations. In vitro biorelevant models can be useful in the comparison of the release behavior from different delayed and extended release mesalamine formulations as well as forecasting effects of concomitant meal intake on drug release. Copyright © 2015 Elsevier B.V. All rights reserved.

Porous magnesium loaded with gentamicin sulphate and in vitro release behavior.

PubMed

Li, Qiuyan; Jiang, Guofeng; Wang, Dong; Wang, Huang; Ding, Liang; He, Guo

2016-12-01

Our aim was to develop a biocompatible bone repair material that has the advantage of preventing postoperative infections. Finally, the porous magnesium (p-Mg) loaded with gentamicin sulphate (GS-loaded Mg-G) was fabricated. The GS release behavior of the GS-loaded Mg-G in phosphate buffer saline (PBS) was investigated. The effective release time of GS reached to 14days. In addition, the effects of porosity and pore diameter of p-Mg on the GS release behavior of the GS-loaded Mg-G were studied. In the initial burst release stage, the GS release rate of the GS-loaded Mg-G increased with the increasing porosity or the increasing pore diameter of p-Mg. The GS-loaded Mg-G with larger original pore diameter has higher burst release of GS. Moreover, the in vitro antibacterial test of the GS-loaded Mg-G indicated that this biomaterial has obvious antibacterial effect. This study can provide information for p-Mg loaded with drug(s) as functional bone repair materials with drug-delivery capabilities. Copyright © 2016 Elsevier B.V. All rights reserved.

Silibinin and indocyanine green-loaded nanoparticles inhibit the growth and metastasis of mammalian breast cancer cells in vitro.

PubMed

Sun, Hui-Ping; Su, Jing-Han; Meng, Qing-Shuo; Yin, Qi; Zhang, Zhi-Wen; Yu, Hai-Jun; Zhang, Peng-Cheng; Wang, Si-Ling; Li, Ya-Ping

2016-07-01

To improve the therapeutic efficacy of cancer treatments, combinational therapies based on nanosized drug delivery system (NDDS) has been developed recently. In this study we designed a new NDDS loaded with an anti-metastatic drug silibinin and a photothermal agent indocyanine green (ICG), and investigated its effects on the growth and metastasis of breast cancer cells in vitro. Silibinin and ICG were self-assembled into PCL lipid nanoparticles (SIPNs). Their physical characteristics including the particle size, zeta potential, morphology and in vitro drug release were examined. 4T1 mammalian breast cancer cells were used to evaluate their cellular internalization, cytotoxicity, and their influences on wound healing, in vitro cell migration and invasion. SIPNs showed a well-defined spherical shape with averaged size of 126.3±0.4 nm and zeta potential of -10.3±0.2 mV. NIR laser irradiation substantially increased the in vitro release of silibinin from the SIPNs (58.3% at the first 8 h, and 97.8% for the total release). Furthermore, NIR laser irradiation markedly increased the uptake of SIPNs into 4T1 cells. Under the NIR laser irradiation, both SIPNs and IPNs (PCL lipid nanoparticles loaded with ICG alone) caused dose-dependent ablation of 4T1 cells. The wound healing, migration and invasion experiments showed that SIPNs exposed to NIR laser irradiation exhibited dramatic in vitro anti-metastasis effects. SIPNs show temperature-sensitive drug release following NIR laser irradiation, which can inhibit the growth and metastasis of breast cancer cells in vitro.

In vitro-in vivo correlation strategy applied to an immediate-release solid oral dosage form with a biopharmaceutical classification system IV compound case study.

PubMed

Bredael, Gerard M; Bowers, Niya; Boulineau, Fabien; Hahn, David

2014-07-01

The ability to predict in vivo response of an oral dosage form based on an in vitro technique has been a sought after goal of the pharmaceutical scientist. Dissolution testing that demonstrates discrimination to various critical formulations or process attributes provides a sensitive quality check that may be representative or may be overpredictive of potential in vivo changes. Dissolution methodology with an established in vitro-in vivo relationship or correlation may provide the desired in vivo predictability. To establish this in vitro-in vivo link, a clinical study must be performed. In this article, recommendations are given in the selection of batches for the clinical study followed by potential outcome scenarios. The investigation of a Level C in vitro-in vivo correlation (IVIVC), which is the most common correlation for immediate-release oral dosage forms, is presented. Lastly, an IVIVC case study involving a biopharmaceutical classification system class IV compound is presented encompassing this strategy and techniques. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Surface Modifications of Titanium Implants by Multilayer Bioactive Coatings with Drug Delivery Potential: Antimicrobial, Biological, and Drug Release Studies

NASA Astrophysics Data System (ADS)

Ordikhani, Farideh; Zustiak, Silviya Petrova; Simchi, Abdolreza

2016-04-01

Recent strategies to locally deliver antimicrobial agents to combat implant-associated infections—one of the most common complications in orthopedic surgery—are gaining interest. However, achieving a controlled release profile over a desired time frame remains a challenge. In this study, we present an innovative multifactorial approach to combat infections which comprises a multilayer chitosan/bioactive glass/vancomycin nanocomposite coating with an osteoblastic potential and a drug delivery capacity. The bioactive drug-eluting coating was prepared on the surface of titanium foils by a multistep electrophoretic deposition technique. The adopted deposition strategy allowed for a high antibiotic loading of 1038.4 ± 40.2 µg/cm2. The nanocomposite coating exhibited a suppressed burst release with a prolonged sustained vancomycin release for up to 6 weeks. Importantly, the drug release profile was linear with respect to time, indicating a zero-order release kinetics. An in vitro bactericidal assay against Staphylococcus aureus confirmed that releasing the drug reduced the risk of bacterial infection. Excellent biocompatibility of the developed coating was also demonstrated by in vitro cell studies with a model MG-63 osteoblast cell line.

Release of small phenolic compounds from brewer's spent grain and its lignin fractions by human intestinal microbiota in vitro.

PubMed

Aura, Anna-Marja; Niemi, Piritta; Mattila, Ismo; Niemelä, Klaus; Smeds, Annika; Tamminen, Tarja; Faulds, Craig; Buchert, Johanna; Poutanen, Kaisa

2013-10-09

Brewer's spent grain (BSG), the major side-stream from brewing, is rich in protein, lignin, and nonstarch polysaccharides. Lignin is a polyphenolic macromolecule considered resilient toward breakdown and utilization by colon microbiota, although some indications of release of small phenolic components from lignin in animals have been shown. The aim of this study was to investigate if the human intestinal microbiota can release lignans and small phenolic compounds from whole BSG, a lignin-enriched insoluble fraction from BSG and a deferuloylated fraction, in a metabolic in vitro colon model. The formation of short-chain fatty acid (SCFA) was also investigated. More lignin-related monomers and dilignols were detected from the lignin-enriched fraction than from BSG or deferuloylated BSG. SCFA formation was not suppressed by any of the fractions. It was shown that small lignin-like compounds were released from these samples in the in vitro colon model, originating most likely from lignin.

In vitro evaluation of suspoemulsions for in situ-forming polymeric microspheres and controlled release of progesterone.

PubMed

Turino, Ludmila N; Mariano, Rodolfo N; Mengatto, Luciano N; Luna, Julio A

2015-01-01

One possibility to obtain a higher dose of drug in a lower formulation volume can be by using of saturated quantity of drug in one of the phases of an emulsion. These formulations are called suspoemulsions (S/O/W). When a hydrophobic polymer is added to the organic phase of suspoemulsions, these formulations can be used to entrap the drug inside microspheres after in situ precipitation of the polymer-drug-excipients mix. In this work, performance and stability of progesterone suspensions in triacetin as organic phase of suspoemulsions were evaluated. These formulations were compared with O/W emulsions. Mathematical models were used to study in vitro release profiles. The results confirmed that S/O/W systems could be an attractive alternative to O/W formulations for the entrapment of progesterone inside poly(d,l-lactide-co-glycolide) microspheres. Diffusive-based models fit the in vitro release of progesterone from in situ-formed microspheres. For longer release periods, a time-dependent diffusion coefficient was successfully estimated.

Mucoadhesive buccal patches based on interpolymer complexes of chitosan–pectin for delivery of carvedilol

PubMed Central

Kaur, Amanpreet; Kaur, Gurpreet

2011-01-01

The study was designed to develop bioadhesive patches of carvedilol hydrochloride using chitosan (CH) and pectin (PE) interpolymer complexes and to systematically evaluate their in vitro and in vivo performances. Mucoadhesive buccal patches of carvedilol were prepared using solvent casting method. The physicochemical interaction between CH and PE was investigated by FTIR and DSC studies. The patches were evaluated for their physical characteristics like mass variation, content uniformity, folding endurance, ex vivo mucoadhesion strength, ex vivo mucoadhesion time, surface pH, in vitro drug release, in situ release study, and in vivo bioavailability study. The swelling index of the patches was found to be proportional to the PE concentration. The surface pH of all the formulated bioadhesive patches was found to lie between 6.2 and 7.2. The optimized bioadhesive patch (C1, CH:PE 20:80) showed bioadhesive strength of 22.10 ± 0.20 g, in vitro release of 98.73% and ex vivo mucoadhesion time of 451 min with in a period of 8 h. The optimized patch demonstrated good in vitro and in vivo results. The buccal delivery of carvedilol in rabbits showed a significant improvement in bioavailability of carvedilol from patches when compared to oral route. PMID:23960773

Mucoadhesive buccal patches based on interpolymer complexes of chitosan-pectin for delivery of carvedilol.

PubMed

Kaur, Amanpreet; Kaur, Gurpreet

2012-01-01

The study was designed to develop bioadhesive patches of carvedilol hydrochloride using chitosan (CH) and pectin (PE) interpolymer complexes and to systematically evaluate their in vitro and in vivo performances. Mucoadhesive buccal patches of carvedilol were prepared using solvent casting method. The physicochemical interaction between CH and PE was investigated by FTIR and DSC studies. The patches were evaluated for their physical characteristics like mass variation, content uniformity, folding endurance, ex vivo mucoadhesion strength, ex vivo mucoadhesion time, surface pH, in vitro drug release, in situ release study, and in vivo bioavailability study. The swelling index of the patches was found to be proportional to the PE concentration. The surface pH of all the formulated bioadhesive patches was found to lie between 6.2 and 7.2. The optimized bioadhesive patch (C1, CH:PE 20:80) showed bioadhesive strength of 22.10 ± 0.20 g, in vitro release of 98.73% and ex vivo mucoadhesion time of 451 min with in a period of 8 h. The optimized patch demonstrated good in vitro and in vivo results. The buccal delivery of carvedilol in rabbits showed a significant improvement in bioavailability of carvedilol from patches when compared to oral route.

[Analysis the cupric ion release characteristics of different copper raw materials in intrauterine device in vitro using ICP method].

PubMed

Lu, Hua; Ding, Tingting; Yao, Tianping; Sun, Jiao

2014-05-01

To study the Cupric ion release characteristics of different copper raw materials in intrauterine device in vitro by ICP. Reveal the relationship between purity and shape of Cu-IUD copper and copper ion release. According to a certain proportion, the copper raw materials were 100 times diluted into the simulated uterine solution at 37 +/- 0.5 degrees C. Replaced medium at certain time points and collected soaking liquid. Using ICP analyzed the concentration of copper ion released. The largest daily release of copper ions was in the first 7 days. There was no statistically significant difference between the copper ion release amount of 99.99% and 99.95% purity copper wire (P > 0.05). The release of copper ion of the copper wire was far greater than that of the copper pipe in early stage (P < 0.01). The release amount decreased and stabilized at 56 day. Release characteristics of copper ion could effectively analysis by ICP. And in the same area, the release amount of copper ions of copper wire was greater than that of copper pipe.

The impact of manufacturing variables on in vitro release of clobetasol 17-propionate from pilot scale cream formulations.

PubMed

Fauzee, Ayeshah Fateemah Beebee; Khamanga, Sandile Maswazi; Walker, Roderick Bryan

2014-12-01

The purpose of the study was to evaluate the effect of different homogenization speeds and times, anchor speeds and cooling times on the viscosity and cumulative % clobetasol 17-propionate released per unit area at 72 h from pilot scale cream formulations. A 2(4) full factorial central composite design for four independent variables were investigated. Thirty pilot scale batches of cream formulations were manufactured using a Wintech® cream/ointment plant. The viscosity and in vitro release of CP were monitored and compared to an innovator product that is commercially available on the South African market, namely, Dermovate® cream. Contour and three-dimensional response surface plots were produced and the viscosity and cumulative % CP released per unit area at 72 h were found to be primarily dependent on the homogenization and anchor speeds. An increase in the homogenization and anchor speeds appeared to exhibit a synergistic effect on the resultant viscosity of the cream whereas an antagonistic effect was observed for the in vitro release of CP from the experimental cream formulations. The in vitro release profiles were best fitted to a Higuchi model and diffusion proved to be the dominant mechanism of drug release that was confirmed by use of the Korsmeyer-Peppas model. The research was further validated and confirmed by the high prognostic ability of response surface methodology (RSM) with a resultant mean percentage error of (±SD) 0.17 ± 0.093 suggesting that RSM may be an efficient tool for the development and optimization of topical formulations.

Formulation and evaluation of chitosan/polyethylene oxide nanofibers loaded with metronidazole for local infections.

PubMed

Zupančič, Špela; Potrč, Tanja; Baumgartner, Saša; Kocbek, Petra; Kristl, Julijana

2016-12-01

Nanofibers combined with an antimicrobial represent a powerful strategy for treatment of various infections. Local infections usually have a low fluid volume available for drug release, whereas pharmacopoeian dissolution tests include a much larger receptor volume. Therefore, the development of novel drug-release methods that more closely resemble the in-vivo conditions is necessary. We first developed novel biocompatible and biodegradable chitosan/polyethylene oxide nanofibers using environmentally friendly electrospinning of aqueous polymer solutions, with the inclusion of the antimicrobial metronidazole. Here, the focus is on the characterization of these nanofibers, which have high potential for bioadhesion and retention at the site of application. These can be used where prolonged retention of the delivery system at an infected target site is needed. Drug release was studied using three in-vitro methods: a dissolution apparatus (Apparatus 1 of the European Pharmacopoeia), vials, and a Franz diffusion cell. In contrast to other studies, here the Franz diffusion cell method was modified to introduce a small volume of medium with the nanofibers in the donor compartment, where the nanofibers swelled, eroded, and released the metronidazole, which then diffused into the receptor compartment. This set-up with nanofibers in a limited amount of medium released the drug more slowly compared to the other two in-vitro methods that included larger volumes of medium. These findings show that drug release from nanofibers strongly depends on the release method used. Therefore, in-vitro test methods should closely resemble the in-vivo conditions for more accurate prediction of drug release at a therapeutic site. Copyright © 2016 Elsevier B.V. All rights reserved.

Development of a level A in vitro-in vivo correlation for extended release dosage forms of quetiapine fumarate.

PubMed

Gonçalves de Lima, L; Rossi de Campos, D

2016-05-01

Quetiapine is an atypical antipsychotic recommended as first-line treatment for acute bipolar depression. The extended-release quetiapine formulation is intended to be administered as an once-daily dosing. The development of an in vitro-in vivo correlation (IVIVC) and the use of in vitro data to predict in vivo bioavailability parameters has been of great interest for the rational development and evaluation process for extended release dosage forms. The aim of this study was to develop an IVIVC for quetiapine extended release formulation. In vitro dissolution rate data were obtained using USP apparatus 2 at 50 rpm, in 3 bio-relevant dissolution media with different pH values (1.2, 4.5 and 6.8). The drug release profiles of the 2 extended release dosage forms were compared using the similarity factor (f 2). The relative bioavailability of quetiapine was evaluated by a single-dose, randomized-sequence, open-label, 2 period cross over study with 16 healthy volunteers. A linear level A IVIVC model was established using percentage of absorbed and dissolved data obtained at pH 1.2. The developed IVIVC model was employed to predict quetiapine concentration-time profiles, as well as the bioequivalence parameters for test formulation. Percent prediction errors were estimated for Cmax and AUC to evaluate the validity of the correlation. The values did not exceed 15%, proving the predictability of the correlation model. In conclusion, the established level A IVIVC model proved to be an excellent tool for predicting the rate and extent of quetiapine absorption as characterized by Cmax and AUC for test formulation. © Georg Thieme Verlag KG Stuttgart · New York.

Bifunctional capsular dosage form: novel fanicular cylindrical gastroretentive system of clarithromycin and immediate release granules of ranitidine HCl for simultaneous delivery.

PubMed

Rajput, Pallavi; Singh, Deshvir; Pathak, Kamla

2014-01-30

The study was aimed to develop a bifunctional single unit capsular system containing gastroretentive funicular cylindrical system (FCS) for controlled local delivery of clarithromycin and immediate release of ranitidine HCl. A 2(3) full factorial design was used to prepare gastroretentive FCS of clarithromycin using polyacrylamide (PAM), HPMC E15LV and Carbopol 934 P. The FCSs were evaluated for % cumulative drug release, floating time and in vitro detachment stress. Among the eight formulations, FCS5 (containing PAM and Carbopol 934 P at high and HPMC E15LV at low levels) showed % cumulative drug release of 97.09±1.14% in 8 h, floating time of 3 h and detachment stress of 8303.64±0.34 dynes/cm(2). Evaluation of optimized FCS by novel dynamic in vitro test proved superior bioadhesivity than cylindrical system under aggressive simulated peristaltic activity. Magnetic resonance imaging elucidated zero order release via constant swelling and erosion of FCS5. In vitro permeability across gastric mucin ensured its potential for effective eradication of deep seated Helicobactor pylori in gastric linings. The optimized FCS was combined with immediate release granules of rantidine HCl to get a bifunctional capsular dosage form. In vitro simultaneous drug release of clarithromycin and rantidine estimated by Vierordt's method exhibited a controlled drug release of 97.72±0.4% in 8 h for clarithromycin through FCS5 and 98.8±1.2% in 60 min from IR granules of ranitidine HCl. The novel system thus established its capability of simultaneous variable delivery of acid suppression agent and macrolide antibiotic that can be advantageous in clinical setting. Copyright © 2013 Elsevier B.V. All rights reserved.

Evaluation in vitro and in vivo of dimethicone transdermal therapeutic systems. Influence of propylene glycol on drug release.

PubMed

Ritschel, W A; Nayak, P M

1987-03-01

Coumarin-containing transdermal drug delivery systems were studied in vitro for drug release and in vivo in rats for drug absorption. The matrix of the transdermal delivery system, dimethicone, was a commercially available silicone elastomer. The devices containing 1, 3 and 5% coumarin released in vitro 8.8 (87.4%), 23.4 (74.5%) and 31.6 mg (63.3%) of drug within 24 h. The device containing 5% coumarin was selected for further studies in which 5, 10, 20, 30, 50 and 70% propylene glycol was added. Up to 20% propylene glycol content did not change the amount released. The preparations with 30, 50 and 70% propylene glycol released 69.3, 73.6 and 87.9%, respectively. The 50 and 70% preparations were physically not acceptable. Only the preparations containing 5% coumarin without propylene glycol and 5% coumarin and 30% propylene glycol in the elastomer were evaluated in vivo. The area under the blood level-time curve of the propylene glycol-containing system was twice that of the device without propylene glycol. Blood levels were maintained between about 2 micrograms/ml and 5 micrograms/ml during the time the device was kept on the skin (24 h).

In vitro and in vivo evaluation of novel ciprofloxacin-releasing silicone hydrogel contact lenses.

PubMed

Hui, Alex; Willcox, Mark; Jones, Lyndon

2014-07-15

The purpose of this study was to evaluate ciprofloxacin-releasing silicone hydrogel contact lens materials in vitro and in vivo for the treatment of microbial keratitis. Model silicone hydrogel contact lens materials were manufactured using a molecular imprinting technique to modify ciprofloxacin release kinetics. Various contact lens properties, including light transmission and surface wettability, were determined, and the in vitro ciprofloxacin release kinetics elucidated using fluorescence spectrophotometry. The materials then were evaluated for their ability to inhibit Pseudomonas aeruginosa growth in vitro and in an in vivo rabbit model of microbial keratitis. Synthesized lenses had similar material properties to commercial contact lens materials. There was a decrease in light transmission in the shorter wavelengths due to incorporation of the antibiotic, but over 80% light transmission between 400 and 700 nm. Modified materials released for more than 8 hours, significantly longer than unmodified controls (P < 0.05). In vivo, there was no statistically significant difference between the number of colony-forming units (CFU) recovered from corneas treated with eye drops and those treated with one of two modified contact lenses (P > 0.05), which is significantly less than corneas treated with unmodified control lenses or those that received no treatment at all (P < 0.05). These novel contact lenses designed for the extended release of ciprofloxacin may be beneficial to supplement or augment future treatments of sight-threatening microbial keratitis. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Preparation and evaluation of sustained release microballoons of propranolol

PubMed Central

Porwal, A; Swami, G; Saraf, SA

2011-01-01

Background and the purpose of the study The purpose of the present investigation was to characterize, optimize and evaluate microballoons of Propranolol hydrochloride and to increase its boioavailability by increasing the retention time of the drug in the gastrointestinal tract. Methods Propranolol hydrochloride-loaded microballoons were prepared by the non-aqueous O/O emulsion solvent diffusion evaporation method using Eudragit RSPO as polymer. It was found that preparation temperature determined the formation of cavity inside the microballoon and this in turn determined the buoyancy. Microballoons were subjected to particle size determination, micromeritic properties, buoyancy, entrapment efficiency, drug loading, in vitro drug release and IR study. The correlation between the buoyancy, bulk density and porosity of microballoons were elucidated. The release rate was determined in simulated gastric fluid (SGF) of pH 1.2 at 37±0.5°C. Results The microballoons presented spherical and smooth morphologies (SEM) and were porous due to presence of hollow cavity. Microballoons remained buoyant for >12 hrs for the optimized formulation. The formulation demonstrated favorable in vitro floating and release characteristics. The encapsulation efficiency was high. In vitro dissolution kinetics followed the Higuchi model. The drug release from microballoons was mainly controlled by diffusion and showed a biphasic pattern with an initial burst release, followed by sustained release for 12 hrs. The amount of the drug which released up to 12 hrs was 82.05±0.64%. Statistical analysis (ANOVA) showed significant difference (p<0.05) in the cumulative amount of drug released after 30 min, and up to 12 hrs from optimized formulations. Conclusion The designed system for propanolol would possibly be advantageous in terms of increased bioavailability and patient compliance. PMID:22615657

Capsaicin-evoked iCGRP release from human dental pulp: a model system for the study of peripheral neuropeptide secretion in normal healthy tissue

PubMed Central

Fehrenbacher, Jill C.; Sun, Xiaoling X.; Locke, Erin E.; Henry, Michael A.; Hargreaves, Kenneth M.

2009-01-01

The mechanisms underlying trigeminal pain conditions are incompletely understood. In vitro animal studies have elucidated various targets for pharmacological intervention; however, a lack of clinical models that allow evaluation of viable innervated human tissue has impeded successful translation of many preclinical findings into clinical therapeutics. Therefore, we developed and characterized an in vitro method that evaluates the responsiveness of isolated human nociceptors by measuring basal and stimulated release of neuropeptides from collected dental pulp biopsies. Informed consent was obtained from patients presenting for extraction of normal wisdom teeth. Patients were anesthetized using nerve block injection, teeth were extracted and bisected, and pulp was removed and superfused in vitro. Basal and capsaicin-evoked peripheral release of immunoreactive calcitonin gene-related peptide (iCGRP) was analyzed by enzyme immunoassay. The presence of nociceptive markers within neurons of the dental pulp was characterized using confocal microscopy. Capsaicin increased the release of iCGRP from dental pulp biopsies in a concentration-dependent manner. Stimulated release was dependent on extracellular calcium, reversed by a TRPV1 receptor antagonist, and desensitized acutely (tachyphylaxis) and pharmacologically by pretreatment with capsaicin. Superfusion with phorbol 12-myristate 13-acetate (PMA) increased basal and stimulated release, whereas PGE2 augmented only basal release. Compared with vehicle treatment, pretreatment with PGE2 induced competence for DAMGO to inhibit capsaicin-stimulated iCGRP release, similar to observations in animal models where inflammatory mediators induce competence for opioid inhibition. These results indicate the release of iCGRP from human dental pulp provides a novel tool to determine the effects of pharmacological compounds on human nociceptor sensitivity. PMID:19428185

Formulation and In-vitro Evaluation of Tretinoin Microemulsion as a Potential Carrier for Dermal Drug Delivery

PubMed Central

Mortazavi, Seyed Alireza; Pishrochi, Sanaz; Jafari azar, Zahra

2013-01-01

In this study, tretinoin microemulsion has been formulated based on phase diagram studies by changing the amounts and proportions of inactive ingredients, such as surfactants, co-surfactants and oils. The effects of these variables have been determined on microemulsion formation, particle size of the dispersed phase and release profile of tretinoin from microemulsion through dialysis membrane. In released studies, static Franz diffusion cells mounted with dialysis membrane were used. Sampling was conducted every 3 h at room temperature over a period of 24 h. The amount of released drug was measured with UV-spectrophotometer and the percentage of drug released was calculated. Based on the results obtained, the oil phase concentration had a proportional effect on particle size which can consequently influence on drug release. The particle size and the amount of released drug were affected by the applied surfactants. The components of the optimized microemulsion formulation were 15% olive oil, 12% propylene glycol (as co-surfactant), 33% Tween®80 (as surfactant) and 40% distilled water, which was tested for viscosity and rheological behavior. The prepared tretinoin microemulsion showed pseudoplastic-thixotropic behavior. The profile of drug release follows zero order kinetics. The optimized tretinoin microemulsion showed enhanced in-vitro release profile compared to the commercial gels and creams. PMID:24523740

Formulation and In-vitro Evaluation of Tretinoin Microemulsion as a Potential Carrier for Dermal Drug Delivery.

PubMed

Mortazavi, Seyed Alireza; Pishrochi, Sanaz; Jafari Azar, Zahra

2013-01-01

In this study, tretinoin microemulsion has been formulated based on phase diagram studies by changing the amounts and proportions of inactive ingredients, such as surfactants, co-surfactants and oils. The effects of these variables have been determined on microemulsion formation, particle size of the dispersed phase and release profile of tretinoin from microemulsion through dialysis membrane. In released studies, static Franz diffusion cells mounted with dialysis membrane were used. Sampling was conducted every 3 h at room temperature over a period of 24 h. The amount of released drug was measured with UV-spectrophotometer and the percentage of drug released was calculated. Based on the results obtained, the oil phase concentration had a proportional effect on particle size which can consequently influence on drug release. The particle size and the amount of released drug were affected by the applied surfactants. The components of the optimized microemulsion formulation were 15% olive oil, 12% propylene glycol (as co-surfactant), 33% Tween(®)80 (as surfactant) and 40% distilled water, which was tested for viscosity and rheological behavior. The prepared tretinoin microemulsion showed pseudoplastic-thixotropic behavior. The profile of drug release follows zero order kinetics. The optimized tretinoin microemulsion showed enhanced in-vitro release profile compared to the commercial gels and creams.

Overactive and Underactive Bladder Dysfunction is Reflected by Alterations in Urothelial ATP and NO Release

PubMed Central

Munoz, Alvaro; Smith, Christopher P.; Boone, Timothy B.; Somogyi, George T.

2011-01-01

ATP and NO are released from the urothelium in the bladder. Detrusor Overactivity (DO) following spinal cord injury results in higher ATP and lower NO release from the bladder urothelium. Our aim was to study the relationship between ATP and NO release in 1) early diabetic bladders, an overactive bladder model; and 2) in “diuretic” bladders, an underactive bladder model. To induce diabetes mellitus female rats received 65 mg/kg streptozocin (i.v.). To induce chronic diuresis rats were fed with 5% sucrose. At 28 days, in vivo open cystometry was performed. Bladder wash was collected to analyze the amount of ATP and NO released into the bladder lumen. For in vitro analysis of ATP and NO release, a Ussing chamber was utilized and hypoosmotic Krebs was perfused on the urothelial side of the chamber. ATP was analyzed with luminometry or HPLC-fluorometry while NO was measured with a Sievers NO-analyzer. In vivo ATP release was increased in diabetic bladders and unchanged in diuretic bladders. In vitro release from the urothelium followed the same pattern. NO release was unchanged both in vitro and in vivo in overactive bladders whereas it was enhanced in underactive bladders. We found that the ratio of ATP/NO, representing sensory transmission in the bladder, was high in overactive and low in underactive bladder dysfunction. In summary, ATP release has a positive correlation while NO release has a negative correlation with the bladder contraction frequency. The urinary ATP/NO ratio may be a clinically relevant biomarker to characterize the extent of bladder dysfunction. PMID:21145365

In Vivo Release of Vancomycin from Calcium Phosphate Cement.

PubMed

Uchida, Kentaro; Sugo, Ken; Nakajima, Takehiko; Nakawaki, Mitsufumi; Takano, Shotaro; Nagura, Naoshige; Takaso, Masashi; Urabe, Ken

2018-01-01

Calcium phosphate cement (CPC) has good release efficiency and has therefore been used as a drug delivery system for postoperative infection. The release profile of CPC has mainly been evaluated by in vitro studies, which are carried out by immersing test specimens in a relatively large amount of solvent. However, it remains unclear whether antibiotic-impregnated CPC has sufficient clinical effects and release in vivo . We examined the in vivo release profile of CPC impregnated with vancomycin (VCM) and compared this with that of polymethylmethacrylate (PMMA) cement. To evaluate the release profile in vitro , the test specimens were immersed in 10 mL sterile phosphate-buffered saline per gram of test specimen and incubated at 37°C for 56 days in triplicate. For in vivo experiments, the test specimens were implanted between the fascia and muscle of the femur of rats. Residual VCM was extracted from the removed test specimens to determine the amount of VCM released into rat tissues. CPC released more VCM over a longer duration than PMMA in vitro . Released levels of VCM from CPC/VCM in vivo were 3.4-fold, 5.0-fold, and 8.6-fold greater on days 1, 7, and 28, respectively, than those released on the corresponding days from PMMA/VCM and were drastically greater on day 56 due to inefficient release from PMMA/VCM. The amount of VCM released from CPC and PMMA was much higher than the minimum inhibitory concentration (1.56  μ g) and lower than the detection limit, respectively. Our findings suggest that CPC is a suitable material for releasing antibiotics for local action against established postoperative infection.

Sol-gel processed porous silica carriers for the controlled release of diclofenac diethylamine.

PubMed

Czarnobaj, Katarzyna; Czarnobaj, Joanna

2008-10-01

Silica xerogels doped with diclofenac diethylamine were prepared by the sol-gel method from a hydrolysed tetraethoxysilane (TEOS) solution containing diclofenac diethylamine. Two different catalysts, drying conditions and levels of water content were used to alter the microstructure of the silica xerogels. The aim of this study was to determine the rate of Diclofenac release from the silica xerogels. This in vitro study showed that the sol-gel method is useful for entrapping Diclofenac in the pores of xerogels. It also showed that, in vitro, Diclofenac is released from the silica xerogel, through the pores, by diffusion. Base-catalysed gels proved to be much more effective than acid-catalyzed gels. (c) 2008 Wiley Periodicals, Inc.

A novel accelerated in vitro release method to evaluate the release of thymopentin from PLGA microspheres.

PubMed

Xie, Xiangyang; Li, Zhiping; Zhang, Ling; Chi, Qiang; Yang, Yanfang; Zhang, Hui; Yang, Yang; Mei, Xingguo

2015-01-01

A novel accelerated method of good correlations with "real-time" release to evaluate in vitro thymopentin release from poly (D, L-lactide-co-glycolide) (PLGA) microsphere was developed. Thymopentin-loaded microspheres were made from three types of PLGA, and peptide release was studied in various conditions. Incomplete release of peptide (<60%) from microspheres was found in accelerated testing with two typical release media. This problem was circumvented by adding organic solvents to the release media and varying the temperature in the media heating process. Release media containing three kinds of organic solvents at 50 °C were tested, respectively, and hydro-alcoholic solution was selected for further study. After the surfactant concentration (0.06%, W/V) and ethanol concentration (20%, V/V) were fixed, a gradient heating program, consisting of three stages and each stage with a different temperature, was introduced to enhance the correlations between the short- and long-term release. After adjusting the heating time of each stage, a good correlation (R(2) = 9896, formulation 8 K; R(2) = 0.9898, formulation 13 K; R(2) = 0.9886, formulation 28 K) between accelerated and "real-time" release was obtained. By optimizing the conditions as ethanol concentration and temperature gradients, this accelerated method may be appropriate for similar peptide formulations that not well correlate with "real-time" release.

In vitro-ex vivo correlations between a cell-laden hydrogel and mucosal tissue for screening composite delivery systems

PubMed Central

Blakney, Anna K.; Little, Adam B.; Jiang, Yonghou; Woodrow, Kim A.

2017-01-01

Composite delivery systems where drugs are electrospun in different layers and vary the drug stacking-order are posited to affect bioavailability. We evaluated how the formulation characteristics of both burst- and sustained-release electrospun fibers containing three physicochemically diverse drugs: dapivirine (DPV), maraviroc (MVC) and tenofovir (TFV) affect in vitro and ex vivo release. We developed a poly(hydroxyethyl methacrylate) (pHEMA) hydrogel release platform for the rapid, inexpensive in vitro evaluation of burst- and sustained-release topical or dermal drug delivery systems with varying microarchitecture. We investigated properties of the hydrogel that could recapitulate ex vivo release into nonhuman primate vaginal tissue. Using a DMSO extraction protocol and HPLC analysis, we achieved >93% recovery from the hydrogels and >88% recovery from tissue explants for all three drugs. We found that DPV loading, but not stacking order (layers of fiber containing a single drug) or microarchitecture (layers with isolated drug compared to all drugs in the same layer) impacted the burst release in vitro and ex vivo. Our burst-release formulations showed a correlation for DPV accumulation between the hydrogel and tissue (R2=0.80), but the correlation was not significant for MVC or TFV. For the sustained release formulations, the PLGA/PCL content did not affect TFV release in vitro or ex vivo. Incorporation of cells into the hydrogel matrix improved the correlation between hydrogel and tissue explant release for TFV. We expect that this hydrogel tissue mimic maybe a promising preclinical model to evaluate topical or transdermal drug delivery systems with complex microarchitectures. PMID:28222612

Preparation and In vitro Evaluation of Naproxen Suppositories

PubMed Central

Hargoli, S.; Farid, J.; Azarmi, S. H.; Ghanbarzadeh, S.; Zakeri-Milani, P.

2013-01-01

The aim of this work was to develop the best formulations for naproxen suppositories. The effects of different bases and surfactants on the physicochemical characteristics of the suppositories were determined by several tests such as weight variation, melting point, assay, hardness, and release rate. All formulations met the standard criteria for tested physicochemical parameters; weight variation (97-112%), content uniformity (97-105%), melting point (4.66-8.7 min) and hardness tests (>5400 g). Based on release rate studies, hydrophilic, and lipophilic bases without surfactants were not suitable bases for naproxen suppository. Amongst the formulations containing surfactants only Witepsol H15 with 0.5% w/w of Tween 80 and Witepsol W35 with 0.5% of cetylpyridinium chloride were suitable and released nearly complete drug during 30 and 60 min, respectively. This study demonstrates the effects of incorporation of known agents on the in vitro release characteristics of naproxen suppository. PMID:24019561

PLGA-mPEG nanoparticles of cisplatin: in vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties.

PubMed

Avgoustakis, K; Beletsi, A; Panagi, Z; Klepetsanis, P; Karydas, A G; Ithakissios, D S

2002-02-19

The in vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties of PLGA-mPEG nanoparticles of cisplatin were investigated. The nanoparticles were prepared by a double emulsion method and characterized with regard to their morphology, size, zeta potential and drug loading. The rate of in vitro degradation of the PLGA-mPEG nanoparticles in PBS (pH 7.4) depended on their composition, increasing when the mPEG content (mPEG:PLGA ratio) of the nanoparticles increased. Sustained cisplatin release over several hours from the PLGA-mPEG nanoparticles in vitro (PBS) was observed. The composition of the nanoparticles affected drug release: the rate of release increased when the mPEG content of the nanoparticles increased. Within the range of drug loadings investigated, the drug loading of the nanoparticles did not have any significant effect on drug release. The loading efficiency was low and needs improvement in order to obtain PLGA-mPEG nanoparticles with a satisfactory cisplatin content for therapeutic application. The i.v. administration of PLGA-mPEG nanoparticles of cisplatin in BALB/c mice resulted in prolonged cisplatin residence in systemic blood circulation. The results appear to justify further investigation of the suitability of the PLGA-mPEG nanoparticles for the controlled i.v. delivery and/or targeting of cisplatin.

Polyisoprene matrix for progesterone release: in vitro and in vivo studies.

PubMed

Heredia, V; Bianco, I D; Tríbulo, H; Tríbulo, R; Seoane, M Ferro; Faudone, S; Cuffini, S L; Demichelis, N A; Schalliol, H; Beltramo, D M

2009-12-01

Latex, a polyisoprene (PI) hydrophobic elastomer, was evaluated in vitro and in vivo as a matrix for intravaginal steroid hormone delivery. Matrices containing hormone were prepared by swelling latex in chloroform that contained soluble progesterone (P4). In vitro studies demonstrate that P4 release from PI follows a zero order model during at least 100 h and depends on initial load up to 10 mg cm(-2). The release of P4 from a PI matrix was found to be two times faster than from a polydimethylsiloxane (PDMS) matrix. FT-IR and X-ray powder diffraction analysis of P4 polymorphs show that when nucleated in PDMS, the hormone crystallizes only in alpha-form while in latex, crystallizes as a mixture of alpha- and beta-form. In vivo studies show that devices with a PI matrix containing 0.5 g of P4 are effective to reach plasma levels above 1 ng ml(-1) that are needed to synchronize estrous in cattle. Altogether, the results show that PI, a vulcanized polymer with a carbon-carbon backbone, can be used as a new matrix for the intravaginal administration of progesterone with improved release profile than silicone and that the matrix can influence the crystalline state of the hormone.

Application of a Compact Magnetic Resonance Imaging System with 1.5 T Permanent Magnets to Visualize Release from and the Disintegration of Capsule Formulations in Vitro and in Vivo.

PubMed

Takeshita, Keizo; Okazaki, Shoko; Shinada, Kyosuke; Shibamoto, Yuma

2017-01-01

Although magnetic resonance imaging (MRI) has potential in assessments of formulations, few studies have been conducted because of the size and expense of the instrument. In the present study, the processes of in vitro and in vivo release in a gelatin capsule formulation model were visualized using a compact MRI system with 1.5 T permanent magnets, which is more convenient than the superconducting MRI systems typically used for clinical and experimental purposes. A Gd-chelate of diethylenetriamine-N,N,N',N″,N″-pentaacetic acid, a contrast agent that markedly enhances proton signals via close contact with water, was incorporated into capsule formulations as a marker compound. In vitro experiments could clearly demonstrate the preparation-dependent differences in the release/disintegration of the formulations. In some preparations, the penetration of water into the formulation and generation of bubbles in the capsule were also observed prior to the disintegration of the formulation. When capsule formulations were orally administered to rats, the release of the marker into the stomach and its transit to the duodenum were visualized. These results strongly indicate that the compact MRI system is a powerful tool for pharmaceutical studies.

Evaluation of intratympanic formulations for inner ear delivery: methodology and sustained release formulation testing

PubMed Central

Liu, Hongzhuo; Feng, Liang; Tolia, Gaurav; Liddell, Mark R.; Hao, Jinsong; Li, S. Kevin

2013-01-01

A convenient and efficient in vitro diffusion cell method to evaluate formulations for inner ear delivery via the intratympanic route is currently not available. The existing in vitro diffusion cell systems commonly used to evaluate drug formulations do not resemble the physical dimensions of the middle ear and round window membrane. The objectives of this study were to examine a modified in vitro diffusion cell system of a small diffusion area for studying sustained release formulations in inner ear drug delivery and to identify a formulation for sustained drug delivery to the inner ear. Four formulations and a control were examined in this study using cidofovir as the model drug. Drug release from the formulations in the modified diffusion cell system was slower than that in the conventional diffusion cell system due to the decrease in the diffusion surface area of the modified diffusion cell system. The modified diffusion cell system was able to show different drug release behaviors among the formulations and allowed formulation evaluation better than the conventional diffusion cell system. Among the formulations investigated, poly(lactic-co-glycolic acid)–poly(ethylene glycol)–poly(lactic-co-glycolic acid) triblock copolymer systems provided the longest sustained drug delivery, probably due to their rigid gel structures and/or polymer-to-cidofovir interactions. PMID:23631539

In Vitro Drug Release After Crushing: Evaluation of Xtampza® ER and Other ER Opioid Formulations.

PubMed

Mayock, Stephen P; Saim, Said; Fleming, Alison B

2017-12-01

Extended-release (ER) opioids are associated with high rates of abuse. Recreational opioid users often manipulate ER formulations to achieve a high plasma concentration in a short amount of time, resulting in a more rapid and intense high. Patients may also manipulate ER tablets to facilitate swallowing, without recognizing that manipulation could increase release rate. The goal of this study was to assess the ability of oxycodone DETERx (Xtampza ® ER, Collegium Pharmaceutical, Inc., Canton, MA, USA) and other commercially available ER opioid formulations with and without physicochemical abuse-deterrent characteristics to be manipulated by crushing in an in vitro setting. In vitro dissolution techniques were used to compare the opioid release from a variety of ER opioid formulations. Dissolution was assessed for intact and crushed dosage forms. Opioid release was quantified using high-performance liquid chromatography. Intact formulations exhibited drug release rates characteristic of 12- or 24-h dosage forms. After crushing using commonly available household tools, only Xtampza ER maintained ER of opioid. Xtampza ER maintained its ER characteristics after crushing, unlike many other commercially available opioid formulations, including some formulated with abuse-deterrent properties. As such, Xtampza ER may be less appealing to abusers and offer a margin of safety for patients who manipulate dosage forms to facilitate swallowing.

Preparation and characterization of poly(lactic acid) nanoparticles for sustained release of pyridostigmine bromide.

PubMed

Tan, Q Y; Xu, M L; Wu, J Y; Yin, H F; Zhang, J Q

2012-04-01

A novel pyridostigmine bromide poly (lactic acid) nanoparticles (PBPNPs) was prepared to obtain sustained release characteristics of PB. A central composite design approach was employed for process optimization. The in vitro release studies were carried out by dialysis method and conducted using four different dissolution media. Similar factor method was investigated for dissolution profile comparison. Multiple linear regression analysis for process optimization revealed that the optimal PBPNPs were obtained where the values of the amount of PB (X1, mg), PLA concentration (X2, % w:v), and PVA concentration (X3, % w:v) were 49.20 mg, 3.31% and 3.41%, respectively. The average particle size and zeta potential of PBPNPs with the optimized formulation were 722.9 +/- 4.3 nm, and -25.12 +/- 1.2 mV, respectively. PBPNPs provided an initial burst of drug release followed by a very slow release over an extended period of time (72 h). Compared with free PB, PBPNPs had a significantly lower release rate of PB in vitro. The in vitro release profile of the PBPNPs could be described by Weibull models, regardless of type of dissolution medium. Statistical significance of similarity between every two dissolution profiles of PBPNPs in different dissolution media was found, and the difference between the curves of PBPNPs and pure PB was statistically significant.

Low dietary protein is associated with an increase in food intake and a decrease in the in vitro release of radiolabeled glutamate and GABA from the lateral hypothalamus.

PubMed

White, B D; Du, F; Higginbotham, D A

2003-12-01

Moderately low-protein diets lead to a rapid increase in food intake and body fat. The increase in feeding is associated with a decrease in the concentration of serum urea nitrogen, suggesting that the low-protein-induced increase in food intake may be related to the decreased metabolism of nitrogen from amino acids. We hypothesized that low dietary protein would be associated with a decrease in the synaptic release of two nitrogen-containing neurotransmitters, GABA and glutamate, whose nitrogen can be derived from amino acids. In this study, we examined the effects of a low-protein diet (10% casein) in Sprague-Dawley rats on the in vitro release of 3H-GABA and 14C-glutamate from the lateral and medial hypothalamus. The low-protein diet increased food intake by about 25% after one day. After four days, the in vitro release of radiolabeled GABA and glutamate was assessed. The calcium-dependent, potassium-stimulated release of radiolabeled GABA and glutamate from the lateral hypothalamus was decreased in rats fed the low-protein diet. The magnitude of neurotransmitter release from the lateral hypothalamus inversely correlated with food intake. No dietary differences in the release of neurotransmitters from the medial hypothalamus were observed. These results support the contention that alterations in nitrogen metabolism are associated with low-protein-induced feeding.

Thermoresponsive core-shell magnetic nanoparticles for combined modalities of cancer therapy.

PubMed

Purushotham, S; Chang, P E J; Rumpel, H; Kee, I H C; Ng, R T H; Chow, P K H; Tan, C K; Ramanujan, R V

2009-07-29

Thermoresponsive polymer-coated magnetic nanoparticles loaded with anti-cancer drugs are of considerable interest for novel multi-modal cancer therapies. Such nanoparticles can be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release. Gamma-Fe(2)O(3) iron oxide magnetic nanoparticles (MNP) with average sizes of 14, 19 and 43 nm were synthesized by high temperature decomposition. Composite magnetic nanoparticles (CNP) of 43 nm MNP coated with the thermoresponsive polymer poly-n-isopropylacrylamide (PNIPAM) were prepared by dispersion polymerization of n-isopropylacrylamide monomer in the presence of the MNP. In vitro drug release of doxorubicin-(dox) loaded dehydrated CNP at temperatures below and above the lower critical solution temperature of PNIPAM (34 degrees C) revealed a weak dependence of drug release on swelling behavior. The particles displayed Fickian diffusion release kinetics; the maximum dox release at 42 degrees C after 101 h was 41%. In vitro simultaneous hyperthermia and drug release of therapeutically relevant quantities of dox was achieved, 14.7% of loaded dox was released in 47 min at hyperthermia temperatures. In vivo magnetic targeting of dox-loaded CNP to hepatocellular carcinoma (HCC) in a buffalo rat model was studied by magnetic resonance imaging (MRI) and histology. In summary, the good in vitro and in vivo performance of the doxorubicin-loaded thermoresponsive polymer-coated magnetic nanoparticles suggests considerable promise for applications in multi-modal treatment of cancer.

Evaluation of mucoadhesive potential of gum cordia, an anionic polysaccharide.

PubMed

Ahuja, Munish; Kumar, Suresh; Kumar, Ashok

2013-04-01

The study involves mucoadhesive evaluation by formulating buccal discs using fluconazole as the model drug. The effect of compression pressure and gum cordia/lactose ratio on the ex vivo bioadhesion time and in vitro release of fluconazole was optimized using central composite experimental design. It was observed that the response ex vivo bioadhesion time was affected significantly by the proportion of gum cordia in the buccal discs while the in vitro release of fluconazole from the buccal discs was influenced significantly by the compression pressure. The optimized batch of buccal discs comprised of gum cordia/lactose - 0.66, fluconazole - 20 mg and was compressed at the pressure of 6600 kg. Further, it provided the ex vivo bioadhesion of 22 h and in vitro release of 80% in 24h. In conclusion, gum cordia is a promising bucoadhesive polymer. Copyright © 2012 Elsevier B.V. All rights reserved.

Formulation and in vitro evaluation of Hydrodynamically balanced system for theophylline delivery.

PubMed

Nayak, Amit Kumar; Malakar, Jadupati

2011-06-01

The objective of the present study was to formulate hydrodynamically balanced systems (HBSs) of theophylline as single unit capsules. They were formulated by physical blending of theophylline with hydroxypropyl methyl cellulose, polyethylene oxide, polyvinyl pyrrolidone, ethyl cellulose, liquid paraffin, and lactose in different ratios. These theophylline HBS capsules were evaluated for weight uniformity, drug content uniformity, in vitro floating behavior and drug release in simulated gastric fluids (pH 1.2). All these formulated HBS capsules containing theophylline were floated well over 6 hours with no floating lag time, and also showed sustained in vitro drug release in simulated gastric fluid over 6 hours. The theophylline release from these capsules was more sustained with the addition of release modifiers (ethyl cellulose and liquid paraffin). The drug release pattern from these capsules was correlated well with first order model (F-1 to F-5) and Korsmeyer-Peppas model (F-6 and F-7) with the non-Fickian (anomalous) diffusion mechanism. These experimental results clearly indicated that these theophylline HBS capsules were able to remain buoyant in the gastric juice for longer period, which may improve oral bioavailability of theophylline.

Ketoprofen suppository dosage forms: in vitro release and in vivo absorption studies in rabbits.

PubMed

Babar, A; Bellete, T; Plakogiannis, F M

1999-02-01

In vitro release of ketoprofen from suppository bases and in vivo absorption in rabbits were studied. Suppositories containing 50 mg of ketoprofen were prepared using theobroma oil, esterified (c10-c18) fatty acids, and polyethylene glycol 1000 bases. The displacement values of the drug were determined and found to be of the order of theobroma oil > esterified (c10-c18) fatty acids and polyethylene glycol 1000 bases. The suppository hardness data revealed that the theobroma oil base produced relatively brittle suppositories. Using the USP dissolution method, the release of ketoprofen was observed to be greatest from polyethylene glycol 1000 suppositories. With the dialysis technique, the maximum release of drug was obtained from theobroma oil suppository containing polysorbate 40 at a 6% level. Selected suppository formulations were evaluated for rectal absorption studies in rabbits. The in vivo data showed that the optimum drug absorption took place from the polyethylene glycol 1000 base and theobroma oil formulation containing 6% polysorbate 40.

Hydrophobic Drug-Loaded PEGylated Magnetic Liposomes for Drug-Controlled Release

NASA Astrophysics Data System (ADS)

Hardiansyah, Andri; Yang, Ming-Chien; Liu, Ting-Yu; Kuo, Chih-Yu; Huang, Li-Ying; Chan, Tzu-Yi

2017-05-01

Less targeted and limited solubility of hydrophobic-based drug are one of the serious obstacles in drug delivery system. Thus, new strategies to enhance the solubility of hydrophobic drug and controlled release behaviors would be developed. Herein, curcumin, a model of hydrophobic drug, has been loaded into PEGylated magnetic liposomes as a drug carrier platform for drug controlled release system. Inductive magnetic heating (hyperthermia)-stimulated drug release, in vitro cellular cytotoxicity assay of curcumin-loaded PEGylated magnetic liposomes and cellular internalization-induced by magnetic guidance would be investigated. The resultant of drug carriers could disperse homogeneously in aqueous solution, showing a superparamagnetic characteristic and could inductive magnetic heating with external high-frequency magnetic field (HFMF). In vitro curcumin release studies confirmed that the drug carriers exhibited no significant release at 37 °C, whereas exhibited rapid releasing at 45 °C. However, it would display enormous (three times higher) curcumin releasing under the HFMF exposure, compared with that without HFMF exposure at 45 °C. In vitro cytotoxicity test shows that curcumin-loaded PEGylated magnetic liposomes could efficiently kill MCF-7 cells in parallel with increasing curcumin concentration. Fluorescence microscopy observed that these drug carriers could internalize efficiently into the cellular compartment of MCF-7 cells. Thus, it would be anticipated that the novel hydrophobic drug-loaded PEGylated magnetic liposomes in combination with inductive magnetic heating are promising to apply in the combination of chemotherapy and thermotherapy for cancer therapy.

Development and evaluation of nanoparticles based on mPEG-PLA for controlled delivery of vinpocetine: in vitro and in vivo studies.

PubMed

Wang, Run; Xu, Yong

2017-02-01

The aim of present study was to develop VIN-loaded mPEG-PLA nanoparticle systems. The VIN mPEG-PLA nanoparticles were prepared using an emulsion solvent evaporation method, and studied their particle size, morphology, encapsulation efficiency and drug-loading coefficient. Moreover, the nanoparticles were evaluated on the drug release behaviors in vitro and bioavailability in vivo. The results show that the spherical nanoparticles obtained were negatively charged with a zeta potential of about -23.4 mV and characterized ∼110 nm with a narrow size distribution. The encapsulation efficiency and drug loading of prepared NPs were 76.4 ± 6.3 and 9.2 ± 2.2% (n=5), respectively. The in vitro release showed that the percent of accumulated dissolution of VIN NPs in phosphate-buffered saline 6.8 over 24 h was <80%, which was almost 100% of VIN in commercial injections. The in vivo study indicated that systemic absorption of VIN was significantly enhanced by incorporating into mPEG-PLA NPs compared with VIN injection (2.87-fold in AUC 0- t ). The results suggested that the form of VIN in mPEG-PLA NPs could enter the body circulation to perform sustained release in vitro and in vivo.

In vitro-ex vivo correlations between a cell-laden hydrogel and mucosal tissue for screening composite delivery systems.

PubMed

Blakney, Anna K; Little, Adam B; Jiang, Yonghou; Woodrow, Kim A

2016-11-01

Composite delivery systems where drugs are electrospun in different layers and vary the drug stacking-order are posited to affect bioavailability. We evaluated how the formulation characteristics of both burst- and sustained-release electrospun fibers containing three physicochemically diverse drugs: dapivirine (DPV), maraviroc (MVC) and tenofovir (TFV) affect in vitro and ex vivo release. We developed a poly(hydroxyethyl methacrylate) (pHEMA) hydrogel release platform for the rapid, inexpensive in vitro evaluation of burst- and sustained-release topical or dermal drug delivery systems with varying microarchitecture. We investigated properties of the hydrogel that could recapitulate ex vivo release into nonhuman primate vaginal tissue. Using a dimethyl sulfoxide extraction protocol and high-performance liquid chromatography analysis, we achieved >93% recovery from the hydrogels and >88% recovery from tissue explants for all three drugs. We found that DPV loading, but not stacking order (layers of fiber containing a single drug) or microarchitecture (layers with isolated drug compared to all drugs in the same layer) impacted the burst release in vitro and ex vivo. Our burst-release formulations showed a correlation for DPV accumulation between the hydrogel and tissue (R 2 =   0.80), but the correlation was not significant for MVC or TFV. For the sustained-release formulations, the PLGA/PCL content did not affect TFV release in vitro or ex vivo. Incorporation of cells into the hydrogel matrix improved the correlation between hydrogel and tissue explant release for TFV. We expect that this hydrogel-tissue mimic may be a promising preclinical model to evaluate topical or transdermal drug delivery systems with complex microarchitectures.

A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling.

PubMed

Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

2016-01-01

Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients' compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box-Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box-Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of amoxicillin. In vitro release study firstly indicated a three-pulse release profile of the tablet. Later the pulse tablet was found to generate the sustained release of amoxicillin in beagle dogs. Furthermore, the Simcyp® software was used to simulate the in vivo concentration time curve model of the three-pulse release tablet for amoxicillin in both human and beagle dog. The prediction by PBPK model nicely fitted the observation in human and beagle dog. This study has demonstrated the interrelation of factors affecting the pulsatile formulation of amoxicillin using a Box-Behnken design. The three-pulse release tablets of amoxicillin were proven to generate pulsatile release in vitro and sustained release in vivo. This formulation was also found to extend the effective plasma concentration in human compared to the tablet of immediate release based on the simulation data by PBPK modeling. This study provides an example of using PBPK to guide the development of pulsatile dosage forms.

In vitro dissolution profile of two commercially available iron preparations.

PubMed

Patrício, José P H; Santos, Cristina; Cerdeira, Rui

2012-03-01

Current scientific evidence indicates that anemia in pregnancy, regardless of severity, is associated with an increased risk of maternal and fetal mortality. There is little published information about the bioavailability and bioequivalence of formulations containing both iron and folic acid. However, in vitro dissolution studies can provide important information on the likely relative bioavailability of various formulations. The objective of our study was to compare the in vitro dissolution of two similar commercially available formulations of iron- and folic acid-containing supplements, Folifer® (Bialport - Produtos Farmacêuticos, S.A., Portugal) and Ferroliver® (SM Pharma c.a., Venezuela), in order to determine the in vitro availability of their iron content. Folifer® and Ferroliver® were chosen because they contained similar amounts of elemental iron. The amount of iron released from each tablet was evaluated over a 4-hour period in three dissolution media replicating gastric or intestinal juices with pH values ranging from 1.5 to 6.9. The samples were then titrated with a solution of cerium ammonium sulfate in order to calculate the amount of iron released in each specific pH condition. The percentage of dissolved iron was calculated as a cumulative frequency, using the percentage of dissolved iron at all timepoints. The dissolution similarity between the two commercially available formulations was evaluated using the &U0192;(2) statistic formula. During a 4-hour dissolution test, Folifer® released 59.4 mg of iron compared with 48.5 mg released by Ferroliver®. The value obtained for the similarity factor, an indicator of likely bioequivalence, was 41. These data suggest that Folifer® releases more iron than Ferroliver®, and that the two formulations are not equivalent in vitro. The superior dissolution of ferrous sulfate with Folifer® compared with ferrous fumarate in Ferroliver® might be responsible for the observed difference.

Characterization of Porous, Dexamethasone-Releasing Polyurethane Coatings for Glucose Sensors

PubMed Central

Vallejo-Heligon, Suzana G.; Klitzman, Bruce; Reichert, William M.

2014-01-01

Commercially available implantable needle-type glucose sensors for diabetes management are robust analytically but can be unreliable clinically primarily due to tissue-sensor interactions. Here, we present the physical, drug release, and bioactivity characterization of tubular, porous dexamethasone (Dex) releasing polyurethane coatings designed to attenuate local inflammation in the tissue-sensor interface. Porous polyurethane coatings were produced by the salt-leaching/gas-foaming method. Scanning electron microscopy (SEM) and Micro-computed tomography (Micro-CT) showed a controlled porosity and coating thickness. In vitro drug release from coatings monitored over two weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture. Acute animal studies were used to determine the appropriate Dex payload for the implanted porous coatings. Pilot short-term animal studies showed that Dex released from porous coatings implanted in rat subcutis attenuated the initial inflammatory response to sensor implantation. These results suggest that deploying sensors with the porous, Dex-releasing coatings is a promising strategy to improve glucose sensor performance. PMID:25065548

Towards more realistic in vitro release measurement techniques for biodegradable microparticles.

PubMed

Klose, D; Azaroual, N; Siepmann, F; Vermeersch, G; Siepmann, J

2009-03-01

To better understand the importance of the environmental conditions for drug release from biodegradable microparticles allowing for the development of more appropriate in vitro release measurement techniques. Propranolol HCl diffusion in various agarose gels was characterized by NMR and UV analysis. Fick's law was used to theoretically predict the mass transport kinetics. Drug release from PLGA-based microparticles in such agarose gels was compared to that measured in agitated bulk fluids ("standard" method). NMR analysis revealed that the drug diffusivity was almost independent of the hydrogel concentration, despite of the significant differences in the systems' mechanical properties. This is due to the small size of the drug molecules/ions with respect to the hydrogel mesh size. Interestingly, the theoretically predicted drug concentration-distance-profiles could be confirmed by independent experiments. Most important from a practical point of view, significant differences in the release rates from the same batch of PLGA-based microparticles into a well agitated bulk fluid versus a semi-solid agarose gel were observed. Great care must be taken when defining the in vitro conditions for drug release measurements from biodegradable microparticles. The obtained new insight can help facilitating the development of more appropriate in vitro release testing procedures.

Developing dissolution testing methodologies for extended-release oral dosage forms with supersaturating properties. Case example: Solid dispersion matrix of indomethacin.

PubMed

Tajiri, Tomokazu; Morita, Shigeaki; Sakamoto, Ryosaku; Mimura, Hisahi; Ozaki, Yukihiro; Reppas, Christos; Kitamura, Satoshi

2015-07-25

The objective of this study was to develop an in vitro dissolution test method with discrimination ability for an extended-release solid dispersion matrix of a lipophilic drug using the United States Pharmacopeia (USP) Apparatus 4, flow-through cell apparatus. In the open-loop configuration, the sink condition was maintained by manipulating the flow rate of the dissolution medium. To evaluate the testing conditions, the drug release mechanism from an extended-release solid dispersion matrix containing hydrophobic and hydrophilic polymers was investigated. As the hydroxypropyl methylcellulose (HPMC) maintained concentrations of indomethacin higher than the solubility in a dissolution medium, the release of HPMC into the dissolution medium was also quantified using size-exclusion chromatography. We concluded that the USP Apparatus 4 is suitable for application to an in vitro dissolution method for orally administered extended-release solid dispersion matrix formulations containing poorly water-soluble drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Chitosan-poly (lactide-co-glycolide) (CS-PLGA) nanoparticles containing metformin HCl: preparation and in vitro evaluation.

PubMed

Gundogdu, Nuran; Cetin, Meltem

2014-11-01

In this study, the preparation and in vitro characterisation of metformin HCl-loaded CS-PLGA nanoparticles (NPs) were aimed. The prepared nanoparticles (blank nanoparticles (C-1), 50 mg of metformin HCl loaded nanoparticles (C-2) and 75 mg of metformin HCl loaded nanoparticles (C-3) ranged in size from 506.67±13.61 to 516.33±16.85 nm and had surface charges of 22.57±1.21 to 32.37±0.57 mV. Low encapsulation efficiency was observed for both nanoparticle formulations due to the leakage of metformin HCl to the external medium during preparation of nanoparticles. Nanoparticle formulations showed highly reproducible drug release profiles. ~20% of metformin HCl was released within 30 minutes and approximately 98% of the loaded metformin HCl was released at 144 hours in a phosphate buffer (PB; pH 6.8). No statistically significant difference was noted between the in vitro release profiles of the nanoparticles (C-2 and C-3) containing metformin HCl. Also, nanoparticles were characterised using FT-IR and DSC.

Preparation and evaluation of sustained release microballoons of propranolol.

PubMed

Porwal, A; Swami, G; Saraf, Sa

2011-01-01

The purpose of the present investigation was to characterize, optimize and evaluate microballoons of Propranolol hydrochloride and to increase its boioavailability by increasing the retention time of the drug in the gastrointestinal tract. Propranolol hydrochloride-loaded microballoons were prepared by the non-aqueous O/O emulsion solvent diffusion evaporation method using Eudragit RSPO as polymer. It was found that preparation temperature determined the formation of cavity inside the microballoon and this in turn determined the buoyancy. Microballoons were subjected to particle size determination, micromeritic properties, buoyancy, entrapment efficiency, drug loading, in vitro drug release and IR study. The correlation between the buoyancy, bulk density and porosity of microballoons were elucidated. The release rate was determined in simulated gastric fluid (SGF) of pH 1.2 at 37±0.5°C. The microballoons presented spherical and smooth morphologies (SEM) and were porous due to presence of hollow cavity. Microballoons remained buoyant for >12 hrs for the optimized formulation. The formulation demonstrated favorable in vitro floating and release characteristics. The encapsulation efficiency was high. In vitro dissolution kinetics followed the Higuchi model. The drug release from microballoons was mainly controlled by diffusion and showed a biphasic pattern with an initial burst release, followed by sustained release for 12 hrs. The amount of the drug which released up to 12 hrs was 82.05±0.64%. Statistical analysis (ANOVA) showed significant difference (p<0.05) in the cumulative amount of drug released after 30 min, and up to 12 hrs from optimized formulations. The designed system for propanolol would possibly be advantageous in terms of increased bioavailability and patient compliance.

Development of a reservoir type prolonged release system with felodipine via simplex methodology

PubMed Central

IOVANOV, RAREŞ IULIU; TOMUŢĂ, IOAN; LEUCUŢA, SORIN EMILIAN

2016-01-01

Background and aims Felodipine is a dihydropyridine calcium antagonist that presents good characteristics to be formulated as prolonged release preparations. The aim of the study was the formulation and in vitro characterization of a reservoir type prolonged release system with felodipine, over a 12 hours period using the Simplex method. Methods The first step of the Simplex method was to study the influence of the granules coating method on the felodipine release. Furthermore the influence of the coating polymer type, the percent of the coating polymer and the percent of pore forming agent in the coating on the felodipine release were studied. Afterwards these two steps of the experimental design the percent of Surelease applied on the felodipine loaded granules and the percent of pore former in the polymeric coating formulation variables were studied. The in vitro dissolution of model drug was performed in phosphate buffer solution (pH 6.5) with 1% sodium lauryl sulfate. The released drug quantification was done using an HPLC method. The release kinetics of felodipine from the final granules was assessed using different mathematical models. Results A 12 hours release was achieved using granules with the size between 315–500 μm coated with 45% Surelease with different pore former ratios in the coating via the top-spray method. Conclusion We have prepared prolonged release coated granules with felodipine using a fluid bed system based on the Simplex method. The API from the studied final formulations was released over a 12 hours period and the release kinetics of the model drug substance from the optimized preparations fitted best the Higuchi and Peppas kinetic models. PMID:27004036

Chronomodulated drug delivery system of urapidil for the treatment of hypertension

PubMed Central

Chaudhary, Sona S.; Patel, Hetal K.; Parejiya, Punit B.; Shelat, Pragna K.

2015-01-01

Introduction: Hypertension is a disease which shows circadian rhythm in the pattern of two peaks, one in the evening at about 7pm and other in the early morning between 4 am to 8 am. Conventional therapies are incapable to target those time points when actually the symptoms get worsened. To achieve drug release at two time points, chronomodulated delivery system may offer greater benefits. Materials and methods: The chronomodulated system comprised of dual approach; immediate release granules (IRG) and pulsatile release mini-tablets (PRM) filled in the hard gelatin capsule. The mini-tablets were coated using Eudragit S-100 which provided the lag time. To achieve the desired release, various parameters like coating duration and coat thickness were studied. The immediate release granules were evaluated for micromeritical properties and drug release, while mini-tablets were evaluated for various parameters such as hardness, thickness, friability, weight variation, drug content, and disintegration time and in-vitro drug release. Compatibility of drug-excipient was checked by fourier transform infrared spectroscopy and Differential scanning calorimetry studies and pellets morphology was done by Scanning electron microscopy studies. Results: The in-vitro release profile suggested that immediate release granules gives drug release within 20 min at the time of evening attack while the programmed pulsatile release was achieved from coated mini-tablets after a lag time of 9hrs, which was consistent with the demand of drug during early morning hour attack. Pellets found to be spherical in shape with smooth surface. Moreover compatibility studies illustrated no deleterious reaction between drug and polymers used in the study. Conclusions: The dual approach of developed chronomodulated formulation found to be satisfactory in the treatment of hypertension. PMID:25838996

Transmucosal delivery of domperidone from bilayered buccal patches: in vitro, ex vivo and in vivo characterization.

PubMed

Palem, Chinna Reddy; Gannu, Ramesh; Doodipala, Narender; Yamsani, Vamshi Vishnu; Yamsani, Madhusudan Rao

2011-10-01

Bilayered mucoadhesive buccal patches for systemic administration of domperidone (DOM), a dopamine-receptor (D(2)) antagonist, were developed using hydroxy propyl methyl cellulose and PVPK30 as a primary layer and Eudragit RLPO and PEO as a secondary layer. Ex vivo drug permeation through porcine buccal membrane was performed. Bilayered buccal patches were developed by solvent casting technique and evaluated for in vitro drug release, moisture absorption, mechanical properties, surface pH, in vitro bioadhesion, in vivo residence time and ex vivo permeation of DOM through porcine buccal membrane from a bilayered buccal patch. Formulation DB4 was associated with 99.5% drug release with a higuchi model release profile and 53.9% of the drug had permeated in 6 h, with a flux of 0.492 mg/h/cm(2) through porcine buccal membrane. DB4 showed 5.58 N and 3.28 mJ peak detachment force and work of adhesion, respectively. The physicochemical interactions between DOM and the polymer were investigated by differential scanning calorimetry (DSC) and fourier transform infrared (FTIR) Spectroscopy. DSC and FTIR studies revealed no interaction between drug and polymer. Stability studies for optimized patch DB4 was carried out at 40°C/75% relative humidity. The formulations were found to be stable over a period of 3 months with respect to drug content, in vitro release and ex vivo permeation through porcine buccal membrane. The results indicate that suitable bilayered mucoadhesive buccal patches with desired permeability could be prepared.

Time and pH dependent colon specific, pulsatile delivery of theophylline for nocturnal asthma.

PubMed

Mastiholimath, V S; Dandagi, P M; Jain, S Samata; Gadad, A P; Kulkarni, A R

2007-01-02

In this study, investigation of an oral colon specific, pulsatile device to achieve time and/or site specific release of theophylline, based on chronopharmaceutical consideration. The basic design consists of an insoluble hard gelatin capsule body, filled with eudragit microcapsules of theophylline and sealed with a hydrogel plug. The entire device was enteric coated, so that the variability in gastric emptying time can be overcome and a colon-specific release can be achieved. The theophylline microcapsules were prepared in four batches, with Eudragit L-100 and S-100 (1:2) by varying drug to polymer ratio and evaluated for the particle size, drug content and in vitro release profile and from the obtained results; one better formulation was selected for further fabrication of pulsatile capsule. Different hydrogel polymers were used as plugs, to maintain a suitable lag period and it was found that the drug release was controlled by the proportion of polymers used. In vitro release studies of pulsatile device revealed that, increasing the hydrophilic polymer content resulted in delayed release of theophylline from microcapsules. The gamma scintigraphic study pointed out the capability of the system to release drug in lower parts of GIT after a programmed lag time for nocturnal asthma. Programmable pulsatile, colon-specific release has been achieved from a capsule device over a 2-24h period, consistent with the demands of chronotherapeutic drug delivery.

Enhanced in vitro biological activity generated by surface characteristics of anodically oxidized titanium--the contribution of the oxidation effect.

PubMed

Wurihan; Yamada, A; Suzuki, D; Shibata, Y; Kamijo, R; Miyazaki, T

2015-05-20

Anodically oxidized titanium surfaces, prepared by spark discharge, have micro-submicron surface topography and nano-scale surface chemistry, such as hydrophilic functional groups or hydroxyl radicals in parallel. The complexity of the surface characteristics makes it difficult to draw a clear conclusion as to which surface characteristic, of anodically oxidized titanium, is critical in each biological event. This study examined the in vitro biological changes, induced by various surface characteristics of anodically oxidized titanium with, or without, release of hydroxyl radicals onto the surface. Anodically oxidized titanium enhanced the expression of genes associated with differentiating osteoblasts and increased the degree of matrix mineralization by these cells in vitro. The phenotypes of cells on the anodically oxidized titanium were the same with, or without, release of hydroxyl radicals. However, the nanomechanical properties of this in vitro mineralized tissue were significantly enhanced on surfaces, with release of hydroxyl radicals by oxidation effects. In addition, the mineralized tissue, produced in the presence of bone morphogenetic protein-2 on bare titanium, had significantly weaker nanomechanical properties, despite there being higher osteogenic gene expression levels. We show that enhanced osteogenic cell differentiation on modified titanium is not a sufficient indicator of enhanced in vitro mineralization. This is based on the inferior mechanical properties of mineralized tissues, without either being cultured on a titanium surface with release of hydroxyl radicals, or being supplemented with lysyl oxidase family members.

Effect of endothelin-1 and endothelin receptor blockade on the release of microparticles.

PubMed

Jung, Christian; Lichtenauer, Michael; Wernly, Bernhard; Franz, Marcus; Goebel, Bjoern; Rafnsson, Arnar; Figulla, Hans-Reiner; Pernow, John

2016-08-01

Increased levels of endothelial cell microparticles (EMP) are known to reflect endothelial dysfunction (ED). In diabetes mellitus type 2 (T2DM), the expression of endothelin (ET)-1 is increased. As treatment with an ET-1 antagonist significantly inhibited atherosclerosis in animal models, we sought to investigate whether treatment with ET-1 antagonists affects EMP levels in vitro and in vivo in patients with T2DM. In vitro study: Human umbilical vein endothelial cells (HUVEC) were stimulated with ET-1 alone and ET-1 in combination with a dual ET-A and ET-B endothelin receptor blocker. In vivo study: Patients with T2DM were randomized to treatment with the ET receptor antagonist bosentan or placebo. After 4 weeks, the patients were re-examined and blood samples were obtained. EMP counts in supernatants and plasma samples were determined using flow cytometry. In vitro study: In supernatants of ET-1-stimulated HUVECs, the increased release of EMP was reduced significantly by co-incubation with an ET-1 receptor antagonist (e.g. CD31+/CD42b-EMP decreased from 37·1% ± 2·8 to 31·5% ± 2·8 SEM, P = 0·0078). In vivo study: No changes in EMP levels in blood samples of patients with T2DM were found after 4 weeks of bosentan treatment (n = 36, P = ns). Our in vitro results suggest that ET-1 stimulates the release of EMP from HUVECs via a receptor-dependent mechanism. Co-incubation with an endothelin receptor blocker abolished ET-1-dependent EMP release. However, treatment with bosentan for 4 weeks failed to alter EMP levels in patients with T2DM. Other factors seem to have influenced EMP release in patients with T2DM independent of ET-1 receptor-mediated mechanisms. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

Experimental study of PLLA/INH slow release implant fabricated by three dimensional printing technique and drug release characteristics in vitro.

PubMed

Wu, Gui; Wu, Weigang; Zheng, Qixin; Li, Jingfeng; Zhou, Jianbo; Hu, Zhilei

2014-07-19

Local slow release implant provided long term and stable drug release in the lesion. The objective of this study was to fabricate biodegradable slow release INH/PLLA tablet via 3 dimensional printing technique (3DP) and to compare the drug release characteristics of three different structured tablets in vitro. Three different drug delivery systems (columnar-shaped tablet (CST), doughnut-shaped tablet (DST) and multilayer doughnut-shaped tablet (MDST)) were manufactured by the three dimensional printing machine and isoniazid was loaded into the implant. Dynamic soaking method was used to study the drug release characteristics of the three implants. MTT cytotoxicity test and direct contact test were utilized to study the biocompatibility of the implant. The microstructures of the implants' surfaces were observed with electron microscope. The PLLA powder in the tablet could be excellently combined through 3DP without disintegration. Electron microscope observations showed that INH distributed evenly on the surface of the tablet in a "nest-shaped" way, while the surface of the barrier layer in the multilayer doughnut shaped tablet was compact and did not contain INH. The concentration of INH in all of the three tablets were still higher than the effective bacteriostasis concentration (Isoniazid: 0.025 ~ 0.05 μg/ml) after 30 day's release in vitro. All of the tablets showed initial burst release of the INH in the early period. Drug concentration of MDST became stable and had little fluctuation starting from the 6th day of the release. Drug concentration of DST and CST decreased gradually and the rate of decrease in concentration was faster in DST than CST. MTT cytotoxicity test and direct contact test indicated that the INH-PLLA tablet had low cytotoxicity and favorable biocompatibility. Three dimensional printing technique was a reliable technique to fabricate complicated implants. Drug release pattern in MDST was the most stable among the three implants. It was an ideal drug delivery system for the antibiotics. Biocompatibility tests demonstrated that the INH-PLLA implant did not have cytotoxicity. The multilayer donut-shaped tablet provided a new constant slow release method after an initial burst for the topical application of the antibiotic.

Experimental study of PLLA/INH slow release implant fabricated by three dimensional printing technique and drug release characteristics in vitro

PubMed Central

2014-01-01

Background Local slow release implant provided long term and stable drug release in the lesion. The objective of this study was to fabricate biodegradable slow release INH/PLLA tablet via 3 dimensional printing technique (3DP) and to compare the drug release characteristics of three different structured tablets in vitro. Methods Three different drug delivery systems (columnar-shaped tablet (CST), doughnut-shaped tablet (DST) and multilayer doughnut-shaped tablet (MDST)) were manufactured by the three dimensional printing machine and isoniazid was loaded into the implant. Dynamic soaking method was used to study the drug release characteristics of the three implants. MTT cytotoxicity test and direct contact test were utilized to study the biocompatibility of the implant. The microstructures of the implants’ surfaces were observed with electron microscope. Results The PLLA powder in the tablet could be excellently combined through 3DP without disintegration. Electron microscope observations showed that INH distributed evenly on the surface of the tablet in a “nest-shaped” way, while the surface of the barrier layer in the multilayer doughnut shaped tablet was compact and did not contain INH. The concentration of INH in all of the three tablets were still higher than the effective bacteriostasis concentration (Isoniazid: 0.025 ~ 0.05 μg/ml) after 30 day’s release in vitro. All of the tablets showed initial burst release of the INH in the early period. Drug concentration of MDST became stable and had little fluctuation starting from the 6th day of the release. Drug concentration of DST and CST decreased gradually and the rate of decrease in concentration was faster in DST than CST. MTT cytotoxicity test and direct contact test indicated that the INH-PLLA tablet had low cytotoxicity and favorable biocompatibility. Conclusions Three dimensional printing technique was a reliable technique to fabricate complicated implants. Drug release pattern in MDST was the most stable among the three implants. It was an ideal drug delivery system for the antibiotics. Biocompatibility tests demonstrated that the INH-PLLA implant did not have cytotoxicity. The multilayer donut-shaped tablet provided a new constant slow release method after an initial burst for the topical application of the antibiotic. PMID:25038793

Transbuccal delivery of chlorpheniramine maleate from mucoadhesive buccal patches.

PubMed

Sekhar, K Chandra; Naidu, K V S; Vishnu, Y Vamshi; Gannu, Ramesh; Kishan, V; Rao, Y Madhusudan

2008-01-01

This article describes buccal permeation of chlorpheniramine maleate (CPM) and its transbuccal delivery using mucoadhesive buccal patches. Permeation of CPM was calculated in vitro using porcine buccal membrane and in vivo in healthy humans. Buccal formulations were developed with hydroxyethylcellulose (HEC) and evaluated for in vitro release, moisture absorption, mechanical properties, and bioadhesion, and optimized formulation was subjected for bioavailability studies in healthy human volunteers. In vitro flux of CPM was calculated to be 0.14 +/- 0.03 mg.h(-1).cm(-2) and buccal absorption also was demonstrated in vivo in human volunteers. In vitro drug release and moisture absorbed were governed by HEC content and formulations exhibited good tensile and mucoadhesive properties. Bioavailability from optimized buccal patch was 1.46 times higher than the oral dosage form and the results showed statistically significant difference.

mRNA expression pattern of selected candidate genes differs in bovine oviductal epithelial cells in vitro compared with the in vivo state and during cell culture passages.

PubMed

Danesh Mesgaran, Sadjad; Sharbati, Jutta; Einspanier, Ralf; Gabler, Christoph

2016-08-15

The mammalian oviduct provides the optimal environment for gamete maturation including sperm capacitation, fertilization, and development of the early embryo. Various cell culture models for primary bovine oviductal epithelial cells (BOEC) were established to reveal such physiological events. The aim of this study was to evaluate 17 candidate mRNA expression patterns in oviductal epithelial cells (1) in transition from in vivo cells to in vitro cells; (2) during three consecutive cell culture passages; (3) affected by the impact of LOW or HIGH glucose content media; and (4) influenced by different phases of the estrous cycle in vivo and in vitro. In addition, the release of a metabolite and proteins from BOEC at two distinct cell culture passage numbers was estimated to monitor the functionality. BOEC from 8 animals were isolated and cultured for three consecutive passages. Total RNA was extracted from in vivo and in vitro samples and subjected to reverse transcription quantitative polymerase chain reaction to reveal mRNA expression of selected candidate genes. The release of prostaglandin E2 (PGE2), oviduct-specific glycoprotein 1 (OVGP1) and interleukin 8 (IL8) by BOEC was measured by EIA or ELISA after 24 h. Almost all candidate genes (prostaglandin synthases, enzymes of cellular metabolism and mucins) mRNA expression pattern differed compared in vivo with in vitro state. In addition, transcription of most candidate genes was influenced by the number of cell culture passages. Different glucose medium content did not affect mRNA expression of most candidate genes. The phase of the estrous cycle altered some candidate mRNA expression in BOEC in vitro at later passages. The release of PGE2 and OVGP1 between passages did not differ. However, BOEC in passage 3 released significantly higher amount of IL8 compared with cells in passage 0. This study supports the hypothesis that candidate mRNA expression in BOEC was influenced by transition from the in vivo situation to the new in vitro environment and during consecutive passages. The consequence of cell culture passaging on BOEC ability to release bioactive compounds should be considered.

In-vitro release and permeation studies of ketoconazole from optimized dermatological vehicles using powder, nanoparticles and solid dispersion forms of drug

NASA Astrophysics Data System (ADS)

Mohammed, Irfan A.

To optimize the clinical efficacy of Ketoconazole from an externally applied product, this project was undertaken to evaluate the drug release/permeation profile from various dermatological vehicles using regular powder, nanoparticles and solid dispersion forms with reduced level of drug. Nanoparticles of drug were prepared by wet media milling method using Polyvinylpyrrolidone (PVP-10K) as a stabilizer. The nanoparticles were in the size range of 250-300nm. Solid dispersion was prepared by solvent evaporation method using drug to PVP-10K at a weight ratio of (1:2). Formulations containing 1% w/w drug were developed using HPMC gel, Carbomer gel and a cationic cream as the vehicles. Penetration enhancers including propylene glycol (PG), dimethylsulfoxide (DMSO) and polyethylene glycol 400 (PEG-400) at various levels were evaluated. A commercial 2% w/w ketoconazole product was included as a control for comparison. Studies were carried out with Franz Diffusion Cells using cellulose membrane and human cadaver skin for two and six hour studies. Among the formulations evaluated, the general rank order of the drug release through the cellulose membrane was observed to be: HPMC gel base > Anionic gel base > Cationic gel base > Commercial product. The addition of penetration enhancers showed variable effects in all samples evaluated. However, the HPMC gel-based vehicle showed significant effect in enhancing the drug release in the presence of DMSO. The formulation containing 1% w/w ketoconazole and 20% w/w DMSO gave a maximum drug release of 20.21% when compared to only 1.60% from the commercial product. This represents a twelve fold increase in the release of ketoconazole from the formulation. Furthermore, when the optimum gel-based formulation containing 1% w/w ketoconazole was studied over an extended period of 6 hours, it gave 36.01% drug release from the sample formulation compared to only 2.00% from the commercial product. Finally, this formulation was selected to study for its drug release/permeation profile using the human cadaver skin as the diffusion barrier. Here, as expected, the drug release from both the formulations tested was significantly reduced due to the resistance posed by the skin. After 6 hours, the drug release form the commercial product was 0.17% when compared to 2.80% from the optimum formulation. Once again, this indicated that the experimental formulation exhibits superior drug release dynamics. The selected formulations were further evaluated for their in-vitro anti-fungal activities using yeast microorganisms. The results correlated to the in-vitro drug release profile, where HPMC based formulations exhibited a greater area of zone of inhibition for the growth of microorganisms when compared to diminutive area of zone of inhibition for the commercial product. The release data from all the samples were treated to calculate various physical parameters including: diffusion co-efficient, partition co-efficient, steady state flux and lag period etc. Interestingly, the values for the steady state flux and diffusion coefficient were found to be the highest from the optimum formulation and the values for the lag time and partition coefficient were observed to be the lowest. This supports the evidence that the drug from this formulation is readily diffusible to the skin at a steady rate after its application at the site. In-vitro drug diffusion studies and in-vitro anti-fungal studies proved useful in screening various dermatological formulations of ketoconazole compared to the commercial product containing 2% w/w drug. The HPMC based optimum formulation with reduced level of drug represents 15 folds increase through human cadaver skin and also exhibited augmented anti-fungal activity. This supports that by using an appropriate vehicle and proper incorporation of drug, one can optimize the drug release from topical formulation for maximum therapeutic effect.

Impact of release characteristics of sinomenine hydrochloride dosage forms on its pharmacokinetics in beagle dogs

PubMed Central

Sun, Jin; Shi, Jie-Ming; Zhang, Tian-Hong; Gao, Kun; Mao, Jing-Jing; Li, Bing; Sun, Ying-Hua; He, Zhong-Gui

2005-01-01

AIM: To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride (SM•HCl) on its pharmacokinetics in beagle dogs. METHODS: The in vitro release behavior of two SM•HCl dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo SM•HCl pharmacokinetics was investigated and compared. RESULTS: The optimal SM•HCl sustained-release formulation was achieved by mixing slow- and rapid-release pellets (9:1, w/w). The SM•HCl release profiles of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs 68.7%. From a pharmacokinetic standpoint, the 24-h SM•HCl sustained-release pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67×0.52 h vs 9.83×0.98 h and the Cmax being 1 334.45±368.76 ng/mL vs 893.12±292.55 ng/mL, respectively. However, the AUC0-tn of two SM•HCl dosage forms was comparable and both preparations were statistically bioequivalent. Furthermore, the two preparations had good correlations between SM•HCl percentage absorption in vivo and the cumulative percentage release in vitro. CONCLUSION: The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves. PMID:16052686

Preparation and In Vitro/Ex Vivo Evaluation of Moxifloxacin-Loaded PLGA Nanosuspensions for Ophthalmic Application.

PubMed

Mudgil, Meetali; Pawar, Pravin K

2013-01-01

The aim of the present investigation was to prepare a colloidal ophthalmic formulation to improve the residence time of moxifloxacin. Moxifloxacin-loaded poly(dl-lactide-co-glycolide) (PLGA) nanosuspensions were prepared by using the solvent evaporation technique. The nanosuspensions were characterised physically by using different techniques like particle size, zeta potential, FTIR, DSC, and XRD analysis. In vitro and ex vivo studies of nanosuspensions were carried out using a modified USP dissolution apparatus and all-glass Franz diffusion cells, respectively. The antibacterial activities of the nanosuspension and marketed formulations were performed against S. aureus and P. aeroginosa. The moxifloxacin-loaded PLGA nanosuspensions showed uniform particle size, ranging between 164-490 nm with negative zeta potential for all batches. The percentage entrapment efficiency of the drug-loaded nano-suspension was found to be between 84.09 to 92.05%. In vitro drug release studies suggest that all of the formulations showed extended drug release profiles and follow Korsemeyer-Peppas release kinetics. In vitro corneal permeability was found to be comparable with that of the marketed formulation across isolated goat cornea, indicating the suitability of the nanosuspension formulation in the ophthalmic delivery of moxifloxacin. The optimised nano-suspension was found to be more active against S. aureus and P. aeruginosa compared to the marketed eye drops.

Characterization and evaluation of 5-fluorouracil-loaded solid lipid nanoparticles prepared via a temperature-modulated solidification technique.

PubMed

Patel, Meghavi N; Lakkadwala, Sushant; Majrad, Mohamed S; Injeti, Elisha R; Gollmer, Steven M; Shah, Zahoor A; Boddu, Sai Hanuman Sagar; Nesamony, Jerry

2014-12-01

The aim of this research was to advance solid lipid nanoparticle (SLN) preparation methodology by preparing glyceryl monostearate (GMS) nanoparticles using a temperature-modulated solidification process. The technique was reproducible and prepared nanoparticles without the need of organic solvents. An anticancer agent, 5-fluorouracil (5-FU), was incorporated in the SLNs. The SLNs were characterized by particle size analysis, zeta potential analysis, differential scanning calorimetry (DSC), infrared spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), drug encapsulation efficiency, in vitro drug release, and in vitro cell viability studies. Particle size of the SLN dispersion was below 100 nm, and that of redispersed lyophilizates was ~500 nm. DSC and infrared spectroscopy suggested that the degree of crystallinity did not decrease appreciably when compared to GMS. TEM and AFM images showed well-defined spherical to oval particles. The drug encapsulation efficiency was found to be approximately 46%. In vitro drug release studies showed that 80% of the encapsulated drug was released within 1 h. In vitro cell cultures were biocompatible with blank SLNs but demonstrated concentration-dependent changes in cell viability to 5-FU-loaded SLNs. The 5-FU-loaded SLNs can potentially be utilized in an anticancer drug delivery system.

Development and characterisation of electrospun timolol maleate-loaded polymeric contact lens coatings containing various permeation enhancers.

PubMed

Mehta, Prina; Al-Kinani, Ali A; Arshad, Muhammad Sohail; Chang, Ming-Wei; Alany, Raid G; Ahmad, Zeeshan

2017-10-30

Despite exponential growth in research relating to sustained and controlled ocular drug delivery, anatomical and chemical barriers of the eye still pose formulation challenges. Nanotechnology integration into the pharmaceutical industry has aided efforts in potential ocular drug device development. Here, the integration and in vitro effect of four different permeation enhancers (PEs) on the release of anti-glaucoma drug timolol maleate (TM) from polymeric nanofiber formulations is explored. Electrohydrodynamic (EHD) engineering, more specifically electrospinning, was used to engineer nanofibers (NFs) which coated the exterior of contact lenses. Parameters used for engineering included flow rates ranging from 8 to 15μL/min and a novel EHD deposition system was used; capable of hosting four lenses, masked template and a ground electrode to direct charged atomised structures. SEM analysis of the electrospun structures confirmed the presence of smooth nano-fibers; whilst thermal analysis confirmed the stability of all formulations. In vitro release studies demonstrated a triphasic release; initial burst release with two subsequent sustained release phases with most of the drug being released after 24h (86.7%) Biological evaluation studies confirmed the tolerability of all formulations tested with release kinetics modelling results showing drug release was via quasi-Fickian or Fickian diffusion. There were evident differences (p<0.05) in TM release dependant on permeation enhancer. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

[Study on solid dispersion of precipitated calcium carbonate-based oleanolic acid].

PubMed

Yan, Hong-mei; Zhang, Zhen-hai; Jia, Xiao-bin; Jiang, Yan-rong; Sun, E

2015-05-01

Oleanolic acid-precipitated calcium carbonate solid dispersion was prepared by using solvent evaporation method. The microscopic structure and physicochemical properties of solid dispersion were analyzed using differential scanning calorimetry and scanning electron microscopy (SEM). And its in vitro release also was investigated. The properties of the precipitated calcium carbonate was studied which was as a carrier of oleanolic acid solid dispersion. Differential scanning calorimetry analysis suggested that oleanolic acid may be present in solid dispersion as amorphous substance. The in vitro release determination results of oleanolic acid-precipitated calcium carbonate (1: 5) solid dispersion showed accumulated dissolution rate of.oleanolic acid was up to 90% at 45 min. Accelerating experiment showed that content and in vitro dissolution of oleanolic acid solid dispersion did not change after storing over 6 months. The results indicated that in vitro dissolution of oleanolic acid was improved greatly by the solid dispersion with precipitated calcium carbonate as a carrier. The solid dispersion is a stabilizing system which has actual applied value.

In vitro and In vivo characterization of quercetin loaded multiphase hydrogel for wound healing application.

PubMed

Jangde, Rajendra; Srivastava, Shikha; Singh, Manju R; Singh, Deependra

2018-05-03

The present work aim to prepare and evaluate multiphase hydrogel system incorporated with quercetin loaded liposomes (QLH), for wound healing. The quercetin loaded liposomal hydrogel were prepared by taking 15% carbopol and varying gelatin ratio. The clear and transparent hydrogel was obtained by taking ratio of gelatin to carbapol (6/4) compared to other ratios. The best prepared hydrogel were characterized for surface morphology, water vapor transmission rate (WVTR), swelling ratio, hemocompatibility, stability, in-vitro release and in-vivo studies. The evaluated results of (QLH) for surface morphology, WVTR, swelling ratio, hemocompatibility and in-vitro release were found to be significant compared to other prepared formulations. Consequently, on basis of optimized hydrogel was selected to study wound healing activity in albino rats. The results demonstrated accelerated wound-healing with significant decrease in wound closure time compared to conventional dosage form. The results of in-vitro and in-vivo promises reliable mode of treatment for connective tissue disorder as wound healing. Copyright © 2018. Published by Elsevier B.V.

Redox-responsive microbeads containing thiolated pectin-doxorubicin conjugate inhibit tumor growth and metastasis: An in vitro and in vivo study.

PubMed

Cheewatanakornkool, Kamonrak; Niratisai, Sathit; Dass, Crispin R; Sriamornsak, Pornsak

2018-07-10

The objective of this study was to investigate the in vitro cytotoxicity and in vivo anticancer efficacy of redox-responsive microbeads containing thiolated pectin-doxorubicin (DOX) conjugate. Oral microbeads were coated with an enteric polymer to protect the drug from release in the upper gastrointestinal (GI) tract and allow redox-triggered drug release in the colon. Morphology, particle size, drug content, and in vitro drug release behavior of the microbeads were characterized; in vitro cytotoxicity was tested on mouse colon carcinoma, human colorectal adenocarcinoma, and human bone osteosarcoma cell lines. In vivo anticancer efficacy of coated microbeads was examined in BALB/c mice with murine colon carcinoma. These coated microbeads significantly inhibited the growth of all cell lines. The in vivo study confirmed delivery of DOX to the colorectal tumor site, redox-responsiveness, and anticancer efficacy of coated microbeads. Coated microbeads also effectively inhibited primary tumor growth and suppressed tumor metastases without gross toxicity to the non-target tissue. No noticeable damage was found in mouse GI tissues, indicating lack of DOX toxicity. These novel coated microbeads containing thiolated pectin-DOX conjugate may be a promising vehicle for targeted clinical delivery of DOX to the colorectal cancer site by oral administration. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

Polycaprolactone nanofibres loaded with 20(S)-protopanaxadiol for in vitro and in vivo anti-tumour activity study

PubMed Central

Liu, Dan-qing; Cheng, Zhi-qiang; Feng, Qing-jie; Li, He-jie; Ye, Shu-feng

2018-01-01

In this work, 20(S)-protopanaxadiol (PPD)-loaded polycaprolactone (PCL) nanofibres were successfully fabricated by the electrospinning technique using Tween 80 as a solubilizer. Firstly, smooth and continuous nanofibres were collected using suitable solvents and appropriate spinning conditions. Secondly, nanofibre mats were characterized by scanning electron microscopy, thermogravimetric (TG) analysis, Fourier transform infrared spectroscopy and mechanical testing. Finally, nanofibrous membranes were evaluated using water contact angle, in vitro drug release, biodegradation test, in vitro and in vivo anti-tumour activity and cell apoptosis assay. Scanning electron microscopic observations indicated that the diameter of the drug-loaded nanofibres increased with the increase of drug concentration. TG analysis and mechanical test showed that nanofibres were equipped with great thermal and mechanical properties. Biodegradation test exhibited that the structure of fabricated nanofibres had a certain degree of change after 15 days. An in vitro release study showed that PPD from drug-loaded nanofibres could be released in a sustained and prolonged mode. The cytotoxic effect of drug-loaded nanofibre mats examined on human laryngeal carcinoma cells (Hep-2 cells) demonstrated that the prepared nanofibres had a remarkable anti-tumour effect. Meanwhile, the drug-loaded fibre mats showed a super anti-tumour effect in an in vivo anti-tumour study. All in all, PCL nanofibres could be a potential carrier of PPD for cancer treatment. PMID:29892448

Nanoencapsulation of dietary flavonoid fisetin: Formulation and in vitro antioxidant and α-glucosidase inhibition activities.

PubMed

Sechi, Mario; Syed, Deeba N; Pala, Nicolino; Mariani, Alberto; Marceddu, Salvatore; Brunetti, Antonio; Mukhtar, Hasan; Sanna, Vanna

2016-11-01

The bioactive flavonoid fisetin (FS) is a diet-derived antioxidant that is being increasingly investigated for its health-promoting effects. Unfortunately, the poor physicochemical and pharmacokinetic properties affect and limit the clinical application. In this study, novel polymeric nanoparticles (NPs), based on Poly-(ε-caprolactone) (PCL) and PLGA-PEG-COOH, encapsulating FS were formulated as suitable oral controlled release systems. Results showed NPs having a mean diameter of 140-200nm, and a percent loading of FS ranging from 70 to 82%. In vitro release studies revealed that NPs are able to protect and preserve the release of FS in gastric simulated conditions, also controlling the release in the intestinal medium. Moreover, the DPPH and ABTS scavenging capacity of FS, as well as α-glucosidase inhibition activity, that resulted about 20-fold higher than commercial Acarbose, were retained during nanoencapsulation process. In summary, our developed NPs can be proposed as an attractive delivery system to control the release of antioxidant and anti-hyperglycemic FS for nutraceutical and/or therapeutic application. Copyright © 2016 Elsevier B.V. All rights reserved.

Externally controlled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers.

PubMed

Nair, Madhavan; Guduru, Rakesh; Liang, Ping; Hong, Jeongmin; Sagar, Vidya; Khizroev, Sakhrat

2013-01-01

Although highly active anti-retroviral therapy has resulted in remarkable decline in the morbidity and mortality in AIDS patients, inadequately low delivery of anti-retroviral drugs across the blood-brain barrier results in virus persistence. The capability of high-efficacy-targeted drug delivery and on-demand release remains a formidable task. Here we report an in vitro study to demonstrate the on-demand release of azidothymidine 5'-triphosphate, an anti-human immunodeficiency virus drug, from 30 nm CoFe2O4@BaTiO3 magneto-electric nanoparticles by applying a low alternating current magnetic field. Magneto-electric nanoparticles as field-controlled drug carriers offer a unique capability of field-triggered release after crossing the blood-brain barrier. Owing to the intrinsic magnetoelectricity, these nanoparticles can couple external magnetic fields with the electric forces in drug-carrier bonds to enable remotely controlled delivery without exploiting heat. Functional and structural integrity of the drug after the release was confirmed in in vitro experiments with human immunodeficiency virus-infected cells and through atomic force microscopy, spectrophotometry, Fourier transform infrared and mass spectrometry studies.

Regulating Drug Release Behavior and Kinetics from Matrix Tablets Based on Fine Particle-Sized Ethyl Cellulose Ether Derivatives: An In Vitro and In Vivo Evaluation

PubMed Central

Shah, Kifayat Ullah; Khan, Gul Majid

2012-01-01

The design and fabrication of sustained/controlled release dosage forms, employing new excipients capable of extending/controlling the release of drugs from the dosage forms over prolonged periods, has worked well in achieving optimally enhanced therapeutic levels of the drugs. In this sense, the objective of this study was to investigate the suitability of selected cellulose ether derivatives for use in direct compression (DC) and as efficient drug release controlling agents. Controlled release matrix tablets of ciprofloxacin were prepared at different drug-to-polymer (D : P) ratios by direct compression using a fine particle sized ethylcellulose ether derivative (ETHOCEL Standard Premium 7FP) as rate controlling polymer. The tablets obtained were evaluated for various physico-chemical characteristics and in-vitro drug release studies were conducted in phosphate buffer (pH 7.4) using PharmaTest dissolution apparatus at constant temperature of 37°C ± 0.1. Similarity factor f 2 was employed to the release profiles of test formulations and were compared with marketed ciprofloxacin conventional tablets. Drug release mechanism and the kinetics involved were investigated by fitting the release profile data to various kinetic models. It was found that with increasing the proportion of ethylcellulose ether derivative in the matrix, the drug release was significantly extended up to 24 hours. The tablets exhibited zero order or nearly zero order drug transport mechanism. In vivo drug release performance of the developed controlled release tablets and reference conventional tablets containing ciprofloxacin were determined in rabbit serum according to randomized two-way crossover study design using High Performance Liquid Chromatography. Several bioavailability parameters of both the test tablets and conventional tablets including C max⁡, T max⁡ and AUC0-t were compared which showed an optimized C max⁡ and T max⁡ (P < 0.05). A good correlation was obtained between in vitro drug release and in vivo drug absorption with correlation value (R 2 = 0.934). Relative bioavailability was found to be 93%. Reproducibility of manufacturing process and accelerated stability of the developed tablets were performed in stability chamber at 40 ± 2°C and 75 ± 5% relative humidity for a period of 6 months and were found to be stable throughout the stability period. PMID:22649325

A novel automated alternating current biosusceptometry method to characterization of controlled-release magnetic floating tablets of metronidazole.

PubMed

Ferrari, Priscileila Colerato; dos Santos Grossklauss, Dany Bruno Borella; Alvarez, Matheus; Paixão, Fabiano Carlos; Andreis, Uilian; Crispim, Alexandre Giordano; de Castro, Ana Dóris; Evangelista, Raul Cesar; de Arruda Miranda, José Ricardo

2014-08-01

Alternating Current Biosusceptometry is a magnetically method used to characterize drug delivery systems. This work presents a system composed by an automated ACB sensor to acquire magnetic images of floating tablets. The purpose of this study was to use an automated Alternating Current Biosusceptometry (ACB) to characterize magnetic floating tablets for controlled drug delivery. Floating tablets were prepared with hydroxypropyl methylcellulose (HPMC) as hydrophilic gel material, sodium bicarbonate as gas-generating agent and ferrite as magnetic marker. ACB was used to characterize the floating lag time and the tablet hydration rate, by quantification of the magnetic images to magnetic area. Besides the buoyancy, the floating tablets were evaluated for weight uniformity, hardness, swelling and in vitro drug release. The optimized tablets were prepared with equal amounts of HPMC and ferrite, and began to float within 4 min, maintaining the flotation during more than 24 h. The data of all physical parameters lied within the pharmacopeial limits. Drug release at 24 h was about 40%. The ACB results showed that this study provided a new approach for in vitro investigation of controlled-release dosage forms. Moreover, using automated ACB will also be possible to test these parameters in humans allowing to establish an in vitro.in vivo correlation (IVIVC).

Optimization of gatifloxacin liposomal hydrogel for enhanced transcorneal permeation.

PubMed

Hosny, Khaled Mohamed

2010-03-01

The aim of this study was to prepare and characterize a topically effective prolonged-release ophthalmic gatifloxacin liposomal hydrogel formulation. Reverse-phase evaporation was used for the preparation of liposomes consisting of phosphatidylcholine (PC) and cholesterol (CH). The effect of PC:CH molar ratio on the percentage of drug encapsulated was investigated. The effect of additives, such as stearylamine (SA) or dicetyl phosphate (DP), as positive and negative charge inducers, respectively, was studied. Morphology, mean size, encapsulation efficiency, and in vitro release of gatifloxacin from liposomes were evaluated. For hydrogel preparation, carbopol 940 was applied. In vitro transcorneal permeation through excised albino rabbit cornea was also determined. Optimal encapsulation efficiency was found at the 5:3 PC:CH molar ratio; by increasing CH content above this limit, the encapsulation efficiency decreased. Positively charged liposomes showed superior entrapment efficiency over other liposomes. Hydrogel-containing liposomes with lipid content PC, CH, and SA in a molar ratio of 5:3:1, respectively, showed best release and transcorneal permeation. These results suggest that the encapsulation of gatifloxacin into liposomes prolonged the in vitro release, depending on composition of the vesicles. In addition, the polymer hydrogel used in the preparation ensured steady, prolonged transcorneal permeation. In conclusion, gatifloxacin liposomal hydrogel is a suitable delivery system for the improvement of the ocular bioavailability of gatifloxacin.

Innovation of novel 'Tab in Tab' system for release modulation of milnacipran HCl: optimization, formulation and in vitro investigations.

PubMed

Parejiya, Punit B; Barot, Bhavesh S; Patel, Hetal K; Shelat, Pragna K; Shukla, Arunkumar

2013-11-01

The study was aimed toward development of modified release oral drug delivery system for highly water soluble drug, Milnacipran HCl (MH). Novel Tablet in Tablet system (TITs) comprising immediate and extended release dose of MH in different parts was fabricated. The outer shell was composed of admixture of MH, lactose and novel herbal disintegrant obtained from seeds of Lepidium sativum. In the inner core, MH was matrixed with blend of hydrophilic (Benecel®) and hydrophobic (Compritol®) polymers. 3² full factorial design and an artificial neuron network (ANN) were employed for correlating effect of independent variables on dependent variables. The TITs were characterized for pharmacopoeial specifications, in vitro drug release, SEM, drug release kinetics and FTIR study. The release pattern of MH from batch A10 containing 25.17% w/w Benecel® and 8.21% w/w of Compritol® exhibited drug release pattern close proximal to the ideal theoretical profile (t(50%) = 5.92 h, t(75%) = 11.9 h, t(90%) = 18.11 h). The phenomenon of drug release was further explained by concept of percolation and the role of Benecel® and Compritol® in drug release retardation was studied. The normalized error obtained from ANN was less, compared with the multiple regression analysis, and exhibits the higher accuracy in prediction. The results of short-term stability study revealed stable chataracteristics of TITs. SEM study of TITs at different dissolution time points confirmed both diffusion and erosion mechanisms to be operative during drug release from the batch A10. Novel TITs can be a succesful once a day delivery system for highly water soluble drugs.

The release profiles of intact and enzymatically digested hyaluronic acid from semisolid formulations using multi-layer membrane system.

PubMed

Alkrad, Jamal Alyoussef; Mrestani, Yahya; Neubert, Reinhard H H

2003-07-01

A multi-layer membrane system was used to measure in vitro release of hydrophilic macromolecules such as hyaluronic acid (HA) from semisolid formulations. One enzymatically digested HA-derivative with molecular mass of 22 kDa (HA-D) and 1200 kDa intact HA (HA) were incorporated into three semisolid formulations: water-containing hydrophilic ointment (WHO), amphiphilic cream (AC) and water-containing wool wax alcohol ointment (WWO). Because of the high hydrophilic properties of HA-D and HA, the artificial model membranes consisted of collodion as the matrix and glycerol as the hydrophilic acceptor phase. The area under the concentration-time curve and the mean dissolution time were used as a quantitative parameter to characterise the rate and extent of release in vitro. This study showed that the HA-D and HA release as hydrophilic substances from WHO was higher than both from AC and WWO. It was observed that 83% of HA-D1 was released from WHO after 2 h; in contrast, only 10% was released from 2% HA from the same vehicle during the same time. In conclusion, the in vitro availability of enzymatically digested HA-D was higher for WHO than for the other formulations, AC and WWO. Similarly, the availability of HA-D was higher than that of HA from the same formulations.

In Vitro Release and Bioavailability of Silybin from Micelle-Templated Porous Calcium Phosphate Microparticles.

PubMed

Zhu, Yuan; Wang, Miaomiao; Zhang, Ya; Zeng, Jin; Omari-Siaw, E; Yu, Jiangnan; Xu, Ximing

2016-10-01

Developing a promising carrier for the delivery of poorly water-soluble drugs, such as silybin, to improve oral absorption has become a very worthy of consideration. The goal of this study was to prepare a novel porous calcium phosphate microparticle using povidone-mixed micelles as template while evaluating its in vitro and in vivo properties with silybin as a model drug. The particle characterization, in vitro drug release behavior, and pharmacokinetic parameters of the prepared silybin-loaded calcium phosphate microparticle were investigated. The mean particle size was found to be 3.54 ± 0.32 μm with a rough surface porous structure. Additionally, the silybin-loaded calcium phosphate microparticle compared with the free silybin showed a prolonged 72-h release in vitro and a higher C max (418.5 ± 23.7 ng mL(-1)) with 167.5% oral relative bioavailability. A level A in vitro-in vivo correlation (IVIVC), established for the first time, demonstrated an excellent IVIVC of the formulated silybin in oral administration. In conclusion, this povidone-mixed micelle-based microparticle was successfully prepared to enhance the oral bioavailability of silybin. Therefore, application of this novel porous calcium phosphate microparticle holds a significant potential for the development of poorly water-soluble drugs.

The effect of orthodontic bonding materials on dental plaque accumulation and composition in vitro.

PubMed

Badawi, H; Evans, R D; Wilson, M; Ready, D; Noar, J H; Pratten, J

2003-08-01

The aim of this study was to investigate the accumulation and composition of microcosm dental plaque on different orthodontic bonding materials using an in vitro model. Microcosm plaques were grown on discs of a range of bonding materials in a constant depth film fermentor. The biofilms were derived from human saliva and supplied with artificial saliva as a source of nutrients. The number of viable bacteria in the biofilms was determined and the streptococci present were identified to species level. The results showed that there was no significant difference in bacterial accumulation between different bonding materials, however, biofilms grown on materials which were fluoride releasing, did not contain Streptococcus mutans. This in vitro study has shown that the use of fluoride-releasing bonding materials may support the growth of supragingival plaque, which does not contain S. mutans.

Vincristine-sulphate-loaded liposome-templated calcium phosphate nanoshell as potential tumor-targeting delivery system.

PubMed

Thakkar, Hetal Paresh; Baser, Amit Kumar; Parmar, Mayur Prakashbhai; Patel, Ketul Harshadbhai; Ramachandra Murthy, Rayasa

2012-06-01

Vincristine-sulfate-loaded liposomes were prepared with an aim to improve stability, reduce drug leakage during systemic circulation, and increase intracellular uptake. Liposomes were prepared by the thin-film hydration method, followed by coating with calcium phosphate, using the sequential addition approach. Prepared formulations were characterized for size, zeta potential, drug-entrapment efficiency, morphology by transmission electron microscopy (TEM), in vitro drug-release profile, and in vitro cell cytotoxicity study. Effect of formulation variables, such as drug:lipid ratio as well as nature and volume of hydration media, were found to affect drug entrapment, and the concentration of calcium chloride in coating was found to affect size and coating efficiency. Size, zeta potential, and TEM images confirmed that the liposomes were effectively coated with calcium phosphate. The calcium phosphate nanoshell exhibited pH-dependent drug release, showing significantly lower release at pH 7.4, compared to the release at pH 4.5, which is the pH of the tumor interstitium. The in vitro cytotoxicity study done on the lung cancer cell line indicated that coated liposomes are more cytotoxic than plain liposomes and drug solution, indicating their potential for intracellular drug delivery. The cell-uptake study done on the lung cancer cell line indicated that calcium-phosphate-coated liposomes show higher cell uptake than uncoated liposomes.

Development and characterization of novel hydrogel containing antimicrobial drug for treatment of burns

PubMed Central

Thakkar, Vaishali; Korat, Vaishali; Baldaniya, Lalji; Gohel, Mukesh; Gandhi, Tejal; Patel, Nirav

2016-01-01

Introduction: The aim of burn management and therapy is fast healing and epithelisation to prevent infection. The present study is concerned with the development and characterization of a novel nanaoparticulate system; cubosomes, loaded with silver sulfadiazine (SSD) and Aloe vera for topical treatment of infected burns. Methods: Cubosome dispersions were formulated by an emulsification technique using different concentrations of a lipid phase Glyceryl Monooleate (GMO) and Poloxamer 407. The optimum formulae were incorporated in an aloe vera gel containing carbopol 934, to form cubosomal hydrogels (cubogels). The cubogels were characterized by in vitro release of SSD, rheological properties, pH, bioadhesion, Transmission Electron Microscopy and in-vivo Wound Healing Study. Results: The results show that the different concentration of GMO had significant effect on particle size, % EE and in vitro drug release. From the in-vitro drug release pattern and similarity factor (f2), it was concluded that batch CG3 (15% GMO and 1% P407) exhibited complete and controlled drug release within 12 hour (i.e. 98.25%), better bio adhesion and superior burn healing as compared to the marketed product. Conclusion: The in vivo burns healing study in rats revealed that the prepared optimized cubogel containing SSD and aloe vera has superior burns healing rate than cubogel with only SSD and marketed preparation so, it may be successfully used in the treatment of deep second degree burn. PMID:27606259

Development and characterization of novel hydrogel containing antimicrobial drug for treatment of burns.

PubMed

Thakkar, Vaishali; Korat, Vaishali; Baldaniya, Lalji; Gohel, Mukesh; Gandhi, Tejal; Patel, Nirav

2016-01-01

The aim of burn management and therapy is fast healing and epithelisation to prevent infection. The present study is concerned with the development and characterization of a novel nanaoparticulate system; cubosomes, loaded with silver sulfadiazine (SSD) and Aloe vera for topical treatment of infected burns. Cubosome dispersions were formulated by an emulsification technique using different concentrations of a lipid phase Glyceryl Monooleate (GMO) and Poloxamer 407. The optimum formulae were incorporated in an aloe vera gel containing carbopol 934, to form cubosomal hydrogels (cubogels). The cubogels were characterized by in vitro release of SSD, rheological properties, pH, bioadhesion, Transmission Electron Microscopy and in-vivo Wound Healing Study. The results show that the different concentration of GMO had significant effect on particle size, % EE and in vitro drug release. From the in-vitro drug release pattern and similarity factor (f2), it was concluded that batch CG3 (15% GMO and 1% P407) exhibited complete and controlled drug release within 12 hour (i.e. 98.25%), better bio adhesion and superior burn healing as compared to the marketed product. The in vivo burns healing study in rats revealed that the prepared optimized cubogel containing SSD and aloe vera has superior burns healing rate than cubogel with only SSD and marketed preparation so, it may be successfully used in the treatment of deep second degree burn.

Formulation and characterization of modified release tablets containing isoniazid using swellable polymers.

PubMed

Akhtar, M F; Rabbani, M; Sharif, A; Akhtar, B; Saleem, A; Murtaza, G

2011-01-01

The aim of this work was to develop swellable modified release (MR) isoniazid tablets using different combinations of polyvinyl acetate (PVAc) and sodium-carboxymethylcellulose (Na-CMC). Granules were prepared by moist granulation technique and then compressed into tablets. In vitro release studies for 12 hr were carried out in dissolution media of varying pH i.e. pH 1.2, 4.5, 7.0 and 7.5. Tablets of all formulations were found to be of good physical quality with respect to appearance (width and thickness), content uniformity, hardness, weight variation and friability. In vitro release data showed that increasing total polymer content resulted in more retarding effect. Formulation with 35% polymer content exhibited zero order release profile and it released 35% of the drug in first hr, later on, controlled drug release was observed upto the 12(th) hour. Formulations with PVAc to Na-CMC ratio 20:80 exhibited zero order release pattern at levels of studied concentrations, which suggested that this combination can be used to formulate zero order release tablets of water soluble drugs like isoniazid. Korsmeyer-Peppas modeling of drug release showed that non-Fickian transport is the primary mechanism of isoniazid release from PVAc and Na-CMC based tablets. The value of mean dissolution time decreased with the increase in the release rate of drug clearly showing the retarding behavior of the swellable polymers. The application of a mixture of PVAc to Na-CMC in a specific ratio may be feasible to formulate zero order release tablets of water soluble drugs like isoniazid.

Pharmacokinetics of ketorolac tromethamine compression-coated tablets for colon delivery.

PubMed

Vemula, Sateesh Kumar; Veerareddy, Prabhakar Reddy; Devadasu, Venkat Ratnam

2014-08-01

Present research efforts are focused in developing compression-coated ketorolac tromethamine tablets to improve the drug levels in colon by retarding the drug release in the stomach and small intestine. To achieve this objective, core tablets containing ketorolac tromethamine were prepared by direct compression and compression coated with sodium alginate. The developed tablets were evaluated for physical properties, in vitro drug release, X-ray imaging, and pharmacokinetic studies in human volunteers. Based on the in vitro drug release study, the optimized formulation showed very little drug release (6.75 ± 0.49 %) in the initial lag period of 5 h, followed by progressive release up to 97.47 ± 0.93 % within 24 h. The X-ray imaging of tablets in human volunteers showed that the tablets reached the colon without disintegrating in the upper gastrointestinal tract. From the pharmacokinetic study, the C max of colon-targeted tablets was 3,486.70 ng/ml at T max 10 h, whereas in the case of immediate-release tablets, the C max of 4,506.31 ng/ml at T max 2 h signifies the ability of compression-coated tablets to target the colon. In conclusion, compression-coated tablets are suitable to deliver ketorolac tromethamine to the colon.

Studies on applicability of press-coated tablets using hydroxypropylcellulose (HPC) in the outer shell for timed-release preparations.

PubMed

Fukui, E; Uemura, K; Kobayashi, M

2000-08-10

Press-coated tablets, containing diltiazem hydrochloride (DIL) in the core tablet and coated with hydroxypropylcellulose (HPC) as the outer shell, were examined for applicability as timed-release tablets with a predetermined lag time and subsequent rapid drug release phase. Various types of press-coated tablets were prepared using a rotary tabletting machine and their DIL dissolution behavior was evaluated by the JP paddle method. The results indicated that tablets with the timed-release function could be prepared, and that the lag times were prolonged as the viscosity of HPC and the amount of the outer shell were increased. The lag times could be controlled widely by the above method, however, the compression load had little effect. Two different kinds of timed-release press-coated tablets that showed lag times of 3 and 6 h in the in vitro test (denoted PCT(L3) and PCT(L6), respectively) were administered to beagle dogs. DIL was first detected in the plasma more than 3 h after administration, and both tablets showed timed-release. The lag times showed a good agreement between the in vivo and in vitro tests in PCT(L3). However, the in vivo lag times were about 4 h in PCT(L6) and were much shorter than the in vitro lag time. The dissolution test was performed at different paddle rotation speeds, and good agreement was obtained between the in vivo and in vitro lag times at 150 rpm. This suggested that the effects of gastrointestinal peristalsis and contraction should also be taken into consideration for the further development of drug delivery systems.

QbD-Oriented Development and Characterization of Effervescent Floating-Bioadhesive Tablets of Cefuroxime Axetil.

PubMed

Bansal, Sanjay; Beg, Sarwar; Garg, Babita; Asthana, Abhay; Asthana, Gyati S; Singh, Bhupinder

2016-10-01

The objective of the present studies was systematic development of floating-bioadhesive gastroretentive tablets of cefuroxime axetil employing rational blend of hydrophilic polymers for attaining controlled release drug delivery. As per the QbD-based approach, the patient-centric target product profile and quality attributes of tablet were earmarked, and preliminary studies were conducted for screening the suitability of type of polymers, polymer ratio, granulation technique, and granulation time for formulation of tablets. A face-centered cubic design (FCCD) was employed for optimization of the critical material attributes, i.e., concentration of release controlling polymers, PEO 303 and HPMC K100 LV CR, and evaluating in vitro buoyancy, drug release, and ex vivo mucoadhesion strength. The optimized formulation was embarked upon through numerical optimization, which yield excellent floatation characteristic with drug release control (i.e., T 60% > 6 h) and bioadhesion strength. Drug-excipient compatibility studies through FTIR and P-XRD revealed the absence of any interaction between the drug and polymers. In vivo evaluation of the gastroretentive characteristics through X-ray imaging and in vivo pharmacokinetic studies in rabbits revealed significant extension in the rate of drug absorption (i.e., T max, K a, and MRT) from the optimized tablet formulation as compared to the marketed formulation. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC) substantiated high degree of prognostic ability of in vitro dissolution conditions in predicting the in vivo performance. In a nutshell, the studies demonstrate successful development of the once-a-day gastroretentive formulations of cefuroxime axetil with controlled drug release profile and improved compliance.

Albumin nanoparticles coated with polysorbate 80 as a novel drug carrier for the delivery of antiretroviral drug—Efavirenz

PubMed Central

Jenita, Josephine Leno; Chocalingam, Vijaya; Wilson, Barnabas

2014-01-01

Purpose of the study: The antiretroviral therapy (ART) has dramatically improved human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) treatment, prevention and also has been found to increase the lifespan of HIV/AIDS patients by providing durable control of the HIV replication in patients. Efavirenz is a non-nucleoside reverse transcriptase inhibitor of HIV-1. The purpose of this study is to formulate efavirenz-loaded bovine serum albumin nanoparticles to improve efavirenz delivery into various organs. Materials and Methods: Nanoparticles were prepared by desolvation technique and coated with polysorbate 80. Ethanol, glutaraldehyde, and mannitol were used as desolvating, cross linking agent, and cryoprotectant, respectively. Drug to polymer ratio was chosen at five levels from 1:2, 1:3, 1:4, 1:5, and 1:6 (by weight). The formulated nanoparticles were characterized for Fourier Transform Infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) studies, entrapment efficiency, particle size, surface charge, surface morphology, in vitro drug release, release kinetics, stability studies, and biodistribution studies. Results and Major Conclusion: The particle size of the prepared formulations was found below 250nm with narrow size distribution, spherical in shape and showed good entrapment efficiency (45.62-72.49%). The in vitro drug release indicated biphasic release and its data were fitted to release kinetics models and release pattern was Fickian diffusion controlled release profile. The prepared nanoparticles increased efavirenz delivery into various organs by several fold in comparison with the free drug. PMID:25126528

Superporous hybrid hydrogels based on polyacrylamide and chitosan: Characterization and in vitro drug release

PubMed Central

Nagpal, Manju; Singh, Shailendra Kumar; Mishra, Dinanath

2013-01-01

Objective: Current research was aimed at the development of the drug delivery systems based on the superporous hydrogels (SPH) with the desired swelling and the mechanical properties. Materials and Methods: Superporous hydrogel composites (SPHCs) and superporous hybrid hydrogels (SPHHs) based on the chitosan and the polyacrylamide were synthesized using the gas blowing technique. The prepared hydrogels were evaluated for swelling studies, mechanical strength and scanning electron microscopy. The selected hydrogels were loaded with the drug (verapamil hydrochloride) by aqueous loading method. Drug integrity with in polymeric network was evaluated via fourier transform infrared spectroscopy (FTIR), X-ray diffraction (X-RD), differential scanning calorimetry (DSC), proton nuclear magnetic resonance (1HNMR) studies. In vitro drug release studies were carried out using the united state pharmacopoeial (USP) dissolution apparatus (type II). Results and Discussion: The mechanical strength was observed to be higher in SPH hybrids in comparison to that in SPHCs while no significant difference was observed in swelling behavior. In situ crosslinking of chitosan with glutaraldehyde (GA) may be responsible for high mechanical strength. The equilibrium swelling time was slight higher in SPHH than in SPHCs. The integrity of pores was maintained in ethanol treated hydrogels as observed in scanning electron micrographs. Whereas, freeze dried SPH samples showed non-uniform pores. No drug polymer interaction was observed as indicated by DSC, FTIR, X-RD and NMR studies. However, the crosslinking of chitosan with GA was clearly indicated by these studies. The in vitro drug release studies from SPH hybrids indicated initial fast release (65%) with in first 2 h and then sustained release at the end of 24 h (95%). The addition of hydroxypropyl methyl cellulose with drug; however, leads to a significant decrease in drug release (56% at the end of 24 h). Conclusion: Superporous hybrid hydrogels can be promising devices for the sustained delivery of drug candidates to the gastrointestinal region. PMID:24015380

Effects of gentamicin and monomer on bone. An in vitro study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pedersen, J.G.; Lund, B.

1988-01-01

Gentamicin-loaded bone cement is used with increasing frequency in primary and revision arthroplasty. Considering the high local concentration and the well-known toxic effect of gentamicin on the kidney, a similar inhibiting effect on bone tissue might be expected. In a series of in vitro studies using paired mouse calvaries cultured for 2 days, the authors found a dose-dependent decrease in the release of previously incorporated calcium-45 (UVCa) or tritiated proline and a decrease in alkaline phosphatase activity. In combination with methylmethacrylate, a small additional reduction in UVCa release and a marked decrease in alkaline phosphatase activity were recorded. These resultsmore » indicate that released gentamicin and monomer from antibiotic-supplemented bone cement depresses bone turnover and might thus play an important part in the pathogenesis of loosening.« less

[In vitro evaluation of the gels properties prepared thermosensitive polymers as vehicles for administration substance by injection].

PubMed

Karolewicz, Bozena; Owczarek, Artur; Pluta, Janusz

2011-01-01

The aim of this study was to prepare a thermoresponsive formulations, which are a carrier for substance administered directly into site of action and which obtain sol-gel transitions at physiological ranges of temperature. The investigated formulations of liquid consistency at room temperature were obtained in sterile conditions on the basis of nonionic polymers Pluronic F-127, Pluronic F-68 and anionic polymer hyaluronic acid in different concentrations. The sol-gel transition temperature of the formulations was investigated and their physicochemical properties such as pH, density, osmotic pressure, sol-gel transition temperature, texture and release of vancomycin hydrochloride were studied. In vitro release experiments indicated that the optimised platform was able to prolong vancomycin hydrochloride release and their physico-chemical properties allow for application by injection form.

Modelling Simple Experimental Platform for In Vitro Study of Drug Elution from Drug Eluting Stents (DES)

NASA Astrophysics Data System (ADS)

Kalachev, L. V.

2016-06-01

We present a simple model of experimental setup for in vitro study of drug release from drug eluting stents and drug propagation in artificial tissue samples representing blood vessels. The model is further reduced using the assumption on vastly different characteristic diffusion times in the stent coating and in the artificial tissue. The model is used to derive a relationship between the times at which the measurements have to be taken for two experimental platforms, with corresponding artificial tissue samples made of different materials with different drug diffusion coefficients, to properly compare the drug release characteristics of drug eluting stents.

Biodegradable drug-eluting nanofiber-enveloped implants for sustained release of high bactericidal concentrations of vancomycin and ceftazidime: in vitro and in vivo studies

PubMed Central

Hsu, Yung-Heng; Chen, Dave Wei-Chih; Tai, Chun-Der; Chou, Ying-Chao; Liu, Shih-Jung; Ueng, Steve Wen-Neng; Chan, Err-Cheng

2014-01-01

We developed biodegradable drug-eluting nanofiber-enveloped implants that provided sustained release of vancomycin and ceftazidime. To prepare the biodegradable nanofibrous membranes, poly(D,L)-lactide-co-glycolide and the antibiotics were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. They were electrospun into biodegradable drug-eluting membranes, which were then enveloped on the surface of stainless plates. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vivo and in vitro release rates of the antibiotics from the nanofiber-enveloped plates. The results showed that the biodegradable nanofiber-enveloped plates released high concentrations of vancomycin and ceftazidime (well above the minimum inhibitory concentration) for more than 3 and 8 weeks in vitro and in vivo, respectively. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The bioactivity ranged from 25% to 100%. In addition, the serum creatinine level remained within the normal range, suggesting that the high vancomycin concentration did not affect renal function. By adopting the electrospinning technique, we will be able to manufacture biodegradable drug-eluting implants for the long-term drug delivery of different antibiotics. PMID:25246790

Capsule shell material impacts the in vitro disintegration and dissolution behaviour of a green tea extract☆

PubMed Central

Glube, Natalie; Moos, Lea von; Duchateau, Guus

2013-01-01

Purpose In vitro disintegration and dissolution are routine methods used to assess the performance and quality of oral dosage forms. The purpose of the current work was to determine the potential for interaction between capsule shell material and a green tea extract and the impact it can have on the release. Methods A green tea extract was formulated into simple powder-in-capsule formulations of which the capsule shell material was either of gelatin or HPMC origin. The disintegration times were determined together with the dissolution profiles in compendial and biorelevant media. Results All formulations disintegrated within 30 min, meeting the USP criteria for botanical formulations. An immediate release dissolution profile was achieved for gelatin capsules in all media but not for the specified HPMC formulations. Dissolution release was especially impaired for HPMCgell at pH 1.2 and for both HPMC formulations in FeSSIF media suggesting the potential for food interactions. Conclusions The delayed release from studied HPMC capsule materials is likely attributed to an interaction between the catechins, the major constituents of the green tea extract, and the capsule shell material. An assessment of in vitro dissolution is recommended prior to the release of a dietary supplement or clinical trial investigational product to ensure efficacy. PMID:25755998

Capsule shell material impacts the in vitro disintegration and dissolution behaviour of a green tea extract.

PubMed

Glube, Natalie; Moos, Lea von; Duchateau, Guus

2013-01-01

In vitro disintegration and dissolution are routine methods used to assess the performance and quality of oral dosage forms. The purpose of the current work was to determine the potential for interaction between capsule shell material and a green tea extract and the impact it can have on the release. A green tea extract was formulated into simple powder-in-capsule formulations of which the capsule shell material was either of gelatin or HPMC origin. The disintegration times were determined together with the dissolution profiles in compendial and biorelevant media. All formulations disintegrated within 30 min, meeting the USP criteria for botanical formulations. An immediate release dissolution profile was achieved for gelatin capsules in all media but not for the specified HPMC formulations. Dissolution release was especially impaired for HPMCgell at pH 1.2 and for both HPMC formulations in FeSSIF media suggesting the potential for food interactions. The delayed release from studied HPMC capsule materials is likely attributed to an interaction between the catechins, the major constituents of the green tea extract, and the capsule shell material. An assessment of in vitro dissolution is recommended prior to the release of a dietary supplement or clinical trial investigational product to ensure efficacy.

The effects of dynamic compressive loading on biodegradable implants of 50-50% polylactic Acid-polyglycolic Acid.

PubMed

Thompson, D E; Agrawal, C M; Athanasiou, K

1996-01-01

Biodegradable implants that release growth factors or other bioactive agents in a controlled manner are investigated to enhance the repair of musculoskeletal tissues. In this study, the in vitro release characteristics and mechanical properties of a 50:50 polylactic acid/polyglycolic acid two phase implant were examined over a 6-week period under no-load conditions or under a cyclic compressive load, such as that experienced when walking slowly during rehabilitation. The results demonstrated that a cyclic compressive load significantly slows the decrease of molecular chain size during the first week, significantly increases protein release for the first 2-3 weeks, and significantly stiffens the implant for the first 3 weeks. It was also shown that protein release is initially high and steadily decreases with time until the molecular weight declines to about 20% of its original value (approximately 4 weeks). Once this threshold is reached, increased protein release, surface deformation, and mass loss occurs. This study also showed that dynamic loading and the environment in which an implant is placed affect its biodegradation. Therefore, it may be essential that in vitro degradation studies of these or similar implants include a dynamic functional environment.

Mathematical Models for Controlled Drug Release Through pH-Responsive Polymeric Hydrogels.

PubMed

Manga, Ramya D; Jha, Prateek K

2017-02-01

Hydrogels consisting of weakly charged acidic/basic groups are ideal candidates for carriers in oral delivery, as they swell in response to pH changes in the gastrointestinal tract, resulting in drug entrapment at low pH conditions of the stomach and drug release at high pH conditions of the intestine. We have developed 1-dimensional mathematical models to study the drug release behavior through pH-responsive hydrogels. Models are developed for 3 different cases that vary in the level of rigor, which together can be applied to predict both in vitro (drug release from carrier) and in vivo (drug concentration in the plasma) behavior of hydrogel-drug formulations. A detailed study of the effect of hydrogel and drug characteristics and physiological conditions is performed to gain a fundamental insight into the drug release behavior, which may be useful in the design of pH-responsive drug carriers. Finally, we describe a successful application of these models to predict both in vitro and in vivo behavior of docetaxel-loaded micelle in a pH-responsive hydrogel, as reported in a recent experimental study. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Effect of particle size of calcium phosphate based bioceramic drug delivery carrier on the release kinetics of ciprofloxacin hydrochloride: an in vitro study

NASA Astrophysics Data System (ADS)

Sasikumar, Swamiappan

2013-09-01

Hydroxyapatite (HAP) is the constituent of calcium phosphate based bone cement and it is extensively used as a bone substitute and drug delivery vehicle in various biomedical applications. In the present study we investigated the release kinetics of ciprofloxacin loaded HAP and analyzed its ability to function as a targeted and sustained release drug carrier. Synthesis of HAP was carried out by combustion method using tartaric acid as a fuel and nitric acid as an oxidizer. Powder XRD and FTIR techniques were employed to characterize the phase purity of the drug carrier and to verify the chemical interaction between the drug and carrier. The synthesized powders were sieve separated to make two different drug carriers with different particle sizes and the surface topography of the pellets of the drug carrier was imaged by AFM. Surface area and porosity of the drug carrier was carried out using surface area analyzer. The in-vitro drug release kinetics was performed in simulated body fluid, at 37.3°C. The amount of ciprofloxacin released is measured using UV-visible spectroscopy following the characteristic λ max of 278 nm. The release saturates around 450 h which indicates that it can be used as a targeted and sustained release carrier for bone infections.

Determination of the mitigating effect of colon-specific bioreversible codrugs of mycophenolic acid and aminosugars in an experimental colitis model in Wistar rats

PubMed Central

Chopade, Shakuntala Santosh; Dhaneshwar, Suneela Sunil

2018-01-01

AIM To design colon-targeted codrugs of mycophenolic acid (MPA) and aminosugars as a safer option to mycophenolate mofetil (MMF) in the management of inflammatory bowel disease. METHODS Codrugs were synthesized by coupling MPA with aminosugars (D-glucosamine and D-galactosamine) using EDCI coupling. The structures were confirmed by infrared radiation, nuclear magnetic resonance, mass spectroscopy and elemental analysis. The release profile of codrugs was extensively studied in aqueous buffers, upper gastrointestinal homogenates, faecal matter and caecal homogenates (in vitro) and rat blood (in vitro). Anti-colitic activity was assessed in 2,4,6-trinitrobezenesulfonic acid-induced colitis in Wistar rats by the estimation of various demarcating parameters. Statistical evaluation was performed by applying one-way and two-way ANOVA when compared with the disease control. RESULTS The prodrugs resisted activation in HCl buffer (pH 1.2) and stomach homogenates of rats with negligible hydrolysis in phosphate buffer (pH 7.4) and intestinal homogenates. Incubation with colon homogenates (in vitro) produced 76% to 89% release of MPA emphasizing colon-specific activation of codrugs and the release of MPA and aminosugars at the site of action. In the in vitro studies, the prodrug of MPA with D-glucosamine (MGLS) was selected which resulted in 68% release of MPA in blood. in vitro studies on MGLS revealed its colon-specific activation after a lag time of 8 h which could be ascribed to the hydrolytic action of N-acyl amidases found in the colon. The synthesized codrugs markedly diminished disease activity score and revived the disrupted architecture of the colon that was comparable to MMF but superior to MPA. CONCLUSION The significant attenuating effect of prodrugs and individual aminosugars on colonic inflammation proved that the rationale of the codrug approach is valid. PMID:29563754

The ameliorated longevity and pharmacokinetics of valsartan released from a gel system of ultradeformable vesicles.

PubMed

Ahad, Abdul; Aqil, Mohd; Kohli, Kanchan; Sultana, Yasmin; Mujeeb, Mohd

2016-09-01

The present study traces the development and characterization of the gel formulation of valsartan-loaded ultradeformable vesicles for management of hypertension. The prepared gel formulation of ultradeformable vesicles was evaluated for in vitro skin permeation, release kinetics, skin irritation, pharmacokinetics, and stability. The in vitro skin permeation study showed that the gel formulation of ultradeformable vesicles presented a flux value of 368.74 μg/cm(2)/h, in comparison to that of the traditional liposomal gel formulation, with an enhancement ratio of 26.91, through rat skin. The data for release kinetics showed that the release profile followed zero-order kinetics, and that the drug release mechanism was non-Fickian. The results of the skin irritation study demonstrated that the prepared formulation was safe, less irritant, and well-tolerated for transdermal delivery. The results of the pharmacokinetic study demonstrated that the AUC value of valsartan after transdermal administration was apparently increased. The formulation stored under a refrigerated condition showed greater stability, and results were found to be within the specification under storage conditions. It is evident from this study that the gel formulation of ultradeformable vesicles of valsartan is a promising delivery system for lipophilic drugs, and has reasonably good stability characteristics.

In vitro and in vivo drug release and antibacterial properties of the novel vancomycin-loaded bone-like hydroxyapatite/poly amino acid scaffold

PubMed Central

Cao, Zhidong; Jiang, Dianming; Yan, Ling; Wu, Jun

2017-01-01

Antibiotic-loaded carriers were developed to fill cavities and locally deliver antibiotics following implantation. However, the most commonly used antibiotic carrier, polymethyl methacrylate (PMMA), has many disadvantages including that it does not promote bone regeneration or conduction. Vancomycin-loaded bone-like hydroxyapatite/poly amino acid (V-BHA/PAA) was successfully fabricated by a homogeneous method, certified as biosafe and known to promote osteogenesis. To evaluate its drug-release features, the quantity of the vancomycin in the elution was obtained every 2 days after in vitro simulated body fluid immersion. The drug concentration in the elution was determined to obtain the drug-release curve. The in vitro drug release was a three-phase process with two release peaks. Its antibacterial activity was evaluated in vitro using an antibacterial zone assay, antibacterial inhibition, and scanning electron microscopy (SEM) observation. Scaffolds of V-BHA/PAA were implanted into a rabbit model of chronic osteomyelitis. The antibacterial activity of the material was evaluated in vivo by gross observations, X-ray, and histological and ultrastructural observations. During the first 48 h, the vancomycin release was more rapid, followed by a period of sustained slow release. Use of V-BHA/PAA could achieve relatively long-term vancomycin delivery of 38 days in vitro and 42 days in vivo. V-BHA/PAA showed a significant and consistent bactericidal effect toward both Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) in vitro and in vivo. Moreover, the bactericidal effect was stronger than that of vancomycin-loaded polymethyl meth acrylate (V-PMMA). The duration of the antibacterial effect of V-BHA/PAA toward both S. aureus and MRSA exceeded 28 days in vitro, while that of V-PMMA lasted only 14 days. The curative rate for V-BHA/PAA in the chronic osteomyelitis model was 75% for regular S. aureus and 66.67% for MRSA infection, which significantly exceeded that of V-PMMA (50% and 41.67%, respectively). Vancomycin released from the V-BHA/PAA scaffold was significantly superior to that delivered by V-PMMA. PMID:28331309

The Influence of Polyethylene Glycol Solution on the Dissolution Rate of Sustained Release Morphine.

PubMed

Hodgman, Michael; Holland, Michael G; Englich, Ulrich; Wojcik, Susan M; Grant, William D; Leitner, Erich

2016-12-01

Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations. An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations. In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG. The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.

[In vitro release of [5Met]- and [5Leu]-enkephalins from the rat brain crude synaptosomal (P2) fraction: Ca2+-dependency of K+-stimulation and effects of various drugs].

PubMed

Koida, M; Takahashi, M; Takenaga, K

1983-01-01

The rat brain P2 fraction was suspended in Krebs Ringer bicarbonate buffer containing 20 microM bacitracin and incubated at 37 degrees C for 10 min under an atmosphere of 95% O2-5% CO2. Incubation was terminated by centrifugation at 4 degrees C and 10,000 X g for 10 min. The supernatant was designated as the S1 fraction, and from the pellet, the S2 to S4 fractions were collected by repeated suspension, incubation, and centrifugation. The radioimmunoassays of each S fraction revealed the spontaneous release of [5Met]- and [5Leu]-enkephalins at the ratio of 2 to 1. The peptide contents gradually decreased from S1 to S4, but the release tended to become constant in S3 and S4. Thus, the effects of some ions and drugs on the release were compared at the stage of obtaining the S3 fraction. The release of both peptides were significantly stimulated in 50 mM KCl buffer, and the stimulatory effect appears to be dependent on Ca2+ concentration. Veratrine and A23187 were also effective stimulants of the release. On the other hand, neither spontaneous nor K+-stimulated release of enkephalins was affected by morphine (1 microM), naloxone (1 microM), kyotorphin (1 or 10 microM), and Li+ (50 mM). Similar results were obtained with the release of 3H-noradrenaline taken up in vitro by the P2 fraction. The usability of the P2 fraction as an in vitro model for the study of stimulus-coupled release of enkephalins was discussed with some limitations found herein.

Biodegradable nano-micro carrier systems for sustained pulmonary drug delivery: (I) Self-assembled nanoparticles encapsulated in respirable/swellable semi-IPN microspheres

PubMed Central

El-Sherbiny, I. M.; Smyth, H. D. C.

2012-01-01

Design of appropriate inhaled carriers with adequate aerodynamic properties, drug release, biodegradation and evasion of macrophage uptake is a major challenge for controlled release pulmonary drug delivery. In this study, PEG graft copolymerized onto N-phthaloyl chitosan (NPHCs) was synthesized then characterized using FTIR, EA, DSC and 2D-XRD. The resulting PEG-g-NPHCs copolymers were self-assembled into drug loaded nanoparticles and encapsulated in respirable/swellable sodium alginate semi-IPN hydrogel microspheres as novel biodegradable carriers for controlled release pulmonary drug delivery. The developed nano-/microspheres carrier systems were formed via spray drying followed by ionotropic crosslinking in mild aqueous medium. The size of the developed self-assembled nanoparticles and the microspheres was measured using dynamic light scattering and laser diffraction, respectively. Morphology, moisture content, in-vitro biodegradation and dynamic swelling studies were also investigated for the developed carriers. A model protein was entrapped and the in-vitro release profiles were determined in PBS, pH 7.4 at 37°C. A dry powder aerosolization study was conducted using a Next Generation Impactor (NGI). The developed microspheres had suitable aerodynamic diameters (1.02–2.63 μm) and an excellent fine particle fraction, FPF of 31.52%. The microspheres showed also a very fast initial swelling within the first 2 min and started to enzymatically degrade within the first two hours. Moreover, the microspheres entrapped up 90% of the model drug and showed promising in-vitro sustained release profiles as compared to the control formulation. PMID:20580794

Wheat germ agglutinin-conjugated chitosan-Ca-alginate microparticles for local colon delivery of 5-FU: development and in vitro characterization.

PubMed

Glavas Dodov, M; Calis, S; Crcarevska, M S; Geskovski, N; Petrovska, V; Goracinova, K

2009-11-03

The aim of this work was to prepare lectin-conjugated chitosan-Ca-alginate microparticles (MPs) loaded with acid-resistant particles of 5-fluorouracil (5-FU) for efficient local treatment of colon cancer. MPs were prepared by a novel one-step spray-drying technique and after wheat germ agglutinin (WGA) conjugation, they were characterized for size, swelling behavior, surface charge, entrapment efficiency and in vitro drug release. Prepared particles were spherical, with 6.73 microg/mg of WGA conjugated onto their surface. The size and zeta potential increased after conjugation, from 6.6 to 14.7 microm and from 9.6 to 15.3 mV, while drug encapsulation was 75.6 and 72.8%, respectively after conjugation. The swelling behavior of beads was mainly determined by properties of the cross-linked chitosan-alginate network. In vitro drug release studies carried out in simulated in vivo conditions with respect to pH, confirmed the potential of the particles to release the drug in a controlled manner. Also, the drug release was not significantly affected by WGA conjugation. The retention of biorecognitive activity of WGA after covalent coupling to MPs was confirmed by haemagglutination test. Functionalized MPs showed excessive mucoadhesiveness in vitro, due to the positive surface charge, pH-dependent swelling of the matrix and lectin-sugar recognition.

Lyophilized insulin nanoparticles prepared from quaternized N-aryl derivatives of chitosan as a new strategy for oral delivery of insulin: in vitro, ex vivo and in vivo characterizations.

PubMed

Mahjub, Reza; Radmehr, Moojan; Dorkoosh, Farid Abedin; Ostad, Seyed Naser; Rafiee-Tehrani, Morteza

2014-12-01

The purpose of this research was the development, in vitro, ex vivo and in vivo characterization of lyophilized insulin nanoparticles prepared from quaternized N-aryl derivatives of chitosan. Insulin nanoparticles were prepared from methylated N-(4-N,N-dimethylaminobenzyl), methylated N-(4 pyridinyl) and methylated N-(benzyl). Insulin nanoparticles containing non-modified chitosan and also trimethyl chiotsan (TMC) were also prepared as control. The effects of the freeze-drying process on physico-chemical properties of nanoparticles were investigated. The release of insulin from the nanoparticles was studied in vitro. The mechanism of the release of insulin from different types of nanoparticles was determined using curve fitting. The secondary structure of the insulin released from the nanoparticles was analyzed using circular dichroism and the cell cytotoxicity of nanoparticles on a Caco-2 cell line was determined. Ex vivo studies were performed on excised rat jejunum using Frantz diffusion cells. In vivo studies were performed on diabetic male Wistar rats and blood glucose level and insulin serum concentration were determined. Optimized nanoparticles with proper physico-chemical properties were obtained. The lyophilization process was found to cause a decrease in zeta potential and an increase in PdI as well as and a decrease in entrapment efficiency (EE%) and loading efficiency (LE%) but conservation in size of nanoparticles. Atomic force microscopy (AFM) images showed non-aggregated, stable and spherical to sub-spherical nanoparticles. The in vitro release study revealed higher release rates for lyophilized compared to non-lyophilized nanoparticles. Cytotoxicity studies on Caco-2 cells revealed no significant cytotoxicity for prepared nanoparticles after 3-h post-incubation but did show the concentration-dependent cytotoxicity after 24 h. The percentage of cumulative insulin determined from ex vivo studies was significantly higher in nanoparticles prepared from quaternized aromatic derivatives of chitosan. In vivo data showed significantly higher insulin intestinal absorption in nanoparticles prepared from methylated N-(4-N, N-dimethylaminobenzyl) chitosan nanoparticles compared to trimethyl chitosan. These data obtained demonstrated that as the result of optimized physico-chemical properties, drug release rate, cytotoxicity profile, ex vivo permeation enhancement and increased in vivo absorption, nanoparticles prepared from N-aryl derivatives of chitosan can be considered as valuable method for the oral delivery of insulin.

Development and optimization of enteric coated mucoadhesive microspheres of duloxetine hydrochloride using 3(2) full factorial design.

PubMed

Setia, Anupama; Kansal, Sahil; Goyal, Naveen

2013-07-01

Microspheres constitute an important part of oral drug delivery system by virtue of their small size and efficient carrier capacity. However, the success of these microspheres is limited due to their short residence time at the site of absorption. The objective of the present study was to formulate and systematically evaluate in vitro performance of enteric coated mucoadhesive microspheres of duloxetine hydrochloride (DLX), an acid labile drug. DLX microspheres were prepared by simple emulsification phase separation technique using chitosan as carrier and glutaraldehyde as a cross-linking agent. Microspheres prepared were coated with eudragit L-100 using an oil-in-oil solvent evaporation method. Eudragit L-100was used as enteric coating polymer with the aim to release the drug in small intestine The microspheres prepared were characterized by particle size, entrapment efficiency, swelling index (SI), mucoadhesion time, in vitro drug release and surface morphology. A 3(2) full factorial design was employed to study the effect of independent variables polymer-to-drug ratio (X1) and stirring speed (X2) on dependent variables, particle size, entrapment efficiency, SI, in vitro mucoadhesion and drug release up to 24 h (t24). Microspheres formed were discrete, spherical and free flowing. The microspheres exhibited good mucoadhesive property and also showed high percentage entrapment efficiency. The microspheres were able to sustain the drug release up to 24 h. Thus, the prepared enteric coated mucoadhesive microspheres may prove to be a potential controlled release formulation of DLX for oral administration.

Efficacy, pharmacokinetics, and biodistribution of thermosensitive chitosan/β-glycerophosphate hydrogel loaded with docetaxel.

PubMed

Li, Cuiyun; Ren, Shuangxia; Dai, Yu; Tian, Fengjie; Wang, Xin; Zhou, Sufeng; Deng, Shuhua; Liu, Qi; Zhao, Jie; Chen, Xijing

2014-04-01

Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/β-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development.

Oral matrix tablet formulations for concomitant controlled release of anti-tubercular drugs: design and in vitro evaluations.

PubMed

Hiremath, Praveen S; Saha, Ranendra N

2008-10-01

The aim of the present investigation was to develop controlled release (C.R.) matrix tablet formulations of rifampicin and isoniazid combination, to study the design parameters and to evaluate in vitro release characteristics. In the present study, a series of formulations were developed with different release rates and duration using hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow linear release profile with time from HPMC formulations. In case of formulations with HPC, there was an initial higher release in simulated gastric fluid (SGF) followed by zero order release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid was found to be predominantly by diffusion mechanism in case of HPMC formulations, and with HPC formulations release was due to combination of diffusion and erosion. The initial release was sufficiently higher for rifampicin from HPC thus ruling out the need to incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in all formulations. Thus, with the use of suitable polymer or polymer combinations and with the proper optimization of the processing techniques it was possible to design the C.R. formulations of rifampicin and isoniazid combination that could provide the sufficient initial release and release extension up to 24h for both the drugs despite of the wide variations in their physicochemical properties.

An overview of in vitro dissolution/release methods for novel mucosal drug delivery systems.

PubMed

Jug, Mario; Hafner, Anita; Lovrić, Jasmina; Kregar, Maja Lusina; Pepić, Ivan; Vanić, Željka; Cetina-Čižmek, Biserka; Filipović-Grčić, Jelena

2018-01-05

In vitro dissolution/release tests are an important tool in the drug product development phase as well as in its quality control and the regulatory approval process. Mucosal drug delivery systems are aimed to provide both local and systemic drug action via mucosal surfaces of the body and exhibit significant differences in formulation design, as well as in their physicochemical and release characteristics. Therefore it is not possible to devise a single test system which would be suitable for release testing of such complex dosage forms. This article is aimed to provide a comprehensive review of both compendial and noncompendial methods used for in vitro dissolution/release testing of novel mucosal drug delivery systems aimed for ocular, nasal, oromucosal, vaginal and rectal administration. Copyright © 2017 Elsevier B.V. All rights reserved.

A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling

PubMed Central

Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

2016-01-01

Background Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients’ compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. Methods The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box–Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Results and Discussion Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box–Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of amoxicillin. In vitro release study firstly indicated a three-pulse release profile of the tablet. Later the pulse tablet was found to generate the sustained release of amoxicillin in beagle dogs. Furthermore, the Simcyp® software was used to simulate the in vivo concentration time curve model of the three-pulse release tablet for amoxicillin in both human and beagle dog. The prediction by PBPK model nicely fitted the observation in human and beagle dog. Conclusions This study has demonstrated the interrelation of factors affecting the pulsatile formulation of amoxicillin using a Box–Behnken design. The three-pulse release tablets of amoxicillin were proven to generate pulsatile release in vitro and sustained release in vivo. This formulation was also found to extend the effective plasma concentration in human compared to the tablet of immediate release based on the simulation data by PBPK modeling. This study provides an example of using PBPK to guide the development of pulsatile dosage forms. PMID:27479702

Formulation and evaluation of once-a-day transdermal gels of diclofenac diethylamine.

PubMed

Baboota, S; Shakeel, F; Kohli, K

2006-03-01

The present study was undertaken to prepare and evaluate transdermal gels of diclofenac diethylamine (DDEA) containing penetration enhancers such as olesan oil and dimethyl sulfoxide (DMSO). Transdermal gels were prepared using different polymers such as carbopol-940, polyvinyl alcohol (PVA), hydroxy propyl methyl cellulose-K(4) M, hydroxy propyl cellulose-M, and sodium carboxy methyl cellulose. The formulated gels were subjected to physicochemical studies, in vitro release studies and in vitro skin permeations studies and were evaluated for drug content, viscosity, extrudability, spreadability, and pH. The in vitro release studies of prepared gels were performed using specially designed Fites cell and in vitro skin permeation studies were performed using keshary-chien diffusion cell through rat skin. Selected formulations were evaluated for their antiinflammatory activity using the carrageenan-induced paw edema in rats. The carbopol-940 and PVA gels containing 10% DMSO showed best in vitro skin permeation of DDEA. In vivo study for the selected formulation showed a sustained reduction in inflammation in the carrageenan induced paw edema in rats. The efficacies of carbopol-940 and PVA gels were also compared with that of the marketed Voveran gel,(R) and it was found that carbopol and PVA gels produced better results than the Voveran gel. (c) 2006 Prous Science. All rights reserved. (c) 2006 Prous Science. All rights reserved.

Loteprednol Etabonate Nanoparticles: Optimization via Box-Behnken Design Response Surface Methodology and Physicochemical Characterization.

PubMed

Sah, Abhishek K; Suresh, Preeti K

2017-01-01

Abstract: The objective of the present work was to prepare and optimize the loteprednoletabonate (LE) loaded poly (D,L-lactide co-glycolide) (PLGA) polymer based nanoparticle carrier. The review on recent patents (US9006241, US20130224302A1, US2012/0028947A1) assisted in the selection of drug and polymer for designing nanoparticles for ocular delivery applications. The nanoparticles were prepared by solvent evaporation followed by high speed homogenization. Biodegradable polymer PLGA (50:50) grade was utilized to develop various formulations with different drug:polymer ratio. A Box-Behnken design with 33 factorial design was selected for the present study and 17 runs were carried out in totality. The influence of various process variables (viz., polymer concentration, homogenization speed and sonication time) on the characteristics of nanoparticles including the in vitro drug release profile were studied. The nanoparticulate formulations were evaluated for mean spherical diameter, polydispersity index (PDI), zeta potential, surface morphology, drug entrapment and in-vitro drug release profile. The entrapment efficiency, drug loading and mean particle size were found to be 96.31±1.68 %, 35.46±0.35 % and 167.6±2.1 nm respectively. The investigated process and formulation variables were found to have significant effect on the particle size, drug loading (DL), entrapment efficiency (EE), and in vitro drug release profile. A biphasic in vitro drug release profile was apparent from the optimized nanoparticles (NPs) for 24 hours. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Release and skin distribution of silicone-related compound(s) from a silicone gel sheet in vitro.

PubMed

Shigeki, S; Nobuoka, N; Murakami, T; Ikuta, Y

1999-01-01

The efficacy of topical silicone gel sheeting in prevention and/or reduction of keloids and hypertrophic scars is well recognized. In the present study, we reexamined the possible release of silicone-related compound(s) from a commercially available silicone gel sheet (Cica-Care, Smith and Nephew, Hull, England) in aqueous media in vitro. The silicone gel sheet was also applied on the excised skin surface to examine the possible distribution of silicone-related compounds into the skin in vitro. Silicone-related compounds were measured as silicon by an inductively coupled plasma-atomic emission spectrophotometer. When a piece of silicone gel sheet was placed in phosphate buffer solution (pH 3-9) at 37 degrees C for 7 days, the concentration of silicon in the medium increased with time, depending on the pH of the medium. This indicates that the released silicone-related compounds are water-soluble. When Cica-Care was applied on the surface of excised rat skin, human axilla skin and hypertrophic scars under hydrated conditions in vitro, silicon was detected in all skin samples. Greater distribution was observed in rat skin than in human axilla skin and hypertrophic scars. The release of silicone-related compounds from a silicone gel sheet (Cica-Care) and their distribution into the skin were demonstrated in vitro. Silicone-related compounds distributed into the skin may have pharmacological effects on the skin. Further investigation will be necessary to investigate in detail the action of silicone-related compounds on the proliferation of fibroblasts and excessive production of collagen.

Supramolecular nanofibers of triamcinolone acetonide for uveitis therapy

NASA Astrophysics Data System (ADS)

Li, Xingyi; Wang, Yuqin; Yang, Chengbiao; Shi, Shuai; Jin, Ling; Luo, Zichao; Yu, Jing; Zhang, Zhaoliang; Yang, Zhimou; Chen, Hao

2014-11-01

Supramolecular nanofibers of prodrugs hold advantages for drug release due to their high drug payload, sustained and constant drug release behavior, and stimuli responsiveness. In this study, we report on a supramolecular hydrogel mainly formed by a clinically used drug triamcinolone acetonide (TA). Such a hydrogel could only be prepared via an ester bond hydrolysis process from its prodrug of succinated triamcinolone acetonide (STA). The resulting hydrogel could constantly release TA in the in vitro release experiment. The TA hydrogel possessed an excellent transscleral penetration ability, as evaluated by the in vitro transscleral transport study. The developed TA hydrogel also exhibited a great ocular compatibility in rats, as indicated by the optical coherence tomography (OCT) images, HE observation, and glial fibrillary acidic protein (GFAP) and vimentin immuno-staining assays of the retinas. Our TA hydrogel showed a decreased efficacy to inhibit ocular inflammation in the rat's experiment autoimmune uveitis (EAU) model compared to the commercial TA suspension (Transton®), but without causing complications such as high intraocular pressure and cataracts. These promising properties of the hydrogel indicated its great potential for the treatment of eye diseases.Supramolecular nanofibers of prodrugs hold advantages for drug release due to their high drug payload, sustained and constant drug release behavior, and stimuli responsiveness. In this study, we report on a supramolecular hydrogel mainly formed by a clinically used drug triamcinolone acetonide (TA). Such a hydrogel could only be prepared via an ester bond hydrolysis process from its prodrug of succinated triamcinolone acetonide (STA). The resulting hydrogel could constantly release TA in the in vitro release experiment. The TA hydrogel possessed an excellent transscleral penetration ability, as evaluated by the in vitro transscleral transport study. The developed TA hydrogel also exhibited a great ocular compatibility in rats, as indicated by the optical coherence tomography (OCT) images, HE observation, and glial fibrillary acidic protein (GFAP) and vimentin immuno-staining assays of the retinas. Our TA hydrogel showed a decreased efficacy to inhibit ocular inflammation in the rat's experiment autoimmune uveitis (EAU) model compared to the commercial TA suspension (Transton®), but without causing complications such as high intraocular pressure and cataracts. These promising properties of the hydrogel indicated its great potential for the treatment of eye diseases. Electronic supplementary information (ESI) available: Synthesis and characterization of the STA agent. SEM image of TA suspension (Transton®). See DOI: 10.1039/c4nr04761c

Preparation and evaluation of a controlled drug release of repaglinide through matrix pellets: in vitro and in vivo studies.

PubMed

Tavakoli, Naser; Minaiyan, Mohsen; Tabbakhian, Majid; Pendar, Yaqub

2014-01-01

Repaglinide, an oral antidiabetic agent, has a rapid onset of action and short half-life of approximately 1 h. Designing a controlled release dosage form of the drug is required to maintain its therapeutic blood level and to eliminate its adverse effects, particularly the hypoglycaemia. Repaglinide sustained release matrix pellets consisting of Avicel, lactose and different polymers were prepared using extrusion-spheronisation method. The effect of different formulation components on in vitro drug release were evaluated using USP apparatus (paddle) for 12 h in phosphate buffer. The optimised formulation was orally administrated to normal and STZ induced diabetic rats. Most pellet formulations had acceptable physical properties with regard to size distribution, flowability and friability. Repaglinide pellets comprising Avicel 50%, lactose 47% and SLS 1% were released 94% of its drug content after 12 h. The optimised formulation was able to decrease blood glucose level in normal rats and those with diabetes throughout 8-12 h.

Release of metal ions from fixed orthodontic appliance: an in vitro study in continuous flow system.

PubMed

Mikulewicz, Marcin; Chojnacka, Katarzyna; Wołowiec, Paulina

2014-01-01

To evaluate the release of metal ions from fixed orthodontic appliances. A new system for in vitro testing of dental materials was constructed and consisted of a thermostatic glass reactor that enabled immersion of the studied material. Experimental conditions reflected the human oral cavity, with a temperature of 37°C and a saliva flow rate of 0.5mL/min. The simulated fixed orthodontic appliance made of stainless steel was evaluated. Sampling was performed at several time points during the 28-day study, and the metal ion concentration was determined by inductively coupled plasma optical emission spectrometry. The total mass of released metal ions from the appliance during 4 weeks of the experiment was as follows nickel 18.7 μg, chromium 5.47 μg, copper 31.3 μg. The estimated doses of nickel, chromium, and copper determined by extrapolation of experimental data released during the treatment period were far below the toxic dose to humans. This shows that orthodontic treatment might not be a significant source of exposure to these metal ions.

Preparation and evaluation of a phospholipid-based injectable gel for the long term delivery of leuprolide acetaterrh.

PubMed

Long, Danhong; Gong, Tao; Zhang, Zhirong; Ding, Rui; Fu, Yao

2016-07-01

A phospholipid-based injectable gel was developed for the sustained delivery of leuprolide acetate (LA). The gel system was prepared using biocompatible materials (SPME), including soya phosphatidyl choline (SPC), medium chain triglyceride (MCT) and ethanol. The system displayed a sol state with low viscosity in vitro and underwent in situ gelation in vivo after subcutaneous injection. An in vitro release study was performed using a dialysis setup with different release media containing different percentages of ethanol. The stability of LA in the SPME system was investigated under different temperatures and in the presence of various antioxidants. In vivo studies in male rats were performed to elucidate the pharmacokinetic profiles and pharmacodynamic efficacy. A sustained release of LA for 28 days was observed without obvious initial burst in vivo. The pharmacodynamic study showed that once-a-month injection of LA-loaded SPME (SPME-LA) led to comparable suppression effects on the serum testosterone level as observed in LA solution except for the onset time. These findings demonstrate excellent potential for this novel SPME system as a sustained release delivery system for LA.

Bubble-generating nano-lipid carriers for ultrasound/CT imaging-guided efficient tumor therapy.

PubMed

Zhang, Nan; Li, Jia; Hou, Ruirui; Zhang, Jiangnan; Wang, Pei; Liu, Xinyang; Zhang, Zhenzhong

2017-12-20

Ideal therapeutic effectiveness of chemotherapy is obtained only when tumor cells are exposed to a maximal drug concentration, which is often hindered by dose-limiting toxicity. We designed a bubble-generating liposomal delivery system by introducing ammonium bicarbonate and gold nanorods into folic acid-conjugated liposomes to allow both multimodal imaging and the local release of drug (doxorubicin) with hyperthermia. The key component, ammonium bicarbonate, allows a controlled, rapid release of doxorubicin to provide an effective drug concentration in the tumor microenvironment. An in vitro temperature-triggered drug release study showed that cumulative release improved more than two-fold. In addition, in vitro and in vivo studies indicated that local heat treatment or ultrasonic cavitation enhanced the therapeutic efficiency greatly. The delivery system could also serve as an excellent contrast agent to allow ultrasonic imaging and computerized tomography imaging simultaneously to further achieve the aim of accurate diagnostics. Results of this study showed that this versatile bubble-generating liposome is a promising system to provide optimal therapeutic effects that are guided by multimodal imaging. Copyright © 2017 Elsevier B.V. All rights reserved.

Sintering of wax for controlling release from pellets.

PubMed

Singh, Reena; Poddar, S S; Chivate, Amit

2007-09-14

The purpose of the present study was to investigate incorporation of hydrophobic (ie, waxy) material into pellets using a thermal sintering technique and to evaluate the pellets in vitro for controlled release. Pellets prepared by extrusion-spheronization technology were formulated with a water-soluble drug, microcrystalline cellulose, and carnauba wax. Powdered carnauba wax (4%-20%) prepared by grinding or by emulsification was studied with an attempt to retard the drug release. The inclusion of ground or emulsified carnauba wax did not sustain the release of theophylline for more than 3 hours. Matrix pellets of theophylline prepared with various concentrations of carnauba wax were sintered thermally at various times and temperatures. In vitro drug release profiles indicated an increase in drug release retardation with increasing carnauba wax concentration. Pellets prepared with ground wax showed a higher standard deviation than did those prepared with emulsified wax. There was incomplete release at the end of 12 hours for pellets prepared with 20% ground or emulsified wax. The sintering temperature and duration were optimized to allow for a sustained release lasting at least 12 hours. The optimized temperature and duration were found to be 100 degrees C and 140 seconds, respectively. The sintered pellets had a higher hydrophobicity than did the unsintered pellets. Scanning electron micrographs indicated that the carnauba wax moved internally, thereby increasing the surface area of wax within the pellets.

Design and In Vitro Evaluation of Compression-coated Pulsatile Release Tablets of Losartan Potassium

PubMed Central

Bajpai, M.; Singh, D. C. P.; Bhattacharya, A.; Singh, A.

2012-01-01

In majority of individuals blood pressure rises in the early morning hours, which lead to serious cardiovascular complications. Formulation of pulsatile system makes it possible to deliver drug at definite period of time when symptoms of the disease condition are most critical. The purpose of the present work was to develop pulsatile release tablet of losartan potassium for chronotherapy in hypertension. The prepared system consisted of a core tablet coated with versatile and safe hydrophilic cellulosic ethers such as, hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxy methylcellulose to produce burst release after predetermined lag time. Various formulation factors were studied through series of test and in vitro dissolution study. It was found that core tablets containing superdisintegrant failed to produce burst drug release pattern while effervescent agent was able to do so. Results also reveal that coating composition and coating level affects lag time. Formulation containing effervescent agent in core and coated with 200 mg hydroxypropyl cellulose provide lag time of 4.5 h with 73% drug release in 6 h that followed a sigmoidal release pattern. These values were close to the desired objective of producing lag time of 5-6 h followed by fast drug release. This approach can thus provide a useful means for timed release of losartan and is helpful for patients with morning surge. PMID:23325989

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization, in vitro and in vivo pharmacokinetic studies.

PubMed

Thakar, Krishna; Joshi, Garima; Sawant, Krutika K

2013-06-01

The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS). Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3(2) factorial design was done using Polyox WSR 303 (X1) and HPMC K4M (X2) as independent variables and cumulative percentage drug released at 6 h (Q6h) as dependent variable. Optimized formulation showed floating lag time of 4-5 s, floated for more than 12 h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6 h. In vivo pharmacokinetic studies in rabbits showed Cmax of 189.96 ± 13.04 ng/mL and Tmax of 4 ± 0.35 h for GFDDS. The difference for AUC(0-T) and AUC(0-∞) between the test and reference formulation was statistically significant (p > 0.05). AUC(0-T) and AUC(0-∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively. GFDDS provided prolonged gastric residence and showed significant increase in bioavailability of baclofen.

Design Optimization and In Vitro-In Vivo Evaluation of Orally Dissolving Strips of Clobazam

PubMed Central

Bala, Rajni; Khanna, Sushil; Pawar, Pravin

2014-01-01

Clobazam orally dissolving strips were prepared by solvent casting method. A full 32 factorial design was applied for optimization using different concentration of film forming polymer and disintegrating agent as independent variable and disintegration time, % cumulative drug release, and tensile strength as dependent variable. In addition the prepared films were also evaluated for surface pH, folding endurance, and content uniformity. The optimized film formulation showing the maximum in vitro drug release, satisfactory in vitro disintegration time, and tensile strength was selected for bioavailability study and compared with a reference marketed product (frisium5 tablets) in rabbits. Formulation (F6) was selected by the Design-expert software which exhibited DT (24 sec), TS (2.85 N/cm2), and in vitro drug release (96.6%). Statistical evaluation revealed no significant difference between the bioavailability parameters of the test film (F6) and the reference product. The mean ratio values (test/reference) of C max (95.87%), t max (71.42%), AUC0−t (98.125%), and AUC0−∞ (99.213%) indicated that the two formulae exhibited comparable plasma level-time profiles. PMID:25328709

Development and in vitro evaluation of carboxymethyl chitosan based drug delivery system for the controlled release of propranolol hydrochloride

NASA Astrophysics Data System (ADS)

Hernawan; Nur Hayati, Septi; Nisa, Khoirun; Wheni Indrianingsih, Anastasia; Darsih, Cici; Kismurtono, Muhammad

2017-12-01

Propranolol hydrochloride is a nonselective β-adrenergic drug and has been used as angina pectoris, antihypertensive, and that of many other cardiovascular disorders. It has a relatively short plasma half-life and duration of action are considered too short in certain circumstances. Thus, it’s fascinating to elongate the action. The tablet formula was based on extended-release by a propranolol hydrochloride based carboxymethyl chitosan matrix. Here we used direct compression technique with internal wet granulation to prepare the tablets. The tablets were evaluated for physical properties (hardness, weight variation test, friability) and in vitro release studies. There was no interaction observed between propranolol hydrochloride and excipients. Dissolution profiles of each formulation were followed zero order model. In conclusion, these results strongly suggest that in appropriate proportions carboxymethyl chitosan with internal granulation is suitable for formulating propranolol hydrochloride controlled release.

The effect of pH, buffer capacity and ionic strength on quetiapine fumarate release from matrix tablets prepared using two different polymeric blends.

PubMed

Hamed, Rania; AlJanabi, Reem; Sunoqrot, Suhair; Abbas, Aiman

2017-08-01

The objective of this study was to investigate the effect of the different physiological parameters of the gastrointestinal (GI) fluid (pH, buffer capacity, and ionic strength) on the in vitro release of the weakly basic BCS class II drug quetiapine fumarate (QF) from two once-a-day matrix tablet formulations (F1 and F2) developed as potential generic equivalents to Seroquel ® XR. F1 tablets were prepared using blends of high and low viscosity grades of hydroxypropyl methylcellulose (HPMC K4M and K100LV, respectively), while F2 tablets were prepared from HPMC K4M and PEGylated glyceryl behenate (Compritol ® HD5 ATO). The two formulations attained release profiles of QF over 24 h similar to that of Seroquel ® XR using the dissolution medium published by the Food and Drug Administration (FDA). A series of solubility and in vitro dissolution studies was then carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH, buffer capacity and ionic strength range of the GIT. Solubility studies revealed that QF exhibits a typical weak base pH-dependent solubility profile and that the solubility of QF increases with increasing the buffer capacity and ionic strength of the media. The release profiles of QF from F1, F2 and Seroquel ® XR tablets were found to be influenced by the pH, buffer capacity and ionic strength of the dissolution media to varying degrees. Results highlight the importance of studying the physiological variables along the GIT in designing controlled release formulations for more predictive in vitro-in vivo correlations.

Assessment of PLGA-PEG-PLGA Copolymer Hydrogel for Sustained Drug Delivery in the Ear

PubMed Central

Feng, Liang; Ward, Jonette A.; Li, S. Kevin; Tolia, Gaurav; Hao, Jinsong; Choo, Daniel I.

2014-01-01

Temperature sensitive copolymer systems were previously studied using modified diffusion cells in vitro for intratympanic injection, and the PLGA-PEG-PLGA copolymer systems were found to provide sustained drug delivery for several days. The objectives of the present study were to assess the safety of PLGA-PEG-PLGA copolymers in intratympanic injection in guinea pigs in vivo and to determine the effects of additives glycerol and poloxamer in PLGA-PEG-PLGA upon drug release in the diffusion cells in vitro for sustained inner ear drug delivery. In the experiments, the safety of PLGA-PEG-PLGA copolymers to inner ear was evaluated using auditory brainstem response (ABR). The effects of the additives upon drug release from PLGA-PEG-PLGA hydrogel were investigated in the modified Franz diffusion cells in vitro with cidofovir as the model drug. The phase transition temperatures of the PLGA-PEG-PLGA copolymers in the presence of the additives were also determined. In the ABR safety study, the PLGA-PEG-PLGA copolymer alone did not affect hearing when delivered at 0.05-mL dose but caused hearing loss after 0.1-mL injection. In the drug release study, the incorporation of the bioadhesive additive, poloxamer, in the PLGA-PEG-PLGA formulations was found to decrease the rate of drug release whereas the increase in the concentration of the humectant additive, glycerol, provided the opposite effect. In summary, the PLGA-PEG-PLGA copolymer did not show toxicity to the inner ear at the 0.05-mL dose and could provide sustained release that could be controlled by using the additives for inner ear applications. PMID:24438444

Sustained release of bactericidal concentrations of penicillin in the pleural space via an antibiotic-eluting pigtail catheter coated with electrospun nanofibers: results from in vivo and in vitro studies.

PubMed

Chao, Yin-Kai; Lee, Cheng-Hung; Liu, Kuo-Sheng; Wang, Yi-Chuan; Wang, Chih-Wei; Liu, Shih-Jung

2015-01-01

Inadequate intrapleural drug concentrations caused by poor penetration of systemic antibiotics into the pleural cavity is a major cause of treatment failure in empyema. Herein, we describe a novel antibiotic-eluting pigtail catheter coated with electrospun nanofibers used for the sustained release of bactericidal concentrations of penicillin in the pleural space. Electrospun nanofibers prepared using polylactide-polyglycolide copolymer and penicillin G sodium dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol were used to coat the surface of an Fr6 pigtail catheter. The in vitro patterns of drug release were tested by placing the catheter in phosphate-buffered saline. In vivo studies were performed using rabbits treated with penicillin either intrapleurally (Group 1, 20 mg delivered through the catheter) or systemically (Group 2, intramuscular injection, 10 mg/kg). Penicillin concentrations in the serum and pleural fluid were then measured and compared. In vitro studies revealed a burst release of penicillin (10% of the total dose) occurring in the first 24 hours, followed by a sustained release in the subsequent 30 days. Intrapleural drug levels were significantly higher in Group 1 than in Group 2 (P<0.001). In the former, penicillin concentrations remained above the minimum inhibitory concentration breakpoint throughout the entire study period. In contrast, serum penicillin levels were significantly higher in Group 2 than in Group 1 (P<0.001). Notably, all Group 2 rabbits showed signs of systemic toxicity (paralytic ileus and weight loss). We conclude that our antibiotic-eluting catheter may serve as a novel therapeutic option to treat empyema.

Modulation of the formation and release of bovine SRS-A in vitro by several anti-anaphylactic drugs.

PubMed

Burka, J F; Eyre, P

1975-01-01

Slow-reacting substance of anaphylaxis (SRS-A) is released immunologically from bovine lung in vitro. Various drugs known to protect calves and other animals during anaphylaxis were tested to investigate their modulation of the formation and release of SRS-A. The anti-inflammatory drugs, meclofenamate and aspirin, potentiated SRS-A release. Chlorphenesin and diethylcarbamazine citrate at high concentrations both inhibited SRS-A release. Two new anti-anaphylactic drugs, PR-D-92-EA and M&B 22,948, were particularly effective in inhibiting SRS-A release at low concentrations. The possible modes of actions of these drugs are discussed.

Preparation and in vitro evaluation of heparin-loaded polymeric nanoparticles.

PubMed

Jiao, Y Y; Ubrich, N; Marchand-Arvier, M; Vigneron, C; Hoffman, M; Maincent, P

2001-01-01

Nanoparticles of a highly soluble macromolecular drug, heparin, were formulated with two biodegradable polymers (poly-E-caprolactone [PCL] and poly (D, L-lactic-co-glycolic-acid) 50/50 [PLAGA]) and two nonbiodegradable positively charged polymers (Eudragit RS and RL) by the double emulsion and solvent evaporation method, using a high-pressure homogenization device. The encapsulation efficiency and heparin release profiles were studied as a function of the type of polymers employed (alone or in combination) and the concentration of heparin. Optimal encapsulation efficiency was observed when 5000 IU of heparin were incorporated in the first emulsion. High drug entrapment efficiency was observed in both Eudragit RS and RL nanoparticles (60% and 98%, respectively), compared with PLAGA and PCL nanoparticles (<14%). The use of the two types of Eudragit in combination with PCL and PLAGA increased the encapsulation efficiency compared with these two biodegradable polymers used alone; however, the in vitro drug release was not modified and remained low. On the other hand, the addition of esterase to the dissolution medium resulted in a significant increase in heparin release. The in vitro biological activity of released heparin, evaluated by measuring the anti-Xa activity by a colorimetric assay, was conserved after the encapsulation process.

Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt.

PubMed

Arora, Priyanka; Mukherjee, Biswajit

2002-09-01

In this study, matrix-type transdermal patches containing diclofenac diethylamine were prepared using different ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinylalcohol backing membrane. All the prepared formulations were subjected to physical studies (moisture content, moisture uptake, and flatness), in vitro release studies and in vitro skin permeation studies. In vitro permeation studies were performed across cadaver skin using a modified diffusion cell. Variations in drug release profiles among the formulations studied were observed. Based on a physicochemical and in vitro skin permeation study, formulation PA4 (PVP/EC, 1:2) and PA5 (PVP/EC, 1:5) were chosen for further in vivo experiments. The antiinflammatory effect and a sustaining action of diclofenac diethylamine from the two transdermal patches selected were studied by inducing paw edema in rats with 1% w/v carrageenan solution. When the patches were applied half an hour before the subplantar injection of carrageenan in the hind paw of male Wistar rats, it was observed that formulation PA4 produced 100% inhibition of paw edema in rats 12 h after carrageenan insult, whereas in the case of formulation PA5, 4% mean paw edema was obtained half an hour after the carrageenan injection and the value became 19.23% 12 h after the carrageenan insult. The efficacy of transdermal patches was also compared with the marketed Voveran gel and it was found that PA4 transdermal patches produced a better result as compared with the Voveran gel. Hence, it can be reasonably concluded that diclofenac diethylamine can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP/EC, 1:2) was found to be the best choice for manufacturing transdermal patches of diclofenac diethylamine among the formulations studied. Copyright 2002 Wiley-Liss, Inc.

Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories.

PubMed

Chicco, D; Grabnar, I; Skerjanec, A; Vojnovic, D; Maurich, V; Realdon, N; Ragazzi, E; Belic, A; Karba, R; Mrhar, A

1999-11-05

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro-in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.

Preparation and in vitro-in vivo evaluation of none gastric resident dipyridamole (DIP) sustained-release pellets with enhanced bioavailability.

PubMed

Xu, Lishuang; Luo, Yanfei; Feng, Jia; Xu, Ming; Tao, Xiaoguang; He, Haibing; Tang, Xing

2012-01-17

The objective of this study was to develop none gastric resident sustained-release pellets loaded with dipyridamole with a high bioavailability. Two different kinds of core pellets, one containing citric acid as a pH-modifier (CAP) and, the other without pH-modifier (NCAP) were prepared by extrusion-spheronization and then coated with mixtures of enteric soluble and insoluble polymers (referred to as CAP(1) and NCAP(1)) or insoluble polymer alone (referred to as CAP(2) and NCAP(2)). The relative bioavailability of the sustained-release pellets was studied in fasted beagle dogs after oral administration using a commercially available immediate release tablet (IRT) as a reference. The in vitro release, in vivo absorption and in vitro-in vivo correlation were also evaluated. Results revealed that the plasma drug concentrations after administration of CAP(2), NCAP(1) and NCAP(2) were undetectable, indicating that the drug release was almost zero from the preparations throughout the gastro-intestinal tract. The C(max), T(max) and AUC((0→24)) of CAP(1) were 0.78 ± 0.23 (μg/ml), 3.80 ± 0.30 (h), and 6.74 ± 0.47 (μg/mlh), respectively. While the corresponding values were 2.23 ± 0.32 (μg/ml), 3.00 ± 0.44 (h) and 9.42 ± 0.69 (μg/mlh) for IRT. The relative bioavailability of CAP(1) was 71.55% compared with IRT. By combined incorporation of a pH-modifier into the core of pellets to modify the inner micro-environment and employing mixtures of enteric soluble and insoluble polymers as a retarding layer, drugs with high solubility in stomach and limited solubility in small intestine, such as DIP, could be successfully formulated as sustained release preparations with no pH-dependence in drug release and enhanced bioavailability. Copyright © 2011 Elsevier B.V. All rights reserved.

NCL-01: Nanomedicine Drug Release Study in Human Plasma Using Stable Isotope Tracer Ultrafiltration Assay (SITUA)  | Frederick National Laboratory for Cancer Research

Cancer.gov

The Nanotechnology Characterization Laboratory will evaluate drug release from a nanoparticulate formulation in vitro in human plasma, using a novel stable isotope tracer ultrafiltration assay (SITUA) developed at the laboratory. The SITUA is a metho

S-protected thiolated chitosan: Synthesis and in vitro characterization

PubMed Central

Dünnhaupt, Sarah; Barthelmes, Jan; Thurner, Clemens C.; Waldner, Claudia; Sakloetsakun, Duangkamon; Bernkop-Schnürch, Andreas

2012-01-01

Purpose of the present study was the generation and evaluation of novel thiolated chitosans, so-named S-protected thiolated chitosans as mucosal drug delivery systems. Stability of all conjugates concerning swelling and disintegration behavior as well as drug release was examined. Mucoadhesive properties were evaluated in vitro on intestinal mucosa. Different thiolated chitosans were generated displaying increasing amounts of attached free thiol groups on the polymer, whereby more than 50% of these thiol groups were linked with 6-mercaptonicotinamide. Based on the implementation of this hydrophobic residue, the swelling behavior was 2-fold decreased, whereas stability was essentially improved. Their mucoadhesive properties were 2- and 14-fold increased compared to corresponding thiolated and unmodified chitosans, respectively. Release studies out of matrix tablets comprising the novel conjugates revealed a controlled release of a model peptide. Accordingly, S-protected thiomers represent a promising type of mucoadhesive polymers for the development of various mucosal drug delivery systems. PMID:22839999

PLGA/Ag nanocomposites: in vitro degradation study and silver ion release.

PubMed

Fortunati, E; Latterini, L; Rinaldi, S; Kenny, J M; Armentano, I

2011-12-01

New nanocomposite films based on a biodegradable poly (DL-Lactide-co-Glycolide) copolymer (PLGA) and different concentration of silver nanoparticles (Ag) were developed by solvent casting. In vitro degradation studies of PLGA/Ag nanocomposites were conducted under physiological conditions, over a 5 week period, and compared to the behaviour of the neat polymer. Furthermore the silver ions (Ag(+)) release upon degradation was monitored to obtain information on the properties of the nanocomposites during the incubation. The obtained results suggest that the PLGA film morphology can be modified introducing a small percentage of silver nanoparticles that do not affect the degradation mechanism of PLGA polymer in the nanocomposite. However results clearly evinced the stabilizing effect of the Ag nanoparticles in the PLGA polymer and the mineralization process induced by the combined effect of silver and nanocomposite surface topography. The Ag(+) release can be controlled by the polymer degradation processes, evidencing a prolonged antibacterial effect.

pH-sensitive poly(lactide-co-glycolide) nanoparticle composite microcapsules for oral delivery of insulin

PubMed Central

Sun, Shaoping; Liang, Na; Yamamoto, Hiromitsu; Kawashima, Yoshiaki; Cui, Fude; Yan, Pengfei

2015-01-01

This study proposes a new concept of pH-sensitive poly(lactide-co-glycolide) (PLGA) nanoparticle composite microcapsules for oral delivery of insulin. Firstly, insulin–sodium oleate complex was prepared by the hydrophobic ion pairing method and then encapsulated into PLGA nanoparticles by the emulsion solvent diffusion method. In order to reduce the burst release of insulin from PLGA nanoparticles and deliver insulin to specific gastrointestinal regions, hence to enhance bioavailability of insulin, the PLGA nanoparticles were further encapsulated into Eudragit® FS 30D to prepare PLGA nanoparticle composite microcapsules by organic spray-drying method. The preparation was evaluated in vitro and in vivo, and the absorption mechanism was discussed. The in vitro drug release studies revealed that the drug release was pH dependent, and the in vivo results demonstrated that the formulation of PLGA nanoparticle composite microcapsules was an effective candidate for oral insulin delivery. PMID:25999713

pH-sensitive poly(lactide-co-glycolide) nanoparticle composite microcapsules for oral delivery of insulin.

PubMed

Sun, Shaoping; Liang, Na; Yamamoto, Hiromitsu; Kawashima, Yoshiaki; Cui, Fude; Yan, Pengfei

2015-01-01

This study proposes a new concept of pH-sensitive poly(lactide-co-glycolide) (PLGA) nanoparticle composite microcapsules for oral delivery of insulin. Firstly, insulin-sodium oleate complex was prepared by the hydrophobic ion pairing method and then encapsulated into PLGA nanoparticles by the emulsion solvent diffusion method. In order to reduce the burst release of insulin from PLGA nanoparticles and deliver insulin to specific gastrointestinal regions, hence to enhance bioavailability of insulin, the PLGA nanoparticles were further encapsulated into Eudragit(®) FS 30D to prepare PLGA nanoparticle composite microcapsules by organic spray-drying method. The preparation was evaluated in vitro and in vivo, and the absorption mechanism was discussed. The in vitro drug release studies revealed that the drug release was pH dependent, and the in vivo results demonstrated that the formulation of PLGA nanoparticle composite microcapsules was an effective candidate for oral insulin delivery.

In vitro-in vivo evaluation of in situ gelling and thermosensitive ketoprofen liquid suppositories.

PubMed

Ozgüney, Işık; Kardhiqi, Anita; Yıldız, Gülbeyaz; Ertan, Gökhan

2014-12-01

The main objective of this study was to investigate the release and pharmacokinetic profiles of ketoprofen (KP) from developed thermosensitive and mucoadhesive liquid suppositories. Thermosensitive liquid suppositories were prepared using KP, poloxamer 407 (P 407), poloxamer 188 (P 188) and various amounts of different mucoadhesive polymers. In vitro release studies was monitored by the USP XXVI paddle method. The results thus obtained were evaluated kinetically and mechanism of release was analyzed. Identification of poloxamer gel localization in vivo was conducted using white male rabbits by adding 1 % methylene blue. For in vivo studies, twenty-four white male rabbits were randomly divided into three groups. The rabbits in each group were administered with liquid suppository F1 [P407/P188/KP (4/20/2.5 %)], F5 [P407/P188/KP/C (4/20/2.5/0.8 %)] or conventional suppository (F-C) into the rectum. The plasma concentration of KP was analyzed by high performance liquid chromatography (HPLC). C max, AUC, MRT and T max were evaluated. The release of KP was variously affected by the mucoadhesive polymers. In vitro release studies showed that Carbopol 934 P(C) has significant effect on release rate among the mucoadhesive polymers. When the formulations were evaluated kinetically, different kinetic models were obtained. Formulation F6 [P407/P188/KP/C (4/20/2.5/1.6 %)] which contains the highest C concentration and very high viscosity, shows a significantly better fit with Higuchi kinetic model. n value of this formulation was also found approximately 0.5. n exponent results of the other formulations showed that KP might be released from the suppositories by non-Fickian diffusion. Identification of poloxamer gel localization in vivo showed that the suppositories remain in the rectum without leakage after administration. With regard to the results of in vivo studies, the AUC6→14 values of KP in liquid suppository containing C are significantly higher than those in liquid suppository without C. MRT0→24 and MRT0→∞ values of liquid suppository containing C are significantly higher than those in liquid suppository without C and conventional suppository. Conventional suppository and liquid suppository without C significantly gave faster time to reach the maximum plasma concentrations of KP. With regard to the in vitro and in vivo experiments, liquid suppository formulation F5 might be a promising formulation for the development of an effective rectal dosage form.

Effect of Quaternary Ammonium Carboxymethylchitosan on Release Rate In-vitro of Aspirin Sustained-release Matrix Tablets

PubMed Central

Meng, Lingbin; Teng, Zhongqiu; Zheng, Nannan; Meng, Weiwei; Dai, Rongji; Deng, Yulin

2013-01-01

The aim of this study was to develop a derivative of chitosan as pharmaceutical excipient used in sustained-release matrix tablets of poorly soluble drugs. A water-soluble quaternary ammonium carboxymethylchitosan was synthesized by a two-step reaction with carboxymethylchitosan (CMCTS), decylalkyl dimethyl ammonium and epichlorohydrin. The elemental analysis showed that the target product with 10.27% of the maximum grafting degree was obtained. To assess the preliminary safety of this biopolymer, cell toxicity assay was employed. In order to further investigate quaternary ammonium carboxymethylchitosan application as pharmaceutical excipient, aspirin was chosen as model drug. The effect of quaternary ammonium CMCTS on aspirin release rate from sustained-release matrix tablets was examined by in-vitro dissolution experiments. The results showed that this biopolymer had a great potential in increasing the dissolution of poorly soluble drug. With the addition of CMCTS-CEDA, the final cumulative release rate of drug rose up to 90%. After 12 h, at the grade of 10, 20 and 50 cps, the drug release rate increased from 58.1 to 90.7%, from 64.1 to 93.9%, from 69.3 to 96.1%, respectively. At the same time, aspirin release rate from sustainedrelease model was found to be related to the amount of quaternary ammonium CMCTS employed. With the increase of CMCTS-CEDA content, the accumulated release rate increased from 69.1% to 86.7%. The mechanism of aspirin release from sustained-release matrix tablets was also preliminary studied to be Fick diffusion. These data demonstrated that the chitosan derivative has positive effect on drug release from sustained-release matrix tablets. PMID:24250627

Preparation and In Vitro/Ex Vivo Evaluation of Moxifloxacin-Loaded PLGA Nanosuspensions for Ophthalmic Application

PubMed Central

Mudgil, Meetali; Pawar, Pravin K.

2013-01-01

The aim of the present investigation was to prepare a colloidal ophthalmic formulation to improve the residence time of moxifloxacin. Moxifloxacin-loaded poly(dl-lactide-co-glycolide) (PLGA) nanosuspensions were prepared by using the solvent evaporation technique. The nanosuspensions were characterised physically by using different techniques like particle size, zeta potential, FTIR, DSC, and XRD analysis. In vitro and ex vivo studies of nanosuspensions were carried out using a modified USP dissolution apparatus and all-glass Franz diffusion cells, respectively. The antibacterial activities of the nanosuspension and marketed formulations were performed against S. aureus and P. aeroginosa. The moxifloxacin-loaded PLGA nanosuspensions showed uniform particle size, ranging between 164–490 nm with negative zeta potential for all batches. The percentage entrapment efficiency of the drug-loaded nano-suspension was found to be between 84.09 to 92.05%. In vitro drug release studies suggest that all of the formulations showed extended drug release profiles and follow Korsemeyer-Peppas release kinetics. In vitro corneal permeability was found to be comparable with that of the marketed formulation across isolated goat cornea, indicating the suitability of the nanosuspension formulation in the ophthalmic delivery of moxifloxacin. The optimised nano-suspension was found to be more active against S. aureus and P. aeruginosa compared to the marketed eye drops. PMID:23833723

Evaluation of metal ion release from Ti6Al4V and Co-Cr-Mo casting alloys: in vivo and in vitro study.

PubMed

El Sawy, Amal A; Shaarawy, Mohammed A

2014-02-01

The aim of this study was to evaluate the amount of ions released from Ti6Al4V and Co-Cr-Mo alloys both in vivo and in vitro. Twenty-one discs of each alloy were constructed and divided into seven groups. Three specimens from each group were immersed in a buffered saline solution over a period of 1, 3, 5, 7, 14, 21, and 28 days. Twenty-eight participants were also included in the study, where the study group consisted of 14 mandibular partially edentulous patients, and the control group consisted of 14 volunteers. The study group was further divided into two equal groups: the first group received removable partial dentures (RPDs) constructed from Co-Cr-Mo alloy, while the second group received RPDs constructed from Ti6Al4V alloy. Saliva samples were collected from each participant over the same study period. The conditioning media and saliva samples were analyzed using a spectrophotometer. One-way ANOVA and Tukey tests were used for statistical analysis (p < 0.05). The concentrations of metal ions released from the studied alloys were significantly higher in the in vitro than in the in vivo study group during the follow-up periods. A statistically significant increase in ion concentrations of the different elements for both alloys was found with time (p < 0.05). The amounts of released metallic ions from Co-Cr-Mo and Ti6Al4V alloys were higher in the buffered saline solutions than in the studied saliva samples and control groups; however, these amounts were still within the physiological limit of trace elements in the human body. © 2013 by the American College of Prosthodontists.

Preparation and characterization of pH-sensitive methyl methacrylate-g-starch/hydroxypropylated starch hydrogels: in vitro and in vivo study on release of esomeprazole magnesium.

PubMed

Kumar, Pankaj; Ganure, Ashok Laxmanrao; Subudhi, Bharat Bhushan; Shukla, Shubhanjali

2015-06-01

In the present study, novel hydrogels were prepared through graft copolymerization of methyl methacrylate onto starch and hydroxypropylated starch for intestinal drug delivery. The successful grafting has been confirmed by FTIR, NMR spectroscopy, and elemental analysis. Morphological examination of copolymeric hydrogels by scanning electron microscopy (SEM) confirms the macroporous nature of the copolymers. The high decomposition temperature was observed in thermograms indicating the thermal stability of the hydrogels. To attain a hydrogel with maximum percent graft yield, the impact of reaction variables like concentration of ceric ammonium nitrate as initiator and methyl methacrylate as monomer were consistently optimized. X-ray powder diffraction and differential scanning calorimetric analysis supported the successful entrapment of the drug moiety (esomeprazole magnesium; proton pump inhibitor) within the hydrogel network. Drug encapsulation efficiency of optimized hydrogels was found to be >78%. Furthermore, swelling capacity of copolymeric hydrogels exhibited a pH-responsive behavior which makes the synthesized hydrogels potential candidates for controlled delivery of medicinal agents. In vitro drug release was found to be sustained up to 14 h with 80-90% drug release in pH 6.8 solution; however, the cumulative release was 40-45% in pH 1.2. The gastrointestinal transit behavior of optimized hydrogel was determined by gamma scintigraphy, using (99m)Tc as marker. The amount of radioactive tracer released from the labeled hydrogel was minimal when the hydrogel was in the stomach, whereas it increased as hydrogel reached in intestine. Well-correlated results of in vitro and in vivo analysis proved their controlled release behavior with preferential delivery into alkaline pH environment.

Hydrophilic absorbable copolyester exhibiting zero-order drug release.

PubMed

Andjelić, Sasa; Yuan, Jenny; Jamiolkowski, Dennis D; Diluccio, Robert; Bezwada, Rao; Zhang, Hua; Mijović, Jovan

2006-04-01

A novel absorbable hydrophilic copolyester developed in our laboratory, amorphous 40/60 poly(ethylene diglycolate-co-glycolide), exhibits outstanding physical properties. Films made from this material appear fully transparent, colorless, soft and slightly elastic, but relatively strong and durable materials so that they can be potentially used as stand-alone devices in various in-vivo medical applications. In this study, in-vitro drug release characteristics of this copolyester were examined. High Performance Liquid Chromatography was used to generate release profiles on selected non-steroidal anti-inflammatory agents, NSAIDs. In addition, dielectric relaxation spectroscopy, as well as mid- and near infrared spectroscopy, were used to study specific polymer chain interactions in water and buffer solution as a function of aging time at 37 degrees C. This copolyester, compression molded into a film, exhibited nearly constant in-vitro release of various hydrophilic and hydrophobic drugs. The release profile showed minimal or, in most cases, no burst effect. The effect was observed with the three NSAIDs that were tested as model compounds; however, this system may prove generally useful for other drug entities. In-vitro hydrolysis conducted at 37 degrees C on this hydrophilic copolyester revealed an unusually long induction period (no hydrolysis for up to 6 days), followed by the relatively rapid hydrolysis. Data from dipole relaxation spectroscopy indicated that the water molecules do not structurally associate with the polymer chains in phosphate buffer during initial hydrolysis period. The results suggest unique dynamics of water diffusion through the polymer matrix that may play a critical role in achieving controlled release properties. Furthermore, we suspect that the molecular interactions associated with this new synthetic absorbable material may find a critical utility in important medical applications.

Growth factor release by vesicular phospholipid gels: in-vitro results and application for rotator cuff repair in a rat model.

PubMed

Buchmann, Stefan; Sandmann, Gunther H; Walz, Lars; Reichel, Thomas; Beitzel, Knut; Wexel, Gabriele; Tian, Weiwei; Battmann, Achim; Vogt, Stephan; Winter, Gerhard; Imhoff, Andreas B

2015-04-10

Biological augmentation of rotator cuff repair is of growing interest to improve biomechanical properties and prevent re-tearing. But intraoperative single shot growth factor application appears not sufficient to provide healing support in the physiologic growth factor expression peaks. The purpose of this study was to establish a sustained release of granulocyte-colony stimulating factor (G-CSF) from injectable vesicular phospholipid gels (VPGs) in vitro and to examine biocompatibility and influence on histology and biomechanical behavior of G-CSF loaded VPGs in a chronic supraspinatus tear rat model. G-CSF loaded VPGs were produced by dual asymmetric centrifugation. In vitro the integrity, stability and release rate were analyzed. In vivo supraspinatus tendons of 60 rats were detached and after 3 weeks a transosseous refixation with G-CSF loaded VPGs augmentation (n = 15; control, placebo, 1 and 10 μg G-CSF/d) was performed. 6 weeks postoperatively the healing site was analyzed histologically (n = 9; H&E by modified MOVIN score/Collagen I/III) and biomechanically (n = 6). In vitro testing revealed stable proteins after centrifugation and a continuous G-CSF release of up to 4 weeks. Placebo VPGs showed histologically no negative side effects on the healing process. Histologically in vivo testing demonstrated significant advantages for G-CSF 1 μg/d but not for G-CSF 10 μg/d in Collagen III content (p = 0.035) and a higher Collagen I/III ratio compared to the other groups. Biomechanically G-CSF 1 μg/d revealed a significant higher load to failure ratio (p = 0.020) compared to control but no significant differences in stiffness. By use of VPGs a continuous growth factor release could be obtained in vitro. The in vivo results demonstrate an improvement of immunohistology and biomechanical properties with a low dose G-CSF application via VPG. The VPG itself was well tolerated and had no negative influence on the healing behavior. Due to the favorable properties (highly adhesive, injectable, biocompatible) VPGs are a very interesting option for biologic augmentation. The study may serve as basis for further research in growth factor application models.

Formulation and evaluation of buccal film of Ivabradine hydrochloride for the treatment of stable angina pectoris

PubMed Central

Lodhi, Mohasin; Dubey, Akhilesh; Narayan, Reema; Prabhu, Prabhakara; Priya, Sneh

2013-01-01

Background: Ivabradine hydrochloride is an anti-anginal drug with a biological half-life of about 2 h, and repeated daily administration is needed to maintain effective plasma level. Present investigation of buccal films of Ivabradine hydrochloride is an attempt to avoid the repeated administration and release of drug in more controlled fashion, thereby, to improve the bioavailability. Materials and Methods: Buccal patches were fabricated by solvent casting technique and were evaluated for its physical properties like physical appearance, weight uniformity, thickness, swelling index, surface pH, mucoadhesive time, and folding endurance, in vitro and ex vivo release studies. Results: A combination of hydroxypropyl methyl cellulose (HPMC) K15M and K100M with carbopol 940, PEG 6000 gave promising results. Further, the drug content of all the formulations was determined and was found to be uniform. All the formulations were subjected to in vitro release study using phosphate buffer pH 6.6. Patches exhibited drug release in the range of 90.36% ± 0.854 to 98.37% ± 0.589 at the end of six hrs. The best formulations (F2 and F5) containing the composition of HPMC K15-37.50 mg, carbopol-0.42 mg, PEG6000-16.87 mg, Aspertane-0.28 mg, Tween-0.0023 mg and HPMC K100-37.50 mg, carbopol-0.42 mg, PEG6000-16.87 mg, Aspertane-0.28 mg, Tween-0.0023 mg respectively exhibited in vitro drug release of 97.61% ± 0.589 and 98.37% ± 0.114 respectively. The results of ex vivo diffusion using goat cheek pouch revealed that the drug release rate was retarded up to seven hrs. Films prepared with permeation enhancer (Tween 80) showed faster drug release. Finally, stability studies were carried out by using human saliva for the optimized formulation (F2-F5). Conclusion: The present study indicated enormous potential of mucoadhesive buccal patches containing Ivabradine for systemic delivery with an added advantage of circumventing hepatic first pass metabolism. Further work is recommended to support its efficacy claims by long term pharmacokinetic and pharmacodynamic studies in human beings. PMID:23799205

A case study on the in silico absorption simulations of levothyroxine sodium immediate-release tablets.

PubMed

Kocic, Ivana; Homsek, Irena; Dacevic, Mirjana; Grbic, Sandra; Parojcic, Jelena; Vucicevic, Katarina; Prostran, Milica; Miljkovic, Branislava

2012-04-01

The aim of this case study was to develop a drug-specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus™ software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration-time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate-release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro-in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets. Copyright © 2012 John Wiley & Sons, Ltd.

Development and Evaluation of Chitosan Microparticles Based Dry Powder Inhalation Formulations of Rifampicin and Rifabutin.

PubMed

Pai, Rohan V; Jain, Rajesh R; Bannalikar, Anilkumar S; Menon, Mala D

2016-04-01

The lung is the primary entry site and target for Mycobacterium tuberculosis; more than 80% of the cases reported worldwide are of pulmonary tuberculosis. Hence, direct delivery of anti-tubercular drugs to the lung would be beneficial in reducing both, the dose required, as well as the duration of therapy for pulmonary tuberculosis. In the present study, microsphere-based dry powder inhalation systems of the anti-tubercular drugs, rifampicin and rifabutin, were developed and evaluated, with a view to achieve localized and targeted delivery of these drugs to the lung. The drug-loaded chitosan microparticles were prepared by an ionic gelation method, followed by spray-drying to obtain respirable particles. The microparticles were evaluated for particle size and drug release. The drug-loaded microparticles were then adsorbed onto an inhalable lactose carrier and characterized for in vitro lung deposition on an Andersen Cascade Impactor (ACI) followed by in vitro uptake study in U937 human macrophage cell lines. In vivo toxicity of the developed formulations was evaluated using Sprague Dawley rats. Both rifampicin and rifabutin-loaded microparticles had MMAD close to 5 μm and FPF values of 21.46% and 29.97%, respectively. In vitro release study in simulated lung fluid pH 7.4 showed sustained release for 12 hours for rifampicin microparticles and up to 96 hours for rifabutin microparticles, the release being dependent on both swelling of the polymer and solubility of the drugs in the dissolution medium. In vitro uptake studies in U937 human macrophage cell line suggested that microparticles were internalized within the macrophages. In vivo acute toxicity study of the microparticles in Sprague Dawley rats revealed no significant evidence for local adverse effects. Thus, spray-dried microparticles of the anti-tubercular drugs, rifampicin and rifabutin, could prove to be an improved, targeted, and efficient system for treatment of tuberculosis.

Formulation and in Vitro, ex Vivo and in Vivo Evaluation of Elastic Liposomes for Transdermal Delivery of Ketorolac Tromethamine.

PubMed

Nava, Guadalupe; Piñón, Elizabeth; Mendoza, Luis; Mendoza, Néstor; Quintanar, David; Ganem, Adriana

2011-12-15

The objective of the current study was to formulate ketorolac tromethamine-loaded elastic liposomes and evaluate their in vitro drug release and their ex vivo and in vivo transdermal delivery. Ketorolac tromethamine (KT), which is a potent analgesic, was formulated in elastic liposomes using Tween 80 as an edge activator. The elastic vesicles were prepared by film hydration after optimizing the sonication time and number of extrusions. The vesicles exhibited an entrapment efficiency of 73 ± 11%, vesicle size of 127.8 ± 3.4 nm and a zeta potential of -12 mV. In vitro drug release was analyzed from liposomes and an aqueous solution, using Franz diffusion cells and a cellophane dialysis membrane with molecular weight cut-off of 8000 Da. Ex vivo permeation of KT across pig ear skin was studied using a Franz diffusion cell, with phosphate buffer (pH 7.4) at 32 °C as receptor solution. An in vivo drug permeation study was conducted on healthy human volunteers using a tape-stripping technique. The in vitro results showed (i) a delayed release when KT was included in elastic liposomes, compared to an aqueous solution of the drug; (ii) a flux of 0.278 mg/cm2h and a lag time of about 10 h for ex vivo permeation studies, which may indicate that KT remains in the skin (with the possibility of exerting a local effect) before reaching the receptor medium; (iii) a good correlation between the total amount permeated, the penetration distance (both determined by tape stripping) and transepidermal water loss (TEWL) measured during the in vivo permeation studies. Elastic liposomes have the potential to transport the drug through the skin, keep their size and drug charge, and release the drug into deep skin layers. Therefore, elastic liposomes hold promise for the effective topical delivery of KT.

Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques.

PubMed

Malcolm, R Karl; Veazey, Ronald S; Geer, Leslie; Lowry, Deborah; Fetherston, Susan M; Murphy, Diarmaid J; Boyd, Peter; Major, Ian; Shattock, Robin J; Klasse, Per Johan; Doyle, Lara A; Rasmussen, Kelsi K; Goldman, Laurie; Ketas, Thomas J; Moore, John P

2012-05-01

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 μg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ~10(6)-fold greater than the 50% inhibitory concentrations (IC(50)s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

PubMed Central

Veazey, Ronald S.; Geer, Leslie; Lowry, Deborah; Fetherston, Susan M.; Murphy, Diarmaid J.; Boyd, Peter; Major, Ian; Shattock, Robin J.; Klasse, Per Johan; Doyle, Lara A.; Rasmussen, Kelsi K.; Goldman, Laurie; Ketas, Thomas J.; Moore, John P.

2012-01-01

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 μg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ∼106-fold greater than the 50% inhibitory concentrations (IC50s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle. PMID:22330914

Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system.

PubMed

Chen, Zhi-Qiang; Liu, Ying; Zhao, Ji-Hui; Wang, Lan; Feng, Nian-Ping

2012-01-01

Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin. A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats. The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor(®) EL:Transcutol(®) P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS. The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin.

Liposomal Aloe vera trans-emulgel drug delivery of naproxen and nimesulide: A study

PubMed Central

Venkataharsha, Panuganti; Maheshwara, Ellutla; Raju, Y Prasanna; Reddy, Vayalpati Ashok; Rayadu, Bandugalla Sanjeev; Karisetty, Basappa

2015-01-01

Introduction: The present aim of this study was to formulate naproxen and nimesulide liposomal formulation for incorporation in Aloe vera transemulgel and to carry out in vitro and in vivo evaluation of the formulation. Material and Methods: A. vera gel was prepared and used as a gel base for formulation. Carbopol 934 is used as a gelling agent and Methyl paraben was used as a preservative for the formulation of the gel. Liposomes was formulated by using hydration method. The formulated naproxen and nimesulide liposomal formulation using A. vera trans-emul gel were evaluated for in vitro studies such as drug release, permeation study, and drug content and entrapment efficiency. Paw edema method in Wistar rats induced by carrageenan is used to study in vivo anti-inflammatory action. Result: From the in vitro studies such permeability drug release naproxen 65% (69.6), Nimesulide 65% (61.1), and commercial Nimsulide gel (60.82) at 240 min. In vivo data shows that formulated liposomal transemulgel formulation are superior in their efficacy compared to commercial and A. vera gel. The results are compared with the commercial formulations. Conclusion: From our results, it is concluded that the A. vera trans emul gel using nimesulide and naproxen liposomal formulation is stable and prepared gel base is effective for formulation with high drug release and drug content compared with commercial formulation with significant anti-inflammatory effect. PMID:25599030

Floating modular drug delivery systems with buoyancy independent of release mechanisms to sustain amoxicillin and clarithromycin intra-gastric concentrations.

PubMed

Rossi, Alessandra; Conti, Chiara; Colombo, Gaia; Castrati, Luca; Scarpignato, Carmelo; Barata, Pedro; Sandri, Giuseppina; Caramella, Carla; Bettini, Ruggero; Buttini, Francesca; Colombo, Paolo

2016-01-01

Release modules of amoxicillin and clarithromycin combined in a single dosage form designed to float in the gastric content and to sustain the intra-gastric concentrations of these two antibiotics used for the eradication of Helicobacter pylori have been studied. The modules having a disc shape with curved bases were formulated as hydrophilic matrices. Two modules of clarithromycin were assembled by sticking the concave base of one module to the concave base of the other, creating an internal void chamber. The final dosage form was a floating assembly of three modules of clarithromycin and two of amoxicillin in which the drug release mechanism did not interfere with the floatation mechanism. The assembled system showed immediate in vitro floatation at pH 1.2, lasting 5 h. The in vitro antibiotics release profiles from individual modules and assembled systems exhibited linear release rate during buoyancy for at least 8 h. The predicted antibiotic concentrations in the stomach maintained for long time levels significantly higher than the respective minimum inhibitory concentrations (MIC). In addition, an in vivo absorption study performed on beagle dogs confirmed the slow release of clarithromycin and amoxicillin from the assembled system during the assembly's permanence in the stomach for at least 4 h.

Natural Non-Mulberry Silk Nanoparticles for Potential-Controlled Drug Release

PubMed Central

Wang, Juan; Yin, Zhuping; Xue, Xiang; Kundu, Subhas C.; Mo, Xiumei; Lu, Shenzhou

2016-01-01

Natural silk protein nanoparticles are a promising biomaterial for drug delivery due to their pleiotropic properties, including biocompatibility, high bioavailability, and biodegradability. Chinese oak tasar Antheraea pernyi silk fibroin (ApF) nanoparticles are easily obtained using cations as reagents under mild conditions. The mild conditions are potentially advantageous for the encapsulation of sensitive drugs and therapeutic molecules. In the present study, silk fibroin protein nanoparticles are loaded with differently-charged small-molecule drugs, such as doxorubicin hydrochloride, ibuprofen, and ibuprofen-Na, by simple absorption based on electrostatic interactions. The structure, morphology and biocompatibility of the silk nanoparticles in vitro are investigated. In vitro release of the drugs from the nanoparticles depends on charge-charge interactions between the drugs and the nanoparticles. The release behavior of the compounds from the nanoparticles demonstrates that positively-charged molecules are released in a more prolonged or sustained manner. Cell viability studies with L929 demonstrated that the ApF nanoparticles significantly promoted cell growth. The results suggest that Chinese oak tasar Antheraea pernyi silk fibroin nanoparticles can be used as an alternative matrix for drug carrying and controlled release in diverse biomedical applications. PMID:27916946

Nanocomposites coated with xyloglucan for drug delivery: In vitro studies.

PubMed

Ribeiro, C; Arizaga, G G C; Wypych, F; Sierakowski, M-R

2009-02-09

Enalaprilate (Enal), an active pharmaceutical component, was intercalated into a layered double hydroxide (Mg/Al-LDH) by an ion exchange reaction. The use of a layered double hydroxide (LDH) to release active drugs is limited by the low pH of the stomach (pH approximately 1.2), in whose condition it is readily dissolved. To overcome this limitation, xyloglucan (XG) extracted from Hymenaea courbaril (jatobá) seeds, Brazilian species, was used to protect the LDH and allow the drug to pass through the gastrointestinal tract. All the materials were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, elemental analyses, transmission electronic microscopy, thermal analyses, and a kinetic study of the in vitro release was monitored by ultraviolet spectroscopy. The resulting hybrid system containing HDL-Enal-XG(3) slowly released the Enal. In an 8-h of test, the system protected 40% (w/v) of the drug. The kinetic profile showed that the drug release was a co-effect behavior, involving dissolution of inorganic material and ion exchange between the intercalated anions in the lamella and those of phosphate in the buffer solution. The nanocomposite coated protection with XG was therefore efficient in obtaining a slow release of Enal.

Injectable visible light-cured glycol chitosan hydrogels with controlled release of anticancer drugs for local cancer therapy in vivo: a feasible study.

PubMed

Hyun, Hoon; Park, Min Ho; Lim, Wonbong; Kim, So Yeon; Jo, Danbi; Jung, Jin Seok; Jo, Gayoung; Um, Sewook; Lee, Deok-Won; Yang, Dae Hyeok

2018-05-11

Currently available chemotherapy is associated with serious side effects, and therefore novel drug delivery systems (DDSs) are required to specifically deliver anticancer drugs to targeted sites. In this study, we evaluated the feasibility of visible light-cured glycol chitosan (GC) hydrogels with controlled release of doxorubicin⋅hydrochloride (DOX⋅HCl) as local DDSs for effective cancer therapy in vivo. The storage modulus of the hydrogel precursor solutions was increased as a function of visible light irradiation time. In addition, the swelling ratio of the hydrogel irradiated for 10 s (GC 10 /DOX) was greater than in 60 s (GC 60 /DOX). In vitro release test showed that DOX was rapidly released in GC 10 /DOX compared with GC 60 /DOX due to the density of cross-linking. In vitro and in vivo tests including cell viability and measurement of tumor volume showed that the local treatment of GC 10 /DOX yielded substantially greater antitumor effect compared with that of GC 60 /DOX. Therefore, the visible light-cured GC hydrogel system may exhibit clinical potential as a local DDS of anticancer drugs with controlled release, by modulating cross-linking density.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albertson, B.; Binney, S.

This paper describes research on the following: the structure of {sup 10}B{sub 10}-ovine corticotropin releasing hormone and {sup 10}B{sub 10}-growth hormone releasing hormone; the BNCT effect on AtT-20 cell {sup 10}B{sub 10}-CRH incubations in vitro; BNCT effects on GH{sub 4}C{sub 1} cell {sup 10}B{sub 10} growth hormone releasing factor incubation in vitro; and competitive inhibition of AtT-20 cell BNCT effect.

Hydrogels containing redispersible spray-dried melatonin-loaded nanocapsules: a formulation for transdermal-controlled delivery

NASA Astrophysics Data System (ADS)

Hoffmeister, Cristiane RD; Durli, Taís L.; Schaffazick, Scheila R.; Raffin, Renata P.; Bender, Eduardo A.; Beck, Ruy CR; Pohlmann, Adriana R.; Guterres, Sílvia S.

2012-05-01

The aim of the present study was to develop a transdermal system for controlled delivery of melatonin combining three strategies: nanoencapsulation of melatonin, drying of melatonin-loaded nanocapsules, and incorporation of nanocapsules in a hydrophilic gel. Nanocapsules were prepared by interfacial deposition of the polymer and were spray-dried using water-soluble excipients. In vitro drug release profiles were evaluated by the dialysis bag method, and skin permeation studies were carried out using Franz cells with porcine skin as the membrane. The use of 10% ( w/ v) water-soluble excipients (lactose or maltodextrin) as spray-drying adjuvants furnished redispersible powders (redispersibility index approximately 1.0) suitable for incorporation into hydrogels. All formulations showed a better controlled in vitro release of melatonin compared with the melatonin solution. The best controlled release results were achieved with hydrogels prepared with dried nanocapsules (hydrogels > redispersed dried nanocapsules > nanocapsule suspension > melatonin solution). The skin permeation studies demonstrated a significant modulation of the transdermal melatonin permeation for hydrogels prepared with redispersible nanocapsules. In this way, the additive effect of the different approaches used in this study (nanoencapsulation, spray-drying, and preparation of semisolid dosage forms) allows not only the control of melatonin release, but also transdermal permeation.

Controlled porosity osmotic pump-based controlled release systems of pseudoephedrine. I. Cellulose acetate as a semipermeable membrane.

PubMed

Makhija, Sapna N; Vavia, Pradeep R

2003-04-14

A controlled porosity osmotic pump-based drug delivery system has been described in this study. Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channeling agents in the coating. The usual dose of pseudoephedrine is 60 mg to be taken three or four times daily. It has a short plasma half life of 5-8 h. Hence, pseudoephedrine was chosen as a model drug with an aim to develop a controlled release system for a period of 12 h. Sodium bicarbonate was used as the osmogent. The effect of different ratios of drug:osmogent on the in-vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. Different channeling agents tried were diethylphthalate (DEP), dibutylphthalate (DBP), dibutylsebacate (DBS) and polyethyleneglycol 400 (PEG 400). The effect of polymer loading on in-vitro drug release was studied. It was found that drug release rate increased with the amount of osmogent due to the increased water uptake, and hence increased driving force for drug release. This could be retarded by the proper choice of channeling agent in order to achieve the desired zero order release profile. Also the lag time seen with tablets coated using diethylphthalate as channeling agent was reduced by using a hydrophilic plasticizer like polyethyleneglycol 400 in combination with diethylphthalate. This system was found to deliver pseudoephedrine at a zero order rate for 12 h. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per ICH guidelines at different temperature and humidity conditions.

Effect of palmitic acid on the characteristics and release profiles of rotigotine-loaded microspheres.

PubMed

Wang, Aiping; Liang, Rongcai; Liu, Wanhui; Sha, Chunjie; Li, Youxin; Sun, Kaoxiang

2016-01-01

The initial burst release is a major obstacle to the development of microsphere-formulated drug products. To investigate the influence of palmitic acid on the characteristics and release profiles of rotigotine-loaded poly(d,l-lactide-co-glycolide) microspheres. Rotigotine-loaded microspheres (RMS) were prepared using the oil-in-water emulsion solvent evaporation technique. The in vitro characteristics of the RMS were evaluated with scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and a particle size analyzer. The in vitro drug release and in vivo pharmacokinetics of the RMS were investigated. The SEM results showed that the addition of palmitic acid changed the surface morphology of the microspheres from smooth to dimpled and then to non-smooth as the palmitic acid content increased. DSC revealed the existence of molecularly dispersed forms of palmitic acid in the microspheres. The in vitro and in vivo release profiles indicated that the addition of 5% and 8% palmitic acid significantly decreased the burst release of rotigotine from the microspheres, and the late-stage release was delayed as the palmitic acid content increased across the investigated range (5-15%). The addition of palmitic acid to the microspheres significantly affects the release profile of rotigotine from RMS.

Adverse reactions to suxamethonium and other muscle relaxants under general anesthesia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vervloet, D.; Nizankowska, E.; Arnaud, A.

The mechanisms of anaphylactic reactions to muscle relaxants under general anesthesia are not completely understood. Extending an earlier study, we report 41 cases of anaphylactic shock investigated by intradermal skin tests with muscle relaxants (suxamethonium, pancuronium, gallamine, nortoxiferine), in vitro leukocyte histamine release, and Prausnitz-Kuestner tests. Intradermal tests were significantly positive at concentrations ranging from 10 to 10(5) times less than those in controls. Reproducibility tested for suxamethonium at a 1-year interval in five patients was good. Histamine release induced by muscle relaxants in Tris-albumin-Ca++-Mg++ buffer showed positive results in 8/25 instances and was inhibited by antigen excess in sevenmore » cases. Addition of 50% deuterium oxide (D2O) caused significant increase of histamine release in positive cases and induced release in all five negative cases studied. Muscle relaxant-induced histamine release was inhibited by in vitro anti-IgE leukocyte desensitization. The mean maximal histamine release dropped from 58.2% +/- 9.7 to 5.8% +/- 2 (p less than 0.01). Similarly, leukocyte desensitization also inhibited histamine release induced by anti-IgE but not by formyl-L-methionyl-L-leucyl-L-phenylalanine or poly-L-arginine. Prausnitz-Kuestner tests were positive in five out of 21 cases studied and became negative after heat inactivation. These results confirm the usefulness of intradermal skin tests in diagnosis of patients' reaction to muscle relaxants and suggest an IgE-mediated rather than an idiosyncratic mechanism.« less

Formulation and in-vitro evaluation of floating bilayer tablet of lisinopril maleate and metoprolol tartrate.

PubMed

Ijaz, Hira; Qureshi, Junaid; Danish, Zeeshan; Zaman, Muhammad; Abdel-Daim, Mohamed; Hanif, Muhammad; Waheed, Imran; Mohammad, Imran Shair

2015-11-01

The purpose of this study was to introduce the technology for the development of rate-controlled oral drug delivery system to overcome various physiological problems. Several approaches are being used for the purpose of increasing the gastric retentive time, including floating drug delivery system. Gastric floating lisinopril maleate and metoprolol tartrate bilayer tablets were formulated by direct compression method using the sodium starch glycolate, crosscarmellose sodium for IR layer. Eudragit L100, pectin, acacia as sustained release polymers in different ratios for SR metoprolol tartrate layer and sodium bicarbonate, citric acid as gas generating agents for the floating extended release layer. The floating bilayer tablets of lisinopril maleate and metoprolol tartrate were designed to overcome the various problems associated with conventional oral dosage form. Floating tablets were evaluated for floating lag time, drug contents and in-vitro dissolution profile and different kinetic release models were applied. It was clear that the different ratios of polymers affected the drug release and floating time. L2 and M4 showed good drug release profile and floating behavior. The linear regression and model fitting showed that all formulation followed Higuchi model of drug release model except M4 that followed zero order kinetic. From the study it is evident that a promising controlled release by floating bilyer tablets of lisinopril maleate and metoprolol tartrate can be developed successfully.

Injectable, in situ forming poly(propylene fumarate)-based ocular drug delivery systems.

PubMed

Ueda, H; Hacker, M C; Haesslein, A; Jo, S; Ammon, D M; Borazjani, R N; Kunzler, J F; Salamone, J C; Mikos, A G

2007-12-01

This study sought to develop an injectable formulation for long-term ocular delivery of fluocinolone acetonide (FA) by dissolving the anti-inflammatory drug and the biodegradable polymer poly(propylene fumarate) (PPF) in the biocompatible, water-miscible, organic solvent N-methyl-2-pyrrolidone (NMP). Upon injection of the solution into an aqueous environment, a FA-loaded PPF matrix is precipitated in situ through the diffusion/extraction of NMP into surrounding aqueous fluids. Fabrication of the matrices and in vitro release studies were performed in phosphate buffered saline at 37 degrees C. Drug loadings up to 5% were achieved. High performance liquid chromatography was employed to determine the released amount of FA. The effects of drug loading, PPF content of the injectable formulation, and additional photo-crosslinking of the matrix surface were investigated. Overall, FA release was sustained in vitro over up to 400 days. After an initial burst release of 22 to 68% of initial FA loading, controlled drug release driven by diffusion and bulk erosion was observed. Drug release rates in a therapeutic range were demonstrated. Release kinetics were found to be dependent on drug loading, formulation PPF content, and extent of surface crosslinking. The results suggest that injectable, in situ formed PPF matrices are promising candidates for the formulation of long-term, controlled delivery devices for intraocular drug delivery. Copyright 2007 Wiley Periodicals, Inc.

Tapioca starch blended alginate mucoadhesive-floating beads for intragastric delivery of Metoprolol Tartrate.

PubMed

Biswas, Nikhil; Sahoo, Ranjan Kumar

2016-02-01

The objective of the study was to develop tapioca starch blended alginate mucoadhesive-floating beads for the intragastric delivery of Metoprolol Tartrate (MT). The beads were prepared by ionotropic gelation method using calcium chloride as crosslinker and gas forming calcium carbonate (CaCO3) as floating inducer. The alginate gel beads having 51-58% entrapped MT showed 90% release within 45 min in gastric medium (pH 1.2). Tapioca starch blending markedly improved the entrapment efficiency (88%) and sustained the release for 3-4 h. A 12% w/w HPMC coating on these beads extended the release upto 9-11 h. In vitro wash off and buoyancy test in gastric media revealed that the beads containing CaCO3 has gastric residence of more than 12 h. In vitro optimized multi-unit formulation consisting of immediate and sustained release mucoadhesive-floating beads (40:60) showed good initial release of 42% MT within 1h followed by a sustained release of over 90% for 11 h. Pharmacokinetic study performed in rabbit model showed that the relative oral bioavailability of MT after administration of oral solution, sustain release and optimized formulation was 51%, 67% and 87%, respectively. Optimized formulation showed a higher percent inhibition of isoprenaline induced heart rate in rabbits for almost 12 h. Copyright © 2015 Elsevier B.V. All rights reserved.

Enteric-coated sustained-release nanoparticles by coaxial electrospray: preparation, characterization, and in vitro evaluation

NASA Astrophysics Data System (ADS)

Hao, Shilei; Wang, Bochu; Wang, Yazhou; Xu, Yingqian

2014-02-01

Enteric-coated formulations can delay the release of drugs until they have passed through the stomach. However, high concentration of drugs caused by rapidly released in the small intestine leads to the intestinal damage, and frequent administration would increase the probability of missing medication and reduce the patient compliance. To solve the above-mentioned problems, aspirin-loaded enteric-coated sustained-release nanoparticles with core-shell structure were prepared via one-step method using coaxial electrospray in this study. Eudragit L100-55 as pH-sensitive polymer and Eudragit RS as sustained-release polymer were used for the outer coating and inner core of the nanoparticles, respectively. The maximum loading capacity of nanoparticles was 23.66 % by changing the flow rate ratio of outer/inner solutions, and the entrapment efficiency was nearly 100 %. Nanoparticles with core-shell structure were observed via fluorescence microscope and transmission electron microscope. And pH-sensitive and sustained drug release profiles were observed in the media with different pH values (1.2 and 6.8). In addition, mild cytotoxicity in vitro was detected, and the nanoparticles could be taken up by Caco-2 cells within 1.0 h in cellular uptake study. These results indicate that prepared enteric-coated sustained-release nanoparticles would be a more safety and effective carrier for oral drug delivery.

Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study

PubMed Central

Nicola, Valentina G.; Vischer, Nerina; Donzelli, Massimiliano; Krähenbühl, Stephan; Grouzmann, Eric; Huwyler, Jörg; Hoener, Marius C.; Liechti, Matthias E.

2012-01-01

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4–methylenedioxy­methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence. Trial Registration Clinicaltrials.gov NCT00990067 PMID:22574166

Topical phenytoin nanostructured lipid carriers: design and development.

PubMed

Motawea, Amira; Borg, Thanaa; Abd El-Gawad, Abd El-Gawad H

2018-01-01

Phenytoin (PHT) is an antiepileptic drug that was reported to exhibit high wound healing activity. Nevertheless, its limited solubility, bioavailability, and inefficient distribution during topical administration limit its use. Therefore, this study aims to develop, characterize nanostructured lipid carriers (NLCs), and evaluate their potential in topical delivery of PHT to improve the drug entrapment efficiency and sustained release. The NLCs were prepared by hot homogenization followed by ultra sonication method using 2 3 factorial design. NLC formulations were characterized regarding their particle size (PS), zeta potential (ZP), entrapment efficiency percent (%EE), surface morphology, physicochemical stability, and in vitro release studies. The optimized NLC (F7) was further incorporated in 1%w/v carbopol gel and then characterized for appearance, pH, viscosity, stability, and in vitro drug release. The prepared NLCs were spherical in shape and possessed an average PS of 121.4-258.2 nm, ZP of (-15.4)-(-32.2) mV, and 55.24-88.80 %EE. Solid-state characterization revealed that the drug is dispersed in an amorphous state with hydrogen bond interaction between the drug and the NLC components. NLC formulations were found to be stable at 25 °C for six months. The stored F7-hydrogel showed insignificant changes in viscosity and drug content (p>.05) up to six months at 25 °C that pave a way for industrial fabrication of efficient PHT products. In vitro release studies showed a sustained release from NLC up to 48 h at pH 7.4 following non-Fickian Higuchi kinetics model. These promising findings encourage the potential use of phenytoin loaded lipid nanoparticles for future topical application.

Evidence from immunoneutralization and antisense studies that the inhibitory actions of glucocorticoids on growth hormone release in vitro require annexin 1 (lipocortin 1)

PubMed Central

Taylor, A D; Christian, H C; Morris, J F; Flower, R J; Buckingham, J C

2000-01-01

Our previous studies have identified a role for annexin 1 as a mediator of glucocorticoid action in the neuroendocrine system. The present study centred on growth hormone (GH) and exploited antisense and immunoneutralization strategies to examine in vitro the potential role of annexin 1 in effecting the regulatory actions of glucocorticoids on the secretion of this pituitary hormone. Rat anterior pituitary tissue responded in vitro to growth hormone releasing hormone, forskolin, 8-Bromo-cyclic adenosine 3′5′-monophosphate (8-Br-cyclic AMP) and an L-Ca2+ channel opener (BAY K8644) with concentration-dependent increases GH release which were readily inhibited by corticosterone and dexamethasone. The inhibitory actions of the steroids on GH release elicited by the above secretagogues were effectively reversed by an annexin 1 antisense oligodeoxynucleotide (ODN), but not by control (sense or scrambled) ODNs, as also were the glucocorticoid-induced increases in annexin 1. Similarly, a specific anti-annexin 1 monoclonal antibody quenched the corticosterone-induced suppression of secretagogue-evoked GH release while an isotype matched control antibody was without effect. Transmission electron micrographs showed that the integrity and ultrastructural morphology of the pituitary cells were well preserved at the end of the incubation and unaffected by exposure to the ODNs, antibodies, steroids or secretagogues. The results provide novel evidence for a role for annexin 1 as a mediator of the inhibitory actions of glucocorticoids on the secretion of GH by the anterior pituitary gland and suggest that its actions are effected at a point distal to the formation of cyclic AMP and Ca2+ entry. PMID:11090102

Evidence from immunoneutralization and antisense studies that the inhibitory actions of glucocorticoids on growth hormone release in vitro require annexin 1 (lipocortin 1).

PubMed

Taylor, A D; Christian, H C; Morris, J F; Flower, R J; Buckingham, J C

2000-12-01

1. Our previous studies have identified a role for annexin 1 as a mediator of glucocorticoid action in the neuroendocrine system. The present study centred on growth hormone (GH) and exploited antisense and immunoneutralization strategies to examine in vitro the potential role of annexin 1 in effecting the regulatory actions of glucocorticoids on the secretion of this pituitary hormone. 2. Rat anterior pituitary tissue responded in vitro to growth hormone releasing hormone, forskolin, 8-Bromo-cyclic adenosine 3'5'-monophosphate (8-Br-cyclic AMP) and an L-Ca(2+) channel opener (BAY K8644) with concentration-dependent increases GH release which were readily inhibited by corticosterone and dexamethasone. 3. The inhibitory actions of the steroids on GH release elicited by the above secretagogues were effectively reversed by an annexin 1 antisense oligodeoxynucleotide (ODN), but not by control (sense or scrambled) ODNs, as also were the glucocorticoid-induced increases in annexin 1. Similarly, a specific anti-annexin 1 monoclonal antibody quenched the corticosterone-induced suppression of secretagogue-evoked GH release while an isotype matched control antibody was without effect. 4. Transmission electron micrographs showed that the integrity and ultrastructural morphology of the pituitary cells were well preserved at the end of the incubation and unaffected by exposure to the ODNs, antibodies, steroids or secretagogues. 5. The results provide novel evidence for a role for annexin 1 as a mediator of the inhibitory actions of glucocorticoids on the secretion of GH by the anterior pituitary gland and suggest that its actions are effected at a point distal to the formation of cyclic AMP and Ca(2+) entry.

Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo

PubMed Central

Luo, Yuling; Liu, Zhongbing; Zhang, Xiaoqin; Huang, Juan; Yu, Xin; Li, Jinwei; Xiong, Dan; Sun, Xiaoduan; Zhong, Zhirong

2016-01-01

The aim of the present study was to develop a novel dosage form of multivesicular liposomes for oleanolic acid (OA) to overcome its poor solubility, prolong therapeutic drug levels in the blood, and enhance the antitumor effect on hepatocellular carcinoma. OA-encapsulated multivesicular liposomes (OA-MVLs) were prepared by a double-emulsion method, and the formulation was optimized by the central composite design. The morphology, particle size, and drug-loading efficiency of OA-MVLs were investigated. Furthermore, OA-MVLs were also characterized both in vitro and in vivo. The results showed that OA-MVLs were spherical particles with an average particle size of 11.57 μm and an encapsulation efficiency of 82.3%±0.61%. OA-MVLs exhibited a sustained-release pattern in vitro, which was fitted to Ritger–Peppas equation. OA-MVLs inhibited the growth of human HepG2 cells which was confirmed by the MTT assay and fluorescence microscopy detection. The in vivo release of OA from OA-MVLs exhibited a sustained manner, indicating a longer circulation time compared to OA solution. The in vivo toxicity study indicated that medium-dose OA-MVLs exerted no toxic effect on the hosts. Importantly, OA-MVLs suppressed the growth of murine H22 hepatoma and prolonged the survival of tumor-bearing mice. In conclusion, the poorly soluble OA could be encapsulated into MVLs to form a novel controlled-release drug delivery system. The present study may hold promise for OA-MVLs as a new dosage form for sustained-release drug delivery in cancer therapy. PMID:27471381

Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state.

PubMed

Miao, Yanfei; Sun, Jiqin; Chen, Guoguang; Lili, Ren; Ouyang, Pingkai

2016-08-01

The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs). The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control. The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5 min. Pharmacokinetic study showed that the AUC(0-∞) and Cmax for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption. It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.

Combination of injectable ethinyl estradiol and drospirenone drug-delivery systems and characterization of their in vitro release.

PubMed

Nippe, Stefanie; General, Sascha

2012-11-20

Our aim was to investigate the in vitro release and combination of ethinyl estradiol (EE) and drospirenone (DRSP) drug-delivery systems. DRSP poly(lactic-co-glycolic acid) (PLGA) microparticles and organogels containing DRSP microcrystals were prepared and characterized with regard to properties influencing drug release. The morphology and release kinetics of DRSP PLGA microparticles indicated that DRSP is dispersed in the polymer. The in vitro release profiles correlated well with in vivo data. Although DRSP degradation is known to be acid-catalyzed, DRSP was relatively stable in the PLGA matrix. Aqueous DRSP PLGA microparticle suspensions were combinable with EE PLGA microparticles and EE poly(butylcyanoacrylate) (PBCA) microcapsules without interacting. EE release from PLGA microparticles was faster than DRSP release; EE release is assumed to be primarily controlled by drug diffusion. Liquid-filled EE PBCA microcapsules were shown to be more robust than air-filled EE PBCA microcapsules; the bursting of microcapsules accelerating the drug delivery was therefore delayed. The drug release profile for DRSP organogels was fairly linear with the square root of time. The system was not combinable with EE PBCA microcapsules. In contrast, incorporation of EE PLGA microparticles in organogels resulted in prolonged EE release. The drug release of EE and DRSP was thus approximated. Copyright © 2012 Elsevier B.V. All rights reserved.

Targeted killing of cancer cells in vivo and in vitro with IGF-IR antibody-directed carbon nanohorns based drug delivery.

PubMed

Li, Nannan; Zhao, Qian; Shu, Chang; Ma, Xiaona; Li, Ruixin; Shen, Hongjun; Zhong, Wenying

2015-01-30

Oxidized single-wall carbon nanohorns (oxSWNHs) have shown great potential in drug delivery. The purpose of this study was to design an effective targeted drug delivery system (DDS) based on oxSWNHs, which could carry high dose of drug to tumor sites and improve the therapeutic efficacy with less adverse effects. OxSWNHs incorporated the anticancer drug vincristine (VCR) via physical adsorption, then wrapped DSPE-PEG-IGF-IR monoclonal antibody (mAb) through an amide liker to obtain the drug delivery system, VCR@oxSWNHs-PEG-mAb. The in vitro release behavior study indicated that the DDS had good sustained release and the cumulative release of VCR was 80% at 144h. Compared with free VCR, the tumor targeting drug delivery efficiently enhanced the cytotoxicity in cultured MCF-7 cells in vitro, and afforded higher antitumor efficacy without obvious toxic effects to normal organs in tumor mice in vivo. In addition, the targeted DDS could reduce the toxicity of VCR to the living mice. This study demonstrated that VCR@oxSWNHs-PEG-mAb might be promising for high treatment efficacy with minimal side effects in future cancer therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Is Andrographis paniculata extract and andrographolide anaphylactic?

PubMed

Richard, Edwin Jothie; Murugan, Sasikumar; Bethapudi, Bharathi; Illuri, Ramanaiah; Mundkinajeddu, Deepak; Chinampudur Velusami, Chandrasekaran

2017-01-01

Andrographis paniculata, "King of bitters" is a popularly known medicinal plant extensively used in many parts of the world for treatment of various diseases. Since recent past, anaphylactic/allergic type adverse events were reported upon A. paniculata usage, the study aimed to evaluate the anaphylactic and anaphylactoid potential of A. paniculata extract and andrographolide (a major phytoactive of A. paniculata ). The anaphylactic potential was evaluated using active systemic anaphylaxis (ASA) assay in guinea pigs. Further, the release of allergic mediators was measured in immunoglobulin E (IgE) sensitized and non-IgE sensitized Rat Basophilic Leukemia (RBL-2H3) cell lines in-vitro . A. paniculata extract or andrographolide sensitized guinea pigs following the challenge antigen administration orally and intravenously did not demonstrate any clinical signs of anaphylaxis. IgE sensitized and non- IgE sensitized RBL-2H3 cells treated with A. paniculata extract did not induce release of allergic mediators. Whereas IgE sensitized and non- IgE sensitized RBL-2H3 cells treated with andrographolide demonstrated mild to moderate release of allergic mediators. A. paniculata extract has no anaphylactic and anaphylactoid potential in in-vivo and in-vitro studies. Whereas, andrographolide effects on allergic mediators in in-vitro studies needs to be scrutinized if they are of biologically important.

Pharmacokinetics and analgesic effect of ketorolac floating delivery system.

PubMed

Radwan, Mahasen A; Abou El Ela, Amal El Sayeh F; Hassan, Maha A; El-Maraghy, Dalia A

2015-05-01

The efficacy of ketorolac tromethamine (KT) floating alginate beads as a drug delivery system for better control of KT release was investigated. The formulation with the highest drug loading, entrapment efficiency, swelling, buoyancy, and in vitro release would be selected for further in vivo analgesic effect in the mice and pharmacokinetics study in rats compared to the tablet dosage form. KT floating alginate beads were prepared by extrusion congealing technique. KT in plasma samples was analyzed using a UPLC MS/MS assay. The percentage yield, drug loading and encapsulation efficiency were increased proportionally with the hydroxypropylmethyl cellulose (HPMC) polymer amount in the KT floating beads. A reverse relationship was observed between HPMC amount in the beads and the KT in vitro release rate. F3-floating beads were selected, due to its better in vitro results (continued floating for >8 h) than others. A longer analgesic effect was observed for F3 in fed mice as compared to the tablets. After F3 administration to rats, the Cmax (2.2 ± 0.3 µg/ml) was achieved at ∼2 h and the decline in KT concentration was slower. F3 showed a significant increase in the AUC (1.89 fold) in rats as compared to the tablets. KT was successfully formulated as floating beads with prolonged in vitro release extended to a better in vivo characteristic with higher bioavailability in rats. KT in floating beads shows a superior analgesic effect over tablets, especially in fed mice.

Pharmacokinetics, brain distribution, release and blood-brain barrier transport of Shunaoxin pills.

PubMed

Wu, Kai; Wang, Zhan-Zhang; Liu, Dan; Qi, Xian-Rong

2014-02-12

Shunaoxin pills, a traditional Chinese medicine (TCM) product, have been used to treat cerebrovascular diseases in China since 2005. The main active components of Shunaoxin pills are ferulic acid and ligustilide from Chuanxiong (Ligusticum chuanxiong Hort, Umbelliferae) and Danggui (Angelica sinensis radix, Umbelliferae). As Shunaoxin shows excellent activity in the central nervous system (CNS), the extent to which the major constituents of Shunaoxin reach the CNS should be investigated. Moreover, the in vivo-in vitro correlations (IVIVC) of the formulation should be studied to elucidate the mechanisms of action of TCM in the CNS. However, these data have not previously been available. Thus we intended to investigate what the extent when these constituents of Shunaoxin pills reach the CNS, and evaluate the IVIVC of release and pharmacokinetics. In this study, we evaluated the release of ferulic acid and ligustilide from Shunaoxin pills, and their transport across an in vitro model of the BBB. We also evaluated their pharmacokinetics and brain distribution in vivo. High-performance liquid chromatography (HPLC) was used to quantify both compounds simultaneously. Based on the release in vitro and absorption of ferulic acid and ligustilide in vivo, IVIVC permitted prediction of the pharmacokinetics of these compounds. The release of ferulic acid and ligustilide reached a platform phase within 1h. Ferulic acid and ligustilide rapidly crossed the BBB in different patterns; the transport ratio increased over time. After intragastric (i.g.) administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed into brain, which may result in a rapid onset of action. Ferulic acid and ligustilide were transported across a model BBB. After i.g. administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed in brain; this may lead to rapid pharmacological onset. The IVIVC can be used to predict in vivo pharmacokinetics from in vitro experimental results. These results provide support for the clinical use of Shunaoxin pills. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Development and optimization of enteric coated mucoadhesive microspheres of duloxetine hydrochloride using 32 full factorial design

PubMed Central

Setia, Anupama; Kansal, Sahil; Goyal, Naveen

2013-01-01

Background: Microspheres constitute an important part of oral drug delivery system by virtue of their small size and efficient carrier capacity. However, the success of these microspheres is limited due to their short residence time at the site of absorption. Objective: The objective of the present study was to formulate and systematically evaluate in vitro performance of enteric coated mucoadhesive microspheres of duloxetine hydrochloride (DLX), an acid labile drug. Materials and Methods: DLX microspheres were prepared by simple emulsification phase separation technique using chitosan as carrier and glutaraldehyde as a cross-linking agent. Microspheres prepared were coated with eudragit L-100 using an oil-in-oil solvent evaporation method. Eudragit L-100was used as enteric coating polymer with the aim to release the drug in small intestine The microspheres prepared were characterized by particle size, entrapment efficiency, swelling index (SI), mucoadhesion time, in vitro drug release and surface morphology. A 32 full factorial design was employed to study the effect of independent variables polymer-to-drug ratio (X1) and stirring speed (X2) on dependent variables, particle size, entrapment efficiency, SI, in vitro mucoadhesion and drug release up to 24 h (t24). Results: Microspheres formed were discrete, spherical and free flowing. The microspheres exhibited good mucoadhesive property and also showed high percentage entrapment efficiency. The microspheres were able to sustain the drug release up to 24 h. Conclusion: Thus, the prepared enteric coated mucoadhesive microspheres may prove to be a potential controlled release formulation of DLX for oral administration. PMID:24167786

3D printed, controlled release, tritherapeutic tablet matrix for advanced anti-HIV-1 drug delivery.

PubMed

Siyawamwaya, Margaret; du Toit, Lisa C; Kumar, Pradeep; Choonara, Yahya E; Kondiah, Pierre P P D; Pillay, Viness

2018-04-12

A 3D-Bioplotter® was employed to 3D print (3DP) a humic acid-polyquaternium 10 (HA-PQ10) controlled release fixed dose combination (FDC) tablet comprising of the anti-HIV-1 drugs, efavirenz (EFV), tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). Chemical interactions, surface morphology and mechanical strength of the FDC were ascertained. In vitro drug release studies were conducted in biorelevant media followed by in vivo study in the large white pigs, in comparison with a market formulation, Atripla®. In vitro-in vivo correlation of results was undertaken. EFV, TDF and FTC were successfully entrapped in the 24-layered rectangular prism-shaped 3DP FDC with a loading of ∼12.5 mg/6.3 mg/4 mg of EFV/TDF/FTC respectively per printed layer. Hydrogen bonding between the EFV/TDF/FTC and HA-PQ10 was detected which was indicative of possible drug solubility enhancement. The overall surface of the tablet exhibited a fibrilla structure and the 90° inner pattern was determined to be optimal for 3DP of the FDC. In vitro and in vivo drug release profiles from the 3DP FDC demonstrated that intestinal-targeted and controlled drug release was achieved. A 3DP FDC was successfully manufactured with the aid of a 3D-Bioplotter in a single step process. The versatile HA-PQ10 entrapped all drugs and achieved an enhanced relative bioavailability of EFV, TDF, and FTC compared to the market formulation for potentially enhanced HIV treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Dissofilm: A Novel Approach for Delivery of Phenobarbital; Design and Characterization

PubMed Central

Yellanki, SK; Jagtap, S; Masareddy, R

2011-01-01

An attempt to develop and evaluate mouth-dissolving film of phenobarbital for quick effect in treatment of epilepsy occurring in pediatric population has been made in the present study. Suitable film formers and plasticizers are selected based on optimization studies. Effect of superdisintegrants in formulation of mouth dissolving films at different concentrations has been investigated. Films were prepared by solvent casting method. The prepared films were evaluated for physicochemical parameters, in vitro disintegration and dissolution time, in vitro release rate study, stability study, and in vivo animal safety study. The best formulation was found to be F3 showing 96.57% drug release in 14 min, following first-order kinetics. X-Ray diffraction studies show change in crystalline nature of drug in formulation. In vivo studies in hamster reports effective and safe use of formulation in animals. PMID:21897656

Developing a new formulation of sodium phenylbutyrate.

PubMed

Guffon, Nathalie; Kibleur, Yves; Copalu, William; Tissen, C; Breitkreutz, Joerg

2012-12-01

Sodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control. A new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers. The in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of ∼10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (C(max)) or for area under the plasma concentration-time curve (AUC). CI for C(max) and AUC(0-inf) of NaPB were included in the bioequivalence range of 0.80-1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements. In vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD.

Systematic development of design of experiments (DoE) optimised self-microemulsifying drug delivery system of Zotepine.

PubMed

Dalvadi, Hitesh; Patel, Nikita; Parmar, Komal

2017-05-01

The aim of present investigation is to improve dissolution rate of poor soluble drug Zotepine by a self-microemulsifying drug delivery system (SMEDDS). Ternary phase diagram with oil (Oleic acid), surfactant (Tween 80) and co-surfactant (PEG 400) at apex were used to identify the efficient self-microemulsifying region. Box-Behnken design was implemented to study the influence of independent variables. Principal Component Analysis was used for scrutinising critical variables. The liquid SMEDDS were characterised for macroscopic evaluation, % Transmission, emulsification time and in vitro drug release studies. Optimised formulation OL1 was converted in to S-SMEDDS by using Aerosil ® 200 as an adsorbent in the ratio of 3:1. The S-SMEDDS was characterised by SEM, DSC, globule size (152.1 nm), zeta-potential (-28.1 mV), % transmission study (98.75%), in vitro release (86.57%) at 30 min. The optimised solid SMEDDS formulation showed faster drug release properties as compared to conventional tablet of Zotepine.

Formulation and evaluation of Alendronate Sodium gel for the treatment of bone resorptive lesions in Periodontitis.

PubMed

Reddy, G Thirumal; Kumar, T M Pramod; Veena

2005-01-01

Alendronate sodium is formulated into gels and evaluated for the treatment of bone resorptive lesions in periodontitis. Carbopol 934P was used for the preparation of gels in three different concentrations. The prepared gel was evaluated for various properties such as preformulation, content uniformity, viscosity, compatibility, sterility, in vitro diffusion, and in vivo studies. The drug and the polymer were found to be compatible and confirmed by Fourier transform infrared spectroscopy. Viscosity of the gels increased with the increase in the polymer concentration. The formulations were found to be sterile. In vitro release study revealed that drug released from the gel follows non-Fickian diffusion followed by first-order release. In vivo studies were carried out for 6 months in patients. The results revealed a significant improvement in the clinical parameters such as gingival index, probing pocket depth, clinical attachment level, and potent inhibitory effect on bone resorption by inhibition of osteoclasts. In addition, there was increase in the new bone formation.

3D printed alendronate-releasing poly(caprolactone) porous scaffolds enhance osteogenic differentiation and bone formation in rat tibial defects.

PubMed

Kim, Sung Eun; Yun, Young-Pil; Shim, Kyu-Sik; Kim, Hak-Jun; Park, Kyeongsoon; Song, Hae-Ryong

2016-09-29

The aim of this study was to evaluate the in vitro osteogenic effects and in vivo new bone formation of three-dimensional (3D) printed alendronate (Aln)-releasing poly(caprolactone) (PCL) (Aln/PCL) scaffolds in rat tibial defect models. 3D printed Aln/PCL scaffolds were fabricated via layer-by-layer deposition. The fabricated Aln/PCL scaffolds had high porosity and an interconnected pore structure and showed sustained Aln release. In vitro studies showed that MG-63 cells seeded on the Aln/PCL scaffolds displayed increased alkaline phosphatase (ALP) activity and calcium content in a dose-dependent manner when compared with cell cultures in PCL scaffolds. In addition, in vivo animal studies and histologic evaluation showed that Aln/PCL scaffolds implanted in a rat tibial defect model markedly increased new bone formation and mineralized bone tissues in a dose-dependent manner compared to PCL-only scaffolds. Our results show that 3D printed Aln/PCL scaffolds are promising templates for bone tissue engineering applications.

[Studies on preparation of sustained-release Shuxiong formulation, a traditional Chinese medicine compound recipe, using time-controlled release techniques].

PubMed

Song, Hong-Tao; Zhang, Qian; Jiang, Peng; Guo, Tao; Chen, Da-Wei; He, Zhong-Gui

2006-09-01

To prepare a sustained-release formulation of traditional Chinese medicine compound recipe by adopting time-controlled release techniques. Shuxiong tablets were chosen as model drug. The prescription and technique of core tablets were formulated with selecting disintegrating time and swelling volume of core tablets in water as index. The time-controlled release tablets were prepared by adopting press-coated techniques, using PEG6000, HCO and EVA as coating materials. The influences of compositions, preparation process and dissolution conditions in vitro on the lag time (T(lag)) of drug release were investigated. The composition of core tablets was as follow: 30% of drug, 50% MCC and 20% CMS-Na. The T(lag) of time-controlled release tablets was altered remarkably by PEG6000 content of the outer layer, the amount of outer layer and hardness of tablet. The viscosity of dissolution media and basket rotation had less influence on the T(lag) but more on rate of drug release. The core tablets pressed with the optimized composition had preferable swelling and disintegrating properties. The shuxiong sustained-release formulations which contained core tablet and two kinds of time-controlled release tablets with 3 h and 6 h of T(lag) could release drug successively at 0 h, 3 h and 6 h in vitro. The technique made it possible that various components with extremely different physicochemical properties in these preparations could release synchronously.

Novel osteoinductive photo-cross-linkable chitosan-lactide-fibrinogen hydrogels enhance bone regeneration in critical size segmental bone defects

PubMed Central

Kim, Sungwoo; Bedigrew, Katherine; Guda, Teja; Maloney, William J.; Park, Sangwon; Wenke, Joseph C.; Yang, Yunzhi Peter

2014-01-01

The purpose of this study was to develop and characterize a novel photo-cross-linkable chitosan-lactide-fibrinogen (CLF) hydrogel and evaluate the efficacy of bone morphogenetic protein-2 (BMP-2) containing CLF hydrogel for osteogenesis in vitro and in vivo. We synthesized the CLF hydrogels and characterized their chemical structure, degradation rate, compressive modulus, and in vitro BMP-2 release kinetics. We evaluated bioactivities of the BMP-2 containing CLF hydrogels (0, 50, 100, and 500 ng/ml) in vitro using W-20-17 preosteoblast mouse bone marrow stromal cells and C2C12 mouse myoblast cells. The effect of BMP-2 containing CLF gels (0, 0.5, 1, 2, and 5μg) on bone formation was evaluated using rat critical size segmental bone defects for 4 weeks. FTIR spectra and SEM images showed chemical and structural changes by addition of fibrinogen into chitosan-lactide copolymer. Incorporation of fibrinogen molecules significantly increased compressive modulus of the hydrogels. In vitro BMP-2 release study showed initial burst releases from the CLF hydrogels followed by sustained releases, regardless of the concentration of the BMP-2 over 4 weeks. Cells in all groups were viable in the presence of the hydrogels regardless of BMP-2 doses, indicating non-cytotoxicity of hydrogels. Alkaline phosphate activity and mineralization of cells exhibited dose dependence on BMP-2 containing CLF hydrogels. Radiographs, microcomputed tomography, and histology confirmed that the BMP-2 containing CLF hydrogels prompted neo-osteogenesis and accelerated healing of the defects in a dose-dependent manner. Thus the CLF hydrogel is a promising delivery system of growth factors for bone regeneration. PMID:25174669

Packing Polymorphism of Dapivirine and Its Impact on the Performance of a Dapivirine-Releasing Silicone Elastomer Vaginal Ring.

PubMed

McCoy, Clare F; Murphy, Diarmaid J; Boyd, Peter; Derrick, Tiffany; Spence, Patrick; Devlin, Brid; Malcolm, R Karl

2017-08-01

A silicone elastomer vaginal ring providing sustained release over 28 days of the anti-retroviral microbicide dapivirine has recently completed phase III clinical testing and showed moderate protection against HIV acquisition. In support of the product licensure program, we report the impact of dapivirine packing polymorphism on the thermal and solubility characteristics of dapivirine and on the in vitro performance of the 25 mg dapivirine ring product. This is the first time that polymorphism has been reported for a drug-releasing vaginal ring product. Thermal, particle size, powder X-ray diffraction, and thermodynamic solubility analyses of dapivirine polymorphic forms I and IV, both of which are persistent at room temperature and with form I being the thermodynamically stable form, were conducted for both micronized and non-micronized materials. No significant differences in solubility between DPV forms I and IV were observed in media commonly used for in vitro release testing. Matrix-type silicone elastomer vaginal rings were manufactured and the impact of dapivirine polymorphism on key in vitro parameters (compression and tensile behavior; content assay; in vitro release; residual content assay) was investigated. The data demonstrate that dapivirine packing polymorphism has no significant impact on in vitro performance of the 25 mg dapivirine vaginal ring. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Gamma scintigraphic study of the hydrodynamically balanced matrix tablets of Metformin HCl in rabbits

PubMed Central

Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Sarji, Sazilah Ahmad; Chung, Lip Yong; Nyamathulla, Shaik; Noordin, Mohamed Ibrahim

2015-01-01

The purpose of this study is to evaluate the in vitro and in vivo performance of gastro-retentive matrix tablets having Metformin HCl as model drug and combination of natural polymers. A total of 16 formulations were prepared by a wet granulation method using xanthan, tamarind seed powder, tamarind kernel powder and salep as the gel-forming agents and sodium bicarbonate as a gas-forming agent. All the formulations were evaluated for compendial and non-compendial tests and in vitro study was carried out on a USP-II dissolution apparatus at a paddle speed of 50 rpm. MOX2 formulation, composed of salep and xanthan in the ratio of 4:1 with 96.9% release, was considered as the optimum formulation with more than 90% release in 12 hours and short floating lag time. In vivo study was carried out using gamma scintigraphy in New Zealand White rabbits, optimized formulation was incorporated with 10 mg of 153Sm for labeling MOX2 formulation. The radioactive samarium oxide was used as the marker to trace transit of the tablets in the gastrointestinal tract. The in vivo data also supported retention of MOX2 formulation in the gastric region for 12 hours and were different from the control formulation without a gas and gel forming agent. It was concluded that the prepared floating gastro-retentive matrix tablets had a sustained-release effect in vitro and in vivo, gamma scintigraphy played an important role in locating the oral transit and the drug-release pattern. PMID:26124637

Development and evaluation of a novel biodegradable sustained release microsphere formulation of paclitaxel intended to treat breast cancer

PubMed Central

Shiny, Jacob; Ramchander, Thadkapally; Goverdhan, Puchchakayala; Habibuddin, Mohammad; Aukunuru, Jithan Venkata

2013-01-01

Objective: The objective of this study was to develop a novel 1 month depot paclitaxel (PTX) microspheres that give a sustained and complete drug release. Materials and Methods: PTX loaded microspheres were prepared by o/w emulsion solvent evaporation technique using the blends of poly(lactic-co-glycolic acid) (PLGA) 75/25, polycaprolactone 14,000 and polycaprolactone 80,000. Fourier transform infrared spectroscopy was used to investigate drug excipient compatibility. Compatible blends were used to prepare F1-F6 microspheres, the process was characterised and the optimum formulation was selected based on the release. Optimised formulation was characterised for solid state of the drug using the differential scanning calorimetry (DSC) studies, surface morphology using the scanning electron microscopy (SEM), in vivo drug release, in vitro in vivo correlation (IVIVC) and anticancer activity. Anticancer activity of release medium was determined using the cell viability assay in Michigan Cancer Foundation (MCF-7) cell line. Results: Blend of PLGA with polycaprolactone (Mwt 14,000) at a ratio of 1:1 (F5) resulted in complete release of the drug in a time frame of 30 days. F5 was considered as the optimised formulation. Incomplete release of the drug resulted from other formulations. The surface of the optimised formulation was smooth and the drug changed its solid state upon fabrication. The formulation also resulted in 1-month drug release in vivo. The released drug from F5 demonstrated anticancer activity for 1-month. Cell viability was reduced drastically with the release medium from F5 formulation. A 100% IVIVC was obtained with F5 formulation suggesting the authenticity of in vitro release, in vivo release and the use of the formulation in breast cancer. Conclusions: From our study, it was concluded that with careful selection of different polymers and their combinations, PTX 1 month depot formulation with 100% drug release and that can be used in breast cancer was developed. PMID:24167783

Iron bioavailability studies of the first generation of iron-biofortified beans released in Rwanda

USDA-ARS?s Scientific Manuscript database

This paper represents a series of in vitro Fe bioavailability experiments, Fe content analysis and polyphenolic profile of the first generation of Fe biofortified beans (Phaseolus vulgaris) selected for human trials in Rwanda and released to farmers of that region. The objective of the present stud...

"Effect of nano-filled surface coating agent on fluoride release from conventional glass ionomer cement: an in vitro trial".

PubMed

Tiwari, S; Nandlal, B

2013-01-01

To overcome the drawbacks of glass ionomer cement of sensitivity to initial desiccation and moisture contamination the use of surface coating agent is recommended. The search in this area led to invent of use of nanofillers in surface coating agent, but its effect on fluoride release is not clear. The aim of this study is to evaluate and compare the fluoride release from conventional glass ionomer cement with and without surface coating agent. This in vitro study comprised of total 80 samples (40 samples of each with and without surface coating). Specimens were prepared, G coat plus was applied and light cured. Fluoride release of the sample was measured every 24 h for 7 days and weekly from 7th to 21 st day using Sension4 pH/ISE/MV Meter. Descriptive Statistics, Repeated Measure ANOVA, Paired Sample t-test, Independent Sample t-test, Scheffe post hoc test. Mean values clearly reveal a significant decrease in the fluoride release from day 1 to day 21 for both groups. Non-coated group released significantly more fluoride than surface coated group (P<0.001). It can be concluded that nanofilled surface coating agent will reduce the amount of fluoride released into oral environment as compared to non-coated group and at the same time releasing fluoride into surrounding cavity walls to create zones of inhibition into the cavity floor to help internal remineralization.

Formulation and in vitro characterization of xanthan gum-based sustained release matrix tables of isosorbide-5- mononitrate.

PubMed

Kar, Rajat; Mohapatra, Snehamayee; Bhanja, Satyabrata; Das, Debjyoti; Barik, Bhaktibhusan

2010-01-01

In the present investigation an attempt has been made to increase therapeutic efficacy, to reduce frequency of administration and to improve patient compliance by developing a sustained release matrix tablets of isosorbide-5-mononitrate. Sustained release matrix tablets of isosorbide-5-mononitrate were developed by using different drug: polymer ratios, such in F1 (1:0.75), F2 (1:1), F3 (1:1.5), F4 (1:1.75) and F6 (1:2). Xanthan gum was used as matrix former and microcrystalline cellulose as diluent. All the lubricated formulations were compressed, using 8mm flat faced punches. Compressed tablets were evaluated for uniformity of weight, content of active ingredient, friability, hardness, thickness, in vitro dissolution study using basket method and swelling index. Each formulation showed compliance with pharmacopoeial standards. Among all formulations, F5 showed a greater sustained release pattern of drug over a 12 h period with 92.12% of drug being released. The kinetic studies showed that drug release follows the Higuchi model (r(2) =0.9851). Korsemeyer and Peppas equation gave an n-value of 0.4566, which was close to 0.5, indicating that drug release follows the Fickian diffusion. Thus, xanthan gum can be used as an effective matrix former to extend the release of isosorbide-5-mononitrate. No significant difference was observed in the dissolution profile of optimized formulation, using basket and paddle apparatus.

Development, characterization, and in vitro and in vivo evaluation of benzocaine- and lidocaine-loaded nanostructrured lipid carriers.

PubMed

Puglia, Carmelo; Sarpietro, Maria Grazia; Bonina, Francesco; Castelli, Francesco; Zammataro, Magda; Chiechio, Santina

2011-05-01

The present study concerns the in vitro and in vivo evaluation of benzocaine (BENZO) and lidocaine (LIDO) topical delivery from nanostructured lipid carriers (NLCs). Morphology and dimensional distribution of NLCs have been, respectively, characterized by differential scanning calorimetry (DSC) and photon correlation spectroscopy. The release pattern of BENZO and LIDO from NLCs was evaluated in vitro determining drug percutaneous absorption through excised human skin. Radiant heat tail-flick test was carried out in mice to determine the antinociceptive effect of BENZO and LIDO from NLC. DSC studies revealed that the inner oil phase of NLC plays a significant role in stabilizing the particle architecture and increasing the drug solubility. In vitro evidences show that BENZO and LIDO, when incorporated in viscosized NLC dispersions, exhibited a lower flux with respect to formulations containing the free drugs in the aqueous phase. In vivo study enabled to demonstrate that BENZO and LIDO can be released in a prolonged fashion when incorporated into lipid carriers. The results obtained pointed out NLC capability to act as an effective drug reservoir, thus prolonging the anesthetic effect of BENZO and LIDO. Copyright © 2010 Wiley-Liss, Inc.

Synthesis characterization and in vitro drug release from acrylamide and sodium alginate based superporous hydrogel devices

PubMed Central

Nagpal, Manju; Singh, Shailendra Kumar; Mishra, Dinanath

2013-01-01

Objective: Present investigation was aimed at developing gastroretentive superporous hydrogels (SPHs) having desired mechanical characteristics with sustained release. Materials and Methods: The acrylamide based SPHs of various generations (1st, 2nd and 3rd) were synthesized by gas blowing technique. The prepared SPHs were evaluated for swelling, mechanical strength studies and scanning electron microscopy studies. Verapamil hydrochloride was loaded into selected SPHs by aqueous drug loading method and characterized via Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (X-RD), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) and in vitro drug release studies. Results: SPHs of third generation were observed to have desired mechanical strength with sufficient swelling properties. Integrity of the drug was maintained in hydrogel polymeric network as indicated by FTIR, X-RD, and DSC and NMR studies. Initially, fast drug release (up to 60%) was observed in 30 min in formulation batches containing pure drug only (A, C and E), which was further sustained untill 24 h. Discussion: The increase in mechanical strength was due to the chemical cross-linking of secondary polymer in hydrogel network. The initial burst release was due to the presence of free drug at the surface and later sustained drug release was due to diffusion of entrapped drug in polymeric network. Significant decrease in drug release was observed by the addition of hydroxypropyl methyl cellulose. Conclusion: SPH interpenetrating networks with fast swelling and sufficient mechanical strength were prepared, which can be potentially exploited for designing gastroretentive drug delivery devices. PMID:24167785

Comparative evaluation of single and bilayered lamotrigine floating tablets

PubMed Central

Lakshmi, PK; Sridhar, M; Shruthi, B

2013-01-01

Aim: The purpose of this study was to prepare lamotrigine (LM) bilayered and single layered floating tablets and to compare their release profiles. Materials and Methods: LM floating tablets were prepared by direct compression method. Drug, hydroxy propyl methyl cellulose K4M, lactose monohydrate and polyvinylpyrrolidone K30 constitute controlled release layer components and floating layer components includes polymers and sodium bicarbonate. The prepared tablets were evaluated for physicochemical parameters such as hardness, friability, weight variation, thickness, floating lag time (FLT), floating time, in vitro buoyancy study, in vitro release studies. The drug-polymer interaction was studied by fourier transform infrared and differential scanning calorimetry. Results and Discussion: The FLT of all the formulations were within the prescribed limits (<3 min). When ethyl cellulose was used as floating layer component, tablets showed good buoyancy effect but eroded within 6-8 h. Hence it was replaced with hydroxypropyl cellulose -M hydrophilic polymer, which showed good FLT and floating duration for 16 h. Formulation LFC4 was found to be optimized with dissolution profile of zero order kinetics showing fickian diffusion. A comparative study of bilayered and single layered tablets of LM showed a highest similarity factor of 83.03, difference factor of 2.74 and t-test (P < 0.05) indicates that there is no significant difference between them. Conclusion: Though bilayered tablet possess many advantages, single layered tablet would be economical, cost-effective and reproducible for large scale production in the industry. However, the results of present study demonstrated that the in vitro development of bilayered gastro retentive floating tablets with controlled drug release profile for LM is feasible. PMID:24167788

Inflammation-Related Effects of Diesel Engine Exhaust Particles: Studies on Lung Cells In Vitro

PubMed Central

Schwarze, P. E.; Totlandsdal, A. I.; Låg, M.; Refsnes, M.; Holme, J. A.; Øvrevik, J.

2013-01-01

Diesel exhaust and its particles (DEP) have been under scrutiny for health effects in humans. In the development of these effects inflammation is regarded as a key process. Overall, in vitro studies report similar DEP-induced changes in markers of inflammation, including cytokines and chemokines, as studies in vivo. In vitro studies suggest that soluble extracts of DEP have the greatest impact on the expression and release of proinflammatory markers. Main DEP mediators of effects have still not been identified and are difficult to find, as fuel and engine technology developments lead to continuously altered characteristics of emissions. Involved mechanisms remain somewhat unclear. DEP extracts appear to comprise components that are able to activate various membrane and cytosolic receptors. Through interactions with receptors, ion channels, and phosphorylation enzymes, molecules in the particle extract will trigger various cell signaling pathways that may lead to the release of inflammatory markers directly or indirectly by causing cell death. In vitro studies represent a fast and convenient system which may have implications for technology development. Furthermore, knowledge regarding how particles elicit their effects may contribute to understanding of DEP-induced health effects in vivo, with possible implications for identifying susceptible groups of people and effect biomarkers. PMID:23509760

Hapten-specific T-Cell Unresponsiveness Induced by Benzylpenicilloyl Autologous Gamma Globulin Conjugates in Human Lymphocytes In Vitro

PubMed Central

Geha, Raif S.; Fruchter, Lazar; Borel, Yves

1980-01-01

The aim of these studies was to determine whether unresponsiveness to the main determinant of penicillin, benzylpenicilloyl, can be induced in human peripheral lymphocytes in vitro by conjugates of benzylpenicilloyl (BPO) autologous gamma globulin (HGG). Initially it was shown that conjugates of BPO-keyhole limpet hemocyanin (KLH) elicited lymphocyte proliferation in the peripheral blood lymphocytes of six out of nine adult individuals in vitro. In contrast, conjugates of dinitrophenylated KLH and of BPO-HGG and the carriers HGG and KLH alone failed to do so. Similarly, release of the non-specific helper factor, lymphocyte mitogenic factor (LMF) occurred only after BPO-KLH stimulation. LMF activity was measured by B-cell proliferation and incorporation of radioactive amino acids into secreted immunoglobulin. Treatment with BPO-HGG for 24 h in vitro inhibited BPO-KLH-induced lymphocyte proliferation and LMF release. Treatment with either HGG, dinitrophenylated HGG, BPO-KLH, or BPO-human serum albumin failed to abrogate T-cell lymphocyte proliferation of human lymphocytes in vitro. The antigen specificity of the reduced immunologic responsiveness was further demonstrated by the observation that lymphocytes treated with BPO-HGG for 24 h in vitro responded normally to tetanus toxoid antigen. The data suggest that conjugates of BPO-HGG induce hapten-specific helper T-cell unresponsiveness in vitro. PMID:6157701

Preparation and evaluation of metoprolol tartrate sustained-release pellets using hot melt extrusion combined with hot melt coating.

PubMed

Yang, Yan; Shen, Lian; Li, Juan; Shan, Wei-Guang

2017-06-01

The objective of this study was to prepare and evaluate metoprolol tartrate sustained-release pellets. Cores were prepared by hot melt extrusion and coated pellets were prepared by hot melt coating. Cores were found to exist in a single-phase state and drug in amorphous form. Plasticizers had a significant effect on torque and drug content, while release modifiers and coating level significantly affected the drug-release behavior. The mechanisms of drug release from cores and coated pellets were Fickian diffusion and diffusion-erosion. The coated pellets exhibited sustained-release properties in vitro and in vivo.

Oxaliplatin loaded PLAGA microspheres: design of specific release profiles.

PubMed

Lagarce, F; Cruaud, O; Deuschel, C; Bayssas, M; Griffon-Etienne, G; Benoit, J

2002-08-21

Oxaliplatin loaded PLAGA microspheres have been prepared by solvent extraction process. Parameters affecting the release kinetics in vitro have been studied in order to design specific release profiles suitable for direct intra-tumoral injection. By varying the nature and the relative proportions of different polymers we managed to prepare microspheres with good encapsulation efficiency (75-90%) and four different release profiles: zero order kinetics (type II) and the classical sigmoïd release profile with three different sizes of plateau and burst. These results, if correlated with in vivo activity, are promising to enhance effectiveness of local tumor treatment.

Targeted antitumoral dehydrocrotonin nanoparticles with L-ascorbic acid 6-stearate.

PubMed

Frungillo, Lucas; Martins, Dorival; Teixeira, Sérgio; Anazetti, Maristela Conti; Melo, Patrícia da Silva; Durán, Nelson

2009-12-01

Tumoral cells are known to have a higher ascorbic acid uptake than normal cells. Therefore, the aim of this study was to obtain polymeric nanoparticles containing the antitumoral compound trans-dehydrocrotonin (DHC) functionalized with L-ascorbic acid 6-stearate (AAS) to specifically target this system tumoral cells. Nanoparticle suspensions (NP-AAS-DHC) were prepared by the nanoprecipitation method. The systems were characterized for AAS presence by thin-layer chromatography and for drug loading (81-88%) by UV-Vis spectroscopy. To further characterize these systems, in vitro release kinetics, size distribution (100-140 nm) and Zeta potential by photon-correlation spectroscopic method were used. In vitro toxicity against HL60 cells was evaluated by tetrazolium reduction and Trypan blue exclusion assays. Cell death by apoptosis was quantified and characterized by flow cytometry and caspase activity. Zeta potential analyses showed that the system has a negatively charged outer surface and also indicate that AAS is incorporated on the external surface of the nanoparticles. In vitro release kinetics assay showed that DHC loaded in nanoparticles had sustained release behavior. In vitro toxicity assays showed that NP-AAS-DHC suspension was more effective as an antitumoral than free DHC or NP-DHC and increased apoptosis induction by receptor-mediated pathway. 2009 Wiley-Liss, Inc. and the American Pharmacists Association

The relationship between functional sciatic nerve block duration and the rate of release of lidocaine from a controlled-release matrix.

PubMed

Gerner, Peter; Wang, Chi-Fei; Lee, Byung-Sang; Suzuki, Suzuko; Degirolami, Umberto; Gandhi, Ankur; Knaack, David; Strichartz, Gary

2010-07-01

Nerve blocks of long duration are often desirable in perioperative and postoperative situations. The relationship between the duration of such blocks and the rate at which a local anesthetic is released is important to know for developing a localized drug delivery system that will optimize block duration. Lidocaine concentration was varied in 1 series of formulations (OSB-L) containing a constant amount of release rate modifier. In another series (OST-R), the release rate modifier was varied while the lidocaine content was held constant. Release kinetics were measured in vitro and correlated to the in vivo duration of antinociceptive and motor block effects when the formulation was implanted next to the rat sciatic nerve. In parallel studies, rats receiving different formulations of slow-release lidocaine were fixed by intracardiac perfusion with 4% paraformaldehyde and nerve-muscle tissue taken for histopathological analysis. In this study, we have demonstrated that the most important variable for effecting functional nerve block, i.e., the blockade of impulses in the relevant fibers of the sciatic nerve, is the rate of lidocaine release at that time. For the OSB-L formulations (lidocaine concentrations of 1.875%, 3.75%, 7.5%, and 15% at a constant release rate modifier of 5%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 0.91 +/- 0.28 and 1.75 +/- 0.61 mg/h, respectively. For the OST-R formulations (16% lidocaine with release rate modifier concentrations of 1.875%, 3.75%, 7.5%, and 15%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 2.33 +/- 1.39 and 4.34 +/- 1.09 mg/h, respectively. The OSB-L formulations showed a dose-dependent increase in block duration proportional to an increase in initial lidocaine concentration, whereas the OST-R formulations showed a nonmonotonic relationship between release rate modifier concentration and block duration. The histopathological studies at 24 hours, 3, 5, or 7 days, and 4 weeks after the implantation revealed inflammatory reactions with degrees correlated with lidocaine content, but limited to the connective tissue and muscle immediately surrounding the implanted material. Despite these observed inflammatory reactions, nociceptive and motor block function returned to normal, preimplantation values in all animals. Increasing initial lidocaine content proportionately increased the duration of functional sciatic nerve block. However, decreasing the release rate per se does not give a proportional increase in block duration. Instead, there seems to be an optimal, intermediate release rate for achieving the maximum duration of block.

Development of a rectal nicotine delivery system for the treatment of ulcerative colitis.

PubMed

Dash, A K; Gong, Z; Miller, D W; Huai-Yan, H; Laforet, J

1999-11-10

The aims of this investigation were: i. to develop a rectal nicotine delivery system with bioadhesives for the treatment of ulcerative colitis and ii. to evaluate nicotine transport and cytotoxicity of the delivery system using Caco-2 cell culture systems. Rectal nicotine suppository formulations were prepared in semi-synthetic glyceride bases (Suppocire AM and AI, Gattefosse Inc.) by fusion method. The in vitro release of nicotine was carried out in modified USP dissolution apparatus 1. Differential scanning calorimetry (DSC) and powder X-ray diffraction were used to study the polymorphic changes if any in the formulations. An LC method was used for the assay of nicotine. The effect of bioadhesives (glyceryl monooleate (GMO), and Carbopol) on the nicotine flux was evaluated using Caco-2 cell permeability studies and Caco-2 cell viability was determined using the MTT toxicity assay. In vitro release studies indicated that the low melting AI base was superior to that of the AM base. Presence of GMO in the formulation enhanced the release of nicotine whereas Carbopol showed an opposite effect. The enhanced release of nicotine in the presence of GMO was found to be partly due to the melting point lowering effect of this compound. Caco-2 cell absorption studies showed that there was a decrease in the flux of nicotine in the presence of both the bioadhesives. The flux of the fluorescein marker which is used to study the integrity of the cell monolayers was found to be slightly higher only in the presence of 10% (w/w) Carbopol. Nicotine, Carbopol, and GMO do not have any cytotoxic effect on these cell monolayers within the concentration range used in the formulations. Rectal nicotine formulations containing bioadhesives were developed and characterized. Both in vitro release and cell culture studies have indicated that one can manipulate the nicotine release from these rectal delivery systems by incorporation of various bioadhesives or the use of different bases in the formulation. Nicotine concentration below 2% (w/v) and bioadhesive concentration below 10% (w/w) do not have any cytotoxic effect on Caco-2 cells.

Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes.

PubMed

Jensen, J L; Appel, L E; Clair, J H; Zentner, G M

1995-05-01

The feasibility of using modified Eudragit acrylic latexes as microporous coatings for osmotic devices was investigated. Potassium chloride tablets were coated with mixtures of Eudragit RS30D and RL30D acrylic latexes that also contained a plasticizer (triethyl citrate or acetyl tributyl citrate) and a pore-forming agent (urea). A 2(5-1) fractional factorial experimental design was employed to determine the effect of five formulation variables (RS30D:RL30D polymer ratio plasticizer type, plasticizer level, urea level, and cure) on the in vitro release rate of KCl in deionized water (di water), lag time, and coat burst strength. The RS30D:RL30D polymer ratio had the greatest effect on the release rate, and both lag time and burst strength were most affected by the urea level. Statistical optimization was performed, and a coat formulation with predicted desirable in vitro performance was prepared and tested. The in vitro release rate (di water), lag time, and coat burst strength agreed well with the prediction. Dissolutions were also performed in phosphate buffered saline (PBS; pH 7.4); several formulations released markedly slower in PBS than in di water. This discrepancy was dependent on the type of plasticizer and the amount of pore former. Only those coat formulations containing acetyl tributyl citrate as the plasticizer and a 100% urea [(g urea/g polymer solids) x 100] level exhibited similar release rates in di water and PBS. The mechanism of release from these devices was primarily osmotic, whereas the release from devices coated with a formulation containing triethyl citrate and 50% urea was not dependent on the osmotic pressure difference. Devices with an osmotic release mechanism behaved similarly in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis, characterization and in vitro cytotoxicity analysis of a novel cellulose based drug carrier for the controlled delivery of 5-fluorouracil, an anticancer drug

NASA Astrophysics Data System (ADS)

Anirudhan, Thayyath S.; Nima, Jayachandran; Divya, Peethambaran L.

2015-11-01

The present investigation concerns the development and evaluation of a novel drug delivery system, aminated-glycidylmethacrylate grafted cellulose-grafted polymethacrylic acid-succinyl cyclodextrin (Cell-g-(GMA/en)-PMA-SCD) for the controlled release of 5-Fluorouracil, an anticancer drug. The prepared drug carrier was characterized by FT-IR, XRD and SEM techniques. Binding kinetics and isotherm studies of 5-FU onto Cell-g-(GMA/en)-PMA-SCD were found to follow pseudo-second-order and Langmuir model respectively. Maximum binding capacity of drug carrier was found to be 149.09 mg g-1 at 37 °C. Swelling studies, in vitro release kinetics, drug loading efficiency and encapsulation efficiency of Cell-g-(GMA/en)-PMA-SCD were studied. The release kinetics was analyzed using Ritger-Peppas equation at pH 7.4. Cytotoxicity analysis on MCF-7 (human breast carcinoma) cells indicated that the drug carrier shows sustained and controlled release of drug to the target site. Hence, it is evident from this investigation that Cell-g-(GMA/en)-PMA-SCD could be a promising carrier for 5-FU.

Preparation and evaluation of a timolol maleate drug-resin ophthalmic suspension as a sustained-release formulation in vitro and in vivo.

PubMed

Qin, Fuhong; Zeng, Li; Zhu, Yongtao; Cao, Jingjing; Wang, Xiaohui; Liu, Wei

2016-01-01

The aim of this work was to assess the performance of resin as an ocular delivery system. Timolol maleate (TM) was chosen as the model drug and an ion exchange resin (IER) as the carrier. The drug-resin complex was prepared using an oscillation method and then characterized regarding particle size, zeta potential, morphology, and drug content. After in vitro drug release study and corneal permeation study were performed, in vivo studies were performed in New Zealand albino rabbits using a suspension with particles sized 4.8 ± 1.2 μm and drug loading at 43.00 ± 0.09%. The results indicate that drug released from the drug-resin ophthalmic suspension permeated the cornea and displayed a sustained-release behavior. Drug levels in the ocular tissues after administration of the drug-resin ophthalmic suspension were significantly higher than after treatment with an eye drop formulation but were lower in body tissues and in the plasma. In conclusion, resins have great potential as effective ocular drug delivery carriers to increase ocular bioavailability of timolol while simultaneously reducing systemic drug absorption.

[Anti-tumor effects of DDP-PLLA-CNTs on human cholangiocarcinoma cell line in vitro].

PubMed

Li, Maolan; Lu, Wei; Zhang, Fei; Ding, Qichen; Wu, Xiangsong; Tan, Zhujun; Wu, Wenguang; Weng, Hao; Wang, Xuefeng; Shi, Weibin; Dong, Ping; Gu, Jun; Liu, Yingbin

2014-11-04

To explore the antitumor effects of DDP-PLLA-CNTs on human cholangiocarcinoma cell line. DDP-PLLA-CNTs were prepared with the method of ultrasound emulsification. The morphology of DDP-PLLA-CNTs was determined by scanning electron microscope (SEM). And its drug loading and drug release curve in vitro was detected by UV-Vis-NIR spectrophotometer. CCK8 was used to test the cytotoxic effects of DDP-PLLA-CNTs at different concentrations on QBC939 cell proliferation.Flow cytometry was employed to measure the changes of apoptotic rate. With excellent controlled-release characteristic of in vitro drug release, DDP-PLLA-CNTs inhibited the proliferation and significantly increased the apoptotic rate of QBC939 cell line. DDP-PLLA-CNTs have drug sustained-release characteristics and can significantly inhibit the proliferation of QBC939 cell line.

In vitro BMP-2 peptide release from thiolated chitosan based hydrogel.

PubMed

Liu, Xujie; Yu, Bo; Huang, Qianli; Liu, Rui; Feng, Qingling; Cai, Qiang; Mi, Shengli

2016-12-01

Thiolated chitosan based thermo-sensitive hydrogel is a water soluble system and the existing thiol groups are beneficial for the delivery of cysteine-rich peptides. In the present study, a kind of thiolated chitosan, i.e. chitosan-4-thio-butylamidine (CS-TBA) conjugate was characterized and used to prepare CS-TBA/hydroxyapatite (HA)/beta-glycerophosphate disodium (β-GP) thermo-sensitive hydrogel. The cysteine terminated peptide 24 (P24) containing residues 73-92 of the knuckle epitope of BMP-2 (N→C: KIPKASSVPTELSAISTLYLSGGC) was synthesized and characterized. The release behavior of P24 from CS-TBA based hydrogel was investigated in vitro. The thiol groups in CS-TBA may react with thiol groups in P24, thus decreases the P24 release rate and maintains the peptide release for a longer time compared with unmodified chitosan based hydrogel. Moreover, the bioactivity of P24 is preserved during release process. These results indicate that P24 loaded CS-TBA based thermosensitive hydrogel is a potential material for minimally invasive surgery of bone repair. Copyright © 2016 Elsevier B.V. All rights reserved.

Magnetically stimulated ciprofloxacin release from polymeric microspheres entrapping iron oxide nanoparticles

PubMed Central

Sirivisoot, Sirinrath; Harrison, Benjamin S

2015-01-01

To extend the external control capability of drug release, iron oxide nanoparticles (NPs) encapsulated into polymeric microspheres were used as magnetic media to stimulate drug release using an alternating magnetic field. Chemically synthesized iron oxide NPs, maghemite or hematite, and the antibiotic ciprofloxacin were encapsulated together within polycaprolactone microspheres. The polycaprolactone microspheres entrapping ciprofloxacin and magnetic NPs could be triggered for immediate drug release by magnetic stimulation at a maximum value of 40%. Moreover, the microspheres were cytocompatible with fibroblasts in vitro with a cell viability percentage of more than 100% relative to a nontreated control after 24 hours of culture. Macrophage cell cultures showed no signs of increased inflammatory responses after in vitro incubation for 56 hours. Treatment of Staphylococcus aureus with the magnetic microspheres under an alternating (isolating) magnetic field increased bacterial inhibition further after 2 days and 5 days in a broth inhibition assay. The findings of the present study indicate that iron oxide NPs, maghemite and hematite, can be used as media for stimulation by an external magnetic energy to activate immediate drug release. PMID:26185446

Preparation of Spray-Dried Soy Isoflavone-Loaded Gelatin Microspheres for Enhancement of Dissolution: Formulation, Characterization and in Vitro Evaluation

PubMed Central

Panizzon, Gean Pier; Bueno, Fernanda Giacomini; Ueda-Nakamura, Tânia; Nakamura, Celso Vataru; Dias Filho, Benedito Prado

2014-01-01

The most bioactive soy isoflavones (SI), daidzein (DAI) and genistein (GEN) have poor water solubility, which reduces their bioavailability and health benefits and limits their use in industry. The goal of this study was to develop and characterize a new gelatin matrix to microencapsulate DAI and GEN from soy extract (SE) by spray drying, in order to obtain solid dispersions to overcome solubility problems and to allow controlled release. The influences of 1:2 (MP2) and 1:3 (MP3) SE/polymer ratios on the solid state, yield, morphology, encapsulation efficiency, particle size distribution, release kinetics and cumulative release were evaluated. Analyses showed integral microparticles and high drug content. MP3 and MP2 yield were 43.6% and 55.9%, respectively, with similar mean size (p > 0.05), respectively. X-ray diffraction revealed the amorphous solid state of SE. In vitro release tests showed that dissolution was drastically increased. The results indicated that SE microencapsulation might offer a good system to control SI release, as an alternative to improve bioavailability and industrial applications. PMID:25494200

In vitro chlorhexidine release from alginate based microbeads for periodontal therapy

PubMed Central

Reske, Thomas; Böhmer, Femke; Hornung, Anne; Grabow, Niels; Lang, Hermann

2017-01-01

Periodontitis is one of the most common infectious diseases globally that, if untreated, leads to destruction of the tooth supporting tissues and finally results in tooth loss. Evidence shows that standard procedures as mechanical root cleaning could be supported by further treatment options such as locally applied substances. Due to gingival crevicular fluid flow, substances are commonly washed out off the periodontal pockets. The evaluation of administration techniques and the development of local drug releasing devices is thus an important aspect in periodontal research. This study describes the development and examination of a new alginate based, biodegradable and easily applicable drug delivery system for chlorhexidine (CHX). Different micro beads were produced and loaded with CHX and the release profiles were investigated by high performance liquid chromatography (HPLC). The in vitro-demonstrated release of CHX from alginate based beads shows comparable releasing characteristics as clinically approved systems. Yet many characteristics of this new delivery system show to be favourable for periodontal therapy. Easy application by injection, low production costs and multifunctional adaptions to patient related specifics may improve the usage in routine care. PMID:28973028

Topical Delivery of Erythromycin Through Cubosomes for Acne.

PubMed

Khan, Sana; Jain, Poorva; Jain, Sourabh; Jain, Richa; Bhargava, Saurabh; Jain, Aakanchha

2018-01-01

Topical delivery is an attractive route for local and systemic treatment. The novel topical application has many advantages like averting the GI-irritation, preventing the metabolism of drugs in the liver and increasing the bioavailability of the drug over the conventional dosage forms. The aim of present work was to prepare and characterized erythromycin encapsulated cubosomes using different concentrations of glyceryl monooleate and poloxamer 407 by the emulsification method. The prepared dispersion of cubosomes was characterized for surface morphology, particle size, entrapment efficiency and in vitro release. Further, optimized formulation was converted to cubosomal gel by incorporating carbopol 934 at different concentrations. The prepared gel was characterized for homogeneity, pH, viscosity, spreadibility, drug content and in vitro drug release study. The result of optimized cubosomes showed average particle size of 264.5±2.84nm and entrapment efficiency about 95.29±1.32 % and the pH of optimized cubosomal was found to be 6.5, viscosity 2475-8901(cp), drug content 95.29% and the spreadability was found to be 11.74 gm.cm/sec. The in vitro drug release kinetics of optimized formulation was found to follow Korsmeyer peppas model having highest R2 value 0.835 and in vitro drug release of optimized erythromycin loaded cubosomal gel and plain drug gel in 24 hr was found to be 89.91±0.73 and 88.64±2.16, while in 36 hr plain drug gel and cubosomal gel showed drug release about 87.64±0.97 and 91.55±1.09, and sustained release was obtained after 24 hr in case of cubosomal gel. Thus, as a whole it can be concluded that erythromycin loaded cubosomes are effective in topically delivering drug in sustained and non-invasive manner for treatment and prevention of acne. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Setting accelerated dissolution test for PLGA microspheres containing peptide, investigation of critical parameters affecting drug release rate and mechanism.

PubMed

Tomic, I; Vidis-Millward, A; Mueller-Zsigmondy, M; Cardot, J-M

2016-05-30

The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45°C, in phosphate buffer saline (PBS) 0.02M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45°C to 40°C, release rate showed three-fold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01M (200 mOsm/kg) and PBS 0.01M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Galanin inhibits acetylcholine release in the ventral hippocampus of the rat: histochemical, autoradiographic, in vivo, and in vitro studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fisone, G.; Wu, C.F.; Consolo, S.

1987-10-01

A high density of galanin binding sites was found by using /sup 125/I-labeled galanin, iodinated by chloramine-T, followed by autoradiography in the ventral, but not in the dorsal, hippocampus of the rat. Lesions of the fimbria and of the septum caused disappearance of a major population of these binding sites, suggesting that a large proportion of them is localized on cholinergic nerve terminals of septal afferents. As a functional correlate to these putative galanin receptor sites, it was shown, both in vivo and in vitro, that galanin, in a concentration-dependent manner, inhibited the evoked release of acetylcholine in the ventral,more » but not in the dorsal, hippocampus. Intracerebroventricularly applied galanin fully inhibited the scopolamine stimulated release of acetylcholine in the ventral, but not in the dorsal, hippocampus, as measured by the microdialysis technique. In vitro, galanin inhibited the 25 mM K/sup +/-evoked release of (/sup 3/H)acetylcholine from slices of the ventral hippocampus, with an IC/sub 50/ value of approx. = 50 nM. These results are discussed with respect to the colocalization of galanin- and choline acetyltransferase-like immunoreactivity in septal somata projecting to the hippocampus.« less

Lornoxicam gastro retentive floating matrix tablets: Design and in vitro evaluation.

PubMed

Sathiyaraj, S; Devi, Ramya D; Hari, Vedha B N

2011-07-01

The objective of this present investigation is to prolong the gastric residence time of Lornoxicam by fabricating it into a floating sustained release matrix tablets. Lornoxicam, a potent oxicam group of non-steroidal anti-inflammatory drugs, suffers from relatively short half life of 2 to 3 hrs showing maximal absorption in proximal gastro intestinal tract region necessitating its need to be formulated as a floating sustained release matrix tablets. In this current investigation, hydroxyl propyl methyl cellulose K15M, a high viscous grade polymer with apparent viscosity of 15,000 cps, was kept as a variable (10-50%) and calcium carbonate (13%) was used as a gas generator. The prepared blends were subjected for its pre-formulation characterization. The directly compressed tablets were evaluated for physical parameters such as weight uniformity, hardness, friability, drug content, in-vitro buoyancy with axial and radial enlargement measurement, swelling index. From the investigation it was observed that the buoyancy lasted for up to 24 hrs. Fourier transform infra-red spectroscopy peaks assured the compatibility of the drug with excipients and confirmed the presence of pure drug in the formulation. It was supported by in-vitro dissolution studies; and the dissolution data was subjected to various release kinetic models to understand the mechanism of drug release.

In vitro and in vivo evaluation of novel NGR-modified liposomes containing brucine.

PubMed

Li, Shu; Wang, Xi-Peng

2017-01-01

In this study, a novel NGR (Asn-Gly-Arg) peptide-modified liposomal brucine was prepared by using spray-drying method. The surface morphology of the liposomes, encapsulation efficiency and particle size were investigated. The data showed that the addition of NGR did not produce any significant influence on brucine liposomes in terms of particle size or zeta potential. In addition, after 3 months of storage, no dramatic change such as visible aggregation, drug content changes or precipitation in the appearance of NGR-brucine liposomes occurred. The in vitro release results indicated that the release of brucine from NGR liposomes was similar to that of liposomes, demonstrating that the NGR modification did not affect brucine release. The in vitro drug-release kinetic model of NGR-brucine liposomes fitted well with the Weibull's equation. In vivo, NGR-brucine liposomes could significantly extend the bioavailability of brucine; however, there was no significant difference observed in the pharmacokinetic parameters between liposomes and NGR liposomes after intravenous administration. Antitumor activity results showed that NGR-modified liposomes exhibited less toxicity and much higher efficacy in HepG2-bearing mice compared with non-modified liposomes. The enhanced antitumor activity might have occurred because brucine was specifically recognized by NGR receptor on the surface of tumor cells, which enhanced the intracellular uptake of drugs.

[Comparison of in vitro model examinaitons with respect to drug release from suppositories].

PubMed

Regdon, G; Vágó, I; Mándi, E; Regdon, G; Erós, I

2000-04-01

9 lipophilic suppository bases with different physical-chemical parameters were examined. Buspiron-hydrochloride, an anxiolytic drug with good water-solubility was used--partly as a model--as a pharmacon, in a concentration of 10.0 mg/2.00 g. The rate and extent of in vitro drug release was monitored with static and dynamic methods. Kidney-dialysing membranes with various surfaces were used. The quantitative measurements were carried out spectrophotometrically and the amount of the diffused drug was determined at lambda = 298 nm. The mean values were calculated from 5 parallel measurements each time. The percentage values of in vitro relative availability revealed that the results of the two static diffusion studies did not differ significantly (p < 0.05) and were almost independent of the size of the membrane surface. The results of the dynamic diffusion method were well-reproducible but were vehicle-dependent. The process of release was characterized by the mathematical transformation of the release curves, while the correlation coefficients described the closeness of the relation. Two German vehicles, namely Witepsol H 15 with a medium hydroxyl value and Massa Estarinum 299, and a French vehicle, Suppocire AS2X were found to be excellent for the formulation of suppositories containing Buspiron-hydrochloride.

Pyrogen release in vitro by lymphoid tissues from patients with Hodgkin's disease.

PubMed

Bodel, P

1974-01-01

The mechanism of fever in patients with Hodgkin's disease was investigated by examining endogenous pyrogen production by blood, spleen, and lymph node cells incubated in vitro. Blood leucocytes from febrile or afebrile patients with Hodgkin's disease did not produce pyrogen spontaneously. Spleen cells, however, frequently released pyrogen during initial incubations, unlike spleen cells from patients with non-malignant diseases. Pyrogen production occurred from spleens without observed pathologic infiltrates of Hodgkin's disease. Lymph nodes involved with Hodgkin's disease produced pyrogen more frequently than did nodes involved with other diseases. Pyrogen production by tissue cells was prolonged, required protein synthesis, and in some cases was due to mononuclear cells; it did not correlate with fever in the patient. These studies demonstrate spontaneous production of endogenous pyrogen in vitro by lymphoid tissue cells from patients with Hodgkin's disease.

Comparison of lipases for in vitro models of gastric digestion: lipolysis using two infant formulas as model substrates.

PubMed

Sassene, P J; Fanø, M; Mu, H; Rades, T; Aquistapace, S; Schmitt, B; Cruz-Hernandez, C; Wooster, T J; Müllertz, A

2016-09-14

The aim of this study was to find a lipase suitable as a surrogate for Human Gastric Lipase (HGL), since the development of predictive gastrointestinal lipolysis models are hampered by the lack of a lipase with similar digestive properties as HGL. Three potential surrogates for HGL; Rhizopus Oryzae Lipase (ROL), Rabbit Gastric Lipase (RGL) and recombinant HGL (rHGL), were used to catalyze the in vitro digestion of two infant formulas (a medium-chain triacylglyceride enriched formula (MC-IF) and a predominantly long-chain triacylglyceride formula (LC-IF)). Digesta were withdrawn after 0, 5, 15, 30, 60 min of gastric digestion and after 90 or 180 min of intestinal digestion with or without the presence of pancreatic enzymes, respectively. The digesta were analyzed by scanning electron microscopy and gas chromatography to quantify the release of fatty acids (FAs). Digestions of both formulas, catalyzed by ROL, showed that the extent of gastric digestion was higher than expected from previously published in vivo data. ROL was furthermore insensitive to FA chain length and all FAs were released at the same pace. RGL and rHGL favoured the release of MC-FAs in both formulas, but rHGL did also release some LC-FAs during digestion of MC-IF, whereas RGL only released MC-FAs. Digestion of a MC-IF by HGL in vivo showed that MC-FAs are preferentially released, but some LC-FAs are also released. Thus of the tested lipase rHGL replicated the digestive properties of HGL the best and is a suitable surrogate for HGL for use in in vitro gastrointestinal lipolysis models.

Feasibility of CRISPR-Cas9-Based In Vitro Drug Target Identification for Personalized Prostate Cancer Medicine

DTIC Science & Technology

2017-09-01

AWARD NUMBER: W81XWH-16-1-0502 TITLE: Feasibility of CRISPR -Cas9-Based In Vitro Drug Target Identification for Personalized Prostate Cancer Medicine...CONTRACT NUMBER Feasibility of CRISPR -Cas9-Based In Vitro Drug Target Identification for Personalized Prostate Cancer Medicine 5b. GRANT NUMBER...Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT This study tests the feasibility of using CRISPR -Cas9 to

In Vitro and In Vivo Short-Term Pulmonary Toxicity of Differently Sized Colloidal Amorphous SiO2

PubMed Central

Wiemann, Martin; Sauer, Ursula G.; Vennemann, Antje; Bäcker, Sandra; Keller, Johannes-Georg; Ma-Hock, Lan; Wohlleben, Wendel; Landsiedel, Robert

2018-01-01

In vitro prediction of inflammatory lung effects of well-dispersed nanomaterials is challenging. Here, the in vitro effects of four colloidal amorphous SiO2 nanomaterials that differed only by their primary particle size (9, 15, 30, and 55 nm) were analyzed using the rat NR8383 alveolar macrophage (AM) assay. Data were compared to effects of single doses of 15 nm and 55 nm SiO2 intratracheally instilled in rat lungs. In vitro, all four elicited the release of concentration-dependent lactate dehydrogenase, β-glucuronidase, and tumor necrosis factor alpha, and the two smaller materials also released H2O2. All effects were size-dependent. Since the colloidal SiO2 remained well-dispersed in serum-free in vitro conditions, effective particle concentrations reaching the cells were estimated using different models. Evaluating the effective concentration–based in vitro effects using the Decision-making framework for the grouping and testing of nanomaterials, all four nanomaterials were assigned as “active.” This assignment and the size dependency of effects were consistent with the outcomes of intratracheal instillation studies and available short-term rat inhalation data for 15 nm SiO2. The study confirms the applicability of the NR8383 AM assay to assessing colloidal SiO2 but underlines the need to estimate and consider the effective concentration of such well-dispersed test materials. PMID:29534009

Regulation of serotonin release from enterochromaffin cells of rat cecum mucosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simon, C.; Ternaux, J.P.

1990-05-01

The release of endogenous serotonin or previously taken up tritiated serotonin from isolated strips of rat cecum mucosa containing enterochromaffin cells was studied in vitro. Release of tritiated serotonin was increased by potassium depolarization and was decreased by tetrodotoxin, veratridine and the absence of calcium. Endogenous serotonin was released at a lower rate than tritiated serotonin; endogenous serotonin release was stimulated by potassium depolarization but was unaffected by tetrodotoxin, veratridine or the absence of calcium. Carbachol, norepinephrine, clonidine and isoproterenol decreased release of tritiated serotonin but had less or reverse effect on release of endogenous serotonin. The results suggest twomore » different serotoninergic pools within the enterochromaffin cell population.« less

Biodegradable Polymer Releasing Antibiotic Developed for Drainage Catheter of Cerebrospinal Fluid: In Vitro Results

PubMed Central

Han, Song Yup; Cho, Ki Hong; Cho, Han Jin; An, Jeong Ho; Ra, Young Sin

2005-01-01

The authors developed a biodegradable polymer that releases an antibiotic (nalidixic acid) slowly and continuously, for prevention of catheter-induced infection during drainage of cerebrospinal fluid. We investigated the in vitro antibiotic releasing characteristics and bacterial killing effects of the new polymer against E. coli. The novel fluoroquinolone polymer was prepared using diisopropylcarbodiimide, poly (e-caprolactone) diol, and nalidixic acid. FT-IR, mass spectrometry, and elemental analysis proved that the novel antibacterial polymer was prepared successfully without any side products. Negative MS showed that the released drug has a similar molecular weight (M.W.=232, 350) to pure drug (M.W.=232). In high pressure liquid chromatography, the released drug and drug-oligomer showed similar retention times (about 4.5-5 min) in comparison to pure drug (4.5 min). The released nalidixic acid and nalidixic acid derivatives have antibacterial characteristics against E. coli, Staphylococcus aureus, and Salmonella typhi, of more than 3 months duration. This study suggests the possibility of applying this new polymer to manufacture drainage catheters that resist catheter-induced infection, by delivering antibiotics for a longer period of more than 1 month. PMID:15832004

Coupling in vitro and in vivo neurochemical-based assessments of wastewater effluents from the Maumee River Area of Concern (AOC)

EPA Science Inventory

Here we utilize in vivo and in vitro approaches to study whether real world effluents released in the Maumee River (Toledo, OH) Area of Concern (AOC) contain neuroactive substances that may impair fish reproduction and behavior. Our approaches help extend the concept of endocrine...

Intragastric Gelation of Heated Soy Protein Isolate-Alginate Mixtures and Its Effect on Sucrose Release.

PubMed

Huang, Zhaozhi; Gruen, Ingolf; Vardhanabhuti, Bongkosh

2018-06-15

The goal of our study was to investigate the effect of alginate on in vitro gastric digestion and sucrose release of soy protein isolate (SPI) in model beverages. Model beverages containing 5% w/w SPI, 0% to 0.20% w/w alginate, and 10% w/w sucrose were prepared by heating the mixtures at 85 °C for 30 min at pH 6.0 or 7.0. Characterizations of beverages included determination of zeta potential, particle size and rheological properties. Digestion patterns and sucrose release profiles were determined during 2 hr in vitro gastric digestion using SDS-PAGE and HPLC analysis, respectively. Increasing alginate concentration led to increased negative surface charge, particle size, as well as viscosity and pseudoplastic behavior; however, no phase separation was observed. SPI beverages formed intragastric gel during in vitro gastric digestion when the formulations contained alginate or at pH 6.0 without alginate. Formation of the intragastric gel led to delayed protein digestion and release of sucrose. Higher resistance to digestion and a slower sucrose release rate were exhibited at increased alginate concentration, and to a lesser extent, at pH 6.0. This suggests that electrostatic interaction between SPI and alginate that occurred when the beverages were under gastric condition could be responsible for the intragastric gelation. These results could potentially lead to the formulation of SPI beverages with functionality to lower postprandial glycemic response. The results could be used to design beverages or semi solid food products with altered digestion properties and lowered or slower glucose release. © 2018 Institute of Food Technologists®.

Positively Charged Nanostructured Lipid Carriers and Their Effect on the Dissolution of Poorly Soluble Drugs.

PubMed

Choi, Kyeong-Ok; Choe, Jaehyeog; Suh, Seokjin; Ko, Sanghoon

2016-05-20

The objective of this study is to develop suitable formulations to improve the dissolution rate of poorly water soluble drugs. We selected lipid-based formulation as a drug carrier and modified the surface using positively charged chitosan derivative (HTCC) to increase its water solubility and bioavailability. Chitosan and HTCC-coated lipid particles had higher zeta-potential values than uncoated one over the whole pH ranges and improved encapsulation efficiency. In vitro drug release showed that all NLC formulations showed higher in vitro release efficiency than drug particle at pH 7.4. Furthermore, NLC formulation prepared with chitosan or HTCC represented good sustained release property. The results indicate that chitosan and HTCC can be excellent formulating excipients of lipid-based delivery carrier for improving poorly water soluble drug delivery.

Development of Multiple-Unit Floating Drug Delivery System of Clarithromycin: Formulation, in vitro Dissolution by Modified Dissolution Apparatus, in vivo Radiographic Studies in Human Volunteers.

PubMed

Reddy, Arun B; Reddy, Narendar D

2017-07-01

Clarithromycin (CM), a broad spectrum macrolide antibiotic used to eradicate H. pylori in peptic ulcer. Clarithromycin (CM) is well absorbed from the gastrointestinal tract, but has a bioavailability of 50% due to rapid biodegradation. The aim of this investigation was to increase the gastric residence time, and to control the drug release of clarithromycin by formulating into multiple unit floating mini-tablets. Floating tablets were prepared by using direct compression method with HPMC K 4 M and Polyox WSR 1105 as release retarded polymers and sodium bicarbonate as gas generating agent. The prepared mini-tablets were evaluated for thickness, weight variation, friability, hardness, drug content, in vitro buoyancy, swelling studies, in vitro dissolution studies by using modified Rossett-Rice test and in vivo radiographic studies in healthy human volunteers in fasting conditions. DSC analysis revealed that no interaction between drug and excipients. All the physical parameters of the tablets were within the acceptable limits. The optimized formulation (F6) had showed controlled drug release of 99.16±3.22% in 12 h, by zero-order release kinetics, along with floating lag time of 9.5±1.28 s and total floating time of 12±0.14 h. X-ray imaging studies revealed that in vivo gastric residence time of clarithromycin floating mini-tablet in the stomach was about 3.5 h. The results demonstrated that the developed floating mini-tablets of clarithromycin caused significant enhancement in gastric retention time along with sustained effect and increased oral bioavailability. © Georg Thieme Verlag KG Stuttgart · New York.

RANKL release from self-assembling nanofiber hydrogels for inducing osteoclastogenesis in vitro.

PubMed

Xing, James Z; Lu, Lei; Unsworth, Larry D; Major, Paul W; Doschak, Michael R; Kaipatur, Neelambar R

2017-02-01

To develop a nanofiber hydrogel (NF-hydrogel) for sustained and controlled release of the recombinant receptor activator of NF-kB ligand; (RANKL) and to characterize the release kinetics and bioactivity of the released RANKL. Various concentrations of fluorescently-labelled RANKL protein were added to NF-hydrogels, composed of Acetyl-(Arg-Ala-Asp-Ala) 4 -CONH 2 [(RADA) 4 ] of different concentrations, to investigate the resulting in vitro release rates. The nano-structures of NF-hydrogel, with and without RANKL, were determined using atomic force microscopy (AFM). Released RANKL was further analyzed for changes in secondary and tertiary structure using CD spectroscopy and fluorescent emission spectroscopy, respectively. Bioactivity of released RANKL protein was determined using NFATc1 gene expression and tartrate resistant acid phosphatase (TRAP) activity of osteoclast cells as biomarkers. NF-hydrogel concentration dependent sustained release of RANKL protein was measured at concentrations between 0.5 and 2%(w/v). NF-hydrogel at 2%(w/v) concentration exhibited a sustained and slow-release of RANKL protein up to 48h. Secondary and tertiary structure analyses confirmed no changes to the RANKL protein released from NF-hydrogel in comparison to native RANKL. The results of NFATc1 gene mRNA expression and TRAP activities of osteoclast, showed that the release process did not affect the bioactivity of released RANKL. This novel study is the first of its kind to attempt in vitro characterization of NF-hydrogel based delivery of RANKL protein to induce osteoclastogenesis. We have shown the self-assembling NF-hydrogel peptide system is amenable to the sustained and controlled release of RANKL locally; that could in turn increase local concentration of RANKL to induce osteoclastogenesis, for application to the controlled mobilization of tooth movement in orthodontic procedures. Orthodontic tooth movement (OTM) occurs through controlled application of light forces to teeth, facilitating the required changes in the surrounding alveolar bone through the process of bone remodelling. The RANKL system regulates alveolar bone remodelling and controls root resorption during OTM. The use of exogenous RANKL to accelerate OTM has not been attempted to date because large quantities of RANKL for systemic therapy may subsequently cause serious systemic loss of skeletal bone. The controlled and sustained local release of RANKL from a carrier matrix could maximize its therapeutic benefit whilst minimizing systemic side effects. In this study a NF-hydrogel was used for sustained and controlled release of RANKL and the release kinetics and biofunctionality of the released RANKL was characterized. Our results provide fundamental insight for further investigating the role of RANKL NF-hydrogel release systems for inducing osteoclastogenesis in vivo. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

In situ forming implants for the delivery of metronidazole to periodontal pockets: formulation and drug release studies.

PubMed

Kilicarslan, Muge; Koerber, Martin; Bodmeier, Roland

2014-05-01

This study was performed to obtain prolonged drug release with biodegradable in situ forming implants for the local delivery of metronidazole to periodontal pockets. The effect of polymer type (capped and uncapped PLGA), solvent type (water-miscible and water-immiscible) and the polymer/drug ratio on in vitro drug release studies were investigated. In situ implants with sustained metronidazole release and low initial burst consisted of capped PLGA and N-methyl-2-pyrolidone as solvent. Mucoadhesive polymers were incorporated into the in situ implants in order to modify the properties of the delivery systems towards longer residence times in vivo. Addition of the polymers changed the adhesiveness and increased the viscosity and drug release of the formulations. However, sustained drug release over 10 days was achievable. Biodegradable in situ forming implants are therefore an attractive delivery system to achieve prolonged release of metronidazole at periodontal therapy.

Development of ligustrazine hydrochloride carboxymethyl chitosan and collagen microspheres: Formulation optimization, characterization, and vitro release

PubMed Central

Lin, Qiang; Huo, Qing; Qin, Yingzhe; Zhao, Zhuo; Tao, Fengyun

2017-01-01

ABSTRACT This study investigates the preparation of ligustrazine hydrochloride carboxymethyl chitosan and collagen microspheres. This experiment investigates effects of the ratio of carboxymethyl chitosan and collagen blend, water to oil ratio, stirring speed, and other factors on the microsphere properties. The experiment had the following conditions: a 1:2 proportion of carboxymethyl chitosan and collagen, a 1:2 proportion of drugs and materials, a 5:1 proportion of oil phase and water phase, 0.5% of span80, a 600r/min stirring speed, 3 ml of a cross-linking agent, 3 h of cross-linking curing, 1.25 ± 0.05 mm diameter LTH microcapsules, a 54.08% envelop rate, and a 14.16% carrier rate. The microspheres release rate reached 66% within 1 h, then steadily released within 5 h in vitro. The experimental results showed that the ligustrazine hydrochloride microsphere production process was stable and exhibited a good release effect compared with other ligustrazine hydrochloride tablets and pills. PMID:27689792

A method for hormonal induction of sperm release in anurans (eight species) and in vitro fertilization in lepidobatrachus species.

PubMed

Waggener, W L; Carroll, E J

1998-02-01

Injections of synthetic human gonadotropin releasing hormone (GnRH) into the dorsal pelvic area were used in an attempt to stimulate sperm release in isolated males of eight anuran species including Xenopus laevis, Rana pipiens and Lepidobatrachus laevis. Sperm were obtained within 1-5 h post injection either by mechanical stimulation or by cloacal lavage. Sperm suspensions varied from 8 microL to 7 mL and the cell densities ranged from 4 x 10(5) to 4 x 10(7) sperm/mL. The sperm obtained from seven species using GnRH-induced release were viable based on light microscopic observations of motility. In addition, sperm preparations fertilized eggs in vitro and produced normal tadpoles in the case of L. laevis and L. Ilanensis. This hormonal method of anuran sperm collection will provide a convenient non-injurious way to obtain anuran sperm for basic studies of reproduction and development.

In vitro release kinetics of Tolmetin from tabletted Eudragit microparticles.

PubMed

Pignatello, R; Consoli, P; Puglisi, G

2000-01-01

In a previous paper the preparation has been described, by three different techniques, of microparticles made of Eudragit RS 100 and RL 100 containing a NSAI agent, Tolmetin. Freely flowing microparticles failed to affect significantly the in vitro drug release, which displayed a similar dissolution profile after micro-encapsulation to the free drug powder. Microparticles were then converted into tablets and the effect of compression on drug delivery, as well as that of the presence of co-additives, was studied in the present work. Furthermore, microparticles were also prepared by adding MgO to the polymer matrix, to reduce the sensitivity of the drug to pH changes during its dissolution. Similarly, magnesium stearate was also used for microparticle formation as a droplet stabilizer, in order to reduce particle size and hinder rapid drug release. A mathematical evaluation, by using two semi-empirical equations, was applied to evaluate the influence of dissolution and diffusion phenomena upon drug release from microparticle tablets.

In vitro dissolution method fitted to in vivo absorption profile of rivaroxaban immediate-release tablets applying in silico data.

PubMed

Wingert, Nathalie R; Dos Santos, Natália O; Campanharo, Sarah C; Simon, Elisa S; Volpato, Nadia M; Steppe, Martin

2018-05-01

This study aimed to develop and validate an in vitro dissolution method based on in silico-in vivo data to determine whether an in vitro-in vivo relationship could be established for rivaroxaban in immediate-release tablets. Oral drugs with high permeability but poorly soluble in aqueous media, such as the anticoagulant rivaroxaban, have a major potential to reach a high level of in vitro-in vivo relationship. Currently, there is no study on scientific literature approaching the development of RIV dissolution profile based on its in vivo performance. Drug plasma concentration values were modeled using computer simulation with adjustment of pharmacokinetic properties. Those values were converted into drug fractions absorbed by the Wagner-Nelson deconvolution approach. Gradual and continuous dissolution of RIV tablets was obtained with a 30 rpm basket on 50 mM sodium acetate +0.2% SDS, pH 6.5 medium. Dissolution was conducted for up to 180 min. The fraction absorbed was plotted against the drug fraction dissolved, and a linear point-to-point regression (R 2  = 0.9961) obtained. The in vitro dissolution method designed promoted a more convenient dissolution profile of RIV tablets, whereas it suggests a better relationship with in vivo performance.

Characterization of Nano Bamboo Charcoal Drug Delivery System for Eucommia ulmoides Extract and Its Anticancer Effect In vitro.

PubMed

Zeng, Zhaoyan; Li, Xiangzhou; Zhang, Sheng; Huang, Dan

2017-01-01

Nano bamboo charcoal is being widely used as sustained release carrier for chemicals for its high specific surface area, sound biocompatibility, and nontoxicity; however, there have been no reports on nano bamboo charcoal as sustained release carrier for traditional Chinese medicine (TCM). To study the effect of nano bamboo charcoal in absorbing and sustained releasing Eucommia ulmoides extract (EUE) and to verify the in vitro anticancer effect of the sustained release liquid, so as to provide a theoretical basis for the development and utilization of nano bamboo charcoal as TCM sustained-release preparation. The adsorption capacity for the nano bamboo charcoal on EUE was measured by Langmuir model, and the release experiment was carried out under intestinal fluid condition. Characteristic changes for the nano bamboo charcoal nano-drug delivery system with and without adsorption of E. ulmoides were evaluated by scanning electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and specific surface area. In addition, the anticancer effect from this novel bamboo charcoal E. ulmoides delivery system was evaluated against a human colon cancer cell line (HCT116). It was found that nano bamboo charcoal exhibits good adsorption capacity (up to 462.96 mg/g at 37°C). The cumulative release rate for EUE from this nano bamboo charcoal delivery system was 70.67%, and specific surface area for the nano bamboo charcoal decreased from 820.32 m 2 /g to 443.80 m 2 /g after EUE was loaded. An in vitro anticancer study showed that the inhibition rate for E. ulmoides against HCT116 cancer cells was 23.07%, for this novel bamboo charcoal nano-drug delivery system. This study provides a novel strategy for the delivery of traditional Chinese medicine using bamboo charcoal nano-drug delivery system. The adsorption equilibrium was reached after 30 min of ultrasonic treatmentThe saturated adsorption capacity of Eucommia ulmoides extract by nano bamboo charcoal under ultrosonic condition was 462. 96 mg/gThe cumulative release rate of E. ulmoides extract from the nano bamboo charcoal delivery system in artificial intestinal juice was 70.67%The inhibition ratio of HCT116 cancer cells by sustained release liquid was 23.07%. Abbreviation used: EUE: Eucommia ulmoides extract.

In vitro culture of human osteosarcoma cell lines: a comparison of functional characteristics for cell lines cultured in medium without and with fetal calf serum.

PubMed

Bruserud, Oystein; Tronstad, Karl Johan; Berge, Rolf

2005-06-01

Experimental in vitro models including well-characterised cell lines can be used to identify possible new therapeutic targets for the treatment of osteosarcoma. Culture media including inactivated serum is often recommended for in vitro culture of osteosarcoma cells, but the serum component then represents a nonstandardised parameter including a wide range of unidentified mediators. To improve the standardisation we have investigated whether serum-free culture media can be used in experimental in vitro studies of osteosarcoma cell lines. The seven osteosarcoma cell lines Cal72, SJSA-1, Saos-2, SK-ES-1, U2OS, 143.98.2, and KHOS-32IH were cultured in vitro in various serum-free media and media supplemented with 10% heat-inactivated fetal calf serum (FCS). Although proliferation often was relatively low in serum-free media (X-vivo 10, X-vivo 15, X-vivo 20, Stem Span SFEM), some cell lines (Cal72, KHOS-32IH, Saos-2) showed proliferation comparable with the recommended FCS-containing media even when using serum-free conditions. The optimal serum-free medium then varied between cell lines. We also compared 6 different FCS-containing media (including Stem Span with 10% FCS) and the optimal FCS-containing medium varied between cell lines. However, all cell lines proliferated well in Stem Span with FCS, and this medium was regarded as optimal for four of the lines. FCS could not be replaced by fatty acids or low density lipoprotein when testing the Stem Span medium. The release of a wide range of soluble mediators showed only minor differences when using serum-free and FCS-containing media (including Stem Span with and without FCS), and serum-free Stem Span could also be used for in vitro studies of mitogen-stimulated T cell activation in the presence of accessory osteosarcoma cells. The use of Stem Span with 10% FCS allowed the release of a wide range of chemokines by osteosarcoma cell lines (Cal72, SJSA-1), and the chemokine release profile was very similar to the fibroblast lines Hs27 and HFL1. Serum-free culture media can be used for in vitro studies of several osteosarcoma cell lines, but the optimal medium varies between cell lines and thus depends on: (i) the cell lines to be investigated/compared; (ii) the functional characteristic that is evaluated (proliferation, cytokine release); and (iii) whether coculture experiments are included.

Photoacoustic methods for in vitro study of kinetics progesterone release from the biodegradation of polyhydroxybutyrate/polycaprolactone used as intravaginal devices

DOE Office of Scientific and Technical Information (OSTI.GOV)

Souza Filho, N. E.; Universidade Federal de Santa Maria, Departamento de Eng. Acústica, Av. Roraima 1000, CEP 97105–900, Santa Maria-RS; Mariucci, V. V. G.

Intravaginal devices composed of polyhydroxybutyrate/polycaprolactone blends incorporating progesterone were used over eight days in crossbred cow ovariectomized, and then analyzed with photoacoustic methods, measuring the absorption spectra, thermal diffusivity, and inspecting its degradation by means of scanning electron microscopy. The characteristic time found for progesterone release was TR ∼ 53 h, and the typical time found for biodegradation was TB ∼ 30 h. Morphological analysis complements the study showing that release of progesterone and biodegradation of the blend occurs on sample surface.

Photoacoustic methods for in vitro study of kinetics progesterone release from the biodegradation of polyhydroxybutyrate/polycaprolactone used as intravaginal devices

NASA Astrophysics Data System (ADS)

Souza Filho, N. E.; Mariucci, V. V. G.; Dias, G. S.; Szpak, W.; Miguez, P. H. P.; Madureira, E. H.; Medina, A. N.; Baesso, M. L.; Bento, A. C.

2013-09-01

Intravaginal devices composed of polyhydroxybutyrate/polycaprolactone blends incorporating progesterone were used over eight days in crossbred cow ovariectomized, and then analyzed with photoacoustic methods, measuring the absorption spectra, thermal diffusivity, and inspecting its degradation by means of scanning electron microscopy. The characteristic time found for progesterone release was TR ˜ 53 h, and the typical time found for biodegradation was TB ˜ 30 h. Morphological analysis complements the study showing that release of progesterone and biodegradation of the blend occurs on sample surface.

Targeted delivery of mesoporous silica nanoparticles loaded monastrol into cancer cells: an in vitro study

NASA Astrophysics Data System (ADS)

Hanif, Huzaifa; Nazir, Samina; Mazhar, Kehkashan; Waseem, Muhammad; Bano, Shazia; Rashid, Umer

2017-11-01

Monastrol is a simple low molecular weight dihydropyrimidine-based kinesin Eg5 inhibitor. Its low cellular activity and its non-drug-like properties have impeded its further development. In a previous report, we have reported various topological parameters to improve the pharmacokinetic properties of monastrol. The purpose of this study is to determine the loading and release feasibility of poorly water-soluble monastrol into the synthesized mesoporous silica nanoparticles (MSNs). The synthesis of MSNs was attained by the ammonia-catalysed hydrolysis and condensation of TEOS in ethanol using polysorbate-80 as surfactant. These were characterized by BET surface area and pore size distribution analyses, SEM, XRD, UV and FTIR spectroscopy. The synthesized monastrol was successfully loaded on MSNPs and coated by hydrogels for successful controlled drug delivery. In vitro release studies are done by simple dialysis method. Monastrol-loaded MSNPs were tested on human cervical epithelial malignant carcinoma (HeLa) cell lines for studying their anticancer activity. Our presented system described a reliable method for targeted delivery of monastrol into the cancer cells in vitro.

In vitro evaluation of α-lipoic acid-loaded lipid nanocapsules for topical delivery.

PubMed

Xia, Nan; Liu, Tian; Wang, Qiang; Xia, Qiang; Bian, Xiaoli

2017-09-01

This study aimed at in vitro evaluation of α-lipoic acid-loaded lipid nanocapsules for topical delivery, which was prepared by hot high-pressure homogenisation. Stable particles could be formed and particle size was 148.54 ± 2.31 nm with polydispersity index below 0.15. Encapsulation efficiency and drug loading of α-lipoic acid were 95.23 ± 0.45% and 2.81 ± 0.37%. Antioxidant study showed α-lipoic acid could be protected by lipid nanocapsules without loss of antioxidant activity. Sustained release of α-lipoic acid from lipid nanocapsules was obtained and cumulative release was 62.18 ± 1.51%. In vitro percutaneous study showed the amount of α-lipoic acid distributed in skin was 1.7-fold than permeated. Cytotoxicity assay and antioxidant activity on L929 cells indicated this formulation had low cytotoxicity and ability of protecting cells from oxidative damage within specific concentration. These studies suggested α-lipoic acid-loaded lipid nanocapsules could be potential formulation for topical delivery.

Smart pH- and reduction-dual-responsive folate-PEG-coated polymeric lipid vesicles for tumor-triggered targeted drug delivery

NASA Astrophysics Data System (ADS)

Wang, Sheng; Wang, Hanjie; Liu, Zhongyun; Wang, Liangliang; Wang, Xiaomin; Su, Lin; Chang, Jin

2014-06-01

To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a nano-sized structure (~50 nm) with a PEG coating. The in vitro DOX release profiles showed that the FPPLVs achieved a triggered drug release in response to acidic pH and reducing environments due to the cleavage of hydrazone bonds and disulfide bonds. It has also been demonstrated by an in vitro cellular uptake study that the FPPLVs lose their PEG coating as well as expose the folate in acidic conditions, which allows them to efficiently enter tumor cells through ligand-receptor interactions. In vitro cytotoxicity measurements also confirmed that FPPLVs exhibited pronounced antitumor activity against HeLa cells. These results suggest that FPPLVs are promising carriers for smart antitumor drug delivery applications.To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a nano-sized structure (~50 nm) with a PEG coating. The in vitro DOX release profiles showed that the FPPLVs achieved a triggered drug release in response to acidic pH and reducing environments due to the cleavage of hydrazone bonds and disulfide bonds. It has also been demonstrated by an in vitro cellular uptake study that the FPPLVs lose their PEG coating as well as expose the folate in acidic conditions, which allows them to efficiently enter tumor cells through ligand-receptor interactions. In vitro cytotoxicity measurements also confirmed that FPPLVs exhibited pronounced antitumor activity against HeLa cells. These results suggest that FPPLVs are promising carriers for smart antitumor drug delivery applications. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr00843j

In silico and in vitro methods to optimize the performance of experimental gastroretentive floating mini-tablets.

PubMed

Eberle, Veronika A; Häring, Armella; Schoelkopf, Joachim; Gane, Patrick A C; Huwyler, Jörg; Puchkov, Maxim

2016-01-01

Development of floating drug delivery systems (FDDS) is challenging. To facilitate this task, an evaluation method was proposed, which allows for a combined investigation of drug release and flotation. It was the aim of the study to use functionalized calcium carbonate (FCC)-based lipophilic mini-tablet formulations as a model system to design FDDS with a floating behavior characterized by no floating lag time, prolonged flotation and loss of floating capability after complete drug release. Release of the model drug caffeine from the mini-tablets was assessed in vitro by a custom-built stomach model. A cellular automata-based model was used to simulate tablet dissolution. Based on the in silico data, floating forces were calculated and analyzed as a function of caffeine release. Two floating behaviors were identified for mini-tablets: linear decrease of the floating force and maintaining of the floating capability until complete caffeine release. An optimal mini-tablet formulation with desired drug release time and floating behavior was developed and tested. A classification system for a range of varied floating behavior of FDDS was proposed. The FCC-based mini-tablets had an ideal floating behavior: duration of flotation is defined and floating capability decreases after completion of drug release.

Risperidone mucoadhesive buccal tablets: formulation design, optimization and evaluation

PubMed Central

Çelik, Burak

2017-01-01

The aim of this study was to design and optimize risperidone (RIS) mucoadhesive buccal tablets for systemic delivery as an alternative route. Direct compression method was used for the preparation of buccal tablets, and screening studies were conducted with different polymers to determine their effects on tablet characteristics. Carbopol® (CP) and sodium alginate (SA) were selected as two polymer types for further optimization studies by applying response surface methodology. Tablet hardness (TH), ex vivo residence time (RT), and peak detachment force (DF) from buccal mucosa were selected as three important responses. Physicochemical compatibility of formulation excipients and RIS was evaluated by using Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) analysis. In vitro drug release profiles and release kinetics were investigated; swelling index and matrix erosion studies were conducted. Optimum formulation consisted of 16.4% CP and 20.3% SA, which provided 7.67±0.29 hour ex vivo RT, 45.52±4.85 N TH, and 2.12±0.17 N DF. FT-IR spectroscopy and DSC analysis revealed that there was no chemical interaction present between tablet ingredients. Cumulative RIS release of >90% was achieved after 8 hours of in vitro dissolution studies, which was supported by swelling and matrix erosion analysis. Mechanism of RIS release was fitted best to zero-order model, while release exponent (n) value of 0.77 demonstrated an anomalous (non-Fickian) release, indicating combined erosion and swelling mechanism. The results suggested that optimized buccal tablets of RIS would be a promising and alternative delivery system for the treatment of schizophrenia. PMID:29225461

IVIVC for fenofibrate immediate release tablets using solubility and permeability as in vitro predictors for pharmacokinetics.

PubMed

Buch, Philipp; Holm, Per; Thomassen, Jesper Qvist; Scherer, Dieter; Branscheid, Robert; Kolb, Ute; Langguth, Peter

2010-10-01

The goal of this study was to investigate the in vitro-in vivo correlation (IVIVC) for fenofibrate immediate release (IR) tablet formulations based on MeltDose-technique. The in vitro determined drug solubility and permeability data were related to the C(max) values observed from two in vivo human studies. Solubility and permeation studies of fenofibrate were conducted in medium simulating the fasted state conditions in the upper jejunum, containing the surfactant compositions of the six formulations at different concentrations. The behavior of all surfactant compositions was characterized by surface tension, dynamic light scattering, and cryo-TEM. The obtained solubility and permeation data were combined and compared with the C(max) values for the fenofibrate formulations, assuming a 50 mL in vivo dissolution volume. A good IVIVC was observed for five fenofibrate formulations (R(2) = 0.94). The in vitro studies revealed that the formulation compositions containing sodium lauryl sulfate (SLS) interfered with the vesicular drug solubilizing system of the biorelevant medium and antagonized its solubilization capacity. The opposing interaction of surfactants with the emulsifying physiological constituents in intestinal juice should be taken into consideration in order to prevent unsatisfactory in vivo performance of orally administered formulations with low soluble active pharmaceutical ingredients.

Lactic acid polymers as biodegradable carriers of fluoroquinolones: an in vitro study.

PubMed

Kanellakopoulou, K; Kolia, M; Anastassiadis, A; Korakis, T; Giamarellos-Bourboulis, E J; Andreopoulos, A; Dounis, E; Giamarellou, H

1999-03-01

A biodegradable polymer of DL-dilactide that facilitates release of ciprofloxacin or pefloxacin at levels exceeding MICs for the causative microorganisms of chronic osteomyelitis is described. Duration and peak of release were found to depend on the molecular weight of the polymer. Its characteristics make it promising for treating chronic bone infections.

Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues.

PubMed

Bonano, J S; Banks, M L; Kolanos, R; Sakloth, F; Barnier, M L; Glennon, R A; Cozzi, N V; Partilla, J S; Baumann, M H; Negus, S S

2015-05-01

Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure-activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es ), electronic (σp ) and lipophilic (πp ) parameters of the para substituents. For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation. MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation. Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es ) are key determinants of this selectivity. © 2014 The British Pharmacological Society.

Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system

PubMed Central

Chen, Zhi-Qiang; Liu, Ying; Zhao, Ji-Hui; Wang, Lan; Feng, Nian-Ping

2012-01-01

Background Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin. Methods A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats. Results The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor® EL:Transcutol® P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS. Conclusion The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin. PMID:22403491

Quantitative structure–activity relationship analysis of the pharmacology of para-substituted methcathinone analogues

PubMed Central

Bonano, J S; Banks, M L; Kolanos, R; Sakloth, F; Barnier, M L; Glennon, R A; Cozzi, N V; Partilla, J S; Baumann, M H; Negus, S S

2015-01-01

Background and Purpose Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure–activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es), electronic (σp) and lipophilic (πp) parameters of the para substituents. Experimental Approach For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation. Key Results MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation. Conclusions and Implications Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es) are key determinants of this selectivity. PMID:25438806

Ciprofloxacin as ocular liposomal hydrogel.

PubMed

Hosny, Khaled Mohamed

2010-03-01

The purpose of this study was to prepare and characterize an ocular effective prolonged-release liposomal hydrogel formulation containing ciprofloxacin. Reverse-phase evaporation was used for preparation of liposomes consisting of soybean phosphatidylcholine (PC) and cholesterol (CH). The effect of PC/CH molar ratio on the percentage drug encapsulation was investigated. The effect of additives such as stearylamine (SA) or dicetyl phosphate (DP) as positive and negative charge inducers, respectively, were studied. Morphology, mean size, encapsulation efficiency, and in vitro release of ciprofloxacin from liposomes were evaluated. For hydrogel preparation, Carbopol 940 was applied. In vitro transcorneal permeation through excised albino rabbit cornea was also determined. Optimal encapsulation efficiency of 73.04 +/- 3.06% was obtained from liposomes formulated with PC/CH at molar ratio of 5:3 and by increasing CH content above this limit, the encapsulation decreased. Positively charged liposomes showed superior entrapment efficiency (82.01 +/- 0.52) over the negatively charged and the neutral liposomes. Hydrogel containing liposomes with lipid content PC, CH, and SA in molar ratio 5:3:1, respectively, showed the best release and transcorneal permeation with the percentage permeation of 30.6%. These results suggest that the degree of encapsulation of ciprofloxacin into liposomes and prolonged in vitro release depend on composition of the vesicles. In addition, the polymer hydrogel used in preparation ensure steady and prolonged transcorneal permeation. In conclusion, ciprofloxacin liposomal hydrogel is a suitable delivery system for improving the ocular bioavailability of ciprofloxacin.

Formulation and performance characterization of radio-sterilized "progestin-only" microparticles intended for contraception.

PubMed

Puthli, Shivanand; Vavia, Pradeep

2009-01-01

The aim of this study was to formulate and characterize a microparticulate system of progestin-only contraceptive. Another objective was to evaluate the effect of gamma radio-sterilization on in vitro and in vivo drug release characteristics. Levonorgestrel (LNG) microspheres were fabricated using poly(lactide-co-glycolide) (PLGA) by a novel solvent evaporation technique. The formulation was optimized for drug/polymer ratio, emulsifier concentration, and process variables like speed of agitation and evaporation method. The drug to polymer ratio of 1:5 gave the optimum encapsulation efficiency. Speed of agitation influenced the spherical shape of the microparticles, lower speeds yielding less spherical particles. The speed did not have a significant influence on the drug payloads. A combination of stabilizers viz. methyl cellulose and poly vinyl alcohol with in-water solvent evaporation technique yielded microparticles without any free drug crystals on the surface. This aspect significantly eliminated the in vitro dissolution "burst effect". The residual solvent content was well within the regulatory limits. The microparticles passed the test for sterility and absence of pyrogens. In vitro dissolution conducted on the product before and after gamma radiation sterilization at 2.5 Mrad indicated no significant difference in the drug release patterns. The drug release followed zero-order kinetics in both static and agitation conditions of dissolution testing. The in vivo studies conducted in rabbits exhibited LNG release up to 1 month duration with drug levels maintained within the effective therapeutic window.

Protein breakdown and release of β-casomorphins during in vitro gastro-intestinal digestion of sterilised model systems of liquid infant formula.

PubMed

Cattaneo, Stefano; Stuknytė, Milda; Masotti, Fabio; De Noni, Ivano

2017-02-15

Protein modifications occurring during sterilisation of infant formulas can affect protein digestibility and release of bioactive peptides. The effect of glycation and cross-linking on protein breakdown and release of β-casomorphins was evaluated during in vitro gastro-intestinal digestion (GID) of six sterilised model systems of infant formula. Protein degradation during in vitro GID was evaluated by SDS-PAGE and by measuring the nitrogen content of ultrafiltration (3kDa) permeates before and after in vitro GID of model IFs. Glycation strongly hindered protein breakdown, whereas cross-linking resulting from β-elimination reactions had a negligible effect. Only β-casomorphin 7 (β-CM7) was detected (0.187-0.858mgL(-1)) at the end of the intestinal digestion in all untreated IF model systems. The level of β-CM7 in the sterilised model systems prepared without addition of sugars ranged from 0.256 to 0.655mgL(-1). The release of this peptide during GID was hindered by protein glycation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Investigating the role of ion-pair strategy in regulating nicotine release from patch: Mechanistic insights based on intermolecular interaction and mobility of pressure sensitive adhesive.

PubMed

Li, Qiaoyun; Wan, Xiaocao; Liu, Chao; Fang, Liang

2018-07-01

The aim of this study was to prepare a drug-in-adhesive patch of nicotine (NIC) and use ion-pair strategy to regulate drug delivery rate. Moreover, the mechanism of how ion-pair strategy regulated drug release was elucidated at molecular level. Formulation factors including pressure sensitive adhesives (PSAs), drug loading and counter ions (C 4 , C 6 , C 8 , C 10 , and C 12 ) were screened. In vitro release experiment and in vitro transdermal experiment were conducted to determine the rate-limiting step in drug delivery process. FT-IR and molecular modeling were used to characterize the interaction between drug and PSA. Thermal analysis and rheology study were conducted to investigate the mobility variation of PSA. The optimized patch prepared with NIC-C 8 had the transdermal profile fairly close to that of the commercial product (p > 0.05). The release rate constants (k) of NIC, NIC-C 4 and NIC-C 10 were 21.1, 14.4 and 32.4, respectively. Different release rates of NIC ion-pair complexes were attributed to the dual effect of ion-pair strategy on drug release. On one hand, ion-pair strategy enhanced the interaction between drug and PSA, which inhibited drug release. On the other hand, using ion-pair strategy improved the mobility of PSA, which facilitated drug release. Drug release behavior was determined by combined effect of two aspects above. These conclusions provided a new idea for us to regulate drug release behavior from patch. Copyright © 2018 Elsevier B.V. All rights reserved.

Preparation and in vitro evaluation of guar gum based triple-layer matrix tablet of diclofenac sodium

PubMed Central

Chavda, H.V.; Patel, M.S.; Patel, C.N.

2012-01-01

The objective of the present study was to design an oral controlled drug delivery system for sparingly soluble diclofenac sodium (DCL) using guar gum as triple-layer matrix tablets. Matrix tablet granules containing 30% (D1), 40% (D2) or 50% (D3) of guar gum were prepared by the conventional wet granulation technique. Matrix tablets of diclofenac sodium were prepared by compressing three layers one by one. Centre layer of sandwich like structure was incorporated with matrix granules containing DCL which was covered on either side by guar gum granule layers containing either 70, 80 or 87% of guar gum as release retardant layers. The tablets were evaluated for hardness, thickness, drug content, and drug release studies. To ascertain the kinetics of drug release, the dissolution profiles were fitted to various mathematical models. The in vitro drug release from proposed system was best explained by the Hopfenberg model indicating that the release of drug from tablets displayed heterogeneous erosion. D3G3, containing 87% of guar gum in guar gum layers and 50% of guar gum in DCL matrix granule layer was found to provide the release rate for prolonged period of time. The results clearly indicate that guar gum could be a potential hydrophilic carrier in the development of oral controlled drug delivery systems. PMID:23181081

Microencapsulation of rifampicin for the prevention of endophthalmitis: In vitro release studies and antibacterial assessment.

PubMed

Lee, Mi Yeon; Bourgeois, Sandrine; Almouazen, Eyad; Pelletier, Jocelyne; Renaud, François; Fessi, Hatem; Kodjikian, Laurent

2016-05-30

Rifampicin encapsulated microparticles were designed for intraocular injection after cataract surgery to prevent postoperative endophthalmitis. Microparticles were formulated by emulsification diffusion method using poly(lactic acid-co-glycolic acid) (PLGA) as polymer in order to propose a new form of rifampicin that overcome its limitations in intraocular delivery. Depending on processing formulation, different types of microparticles were prepared, characterized and evaluated by in vitro release studies. Two types of microparticles were selected to get a burst release of rifampicin, to reach minimal inhibitory concentrations to inhibit 90% of Staphylococcus epidermidis mainly involved in postoperative endophthalmitis, combined with a sustained release to maintain rifampicin concentration over 24h. The antibacterial activity and antiadhesive property on intraocular lenses were evaluated on S. epidermidis. Microparticles, with a rapid rifampicin release profile, showed an effect towards bacteria development similar to free rifampicin over 48h. However, slow-release profile microparticles exhibited a similar antibacterial effect during the first 24h, and were able to destroy all the S epidermidis in the medium after 30h. The association of the two formulations allowed obtaining interesting antibacterial profile. Moreover, rifampicin-loaded microparticles have shown a very efficient anti-adherent effect of S. epidermidis on intraocular lenses at 24h. These results propose rifampicin microparticles as suitable for antibioprophylaxis of the postoperative endophthalmitis. Copyright © 2016 Elsevier B.V. All rights reserved.

Development of a calcium phosphate co-precipitate/poly(lactide-co-glycolide) DNA delivery system: release kinetics and cellular transfection studies.

PubMed

Kofron, Michelle D; Laurencin, Cato T

2004-06-01

One of the most common non-viral methods for the introduction of foreign deoxyribonucleic acid (DNA) into cultured cells is calcium phosphate co-precipitate transfection. This technique involves the encapsulation of DNA within a calcium phosphate co-precipitate, particulate addition to in vitro cell culture, endocytosis of the co-precipitate, and exogenous DNA expression by the transfected cell. In this study, we fabricated a novel non-viral gene transfer system by adsorbing DNA, encapsulated in calcium phosphate (DNA/Ca-P) co-precipitates, to biodegradable two- and three-dimensional poly(lactide-co-glycolide) matrices (2D-DNA/Ca-P/PLAGA, 3D-DNA/Ca-P/PLAGA). Co-precipitate release studies demonstrated an initial burst release over the first 48 h. By day 7, approximately 96% of the initially adsorbed DNA/Ca-P co-precipitate had been released. This was followed by low levels of co-precipitate release for 42 days. Polymerase chain reaction was used to demonstrate the ability of the released DNA containing co-precipitates to transfect SaOS-2 cells cultured in vitro on the 3D-DNA/Ca-P/PLAGA matrix and maintenance of the structural integrity of the exogenous DNA. In summary, a promising system for the incorporation and controlled delivery of exogenous genes encapsulated within a calcium phosphate co-precipitate from biodegradable polymeric matrices has been developed and may have applicability to the delivery of therapeutic genes and the transfection of other cell types.

Development of subcutaneous sustained release nanoparticles encapsulating low molecular weight heparin

PubMed Central

Jogala, Satheesh; Rachamalla, Shyam Sunder; Aukunuru, Jithan

2015-01-01

The objective of the present research work was to prepare and evaluate sustained release subcutaneous (s.c.) nanoparticles of low molecular weight heparin (LMWH). The nanoparticles were prepared by water–in-oil in-water (w/o/w) emulsion and evaporation method using different grades of polylactide co-glycolide (50:50, 85:15), and different concentrations of polyvinyl alcohol (0.1%, 0.5%, 1%) aqueous solution as surfactant. The fabricated nanoparticles were evaluated for size, shape, zeta potential, encapsulation efficiency, in vitro drug release, and in vivo biological activity (anti-factor Xa activity) using the standard kit. The drug and excipient compatibility was analyzed by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The formation of nanoparticles was confirmed by scanning electron microscopy; nanoparticles were spherical in shape. The size of prepared nanoparticles was found between 195 nm and 251 nm. The encapsulation efficiency of the nanoparticles was found between 46% and 70%. In vitro drug, release was about 16–38% for 10 days. In vivo drug, release shows the sustained release of drug for 10 days in rats. FTIR studies indicated that there was no loss in chemical integrity of the drug upon fabrication into nanoparticles. DSC and XRD results demonstrated that the drug was changed from the crystalline form to the amorphous form in the formulation during the fabrication process. The results of this study revealed that the s.c. nanoparticles were suitable candidates for sustained delivery of LMWH. PMID:25878975

Formulation and in vitro evaluation of sustained release matrix tablets using cross-linked natural gum.

PubMed

Jamil, Qurratul Ain; Masood, Muhammad Irfan; Jamil, Muhammad Nauman; Masood, Imran; Iqbal, Shahid Muhammad

2017-03-01

Polysaccharide gums because of their biocompatibility, biodegradability and non-immunogenic properties are considered as the best choice for preparing sustained release tablets as compared to their synthetic counterpart. The cross linking of natural gums in matrix tablets increase the sustained release property of matrix tablets. Isoniazid is a first line therapy of tuberculosis, belongs to BCS I with half-life of 3-4 hours. These characteristics make isoniazid a good candidate for sustained release dosage form. Karaya gum crossed linked with trisodium tri metaphosphate was used as release rate retardant for preparing isoniazid cross-linked matrix tablet. Total 8 sustained release formulations were prepared. Both granules and tablets were evaluated under in vitro condition against different parameters. Dissolution studies were performed with all eight formulations for 12 hours using USP apparatus I. Four formulations designated as F1, F2, F3, F4 have drug and karaya gum while other four formulations F5, F6, F7, F8 have drug and crossed linked polymer in ratios of 1:1, 1:2, 1:3 and 1:4 respectively. Dissolution data was analyzed by using different kinetic models. Best fit model for most efficient formulation was zero order while release mechanism was super case I. Formulation 8 showed sufficiently slow release kinetics and about 83% of drug was released in 10 hours, indicating that cross-linked karaya gum proved efficient in preparing sustained release tablets.

Sustained release effects of berberine-loaded chitosan microspheres on in vitro chondrocyte culture.

PubMed

Zhou, Yan; Liu, Shiqing; Ming, Jianghua; Li, Yaming; Deng, Ming; He, Bin

2017-10-01

The low bioavailability and short biological half-life of berberine chloride (BBR) negatively affect the protective role of this compound against osteoarthritis (OA). The present study was performed to evaluate the effectiveness of sustained BBR release system. Novel BBR-loaded chitosan microspheres (BBR-loaded CMs) were successfully synthesized using an ionic cross-linking method for sustained release. The basic characteristics of the prepared microspheres were subsequently evaluated by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) techniques, encapsulation efficiency (EE), and in vitro release experiments. BBR-loaded CMs displayed spherical forms to encapsulate a considerable quantity of BBR (100.8 ± 2.7 mg/g); these microspheres also exhibited an ideal releasing profile. The FT-IR spectra and XRD results revealed that BBR-loaded CMs were successfully synthesized via electrostatic interaction. In vitro experiments further showed that BBR-loaded CMs significantly inhibited sodium nitroprusside (SNP)-stimulated chondrocyte apoptosis as well as cytoskeletal remodeling, and led to increasing mitochondrial membrane potential and maintaining the nuclear morphology. BBR-loaded CMs exerted markedly higher anti-apoptotic activity in the treatment of OA, and markedly inhibited the protein expression levels of caspase-3, a disintegrin, and metalloproteinase with thrombospondin motifs (ADAMTS)-5 and matrix metalloproteinase (MMP)-13 induced by SNP in rat articular chondrocytes, compared with free BBR at equivalent concentration. Therefore, novel BBR-loaded CMs may offer potential for application in the treatment of OA.

Effect of isopropyl myristate on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserinEffect of isopropyl myristate on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserinretain-->.

PubMed

Zhao, Chunyi; Quan, Peng; Liu, Chao; Li, Qiaoyun; Fang, Liang

2016-11-01

The purpose of this study was to investigate the effect of isopropyl myristate (IPM), a penetration enhancer, on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserin. The patches were prepared with DURO-TAK ® 87-2287 as a pressure-sensitive adhesive (PSA) containing 5% ( w / w ) of blonanserin and different concentrations of IPM. An in vitro release experiment was performed and the adhesive performance of the drug-in-adhesive patches with different concentrations of IPM was evaluated by a rolling ball tack test and a shear-adhesion test. The glass transition temperature ( T g ) and rheological parameters of the drug-in-adhesive layers were determined to study the effect of IPM on the mechanical properties of the PSA. The results of the in vitro release experiment showed that the release rate of blonanserin increased with an increasing concentration of IPM. The rolling ball tack test and shear-adhesion test showed decreasing values with increasing IPM concentration. The results were interpreted on the basis of the IPM-induced plasticization of the PSA, as evidenced by a depression of the glass transition temperature and a decrease in the elastic modulus. In conclusion, IPM acted as a plasticizer on DURO-TAK ® 87-2287, and it increased the release of blonanserin and affected the adhesive properties of the PSA.

Hormonal induction of gamete release, and in-vitro fertilisation, in the critically endangered Southern Corroboree Frog, Pseudophryne corroboree

PubMed Central

2010-01-01

Background Conservation Breeding Programs (CBP's) are playing an important role in the protection of critically endangered anuran amphibians, but for many species recruitment is not successful enough to maintain captive populations, or provide individuals for release. In response, there has been an increasing focus on the use of Assisted Reproductive Technologies (ART), including the administration of reproductive hormones to induce gamete release followed by in vitro fertilisation. The objective of this study was to test the efficacy of two exogenous hormones to induce gamete release, for the purpose of conducting in vitro fertilisation (IVF), in one of Australia's most critically endangered frog species, Pseudophryne corroboree. Methods Male frogs were administered a single dose of either human chorionic gonadotropin (hCG) or luteinizing hormone-releasing hormone (LHRHa), while female frogs received both a priming and ovulatory dose of LHRHa. Spermiation responses were evaluated at 3, 7, 12, 24, 36, 48, 60 and 72 h post hormone administration (PA), and sperm number and viability were quantified using fluorescent microscopy. Ovulation responses were evaluated by stripping females every 12 h PA for 5 days. Once gametes were obtained, IVF was attempted by combining spermic urine with oocytes in a dilute solution of simplified amphibian ringer (SAR). Results Administration of both hCG and LHRHa induced approximately 80% of males to release sperm over 72 h. Peak sperm release occurred at 12 h PA for hCG treated males and 36 h PA for LHRHa treated males. On average, LHRHa treated males released a significantly higher total number of live sperm, and a higher concentration of sperm, over a longer period. In female frogs, administration of LHRHa induced approximately 30% of individuals to release eggs. On average, eggs were released between 24 and 48 h PA, with a peak in egg release at 36 h PA. IVF resulted in a moderate percentage (54.72%) of eggs being fertilised, however all resultant embryos failed prior to gastrulation. Conclusions Hormone treatment successfully induced spermiation and ovulation in P. corroboree, but refinement of gamete induction and IVF techniques will be required before ART protocols can be used to routinely propagate this species. PMID:21114857

Biopolymeric mucoadhesive bilayer patch of pravastatin sodium for buccal delivery and treatment of patients with atherosclerosis.

PubMed

Yedurkar, Pramod; Dhiman, Munish Kumar; Petkar, Kailash; Sawant, Krutika

2013-05-01

Mucoadhesive bilayer buccal patch has been developed to improve the bioavailability and therapeutic efficacy along with providing sustained release of pravastatin sodium. Buccal patches comprising of varying composition of Carbopol 934P and HPMC K4M were designed and characterized for surface pH, swelling index, in vitro bioadhesion, mechanical properties, in vitro drug release and in vivo pharmacokinetic and pharmacodynamics performance. All formulations exhibited satisfactory technological parameters and followed non-fickian drug release mechanism. Bilayer buccal patch containing Carbopol 934P and HPMC K4M in 4:6 ratio (PBP5) was considered optimum in terms of swelling, mucoadhesion, mechanical properties and in vitro release profile. Pharmacokinetic studies in rabbits showed significantly higher (p < 0.05) Cmax (75.63 ± 6.98 ng/mL), AUC(0-8) (311.10 ± 5.89 ng/mL/h) and AUC(0-∞) (909.42 ± 5.89 ng/mL/h) than pravastatin oral tablet (Cmax - 67.40 ± 9.23 ng/mL, AUC(0-8)-130.33 ± 10.25 ng/mL/h and AUC(0-∞)-417.17 ± 5.89 ng/mL/h)). While, increased tmax of buccal patch indicated its sustained release property in comparison to oral tablet. Pharmacodynamic studies in rabbits showed statistically significant difference (p < 0.005) in the reduction of TG (131.10 ± 10.23 mg/dL), VLDL (26.00 ± 2.56 mg/dL) and LDL level (8.99 ± 3.01 mg/dL) as compared to oral conventional tablet. In conclusion, bioavailability from the developed buccal patch of pravastatin was 2.38 times higher than the oral dosage form, indicating its therapeutic potential in the treatment of atherosclerosis.

In vitro and in vivo evidence of the cytotoxic and genotoxic effects of metal ions released by orthodontic appliances: A review.

PubMed

Martín-Cameán, Ana; Jos, Ángeles; Mellado-García, Pilar; Iglesias-Linares, Alejandro; Solano, Enrique; Cameán, Ana M

2015-07-01

Intraoral fixed orthodontic appliances are frequently used in the clinical practice of dentistry. They are made from alloys containing different metals at various percentages. The use of these appliances leads to the long-term exposure of patients to these materials, and the potential toxic effects of this exposure raises concerns about patient safety. Thus, the biocompatibility (corrosion behaviour and toxicity) of these materials has to be evaluated prior to clinical use. In the present report, the most recent studies in the scientific literature examining metal ion release from orthodontic appliances and the toxic effects of these ions have been reviewed with a special focus on cytotoxicity and genotoxicity. Previous studies suggest that a case-by-case safety evaluation is required to take into account the increasing variability of materials, their composition and the manufacturing processes. Moreover, in vivo toxicity studies in regard to metal release, cytotoxicity and genotoxicity are still scarce. Therefore, in vitro and in vivo monitoring studies are needed to establish cause-effect relationships between metal ion release and biomarkers of cytotoxicity and genotoxicity. Further investigations could be performed to elucidate the toxic mechanisms involved in the observed effects with a special emphasis on oxidative damage. Copyright © 2015 Elsevier B.V. All rights reserved.

Microencapsulation Approach for Orally Extended Delivery of Glipizide: In vitro and in vivo Evaluation

PubMed Central

Abdelbary, A.; El-gendy, N. A.; Hosny, A.

2012-01-01

Glipizide is an effective antidiabetic agent, however, it suffers from relatively short biological half-life. To solve this encumbrance, it is a prospective candidate for fabricating glipizide extended release microcapsules. Microencapsulation of glipizde with a coat of alginate alone or in combination with chitosan or carbomer 934P was prepared employing ionotropic gelation process. The prepared microcapsules were evaluated in vitro by microscopical examination, determination of the particle size, yield and microencapsulation efficiency. The filled capsules were assessed for content uniformity and drug release characteristics. Stability study of the optimised formulas was carried out at three different temperatures over 12 weeks. In vivo bioavailability study and hypoglycemic activity of C9 microcapsules were done on albino rabbits. All formulas achieved high yield, microencapsulation efficiency and extended t1/2. C9 and C19 microcapsules attained the most optimised results in all tests and complied with the dissolution requirements for extended release dosage forms. These two formulas were selected for stability studies. C9 exhibited longer shelf-life and hence was chosen for in vivo studies. C9 microcapsules showed an improvement in the drug bioavailability and significant hypoglycemic activity compared to immediate release tablets (Minidiab® 5 mg). The optimised microcapsule formulation developed was found to produce extended antidiabetic activity. PMID:23626387

Chlorhexidine salt-loaded polyurethane orthodontic chains: in vitro release and antibacterial activity studies.

PubMed

Padois, Karine; Bertholle, Valérie; Pirot, Fabrice; Hyunh, Truc Thanh Ngoc; Rossi, Alessandra; Colombo, Paolo; Falson, Françoise; Sonvico, Fabio

2012-12-01

The widespread use of indwelling medical devices has enormously increased the interest in materials incorporating antibiotics and antimicrobial agents as a means to prevent dangerous device-related infections. Recently, chlorhexidine-loaded polyurethane has been proposed as a material suitable for the production of devices which are able to resist microbial contamination. The aim of the present study was to characterize the in vitro release of chlorhexidine from new polymeric orthodontic chains realized with polyurethane loaded with two different chlorhexidine salts: chlorhexidine diacetate or chlorhexidine digluconate. The orthodontic chains constituted of three layers: a middle polyurethane layer loaded with chlorhexidine salt inserted between two layers of unloaded polymer. In vitro release of chlorhexidine diacetate and digluconate from orthodontic chains loaded with 10% or 20% (w/w) chlorhexidine salt was sustained for 42 days and followed Fickian diffusion. The drug diffusion through the polyurethane was found to be dependent not only on chlorhexidine loading, but also on the type of chlorhexidine salt. The antibacterial activity of 0.2% (w/w) chlorhexidine diacetate-loaded orthodontic chain was successfully tested towards clinically isolated biofilm forming ica-positive Staphylococcus epidermidis via agar diffusion test. In conclusion, the chlorhexidine salt-loaded chains could provide an innovative approach in the prevention of oral infections related to the use of orthodontic devices.

3D printing of high drug loaded dosage forms using thermoplastic polyurethanes.

PubMed

Verstraete, G; Samaro, A; Grymonpré, W; Vanhoorne, V; Van Snick, B; Boone, M N; Hellemans, T; Van Hoorebeke, L; Remon, J P; Vervaet, C

2018-01-30

It was the aim of this study to develop high drug loaded (>30%, w/w), thermoplastic polyurethane (TPU)-based dosage forms via fused deposition modelling (FDM). Model drugs with different particle size and aqueous solubility were pre-processed in combination with diverse TPU grades via hot melt extrusion (HME) into filaments with a diameter of 1.75 ± 0.05 mm. Subsequently, TPU-based filaments which featured acceptable quality attributes (i.e. consistent filament diameter, smooth surface morphology and good mechanical properties) were printed into tablets. The sustained release potential of the 3D printed dosage forms was tested in vitro. Moreover, the impact of printing parameters on the in vitro drug release was investigated. TPU-based filaments could be loaded with 60% (w/w) fine drug powder without observing severe shark skinning or inconsistent filament diameter. During 3D printing experiments, HME filaments based on hard TPU grades were successfully converted into personalized dosage forms containing a high concentration of crystalline drug (up to 60%, w/w). In vitro release kinetics were mainly affected by the matrix composition and tablet infill degree. Therefore, this study clearly demonstrated that TPU-based FDM feedstock material offers a lot of formulation freedom for the development of personalized dosage forms. Copyright © 2017 Elsevier B.V. All rights reserved.

Optimizing novel implant formulations for the prolonged release of biopharmaceuticals using in vitro and in vivo imaging techniques.

PubMed

Beyer, Susanne; Xie, Li; Schmidt, Mike; de Bruin, Natasja; Ashtikar, Mukul; Rüschenbaum, Sabrina; Lange, Christian M; Vogel, Vitali; Mäntele, Werner; Parnham, Michael J; Wacker, Matthias G

2016-08-10

As a rapidly growing class of therapeutics, biopharmaceuticals have conquered the global market. Despite the great potential from a therapeutic perspective, such formulations often require frequent injections due to their short half-life. Aiming to establish a parenteral dosage form with prolonged release properties, a biodegradable implant was developed, based on a combination of nanoencapsulation of protein-heparin complexes, creation of a slow release matrix by freeze-drying, and compression using hyaluronan and methylcellulose. In order to investigate this novel delivery system, formulations containing IFN-β-1a and trypsinogen as model proteins were developed. No degradation of the proteins was observed at any stage of the formulation processing. The potential of the delivery system was evaluated in vivo and in vitro after fluorescence-labeling of the biopharmaceuticals. An optimized agarose gel was utilized as in vitro release medium to simulate the subcutaneous environment in a biorelevant manner. In addition, the formulations were administered to female SJL mice and release was innovatively tracked by fluorescence imaging, setting up an in vitro-in vivo correlation. A prolonged time of residence of approximately 12days was observed for the selected formulation design. Copyright © 2016 Elsevier B.V. All rights reserved.

S-protected thiolated chitosan: synthesis and in vitro characterization.

PubMed

Dünnhaupt, Sarah; Barthelmes, Jan; Thurner, Clemens C; Waldner, Claudia; Sakloetsakun, Duangkamon; Bernkop-Schnürch, Andreas

2012-10-01

Purpose of the present study was the generation and evaluation of novel thiolated chitosans, so-named S-protected thiolated chitosans as mucosal drug delivery systems. Stability of all conjugates concerning swelling and disintegration behavior as well as drug release was examined. Mucoadhesive properties were evaluated in vitro on intestinal mucosa. Different thiolated chitosans were generated displaying increasing amounts of attached free thiol groups on the polymer, whereby more than 50% of these thiol groups were linked with 6-mercaptonicotinamide. Based on the implementation of this hydrophobic residue, the swelling behavior was 2-fold decreased, whereas stability was essentially improved. Their mucoadhesive properties were 2- and 14-fold increased compared to corresponding thiolated and unmodified chitosans, respectively. Release studies out of matrix tablets comprising the novel conjugates revealed a controlled release of a model peptide. Accordingly, S-protected thiomers represent a promising type of mucoadhesive polymers for the development of various mucosal drug delivery systems. Copyright © 2012 Elsevier Ltd. All rights reserved.

Formulation development of physiological environment responsive periodontal drug delivery system for local delviery of metronidazole benzoate.

PubMed

Dabhi, Mahesh R; Sheth, Navin R

2013-03-01

The objective of the present investigation was to develop and evaluate physiological environment responsive periodontal drug delivery system (PERPDDS) for local delivery of metronidazole benzoate. Poly-ϵ-caprolactone an in situ precipitating polymer was used in combination with, carbopol 934P, a pH simulative polymer to develop PERPDDS. The prepared PERPDDS was evaluated for various parameters such as in vitro gelling capacity, viscosity, rheology, compatibility study, and in vitro diffusion study. A 3(2) full factorial design was used to investigate the influence of formulation variables. Drug release data from all formulations were fitted to different kinetic models and the korsemeyer-peppas model was found the best fit model. The value of diffusional exponent (n) was in between 0.3283 and 0.3979 indicating purely fickian diffusion release mechanism. Increasing the concentration of each polymeric component increases viscosity, and time for 50% and 90% drug release was observed and graphically represented by the surface response and contour plots.

Design and in vitro evaluation of a novel poly(methacrylic acid)/metronidazole antibacterial nanogel as an oral dosage form.

PubMed

Chen, Tao; Chen, Liang; Li, Haicheng; Chen, Yuhui; Guo, Huixin; Shu, Yang; Chen, Zhiyu; Cai, Changhui; Guo, Lina; Zhang, Xianen; Zhou, Lin; Zhong, Qiu

2014-06-01

To overcome the undesirable side-effects of metronidazole (MTZ), ethylene glycol dimethacrylate is used as the cross-linker, and a series of poly(methacrylic acid) (PMAA) nanogels were prepared to load the MTZ. We investigated the morphology, size, in vitro release property in the simulated gastrointestinal medium, long-term antibacterial performance against Bacteroides fragilis, cytotoxicity, stability and activity of this novel MTZ/PMAA nanogel. The results indicate that the MTZ/PMAA nanogel sustained the release of MTZ in long-term antibacterial activity in the simulated gastrointestinal medium. This MTZ/PMAA nanogel exhibits less cytotoxicity than MTZ alone, suggesting that MTZ/PMAA nanogel is a more useful dosage form than MTZ for mild-to-moderate Clostridium difficile infections. The novel aspects of this study include the synthesis of a nanogel and the three-phase study of the release profile, which might be useful for other researchers in this field. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

Formulation development of allopurinol suppositories and injectables.

PubMed

Lee, D K; Wang, D P

1999-11-01

Allopurinol was formulated into injectable and suppository dosage forms. The injectable formulation was prepared by dissolving allopurinol in a cosolvent system consisting of dimethyl sulfoxide (DMSO) and propylene glycol (v/v = 50/50). The stability of allopurinol in the cosolvent system was studied under accelerated storage conditions, and results indicate first-order degradation kinetics with an activation energy of 24.3 kcal/mol. The development of suppository dosage forms was performed by formulating allopurinol with polyethylene glycol (PEG) mixtures of different molecular weights. In vitro release profiles of suppositories formulated with different polyethylene bases were obtained in the pH 7.4 buffer solution using the USP 23 paddle method at 100 rpm. Results indicate that the release rate of the suppository formulations containing PEG 1500/PEG 4000 at the ratio (w/w) of 2.5/10 to 10/2.5 appeared to be similar. However, the addition of sodium lauryl sulfate in the suppository decreased the release rate of allopurinol significantly. A future study to establish in vitro/in vivo correlation (iv/ivc) is suggested.

A study of properties of "micelle-enhanced" polyelectrolyte capsules: Structure, encapsulation and in vitro release.

PubMed

Li, Xiaodong; Lu, Tian; Zhang, Jianxiang; Xu, Jiajie; Hu, Qiaoling; Zhao, Shifang; Shen, Jiacong

2009-07-01

"Micelle-enhanced" polyelectrolyte capsules were fabricated via a layer-by-layer technique, templated on hybrid calcium carbonate particles with built-in polymeric micelles based on polystyrene-b-poly(acrylic acid). Due to the presence of a large number of negatively charged micelles inside the polyelectrolyte capsule, which were liberated from templates, the capsule wall was reconstructed and had properties different to those of conventional polyelectrolyte capsules. This type of capsule could selectively entrap positively charged water-soluble substances. The encapsulation efficiency of positively charged substances was dependent on their molecular weight or size. For some positively charged compounds, such as rhodamine B and lysozyme, the concentration in the capsules was orders of magnitude higher than that in the incubation solution. In addition, in vitro release study suggested that the encapsulated compounds could be released through a sustained manner to a certain degree. All these results point to the fact that these capsules might be used as novel delivery systems for some water-soluble compounds.

Design and in vitro/in vivo evaluation of sustained-release floating tablets of itopride hydrochloride.

PubMed

Ahmed, Sayed M; Ahmed Ali, Adel; Ali, Ahmed Ma; Hassan, Omiya A

2016-01-01

The aim of the present study was to improve the bioavailability of itopride (ITO) and sustain its action by formulating as a floating dosage form. Sustained-release floating tablets of ITO hydrochloride (HCl) were prepared by direct compression using different hydrocolloid polymers such as hydroxypropyl methylcellulose and ethylcellulose and/or methacrylic acid polymers Eudragit RSPM and Carbopol 934P. The floating property was achieved using an effervescent mixture of sodium bicarbonate and anhydrous citric acid (1:1 mol/mol). Hardness, friability, content uniformity, and dissolution rate of the prepared floating tablets were evaluated. The formulation F 10 composed of 28.5% Eudragit RSPM, 3% NaHCO 3 , and 7% citric acid provided sustained drug release. In vitro results showed sustained release of F 10 where the drug release percentage was 96.51%±1.75% after 24 hours ( P =0.031). The pharmacokinetic results indicated that the area under the curve (AUC 0-∞ ) of the prepared sustained-release floating tablets at infinity achieved 93.69 µg·h/mL compared to 49.89 µg·h/mL for the reference formulation (Ganaton ® ) and the relative bioavailability of the sustained-release formulation F 10 increased to 187.80% ( P =0.022). The prepared floating tablets of ITO HCl (F 10 ) could be a promising drug delivery system with sustained-release action and enhanced drug bioavailability.

Influence of drug property and product design on in vitro-in vivo correlation of complex modified-release dosage forms.

PubMed

Qiu, Yihong; Li, Xia; Duan, John Z

2014-02-01

The present study examines how drug's inherent properties and product design influence the evaluation and applications of in vitro-in vivo correlation (IVIVC) for modified-release (MR) dosage forms consisting of extended-release (ER) and immediate-release (IR) components with bimodal drug release. Three analgesic drugs were used as model compounds, and simulations of in vivo pharmacokinetic profiles were conducted using different release rates of the ER component and various IR percentages. Plasma concentration-time profiles exhibiting a wide range of tmax and maximum observed plasma concentration (Cmax) were obtained from superposition of the simulated IR and ER profiles based on a linear IVIVC. It was found that depending on the drug and dosage form design, direct use of the superposed IR and ER data for IVIVC modeling and prediction may (1) be acceptable within errors, (2) become unreliable and less meaningful because of the confounding effect from the non-negligible IR contribution to Cmax, or (3) be meaningless because of the insensitivity of Cmax to release rate change of the ER component. Therefore, understanding the drug, design and drug release characteristics of the product is essential for assessing the validity, accuracy, and reliability of IVIVC of complex MR products obtained via directly modeling of in vivo data. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

In vitro evaluation, in vivo quantification, and microbial diversity studies of nutritional strategies for reducing enteric methane production.

PubMed

Abdalla, Adibe Luiz; Louvandini, Helder; Sallam, Sobhy Mohamed Abdallah Hassan; Bueno, Ives Cláudio da Silva; Tsai, Siu Mui; Figueira, Antonio Vargas de Oliveira

2012-06-01

The main objective of the present work was to study nutritive strategies for lessening the CH(4) formation associated to ruminant tropical diets. In vitro gas production technique was used for evaluating the effect of tannin-rich plants, essential oils, and biodiesel co-products on CH(4) formation in three individual studies and a small chamber system to measure CH(4) released by sheep for in vivo studies was developed. Microbial rumen population diversity from in vitro assays was studied using qPCR. In vitro studies with tanniniferous plants, herbal plant essential oils derived from thyme, fennel, ginger, black seed, and Eucalyptus oil (EuO) added to the basal diet and cakes of oleaginous plants (cotton, palm, castor plant, turnip, and lupine), which were included in the basal diet to replace soybean meal, presented significant differences regarding fermentation gas production and CH(4) formation. In vivo assays were performed according to the results of the in vitro assays. Mimosa caesalpineaefolia, when supplemented to a basal diet (Tifton-85 hay Cynodon sp, corn grain, soybean meal, cotton seed meal, and mineral mixture) fed to adult Santa Ines sheep reduced enteric CH(4) emission but the supplementation of the basal diet with EuO did not affect (P > 0.05) methane released. Regarding the microbial studies of rumen population diversity using qPCR with DNA samples collected from the in vitro trials, the results showed shifts in microbial communities of the tannin-rich plants in relation to control plant. This research demonstrated that tannin-rich M. caesepineapholia, essential oil from eucalyptus, and biodiesel co-products either in vitro or in vivo assays showed potential to mitigate CH(4) emission in ruminants. The microbial community study suggested that the reduction in CH(4) production may be attributed to a decrease in fermentable substrate rather than to a direct effect on methanogenesis.

The effect of additives on release and in vitro skin retention of flavonoids from emulsion and gel semisolid formulations.

PubMed

Dyja, R; Jankowski, A

2017-08-01

To assess the effect of two different additives (propylene glycol (PG) and polyethylene glycol 400 (PEG 400)) on release and in vitro skin retention of quercetin and chrysin from semisolid bases (amphiphilic creams and acidic carbomer gels). For obtaining semisolid formulations, flavonoids were pre-dissolved in the liquid (PG or PEG 400) or directly suspended in the semisolid base. Three chrysin formulations ('cream 0', 'PG-cream' and 'PEG 400-cream') and five quercetin formulations ('cream 0', 'PG cream', 'PEG 400 cream', 'gel 0' and 'PG gel') were prepared. The release studies were carried out in Franz diffusion cells by means of a cellulose membrane. The porcine ear skin was used in in vitro skin retention studies. The dissolution was a prerequisite to increase the release rates of tested flavonoids from obtained semisolid formulations. The cumulative amount of chrysin released after 6 h from 'PEG 400 cream' containing partly dissolved form of that flavonoid was higher than that from 'cream 0' or 'PG cream' containing its suspended form. The formulations containing quercetin dissolved in PG ('PG cream', 'PG gel') or PEG 400 ('PEG 400 cream') exhibited higher release rates of that flavonoid than corresponding semisolid suspensions ('cream 0' or 'gel 0'). The effects of both liquid additives (PG and PEG 400) on the cumulative amount of quercetin released after 6 h were comparable. However, there was no correlation between the release rate and the skin retention. The amounts of the flavonoids found in the skin were strongly affected by the type of the used solvent. While PG increased the skin retention of both flavonoids, PEG 400 had no effect on chrysin skin retention and delayed quercetin skin absorption. The proper choice of the solvent added to the semisolid base is crucial for enhanced skin delivery of the tested flavonoids. PG is more efficient absorption promoter than PEG 400 of both chrysin and quercetin. © 2017 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Docetaxel-loaded polylactic acid-co-glycolic acid nanoparticles: formulation, physicochemical characterization and cytotoxicity studies.

PubMed

Pradhan, Roshan; Poudel, Bijay Kumar; Ramasamy, Thiruganesh; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

2013-08-01

In the present study, we developed novel docetaxel (DTX)-loaded polylactic acid-co-glycolic acid (PLGA) nanoparticles (NPs) using the combination of sodium lauryl sulfate (SLS) and poloxamer 407, the anionic and non-ionic surfactants respectively for stabilization. The NPs were prepared by emulsification/solvent evaporation method. The combination of these surfactants at weight ratio of 1:0.5 was able to produce uniformly distributed small sized NPs and demonstrated the better stability of NP dispersion with high encapsulation efficiency (85.9 +/- 0.6%). The drug/polymer ratio and phase ratio were 2:10 and 1:10, respectively. The optimized formulation of DTX-loaded PLGA NPs had a particle size and polydispersity index of 104.2 +/- 1.5 nm and 0.152 +/- 0.006, respectively, which was further supported by TEM image. In vitro release study was carried out with dialysis membrane and showed 32% drug release in 192 h. When in vitro release data were fitted to Korsmeyer-Peppas model, the n value was 0.481, which suggested the drug was released by anomalous or non-Fickian diffusion. In addition, DTX-loaded PLGA NPs in 72 h, displayed approximately 75% cell viability reduction at 10 microg/ml DTX concentration, in MCF-7 cell lines, indicating sustained release from NPs. Therefore, our results demonstrated that incorporation of DTX into PLGA NPs could provide a novel effective nanocarrier for the treatment of cancer.

A novel submicron emulsion system loaded with vincristine–oleic acid ion-pair complex with improved anticancer effect: in vitro and in vivo studies

PubMed Central

Zhang, Ting; Zheng, Yong; Peng, Qiang; Cao, Xi; Gong, Tao; Zhang, Zhirong

2013-01-01

Background Vincristine (VCR), which is a widely used antineoplastic drug, was integrated with a submicron-emulsion drug-delivery system to enhance the anticancer effect. Methods After the formation of a VCR-oleic acid ion-pair complex (VCR-OA), the VCR-OA-loaded submicron emulsion (VCR-OA-SME), prepared by classical high-pressure homogenization, was characterized and its in vitro anticancer effects were evaluated. Results The submicron-emulsion formulation exhibited a homogeneous round shape. The mean particle size, zeta potential, and encapsulation efficiency were 157.6 ± 12.6 nm, −26.5 ± 5.0 mV and 78.64% ± 3.44%, respectively. An in vitro release study of the VCR-OA-SME revealed that 12.4% of the VCR was released within the first 2 hours (initial burst-release phase) and the rest of the drug was detected in the subsequent sustained-release phase. Compared with VCR solution, the pharmacokinetic study of VCR-OA-SME showed relatively longer mean residence time (mean residence time [0–∞] increased from 187.19 to 227.56 minutes), higher maximum concentration (from 252.13 ng/mL to 533.34 ng/mL), and greater area under the curve (area under the curve [0–∞] from 11,417.77 μg/L/minute to 17,164.34 μg/L/minute. Moreover, the VCR-OA-SME exhibited higher cytotoxicity (P < 0.05) on tumor cells by inducing cell arrest in the G2/M phase or even apoptosis (P < 0.05). Conclusion The VCR-OA-SME formulation in our study displayed great potential for an anticancer effect for VCR. PMID:23658485

In vitro dissolution of generic immediate-release solid oral dosage forms containing BCS class I drugs: comparative assessment of metronidazole, zidovudine, and amoxicillin versus relevant comparator pharmaceutical products in South Africa and India.

PubMed

Reddy, Nallagundla H S; Patnala, Srinivas; Löbenberg, Raimar; Kanfer, Isadore

2014-10-01

Biowaivers are recommended for immediate-release solid oral dosage forms using dissolution testing as a surrogate for in vivo bioequivalence studies. Several guidance are currently available (the World Health Organization (WHO), the US FDA, and the EMEA) where the conditions are described. In this study, definitions, criteria, and methodologies according to the WHO have been applied. The dissolution performances of immediate-release metronidazole, zidovudine, and amoxicillin products purchased in South African and Indian markets were compared to the relevant comparator pharmaceutical product (CPP)/reference product. The dissolution performances were studied using US Pharmacopeia (USP) apparatus 2 (paddle) set at 75 rpm in each of three dissolution media (pH1.2, 4.5, and 6.8). Concentrations of metronidazole, zidovudine, and amoxicillin in each dissolution media were determined by HPLC. Of the 11 metronidazole products tested, only 8 could be considered as very rapidly dissolving products as defined by the WHO, whereas 2 of those products could be considered as rapidly dissolving products but did not comply with the f 2 acceptance criteria in pH 6.8. All 11 zidovudine products were very rapidly dissolving, whereas in the case of the 14 amoxicillin products tested, none of those products met any of the WHO criteria. This study indicates that not all generic products containing the same biopharmaceutics classification system (BCS) I drug and in similar strength and dosage form are necessarily in vitro equivalent. Hence, there is a need for ongoing market surveillance to determine whether marketed generic products containing BCS I drugs meet the release requirements to confirm their in vitro bioequivalence to the respective reference product.

Blood histamine release: A new allergy blood test

DOE Office of Scientific and Technical Information (OSTI.GOV)

Faraj, B.A.; Gottlieb, G.R.; Camp, V.M.

1985-05-01

Allergen-mediated histamine release from human leukocytes represents an important model for in vitro studies of allergic reactions. The purpose of this study was to determine whether the measurement of histamine released in allergic patients (pts) by radioenzymatic assay following mixing of their blood with common allergens represents a reliable index for diagnosis of atopic allergy. Three categories of allergies were used: (1) housedust and mite; (2) cat and dog dander; (3) trees and grasses and ragweed mixture. The presence of allergy was established by intradermal skin testing in the study group of 82 pts. Significant atopy was defined as greatermore » than or equal to 3+ (overall range 0-4 +, negative to maximum) on skin testing. The test was carried out in tubes with 0.5 ml heparinized blood, 0.5 ml tris albumin buffer, and one of the allergens (60-100 PNU/ml). In 20 controls without allergy, there always was less than or equal to 4% histamine release (normal response). A significant allergen-mediated histamine release, ranging from 12 to 30% of the total blood histamine content, was observed in 96% of the pts with skin test sensitivity of greater than or equal to 3+. There was good agreement between skin testing and histamine release in terms of the allergen causing the response. Thus, measurement of histamine release in blood in response to allergen challenge represents a clinically useful in vitro test for the diagnosis of atopic allergy. Because data can be obtained from a single sample and are highly quantitative, this new method should have application to the longitudinal study of allergic pts and to the assessment of interventions.« less

Formulation and optimization of coated PLGA – Zidovudine nanoparticles using factorial design and in vitro in vivo evaluations to determine brain targeting efficiency

PubMed Central

Peter Christoper, G.V.; Vijaya Raghavan, C.; Siddharth, K.; Siva Selva Kumar, M.; Hari Prasad, R.

2013-01-01

In the current study zidovudine loaded PLGA nanoparticles were prepared, coated and further investigated for its effectiveness in brain targeting. IR and DSC studies were performed to determine the interaction between excipients used and to find out the nature of drug in the formulation. Formulations were prepared by adopting 23 factorial designs to evaluate the effects of process and formulation variables. The prepared formulations were subjected for in vitro and in vivo evaluations. In vitro evaluations showed particle size below 100 nm, entrapment efficiency of formulations ranges of 28–57%, process yield of 60–76% was achieved and drug release for the formulations were in the range of 50–85%. The drug release from the formulations was found to follow Higuchi release pattern, n–value obtained after Korsemeyer plot was in the range of 0.56–0.78. In vivo evaluations were performed in mice after intraperitoneal administration of zidovudine drug solution, uncoated and coated formulation. Formulation when coated with Tween 80 achieved a higher concentration in the brain than that of the drug in solution and of the uncoated formulation. Stability studies indicated that there was no degradation of the drug in the formulation after 90 days of preparation when stored in refrigerated condition. PMID:24648825

Are clinical findings of systemic titanium dispersion following implantation explained by available in vitro evidence? An evidence-based analysis.

PubMed

Curtin, Justin Paul; Wang, Minji

2017-08-01

Although the presence of titanium wear particles released into tissues is known to induce local inflammation following the therapeutic implantation of titanium devices into humans, the role that titanium ions play in adverse tissue responses has received little attention. Support that ongoing titanium ion release occurs is evidenced by the presence of ionic titanium bound to transferrin in blood, and ongoing excretion in the urine of patients with titanium devices. However, as reports documenting the presence of titanium within tissues do not distinguish between particulate and ionic forms due to technical challenges, the degree to which ionic titanium is released into tissues is unknown. To determine the potential for titanium ion release into tissues, this study evaluates available in vitro evidence relating to the release of ionic titanium under physiological conditions. This is a systematic literature review of studies reporting titanium ion release into solutions from titanium devices under conditions replicating the interstitial pH and constituents. Inclusion and exclusion criteria were defined. Of 452 articles identified, titanium ions were reported in nine media relevant to human biology in seventeen studies. Only one study, using human serum replicated both physiological pH and the concentration of constituents while reporting the presence of titanium ions. While there is insufficient information to explain the factors that contribute to the presence of titanium ions in serum of humans implanted with titanium devices, currently available information suggests that areas of future inquiry include the role of transferrin and organic acids.

Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid

PubMed Central

Subongkot, Thirapit; Ngawhirunpat, Tanasait

2017-01-01

This study was aimed to develop a novel microemulsion that contained oleth-5 as a surfactant to enhance the oral absorption of all-trans retinoic acid (ATRA). The prepared microemulsion was evaluated for its particle size, shape, zeta potential, in vitro release, in vitro intestinal absorption, intestinal membrane cytotoxicity and stability. The obtained microemulsion was spherical in shape with a particle size of <200 nm and a negative surface charge. The in vitro release of the ATRA-loaded microemulsion was best fit with the zero-order model. This microemulsion significantly improved the intestinal absorption of ATRA. Confocal laser scanning microscopy analysis using a fluorescent dye-loaded microemulsion also confirmed the intestinal absorption result. The intestinal membrane cytotoxicity of the ATRA-loaded microemulsion did not differ from an edible oil (fish oil). Stability testing showed that the ATRA-loaded microemulsion was more stable at 25°C than 40°C. PMID:28831254

Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid.

PubMed

Subongkot, Thirapit; Ngawhirunpat, Tanasait

2017-01-01

This study was aimed to develop a novel microemulsion that contained oleth-5 as a surfactant to enhance the oral absorption of all-trans retinoic acid (ATRA). The prepared microemulsion was evaluated for its particle size, shape, zeta potential, in vitro release, in vitro intestinal absorption, intestinal membrane cytotoxicity and stability. The obtained microemulsion was spherical in shape with a particle size of <200 nm and a negative surface charge. The in vitro release of the ATRA-loaded microemulsion was best fit with the zero-order model. This microemulsion significantly improved the intestinal absorption of ATRA. Confocal laser scanning microscopy analysis using a fluorescent dye-loaded microemulsion also confirmed the intestinal absorption result. The intestinal membrane cytotoxicity of the ATRA-loaded microemulsion did not differ from an edible oil (fish oil). Stability testing showed that the ATRA-loaded microemulsion was more stable at 25°C than 40°C.

9 CFR 113.8 - In vitro tests for serial release.

Code of Federal Regulations, 2013 CFR

2013-01-01

... REQUIREMENTS Applicability § 113.8 In vitro tests for serial release. (a) Master Seed which has been established as pure, safe, and immunogenic shall be used for preparing seed for production as specified in the...) Subjecting the master seed to the applicable requirements prescribed in §§ 113.64, 113.100, 113.200, and 113...

9 CFR 113.8 - In vitro tests for serial release.

Code of Federal Regulations, 2012 CFR

2012-01-01

... REQUIREMENTS Applicability § 113.8 In vitro tests for serial release. (a) Master Seed which has been established as pure, safe, and immunogenic shall be used for preparing seed for production as specified in the...) Subjecting the master seed to the applicable requirements prescribed in §§ 113.64, 113.100, 113.200, and 113...

9 CFR 113.8 - In vitro tests for serial release.

Code of Federal Regulations, 2014 CFR

2014-01-01

... REQUIREMENTS Applicability § 113.8 In vitro tests for serial release. (a) Master Seed which has been established as pure, safe, and immunogenic shall be used for preparing seed for production as specified in the...) Subjecting the master seed to the applicable requirements prescribed in §§ 113.64, 113.100, 113.200, and 113...

Development of bupivacaine decorated reduced graphene oxide and its local anesthetic effect-In vivo study.

PubMed

Zhang, Zhi; Zhang, Xin; Li, Aixiang; Ma, Chuangen

2018-03-01

The present works aims to develop bupivacaine modified reduced graphene oxide (BPV/RGO), and comparative evaluation of their anesthetic effect with free bupivacaine (BPV). The prepared BPV/RGO was studied by using various spectroscopic and microscopic characterization studies. In vitro drug release from BPV/RGO was studied using HPLC analysis. The cytotoxicity of BPV/RGO was studied against fibroblast (3T3) cells. In vivo evaluation of anesthetic effects was performed on animal models. BPV/RGO showed a prolonged in vitro release and lower cytotoxicity when compared to free BPV. Also, BPV/RGO showed a significantly prolonged analgesic effect when compared to free BPV. Further, the prepared BPV/RGO drug delivery system demonstrated to function as gifted to overcome the drawbacks of free BPV and other available drug delivery systems by prolonging the anesthetic effect with poor cytotoxicity. Copyright © 2018. Published by Elsevier B.V.

Development of mucoadhesive patches for buccal administration of carvedilol.

PubMed

Vishnu, Y Vamshi; Chandrasekhar, K; Ramesh, G; Rao, Y Madhusudan

2007-01-01

A buccal patch for systemic administration of carvedilol in the oral cavity has been developed using two different mucoadhesive polymers. The formulations were tested for in vitro drug permeation studies, buccal absorption test, in vitro release studies, moisture absorption studies and in vitro bioadhesion studies. The physicochemical interactions between carvedilol and polymers were investigated by Fourier transform infrared (FTIR) Spectroscopy. According to FTIR the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state. XRD studies reveal that the drug is in crystalline state in the polymer matrix. The results indicate that suitable bioadhesive buccal patches with desired permeability could be prepared. Bioavailability studies in healthy pigs reveal that carvedilol has got good buccal absorption. The bioavailability of carvedilol from buccal patches has increased 2.29 folds when compared to that of oral solution. The formulation AC5 (HPMC E 15) shows 84.85 + 0.089% release and 38.69 + 6.61% permeated through porcine buccal membrane in 4 hr. The basic pharmacokinetic parameters like the C(max), T(max) and AUC(total) were calculated and showed statistically significant difference (P<0.05) when given by buccal route compared to that of oral solution.

In vitro evaluation of (99m)Tc-EDDA/tricine-HYNIC-Q-Litorin in gastrin-releasing peptide receptor positive tumor cell lines.

PubMed

Yurt Lambrecht, Fatma; Durkan, Kübra; Ozgür, Aykut; Gündüz, Cumhur; Avcı, Cığır Biray; Susluer, Sunde Yılmaz

2013-05-01

Bombesin and its derivatives exhibit a high affinity for gastrin-releasing peptide receptor (GRPr), which is over-expressed in a variety of human cancers (prostate, pancreatic, lung, etc.). The aim of this study was to investigate the in vitro potential of the hydrazinonicotinamide (HYNIC)-Q-Litorin. (99m)Tc labeling was performed by using different co-ligands: tricine and ethylenediamine diacetic acid (EDDA). The radiochemical stability of radiolabeled peptide conjugates was checked at room temperature and in cysteine solution up to 24 h. The in vitro cell uptake of (99m)Tc-EDDA-HYNIC-Q-Litorin and (99m)Tc-tricine-HYNIC-Q-Litorin were evaluated on pancreatic tumor and control cell lines. Optimum specific activity and incubation time were determined for all the cell lines. The results showed that the cell uptake of the radiolabeled peptide conjugates in tumor cell lines were higher than in the control cell line. The findings of this study indicated the need for further development of in vivo study as a radiopharmaceutical for pancreatic tumor imaging.

Hematoma-inspired alginate/platelet releasate/CaPO4 composite: initiation of the inflammatory-mediated response associated with fracture repair in vitro and ex vivo injection delivery.

PubMed

McCanless, Jonathan D; Jennings, Lisa K; Bumgardner, Joel D; Cole, Judith A; Haggard, Warren O

2012-08-01

A clinical need continues for consistent bone remodeling within problematic sites such as those of fracture nonunion, avascular necrosis, or irregular bone formations. In attempt to address such needs, a biomaterial system is proposed to induce early inflammatory responses after implantation and to provide later osteoconductive scaffolding for bone regeneration. Biomaterial-induced inflammation would parallel the early stage of hematoma-induced fracture repair and allow scaffold-promoted remodeling of osseous tissue to a healthy state. Initiation of the wound healing cascade by two human concentrated platelet releasate-containing alginate/β-tricalcium phosphate biocomposites has been studied in vitro using the TIB-71™ RAW264.7 mouse monocyte cell line. Inflammatory responses inherent to the base material were found and could be modulated through incorporation of platelet releasate. Differences in hydrogel wt% (2 vs. 8 %) and/or calcium phosphate granule vol.% (20 vs. 10 %) allowed for tuning the response associated with platelet releasate-associated growth factor elution. Tunability from completely suppressing the inflammatory response to augmenting the response was observed through varied elution profiles of both releasate-derived bioagents and impurities inherent to alginate. A 2.5-fold upregulation of inducible-nitric oxide synthase gene expression followed by a tenfold increase in nitrite media levels was induced by inclusion of releasate within the 8 wt%/10 vol.% formulation and was comparable to an endotoxin positive control. Whereas, near complete elimination of inflammation was seen when releasate was included within the 2 wt%/20 vol.% formulation. These in vitro results suggested tunable interactions between the multiple platelet releasate-derived bioagents and the biocomposites for enhancing hematoma-like fracture repair. Additionally, minimally invasive delivery for in situ curing of the implant system via injection was demonstrated in rat tail vertebrae using microcomputed tomography.

Design, development and evaluation of clopidogrel bisulfate floating tablets.

PubMed

Rao, K Rama Koteswara; Lakshmi, K Rajya

2014-01-01

The objective of the present work was to formulate and to characterize a floating drug delivery system for clopidogrel bisulphate to improve bioavailability and to minimize the side effects of the drug such as gastric bleeding and drug resistance development. Clopidogrel floating tablets were prepared by direct compression technique by the use of three polymers xanthan gum, hydroxypropyl methylcellulose (HPMC) K15M and HPMC K4M in different concentrations (20%, 25% and 30% w/w). Sodium bicarbonate (15% w/w) and microcrystalline cellulose (30% w/w) were used as gas generating agent and diluent respectively. Studies were carried out on floating behavior and influence of type of polymer on drug release rate. All the formulations were subjected to various quality control and in-vitro dissolution studies in 0.1 N hydrochloric acid (1.2 pH) and corresponding dissolution data were fitted to popular release kinetic equations in order to evaluate release mechanisms and kinetics. All the clopidogrel floating formulations followed first order kinetics, Higuchi drug release kinetics with diffusion as the dominant mechanism of drug release. As per Korsmeyer-Peppas equation, the release exponent "n" ranged 0.452-0.654 indicating that drug release from all the formulations was by non-Fickian diffusion mechanism. The drug release rate of clopidogrel was found to be affected by the type and concentration of the polymer used in the formulation (P < 0.05). As the concentration of the polymer was increased, the drug release was found to be retarded. Based on the results, clopidogrel floating tablets prepared by employing xanthan gum at concentration 25% w/w (formulation F2) was the best formulation with desired in-vitro floating time and drug dissolution.

Investigation of drug release and matrix degradation of electrospun poly(DL-lactide) fibers with paracetanol inoculation.

PubMed

Cui, Wenguo; Li, Xiaohong; Zhu, Xinli; Yu, Guo; Zhou, Shaobing; Weng, Jie

2006-05-01

This study was aimed at assessing the potential use of electrospun fibers as drug delivery vehicles with focus on the different diameters and drug contents to control drug release and polymer fiber degradation. A drug-loaded solvent-casting polymer film was made with an average thickness of 100 microm for comparative purposes. DSC analysis indicated that electrospun fibers had a lower T(g) but higher transition enthalpy than solvent-casting polymer film due to the inner stress and high degree of alignment and orientation of polymer chains caused by the electrospinning process. Inoculation of paracetanol led to a further slight decrease in the T(g) and transition enthalpy. An in vitro drug release study showed that a pronounced burst release or steady release phase was initially observed followed by a plateau or gradual release during the rest time. Fibers with a larger diameter exhibited a longer period of nearly zero order release, and higher drug encapsulation led to a more significant burst release after incubation. In vitro degradation showed that the smaller diameter and higher drug entrapment led to more significant changes of morphologies. The electrospun fiber mat showed almost no molecular weight reduction, but mass loss was observed for fibers with small and medium size, which was characterized with surface erosion and inconsistent with the ordinarily polymer degrading form. Further wetting behavior analysis showed that the high water repellent property of electrospun fibers led to much slower water penetration into the fiber mat, which may contribute to the degradation profiles of surface erosion. The specific degradation profile and adjustable drug release behaviors by variation of fiber characteristics made the electrospun nonwoven mat a potential drug delivery system rather than polymer films and particles.

Two release rates from monolithic carboxymethyl starch tablets: formulation, characterization, and in vitro/in vivo evaluation.

PubMed

Le, Tien Canh; Mateescu, Mircea Alexandru

2017-08-01

Most of non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen at more than 1200 mg/day may generate gastrointestinal and cardiovascular side effects. Bilayer or multiparticulate devices have been developed for controlled release in order to prevent undesired side effects. A new "two release rate (2RR) monolithic tablets" approach is now proposed for controlled release of poorly soluble drugs, particularly NSAIDs. Ibuprofen was used as model drug. This concept is based on a calcium carboxymethyl-starch (CaCMS) complex as a novel, low-cost excipient for monolithic dosage forms easy to manufacture by direct compaction. The in vitro dissolution from CaCMS formulations (tablets containing 400 or 600 mg active principle) showed two distinct release rates: (i) an initial fast release (for 30 min in simulated gastric fluid) of about 200 mg ibuprofen, an amount similar to the dosage of conventional immediate-release form (Motrin® 200 mg), and (ii) a slow release of remaining about 200 or 400 mg for a period of 12 h. A preliminary in vivo study (beagle dogs) showed pharmacokinetic parameters of one single controlled-release dosage of ibuprofen (400 mg) formulated with CaCMS, near equivalence with multiple doses (three tablets of 200 mg ibuprofen) of conventional Motrin®. A marked reduction (with 33%) of administered dose (400 instead 600 mg) was achieved by the new formulation with equivalent therapeutic effects. This dose reduction may be beneficial and is expected to minimize side damage risks. Although the present study was limited to NSAIDs, the 2RR concept can be applied for other drugs, particularly for subjects unable to follow frequent administrations.

Comparison of skin permeability for three diclofenac topical formulations: an in vitro study.

PubMed

Folzer, E; Gonzalez, D; Singh, R; Derendorf, H

2014-01-01

Diclofenac is a hydrophilic non-steroidal anti-inflammatory drug (NSAID) widely used in humans and animals. There are limited published studies evaluating diclofenac's skin permeation following topical administration. The aim of our study was to evaluate and compare the in vitro permeation of three different diclofenac-containing formulations (patch, gel, solution) over 24 hours. These formulations were applied (n = 6 per formulation) to pig skin sandwiched between the two chambers in a static Franz diffusion cell and aliquots from the receptor medium were sampled at pre-defined time points. An HPLC method with UV detection was developed and validated with the aim of characterizing the transepidermal penetration in the in vitro system. Using this assay to determine the permeation parameters, results at 24 hours showed that the Flector patch released the highest drug amount (54.6%), whereas a lower drug amount was delivered with the Voltaren Emulgel (38.2%) and the solution (34.4%). The commercial gel showed the highest flux (39.9 +/- 0.9 microg/cm2/h) and the shortest lag-time (1.97 +/- 0.02 h). Based on these in vitro results using pig skin, the transdermal patch resulted in a long-lasting controlled release of diclofenac, while the gel had the shortest lag-time.

Reinnervation of Paralyzed Muscle by Nerve-Muscle-Endplate Band Grafting

DTIC Science & Technology

2017-10-01

of the NMEG would be a critical factor influencing outcomes. In our previous studies , a NMEG was im- planted into an aneural region in the recipient...and demonstrated a sustained release. The factors could be released locally in vitro over periods of 2 weeks13,40 or 4 weeks.40 Experimental studies sug...regeneration studies , a number of exogenous neurotrophic factors have been extensively investigated.69 Due to their rela- tively short half-life in vivo

Formulation and process factors influencing product quality and in vitro performance of ophthalmic ointments.

PubMed

Xu, Xiaoming; Al-Ghabeish, Manar; Rahman, Ziyaur; Krishnaiah, Yellela S R; Yerlikaya, Firat; Yang, Yang; Manda, Prashanth; Hunt, Robert L; Khan, Mansoor A

2015-09-30

Owing to its unique anatomical and physiological functions, ocular surface presents special challenges for both design and performance evaluation of the ophthalmic ointment drug products formulated with a variety of bases. The current investigation was carried out to understand and identify the appropriate in vitro methods suitable for quality and performance evaluation of ophthalmic ointment, and to study the effect of formulation and process variables on its critical quality attributes (CQA). The evaluated critical formulation variables include API initial size, drug percentage, and mineral oil percentage while the critical process parameters include mixing rate, temperature, time and cooling rate. The investigated quality and performance attributes include drug assay, content uniformity, API particle size in ointment, rheological characteristics, in vitro drug release and in vitro transcorneal drug permeation. Using design of experiments (DoE) as well as a novel principle component analysis approach, five of the quality and performance attributes (API particle size, storage modulus of ointment, high shear viscosity of ointment, in vitro drug release constant and in vitro transcorneal drug permeation rate constant) were found to be highly influenced by the formulation, in particular the strength of API, and to a lesser degree by processing variables. Correlating the ocular physiology with the physicochemical characteristics of acyclovir ophthalmic ointment suggested that in vitro quality metrics could be a valuable predictor of its in vivo performance. Published by Elsevier B.V.

Tunable Biodegradable Nanocomposite Hydrogel for Improved Cisplatin Efficacy on HCT-116 Colorectal Cancer Cells and Decreased Toxicity in Rats.

PubMed

Abdel-Bar, Hend Mohamed; Osman, Rihab; Abdel-Reheem, Amal Youssef; Mortada, Nahed; Awad, Gehanne A S

2016-02-08

This work describes the development of a modified nanocomposite thermosensitive hydrogel for controlled cisplatin release and improved cytotoxicity with decreased side effects. The system was characterized in terms of physical properties, morphological architecture and in vitro cisplatin release. Cytotoxicity was tested against human colorectal carcinoma HCT-116. In vivo studies were conducted to evaluate the acute toxicity in terms of rats' survival rate and body weight loss. Nephro and hepatotoxicities were evaluated followed by histopathological alterations of various tissue organs. Nanocomposite thermosensitive hydrogel containing nanosized carrier conferred density and stiffness allowing a zero order drug release for 14 days. Enhanced cytotoxicity with 2-fold decrease in cisplatin IC50 was accomplished. A linear in vivo-in vitro correlation was proved for the system degradation. Higher animal survival rate and lower tissue toxicities proved the decreased toxicity of cisplatin nanocomposite compared to its solution.

Investigating the correlation between in vivo absorption and in vitro release of fenofibrate from lipid matrix particles in biorelevant medium.

PubMed

Borkar, Nrupa; Xia, Dengning; Holm, René; Gan, Yong; Müllertz, Anette; Yang, Mingshi; Mu, Huiling

2014-01-23

Lipid matrix particles (LMP) may be used as better carriers for poorly water-soluble drugs than liquid lipid carriers because of reduced drug mobilization in the formulations. However, the digestion process of solid lipid particles and their effect on the absorption of poorly water-soluble drugs are not fully understood. This study aimed at investigating the effect of particle size of LMP on drug release in vitro as well as absorption in vivo in order to get a better understanding on the effect of degradation of lipid particles on drug solubilisation and absorption. Fenofibrate, a model poorly water-soluble drug, was incorporated into LMP in this study using probe ultrasound sonication. The resultant LMP were characterised in terms of particle size, size distribution, zeta potential, entrapment efficiency, in vitro lipolysis and in vivo absorption in rat model. LMP of three different particle sizes i.e. approximately 100 nm, 400 nm, and 10 μm (microparticles) were produced with high entrapment efficiencies. The in vitro lipolysis study showed that the recovery of fenofibrate in the aqueous phase for 100 nm and 400 nm LMP was significantly higher (p<0.05) than that of microparticles after 30 min of lipolysis, suggesting that nano-sized LMP were digested to a larger extent due to greater specific surface area. The 100 nm LMP showed faster initial digestion followed by 400 nm LMP and microparticles. The area under the plasma concentration-time curve (AUC) following oral administration of 100 nm LMP was significantly higher (p<0.01) than that of microparticles and fenofibrate crystalline suspension (control). However, no significant difference was observed between the AUCs of 100 nm and 400 nm LMP. The same rank order on the in vivo absorption and the in vitro response was observed. The recovery (%) of fenofibrate partitioning into the aqueous phase during in vitro lipolysis and the AUC of plasma concentration-time curve of fenofibric acid was in the order of 100 nm LMP>microparticles>control. In summary, the present study demonstrated the particle size dependence of bioavailability of fenofibrate loaded LMP in rat model which correlates well with the in vitro drug release performed in the biorelevant medium. Copyright © 2013 Elsevier B.V. All rights reserved.

In vitro digestion behavior of water-in-oil-in-water emulsions with gelled oil-water inner phases.

PubMed

Andrade, Jonathan; Wright, Amanda J; Corredig, Milena

2018-03-01

Double emulsions may be able to protect and release in a controlled manner bioactive compounds during digestion of food matrices. It was hypothesized that the physical state and solid content in the inner phases of water-in-oil-in-water (W 1 /O/W 2 ) emulsions may affect the overall stability and the release behavior of bioactives during in vitro digestion. Therefore, hydrophobic (phytosterols or Vitamin D 3 ) and hydrophilic (Vitamin B 12 ) molecules were incorporated in double emulsions prepared either with a liquid (soybean oil - SO) or oil-fat gel (soybean oil+trimyristin - STO) lipid phase and liquid internal aqueous phase. In addition, the impact of a gelled inner aqueous phase was studied, using high methoxyl pectin. W 1 /O/W 2 emulsions were prepared with polyglycerol polyricinoleate (PGPR) and sodium caseinate as emulsifiers. After the 30min in vitro gastric stage, all double emulsions showed no significant change in size. Lipid crystals were visible in the STO emulsions. Fat crystallization, and the formation of an oil fat gel, led to coalescence of the inner aqueous droplets. The inner aqueous droplets were no longer visible by confocal microscopy after the initial stages of 2h in vitro duodenal digestion. Fat crystals and droplets of non-spherical shape were also noted in the STO double emulsions up to 25min of in vitro duodenal stage. Overall, the STO emulsions had a higher extent of free fatty acid release and consequent bioactive transfer compared to the SO emulsions. The presence of the medium chain fatty acids (from trimyristin), in addition to the surface-to-core distribution of the hydrophobic bioactives within the oil droplet were key factors in lipid digestibility and bioactive release. The STO and SO samples did not differ in terms of the release of the hydrophilic molecule, vitamin B 12 , over time. On the other hand, there was a significant increase in the stability of the inner water phase, after gastric digestion, when this phase was gelled with high methoxyl pectin. This work demonstrated that the physical properties of the different internal phases of W 1 /O/W 2 influenced lipid digestion and bioactive transfer kinetics during in vitro digestion. Copyright © 2017 Elsevier Ltd. All rights reserved.

Controlled nerve growth factor release from multi-ply alginate/chitosan-based nerve conduits.

PubMed

Pfister, Lukas A; Alther, Eva; Papaloïzos, Michaël; Merkle, Hans P; Gander, Bruno

2008-06-01

The delivery kinetics of growth factors has been suggested to play an important role in the regeneration of peripheral nerves following axotomy. In this context, we designed a nerve conduit (NC) with adjustable release kinetics of nerve growth factor (NGF). A multi-ply system was designed where NC consisting of a polyelectrolyte alginate/chitosan complex was coated with layers of poly(lactide-co-glycolide) (PLGA) to control the release of embedded NGF. Prior to assessing the in vitro NGF release from NC, various release test media, with and without stabilizers for NGF, were evaluated to ensure adequate quantification of NGF by ELISA. Citrate (pH 5.0) and acetate (pH 5.5) buffered saline solutions containing 0.05% Tween 20 yielded the most reliable results for ELISA active NGF. The in vitro release experiments revealed that the best results in terms of reproducibility and release control were achieved when the NGF was embedded between two PLGA layers and the ends of the NC tightly sealed by the PLGA coatings. The release kinetics could be efficiently adjusted by accommodating NGF at different radial locations within the NC. A sustained release of bioactive NGF in the low nanogram per day range was obtained for at least 15days. In conclusion, the developed multi-ply NGF loaded NC is considered a suitable candidate for future implantation studies to gain insight into the relationship between local growth factor availability and nerve regeneration.

Polyamide nanocapsules and nano-emulsions containing Parsol® MCX and Parsol® 1789: in vitro release, ex vivo skin penetration and photo-stability studies.

PubMed

Hanno, Ibrahim; Anselmi, Cecilia; Bouchemal, Kawthar

2012-02-01

To prepare polyamide nanocapsules for skin photo-protection, encapsulating α-tocopherol, Parsol®MCX (ethylhexyl methoxycinnamate) and/or Parsol®1789 (butyl methoxydibenzoylmethane). Nanocapsules were obtained by combining spontaneous emulsification and interfacial polycondensation reaction between sebacoyl chloride and diethylenetriamine. Nano-emulsions used as control were obtained by the same process without monomers. The influence of carrier on release rate was studied in vitro with a membrane-free model. Epidermal penetration of encapsulated sunscreens was ex vivo evaluated using Franz diffusion cells. Ability of encapsulated sunscreens to improve photo-stability was verified by comparing percentage of degradation after UV radiation exposure. Sunscreen-containing nanocapsules (260-400 nm) were successfully prepared; yield of encapsulation was >98%. Parsol®MCX and Parsol®1789 encapsulation led to decreased release rate by up to 60% in comparison with nano-emulsion and allowed minimum penetration through pig ear epidermis. Presence of polyamide shell protected encapsulated sunscreen filters from photo-degradation without affecting their activity. Encapsulation of Parsol®MCX and Parsol®1789 into oil-core of polyamide nanocapsules allowed protection from photo-degradation, controlled release from nanocapsules, and limited penetration through pig ear epidermis.

Effect of HPMC - E15 LV premium polymer on release profile and compression characteristics of chitosan/ pectin colon targeted mesalamine matrix tablets and in vitro study on effect of pH impact on the drug release profile.

PubMed

Newton, A M J; Lakshmanan, Prabakaran

2014-04-01

The study was designed to investigate the in vitro dissolution profile and compression characteristics of colon targeted matrix tablets prepared with HPMC E15 LV in combination with pectin and Chitosan. The matrix tablets were subjected to two dissolution models in various simulated fluids such as pH 1.2, 6, 6.8, 7.2, 5.5. The fluctuations in colonic pH conditions during IBD (inflammatory bowel disease) and the nature of less fluid content in the colon may limit the expected drug release in the polysaccharide-based matrices when used alone. The Hydrophilic hydroxyl propyl methylcellulose ether premium polymer (HPMC E15 LV) of low viscosity grade was used in the formulation design, which made an excellent modification in physical and compression characteristics of the granules. The release studies indicated that the prepared matrices could control the drug release until the dosage form reaches the colon and the addition HPMC E15 LV showed the desirable changes in the dissolution profile by its hydrophilic nature since the colon is known for its less fluid content. The hydrophilic HPMC E15 LV allowed the colonic fluids to enter into the matrix and confirmed the drug release at the target site from a poorly water soluble polymer such as Chitosan and also from water soluble Pectin. The dramatic changes occurred in the drug release profile and physicochemical characteristics of the Pectin, Chitosan matrix tablets when a premium polymer HPMC E15 LV added in the formulation design in the optimized concentration. Various drug release mechanisms used for the examination of drug release characteristics. Drug release followed the combined mechanism of diffusion, erosion, swelling and polymer entanglement. In recent decade, IBD attracts many patents in novel treatment methods by using novel drug delivery systems.

Natural gum-type biopolymers as potential modified nonpolar drug release systems.

PubMed

Salamanca, Constain H; Yarce, Cristhian J; Moreno, Roger A; Prieto, Vanessa; Recalde, Juanita

2018-06-01

In this work, the relationship between surface properties and drug release mechanism from binary composition tablets formed by quetiapine fumarate and biopolymer materials was studied. The biopolymers correspond to xanthan and tragacanth gums, which are projected as modified drug release systems. The surface studies were carried out by the sessile drop method, while the surface free energy (SFE) was determinate through Young-Dupree and OWRK semi-empirical models. On the other hand, the drug release studies were performed by in vitro dissolution tests, where the data were analyzed through kinetic models of zero order, first order, Higuchi, and Korsmeyer-Peppas. The results showed that depending on the type and the proportion of biopolymer, surface properties, and the drug release processes are significantly affected, wherein tragacanth gum present a usual erosion mechanism, while xanthan gum describes a swelling mechanism that controls the release of the drug. Copyright © 2018 Elsevier Ltd. All rights reserved.

The antimicrobial efficacy of sustained release silver–carbene complex-loaded l-tyrosine polyphosphate nanoparticles: Characterization, in vitro and in vivo studies

PubMed Central

Hindi, Khadijah M.; Ditto, Andrew J.; Panzner, Matthew J.; Medvetz, Douglas A.; Han, Daniel S.; Hovis, Christine E.; Hilliard, Julia K.; Taylor, Jane B.; Yun, Yang H.; Cannon, Carolyn L.; Youngs, Wiley J.

2009-01-01

The pressing need to treat multi-drug resistant bacteria in the chronically infected lungs of cystic fibrosis (CF) patients has given rise to novel nebulized antimicrobials. We have synthesized a silver–carbene complex (SCC10) active against a variety of bacterial strains associated with CF and chronic lung infections. Our studies have demonstrated that SCC10-loaded into l-tyrosine polyphosphate nanoparticles (LTP NPs) exhibits excellent antimicrobial activity in vitro and in vivo against the CF relevant bacteria Pseudomonas aeruginosa. Encapsulation of SCC10 in LTP NPs provides sustained release of the antimicrobial over the course of several days translating into efficacious results in vivo with only two administered doses over a 72 h period. PMID:19395021

Formulation development of gastroretentive tablets of lamivudine using the floating-bioadhesive potential of optimized polymer blends.

PubMed

Singh, Bhupinder; Garg, Babita; Chaturvedi, Subhash Chand; Arora, Sharry; Mandsaurwale, Rachana; Kapil, Rishi; Singh, Baljinder

2012-05-01

The current studies entail successful formulation of optimized gastroretentive tablets of lamivudine using the floating-bioadhesive potential of carbomers and cellulosic polymers, and their subsequent in-vitro and in-vivo evaluation in animals and humans. Effervescent floating-bioadhesive hydrophilic matrices were prepared and evaluated for in-vitro drug release, floatation and ex-vivo bioadhesive strength. The optimal composition of polymer blends was systematically chosen using central composite design and overlay plots. Pharmacokinetic studies were carried out in rabbits, and various levels of in-vitro/in-vivo correlation (IVIVC) were established. In-vivo gamma scintigraphic studies were performed in human volunteers using (99m) Tc to evaluate formulation retention in the gastric milieu. The optimized formulation exhibited excellent bioadhesive and floatational characteristics besides possessing adequate drug-release control and pharmacokinetic extension of plasma levels. The successful establishment of various levels of IVIVC substantiated the judicious choice of in-vitro dissolution media for simulating the in-vivo conditions. In-vivo gamma scintigraphic studies ratified the gastroretentive characteristics of the optimized formulation with a retention time of 5 h or more. Besides unravelling the polymer synergism, the study helped in developing an optimal once-a-day gastroretentive drug delivery system with improved bioavailability potential exhibiting excellent swelling, floating and bioadhesive characteristics. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Preparation and characterization of oxybenzone-loaded gelatin microspheres for enhancement of sunscreening efficacy.

PubMed

Patel, M; Jain, Sunil K; Yadav, Awesh K; Gogna, D; Agrawal, G P

2006-01-01

The objective of our present study was to prepare and evaluate gelatin microspheres of oxybenzone to enhance its sunscreening efficacy. The gelatin microspheres of oxybenzone were prepared by emulsion method. Process parameters were analyzed to optimize the formulation. The in vitro drug release study was performed in pH 7.4 using cellulose acetate membrane. Microspheres prepared using oxybenzone:gelatin ratio of 1:6 showed slowest drug release and those prepared with oxybenzone:gelatin ratio of 1:2 showed fastest drug release. The gelatin microspheres of oxybenzone were incorporated in aloe vera gel. Sun exposure method using sodium nitroprusside solution was used for in vitro sunscreen efficacy testing. The formulation C5 containing oxybenzone-bearing gelatin microspheres in aloe vera gel showed best sunscreen efficacy. The formulations were evaluated for skin irritation test in human volunteers, sun protection factor, and minimum erythema dose in albino rats. These studies revealed that the incorporation of sunscreening agent-loaded microspheres into aloe vera gel greatly increased the efficacy of sunscreen formulation more than four times.

Validation of the IntelliCap® system as a tool to evaluate extended release profiles in human GI tract using metoprolol as model drug.

PubMed

Söderlind, Erik; Abrahamsson, Bertil; Erlandsson, Fredrik; Wanke, Christoph; Iordanov, Ventzeslav; von Corswant, Christian

2015-11-10

A clinical study was conducted to validate the in vivo drug release performance of IntelliCap® CR capsules. 12 healthy, male volunteers were administered IntelliCap® CR capsules, filled with metoprolol as a BCS 1 model drug, and programmed to release the drug with 3 different release profiles (2 linear profiles extending over 6h and 14h, respectively, and a pulsed profile with two equal pulses separated by 5h) using a cross-over design. An oral metoprolol solution was included as a reference. Standard bioavailability variables were determined. In vivo drug release-time profiles for the IntelliCap® CR capsules were calculated from the plasma drug concentrations by deconvolution, and they were subsequently compared with the in vitro drug release profiles including assessment of level A in vitro/in vivo correlation (IVIVC). The relative bioavailability for the linear, extended release profiles was about 85% which is similar to other extended release administrations of metoprolol. There was an excellent agreement between the predetermined release profiles and the in vivo release for these two administrations. For IntelliCap® CR capsules programmed to deliver 2 distinct and equal drug pulses, the first pulse was delivered as expected whereas only about half of the second dose was released. Thus, it is concluded that the IntelliCap® system is well suited for the fast and reliable generation of in vivo pharmacokinetic data for extended release drug profiles, e.g. in context of regional drug absorption investigations. For immediate release pulses delivered in the distal GI tract this version of the device appears however less suitable. Copyright © 2015 Elsevier B.V. All rights reserved.

Application of a biphasic test for characterization of in vitro drug release of immediate release formulations of celecoxib and its relevance to in vivo absorption.

PubMed

Shi, Yi; Gao, Ping; Gong, Yuchuan; Ping, Haili

2010-10-04

A biphasic in vitro test method was used to examine release profiles of a poorly soluble model drug, celecoxib (CEB), from its immediate release formulations. Three formulations of CEB were investigated in this study, including a commercial Celebrex capsule, a solution formulation (containing cosolvent and surfactant) and a supersaturatable self-emulsifying drug delivery system (S-SEDDS). The biphasic test system consisted of an aqueous buffer and a water-immiscible organic solvent (e.g., octanol) with the use of both USP II and IV apparatuses. The aqueous phase provided a nonsink dissolution medium for CEB, while the octanol phase acted as a sink for CEB partitioning. For comparison, CEB concentration-time profiles of these formulations in the aqueous medium under either a sink condition or a nonsink condition were also explored. CEB release profiles of these formulations observed in the aqueous medium from either the sink condition test, the nonsink condition test, or the biphasic test have little relevance to the pharmacokinetic observations (e.g., AUC, C(max)) in human subjects. In contrast, a rank order correlation among the three CEB formulations is obtained between the in vitro AUC values of CEB from the octanol phase up to t = 2 h and the in vivo mean AUC (or C(max)) values. As the biphasic test permits a rapid removal of drug from the aqueous phase by partitioning into the organic phase, the amount of drug in the organic phase represents the amount of drug accumulated in systemic circulation in vivo. This hypothesis provides the scientific rationale for the rank order relationship among these CEB formulations between their CEB concentrations in the organic phase and the relative AUC or C(max). In addition, the biphasic test method permits differentiation and discrimination of key attributes among the three different CEB formulations. This work demonstrates that the biphasic in vitro test method appears to be useful as a tool in evaluating performance of formulations of poorly water-soluble drugs and to provide potential for establishing an in vitro-in vivo relationship.

3D bioprinting matrices with controlled pore structure and release function guide in vitro self-organization of sweat gland.

PubMed

Liu, Nanbo; Huang, Sha; Yao, Bin; Xie, Jiangfan; Wu, Xu; Fu, Xiaobing

2016-10-03

3D bioprinting matrices are novel platforms for tissue regeneration. Tissue self-organization is a critical process during regeneration that implies the features of organogenesis. However, it is not clear from the current evidences whether 3D printed construct plays a role in guiding tissue self-organization in vitro. Based on our previous study, we bioprinted a 3D matrix as the restrictive niche for direct sweat gland differentiation of epidermal progenitors by different pore structure (300-μm or 400-μm nozzle diameters printed) and reported a long-term gradual transition of differentiated cells into glandular morphogenesis occurs within the 3D construct in vitro. At the initial 14-day culture, an accelerated cell differentiation was achieved with inductive cues released along with gelatin reduction. After protein release completed, the 3D construct guide the self-organized formation of sweat gland tissues, which is similar to that of the natural developmental process. However, glandular morphogenesis was only observed in 300-μm-printed constructs. In the absence of 3D architectural support, glandular morphogenesis was not occurred. This striking finding made us to identify a previously unknown role of the 3D-printed structure in glandular tissue regeneration, and this self-organizing strategy can be applied to forming other tissues in vitro.

Design and in vitro and in vivo characterization of mucoadhesive matrix pellets of metformin hydrochloride for oral controlled release: a technical note.

PubMed

Ige, Pradum Pundlikrao; Gattani, Surendra Ganeshlal

2012-03-01

The aim of the current work was to design and develop matrix pellets of hydroxy propyl methyl cellulose K200M and microcrystalline cellulose in an admixture for a mucoadhesive gastroretentive drug delivery system. Pellets containing metformin hydrochloride (500 mg) were prepared by the pelletization technique using an extruder-spheronizer. Pellets were characterized by differential scanning calorimetry (DSC), x-ray diffraction (XRD), scanning electron microscopy (SEM), circularity, roundness, percent drug content, percent production yield, in vitro swelling, ex vivo mucoadhesion, in vitro drug release and in vivo x-ray imaging studies. Optimized pellets were sufficiently porous spheroids, free flowing, had smooth surfaces, had yields up to 75.45 ± 0.52% and had drug content up to 96.45 ± 0.19%. The average particle size of formulations MF2 and MF6 were 1.13 ± 0.41 mm and 1.22 ± 0.18 mm, respectively. Formulation MF6 exhibited strong adhesion, about 94.67%, to goat mucosal tissue, and the desired in vitro swelling, with a sustained drug release profile for 12 h and with retention in the upper small intestine of rabbits for 10 h. We conclude that hydroxy propyl methyl cellulose K200M and microcrystalline cellulose at a 2.80:1.00 w/w ratio could be an effective carrier for multiple unit controlled delivery of metformin hydrochloride.

Development of PEG-PLGA based Intravenous Low Molecular Weight Heparin (LMWH) Nanoparticles Intended to Treat Venous Thrombosis.

PubMed

Jogala, Satheesh; Rachamalla, Shyam Sunder; Aukunuru, Jithan

2016-01-01

Anticoagulant therapy is effective in the treatment of DVT. In this regard, LMWH demonstrated significant promise. It is widely used clinically. The goal of this study was to prepare and evaluate intravenous sustained release stealth nanoparticles encapsulating LMWH using PLGA (polylactidecoglycolide) and different grades of PEG (poly ethylene glycols). The nanoparticles were prepared using w/o/w solvent evaporation technique. Prepared nanoparticles were evaluated for particle size, encapsulation efficiency, in-vitro drug release, anti-thrombotic activity in venous thrombosis rat model, estimation of aPTT, tissue bio-distribution studies and stability. Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM) studies confirmed the formation of smooth spherical particles. FTIR study reveals successful coating of PEG on the nanoparticles. DSC and XRD results demonstrated that drug changed its physical form in the formulation. The encapsulation efficiency was 63-74%. In vitro drug release was 57-75% for 48 hrs. Macrophage uptake of LMWH with pegylated nanoparticles was less compared to conventional PLGA nanoparticles. In vivo drug release was sustained for 48hrs; Optimized formulation exhibited good enhancement in pharmacokinetic parameters when compared to free drug solution. In vivo sustained release was also demonstrated with antithrombotic activity as well aPTT activity. Optimized formulation demonstrated significant stability, excellent antithrombotic activity in venous thrombosis rat model, improved aPTT levels when compared to free drug solution. An effective stealth LMWH nanoparticle formulation to treat venous thrombosis was successfully developed using w/o/w solvent evaporation technique.

Development of biopolymers based interpenetrating polymeric network of capecitabine: A drug delivery vehicle to extend the release of the model drug.

PubMed

Upadhyay, Mansi; Adena, Sandeep Kumar Reddy; Vardhan, Harsh; Yadav, Sarita K; Mishra, Brahmeshwar

2018-04-27

The research aims the development and optimization of capecitabine loaded interpenetrating polymeric network by ionotropic gelation method using polymers locust bean gum and sodium alginate by QbD approach. FMEA was performed to recognize the risks influencing CQAs. BBD was applied to study the effect of factors (polymer ratio, amount of cross-linker and curing time) on responses (particle size, % drug entrapment and % drug release). Polynomial equations and 3-D graphs were plotted to relate between factors and responses. The results of the optimized batch viz. particle size (457.92 ± 1.6 μm), % drug entrapment (74.11 ± 3.1%) and % drug release (90.23 ± 2.1%) were close to the predicted values generated by Minitab® 17. Characterization techniques SEM, EDX, FTIR, DSC and XRD were also performed for the optimized batch. To study the water transport inside IPN microbeads, swelling study was done. In vitro drug release of optimized batch showed controlled drug release for 12 h. Pharmacokinetic study carried out following oral administration in Albino Wistar rats exhibited that optimized microbeads had better PK parameters than free drug. In vitro cytotoxicity against HT-29 cells revealed significant reduction of the cell growth when treated with optimized formulation indicating IPN microbeads as effective dosage form for treating colon cancer. Copyright © 2018. Published by Elsevier B.V.

Preparation and evaluation of tilmicosin-loaded hydrogenated castor oil nanoparticle suspensions of different particle sizes.

PubMed

Chen, Xiaojin; Wang, Ting; Lu, Mengmeng; Zhu, Luyan; Wang, Yan; Zhou, WenZhong

2014-01-01

Three tilmicosin-loaded hydrogenated castor oil nanoparticle (TMS-HCO-NP) suspensions of different particle sizes were prepared with different polyvinyl alcohol surfactant concentrations using a hot homogenization and ultrasonic technique. The in vitro release, in vitro antibacterial activity, mammalian cytotoxicity, acute toxicity in mice, and stability study were conducted to evaluate the characteristics of the suspensions. The in vitro tilmicosin release rate, antibacterial activity, mammalian cytotoxicity, acute toxicity in mice, and stability of the suspensions were evaluated. When prepared with polyvinyl alcohol concentrations of 0.2%, 1%, and 5%, the mean diameters of the nanoparticles in the three suspensions were 920±35 nm, 452±10 nm, and 151±4 nm, respectively. The three suspensions displayed biphasic release profiles similar to that of freeze-dried TMS-HCO-NP powders, with the exception of having a faster initial release. Moreover, suspensions of smaller-sized particles showed faster initial release, and lower minimum inhibitory concentrations and minimum bactericidal concentrations. Time-kill curves showed that within 12 hours, the suspension with the 151 nm particles had the most potent bactericidal activity, but later, the suspensions with larger-sized particles showed increased antibacterial activity. None of the three suspensions were cytotoxic at clinical dosage levels. At higher drug concentrations, all three suspensions showed similar concentration-dependent cytotoxicity. The suspension with the smallest-sized particle showed significantly more acute toxicity in mice, perhaps due to faster drug release. All three suspensions exhibited good stability at 4°C and at room temperature for at least 6 months. These results demonstrate that TMS-HCO-NP suspensions can be a promising formulation for tilmicosin, and that nanoparticle size can be an important consideration for formulation development.

Preparation and evaluation of tilmicosin-loaded hydrogenated castor oil nanoparticle suspensions of different particle sizes

PubMed Central

Chen, Xiaojin; Wang, Ting; Lu, Mengmeng; Zhu, Luyan; Wang, Yan; Zhou, WenZhong

2014-01-01

Three tilmicosin-loaded hydrogenated castor oil nanoparticle (TMS-HCO-NP) suspensions of different particle sizes were prepared with different polyvinyl alcohol surfactant concentrations using a hot homogenization and ultrasonic technique. The in vitro release, in vitro antibacterial activity, mammalian cytotoxicity, acute toxicity in mice, and stability study were conducted to evaluate the characteristics of the suspensions. The in vitro tilmicosin release rate, antibacterial activity, mammalian cytotoxicity, acute toxicity in mice, and stability of the suspensions were evaluated. When prepared with polyvinyl alcohol concentrations of 0.2%, 1%, and 5%, the mean diameters of the nanoparticles in the three suspensions were 920±35 nm, 452±10 nm, and 151±4 nm, respectively. The three suspensions displayed biphasic release profiles similar to that of freeze-dried TMS-HCO-NP powders, with the exception of having a faster initial release. Moreover, suspensions of smaller-sized particles showed faster initial release, and lower minimum inhibitory concentrations and minimum bactericidal concentrations. Time-kill curves showed that within 12 hours, the suspension with the 151 nm particles had the most potent bactericidal activity, but later, the suspensions with larger-sized particles showed increased antibacterial activity. None of the three suspensions were cytotoxic at clinical dosage levels. At higher drug concentrations, all three suspensions showed similar concentration-dependent cytotoxicity. The suspension with the smallest-sized particle showed significantly more acute toxicity in mice, perhaps due to faster drug release. All three suspensions exhibited good stability at 4°C and at room temperature for at least 6 months. These results demonstrate that TMS-HCO-NP suspensions can be a promising formulation for tilmicosin, and that nanoparticle size can be an important consideration for formulation development. PMID:24920902

Fabrication, characterization, and evaluation of microsponge delivery system for facilitated fungal therapy

PubMed Central

Moin, Afrasim; Deb, Tamal K.; Osmani, Riyaz Ali M.; Bhosale, Rohit R.; Hani, Umme

2016-01-01

Objective: The rationale behind present research vocation was to develop and investigate a novel microsponge based gel as a topical carrier for the prolonged release and cutaneous drug deposition of fluconazole (FLZ); destined for facilitated fungal therapy. Materials and Methods: Microsponges were prepared using quasi-emulsion solvent diffusion method using Eudragit S-100. In the direction of optimization, the effect of formulation variables (drug-polymer ratio and amount of emulsifier) and diverse factors affecting physical characteristics of microsponge were investigated as well. Fabricated microsponges were characterized by differential scanning calorimetry, Fourier transform-infrared, scanning electron microscopy (SEM), particle size analysis, and also evaluated for drug content, encapsulation efficiency, in vitro drug release and in vitro antifungal activity. Results: Compatibility studies results reflected no sign of any chemical interaction between the drug and polymers used. Whereas, varied drug-polymer ratios and emulsifier concentration indicated significant effect on production yield, drug content, encapsulation efficiency, particle size and drug release. Spherical microsponges with a porous surface and 29.327 ± 0.31 μm mean particle size were evident from SEM micrographs. In vitro release outcomes, from microsponge loaded gels depicted that F1 formulation was more efficient to give extended drug release of 85.38% at the end of 8 h, while conventional formulation by releasing 83.17% of drug got exhausted incredibly earlier at the end of 4 h merely. Moreover, microsponge gels demonstrated substantial spreadability and extrudability along with promising antifungal activity. Conclusions: Fabricated microsponges would be impending pharmaceutical topical carriers of FLZ and a leading alternative to conventional therapy for efficient, safe and facilitated eradication of fungal infections. PMID:27057125

[PLA-O-CMC nanoparticles: HGF loading and delivery behaviors in vitro].

PubMed

Li, Zhifeng; Chen, Zhong; Chang, Ren'an

2011-04-01

This paper is aimed to observe the hepatocyte growth factor (HGF) loading and delivery ability of polylactic acid and oxygen carboxymethylated chitosan copolyer nanoparticles (PLA-O-CMC NPs). We prepared PLA-O-CMC NPs loaded with HGF by ultrasound in combination with magnetic stirring method. The NPs were characterized by transmission electron microscopy, embedding ratio; drug loading and drug delivery behaviors were observed by ELISA. The characteristics of PLA-O-CMC NPs loaded with HGF showed that the mean size was 139. 82 nm, polydispersity was 0.108, maximal HGF-embedding ratio was 76. 32%. The cumulative HGF release gradually increased in the first 24 hours in vitro, with sharp increasing in the first 7 hours, and moderate and steady increasing in the following 17 hours. The HGF had a burst release in the first 24 hours, and in this process the released HGF took up 36.7% of the whole release. From the second day,the HGF release decreased obviously, while it kept on releasing steadily (45-55 ng/d) for quite long time up to 30 days. The experiment proved that PLA-O-CMC NPs is a favourable carrier of HGF. PLA-O-CMC NPs loaded with HGF could rapidly release HGF in vitro. The released HGF reached the effective drug concentration and maintained the certain effective drug concentration for a long time.

An in vitro model to consider the effect of 2 mM glutamine and KNK437 on endotoxin-stimulated release of heat shock protein 70 and inflammatory mediators.

PubMed

Marino, Luise V; Pathan, Nazima; Meyer, Rosan W; Wright, Victoria J; Habibi, Parviz

2016-03-01

Glutamine has been shown to promote the release of heat shock protein 70 (HSP70) both within experimental in vitro models of sepsis and in adults with septic shock. This study aimed to investigate the effects of 2 mM glutamine and an inhibitor of HSP70 (KNK437) on the release of HSP70 and inflammatory mediators in healthy adult volunteers. An in vitro whole blood endotoxin stimulation assay was used. The addition of 2 mM glutamine significantly increased HSP70 levels over time (P < 0.05). HSP70 release had a positive correlation at 4 h with IL-1 β (r = 0.51, P = 0.03) and an inverse correlation with TNF-α (r = -0.56, P = 0.02) and IL-8 levels (r = -0.52, P = 0.03), and there were no significant correlations between HSP70 and IL6 or IL-10 or glutamine. Glutamine supplementation significantly (P < 0.05) attenuated the release of IL-10 at 4 h and IL-8 at 24 h, compared with conditions without glutamine. In endotoxin-stimulated blood there were no significant differences in the release of IL-6, TNF-α, and IL-1 β with glutamine supplementation at 4 and 24 h. However, glutamine supplementation (2 mM) appeared to attenuate the release of inflammatory mediators (IL-1 β, IL-6, TNF-α), although this effect was not statistically significant. The addition of KNK437, a HSP70 inhibitor, significantly diminished HSP70 release, which resulted in lower levels of inflammatory mediators (P < 0.05). Glutamine supplementation promotes HSP70 release in an experimental model of sepsis. After the addition of KNK437, the effects of glutamine on HSP70 and inflammatory mediator release appear to be lost, suggesting that HSP70 in part orchestrates the inflammatory mediator response to sepsis. The clinical implications require further investigation. Copyright © 2016 Elsevier Inc. All rights reserved.

Double layer adhesive silicone dressing as a potential dermal drug delivery film in scar treatment.

PubMed

Mojsiewicz-Pieńkowska, Krystyna; Jamrógiewicz, Marzena; Żebrowska, Maria; Mikolaszek, Barbara; Sznitowska, Małgorzata

2015-03-15

The present studies focused on the evaluation of design of an adhesive silicone film intended for scar treatment. Developed silicone double layer film was examined in terms of its future relevance to therapy and applicability on the human skin considering properties which included in vitro permeability of water vapor and oxygen. In order to adapt the patches for medical use in the future there were tested such properties as in vitro adhesion and occlusion related to in vivo hydration. From the silicone rubbers double layer silicone film was prepared: a non-adhesive elastomer as a drug carrier (the matrix for active substances - enoxaparin sodium - low molecular weight heparin) and an adhesive elastomer, applied on the surface of the matrix. The novel adhesive silicone film was found to possess optimal properties in comparison to commercially available silicone dressing: adhesion in vivo, adhesion in vitro - 11.79N, occlusion F=85% and water vapor permeability in vitro - WVP=105g/m(2)/24h, hydration of stratum corneum in vivoH=61-89 (RSD=1.6-0.9%), oxygen permeation in vitro - 119-391 cm(3)/m(2)/24 (RSD=0.17%). In vitro release studies indicated sufficient LMWH release rate from silicone matrix. Developed novel adhesive silicone films were considered an effective treatment of scars and keloids and a potential drug carrier able to improve the effectiveness of therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

Novel Biocatalytic Polymer-Based Antimicrobial Coatings as Potential Ureteral Biomaterial: Preparation and In Vitro Performance Evaluation▿

PubMed Central

Dave, Rachna N.; Joshi, Hiren M.; Venugopalan, Vayalam P.

2011-01-01

Catheters and other indwelling devices placed inside human body are prone to bacterial infection, causing serious risk to patients. Infections associated with implants are difficult to resolve, and hence the prevention of bacterial colonization of such surfaces is quite appropriate. In this context, the development of novel antimicrobial biomaterials is currently gaining momentum. We describe here the preparation and antibacterial properties of an enzyme-embedded polycaprolactone (PCL)-based coating, coimpregnated with the antibiotic gentamicin sulfate (GS). The enzyme uses PCL itself as substrate; as a result, the antibiotic gets released at a rate controlled by the degradation of the PCL base. In vitro drug release studies demonstrated sustained release of GS from the PCL film throughout its lifetime. By modulating the enzyme concentration in the PCL film, we were able to vary the lifetime of the coating from 33 h to 16 days. In the end, the polymer is completely degraded, delivering the entire load of the antibiotic. The polymer exhibited antibacterial properties against three test isolates: Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Foley urinary catheters coated with the modified polymer exhibited sustained in vitro release of GS over a 60-h period. The results suggest that the antibiotic-plus-enzyme-loaded polymer can be used as tunable self-degrading antimicrobial biomaterial coating on catheters. PMID:21135190

In vitro/in vivo comparison of drug release and polymer erosion from biodegradable P(FAD-SA) polyanhydrides--a noninvasive approach by the combined use of electron paramagnetic resonance spectroscopy and nuclear magnetic resonance imaging.

PubMed

Mäder, K; Crémmilleux, Y; Domb, A J; Dunn, J F; Swartz, H M

1997-06-01

The purpose of this study was to compare drug release and polymer erosion from biodegradable P(FAD-SA) polyanhydrides in vitro and in vivo in real time and with minimal disturbance of the investigated system. P(FAD-SA) 20:80 and P(FAD-SA) 50:50 polymer tablets were loaded with the spin probe 3-carboxy-2,2,5,5-tetramethyl-pyrrollidine-1-oxyl (PCA) and implanted subcutaneously in the neck of rats or placed in 0.1 M phosphate buffer. 1.1 GHz EPR spectroscopy experiments and 7T MRI studies (T1 and T2 weighted) were performed. A front of water penetration was visible by MRI in vitro in the case of P(FAD-SA) 20:80, but not for P(FAD-SA) 50:50. For both polymers, the thickness of the tablets decreased with time and a insoluble, easy deformable residue remained. Important processes such as edema, deformation of the implant, encapsulation and bioresorption were observable by MRI in vivo. P(FAD-SA) 50:50 was almost entirely absorbed by day 44, whereas an encapsulated residue was found for P(FAD-SA) 20:80 after 65 days. The EPR studies gave direct evidence of a water penetration induced changes of the microenvironment inside the tablet. EPR signals were still detectable in P(FAD-SA) 20:80 implants after 65 days, while the nitroxide was released in vitro within 16 days. Important parameters and processes such as edema, deformation of the tablet, microviscosity inside the tablet and encapsulation can be monitored in real time by the combined use of the noninvasive techniques MRI and EPR leading to better understanding of the differences between the in vitro and in vivo situation.

Formulation development of smart gel periodontal drug delivery system for local delivery of chemotherapeutic agents with application of experimental design.

PubMed

Dabhi, Mahesh R; Nagori, Stavan A; Gohel, Mukesh C; Parikh, Rajesh K; Sheth, Navin R

2010-01-01

Smart gel periodontal drug delivery systems (SGPDDS) containing gellan gum (0.1-0.8% w/v), lutrol F127 (14, 16, and 18% w/v), and ornidazole (1% w/v) were designed for the treatment of periodontal diseases. Each formulation was characterized in terms of in vitro gelling capacity, viscosity, rheology, content uniformity, in vitro drug release, and syringeability. In vitro gelation time and the nature of the gel formed in simulated saliva for prepared formulations showed polymeric concentration dependency. Drug release data from all formulations was fitted to different kinetic models and the Korsemeyer-Peppas model was the best fit model. Drug release was significantly decreased as the concentration of each polymer component was increased. Increasing the concentration of each polymeric component significantly increased viscosity, syringeability, and time for 50%, 70%, and 90% drug release. In conclusion, the formulations described offer a wide range of physical and drug release characteristics. The formulation containing 0.8% w/v of gellan gum and 16% w/v of lutrol F127 exhibited superior physical characteristics.

Iron complexation to histone deacetylase inhibitors SAHA and LAQ824 in PEGylated liposomes can considerably improve pharmacokinetics in rats.

PubMed

Wang, Yan; Tu, Sheng; Steffen, Dana; Xiong, May

2014-01-01

The formulation of histone deacetylase inhibitors (HDACi) is challenging due to poor water solubility and rapid elimination of drugs in vivo. This study investigated the effects of complexing iron (Fe3+) to the HDACi suberoylanilide hydroxamic acid (SAHA) and LAQ824 (LAQ) prior to their encapsulation into PEGylated liposomes, and investigated whether this technique could improve drug solubility, in vitro release and in vivo pharmacokinetic (PK) properties. METHODS. The reaction stoichiometry, binding constants and solubility were measured for Fe complexes of SAHA and LAQ. The complexes were passively encapsulated into PEGylated liposomes and characterized by size distribution, zeta-potential, encapsulation efficiency (EE), and in vitro drug release studies. PC-3 cells were used to verify the in vitro anticancer activity of the formulations. In vivo pharmacokinetic properties of liposomal LAQ-Fe (L-LAQ-Fe) was evaluated in rats. RESULTS. SAHA and LAQ form complexes with Fe at 1:1 stoichiometric ratio, with a binding constant on the order of 104 M-1. Fe complexation improved the aqueous solubility and the liposomal encapsulation efficiency of SAHA and LAQ (29-35% EE, final drug concentration > 1 mM). Liposomal encapsulated complexes (L-HDACi-Fe) exhibited sustained in vitro release properties compared to L-HDACi but cytotoxicity on PC-3 cells was comparable to free drugs. The PK of L-LAQ-Fe revealed 15-fold improvement in the plasma t1/2 (12.11 h)and 211-fold improvement in the AUC∞ (105.7 µg·h/ml) compared to free LAQ (0.79 h, 0.5 µg·h/ml). Similarly, the plasma t1/2 of Fe was determined to be 11.83 h in a separate experiment using radioactive Fe-59. The majority of Fe-59 activity was found in liver and spleen of rats and correlates with liposomal uptake by the mononuclear phagocyte system. CONCLUSIONS. We have demonstrated that encapsulation of Fe complexes of HDACi into PEGylated liposomes can improve overall drug aqueous solubility, in vitro release and in vivo pharmacokinetic properties.

Iron Complexation to Histone Deacetylase Inhibitors SAHA and LAQ824 in PEGylated Liposomes Can Considerably Improve Pharmacokinetics in Rats

PubMed Central

Wang, Yan; Tu, Sheng; Steffen, Dana; Xiong, May P.

2015-01-01

PURPOSE The formulation of histone deacetylase inhibitors (HDACi) is challenging due to poor water solubility and rapid elimination of drugs in vivo. This study investigated the effects of complexing iron (Fe3+) to the HDACi suberoylanilide hydroxamic acid (SAHA) and LAQ824 (LAQ) prior to their encapsulation into PEGylated liposomes, and investigated whether this technique could improve drug solubility, in vitro release and in vivo pharmacokinetic (PK) properties. METHODS The reaction stoichiometry, binding constants and solubility were measured for Fe complexes of SAHA and LAQ. The complexes were passively encapsulated into PEGylated liposomes and characterized by size distribution, zeta-potential, encapsulation efficiency (EE), and in vitro drug release studies. PC-3 cells were used to verify the in vitro anticancer activity of the formulations. In vivo pharmacokinetic properties of liposomal LAQ-Fe (L-LAQ-Fe) was evaluated in rats. RESULTS SAHA and LAQ form complexes with Fe at 1:1 stoichiometric ratio, with a binding constant on the order of 104 M−1. Fe complexation improved the aqueous solubility and the liposomal encapsulation efficiency of SAHA and LAQ (29–35% EE, final drug concentration > 1 mM). Liposomal encapsulated complexes (L-HDACi-Fe) exhibited sustained in vitro release properties compared to L-HDACi but cytotoxicity on PC-3 cells was comparable to free drugs. The PK of L-LAQ-Fe revealed 15-fold improvement in the plasma t1/2 (12.11 h) and 211-fold improvement in the AUC∞ (105.7 μg·h/ml) compared to free LAQ (0.79 h, 0.5 μg·h/ml). Similarly, the plasma t1/2 of Fe was determined to be 11.83 h in a separate experiment using radioactive Fe-59. The majority of Fe-59 activity was found in liver and spleen of rats and correlates with liposomal uptake by the mononuclear phagocyte system. CONCLUSIONS We have demonstrated that encapsulation of Fe complexes of HDACi into PEGylated liposomes can improve overall drug aqueous solubility, in vitro release and in vivo pharmacokinetic properties. PMID:25579435

In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet formulations: a pharmacoscintigraphic study in the beagle dog.

PubMed

Ghimire, Manish; McInnes, Fiona J; Watson, David G; Mullen, Alexander B; Stevens, Howard N E

2007-09-01

The aim of the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC). The PCTs showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo gamma-scintigraphic studies were carried out for PCTs containing GB:L-HPC at 65:35 w/w and 75:25 w/w in the barrier layer in four beagle dogs, in either the fed or fasted state. The in-vivo lag time in both the fed and fasted states did not differ significantly (p>0.05) from the in-vitro lag time. Additionally, no significant difference (p<0.05) between in-vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the PCT was not influenced by the presence or absence of food in the gastrointestinal tract. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated (R2=0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC(0-6 dis), K(el), Cmax) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery.

Development and characterization of surface engineered PPI dendrimers for targeted drug delivery.

PubMed

Kaur, Avleen; Jain, Keerti; Mehra, Neelesh Kumar; Jain, N K

2017-05-01

In this study, we reported folate-conjugated polypropylene imine dendrimers (FA-PPI) as efficient carrier for model anticancer drug, methotrexate (MTX), for pH-sensitive drug release, selective targeting to cancer cells, and anticancer activity. In the in vitro drug release studies this nanoconjugate of MTX showed initial rapid release followed by gradual slow release, and the drug release was found to be pH sensitive with greater release at acidic pH. The ex vivo investigations with human breast cancer cell lines, MCF-7, showed enhanced cytotoxicity of MTX-FA-PPI with significantly enhanced intracellular uptake. The biofate of nanoconjugate was determined in Wistar rat where MTX-FA-PPI showed 37.79-fold increase in the concentration of MTX in liver after 24 h in comparison with free MTX formulation.

Shear rheology and in-vitro release kinetic study of apigenin from lyotropic liquid crystal.

PubMed

Fan, Jun; Liu, Feng; Wang, Zhongni

2016-01-30

Apigenin is a flavonoid compound with diverse pharmacological functions which could develop health benefit products, but its formulation is hampered by its poor water solubility and bioavailability. In this paper, in order to overcome these difficulties, apigenin was encapsulated in LLC formed by polyoxyethylene-10-oleyl ether (Brij 97) and sodium deoxycholate (NaDC) mixtures. The hexagonal liquid crystalline phase (H) and the cubic liquid crystalline phase (C) were found in this system. The shear rheology was used to study the structure change with temperature. It was shown that C3 (Brij 97-NaDC/IPM-PEG400/H2O=36:9:55) was C at low temperature. But above 35.6°C, the matrix of C3 completely transformed to polymer solution. The matrix of H3 was H (Brij 97-NaDC:IPM-PEG 400:H2O=50:9:41) below 50°C, but the structural strength change was obvious. Vitro release experiment was used to study drug release kinetics. It was indicated that apigenin encapsulated in LLC conformed to the concentration diffusion model, and cumulative percentage of apigenin released from C3 and H3 had corresponding relationship with the shear rheology at different temperatures. Copyright © 2015. Published by Elsevier B.V.

Metal release from stainless steel powders and massive sheets--comparison and implication for risk assessment of alloys.

PubMed

Hedberg, Yolanda; Mazinanian, Neda; Odnevall Wallinder, Inger

2013-02-01

Industries that place metal and alloy products on the market are required to demonstrate that they are safe for all intended uses, and that any risks to humans, animals or the environment are adequately controlled. This requires reliable and robust in vitro test procedures. The aim of this study is to compare the release of alloy constituents from stainless steel powders of different grades (focus on AISI 316L) and production routes into synthetic body fluids with the release of the same metals from massive sheets in relation to material and surface characteristics. The comparison is justified by the fact that the difference between massive surfaces and powders from a metal release/dissolution and surface perspective is not clearly elucidated within current legislations. Powders and abraded and aged (24 h) massive sheets were exposed to synthetic solutions of relevance for biological settings and human exposure routes, for periods of up to one week. Concentrations of released iron, chromium, nickel, and manganese in solution were measured, and the effect of solution pH, acidity, complexation capacity, and proteins elucidated in relation to surface oxide composition and its properties. Implications for risk assessments based on in vitro metal release data from alloys are elucidated.

Bio-composites composed of a solid free-form fabricated polycaprolactone and alginate-releasing bone morphogenic protein and bone formation peptide for bone tissue regeneration.

PubMed

Kim, MinSung; Jung, Won-Kyo; Kim, GeunHyung

2013-11-01

Biomedical scaffolds should be designed with highly porous three-dimensional (3D) structures that have mechanical properties similar to the replaced tissue, biocompatible properties, and biodegradability. Here, we propose a new composite composed of solid free-form fabricated polycaprolactone (PCL), bone morphogenic protein (BMP-2) or bone formation peptide (BFP-1), and alginate for bone tissue regeneration. In this study, PCL was used as a mechanical supporting component to enhance the mechanical properties of the final biocomposite and alginate was used as the deterring material to control the release of BMP-2 and BFP-1. A release test revealed that alginate can act as a good release control material. The in vitro biocompatibilities of the composites were examined using osteoblast-like cells (MG63) and the alkaline phosphatase (ALP) activity and calcium deposition were assessed. The in vitro test results revealed that PCL/BFP-1/Alginate had significantly higher ALP activity and calcium deposition than the PCL/BMP-2/Alginate composite. Based on these findings, release-controlled BFP-1 could be a good growth factor for enhancement of bone tissue growth and the simple-alginate coating method will be a useful tool for fabrication of highly functional biomaterials through release-control supplementation.

Time-controlled release pseudoephedrine tablets: bioavailability and in vitro/in vivo correlations.

PubMed

Halsas, M; Penttinen, T; Veski, P; Jürjenson, H; Marvola, M

2001-09-01

In chronopharmacotherapy, circadian changes in disease symptoms are taken into account. Press-coated, time-controlled release tablets containing pseudoephedrine hydrochloride as a model drug have been formulated and the suitability of this highly soluble drug in relation to the new drug delivery system was evaluated. Hydroxypropylmethylcellulose was used in the coat of the tablet to adjust drug release. If such a formulation was administered in the evening it would have maximal effect in the early morning, and would be useful for the treatment of nocturnal symptoms. Two cross-over, single-dose bioavailability studies were carried out on eight healthy volunteers. A dissolution test method was developed to establish level A and level C in vitro/in vivo correlation for four formulations. With a low viscosity grade of polymer, peak concentrations were achieved after five hours. The drug was absorbed much more slowly from tablets containing a high viscosity grade polymer, with a plasma peak at ten hours. For further development of the drug delivery system described, a dissolution test method at pH 7.2 at a rotation speed of 150 min-1 is recommended on the basis of level A in vitro/in vivo correlation.

Pancreatic acinar cells-derived cyclophilin A promotes pancreatic damage by activating NF-κB pathway in experimental pancreatitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Ge; Wan, Rong; Hu, Yanling

2014-01-31

Highlights: • CypA is upregulated in experimental pancreatitis. • CCK induces expression and release of CypA in acinar cell in vitro. • rCypA aggravates CCK-induced acinar cell death and inflammatory cytokine production. • rCypA activates the NF-κB pathway in acinar cells in vitro. - Abstract: Inflammation triggered by necrotic acinar cells contributes to the pathophysiology of acute pancreatitis (AP), but its precise mechanism remains unclear. Recent studies have shown that Cyclophilin A (CypA) released from necrotic cells is involved in the pathogenesis of several inflammatory diseases. We therefore investigated the role of CypA in experimental AP induced by administration ofmore » sodium taurocholate (STC). CypA was markedly upregulated and widely expressed in disrupted acinar cells, infiltrated inflammatory cells, and tubular complexes. In vitro, it was released from damaged acinar cells by cholecystokinin (CCK) induction. rCypA (recombinant CypA) aggravated CCK-induced acinar cell necrosis, promoted nuclear factor (NF)-κB p65 activation, and increased cytokine production. In conclusion, CypA promotes pancreatic damage by upregulating expression of inflammatory cytokines of acinar cells via the NF-κB pathway.« less

Pharmacokinetic Evaluation of Improved Oral Bioavailability of Valsartan: Proliposomes Versus Self-Nanoemulsifying Drug Delivery System.

PubMed

Nekkanti, Vijaykumar; Wang, Zhijun; Betageri, Guru V

2016-08-01

The objective of this study was to develop proliposomes and self-nanoemulsifying drug delivery system (SNEDDS) for a poorly bioavailable drug, valsartan, and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin-film hydration method using different lipids such as soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoyl phosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. SNEDDS formulations were prepared using varying concentrations of capmul MCM, labrafil M 2125, and Tween 80. Both proliposomes and SNEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water and 0.1 N HCl using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal permeation techniques. Among the formulations, the proliposomes with drug/DMPG/cholesterol in the ratio of 1:1:0.5 and SNEDDS with capmul MCM (16.0% w/w), labrafil M 2125 (64.0% w/w), and Tween 80 (18.0% w/w) showed the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SNEDDS as compared to pure valsartan. Valsartan permeability across PAMPA and everted rat intestinal permeation models was significantly higher with proliposomes and SNEDDS. Following single oral administration of proliposomes and SNEDDS, a relative bioavailability of 202.36 and 196.87%, respectively, was achieved compared to pure valsartan suspension. The study results indicated that both proliposomes and SNEDDS formulations are comparable in improving the oral bioavailability of valsartan.

In Vitro and Ex Vivo Evaluations on Transdermal Delivery of the HIV Inhibitor IQP-0410

PubMed Central

Ham, Anthony S.; Lustig, William; Yang, Lu; Boczar, Ashlee; Buckheit, Karen W.; Buckheit Jr, Robert W.

2013-01-01

The aim of this study was to investigate the physicochemical and in vitro/ex vivo characteristics of the pyrmidinedione IQP-0410 formulated into transdermal films. IQP-0410 is a potent therapeutic anti-HIV nonnucleoside reverse transcriptase inhibitor that would be subjected to extensive first pass metabolism, through conventional oral administration. Therefore, IQP-0410 was formulated into ethyl cellulose/HPMC-based transdermal films via solvent casting. In mano evaluations were performed to evaluate gross physical characteristics. In vitro release studies were performed in both Franz cells and USP-4 dissolution vessels. Ex vivo release and permeability assays were performed on human epidermal tissue models, and the permeated IQP-0410 was collected for in vitro HIV-1 efficacy assays in CEM-SS cells and PBMCs. Film formulation D3 resulted in pliable, strong transdermal films that were loaded with 2% (w/w) IQP-0410. Composed of 60% (w/w) ethyl cellulose and 20% (w/w) HPMC, the films contained < 1.2% (w/w) of water and were hygroscopic resulting in significant swelling under humid conditions. The water permeable nature of the film resulted in complete in vitro dissolution and drug release in 26 hours. When applied to ex vivo epidermal tissues, the films were non-toxic to the tissue and also were non-toxic to HIV target cells used in the in vitro efficacy assays. Over a 3 day application, the films delivered IQP-0410 through the skin tissue at a zero-order rate of 0.94 ± 0.06 µg/cm2/hr with 134 ± 14.7 µM collected in the basal media. The delivered IQP-0410 resulted in in vitro EC50 values against HIV-1 of 2.56 ± 0.40 nM (CEM-SS) and 0.58 ± 0.03 nM (PBMC). The film formulation demonstrated no significant deviation from target values when packaged in foil pouches under standard and accelerated environmental conditions. It was concluded that the transdermal film formulation was a potentially viable method of administering IQP-0410 that warrants further development. PMID:24058672

Histamine-releasing properties of Polysorbate 80 in vitro and in vivo: correlation with its hypotensive action in the dog.

PubMed

Masini, E; Planchenault, J; Pezziardi, F; Gautier, P; Gagnol, J P

1985-09-01

The solvent of commercial amiodarone (Polysorbate 80) has been reported to produce haemodynamic responses in humans and in dogs similar to those produced by histamine infusion. We therefore evaluated the correlation between hypotension induced by the solvent of amiodarone and its histamine-releasing properties in the awake dog. The solvent of amiodarone administered to a dog, over 5 min in a dose of 10 mg/kg of Polysorbate 80, produced severe hypotension after the first administration; the second injection (24 h later) caused fewer hypotensive effects. Histamine release in the peripheral tissues was demonstrated by a marked increase in plasma histamine concentrations, with the maximum value 10 min after the solvent administration. H1- and H2-receptor blockade with mepyramine (5 mg/kg) and cimetidine (10 mg/kg) significantly reduced the cardiovascular effects of the solvent. Isolated peritoneal mast cells from rats also released histamine in response to Polysorbate 80. These studies show that Polysorbate 80 releases histamine both in vitro and in isolated mast cells from rats and in vivo in the dog, and that the plasma concentrations are correlated with the haemodynamic responses.

Formulation and In Vitro Release Kinetics of Mucoadhesive Blend Gels Containing Matrine for Buccal Administration.

PubMed

Chen, Xiaojin; Yan, Jun; Yu, Shuying; Wang, Pingping

2018-01-01

Enterovirus 71 (EV71) is a pathogenic factor of severe hand, foot, and mouth disease (HFMD). No vaccine or specific treatment is currently available for EV71 infection. Hence, we developed a buccal mucoadhesive gel containing matrine to protect against HFMD. Mucoadhesive gels were prepared by Carbopol 974P and were combined with Carbopol 971P, sodium carboxymethyl cellulose (CMC-Na), or hydroxypropylmethy cellulose (HPMC K100M). The formulations were characterized in terms of tensile testing and continuous flow techniques for mucoadhesion. The rheological studies and in vitro drug release characteristics were also investigated. The results showed that combinations of two polymers significantly improved mucoadhesion, especially Carbopol 974P blended with HPMC. Carbopol 974P to HPMC blend ratios of 1:1 and 2:1 induced better mucoadhesion in the tensile test and continuous flow method, respectively. The most sustained release was obtained at a Carbopol 974P to HPMC ratio of 2.5:1. A predominantly non-Fickian diffusion release mechanism was obtained. The gel containing 2.5% Carbopol 974P combined with 1% HPMC showed good mucoadhesion properties and sustained drug release.

Oral delivery of insulin via polyethylene imine-based nanoparticles for colonic release allows glycemic control in diabetic rats.

PubMed

Salvioni, Lucia; Fiandra, Luisa; Del Curto, Maria Dorly; Mazzucchelli, Serena; Allevi, Raffaele; Truffi, Marta; Sorrentino, Luca; Santini, Benedetta; Cerea, Matteo; Palugan, Luca; Corsi, Fabio; Colombo, Miriam

2016-08-01

In this study, insulin-containing nanoparticles were loaded into pellet cores and orally administered to diabetic rats. Polyethylene imine-based nanoparticles, either placebo or loaded with insulin, were incorporated by extrusion and spheronization technology into cores that were subsequently coated with three overlapping layers and a gastroresistant film. The starting and coated systems were evaluated in vitro for their physico-technololgical characteristics, as well as disintegration and release performance. Nanoparticles-loaded cores showed homogeneous particle size distribution and shape. When a superdisintegrant and a soluble diluent were included in the composition enhanced disintegration and release performance were observed. The selected formulations, coated either with enteric or three-layer films, showed gastroresistant and release delayed behavior in vitro, respectively. The most promising formulations were finally tested for their hypoglycemic effect in diabetic rats. Only the nanoformulations loaded into the three-layer pellets were able to induce a significant hypoglycemic activity in diabetic rats. Our results suggest that this efficient activity could be attributed to a retarded release of insulin into the distal intestine, characterized by relatively low proteolytic activity and optimal absorption. Copyright © 2016 Elsevier Ltd. All rights reserved.

Strategies for neurotrophin-3 and chondroitinase ABC release from freeze-cast chitosan-alginate nerve-guidance scaffolds.

PubMed

Francis, Nicola L; Hunger, Philipp M; Donius, Amalie E; Wegst, Ulrike G K; Wheatley, Margaret A

2017-01-01

Freeze casting, or controlled unidirectional solidification, can be used to fabricate chitosan-alginate (C-A) scaffolds with highly aligned porosity that are suitable for use as nerve-guidance channels. To augment the guidance of growth across a spinal cord injury lesion, these scaffolds are now evaluated in vitro to assess their ability to release neurotrophin-3 (NT-3) and chondroitinase ABC (chABC) in a controlled manner. Protein-loaded microcapsules were incorporated into C-A scaffolds prior to freeze casting without affecting the original scaffold architecture. In vitro protein release was not significantly different when comparing protein loaded directly into the scaffolds with release from scaffolds containing incorporated microcapsules. NT-3 was released from the C-A scaffolds for 8 weeks in vitro, while chABC was released for up to 7 weeks. Low total percentages of protein released from the scaffolds over this time period were attributed to limitation of diffusion by the interpenetrating polymer network matrix of the scaffold walls. NT-3 and chABC released from the scaffolds retained bioactivity, as determined by a neurite outgrowth assay, and the promotion of neurite growth across an inhibitory barrier of chondroitin sulphate proteoglycans. This demonstrates the potential of these multifunctional scaffolds for enhancing axonal regeneration through growth-inhibiting glial scars via the sustained release of chABC and NT-3. Copyright © 2014 John Wiley & Sons, Ltd. Copyright © 2014 John Wiley & Sons, Ltd.

Optimization of nanostructured lipid carriers for topical delivery of nimesulide using Box-Behnken design approach.

PubMed

Moghddam, Seyedeh Marziyeh Mahdavi; Ahad, Abdul; Aqil, Mohd; Imam, Syed Sarim; Sultana, Yasmin

2017-05-01

The aim of the present study was to develop and optimize topically applied nimesulide-loaded nanostructured lipid carriers. Box-Behnken experimental design was applied for optimization of nanostructured lipid carriers. The independent variables were ratio of stearic acid: oleic acid (X 1 ), poloxamer 188 concentration (X 2 ) and lecithin concentration (X 3 ) while particle size (Y 1 ) and entrapment efficiency (Y 2 ) were the chosen responses. Further, skin penetration study, in vitro release, confocal laser scanning microscopy and stability study were also performed. The optimized nanostructured lipid carriers of nimesulide provide reasonable particle size, flux, and entrapment efficiency. Optimized formulation (F9) with mean particle size of 214.4 ± 11 nm showed 89.4 ± 3.40% entrapment efficiency and achieved mean flux 2.66 ± 0.09 μg/cm 2 /h. In vitro release study showed prolonged drug release from the optimized formulation following Higuchi release kinetics with R 2 value of 0.984. Confocal laser scanning microscopy revealed an enhanced penetration of Rhodamine B-loaded nanostructured lipid carriers to the deeper layers of the skin. The stability study confirmed that the optimized formulation was considerably stable at refrigerator temperature as compared to room temperature. Our results concluded that nanostructured lipid carriers are an efficient carrier for topical delivery of nimesulide.

Susceptibility to corrosion and in vitro biocompatibility of a laser-welded composite orthodontic arch wire.

PubMed

Zhang, Chao; Sun, Xinhua; Zhao, Shuang; Yu, Wenwen; Sun, Daqian

2014-01-01

Composite arch-wire (CoAW) is an arch wire formed by solder connection of nickel titanium shape memory alloy and stainless steel wire. The purpose of the present study was to investigate the biocompatibility of CoAW as an important foundation for its clinical application. The electrochemical corrosion and ion release behavior of CoAW upon immersion in solutions simulating oral cavity conditions were measured to evaluate the corrosion behavior of CoAW. Murine L-929 cells were co-cultured with CoAW extract to evaluate the cytotoxicity of the corrosion products in vitro. Polarization tests indicated that CoAW is resistant to corrosion in the tested artificial saliva (AS)-based solutions (chloric solution, simple AS, fluorinated AS, and protein-containing AS), and the amount of toxic copper ions released after immersion was lower than average daily dietary intake levels. The cytotoxicity experiments demonstrated the in vitro biocompatibility of CoAW. Based on the combined advantages of its base materials CoAW, with its resistance to biocorrosion and in vitro cytocompatibility, is a promising alternative material for use in orthodontic fixation applications.

Bimatoprost-Loaded Ocular Inserts as Sustained Release Drug Delivery Systems for Glaucoma Treatment: In Vitro and In Vivo Evaluation

PubMed Central

Franca, Juçara Ribeiro; Foureaux, Giselle; Fuscaldi, Leonardo Lima; Ribeiro, Tatiana Gomes; Rodrigues, Lívia Bomfim; Bravo, Renata; Castilho, Rachel Oliveira; Yoshida, Maria Irene; Cardoso, Valbert Nascimento; Fernandes, Simone Odília; Cronemberger, Sebastião; Ferreira, Anderson José; Faraco, André Augusto Gomes

2014-01-01

The purpose of the present study was to develop and assess a novel sustained-release drug delivery system of Bimatoprost (BIM). Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in vitro drug release. Biodistribution of 99mTc-BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intracameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 µg BIM) were administered once into conjunctival sac, after ocular hypertension confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control. Intraocular pressure (IOP) was monitored for four consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts sustainedly released BIM in vitro during 8 hours. Biodistribution studies showed that the amount of 99mTc-BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after one application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period. IOP results were reflected in RGC counting and optic nerve head cupping damage. BIM-loaded inserts provided sustained release of BIM and seem to be a promising system for glaucoma management. PMID:24788066

Formulation and evaluation of an in situ gel forming system for controlled delivery of triptorelin acetate.

PubMed

Abashzadeh, Sh; Dinarvand, R; Sharifzadeh, M; Hassanzadeh, G; Amini, M; Atyabi, F

2011-11-20

The novel physical hydrogels composed of chitosan or its water soluble derivatives such as carboxymethyl chitosan (CMCh) and sodium carboxymethyl chitosan (NaCMCh) and opened ring polyvinyl pyrrolidone (OP-PVP) were used as a controlled delivery system for triptorelin acetate, a luteinizing-releasing hormone agonist. The in situ gel forming system designed according to physical interactions such as chains entanglements and hydrophilic attractions especially h-bonds of chitosan and/or NaCMCh and OR-PVP. In order to increase in situ gel forming rate the chitosan microspheres prepared through spray drying technique. The chitosan or NaCMCh/OR-PVP blends prepared at different ratios (0.05, 0.10, 0.12, 0.16, 0.20 and 0.24) and suspended in sesame oil as non-aqueous vehicle at different solid content (10-30%). The suitable ratio of polymers with faster in situ gel forming rate was selected for in vivo studies. The gel formation and drug release from the system was evaluated both in vitro and in vivo. In vitro and in vivo results were compared with Diphereline SR 3.75mg, a commercially available controlled delivery system of triptorelin. In vitro release studies showed a sustained release profile for about 192h with first order kinetics. In vivo studies on male rats by determination of serum testosterone were confirmed the acceptable performance of in situ gel forming system compared with Diphereline SR in decreasing the serum testosterone level for 35days, demonstrating the potential of the novel in situ gel forming system for controlled delivery of peptides. Copyright © 2011 Elsevier B.V. All rights reserved.

Shock Wave Treatment Enhances Cell Proliferation and Improves Wound Healing by ATP Release-coupled Extracellular Signal-regulated Kinase (ERK) Activation*

PubMed Central

Weihs, Anna M.; Fuchs, Christiane; Teuschl, Andreas H.; Hartinger, Joachim; Slezak, Paul; Mittermayr, Rainer; Redl, Heinz; Junger, Wolfgang G.; Sitte, Harald H.; Rünzler, Dominik

2014-01-01

Shock wave treatment accelerates impaired wound healing in diverse clinical situations. However, the mechanisms underlying the beneficial effects of shock waves have not yet been fully revealed. Because cell proliferation is a major requirement in the wound healing cascade, we used in vitro studies and an in vivo wound healing model to study whether shock wave treatment influences proliferation by altering major extracellular factors and signaling pathways involved in cell proliferation. We identified extracellular ATP, released in an energy- and pulse number-dependent manner, as a trigger of the biological effects of shock wave treatment. Shock wave treatment induced ATP release, increased Erk1/2 and p38 MAPK activation, and enhanced proliferation in three different cell types (C3H10T1/2 murine mesenchymal progenitor cells, primary human adipose tissue-derived stem cells, and a human Jurkat T cell line) in vitro. Purinergic signaling-induced Erk1/2 activation was found to be essential for this proliferative effect, which was further confirmed by in vivo studies in a rat wound healing model where shock wave treatment induced proliferation and increased wound healing in an Erk1/2-dependent fashion. In summary, this report demonstrates that shock wave treatment triggers release of cellular ATP, which subsequently activates purinergic receptors and finally enhances proliferation in vitro and in vivo via downstream Erk1/2 signaling. In conclusion, our findings shed further light on the molecular mechanisms by which shock wave treatment exerts its beneficial effects. These findings could help to improve the clinical use of shock wave treatment for wound healing. PMID:25118288

Study on fluorouracil-chitosan nanoparticle preparation and its antitumor effect.

PubMed

Chen, Gaimin; Gong, Rudong

2016-05-01

To successfully prepare fluorouracil-chitosan nanoparticles, and further analyze its anti-tumor activity mechanism, this paper makes a comprehensive study of existing preparation prescription and makes a detailed analysis of fluorouracil-chitosan in vitro release and pharmacodynamic behavior of animals. Two-step synthesis method is adopted to prepare 5-FU-CS-mPEG prodrugs, and infrared, (1)H NMR and differential thermal analysis are adopted to analyze characterization synthetic products of prepared drugs. To ensure clinical efficacy of prepared drugs, UV spectrophotometry is adopted for determination of drug loading capacity of prepared drugs, transmission electron microscopy is adopted to observe the appearance, dynamic dialysis method is used to observe in vitro drug release of prepared drugs and fitting of various release models is done. Anti-tumor effect is studied via level of animal pharmacodynamics. After the end of the experiment, tumor inhibition rate, spleen index and thymus index of drugs are calculated. Experimental results show that the prepared drugs are qualified in terms of regular shape, dispersion, drug content, etc. Animal pharmacodynamics experiments have shown that concentration level of drug loading capacity of prepared drugs has a direct impact on anti-tumor rate. The higher the concentration, the higher the anti-tumor rate. Results of pathological tissue sections of mice show that the prepared drugs cause varying degrees of damage to receptor cells, resulting in cell necrosis or apoptosis problem. It can thus be concluded that ion gel method is an effective method to prepare drug-loading nanoparticles, with prepared nanoparticles evenly distributed in regular shape which demonstrate good slow-release characteristics in receptor vitro and vivo. At the same time, after completion of drug preparation, relatively strong anti-tumor activity can be generated for the receptor, so this mode of preparation enjoys broad prospects for development.

Shock wave treatment enhances cell proliferation and improves wound healing by ATP release-coupled extracellular signal-regulated kinase (ERK) activation.

PubMed

Weihs, Anna M; Fuchs, Christiane; Teuschl, Andreas H; Hartinger, Joachim; Slezak, Paul; Mittermayr, Rainer; Redl, Heinz; Junger, Wolfgang G; Sitte, Harald H; Rünzler, Dominik

2014-09-26

Shock wave treatment accelerates impaired wound healing in diverse clinical situations. However, the mechanisms underlying the beneficial effects of shock waves have not yet been fully revealed. Because cell proliferation is a major requirement in the wound healing cascade, we used in vitro studies and an in vivo wound healing model to study whether shock wave treatment influences proliferation by altering major extracellular factors and signaling pathways involved in cell proliferation. We identified extracellular ATP, released in an energy- and pulse number-dependent manner, as a trigger of the biological effects of shock wave treatment. Shock wave treatment induced ATP release, increased Erk1/2 and p38 MAPK activation, and enhanced proliferation in three different cell types (C3H10T1/2 murine mesenchymal progenitor cells, primary human adipose tissue-derived stem cells, and a human Jurkat T cell line) in vitro. Purinergic signaling-induced Erk1/2 activation was found to be essential for this proliferative effect, which was further confirmed by in vivo studies in a rat wound healing model where shock wave treatment induced proliferation and increased wound healing in an Erk1/2-dependent fashion. In summary, this report demonstrates that shock wave treatment triggers release of cellular ATP, which subsequently activates purinergic receptors and finally enhances proliferation in vitro and in vivo via downstream Erk1/2 signaling. In conclusion, our findings shed further light on the molecular mechanisms by which shock wave treatment exerts its beneficial effects. These findings could help to improve the clinical use of shock wave treatment for wound healing. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Thai Silk Fibroin/Gelatin Sponges for the Dual Controlled Release of Curcumin and Docosahexaenoic Acid for Anticancer Treatment.

PubMed

Lerdchai, Kantarat; Kitsongsermthon, Jutarat; Ratanavaraporn, Juthamas; Kanokpanont, Sorada; Damrongsakkul, Siriporn

2016-01-01

In this study, curcumin and/or docosahexaenoic acid (DHA) were encapsulated in Thai silk fibroin/gelatin (SF/G) sponges, prepared at different blending ratios, aimed to be applied as a controlled release system for localized cancer therapy. The SF/G sponges were fabricated by freeze-drying and glutaraldehyde cross-linking techniques. Physicochemical properties of the SF/G sponges were characterized. Then, curcumin and/or DHA were loaded in the sponges by physical adsorption. The encapsulation efficiency and the in vitro release of curcumin and/or DHA from the sponges were evaluated. SF/G sponges could encapsulate curcumin and/or DHA at high encapsulation efficiency. The highly cross-linked and slowly degrading SF/G (50/50) sponge released curcumin and/or DHA at the slowest rate. The in vitro cytotoxicity of the sponges against noncancer cells (L929 mouse fibroblast) and anticancer of curcumin and/or DHA released from the sponges against cervical cancer cells (CaSki) were tested. All sponges were not toxic to L929 mouse fibroblast. The mixed curcumin–DHA at the ratio of 1:4 had the highest inhibiting effect on the growth of CaSki, comparing with the release of curcumin or DHA alone. SF/G sponges could be a potential carrier for dual release of curcumin and DHA for anticancer effect.

Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

PubMed Central

Jwala, Jwala; Boddu, Sai H.S.; Shah, Sujay; Sirimulla, Suman; Pal, Dhananjay

2011-01-01

Abstract Purpose The objective of this study was to develop and characterize polymeric nanoparticles of appropriate stereoisomeric dipeptide prodrugs of acyclovir (L-valine-L-valine-ACV, L-valine-D-valine-ACV, D-valine-L-valine-ACV, and D-valine-D-valine-ACV) for the treatment of ocular herpes keratitis. Methods Stereoisomeric dipeptide prodrugs of acyclovir (ACV) were screened for bioreversion in various ocular tissues, cell proliferation, and uptake across the rabbit primary corneal epithelial cell line. Docking studies were carried out to examine the affinity of prodrugs to the peptide transporter protein. Prodrugs with optimum characteristics were selected for the preparation of nanoparticles using various grades of poly (lactic-co-glycolic acid) (PLGA). Nanoparticles were characterized for the entrapment efficiency, surface morphology, size distribution, and in vitro release. Further, the effect of thermosensitive gels on the release of prodrugs from nanoparticles was also studied. Results L-valine-L-valine-ACV and L-valine-D-valine-ACV were considered to be optimum in terms of enzymatic stability, uptake, and cytotoxicity. Docking results indicated that L-valine in the terminal position increases the affinity of the prodrugs to the peptide transporter protein. Entrapment efficiency values of L-valine-L-valine-ACV and L-valine-D-valine-ACV were found to be optimal with PLGA 75:25 and PLGA 65:35 polymers, respectively. In vitro release of prodrugs from nanoparticles exhibited a biphasic release behavior with initial burst phase followed by sustained release. Dispersion of nanoparticles in thermosensitive gels completely eliminated the burst release phase. Conclusion Novel nanoparticulate systems of dipeptide prodrugs of ACV suspended in thermosensitive gels may provide sustained delivery after topical administration. PMID:21500985

In vitro and in vivo study of sustained nitric oxide release coating using diazeniumdiolate-oped poly(vinyl chloride) matrix with poly(lactide-co-glycolide) additive

PubMed Central

Handa, Hitesh; Brisbois, Elizabeth J.; Major, Terry C.; Refahiyat, Lahdan; Amoako, Kagya A.; Annich, Gail M.; Bartlett, Robert H.; Meyerhoff, Mark E.

2013-01-01

Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion and activation that can be released from a NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) within a polymer coating. In this study, various Food and Drug Administration approved poly(lactic-co-glycolic acid) (PLGA) species were evaluated as additives to promote a prolonged NO release from DBHD/N2O2 within a plasticized poly(vinyl chloride) (PVC) matrix. When using an ester-capped PLGA additive with a slow hydrolysis time, the resulting coatings continuously release between 7–18×10-10 mol cm-2 min-1 NO for 14 d at 37°C in PBS buffer. The corresponding pH changes within the polymer films were visualized using pH sensitive indicators and are shown to correlate with the extended NO release pattern. The optimal combined diazeniumdiolate/PLGA-doped NO release (NOrel) PVC coating was evaluated in vitro and its effect on the hemodynamics was also studied within a 4 h in vivo extracorporeal circulation (ECC) rabbit model of thrombogenicity. Four out of 7 control circuits clotted within 3 h, whereas all the NOrel coated circuits were patent after 4 h. Platelet counts on the NOrel ECC were preserved (79 ± 11% compared to 54 ± 6% controls). The NOrel coatings showed a significant decrease in the thrombus area as compared to the controls. Results suggest that by using ester-capped PLGAs as additives to a conventional plasticized PVC material containing a lipophilic diazeniumdiolates, the NO release can be prolonged for up to 2 weeks by controlling the pH within the organic phase of the coating. PMID:23914297

Effects of atropine on refractive development, dopamine release, and slow retinal potentials in the chick.

PubMed

Schwahn, H N; Kaymak, H; Schaeffel, F

2000-01-01

Atropine has previously been found to suppress visually induced myopia both in animals and humans. The mechanism of its action is unclear. We have studied its retinal effects in an in vitro preparation, using the retina-pigment epithelium-choroid complex of the chick eye. In vivo, deprivation myopia was induced by translucent goggles. Atropine solution was injected into the vitreous at two-day intervals. Dopamine release from the retina following atropine injection in vivo and from the in vitro retina preparation was quantified by HPLC-EC. In vitro preparations of the isolated chick retina-pigment epithelium-choroid were superfused with atropine. Light-induced potentials (local ERG), slow standing potentials from the retinal pigment epithelium/neural retina, and extracellular potassium concentrations were recorded. In line with previous findings, intravitreal injections of atropine (25 microg, 250 microg) reduced deprivation myopia in a dose-dependent manner. Atropine increased the release of the neurotransmitter dopamine into the superfusate in vitro at 100-500 microM and into the vitreous in vivo at 250 microg. Before an increase was measured in the vitreous, the retinal dopamine content was elevated. In concentrations equivalent to the intravitreal concentration to suppress myopia in vivo (200-800 microM), atropine induced spreading depression (SD) in the in vitro preparation. In contrast, muscarinic agonists, acetylcholine and pilocarpine, did not induce SD. Atropine reduced the ERG b- and d-wave, led to damped oscillations of RPE potentials, and reversed the ERG c-wave. Atropine suppressed myopia only at doses at which severe nonspecific side effects were observed in the retina. Atropine seems to intrude massively into the vital functions of the retina as indicated by the occurrence of SD. We conclude that atropine, by inducing SD, boosts neurotransmitter release from cellular stores, which may cancel out a presumed retinal signal that controls eye growth and through this, myopia.

Development and Evaluation of High Bioavailable Sustained-Release Nimodipine Tablets Prepared with Monolithic Osmotic Pump Technology.

PubMed

Kong, Hua; Yu, Fanglin; Liu, Yan; Yang, Yang; Li, Mingyuan; Cheng, Xiaohui; Hu, Xiaoqin; Tang, Xuemei; Li, Zhiping; Mei, Xingguo

2018-01-01

Frequent administration caused by short half-life and low bioavailability due to poor solubility and low dissolution rate limit the further application of poorly water-soluble nimodipine, although several new indications have been developed. To overcome these shortcomings, sophisticated technologies had to be used since the dose of nimodipine was not too low and the addition of solubilizers could not resolve the problem of poor release. The purpose of this study was to obtain sustained and complete release of nimodipine with a simple and easily industrialized technology. The expandable monolithic osmotic pump tablets containing nimodipine combined with poloxamer 188 and carboxymethylcellulose sodium were prepared. The factors affecting drug release including the amount of solubilizing agent, expanding agent, retarding agent in core tablet and porogenic agent in semipermeable film were optimized. The release behavior was investigated both in vitro and in beagle dogs. It was proved that the anticipant release of nimodipine could be realized in vitro. The sustained and complete release of nimodipine was also realized in beagles because the mean residence time of nimodipine from the osmotic pump system was longer and Cmax was lower than those from the sustained-release tablets in market while there was no difference in AUC(0-t) of the monolithic osmotic pump tablets and the sustained release tablets in market. It was reasonable to believe that the sustained and complete release of poorly watersoluble nimodipine could be realized by using simple expandable monolithic osmotic pump technology combined with surfactant. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A novel poloxamers/hyaluronic acid in situ forming hydrogel for drug delivery: rheological, mucoadhesive and in vitro release properties.

PubMed

Mayol, Laura; Quaglia, Fabiana; Borzacchiello, Assunta; Ambrosio, Luigi; La Rotonda, Maria I

2008-09-01

The influence of hyaluronic acid (HA) on the gelation properties of poloxamers blends has been studied with the aim of engineering thermosensitive and mucoadhesive polymeric platforms for drug delivery. The gelation temperature (T(gel)), viscoelastic properties and mucoadhesive force of the systems were investigated and optimised by means of rheological analyses. Poloxamers micellar diameter was evaluated by photon correlation spectroscopy (PCS). Moreover in order to explore the feasibility of these platforms for drug delivery, the optimised systems were loaded with acyclovir and its release properties studied in vitro. By formulating poloxamers/HA platforms, at specific concentrations, it was possible to obtain a thermoreversible gel with a T(gel) close to body temperature. The addition of HA did not hamper the self assembling process of poloxamers just delaying the gelation temperature of few Celsius degrees. Furthermore, HA presence led to a strong increase of the poloxamer rheological properties thus indicating possible HA interactions with micelles through secondary bonds, such as hydrogen ones, which reinforce the gel structure. These interactions could also explain PCS results which show, in systems containing HA, aggregates with hydrodynamic diameters much higher than those of poloxamer micelles. Mucoadhesion experiments showed a rheological synergism between poloxamers/HA gels and mucin dispersion which led to a change of the flow behaviour from a quite Newtonian one of the separate solutions to a pseudoplastic one of their mixture. In vitro release experiments indicated that the optimised platform was able to prolong and control acyclovir release for more than 6h.

Assessment of nickel release from various dental appliances used routinely in pediatric dentistry.

PubMed

Kulkarni, Parimala; Agrawal, Suchi; Bansal, Arpana; Jain, Ankur; Tiwari, Utkarsh; Anand, Ayushi

2016-01-01

The use of nickel-containing alloys in dentistry has been questioned because of the biological liabilities of nickel and the release of nickel ions from dental appliances into the oral cavity. The potential health hazards of nickel and chromium and their compounds have been the focus of attention for more than 100 years. It has established that these metals could cause hypersensitivity. To assess the nickel release from various dental appliances used in pediatric dentistry. It is a in vitro study. The study was undertaken to analyze in vitro biodegradation of space maintainers and stainless steel crowns made out of stainless steel materials from different manufacturers. The leaching effect simulating the use of clinical practice was studied by keeping the respective number of Stainless Steel Crowns and space maintainers in the artificial saliva incubating at 37°C and analyzing for nickel release after 1,7,14,21 and 28 days using atomic absorption spectrophotometer. The results were statistically analyzed by using One way ANOVA and repeated measures of ANOVA was applied at different time intervals i.e. 1,7,14,21,28 days. The critical value for statistical significance was set at P = 0.05. Results showed that there was measurable release of nickel which reached maximum level at the end of 7 days which was statistically significant (P < 0.05). The release of nickel and chromium very much below when compared with the average dietary intake of nickel (200-300 ppm/day) which were not capable of causing any toxic effects.

A novel solid dosage form of rifampicin and isoniazid with improved functionality.

PubMed

Gohel, Mukesh C; Sarvaiya, Krishnakant G

2007-08-24

The aim of the present investigation was to develop a novel dosage form of rifampicin and isoniazid to minimize degradation of rifampicin in acidic medium and to modulate the release of rifampicin in the stomach and isoniazid in the intestine. Gastroretentive tablets of rifampicin (150 mg) were prepared by the wet granulation method using hydroxypropyl methylcellulose, calcium carbonate, and polyethylene glycol 4000. The granules and tablets of rifampicin were characterized. Hard gelatin capsules (size 4) containing a compacted mass of isoniazid (150 mg) and dicalcium phosphate (75 mg) were enteric coated. Two tablets of rifampicin and 1 capsule (size 4) of isoniazid were put into a hard gelatin capsule (size 00). The in vitro drug release and in vitro drug degradation studies were performed. Rifampicin was released over 4 hours by zero-order kinetics from the novel dosage form. More than 90% of isoniazid was released in alkaline medium in 30 minutes. The results of dissolution studies with the US Pharmacopeia XXIII method revealed that a substantial amount of rifampicin was degraded from the immediate release capsule containing rifampicin and isoniazid powder owing to drug accumulation in the dissolution vessel and also to the presence of isoniazid. The degradation of rifampicin to 3-formyl rifampicin SV (3FRSV) was arrested (3.6%-4.8% degradation of rifampicin at 4 hours) because of the minimization of physical contact between the 2 drugs and controlled release of rifampicin in acidic medium in the modified Rossett-Rice apparatus. This study concludes that the problem of rifampicin degradation can be alleviated to a certain extent by this novel dosage form.

Synthesis of Human Neutrophil Extracellular Traps Contributes to Angiopoietin-Mediated In Vitro Proinflammatory and Proangiogenic Activities.

PubMed

Lavoie, Simon S; Dumas, Elizabeth; Vulesevic, Branka; Neagoe, Paul-Eduard; White, Michel; Sirois, Martin G

2018-06-01

Neutrophil extracellular traps (NETs) are composed of nuclear DNA in a web-like structure extruded from neutrophils in response to either bacterial infection or inflammation. We previously reported the expression of angiopoietin Tie2 receptor on human neutrophils and the capacity of both angiopoietins (Ang1 and Ang2) to induce proinflammatory activities, such as synthesis and release of platelet-activating factor, upregulation of β 2 integrin complex (CD11/CD18), and neutrophil chemotaxis. In contrast, only Ang1 but not Ang2 is capable of promoting translational and transcriptional activities in neutrophils. In this article, we addressed whether Ang1 and/or Ang2 could modulate the release of NETs and if they contribute to angiopoietin-mediated proinflammatory activities. We observed that Ang1 and Ang2, alone or combined (10 nM, 3 h), increase NET synthesis and release by ≈2.5-fold as compared with PBS-treated neutrophils. The release of NETs is Tie2 dependent and requires downstream intracellular participation of PI3K, p38, and p42/44 MAPK pathways; reactive oxygen species production; intracellular calcium store depletion; and protein arginine deiminase 4 activation. These isolated NETs induced neutrophil and endothelial cell activation, leading to neutrophil adhesion onto human extracellular matrix and HUVEC and in vitro formation of capillary-like tubes by endothelial cells. Our study reports the capacity of Ang1 and Ang2 to promote the release of NETs and that these NETs contribute to angiopoietin-mediated in vitro proinflammatory and proangiogenic activities. Copyright © 2018 by The American Association of Immunologists, Inc.

Procain and diethylaminoethanol influence on the release of free oxygen radicals by polymorphonuclear leukocytes, in rabbits and humans.

PubMed

Dolganiuc, A; Radu, D; Olinescu, A; Vrăbiescu, A

1998-01-01

The investigations were conducted on 3 groups of New Zealand rabbits: 1) controls; 2) injected with procain, i.m. 15 mg/kg body weight, daily, for 30 days; 3) injected with diethylaminoethanol (DEAE), 15 mg/kg body weight, daily, for 35 days. The study was made also on human leukocytes, isolated from the peripheral blood of 10 clinically healthy subjects (adults), procain and DEAE action being investigated in vitro. The free oxygen radicals (FOR) released by PMN leukocytes were evaluated by chemiluminescence, in vitro. Addition of procain or DEAE had no effect on the release of FOR by PMN leukocytes of control rabbits. In the experiment made on rabbits treated with procain or DEAE, the release of FOR by PMN leukocytes was much more reduced, as compared to controls. In the rabbits treated with procain, the intensity of the emitted light was 2.27 mV, in those treated with DEAE, 3.46 mV, while in the controls, the mean value was 6.74 mV. In the in vitro experiments performed on human PMN cells stimulated with opsonized zymosan (OZ), addition of procain or DEAE had an inhibiting effect on the FOR release. As compared to control, the means of the FOR values decreased from 59 to 41.2 mV in case of procain addition and from 67.7 to 50 mV in case of DEAE addition. The fact that the inflammation is associated with accumulation of free radicals, suggests the opportunity to test these substances, especially DEAE, as antioxidant agents.

Human skin-derived fibroblasts used as a 'Trojan horse' for drug delivery.

PubMed

Coccè, V; Vitale, A; Colombo, S; Bonomi, A; Sisto, F; Ciusani, E; Alessandri, G; Parati, E; Brambilla, P; Brambilla, M; La Porta, C A; Pessina, A

2016-06-01

Drug toxicity currently represents the main challenge of tumour chemotherapy. Our group recently developed a new method for drug delivery inspired by the 'Trojan Horse' concept. Human mesenchymal stem cells (hMSCs) have been shown to play the role of new 'horses' in delivering anti-tumour agents, without involving any genetic manipulation. As human stromal dermal fibroblasts (hSDFs) represent an interesting alternative to hMSCs, being easy to isolate, they could be an ideal candidate for this kind of procedure. To investigate whether hSDFs can take up and deliver paclitaxel (PTX) in sufficient concentrations to inhibit a very aggressive melanoma tumour (IgR39) in vitro. hSDFs were primed with high doses of PTX, and then the effect of drug delivery on IgR39 melanoma proliferation in vitro was evaluated using several assays (antiproliferation, transwell cocultures, rosette assays and colony growth assays). Furthermore, the cell cycle and PTX uptake/release mechanism of hSDFs were studied both under both normal and hypoxic conditions. hSDFs incorporated PTX and then released it with unaffected pharmacological activity, inhibiting human IgR39 melanoma growth in vitro. The hypoxic conditions did not induce changes in cell cycle pattern and the uptake-release mechanism with PTX was not affected. hSDFs can be used as a Trojan horse, as the released drug was functionally active. These results indicated that these cells could be used for clinical treatment as the drug was released into the cellular environment and the primed cells underwent apoptosis. © 2016 British Association of Dermatologists.

Analysis of in vitro release through reconstructed human epidermis and synthetic membranes of multi-vitamins from cosmetic formulations.

PubMed

Gabbanini, Simone; Matera, Riccardo; Beltramini, Claudia; Minghetti, Andrea; Valgimigli, Luca

2010-08-01

A convenient method for in vitro investigation of the release of lipid- and water-soluble vitamins from cosmetic formulations was developed. The permeation of (d)-alpha-tocopherol (vitamin E), retinyl acetate (pro-vitamin A), ascorbic acid (vitamin C) and pyridoxine (vitamin B6) through SkinEthic reconstructed human epidermis (RHE), and synthetic polyethersulfone and polycarbonate membranes was studied in vitro using a Franz-type diffusion apparatus, coupled either to a spectrophotometer for continuous reading (dynamic setting) or to HPLC-DAD analysis of the receptor medium (static setting). O/W and W/O emulsions were compared with simple aqueous solutions for their kinetic of vitamins release, to evaluate the influence of the cosmetic formulation on the bioavailability of active ingredients. Results indicate that synthetic membranes offer a limited barrier to the diffusion of vitamins, but may provide information on the release ability of the formulation. Penetration was more effective when water was the external phase of the formulation, i.e. W/O emulsions were less effective in the release of vitamins than O/W emulsion or aqueous solutions. RHE (17 days old) offered a significantly higher barrier to penetration of vitamins, as expected for native human epidermis. The relative ranking in coefficient of permeability (Ps (cm/h)) was: ascorbic acid>pyridoxine>retinyl acetate>alpha-tocopherol approximately 0, the absolute values depending on the formulation. The method herein described showed to be a practical and convenient tool for the quality-control and efficacy evaluation of cosmetic formulations. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Controlled release of basic fibroblast growth factor for angiogenesis using acoustically-responsive scaffolds.

PubMed

Moncion, Alexander; Lin, Melissa; O'Neill, Eric G; Franceschi, Renny T; Kripfgans, Oliver D; Putnam, Andrew J; Fabiilli, Mario L

2017-09-01

The clinical translation of pro-angiogenic growth factors for treatment of vascular disease has remained a challenge due to safety and efficacy concerns. Various approaches have been used to design spatiotemporally-controlled delivery systems for growth factors in order to recapitulate aspects of endogenous signaling and thus assist in translation. We have developed acoustically-responsive scaffolds (ARSs), which are fibrin scaffolds doped with a payload-containing, sonosensitive emulsion. Payload release can be controlled non-invasively and in an on-demand manner using focused, megahertz-range ultrasound (US). In this study, we investigate the in vitro and in vivo release from ARSs containing basic fibroblast growth factor (bFGF) encapsulated in monodispersed emulsions. Emulsions were generated in a two-step process utilizing a microfluidic device with a flow focusing geometry. At 2.5 MHz, controlled release of bFGF was observed for US pressures above 2.2 ± 0.2 MPa peak rarefactional pressure. Superthreshold US yielded a 12.6-fold increase in bFGF release in vitro. The bioactivity of the released bFGF was also characterized. When implanted subcutaneously in mice, ARSs exposed to superthreshold US displayed up to 3.3-fold and 1.7-fold greater perfusion and blood vessel density, respectively, than ARSs without US exposure. Scaffold degradation was not impacted by US. These results highlight the utility of ARSs in both basic and applied studies of therapeutic angiogenesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cyclic strain alters the expression and release of angiogenic factors by human tendon cells.

PubMed

Mousavizadeh, Rouhollah; Khosravi, Shahram; Behzad, Hayedeh; McCormack, Robert G; Duronio, Vincent; Scott, Alex

2014-01-01

Angiogenesis is associated with the tissue changes underlying chronic overuse tendinopathy. We hypothesized that repetitive, cyclic loading of human tendon cells would lead to increased expression and activity of angiogenic factors. We subjected isolated human tendon cells to overuse tensile loading using an in vitro model (1 Hz, 10% equibiaxial strain). We found that mechanically stimulated human tendon cells released factors that promoted in vitro proliferation and tube formation by human umbilical vein endothelial cells (HUVEC). In response to cyclic strain, there was a transient increase in the expression of several angiogenic genes including ANGPTL4, FGF-2, COX-2, SPHK1, TGF-alpha, VEGF-A and VEGF-C, with no change in anti-angiogenic genes (BAI1, SERPINF1, THBS1 and 2, TIMP1-3). Cyclic strain also resulted in the extracellular release of ANGPTL4 protein by tendon cells. Our study is the first report demonstrating the induction of ANGPTL4 mRNA and release of ANGPTL4 protein in response to cyclic strain. Tenocytes may contribute to the upregulation of angiogenesis during the development of overuse tendinopathy.

Cyclic Strain Alters the Expression and Release of Angiogenic Factors by Human Tendon Cells

PubMed Central

Mousavizadeh, Rouhollah; Khosravi, Shahram; Behzad, Hayedeh; McCormack, Robert G.; Duronio, Vincent; Scott, Alex

2014-01-01

Angiogenesis is associated with the tissue changes underlying chronic overuse tendinopathy. We hypothesized that repetitive, cyclic loading of human tendon cells would lead to increased expression and activity of angiogenic factors. We subjected isolated human tendon cells to overuse tensile loading using an in vitro model (1 Hz, 10% equibiaxial strain). We found that mechanically stimulated human tendon cells released factors that promoted in vitro proliferation and tube formation by human umbilical vein endothelial cells (HUVEC). In response to cyclic strain, there was a transient increase in the expression of several angiogenic genes including ANGPTL4, FGF-2, COX-2, SPHK1, TGF-alpha, VEGF-A and VEGF-C, with no change in anti-angiogenic genes (BAI1, SERPINF1, THBS1 and 2, TIMP1-3). Cyclic strain also resulted in the extracellular release of ANGPTL4 protein by tendon cells. Our study is the first report demonstrating the induction of ANGPTL4 mRNA and release of ANGPTL4 protein in response to cyclic strain. Tenocytes may contribute to the upregulation of angiogenesis during the development of overuse tendinopathy. PMID:24824595

In vitro study on the osteogenesis enhancement effect of BMP-2 incorporated biomimetic apatite coating on titanium surfaces.

PubMed

Zhu, Xiaojing; Zhang, Hui; Zhang, Xinchun; Ning, Chengyun; Wang, Yan

2017-09-26

To fabricate a sustained-release delivery system of bone morphogenetic protein (BMP-2) on titanium surface, explore the effect of BMP-2 concentration on the loading/release behavior of BMP-2 and evaluate the cell compatibility of the system in vitro, pure titanium specimens were immersed into supersaturated calcium phosphate solutions (SCP) containing 4 different concentrations of BMP-2: 0, 50, 100, 200 and 400 ng/mL. Biomimetic calcium phosphate coating was formed on titanium surface and BMP-2 was incorporated into the coating through co-deposition. The release profile of BMP-2 suggested that BMP-2 were delivered sustainably up to 20 days. CCK-8 and ALP assay showed that 200 group and 400 ng/mL BMP-2 group have significant effect on promoting MC3T3-E1 cell proliferation and differentiation. The BMP-2 incorporated into the hybrid coating released in a sustained manner and significantly promoted the proliferation and differentiation of MC3T3-E1 on the titanium surface.

Improvement of Stability and Antioxidant Activities by Using Phycocyanin - Chitosan Encapsulation Technique

NASA Astrophysics Data System (ADS)

Suzery, Meiny; Hadiyanto; Majid, Dian; Setyawan, Deny; Sutanto, Heri

2017-02-01

Encapsulation is a coating process to improve the stability of bioactive compounds. Phycocyanin with high antioxidant activity has been encapsulated with chitosan in microcapsules form. In this study aims to determine the best conditions in the encapsulation process using the extrusion method, characterization of the physicochemical properties of the microcapsules, antioxidant activity test using DPPH, in vitro release performance and evaluate the storage stability against temperature. The results of the encapsulation process is obtained: Na-TPP is better than Na-citrate as crosslinker and chitosan content 3% as a coating with ratio of chitosan to phycocyanin ratio 1: 1. Test of antioxidant activity also showed encapsulation with chitosan content 3% has the highest antioxidant activity. Morphological analysis microcapsules were found to have compact spherical shape with diameter range 900-1000 µm. In vitro release testing showed a quick release in an acidic environment (SGF) for 2 hours and slowly release under alkaline conditions (SIF) for 8 hours under mechanical stirring at 37°C. Phycocyanin much more stable against temperature during storage in microcapsules.

Design and in vitro/in vivo evaluation of sustained-release floating tablets of itopride hydrochloride

PubMed Central

Ahmed, Sayed M; Ahmed Ali, Adel; Ali, Ahmed MA; Hassan, Omiya A

2016-01-01

Purpose The aim of the present study was to improve the bioavailability of itopride (ITO) and sustain its action by formulating as a floating dosage form. Materials and methods Sustained-release floating tablets of ITO hydrochloride (HCl) were prepared by direct compression using different hydrocolloid polymers such as hydroxypropyl methylcellulose and ethylcellulose and/or methacrylic acid polymers Eudragit RSPM and Carbopol 934P. The floating property was achieved using an effervescent mixture of sodium bicarbonate and anhydrous citric acid (1:1 mol/mol). Hardness, friability, content uniformity, and dissolution rate of the prepared floating tablets were evaluated. The formulation F10 composed of 28.5% Eudragit RSPM, 3% NaHCO3, and 7% citric acid provided sustained drug release. Results In vitro results showed sustained release of F10 where the drug release percentage was 96.51%±1.75% after 24 hours (P=0.031). The pharmacokinetic results indicated that the area under the curve (AUC0–∞) of the prepared sustained-release floating tablets at infinity achieved 93.69 µg·h/mL compared to 49.89 µg·h/mL for the reference formulation (Ganaton®) and the relative bioavailability of the sustained-release formulation F10 increased to 187.80% (P=0.022). Conclusion The prepared floating tablets of ITO HCl (F10) could be a promising drug delivery system with sustained-release action and enhanced drug bioavailability. PMID:28008229

A Tunable, Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant Delivering Tenofovir Alafenamide Fumarate for HIV Pre-exposure Prophylaxis

PubMed Central

Schlesinger, Erica; Johengen, Daniel; Luecke, Ellen; Rothrock, Ginger; McGowan, Ian; van der Straten, Ariane; Desai, Tejal

2016-01-01

Purpose The effectiveness of Tenofovir based HIV pre-exposure prophylaxis (PrEP) is proven, but hinges on correct and consistent use. User compliance and therapeutic effectiveness can be improved by long acting drug delivery systems. Here we describe a thin-film polymer device (TFPD) as a biodegradable subcutaneous implant for PrEP. Methods A thin-film polycaprolactone (PCL) membrane controls drug release from a reservoir. To achieve membrane controlled release, TAF requires a formulation excipient such as PEG300 to increase the dissolution rate and reservoir solubility. Short-term In vitro release studies are used to develop an empirical design model, which is applied to the production of in vitro prototype devices demonstrating up to 90-days of linear release and TAF chemical stability. Results The size and shape of the TFPD are tunable, achieving release rates ranging from 0.5–4.4 mg/day in devices no larger than a contraceptive implant. Based on published data for oral TAF, subcutaneous constant-rate release for HIV PrEP is estimated at < 2.8mg/day. Prototype devices demonstrated linear release at 1.2mg/day for up to 90 days and at 2.2mg/day for up to 60 days. Conclusions We present a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape and release rate of the device are tunable over a > 8-fold range. PMID:26975357

Development and evaluation of 6-mercaptopurine and metoclopramide polypill formulation for oral administration: In-vitro and ex vivo studies

PubMed Central

Chowdhary, Rajani; Pai, Roopa S; Singh, Gurinder

2013-01-01

Introduction: The present investigation was to develop a polypill of 6-mercaptopurine and metoclopramide. A polypill with delayed release granules of an anticancer and immediate release mucoadhesive tablet of antiemetic may result in the reduction of emesis caused by oral chemotherapy. Materials and Methods: 6-Mercaptopurine granules were prepared by wet granulation process. Chitosan, hydroxypropyl methylcellulose, and ethylcellulose were used as individually as delayed release polymers. Seven granule formulations (F1-F7) were prepared and evaluated for flow properties and drug content. Immediate release mucoadhesive tablets of metoclopramide were prepared by direct compression technique using pectin and PVPK-40 as mucoadhesive polymers. Three formulations of pectin (L1-L3) and three formulations of PVPK40 (M1-M3) were prepared using lactose, magnesium stearate, and mannitol and talc as diluent and glidant, respectively. Tablets were evaluated for weight variation, hardness, friability, drug content, ex vivo mucoadhesion time, and in vitro dissolution studies. Results: Formulation F2, F4, F5, and F7 showed maximum drug content. Formulation F7 exhibited the drug release up to 2 h and was selected as the best delayed release formulation. All formulations of metoclopramide showed good drug content ranging from 97.6 % to 100.6%. Formulation M2 among tablets prepared with PVP exhibited desired mucoadhesion time of 15.33 min which prolongs the duration of drug release in gastric pouch of the male Wistar rats. Both the selected formulations F7 and M2 were filled into body of capsule size 0 and capsule was evaluated for technological properties. Conclusion: It may be concluded that polypill released the metoclopramide immediately prior to 6-mercaptopurine. PMID:24350042

Influence of the Formulation Parameters on the Particle Size and Encapsulation Efficiency of Resveratrol in PLA and PLA-PEG Blend Nanoparticles: A Factorial Design.

PubMed

Lindner, Gabriela da Rocha; Dalmolin, Luciana Facco; Khalil, Najeh Maissar; Mainardes, Rubiana Mara

2015-12-01

Polymeric nanoparticles are colloidal systems that promote protection and modification of physicochemical characteristics of a drug and that also ensure controlled and extended drug release. This paper reports a 2(3) factorial design study to optimize poly(lactide) (PLA) and poly(lactide)-polyethylene glycol (PLA-PEG) blend nanoparticles containing resveratrol (RVT) for prolonged release. The independent variables analyzed were solvent composition, surfactant concentration and ratio of aqueous to organic phase (two levels each factor). Mean particle size and RVT encapsulation efficiency were set as the dependent variables. The selected optimized parameters were set as organic phase comprised of a mixture of dichloromethane and ethyl acetate, 1% of surfactant polyvinyl alcohol and a 3:1 ratio of aqueous to organic phase, for both PLA and PLA-PEG blend nanoparticles. This formulation originated nanoparticles with size of 228 ± 10 nm and 185 ± 70 nm and RVT encapsulation efficiency of 82 ± 10% and 76 ± 7% for PLA and PLA-PEG blend nanoparticles, respectively. The in vitro release study showed a biphasic pattern with prolonged RVT release and PEG did not influence the RVT release. The in vitro release data were in favor of Higuchi-diffusion kinetics for both nanoformulations and the Kossmeyer-Peppas coefficient indicated that anomalous transport was the main release mechanism of RVT. PLA and PLA-PEG blend nanoparticles produced with single emulsion-solvent evaporation technology were found to be a promising approach for the incorporation of RVT and promoted its controlled release. The factorial design is a tool of great value in choosing formulations with optimized parameters.

Formulation and In-vitro Characterization of Sustained Release Matrix Type Ocular Timolol Maleate Mini-Tablet

PubMed Central

Mortazavi, Seyed Alireza; Jafariazar, Zahra; Ghadjahani, Yasaman; Mahmoodi, Hoda; Mehtarpour, Farzaneh

2014-01-01

The purpose of this study was preparation and evaluation of sustained release matrix type ocular mini-tablets of timolol maleate, as a potential formulation for the treatment of glaucoma. Following the initial studies on timolol maleate powder, it was formulated into ocular mini-tablets. The polymers investigated in this study included cellulose derivatives (HEC, CMC, EC) and Carbopol 971P. Mannitol was used as the solubilizing agent and magnesium stearate as the lubricant. Mini-tablets were prepared by through mixing of the ingredients, followed by direct compression. All the prepared formulations were evaluated in terms of physicochemical tests, including uniformity of weight, thickness, crushing strength, friability and in-vitro drug release. Four groups of formulations were prepared. The presence of different amounts of cellulose derivatives or Carbopol 971P, alone, was studied in group A formulations. In group B formulations, the effect of adding Carbopol 971P alongside different cellulose derivatives was investigated. Group C formulations were made by including mannitol as the solubilizing agent, alongside Carbopol 971P and a cellulose derivative. In group D formulations, mini-tablets were made using Carbopol 971P, alongside two different cellulose derivative. The selected formulation (C1) contained ethyl cellulose, Carbopol 971P, mannitol and magnesium stearate, which showed almost 100% drug release over 5 h. Based on kinetic studies, this formulation was found to best fit the zero-order model of drug release. However, the Higuchi and Hixson -Crowell models also showed a good fit. Hence, overall, formulation C1 was chosen as the best formulation. PMID:24734053

[In vitro drug release behavior of carrier made of porous glass ceramics].

PubMed

Wang, De-ping; Huang, Wen-hai; Zhou, Nai

2002-09-01

To conduct the in vitro test on drug release of rifampin encapsulated in a carrier made of porous phosphate glass ceramics and to analyze main factors which affect the drug release rate. A certain quantitative of rifampin was sealed in a hollow cylindrical capsule which consisted of chopped calcium phosphate crystal fiber obtained from glass crystallization. The rifampin concentration was measured in the simulated physiological solution in which the capsule soaked. Rifampin could be released in a constant rate from the porous glass ceramic carrier in a long time. The release rate was dependent on the size of crystal fiber and the wall thickness of the capsule. This kind of calcium phosphate glass ceramics can be a candidate of the carrier materials used as long term drug therapy after osteotomy surgery.

In vitro release of amoxycillin from lipophilic suppositories.

PubMed

Webster, J A; Dowse, R; Walker, R B

1998-04-01

The in vitro release characteristics of amoxycillin from different lipophilic suppository bases were investigated using the USP rotating basket method. Suppositories containing 250 mg amoxycillin were prepared in theobroma oil and in the semi-synthetic bases Witepsol W35, Suppocire A32, Novata BD, and Novata 299. Both freshly prepared and 1-month-old suppositories were tested. Analysis of amoxycillin was performed using a validated high-performance liquid chromatographic (HPLC) technique. Release profiles differed significantly between bases, with the greatest amount of amoxycillin being released from both newly made and 1-month-old Novata BD bases (87.57 +/- 8.18 and 99.66 +/- 6.63%, respectively), and the lowest amount released from the newly manufactured theobroma suppositories (8.82 +/- 0.75%) and the 1-month-old Suppocire A32 suppositories (7.78 +/- 0.27%).

Preparation, characterization, and in vitro gastrointestinal digestibility of oil-in-water emulsion-agar gels.

PubMed

Wang, Zheng; Neves, Marcos A; Kobayashi, Isao; Uemura, Kunihiko; Nakajima, Mitsutoshi

2013-01-01

Soybean oil-in-water (O/W) emulsion-agar gel samples were prepared and their digestibility evaluated by using an in vitro gastrointestinal digestion model. Emulsion-agar sols were obtained by mixing the prepared O/W emulsions with a 1.5 wt % agar solution at 60 °C, and their subsequent cooling at 5 °C for 1 h formed emulsion-agar gels. Their gel strength values increased with increasing degree of polymerization of the emulsifiers, and the relative gel strength increased in the case of droplets with an average diameter smaller than 700 nm. Flocculation and coalescence of the released emulsion droplets depended strongly on the emulsifier type; however, the emulsifier type hardly affected the ζ-potential of emulsion droplets released from the emulsion-agar gels during in vitro digestion. The total FFA content released from each emulsion towards the end of the digestion period was nearly twice that released from the emulsion-agar gel, indicating that gelation of the O/W emulsion may have delayed lipid hydrolysis.

Modeling the pharmacokinetics of extended release pharmaceutical systems

NASA Astrophysics Data System (ADS)

di Muria, Michela; Lamberti, Gaetano; Titomanlio, Giuseppe

2009-03-01

The pharmacokinetic (PK) models predict the hematic concentration of drugs after the administration. In compartment modeling, the body is described by a set of interconnected “vessels” or “compartments”; the modeling consisting of transient mass balances. Usually the orally administered drugs were considered as immediately available: this cannot describe the administration of extended-release systems. In this work we added to the traditional compartment models the ability to account for a delay in administration, relating this delay to in vitro data. Firstly, the method was validated, applying the model to the dosage of nicotine by chewing-gum; the model was tuned by in vitro/in vivo data of drugs (divalproex-sodium and diltiazem) with medium-rate release kinetics, then it was applied in describing in vivo evolutions due to the assumption of fast- and slow-release systems. The model reveals itself predictive, the same of a Level A in vitro/in vivo correlation, but being physically based, it is preferable to a purely statistical method.

Nickel (II) nitrate hexahydrate triggered canine neutrophil extracellular traps release in vitro.

PubMed

Wei, Zhengkai; Zhang, Xu; Wang, Yanan; Wang, Jingjing; Fu, Yunhe; Yang, Zhengtao

2018-05-30

Nickel (II) nitrate hexahydrate (Ni) is a common heavy metal material in battery manufacturing, electroplating alloy parts and ceramic staining, therefore we frequently contact with Ni-related products in daily life. In this study, we aimed to investigate the effects of Ni on neutrophils extracellular traps (NETs) release by canine polymorphonuclear neutrophils (PMNs). The structure of Ni-induced NETs was observed by fluorescence confocal microscopy. Ni-triggered NETs release was quantified by Pico Green ® and fluorescence microplate reader. In addition, the inhibitors of NADPH oxidase, ERK1/2-, p38 - signaling pathways were used for preliminary inquiry into the potential mechanism of this process. The results showed that Ni markedly triggered the formation of NETs-like structures, and these structures were mainly consisted of DNA decorated with NE and MPO. Furthermore, quantification experiments showed that Ni significantly increased NETs formation compared to control groups. These results forcefully confirmed that nickel nitrate possesses the ability to induce NETs formation. However, inhibiting the NADPH oxidase, ERK1/2- and p38 MAPK-signaling pathways did not significantly change the quantitation of Ni-induced NETs release. To our knowledge, this study is the first report of Ni-triggered NETs release in vitro, which might provide an entirely new mechanism of several diseases and health issues induced by nickel overexposure. Copyright © 2018. Published by Elsevier Ltd.

Novel jojoba oil-based emulsion gel formulations for clotrimazole delivery.

PubMed

Shahin, Mostafa; Hady, Seham Abdel; Hammad, Mohammed; Mortada, Nahed

2011-03-01

Jojoba oil-based emulgel formulations were prepared using different concentrations of various gelling agents, such as hydroxypropyl methylcellulose (HPMC) and Carbopol 934 P and combination of both. The prepared emulgels were physically evaluated for their stability after temperature cycle test, centrifugation and long-term shelf storage for 1 year at room temperature. The in vitro release at 37 °C was studied to define the effect of the concentration and type of the gelling agent. A comparison between the formulated emulgels and two commercially available products, Candistan® and Canesten® creams, was carried out to judge their efficacy and stability. The prepared emulgels exhibited non-Newtonian shear thinning behavior with little or no thixotropy. Four emulgels showed excellent stability as they demonstrated consistent rheological model under different treatment conditions. The in vitro release test showed variation in the extent of percent drug released. The drug release from the commercial preparation was lower than some of the prepared emulgel formulae. One formula containing combination of the two gelling agents (HPMC and Carbopol 934 P), showed excellent stability and high extent of clotrimazole release was microbiologically evaluated against Candida albicans using cylinder and plate method. The selected formula showed superior antimycotic activity compared to the commercially available formulation. Further in vivo animal studies for the obtained stable formula is recommended. © 2011 American Association of Pharmaceutical Scientists

Modifying the release of leuprolide from spray dried OED microparticles.

PubMed

Alcock, R; Blair, J A; O'Mahony, D J; Raoof, A; Quirk, A V

2002-08-21

A range of oligosaccharide ester derivatives (OEDs) have been designed as drug delivery matrices for controlled release. The synthetic hormone analogue, leuprolide, was encapsulated within these matrices using hydrophobic ion pairing and solvent spray drying. The particles produced modified the release of leuprolide in vitro (dissolution in phosphate buffered saline) and in vivo (subcutaneous and pulmonary delivery in the rat). Release rate was dependent on drug loading and could be manipulated by choice of OED and by combining different OEDs in different ratios. Leuprolide encapsulated in the OEDs retained biological activity as evidenced by elevation in plasma luteinising hormone levels following subcutaneous injection of leuprolide recovered from OED particles in vitro prior to in vivo administration.

Mesenchymal Stem Cells and Cardiomyocytes Interplay to Prevent Myocardial Hypertrophy

PubMed Central

Tan, Xueying; Zhang, Yong; Li, Xingda; Wang, Xinyue; Zhu, Jiuxin; Wang, Yang; Yang, Fan; Wang, Baoqiu; Liu, Yanju; Xu, Chaoqian; Pan, Zhenwei; Wang, Ning; Yang, Baofeng

2015-01-01

Bone marrow-derived mesenchymal stem cells (BMSCs) have emerged as a promising therapeutic strategy for cardiovascular disease. However, there is no evidence so far that BMSCs can heal pathological myocardial hypertrophy. In this study, BMSCs were indirectly cocultured with neonatal rat ventricular cardiomyocytes (NRVCs) in vitro or intramyocardially transplanted into hypertrophic hearts in vivo. The results showed that isoproterenol (ISO)-induced typical hypertrophic characteristics of cardiomyocytes were prevented by BMSCs in the coculture model in vitro and after BMSC transplantation in vivo. Furthermore, activation of the Ca2+/calcineurin/nuclear factor of activated T cells cytoplasmic 3 (NFATc3) hypertrophic pathway in NRVCs was abrogated in the presence of BMSCs both in vitro and in vivo. Interestingly, inhibition of vascular endothelial growth factor (VEGF) release from BMSCs, but not basic fibroblast growth factor and insulin-like growth factor 1, abolished the protective effects of BMSCs on cardiomyocyte hypertrophy. Consistently, VEGF administration attenuated ISO-induced enlargement of cellular size; the upregulation of atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain expression; and the activation of Ca2+/calcineurin/NFATc3 hypertrophic pathways, and these pathways can be abrogated by blocking VEGFR-1 in cardiomyocytes, indicating that VEGF receptor 1 is involved in the antihypertrophic role of VEGF. We further found that the ample VEGF secretion contributing to the antihypertrophic effects of BMSCs originates from the crosstalk of BMSCs and cardiac cells but not BMSCs or cardiomyocytes alone. Interplay of mesenchymal stem cells with cardiomyocytes produced synergistic effects on VEGF release. In summary, crosstalk between mesenchymal stem cells and cardiomyocytes contributes to the inhibition of myocardial hypertrophy via inhibiting Ca2+/calcineurin/NFATc3 hypertrophic pathways in cardiac cells. These results provide the first evidence for the treatment of myocardial hypertrophy using BMSCs. Significance This study found that mesenchymal stem cells may crosstalk with cardiomyocytes, which causes a synergistic vascular endothelial growth factor (VEGF) release from both kinds of cells and then inhibits pathological cardiac remodeling following hypertrophic stimulation in cardiomyocytes in vitro and in vivo. Blockage of VEGF release from bone marrow-derived mesenchymal stem cells (BMSCs) abolishes the antihypertrophic actions of BMSCs in vitro and in vivo. On the contrary, VEGF administration attenuates hypertrophic signaling of calcineurin/ nuclear factor of activated T cell cytoplasmic 3 signal pathways. This study provides the first evidence for the treatment of myocardial hypertrophy using BMSCs. PMID:26586774

Forskolin-stimulated vasopressin and oxytocin release from the rat hypothalamo-neurohypophysial system in vitro is inhibited by melatonin.

PubMed

Roszczyk, Magdalena; Juszczak, Marlena

2014-01-01

Previous in vivo and in vitro studies have shown that melatonin changes vasopressin (AVP) and oxytocin (OT) secretion from the rat neurohypophysis. Additionally, melatonin is known to inhibit the forskolin-induced (forskolin is a strong adenylyl cyclase - AC activator) increase in cAMP accumulation in the rat pituitary. To determine whether the possible response of vasopressinergic and/or oxytocinergic neurones to melatonin could be mediated through a cAMP-dependent mechanism, the effect of different concentrations of melatonin (i.e. 10-11, 10-9, 10-7, 10-5 and 10-3 M) on forskolin-stimulated AVP and OT release from the rat hypothalamo-neurohypophysial (H-NH) system was studied in vitro. Male rats served as donors of the H-NH explants, which were placed in 1 mLof normal Krebs-Ringer fluid (nKRF), heated to 37oC and constantly gassed with carbogen (95% O2 and 5% CO2). The H-NH explants were incubated successively in nKRF {fluid B1} and incubation fluid as B1 enriched with an appropriate concentration of melatonin, i.e. 10-11 - 10-3 M and/or forskolin (at a concentration of 10-5 M) or their vehicles (0.1% ethanol or DMSO) {fluid B2}. After 20 min incubation in fluid B1 and next B2, the media were collected and immediately frozen before AVP and OT estimation by the RIA. The AVP and OT secretion was determined by using B2/B1 ratio for each H-NH explant. We have demonstrated that the highly effective AC activator - forskolin significantly stimulated both AVP and OT release from isolated rat H-NH system. Such an effect of forskolin was reduced by melatonin at concentrations of 10-9, 10-7 and 10-5 M. The strongest effect was exerted by this hormone at a concentration of 10-7 M, which inhibited not only forskolin-stimulated, but also basal, AVP and OT release. On the contrary, the highest studied concentration (i.e. 10-3 M) of melatonin stimulated both AVP and OT basal release, but when forskolin was present in the medium melatonin at such a concentration remained inactive in modifying these hormones release from the H-NH system in vitro. Our present results demonstrate that in the male rat: 1. The influence of melatonin on the vasopressinergic and oxytocinergic neurones activity is mediated partly through a cAMP-dependent mechanism. 2. The effect of melatonin in this respect depends on its concentration.

Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baireddy, Praveena; Liu, Jing; Hinsdale, Myron

2011-11-15

Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55.212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in tissues from wild type (+/+) and cannabinoid CB1 receptor knockout (-/-) mice. Mice of both genotypes (n = 5-6/treatment group) were challenged with CPF (300 mg/kg, 2 ml/kg in peanut oil, sc) and evaluated for functional and neurochemicalmore » changes. Both genotypes exhibited similar cholinergic signs and cholinesterase inhibition (82-95% at 48 h after dosing) in cortex, cerebellum and heart. WIN reduced depolarization-induced ACh release in vitro in hippocampal slices from wild type mice, but had no effect in hippocampal slices from knockouts or in striatal slices from either genotype. Chlorpyrifos oxon (CPO, 100 {mu}M) reduced release in hippocampal slices from both genotypes in vitro, but with a greater reduction in tissues from wild types (21% vs 12%). CPO had no significant in vitro effect on ACh release in striatum. CPF reduced ACh release in hippocampus from both genotypes ex vivo, but reduction was again significantly greater in tissues from wild types (52% vs 36%). In striatum, CPF led to a similar reduction (20-23%) in tissues from both genotypes. Thus, while CB1 deletion in mice had little influence on the expression of acute toxicity following CPF, CPF- or CPO-induced changes in ACh release appeared sensitive to modulation by CB1-mediated eCB signaling in a brain-regional manner. -- Highlights: Black-Right-Pointing-Pointer C57Bl/6 mice showed dose-related cholinergic toxicity following subcutaneous chlorpyrifos exposure. Black-Right-Pointing-Pointer Wild type and cannabinoid CB1 receptor knockout littermates responded similarly to the toxic effects of chlorpyrifos. Black-Right-Pointing-Pointer OP-induced changes in acetylcholine release appeared sensitive to modulation by CB1-mediated endocannabinoid signaling.« less