Enhanced oral bioavailability of vinpocetine through mechanochemical salt formation: physico-chemical characterization and in vivo studies.

PubMed

Hasa, Dritan; Voinovich, Dario; Perissutti, Beatrice; Grassi, Mario; Bonifacio, Alois; Sergo, Valter; Cepek, Cinzia; Chierotti, Michele R; Gobetto, Roberto; Dall'Acqua, Stefano; Invernizzi, Sergio

2011-08-01

Enhancing oral bioavailability of vinpocetine by forming its amorphous citrate salt through a solvent-free mechanochemical process, in presence of micronised crospovidone and citric acid. The impact of formulation and process variables (amount of polymer and citric acid, and milling time) on vinpocetine solubilization kinetics from the coground was studied through an experimental design. The best performing samples were characterized by employing a multidisciplinary approach, involving Differential scanning calorimetry, X-ray diffraction, Raman imaging/spectroscopy, X-ray photoelectron spectroscopy, solid-state NMR spectroscopy, porosimetry and in vivo studies on rats to ascertain the salt formation, their solid-state characteristics and oral bioavailability in comparison to vinpocetine citrate salt (Oxopocetine(®)). The analyses attested that the mechanochemical process is a viable way to produce in absence of solvents vinpocetine citrate salt in an amorphous state. From the in vivo studies on rats the obtained salt was four times more bioavailable than its physical mixture and bioequivalent to the commercial salt produced by conventional synthetic process implying the use of solvent.

In Vivo Methods for the Assessment of Topical Drug Bioavailability

PubMed Central

Herkenne, Christophe; Alberti, Ingo; Naik, Aarti; Kalia, Yogeshvar N.; Mathy, François-Xavier; Préat, Véronique

2007-01-01

This paper reviews some current methods for the in vivo assessment of local cutaneous bioavailability in humans after topical drug application. After an introduction discussing the importance of local drug bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described. PMID:17985216

Lipopolysaccharide based oral nanocarriers for the improvement of bioavailability and anticancer efficacy of curcumin.

PubMed

Chaurasia, Sundeep; Patel, Ravi R; Chaubey, Pramila; Kumar, Nagendra; Khan, Gayasuddin; Mishra, Brahmeshwar

2015-10-05

Soluthin MD(®), a unique phosphatidylcholine-maltodextrin based hydrophilic lipopolysaccharide, which exhibits superior biocompatibility and bioavailability enhancer properties for poorly water soluble drug(s). Curcumin (CUR) is a potential natural anticancer drug with low bioavailability due to poor aqueous solubility. The study aims at formulation and optimization of CUR loaded lipopolysaccharide nanocarriers (C-LPNCs) to enhance oral bioavailability and anticancer efficacy in colon-26 tumor-bearing mice in vitro and in vivo. The Optimized C-LPNCs demonstrated favorable mean particle size (108 ± 3.4 nm) and percent entrapment efficiency (65.29 ± 1.0%). Pharmacokinetic parameters revealed ∼130-fold increase in oral bioavailability and cytotoxicity studies demonstrated ∼23-fold reduction in 50% cell growth inhibition when treated with optimized C-LPNCs as compared to pure CUR. In vivo anticancer study performed with optimized C-LPNCs showed significant increase in efficacy compared with pure CUR. Thus, lipopolysaccharide nanocarriers show potential delivery strategy to improve oral bioavailability and anticancer efficacy of CUR in the treatment of colorectal cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

21 CFR 320.22 - Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Criteria for waiver of evidence of in vivo bioavailability or bioequivalence. 320.22 Section 320.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... indication in a Drug Efficacy Study Implementation notice or which is identical, related, or similar to such...

21 CFR 320.22 - Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Criteria for waiver of evidence of in vivo bioavailability or bioequivalence. 320.22 Section 320.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... indication in a Drug Efficacy Study Implementation notice or which is identical, related, or similar to such...

21 CFR 320.22 - Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Criteria for waiver of evidence of in vivo bioavailability or bioequivalence. 320.22 Section 320.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... indication in a Drug Efficacy Study Implementation notice or which is identical, related, or similar to such...

21 CFR 320.22 - Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Criteria for waiver of evidence of in vivo bioavailability or bioequivalence. 320.22 Section 320.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... indication in a Drug Efficacy Study Implementation notice or which is identical, related, or similar to such...

21 CFR 320.22 - Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Criteria for waiver of evidence of in vivo bioavailability or bioequivalence. 320.22 Section 320.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... indication in a Drug Efficacy Study Implementation notice or which is identical, related, or similar to such...

Formulation Optimization and Ex Vivo and In Vivo Evaluation of Celecoxib Microemulsion-Based Gel for Transdermal Delivery.

PubMed

Cao, Mengyuan; Ren, Lili; Chen, Guoguang

2017-08-01

Celecoxib (CXB) is a poorly aqueous solubility sulfonamide non-steroidal anti-inflammatory drug (NSAID). Hence, the formulation of CXB was selected for solubilization and bioavailability. To find out suitable formulation for microemulsion, the solubility of CXB in triacetin (oil phase), Tween 80 (surfactant), and Transcutol-P (co-surfactant) was screened respectively and optimized by using orthogonal experimental design. The Km value and concentration of oil, S mix , and water were confirmed by pseudo-ternary phase diagram studies and central composite design. One percent carbopol 934 was added to form CXB microemulsion-based gel. The final formulation was evaluated for its appearance, pH, viscosity, stability, drug content determination, globule size, and zeta potential. Its ex vivo drug permeation and the in vivo pharmacokinetic was investigated. Further research was performed to ensure the safety and validity by skin irritation study and in vivo anti-inflammatory activity study. Ex vivo permeation study in mice was designed to compare permeation and transdermal ability between microemulsion formulation and conventional gel. The results revealed that optimized microemulsion-based gel gained higher permeation based on smaller globule size and high drug loading of microemulsion. Transdermal ability was also greatly improved. Bioavailability was compared to market Celebrex® by the in vivo pharmacokinetic study in rabbits. The results indicated that CXB microemulsion-based gel had better bioavailability than Celebrex®.

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.

Evaluating In Vitro-In Vivo Extrapolation of Toxicokinetics

PubMed Central

MacMillan, Denise K; Ford, Jermaine; Fennell, Timothy R; Black, Sherry R; Snyder, Rodney W; Sipes, Nisha S; Westerhout, Joost; Setzer, R Woodrow; Pearce, Robert G; Simmons, Jane Ellen; Thomas, Russell S

2018-01-01

Abstract Prioritizing the risk posed by thousands of chemicals potentially present in the environment requires exposure, toxicity, and toxicokinetic (TK) data, which are often unavailable. Relatively high throughput, in vitro TK (HTTK) assays and in vitro-to-in vivo extrapolation (IVIVE) methods have been developed to predict TK, but most of the in vivo TK data available to benchmark these methods are from pharmaceuticals. Here we report on new, in vivo rat TK experiments for 26 non-pharmaceutical chemicals with environmental relevance. Both intravenous and oral dosing were used to calculate bioavailability. These chemicals, and an additional 19 chemicals (including some pharmaceuticals) from previously published in vivo rat studies, were systematically analyzed to estimate in vivo TK parameters (e.g., volume of distribution [Vd], elimination rate). For each of the chemicals, rat-specific HTTK data were available and key TK predictions were examined: oral bioavailability, clearance, Vd, and uncertainty. For the non-pharmaceutical chemicals, predictions for bioavailability were not effective. While no pharmaceutical was absorbed at less than 10%, the fraction bioavailable for non-pharmaceutical chemicals was as low as 0.3%. Total clearance was generally more under-estimated for nonpharmaceuticals and Vd methods calibrated to pharmaceuticals may not be appropriate for other chemicals. However, the steady-state, peak, and time-integrated plasma concentrations of nonpharmaceuticals were predicted with reasonable accuracy. The plasma concentration predictions improved when experimental measurements of bioavailability were incorporated. In summary, HTTK and IVIVE methods are adequately robust to be applied to high throughput in vitro toxicity screening data of environmentally relevant chemicals for prioritizing based on human health risks. PMID:29385628

Application of an in vivo swine model for the determination of arsenic bioavailability in contaminated vegetables.

PubMed

Juhasz, Albert L; Smith, Euan; Weber, John; Rees, Matthew; Rofe, Allan; Kuchel, Tim; Sansom, Lloyd; Naidu, Ravi

2008-05-01

Considerable information is available in the literature regarding the uptake of arsenic (As) from contaminated soil and irrigation water by vegetables. However, few studies have investigated As speciation in these crops while a dearth of information is available on As bioavailability following their consumption. In this study, the concentration and speciation of As in chard, radish, lettuce and mung beans was determined following hydroponic growth of the vegetables using As-contaminated water. In addition, As bioavailability was assessed using an in vivo swine feeding assay. While As concentrations ranged from 3.0 to 84.2mg As kg(-1) (dry weight), only inorganic As (arsenite and arsenate) was detected in the edible portions of the vegetables. When As bioavailability was assessed through monitoring blood plasma As concentrations following swine consumption of As-contaminated vegetables, between 50% and 100% of the administered As dose was absorbed and entered systemic circulation. Arsenic bioavailability decreased in the order mung beans>radish>lettuce=chard.

Bioavailability Challenges Associated with Development of Anti-Cancer Phenolics

PubMed Central

Gao, Song; Hu, Ming

2010-01-01

Phenolics including many polyphenols and flavonoids have the potentials to become chemoprevention and chemotherapy agents. However, poor bioavailability limits their biological effects in vivo. This paper reviews the factors that affect phenolics absorption and their bioavailabilities from the points of view of their physicochemical properties and disposition in the gastrointestinal tract. The up-to-date research data suggested that solubility and metabolism are the primary reasons that limit phenolic aglycones’ bioavailability although stability and poor permeation may also contribute to the poor bioavailabilities of the glycosides. Future investigations should further optimize phenolics’ bioavailabilities and realize their chemopreventive and chemotherapeutic effects in vivo. PMID:20370701

Bioaccessibility and bioavailability of phenolic compounds in bread: a review.

PubMed

Angelino, Donato; Cossu, Marta; Marti, Alessandra; Zanoletti, Miriam; Chiavaroli, Laura; Brighenti, Furio; Del Rio, Daniele; Martini, Daniela

2017-07-19

Cereal-based products, like breads, are a vehicle for bioactive compounds, including polyphenols. The health effects of polyphenols like phenolic acids (PAs) are dependent on their bioaccessibility and bioavailability. The present review summarizes the current understanding of potential strategies to improve phenolic bioaccessibility and bioavailability and the main findings of in vitro and in vivo studies investigating these strategies applied to breads, including the use of raw ingredients with greater phenolic content and different pre-processing technologies, such as fermentation and enzymatic treatment of ingredients. There is considerable variability between in vitro studies, mainly resulting from the use of different methodologies, highlighting the need for standardization. Of the few in vivo bioavailability studies identified, acute, single-dose studies demonstrate that modifications to selected raw materials and bioprocessing of bran could increase the bioavailability, but not necessarily the net content, of bread phenolics. The two medium-term identified dietary interventions also demonstrated greater phenolic content, resulting from the modification of the raw materials used. Overall, the findings suggest that several strategies can be used to develop new bread products with greater phenolic bioaccessibility and bioavailability. However, due to the large variability and the few studies available, further investigations are required to determine better the usefulness of these innovative processes.

Effects of ranitidine (antacid), food, and formulation on the pharmacokinetics of fostamatinib: results from five phase I clinical studies.

PubMed

Flanagan, Talia; Martin, Paul; Gillen, Michael; Mathews, David; Lisbon, Eleanor; Kruusmägi, Martin

2017-02-01

Fostamatinib is an orally dosed phosphate prodrug that is cleaved by intestinal alkaline phosphatase to the active metabolite R406. Clinical studies were performed to assess the effect of food and ranitidine on exposure, to support in vitro-in vivo relationships (IVIVR) understanding and formulation transitions and to investigate absolute oral bioavailability. A series of in vitro dissolution and clinical pharmacokinetic studies were performed to support the design and introduction of a new formulation, understand the impact of changes in in vitro dissolution on in vivo performance for two fostamatinib formulations, to characterize the effects of food and ranitidine on exposure, and determine the absolute oral bioavailability. The in vivo performance of fostamatinib was generally insensitive to changes in in vitro dissolution performance, although marked slowing of the dissolution rate did impact exposures. Food and ranitidine had minor effects on R406 exposure that were not considered clinically relevant. The absolute oral bioavailability of fostamatinib was 54.6 %. The absolute oral bioavailability of fostamatinib was ~55 %. Food and ranitidine had minor effects on R406 exposure. An in vitro dissolution versus clinical performance relationship was determined that supported formulation transitions.

Preparation, characterization and in vivo evaluation of curcumin self-nano phospholipid dispersion as an approach to enhance oral bioavailability.

PubMed

Allam, Ahmed N; Komeil, Ibrahim A; Fouda, Mohamed A; Abdallah, Ossama Y

2015-07-15

The aim of this study was to examine the efficacy of self-nano phospholipid dispersions (SNPDs) based on Phosal(®) to improve the oral bioavailability of curcumin (CUR). SNPDs were prepared with Phosal(®) 53 and Miglyol 812 at different surfactant ratio. Formulations were evaluated for particle size, polydispersity index, zeta potential, and robustness toward dilution, TEM as well as in vitro drug release. The in vivo oral absorption of selected formulations in comparison to drug suspension was evaluated in rats. Moreover, formulations were assessed for in vitro characteristic changes before and after storage. The SNPDs were miscible with water in any ratio and did not show any phase separation or drug precipitation. All the formulas were monodisperse with nano range size from 158±2.6 nm to 610±6.24 nm. They passed the pharmacopeial tolerance for CUR dissolution. No change in dissolution profile and physicochemical characteristics was detected after storage. CUR-SNPDs are found to be more bioavailable compared with suspension during an in vivo study in rats and in vitro release studies failed to imitate the in vivo conditions. These formulations might be new alternative carriers that enhance the oral bioavailability of poorly water-soluble molecules, such as CUR. Copyright © 2015 Elsevier B.V. All rights reserved.

21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE... subjects in the fasting or nonfasting state, depending upon the conditions reflected in the proposed...

Scientific perspectives on extending the provision for waivers of in vivo bioavailability and bioequivalence studies for drug products containing high solubility-low permeability drugs (BCS-Class 3).

PubMed

Stavchansky, Salomon

2008-06-01

Recently, there has been increased interest in extending the provision for waivers of in vivo bioavailability and bioequivalence (BA-BE) studies that appeared in the guidance published by the Food and Drug Administration (FDA) (1) to pharmaceutical products containing Class 3 drugs (High solubility-Low Permeability). The extension of the Biopharmaceutics Classification System (BCS) to Class 3 drugs is meritorious because of its impact on public health policy considerations. The rate limiting step in the absorption of Class 3 drugs is the permeability through the intestinal membrane. This commentary will focus its attention on the scientific considerations which need to be examined to assess the risk and the benefit prior to granting a waiver of in vivo bioavailability and/or bioequivalence studies for Class 3 drugs. It will examine the forces affecting the interconnectivity of the neuronal, immunological and hormonal systems in the gastrointestinal tract that may affect its permeability and functionality. It will also challenge the assumption that in vitro dissolution and in vitro permeability studies in tissue cultures in the presence and absence of excipients are good predictors for in vivo dissolution and in vivo permeability which are at the heart of the BCS.

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

Effect of Different Sampling Schedules on Results of Bioavailability and Bioequivalence Studies: Evaluation by Means of Monte Carlo Simulations.

PubMed

Kano, Eunice Kazue; Chiann, Chang; Fukuda, Kazuo; Porta, Valentina

2017-08-01

Bioavailability and bioequivalence study is one of the most frequently performed investigations in clinical trials. Bioequivalence testing is based on the assumption that 2 drug products will be therapeutically equivalent when they are equivalent in the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed and becomes available at the site of drug action. In recent years there has been a significant growth in published papers that use in silico studies based on mathematical simulations to analyze pharmacokinetic and pharmacodynamic properties of drugs, including bioavailability and bioequivalence aspects. The goal of this study is to evaluate the usefulness of in silico studies as a tool in the planning of bioequivalence, bioavailability and other pharmacokinetic assays, e.g., to determine an appropriate sampling schedule. Monte Carlo simulations were used to define adequate blood sampling schedules for a bioequivalence assay comparing 2 different formulations of cefadroxil oral suspensions. In silico bioequivalence studies comparing different formulation of cefadroxil oral suspensions using various sampling schedules were performed using models. An in vivo study was conducted to confirm in silico results. The results of in silico and in vivo bioequivalence studies demonstrated that schedules with fewer sampling times are as efficient as schedules with larger numbers of sampling times in the assessment of bioequivalence, but only if T max is included as a sampling time. It was also concluded that in silico studies are useful tools in the planning of bioequivalence, bioavailability and other pharmacokinetic in vivo assays. © Georg Thieme Verlag KG Stuttgart · New York.

Curcumin-loaded solid lipid nanoparticles with Brij78 and TPGS improved in vivo oral bioavailability and in situ intestinal absorption of curcumin.

PubMed

Ji, Hongyu; Tang, Jingling; Li, Mengting; Ren, Jinmei; Zheng, Nannan; Wu, Linhua

2016-01-01

The present study was to formulate curcumin solid lipid nanoparticles (Cur-SLNs) with P-gp modulator excipients, TPGS and Brij78, to enhance the solubility and bioavailability of curcumin. The formulation was optimized by Plackett-Burman screening design and Box-Behnken experiment design. Then physiochemical properties, entrapment efficiency and in vitro release of Cur-SLNs were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of Cur-SLNs on the bioavailability and intestinal absorption of curcumin. The optimized formulations showed an average size of 135.3 ± 1.5 nm with a zeta potential value of -24.7 ± 2.1 mV and 91.09% ± 1.23% drug entrapment efficiency, meanwhile displayed a sustained release profile. In vivo pharmacokinetic study showed AUC0→t for Cur-SLNs was 12.27-folds greater than curcumin suspension and the relative bioavailability of Cur-SLNs was 942.53%. Meanwhile, Tmax and t(1/2) of curcumin for Cur-SLNs were both delayed comparing to the suspensions (p < 0.01). The in situ intestinal absorption study revealed that the effective permeability (Peff) value of curcumin for SLNs was significantly improved (p < 0.01) comparing to curcumin solution. Cur-SLNs with TPGS and Brij78 could improve the oral bioavailability and intestinal absorption of curcumin effectively.

Effect of piperine on the bioavailability and pharmacokinetics of emodin in rats.

PubMed

Di, Xin; Wang, Xin; Di, Xin; Liu, Youping

2015-11-10

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) has been widely used as a traditional medicine and was shown to possess a multitude of health-promoting properties in pre-clinical studies, but its bioavailability was low due to the extensive glucuronidation in liver and intestine, hindering the development of emodin as a feasible chemopreventive agent. In this study, piperine, as a bioenhancer, was used to enhance the bioavailability of emodin by inhibiting its glucuronidation. The pharmacokinetic profiles of emodin after oral administration of emodin (20mg/kg) alone and in combination with piperine (20mg/kg) to rats were investigated via a validated LC/MS/MS method. As the in vivo pharmacokinetic studies had indicated, the AUC and Cmax of emodin were increased significantly after piperine treatment, and the glucuronidation of emodin was markedly inhibited. Our study demonstrated that piperine significantly improved the in vivo bioavailability of emodin and the influence of piperine on the pharmacokinetics of emodin may be attributed to the inhibition of glucuronidation of emodin. Further research is needed to investigate the detailed mechanism of improved bioavailability of emodin via its combination with piperine. Copyright © 2015 Elsevier B.V. All rights reserved.

21 CFR 320.26 - Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE... test product and the reference material should be administered to subjects in the fasting state, unless...

Assessment of relative bioavailability of heavy metals in soil using in vivo mouse model and its implication for risk assessment compared with bioaccessibility using in vitro assay.

PubMed

Kang, Yuan; Pan, Weijian; Liang, Siyun; Li, Ning; Zeng, Lixuan; Zhang, Qiuyun; Luo, Jiwen

2016-10-01

There is limited study to simultaneously determine the relative bioavailability of heavy metals such as Cd, Pb, Cu, Cr(VI), and Ni in soil samples. In the present study, the bioaccessibility of heavy metals using in vitro assay was compared with the relative bioavailability of heavy metals using in vivo mouse model. The bioaccessibility of heavy metals ranged from 9.05 ± 0.97 % (Cr) to 42.8 ± 3.52 % (Cd). The uptake profile of heavy metals in soil and solution samples in mouse revealed that the uptake kinetics could be fitted to a two-compartment model. The relative bioavailability of heavy meals ranged from 34.8 ± 7.0 % (Ni) to 131 ± 20.3 % (Cu). Poor correlation between bioaccessibility and relative bioavailability of heavy metals was observed (r (2) = 0.11, p > 0.05). The relative bioavailability of heavy metals was significantly higher than the bioaccessibility of heavy metals (p < 0.05). The present study indicated that the in vitro digestion method should be carefully employed in risk assessment.

Improving oral bioavailability of resveratrol by a UDP-glucuronosyltransferase inhibitory excipient-based self-microemulsion.

PubMed

Yang, Fei-Fei; Zhou, Jing; Hu, Xiao; Cong, Zhao-Qing; Liu, Chun-Yu; Pan, Rui-Le; Chang, Qi; Liu, Xin-Min; Liao, Yong-Hong

2018-03-01

Self-microemulsifying (SME) drug delivery system has been developed to increase oral bioavailabilities, and inhibitory excipients are capable of improving oral bioavailability by inhibiting enzyme mediated intestinal metabolism. However, the potential of enzyme inhibitory excipients containing SME in boosting resveratrol bioavailability remains largely uninvestigated. In this study, we set out to prepare SME-1 with UGT inhibitory excipients (excipients without inhibitory activities named SME-2 as control) to increase the bioavailability of RES by inhibiting intestinal metabolism. Results demonstrated that similar physicochemical properties such as size, polydistribution index and in vitro release, cellular uptake and permeability in Caco-2 cells as well as in vivo lymphatic distribution between inhibitory SME-1 and non-inhibitory SME-2 were observed. In vivo study demonstrated that the molar ratios of RES-G/RES were 7.25±0.48 and 5.06±2.42 for free drug and SME-2, respectively, and the molar ratio decreased to 0.36±0.10 in SME-1 group. Pharmacokinetic study confirmed that the inhibitory excipients containing SME demonstrated potential in increasing bioavailability of RES from 6.5% for the free RES and 12.9% for SME-2 to 76.1% in SME-1 through modulating the glucuronidation by UGT inhibitory excipients. Copyright © 2018 Elsevier B.V. All rights reserved.

Bioavailability of indomethacin-saccharin cocrystals.

PubMed

Jung, Min-Sook; Kim, Jeong-Soo; Kim, Min-Soo; Alhalaweh, Amjad; Cho, Wonkyung; Hwang, Sung-Joo; Velaga, Sitaram P

2010-11-01

Pharmaceutical cocrystals are new solid forms with physicochemical properties that appear promising for drug product development. However, the in-vivo bioavailability of cocrystals has rarely been addressed. The cocrystal of indomethacin (IND), a Biopharmaceutical Classification System class II drug, with saccharin (SAC) has been shown to have higher solubility than IND at all pH. In this study, we aimed to evaluate the in-vitro dissolution and in-vivo bioavailability of IND-SAC cocrystals in comparison with IND in a physical mixture and the marketed product Indomee. Scale-up of the cocrystals was undertaken using cooling batch crystallisation without seeding. The chemical and physical purity of the up-scaled material was verified using high-performance liquid chromatography, differential scanning calorimetry and powder X-ray diffraction. The IND-SAC cocrystals and IND plus SAC were mixed with lactose and the formulations were placed into gelatin capsules. In-vitro dissolution studies were then performed using the rotating basket dissolution method. The intrinsic dissolution rate of IND and IND-SAC cocrystals was also determined. Finally, a bioavailability study for the formulations was conducted in beagle dogs. The plasma samples were analysed using high-performance liquid chromatography and the pharmacokinetic data were analysed using standard methodologies.   The bulk cocrystals (i.e. scaled-up material) were chemically and physically pure. The in-vitro dissolution rate of the cocrystals was higher than that of IND and similar to that of Indomee at pH 7.4 and pH 1.2. The in-vivo bioavailability of the IND-SAC cocrystals in dogs was significantly higher (ANOVA, P<0.05) than that of IND but not significantly different from Indomee (ANOVA, P>0.05). The study indicates that the improved aqueous solubility of the cocrystals leads to improved bioavailability of IND. Thus, the cocrystals are a viable alternative solid form that can improve the dissolution rate and bioavailability of poorly soluble drugs. © 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society of Great Britain.

In vitro and in vivo evaluation of capsaicin-loaded microemulsion for enhanced oral bioavailability.

PubMed

Zhu, Yuan; Zhang, Jiajia; Zheng, Qianfeng; Wang, Miaomiao; Deng, Wenwen; Li, Qiang; Firempong, Caleb Kesse; Wang, Shengli; Tong, Shanshan; Xu, Ximing; Yu, Jiangnan

2015-10-01

Capsaicin, as a food additive, has attracted worldwide concern owing to its pungency and multiple pharmacological effects. However, poor water solubility and low bioavailability have limited its application. This study aims to develop a capsaicin-loaded microemulsion to enhance the oral bioavailability of the anti-neuropathic-pain component, capsaicin, which is poorly water soluble. In this study, the microemulsion consisting of Cremophor EL, ethanol, medium-chain triglycerides (oil phase) and water (external phase) was prepared and characterized (particle size, morphology, stability and encapsulation efficiency). The gastric mucosa irritation test of formulated capsaicin was performed in rats to evaluate its oral feasibility, followed by the pharmacokinetic study in vivo. Under these conditions, the encapsulated capsaicin revealed a faster capsaicin release in vitro coupled with a greater absorption in vivo when compared to the free capsaicin. The oral bioavailability of the formulated capsaicin-loaded microemulsions was 2.64-fold faster than that of free capsaicin. No significant irritation was observed on the mucosa from the pathological section of capsaicin-loaded microemulsion treated stomach. These results indicate that the developed microemulsion represents a safe and orally effective carrier for poorly soluble substances. The formulation could be used for clinical trials and expand the application of capsaicin. © 2014 Society of Chemical Industry.

Bioavailability enhancement of curcumin by complexation with phosphatidyl choline.

PubMed

Gupta, Nishant Kumar; Dixit, Vinod Kumar

2011-05-01

Curcumin is a major constituent of rhizomes of Curcuma longa. Pharmacokinetic studies of curcumin reveal its poor absorption through intestine. Objective of the present study was to enhance bioavailability of curcumin by its complexation with phosphatidyl choline (PC). Complex of curcumin was prepared with PC and characterized on the basis of solubility, melting point, differential scanning calorimetry, thin layer chromatography, and infrared spectroscopic analysis. Everted intestine sac technique was used to study ex vivo drug absorption of curcumin-PC (CU-PC) complex and plain curcumin. Pharmacokinetic studies were performed in rats, and hepatoprotective activity of CU-PC complex was also compared with curcumin and CU-PC physical mixture in isolated rat hepatocytes. Analytical reports along with spectroscopic data revealed the formation of complex. The results of ex vivo study show that CU-PC complex has significantly increased absorption compared with curcumin, when given in equimolar doses. Complex showed enhanced bioavailability, improved pharmacokinetics, and increased hepatoprotective activity as compared with curcumin or CU-PC physical mixture. Enhanced bioavailability of CU-PC complex may be due to the amphiphilic nature of the complex, which greatly enhance the water and lipid solubility of the curcumin. The present study clearly indicates the superiority of complex over curcumin, in terms of better absorption, enhanced bioavailability, and improved pharmacokinetics. Copyright © 2010 Wiley-Liss, Inc.

Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer

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

Burks, Heather E.; Abrams, Tinya; Kirby, Christina A.

Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.

Loading amorphous Asarone in mesoporous silica SBA-15 through supercritical carbon dioxide technology to enhance dissolution and bioavailability.

PubMed

Zhang, Zhengzan; Quan, Guilan; Wu, Qiaoli; Zhou, Chan; Li, Feng; Bai, Xuequn; Li, Ge; Pan, Xin; Wu, Chuanbin

2015-05-01

The aim of this study was to load amorphous hydrophobic drug into ordered mesoporous silica (SBA-15) by supercritical carbon dioxide technology in order to improve the dissolution and bioavailability of the drug. Asarone was selected as a model drug due to its lipophilic character and poor bioavailability. In vitro dissolution and in vivo bioavailability of the obtained Asarone-SBA-15 were significantly improved as compared to the micronized crystalline drug. This study offers an effective, safe, and environmentally benign means of solving the problems relating to the solubility and bioavailability of hydrophobic molecules. Copyright © 2015 Elsevier B.V. All rights reserved.

Dry Gel Containing Optimized Felodipine-Loaded Transferosomes: a Promising Transdermal Delivery System to Enhance Drug Bioavailability.

PubMed

Kassem, Mohammed Ali; Aboul-Einien, Mona Hassan; El Taweel, Mai Magdy

2018-04-30

Felodipine has a very low bioavailability due to first-pass metabolism. The aim of this study was to enhance its bioavailability by transdermal application. Felodipine-loaded transferosomes were prepared by thin-film hydration using different formulation variables. An optimized formula was designed using statistical experimental design. The independent variables were the used edge activator, its molar ratio to phosphatidylcholine, and presence or absence of cholesterol. The responses were entrapment efficiency of transferosomes, their size, polydispersity index, zeta potential, and percent drug released after 8 h. The optimized formula was subjected to differential scanning calorimetry studies and its stability on storage at 4°C for 6 months was estimated. This formula was improved by incorporation of different permeation enhancers where ex vivo drug flux through mice skin was estimated and the best improved formula was formulated in a gel and lyophilized. The prepared gel was subjected to in vivo study using Plendil® tablets as a reference. According to the calculated desirability, the optimized transferosome formula was that containing sodium deoxycholate as edge activator at 5:1 M ratio to phosphatidylcholine and no cholesterol. The thermograms of this formula indicated the incorporation of felodipine inside the prepared vesicles. None of the tested parameters differed significantly on storage. The lyophilized gel of labrasol-containing formula was chosen for in vivo study. The relative bioavailability of felodipine from the designed gel was 1.7. In conclusion, topically applied lyophilized gel containing felodipine-loaded transferosomes is a promising transdermal delivery system to enhance its bioavailability.

Enhanced oral bioavailability and sustained delivery of glimepiride via niosomal encapsulation: in-vitro characterization and in-vivo evaluation.

PubMed

Mohsen, Amira Mohamed; AbouSamra, Mona Mahmoud; ElShebiney, Shaimaa Ahmed

2017-08-01

This study was designed to investigate the potency of niosomes, for glimepiride (GLM) encapsulation, aiming at enhancing its oral bioavailability and hypoglycemic efficacy. Niosomes containing nonionic surfactants (NIS) were prepared by thin film hydration technique and characterized. In-vitro release study was performed using a dialysis technique. In-vivo pharmacodynamic studies, as well as pharmacokinetic evaluation were performed on alloxan-induced diabetic rats. GLM niosomes exhibited high-entrapment efficiency percentages (E.E. %) up to 98.70% and a particle size diameter ranging from 186.8 ± 18.69 to 797.7 ± 12.45 nm, with negatively charged zeta potential (ZP). Different GLM niosomal formulation showed retarded in vitro release, compared to free drug. In-vivo studies revealed the superiority of GLM niosomes in lowering blood glucose level (BGL) and in maintaining a therapeutic level of GLM for a longer period of time, as compared to free drug and market product. There was no significant difference between mean plasma AUC 0-48 hr of GLM-loaded niosomes and that of market product. GLM-loaded niosomes exhibited seven-fold enhancement in relative bioavailability in comparison with free drug. These findings reinforce the potential use of niosomes for enhancing the oral bioavailability and prolonged delivery of GLM via oral administration.

Predicting oral relative bioavailability of arsenic in soil from in vitro bioaccessibility

EPA Science Inventory

Several investigations have been conducted to develop in vitro bioaccessibility (IVBA) assays that reliably predict in vivo oral relative bioavailability (RBA) of arsenic (As). This study describes a meta-regression model relating soil As RBA and IVBA that is based upon data comb...

Improvement of Oral Bioavailability of Lopinavir Without Co-administration of Ritonavir Using Microspheres of Thiolated Xyloglucan.

PubMed

Madgulkar, Ashwini R; Bhalekar, Mangesh R; Kadam, Ashwini A

2018-01-01

Lopinavir is a BCS Class IV drug exhibiting poor bioavailability due to P-gp efflux and limited permeation. The aim of this research was to formulate and characterize microspheres of lopinavir using thiolated xyloglucan (TH-MPs) as carrier to improve its oral bioavailability without co-administration of ritonavir. Thiomeric microspheres were prepared by ionotropic gelation between alginic acid and calcium ions. Interaction studies were performed using Fourier transform infrared spectroscopy (FT-IR). The thiomeric microspheres were characterized for its entrapment efficiency, T 80 , surface morphology, and mucoadhesion employing in vitro wash off test. The microspheres were optimized by 3 2 factorial design. The optimized thiomeric microsphere formulation revealed 93.12% entrapment efficiency, time for 80% drug release (T 80 ) of 358.1 min, and 88% mucoadhesion after 1 h. The permeation of lopinavir from microspheres was enhanced 3.15 times as determined by ex vivo study using everted chick intestine and increased relative bioavailability over 3.22-fold over combination of lopinavir and ritonavir as determined by in vivo study in rat model.

Enhancement of Curcumin Bioavailability by Encapsulation in Sophorolipid-Coated Nanoparticles: An in Vitro and in Vivo Study.

PubMed

Peng, Shengfeng; Li, Ziling; Zou, Liqiang; Liu, Wei; Liu, Chengmei; McClements, David Julian

2018-02-14

There is great interest in developing colloidal delivery systems to enhance the water solubility and oral bioavailability of curcumin, which is a hydrophobic nutraceutical claimed to have several health benefits. In this study, a natural emulsifier was used to form sophorolipid-coated curcumin nanoparticles. The curcumin was loaded into sophorolipid micelles using a pH-driven mechanism based on the decrease in curcumin solubility at lower pH values. The sophorolipid-coated curcumin nanoparticles formed using this mechanism were relatively small (61 nm) and negatively charged (-41 mV). The nanoparticles also had a relatively high encapsulation efficiency (82%) and loading capacity (14%) for curcumin, which was present in an amorphous state. Both in vitro and in vivo studies showed that the curcumin nanoparticles had an appreciably higher bioavailability than that of free curcumin crystals (2.7-3.6-fold), which was mainly attributed to their higher bioaccessibility. These results may facilitate the development of natural colloidal systems that enhance the oral bioavailability and bioactivity of curcumin in food, dietary supplements, and pharmaceutical products.

SOIL REDUCES 2,4,6-TRINITROTOLUENE BIOAVAILABILITY AND GENOTOXICITY IN VIVO

EPA Science Inventory

Soil Reduces 2,4,6- Trinitrotoluene Bioavailability and Genotoxicity In Vivo

As chemicals age in soil, irreversible binding of chemical contaminants to organic components in the soil may occur, impacting the amount of chemical that is biologically available upon exp...

Effects of oils and pharmaceutical excipients on the bioavailability of ampicillin orally administered, different oily and aqueous suspensions in rabbit.

PubMed

Alhamami, Omran M O

2003-01-01

The in vivo bioavailability and in vitro drug-release studies of ampicillin trihydrate in different oily and aqueous suspensions have been investigated. In addition, partition, solubility, and rheological measurements have also been carried out. The in vivo experimental design was based on a 6 x 6 latin square using the rabbit as the test animal. The bioavailability of ampicillin was determined using the plasma levels, which were measured microbiologically. Results of the study showed that oily and sucrose-containing aqueous formulations enhanced the extent of ampicillin absorption, although not statistically significantly, but was close to the borderline of significance. Ampicillin appears to be absorbed at essentially the same rate from both aqueous and oily formulations. The latter showed plasma-level time curves with biphasic absorption and are likely to produce prolonged plasma concentrations of ampicillin because of the effects of enterohepatic recycling. Viscosity appears to play an insignificant role in the results obtained since the bioavailability parameters correlate poorly with the viscosity except Cmax. It is suggested that enhancement in the bioavailability of ampicillin is due to the decrease in the gut transit rate brought about by the oil which predominates and masks the other effects of viscosity and osmotic effects of sucrose. The existence of a correlation between the in vitro drug-release rate (t50%) and viscosity and the lack of a correlation between in vivo and in vitro parameters support the above suggestion and indicate that traditional dissolution rate tests, such as flask-stirrer method, are unsatisfactory as bioavailability indicators when applied to dosage forms that caused marked changes in physiological factors like GER and biliary excretion.

Modification of an Existing In vitro Method to Predict Relative Bioavailable Arsenic in Soils

EPA Science Inventory

The soil matrix can sequester arsenic (As) and reduces its exposure by soil ingestion. In vivo dosing studies and in vitro gastrointestinal (IVG) methods have been used to predict relative bioavailable (RBA) As. Originally, the Ohio State University (OSU-IVG) method predicted R...

The use of caco-2 cells in defining nutrient bioavailability: application to iron bioavailability of foods

USDA-ARS?s Scientific Manuscript database

In vitro models can be a useful and productive approach in many if not all of the life sciences. Furthermore, coupling in vitro studies with in vivo testing can be even more productive as in vitro studies are by nature less expensive, rapid, and often allow greater manipulation and simplification ...

In vivo efficacy and bioavailability of lumefantrine: Evaluating the application of Pheroid technology.

PubMed

du Plessis, Lissinda H; Govender, Katya; Denti, Paolo; Wiesner, Lubbe

2015-11-01

The oral absorption of compounds with low aqueous solubility, such as lumefantrine, is typically limited by the dissolution rate in the gastro-intestinal tract, resulting in erratic absorption and highly variable bioavailability. In previous studies we reported on the ability of Pheroid vesicles to improve the bioavailability of poorly soluble drugs. In the present study a Pro-Pheroid formulation, a modification of the previous formulation, was applied to improve the solubility of lumefantrine after oral administration and compared to lumefantrine in DMSO:water (1:9 v/v) solution (reference solution). A bioavailability study of lumefantrine was conducted in a mouse model in fed and fasted states. When using the reference solution, the bioavailability of the lumefantrine heavily depended on food intake, resulting in a 2.7 times higher bioavailability in the fed state when compared to the fasted state. It also showed large between-subject variability. When formulated using Pro-Pheroid, the bioavailability of lumefantrine was 3.5 times higher as compared to lumefantrine in the reference solution and fasting state. Pro-Pheroid also dramatically reduced the effects of food intake and the between-subject variability for bioavailability observed with the reference. In vivo antimalarial efficacy was also evaluated with lumefantrine formulated using Pro-Pheroid technology compared to the reference solution. The results indicated that lumefantrine in Pro-Pheroid formulation exhibited improved antimalarial activity in vitro by 46.8%, when compared to the reference. The results of the Peters' 4-day suppressive test indicated no significant difference in the efficacy or mean survival time of the mice in the Pro-Pheroid formulation and reference test groups when compared to the positive control, chloroquine. These findings suggest that using the Pro-Pheroid formulation improves the bioavailability of lumefantrine, eliminates the food effect associated with lumefantrine as well as significantly reduces the between subject variability in bioavailability when compared to the reference solution. Copyright © 2015 Elsevier B.V. All rights reserved.

Provesicular granisetron hydrochloride buccal formulations: in vitro evaluation and preliminary investigation of in vivo performance.

PubMed

Ahmed, Sami; El-Setouhy, Doaa Ahmed; El-Latif Badawi, Alia Abd; El-Nabarawi, Mohamed Ahmed

2014-08-18

Granisetron hydrochloride (granisetron) is a potent antiemetic that has been proven to be effective in acute and delayed emesis in cancer chemotherapy. Granisetron suffers from reduced oral bioavailability (≈60%) due to hepatic metabolism. In this study the combined advantage of provesicular carriers and buccal drug delivery has been explored aiming to sustain effect and improve bioavailability of granisetron via development of granisetron provesicular buccoadhesive tablets with suitable quality characteristics (hardness, drug content, in vitro release pattern, exvivo bioadhesion and in vivo bioadhesion behavior). Composition of the reconstituted niosomes from different prepared provesicular carriers regarding type of surfactant used and cholesterol concentration significantly affected both entrapment efficiency (%EE) and vesicle size. Span 80 proniosome-derived niosomes exhibited higher encapsulation efficiency and smaller particle size than those derived from span 20. Also, the effect of %EE and bioadhesive polymer type on in vitro drug release and in vivo performance of buccoadhesive tablets was investigated. Based on achievement of required in vitro release pattern (20-30% at 2h, 40-65% at 6h and 80-95% at 12h), in vivo swelling behavior, and in vivo adhesion time (>14 h) granisetron formulation (F19, 1.4 mg) comprising HPMC:carbopol 974P (7:3) and maltodextrin coated with the vesicular precursors span 80 and cholesterol (9:1) was chosen for in vivo study. In vivo pharmacokinetic study revealed higher bioavailability of buccal formulation relative to conventional oral formulation of granisetron (AUC0-∞ is 89.97 and 38.18 ng h/ml for buccal and oral formulation, respectively). A significantly lower and delayed Cmax (12.09±4.47 ng/ml, at 8h) was observed after buccal application compared to conventional oral tablet (31.66±10.15 ng/ml, at 0.5 h). The prepared provesicular buccoadhesive tablet of granisetron (F19) might help bypass hepatic first-pass metabolism and improve bioavailability of granisetron with the possibility of reducing reported daily dose (2mg) and reducing dosing frequency. Copyright © 2014 Elsevier B.V. All rights reserved.

21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

Code of Federal Regulations, 2014 CFR

2014-04-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE... therapeutic moiety in the body. (2) The test product and the reference material should be administered to...) Measurement of an acute pharmacological effect. When comparison of the test product and the reference material...

21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

Code of Federal Regulations, 2012 CFR

2012-04-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE... therapeutic moiety in the body. (2) The test product and the reference material should be administered to...) Measurement of an acute pharmacological effect. When comparison of the test product and the reference material...

21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

Code of Federal Regulations, 2013 CFR

2013-04-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE... therapeutic moiety in the body. (2) The test product and the reference material should be administered to...) Measurement of an acute pharmacological effect. When comparison of the test product and the reference material...

Niosomes consisting of tween-60 and cholesterol improve the chemical stability and bioavailability of (-)-epigallocatechin gallate during gastrointestinal tract

USDA-ARS?s Scientific Manuscript database

(-)-Epigallocatechin gallate (EGCG), the major polyphenol in green tea, has been shown to protect against chronic diseases. The mechanisms have been attributed to interactions with cell signaling pathways and its antioxidant properties. In vivo studies are difficult because of its limited bioavail...

Statistical modeling, optimization and characterization of solid self-nanoemulsifying drug delivery system of lopinavir using design of experiment.

PubMed

Patel, Grishma; Shelat, Pragna; Lalwani, Anita

2016-10-01

Lopinavir (LPV), an antiretroviral protease inhibitor shows poor bioavailability because of poor aqueous solubility and extensive hepatic first-pass metabolism. The aim of the present work was to investigate the potential of the solid self-nanoemulsifying drug delivery system (S-SNEDDS) in improving dissolution rate and oral bioavailability of LPV. Liquid SNEDDS (L-SNEDDS) of LPV were prepared using Capmul MCM C8, Cremophor RH 40 and propylene glycol and their amounts were optimized by Scheffe's mixture design. L-SNEDDS formulations were evaluated for different physicochemical and in vitro drug release parameters. S-SNEDDS were prepared by adsorbing L-SNEDDS on Neusilin US2 and characterized for solid-state properties. In vivo bioavailability of S-SNEDDS, marketed Lopinavir + Ritonavir (LPV/RTV) formulation and pure LPV was studied in Wistar rats. Stability study of S-SNEDDS was performed as per ICH guidelines. Optimized L-SNEDDS obtained by Scheffe design had drug loading 160 ± 1.15 mg, globule size 32.9 ± 1.45 nm and drug release >95% within 15 min. Solid state studies suggested the transformation of the crystalline drug to amorphous drug. The size and zeta potential of globules obtained on dilution S-SNEDDS remained similar to L-SNEEDS. In vivo bioavailability study revealed that S-SNEDDS has 2.97 and 1.54-folds higher bioavailability than pure LPV and LPV/RTV formulation, respectively. The optimized S-SNEDDS was found to be stable and had a shelf life of 2.85 years. The significant increase in drug dissolution and bioavailability by prepared SNEDDS suggest that the developed S-SNEDDS is a useful solid platform for improving oral bioavailability of poorly soluble LPV.

Oral heparin delivery: design and in vivo evaluation of a stomach-targeted mucoadhesive delivery system.

PubMed

Schmitz, Thierry; Leitner, Verena M; Bernkop-Schnürch, Andreas

2005-05-01

Low molecular weight heparin (LMWH) is an agent of choice in the anti-coagulant therapy and prophylaxis of thrombosis and coronary syndromes. However, the therapeutic use is partially limited due to a poor oral bioavailability. It was therefore the aim of this study to design and evaluate a highly efficient stomach-targeted oral delivery system for LMWH. In order to appraise the influence of the molecular weight on the oral bioavailability, mini-tablets comprising 3 kDa (279 IU) and 6 kDa (300 IU) LMWH, respectively, were generated and tested in vivo in rats. The potential of the test formulations based on thiolated polycarbophil, was evaluated in comparison to hydroxyethylcellulose (HEC) as control carrier matrix. The plasma levels of LMWH after oral versus subcutaneous administration were determined in order to calculate the relative bioavailability. With the delivery system containing 3 kDa LMWH (279 IU) a relative bioavailability of 19.1% was achieved, offering a significantly (p < 0.05) better bioavailability than the control system displaying a relative bioavailability of 8.1% The 6 kDa LMWH (300 IU) formulation displayed a relative bioavailability of 10.7% in contrast to the control displaying a relative bioavailability of 2.1%. In conclusion, these results suggest that mucoadhesive thiolated polymers are a promising tool for the non-invasive stomach-targeted systemic delivery of LMWH as model for a hydrophilic macromolecular polysaccharide. Copyright 2005 Wiley-Liss, Inc

Development and in vitro-in vivo evaluation of a water-in-oil microemulsion formulation for the oral delivery of troxerutin.

PubMed

Xu, Man; Yu, Qing; Zhao, Qianru; Chen, Wei; Lin, Yuanjie; Jin, Yong

2016-01-01

The main objective of this study was to develop and evaluate a W/O microemulsion formulation of troxerutin to improve its oral bioavailability. The W/O microemulsion was optimized using a pseudo-ternary phase diagram and evaluated for physical properties. In vitro MDCK cell permeability studies were carried out to evaluate the permeability enhancement effect of microemulsion, and in vivo absorption of troxerutin microemulsion in the intestine was compared with that of solution after single-dose administration (56.7 mg/kg) in male Wistar rats. The optimal formulation consisted of lecithin, ethanol, isopropyl myristate and water (23.30/11.67/52.45/12.59 w/w) was physicochemical stable and the mean droplet size was about 50.20 nm. In vitro study, the troxerutin-loaded microemulsion showed higher intestinal membrane permeability across MDCK monolayer when compared with the control solution. The W/O microemulsion can significantly promote the intestinal absorption of troxerutin in rats in vivo, and the relative bioavailability of the microemulsion was about 205.55% compared to control solution. These results suggest that novel W/O microemulsion could be used as an effective formulation for improving the oral bioavailability of troxerutin.

Formulation of a danazol cocrystal with controlled supersaturation plays an essential role in improving bioavailability.

PubMed

Childs, Scott L; Kandi, Praveen; Lingireddy, Sreenivas Reddy

2013-08-05

Cocrystals have become an established and adopted approach for creating crystalline solids with improved physical properties, but incorporating cocrystals into enabling pre-clinical formulations suitable for animal dosing has received limited attention. The dominant approach to in vivo evaluation of cocrystals has focused on deliberately excluding additional formulation in favor of "neat" aqueous suspensions of cocrystals or loading neat cocrystal material into capsules. However, this study demonstrates that, in order to take advantage of the improved solubility of a 1:1 danazol:vanillin cocrystal, a suitable formulation was required. The neat aqueous suspension of the danazol:vanillin cocrystal had a modest in vivo improvement of 1.7 times higher area under the curve compared to the poorly soluble crystal form of danazol dosed under identical conditions, but the formulated aqueous suspension containing 1% vitamin E-TPGS (TPGS) and 2% Klucel LF Pharm hydroxypropylcellulose improved the bioavailability of the cocrystal by over 10 times compared to the poorly soluble danazol polymorph. In vitro powder dissolution data obtained under non-sink biorelevant conditions correlate with in vivo data in rats following 20 mg/kg doses of danazol. In the case of the danazol:vanillin cocrystal, using a combination of cocrystal, solubilizer, and precipitation inhibitor in a designed supersaturating drug delivery system resulted in a dramatic improvement in the bioavailability. When suspensions of neat cocrystal material fail to return the anticipated bioavailability increase, a supersaturating formulation may be able to create the conditions required for the increased cocrystal solubility to be translated into improved in vivo absorption at levels competitive with existing formulation approaches used to overcome solubility limited bioavailability.

Enhanced dissolution and bioavailability of Nateglinide by microenvironmental pH-regulated ternary solid dispersion: in-vitro and in-vivo evaluation.

PubMed

Wairkar, Sarika; Gaud, Ram; Jadhav, Namdeo

2017-09-01

Nateglinide, an Antidiabetic drug (BCS II), shows pH-dependent solubility and variable bioavailability. The purpose of study was to increase dissolution and bioavailability of Nateglinide by development of its microenvironmental pH-regulated ternary solid dispersion (MeSD). MeSD formulation of Nateglinide, poloxamer-188 and Na 2 CO 3 was prepared by melt dispersion in 1 : 2 : 0.2 w/w ratio and further characterised for solubility, In-vitro dissolution, microenvironmental pH, crystallinity/amorphism, physicochemical interactions, bioavailability in Wistar rats. Solubility of Nateglinide was increased notably in MeSD, and its in-vitro dissolution study showed fourfold increase in the dissolution, particularly in 1.2 pH buffer. Prominent reduction in the peak intensity of X-ray powder diffraction (XRPD) and absence of endotherm in DSC thermogram confirmed the amorphism of Nateglinide in MeSD. Attenuated total reflectance Fourier transform infrared spectra revealed the hydrogen bond interactions between Nateglinide and poloxamer-188. In-vivo study indicated that MeSD exhibited fourfold increase in area under curve over Nateglinide. Tmax of MeSD was observed at 0.25 h, which is beneficial for efficient management of postprandial sugar. Instead of mere transformation of the Nateglinide to its amorphous form as evidenced by DSC and XRPD, formation of a soluble carboxylate compound of Nateglinide in MeSD was predominantly responsible for dissolution and bioavailability enhancement. The study demonstrates the utility of MeSD in achieving pH-independent dissolution, reduced T max and enhanced bioavailability of Nateglinide. © 2017 Royal Pharmaceutical Society.

Bioavailability Of Arsenic In Arsenical Pesticide-Amended Soils: Preliminary Greenhouse Study

NASA Astrophysics Data System (ADS)

Quazi, S.; Sarkar, D.; Khairom, A.; Datta, R.; Sharma, S.

2005-05-01

Long-term application of arsenical pesticides in agricultural lands has resulted in high levels of arsenic (As). Conversion of former agricultural lands to residential areas has resulted in increased human contact with soil As. Soil ingestion from incidental hand-to-mouth activity by children is now a very important issue in assessing human health risk associated with exposure to arsenical pesticide-applied former agricultural soils. Human health risk from direct exposure to soil As via hand to mouth action is restricted only to those fractions of As in the soil that are available to the human gastrointestinal system. Thus this study aimed at addressing the issue of soil variability on As bioavailability as a function of soil physiochemical properties in a dynamic interaction between soils, water and plants and pesticides. In the current greenhouse study two soils with drastically different chemical characteristics w.r.t As reactivity (Immokalee-low As retention potential and Millhopper-high As retention potential) and one pesticide (sodium arsenate) were used. Soils were amended with sodium arsenate at two rates representing the high and low ends of As contamination, generally representative of Superfunds site conditions: 675 and 1500 mg/kg As. Rice (Oryza sativa) was used as the test crop. Sequential digestion to estimate in-vitro As in the stomach phase and the intestinal phase was employed on soils sampled at 4 times: 0-time, after 3 mo, 6 mo and 9 mo of soil-pesticide equilibration. In-vitro bioavailability experiments were also performed with the same soils in order to obtain an estimate of the amount of As that would be absorbed to the intestinal linings in simulated systems. Following the greenhouse study, selective in-vivo bioavailability studies using As-contaminated soils will be conducted on male and female mice to correlate in-vitro results with the in-vivo data. Treatments will consist of a soil group (As in soil), a positive control group (only As) and a negative control group (no soil, no As). Results from the in-vitro and in-vivo studies will help understand the effects of soil properties on As bioavailability. Keywords: Bioavailability, pesticide, soil, arsenic, greenhouse.

Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.

PubMed

Kou, Dawen; Dwaraknath, Sudharsan; Fischer, Yannick; Nguyen, Daniel; Kim, Myeonghui; Yiu, Hiuwing; Patel, Preeti; Ng, Tania; Mao, Chen; Durk, Matthew; Chinn, Leslie; Winter, Helen; Wigman, Larry; Yehl, Peter

2017-10-02

In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

In vitro and in vivo evaluation of curcumin loaded lauroyl sulphated chitosan for enhancing oral bioavailability.

PubMed

Shelma, R; Sharma, Chandra P

2013-06-05

Curcumin has been demonstrated as a potent anticancer agent but its clinical application has been limited by its poor aqueous solubility and bioavailability. Here we describe encapsulation of curcumin in the lauroyl sulphated chitosan with a view to improve its bioavailability. In vitro antioxidant activity of extract of curcumin loaded matrix was investigated and exhibited dose dependent radical scavenging and reducing activity. Cytotoxicity studies carried out with curcumin loaded carrier on C6 cell line and were found to be toxic. Its in vitro effects on proliferation using the C6 cell lines also studied and observed antiproliferation of C6 cell line. Plasma concentration of curcumin-time profiles from pharmacokinetic studies in rats after oral administration showed a 11.5-fold increased pharmacological availability of curcumin with encapsulated curcumin compared with native curcumin. Overall we demonstrate that the curcumin loaded matrix has shown a superior pharmacological availability in vivo over curcumin. Copyright © 2013 Elsevier Ltd. All rights reserved.

Nanostructured lipid carriers as novel ophthalmic delivery system for mangiferin: improving in vivo ocular bioavailability.

PubMed

Liu, Rui; Liu, Zhidong; Zhang, Chengui; Zhang, Boli

2012-10-01

The aim of this study was to develop a novel nanostructured lipid carriers (NLCs) system to improve ocular bioavailability of mangiferin (MGN) for the potential treatment of cataract. The physicochemical properties of MGN-loaded NLC (MGN-NLC) formulation were characterized by particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading, morphological property, and crystalline state. in vitro characteristics were investigated by drug release from NLC system, physical stability, and corneal permeation through excised rabbit cornea. Moreover, in vivo ocular tolerability was assessed by a modified Draize test and histological microscopy. Preocular retention capability was evaluated by slit-lamp observation. Pharmacokinetic study in the aqueous humor was performed by microdialysis technique. Transmission electron microscopy depicted spherical and uniform morphology. Differential scanning calorimetry and X-ray diffractometry displayed imperfect crystalline lattice. The optimized MGN-NLC formulation exhibited a sustained drug release with 3 months stability and 4.31-fold increase of in vitro corneal permeation. Furthermore, in vivo studies exhibited a high tolerance in the ocular tissues and prolonged drug retention capacity on the corneal surface. Finally, pharmacokinetic study suggested a 5.69-fold increase of ocular bioavailability compared with MGN solution (MGN-SOL). Therefore, NLC system is a promising approach for ocular delivery of MGN. Copyright © 2012 Wiley Periodicals, Inc.

Iron bioavailability in corn-masa tortillas is improved by the addition of disodium EDTA.

PubMed

Walter, Tomás; Pizarro, Fernando; Olivares, Manuel

2003-10-01

Corn-masa flour flat bread tortillas are the main staple of Mexican and Central American populations. Due to high concentrations of inhibitors of iron absorption, the bioavailability from this matrix is unknown. We wanted to determine the most suitable fortificant that would efficaciously improve iron bioavailability. In tortillas prepared with commercial precooked, lime-treated, corn-masa flour, we examined the in vitro solubility of the following forms of iron: native iron with and without Na2EDTA, elemental reduced iron plus Na2EDTA, ferrous fumarate with and without Na2EDTA, bisglycine iron, ferrous sulfate and NaFeEDTA. We also examined the in vivo bioavailability in humans with double radioiron erythrocyte incorporation of ferrous fumarate with and without Na2EDTA, bisglycine iron, NaFeEDTA and native iron plus Na2EDTA, beans and rice. In vitro, solubility ranged from 1% in iron forms without Na2EDTA to 19.4% for NaFeEDTA. Forms of iron with Na2EDTA had intermediate values. In vivo radioiron studies showed that iron forms without Na2EDTA also had low bioavailability (< or =1%). NaFeEDTA had the highest bioavailability (5.3%). The bioavailability of all iron forms improved significantly when tested with Na2EDTA (<0.05). Adding Na2EDTA to ferrous fumarate increased bioavailability from 0.87% to 2.9% (P < 0.001). We conclude that NaFeEDTA is the form of iron best absorbed, but alternatively, ferrous fumarate plus Na2EDTA comprises a feasible option as a fortificant.

Oral bioavailability enhancement of β-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion.

PubMed

Liu, Chengyu; Liu, Zhengsheng; Chen, Yuejie; Chen, Zhen; Chen, Huijun; Pui, Yipshu; Qian, Feng

2018-03-01

The aim of this paper was to compare the in vitro dissolution and in vivo bioavailability of three solubility enhancement technologies for β-lapachone (LPC), a poorly water soluble compound with extremely high crystallization propensity. LPC cocrystal was prepared by co-grinding LPC with resorcinol. LPC crystalline and amorphous solid dispersions (CSD and ASD) were obtained by spray drying with Poloxamer 188 and HPMC-AS, respectively. The cocrystal structure was solved by single crystal x-ray diffraction. All formulations were characterized by WAXRD, DSC, POM and SEM. USP II and intrinsic dissolution studies were used to compare the in vitro dissolution of these formulations, and a crossover dog pharmacokinetic study was used to compare their in vivo bioavailability. An 1:1 LPC-resorcinol cocrystal with higher solubility and faster dissolution rate was obtained, yet it converted to LPC crystal rapidly in solution. LPC/HPMC-AS ASD was confirmed to be amorphous and uniform, while the crystal and crystallite sizes of LPC in CSD were found to be ∼1-3 μm and around 40 nm, respectively. These formulations performed similarly during USP II dissolution, while demonstrated dramatically different oral bioavailability of ∼32%, ∼5%, and ∼1% in dogs, for CSD, co-crystal, and ASD, respectively. CSD showed the fastest intrinsic dissolution rate among the three. The three formulations showed poor IVIVC which could be due to rapid and unpredictable crystallization kinetics. Considering all the reasons, we conclude that for molecules with extremely high crystallization tendency that cannot be inhibited by any pharmaceutical excipients, size-reduction technologies such as CSD could be advantageous for oral bioavailability enhancement in vivo than technologies only generating transient but not sustained supersaturation. Copyright © 2018 Elsevier B.V. All rights reserved.

Curcumin-polymeric nanoparticles against colon-26 tumor-bearing mice: cytotoxicity, pharmacokinetic and anticancer efficacy studies.

PubMed

Chaurasia, Sundeep; Chaubey, Pramila; Patel, Ravi R; Kumar, Nagendra; Mishra, Brahmeshwar

2016-01-01

Curcumin (CUR), can inhibit proliferation and induce apoptosis of tumor cells, its extreme insolubility and limited bioavailability restricted its clinical application. An innovative polymeric nanoparticle of CUR has been developed to enhance the bioavailability and anti-cancer efficacy of CUR, in vitro and in vivo. Cationic copolymer Eudragit E 100 was selected as carrier, which can enhance properties of poor bioavailable chemotherapeutic drugs (CUR). The CUR-loaded Eudragit E 100 nanoparticles (CENPs) were prepared by emulsification-diffusion-evaporation method. The in vitro cytotoxicity study of CENPs was carried out using sulphorhodamine B assay. Pharmacokinetic and anti-cancer efficacy of CENPs was investigated in Wister rats as well as colon-26 tumor-bearing mice after oral administration. CENPs showed acceptable particle size and percent entrapment efficiency. In vitro cytotoxicity studies in terms of 50% cell growth inhibition values demonstrated ∼19-fold reduction when treated with CENPs as compared to pure CUR. ∼91-fold increase in Cmax and ∼95-fold increase in AUC0-12h were observed indicating a significant enhancement in the oral bioavailability of CUR when orally administered as CENPs compared to pure CUR. The in vivo anti-cancer study performed with CENPs showed a significant increase in efficacy compared with pure CUR, as observed by tumor volume, body weight and survival rate. The results clearly indicate that the developed polymeric nanoparticles offer a great potential to improve bioavailability and anticancer efficacy of hydrophobic chemotherapeutic drug.

In vitro and in vivo evaluation of a sublingual fentanyl wafer formulation

PubMed Central

Lim, Stephen CB; Paech, Michael J; Sunderland, Bruce; Liu, Yandi

2013-01-01

Background The objective of this study was to prepare a novel fentanyl wafer formulation by a freeze-drying method, and to evaluate its in vitro and in vivo release characteristics, including its bioavailability via the sublingual route. Methods The wafer formulation was prepared by freeze-drying an aqueous dispersion of fentanyl containing sodium carboxymethylcellulose and amylogum as matrix formers. Uniformity of weight, friability, and dissolution testing of the fentanyl wafer was achieved using standard methods, and the residual moisture content was measured. The fentanyl wafer was also examined using scanning electron microscopy and x-ray diffraction. The absolute bioavailability of the fentanyl wafer was evaluated in 11 opioid-naïve adult female patients using a randomized crossover design. Results In vitro release showed that almost 90% of the fentanyl dissolved in one minute. In vivo, the first detectable plasma fentanyl concentration was observed after 3.5 minutes and the peak plasma concentration between 61.5 and 67 minutes. The median absolute bioavailability was 53.0%. Conclusion These results indicate that this wafer has potential as an alternative sublingual fentanyl formulation. PMID:23596347

Can in vitro assays account for interactions between inorganic co-contaminants observed during in vivo relative bioavailability assessment?

PubMed

Ollson, Cameron J; Smith, Euan; Juhasz, Albert L

2018-02-01

In vitro assays act as surrogate measurements of relative bioavailability (RBA) for inorganic contaminants. The values derived from these assays are routinely used to refine human health risk assessments (HHRA). Extensive in vitro research has been performed on three major inorganic contaminants; As, Cd and Pb. However, the majority of these studies have evaluated the contaminants individually, even in cases when they are found as co-contaminants. Recently, in vivo studies (animal model) have determined that when the three aforementioned contaminants are present in the same soil matrix, they have the ability to influence each other's individual bioavailability. Since in vitro assays are used to inform HHRA, this study investigated whether bioaccessibility methods including the Solubility/Bioavailability Research Consortium (SBRC) assay, and physiologically based extraction test (PBET), have the ability to detect interactions between As, Cd and Pb. Using a similar dosing methodology to recently published in vivo studies, spiked aged (12 years) soil was assessed by evaluating contaminant bioaccessibility individually, in addition to tertiary combinations. In two spiked aged soils (grey and brown chromosols), there was no influence on contaminant bioaccessibility when As, Cd and Pb we present as co-contaminants. However, in a red ferrosol, the presence of As and Pb significantly decreased (p < 0.05) the bioaccessibility of Cd when assessed using gastric and intestinal phases of the SBRC assay and the PBET. Conceivable, differences in key physico-chemical properties (TOC, Fe, Al, P) between the study soils influenced contaminant interactions and bioaccessibility outcomes. Although bioaccessibility methods may not account for interactions between elements as demonstrated in in vivo models, in vitro assessment provides a conservative prediction of contaminant RBA under co-contaminant scenarios. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enhanced oral bioavailability and in vivo antioxidant activity of chlorogenic acid via liposomal formulation.

PubMed

Feng, Yingshu; Sun, Congyong; Yuan, Yangyang; Zhu, Yuan; Wan, Jinyi; Firempong, Caleb Kesse; Omari-Siaw, Emmanuel; Xu, Yang; Pu, Zunqin; Yu, Jiangnan; Xu, Ximing

2016-03-30

In the present study, a formulation system consisting of cholesterol and phosphatidyl choline was used to prepare an effective chlorogenic acid-loaded liposome (CAL) with an improved oral bioavailability and an increased antioxidant activity. The developed liposomal formulation produced regular, spherical and multilamellar-shaped distribution nanoparticles. The pharmacokinetic analysis of CAL compared with chlorogenic acid (CA), showed a higher value of Cmax(6.42 ± 1.49 min versus 3.97 ± 0.39 min) and a delayed Tmax(15 min versus 10 min), with 1.29-fold increase in relative oral bioavailability. The tissue distribution in mice also demonstrated that CAL predominantly accumulated in the liver which indicated hepatic targeting potential of the drug. The increased activities of antioxidant enzymes (Total Superoxide Dismutase (T-SOD) and Glutathione Peroxidase (GSH-Px)) and total antioxidant capacity (T-AOC), in addition to decreased level of malondialdehyde (MDA) in CCl4-induced hepatotoxicity study further revealed that CAL exhibited significant hepatoprotective and antioxidant effects. Collectively, these findings present a liposomal formulation with significantly improved oral bioavailability and an increased in vivo antioxidant activity of CA. Copyright © 2016 Elsevier B.V. All rights reserved.

Formulation of diazepam containing rectal suppositories and experiences of their biopharmaceutical study.

PubMed

Regdon, G; Bácskay, I; Kata, M; Selmeczi, B; Szikszay, M; Sánta, A; Bálint, G S

1994-05-01

Methodology and the results of the in vitro membrane diffusion and in vivo bioavailability studies are presented. The results confirm a correlation between in vitro and in vivo findings. Hydrophilic macrogol-mixture with great molecular mass can be recommended as the optimal vehicle for formulation of diazepam suppositories.

EFFECT OF OIL COMBUSTION PARTICLE BIOAVAILABLE CONSTITUENTS ON EX VIVO VASCULAR FUNCTION OF AORTAS RECOVERED FROM NORMAL AND TYPE 2 DIABETIC RATS

EPA Science Inventory

Effect of Oil Combustion Particle Bioavailable Constituents on Ex Vivo Vascular Function of Aortae Recovered from Healthy and Early Type 2 Diabetic Rats
KL Dreher1, SE Kelly2, SD Proctor2, and JC Russell2. 1National Health and Environmental Effects Laboratory, US EPA, RTP, NC;...

Dose-dependent bioavailability indicators for curcumin and two of its novel derivatives.

PubMed

Abd el Aziz, Mohamed; El-Asmer, Mohamed; Rezq, Ameen; Al-Malki, Abdulrahman; Kumosani, Taha; Fouad, Hanan; Ahmed, Hanan; Taha, Fatma; Hassouna, Amira; Hafez, Hafez

2014-01-01

Novel water-soluble curcumin derivatives have been developed to overcome low in vivo bioavailability of curcumin. The aim of this work is to assess the potential utility of certain downstream targets as bioavailability indicators of systemic activity of pure curcumin and two novel water-soluble curcumin derivatives (NCD) by constructing dose-dependent response curves and to prove whether this novel curcumin derivatives retained, improved, or abolished biological activity of pure curcumin when applied in vivo. Pure curcumin (CUR), curcumin-carboxy derivative (NCD-1), and curcumin protein conjugate (NCD-2) were administered orally to rats at escalating doses: 37, 74, 148, and 296 μM/kg body weight, respectively. Plasma levels of GST activity, cavernous tissue levels of cGMP, and enzymatic activity of both HO-1 and GST were assessed one and half and 24 hours after oral administration of curcumin formulae. This study showed that there was a progressive elevation of cavernous tissue levels of cGMP and enzymatic activity of both HO-1 and GST in a dose-dependent manner that was maintained for 24 h with CUR, NCD-1, and NCD-2. Plasma GST activity was decreased by the lowest doses on the curve. The three dose-dependent bioavailability indicators as surrogates of curcumin and two of its novel derivatives are valid in the studied range of concentration and extended time. The novel curcumin derivatives still conserve with improvement the biological activity of natural curcumin when applied in vivo. © 2013 International Union of Biochemistry and Molecular Biology.

Dietary flavonoids modulate CYP2C to improve drug oral bioavailability and their qualitative/quantitative structure-activity relationship.

PubMed

Wang, Hong-Jaan; Pao, Li-Heng; Hsiong, Cheng-Huei; Shih, Tung-Yuan; Lee, Meei-Shyuan; Hu, Oliver Yoa-Pu

2014-03-01

This study aims to improve the drug oral bioavailability by co-administration with flavonoid inhibitors of the CYP2C isozyme and to establish qualitative and quantitative (QSAR) structure-activity relationships (SAR) between flavonoids and CYP2C. A total of 40 naturally occurring flavonoids were screened in vitro for CYP2C inhibition. Enzyme activity was determined by measuring conversion of tolbutamide to 4-hydroxytolbutamide by rat liver microsomes. The percent inhibition and IC50 of each flavonoid were calculated and used to develop SAR and QSAR. The most effective flavonoid was orally co-administered in vivo with a cholesterol-reducing drug, fluvastatin, which is normally metabolized by CYP2C. The most potent CYP2C inhibitor identified in vitro was tamarixetin (IC50 = 1.4 μM). This flavonoid enhanced the oral bioavailability of fluvastatin in vivo, producing a >2-fold increase in the area under the concentration-time curve and in the peak plasma concentration. SAR analysis indicated that the presence of a 2,3-double bond in the C ring, hydroxylation at positions 5, 6, and 7, and glycosylation had important effects on flavonoid-CYP2C interactions. These findings should prove useful for predicting the inhibition of CYP2C activity by other untested flavonoid-like compounds. In the present study, tamarixetin significantly inhibited CYP2C activity in vitro and in vivo. Thus, the use of tamarixetin could improve the therapeutic efficacy of drugs with low bioavailability.

Enhancement of solubility and bioavailability of ambrisentan by solid dispersion using Daucus carota as a drug carrier: formulation, characterization, in vitro, and in vivo study.

PubMed

Deshmane, Subhash; Deshmane, Snehal; Shelke, Santosh; Biyani, Kailash

2018-06-01

Ambrisentan is an US FDA approved drug, it is the second oral endothelin A receptor antagonist known for the treatment of pulmonary arterial hypertension, but its oral administration is limited due to its poor water solubility. Hence, the objective of the investigation was focused on enhancement of solubility and bioavailability of ambrisentan by solid dispersion technique using natural Daucus carota extract as drug carrier. Drug carrier was evaluated for solubility, swelling index, viscosity, angle of repose, hydration capacity, and acute toxicity test (LD 50 ). Ambrisentan was studied for the saturation solubility, phase solubility, and Gibbs free energy change. Compatibility of drug and the natural carrier was confirmed by DSC, FTIR, and XRD. Solid dispersions were evaluated for drug content, solubility, morphology, in vitro, and in vivo study. Screening of the natural carrier showed the desirable properties like water solubility, less swelling index, less viscosity, and acute toxicity study revealed no any clinical symptoms of toxicity. Drug and carrier interaction study confirmed the compatibility to consider its use in the formulation. Formed particles were found to be spherical with smooth surface. In vitro studies revealed higher drug release from the solid dispersion than that of the physical mixture. Bioavailability study confirms the increased absorption and bioavailability by oral administration of solid dispersion. Hence, it can be concluded that the natural Daucus carota extract can be the better alternative source for the preparation of solid dispersion and/or other dosage forms for improving solubility and bioavailability.

Chitosan-coated diacerein nanosuspensions as a platform for enhancing bioavailability and lowering side effects: preparation, characterization, and ex vivo/in vivo evaluation

PubMed Central

Allam, Ahmed N; Hamdallah, Sherif I; Abdallah, Ossama Y

2017-01-01

Nanodrug delivery systems have been widely reviewed for their use in several drug formulations to improve bioavailability, sustain effect, and decrease side effects of many candidate drugs. The objective of this study was to evaluate the potential of chitosan (CS)-coated nanosuspensions to enhance bioavailability and reduce the diarrheal side effect of diacerein (DCN) after oral administration. DCN nanosuspensions (DNS) were prepared by sonoprecipitation technique using different stabilizers at three different concentrations. The selected DNS with optimum particle size (PS), polydispersity index (PDI), and Zeta potential (ZP) was coated with three different concentrations of CS-coated DNS (CS-DNS) and screened. In vitro dissolution was performed for the selected lyophilized formulae and compared with DCN powder in addition to the assessment of drug crystallinity via scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry. Ex vivo drug permeability using noneverted rat intestine, intraluminal content, and mucoadhesion evaluation was studied for nominated formulae in comparison to DCN suspension. Moreover, in vivo study, pharmacokinetic parameters, and evaluation of diarrheal potential were conducted after oral administration of selected formulae. Polyvinyl pyrrolidone (PVP)-stabilized DNS showed a significant increase (P≤0.05) in PS and PDI as the stabilizer concentration increased. PVP-stabilized DNS with the lowest CS concentration was protected from aggregation by lyophilization with mannitol. A remarked enhancement in dissolution parameters was observed in the nanocrystals’ formulae. Morphological examination and X-ray diffraction confirmed drug crystallinity. The intermediate permeation parameters of CS-DNS-F10, lowest rhein-to-DCN ratio in intraluminal content along with the highest percentage of mucoadhesive, could serve as a sustaining profile of coated formula. CS-DNS-F10 showed a significantly higher Cmax of 0.74±0.15 µg/mL at a delayed Tmax of 3.60±0.55 hours with a relative bioavailability of 172.1% compared to DCN suspension. CS-coated nanosuspensions could serve as promising revenue to enhance bioavailability and reduce the diarrheal side effect of DCN after oral administration. PMID:28740381

Chitosan-coated diacerein nanosuspensions as a platform for enhancing bioavailability and lowering side effects: preparation, characterization, and ex vivo/in vivo evaluation.

PubMed

Allam, Ahmed N; Hamdallah, Sherif I; Abdallah, Ossama Y

2017-01-01

Nanodrug delivery systems have been widely reviewed for their use in several drug formulations to improve bioavailability, sustain effect, and decrease side effects of many candidate drugs. The objective of this study was to evaluate the potential of chitosan (CS)-coated nanosuspensions to enhance bioavailability and reduce the diarrheal side effect of diacerein (DCN) after oral administration. DCN nanosuspensions (DNS) were prepared by sonoprecipitation technique using different stabilizers at three different concentrations. The selected DNS with optimum particle size (PS), polydispersity index (PDI), and Zeta potential (ZP) was coated with three different concentrations of CS-coated DNS (CS-DNS) and screened. In vitro dissolution was performed for the selected lyophilized formulae and compared with DCN powder in addition to the assessment of drug crystallinity via scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry. Ex vivo drug permeability using noneverted rat intestine, intraluminal content, and mucoadhesion evaluation was studied for nominated formulae in comparison to DCN suspension. Moreover, in vivo study, pharmacokinetic parameters, and evaluation of diarrheal potential were conducted after oral administration of selected formulae. Polyvinyl pyrrolidone (PVP)-stabilized DNS showed a significant increase ( P ≤0.05) in PS and PDI as the stabilizer concentration increased. PVP-stabilized DNS with the lowest CS concentration was protected from aggregation by lyophilization with mannitol. A remarked enhancement in dissolution parameters was observed in the nanocrystals' formulae. Morphological examination and X-ray diffraction confirmed drug crystallinity. The intermediate permeation parameters of CS-DNS-F10, lowest rhein-to-DCN ratio in intraluminal content along with the highest percentage of mucoadhesive, could serve as a sustaining profile of coated formula. CS-DNS-F10 showed a significantly higher C max of 0.74±0.15 µg/mL at a delayed T max of 3.60±0.55 hours with a relative bioavailability of 172.1% compared to DCN suspension. CS-coated nanosuspensions could serve as promising revenue to enhance bioavailability and reduce the diarrheal side effect of DCN after oral administration.

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.

[Effect of extrusion on protein and starch bioavailability in corn and lima bean flour blends].

PubMed

Pérez-Navarrete, Cecilia; Betancur-Ancona, David; Casotto, Meris; Carmona, Andrés; Tovar, Juscelino

2007-09-01

Extrusion is used to produce crunchy expanded foods, such as snacks. The nutritional impact of this process has not been studied sufficiently. In this study, in vitro and in vivo protein and starch bioavailability was evaluated in both raw and extruded corn (Zea mays)(C) and lima bean (Phaseolus lunatus)(B) flour blends, prepared in 75C/25B and 50C/ 50B (p/p) proportions. These were processed with a Brabender extruder at 160 degrees C, 100 rpm and 15.5% moisture content. Proximate composition showed that in the extruded products protein and ash contents increased whereas the fat level decreased. In vitro protein digestibility was higher in the extrudates (82%) than in the raw flours (77%). Potentially available starch and resistant starch contents decreased with extrusion. The in vitro assays indicated that extrusion improved protein and starch availability in the studied blends. In vivo bioavailability was evaluated using the rice weevil (Sithophilus oryzae) as a biological model. The most descriptive biomarkers of the changes suggested by the in vivo tests were body protein content (increased by extrusion) and intestinal a-amylase activity (decreased by processing). Overall, results suggest that extrusion notably increases the nutritional quality of corn and lima bean flour blends.

Formulation, optimization, and in vitro/in vivo evaluation of furosemide nanosuspension for enhancement of its oral bioavailability

NASA Astrophysics Data System (ADS)

Sahu, Bhanu P.; Das, Malay K.

2014-04-01

Furosemide is a poorly soluble diuretic used for treatment of hypertension and edema. It has very poor or variable oral bioavailability due to its reduced solubility in gastric fluid and reduced permeability in intestinal fluid. The aim of this study was to prepare nanosuspension of furosemide to enhance its oral bioavailability by increasing its dissolution in stomach where it has better permeability. Full factorial design was used for a systematic approach of formulation and optimization. The nanosuspensions were prepared by precipitation with ultrasonication method. Polyvinyl acetate was used for sterically stabilizing the nanosuspensions. The diffusing drug concentration and stabilizer were used as the factors and the particle size, polydispersity index, and drug release were selected as dependent variables and characterized. The effect of nanoprecipitation on enhancement of oral bioavailability of furosemide nanosuspension was studied by in vitro dissolution and in vivo absorption studies in rats and compared to pure drug. Quality by design using full factorial design provided a systematic approach in optimizing nanosuspensions to produce products with desired quality. Stable nanosuspension were obtained with average size range of the precipitated nanoparticles between 150 and 300 nm and were found to be homogenous showing a narrow polydispersity index of 0.3 ± 0.1. The in vivo studies on rats revealed a significant increase in the oral absorbtion of furosemide in the nanosuspension compared to pure drug. The AUC0→24 and C max values of nanosuspension were approximately 1.38- and 1.68-fold greater than that of pure drug, respectively. Furosemide nanosuspension showed 20.06 ± 0.02 % decrease in systolic blood pressure compared to 13.37 + 0.02 % in plain furosemide suspension, respectively. The improved oral bioavailability and pharmacodynamic effect of furosemide may be due to the improved dissolution of furosemide in simulated gastric fluid which results in enhanced oral systemic absorption of furosemide from stomach region where it has better permeability.

Experimental determination of the oral bioavailability and bioaccessibility of lead particles

PubMed Central

2012-01-01

In vivo estimations of Pb particle bioavailability are costly and variable, because of the nature of animal assays. The most feasible alternative for increasing the number of investigations carried out on Pb particle bioavailability is in vitro testing. This testing method requires calibration using in vivo data on an adapted animal model, so that the results will be valid for childhood exposure assessment. Also, the test results must be reproducible within and between laboratories. The Relative Bioaccessibility Leaching Procedure, which is calibrated with in vivo data on soils, presents the highest degree of validation and simplicity. This method could be applied to Pb particles, including those in paint and dust, and those in drinking water systems, which although relevant, have been poorly investigated up to now for childhood exposure assessment. PMID:23173867

Anti-cancerous efficacy and pharmacokinetics of 6-mercaptopurine loaded chitosan nanoparticles.

PubMed

Kumar, G Prem; Sanganal, Jagadeesh S; Phani, A R; Manohara, C; Tripathi, Syamantak M; Raghavendra, H L; Janardhana, P B; Amaresha, S; Swamy, K B; Prasad, R G S V

2015-10-01

6-Mercaptopurine is a cytotoxic and immunosuppressant drug. The use of this drug is limited due to its poor bioavailability and short plasma half-life. In order to nullify these drawbacks, 6-mercaptopurine-chitosan nanoparticles (6-MP-CNPs) were prepared and evaluated to study the influence of preparation conditions on the physicochemical properties by using DLS, SEM, XRD and FTIR. The in vitro drug release profile at pH 4.8 and 7.4 revealed sustained release patterns for a period of 2 days. The nanoformulations showed enhanced in vitro anti-cancer activities (MTT assay, apoptosis assay, cell cycle arrest and ROS indices) on HT-1080 and MCF-7 cells. In vivo pharmacokinetics profiles of 6-MP-CNPs showed improved bioavailability. Thus, the results of the present study revealed that, the prepared 6-MP-CNPs have a significant role in increasing anti-cancer efficacy, bioavailability and in vivo pharmacokinetics profiles. Copyright © 2015 Elsevier Ltd. All rights reserved.

Improved oral bioavalability of mebudipine upon administration in PhytoSolve and Phosal-based formulation (PBF).

PubMed

Khani, Samira; Keyhanfar, Fariborz

2014-02-01

The aim of this investigation was to examine the efficacy of PhytoSolve and Phosal-based formulation (PBF) to enhance the oral bioavailability of mebudipine, which is a poorly water-soluble calcium channel blocker. The solubility of mebudipine in various oils was determined. PhytoSolve was prepared with a medium-chain triglyceride (MCT) oil (20%), soybean phospholipids (5%), and a 70% fructose solution (75%). The influence of the weight ratio of Phosal 50PG to glycerol in PBF on the mean globule size was studied with dynamic light scattering. The optimized formulation was evaluated for robustness toward dilution, transparency, droplet size, and zeta potential. The in vivo oral absorption of different mebudipine formulations (PhytoSolve, PBF, oily solution, and suspension) were evaluated in rats. The optimized PBF contained Phosal 50PG/glycerol in a 6:4 ratio (w/w). The PBF and PhytoSolve formulations were miscible with water in any ratio and did not demonstrate any phase separation or drug precipitation over 1 month of storage. The mean particle size of PhytoSolve and PBF were 138.5 ± 9.0 and 74.4 ± 2.5 nm, respectively. The in vivo study demonstrated that the oral bioavailability of PhytoSolve and PBF in rats was significantly higher than that of the other formulations. The PhytoSolve and PBF formulations of mebudipine are found to be more bioavailable compared with suspension and oily solutions during an in vivo study in rats. These formulations might be new alternative carriers that increase the oral bioavailability of poorly water-soluble molecules, such as mebudipine.

21 CFR 320.23 - Basis for measuring in vivo bioavailability or demonstrating bioequivalence.

Code of Federal Regulations, 2014 CFR

2014-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS... bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which... labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is...

21 CFR 320.23 - Basis for measuring in vivo bioavailability or demonstrating bioequivalence.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS... bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which... labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is...

21 CFR 320.23 - Basis for measuring in vivo bioavailability or demonstrating bioequivalence.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS... bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which... labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is...

21 CFR 320.23 - Basis for measuring in vivo bioavailability or demonstrating bioequivalence.

Code of Federal Regulations, 2013 CFR

2013-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS... bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which... labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is...

21 CFR 320.23 - Basis for measuring in vivo bioavailability or demonstrating bioequivalence.

Code of Federal Regulations, 2012 CFR

2012-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS... bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which... labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is...

Assessing the bioavailability and risk from metal-contaminated ...

EPA Pesticide Factsheets

Exposure to contaminated soil and dust is an important pathway in human health risk assessment. Physical and chemical characteristics, as well as biological factors, determine the bioaccessibility/bioavailability of soil and dust contaminants. Within a single sample, contamination may arise from multiple sources of toxic elements that may exist as different forms (species) which impact bioavailability. In turn, the bioaccessibility/bioavailability of soil and dust contaminants has a direct impact on human health risk assessment and risk management practices. Novel research efforts focusing on development and application of in vitro and in vivo methods to measure the bioaccessibility/bioavailability of metal contaminated soils have advanced in the past few years. The objective of this workshop was to focus on recent developments in assessing the bioaccessibility/bioavailability of arsenic contaminated soils, metal contamination in urban residences in Canada and potential children’s exposures to toxic elements in house dust, a community-based study known as the West Oakland Residential Lead Assessment , studies of the bioavailability of soil cadmium, chromium, nickel and mercury and human exposures to contaminated Brownfield soils. These presentations covered issues related to human health and bioavailability along with the most recent studies on community participation in assessing metal contamination, studies of exposures to residential contamination, and

The ethanol metabolite acetaldehyde increases paracellular drug permeability in vitro and oral bioavailability in vivo.

PubMed

Fisher, Scott J; Swaan, Peter W; Eddington, Natalie D

2010-01-01

Alcohol consumption leads to the production of the highly reactive ethanol metabolite, acetaldehyde, which may affect intestinal tight junctions and increase paracellular permeability. We examined the effects of elevated acetaldehyde within the gastrointestinal tract on the permeability and bioavailability of hydrophilic markers and drug molecules of variable molecular weight and geometry. In vitro permeability was measured unidirectionally in Caco-2 and MDCKII cell models in the presence of acetaldehyde, ethanol, or disulfiram, an aldehyde dehydrogenase inhibitor, which causes acetaldehyde formation when coadministered with ethanol in vivo. Acetaldehyde significantly lowered transepithelial resistance in cell monolayers and increased permeability of the low-molecular-weight markers, mannitol and sucrose; however, permeability of high-molecular-weight markers, polyethylene glycol and inulin, was not affected. In vivo permeability was assessed in male Sprague-Dawley rats treated for 6 days with ethanol, disulfiram, or saline alone or in combination. Bioavailability of naproxen was not affected by any treatment, whereas that of paclitaxel was increased upon acetaldehyde exposure. Although disulfiram has been shown to inhibit multidrug resistance-1 P-glycoprotein (P-gp) in vitro, our data demonstrate that the known P-gp substrate paclitaxel is not affected by coadministration of disulfiram. In conclusion, we demonstrate that acetaldehyde significantly modulates tight junctions and paracellular permeability in vitro as well as the oral bioavailability of low-molecular-weight hydrophilic probes and therapeutic molecules in vivo even when these molecules are substrates for efflux transporters. These studies emphasize the significance of ethanol metabolism and drug interactions outside of the liver.

Sildenafil citrate as oral solid lipid nanoparticles: a novel formula with higher bioavailability and sustained action for treatment of erectile dysfunction.

PubMed

Hosny, Khaled M; Aljaeid, Bader M

2014-07-01

The aim of this study was to prepare sildenafil citrate as solid lipid nanoparticles (SLNs), in order to find an innovative way for alleviating the disadvantages associated with commercially available sildenafil citrate tablets. These limitations include poor solubility and extensive first-pass metabolism, resulting in low (40%) bioavailability and short elimination half-life (4 h). SLNs were prepared by hot homogenization followed by ultrasonication. Solubility of sildenafil citrate in different solid lipids was measured, effect of process variables as surfactant type and concentration, homogenization time, ultrasonication time and charge-inducing agent on the particle size, zeta potential and encapsulation efficiency were also determined. Furthermore, in vitro drug release, stability and in vivo pharmacokinetics were studied in rabbits Results: The best SLN formula consisted of 2% precirol ATO5, 0.5% phosphatidylcholine, 2.5% gelucire 44/14, 0.125% stearylamine, had an average particle size of 28.5 nm with 95.34% entrapment efficiency and demonstrated a controlled drug release over 24 h. An in vivo pharmacokinetic study revealed enhanced bioavailability by > 1.87 fold, and the mean residence time was longer than that for the commercially available tablet. SLN could be a promising carrier for sustained/prolonged sildenafil citrate release with enhanced oral bioavailability.

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.

Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate.

PubMed

O'Shea, Joseph P; Nagarsekar, Kalpa; Wieber, Alena; Witt, Vanessa; Herbert, Elisabeth; O'Driscoll, Caitriona M; Saal, Christoph; Lubda, Dieter; Griffin, Brendan T; Dressman, Jennifer B

2017-10-01

Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed. Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency. The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation. © 2017 Royal Pharmaceutical Society.

Effect of aggregation form on bioavailability of zeaxanthin in humans: a randomised cross-over study.

PubMed

Hempel, Judith; Fischer, Anja; Fischer, Monique; Högel, Josef; Bosy-Westphal, Anja; Carle, Reinhold; Schweiggert, Ralf M

2017-11-01

Carotenoid bioavailability from plant and animal food is highly variable depending on numerous factors such as the physical deposition form of carotenoids. As the carotenoid zeaxanthin is believed to play an important role in eye and brain health, we sought to compare the human bioavailability of an H-aggregated with that of a J-aggregated deposition form of zeaxanthin encapsulated into identical formulation matrices. A randomised two-way cross-over study with sixteen participants was designed to compare the post-prandial bioavailability of an H-aggregated zeaxanthin and a J-aggregated zeaxanthin dipalmitate formulation, both delivering 10 mg of free zeaxanthin. Carotenoid levels in TAG-rich lipoprotein fractions were analysed over 9·5 h after test meal consumption. Bioavailability from the J-aggregated formulation (AUC=55·9 nmol h/l) was 23 % higher than from the H-aggregated one (AUC=45·5 nmol h/l), although being only marginally significant (P=0·064). Furthermore, the same formulations were subjected to an internationally recognised in vitro digestion protocol to reveal potential strengths and weaknesses of simulated digestions. In agreement with our human study, liberation of zeaxanthin from the J-aggregated formulation into the simulated duodenal fluids was superior to that from the H-aggregated form. However, micellization rate (bioaccessibility) of the J-aggregated zeaxanthin dipalmitate was lower than that of the H-aggregated zeaxanthin, being contradictory to our in vivo results. An insufficient ester cleavage during simulated digestion was suggested to be the root cause for these observations. In brief, combining our in vitro and in vivo observations, the effect of the different aggregation forms on human bioavailability was lower than expected.

The influence of droplet size on the stability, in vivo digestion, and oral bioavailability of vitamin E emulsions.

PubMed

Parthasarathi, S; Muthukumar, S P; Anandharamakrishnan, C

2016-05-18

Vitamin E (α-tocopherol) is a nutraceutical compound, which has been shown to possess potent antioxidant and anticancer activity. However, its biological activity may be limited by its poor bioavailability. Colloidal delivery systems have shown wide applications in the food and pharmaceutical industries to deliver lipophilic bioactive compounds. In this study, we have developed conventional and nanoemulsions of vitamin E from food grade ingredients (sunflower oil, saponin, and water) and showed the nanoemulsion formulation increased the oral bioavailability when compared to the conventional emulsion. The mean droplet diameters in the nano and conventional emulsions were 0.277 and 1.285 μm, respectively. The stability of the emulsion formulation after thermal processing, long-term storage at different temperatures, mechanical stress and in plasma was determined. The results showed that the saponin coated nanoemulsion was stable to droplet coalescence during thermal processing (30-90 °C), long-term storage and mechanical stress when compared to the conventional emulsion. The biological fate of the emulsion formulations were studied using male Wistar rats as an animal model. The emulsion droplet stability during passage through the gastrointestinal tract was evaluated by their introduction into rat stomachs. Microscopy was used to investigate the structural changes that occurred during digestion. Both the conventional emulsion and nanoemulsion formulations showed strong evidence of droplet flocculation and coalescence during in vivo digestion. The in vivo oral bioavailability study revealed that vitamin E in a nanoemulsion form showed a 3-fold increase in the AUC when compared to the conventional emulsion. The information reported in this study will facilitate the design of colloidal delivery systems using nanoemulsion formulations.

Nano-transfersomal formulations for transdermal delivery of asenapine maleate: in vitro and in vivo performance evaluations.

PubMed

Shreya, A B; Managuli, Renuka S; Menon, Jyothsna; Kondapalli, Lavanya; Hegde, Aswathi R; Avadhani, Kiran; Shetty, Pallavi K; Amirthalingam, Muthukumar; Kalthur, Guruprasad; Mutalik, Srinivas

2016-09-01

Asenapine maleate (ASPM) is an antipsychotic drug for the treatment of schizophrenia and bipolar disorder. Extensive metabolism makes the oral route inconvenient for ASPM. The objective of this study is to increase ASPM bioavailability via transdermal route by improving the skin permeation using combined strategy of chemical and nano-carrier (transfersomal) based approaches. Transfersomes were prepared by the thin film hydration method using soy-phosphatidylcholine (SPC) and sodium deoxycholate (SDC). Transfersomes were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, surface morphology, and in vitro skin permeation studies. Various chemical enhancers were screened for skin permeation enhancement of ASPM. Optimized transfersomes were incorporated into a gel base containing suitable chemical enhancer for efficient transdermal delivery. In vivo pharmacokinetic study was performed in rats to assess bioavailability by transdermal route against oral administration. Optimized transfersomes with drug:SPC:SDC weight ratio of 5:75:10 were spherical with an average size of 126.0 nm, PDI of 0.232, ZP of -43.7 mV, and entrapment efficiency of 54.96%. Ethanol (20% v/v) showed greater skin permeation enhancement. The cumulative amount of ASPM permeated after 24 h (Q24) by individual effect of ethanol and transfersome, and in combination was found to be 160.0, 132.9, and 309.3 μg, respectively, indicating beneficial synergistic effect of combined approach. In vivo pharmacokinetic study revealed significant (p < 0.05) increase in bioavailability upon transdermal application compared with oral route. Dual strategy of permeation enhancement was successful in increasing the transdermal permeation and bioavailability of ASPM.

21 CFR 320.28 - Correlation of bioavailability with an acute pharmacological effect or clinical evidence.

Code of Federal Regulations, 2010 CFR

2010-04-01

... pharmacological effect or clinical evidence. 320.28 Section 320.28 Food and Drugs FOOD AND DRUG ADMINISTRATION... Correlation of bioavailability with an acute pharmacological effect or clinical evidence. Correlation of in vivo bioavailability data with an acute pharmacological effect or clinical evidence of safety and...

In Vitro And In Vivo Approaches For The Measurement Of Oral Bioavailability Of Lead (Pb) In Contaminated Soils: A Review

EPA Science Inventory

We reviewed the published evidence of lead (Pb) contamination of urban soils, soil Pb risk to children through hand-to-mouth activity, reduction of soil Pb bioavailability due to soil amendments, and methods to assess bioaccessibility which correlate with bioavailability of soil ...

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.

Development of sustained release floating drug delivery system for norfloxacin: in vitro and in vivo evaluation.

PubMed

Guguloth, Mohan; Bomma, Ramesh; Veerabrahma, Kishan

2011-01-01

Norfloxacin is a drug with an absorption window. Its oral bioavailability is 30-40% and is a case for improvement by appropriate formulation design. In our previous study, gastroretentive floating tablets for norfloxacin were developed employing three different polymers such as HPMC K4M, HPMC K100M, and xanthan gum. The purpose of this investigation is to further improve and evaluate the in vitro and in vivo performance of the prepared floating tablets by inclusion of citric acid as an acidifier, which is also useful in a fed state. The prepared tablets were characterized and found to exhibit satisfactory physico-chemical characteristics. The effects of citric acid at different concentrations on drug release and floating properties were studied. All the prepared batches showed good in vitro buoyancy. It was observed that the tablets remained buoyant for 24 h. The best formulation (F4c), consisting of 1.5% citric acid and 18% HPMC K4M, was selected based on in vitro characteristics and used in vivo radiographic studies by incorporating barium sulphate. These studies revealed that the tablets remained in the stomach for 205 ± 8.4 min in fasting human volunteers. In vivo studies were carried out for the best formulation in eight healthy male human volunteers, and the pharmacokinetic parameters of the developed formulation were compared with marketed conventional (Norbid) tablets. Based on the in vivo performance in a two-way, crossover study design in healthy subjects, the developed floating tablets showed superior bioavailability than the Norbid tablets. The increased bioavailability of developed formulation was found to be 16.27%. Norfloxacin is a broad-spectrum antibiotic used to treat bacterial infections such as respiratory and urinary tract infections. Conventional norfloxacin tablets show incomplete drug absorption resulting in lower bioavailabilty. Norfloxacin is better absorbed in the stomach. The dosage forms that remain in the stomach are referred to as gastroretentive drug delivery systems. Gastroretentive floating tablets of norfloxcin were developed by employing three different polymers, which prolonged the drug release from the dosage forms. Tablet floatation was achieved by an effervescent mechanism. Citric acid at different concentrations was used in formulations to provide an acidic microenvironment. The prepared tablets were characterized for hardness, weight variation, thickness, friability, floating lag time, and dissolution. Around 12 tablet formulations were prepared as a continuation of the previous work. The best formulation (F4c) was selected based on in vitro characteristics and used in vivo radiographic studies by incorporating barium sulphate as a radio-opaque agent. The tablets remained in the stomach for about 205 ± 8.4 min. Bioavailability studies were conducted in healthy male human volunteers, and the pharmacokinetic parameters of the best formulation were compared with that of the marketed conventional (Norbid) tablet. The increased bioavailability of the developed formulation was found to be 16.27%.

Novel orally active growth hormone secretagogues.

PubMed

Hansen, T K; Ankersen, M; Hansen, B S; Raun, K; Nielsen, K K; Lau, J; Peschke, B; Lundt, B F; Thøgersen, H; Johansen, N L; Madsen, K; Andersen, P H

1998-09-10

A novel class of growth hormone-releasing compounds with a molecular weight in the range from 500 to 650 has been discovered. The aim of this study was to obtain growth hormone secretagogues with oral bioavailability. By a rational approach we were able to reduce the size of the lead compound ipamorelin (4) and simultaneously to reduce hydrogen-bonding potential by incorporation of backbone isosters while retaining in vivo potency in swine. A rat pituitary assay was used for screening of all compounds and to evaluate which compounds should be tested further for in vivo potency in swine and oral bioavailability, fpo, in dogs. Most of the tested compounds had fpo in the range of 10-55%. In vivo potency in swine after iv dosing is reported, and ED50 was found to be 30 nmol/kg of body weight for the most potent compound.

Effects of alga polysaccharide capsule shells on in-vivo bioavailability and disintegration

NASA Astrophysics Data System (ADS)

Li, Ting; Guo, Shuju; Ma, Lin; Yuan, Yi; Han, Lijun

2012-01-01

Gelatin has been used in hard capsule shells for more than a century, and some shortcomings have appeared, such as high moisture content and risk of transmitting diseases of animal origin to people. Based on available studies regarding gelatin and vegetable shells, we developed a new type of algal polysaccharide capsule (APPC) shells. To test whether our products can replace commercial gelatin shells, we measured in-vivo plasma concentration of 12 selected volunteers with a model drug, ibuprofen, using high performance liquid chromatography (HPLC), by calculating the relative bioavailability of APPC and Qualicaps® referenced to gelatin capsules and assessing bioequivalence of the three types of shells, and calculated pharmacokinetic parameters with the software DAS 2.0 (China). The results show that APPC shells possess bioequivalence with Qualicaps® and gelatin shells. Moreover, the disintegration behavior of four types of shells (APPC, Vegcaps®, Qualicaps® and gelatin shells) with the content of lactose and radioactive element (99mTc) was observed via gamma-scintigraphic images. The bioavailability and gamma-scintigraphic studies showed that APPC was not statistically different from other vegetable and gelatin capsule shells with respect to in-vivo behavior. Hence, it can be concluded that APPCs are exchangeable with other vegetable and gelatin shells.

Enhancing the bioavailability of resveratrol by combining it with piperine

PubMed Central

Johnson, Jeremy J.; Nihal, Minakshi; Siddiqui, Imtiaz A.; Scarlett, Cameron O.; Bailey, Howard H.; Mukhtar, Hasan; Ahmad, Nihal

2012-01-01

Scope Resveratrol (3,5,4′-trihydroxystilbene) is a phytoalexin shown to possess a multitude of health-promoting properties in pre-clinical studies. However, the poor in vivo bioavailability of resveratrol due to its rapid metabolism is being considered as a major obstacle in translating its effects in humans. In this study, we examined the hypothesis that piperine will enhance the pharmacokinetic parameters of resveratrol via inhibiting its glucuronidation, thereby slowing its elimination. Methods and results Employing a standardized LC/MS assay, we determined the effect of piperine co-administration with resveratrol on serum levels resveratrol and resveratrol-3-O-β-d-glucuronide in C57BL mice. Mice were administered resveratrol (100 mg/kg; oral gavage) or resveratrol (100 mg/kg; oral gavage) + piperine (10 mg/kg; oral gavage), and the serum levels of resveratrol and resveratrol-3-O-β-d-glucuronide were analyzed at different times. We found that the degree of exposure (i.e. AUC) to resveratrol was enhanced to 229% and the maximum serum concentration (Cmax) was increased to 1544% with the addition of piperine. Conclusion Our study demonstrated that piperine significantly improves the in vivo bioavailability of resveratrol. However, further detailed research is needed to study the mechanism of improved bioavailability of resveratrol via its combination with piperine as well as its effect on resveratrol metabolism. PMID:21714124

Optimizing Oral Bioavailability in Drug Discovery: An Overview of Design and Testing Strategies and Formulation Options.

PubMed

Aungst, Bruce J

2017-04-01

For discovery teams working toward new, orally administered therapeutic agents, one requirement is to attain adequate systemic exposure after oral dosing, which is best accomplished when oral bioavailability is optimized. This report summarizes the bioavailability challenges currently faced in drug discovery, and the design and testing methods and strategies currently utilized to address the challenges. Profiling of discovery compounds usually includes separate assessments of solubility, permeability, and susceptibility to first-pass metabolism, which are the 3 most likely contributors to incomplete oral bioavailability. An initial assessment of absorption potential may be made computationally, and high throughput in vitro assays are typically performed to prioritize compounds for in vivo studies. The initial pharmacokinetic study is a critical decision point in compound evaluation, and the importance of the effect the dosing vehicle or formulation can have on oral bioavailability, especially for poorly water soluble compounds, is emphasized. Dosing vehicles and bioavailability-enabling formulations that can be used for discovery and preclinical studies are described. Optimizing oral bioavailability within a chemical series or for a lead compound requires identification of the barrier limiting bioavailability, and methods used for this purpose are outlined. Finally, a few key guidelines are offered for consideration when facing the challenges of optimizing oral bioavailability in drug discovery. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

A critical review of approaches and limitations of inhalation bioavailability and bioaccessibility of metal(loid)s from ambient particulate matter or dust.

PubMed

Kastury, Farzana; Smith, Euan; Juhasz, Albert L

2017-01-01

Inhalation of metal(loid)s in ambient particulate matter (APM) represents a significant exposure pathway to humans. Although exposure assessment associated with this pathway is currently based on total metal(loid) content, a bioavailability (i.e. absorption in the systemic circulation) and/or bioaccessibility (i.e. solubility in simulated lung fluid) based approach may more accurately quantify exposure. Metal(loid) bioavailability-bioaccessibility assessment from APM is inherently complex and lacks consensus. This paper reviews the discrepancies that impede the adoption of a universal protocol for the assessment of inhalation bioaccessibility. Exposure assessment approaches for in-vivo bioavailability, in-vitro cell culture and in-vitro bioaccessibility (composition of simulated lungs fluid, physico-chemical and methodological considerations) are critiqued in the context of inhalation exposure refinement. An important limitation of bioavailability and bioaccessibility studies is the use of considerably higher than environmental metal(loid) concentration, which diminishing their relevance to human exposure scenarios. Similarly, individual metal(loid) studies have been criticised due to complexities of APM metal(loid) mixtures which may impart synergistic or antagonistic effects compared to single metal(loid) exposure. Although a number of different simulated lung fluid (SLF) compositions have been used in metal(loid) bioaccessibility studies, information regarding the comparative leaching efficiency among these different SLF and comparisons to in-vivo bioavailability data is lacking. In addition, the particle size utilised is often not representative of what is deposited in the lungs while assay parameters (extraction time, solid to liquid ratio, temperature and agitation) are often not biologically relevant. Research needs are identified in order to develop robust in-vitro bioaccessibility protocols for the assessment or prediction of metal(loid) bioavailability in APM for the refinement of inhalation exposure. Copyright © 2016 Elsevier B.V. All rights reserved.

In vitro and in vivo studies of pharmacokinetics and antitumor efficacy of D07001-F4, an oral gemcitabine formulation.

PubMed

Hao, Wei-Hua; Wang, Jong-Jing; Hsueh, Shu-Ping; Hsu, Pei-Jing; Chang, Li-Chien; Hsu, Chang-Shan; Hsu, Kuang-Yang

2013-02-01

The chemotherapy agent gemcitabine is currently administered intravenously because the drug has poor oral bioavailability. In order to assess the pharmacokinetics and antitumor activity of D07001-F4, a new self-microemulsifying oral drug delivery system preparation of gemcitabine, this study was performed to compare the effect of D07001-F4 with administered gemcitabine in vitro and in vivo. D07001-F4 pharmacokinetics was examined by evaluation of in vitro deamination of D07001-F4 and gemcitabine hydrochloride by recombinant human cytidine deaminase (rhCDA) and in vivo evaluation of D07001-F4 pharmacokinetics in mice. Antitumor activity was evaluated by comparing the effect of D07001-F4 and gemcitabine hydrochloride in inhibiting growth in nine cancer cell lines and by examining the effect of D07001-F4 and gemcitabine in two xenograft tumor models in mice. In vitro deamination of D07001-F4 by rhCDA was 3.3-fold slower than deamination of gemcitabine hydrochloride. Growth inhibition by D07001-F4 of 7 of the 8 cancer cell lines was increased compared with that seen with gemcitabine hydrochloride, and D07001-F4 inhibited the growth of pancreatic and colon cancer xenografts. In vivo pharmacokinetics showed the oral bioavailability of D07001-F4 to be 34%. D07001-F4 was effective against several cancer types, was metabolized more slowly than gemcitabine hydrochloride, and exhibited enhanced oral bioavailability.

Lead optimization of antimalarial propafenone analogues.

PubMed

Lowes, David; Pradhan, Anupam; Iyer, Lalitha V; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W Armand; Sigal, Martina; Clark, Julie A; Wilson, Emily; Tang, Liang; Connelly, Michele C; Derisi, Joseph L; Kyle, Dennis E; Mirsalis, Jon; Guy, R Kiplin

2012-07-12

Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges.

Administration of resveratrol: What formulation solutions to bioavailability limitations?

PubMed

Amri, A; Chaumeil, J C; Sfar, S; Charrueau, C

2012-03-10

Resveratrol (3,5,4'-trihydroxystilbene), a naturally occurring polyphenol, has attracted considerable interest for its beneficial potentials for human health, which include anti-oxidant, anti-inflammatory, cardioprotective and anti-tumor activities. However, the in vivo biological effects of resveratrol appear strongly limited by its low bioavailability, which is a barrier to the development of therapeutic applications. In this context, an increasing number of recent studies have aimed at designing novel resveratrol formulations to overcome its poor solubility, limited stability, high metabolization and weak bioavailability. This review outlines physicochemical and pharmacokinetic limitations to resveratrol bioavailability, describes formulations tested for resveratrol administration, controlled release and targeting, and identifies future opportunities for resveratrol delivery. Copyright © 2011 Elsevier B.V. All rights reserved.

Effect of Emulsification Method and Particle Size on the Rate of in vivo Oral Bioavailability of Kenaf (Hibiscus cannabinus L.) Seed Oil.

PubMed

Cheong, Ai Mun; Tan, Chin Ping; Nyam, Kar Lin

2018-05-26

Kenaf (Hibiscus cannabinus L.) seed oil-in-water nanoemulsions stabilized by complexation of beta-cyclodextrin with sodium caseinate and Tween 20 have been shown to have higher bioaccessibility of vitamin E and total phenolic content than nonemulsified kenaf seed oil in the previous in vitro gastrointestinal digestion study. However, its oral bioavailability was unknown. Therefore, the aim of this study was to evaluate the rate of in vivo oral bioavailability of kenaf seed oil-in-water nanoemulsions in comparison with nonemulsified kenaf seed oil and kenaf seed oil macroemulsions during the 180 min of gastrointestinal digestion. Kenaf seed oil macroemulsions were produced by using conventional method. Kenaf seed oil-in-water nanoemulsions had shown improvement in the rate of absorption. At 180 min of digestion time, the total α-tocopherol bioavailability of kenaf seed oil nanoemulsions was increased by 1.7- and 1.4-fold, compared to kenaf seed oil and macroemulsion, respectively. Kenaf seed oil-in-water nanoemulsions were stable in considerably wide range of pH (>5 and <3), suggesting that it can be fortified into beverages within this pH range PRACTICAL APPLICATION: The production of kenaf seed oil-in-water nanoemulsions had provided a delivery system to encapsulate the kenaf seed oil, as well as enhanced the bioaccessibility and bioavailability of kenaf seed oil. Therefore, kenaf seed oil-in-water nanoemulsions exhibit a great potential application in nutraceutical fields. © 2018 Institute of Food Technologists®.

Oral relative bioavailability of Dichlorodiphenyltrichloroethane (DDT) in contaminated soil and its prediction using in vitro strategies for exposure refinement

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

Juhasz, Albert L., E-mail: Albert.Juhasz@unisa.edu

In this study, the bioavailability of DDTr (sum of DDT, DDD and DDE isomers) in pesticide-contaminated soil was assessed using an in vivo mouse model. DDTr relative bioavailability (RBA) ranged from 18.7±0.9 (As35) to 60.8±7.8% (As36) indicating that a significant portion of soil-bound DDTr was not available for absorption following ingestion. When DDTr bioaccessibility was assessed using the organic Physiologically Based Extraction Test (org-PBET), the inclusion of a sorption sink (silicone cord) enhanced DDTr desorption by up to 20-fold (1.6–3.8% versus 18.9–56.3%) compared to DDTr partitioning into gastrointestinal fluid alone. Enhanced desorption occurred as a result of the silicone cordmore » acting as a reservoir for solubilized DDTr to partition into, thereby creating a flux for further desorption until equilibrium was achieved. When the relationship between in vivo and in vitro data was assessed, a strong correlation was observed between the mouse bioassay and the org-PBET+silicone cord (slope=0.94, y-intercept=3.5, r{sup 2}=0.72) suggesting that the in vitro approach may provide a robust surrogate measure for the prediction of DDTr RBA in contaminated soil. - Highlights: • An optimised mouse assay was used to quantify DDTr relative bioavailability in soil. • DDTr bioaccessibility was also determined using an in vitro sorption sink approach. • A strong correlation was observed between in vivo and in vitro data. • The sorption sink approach may be used to predict DDTr relative bioavailability.« less

Nanoemulsions as self-emulsified drug delivery carriers for enhanced permeability of the poorly water-soluble selective β₁-adrenoreceptor blocker Talinolol.

PubMed

Ghai, Damanjeet; Sinha, Vivek Ranjan

2012-07-01

To enhance the bioavailability of the poorly water-soluble drug talinolol, a self-nanoemulsifying drug delivery system (SNEDDS) comprising 5% (w/v) Brij-721 ethanolic solution (Smix), triacetin, and water, in the ratio of 40:20:40 (% w/w) was developed by constructing pseudo-ternary phase diagrams and evaluated for droplet size, polydispersity index, and surface morphology of nanoemulsions. The effect of nanodrug carriers on drug release and permeability was assessed using stripped porcine jejunum and everted rat gut sac method and compared with hydroalcoholic drug solution, oily solution, and conventional emulsion and suspension. The SNEDDS showed a significant (P < 0.001) increase in drug release, permeability, and in vivo bioavailability as compared to drug suspension. This may be attributed to increased solubility and enhanced permeability of the drug from nanosized emulsion. In this study, a self-nanoemulsifying drug delivery system was utilized to enhance the bioavailability of the poorly water-soluble beta-blocker talinolol. Significant increase in drug release, permeability, and in vivo bioavailability were demonstrated as compared to standard drug suspension. Copyright © 2012 Elsevier Inc. All rights reserved.

Formulation and Characterization of Fast-Dissolving Sublingual Film of Iloperidone Using Box-Behnken Design for Enhancement of Oral Bioavailability.

PubMed

Londhe, Vaishali; Shirsat, Rucha

2018-04-01

Iloperidone is a second-generation antipsychotic drug which is used for the treatment of schizophrenia and has very low aqueous solubility and bioavailability. This drug also undergoes first-pass metabolism. The aim of this work is to formulate fast-dissolving sublingual films of iloperidone to improve its bioavailability. Sublingual films were prepared by solvent casting method. Hydroxypropyl methyl cellulose E5, propylene glycol 400, and transcutol HP were optimized using Box-Behnken three-level statistical design on the basis of disintegration time and folding endurance of films. Iloperidone:hydroxypropyl-β-cyclodextrin kneaded complex was used in films instead of plain drug due to its low solubility. Optimized film was further evaluated for drug content, pH, dissolution studies, ex vivo permeation studies, and pharmacokinetic studies in rats. The optimized film disintegrated within 30 s. The in vitro dissolution of the film showed 80.3 ± 3.4% drug dissolved within first 5 min. In ex vivo permeation studies using sublingual tissue, flux achieved within first 15 min by film was around 117.1 ± 0.35 (mcg/cm 2 /h) which was ten times more than that of plain drug. This formulation showed excellent uniformity. AUC and C max of film were significantly higher (p < 0.001) as compared to plain drug and relative bioavailability of the films was 148% when compared to the plain drug. Thus, this study showed optimized fast-dissolving sublingual film to improve permeation and bioavailability of iloperidone. Fast-dissolving films will be customer-friendly approach for geadiatric schizophrenic patients.

Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study.

PubMed

Shah, Nirmal V; Seth, Avinash K; Balaraman, R; Aundhia, Chintan J; Maheshwari, Rajesh A; Parmar, Ghanshyam R

2016-05-01

The objective of present work was to utilize potential of nanostructured lipid carriers (NLCs) for improvement in oral bioavailability of raloxifene hydrochloride (RLX). RLX loaded NLCs were prepared by solvent diffusion method using glyceryl monostearate and Capmul MCM C8 as solid lipid and liquid lipid, respectively. A full 3(2) factorial design was utilized to study the effect of two independent parameters namely solid lipid to liquid lipid ratio and concentration of stabilizer on the entrapment efficiency of prepared NLCs. The statistical evaluation confirmed pronounced improvement in entrapment efficiency when liquid lipid content in the formulation increased from 5% w/w to 15% w/w. Solid-state characterization studies (DSC and XRD) in optimized formulation NLC-8 revealed transformation of RLX from crystalline to amorphous form. Optimized formulation showed 32.50 ± 5.12 nm average particle size and -12.8 ± 3.2 mV zeta potential that impart good stability of NLCs dispersion. In vitro release study showed burst release for initial 8 h followed by sustained release up to 36 h. TEM study confirmed smooth surface discrete spherical nano sized particles. To draw final conclusion, in vivo pharmacokinetic study was carried out that showed 3.75-fold enhancements in bioavailability with optimized NLCs formulation than plain drug suspension. These results showed potential of NLCs for significant improvement in oral bioavailability of poorly soluble RLX.

Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study

PubMed Central

Shah, Nirmal V.; Seth, Avinash K.; Balaraman, R.; Aundhia, Chintan J.; Maheshwari, Rajesh A.; Parmar, Ghanshyam R.

2016-01-01

The objective of present work was to utilize potential of nanostructured lipid carriers (NLCs) for improvement in oral bioavailability of raloxifene hydrochloride (RLX). RLX loaded NLCs were prepared by solvent diffusion method using glyceryl monostearate and Capmul MCM C8 as solid lipid and liquid lipid, respectively. A full 32 factorial design was utilized to study the effect of two independent parameters namely solid lipid to liquid lipid ratio and concentration of stabilizer on the entrapment efficiency of prepared NLCs. The statistical evaluation confirmed pronounced improvement in entrapment efficiency when liquid lipid content in the formulation increased from 5% w/w to 15% w/w. Solid-state characterization studies (DSC and XRD) in optimized formulation NLC-8 revealed transformation of RLX from crystalline to amorphous form. Optimized formulation showed 32.50 ± 5.12 nm average particle size and −12.8 ± 3.2 mV zeta potential that impart good stability of NLCs dispersion. In vitro release study showed burst release for initial 8 h followed by sustained release up to 36 h. TEM study confirmed smooth surface discrete spherical nano sized particles. To draw final conclusion, in vivo pharmacokinetic study was carried out that showed 3.75-fold enhancements in bioavailability with optimized NLCs formulation than plain drug suspension. These results showed potential of NLCs for significant improvement in oral bioavailability of poorly soluble RLX. PMID:27222747

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.

Enhanced Bioavailability and Anticancer Effect of Curcumin-Loaded Electrospun Nanofiber: In Vitro and In Vivo Study

NASA Astrophysics Data System (ADS)

Wang, Chuan; Ma, Chao; Wu, Zhenkai; Liang, He; Yan, Peng; Song, Jia; Ma, Nan; Zhao, Qinghua

2015-11-01

Nanofibers have attracted increasing attention in drug delivery and other biomedical applications due to their some special properties. The present study aims to prepare a fiber-based nanosolid dispersion system to enhance the bioavailability of curcumin (CUR). CUR-loaded polyvinyl pyrrolidone (CUR@PVP) nanofibers were successfully prepared via electrospinning. Scanning electron microscopy (SEM) was employed to observe the morphology of the nanofibers, and the SEM image showed that the drug-loaded nanofibers were smooth, and no CUR clusters were found on the surface of the nanofibers. The results of X-ray diffraction (XRD) demonstrated that the CUR was evenly distributed in the nanofibers in an amorphous state. Fourier transform infrared (FTIR) spectroscopy analysis indicated that intermolecular hydrogen bonding occurred between the CUR and the polymer matrix. In vitro dissolution profiles showed that CUR@PVP nanofiber could be quickly dissolved in phosphate-buffered saline (PBS) solution, while negligible dissolution was observed in pure CUR sample. Importantly, in vitro cell viability assays and in vivo animal tests revealed that the nanosolid dispersion system dramatically enhanced the bioavailability and showed effective anticancer effect of the CUR.

Soya phospholipid complex of mangiferin enhances its hepatoprotectivity by improving its bioavailability and pharmacokinetics.

PubMed

Bhattacharyya, Sauvik; Ahmmed, Sk Milan; Saha, Bishnu Pada; Mukherjee, Pulok K

2014-05-01

Mangiferin is a xanthonoid present in Mangifera indica. It has been reported for a variety of pharmacological activities, including hepatoprotection. However, the major disadvantage of mangiferin is its reduced biological activity due to poor absorption, low bioavailability and rapid elimination from the body after administration. The aim of this study was to prepare a phospholipid complex of mangiferin to overcome these limitations and to investigate the impact of the complex on hepatoprotective activity and bioavailability. The results showed that the complex has an enhanced hepatoprotective and in vivo antioxidant activity as compared to pure mangiferin at the same dose level (30 and 60 mg kg⁻¹). The complex restored the levels of serum hepatic marker enzymes and liver antioxidant enzymes with respect to carbon tetrachloride-treated animals. The complex also increased the bioavailability of mangiferin in rat serum by 9.75-fold compared to pure mangiferin at the same dose level and enhanced the elimination half-life (t(1/2 el)) from 1.71 ± 0.12 h⁻¹ to 3.52 ± 0.27 h⁻¹. The results suggested that the complexation of mangiferin with soya phospholipid enhanced the hepatoprotection and in vivo antioxidant activity, which may be due to the improved bioavailability and pharmacokinetics of mangiferin in rat serum. © 2013 Society of Chemical Industry.

Lead Optimization of Anti-Malarial Propafenone Analogs

PubMed Central

Lowes, David; Pradhan, Anupam; Iyer, Lalitha V.; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W. Armand; Sigal, Martina; Clark, Julie A.; Wilson, Emily; Tang, Liang; Connelly, Michele C.; DeRisi, Joseph L.; Kyle, Dennis E.; Mirsalis, Jon; Guy, R. Kiplin

2015-01-01

Previously reported studies identified analogs of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are non-toxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges. PMID:22708838

The combined application of the Caco-2 cell bioassay coupled with in vivo (Gallus gallus) feeding trial represents an effective approach to predicting Fe bioavailability in humans

USDA-ARS?s Scientific Manuscript database

Research methods that predict Fe bioavailability for humans can be extremely useful in evaluating food fortification strategies, developing Fe-biofortified enhanced staple food crops and assessing the Fe bioavailability of meal plans that include such crops. In this review, research from four recent...

Oral bioavailability enhancement of raloxifene by developing microemulsion using D-optimal mixture design: optimization and in-vivo pharmacokinetic study.

PubMed

Shah, Nirmal; Seth, Avinashkumar; Balaraman, R; Sailor, Girish; Javia, Ankur; Gohil, Dipti

2018-04-01

The objective of this work was to utilize a potential of microemulsion for the improvement in oral bioavailability of raloxifene hydrochloride, a BCS class-II drug with 2% bioavailability. Drug-loaded microemulsion was prepared by water titration method using Capmul MCM C8, Tween 20, and Polyethylene glycol 400 as oil, surfactant, and co-surfactant respectively. The pseudo-ternary phase diagram was constructed between oil and surfactants mixture to obtain appropriate components and their concentration ranges that result in large existence area of microemulsion. D-optimal mixture design was utilized as a statistical tool for optimization of microemulsion considering oil, S mix , and water as independent variables with percentage transmittance and globule size as dependent variables. The optimized formulation showed 100 ± 0.1% transmittance and 17.85 ± 2.78 nm globule size which was identically equal with the predicted values of dependent variables given by the design expert software. The optimized microemulsion showed pronounced enhancement in release rate compared to plain drug suspension following diffusion controlled release mechanism by the Higuchi model. The formulation showed zeta potential of value -5.88 ± 1.14 mV that imparts good stability to drug loaded microemulsion dispersion. Surface morphology study with transmission electron microscope showed discrete spherical nano sized globules with smooth surface. In-vivo pharmacokinetic study of optimized microemulsion formulation in Wistar rats showed 4.29-fold enhancements in bioavailability. Stability study showed adequate results for various parameters checked up to six months. These results reveal the potential of microemulsion for significant improvement in oral bioavailability of poorly soluble raloxifene hydrochloride.

Preparation, characterization and in vitro/vivo evaluation of tectorigenin solid dispersion with improved dissolution and bioavailability.

PubMed

Shuai, Shuping; Yue, Shanlan; Huang, Qingting; Wang, Wei; Yang, Junyi; Lan, Ke; Ye, Liming

2016-08-01

The purpose of this study was to develop and evaluate a novel amorphous solid dispersion system for tectorigenin (TG). TG is one of isoflavone aglycones extracted from Iris tectorum and flowers of Pueraria thunbergiana, but its poor water solubility and low membrane permeability have severely restricted the clinical application. To increase the aqueous solubility and oral bioavailability of TG, we prepared the solid dispersions of tectorigenin (TG-SD) using a simple solvent evaporation process with TG, polyvinylpyrrolidone (PVP) and PEG4000 at weight ratio of 7:54:9 after tested in several ratios. The prepared solid dispersions of tectorigenin are duly characterized for drug morphological conversion, in vitro dissolution and in vivo bioavailability. The X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) studies have indicated the morphological conversion of tectorigenin to amorphous form. In vitro release profiles revealed that the % release of TG-SD was achieved 4.35-fold higher than that of the pure drug after 150 min. The oral bioavailability of the solid dispersion in rats was also increased based on AUC0-t and C max of TG-SD, which were 4.8- and 13.1-fold higher than that of TG crystal, respectively. It is worth noting that physical mixture containing TG, PEG4000 and PVP produced a similar level of oral exposure as TG-SD, suggesting that PEG4000 and PVP were able to enhance bioavailability of TG in rats. However, with the reduction of particle size, TG-SD provided the fastest oral absorption compared to physical mixture and pure drug. These results demonstrated that the efficacy of solid dispersions for the enhancement of TG oral bioavailability was by increasing its aqueous solubility and the solid dispersion formulation could be a viable option for enhancing the oral bioavailability of TG.

Studies of Cream Seeded Carioca Beans (Phaseolus vulgaris L.) from a Rwandan Efficacy Trial: In Vitro and In Vivo Screening Tools Reflect Human Studies and Predict Beneficial Results from Iron Biofortified Beans

PubMed Central

Tako, Elad; Reed, Spenser; Anandaraman, Amrutha; Beebe, Steve E.; Hart, Jonathan J.; Glahn, Raymond P.

2015-01-01

Iron (Fe) deficiency is a highly prevalent micronutrient insufficiency predominantly caused by a lack of bioavailable Fe from the diet. The consumption of beans as a major food crop in some populations suffering from Fe deficiency is relatively high. Therefore, our objective was to determine whether a biofortified variety of cream seeded carioca bean (Phaseolus vulgaris L.) could provide more bioavailable-Fe than a standard variety using in-vivo (broiler chicken, Gallus gallus) and in-vitro (Caco-2 cell) models. Studies were conducted under conditions designed to mimic the actual human feeding protocol. Two carioca-beans, a standard (G4825; 58μg Fe/g) and a biofortified (SMC; 106μg Fe/g), were utilized. Diets were formulated to meet the nutrient requirements of Gallus gallus except for Fe (33.7 and 48.7μg Fe/g, standard and biofortified diets, respectively). In-vitro observations indicated that more bioavailable-Fe was present in the biofortified beans and diet (P<0.05). In-vivo, improvements in Fe-status were observed in the biofortified bean treatment, as indicated by the increased total-body-Hemoglobin-Fe, and hepatic Fe-concentration (P<0.05). Also, DMT-1 mRNA-expression was increased in the standard bean treatment (P<0.05), indicating an upregulation of absorption to compensate for less bioavailable-Fe. These results demonstrate that the biofortified beans provided more bioavailable Fe; however, the in vitro results revealed that ferritin formation values were relatively low. Such observations are indicative of the presence of high levels of polyphenols and phytate that inhibit Fe absorption. Indeed, we identified higher levels of phytate and quercetin 3–glucoside in the Fe biofortified bean variety. Our results indicate that the biofortified bean line was able to moderately improve Fe-status, and that concurrent increase in the concentration of phytate and polyphenols in beans may limit the benefit of increased Fe-concentration. Therefore, specific targeting of such compounds during the breeding process may yield improved dietary Fe-bioavailability. Our findings are in agreement with the human efficacy trial that demonstrated that the biofortified carioca beans improved the Fe-status of Rwandan women. We suggest the utilization of these in vitro and in vivo screening tools to guide studies aimed to develop and evaluate biofortified staple food crops. This approach has the potential to more effectively utilize research funds and provides a means to monitor the nutritional quality of the Fe-biofortified crops once released to farmers. PMID:26381264

Studies of Cream Seeded Carioca Beans (Phaseolus vulgaris L.) from a Rwandan Efficacy Trial: In Vitro and In Vivo Screening Tools Reflect Human Studies and Predict Beneficial Results from Iron Biofortified Beans.

PubMed

Tako, Elad; Reed, Spenser; Anandaraman, Amrutha; Beebe, Steve E; Hart, Jonathan J; Glahn, Raymond P

2015-01-01

Iron (Fe) deficiency is a highly prevalent micronutrient insufficiency predominantly caused by a lack of bioavailable Fe from the diet. The consumption of beans as a major food crop in some populations suffering from Fe deficiency is relatively high. Therefore, our objective was to determine whether a biofortified variety of cream seeded carioca bean (Phaseolus vulgaris L.) could provide more bioavailable-Fe than a standard variety using in-vivo (broiler chicken, Gallus gallus) and in-vitro (Caco-2 cell) models. Studies were conducted under conditions designed to mimic the actual human feeding protocol. Two carioca-beans, a standard (G4825; 58 μg Fe/g) and a biofortified (SMC; 106 μg Fe/g), were utilized. Diets were formulated to meet the nutrient requirements of Gallus gallus except for Fe (33.7 and 48.7 μg Fe/g, standard and biofortified diets, respectively). In-vitro observations indicated that more bioavailable-Fe was present in the biofortified beans and diet (P<0.05). In-vivo, improvements in Fe-status were observed in the biofortified bean treatment, as indicated by the increased total-body-Hemoglobin-Fe, and hepatic Fe-concentration (P<0.05). Also, DMT-1 mRNA-expression was increased in the standard bean treatment (P<0.05), indicating an upregulation of absorption to compensate for less bioavailable-Fe. These results demonstrate that the biofortified beans provided more bioavailable Fe; however, the in vitro results revealed that ferritin formation values were relatively low. Such observations are indicative of the presence of high levels of polyphenols and phytate that inhibit Fe absorption. Indeed, we identified higher levels of phytate and quercetin 3-glucoside in the Fe biofortified bean variety. Our results indicate that the biofortified bean line was able to moderately improve Fe-status, and that concurrent increase in the concentration of phytate and polyphenols in beans may limit the benefit of increased Fe-concentration. Therefore, specific targeting of such compounds during the breeding process may yield improved dietary Fe-bioavailability. Our findings are in agreement with the human efficacy trial that demonstrated that the biofortified carioca beans improved the Fe-status of Rwandan women. We suggest the utilization of these in vitro and in vivo screening tools to guide studies aimed to develop and evaluate biofortified staple food crops. This approach has the potential to more effectively utilize research funds and provides a means to monitor the nutritional quality of the Fe-biofortified crops once released to farmers.

Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice

PubMed Central

Prasad, Sahdeo; Tyagi, Amit K.

2014-01-01

Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antibacterial activities as indicated by over 6,000 citations. In addition, over one hundred clinical studies have been carried out with curcumin. One of the major problems with curcumin is perceived to be the bioavailability. How curcumin should be delivered in vivo, how bioavailable is it, how well curcumin is absorbed and how it is metabolized, is the focus of this review. Various formulations of curcumin that are currently available are also discussed. PMID:24520218

Porous aerosil loading probucol using supercritical carbon dioxide: preparation, in vitro and in vivo characteristics.

PubMed

Chu, Chunxia; Liu, Muhua; Wang, Dongmei; Guan, Jibin; Cai, Cuifang; Sun, Yuanpeng; Zhang, Tianhong

2014-06-01

The aim of this study was to enhance the dissolution rate and oral bioavailability of probucol. Probucol was adsorbed onto aerosils via supercritical carbon dioxide (ScCO2) and the physicochemistry properties of probucol-aerosil powder were evaluated by differential scanning calorimetry, X-ray diffraction, infrared spectroscopy and scanning electron microscopy. Tablets of the probucol-aerosil powder were prepared by direct compression method. In the dissolution test, the probucol-aerosil tablets showed a significant enhanced dissolution rate compared with commercial tablets. Bioavailability study was carried out in beagle dogs. Probucol-aerosil tablets exhibited higher AUC and Cmax than commercial tablets. The improved dissolution and bioavailability of probucol-aerosil tablets were attributed to the amorphous state and good dispersion of probucol. It is a feasible method to enhance the oral bioavailability by adsorbing probucol onto aerosils via ScCO2.

Formulation and Optimization of Candesartan Cilexetil Nano Lipid Carrier: In Vitro and In Vivo Evaluation.

PubMed

Paudel, Anjan; Ameeduzzafar; Imam, Syed Sarim; Fazil, Mohd; Khan, Shahroz; Hafeez, Abdul; Ahmad, Farhan Jalees; Ali, Asgar

2017-01-01

The objective of this study was to formulate and optimize Candesartan Cilexetil (CC) loaded nanostructured lipid carriers (NLCs) for enhanced oral bioavailability. Glycerol monostearate (GMS), Oleic acid, Tween 80 and Span 40 were selected as a solid lipid, liquid lipid, surfactant and co- surfactant, respectively. The CC-NLCs were prepared by hot emulsion probe sonication technique and optimized using experimental design approach. The formulated CC-NLCs were evaluated for various physicochemical parameters and further optimized formulation (CC-NLC-Opt) was assessed for in vivo pharmacokinetic and pharmacodynamic activity. The optimized formulation (CC-NLC-Opt) showed particle size (183.5±5.89nm), PDI (0.228±0.13), zeta potential (-28.2±0.99mV), and entrapment efficiency (88.9±3.69%). The comparative in vitro release study revealed that CC-NLC-Opt showed significantly better (p<0.05) release and enhanced permeation as compared to CC-suspension. The in vivo pharmacokinetic study gave many folds increase in oral bioavailability than CC suspension, which was further confirmed by antihypertensive activity in a murine model. Thus, the results of ex vivo permeation, pharmacokinetic study and pharmacodynamics study suggest the potential of CC-NLCs for improved oral delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Silymarin liposomes improves oral bioavailability of silybin besides targeting hepatocytes, and immune cells.

PubMed

Kumar, Nitesh; Rai, Amita; Reddy, Neetinkumar D; Raj, P Vasanth; Jain, Prateek; Deshpande, Praful; Mathew, Geetha; Kutty, N Gopalan; Udupa, Nayanabhirama; Rao, C Mallikarjuna

2014-10-01

Silymarin, a hepatoprotective agent, has poor oral bioavailability. However, the current dosage form of the drug does not target the liver and inflammatory cells selectively. The aim of the present study was to develop lecithin-based carrier system of silymarin by incorporating phytosomal-liposomal approach to increase its oral bioavailability and to make it target-specific to the liver for enhanced hepatoprotection. The formulation was prepared by film hydration method. Release of drug was assessed at pH 1.2 and 7.4. Formulation was assessed for in vitro hepatoprotection on Chang liver cells, lipopolysaccharide-induced reactive oxygen species (ROS) production by RAW 267.4 (murine macrophages), in vivo efficacy against paracetamol-induced hepatotoxicity and pharmacokinetic study by oral route in Wistar rat. The formulation showed maximum entrapment (55%) for a lecithin-cholesterol ratio of 6:1. Comparative release profile of formulation was better than silymarin at pH 1.2 and pH 7.4. In vitro studies showed a better hepatoprotection efficacy for formulation (one and half times) and better prevention of ROS production (ten times) compared to silymarin. In in vivo model, paracetamol showed significant hepatotoxicity in Wistar rats assessed through LFT, antioxidant markers and inflammatory markers. The formulation was found more efficacious than silymarin suspension in protecting the liver against paracetamol toxicity and the associated inflammatory conditions. The liposomal formulation yielded a three and half fold higher bioavailability of silymarin as compared with silymarin suspension. Incorporating the phytosomal form of silymarin in liposomal carrier system increased the oral bioavailability and showed better hepatoprotection and better anti-inflammatory effects compared with silymarin suspension. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Enhanced anticancer activity and oral bioavailability of ellagic acid through encapsulation in biodegradable polymeric nanoparticles.

PubMed

Mady, Fatma M; Shaker, Mohamed A

2017-01-01

Despite the fact that various studies have investigated the clinical relevance of ellagic acid (EA) as a naturally existing bioactive substance in cancer therapy, little has been reported regarding the efficient strategy for improving its oral bioavailability. In this study, we report the formulation of EA-loaded nanoparticles (EA-NPs) to find a way to enhance its bioactivity as well as bioavailability after oral administration. Poly(ε-caprolactone) (PCL) was selected as the biodegradable polymer for the formulation of EA-NPs through the emulsion-diffusion-evaporation technique. The obtained NPs have been characterized by measuring particle size, zeta potential, Fourier transform infrared, differential scanning calorimetry, and X-ray diffraction. The entrapment efficiency and the release profile of EA was also determined. In vitro cellular uptake and cytotoxicity of the obtained NPs were evaluated using Caco-2 and HCT-116 cell lines, respectively. Moreover, in vivo study has been performed to measure the oral bioavailability of EA-NPs compared to free EA, using New Zealand white rabbits. NPs with distinct shape were obtained with high entrapment and loading efficiencies. Diffusion-driven release profile of EA from the prepared NPs was determined. EA-NP-treated HCT-116 cells showed relatively lower cell viability compared to free EA-treated cells. Fluorometric imaging revealed the cellular uptake and efficient localization of EA-NPs in the nuclear region of Caco-2 cells. In vivo testing revealed that the oral administration of EA-NPs produced a 3.6 times increase in the area under the curve compared to that of EA. From these results, it can be concluded that incorporation of EA into PCL as NPs enhances its oral bioavailability and activity.

Enhanced anticancer activity and oral bioavailability of ellagic acid through encapsulation in biodegradable polymeric nanoparticles

PubMed Central

Mady, Fatma M; Shaker, Mohamed A

2017-01-01

Despite the fact that various studies have investigated the clinical relevance of ellagic acid (EA) as a naturally existing bioactive substance in cancer therapy, little has been reported regarding the efficient strategy for improving its oral bioavailability. In this study, we report the formulation of EA-loaded nanoparticles (EA-NPs) to find a way to enhance its bioactivity as well as bioavailability after oral administration. Poly(ε-caprolactone) (PCL) was selected as the biodegradable polymer for the formulation of EA-NPs through the emulsion–diffusion–evaporation technique. The obtained NPs have been characterized by measuring particle size, zeta potential, Fourier transform infrared, differential scanning calorimetry, and X-ray diffraction. The entrapment efficiency and the release profile of EA was also determined. In vitro cellular uptake and cytotoxicity of the obtained NPs were evaluated using Caco-2 and HCT-116 cell lines, respectively. Moreover, in vivo study has been performed to measure the oral bioavailability of EA-NPs compared to free EA, using New Zealand white rabbits. NPs with distinct shape were obtained with high entrapment and loading efficiencies. Diffusion-driven release profile of EA from the prepared NPs was determined. EA-NP-treated HCT-116 cells showed relatively lower cell viability compared to free EA-treated cells. Fluorometric imaging revealed the cellular uptake and efficient localization of EA-NPs in the nuclear region of Caco-2 cells. In vivo testing revealed that the oral administration of EA-NPs produced a 3.6 times increase in the area under the curve compared to that of EA. From these results, it can be concluded that incorporation of EA into PCL as NPs enhances its oral bioavailability and activity. PMID:29066891

Simulation of Food Folate Digestion and Bioavailability of an Oxidation Product of 5-Methyltetrahydrofolate

PubMed Central

Ringling, Christiane

2017-01-01

Generating bioavailability data from in vivo studies is time-consuming and expensive. In vitro simulation can help to investigate factors influencing bioavailability or facilitate quantifying the impact of such factors. For folates, an efficient deconjugation of polyglutamates to the corresponding monoglutamates is crucial for bioavailability and highly dependent on the food matrix. Therefore, the bioaccessibility of folates of different foodstuffs was examined using a simulated digestion model with respect to folate stability and the efficiency of deconjugation. For realistic simulated deconjugation, porcine brush border membrane was used during the phase of the simulated digestion in the small intestine. For a better understanding of folate behaviour during digestion, single folate monoglutamates were also investigated with this in vitro digestion model. The results for bioaccessibility were compared with data from a human bioavailability study. They support the idea that both stability and deconjugation have an influence on bioaccessibility and thus on bioavailability. Tetrahydrofolate is probably lost completely or at least to a high extent and the stability of 5-methyltetrahydrofolate depends on the food matrix. Additionally, 5-methyltetrahydrofolate can be oxidised to a pyrazino-s-triazine (MeFox), whose absorption in the human intestinal tract was shown tentatively. PMID:28862677

Simulation of Food Folate Digestion and Bioavailability of an Oxidation Product of 5-Methyltetrahydrofolate.

PubMed

Ringling, Christiane; Rychlik, Michael

2017-09-01

Generating bioavailability data from in vivo studies is time-consuming and expensive. In vitro simulation can help to investigate factors influencing bioavailability or facilitate quantifying the impact of such factors. For folates, an efficient deconjugation of polyglutamates to the corresponding monoglutamates is crucial for bioavailability and highly dependent on the food matrix. Therefore, the bioaccessibility of folates of different foodstuffs was examined using a simulated digestion model with respect to folate stability and the efficiency of deconjugation. For realistic simulated deconjugation, porcine brush border membrane was used during the phase of the simulated digestion in the small intestine. For a better understanding of folate behaviour during digestion, single folate monoglutamates were also investigated with this in vitro digestion model. The results for bioaccessibility were compared with data from a human bioavailability study. They support the idea that both stability and deconjugation have an influence on bioaccessibility and thus on bioavailability. Tetrahydrofolate is probably lost completely or at least to a high extent and the stability of 5-methyltetrahydrofolate depends on the food matrix. Additionally, 5-methyltetrahydrofolate can be oxidised to a pyrazino-s-triazine (MeFox), whose absorption in the human intestinal tract was shown tentatively.

Pharmacokinetics of the Novel, Selective, Non-steroidal Mineralocorticoid Receptor Antagonist Finerenone in Healthy Volunteers: Results from an Absolute Bioavailability Study and Drug-Drug Interaction Studies In Vitro and In Vivo.

PubMed

Heinig, Roland; Gerisch, Michael; Engelen, Anna; Nagelschmitz, Johannes; Loewen, Stephanie

2018-05-19

Finerenone is a selective, non-steroidal mineralocorticoid receptor antagonist. In vivo and in vitro studies were performed to assess absolute bioavailability of finerenone, the effect of metabolic enzyme inhibitors on the pharmacokinetics of finerenone and its metabolites, the quantitative contribution of the involved enzymes cytochrome P450 (CYP) 3A4 and CYP2C8 and the relevance of gut wall versus liver metabolism. The pharmacokinetics, safety and tolerability of finerenone (1.25-10 mg orally or 0.25-1.0 mg intravenously) were evaluated in healthy male volunteers in four crossover studies. Absolute bioavailability was assessed in volunteers receiving finerenone orally and by intravenous infusion (n = 15) and the effects of erythromycin (n = 15), verapamil (n = 13) and gemfibrozil (n = 16) on finerenone pharmacokinetics were investigated. Finerenone was also incubated with cryopreserved human hepatocytes in vitro in the presence of erythromycin, verapamil or gemfibrozil. Finerenone absolute bioavailability was 43.5% due to first-pass metabolism in the gut wall and liver. The geometric mean AUC 0-∞ ratios of finerenone (drug + inhibitor/drug alone) were 3.48, 2.70 and 1.10 with erythromycin, verapamil and gemfibrozil, respectively. The contribution ratio of CYP3A4 to the metabolic clearance of finerenone derived from these values was 0.88-0.89 and was consistent with estimations based on in vitro data, with the remaining metabolic clearance due to CYP2C8 involvement. Finerenone is predominantly metabolized by CYP3A4 in the gut wall and liver. Increases in systemic exposure upon concomitant administration of inhibitors of this isoenzyme are predictable and consistent with in vitro data. Inhibition of CYP2C8, the second involved metabolic enzyme, has no relevant effect on finerenone in vivo.

Controlled-release systemic delivery - a new concept in cancer chemoprevention

PubMed Central

2012-01-01

Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo. PMID:22696595

Preparation and evaluation of self-microemulsions for improved bioavailability of ginsenoside-Rh1 and Rh2.

PubMed

Yang, Feifei; Zhou, Jing; Hu, Xiao; Yu, Stephanie Kyoungchun; Liu, Chunyu; Pan, Ruile; Chang, Qi; Liu, Xinmin; Liao, Yonghong

2017-10-01

Due to intestinal cytochrome P450 (CYP450)-mediated metabolism and P-glycoprotein (P-gp) efflux, poor oral bioavailability hinders ginsenoside-Rh1 (Rh1) and ginsenoside-Rh2 (Rh2) from clinical application. In this study, Rh1 and Rh2 were incorporated into two self-microemulsions (SME-1 and SME-2) to improve oral bioavailability. SME-1 contained both CYP450 and P-gp inhibitory excipients while SME-2 only consisted of P-gp inhibitory excipients. Results for release, cellular uptake, transport, and lymph node distribution demonstrated no significant difference between either self-microemulsions in vivo, but were elevated significantly in comparison to the free drug. The pharmaceutical profiles in vivo showed that the bioavailability of Rh1 in SME-1 (33.25%) was significantly higher than that in either SME-2 (21.28%) or free drug (12.92%). There was no significant difference in bioavailability for Rh2 between SME-1 (48.69%) or SME-2 (41.73%), although they both had remarkable increase in comparison to free drug (15.02%). We confirmed that SME containing CYP450 and P-gp inhibitory excipient could distinctively improve the oral availabilities of Rh1 compared to free drug or SME containing P-gp inhibitory excipient. No notable increase was observed between either SME for Rh2, suggesting that Rh2 undergoes P-gp-mediated efflux, but may not undergo distinct CYP450-mediated metabolism.

Enhancing oral bioavailability using preparations of apigenin-loaded W/O/W emulsions: In vitro and in vivo evaluations.

PubMed

Kim, Bum-Keun; Cho, Ah-Ra; Park, Dong-June

2016-09-01

We analyzed the physical properties and digestibility of apigenin-loaded emulsions as they passed through a simulated digestion model. As the emulsion passed through the simulated stages of digestion, the particle size and zeta potential of all the samples changed, except for the soybean oil-Tween 80 emulsion, in which zeta potential remained constant, through all stages, indicating that soybean oil-Tween 80 emulsions may have an effect on stability during all stages of digestion. Fluorescence microscopy was used to observe the morphology of the emulsions at each step. The in vivo pharmacokinetics revealed that apigenin-loaded soybean oil-Tween 80 emulsions had a higher oral bioavailability than did the orally administrated apigenin suspensions. These results suggest that W/O/W multiple emulsions formulated with soybean oil and tween 80 have great potential as targeted delivery systems for apigenin, and may enhance in vitro and in vivo bioavailability when they pass through the digestive tract. Copyright © 2016 Elsevier Ltd. All rights reserved.

Self-microemulsifying drug delivery system improves curcumin dissolution and bioavailability.

PubMed

Wu, Xuemei; Xu, Jianhua; Huang, Xiuwang; Wen, Caixia

2011-01-01

Curcumin has a wide spectrum of biological and pharmacological activities, but it has not yet been approved as a therapeutic agent because of its low solubility and stability in aqueous solution, and the relatively low bioavailability in vivo. To overcome these limitations, self-microemulsifying drug delivery system (SMEDDS) of curcumin was developed. Various oils, surfactants, and cosurfactants were selected to optimize the formulation. Pseudoternary phase diagrams were constructed and orthogonal design was used to compare the oil-in-water (o/w) microemulsion-forming capacity of different oils/surfactants/cosurfactants. The solubility of curcumin in various oils and cosurfactants was determined to find suitable ingredients with a good solubilizing capacity. Droplet size was measured to obtain the concentration of oil, surfactant, and cosurfactant for forming stable microemulsion. Furthermore, its quality and bioavailability in mice were assessed. Pseudoternary phase diagrams and solubility test showed that the formulation of SMEDDS composed of 20% ethanol, 60% Cremophor RH40®, and 20% isopropyl myristate, in which the concentration of curcumin reached 50 mg/mL. Curcumin was released completely from SMEDDS at 10 minutes. The developed SMEDDS formulation improved the oral bioavailability of curcumin significantly, and the relative oral bioavailability of SMEDDS compared with curcumin suspension was 1213%. The SMEDDS can significantly increase curcumin dissolution in vitro and bioavailability in vivo.

Sublingual Delivery of Frovatriptan: An Indication of Potential Alternative Route

PubMed Central

Verma, Surajpal; Prasad, Shyam Baboo

2014-01-01

Frovatriptan, a 5-HT1B and 5-HT1D receptor agonist, is used for the treatment of acute migraine attack. This molecule is classified into second line therapy because of its slow onset of action (peak response obtained after 4 hours of administration) and low bioavailability (25%). Moreover, its therapy is the most costly among all triptans. Attempt has been made in present work to suggest a way out to fasten its onset of action and to enhance its bioavailability. Prepared tablets were evaluated by physicochemical tests, in vitro permeation studies, ex vivo permeation studies, and histopathological studies. Suitable mathematical calculations were performed to calculate the minimum amount of bioavailability that could be enhanced. Tablets containing chitosan (5% w/w) were found to give optimum results. Prepared tablets can double the bioavailability of frovatriptan and can initiate its response within 10 minutes of its administration. Suggestive alternative has the potential to increase the efficacy of frovatriptan for treating acute migraine attack. PMID:27433492

Improvement of effect of water-in-oil microemulsion as an oral delivery system for fexofenadine: in vitro and in vivo studies

PubMed Central

Gundogdu, E; Alvarez, I Gonzalez; Karasulu, E

2011-01-01

Fexofenadine (FEX) has high solubility and low permeability (BCS, Class III). In this work, novel FEX loaded water in oil microemulsion (w/o) was designed to improve bioavailability and compared with Fexofen® syrup in in vitro and in vivo studies. In addition, pharmacokinetic parameters in permeability studies were estimated by using WinNonLin software program. w/o microemulsion system was optimized using a pseudoternary phase diagram, composed of span 80/lutrol F 68 (9.5:0.5 w/w), oleic acide, isopropyl alcohol and water as surfactant mixture; oil and cosurfactant was developed for oral drug delivery. w/o microemulsion systems were characterized by phase behavior, particle size, viscosity and solubilization capacity. In vitro studies were studied using Caco-2 cell monolayer. Pharmacokinetic parameters of w/o microemulsion were investigated in rabbits and compared to Fexofen® syrup. Fexofen® syrup and microemulsion were administered by oral gavage at 6 mg/kg of the same concentration. The experimental results indicated that microemulsion (HLB = 5.53) formed nanometer sized droplets (33.29 ± 1.76) and had good physical stability. This microemulsion increased the oral bioavailability of FEX which was highly water-soluble but fairly impermeable. The relative bioavailability of FEX microemulsion was about 376.76% compared with commercial syrup in rabbits. In vitro experiments were further employed for the enhanced effect of the microemulsion for FEX. These results suggest that novel w/o microemulsion plays an important role in enhancing oral bioavailability of low permeability drugs. PMID:21904453

In vivo bioavailability and in vitro bioaccessibility of perfluorooctanoic acid (PFOA) in food matrices: correlation analysis and method development.

PubMed

Li, Kan; Li, Chao; Yu, Nan-Yang; Juhasz, Albert L; Cui, Xin-Yi; Ma, Lena Q

2015-01-06

Food is a major source of human exposure to perfluorooctanoic acid (PFOA), however, PFOA bioavailability in food has not been studied. An in vivo mouse model and three in vitro methods (unified BARGE method, UBM; physiologically based extraction test, PBET; and in vitro digestion method, IVD) were used to determine the relative bioavailability and bioaccessibility of PFOA in the presence of 17 foods. PFOA was mixed with foods of different nutritional compositions and fed to mice over a 7-d period. PFOA relative bioavailability was determined by comparing PFOA accumulation in the liver following PFOA exposure via food to that in water. PFOA bioavailability relative to water ranged from 4.30 ± 0.80 to 69.0 ± 11.9% and was negatively correlated with lipid content (r = 0.76). This was possibly due to competitive sorption of free fatty acids with PFOA onto transporters on intestine epithelial cells. Besides, cations in the gastrointestinal tract, such as Ca(2+) and Mg(2+), are capable of complexing PFOA and partitioning to the lipid phase. On the other hand, when assessed using in vitro assays, PFOA bioaccessibility varied with methods, being 8.7-73% (UBM), 9.8-99% (PBET), and 21-114% (IVD). PFOA bioaccessibility was negatively correlated with lipid content when assessed using UBM (r = 0.82); however, a poor correlation with food composition was observed for PBET and IVD (r = 0.01-0.50). When in vivo and in vitro data were compared, a strong correlation was observed for UBM (r = 0.79), but poor relationships were observed for PBET and IVD (r = 0.11-0.22). This was probably because the higher lipolysis ability and presence of Ca(2+) and Mg(2+) in the gastrointestinal fluid of UBM resulted in a lower potential to form stable micelles compared to PBET and IVD. These results indicated that PFOA relative bioavailability was mainly affected by lipid content in foods, and UBM has the potential to determine PFOA bioaccessibility in food samples.

Influence of compost addition on lead and arsenic bioavailability in reclaimed orchard soil assessed using Porcellio scaber bioaccumulation test

PubMed Central

Udovic, M.; McBride, M.B.

2015-01-01

A long history of lead arsenate application in orchards has led to significant accumulation of Pb and As in the topsoil. Besides the threat that such soils represent for the environment, reclamation of old orchards for agricultural purposes implies the exposure of humans to Pb and As. In this study we assessed the influence of vegetable compost addition (as a sustainable agricultural practice) to contaminated acidic orchard soil on Pb and As bioavailability, assessed with two selective non-exhaustive chemical extractions and with an in vivo bioaccumulation test with an isopod (P. scaber). The treatment with compost caused a significant increase in soil pH and total carbon content, resulting in a consistent decrease of Pb bioavailability. In contrast, the bioavailability of As increased, indicating that a complementary treatment should be used for reducing the bioavailability of As in old orchard soils. This is the first report on the use of As accumulation in P. scaber as a tool for the assessment of As bioavailability in contaminated orchard soil. PMID:22240057

Nonlinear absorption kinetics of self-emulsifying drug delivery systems (SEDDS) containing tocotrienols as lipophilic molecules: in vivo and in vitro studies.

PubMed

Alqahtani, Saeed; Alayoubi, Alaadin; Nazzal, Sami; Sylvester, Paul W; Kaddoumi, Amal

2013-07-01

Self-emulsifying drug delivery systems (SEDDS) have been broadly used to promote the oral absorption of poorly water-soluble drugs. The purpose of the current study was to evaluate the in vivo oral bioavailability of vitamin E isoforms, δ-tocotrienol (δ-T3) and γ-tocotrienol (γ-T3) administered as SEDDS, as compared to commercially available UNIQUE E® Tocotrienols capsules. Results from studies in rats showed that low dose treatment with δ-T3 (90%) and γ-T3 (10%) formulated SEDDS showed bioavailability of 31.5% and 332%, respectively. However, bioavailability showed a progressive decrease with increased treatment dose that displayed nonlinear absorption kinetics. Additional in vitro studies examining cellular uptake studies in Caco 2 cells revealed that the SEDDS formulation increased passive permeability of δ-T3 and γ-T3 by threefold as compared to the commercial capsule formulation. These studies also showed that free surfactants decreased δ-T3 and γ-T3 absorption. Specifically, combined treatment cremophor EL or labrasol with tocotrienols caused a 60-85% reduction in the cellular uptake of δ-T3 and γ-T3 and these effects appear to result from surfactant-induced inhibition of the δ-T3 and γ-T3 transport protein Niemann-Pick C1-like 1 (NPC1L1). In summary, results showed that SEDDS formulation significantly increases the absorption and bioavailability δ-T3 and γ-T3. However, this effect is self-limiting because treatment with increasing doses of SEDDS appears to be associated with a corresponding increase in free surfactants levels that directly and negatively impact tocotrienol transport protein function and results in nonlinear absorption kinetics and a progressive decrease in δ-T3 and γ-T3 absorption and bioavailability.

Pharmacokinetics and Bioavailability of the Isoflavones Formononetin and Ononin and Their in Vitro Absorption in Ussing Chamber and Caco-2 Cell Models.

PubMed

Luo, Li-Yu; Fan, Miao-Xuan; Zhao, Hai-Yu; Li, Ming-Xing; Wu, Xu; Gao, Wen-Yuan

2018-03-21

Formononetin and its glycoside ononin are bioactive isoflavones widely present in legumes. The present study investigated the pharmacokinetics, bioavailability, and in vitro absorption of formononetin and ononin. After an oral administration to rats, formononetin showed a higher systemic exposure over ononin. The oral bioavailability of formononetin and ononin were 21.8% and 7.3%, respectively. Ononin was more bioavailable than perceived, and its bioavailability reached 21.7% when its metabolite formononetin was taken into account. Both formononetin and ononin exhibited better absorption in large intestine segments than that in small intestine segments. Formononetin displayed a better permeability in all intestinal segments over ononin. Transport of formononetin across Caco-2 cell monolayer was mainly through passive diffusion, while ononin was actively pumped out by MRP2 but not P-gp. The results provide evidence for better understanding of the pharmacological actions of formononetin and ononin, which advocates more in vivo evaluations or human trials.

In vitro evaluation of dietary compounds to reduce mercury bioavailability.

PubMed

Jadán-Piedra, Carlos; Vélez, Dinoraz; Devesa, Vicenta

2018-05-15

Mercury in foods, in inorganic form [Hg(II)] or as methylmercury (CH 3 Hg), can have adverse effects. Its elimination from foods is not technologically viable. To reduce human exposure, possible alternatives might be based on reducing its intestinal absorption. This study evaluates the ability of 23 dietary components to reduce the amount of mercury that is absorbed and reaches the bloodstream (bioavailability). We determined their effect on uptake of mercury in Caco-2 cells, a model of intestinal epithelium, exposed to Hg(II) and CH 3 Hg standards and to swordfish bioaccessible fractions. Cysteine, homocysteine, glutathione, quercetin, albumin and tannic reduce bioavailability of both mercury species. Fe(II), lipoic acid, pectin, epigallocatechin and thiamine are also effective for Hg(II). Some of these strategies also reduce Hg bioavailability in swordfish (glutathione, cysteine, homocysteine). Moreover, extracts and supplements rich in these compounds are also effective. This knowledge may help to define dietary strategies to reduce in vivo mercury bioavailability. Copyright © 2017 Elsevier Ltd. All rights reserved.

Topical bioavailability of diclofenac from locally-acting, dermatological formulations.

PubMed

Cordery, S F; Pensado, A; Chiu, W S; Shehab, M Z; Bunge, A L; Delgado-Charro, M B; Guy, R H

2017-08-30

Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo - in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated. Copyright © 2017 Elsevier B.V. All rights reserved.

Microparticles Containing Curcumin Solid Dispersion: Stability, Bioavailability and Anti-Inflammatory Activity.

PubMed

Teixeira, C C C; Mendonça, L M; Bergamaschi, M M; Queiroz, R H C; Souza, G E P; Antunes, L M G; Freitas, L A P

2016-04-01

This work aimed at improving the solubility of curcumin by the preparation of spray-dried ternary solid dispersions containing Gelucire®50/13-Aerosil® and quantifying the resulting in vivo oral bioavailability and anti-inflammatory activity. The solid dispersion containing 40% of curcumin was characterised by calorimetry, infrared spectroscopy and X-ray powder diffraction. The solubility and dissolution rate of curcumin in aqueous HCl or phosphate buffer improved up to 3600- and 7.3-fold, respectively. Accelerated stability test demonstrated that the solid dispersion was stable for 9 months. The pharmacokinetic study showed a 5.5-fold increase in curcumin in rat blood plasma when compared to unprocessed curcumin. The solid dispersion also provided enhanced anti-inflammatory activity in rat paw oedema. Finally, the solid dispersion proposed here is a promising way to enhance curcumin bioavailability at an industrial pharmaceutical perspective, since its preparation applies the spray drying, which is an easy to scale up technique. The findings herein stimulate further in vivo evaluations and clinical tests as a cancer and Alzheimer chemoprevention agent.

BIOAVAILABLE AIR PARTICULATE POLLUTION CONSTITUENTS DIRECTLY ALTER CARDIOVASCULAR FUNCTION EX VIVO

EPA Science Inventory

Epidemiological studies have reported associations between particulate air pollution exposure and cardiovascular (CV) effects within susceptible individuals. Particle characteristics and biological mechanisms responsible for these observations are not known. We examined whether s...

Flavones: Food Sources, Bioavailability, Metabolism, and Bioactivity12

PubMed Central

Hostetler, Gregory L; Ralston, Robin A; Schwartz, Steven J

2017-01-01

Flavones are a class of flavonoids that are a subject of increasing interest because of their biological activities in vitro and in vivo. This article reviews the major sources of flavones and their concentrations in food and beverages, which vary widely between studies. It also covers the roles of flavones in plants, the influence of growing conditions on their concentrations, and their stability during food processing. The absorption and metabolism of flavones are also reviewed, in particular the intestinal absorption of both O- and C-glycosides. Pharmacokinetic studies in both animals and humans are described, comparing differences between species and the effects of glycosylation on bioavailability. Biological activity in animal models and human dietary intervention studies is also reviewed. A better understanding of flavone sources and bioavailability is needed to understand mechanisms of action and nutritional intervention. PMID:28507008

Pediatric suppositories of sulpiride solid dispersion for treatment of Tourette syndrome: in vitro and in vivo investigations.

PubMed

Zidan, Ahmed S; Emam, Sherif E; Shehata, Tamer M; Ghazy, Fakhr-eldin S

2015-06-01

Pharmaceutical development was adopted in the current study to propose a pediatric rectal formulation of sulpiride as a substitute to the available oral or parenteral formulations in the management of Tourette syndrome (TS). The goal was to formulate a product that is easy to use, stable, and highly bioavailable and to achieve a rapid clinical efficacy. Towards this aim, sulpiride solid dispersion (SD) with tartaric acid at a weight ratio of 1:0.25 was incorporated into different suppository bases, namely witepsol W25, witepsol H15, witepsol E75, suppocire NA, suppocire A, glycerogelatin, and polyethylene glycols. The formulae were evaluated in vitro using different pharmacotechnical methods such as visual, melting, weight and content uniformities, drug release, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and X-ray diffraction (XRD) analyses. In vivo bioavailability was also assessed in rabbits to compare the bioavailability of either raw sulpiride-incorporated or its SD-incorporated witepsol H15-based suppositories to its oral suspension (reference). Sulpiride SD-incorporated witepsol H15 formulation showed acceptable in vitro characteristics with a bioavailability of 117% relative to oral dosing, which excel that in humans (27% after dosing of oral product). In addition, the proposed formula not only passed the 6-month stability study but also proposed a promising scale-up approach. Hence, it showed a great potential for pediatric product development to manage TS in rural areas.

Solid lipid nanoparticles loaded with iron to overcome barriers for treatment of iron deficiency anemia.

PubMed

Hosny, Khaled Mohamed; Banjar, Zainy Mohammed; Hariri, Amani H; Hassan, Ali Habiballah

2015-01-01

According to the World Health Organization, 46% of the world's children suffer from anemia, which is usually treated with iron supplements such as ferrous sulfate. The aim of this study was to prepare iron as solid lipid nanoparticles, in order to find an innovative way for alleviating the disadvantages associated with commercially available tablets. These limitations include adverse effects on the digestive system resulting in constipation and blood in the stool. The second drawback is the high variability in the absorption of iron and thus in its bioavailability. Iron solid lipid nanoparticles (Fe-SLNs) were prepared by hot homogenization/ultrasonication. Solubility of ferrous sulfate in different solid lipids was measured, and effects of process variables such as the surfactant type and concentration, homogenization and ultrasonication times, and charge-inducing agent on the particle size, zeta potential, and encapsulation efficiency were determined. Furthermore, in vitro drug release and in vivo pharmacokinetics were studied in rabbits. Results indicated that Fe-SLNs consisted of 3% Compritol 888 ATO, 1% Lecithin, 3% Poloxamer 188, and 0.2% dicetylphosphate, with an average particle size of 25 nm with 92.3% entrapment efficiency. In vivo pharmacokinetic study revealed more than fourfold enhanced bioavailability. In conclusion, Fe-SLNs could be a promising carrier for iron with enhanced oral bioavailability.

Novel flavonoid-based biodegradable nanoparticles for effective oral delivery of etoposide by P-glycoprotein modulation: an in vitro, ex vivo and in vivo investigations.

PubMed

Fatma, Sharmeen; Talegaonkar, Sushama; Iqbal, Zeenat; Panda, Amulya Kumar; Negi, Lalit Mohan; Goswami, Dinesh Giri; Tariq, Mohammad

2016-01-01

A receptor level interaction of etoposide with P-glycoprotein (P-gp) and subsequent intestinal efflux has an adverse effect on its oral absorption. The present work is aimed to enhance the bioavailability of etoposide by co-administering it with quercetin (a P-gp inhibitor) in dual-loaded polymeric nanoparticle formulation. Poly-lactic-co-glycolic acid (PLGA) nanoparticles were optimized for various parameters like o/w phase volume ratio, poly-vinyl alcohol concentration, PLGA concentration and sonication time. The cytotoxicity studies (MTT assay) revealed a 9- and 11-fold decrease in the IC 50 values for etoposide-loaded nanoparticles (ENP) and etoposide + quercetin dual-loaded nanoparticles (EQNP) when compared to that of free etoposide, respectively, and the results were further supported by florescent-activated cell sorter studies. The confocal imaging of the intestinal sections treated with ENP and EQNP containing fluorescent probe (rhodamine) showed the superiority of the EQNP to permeate deeper. Furthermore, pharmacokinetic studies on rats revealed that EQNP exhibited a 2.4-fold increase in bioavailability of etoposide than ENP with no quercetin. The developed loaded nanoparticles have the high potential to enhance the bioavailability of the etoposide and sensitize the resistant cells.

A novel surfactant-free lipid-based formulation for improving oral bioavailability of loratadine using colloidal silicon dioxide as emulsifier and solid carrier.

PubMed

Huang, Ri; Tan, Yonggang; Shen, Lao; Wang, Tao; Quan, Dongqin

2018-05-08

The purpose of this study was to develop an innovative surfactant-free lipid-based formulation (LF) for improving oral bioavailability of loratadine based on using solid particles colloidal silicon dioxide (CSD) as emulsifier and solid carrier. Loratadine was dissolved in oil solution with the aid of co-solvent and LF were prepared by a simple adsorption and milling technique. The LF Powder was evaluated in terms of angle of repose and X-ray powder diffraction. After dispersing and emulsifying in water, the particle size and morphology were also characterized. In vitro dissolution and pharmacokinetic behavior in vivo were also studied. Orthogonal design indicated that the amount of CSD in formulations had a major and significant influence on emulsification. The optimal formulation showed LF with good flowability and without crystallization or deposition of loratadine in it. After dispersing in water, an emulsion with mean droplet size of 1.2μm was obtained. Although the dissolution of drug from LF was slower in vitro in acidic aqueous solution, pharmacokinetic studies in vivo showed that the bioavailability of loratadine increased 2.49-fold by CF compared to commercial tablet. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Lipid-based liquid crystalline nanoparticles as oral drug delivery vehicles for poorly water-soluble drugs: cellular interaction and in vivo absorption

PubMed Central

Zeng, Ni; Gao, Xiaoling; Hu, Quanyin; Song, Qingxiang; Xia, Huimin; Liu, Zhongyang; Gu, Guangzhi; Jiang, Mengyin; Pang, Zhiqing; Chen, Hongzhuan; Chen, Jun; Fang, Liang

2012-01-01

Background Lipid-based liquid crystalline nanoparticles (LCNPs) have attracted growing interest as novel drug-delivery systems for improving the bioavailability of both hydrophilic and hydrophobic drugs. However, their cellular interaction and in vivo behavior have not been fully developed and characterized. Methods In this study, self-assembled LCNPs prepared from soy phosphatidylcholine and glycerol dioleate were developed as a platform for oral delivery of paclitaxel. The particle size of empty LCNPs and paclitaxel-loaded LCNPs was around 80 nm. The phase behavior of the liquid crystalline matrix was characterized using crossed polarized light microscopy and small-angle X-ray scattering, and showed both reversed cubic and hexagonal phase in the liquid crystalline matrix. Transmission electron microscopy and cryofield emission scanning electron microscopy analysis revealed an inner winding water channel in LCNPs and a “ ball-like”/“hexagonal” morphology. Results Cellular uptake of LCNPs in Caco-2 cells was found to be concentration-dependent and time-dependent, with involvement of both clathrin and caveolae/lipid raft-mediated endocytosis. Under confocal laser scanning microscopy, soy phosphatidylcholine was observed to segregate from the internalized LCNPs and to fuse with the cell membrane. An in vivo pharmacokinetic study showed that the oral bioavailability of paclitaxel-loaded LCNPs (13.16%) was 2.1 times that of Taxol® (the commercial formulation of paclitaxel, 6.39%). Conclusion The findings of this study suggest that this LCNP delivery system may be a promising candidate for improving the oral bioavailability of poorly water-soluble agents. PMID:22888230

Preclinical pilot study monitoring topical drug penetration and dermal bioavailability of a peptidase inhibitor from different galenic formulations into pig dermis, using cutaneous microdialysis.

PubMed

Quist, S R; Heimburg, A; Bank, U; Mahnkopf, D; Koch, G; Gollnick, H; Täger, M; Ansorge, S

2017-08-01

Cutaneous microdialysis (CM) is an ex vivo technique that allows study of tissue chemistry, including bioavailability of actual tissue concentration of unbound drug in the interstitial fluid of the body. To test the penetration and dermal bioavailability of galenic formulations of the small-molecule IP10.C8, a dual-protease inhibitor of the dipeptidyl peptidase and aminopeptidase families. Using CM, we tested the penetration and dermal bioavailability of IP10.C8 into the dermis and subcutis of pigs, and determined the tissue concentration of IP10.C8 enzymatically, using an enzyme activity assay (substrate Gly-Pro-pNA) and high performance liquid chromatography. Dermal bioavailability was enhanced by using microemulsion or the addition of the penetration enhancer oleic acid to a hydroxyethylcellulose (HEC) gel formulation. Dermal bioavailability was also enhanced when galenic formulations were prepared with higher pH (7.5 vs. 6.5) or higher drug concentration (5% vs. 1%) in HEC gel. It seems possible, using CM for topical skin penetration testing in anaesthetized domestic pigs, to test the bioavailability of newly designed drugs. However, the experimental time is limited due to the anaesthesia, and is dependent on drug recovery. Validation of this technique for routine use is challenging, and more experiments are needed to validate this preclinical set-up. © 2017 British Association of Dermatologists.

Optimized nano-transfersomal films for enhanced sildenafil citrate transdermal delivery: ex vivo and in vivo evaluation

PubMed Central

Badr-Eldin, Shaimaa M; Ahmed, Osamaa AA

2016-01-01

Sildenafil citrate (SLD) is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor used for the oral treatment of erectile dysfunction and, more recently, for other indications, including pulmonary hypertension. The challenges facing the oral administration of the drug include poor bioavailability and short duration of action that requires frequent administration. Thus, the objective of this work is to formulate optimized SLD nano-transfersomal transdermal films with enhanced and controlled permeation aiming at surmounting the previously mentioned challenges and hence improving the drug bioavailability. SLD nano-transfersomes were prepared using modified lipid hydration technique. Central composite design was applied for the optimization of SLD nano-transfersomes with minimized vesicular size. The independent variables studied were drug-to-phospholipid molar ratio, surfactant hydrophilic lipophilic balance, and hydration medium pH. The optimized SLD nano-transfersomes were developed and evaluated for vesicular size and morphology and then incorporated into hydroxypropyl methyl cellulose transdermal films. The optimized transfersomes were unilamellar and spherical in shape with vesicular size of 130 nm. The optimized SLD nano-transfersomal films exhibited enhanced ex vivo permeation parameters with controlled profile compared to SLD control films. Furthermore, enhanced bioavailability and extended absorption were demonstrated by SLD nano-transfersomal films as reflected by their significantly higher maximum plasma concentration (Cmax) and area under the curve and longer time to maxi mum plasma concentration (Tmax) compared to control films. These results highlighted the potentiality of optimized SLD nano-transfersomal films to enhance the transdermal permeation and the bioavailability of the drug with the possible consequence of reducing the dose and administration frequency. PMID:27103786

Optimized nano-transfersomal films for enhanced sildenafil citrate transdermal delivery: ex vivo and in vivo evaluation.

PubMed

Badr-Eldin, Shaimaa M; Ahmed, Osamaa Aa

2016-01-01

Sildenafil citrate (SLD) is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor used for the oral treatment of erectile dysfunction and, more recently, for other indications, including pulmonary hypertension. The challenges facing the oral administration of the drug include poor bioavailability and short duration of action that requires frequent administration. Thus, the objective of this work is to formulate optimized SLD nano-transfersomal transdermal films with enhanced and controlled permeation aiming at surmounting the previously mentioned challenges and hence improving the drug bioavailability. SLD nano-transfersomes were prepared using modified lipid hydration technique. Central composite design was applied for the optimization of SLD nano-transfersomes with minimized vesicular size. The independent variables studied were drug-to-phospholipid molar ratio, surfactant hydrophilic lipophilic balance, and hydration medium pH. The optimized SLD nano-transfersomes were developed and evaluated for vesicular size and morphology and then incorporated into hydroxypropyl methyl cellulose transdermal films. The optimized transfersomes were unilamellar and spherical in shape with vesicular size of 130 nm. The optimized SLD nano-transfersomal films exhibited enhanced ex vivo permeation parameters with controlled profile compared to SLD control films. Furthermore, enhanced bioavailability and extended absorption were demonstrated by SLD nano-transfersomal films as reflected by their significantly higher maximum plasma concentration (C max) and area under the curve and longer time to maxi mum plasma concentration (T max) compared to control films. These results highlighted the potentiality of optimized SLD nano-transfersomal films to enhance the transdermal permeation and the bioavailability of the drug with the possible consequence of reducing the dose and administration frequency.

Volume to dissolve applied dose (VDAD) and apparent dissolution rate (ADR): tools to predict in vivo bioavailability from orally applied drug suspensions.

PubMed

Muenster, Uwe; Pelzetter, Christian; Backensfeld, Thomas; Ohm, Andreas; Kuhlmann, Thomas; Mueller, Hartwig; Lustig, Klemens; Keldenich, Jörg; Greschat, Susanne; Göller, Andreas H; Gnoth, Mark Jean

2011-08-01

Low solubility of drug candidates generated in research contributes to their elimination during subsequent development due to insufficient oral bioavailability (BA) of crystalline compound. Therefore, the purpose of the study was to identify critical in vitro solubility and dissolution parameter that would predict critical in vivo dissolution by means of in vitro-in vivo correlation. Thermodynamic solubility and apparent dissolution rate (ADR) were determined using the shake-flask method and mini-flow-through-cell, respectively. Oral BA studies in rats and humans were conducted from drug solution and suspension/tablets. Relative BA was calculated using F(rel) [%]=AUC(suspension)/AUC(solution)*100, representing a measure of in vivo dissolution. Roughly, F(rel) rat >50% translates into F(rel) human of >90%. Both, ADR and log volume to dissolve applied dose (VDAD), when plotted against F(rel) rat, revealed certain threshold levels, (ADR, ∼150-200 μg of compound dissolved under respective assay conditions; VDAD, ∼100-500 ml/kg) which translate into F(rel) in rats of >50%. Thus, assuming that F(rel)>50% in rats is indicative of sufficient in vivo dissolution in humans after oral application, drugs should exhibit a VDAD of ∼100-500 ml/kg or less in aqueous media to avoid insufficient or varying drug absorption. Copyright © 2011 Elsevier B.V. All rights reserved.

In vivo application of chitosan to improve bioavailability of cyanocobalamin, a form of vitamin B12, following intraintestinal administration in rats.

PubMed

Goto, Yuko; Masuda, Ayumi; Aiba, Tetsuya

2015-04-10

The effect of chitosan on the intestinal absorption of cyanocobalamin (VB12), a stable form of vitamin B12, was investigated in vivo in rats, with the aim of improving the oral bioavailability of VB12 for anemia treatment in patients with gastrectomy. The bioavailability was evaluated based on the plasma concentration profile of VB12 following intraintestinal administration of the VB12 solution containing chitosan at various concentrations. The bioavailability of VB12 was 0.6±0.2% when the chitosan-free VB12 solution was administered, while it increased to 10.5±3.3% when chitosan was dissolved in the VB12 solution at a concentration of 1%. The bioavailability of VB12 increases with the chitosan concentration, in which chitosan seems to augment the amount of VB12 absorbed without affecting the absorption rate constant of VB12. It was also shown that the bioavailability of VB12 does not increase further when the degree of chitosan deacetylation is increased from 83 to 100% by substitutively employing the fully deacetylated chitosan. These findings suggest that the oral administration of VB12 with readily available chitosan may be a practical approach for anemia treatment in patients with gastrectomy. Copyright © 2015 Elsevier B.V. All rights reserved.

Development and evaluation of a novel microemulsion formulation of elacridar to improve its bioavailability

PubMed Central

Sane, Ramola; Mittapalli, Rajendar K.; Elmquist, William F.

2014-01-01

The study objective was to develop a formulation of elacridar to overcome its dissolution-rate limited bioavailability. Elacridar is a P-gp and BCRP inhibitor that has been used to improve the brain distribution of drugs that are substrates of P-gp and BCRP. The chronic use of elacridar is restricted due to poor solubility leading to poor oral bioavailability. A microemulsion formulation using Cremophor EL, Carbitol and Captex 355 (6:3:1) was developed. The elacridar microemulsion was effective in the inhibition of P-gp and Bcrp in MDCKII-transfected cells. FVBn mice were used to determine the bioavailability of elacridar after a 10 mg/kg dose of elacridar in the microemulsion, intraperitoneally and orally; and the absolute bioavailability was determined to be 1.3 and 0.47, respectively. Co-administration of elacridar microemulsion intraperitoneally with oral erlotinib in FVBn mice improved the erlotinib brain penetration three-fold. The current study shows that a microemulsion formulation of elacridar is effective in improving the bioavailability of elacridar and is an effective inhibitor of P-gp and Bcrp; in-vitro and in-vivo. It offers an alternative to the suspension and allows a decrease in the dose required to achieve a significant inhibitory effect at the blood-brain barrier. PMID:23334925

The Reciprocal Interactions between Polyphenols and Gut Microbiota and Effects on Bioaccessibility

PubMed Central

Ozdal, Tugba; Sela, David A.; Xiao, Jianbo; Boyacioglu, Dilek; Chen, Fang; Capanoglu, Esra

2016-01-01

As of late, polyphenols have increasingly interested the scientific community due to their proposed health benefits. Much of this attention has focused on their bioavailability. Polyphenol–gut microbiota interactions should be considered to understand their biological functions. The dichotomy between the biotransformation of polyphenols into their metabolites by gut microbiota and the modulation of gut microbiota composition by polyphenols contributes to positive health outcomes. Although there are many studies on the in vivo bioavailability of polyphenols, the mutual relationship between polyphenols and gut microbiota is not fully understood. This review focuses on the biotransformation of polyphenols by gut microbiota, modulation of gut microbiota by polyphenols, and the effects of these two-way mutual interactions on polyphenol bioavailability, and ultimately, human health. PMID:26861391

Application of in vitro bioaccessibility and bioavailability methods for calcium, carotenoids, folate, iron, magnesium, polyphenols, zinc, and vitamins B6, B12, D, and E

PubMed Central

Etcheverry, Paz; Grusak, Michael A.; Fleige, Lisa E.

2012-01-01

A review of in vitro bioaccessibility and bioavailability methods for polyphenols and selected nutrients is presented. The review focuses on in vitro solubility, dialyzability, the dynamic gastrointestinal model (TIM)™, and Caco-2 cell models, the latter primarily for uptake and transport, and a discussion of how these methods have been applied to generate data for a range of nutrients, carotenoids, and polyphenols. Recommendations are given regarding which methods are most justified for answering bioaccessibility or bioavailability related questions for specific nutrients. The need for more validation studies in which in vivo results are compared to in vitro results is also discussed. PMID:22934067

In vivo postprandial bioavailability of interesterified-lipids in sodium-caseinate or chitosan based O/W emulsions.

PubMed

Farfán, M; Villalón, M J; Ortíz, M E; Nieto, S; Bouchon, P

2015-03-15

Recent studies have shown that it should be possible to control lipid bioavailability through food structural approaches. Nevertheless, the gastrointestinal-tract physiological conditions must also be considered. To get a better understanding of this phenomenon, we evaluated the effect of emulsification, as well as the use of sodium caseinate or chitosan, on the postprandial bioavailability of interesterified-lipids in O/W emulsions after oral gastric feeding Sprague-Dawley rats. We verified that emulsification may increase lipid absorption, as determined after feeding sodium-caseinate emulsions. However, this result could not be generalised. Interesterified-lipids that were emulsified with chitosan were equally absorbed as those contained in non-emulsified interesterified-lipids/distilled-water blends. Copyright © 2014. Published by Elsevier Ltd.

In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol.

PubMed

Jinno, Jun-ichi; Kamada, Naoki; Miyake, Masateru; Yamada, Keigo; Mukai, Tadashi; Odomi, Masaaki; Toguchi, Hajime; Liversidge, Gary G; Higaki, Kazutaka; Kimura, Toshikiro

2008-08-25

The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. Irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively.

Sodium Dodecyl Sulfate-Modified Doxorubicin-Loaded Chitosan-Lipid Nanocarrier with Multi Polysaccharide-Lecithin Nanoarchitecture for Augmented Bioavailability and Stability of Oral Administration In Vitro and In Vivo.

PubMed

Su, Chia-Wei; Chiang, Min-Yu; Lin, Yu-Ling; Tsai, Nu-Man; Chen, Yen-Po; Li, Wei-Ming; Hsu, Chin-Hao; Chen, San-Yuan

2016-05-01

For oral anti-cancer drug delivery, a new chitosan-lipid nanoparticle with sodium dodecyl sulfate modification was designed and synthesized using a double emulsification. TEM examination showed that the DOX-loaded nanoparticles, termed D-PL/TG NPs, exhibited a unique core-shell configuration composed of multiple amphiphilic chitosan-lecithin reverse micelles as the core and a triglyceride shell as a physical barrier to improve the encapsulation efficiency and reduce the drug leakage. In addition, the D-PL/TG NPs with sodium dodecyl sulfate modification on the surface have enhanced stability in the GI tract and increased oral bioavailability of doxorubicin. In vitro transport studies performed on Caco-2 monolayers indicated that the D-PL/TG NPs enhanced the permeability of DOX in the Caco-2 monolayers by altering the transport pathway from passive diffusion to transcytosis. The in vivo intestinal absorption assay suggested that the D-PL/TG NPs were preferentially absorbed through the specialized membranous epithelial cells (M cells) of the Peyer's patches, resulting in a significant improvement (8-fold) in oral bioavailability compared to that of free DOX. The experimental outcomes in this work demonstrate that the D-PL/TG NPs provide an exciting opportunity for advances in the oral administration of drugs with poor bioavailability that are usually used in treating tough and chronic diseases.

Improved oral bioavailability for lutein by nanocrystal technology: formulation development, in vitro and in vivo evaluation.

PubMed

Chang, Daoxiao; Ma, Yanni; Cao, Guoyu; Wang, Jianhuan; Zhang, Xia; Feng, Jun; Wang, Wenping

2018-08-01

Lutein is a kind of natural carotenoids possessing many pharmacological effects. The application of lutein was limited mainly due to its low oral bioavailability caused by poor aqueous solubility. Nanocrystal formulation of lutein was developed to improve the oral bioavailability in this study. The nanosuspension was prepared by the anti-solvent precipitation-ultrasonication method and optimized by Box-Behnken design, followed by freeze-drying to obtain lutein nanocrystals. The nanocrystals were characterized on their physical properties, in vitro dissolution and in vivo absorption performance. Lutein nanocrystals showed as tiny spheres with an average particle size of 110.7 nm. The result of diffractograms indicated that the percent crystallinity of lutein was 89.4% in coarse powder and then declined in nanocrystal formulation. The saturated solubility of lutein in water increased from 7.3 μg/ml for coarse powder up to 215.7 μg/ml for lutein nanocrystals. The dissolution rate of lutein nanocrystals was significantly higher than that of coarse powder or the physical mixture. The C max and AUC 0-24 h of lutein nanocrystals after oral administration in rats was 3.24 and 2.28 times higher than those of lutein suspension, respectively. These results indicated that the nanocrystal formulation could significantly enhance the dissolution and absorption of lutein and might be a promising approach for improving its oral bioavailability.

Formulation and Pharmacokinetic Evaluation of Polymeric Dispersions Containing Valsartan.

PubMed

Chella, Naveen; Daravath, Bhaskar; Kumar, Dinesh; Tadikonda, Rama Rao

2016-10-01

Valsartan exhibits poor aqueous solubility and dissolution rate limited absorption. The lower solubility in the upper part of gastrointestinal tract (pH-dependant solubility) where its absorption window exists further contributes to the low oral bioavailability of valsartan. The present work was aimed to improve the in vivo pharmacokinetics of valsartan by preparing amorphous polymeric dispersions using Eudragit E 100 as carrier. Eudragit E 100 is a cationic polymer soluble in gastric fluid up to pH 5.0 and exhibits pH-dependent release. Hence, the dispersions prepared using Eudragit E 100 rapidly dissolves at lower pH presenting drug in molecularly dispersed and soluble form at its absorption site. Polymeric solid dispersions were prepared in different drug-to-carrier ratios. The prepared dispersions were evaluated for drug-carrier interactions, solid-state transitions and drug-release properties with the help of Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and in vitro dissolution studies. The optimized formulation containing valsartan was tested in rats for bioavailability and pharmacokinetic parameters and compared with that of valsartan pure drug. The results from FTIR studies indicated no interactions between drug and excipients. DSC studies confirmed reduction in crystallinity of drug. The dissolution studies performed in 0.1 N HCl showed significant improvement (p < 0.05) in the dissolution of valsartan. In vivo pharmacokinetic studies showed 199 % relative bioavailability with significant improvement (p < 0.05) in area under the curve compared to valsartan pure drug. Eudragit E 100 can be used to improve the dissolution of drugs that show low solubility at lower pH and thereby enhancing the bioavailability.

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.

Wine Flavonoids in Health and Disease Prevention.

PubMed

Fernandes, Iva; Pérez-Gregorio, Rosa; Soares, Susana; Mateus, Nuno; de Freitas, Victor

2017-02-14

Wine, and particularly red wine, is a beverage with a great chemical complexity that is in continuous evolution. Chemically, wine is a hydroalcoholic solution (~78% water) that comprises a wide variety of chemical components, including aldehydes, esters, ketones, lipids, minerals, organic acids, phenolics, soluble proteins, sugars and vitamins. Flavonoids constitute a major group of polyphenolic compounds which are directly associated with the organoleptic and health-promoting properties of red wine. However, due to the insufficient epidemiological and in vivo evidences on this subject, the presence of a high number of variables such as human age, metabolism, the presence of alcohol, the complex wine chemistry, and the wide array of in vivo biological effects of these compounds suggest that only cautious conclusions may be drawn from studies focusing on the direct effect of wine and any specific health issue. Nevertheless, there are several reports on the health protective properties of wine phenolics for several diseases such as cardiovascular diseases, some cancers, obesity, neurodegenerative diseases, diabetes, allergies and osteoporosis. The different interactions that wine flavonoids may have with key biological targets are crucial for some of these health-promoting effects. The interaction between some wine flavonoids and some specific enzymes are one example. The way wine flavonoids may be absorbed and metabolized could interfere with their bioavailability and therefore in their health-promoting effect. Hence, some reports have focused on flavonoids absorption, metabolism, microbiota effect and overall on flavonoids bioavailability. This review summarizes some of these major issues which are directly related to the potential health-promoting effects of wine flavonoids. Reports related to flavonoids and health highlight some relevant scientific information. However, there is still a gap between the knowledge of wine flavonoids bioavailability and their health-promoting effects. More in vivo results as well as studies focused on flavonoid metabolites are still required. Moreover, it is also necessary to better understand how biological interactions (with microbiota and cells, enzymes or general biological systems) could interfere with flavonoid bioavailability.

Bioavailability enhancers of herbal origin: An overview

PubMed Central

Kesarwani, Kritika; Gupta, Rajiv

2013-01-01

Recently, the use of herbal medicines has been increased all over the world due to their therapeutic effects and fewer adverse effects as compared to the modern medicines. However, many herbal drugs and herbal extracts despite of their impressive in-vitro findings demonstrates less or negligible in-vivo activity due to their poor lipid solubility or improper molecular size, resulting in poor absorption and hence poor bioavailability. Nowadays with the advancement in the technology, novel drug delivery systems open the door towards the development of enhancing bioavailability of herbal drug delivery systems. For last one decade many novel carriers such as liposomes, microspheres, nanoparticles, transferosomes, ethosomes, lipid based systems etc. have been reported for successful modified delivery of various herbal drugs. Many herbal compounds including quercetin, genistein, naringin, sinomenine, piperine, glycyrrhizin and nitrile glycoside have demonstrated capability to enhance the bioavailability. The objective of this review is to summarize various available novel drug delivery technologies which have been developed for delivery of drugs (herbal), and to achieve better therapeutic response. An attempt has also been made to compile a profile on bioavailability enhancers of herbal origin with the mechanism of action (wherever reported) and studies on improvement in drug bioavailability, exhibited particularly by natural compounds. PMID:23620848

A microemulsion of puerarin-phospholipid complex for improving bioavailability: preparation, in vitro and in vivo evaluations.

PubMed

Wu, Jun-Yong; Li, Yong-Jiang; Han, Meng; Hu, Xiong-Bin; Yang, Le; Wang, Jie-Min; Xiang, Da-Xiong

2018-08-01

Puerarin is a phytochemical with various pharmacological effects, but poor water solubility and low oral bioavailability limited usage of puerarin. The purpose of this study was to develop a new microemulsion (ME) based on phospholipid complex technique to improve the oral bioavailability of puerarin. Puerarin phospholipid complex (PPC) was prepared by a solvent evaporation method and was characterized by X-ray diffraction and infrared spectroscopy. Pseudo-ternary phase diagrams were constructed to investigate the effects of different oil on the emulsifying performance of the blank ME. Intestinal mucosal injury test was conducted to evaluate safety of PPC-ME, and no sign of damage on duodenum, jejunum and ileum of rats was observed using hematoxylin-eosin staining. In pharmacokinetic study of PPC-ME, a significantly greater C max (1.33 µg/mL) was observed when compared to puerarin (C max 0.55 µg/mL) or PPC (C max 0.70 µg/mL); the relative oral bioavailability of PPC-ME was 3.16-fold higher than puerarin. In conclusion, the ME combined with the phospholipid complex technique was a promising strategy to enhance the oral bioavailability of puerarin.

Fabrication and Optimization of Self-Microemulsions to Improve the Oral Bioavailability of Total Flavones of Hippophaë rhamnoides L.

PubMed

Guo, Ruixue; Guo, Xinbo; Hu, Xiaodan; Abbasi, Arshad Mehmood; Zhou, Lin; Li, Tong; Fu, Xiong; Liu, Rui Hai

2017-12-01

The purpose of this work was to improve the oral bioavailability of a poorly soluble functional food ingredient, the total flavones of Hippophaë rhamnoides L. (TFH). A self-microemulsion drug delivery system (SMEDDS) was developed to overcome the problems of poor absorption of TFH in vivo. The optimal SMEDDS significantly enhanced the solubility of TFH up to 530 times compared to that in water. The mean droplet size was 61.76 nm with uniform distribution. And the loaded system was stable at 25 °C for 3 mo with transparent appearance. The in vitro release of TFH from SMEDDS was faster and more complete than that from suspension. After oral administration of TFH-SMEDDS in rats, the relative bioavailability of TFH was dramatically improved for 3.09 times compared with the unencapsulated form. The investigation indicated the potential application of SMEDDS as a vehicle to improve the oral bioavailability of TFH. The lipid-based nanotechnology, namely self-microemulsion drug delivery system (SMEDDS) was used to improve the bioavailability and oral delivery of total flavones of Hippophaë rhamnoides L. (TFH). The relevant bioavailability of TFH could be remarkably 3-fold improved by the optimized SMEDDS. The SMEDDS produced via a simple one-step process for poorly soluble TFH to achieve a significant improvement in the bioavailability, may endorse the promising utilization of TFH in functional foods as well as pharmaceutical fields with an enhanced absorption in vivo. © 2017 Institute of Food Technologists®.

Luteolin-loaded solid lipid nanoparticles synthesis, characterization, & improvement of bioavailability, pharmacokinetics in vitro and vivo studies

NASA Astrophysics Data System (ADS)

Dang, Hao; Meng, Murtaza Hasan Weiwei; Zhao, Haiwei; Iqbal, Javed; Dai, Rongji; Deng, Yulin; Lv, Fang

2014-04-01

Luteolin (LU, 5,7,3',4'-tetrahydroxyflavone) most active compound in Chinese herbal flavones has been acting as a antimicrobial, anti-inflammatory, anti-cancer, and antimutagen. However, its poor bioavailability, hydrophobicity, and pharmacokinetics restrict clinical application. Here in this study, LU-loaded solid lipid nanoparticles have been prepared by hot-microemulsion ultrasonic technique to improve the bioavailability & pharmacokinetics of compound. LU-loaded solid lipid nanoparticle size was confirmed by particle size analyzer with range from 47 to 118 nm, having zepta potential -9.2 mV and polydisperse index 0.247, respectively. Round-shaped SLNPs were obtained by using transmission electron microscope, and encapsulation efficiency 74.80 % was calculated by using HPLC. Both in vitro and vivo studies, LC-MS/MS technique was used for quantification of Luteolin in rat. The T max value of drug with LU-SLNs after the administration was Ten times shorter than pure Luteolin suspension administration. C max value of drug after the administration of LU-SLNs was five times higher than obtained with native drug suspension. Luteolin with SLNs has increased the half-life approximately up to 2 h. Distribution and clearance of drug with SLNs were significantly decreased by 2.16-10.57 fold, respectively. In the end, the relative bioavailability of SLNs has improved about 4.89 compared to Luteolin with SLNs. From this study, it can be concluded that LU-SLNs have not only great potential for improving solubility but also increased the drug concentration in plasma. Furthermore, use of LC-MS/MS for quantification of LU-SLNs in rat plasma is reliable and of therapeutic usefulness, especially for neurodegenerative and cancerous disorders in humans.

Effect of Catnip Charcoal on the In Vivo Pharmacokinetics of the Main Alkaloids of Rhizoma Coptidis.

PubMed

He, Yanfei; Chen, Siyu; Yu, Hai; Zhu, Long; Liu, Yayun; Han, Chunyang; Liu, Cuiyan

2016-01-01

This study aims to explore the effect of catnip Nepeta cataria (CNC) charcoal on the pharmacokinetics of the main alkaloids of Rhizoma Coptidis in vivo. Twenty-four rabbits were randomly divided into four groups and given oral administration of an aqueous extract of Rhizoma Coptidis (RCAE), RCAE plus CNC, RCAE plus activated carbon (AC), or distilled water, respectively. Plasma samples were collected after administration. The concentrations of berberine, coptisine, palmatine, and epiberberine in plasma were measured by high-performance liquid chromatography (HPLC). The pharmacokinetics data were calculated using pharmacokinetic DAS 2.0 software. The results showed that the area under the concentration-time curve (AUC) of berberine increased, while the AUC of coptisine, palmatine, and epiberberine decreased in the rabbits that received RCAE plus CNC. Meanwhile, the AUC of berberine, coptisine, palmatine, and epiberberine decreased in the group given RCAE plus AC. The difference of main pharmacokinetics parameters among the four groups was significant (P < 0.05). This study showed that CNC improved the bioavailability of berberine in comparison to AC and prolonged its release in comparison to RCAE alone. However, it decreased the bioavailability of coptisine, palmatine, and epiberberine. In comparison, AC uniformly declined the bioavailability of berberine, coptisine, palmatine, and epiberberine.

Effect of Catnip Charcoal on the In Vivo Pharmacokinetics of the Main Alkaloids of Rhizoma Coptidis

PubMed Central

He, Yanfei; Chen, Siyu; Yu, Hai; Zhu, Long; Liu, Yayun; Han, Chunyang; Liu, Cuiyan

2016-01-01

This study aims to explore the effect of catnip Nepeta cataria (CNC) charcoal on the pharmacokinetics of the main alkaloids of Rhizoma Coptidis in vivo. Twenty-four rabbits were randomly divided into four groups and given oral administration of an aqueous extract of Rhizoma Coptidis (RCAE), RCAE plus CNC, RCAE plus activated carbon (AC), or distilled water, respectively. Plasma samples were collected after administration. The concentrations of berberine, coptisine, palmatine, and epiberberine in plasma were measured by high-performance liquid chromatography (HPLC). The pharmacokinetics data were calculated using pharmacokinetic DAS 2.0 software. The results showed that the area under the concentration-time curve (AUC) of berberine increased, while the AUC of coptisine, palmatine, and epiberberine decreased in the rabbits that received RCAE plus CNC. Meanwhile, the AUC of berberine, coptisine, palmatine, and epiberberine decreased in the group given RCAE plus AC. The difference of main pharmacokinetics parameters among the four groups was significant (P < 0.05). This study showed that CNC improved the bioavailability of berberine in comparison to AC and prolonged its release in comparison to RCAE alone. However, it decreased the bioavailability of coptisine, palmatine, and epiberberine. In comparison, AC uniformly declined the bioavailability of berberine, coptisine, palmatine, and epiberberine. PMID:27313645

Interaction of plant phenols with food macronutrients: characterisation and nutritional-physiological consequences.

PubMed

Zhang, Hao; Yu, Dandan; Sun, Jing; Liu, Xianting; Jiang, Lu; Guo, Huiyuan; Ren, Fazheng

2014-06-01

Polyphenols are dietary constituents of plants associated with health-promoting effects. In the human diet, polyphenols are generally consumed in foods along with macronutrients. Because the health benefits of polyphenols are critically determined by their bioavailability, the effect of interactions between plant phenols and food macronutrients is a very important topic. In the present review, we summarise current knowledge, with a special focus on the in vitro and in vivo effects of food macronutrients on the bioavailability and bioactivity of polyphenols. The mechanisms of interactions between polyphenols and food macronutrients are also discussed. The evidence collected in the present review suggests that when plant phenols are consumed along with food macronutrients, the bioavailability and bioactivity of polyphenols can be significantly affected. The protein-polyphenol complexes can significantly change the plasma kinetics profile but do not affect the absorption of polyphenols. Carbohydrates can enhance the absorption and extend the time needed to reach a maximal plasma concentration of polyphenols, and fats can enhance the absorption and change the absorption kinetics of polyphenols. Moreover, as highlighted in the present review, not only a nutrient alone but also certain synergisms between food macronutrients have a significant effect on the bioavailability and biological activity of polyphenols. The review emphasises the need for formulations that optimise the bioavailability and in vivo activities of polyphenols.

Solid dispersion tablets of breviscapine with polyvinylpyrrolidone K30 for improved dissolution and bioavailability to commercial breviscapine tablets in beagle dogs.

PubMed

Cong, Wenjuan; Shen, Lan; Xu, Desheng; Zhao, Lijie; Ruan, Kefeng; Feng, Yi

2014-09-01

Breviscapine, one of cardiovascular drugs extracted from a Chinese herb Erigeron breviscapinus, has been frequently used to treat cardiovascular diseases such as hypertension, angina pectoris, coronary heart disease and stroke. However, its poor water solubility and low bioavailability in vivo severely restrict the clinical application. To overcome these drawbacks, breviscapine solid dispersion tablets consisting of breviscapine, polyvinylpyrrolidone K30 (PVP K30), microcrystalline cellulose and crospovidone were appropriately prepared. In vitro dissolution profiles showed that breviscapine released percentage of solid dispersion tablets reached 90 %, whereas it was only 40 % for commercial breviscapine tablets. Comparative pharmacokinetic study between solid dispersion tablets and commercial products was investigated on the normal beagle dogs after oral administration. Results showed that the bioavailability of breviscapine was greatly increased by 3.45-fold for solid dispersion tablets. The greatly improved dissolution rate and bioavailability might be attributed to intermolecular hydrogen bonding reactions between PVP K30 and scutellarin. These findings suggest that our solid dispersion tablets can greatly improve the bioavailability as well as the dissolution rate of breviscapine.

Enhancement of dissolution and oral bioavailability of lacidipine via pluronic P123/F127 mixed polymeric micelles: formulation, optimization using central composite design and in vivo bioavailability study.

PubMed

Fares, Ahmed R; ElMeshad, Aliaa N; Kassem, Mohamed A A

2018-11-01

This study aims at preparing and optimizing lacidipine (LCDP) polymeric micelles using thin film hydration technique in order to overcome LCDP solubility-limited oral bioavailability. A two-factor three-level central composite face-centered design (CCFD) was employed to optimize the formulation variables to obtain LCDP polymeric micelles of high entrapment efficiency and small and uniform particle size (PS). Formulation variables were: Pluronic to drug ratio (A) and Pluronic P123 percentage (B). LCDP polymeric micelles were assessed for entrapment efficiency (EE%), PS and polydispersity index (PDI). The formula with the highest desirability (0.959) was chosen as the optimized formula. The values of the formulation variables (A and B) in the optimized polymeric micelles formula were 45% and 80%, respectively. Optimum LCDP polymeric micelles had entrapment efficiency of 99.23%, PS of 21.08 nm and PDI of 0.11. Optimum LCDP polymeric micelles formula was physically characterized using transmission electron microscopy. LCDP polymeric micelles showed saturation solubility approximately 450 times that of raw LCDP in addition to significantly enhanced dissolution rate. Bioavailability study of optimum LCDP polymeric micelles formula in rabbits revealed a 6.85-fold increase in LCDP bioavailability compared to LCDP oral suspension.

21 CFR 320.25 - Guidelines for the conduct of an in vivo bioavailability study.

Code of Federal Regulations, 2014 CFR

2014-04-01

... physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of... to or to meet any comparative labeling claims made in relation to the drug product that is the...

21 CFR 320.25 - Guidelines for the conduct of an in vivo bioavailability study.

Code of Federal Regulations, 2012 CFR

2012-04-01

... physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of... to or to meet any comparative labeling claims made in relation to the drug product that is the...

21 CFR 320.25 - Guidelines for the conduct of an in vivo bioavailability study.

Code of Federal Regulations, 2011 CFR

2011-04-01

... physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of... to or to meet any comparative labeling claims made in relation to the drug product that is the...

21 CFR 320.25 - Guidelines for the conduct of an in vivo bioavailability study.

Code of Federal Regulations, 2013 CFR

2013-04-01

... physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of... to or to meet any comparative labeling claims made in relation to the drug product that is the...

N,N'-dihydroxyamidines: a new prodrug principle to improve the oral bioavailability of amidines.

PubMed

Reeh, Christiane; Wundt, Judith; Clement, Bernd

2007-12-27

N, N'-dihydroxybenzamdine represents a model compound for a new prodrug principle to improve the oral bioavailability of drugs containing amidine functions. The activation of the prodrug could be demonstrated in vitro by porcine and human subcellular enzyme fractions, the mitochondrial benzamidoxime reducing system, and porcine hepatocytes. In vivo, the bioavailability of benzamidine after oral application of N, N'-dihydroxybenzamidine was about 91% and exceeded that of benzamidine after oral application of benzamidoxime, being about 74% (Liu, L.; Ling, Y.; Havel, C.; Bashnick, L.; Young, W.; Rai, R.; Vijaykumar, D.; Riggs, J. R.; Ton, T.; Shaghafi, M.; Graupe, D.; Mordenti, J.; Sukbuntherng, J. Species comparison of in vitro and in vivo conversion of five N-hydroxyamidine prodrugs of fVIIA inhibitors to their corresponding active amidines. Presented at the 13th North America ISSX Meeting, Maui, HI, 2005).

Development of a biocompatible creatinine-based niosomal delivery system for enhanced oral bioavailability of clarithromycin.

PubMed

Ullah, Shafi; Shah, Muhammad Raza; Shoaib, Mohammad; Imran, Muhammad; Elhissi, Abdelbary M A; Ahmad, Farid; Ali, Imdad; Shah, Syed Wadood Ali

2016-11-01

Nonionic surfactant vesicles have gained increasing scientific attention for hydrophobic drugs delivery due to their biocompatibility, stability and low cost. The aim of the present study was to synthesize and evaluate a novel creatinine-based nonionic surfactant in terms of its ability to generate biocompatible niosomal system for the delivery of Clarithromycin. The surfactant was synthesized by reacting creatinine with lauroyl chloride followed by characterization using 1 HNMR and MS. The drug-loaded niosomal vesicles of the surfactant were characterized for drug encapsulation efficiency (EE) using LC-MS, vesicle size using dynamic light scattering (DLS) and vesicle shape using atomic force microscopy (AFM). The surfactant was also investigated for blood hemolysis, in vitro cytotoxicity against different cell lines and in vivo acute toxicity in mice. Furthermore, the in vivo bioavailability of Clarithromycin encapsulated in the novel niosomal formulation was investigated using rabbits and quantified through validated LC-MS/MS method. Findings showed that vesicles were able to entrap up to 67.82 ± 1.27% of the drug, and were rounded in shape with a size around 202.73 ± 5.30 nm and low polydispersity. The surfactant caused negligible blood hemolysis, very low cytotoxicity and was found to be safe up to 2500 mg/kg body weight using mice. The niosomal formulation showed twofold enhanced oral bioavailability of Clarithromycin as compared to commercial formulations of the drug. The study has shown that the creatinine-based niosomes developed in our laboratory were biocompatible, safe and increased the oral bioavailability of the model hydrophobic Clarithromycin using experimental animals.

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

Relative Bioavailability and Bioaccessability and Speciation of ...

EPA Pesticide Factsheets

Background: Assessment of soil arsenic (As) bioavailability may profoundly affect the extent of remediation required at contaminated sites by improving human exposure estimates. Because small adjustments in soil As bioavailability estimates can significantly alter risk assessments and remediation goals, convenient, rapid, reliable, and inexpensive tools are needed to determine soil As bioavailability. Objectives: We evaluated inexpensive methods for assessing As bioavailability in soil as a means to improve human exposure estimates and potentially reduce remediation costs. Methods: Nine soils from residential sites affected by mining or smelting activity and two National Institute of Standards and Technology standard reference materials were evaluated for As bioavailability, bioaccessibility, and speciation. Arsenic bioavailability was determined using an in vivo mouse model, and As bioaccessibility was determined using the Solubility/Bioavailability Research Consortium in vitro assay. Arsenic speciation in soil and selected soil physicochemical properties were also evaluated to determine whether these parameters could be used as predictors of As bio¬availability and bioaccessibility. Results: In the mouse assay, we compared bioavailabilities of As in soils with that for sodium arsenate. Relative bioavailabilities (RBAs) of soil As ranged from 11% to 53% (mean, 33%). In vitro soil As bioaccessibility values were strongly correlated with soil As RBAs (R

The formulation of a nasal nanoemulsion zaleplon in situ gel for the treatment of insomnia.

PubMed

Hosny, Khaled Mohamed; Banjar, Zainy Mohammed

2013-08-01

Zaleplon is a drug used for the treatment of insomnia and is available in tablet form; however, it has two major problems. First, the drug undergoes extensive first pass metabolism, resulting in only 30% bioavailability, and second, the drug has a poor aqueous solubility, which delays the onset of action. The objective of this study is to utilise nanotechnology to formulate zaleplon into a nasal in situ nanoemulsion gel (NEG) to provide a solution for the previously mentioned problems. The solubility of zaleplon in various oils, surfactants and co-surfactants was estimated. Pseudo-ternary phase diagrams were developed and various nanoemulsion (NE) formulations were prepared; these formulations were subjected to visual characterisation, thermodynamic stability study and droplet size and conductivity measurements. Carbopol 934 was used as an in situ gelling agent. The gel strength, pH, gelation time, in vitro release and ex vivo nasal permeation were determined. The pharmacokinetic study of the NEG was carried out in rabbits. Stable NEs were successfully developed with a droplet size range of 35 to 73 nm. A NEG composed of 15% Miglyol, 30% Labrasol and 10% PEG 200 successfully provided the maximum in vitro and ex vivo permeation and enhanced the bioavailability in the rabbits by eightfold, when compared with the marketed tablets. The nasal NEG is a promising novel formula for zaleplon that has higher nasal tissue permeability and enhanced systemic bioavailability.

Uptake and bioavailability of anthocyanins and phenolic acids from grape/blueberry juice and smoothie in vitro and in vivo.

PubMed

Kuntz, Sabine; Rudloff, Silvia; Asseburg, Heike; Borsch, Christian; Fröhling, Bettina; Unger, Franziska; Dold, Sebastian; Spengler, Bernhard; Römpp, Andreas; Kunz, Clemens

2015-04-14

The goal of eating five servings of fruits and vegetables a day has not yet been achieved. The intake of polyphenols such as anthocyanins (ACN) could be improved by consuming smoothies and juices that are increasingly popular, especially in children; however, bioavailability data concerning food matrix effects are scarce. Thus, we conducted a randomised, cross-over, bioavailability study (n 10) to determine the bioavailability of ACN and their metabolites from an ACN-rich grape/blueberry juice (841 mg ACN/litre) and smoothie (983 mg ACN/litre) in vivo, and the uptake of a corresponding grape/blueberry extract in vitro. After the intake of beverage (0·33 litres), plasma and fractionated urine samples were collected and analysed by ultra-performance liquid chromatography coupled to MS. The most abundant ACN found in plasma and urine were malvidin and peonidin as native ACN and as glucuronidated metabolites as well as 3,4-dihydroxybenzoic acid (3,4-DHB); minor ACN (delphinidin, cyanidin and petunidin) were only detected as native glycosides. Plasma pharmacokinetics and recoveries of urinary metabolites of ACN were not different for juice or smoothie intake; however, the phenolic acid 3,4-DHB was significantly better bioavailable from juice in comparison to smoothie. In vitro data with absorptive intestinal cells indicated that despite their weak chemical stability, ACN and 3,4-DHB could be detected at the basal side in their native forms. Whether smoothies as well as juices should be recommended to increase the intake of potentially health-promoting ACN and other polyphenols requires the consideration of other ingredients such as their relatively high sugar content.

In Situ Formation of Pyromorphite Is Not Required for the Reduction of in Vivo Pb Relative Bioavailability in Contaminated Soils

EPA Science Inventory

The effect of phosphate treatment on lead relative bioavailability (Pb RBA) was assessed in three distinct Pb-contaminated soils. Phosphoric acid (PA) or rock phosphate were added to smelter (PP2), nonferrous slag (SH15), and shooting range (SR01) impacted soils at a P:Pb molar ...

Enhancement of oral bioavailability of E804 by self-nanoemulsifying drug delivery system (SNEDDS) in rats.

PubMed

Heshmati, Nasim; Cheng, Xinlai; Eisenbrand, Gerhard; Fricker, Gert

2013-10-01

Indirubin and its derivatives have been shown to interrupt the cell cycle by inhibiting cyclin-dependent kinases, explaining their long-time use in traditional Chinese medicine for the treatment of chronic myelocytic leukemia. A potent derivative of indirubin, indirubin-3'-oxime 2,3-dihydroxypropyl ether (E804), has been shown to block the Src-Stat3 and Src-Stat5 signaling pathway in human cancer cells, inducing apoptosis. The anticancer effects of E804, however, cannot be easily examined in vivo because of its poor water solubility and low absorption. The aim of this study was to develop and evaluate a self-nanoemulsifying drug delivery system (SNEDDS) containing E804 for enhancing its solubility and bioavailability. Solubility of E804 was determined in various vehicles, and pseudoternary phase diagram was used to evaluate the self-emulsifying existence area. The SNEDDS composed of Capmul MCM (oil), Solutol HS 15 (surfactant), and polyethylene glycol 400 (cosurfactant) on the ratio of 20.5:62.5:16 loaded 1.5% of E804. The particle size of droplets was found to be 16.8 and 140 nm, and SNEDDS was stable after freeze-thaw cycles and upon dilution in HCl 0.1 N and pH 7.4 HBSS++. The ability of formulation for absorption enhancement was studied in rats in vivo after oral administration. The results showed that the developed SNEDDS increased the E804 bioavailability 984.23% compared with the aqueous suspension. Our studies for the first time show that the developed SNEDDS can be used as a possible formulation for E804 to improve its solubility and oral bioavailability. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

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.

Enhanced oral absorption of 20(S)-protopanaxadiol by self-assembled liquid crystalline nanoparticles containing piperine: in vitro and in vivo studies

PubMed Central

Jin, Xin; Zhang, Zhen-hai; Sun, E; Tan, Xiao-bin; Li, Song-lin; Cheng, Xu-dong; You, Ming; Jia, Xiao-bin

2013-01-01

Background 20(S)-protopanaxadiol (PPD), similar to several other anticancer agents, has low oral absorption and is extensively metabolized. These factors limit the use of PPD for treatment of human diseases. Methods In this study, we used cubic nanoparticles containing piperine to improve the oral bioavailability of PPD and to enhance its absorption and inhibit its metabolism. Cubic nanoparticles loaded with PPD and piperine were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel and verified using transmission electron microscopy and differential scanning calorimetry. We evaluated the in vitro release of PPD from these nanoparticles and its absorption across the Caco-2 cell monolayer model, and subsequently, we examined the bioavailability and metabolism of PPD and its nanoparticles in vivo. Results The in vitro release of PPD from these nanoparticles was less than 5% at 12 hours. PPD-cubosome and PPD-cubosome loaded with piperine (molar ratio PPD/piperine, 1:3) increased the apical to basolateral permeability values of PPD across the Caco-2 cell monolayer from 53% to 64%, respectively. In addition, the results of a pharmacokinetic study in rats showed that the relative bioavailabilities of PPD-cubosome [area under concentration–time curve (AUC)0–∞] and PPD-cubosome containing piperine (AUC0–∞) compared to that of raw PPD (AUC0–∞) were 166% and 248%, respectively. Conclusion The increased bioavailability of PPD-cubosome loaded with piperine is due to an increase in absorption and inhibition of metabolism of PPD by cubic nanoparticles containing piperine rather than because of improved release of PPD. The cubic nanoparticles containing piperine may be a promising oral carrier for anticancer drugs with poor oral absorption and that undergo extensive metabolism by cytochrome P450. PMID:23426652

Capsaicin pretreatment enhanced the bioavailability of fexofenadine in rats by P-glycoprotein modulation: in vitro, in situ and in vivo evaluation.

PubMed

Bedada, Satish Kumar; Appani, Ramgopal; Boga, Praveen Kumar

2017-06-01

Capsaicin is the main pungent principle present in chili peppers has been found to possess P-glycoprotein (P-gp) inhibition activity in vitro, which may have the potential to modulate bioavailability of P-gp substrates. Therefore, purpose of this study was to evaluate the effect of capsaicin on intestinal absorption and bioavailability of fexofenadine, a P-gp substrate in rats. The mechanistic evaluation was determined by non-everted sac and intestinal perfusion studies to explore the intestinal absorption of fexofenadine. These results were confirmed by an in vivo pharmacokinetic study of oral administered fexofenadine in rats. The intestinal transport and apparent permeability (P app ) of fexofenadine were increased significantly by 2.8 and 2.6 fold, respectively, in ileum of capsaicin treated rats when compared to control group. Similarly, absorption rate constant (K a ), fraction absorbed (F ab ) and effective permeability (P eff ) of fexofenadine were increased significantly by 2.8, 2.9 and 3.4 fold, respectively, in ileum of rats pretreated with capsaicin when compared to control group. In addition, maximum plasma concentration (C max ) and area under the concentration-time curve (AUC) were increased significantly by 2.3 and 2.4 fold, respectively, in rats pretreated with capsaicin as compared to control group. Furthermore, obtained results in rats pretreated with capsaicin were comparable to verapamil (positive control) treated rats. Capsaicin pretreatment significantly enhanced the intestinal absorption and bioavailability of fexofenadine in rats likely by inhibition of P-gp mediated cellular efflux, suggesting that the combined use of capsaicin with P-gp substrates may require close monitoring for potential drug interactions.

Oral nano-delivery of anticancer ginsenoside 25-OCH3-PPD, a natural inhibitor of the MDM2 oncogene: Nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action.

PubMed

Voruganti, Sukesh; Qin, Jiang-Jiang; Sarkar, Sushanta; Nag, Subhasree; Walbi, Ismail A; Wang, Shu; Zhao, Yuqing; Wang, Wei; Zhang, Ruiwen

2015-08-28

The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro and in vivo models of human prostate cancer. Our results indicated that, compared with the unencapsulated GS25, GS25NP demonstrated better MDM2 inhibition, improved oral bioavailability and enhanced in vitro and in vivo activities. In conclusion, the validated nano-formulation for GS25 oral delivery improves its molecular targeting, oral bioavailability and anticancer efficacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention.

Development and evaluation of a monolithic floating dosage form for furosemide.

PubMed

Menon, A; Ritschel, W A; Sakr, A

1994-02-01

The poor bioavailability of orally dosed furosemide (60%), a weakly acidic drug, is due to the presence of a biological window comprised of the upper gastrointestinal tract. The purpose of the present study was to develop and optimize in vitro a monolithic modified-release dosage form (MMR) for furosemide with increased gastric residence time and to evaluate the in vivo performance of the dosage form. The principle of floatation was used to restrict the MMR to the stomach. A two-factor three-level full factorial experimental design was employed for formulation development. A flow-through cell was designed to evaluate in vitro dissolution parameters. Quadratic regression models indicated the polymer viscosity and polymer:drug ratio to be significant (p < 0.05) formulation factors in determining the duration of buoyancy and the release profile. Statistical optimization using response surface methodology with certain physiological constraints relating to gastric emptying time predicted an optimal MMR. In vivo evaluation of the optimized MMR in beagle dogs resulted in a significant increase (p < 0.05) in the absolute bioavailability for the MMR dosage form (42.9%) as compared to the commercially available tablet (33.4%) and enteric product (29.5%). Significant in vitro/in vivo correlations (p < 0.05) were obtained for the MMR using deconvolution analysis normalized for bioavailability. The floating dosage form was found to be a feasible approach in delivering furosemide to the upper gastrointestinal tract to maximize drug absorption.

The pharmacokinetics study of ginkgolide A, B and the effect of food on bioavailability after oral administration of ginkgolide extracts in beagle dogs.

PubMed

Aa, Lixiang; Fei, Fei; Tan, Zhaoyi; Aa, Jiye; Wang, Guangji; Liu, Changxiao

2018-06-01

Ginkgolides are the primarily active components in Ginkgo products that are popular worldwide. However, few studies have evaluated the bioavailability of ginkgolides and the effects of food on it after oral administration of ginkgolides. In this article, pharmacokinetics and absolute bioavailability of the primary components in ginkgolide extracts were evaluated in beagle dogs. For the first time, we showed that the fed dogs had significantly increased area under the concentration-time curve and peak concentration relative to the fasted dogs based on the data from both the prototype form and total lactones of ginkgolide A (GA) and ginkgolide B (GB). In terms of the free form of the prototype ginkgolides, the absolute bioavailabilities of GA and GB were 34.8 and 5.2% in the fasted dogs, respectively, which significantly increased to an average of 78.6 and 17.0%, respectively, in the fed dogs. In terms of acidified total lactones, the absolute bioavailabilities of GA and GB were 7.5 and 14.5% in the fed dogs, and the percentages declined to 4.1 and 3.7% in the fasted dogs, respectively. It was suggested that administration of ginkgolides after meals could promote the in vivo exposure and the bioavailability of GA and GB, and hence potentially enhance therapeutic outcomes. Copyright © 2018 John Wiley & Sons, Ltd.

Curcumin-3,4-Dichloro Phenyl Pyrazole (CDPP) overcomes curcumin's low bioavailability, inhibits adipogenesis and ameliorates dyslipidemia by activating reverse cholesterol transport.

PubMed

Gupta, Abhishek; Singh, Vinay Kumar; Kumar, Durgesh; Yadav, Pragya; Kumar, Santosh; Beg, Muheeb; Shankar, Kripa; Varshney, Salil; Rajan, Sujith; Srivastava, Ankita; Choudhary, Rakhi; Balaramnavar, Vishal M; Bhatta, Rabi; Tadigoppula, Narender; Gaikwad, Anil Nilkanth

2017-08-01

Adipocyte dysfunction, obesity and associated metabolic disorders are of prime healthcare concern worldwide. Among available medications, natural products and inspired molecules hold 40% space in clinically prescribed medicines. In queue, this study overcomes the drawback of curcumin's low bioavailability with potent anti-adipogenic and anti-dyslipidemic activity. To evaluate the role of CDPP on adipocyte differentiation, 3T3-L1 adipocytes were used as an in-vitro model. Flow cytometry was performed for cell cycle analysis. Syrian golden hamsters were used to study pharmacokinetic profile and dyslipidemic activity exhibited by CDPP. CDPP was found to be a potent inhibitor of adipogenesis in-vitro. It blocked mitotic clonal expansion by causing cell cycle arrest. CDPP showed marked improvement in gastrointestinal stability and bioavailability in-vivo as compared to curcumin. Administration of CDPP (100mg/kg) significantly improved HFD induced dyslipidemic profile in hamsters and activated reverse cholesterol transport machinery. CDPP could be used as a potential drug candidate against adipogenesis and dyslipidemia with enhanced gastrointestinal stability and bioavailability. Copyright © 2017 Elsevier Inc. All rights reserved.

Enhanced bioavailability and bioefficacy of an amorphous solid dispersion of curcumin.

PubMed

Chuah, Ai Mey; Jacob, Bindya; Jie, Zhang; Ramesh, Subbarayan; Mandal, Shibajee; Puthan, Jithesh K; Deshpande, Parag; Vaidyanathan, Vadakkanchery V; Gelling, Richard W; Patel, Gaurav; Das, Tapas; Shreeram, Sathyavageeswaran

2014-08-01

Curcumin has been shown to have a wide variety of biological activities for various human diseases including inflammation, diabetes and cancer. However, the poor oral bioavailability of curcumin poses a significant pharmacological barrier to its use therapeutically and/or as a functional food. Here we report the evaluation of the bioavailability and bio-efficacy of curcumin as an amorphous solid dispersion (ASD) in a matrix consisting of hydroxypropyl methyl cellulose (HPMC), lecithin and isomalt using hot melt extrusion for application in food products. Oral pharmacokinetic studies in rats showed that ASD curcumin was ∼13-fold more bioavailable compared to unformulated curcumin. Evaluation of the anti-inflammatory activity of ASD curcumin in vivo demonstrated enhanced bio-efficacy compared to unformulated curcumin at 10-fold lower dose. Thus ASD curcumin provides a more potent and efficacious formulation of curcumin which may also help in masking the colour, taste and smell which currently limit its application as a functional food ingredient. Copyright © 2014 Elsevier Ltd. All rights reserved.

Improving oral bioavailability of acyclovir using nanoparticulates of thiolated xyloglucan.

PubMed

Madgulkar, Ashwini; Bhalekar, Mangesh R; Dikpati, Amrita A

2016-08-01

Acyclovir a BCS class III drug exhibits poor bioavailability due to limited permeability. The intention of this research work was to formulate and characterize thiolated xyloglucan polysaccharide nanoparticles (TH-NPs) of acyclovir with the purpose of increasing its oral bioavailability. Acyclovir-loaded TH-NPs were prepared using a cross-linking agent. Interactions of formulation excipients were reconnoitered using Fourier transform infrared spectroscopy (FT-IR). The formulated nanoparticles were lyophilised by the addition of a cryoprotectant and characterized for its particle size, morphology and stability and optimized using Box Behnken Design.The optimized TH-NP formulation exhibited particle size of 474.4±2.01 and an entrapment efficiency of 81.57%. A marked enhancement in the mucoadhesion was also observed. In-vivo study in a rat model proved that relative bioavailability of acyclovir TH-NPs is ∼2.575 fold greater than that of the marketed acyclovir drug suspension. Copyright © 2016 Elsevier B.V. All rights reserved.

Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability.

PubMed

Andersson, Vincent; Bergström, Fredrik; Brånalt, Jonas; Grönberg, Gunnar; Gustafsson, David; Karlsson, Staffan; Polla, Magnus; Bergman, Joakim; Kihlberg, Jan

2016-07-28

The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.

Nanostructured lipid carriers versus microemulsions for delivery of the poorly water-soluble drug luteolin.

PubMed

Liu, Ying; Wang, Lan; Zhao, Yiqing; He, Man; Zhang, Xin; Niu, Mengmeng; Feng, Nianping

2014-12-10

Nanostructured lipid carriers and microemulsions effectively deliver poorly water-soluble drugs. However, few studies have investigated their ability and difference in improving drug bioavailability, especially the factors contributed to the difference. Thus, this study was aimed at investigating their efficiency in bioavailability enhancement based on studying two key processes that occur in NLC and ME during traverse along the intestinal tract: the solubilization process and the intestinal permeability process. The nanostructured lipid carriers and microemulsions had the same composition except that the former were prepared with solid lipids and the latter with liquid lipids; both were evaluated for particle size and zeta potential. Transmission electron microscopy, differential scanning calorimetry, and X-ray diffraction were performed to characterize their properties. Furthermore, in vitro drug release, in situ intestinal absorption, and in vitro lipolysis were studied. The bioavailability of luteolin delivered using nanostructured lipid carriers in rats was compared with that delivered using microemulsions and suspensions. The in vitro analysis revealed different release mechanisms for luteolin in nanostructured lipid carriers and microemulsions, although the in situ intestinal absorption was similar. The in vitro lipolysis data indicated that digestion speed and extent were higher for microemulsions than for nanostructured lipid carriers, and that more of the former partitioned to the aqueous phase. The in vivo bioavailability analysis in rats indicated that the oral absorption and bioavailability of luteolin delivered using nanostructured lipid carriers and microemulsions were higher than those of luteolin suspensions. Nanostructured lipid carriers and microemulsions improved luteolin's oral bioavailability in rats. The rapid lipid digestion and much more drug solubilized available for absorption in microemulsions may contribute to better absorption and higher bioavailability. Copyright © 2014 Elsevier B.V. All rights reserved.

Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets.

PubMed

Eddington, N D; Ashraf, M; Augsburger, L L; Leslie, J L; Fossler, M J; Lesko, L J; Shah, V P; Rekhi, G S

1998-11-01

The purpose of this study was to evaluate the effect of formulation and processing changes on the dissolution and bioavailability of propranolol hydrochloride tablets. Directly compressed blends of 6 kg (20,000 units) were prepared by mixing in a 16-qt V blender and tablets were compressed on an instrumented Manesty D3B tablet press. A half-factorial (2(5-1), Resolution V) design was used to study the following variables: filler ratio (lactose/dicalcium phosphate), sodium starch glycolate level, magnesium stearate level, lubricant blend time, and compression force. The levels and ranges of the excipients and processing changes studied represented level 2 or greater changes as indicated by the Scale-up and Post Approval Changes (SUPAC-IR) Guidance. Changes in filler ratio, disintegrant level, and compression force were significant in affecting percent drug released (Q) in 5 min (Q5) and Q10. However, changes in magnesium stearate level and lubricant blend time did not influence Q5 and Q10. Hardness was found to be affected by changes in all of the variables studied. Some interaction effects between the variables studied were also found to be significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Thirteen subjects received four propranolol treatments (slow-, medium-, and fast-dissolving formulations and Inderal 80 mg) separated by 1 week washout according to a randomized crossover design. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that (i) bioavailability/bioequivalency studies may not be necessary for propranolol and perhaps other class 1 drugs after level 2 type changes, and (ii) in vitro dissolution tests may be used to show bioequivalence of propranolol formulations with processing or formulation changes within the specified level 2 ranges examined.

Caecal absorption of vitexin-2-O-xyloside and its aglycone apigenin, in the rat

USDA-ARS?s Scientific Manuscript database

The in vivo bioavailability of the flavone-C-glycosides has been little studied compared to their O-glycoside analogues, which are both more common in nature and considered more easily hydrolyzed than C-glycosides, by enterocytes and gut microbiota. In this study, we used vitexin-2-O-xyloside (VOX),...

Effects of polymer molecular weight on relative oral bioavailability of curcumin.

PubMed

Tsai, Yin-Meng; Chang-Liao, Wan-Ling; Chien, Chao-Feng; Lin, Lie-Chwen; Tsai, Tung-Hu

2012-01-01

Polylactic-co-glycolic acid (PLGA) nanoparticles have been used to increase the relative oral bioavailability of hydrophobic compounds and polyphenols in recent years, but the effects of the molecular weight of PLGA on bioavailability are still unknown. This study investigated the influence of polymer molecular weight on the relative oral bioavailability of curcumin, and explored the possible mechanism accounting for the outcome. Curcumin encapsulated in low (5000-15,000) and high (40,000-75,000) molecular weight PLGA (LMw-NPC and HMw-NPC, respectively) were prepared using an emulsification-solvent evaporation method. Curcumin alone and in the nanoformulations was administered orally to freely mobile rats, and blood samples were collected to evaluate the bioavailability of curcumin, LMw-NPC, and HMw-NPC. An ex vivo experimental gut absorption model was used to investigate the effects of different molecular weights of PLGA formulation on absorption of curcumin. High-performance liquid chromatography with diode array detection was used for quantification of curcumin in biosamples. There were no significant differences in particle properties between LMw-NPC and HMw-NPC, but the relative bioavailability of HMw-NPC was 1.67-fold and 40-fold higher than that of LMw-NPC and conventional curcumin, respectively. In addition, the mean peak concentration (C(max)) of conventional curcumin, LMw-NPC, and HMw-NPC was 0.028, 0.042, and 0.057 μg/mL, respectively. The gut absorption study further revealed that the HMw-PLGA formulation markedly increased the absorption rate of curcumin in the duodenum and resulted in excellent bioavailability compared with conventional curcumin and LMw-NPC. Our findings demonstrate that different molecular weights of PLGA have varying bioavailability, contributing to changes in the absorption rate at the duodenum. The results of this study provide the rationale for design of a nanomedicine delivery system to enhance the bioavailability of water-insoluble pharmaceutical compounds and functional foods.

Effects of polymer molecular weight on relative oral bioavailability of curcumin

PubMed Central

Tsai, Yin-Meng; Chang-Liao, Wan-Ling; Chien, Chao-Feng; Lin, Lie-Chwen; Tsai, Tung-Hu

2012-01-01

Background Polylactic-co-glycolic acid (PLGA) nanoparticles have been used to increase the relative oral bioavailability of hydrophobic compounds and polyphenols in recent years, but the effects of the molecular weight of PLGA on bioavailability are still unknown. This study investigated the influence of polymer molecular weight on the relative oral bioavailability of curcumin, and explored the possible mechanism accounting for the outcome. Methods Curcumin encapsulated in low (5000–15,000) and high (40,000–75,000) molecular weight PLGA (LMw-NPC and HMw-NPC, respectively) were prepared using an emulsification-solvent evaporation method. Curcumin alone and in the nanoformulations was administered orally to freely mobile rats, and blood samples were collected to evaluate the bioavailability of curcumin, LMw-NPC, and HMw-NPC. An ex vivo experimental gut absorption model was used to investigate the effects of different molecular weights of PLGA formulation on absorption of curcumin. High-performance liquid chromatography with diode array detection was used for quantification of curcumin in biosamples. Results There were no significant differences in particle properties between LMw-NPC and HMw-NPC, but the relative bioavailability of HMw-NPC was 1.67-fold and 40-fold higher than that of LMw-NPC and conventional curcumin, respectively. In addition, the mean peak concentration (Cmax) of conventional curcumin, LMw-NPC, and HMw-NPC was 0.028, 0.042, and 0.057 μg/mL, respectively. The gut absorption study further revealed that the HMw-PLGA formulation markedly increased the absorption rate of curcumin in the duodenum and resulted in excellent bioavailability compared with conventional curcumin and LMw-NPC. Conclusion Our findings demonstrate that different molecular weights of PLGA have varying bioavailability, contributing to changes in the absorption rate at the duodenum. The results of this study provide the rationale for design of a nanomedicine delivery system to enhance the bioavailability of water-insoluble pharmaceutical compounds and functional foods. PMID:22745556

Bioavailable Citrus sinensis Extract: Polyphenolic Composition and Biological Activity.

PubMed

Pepe, Giacomo; Pagano, Francesco; Adesso, Simona; Sommella, Eduardo; Ostacolo, Carmine; Manfra, Michele; Chieppa, Marcello; Sala, Marina; Russo, Mariateresa; Marzocco, Stefania; Campiglia, Pietro

2017-04-15

Citrus plants contain large amounts of flavonoids with beneficial effects on human health. In the present study, the antioxidant and anti-inflammatory potential of bioavailable polyphenols from Citrus sinensis was evaluated in vitro and ex vivo, using the murine macrophages cell line J774A.1 and primary peritoneal macrophages. Following simulated gastro-intestinal digestion, the in vitro bioavailability of Citrus sinensis polyphenolic extract was assessed using the human cell line Caco-2 grown as monolayers on a transwell membrane. Data demonstrated a relative permeation of its compounds (8.3%). Thus, the antioxidant and anti-inflammatory effect of polyphenolic Citrus sinensis fraction (Cs) was compared to the bioavailable one (CsB). Results revealed that Citrus extract were able to reduce macrophages pro-inflammatory mediators, including nitric oxide, iNOS, COX-2 and different cytokines. Moreover, the effect of Citrus sinensis polyphenols was associated with antioxidant effects, such as a reduction of reactive oxygen species (ROS) and heme-oxygenase-1 (HO-1) increased expression. Our results provide evidence that the bioavailable polyphenolic constituents of the Citrus sinensis extract accumulate prevalently at intestinal level and could reach systemic circulation exerting their effect. The bioavailable fraction showed a higher anti-inflammatory and antioxidant potential compared to the initial extract, thus highlighting its potential nutraceutical value.

Linking existing in vitro dermal absorption data to physicochemical properties: Contribution to the design of a weight-of-evidence approach for the safety evaluation of cosmetic ingredients with low dermal bioavailability.

PubMed

Ates, Gamze; Steinmetz, Fabian P; Doktorova, Tatyana Yordanova; Madden, Judith C; Rogiers, Vera

2016-04-01

To characterize the risk of cosmetic ingredients when threshold toxicity is assumed, often the "margin of safety" (MoS) is calculated. This uncertainty factor is based on the systemic no observable (adverse) effect level (NO(A)EL) which can be derived from in vivo repeated dose toxicity studies. As in vivo studies for the purpose of the cosmetic legislation are no longer allowed in Europe and a validated in vitro alternative is not yet available, it is no longer possible to derive a NO(A)EL value for a new cosmetic ingredient. Alternatively, cosmetic ingredients with a low dermal bioavailability might not need repeated dose data, as internal exposure will be minimal and systemic toxicity might not be an issue. This study shows the possibility of identifying compounds suspected to have a low dermal bioavailability based on their physicochemical properties (molecular weight, melting point, topological polar surface area and log P) and their in vitro dermal absorption data. Although performed on a limited number of compounds, the study suggests a strategic opportunity to support the safety assessor's reasoning to omit a MoS calculation and to focus more on local toxicity and mutagenicity/genotoxicity for ingredients for which limited systemic exposure is to be expected. Copyright © 2016 Elsevier Inc. All rights reserved.

Optimization and charaterization of repaglinide biodegradable polymeric nanoparticle loaded transdermal patchs: in vitro and in vivo studies.

PubMed

Vijayan, V; Reddy, K Ravindra; Sakthivel, S; Swetha, C

2013-11-01

Biodegradable polymeric nanoparticles loaded Repaglinide were prepared by solvent extraction method. In this method chitosan, PLA and PCL were employed to prepare Repaglinide polymeric nanoparticles. Some of the formulation parameters were optimized to obtain high quality nanoparticles. The particles were spherical shape with sizes of 108.6 ± 3.4 nm to 220.6 ± 1.2 nm and the poly dispersity indexes were in the range of 0.06 to 0.44. The zeta potential was in the range between - 16.48 ± 2.02 and 30.52 ± 3.20 mV. The percentage entrapment efficiency (EE%) was 81.4 ± 1.8% to 92.7 ± 1.4%. The drug release behavior was studied by externally sink method and the release pattern of drug was found to follow zero order, Higuchi and Peppas equations. The optimized PLA-Repaglinide nanoparticles were loaded in Methocel transdermal patches. These transdermal patches were evaluated by physiochemical parameters, in vitro, ex vivo and in vivo studies. Based on in vivo hypoglycemic results, bioavailability parameters like AUC, AUMC, Cmax, Tmax, MRT, t1/2 and relative bioavailability were found to be 2218.88 μIU/mL/h, 381630.3 μIU/mL/h, 41.88 μIU/mL, 36 h, 83.24h, and 52.79 h respectively. The transdermal patch containing Repaglinide nanoparticles showed 76 fold effective than conventional oral administrations. Copyright © 2013 Elsevier B.V. All rights reserved.

Improvement of Intestinal Absorption of Forsythoside A and Chlorogenic Acid by Different Carboxymethyl Chitosan and Chito-oligosaccharide, Application to Flos Lonicerae - Fructus Forsythiae Herb Couple Preparations

PubMed Central

Zhou, Wei; Wang, Haidan; Zhu, Xuanxuan; Shan, Jinjun; Yin, Ailing; Cai, Baochang; Di, Liuqing

2013-01-01

The current study aims to investigate the effect of chitosan derivatives on the intestinal absorption and bioavailabilities of forsythoside A (FTA) and Chlorogenic acid (CHA), the major active components in Flos Lonicerae - Fructus Forsythiae herb couple. Biopharmaceutics and pharmacokinetics properties of the two compounds have been characterized in vitro, in situ as well as in rats. Based on the identified biopharmaceutics characteristics of the two compounds, the effect of chitosan derivatives as an absorption enhancer on the intestinal absorption and pharmacokinetics of FTA and CHA in pure compound form as well as extract form were investigated in vitro, in situ and in vivo. Both FTA and CHA demonstrated very limited intestinal permeabilities, leading to oral bioavailabilities being only 0.50% and 0.13% in rats, respectively. Results from both in vitro, in situ as well as in vivo studies consistently indicated that Chito-oligosaccharide (COS) at dosage of 25 mg/kg could enhance intestinal permeabilities significantly as well as the in vivo bioavailabilities of both FTA and CHA than CMCs in Flos Lonicerae - Fructus Forsythiae herb couple preparations, and was safe for gastrointestine from morphological observation. Besides, treatment with Flos Lonicerae - Fructus Forsythiae herb couple preparations with COS at the dosage of 25 mg/kg prevented MDCK damage after influenza virus propagation, which was significantly better than control. The current findings not only identified the usefulness of COS for the improved delivery of Flos Lonicerae - Fructus Forsythiae preparations but also demonstrated the importance of biopharmaceutical characterization in the dosage form development of traditional Chinese medicine. PMID:23675483

Design and in vivo evaluation of a patch system based on thiolated polymers.

PubMed

Hoyer, Herbert; Greindl, Melanie; Bernkop-Schnürch, Andreas

2009-02-01

A new oral patch delivery system has been designed to increase the overall oral bioavailability of drugs within the gastrointestinal tract. The patch system consists of four layered films: a mucoadhesive matrix layer, a water insoluble backing layer, a middle layer and an enteric surface layer. The separation layer between the two matrix layers contained lactose, starch and confectioners' sugar. The matrix layer, exhibiting a diameter of 2.5 mm and a weight of 5 mg, comprised Polycarbophil-cysteine conjugate (49%), fluoresceine isothiocyanate-dextran (26%), glutathione (5%), and mannitol (20%). A standard tablet formulation consisting of the same matrix served as control. Entire fluoresceine isothiocyanate-dextran (FD(4)) was released from the delivery system within 2 h. For in vivo studies patch systems were administered orally to male Sprague-Dawley rats. Maximum FD(4) concentration in blood of the patch system was 46.1 +/- 8.9 ng/mL and was reached 3 h after administration. In contrast c(max) of control tablets displayed 50.5 +/- 14.9 ng/mL after 2 h and the absorption of FD(4) after administration in oral solution was negligible. The absolute bioavailability of orally administered patch systems and control tablets was 0.54% and 0.32% respectively. Results of this study indicate that a prolonged and higher oral bioavailability of FD(4) is obtained with patches than with tablets.

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons.

PubMed

Chokshi, Rina J; Zia, Hossein; Sandhu, Harpreet K; Shah, Navnit H; Malick, Waseem A

2007-01-01

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.

Fabrication and in vivo evaluation of Nelfinavir loaded PLGA nanoparticles for enhancing oral bioavailability and therapeutic effect

PubMed Central

Venkatesh, D. Nagasamy; Baskaran, Mahendran; Karri, Veera Venkata Satyanarayana Reddy; Mannemala, Sai Sandeep; Radhakrishna, Kollipara; Goti, Sandip

2015-01-01

Nelfinavir mesylate (NFV) is an anti-viral drug, used in the treatment of Acquired Immunodeficiency Syndrome (AIDS). Poor oral bioavailability and shorter half-life (3.5–5 h) remain a major clinical limitation of NFV leading to unpredictable drug bioavailability and frequent dosing. In this context, the objective of the present study was to formulate NFV loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), which can increase the solubility and oral bioavailability along with sustained release of the drug. NFV loaded PLGA-NPs were prepared by nanoprecipitation method using PLGA and Poloxomer 407. The prepared NPs were evaluated for particle size, zeta potential, morphology, drug content, entrapment efficiency (EE) and in vitro dissolution studies. Oral bioavailability studies were carried out in New Zealand rabbits by administering developed NFV PLGA-NPs and pure drug suspension. PLGA-NPs prepared by using 1:4 ratio of drug and PLGA, with a stirring rate of 1500 rpm for 4 h. The prepared NPs were in the size of 185 ± 0.83 nm with a zeta potential of 28.7 ± 0.09 mV. The developed NPs were found to be spherical with uniform size distribution. The drug content and EE of the optimized formulation were found to be 36 ± 0.19% and 72 ± 0.47% respectively. After oral administration of NFV PLGA-NPs, the relative bioavailability was enhanced about 4.94 fold compared to NFV suspension as a control. The results describe an effective strategy for oral delivery of NFV loaded PLGA NPs that helps in enhancing bioavailability and reduce the frequency of dosing. PMID:26702262

Pharmacokinetics of avenanthramides (AV) from AV-enriched malted oats in healthy older adults

USDA-ARS?s Scientific Manuscript database

Avenanthramides (AV) are a unique group of phytochemicals found in oat bran. In vitro studies show both purified AV and concentrated oat AV mixtures have anti-atherogenic and anti-inflammatory activity, suggesting they may have similar effects in vivo if they are sufficiently bioavailable. The bioav...

Oral bioavailability of ketoprofen in suspension and solution formulations in rats: the influence of poloxamer 188.

PubMed

Fischer, Sarah Maud; Parmentier, Johannes; Buckley, Stephen Timothy; Reimold, Isolde; Brandl, Martin; Fricker, Gert

2012-11-01

The aim of the current study was to investigate the effect of poloxamer 188 (P-188) on the bioavailability of the BCS class 2 drug ketoprofen in vivo. Aqueous suspension and solution formulations of ketoprofen with and without P-188 were orally administered to fasted male Wistar rats. The intrinsic dissolution rate and solubility of ketoprofen in simulated intestinal fluid, in both the presence and absence of P-188, was measured. The AUC and C(max) were found to be significantly enhanced when ketoprofen was administered as suspension and P-188 was present in the formulation (Susp P-188) as compared to the surfactant-free formulation (∼4-fold higher AUC, 7-fold higher C(max) ). While drug solubility appeared to be almost unaffected by P-188, a significantly faster dissolution was observed. In addition, the influence of P-188 on the drug absorption process was investigated by comparison of solution formulations with and without P-188. The in-vivo performance of these solutions, a pure buffer solution and a P-188-containing buffer solution showed no significant difference, suggesting that the increase in bioavailability for Susp P-188 was primarily a consequence of the dissolution rate-enhancing effect. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Oral relative bioavailability of Dichlorodiphenyltrichloroethane (DDT) in contaminated soil and its prediction using in vitro strategies for exposure refinement.

PubMed

Juhasz, Albert L; Herde, Paul; Smith, Euan

2016-10-01

In this study, the bioavailability of DDTr (sum of DDT, DDD and DDE isomers) in pesticide-contaminated soil was assessed using an in vivo mouse model. DDTr relative bioavailability (RBA) ranged from 18.7±0.9 (As35) to 60.8±7.8% (As36) indicating that a significant portion of soil-bound DDTr was not available for absorption following ingestion. When DDTr bioaccessibility was assessed using the organic Physiologically Based Extraction Test (org-PBET), the inclusion of a sorption sink (silicone cord) enhanced DDTr desorption by up to 20-fold (1.6-3.8% versus 18.9-56.3%) compared to DDTr partitioning into gastrointestinal fluid alone. Enhanced desorption occurred as a result of the silicone cord acting as a reservoir for solubilized DDTr to partition into, thereby creating a flux for further desorption until equilibrium was achieved. When the relationship between in vivo and in vitro data was assessed, a strong correlation was observed between the mouse bioassay and the org-PBET+silicone cord (slope=0.94, y-intercept=3.5, r(2)=0.72) suggesting that the in vitro approach may provide a robust surrogate measure for the prediction of DDTr RBA in contaminated soil. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Sodium Lauryl Sulfate Competitively Interacts with HPMC-AS and Consequently Reduces Oral Bioavailability of Posaconazole/HPMC-AS Amorphous Solid Dispersion.

PubMed

Chen, Yuejie; Wang, Shujing; Wang, Shan; Liu, Chengyu; Su, Ching; Hageman, Michael; Hussain, Munir; Haskell, Roy; Stefanski, Kevin; Qian, Feng

2016-08-01

Sodium lauryl sulfate (SLS), as an effective surfactant, is often used as a solubilizer and/or wetting agent in various dosage forms for the purpose of improving the solubility and dissolution of lipophilic, poorly water-soluble drugs. This study aims to understand the impact of SLS on the solution behavior and bioavailability of hypromellose acetate succinate (HPMC-AS)-based posaconazole (PSZ) ASDs, and to identify the underlying mechanisms governing the optimal oral bioavailability of ASDs when surfactants such as SLS are used in combination. Fluorescence spectroscopy and optical microscopy showed that "oil-out" or "liquid-liquid phase separation (LLPS)" occurred in the supersaturated PSZ solution once drug concentration surpassed ∼12 μg/mL, which caused the formation of drug-rich oily droplets with initial size of ∼300-400 nm. Although FT-IR study demonstrated the existence of specific interactions between PSZ and HPMC-AS in the solid state, predissolved HPMC-AS was unable to delay LLPS of the supersaturated PSZ solution and PSZ-rich amorphous precipitates with ∼16-18% HPMC-AS were formed within 10 min. The coprecipitated HPMC-AS was found to be able to significantly delay the crystallization of PSZ in the PSZ-rich amorphous phase from less than 10 min to more than 4 h, yet coexistent SLS was able to negate this crystallization inhibition effect of HPMC-AS in the PSZ-rich amorphous precipitates and cause fast PSZ crystallization within 30 min. 2D-NOESY and the CMC/CAC results demonstrated that SLS could assemble around HPMC-AS and competitively interact with HPMC-AS in the solution, thus prevent HPMC-AS from acting as an effective crystallization inhibitor. In a crossover dog PK study, this finding was found to be correlating well with the in vivo bioavailability of PSZ ASDs formulated with or without SLS. The SLS containing PSZ ASD formulation demonstrated an in vivo bioavailability ∼30% of that without SLS, despite the apparently better in vitro dissolution, which only compared the dissolved drug in solution, a small fraction of the total PSZ dose. We conclude that the bioavailability of ASDs is highly dependent on the molecular interactions between drug, surfactant, and polymer, not only in the solution phase but also in the drug-rich "oily" phase caused by supersaturation.

Creatinine-based non-phospholipid vesicular carrier for improved oral bioavailability of Azithromycin.

PubMed

Ullah, Shafi; Shah, Muhammad Raza; Shoaib, Mohammad; Imran, Muhammad; Shah, Syed Wadood Ali; Ali, Imdad; Ahmed, Farid

2017-06-01

Novel, safe, efficient and cost effective nano-carriers from renewable resources have got greater interest for enhancing solubility and bioavailability of hydrophobic dugs. This study reports the synthesis of a novel biocompatible non-phospholipid human metabolite "Creatinine" based niosomal delivery system for Azithromycin improved oral bioavailability. Synthesized surfactant was characterized through spectroscopic and spectrometric techniques and then the potential for niosomal vesicle formation was evaluated using Azithromycin as model drug. Drug loaded vesicles were characterized for size, polydispersity index (PDI), shape, drug encapsulation efficiency (EE), in vitro release and drug-excipient interaction using zetasizer, atomic force microscope (AFM), LC-MS/MS and FTIR. The biocompatibility of surfactant was investigated through cells cytotoxicity, blood hemolysis and acute toxicity. Azithromycin encapsulated in niosomes was investigated for in vivo bioavailability in rabbits. The vesicles were spherical with 247 ± 4.67 nm diameter hosting 73.29 ± 3.51% of the drug. Surfactant was nontoxic against cell cultures and caused 5.80 ± 0.51% hemolysis at 1000 µg/mL. It was also found safe in mice up to 2.5 g/kg body weight. Synthesized surfactant based niosomal vesicles revealed enhanced oral bioavailability of Azithromycin in rabbits. The results of the present study confirm that the novel surfactant is highly biocompatible and the niosomal vesicles can be efficiently used for improving the oral bioavailability of poor water soluble drugs.

Transporter-targeted cholic acid-cytarabine conjugates for improved oral absorption.

PubMed

Zhang, Dong; Li, Dongpo; Shang, Lei; He, Zhonggui; Sun, Jin

2016-09-10

Cytarabine has a poor oral absorption due to its rapid deamination and poor membrane permeability. Bile acid transporters are highly expressed both in enterocytes and hepatocytes and to increase the oral bioavailability and investigate the potential application of cytarabine for liver cancers, a transporter- recognizing prodrug strategy was applied to design and synthesize four conjugates of cytarabine with cholic acid (CA), chenodeoxycholic acid (CDCA), hyodeoxycholic acid (HDCA) and ursodeoxycholic acid (UDCA). The anticancer activities against HepG2 cells were evaluated by MTT assay and the role of bile acid transporters during cellular transport was investigated in a competitive inhibition experiment. The in vitro and in vivo metabolic stabilities of these conjugates were studied in rat plasma and liver homogenates. Finally, an oral bioavailability study was conducted in rats. All the cholic acid-cytarabine conjugates (40μM) showed potent antiproliferative activities (up to 70%) against HepG2 cells after incubation for 48h. The addition of bile acids could markedly reduce the antitumor activities of these conjugates. The N(4)-ursodeoxycholic acid conjugate of cytarabine (compound 5) exhibited optimal stability (t1/2=90min) in vitro and a 3.9-fold prolonged half-life of cytarabine in vivo. More importantly, compound 5 increased the oral bioavailability 2-fold compared with cytarabine. The results of the present study suggest that the prodrug strategy based on the bile acid transporters is suitable for improving the oral absorption and the clinical application of cytarabine. Copyright © 2016 Elsevier B.V. All rights reserved.

Preparation, characterization and in vivo evaluation of formulation of repaglinide with hydroxypropyl-β-cyclodextrin.

PubMed

Liu, Meina; Cao, Wen; Sun, Yinghua; He, Zhonggui

2014-12-30

The therapeutic efficacy of repaglinide (RPG) is limited by the low and variable oral bioavailability owing to its limited aqueous solubility. In our present study, the development and evaluation of inclusion complex applying hydroxypropyl-β-cyclodextrin (HP-β-CD) for the improvement of oral bioavailability of repaglinide was investigated systematically. The inclusion complex of repaglinide was prepared by lyophilization technique using drug: hydroxypropyl-β-cyclodextrin (1:15 mole). The prepared complexation was characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), NMR spectroscopy and evaluated by dissolution studies. The (1)H NMR was used in the structure study of repaglinide-HP-β-CD (RPG-HP-β-CD) inclusion complex. The analysis proved the higher probability of the repaglinide A-ring into the narrow rim of the β-cyclodextrin molecule. All the characterization information confirmed the formation of RPG-HP-β-CD inclusion complex. The in vivo pharmacokinetics of RPG-HP-β-CD and their physical mixture were performed in beagle dogs. For the first time, a simple, rapid, and sensitive LC-MS/MS method for determination of RPG in beagle dog plasma was developed. The Cmax and AUC0-t of RPG-HP-β-CD were 2.5 and 2 times higher than that of the physical mixture. These results suggested that the interaction of repaglinide with HP-β-CD could notably improve the dissolution rate and bioavailability of repaglinide comparing with its physical mixture. Copyright © 2014 Elsevier B.V. All rights reserved.

The Combined Application of the Caco-2 Cell Bioassay Coupled with In Vivo (Gallus gallus) Feeding Trial Represents an Effective Approach to Predicting Fe Bioavailability in Humans

PubMed Central

Tako, Elad; Bar, Haim; Glahn, Raymond P.

2016-01-01

Research methods that predict Fe bioavailability for humans can be extremely useful in evaluating food fortification strategies, developing Fe-biofortified enhanced staple food crops and assessing the Fe bioavailability of meal plans that include such crops. In this review, research from four recent poultry (Gallus gallus) feeding trials coupled with in vitro analyses of Fe-biofortified crops will be compared to the parallel human efficacy studies which used the same varieties and harvests of the Fe-biofortified crops. Similar to the human studies, these trials were aimed to assess the potential effects of regular consumption of these enhanced staple crops on maintenance or improvement of iron status. The results demonstrate a strong agreement between the in vitro/in vivo screening approach and the parallel human studies. These observations therefore indicate that the in vitro/Caco-2 cell and Gallus gallus models can be integral tools to develop varieties of staple food crops and predict their effect on iron status in humans. The cost-effectiveness of this approach also means that it can be used to monitor the nutritional stability of the Fe-biofortified crop once a variety has released and integrated into the food system. These screening tools therefore represent a significant advancement to the field for crop development and can be applied to ensure the sustainability of the biofortification approach. PMID:27869705

Development and in vitro/in vivo evaluation of Zn-pectinate microparticles reinforced with chitosan for the colonic delivery of progesterone.

PubMed

Gadalla, Hytham H; Soliman, Ghareb M; Mohammed, Fergany A; El-Sayed, Ahmed M

2016-09-01

The colon is a promising target for drug delivery owing to its long transit time of up to 78 h, which is likely to increase the time available for drug absorption. Progesterone has a short elimination half-life and undergoes extensive first-pass metabolism, which results in very low oral bioavailability (∼25%). To overcome these shortcomings, we developed an oral multiparticulate system for the colonic delivery of progesterone. Zn-pectinate/chitosan microparticles were prepared by ionotropic gelation and characterized for their size, shape, weight, drug entrapment efficiency, mucoadhesion and swelling behavior. The effect of cross-linking pH, cross-linking time and chitosan concentration on progesterone release were also studied. Spherical microparticles having a diameter of 580-720 µm were obtained. Drug entrapment efficiency of ∼75-100% was obtained depending on the microparticle composition. Microparticle mucoadhesive properties were dependent on the pectin concentration, as well as the cross-linking pH. Progesterone release in simulated gastric fluids was minimal (3-9%), followed by burst release at pH 6.8 and a sustained phase at pH 7.4. The in vivo study revealed that the microparticles significantly increased progesterone residence time in the plasma and increased its relative bioavailability to ∼168%, compared to the drug alone. This study confirms the potential of Zn-pectinate/chitosan microparticles as a colon-specific drug delivery system able to enhance the oral bioavailability of progesterone or similar drugs.

Relative bioavailability of 13C5-folic acid in pectin-coated folate fortified rice in humans using stable isotope techniques.

PubMed

de Ambrosis, A; Vishnumohan, S; Paterson, J; Haber, P; Arcot, J

2017-01-01

The aim of the study was to measure the relative bioavailability of labeled pteroylglutamic acid (13C5-PteGlu) from a pectin-coated fortified rice in vivo to measure any effect of the edible coating on folic acid bioavailability. Healthy volunteers (N=26) aged 18-39 years received three test meals in three randomized short-term cross-over trials: Trial 1: aqueous 400 μg 13C5-PteGlu, Trial 2: 200 g cooked white rice+400 μg 13C5-PteGlu,Trial 3: 200 g fortified cooked white rice with pectin-coated premix containing 400 μg 13C5-PteGlu. Blood samples were drawn at 0,1,2,5 and 8 h postprandial. The concentration of 13C5-5 methyl-tetrahydrofolate appearing in plasma was quantified using high performance liquid chromatography-mass spectrometry (MS)/MS. For 24 h before baseline estimation and during the area under the curve (AUC) study, the subjects were placed on a low folate diet (∼100 μg/day). The relative bioavailability of the folic acid following Trial 3 was measured by comparing the 13C5-5 methyl-tetrahydrofuran (THF) AUC with Trials 1 and 2. The bioavailability of folic acid in a pectin-coated rice premix was 68.7% (range 47-105) and 86.5% (range 65-115) in uncoated fortified rice relative to aqueous folic acid. This study is the first demonstration of the bioavailability of folate in pectin-coated fortified rice in humans.

Assessing arsenic bioavailability through the use of bioassays

NASA Astrophysics Data System (ADS)

Diesel, E.; Nadimpalli, M.; Hull, M.; Schreiber, M. E.; Vikesland, P.

2009-12-01

Various methods have been used to characterize the bioavailability of a contaminant, including chemical extractions from soils, toxicity tests, bioaccumulation measurements, estimation from soil properties, in vitro/in vivo tests, and microbial biossays. Unfortunately, these tests are all unique (i.e. they measure bioavailability through different mechanisms) and it is difficult to compare measurements collected using one method to those collected from another. Additionally, there are fundamental aspects of bioavailability research that require further study. In particular, changes in bioavailability over time are not well understood, as well as what the geochemical controls are on changes in bioavailability. In addition, there are no studies aimed at the integration of bioavailability measurements and potential geochemical controls. This research project seeks to find a standard set of assays and sensors that can be used to assess arsenic bioavailability at any field site, as well as to use these tools and techniques to better understand changes in, and controls on, arsenic bioavailability. The bioassays to be utilized in this research are a bioluminescent E. coli assay and a Corbicula fluminea (Asian clam) assay. Preliminary experiments to determine the suitability of the E. coli and C. fluminea assays have been completed. The E. coli assay can be utilized to analyze As(III) and As(V) with a linear standard curve between 5 and 200 ppb for As(III) and 100 ppb and 5 ppm for As(V); no bioluminescent response above background was elicited in the presence of Roxarsone, an organoarsenical. The C. fluminea assay is capable of bioaccumulating As(III), As(V), Roxarsone, and MSMA, with As(III) being the most readily accumulated, followed by As(V), Roxarsone and MSMA, respectively. Additional research will include assessing bioavailability of various arsenic species adsorbed to natural colloidal materials (i.e. clays, iron oxides, NOM) to the E. coli and C. fluminea assays, as well as with natural samples collected at an arsenic contaminated field site. Once the testing of these assays has been completed, they will be used in conjunction with an electrochemical sensor array to determine arsenic bioavailability controls and changes at a contaminated field site.

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.

Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.

PubMed

Muenster, Uwe; Mueck, Wolfgang; van der Mey, Dorina; Schlemmer, Karl-Heinz; Greschat-Schade, Susanne; Haerter, Michael; Pelzetter, Christian; Pruemper, Christian; Verlage, Joerg; Göller, Andreas H; Ohm, Andreas

2016-05-01

The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery. Copyright © 2016 Elsevier B.V. All rights reserved.

Preparation and in Vivo Evaluation of a Dutasteride-Loaded Solid-Supersaturatable Self-Microemulsifying Drug Delivery System

PubMed Central

Kim, Min-Soo; Ha, Eun-Sol; Choo, Gwang-Ho; Baek, In-Hwan

2015-01-01

The purpose of this study was to prepare a dutasteride-loaded solid-supersaturatable self-microemulsifying drug delivery system (SMEDDS) using hydrophilic additives with high oral bioavailability, and to determine if there was a correlation between the in vitro dissolution data and the in vivo pharmacokinetic parameters of this delivery system in rats. A dutasteride-loaded solid-supersaturatable SMEDDS was generated by adsorption of liquid SMEDDS onto Aerosil 200 colloidal silica using a spray drying process. The dissolution and oral absorption of dutasteride from solid SMEDDS significantly increased after the addition of hydroxypropylmethyl cellulose (HPMC) or Soluplus. Solid SMEDDS/Aerosil 200/Soluplus microparticles had higher oral bioavailability with 6.8- and 5.0-fold higher peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) values, respectively, than that of the equivalent physical mixture. A linear correlation between in vitro dissolution efficiency and in vivo pharmacokinetic parameters was demonstrated for both AUC and Cmax values. Therefore, the preparation of a solid-supersaturatable SMEDDS with HPMC or Soluplus could be a promising formulation strategy to develop novel solid dosage forms of dutasteride. PMID:25984604

Pharmaceutical development and optimization of azithromycin suppository for paediatric use.

PubMed

Kauss, Tina; Gaubert, Alexandra; Boyer, Chantal; Ba, Boubakar B; Manse, Muriel; Massip, Stephane; Léger, Jean-Michel; Fawaz, Fawaz; Lembege, Martine; Boiron, Jean-Michel; Lafarge, Xavier; Lindegardh, Niklas; White, Nicholas J; Olliaro, Piero; Millet, Pascal; Gaudin, Karen

2013-01-30

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought. Copyright © 2012 Elsevier B.V. All rights reserved.

Pharmaceutical development and optimization of azithromycin suppository for paediatric use

PubMed Central

Kauss, Tina; Gaubert, Alexandra; Boyer, Chantal; Ba, Boubakar B.; Manse, Muriel; Massip, Stephane; Léger, Jean-Michel; Fawaz, Fawaz; Lembege, Martine; Boiron, Jean-Michel; Lafarge, Xavier; Lindegardh, Niklas; White, Nicholas J.; Olliaro, Piero; Millet, Pascal; Gaudin, Karen

2013-01-01

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought. PMID:23220079

Quercetin does not alter the oral bioavailability of Atorvastatin in rats.

PubMed

Koritala, Rekha; Challa, Siva Reddy; Ragam, Satheesh Kumar; Geddam, Lal Babu; Venkatesh Reddy Challa, Venkatesh Reddy; Devi, Renuka; Sattenapalli, Srinu; Babu, Narendra

2015-09-01

The study was undertaken to evaluate the effect of Quercetin on the pharmacokinetics of Atorvastatin Calcium. In-vivo Pharmacokinetic studies were performed on rats in a single dose study and multiple dose study. Rats were treated with Quercetin (10 mg/kg) and Atorvastatin Calcium (20 mg/kg) orally and blood samples were collected at (0) pretreatment and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24 hours post treatment. Plasma concentrations of Atorvastatin were estimated by HPLC method. Quercetin treatment did not significantly alter the pharmacokinetic parameters of atorvastatin like AUC(0-24), AUC(0-α) , T(max), C(max) and T(½) in both single dose and multiple dose studies of Atorvastatin Calcium. Quercetin does not alter the oral bioavailability of Atorvastatin Calcium in rats.

A new series of highly potent growth hormone-releasing peptides derived from ipamorelin.

PubMed

Ankersen, M; Johansen, N L; Madsen, K; Hansen, B S; Raun, K; Nielsen, K K; Thogersen, H; Hansen, T K; Peschke, B; Lau, J; Lundt, B F; Andersen, P H

1998-09-10

A new series of GH secretagogues derived from ipamorelin is described. In an attempt to obtain oral bioavailability, by reducing the size and the number of potential hydrogen-bonding sites of the compounds, a strategy using the peptidomimetic fragment 3-(aminomethyl)benzoic acid and sequential backbone N-methylations was applied. Several compounds from this series release GH with high in vitro potency and efficacy in a rat pituitary cell assay and high in vivo potency and efficacy in anesthetized rats. The tetrapeptide NNC 26-0235 (3-(aminomethyl)benzoyl-D-2Nal-N-Me-D-Phe-Lys-NH2) shows, following iv administration, comparable in vivo potency to ipamorelin, GHRP-2, and GHRP-6 with an ED50 in swine at 2 nmol/kg. NNC 26-0235 demonstrated a 10% oral bioavailability in dogs, and NNC 26-0235 and ipamorelin were able to increase basal GH level by more than 10-fold after oral administration of a dose of 1.8 and 2.7 mg/kg, respectively. The tripeptide NNC 26-0323 (3-(aminomethyl)benzoic acid-N-Me-D-2Nal-N-Me-D-Phe-ol) which showed moderate in vitro potency but lacked in vivo potency demonstrated a 20% oral bioavailability in rats.

In vitro and in vivo evaluation of cyclodextrin-based nanosponges for enhancing oral bioavailability of atorvastatin calcium.

PubMed

Zidan, Mohamed F; Ibrahim, Hany M; Afouna, Mohsen I; Ibrahim, Elsherbeny A

2018-08-01

The aim of this study was to explore the feasibility of complexing the poorly water-soluble drug atorvastatin calcium (AC) with β-cyclodextrin (β-CD) based nanosponges (NS), which offer advantages of improving dissolution rate and eventually oral bioavailability. Blank NS were fabricated at first by reacting β-CD with the cross-linker carbonyldiimidazole at different molar ratios (1:2, 1:4, and 1:8), then NS of highest solubilization extent for AC were complexed with AC. AC loaded NS (AC-NS) were characterized for various physicochemical properties. Pharmacokinetic, pharmacodynamics and histological finding of AC-NS were performed in rats. The prepared AC-NS showed particles size ranged from 408.7 ± 12.9 to 423 ± 15.9 nm while zeta potential values varied from -21.7 ± 0.90 to -22.7 ± 0.85 mV. The loading capacity varied from 17.9 ± 1.21 to 34.1 ± 1.16%. DSC, FT-IR, and PXRD studies confirmed the complexation of AC with NS and amorphous state of the drug in the complex. AC-NS displayed a biphasic release pattern with increase in the dissolution rate of AC as compared to plain AC. Oral administration of AC-NS (1:4 w/w, drug: NS) to rats led to 2.13-folds increase in the bioavailability as compared to AC suspension. Pharmacodynamics studies in rats with fatty liver revealed significant reduction (p < .05) in total cholesterol, triglyceride, LDL-C and increased level of beneficial HDL-C along with improvement in the associated liver steatosis as confirmed through photomicrographs of liver sections. In this study, we confirmed that complexation of AC with NS would be a viable approach for improving oral bioavailability and in vivo performance of AC.

Curcumin micelles improve mitochondrial function in neuronal PC12 cells and brains of NMRI mice - Impact on bioavailability.

PubMed

Hagl, Stephanie; Kocher, Alexa; Schiborr, Christina; Kolesova, Natalie; Frank, Jan; Eckert, Gunter P

2015-10-01

Curcumin, a polyphenolic compound abundant in the rhizome of Curcuma longa, has been reported to have various beneficial biological and pharmacological activities. Recent research revealed that curcumin might be valuable in the prevention and therapy of numerous disorders including neurodegenerative diseases like Alzheimer's disease. Due to its low absorption and quick elimination from the body, curcumin bioavailability is rather low which poses major problems for the use of curcumin as a therapeutic agent. There are several approaches to ameliorate curcumin bioavailability after oral administration, amongst them simultaneous administration with secondary plant compounds, micronization and micellation. We examined bioavailability in vivo in NMRI mice and the effects of native curcumin and a newly developed curcumin micelles formulation on mitochondrial function in vitro in PC12 cells and ex vivo in isolated mouse brain mitochondria. We found that curcumin micelles improved bioavailability of native curcumin around 10- to 40-fold in plasma and brain of mice. Incubation with native curcumin and curcumin micelles prevented isolated mouse brain mitochondria from swelling, indicating less mitochondrial permeability transition pore (mPTP) opening and prevention of injury. Curcumin micelles proved to be more efficient in preventing mitochondrial swelling in isolated mouse brain mitochondria and protecting PC12 cells from nitrosative stress than native curcumin. Due to their improved effectivity, curcumin micelles might be a suitable formulation for the prevention of mitochondrial dysfunction in brain aging and neurodegeneration. Copyright © 2015 Elsevier Ltd. All rights reserved.

Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo.

PubMed

Anand, Preetha; Nair, Hareesh B; Sung, Bokyung; Kunnumakkara, Ajaikumar B; Yadav, Vivek R; Tekmal, Rajeshwar R; Aggarwal, Bharat B

2010-02-01

Curcumin, a yellow pigment present in the spice turmeric (Curcuma longa), has been linked with antioxidant, anti-inflammatory, antiproliferative, anticancer, antidiabetic, antirheumatic, and antiviral effects, but its optimum potential is limited by its lack of solubility in aqueous solvents and poor oral bioavailability. We employed a polymer-based nanoparticle approach to improve bioavailability. Curcumin was encapsulated with 97.5% efficiency in biodegradable nanoparticulate formulation based on poly (lactide-co-glycolide) (PLGA) and a stabilizer polyethylene glycol (PEG)-5000. Dynamic laser light scattering and transmission electron microscopy indicated a particle diameter of 80.9 nm. This curcumin, renamed from hereon "as curcumin (NP)", was characterized for its biological activity. In vitro curcumin (NP) exhibited very rapid and more efficient cellular uptake than curcumin. Estrase staining revealed that curcumin (NP) was at least as potent as or more potent than curcumin in inducing apoptosis of leukemic cells and in suppressing proliferation of various tumor cell lines. When examined by electrophoretic gel shift mobility assay, curcumin (NP) was more active than curcumin in inhibiting TNF-induced NF-kappaB activation and in suppression of NF-kappaB-regulated proteins involved in cell proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF). In mice, curcumin (NP) was more bioavailable and had a longer half-life than curcumin. Overall we demonstrate that curcumin-loaded PLGA nanoparticles formulation has enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo over curcumin.

Digestive solubilization of sediment-associated pollutants: In vitro extraction vs. in vivo bioavailability

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

Weston, D.P.; Mayer, L.M.

1995-12-31

A method using polychaete digestive fluids as a more biologically realistic extractant has recent been proposed as a means to quantify this bioavailable fraction. This work was intended to evaluate this approach with polynuclear aromatic hydrocarbons (PAH), and, in particular, to relate in vitro measures of PAH solubilization by digestive fluids to bioavailability as perceived by the whole animal. In tests with a variety of PAH-contaminated sediments, there were dramatic differences among the sediments in the amounts of PAH extracted by digestive fluids. About 50% of a PAH spike was extracted from a low organic carbon sediment during digestive fluidmore » extraction, while only 20% was extracted from a high organic carbon sediment. The relationships between these differences in PAH solubilization and true bioavailability were evaluated in polychaete bioaccumulation tests measuring PAH uptake rate coefficients and steady state body burdens. The work has also shown that desorption of PAH from ingested sediments in the whole animal approximated the quantities extracted in the in vitro tests. Moreover, desorption of PAH from ingested sediments was found to be greatest in that portion of the polychaete gut with the highest enzymatic activity and from which the digestive fluids had been collected. The digestive fluid extraction approach provides a new tool to examine digestive uptake of contaminants by manipulations that would be impossible in vivo, and may help to quantify a bioavailable contaminant fraction.« less

Characterization and evaluation in vivo of baicalin-nanocrystals prepared by an ultrasonic-homogenization-fluid bed drying method.

PubMed

Shi-Ying, Jin; Jin, Han; Shi-Xiao, Jin; Qing-Yuan, Lv; Jin-Xia, Bai; Chen, Hong-Ge; Rui-Sheng, Li; Wei, Wu; Hai-Long, Yuan

2014-01-01

To improve the absorption and bioavailability of baicalin using a nanocrystal (or nanosuspension) drug delivery system. A tandem, ultrasonic-homogenization-fluid bed drying technology was applied to prepare baicalin-nanocrystal dried powders, and the physicochemical properties of baicalin-nanocrystals were characterized by scanning electron microscopy, photon correlation spectroscopy, powder X-ray diffraction, physical stability, and solubility experiments. Furthermore, in situ intestine single-pass perfusion experiments and pharmacokinetics in rats were performed to make a comparison between the microcrystals of baicalin and pure baicalin in their absorption properties and bioavailability in vivo. The mean particle size of baicalin-nanocrystals was 236 nm, with a polydispersity index of 0.173, and a zeta potential value of -34.8 mV, which provided a guarantee for the stability of the reconstituted nanosuspension. X-Ray diffraction results indicated that the crystallinity of baicalin was decreased through the ultrasonic-homogenization process. Physical stability experiments showed that the prepared baicalin-nanocrystals were sufficiently stable. It was shown that the solubility of baicalin in the form of nanocrystals, at 495 μg·mL(-1), was much higher than the baicalin-microcrystals and the physical mixture (135 and 86.4 μg·mL(-1), respectively). In situ intestine perfusion experiments demonstrated a clear advantage in the dissolution and absorption characteristics for baicalin-nanocrystals compared to the other formulations. In addition, after oral administration to rats, the particle size decrease from the micron to nanometer range exhibited much higher in vivo bioavailability (with the AUC(0-t) value of 206.96 ± 21.23 and 127.95 ± 14.41 mg·L(-1)·h(-1), respectively). The nanocrystal drug delivery system using an ultrasonic-homogenization-fluid bed drying process is able to improve the absorption and in vivo bioavailability of baicalin, compared with pure baicalin coarse powder and micronized baicalin. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Improving the oral bioavailability of curcumin using novel organogel-based nanoemulsions.

PubMed

Yu, Hailong; Huang, Qingrong

2012-05-30

Curcumin is a natural bioactive compound with many health-promoting benefits. Its low oral bioavailability limits its application in functional foods. In the present study, novel organogel-based nanoemulsions have been developed for oral delivery of curcumin and improvement of its bioavailability. Recently developed curcumin organogel was used as the oil phase in the curcumin nanoemulsion formulation. Tween 20 was selected as the emulsifier on the basis of maximum in vitro bioaccessibility of curcumin in the nanoemulsion. In vitro lipolysis profile revealed that the digestion of nanoemulsion was significantly faster and more complete than the organogel. Permeation experiments on Caco-2 cell monolayers suggested that digestion-diffusion was the major absorption mechanism for curcumin in the nanoemulsion. Furthermore, in vivo pharmacokinetics analysis on mice confirmed that the oral bioavailability of curcumin in the nanoemulsion was increased by 9-fold compared with unformulated curcumin. This novel formulation approach may also be used for oral delivery of other poorly soluble nutraceuticals with high loading capacity, which has significant impact in functional foods, dietary supplements and pharmaceutical industries.

Modulatory effects of silibinin in various cell signaling pathways against liver disorders and cancer - A comprehensive review.

PubMed

Polachi, Navaneethakrishnan; Bai, Guirong; Li, Tingyang; Chu, Yang; Wang, Xiangyang; Li, Shuming; Gu, Ning; Wu, Jiang; Li, Wei; Zhang, Yanjun; Zhou, Shuiping; Sun, He; Liu, Changxiao

2016-11-10

Silibinin, a natural flavanone, derived from the milk thistle plant (Silybum marianum), was illustrated for several medicinal uses such as liver-protective, anti-oxidant, anti-cancer, anti-inflammation and many other. However, silibinin has poor absorbance and bioavailability due to low water solubility, thereby limiting its clinical applications and therapeutic efficiency. To overcome this problem, the combination of silibinin with phosphatidylcholine (PC) as a formulation was used to enhance the solubility and bioavailability. The results indicated that silibinin-PC taken orally markedly enhanced bioavailability and therapeutic efficiency. In addition, a deeper understanding of the signaling pathways modulated by silibinin is important to realize its potential in developing targeted therapies against liver disorders and cancer. Silibinin has been shown to inhibit many cell signaling pathways in preclinical models, demonstrating promising effects against liver disorders and cancer through in vitro and in vivo studies. This review summarizes the pharmacokinetic properties, bioavailability, safety data, clinical activities and modulatory effects of silibinin in different cell signaling pathways against liver disorders and cancer. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities.

PubMed

Harland, Aubrie A; Yeomans, Larisa; Griggs, Nicholas W; Anand, Jessica P; Pogozheva, Irina D; Jutkiewicz, Emily M; Traynor, John R; Mosberg, Henry I

2015-11-25

In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.

STRUCTURAL CHARACTERISTICS AND ANTIHYPERTENSIVE EFFECTS OF ANGIOTENSIN-I-CONVERTING ENZYME INHIBITORY PEPTIDES IN THE RENIN-ANGIOTENSIN AND KALLIKREIN KININ SYSTEMS

PubMed Central

Manoharan, Sivananthan; Shuib, Adawiyah Suriza; Abdullah, Noorlidah

2017-01-01

Background: The commercially available synthetic angiotensin-I-converting enzyme (ACE) inhibitors are known to exert negative side effects which have driven many research groups globally to discover the novel ACE inhibitors. Method: Literature search was performed within the PubMed, ScienceDirect.com and Google Scholar. Results: The presence of proline at the C-terminal tripeptide of ACE inhibitor can competitively inhibit the ACE activity. The effects of other amino acids are less studied leading to difficulties in predicting potent peptide sequences. The broad specificity of the enzyme may be due to the dual active sites observed on the somatic ACE. The inhibitors may not necessarily competitively inhibit the enzyme which explains why some reported inhibitors do not have the common ACE inhibitor characteristics. Finally, the in vivo assay has to be carried out before the peptides as the antihypertensive agents can be claimed. The peptides must be absorbed into circulation without being degraded, which will affect their bioavailability and potency. Thus, peptides with strong in vitro IC50 values do not necessarily have the same effect in vivo and vice versa. Conclusion: The relationship between peptide amino acid sequence and inhibitory activity, in vivo studies of the active peptides and bioavailability must be studied before the peptides as antihypertensive agents can be claimed. PMID:28573254

Enhancement of the dissolution rate and bioavailability of fenofibrate by a melt-adsorption method using supercritical carbon dioxide

PubMed Central

Cha, Kwang-Ho; Cho, Kyung-Jin; Kim, Min-Soo; Kim, Jeong-Soo; Park, Hee Jun; Park, Junsung; Cho, Wonkyung; Park, Jeong-Sook; Hwang, Sung-Joo

2012-01-01

Background: The aim of this study was to enhance the bioavailability of fenofibrate, a poorly water-soluble drug, using a melt-adsorption method with supercritical CO2. Methods: Fenofibrate was loaded onto Neusilin® UFL2 at different weight ratios of fenofibrate to Neusilin UFL2 by melt-adsorption using supercritical CO2. For comparison, fenofibrate-loaded Neusilin UFL2 was prepared by solvent evaporation and hot melt-adsorption methods. The fenofibrate formulations prepared were characterized by differential scanning calorimetry, powder x-ray diffractometry, specific surface area, pore size distribution, scanning electron microscopy, and energy-dispersive x-ray spectrometry. In vitro dissolution and in vivo bioavailability were also investigated. Results: Fenofibrate was distributed into the pores of Neusilin UFL2 and showed reduced crystal formation following adsorption. Supercritical CO2 facilitated the introduction of fenofibrate into the pores of Neusilin UFL2. Compared with raw fenofibrate, fenofibrate from the prepared powders showed a significantly increased dissolution rate and better bioavailability. In particular, the area under the drug concentration-time curve and maximal serum concentration of the powders prepared using supercritical CO2 were 4.62-fold and 4.52-fold greater than the corresponding values for raw fenofibrate. Conclusion: The results of this study highlight the usefulness of the melt-adsorption method using supercritical CO2 for improving the bioavailability of fenofibrate. PMID:23118538

Inclusion complex of novel curcumin analogue CDF and β-cyclodextrin (1:2) and its enhanced in vivo anticancer activity against pancreatic cancer.

PubMed

Dandawate, Prasad R; Vyas, Alok; Ahmad, Aamir; Banerjee, Sanjeev; Deshpande, Jyoti; Swamy, K Venkateswara; Jamadar, Abeda; Dumhe-Klaire, Anne Catherine; Padhye, Subhash; Sarkar, Fazlul H

2012-07-01

Several formulations have been proposed to improve the systemic delivery of novel cancer therapeutic compounds, including cyclodextrin derivatives. We aimed to synthesize and characterize of CDF-β-cyclodextrin inclusion complex (1:2) (CDFCD). The compound was characterized by Fourier transform infrared, differential scanning calorimetry, powder X-ray diffraction studies, H1 & C13 NMR studies and scanning electron microscopic analysis. Its activity was tested against multiple cancer cell lines, and in vivo bioavailability was checked. CDF-β-cyclodextrin was found to lower IC(50) value by half when tested against multiple cancer cell lines. It preferentially accumulated in the pancreas, where levels of CDF-β-cyclodextrin in mice were 10 times higher than in serum, following intravenous administration of an aqueous CDF-β-cyclodextrin preparation. Novel curcumin analog CDF preferentially accumulates in the pancreas, leading to its potent anticancer activity against pancreatic cancer cells. Synthesis of such CDF-β-cyclodextrin self-assembly is an effective strategy to enhance its bioavailability and tissue distribution, warranting further evaluation for CDF delivery in clinical settings for treatment of human malignancies.

Preparation and in vitro/in vivo evaluation of metformin hydrochloride rectal dosage forms for treatment of patients with type II diabetes.

PubMed

Zaghloul, Abdel-Azim; Lila, Ahmad; Abd-Allah, Fathy; Nada, Aly

2017-06-01

Metformin hydrochloride (MtHCL) is an oral antidiabetic drug and has many other therapeutic benefits. It has poor bioavailability, narrow absorption window and extensive liver metabolism. Moreover, children and elders face difficulty to swallow the commercial oral tablets. Preparation, in vitro/in vivo evaluation of MtHCL suppositories for rectal administration to solve some of these problems. Suppository fatty bases (Witepsol ® , Suppocire ® and Massa ® ; different grades) and PEG bases 1000, 4000 and 6000 (different ratios), were used to prepare rectal suppository formulations each containing 500 mg drug. These were characterized for manufacturing defects, and pharmacotechnical performance and formulations showing superior results were subjected to bioavailability testing in human volunteers compared with the commercial oral tablet (Ref) applying LC-MS/MS developed analytical technique. The preparation method produced suppositories with satisfactory characteristics and free of manufacturing defects. The fatty bases were superior compared with PEG bases regarding the physical characteristics. Three formulations were chosen for bioavailability testing and the results showed comparable bioavailability compared to the Ref. The fatty bases showed superior characteristics compared with the PEG bases. MtHCL formulated in selected fatty bases could be a potential alternative to the commercial oral tablets particularly for pediatric and geriatric patients.

Ramizol® encapsulation into extended release PLGA micro- and nanoparticle systems for subcutaneous and intramuscular administration: in vitro and in vivo evaluation.

PubMed

Wright, Leah; Rao, Shasha; Thomas, Nicky; Boulos, Ramiz A; Prestidge, Clive A

2018-04-11

Novel antibiotic Ramizol ® is advancing to clinical trials for the treatment of gastrointestinal Clostridium difficile associated disease. Despite this, previous studies have shown a rapid plasma clearance upon intravenous administration and low oral bioavailability indicating pure drug is unsuitable for systemic infection treatment following oral dosing. The current study aims to investigate the development of poly-lactic-(co-glycolic) acid (PLGA) particles to overcome this limitation and increase the systemic half-life following subcutaneous and intramuscular dosing. The development of new antibiotic treatments will help in combatting the rising incidence of antimicrobial resistance. Ramizol ® was encapsulated into PLGA nano and microparticles using nanoprecipitation and emulsification solvent evaporation techniques. Formulations were analyzed for particle size, loading level and encapsulation efficiency as well as in vitro drug release profiles. Final formulation was advanced to in vivo pharmacokinetic studies in Sprague-Dawley rats. Formulation technique showed major influence on particle size and loading levels with optimal loading of 9.4% and encapsulation efficiency of 92.06%, observed using emulsification solvent evaporation. Differences in formulation technique were also linked with subsequent differences in release profiles. Pharmacokinetic studies in Sprague-Dawley rats confirmed extended absorption and enhanced bioavailability following subcutaneous and intramuscular dosing with up to an 8-fold increase in T max and T 1/2 when compared to the oral and IV routes. Subcutaneous and intramuscular dosing of PLGA particles successfully increased systemic half-life and bioavailability of Ramizol ® . This formulation will allow further development of Ramizol ® for systemic infection eradication.

Implications of formulation design on lipid-based nanostructured carrier system for drug delivery to brain.

PubMed

Salunkhe, Sachin S; Bhatia, Neela M; Bhatia, Manish S

2016-05-01

The aim of present investigation was to formulate and develop lipid-based nanostructured carriers (NLCs) containing Idebenone (IDE) for delivery to brain. Attempts have been made to evaluate IDE NLCs for its pharmacokinetic and pharmacodynamic profile through the objective of enhancement in bioavailability and effectivity of drug. Nanoprecipitation technique was used for development of drug loaded NLCs. The components solid lipid Precirol ATO 5, oil Miglyol 840, surfactants Tween 80 and Labrasol have been screened out for formulation development by consideration of preformulation parameters including solubility, Required Hydrophilic lipophilic balance (HLB) of lipids and stability study. Developed IDE NLCs were subjected for particle size, zeta potential, entrapment efficiency (%EE), crystallographic investigation, transmission electron microscopy, in vitro drug release, pharmacokinetics, in vivo and stability study. Formulation under investigation has particle size 174.1 ± 2.6 nm, zeta potential -18.65 ± 1.13 mV and% EE 90.68 ± 2.90. Crystallographic studies exemplified for partial amorphization of IDE by molecularly dispersion within lipid crust. IDE NLCs showed drug release 93.56 ± 0.39% at end of 24 h by following Higuchi model which necessitates for appropriate drug delivery with enhancement in bioavailability of drug by 4.6-fold in plasma and 2.8-fold in brain over plain drug loaded aqueous dispersions. In vivo studies revealed that effect of drug was enhanced by prepared lipid nanocarriers. IDE lipid-based nanostructured carriers could have potential for efficient drug delivery to brain with enhancement in bioavailability of drug over the conventional formulations.

Pharmacological evaluation of mangiferin herbosomes for antioxidant and hepatoprotection potential against ethanol induced hepatic damage.

PubMed

Jain, Pushpendra Kumar; Kharya, Murlidhar; Gajbhiye, Asmita

2013-11-01

Fatty liver is the first stage of alcoholic damage which is reversible with abstinence from alcohol. Mangiferin (MF) showed potent scavenging activity on diphenyl-1-picrylhydrazyl radicals which stimulate liver regeneration in various liver injuries. Although, MF shows hepatoprotection against various liver disorders but due to rapid clearance and limited solubility in lipoid environment, there is problem of its poor absorption from intestine hence poor bioavailability. Owing to which there is a need to develop MF herbosomes to resolve the problem of poor bioavailability to enhance the therapeutic potential. Successfully prepared MF herbosomes through complexation with phospholipids were characterized by physicochemical, chromatography, spectroscopy (differential scanning calorimetry (DSC), infrared (IR), and nuclear magnetic resonance (NMR)), ex vivo absorption using everted small intestine sac technique and in vivo studies using ethanol inducing hepatotoxicity in albino rats and comparing the results against plain MF. Ex vivo study showed significant increased absorption of MF from prepared MF herbosomes as compared to plain MF. The hepatoprotective potential of MF herbosomes evaluated by in vivo study revealed significantly decreased levels of serum glutamate oxaloacetate transminase (SGOT), serum glutamate pyruvate transminase (SGPT), total bilirubin, and alkaline phosphatase (ALP) in MF herbosomes as compared to plain MF. MF herbosomes also showed significantly decreased level of malonyl dehydrogenase along with increased levels of reduced glutathione, superoxide dismutase (SOD) and catalase as compared to plain MF which was also comparable to the standard drug, silymarin (SL). The above mentioned results showed that hepatoprotective and antioxidant potency of MF enhanced due to the preparation of its herbosomes.

Development and optimisation of atorvastatin calcium loaded self-nanoemulsifying drug delivery system (SNEDDS) for enhancing oral bioavailability: in vitro and in vivo evaluation.

PubMed

Kassem, Abdulsalam M; Ibrahim, Hany M; Samy, Ahmed M

2017-05-01

The objective of this study was to develop and optimise self-nanoemulsifying drug delivery system (SNEDDS) of atorvastatin calcium (ATC) for improving dissolution rate and eventually oral bioavailability. Ternary phase diagrams were constructed on basis of solubility and emulsification studies. The composition of ATC-SNEDDS was optimised using the Box-Behnken optimisation design. Optimised ATC-SNEDDS was characterised for various physicochemical properties. Pharmacokinetic, pharmacodynamic and histological findings were performed in rats. Optimised ATC-SNEDDS resulted in droplets size of 5.66 nm, zeta potential of -19.52 mV, t 90 of 5.43 min and completely released ATC within 30 min irrespective of pH of the medium. Area under the curve of optimised ATC-SNEDDS in rats was 2.34-folds higher than ATC suspension. Pharmacodynamic studies revealed significant reduction in serum lipids of rats with fatty liver. Photomicrographs showed improvement in hepatocytes structure. In this study, we confirmed that ATC-SNEDDS would be a promising approach for improving oral bioavailability of ATC.

Lyotropic Liquid Crystalline Nanoparticles of Amphotericin B: Implication of Phytantriol and Glyceryl Monooleate on Bioavailability Enhancement.

PubMed

Jain, Sanyog; Yadav, Pooja; Swami, Rajan; Swarnakar, Nitin Kumar; Kushwah, Varun; Katiyar, Sameer S

2018-05-01

Implication of different dietary specific lipids such as phytantriol (PT) and glyceryl monooleate (GMO) on enhancing the oral bioavailability of amphotericin B (AmB) was examined. Liquid crystalline nanoparticles (LCNPs) were prepared using hydrotrope method, followed by in vitro characterization, Caco-2 cell monolayer uptake, and in vivo pharmacokinetic and toxicity evaluation. Optimized AmB-LCNPs displayed small particle size (< 210 nm) with a narrow distribution (~ 0.2), sustained drug release and high gastrointestinal stability, and reduced hemolytic toxicity. PLCNPs presented slower release, i.e., ~ 80% as compared to ~ 90% release in case of GLCNPs after 120 h. Significantly higher uptake in Caco-2 monolayer substantiated the role of LCNPs in increasing the intestinal permeability followed by increased drug titer in plasma. Pharmacokinetic studies demonstrated potential of PT in enhancing the bioavailability (approximately sixfold) w.r.t. of its native counterpart with reduced nephrotoxicity as presented by reduced nephrotoxicity biomarkers and histology studies. These studies established usefulness of PLCNPs over GLCNPs and plain drug. It can be concluded that acid-resistant lipid, PT, can be utilized efficiently as an alternate lipid for the preparation of LCNPs to enhance bioavailability and to reduce nephrotoxicity of the drug as compared to other frequently used lipid, i.e., GMO.

Bioavailability of trans-resveratrol from red wine in humans.

PubMed

Vitaglione, Paola; Sforza, Stefano; Galaverna, Gianni; Ghidini, Cristiana; Caporaso, Nicola; Vescovi, Pier Paolo; Fogliano, Vincenzo; Marchelli, Rosangela

2005-05-01

Many in vitro studies demonstrated significant biological effects of trans-resveratrol. Thus, understanding the rate of intestinal absorption and metabolization in vivo of trans-resveratrol is the prerequisite to evaluate its potential health impact. Bioavailability studies mainly in animals or in humans using the pure compound at very high doses were performed. In this work, trans-resveratrol bioavailability from a moderate consumption of red wine in 25 healthy humans has been studied by three different experiments. The wine ingestion was associated to three different dietary approaches: fasting, a standard meal, a meal with high and low amount of lipids. Trans-resveratrol 3- and 4'-glucuronides were synthesized, purified, and characterized as pure standards. Bioavailability data were obtained by measuring the concentration of free, 3-glucuronide and 4'-glucuronide trans-resveratrol by high-performance liquid chromatography (HPLC), both with ultraviolet (UV) and mass spectrometry (MS) detection, in serum samples taken at different times after red wine administration. Free trans-resveratrol was found, in trace amounts, only in some serum samples collected 30 min after red wine ingestion while after longer times resveratrol glucuronides predominated. Trans-resveratrol bioavailability was shown to be independent from the meal or its lipid content. The finding in human serum of trans-resveratrol glucuronides, rather than the free form of the compound, with a high interindividual variability, raises some doubts about the health effects of dietary resveratrol consumption and suggests that the benefits associated to red wine consumption could be probably due to the whole antioxidant pool present in red wine.

Metabolic fate of poly-(lactic-co-glycolic acid)-based curcumin nanoparticles following oral administration.

PubMed

Harigae, Takahiro; Nakagawa, Kiyotaka; Miyazawa, Taiki; Inoue, Nao; Kimura, Fumiko; Ikeda, Ikuo; Miyazawa, Teruo

2016-01-01

Curcumin (CUR), the main polyphenol in turmeric, is poorly absorbed and rapidly metabolized following oral administration, which severely curtails its bioavailability. Poly-(lactic-co-glycolic acid)-based CUR nanoparticles (CUR-NP) have recently been suggested to improve CUR bioavailability, but this has not been fully verified. Specifically, no data are available about curcumin glucuronide (CURG), the major metabolite of CUR found in the plasma following oral administration of CUR-NP. Herein, we investigated the absorption and metabolism of CUR-NP and evaluated whether CUR-NP improves CUR bioavailability. Following oral administration of CUR-NP in rats, we analyzed the plasma and organ distribution of CUR and its metabolites using high-performance liquid chromatography-tandem mass spectrometry. To elucidate the mechanism of increased intestinal absorption of CUR-NP, we prepared mixed micelles comprised of phosphatidylcholine and bile salts and examined the micellar solubility of CUR-NP. Additionally, we investigated the cellular incorporation of the resultant micelles into differentiated Caco-2 human intestinal cells. Following in vivo administration of CUR-NP, CUR was effectively absorbed and present mainly as CURG in the plasma which contained significant amounts of the metabolite compared with other organs. Thus, CUR-NP increased intestinal absorption of CUR rather than decreasing metabolic degradation and conversion to other metabolites. In vitro, CUR encapsulated in CUR-NP was solubilized in mixed micelles; however, whether the micelles contained CUR or CUR-NP had little influence on cellular uptake efficiency. Therefore, we suggest that the high solubilization capacity of CUR-NP in mixed micelles, rather than cellular uptake efficiency, explains the high intestinal absorption of CUR-NP in vivo. These findings provide a better understanding of the bioavailability of CUR and CUR-NP following oral administration. To improve the bioavailability of CUR, future studies should focus on enhancing the resistance to metabolic degradation and conversion of CUR to other metabolites, which may lead to novel discoveries regarding food function and disease prevention.

N-trimethyl chitosan nanoparticles and CSKSSDYQC peptide: N-trimethyl chitosan conjugates enhance the oral bioavailability of gemcitabine to treat breast cancer.

PubMed

Chen, Guanyu; Svirskis, Darren; Lu, Weiyue; Ying, Man; Huang, Yuan; Wen, Jingyuan

2018-05-10

Gemcitabine is a nucleoside analogue effective against a number of cancers. However, the full potential of this drug has not been realised, in part due to low oral bioavailability and frequent dosing requirements. This study reports the synthesis, in-vitro, ex-vivo and in-vivo evaluation of trimethyl chitosan (TMC) - CSKSSDYQC (CSK) peptide conjugates capable of enhancing the oral bioavailability of gemcitabine due to the ability to target intestinal goblet cells and promote intestinal cellular uptake. TMC was synthesized by a novel two-step methylation method to improve quanternization and yield. The CSK-TMC conjugates were prepared by ionic gelation to achieve particles sized at 173.6 ± 6.8 nm, zeta potential of +18.5 ± 0.2 mV and entrapment efficiency of 66.4 ± 0.1%, capable of sustained drug release. By encapsulating gemcitabine into CSK-TMC conjugates, an increased amount of drug permeated through porcine intestinal epithelial membranes compared with the unconjugated TMC nanoparticles (NPs). The rate of cellular uptake of drug loaded conjugates into HT29-MTX-E12 intestinal goblet cells, was time- and concentration-dependant. The conjugates underwent active transport associated with adsorptive mediated, clathrin and caveolae mediated endocytosis. In cellular transport studies, drug loaded conjugates had greater drug transport capability compared with drug solution and TMC NPs over the co-cultured Caco-2/HT29-MTX-E12 cell monolayer. The drug loaded conjugates exhibited electrostatic interaction with the intestinal epithelial cells. Both P-glycoprotein (P-gp) and multiple resistance protein-2 (MRP2) efflux affected the cellular transport of the conjugates. Importantly, during the pharmacokinetic studies, the orally administrated drug loaded into TMC NPs showed an improved oral bioavailability of 54.0%, compared with gemcitabine solution of 9.9%. Notable, the CSK-TMC conjugates further improved oral bioavailability to 60.1% and reduced the tumour growth rate in a BALB/c nude mouse model, with a 5.1-fold and 3.3-fold reduction compare with the non-treated group and gemcitabine solution group. Furthermore, no major evidence of toxicity was discernible on histologic studies of selected organs. In conclusion, the presented CSK-TMC conjugates and TMC nanoparticles both significantly improve the oral bioavailability of gemcitabine and have the potential for the treatment of breast cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

A Comparison between Use of Spray and Freeze Drying Techniques for Preparation of Solid Self-Microemulsifying Formulation of Valsartan and In Vitro and In Vivo Evaluation

PubMed Central

Singh, Sanjay Kumar; Vuddanda, Parameswara Rao; Singh, Sanjay; Srivastava, Anand Kumar

2013-01-01

The objective of the present study was to develop self micro emulsifying formulation (SMEF) of valsartan to improve its oral bioavailability. The formulations were screened on the basis of solubility, stability, emulsification efficiency, particle size and zeta potential. The optimized liquid SMEF contains valsartan (20% w/w), Capmul MCM C8 (16% w/w), Tween 80 (42.66% w/w) and PEG 400 (21.33% w/w) as drug, oil, surfactant and co-surfactant, respectively. Further, Liquid SMEF was adsorbed on Aerosol 200 by spray and freeze drying methods in the ratio of 2 : 1 and transformed into free flowing powder. Both the optimized liquid and solid SMEF had the particle size <200 nm with rapid reconstitution properties. Both drying methods are equally capable for producing stable solid SMEF and immediate release of drug in in vitro and in vivo conditions. However, the solid SMEF produced by spray drying method showed high flowability and compressibility. The solid state characterization employing the FTIR, DSC and XRD studies indicated insignificant interaction of drug with lipid and adsorbed excipient. The relative bioavailability of solid SMEF was approximately 1.5 to 3.0 folds higher than marketed formulation and pure drug. Thus, the developed solid SMEF illustrates an alternative delivery of valsartan as compared to existing formulations with improved bioavailability. PMID:23971048

Gastric retention pellets of edaravone with enhanced oral bioavailability: Absorption mechanism, development, and in vitro/in vivo evaluation.

PubMed

Li, Qingguo; Huang, Wenhai; Yang, Juan; Wang, Jianfeng; Hu, Min; Mo, Jianmei; Cheng, Yuzhu; Ou, Zhanlun; Zhang, Zhenyu Jason; Guan, Shixia

2018-07-01

Absorption mechanism of edaravone (EDR) was studied to inform the preparation of gastric retention pellets with the aim to enhance its oral bioavailability. Three different models, namely, Caco-2 cells model, in situ single-pass intestinal perfusion model, and everted gut sac model in rats, were employed to characterize the gastrointestinal absorption kinetics of EDR. And it was found that passive transfer plays a vital role for the transport of EDR, and acidic condition is preferable for EDR absorption. Further, it is likely that EDR acts as a substrate for P-glycoprotein and multidrug-resistance protein. And hence, an orally available gastric retention pellets were developed accordingly. Pharmacokinetic experiments performed with rats and beagles showed that the absolute bioavailability of EDR solution and enteric-coated pellets following oral administration were 33.85% ± 2.45% and 7.64% ± 1.03%, indicating that stomach absorption is better than intestinal adsorption for EDR. However, the gastric retention pellets resulted in 68.96% absolute bioavailability and about 200% relative bioavailability in comparison to EDR solution, which was 9 times that of enteric-coated pellets. The present work demonstrates that gastric retention pellets has excellent potential as oral administration route for EDR. Copyright © 2018 Elsevier B.V. All rights reserved.

Enhanced oral bioavailability of docetaxel in rats combined with myricetin: In situ and in vivo evidences.

PubMed

Hao, Tianyun; Ling, Yunni; Wu, Meijuan; Shen, Yajing; Gao, Yu; Liang, Shujun; Gao, Yuan; Qian, Shuai

2017-04-01

The purpose of this study was to investigate the effect of myricetin on the pharmacokinetics of docetaxel in rats. In comparison to oral docetaxel alone (40mg/kg), the bioavailability of docetaxel could be significantly enhanced by 1.6-2.4-fold via oral co-administration with various flavonoids (apigenin, naringenin, baicalein, quercetin and myricetin) at a dosage of 10mg/kg, and myricetin showed the highest bioavailability improvement. Further pharmacokinetic studies demonstrated that the presence of myricetin (5-20mg/kg) enhanced both C max and AUC of docetaxel with the highest C max (162ng/mL, 2.3-fold) and relative bioavailability (244%) achieved at 10mg/kg of myricetin, while t 1/2 was not influenced. In order to explore the reasons for such bioavailability enhancement of docetaxel, rat in situ single-pass intestinal perfusion model and intravenous docetaxel co-administrated with oral myricetin were carried out. After combining with myricetin, the permeability coefficient (P blood ) of docetaxel based on its appearance in mesenteric blood was significantly increased up to 3.5-fold in comparison to that of docetaxel alone. Different from oral docetaxel, the intravenous pharmacokinetics of docetaxel was not affected by co-administration of myricetin, indicating the limited effect of myricetin on the elimination of docetaxel. The above findings suggested that the oral bioavailability enhancement of docetaxel via co-administration with myricetin might be mainly attributed to the enhanced absorption in gastrointestinal tract rather than modulating the elimination of docetaxel. Copyright © 2017 Elsevier B.V. All rights reserved.

Selenium species-dependent toxicity, bioavailability and metabolic transformations in Caenorhabditis elegans.

PubMed

Rohn, Isabelle; Marschall, Talke Anu; Kroepfl, Nina; Jensen, Kenneth Bendix; Aschner, Michael; Tuck, Simon; Kuehnelt, Doris; Schwerdtle, Tanja; Bornhorst, Julia

2018-05-17

The essential micronutrient selenium (Se) is required for various systemic functions, but its beneficial range is narrow and overexposure may result in adverse health effects. Additionally, the chemical form of the ingested selenium contributes crucially to its health effects. While small Se species play a major role in Se metabolism, their toxicological effects, bioavailability and metabolic transformations following elevated uptake are poorly understood. Utilizing the tractable invertebrate Caenorhabditis elegans allowed for an alternative approach to study species-specific characteristics of organic and inorganic Se forms in vivo, revealing remarkable species-dependent differences in the toxicity and bioavailability of selenite, selenomethionine (SeMet) and Se-methylselenocysteine (MeSeCys). An inverse relationship was found between toxicity and bioavailability of the Se species, with the organic species displaying a higher bioavailability than the inorganic form, yet being less toxic. Quantitative Se speciation analysis with HPLC/mass spectrometry revealed a partial metabolism of SeMet and MeSeCys. In SeMet exposed worms, identified metabolites were Se-adenosylselenomethionine (AdoSeMet) and Se-adenosylselenohomocysteine (AdoSeHcy), while worms exposed to MeSeCys produced Se-methylselenoglutathione (MeSeGSH) and γ-glutamyl-MeSeCys (γ-Glu-MeSeCys). Moreover, the possible role of the sole selenoprotein in the nematode, thioredoxin reductase-1 (TrxR-1), was studied comparing wildtype and trxr-1 deletion mutants. Although a lower basal Se level was detected in trxr-1 mutants, Se toxicity and bioavailability following acute exposure was indistinguishable from wildtype worms. Altogether, the current study demonstrates the suitability of C. elegans as a model for Se species dependent toxicity and metabolism, while further research is needed to elucidate TrxR-1 function in the nematode.

Enhancement of solubility and oral bioavailability of manidipine by formation of ternary solid dispersion with d-α-tocopherol polyethylene glycol 1000 succinate and copovidone.

PubMed

Chamsai, Benchawan; Limmatvapirat, Sontaya; Sungthongjeen, Srisagul; Sriamornsak, Pornsak

2017-12-01

Low bioavailability of oral manidipine (MDP) is due to its low water solubility. The objective of this study was to increase the solubility and bioavailability of MDP by fabricating ternary solid dispersion (tSD) with d-α-tocopherol polyethyleneglycol-1000-succinate and copovidone. In this study, solid ternary phase diagram was applied in order to check the homogeneity of tSD prepared by melting and solidifying with dry ice. The physicochemical properties of different formulations were determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR) and hot stage microscopy. Their solubility, dissolution, stability and bioavailability were also investigated. The results demonstrated that tSD obtained from ternary phase diagram divided into homogeneous and non-homogeneous regions. In the homogenous region, the transparent characteristics of tSD was observed and considered as a glass solution, which have a higher MDP solubility than that in non-homogenous region. The hot stage microscopy, DSC and PXRD confirmed that solid dispersion was formed in which MDP was molecularly dispersed in the carriers, especially in the homogenous region of phase diagram. FTIR analysis demonstrated strong hydrogen bonding between amine groups of MDP and carbonyl groups of copovidone, which supported a higher solubility and dissolution of tSD. The pharmacokinetic study in Wistar rats showed that the tSD had the greatest effect on oral bioavailability. Immediate hypotensive effect of tSD was also observed in vivo. The improvement of stability, dissolution and oral bioavailability of MDP could be achieved by using tSD technique.

Evaluation of Small Arms Range Soils for Metal Contamination and Lead Bioavailability

DTIC Science & Technology

2009-11-03

measured by an in vivo or in vitro method. Risk assessment and/or remediation of small arms ranges should therefore assume a high relative bioavailability of...lead for the eight soils was about 100% (108 ( 18% and 95 ( 6%, respectively) showing good agreement between both methods. Risk assessment and/ or...significant efforts in stewardship, environmental risk assessment , and reme- diation, so that training of personnel and future land use can be

Topically applied vitamin C and cysteine derivatives protect against UVA-induced photodegradation of suprofen in ex vivo pigskin.

PubMed

Moison, Ralf M W; Rijnkels, Jolanda M; Podda, Elena; Righele, Francesca; Tomasello, Federica; Caffieri, Sergio; Beijersbergen van Henegouwen, Gerard M J

2003-04-01

Exposure of the nonsteroidal anti-inflammatory drug suprofen (SUP) to UV-radiation results in the formation of radicals, reactive oxygen species (ROS), photodecarboxylated products and photoadducts with biomacromolecules. Using an ex vivo pigskin explant model, we investigated whether topical coapplication of the water-soluble antioxidants vitamin C (Lascorbic acid, ASC), N-acetyl-L-cysteine (NAC) or L-cysteine ethylester (CYSET) with SUP reduced ultraviolet A (UVA)-induced decomposition of SUP. UVA-induced changes in antioxidant bioavailability in the stratum corneum and epidermis were also studied. Epidermal bioavailability of SUP in sham-irradiated pigskin increased 2.2- to 4.1-fold after the lowest antioxidant doses (P < 0.05). As compared with no applied antioxidant, increasing doses of all tested antioxidants resulted in increased levels of SUP and decreased levels of photoproducts (P < 0.05). A maximal protection against SUP photodegradation of 70% was found after an ASC dose of 1 micromol/cm2; these values were 60% for a NAC dose of 10 micromol/cm2 and 50% for a CYSET dose of 5 micromol/cm2. Skin antioxidant levels increased with increasing applied dose (P < 0.05); the bioavailability of CYSET was approximately three-fold lower than that of ASC and NAC. UVA exposure resulted in 30-50% consumption of the topically applied ASC or NAC in the stratum corneum, whereas CYSET was not consumed. In conclusion, the topically applied water-soluble antioxidants ASC, NAC and CYSET protect against UVA-induced decomposition of SUP by scavenging radicals and ROS. Coapplication of these antioxidants may therefore be an effective way to reduce or prevent the phototoxic effects of SUP in vivo.

Enterohepatic recirculation of bioactive ginger phytochemicals is associated with enhanced tumor growth-inhibitory activity of ginger extract

PubMed Central

Gundala, Sushma R.; Mukkavilli, Rao; Yang, Chunhua; Aneja, Ritu

2014-01-01

Phytochemical complexity of plant foods confers health-promoting benefits including chemopreventive and anticancer effects. Isolating single constituents from complex foods may render them inactive, emphasizing the importance of preserving the natural composition of whole extracts. Recently, we demonstrated in vitro synergy among the most abundant bioactive constituents of ginger extract (GE), viz., 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G) and 6-shogaol (6S). However, no study has yet examined the in vivo collaboration among ginger phytochemicals or evaluated the importance, if any, of the natural ‘milieu’ preserved in whole extract. Here, we comparatively evaluated in vivo efficacy of GE with an artificial quasi-mixture (Mix) formulated by combining four most active ginger constituents at concentrations equivalent to those present in whole extract. Orally fed GE showed 2.4-fold higher tumor growth-inhibitory efficacy than Mix in human prostate tumor xenografts. Pharmacokinetic evaluations and bioavailability measurements addressed the efficacy differences between GE and Mix. Plasma concentration-time profiles revealed multiple peaking phenomenon for ginger constituents when they were fed as GE as opposed to Mix, indicating enterohepatic recirculation. Bioavailability of 6G, 8G, 10G and 6S was 1.6-, 1.1-, 2.5- and 3.4-fold higher, respectively, when dosed with GE compared with Mix. In addition, gingerol glucuronides were detected in feces upon intravenous administration confirming hepatobiliary elimination. These data ascribe the superior in vivo efficacy of GE to higher area under the concentration time curves, greater residence time and enhanced bioavailability, of ginger phytochemicals, when fed as a natural extract compared with artificial Mix, emphasizing the usefulness of consuming whole foods over single agents. PMID:24431413

Brain-targeted intranasal zaleplon solid dispersion in hydrophilic carrier system; 23 full-factorial design and in vivo determination of GABA neurotransmitter.

PubMed

Abd-Elrasheed, Eman; Nageeb El-Helaly, Sara; El-Ashmoony, Manal M; Salah, Salwa

2018-05-01

Intranasal zaleplon solid dispersion was formulated to enhance the solubility, bioavailability and deliver an effective therapy. Zaleplon belongs to Class II drugs, and undergoes extensive first-pass metabolism after oral absorption exhibiting 30% bioavailability. A 2 3 full-factorial design was chosen for the investigation of solid dispersion formulations. The effects of different variables include drug to carrier ratio (1:1 and 1:2), carrier type (polyethylene glycol 4000 and poloxamer 407), and preparation method (solvent evaporation and freeze drying) on different dissolution parameters were studied. The dependent variables determined from the in vitro characterization and their constraints were set as follows: minimum mean dissolution time, maximum dissolution efficiency and maximum percentage release. Numerical optimization was performed according to the constraints set based on the utilization of desirability functions. Differential scanning calorimetry, infrared spectroscopy, X-ray diffraction and scanning electron microscopy were performed. Ex vivo estimation of nasal cytotoxicity and assessment of the γ-aminobutyric acid level in plasma and brain 1 h after nasal SD administration in rabbits compared to the oral market product were conducted. The selected ZP-SD, with a desirability 0.9, composed of poloxamer 407 at drug to carrier ratio 1:2 successfully enhanced the bioavailability showing 44% increase in GABA concentration than the marketed tablets.

In vivo bioavailability of polyphenols from grape by-product extracts, and effect on lipemia of normocholesterolemic Wistar rats.

PubMed

Olivero-David, Raul; Ruiz-Roso, Maria Belen; Caporaso, Nicola; Perez-Olleros, Lourdes; De Las Heras, Natalia; Lahera, Vicente; Ruiz-Roso, Baltasar

2018-04-24

The direct use of phenolic extracts from grape by-products can be useful to formulate functional food to improve consumers' health. The use of phenolic extracts instead of pure polyphenols as an ingredient is relevant in this context. The current work studied the bioavailability and absorption of polyphenols from grape by-product extracts and their health effect on cholesterolemia, by adding the extract (GE) to Wistar rats diet (50 g/kg) in vivo. GE caused the appearance of (+)-catechin, myricetin and quercetic acid in plasma and liver. (+)-Catechin was the most abundant compound, with 6 μg/mL in plasma and 0.7 μg/mg protein in liver, while no phenolic compounds were detected in plasma or liver in the control group. Similarly, 3,4-hydroxyphenylacetic (DOPAC), a major product of polyphenol digestion, was detected in the plasma, liver and urine of the GE-group only. GE-group had significantly lower cholesterol level and lower total cholesterol/HDL ratio in plasma. Total bile acid (TBA) content significantly increased in faecal matter after 24 h administration of the GE-enriched diet. Grape extract polyphenols are partially bioavailable and showed improvement in lipid metabolism. Thus, the results suggest that GE is promising as a functional ingredient in the prevention of hypercholesterolemia. This article is protected by copyright. All rights reserved.

Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential.

PubMed

Telange, Darshan R; Patil, Arun T; Pethe, Anil M; Fegade, Harshal; Anand, Sridhar; Dave, Vivek S

2017-10-15

The apigenin-phospholipid phytosome (APLC) was developed to improve the aqueous solubility, dissolution, in vivo bioavailability, and antioxidant activity of apigenin. The APLC synthesis was guided by a full factorial design strategy, incorporating specific formulation and process variables to deliver an optimized product. The design-optimized formulation was assayed for aqueous solubility, in vitro dissolution, pharmacokinetics, and antioxidant activity. The pharmacological evaluation was carried out by assessing its effects on carbon tetrachloride-induced elevation of liver function marker enzymes in a rat model. The antioxidant activity was assessed by studying its effects on the liver antioxidant marker enzymes. The developed model was validated using the design-optimized levels of formulation and process variables. The physical-chemical characterization confirmed the formation of phytosomes. The optimized formulation demonstrated over 36-fold higher aqueous solubility of apigenin, compared to that of pure apigenin. The formulation also exhibited a significantly higher rate and extent of apigenin release in dissolution studies. The pharmacokinetic analysis revealed a significant enhancement in the oral bioavailability of apigenin from the prepared formulation, compared to pure apigenin. The liver function tests indicated that the prepared phytosome showed a significantly improved restoration of all carbon tetrachloride-elevated rat liver function marker enzymes. The prepared formulation also exhibited antioxidant potential by significantly increasing the levels of glutathione, superoxide dismutase, catalase, and decreasing the levels of lipid peroxidase. The study shows that phospholipid-based phytosome is a promising and viable strategy for improving the delivery of apigenin and similar phytoconstituents with low aqueous solubility. Copyright © 2016 Elsevier B.V. All rights reserved.

Preparation and characterization of intravaginal vardenafil suppositories targeting a complementary treatment to boost in vitro fertilization process.

PubMed

Gomaa, Eman; Abu Lila, Amr S; Hasan, Azza A; Ghazy, Fakhr-Eldin S

2018-01-01

Vaginal route has been recently considered as a potential route for systemic delivery of drugs with poor oral bioavailability. Vardenafil (VDF) is a relatively new phosphodiesterase-5 inhibitor that exhibits a limited oral bioavailability (≈15%) due to extensive first-pass metabolism. In this study, we attempted to enhance the systemic bioavailability of VDF via its formulation within vaginal suppositories. Witepsol H15 and Suppocire NA50 were adopted as lipophilic suppository bases while polyethylene glycol 4000/400 and glycerogelatin were used as hydrophilic suppository bases. The effect of different base types and/or the incorporation of bioadhesive polymer on in vitro release of VDF were evaluated. The in vivo fate and organ biodistribution of VDF following intravaginal (IVG) administration were also investigated. VDF release from water-soluble bases was higher than that from lipophilic bases. The incorporation of bioadhesive polymers, such as Na alginate, remarkably sustained drug release from suppository base. The organ biodistribution study showed a higher C max (32 times) and AUC 0-4h (20 times) of VDF in uterus following IVG administration of conventional suppositories, compared to oral administration of VDF suspension. In addition, cyclic guanosine monophosphate (cGMP) serum levels, used as an indicator of the in vivo activity of VDF, in animals were higher following IVG administration rather than oral administration. This study suggests that IVG administration of VDF might represent a potential alternative to oral route with superior therapeutic benefits especially when targeting the uterus. Copyright © 2017 Elsevier B.V. All rights reserved.

Solution behavior of PVP-VA and HPMC-AS-based amorphous solid dispersions and their bioavailability implications.

PubMed

Qian, Feng; Wang, Jennifer; Hartley, Ruiling; Tao, Jing; Haddadin, Raja; Mathias, Neil; Hussain, Munir

2012-10-01

To identify the mechanism behind the unexpected bio-performance of two amorphous solid dispersions: BMS-A/PVP-VA and BMS-A/HPMC-AS. Solubility of crystalline BMS-A in PVP-VA and HPMC-AS was measured by DSC. Drug-polymer interaction parameters were obtained by Flory-Huggins model fitting. Drug dissolution kinetics of spray-dried dispersions were studied under sink and non-sink conditions. BMS-A supersaturation was studied in the presence of pre-dissolved PVP-VA and HPMC-AS. Potency and crystallinity of undissolved solid dispersions were determined by HPLC and DSC. Polymer dissolution kinetics were obtained by mass balance calculation. Bioavailability of solid dispersions was assessed in dogs. In solid state, both polymers are miscible with BMS-A, while PVP-VA solublizes the drug better. BMS-A dissolves similarly from both solid dispersions in vitro regardless of dissolution method, while the HPMC-AS dispersion performed much better in vivo. At the same concentration, HPMC-AS is more effective in prolonging BMS-A supersaturation; this effect was negated by the slow dissolution rate of HPMC-AS. Further study revealed that fast PVP-VA dissolution resulted in elevated drug loading in undissolved dispersions and facilitated drug recrystallization before complete release. In contrast, the hydrophobicity and slower HPMC-AS dissolution prevented BMS-A recrystallization within the HPMC-AS matrix for >24 h. The lower bioavailability of PVP-VA dispersion was attributed to BMS-A recrystallization within the undissolved dispersion, due to hydrophilicity and fast PVP-VA dissolution rate. Polymer selection for solid dispersion development has significant impact on in vivo performance besides physical stability.

Preparation of novel porous starch microsphere foam for loading and release of poorly water soluble drug.

PubMed

Jiang, Tongying; Wu, Chao; Gao, Yikun; Zhu, Wenquan; Wan, Long; Wang, Zhanyou; Wang, Siling

2014-02-01

Organic porous material is a promising carrier for enhancing the dissolution of poorly water soluble drug. The aim of the present study was to enhance dissolution and oral bioavailability of lovastatin (LV) by preparing a porous starch microsphere foam (PSM) using a novel method, meanwhile, looking into the mechanism of improving dissolution of LV. PSM was prepared by the W/O emulsion-freeze thawing method. The porous structure of PSM was characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis. The adsorption role of nanopores on the drug dissolution and physical state of LV was systematically studied by instrumental analysis, and in vitro and in vivo drug dissolution studies. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate carrier cytotoxicity. The SEM images of PSM showed nanometer-sized pores. Physical state characterization indicated that porous structure effectively limited the degree of crystallinity of LV. The results of in vitro and in vivo tests testified that PSM accelerated the release of LV and enhanced its oral bioavailability in comparison with crude LV and commercial capsules. The loaded PSM powder indicated a good physical stability under storage for 12 months. MTT assay shows PSM has no toxicity for Caco-2 cell. The preparation was a promising method to produce small and uniform PSM with markedly enhanced dissolution rate and oral bioavailability due to the spatial confinement effect of porous structure. The present work demonstrates the significant potential for the use of PSM as a novel delivery system for poorly water soluble drugs.

Pantoprazole Sodium Loaded Microballoons for the Systemic Approach: In Vitro and In Vivo Evaluation.

PubMed

Gupta, Pravin; Kumar, Manish; Kaushik, Darpan

2017-09-01

Purpose: Various floating and pulsatile drug delivery systems suffer from variations in the gastric transit time affecting the bioavailability of drugs. The objective of the study was to develop Pantoprazole Sodium (PAN) microballoons that may prolong the gastric residence time and could enhance the drug bioavailability. Methods: Microballoons were prepared using Eudragit ® L100 by adopting emulsion solvent diffusion method with non-effervescent approach, in vitro studies were performed and the in vivo evaluation was carried out employing ethanol induced ulceration method. Optimization and validation were carried out through Design Expert ® software. Results: The results demonstrate an increase in percentage yield, buoyancy, encapsulation efficacy and swelling. Particles were in the size range 80-100 µm following zero order release pattern. SEM study revealed their rough surface with spherical shape, internal cavity and porous walls. DSC thermo gram confirms the encapsulation of drug in amorphous form. Significant anti ulcer activity was observed for the prepared microballoons. The calculated ulcer index and protection were 0.20±0.05 and 97.43 % respectively for LRS-O (optimized formulation). Conclusion: This kind of pH dependent drug delivery may provide an efficient dosage regimen with enhanced patient compliance.

Cytotoxicity and apoptotic signalling cascade induced by chelidonine-loaded PLGA nanoparticles in HepG2 cells in vitro and bioavailability of nano-chelidonine in mice in vivo.

PubMed

Paul, Avijit; Das, Sreemanti; Das, Jayeeta; Samadder, Asmita; Khuda-Bukhsh, Anisur Rahman

2013-09-12

Poor oral bioavailability of chelidonine, a bio-active ingredient of Chelidonium majus, showing anti-cancer potentials against cancer cells with multidrug resistance, makes its optimal use rather limited. To address this problem, we encapsulated chelidonine in biodegradable poly(lactide-co-glycolide) (PLGA) polymers and evaluated nano-chelidonine's (NCs) anti-cancer efficacy vis-à-vis free chelidonine (FC) against HepG2 cells and also evaluated its bioavailability in mice. Physicochemical characteristics indicated that stable spherical NC were formed in nanometer size range (123±1.15 nm) with good yield (86.34±1.91%), better encapsulation efficiency (82.6±0.574%), negative surface charge (-19.6±2.48 mV) and ability of prolonged and sustained release of chelidonine. Fourier transform infrared analysis revealed that NC resembled similar peaks as that of FC suggesting effective encapsulation in PLGA. NC exhibited rapid cellular uptake and stronger apoptotic effect (∼46.6% reduced IC₅₀ value) than FC, blocking HepG2 cells at G2/M phase. p53, cyclin-D1, Bax, Bcl-2, cytochrome c, Apaf-1, caspase-9 and caspase-3 expressions also corroborated well to suggest greater anticancer potentials of NC. Our in vivo studies demonstrated NC to be more bio-available than FC and showed a better tissue distribution profile without inducing any toxicity (100 mg/kg bw) in mice. Unlike FC, NC could permeate into brain tissue, indicating thereby NC's better potentials for use in therapeutic oncology. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

In vivo bioavailability of selenium in enriched Pleurotus ostreatus mushrooms.

PubMed

da Silva, Marliane C S; Naozuka, Juliana; Oliveira, Pedro V; Vanetti, Maria C D; Bazzolli, Denise M S; Costa, Neuza M B; Kasuya, Maria C M

2010-02-01

The in vivo bioavailability of Se was investigated in enriched Pleurotus ostreatus mushrooms. A bioavailability study was performed using 64 Wistar male rats separated in 8 groups and fed with different diets: without Se, with mushrooms without Se, with enriched mushrooms containing 0.15, 0.30 or 0.45 mg kg(-1) Se and a normal diet containing 0.15 mg kg(-1) of Se using sodium selenate. The experiment was performed in two periods: depletion (14 days) and repletion (21 days), according to the Association of Official Analytical Chemists. After five weeks, the rats were sacrificed under carbon dioxide, and blood was drawn by heart puncture. Blood plasma was separated by centrifugation. The total Se concentration in the plasma of rats fed with enriched mushrooms was higher than in rats fed with a normal diet containing sodium selenate. The plasma protein profiles were obtained using size exclusion chromatography (SEC) and UV detectors. Aliquots of effluents (0.5 mL per minute) were collected throughout in the end of the chromatographic column. However, Se was determined by graphite furnace atomic absorption spectrometry (GF AAS) only in the aliquots where proteins were detected by SEC-UV. The plasma protein profile of rats fed with different diets was similar. The highest Se concentration was observed in a peptide presenting 8 kDa. Furthermore, the higher Se concentration in this peptide was obtained for rats fed with a diet using enriched mushrooms (7 μg L(-1) Se) compared to other diets (2-5 μg L(-1) Se). These results showed that Se-enriched mushrooms can be considered as an alternative Se food source for humans, due to their high bioavailability.

Folic acid conjugation improves the bioavailability and chemosensitizing efficacy of curcumin-encapsulated PLGA-PEG nanoparticles towards paclitaxel chemotherapy.

PubMed

Thulasidasan, Arun Kumar T; Retnakumari, Archana P; Shankar, Mohan; Vijayakurup, Vinod; Anwar, Shabna; Thankachan, Sanu; Pillai, Kavya S; Pillai, Jisha J; Nandan, C Devika; Alex, Vijai V; Chirayil, Teena Jacob; Sundaram, Sankar; Kumar, Gopalakrishnapillai Sankaramangalam Vinod; Anto, Ruby John

2017-12-08

Nanoencapsulation has emerged as a novel strategy to enhance the pharmacokinetic and therapeutic potential of conventional drugs. Recent studies from our lab have established the efficacy of curcumin in sensitizing cervical cancer cells and breast cancer cells towards paclitaxel and 5-FU chemotherapy respectively. Factors that hinder the clinical use of curcumin as a sensitizer or therapeutic agent include its poor bioavailability and retention time. Earlier reports of improvement in bioavailability and retention of drugs upon nanoencapsulation have motivated us in developing various nanoformulations of curcumin, which were found to exhibit significant enhancement in bioavailability and retention time as assessed by our previous in vitro studies. Among the various formulations tested, curcumin-entrapped in PLGA-PEG nanoparticles conjugated to folic acid (PPF-curcumin) displayed maximum cell death. In the present study, we have demonstrated the efficacy of this formulation in augmenting the bioavailability and retention time of curcumin, in vivo , in Swiss albino mice. Further, the acute and chronic toxicity studies proved that the formulation is pharmacologically safe. We have also evaluated its potential in chemosensitizing cervical cancer cells to paclitaxel and have verified the results using cervical cancer xenograft model in NOD-SCID mice. Folic acid conjugation significantly enhanced the efficacy of curcumin in down-regulating various survival signals induced by paclitaxel in cervical cancer cells and have considerably improved its potential in inhibiting the tumor growth of cervical cancer xenografts. The non-toxic nature coupled with improved chemosensitization potential makes PPF-curcumin a promising candidate formulation for clinical trials.

Folic acid conjugation improves the bioavailability and chemosensitizing efficacy of curcumin-encapsulated PLGA-PEG nanoparticles towards paclitaxel chemotherapy

PubMed Central

Shankar, Mohan; Vijayakurup, Vinod; Anwar, Shabna; Thankachan, Sanu; Pillai, Kavya S.; Pillai, Jisha J.; Nandan, C. Devika; Alex, Vijai V.; Chirayil, Teena Jacob; Sundaram, Sankar; Kumar, Gopalakrishnapillai Sankaramangalam Vinod; Anto, Ruby John

2017-01-01

Nanoencapsulation has emerged as a novel strategy to enhance the pharmacokinetic and therapeutic potential of conventional drugs. Recent studies from our lab have established the efficacy of curcumin in sensitizing cervical cancer cells and breast cancer cells towards paclitaxel and 5-FU chemotherapy respectively. Factors that hinder the clinical use of curcumin as a sensitizer or therapeutic agent include its poor bioavailability and retention time. Earlier reports of improvement in bioavailability and retention of drugs upon nanoencapsulation have motivated us in developing various nanoformulations of curcumin, which were found to exhibit significant enhancement in bioavailability and retention time as assessed by our previous in vitro studies. Among the various formulations tested, curcumin-entrapped in PLGA-PEG nanoparticles conjugated to folic acid (PPF-curcumin) displayed maximum cell death. In the present study, we have demonstrated the efficacy of this formulation in augmenting the bioavailability and retention time of curcumin, in vivo, in Swiss albino mice. Further, the acute and chronic toxicity studies proved that the formulation is pharmacologically safe. We have also evaluated its potential in chemosensitizing cervical cancer cells to paclitaxel and have verified the results using cervical cancer xenograft model in NOD-SCID mice. Folic acid conjugation significantly enhanced the efficacy of curcumin in down-regulating various survival signals induced by paclitaxel in cervical cancer cells and have considerably improved its potential in inhibiting the tumor growth of cervical cancer xenografts. The non-toxic nature coupled with improved chemosensitization potential makes PPF-curcumin a promising candidate formulation for clinical trials. PMID:29296172

Improving the dissolution and bioavailability of 6-mercaptopurine via co-crystallization with isonicotinamide.

PubMed

Wang, Jian-Rong; Yu, Xueping; Zhou, Chun; Lin, Yunfei; Chen, Chen; Pan, Guoyu; Mei, Xuefeng

2015-03-01

6-Mercaptopurine (6-MP) is a clinically important antitumor drug. The commercially available form was provided as monohydrate and belongs to BCS class II category. Co-crystallization screening by reaction crystallization method (RCM) and monitored by powder X-ray diffraction led to the discovery of a new co-crystal formed between 6-MP and isonicotinamide (co-crystal 1). Co-crystal 1 was thoroughly characterized by X-ray diffraction, FT-IR and Raman spectroscopy, and thermal analysis. Noticeably, the in vitro and in vivo studies revealed that co-crystal 1 possesses improved dissolution rate and superior bioavailability on animal model. Copyright © 2015 Elsevier Ltd. All rights reserved.

Design of Curcumin Loaded PLGA Nanoparticles Formulation with Enhanced Cellular Uptake, and Increased Bioactivity in vitro and Superior Bioavailability in vivo

PubMed Central

Anand, Preeta; Nair, Harish B.; Sung, Bokyung; Kunnumakkara, Ajaikumar B.; Yadav, Vivek R.; Tekmal, Rajeshwar R.; Aggarwal, Bharat B.

2011-01-01

Curcumin, a yellow pigment present in the spice turmeric (Curcuma longa), has been linked with antioxidant, anti-inflammatory, anti-proliferative, anticancer, antidiabetic, antirheumatic, and antiviral effects, but its optimum potential is limited by its lack of solubility in aqueous solvents and poor oral bioavailability. We employed a polymer-based nanoparticle approach to improve bioavailability. Curcumin was encapsulated with 97.5% efficiency in biodegradable nanoparticulate formulation based on poly (lactide-co-glycolide) (PLGA) and a stabilizer polyethylene glycol (PEG)-5000. Dynamic laser light scattering and transmission electron microscopy indicated a particle diameter of 80.9 nm. This curcumin, renamed from hereon “as curcumin (NP)”, was characterized for its biological activity. In vitro curcumin (NP) exhibited very rapid (2 h vs > 72 h) and more efficient cellular uptake then curcumin. Estrase staining revealed that curcumin (NP) was at least as potent as or more potent than curcumin in inducing apoptosis of leukemic cells and in suppressing proliferation of various tumor cell lines. When examined by electrophoretic gel shift mobility assay, curcumin (NP) was more active than curcumin in inhibiting TNF-induced NF-κB activation and in suppression of NF-κB-regulated proteins involved in cell proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF). In mice, curcumin (NP) was more bioavailable and had a longer half-life than curcumin. Overall we demonstrate that curcumin-loaded PLGA nanoparticles formulation has enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo over curcumin. PMID:19735646

Bioadhesive Controlled Metronidazole Release Matrix Based on Chitosan and Xanthan Gum

PubMed Central

Eftaiha, Ala’a F.; Qinna, Nidal; Rashid, Iyad S.; Al Remawi, Mayyas M.; Al Shami, Munther R.; Arafat, Tawfiq A.; Badwan, Adnan A.

2010-01-01

Metronidazole, a common antibacterial drug, was incorporated into a hydrophilic polymer matrix composed of chitosan xanthan gum mixture. Hydrogel formation of this binary chitosan-xanthan gum combination was tested for its ability to control the release of metronidazole as a drug model. This preparation (MZ-CR) was characterized by in vitro, ex vivo bioadhesion and in vivo bioavailability study. For comparison purposes a commercial extended release formulation of metronidazole (CMZ) was used as a reference. The in vitro drug-release profiles of metronidazole preparation and CMZ were similar in 0.1 M HCl and phosphate buffer pH 6.8. Moreover, metronidazole preparation and CMZ showed a similar detachment force to sheep stomach mucosa, while the bioadhesion of the metronidazole preparation was higher three times than CMZ to sheep duodenum. The results of in vivo study indicated that the absorption of metronidazole from the preparation was faster than that of CMZ. Also, MZ-CR leads to higher metronidazole Cmax and AUC relative to that of the CMZ. This increase in bioavailability might be explained by the bioadhesion of the preparation at the upper part of the small intestine that could result in an increase in the overall intestinal transit time. As a conclusion, formulating chitosan-xanthan gum mixture as a hydrophilic polymer matrix resulted in a superior pharmacokinetic parameters translated by better rate and extent of absorption of metronidazole. PMID:20559494

Improved oral bioavailability of probucol by dry media-milling.

PubMed

Li, Jia; Yang, Yan; Zhao, Meihui; Xu, Hui; Ma, Junyuan; Wang, Shaoning

2017-09-01

The polymer/probucol co-milled mixtures were prepared to improve drug dissolution rate and oral bioavailability. Probucol, a BCS II drug, was co-milled together with Copovidone (Kollidon VA64, VA64), Soluplus, or MCC using the dry media-milling process with planetary ball-milling equipment. The properties of the milled mixtures including morphology, crystal form, vitro drug dissolution and in vivo oral bioavailability in rats were evaluated. Probucol existed as an amorphous in the matrix of the co-milled mixtures containing VA64, which helped to enhance drug dissolution. The ternary mixture composed of VA64, RH40, and probucol showed increased dissolution rates in both sink and non-sink conditions. It also had a higher oral bioavailability compared to the reference formulation. Dry-media milling of binary or ternary mixtures composed of drug, polymer and surfactant possibly have wide applications to improve dissolution rate and oral bioavailability of water-insoluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new anti-schistosomal drugs.

PubMed

Johann, Laure; Belorgey, Didier; Huang, Hsin-Hung; Day, Latasha; Chessé, Matthieu; Becker, Katja; Williams, David L; Davioud-Charvet, Elisabeth

2015-08-01

Investigations regarding the chemistry and mechanism of action of 2-methyl-1,4-naphthoquinone (or menadione) derivatives revealed 3-phenoxymethyl menadiones as a novel anti-schistosomal chemical series. These newly synthesized compounds (1-7) and their difluoromethylmenadione counterparts (8, 9) were found to be potent and specific inhibitors of Schistosoma mansoni thioredoxin-glutathione reductase (SmTGR), which has been identified as a potential target for anti-schistosomal drugs. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. glutathione reductase (hGR) and selenium-dependent human thioredoxin reductase (hTrxR), to evaluate the specificity of the inhibition. Structure-activity relationships as well as physico- and electro-chemical studies showed a high potential for the 3-phenoxymethyl menadiones to inhibit SmTGR selectively compared to hGR and hTrxR enzymes, in particular those bearing an α-fluorophenol methyl ether moiety, which improves anti-schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative (7) displayed time-dependent SmTGR inactivation, correlating with unproductive NADPH-dependent redox cycling of SmTGR, and potent anti-schistosomal action in worms cultured ex vivo. In contrast, the difluoromethylmenadione analog 9, which inactivates SmTGR through an irreversible non-consuming NADPH-dependent process, has little killing effect in worms cultured ex vivo. Despite ex vivo activity, none of the compounds tested was active in vivo, suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability. © 2015 FEBS.

Effect of piperine on the bioavailability and pharmacokinetics of rosmarinic acid in rat plasma using UPLC-MS/MS.

PubMed

Yang, Jun-Hui; Mao, Kun-Jun; Huang, Ping; Ye, Yin-Jun; Guo, Hua-Shan; Cai, Bao-Chang

2018-02-01

1. The purpose of the present study was to investigate the effect of piperine (PP) on the pharmacokinetics of rosmarinic acid (RA) in rat plasma and to determine whether PP could enhance the oral bioavailability of RA via inhibition of its glucuronidation. 2. The pharmacokinetic profiles of RA between oral administration of RA (50 mg/kg) alone and in combination with different oral dose PP (20, 40, 60, and 80 mg/kg) to rats were investigated via a validated UPLC/MS/MS method. 3. The AUC and C max of RA were significantly increased in combination with different dose PP dose dependently, especially in the presence of 60 and 80 mg/kg PP (p < 0.01). The relative bioavailability of RA in the presence of 20, 40, 60, and 80 mg/kg PP was 1.24-, 1.32-, 2.02-, and 2.26-folds higher, respectively, compared with the control group given RA alone. Compared with RA, the pharmacokinetic modulations of RA glucuronide were even more apparent, and the glucuronidation of RA was remarkedly inhibited. 4. This study demonstrated that PP significantly improved the in vivo bioavailability of RA partly attributing to the inhibition of gut and hepatic metabolism enzymes of RA.

Formulation Development of Spherical Crystal Agglomerates of Itraconazole for Preparation of Directly Compressible Tablets with Enhanced Bioavailability.

PubMed

Fadke, Janki; Desai, Jagruti; Thakkar, Hetal

2015-12-01

The objective of the present work was to formulate tablet dosage form of itraconazole with enhanced bioavailability. Spherical crystal agglomerates (SCA) of itraconazole prepared by quasi emulsification solvent diffusion method using Soluplus and polyethylene glycol 4000 (PEG 4000) showed increased solubility (540 μg/ml) in 0.1 N hydrochloric acid as compared to pure drug (12 μg/ml). A Fourier transform infrared (FTIR) study indicated compatibility of drug with the excipients. The developed SCA were spherical with smooth surface having an average size of 412 μm. The significantly improved micromeritic properties compared to the plain drug suggested its suitability for direct compression. The antifungal activity of itraconazole was retained in the SCA form as evidenced from the results of the disc diffusion method. The optimized SCA formulation could be easily compressed into tablet with desirable characteristics of hardness (5 kg/cm(2)) and disintegration time (6.3 min). The in vitro dissolution studies showed significant difference in the dissolution profiles of pure drug (21%) and SCA formulation (85%) which was even greater than that of marketed preparation (75%). In vivo pharmacokinetic showed significant enhancement in C max and AUC0-t with relative bioavailability of 225%. The SCA formulation seems to be promising for enhancement of oral bioavailability of itraconazole.

Formulation and Characterization of Anthocyanins-Loaded Nanoparticles.

PubMed

Dupeyrón, Danay; Kawakami, Monique; Rieumont, Jacques; Carvalho, José Carlos

2017-01-01

Açaí berry, from the Euterpe oleracea Mart. Palm, has been described as the most important fruit in the Brazilian Amazon. Several studies have reported that anthocyanins (ACNs), one of the components of the açaí, have enormous potential for pharmaceuticals applications. However, the bioavailability of anthocyanins is relatively low compared to that of other flavonoids. Then, in the present work, anthocyanins-loaded nanoparticles have been developed to overcome their poor bioavailability. A two-level factorial design with three factors was considered to evaluate the effect of EUDRAGIT ® L100, polyethylene glycol 2000 (PEG 2000) and polysorbate 80 on encapsulation efficiency (EE) of anthocyanins. Also, major parameters of nanoparticles were assessed by using mainly SEM microscopy and Dynamic light scattering. PEG 2000 was the only individual factor that has statistical significance (95% confidence level). The process yields (PY) were found in between 67% and 92%; the particle size and morphology analysis showed two distribution size, one for NPs and another for the agglomerates. The pH-sensitive polymer together with the hydrophilic polymer showed to be suitable as ACNs delivery system. The delayed release profile of ACNs, observed for all formulations, can enhance their poor bioavailability. Nevertheless, ACNs bioavailability in vivo remains to be studied. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Preparation, characterization and bioavailability by oral administration of O/W curcumin nanoemulsions stabilized with lysophosphatidylcholine.

PubMed

Chávez-Zamudio, Rubi; Ochoa-Flores, Angélica A; Soto-Rodríguez, Ida; Garcia-Varela, Rebeca; García, Hugo Sergio

2017-09-20

Curcumin is the main and most abundant bioactive component in Curcuma longa L. with documented properties in the prevention and treatment of chronic degenerative and infectious diseases. However, curcumin has low solubility in aqueous media, hence low bioavailability when administered orally. The use of nanoemulsions as carriers can provide a partial solution to bioavailability restrictions. In our study, O/W nanoemulsions of curcumin were prepared using lysophosphatidylcholine, a phospholipid with proven emulsification capacity; nevertheless, such qualities have not been previously reported in the preparation of nanoemulsions. Lysophosphatidylcholine was obtained by enzymatic removal of one fatty acid residue from phosphatidylcholine. The objective of our work was to formulate stable curcumin nanoemulsions and evaluate their bioavailability in BALB/c mice plasma after oral administration. Formulated nanoemulsions had a droplet size mean of 154.32 ± 3.10 nm, a polydispersity index of 0.34 ± 0.07 and zeta potential of -10.43 ± 1.10 mV; stability was monitored for 12 weeks. Lastly, in vivo pharmacokinetic parameters, using BALB/c mice, were obtained; namely, C max of 610 ± 65.0 μg mL -1 and T max of 2 h. Pharmacokinetic data revealed a higher bioavailability of emulsified as opposed to free curcumin. Research regarding other potential emulsifiers that may provide better health benefits and carry nano-encapsulated bioactive compounds more effectively, is necessary. This study provides important data on the preparation and design of nanoencapsulated Curcumin using lysophosphatidylcholine as an emulsifier.

Improved oral bioavailability and therapeutic efficacy of dabigatran etexilate via Soluplus-TPGS binary mixed micelles system.

PubMed

Hu, Mei; Zhang, Jinjie; Ding, Rui; Fu, Yao; Gong, Tao; Zhang, Zhirong

2017-04-01

The clinical use of dabigatran etexilate (DABE) is limited by its poor absorption and relatively low bioavailability. Our study aimed to explore the potential of a mixed micelle system composed of Soluplus ® and D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) to improve the oral absorption and bioavailability of DBAE. DBAE was first encapsulated into Soluplus/TPGS mixed micelles by a simple thin film hydration method. The DBAE loaded micelles displayed an average size distribution of around 83.13 nm. The cellular uptake of DBAE loaded micelles in Caco-2 cell monolayer was significantly enhanced by 2-2.6 fold over time as compared with DBAE suspension. Both lipid raft/caveolae and macropinocytosis-mediated the cell uptake of DBAE loaded micelles through P-glycoprotein (P-gp)-independent pathway. Compared with the DBAE suspension, the intestinal absorption of DBAE from DBAE mixed micelles in rats was significantly improved by 8 and 5-fold in ileum at 2 h and 4 h, respectively. Moreover, DBAE mixed micelles were absorbed into systemic circulation via both portal vein and lymphatic pathway. The oral bioavailability of DBAE mixed micelles in rats was 3.37 fold higher than that of DBAE suspension. DBAE mixed micelles exhibited a comparable anti-thrombolytic activity with a thrombosis inhibition rate of 63.18% compared with DBAE suspension in vivo. Thus, our study provides a promising drug delivery system to enhance the oral bioavailability and therapeutic efficacy of DBAE.

In vivo evaluation of an oral drug delivery system for peptides based on S-protected thiolated chitosan.

PubMed

Dünnhaupt, Sarah; Barthelmes, Jan; Iqbal, Javed; Perera, Glen; Thurner, Clemens C; Friedl, Heike; Bernkop-Schnürch, Andreas

2012-06-28

The aim of the present study was the development and evaluation in vitro as well as in vivo of an oral delivery system based on a novel type of thiolated chitosan, so-called S-protected thiolated chitosan, for the peptide drug antide. The sulfhydryl ligand thioglycolic acid (TGA) was covalently attached to chitosan (CS) in the first step of modification. In the second step, these thiol groups of thiolated chitosan were protected by disulfide bond formation with the thiolated aromatic residue 6-mercaptonicotinamide (6-MNA). Absorptive transport studies of antide were evaluated ex vivo using rat intestinal mucosa. Matrix tablets of each polymer sample were prepared and their effect on the absorption of antide evaluated in vivo in male Sprague-Dawley rats. In addition, tablets were examined in terms of their disintegration, swelling and drug release behavior. The resulting S-protected thiomer (TGA-MNA) exhibited 840μmol of covalently linked 6-MNA per gram thiomer. Based on the implementation of this hydrophobic ligand on the thiolated backbone, the disintegration behavior was reduced greatly and a controlled release of the peptide could be achieved. Furthermore, permeation studies with TGA-MNA on rat intestine revealed a 4.5-fold enhanced absorptive transport of the peptide in comparison to antide in solution. Additional in vivo studies confirmed the potential of this novel conjugate. Oral administration of antide in solution led to only very small detectable quantities in plasma with an absolute and relative bioavailability (BA) of 0.003 and 0.03%, only. In contrast, with antide incorporated in TGA-MNA matrix tablets an absolute and relative BA of 1.4 and 10.9% could be reached, resulting in a 421-fold increased area under the plasma concentration time curve (AUC) compared to the antide solution. According to these results, S-protected thiolated chitosan as oral drug delivery system might be a valuable tool for improving the bioavailability of peptides. Copyright © 2012 Elsevier B.V. All rights reserved.

Thiolated chitosan: development and in vivo evaluation of an oral delivery system for leuprolide.

PubMed

Iqbal, Javed; Shahnaz, Gul; Perera, Glen; Hintzen, Fabian; Sarti, Federica; Bernkop-Schnürch, Andreas

2012-01-01

The aim of the present study was to develop an oral delivery system for the peptide drug leuprolide. Gel formulations based on unmodified chitosan/reduced glutathione (GSH) and chitosan-thioglycolic acid (chitosan-TGA)/GSH were prepared, and their effect on the absorption of leuprolide was evaluated in vitro and in vivo in male Sprague Dawley rats. Transport studies were performed with freshly excised rat intestinal mucosa mounted in Ussing-type chambers. Due to the addition of gel formulations comprising 0.5% (m/v) unmodified chitosan/0.5% (m/v) GSH and 0.5% (m/v) chitosan-TGA/0.5% (m/v) GSH, the transport of leuprolide across excised mucosa was improved up to 2.06-fold and 3.79-fold, respectively, in comparison with leuprolide applied in buffer (P(app)=2.87 ± 0.77 × 10⁻⁶ cm/s). In vivo, the addition of oral gel formulation comprising 8 mg of unmodified chitosan, 1mg of GSH and 1mg of leuprolide increased the area under the plasma concentration-time curve (AUC₀₋₈) of leuprolide 1.39-fold in comparison with leuprolide having been administered just in saline. Moreover, the administration of oral gel formulation comprising 8 mg of chitosan-TGA, 1mg of GSH and 1mg of leuprolide resulted in a further enhanced leuprolide plasma concentration, and the area under the plasma concentration-time curve (AUC₀₋₈) of leuprolide was increased 3.72-fold in comparison with the control. With the oral gel formulation comprising 8 mg of chitosan-TGA, a relative bioavailability (versus s.c. injection) of 4.5% was achieved in contrast to the control displaying a relative bioavailability of 1.2%. Thus, according to the achieved results, it is suggested that chitosan-TGA in combination with GSH is a valuable tool for improving the oral bioavailability of the peptide drug leuprolide. Copyright © 2011 Elsevier B.V. All rights reserved.

Regulation of the Bioavailability of TGF-β and TGF-β-Related Proteins

PubMed Central

Robertson, Ian B.; Rifkin, Daniel B.

2016-01-01

The bioavailability of members of the transforming growth factor β (TGF-β) family is controlled by a number of mechanisms. Bona fide TGF-β is sequestered into the matrix in a latent state and must be activated before it can bind to its receptors. Here, we review the molecules and mechanisms that regulate the bioavailability of TGF-β and compare these mechanisms with those used to regulate other TGF-β family members. We also assess the physiological significance of various latent TGF-β activators, as well as other extracellular modulators of TGF-β family signaling, by examining the available in vivo data from knockout mouse models and other biological systems. PMID:27252363

Evaluation of Ocular Irritation and Bioavailability of Voriconazole Loaded Microemulsion.

PubMed

Kumar, Rakesh; Sinha, Vivek Ranjan

2017-01-01

Voriconazole (VCZ), a second-generation antifungal with excellent attributes like, broad-spectrum activity, targeted delivery, and tolerability. VCZ loaded microemulsion could be an effective strategy for efficient ocular delivery of the drug. To perform corneal irritation studies and in vivo delivery of VCZ microemulsion to establish its potential as an efficient ocular delivery system. Ocular irritancy was performed by HETCAM (Hen's Egg Test Chorio Allantoic Membrane) assay, corneal histopathology and Draize test. Ex vivo and in vivo studies were performed to determine permeation efficiency of VCZ microemulsion. The irritation studies suggested the non-irritant nature of the microemulsion. The ex vivo studies performed on excised cornea displayed significant enhancement in drug permeation/penetration from microemulsion in contrast to the drug suspension. Further, the in vivo study confirmed the higher availability of VCZ (from microemulsion) in aqueous humor with minimal nasolacrimal drainage (lower plasma drug content) when compared with the drug suspension. The non-irritant nature and high corneal permeation of VCZ encourages the role of microemulsion as a potential ocular delivery system. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Comparative Plasma Exposure of Albendazole after Administration of Rapidly Disintegrating Tablets in Dogs

PubMed Central

Castro, Silvina G.; Dib, Alicia; Suarez, Gonzalo; Allemandi, Daniel; Lanusse, Carlos; Sanchez Bruni, Sergio; Palma, Santiago D.

2013-01-01

The main objectives of this study were (a) to evaluate the in vitro performance of the rapid disintegration tablets as a way to improve the solid dispersions and (b) to study the in vivo pharmacokinetics of the albendazole modified formulation in dogs. Rapid disintegration of tablets seems to be a key factor for efficiency of solid dispersions with regard to improvement of the albendazole bioavailability. The in vivo assays performed on dogs showed a marked increase in drug plasma exposure when albendazole was given in solid dispersions incorporated into rapid disintegration tablets compared with conventional solid dosage form. PMID:24063016

A newly developed silymarin nanoformulation as a potential antidiabetic agent in experimental diabetes.

PubMed

El-Far, Yousra M; Zakaria, Mahmoud M; Gabr, Mahmoud M; El Gayar, Amal M; El-Sherbiny, Ibrahim M; Eissa, Laila A

2016-10-01

This study aimed to develop a new stable nanoformulation of silymarin (SM) with optimum enhanced oral bioavailability and to evaluate its effect as well as mechanism of action as a superior antidiabetic agent over native SM using streptozotocin-induced diabetic rats. SM-loaded pluronic nanomicelles (SMnp) were prepared and fully characterized. Biochemical parameters were performed as well as histological, confocal and reverse-transcription polymerase chain reaction studies on pancreatic target tissues. SMnp were found to improve significantly the antihyperglycemic, antioxidant and antihyperlipidemic properties as compared with native SM. In addition, SMnp was found to be a more efficient agent over SM in the management of diabetes and its associated complications due to its superior bioavailability in vivo, and the controlled release profile of SM. [Formula: see text].

Mucoadhesive microspheres for gastroretentive delivery of acyclovir: in vitro and in vivo evaluation.

PubMed

Dhaliwal, Sumeet; Jain, Subheet; Singh, Hardevinder P; Tiwary, A K

2008-06-01

The aim of the present investigation was to evaluate the potential use of mucoadhesive microspheres for gastroretentive delivery of acyclovir. Chitosan, thiolated chitosan, Carbopol 71G and Methocel K15M were used as mucoadhesive polymers. Microsphere formulations were prepared using emulsion-chemical crosslinking technique and evaluated in vitro, ex-vivo and in-vivo. Gelatin capsules containing drug powder showed complete dissolution (90.5 +/- 3.6%) in 1 h. The release of drug was prolonged to 12 h (78.8 +/- 3.9) when incorporated into mucoadhesive microspheres. The poor bioavailability of acyclovir is attributed to short retention of its dosage form at the absorption sites (in upper gastrointestinal tract to duodenum and jejunum). The results of mucoadhesion study showed better retention of thiolated chitosan microspheres (8.0 +/- 0.8 h) in duodenal and jejunum regions of intestine. The results of qualitative and quantitative GI distribution study also showed significant higher retention of mucoadhesive microspheres in upper GI tract. Pharmacokinetic study revealed that administration of mucoadhesive microspheres could maintain measurable plasma concentration of acyclovir through 24 h, as compared to 5 h after its administration in solution form. Thiolated chitosan microsphere showed superiority over the other formulations as observed with nearly 4.0-fold higher AUC(0-24) value (1,090 +/- 51 ng h/ml) in comparison to drug solution (281 +/- 28 ng h/ml). Overall, the result indicated prolonged delivery with significant improvement in oral bioavailability of acyclovir from mucoadhesive microspheres due to enhanced retention in the upper GI tract.

Nanoemulsion improves the oral bioavailability of baicalin in rats: in vitro and in vivo evaluation

PubMed Central

Zhao, Ling; Wei, Yumeng; Huang, Yu; He, Bing; Zhou, Yang; Fu, Junjiang

2013-01-01

Baicalin is one of the main bioactive flavone glucuronides derived as a medicinal herb from the dried roots of Scutellaria baicalensis Georgi, and it is widely used for the treatment of fever, inflammation, and other conditions. Due to baicalin’s poor solubility in water, its absolute bioavailability after oral administration is only 2.2%. The objective of this study was to develop a novel baicalin-loaded nanoemulsion to improve the oral bioavailability of baicalin. Based on the result of pseudoternary phase diagram, the nanoemulsion formulation consisting of soy-lecithin, tween-80, polyethylene glycol 400, isopropyl myristate, and water (1:2:1.5:3.75:8.25, w/w) was selected for further study. Baicalin-loaded nanoemulsions (BAN-1 and BAN-2) were prepared by internal or external drug addition and in vivo and in vitro evaluations were performed. The results showed that the mean droplet size, polydispersity index, and drug content of BAN-1 and BAN-2 were 91.2 ± 2.36 nm and 89.7 ± 3.05 nm, 0.313 ± 0.002 and 0.265 ± 0.001, and 98.56% ± 0.79% and 99.40% ± 0.51%, respectively. Transmission electron microscopy revealed spherical globules and confirmed droplet size analysis. After dilution 30-fold with water, the solubilization capacity of BAN-1 and BAN-2 did not change. In vitro release results showed sustained-release characteristics. BAN-1 formulation was stable for at least 6 months and was more stable than BAN-2. In rats, the area under the plasma drug concentration-time curve value of BAN-1 was 1.8-fold and 7-fold greater than those of BAN-2 and free baicalin suspension after oral administration at a dose of 100 mg/kg. In conclusion, these results demonstrated that the baicalin-loaded nanoemulsion formulation, in particular BAN-1, was very effective for improving the oral bioavailability of baicalin and exhibited great potential for future clinical application. PMID:24124365

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics.

PubMed

Ahmed, Osama A A; Hosny, Khaled M; Al-Sawahli, Majid M; Fahmy, Usama A

2015-01-01

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid-liquid phase separation method, according to the Box-Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance.

Consumer product in vitro digestion model: Bioaccessibility of contaminants and its application in risk assessment.

PubMed

Brandon, Esther F A; Oomen, Agnes G; Rompelberg, Cathy J M; Versantvoort, Carolien H M; van Engelen, Jacqueline G M; Sips, Adrienne J A M

2006-03-01

This paper describes the applicability of in vitro digestion models as a tool for consumer products in (ad hoc) risk assessment. In current risk assessment, oral bioavailability from a specific product is considered to be equal to bioavailability found in toxicity studies in which contaminants are usually ingested via liquids or food matrices. To become bioavailable, contaminants must first be released from the product during the digestion process (i.e. become bioaccessible). Contaminants in consumer products may be less bioaccessible than contaminants in liquid or food. Therefore, the actual risk after oral exposure could be overestimated. This paper describes the applicability of a simple, reliable, fast and relatively inexpensive in vitro method for determining the bioaccessibility of a contaminant from a consumer product. Different models, representing sucking and/or swallowing were developed. The experimental design of each model can be adjusted to the appropriate exposure scenarios as determined by the risk assessor. Several contaminated consumer products were tested in the various models. Although relevant in vivo data are scare, we succeeded to preliminary validate the model for one case. This case showed good correlation and never underestimated the bioavailability. However, validation check needs to be continued.

Effect of micro-environment modification and polymer type on the in-vitro dissolution behavior and in-vivo performance of amorphous solid dispersions.

PubMed

Sun, Weiwei; Pan, Baoliang

2017-06-15

This study investigates the effects of micro-environment modification and polymer type on the in-vitro dissolution behavior and in-vivo performance of micro-environment pH modifying solid dispersions (pH M -SD) for the poorly water-soluble model drug Toltrazuril (TOL). Various pH M -SDs were prepared using Ca(OH) 2 as a pH-modifier in hydrophilic polymers, including polyethylene glycol 6000 (PEG6000), polyvinylpyrrolidone k30 (PVPk30) and hydroxypropyl methylcellulose (HPMC). Based on the results of physicochemical characterizations and in-vitro dissolution testing, the representative ternary (Ca(OH) 2 :TOL:PEG6000/HPMC/PVPk30=1:8:24, w/w/w) and binary (TOL:PVPk30=1:3, w/w) solid dispersions were selected and optimized to perform in-vivo pharmacokinetic study. The micro-environment pH modification improved the in-vitro water-solubility and in-vivo bioavailability of parent drug TOL. Furthermore, the addition of alkalizers not only enhanced the release and absorption of prototype drug, but also promoted the generation of active metabolites, including toltrazuril sulfoxide (TOLSO) and toltrazuril sulfone (TOLSO 2 ). The in-vitro dissolution profiles and in-vivo absorption, distribution and metabolism behaviors of the pH M -SDs varied with polymer type. Moreover, in-vivo bioavailability of three active pharmaceutical ingredients increased with an increase in in-vitro dissolution rates of the drug from the pH M -SDs prepared with various polymers. Therefore, a non-sink in-vitro dissolution method can be used to predict the in-vivo performance of pH M -SDs formulated with various polymers with trend consistency. In-vitro and in-vivo screening procedures revealed that the pH M -SD composed of Ca(OH) 2 , TOL and PVPk30 at a weight ratio of 1:8:24, of which the safety was adequately proved via histopathological examination, may be a promising candidate for providing better clinical outcomes. Copyright © 2017. Published by Elsevier B.V.

Comparison of the bioavailability of elemental waste laden soils using in vivo and in vitro analytical methodology and refinement of exposure/dose models. 1998 annual progress report

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

Lioy, P.J.; Gallo, M.; Georgopoulos, P.

1998-06-01

'The authors hypotheses are: (1) the more closely the synthetic, in vitro, extractant mimics the extraction properties of the human digestive bio-fluids, the more accurate will be the estimate of an internal dose; (2) performance can be evaluated by in vivo studies with a rat model and quantitative examination of a mass balance, calculation and dose estimates from model simulations for the in vitro and in vivo system; and (3) the concentration of the elements Pb, Cd, Cr and selected Radionuclides present in the bioavailable fraction obtained with a synthetic extraction system will be a better indicator of contaminant ingestionmore » from a contaminated soil because it represents the portion of the mass which can yield exposure, uptake and then the internal dose to an individual. As of April 15, 1998, they have made significant progress in the development of a unified approach to the examination of bioavailability and bioaccessibility of elemental contamination of soils for the ingestion route of exposure. This includes the initial characterization of the soil, in vitro measurements of bioaccessibility, and in vivo measurements of bioavailability. They have identified the basic chemical and microbiological characteristics of waste laden soils. These have been used to prioritize the soils for potential mobility of the trace elements present in the soil. Subsequently they have employed a mass balance technique, which for the first time tracked the movement and distribution of elements through an in vitro or in vivo experimental protocol to define the bioaccessible and the bioavailable fractions of digested soil. The basic mass balance equation for the in vitro system is: MT = MSGJ + MIJ + MR. where MT is the total mass extractable by a specific method, MSGJ, is the mass extracted by the saliva and the gastric juices, MIJ is the mass extracted by the intestinal fluid, and MR is the unextractable portion of the initial mass. The above is based upon the use of a synthetic digestive bio-fluids model that includes the saliva, gastric juices, and intestinal fluids. The system has been devised to sequentially extract elements from soil by starting with an extraction by the saliva and carrying the entire mixture to the subsequent bio-fluids for further extraction. The residence time of the soil in each extractant and the liquid to mass ratio in the gastric juices are based upon typical values known for the human digestive system. Experiments were conducted to examine the sensitivity of the extractions to changes in these major variables. The results indicated the lack of significant extraction after 2 h of residence in gastric fluid. The range of variation of the liquid to mass ratio was element dependent over the interval 100:1 and 5,000:1. The final values used for the extraction protocol were: 2 h residence time , and a ratio of 1,000:1. Details of the chemical composition of the extraction protocol are found in Hamel, 1998.'« less

Absorption enhancement of adefovir dipivoxil by incorporating MCT and ethyl oleate complex oil phase in emulsion

PubMed Central

Li, Ping; Yu, Hong-zhen; Zhang, Xin-xin; Gan, Li; Zhu, Chun-liu; Gan, Yong

2010-01-01

Aim: To improve the oral absorption of adefovir dipivoxil (ADV) by employing MCT and the esterase inhibitor ethyl oleate (EO) as a complex oil phase in emulsion. Methods: EO was used as the esterase inhibitor, and its inhibitory effect on esterase activity was assessed in rat intestinal homogenates. ADV emulsions with or without EO were prepared. The emulsions' protective effect against intestinal metabolism was evaluated in rat luminal contents, ex vivo, as well as in vivo. Results: The IC50 of EO in intestinal mucosal homogenates was 2.2 mg/mL. The emulsions exhibited significant protective effects in rat luminal contents compared to a simple suspension (98.7%, 96.3%, 95.7% vs 74.7%, P<0.01). The permeability calculated from the emulsion containing EO was significantly different (11.4×10−6 vs 7.4/8.0×10−6, P<0.05) from the simple suspension or the emulsion without EO in an ex vivo assay. A bioavailability study in vivo revealed that emulsions containing both EO and MCT as a complex oil phase demonstrated 1.6- and 1.5-fold enhancements in area under the curve (AUC0–12) values (5358 vs 3386/3618, P<0.05), respectively, when compared with emulsions containing EO or MCT as a single oil phase. Conclusion: Heterotic lipid formulations (emulsions) with an esterase inhibitor (ie, EO) may be useful in protecting ester prodrugs from intestinal metabolism and increasing their oral bioavailability. PMID:20562905

Novel delivery system for natural products: Nano-curcumin formulations.

PubMed

Rahimi, Hamid Reza; Nedaeinia, Reza; Sepehri Shamloo, Alireza; Nikdoust, Shima; Kazemi Oskuee, Reza

2016-01-01

Curcumin is extracted from Curcuma longa and regulates the intracellular signal pathways which control the growth of cancerous cell, inflammation, invasion and apoptosis. Curcumin molecules have special intrinsic features that can target the intracellular enzymes, genome (DNA) and messengers (RNA). A wide range of studies have been conducted on the physicochemical traits and pharmacological effects of curcumin on different diseases like cardiovascular diseases, diabetes, cancer, rheumatoid arthritis, Alzheimer's, inflammatory bowel disease (IBD), and even it has wound healing. Oral bioavailability of curcumin is rather poor, which would certainly put some boundaries in the employment of this drug. Bibliographical searches were performed using MEDLINE/ScienceDirect/OVID up to February 2015 using the following keywords (all fields): ("Curcumin" OR "Curcuma longa") AND [(nanoparticles) OR (Nanomicelles) OR (micro emulsions) OR (liposome) OR (phospholipid). Consequently, for any developments of curcumin in the future, analogues of curcumin that have better bioavailability or substitute formulations are needed crucially. These studies indicated that nanotechnology can formulate curcumin effectively, and this nano-formulated curcumin with a potent ability against various cancer cells, were represented to have better efficacy and bioavailability under in vivo conditions.

Fenofibrate Nanocrystals Embedded in Oral Strip-Films for Bioavailability Enhancement

PubMed Central

Barvaliya, Manish; Zhang, Lu; Anovadiya, Ashish; Brahmbhatt, Harshad; Paul, Parimal; Tripathi, Chandrabhanu

2018-01-01

The aim of the present study was to make a fenofibrate (FNB) nanocrystal (NC) by wet media milling, characterizations and formulates into oral strip-films (OSFs). Mechanical properties, redispersion study, and solid-state characterizations results suggested that reduction of drug crystal size at nanoscale and incorporation into OSFs does not affect the solid-state properties of the drug. In vitro dissolution kinetics showed enhanced dissolution rate was easily manipulated by changing the thickness of the OSF. In situ UV-imaging was used to monitor drug dissolution qualitatively and quantitatively in real time. Results confirm that the intrinsic dissolution rates and surface drug concentration measured with this device were in agreement with the USP-IV dissolution profiles. In vivo pharmacokinetics in rabbits showed a significant difference in the pharmacokinetics parameter (1.4 fold increase bioavailability) of FNB NC-loaded OSFs as compared to the marketed formulation “Tricor” and as-received (pristine) drug. This approach of drug nanocrystallization and incorporation into OSFs may have significant applications in cost-effective tools for bioavailability enhancement of FNB. PMID:29438297

In vitro uptake and immune functionality of digested Rosemary extract delivered through food grade vehicles.

PubMed

Arranz, E; Guri, A; Fornari, T; Mendiola, J A; Reglero, G; Corredig, M

2017-07-01

The digestion, absorption, uptake and bioavailability of a rosemary supercritical fluid extract encapsulated in oil in water emulsion were studied. Two emulsions with opposite surface charge were prepared, containing 7% canola oil, and either 2% lactoferrin or whey protein isolate. When absorption and uptake of carnosic acid and carnosol were followed on Caco-2 cell monolayers, there were no differences with protein type. However, when co-cultures of HT-29 MTX were employed, the presence of mucus caused a higher retention of carnosic acid in the apical layer for lactoferrin emulsions. The immune activity of the bioavailable fractions collected from cell absorption experiments was tested ex vivo on murine splenocytes. Although transport through the intestinal barrier models was low, the bioavailable fractions showed a significant effect on splenocytes proliferation. These results demonstrated the potential of using rosemary supercritical extract through protein stabilized oil in water emulsions, as a food with immunomodulatory functionality. Copyright © 2017 Elsevier Ltd. All rights reserved.

Baicalein-nicotinamide cocrystal with enhanced solubility, dissolution, and oral bioavailability.

PubMed

Huang, Yanting; Zhang, Bowen; Gao, Yuan; Zhang, Jianjun; Shi, Limin

2014-08-01

The purpose of this study was to investigate the effect of preparation methods on cocrystallization between baicalein (BE) and nicotinamide (NCT), their intermolecular interaction, and to demonstrate that BE-NCT cocrystal can achieve the simultaneous enhancement in solubility, dissolution, and oral bioavailability of BE. The cocrystals from three preparation methods have the similar differential scanning calorimetry thermograms and X-ray powder diffraction patterns. Compared with crystalline BE, BE-NCT cocrystal has significantly improved the solubility and dissolution of BE. In addition, the cocrystal exhibits a 2.49-fold higher peak plasma concentration (Cmax) and 2.80-fold higher area under the curve (AUC) in rats. This prominent improvement in oral bioavailability is even greater than the previously reported BE nanocrystal. This investigation enriched the present understanding of cocrystals on their behavior in vitro and in vivo, and built the groundwork for future development of BE as a promising compound into efficacious drug products. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation, characterization, ex vivo, bio-distribution and in vivo pharmacokinetic studies.

PubMed

Nageeb El-Helaly, Sara; Abd Elbary, Ahmed; Kassem, Mohamed A; El-Nabarawi, Mohamed A

2017-11-01

Being one of the highly effective drugs in treatment of Alzheimer's disease, Rivastigmine brain targeting is highly demandable, therefore liposomal dispersion of Rivastigmine was prepared containing 2 mol% PEG-DSPE added to Lecithin, Didecyldimethyl ammonium bromide (DDAB), Tween 80 in 1:0.02:0.25 molar ratio. A major challenge during the preparation of liposomes is maintaining a stable formulation, therefore the aim of our study was to increase liposomal stability by addition of DDAB to give an electrostatic stability and PEG-DSPE to increase stability by steric hindrance, yielding what we called an electrosteric stealth (ESS) liposomes. A medium nano-sized liposome (478 ± 4.94 nm) with a nearly neutral zeta potential (ZP, -8 ± 0.2 mV) and an entrapment efficiency percentage of 48 ± 6.22 was prepared. Stability studies showed no major alteration after three months storage period concerning particle size, polydispersity index, ZP, entrapment efficiency and in vitro release study confirming the successful formation of a stable liposomes. No histopathological alteration was recorded for ESS liposomes of the sheep nasal mucosa. While ESS liposomes showed higher % of drug permeating through the sheep nasal mucosa (48.6%) than the drug solution (28.7%). On completing the in vivo pharmacokinetic studies of 36 rabbits showed 424.2% relative bioavailability of the mean plasma levels of the formula ESS compared to that of RHT intranasal solution and 486% relative bioavailability of the mean brain levels.

In Situ Fixation of Metal(loid)s in Contaminated Soils: A Comparison of Conventional, Opportunistic, and Engineered Soil Amendments

EPA Science Inventory

This study aimed to assess and compare the in vitro and in vivo bioaccessibility/bioavailability of As and Pb in a mining contaminated soil (As 2267 mg kg^-1, Pb 1126 mg kg^-1), after the addition of conventional (phosphoric acid), opportunistic ...

In vitro and in vivo evaluation of silybin nanosuspensions for oral and intravenous delivery

NASA Astrophysics Data System (ADS)

Wang, Yancai; Zhang, Dianrui; Liu, Zhaoping; Liu, Guangpu; Duan, Cunxian; Jia, Lejiao; Feng, Feifei; Zhang, Xiaoyu; Shi, Yanqiu; Zhang, Qiang

2010-04-01

In this study, we evaluate the effect of particle sizes on the physicochemical properties of silybin and identify the influence of silybin nanosuspensions on its permeation across the Caco-2 cell monolayer. In vivo pharmacokinetic evaluation of silybin nanosuspensions was also carried out in beagle dogs. TEM, AFM and SEM analyses revealed the effect of homogenization pressure on particle size and morphology, and confirmed the existence of a surfactant-stabilizer film on the surface of nanoparticles. DSC and XRPD experiments manifested that the crystalline state was maintained as particle size was reduced and the enhanced dissolution property was due to the increased surface area. Nanosuspensions had a significant influence on drug transport across the Caco-2 cell monolayer and the enhanced dissolution velocity was responsible for the increased permeability. A pharmacokinetics study in beagle dogs further confirmed the in vitro results and demonstrated that oral administration of silybin nanosuspensions significantly increase its bioavailability compared to the coarse powder. Nanosuspensions of silybin with smaller particle size reveal a higher potential to increase their oral bioavailability; while for intravenous infusion the lower pressure produced silybin nanosuspensions appeared to maintain a more sustained drug release profile.

Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans

PubMed Central

Inglés, M.; Olaso, G.; Lopez-Grueso, R.; Gimeno-Mallench, L.; Mas-Bargues, C.; Abdelaziz, K. M.; Gomez-Cabrera, M. C.; Vina, J.; Borras, C.

2015-01-01

Plants containing resveratrol have been used effectively in traditional medicine for over 2000 years. It can be found in some plants, fruits, and derivatives, such as red wine. Therefore, it can be administered by either consuming these natural products or intaking nutraceutical pills. Resveratrol exhibits a wide range of beneficial properties, and this may be due to its molecular structure, which endow resveratrol with the ability to bind to many biomolecules. Among these properties its activity as an anticancer agent, a platelet antiaggregation agent, and an antioxidant, as well as its antiaging, antifrailty, anti-inflammatory, antiallergenic, and so forth activities, is worth highlighting. These beneficial biological properties have been extensively studied in humans and animal models, both in vitro and in vivo. The issue of bioavailability of resveratrol is of paramount importance and is determined by its rapid elimination and the fact that its absorption is highly effective, but the first hepatic step leaves little free resveratrol. Clarifying aspects like stability and pharmacokinetics of resveratrol metabolites would be fundamental to understand and apply the therapeutic properties of resveratrol. PMID:26221416

Alendronate Sodium as Enteric Coated Solid Lipid Nanoparticles; Preparation, Optimization, and In Vivo Evaluation to Enhance Its Oral Bioavailability.

PubMed

Hosny, Khaled Mohamed

2016-01-01

Treatment of osteoporosis with alendronate sodium has several challenges. The first challenge is the low bioavailability. The second main challenge is side effects, which include oesophageal ulceration. The aim of this research was to reformulate alendronate sodium as enteric coated solid lipid nanoparticles in order to enhance its bioavailability, and preventing the free alendronate sodium from coming into direct contact with the gastrointestinal mucosa, and thereby reducing the possibility of side effects. Enteric coated solid lipid nanoparticles were prepared according to the Box-Behnken design employing Design expert® software, and characterized for size, morphology, and entrapment efficiency. The optimized formula was coated with an Eudragit S100 and evaluated for drug release in acidic and basic media, stability studies and pharmacokinetic evaluations on rabbits. The results indicated that, using Derringer's desirability functional tool for optimization, the highest entrapment efficiency value of 74.3% and the smallest size value of 98 nm were predicted under optimum conditions with a desirability value of 0.917. The optimized nanoparticles released alendronate sodium only at an alkaline pH. The pharmacokinetic evaluation revealed that alendronate sodium bioavailability was enhanced by more than 7.4-fold in rabbits. In conclusion, enteric coated solid lipid nanoparticles is a promising formula for the delivery of alendronate sodium, eliminating its oesophageal side effects and enhancing its bioavailability.

Alendronate Sodium as Enteric Coated Solid Lipid Nanoparticles; Preparation, Optimization, and In Vivo Evaluation to Enhance Its Oral Bioavailability

PubMed Central

Hosny, Khaled Mohamed

2016-01-01

Treatment of osteoporosis with alendronate sodium has several challenges. The first challenge is the low bioavailability. The second main challenge is side effects, which include oesophageal ulceration. The aim of this research was to reformulate alendronate sodium as enteric coated solid lipid nanoparticles in order to enhance its bioavailability, and preventing the free alendronate sodium from coming into direct contact with the gastrointestinal mucosa, and thereby reducing the possibility of side effects. Enteric coated solid lipid nanoparticles were prepared according to the Box-Behnken design employing Design expert® software, and characterized for size, morphology, and entrapment efficiency. The optimized formula was coated with an Eudragit S100 and evaluated for drug release in acidic and basic media, stability studies and pharmacokinetic evaluations on rabbits. The results indicated that, using Derringer's desirability functional tool for optimization, the highest entrapment efficiency value of 74.3% and the smallest size value of 98 nm were predicted under optimum conditions with a desirability value of 0.917. The optimized nanoparticles released alendronate sodium only at an alkaline pH. The pharmacokinetic evaluation revealed that alendronate sodium bioavailability was enhanced by more than 7.4-fold in rabbits. In conclusion, enteric coated solid lipid nanoparticles is a promising formula for the delivery of alendronate sodium, eliminating its oesophageal side effects and enhancing its bioavailability. PMID:27148747

Effect of potent endomorphin degradation blockers on analgesic and antidepressant-like responses in mice.

PubMed

Cravezic, Aurore; Fichna, Jakub; Gach, Katarzyna; Wyrebska, Anna; Perlikowska, Renata; Costentin, Jean; Bonnet, Jean-Jacques; Janecka, Anna; do Rego, Jean-Claude

2011-12-01

The biological effects of endomorphins (EMs) are short-lasting due to their rapid degradation by endogenous enzymes. Competing enzymatic degradation is an approach to prolong EM bioavailability. In the present study, a series of tetra- and tripeptides of similar to EMs structure was synthesized and tested in vitro and in vivo for their ability to inhibit degradation of EMs. The obtained results indicated that, among the series of analogs, the tetrapeptide Tyr-Pro-d-ClPhe-Phe-NH(2) and the tripeptide Tyr-Pro-Ala-NH(2), which did not bind to the μ-opioid receptors, were potent inhibitors of EM catabolism in rat brain homogenate. In vivo, these two peptides significantly prolonged the analgesic and antidepressant-like effects, induced by exogenous EMs, by blocking EM degrading enzymes. These new potent inhibitors may therefore increase the level and the half life of endogenous EMs and could be used in a new therapeutic strategy against pain and mood disorders, based on increasing of EM bioavailability. Copyright © 2011 Elsevier Ltd. All rights reserved.

General Pharmacokinetic Model for Topically Administered Ocular Drug Dosage Forms.

PubMed

Deng, Feng; Ranta, Veli-Pekka; Kidron, Heidi; Urtti, Arto

2016-11-01

In ocular drug development, an early estimate of drug behavior before any in vivo experiments is important. The pharmacokinetics (PK) and bioavailability depend not only on active compound and excipients but also on physicochemical properties of the ocular drug formulation. We propose to utilize PK modelling to predict how drug and formulational properties affect drug bioavailability and pharmacokinetics. A physiologically relevant PK model based on the rabbit eye was built to simulate the effect of formulation and physicochemical properties on PK of pilocarpine solutions and fluorometholone suspensions. The model consists of four compartments: solid and dissolved drug in tear fluid, drug in corneal epithelium and aqueous humor. Parameter values and in vivo PK data in rabbits were taken from published literature. The model predicted the pilocarpine and fluorometholone concentrations in the corneal epithelium and aqueous humor with a reasonable accuracy for many different formulations. The model includes a graphical user interface that enables the user to modify parameters easily and thus simulate various formulations. The model is suitable for the development of ophthalmic formulations and the planning of bioequivalence studies.

Characterization of Albendazole-Randomly Methylated-β-Cyclodextrin Inclusion Complex and In Vivo Evaluation of Its Antihelmitic Activity in a Murine Model of Trichinellosis

PubMed Central

García, Agustina; Leonardi, Darío; Vasconi, María D.; Hinrichsen, Lucila I.; Lamas, María C.

2014-01-01

Albendazole is a benzimidazole carbamate extensively used in oral chemotherapy against intestinal parasites, due to its broad spectrum activity, good tolerance and low cost. However, the drug has the disadvantage of poor bioavailability due to its very low solubility in water; as a consequence, a very active area of research focuses on the development of new pharmaceutical formulations to increase its solubility, dissolution rate, and bioavailability. The primary objective of this study was to prepare randomly methylated β-cyclodextrins inclusion complexes to increase albendazole dissolution rate, in order to enhance its antiparasitic activity. This formulation therapeutic efficacy was contrasted with that of the pure drug by treating Trichinella spiralis infected mice during the intestinal phase of the parasite cycle, on days five and six post-infection. This protocol significantly decreased muscle larval burden measured in the parenteral stage on day 30 post-infection, when compared with the untreated control. Thus, it could be demonstrated that the inclusion complexes improve the in vivo therapeutic activity of albendazole. PMID:25406084

Anti-Oxidative Polyphenolic Compounds of Cocoa.

PubMed

Nabavi, Seyed F; Sureda, Antoni; Daglia, Maria; Rezaei, Parizad; Nabavi, Seyed M

2015-01-01

Oxidative stress plays a key role in the pathogenesis of different serious chronic diseases such as cancer, diabetes, cardiovascular and neurodegenerative disorders, etc. Recent research has been focused on the beneficial role of dietary antioxidants against oxidative stress both under in vitro and in vivo conditions. Theobroma cacao L. (cacao tree) is an evergreen tree which is native to South America. It is a plant of great economic importance and its seeds are commonly used to produce cocoa powder and chocolate. In addition to its uses in food industry, cocoa is a rich source of polyphenolic antioxidants. There is a plethora of in vitro and in vivo studies that report cocoa antioxidant capacity. The protective activity of cocoa seems to be due to its phytochemical constituents, especially catechins. However, bioavailability of cocoa polyphenolic constituents following oral administration is very low (nanomolar concentrations). In the present paper, we critically reviewed the available literature on the antioxidant and free radical scavenging activities of cocoa and its polyphenolic constituents. In addition to these, we provide brief information about cultivation, phytochemistry, bioavailability and clinical impacts of cocoa.

A novel concept of overcoming the skin barrier using augmented liquid nanocrystals: Box-Behnken optimization, ex vivo and in vivo evaluation.

PubMed

Said, Mayada; Elsayed, Ibrahim; Aboelwafa, Ahmed A; Elshafeey, Ahmed H

2018-06-18

Agomelatine suffers from extensive inactivation through 1 st pass effect with a limited oral bioavailability (5%). The aim of this study was to formulate and optimize liquid nanocrystals (LNC) containing agomelatine to enhance the transdermal permeation of the drug. The independent factors of the employed Box-Behnken design were the Pluronic F127, deoxycholic acid sodium salt and propylene glycol percentages. On the other hand, particle size, polydispersity index, zeta potential, entrapment efficiency, cumulative amount permeated at certain time intervals and permeation enhancement ratio were considered as dependent responses. The optimized formulation was composed of 1.5% Pluronic F127 and 1.5% deoxycholic acid sodium salt and it was found to have significantly higher AUC 0-24h , AUC 0-∞ and elimination t 1/2 than that of the employed reference indicating the enhancement of the drug permeation. The obtained findings indicated the ability of the optimized LNC formulation to improve the drug bioavailability after its transdermal application. Copyright © 2018 Elsevier B.V. All rights reserved.

Studies of cream seeded carioca beans (phaseolus vulgaris L.) from a Rwandan efficacy trial: in vitro and in vivo screening tools reflect human studies and predict beneficial results from iron biofortified beans

USDA-ARS?s Scientific Manuscript database

Iron (Fe) deficiency is a highly prevalent micronutrient insufficiency predominantly caused by a lack of bioavailable Fe from the diet. The consumption of beans as a major food crop in some populations suffering from Fe deficiency is relatively high. Therefore, our objective was to determine whether...

Enhanced oral delivery of docetaxel using thiolated chitosan nanoparticles: preparation, in vitro and in vivo studies.

PubMed

Saremi, Shahrooz; Dinarvand, Rassoul; Kebriaeezadeh, Abbas; Ostad, Seyed Nasser; Atyabi, Fatemeh

2013-01-01

The aim of this study was to evaluate a nanoparticulate system with mucoadhesion properties composed of a core of polymethyl methacrylate surrounded by a shell of thiolated chitosan (Ch-GSH-pMMA) for enhancing oral bioavailability of docetaxel (DTX), an anticancer drug. DTX-loaded nanoparticles were prepared by emulsion polymerization method using cerium ammonium nitrate as an initiator. Physicochemical properties of the nanoparticles such as particle size, size distribution, morphology, drug loading, and entrapment efficiency were characterized. The pharmacokinetic study was carried out in vivo using wistar rats. The half-life of DTX-loaded NPs was about 9 times longer than oral DTX used as positive control. The oral bioavailability of DTX was increased to 68.9% for DTX-loaded nanoparticles compared to 6.5% for positive control. The nanoparticles showed stronger effect on the reduction of the transepithelial electrical resistance (TEER) of Caco-2 cell monolayer by opening the tight junctions. According to apparent permeability coefficient (P(app)) results, the DTX-loaded NPs showed more specific permeation across the Caco-2 cell monolayer in comparison to the DTX. In conclusion, the nanoparticles prepared in this study showed promising results for the development of an oral drug delivery system for anticancer drugs.

Enhanced Oral Delivery of Docetaxel Using Thiolated Chitosan Nanoparticles: Preparation, In Vitro and In Vivo Studies

PubMed Central

Saremi, Shahrooz; Kebriaeezadeh, Abbas; Ostad, Seyed Nasser; Atyabi, Fatemeh

2013-01-01

The aim of this study was to evaluate a nanoparticulate system with mucoadhesion properties composed of a core of polymethyl methacrylate surrounded by a shell of thiolated chitosan (Ch-GSH-pMMA) for enhancing oral bioavailability of docetaxel (DTX), an anticancer drug. DTX-loaded nanoparticles were prepared by emulsion polymerization method using cerium ammonium nitrate as an initiator. Physicochemical properties of the nanoparticles such as particle size, size distribution, morphology, drug loading, and entrapment efficiency were characterized. The pharmacokinetic study was carried out in vivo using wistar rats. The half-life of DTX-loaded NPs was about 9 times longer than oral DTX used as positive control. The oral bioavailability of DTX was increased to 68.9% for DTX-loaded nanoparticles compared to 6.5% for positive control. The nanoparticles showed stronger effect on the reduction of the transepithelial electrical resistance (TEER) of Caco-2 cell monolayer by opening the tight junctions. According to apparent permeability coefficient (P app) results, the DTX-loaded NPs showed more specific permeation across the Caco-2 cell monolayer in comparison to the DTX. In conclusion, the nanoparticles prepared in this study showed promising results for the development of an oral drug delivery system for anticancer drugs. PMID:23971023

Pb Speciation Data to Estimate Lead Bioavailability to Quail

EPA Pesticide Factsheets

Linear combination fitting data for lead speciation of soil samples evaluated through an in-vivo/in-vitro correlation for quail exposure.This dataset is associated with the following publication:Beyer, W.N., N. Basta, R. Chaney, P. Henry, D. Mosby, B. Rattner, K. Scheckel , D. Sprague, and J. Weber. BIOACCESSIBILITY TESTS ACCURATELY ESTIMATE BIOAVAILABILITY OF LEAD TO QUAIL. G.A. Burton, Jr., and C. H. Ward ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, USA, 35(9): 2311-2319, (2016).

Optimized Chemical Probes for REV-ERBα

PubMed Central

Trump, Ryan P.; Bresciani, Stefano; Cooper, Anthony W. J.; Tellam, James P.; Wojno, Justyna; Blaikley, John; Orband-Miller, Lisa A.; Kashatus, Jennifer A.; Dawson, Helen C.; Loudon, Andrew; Ray, David; Grant, Daniel; Farrow, Stuart N.; Willson, Timothy M.; Tomkinson, Nicholas C. O.

2015-01-01

REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either IV or oral dosing. PMID:23656296

Evaluation of iron and zinc bioavailability of beans targeted for biofortification using in vitro and in vivo models and their effect on the nutritional status of preschool children.

PubMed

Vaz-Tostes, Maria das Graças; Verediano, Thaisa Agrizzi; de Mejia, Elvira Gonzalez; Brunoro Costa, Neuza Maria

2016-03-15

Biofortified beans have been produced with higher nutrient concentrations. The objective was to evaluate the in vitro and in vivo iron and zinc bioavailability of common beans Pontal (PO), targeted for biofortification, compared with conventional Perola (PE) and their effects on the iron and zinc nutritional status of preschool children. In Caco-2 cells, PO and PE beans did not show differences in ferritin (PO, 13.1 ± 1.4; PE, 13.6 ± 1.4 ng mg(-1) protein) or zinc uptake (PO, 15.9 ± 1.5; PE, 15.5 ± 3.5 µmol mg(-1) protein). In the rat, PO and PE beans presented high iron bioavailability (PO, 109.6 ± 29.5; PE, 110.7 ± 13.9%). In preschool children, no changes were observed in iron and zinc nutritional status comparing before and after PO consumption (ferritin, 41.2 ± 23.2 and 28.9 ± 40.4 µg L(-1) ; hemoglobin, 13.7 ± 2.2 and 13.1 ± 3.2 g dL(-1) ; plasma zinc, 119.2 ± 24.5 and 133.9 ± 57.7 µg dL(-1) ; erythrocyte zinc, 53.5 ± 13.8 and 59.4 ± 17.1 µg g(-1) hemoglobin). Iron and zinc bioavailability in PO and PE beans was not statistically different using either cell culture, animal or human models. Efforts should focus on increasing mineral bioavailability of beans targeted for biofortification. © 2015 Society of Chemical Industry.

Preparation of liposomes containing zedoary turmeric oil using freeze-drying of liposomes via TBA/water cosolvent systems and evaluation of the bioavailability of the oil.

PubMed

Yang, Zhiwen; Yu, Songlin; Fu, Dahua

2010-02-01

The purpose of this study was to enhance the absorption of zedoary turmeric oil (ZTO) in vivo and develop new formulations of a water-insoluble oily drug. This study described a method for preparing ZTO liposomes, which involved freeze-drying (FD) of liposomes with TBA/water cosolvent systems. The TBA/water cosolvent systems were used to investigate a feasible method of liposomes manufacture; the two factors, sugar/lipid mass ratio and TBA content (concentration), of the preparation process were evaluated in this study. The results showed that the addition of TBA content could significantly enhance the sublimation of ice resulting in short FD cycles time, and reduce the entrapment efficiency of liposomes. In addition, the residual TBA solvents levels were determined to be less than 0.37% under all optimum formulations and processing conditions. Several physical properties of liposomes were examined by H-600 transmission electron microscope (TEM) and zetamaster analyser system. The results revealed that the liposomes were smooth and spherical with an average particle size of 457 +/- 7.8 nm and the zeta potential was more than 3.65 Mv. The bioavailability of the liposomes was evaluated in rabbits, compared with the conventional self-emulsifying formulation for oral administration. Compared with the conventional self-emulsifying formulation, the plasma concentration-time profiles with improved sustained-release characteristics were achieved after oral administration of the liposomes with a bioavailability of 257.7% (a good strategy for improving the bioavailability of an oily drug). In conclusion, the present experimental findings clearly demonstrated the usefulness of ZTO liposome vesicles in improving therapeutic efficacy by enhancing oral bioavailability. Our study offered an alternative method for designing sustained-release preparations of oily drugs.

Enhanced bioavailability of process-induced fast-dissolving ibuprofen cogranulated with beta-cyclodextrin.

PubMed

Ghorab, Mohamed K; Adeyeye, Moji Christianah

2003-08-01

The objectives of this study were to evaluate the bioavailability of cogranulated and oven-dried ibuprofen (IBU) and beta-cyclodextrin (betaCD), in comparison to a physical mixture, and to examine the effect of endogenous bile on the bioavailability of the drug. In vitro dissolution studies were performed using USP type 2 apparatus. The granules and physical mixture were administered perorally in a crossover fashion, to male Wistar bile duct-nonligated rats. The granules were also perorally administered to bile duct-ligated rats. Blood samples were taken at different time intervals and the plasma analyzed for IBU. Dissolution of granules was faster than the physical mixture due to faster IBU-betaCD complex formation in solution from the former than the latter. The in vivo study showed that C(max), AUC(0-8), and the absolute bioavailability for the granules (49.0 microg/mL, 57.0 h x microg/mL and 80.6%, respectively) were almost one and half times that of the physical mixture (32.2 microg/mL, 38.4 h x microg/mL and 53.1%, respectively). However, in bile duct-ligated rats, lower C(max) and AUC(0-8) (15.9 microg/mL and 14.4 h x microg/mL, respectively) were obtained for the granules. Phase solubility study of IBU in an aqueous betaCD solution in the presence of the bile salt (sodium cholate), showed an increase in the solubility of IBU. Moreover, the stability constant value for the IBU-betaCD complex was also found to decrease as the sodium cholate concentration increased. These results indicated that the enhancement in the bioavailability of IBU was due to faster in-solution complex formation, and micelllar solubilization by the bile salt. Copyright 2003 Wiley-Liss, Inc.

Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability.

PubMed

Jain, Sanyog; Reddy, Venkata Appa; Arora, Sumit; Patel, Kamlesh

2016-10-01

Candesartan cilexetil (CC), an ester prodrug of candesartan, is BCS class II drug with extremely low aqueous solubility limiting its oral bioavailability. The present research aimed to develop a nanocrystalline formulation of CC with improved saturation solubility in gastrointestinal fluids and thereby, exhibiting enhanced oral bioavailability. CC nanocrystals were prepared using a low energy antisolvent precipitation methodology. A combination of hydroxypropyl methylcellulose (HPMC) and Pluronic® F 127 (50:50 w/w) was found to be optimum for the preparation of CC nanocrystals. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation was found to be 159 ± 8.1 nm, 0.177 ± 0.043, and -23.7 ± 1.02 mV, respectively. Optimized formulation was found to possess irregular, plate-like morphology as evaluated by scanning electron microscopy and crystalline as evaluated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). A significant increase in saturation solubility and dissolution rate of the optimized nanosuspension was observed at all the tested pH conditions. Optimized CC nanocrystals exhibited a storage stability of more than 3 months when stored under cold and room temperature conditions. In vitro Caco-2 permeability further revealed that CC nanocrystals exhibited nearly 4-fold increase in permeation rate compared to the free CC. In vivo oral bioavailability studies of optimized CC nanocrystals in murine model revealed 3.8-fold increase in the oral bioavailability and twice the C max as compared with the free CC when administered orally. In conclusion, this study has established a crystalline nanosuspension formulation of CC with improved oral bioavailability in murine model. Graphical Abstract Antisolvent precipitation methodology for the preparation of Candesartan Cilexetil nanocrystals for enhanced solubility and oral bioavailability.

A novel osmotic pump-based controlled delivery system consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen: in vitro and in vivo evaluation.

PubMed

Li, Shujuan; Wang, Xiaoyu; Wang, Yingying; Zhao, Qianqian; Zhang, Lina; Yang, Xinggang; Liu, Dandan; Pan, Weisan

2015-01-01

In this study, a novel controlled release osmotic pump capsule consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen (FP) was developed to improve the solubility and oral bioavailability of FP and to minimize the fluctuation of plasma concentration. The pH-modulated solid dispersion containing FP, Kollidon® 12 PF and Na2CO3 at a weight ratio of 1/4.5/0.02 was prepared using the solvent evaporation method. The osmotic pump capsule was assembled by semi-permeable capsule shell of cellulose acetate (CA) prepared by the perfusion method. Then, the solid dispersion, penetration enhancer, and suspending agents were tableted and filled into the capsule. Central composite design-response surface methodology was used to evaluate the influence of factors on the responses. A second-order polynomial model and a multiple linear model were fitted to correlation coefficient of drug release profile and ultimate cumulative release in 12 h, respectively. The actual response values were in good accordance with the predicted ones. The optimized formulation showed a complete drug delivery and zero-order release rate. Beagle dogs were used to be conducted in the pharmacokinetic study. The in vivo study indicated that the relative bioavailability of the novel osmotic pump system was 133.99% compared with the commercial preparation. The novel controlled delivery system with combination of pH-modulated solid dispersion and osmotic pump system is not only a promising strategy to improve the solubility and oral bioavailability of poorly soluble ionizable drugs but also an effective way to reduce dosing frequency and minimize the plasma fluctuation.

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement.

PubMed

Ali, Rashid; Ali, Raisuddin; Jaimini, Abhinav; Nishad, Dhruv Kumar; Mittal, Gaurav; Chaurasia, Om Prakash; Kumar, Raj; Bhatnagar, Aseem; Singh, Shashi Bala

2012-01-01

Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). In vivo toxicity studies were performed in male balb 'C' mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement.

High bioavailability iron maize (Zea mays L.) developed through molecular breeding provides more absorbable iron in vitro (Caco-2 model) and in vivo (Gallus gallus).

PubMed

Tako, Elad; Hoekenga, Owen A; Kochian, Leon V; Glahn, Raymond P

2013-01-04

Iron (Fe) deficiency is the most common micronutrient deficiency worldwide. Iron biofortification is a preventative strategy that alleviates Fe deficiency by improving the amount of absorbable Fe in crops. In the present study, we used an in vitro digestion/Caco 2 cell culture model as the guiding tool for breeding and development of two maize (Zea mays L.) lines with contrasting Fe bioavailability (ie. Low and High). Our objective was to confirm and validate the in vitro results and approach. Also, to compare the capacities of our two maize hybrid varieties to deliver Fe for hemoglobin (Hb) synthesis and to improve the Fe status of Fe deficient broiler chickens. We compared the Fe-bioavailability between these two maize varieties with the presence or absence of added Fe in the maize based-diets. Diets were made with 75% (w/w) maize of either low or high Fe-bioavailability maize, with or without Fe (ferric citrate). Chicks (Gallus gallus) were fed the diets for 6 wk. Hb, liver ferritin and Fe related transporter/enzyme gene-expression were measured. Hemoglobin maintenance efficiency (HME) and total body Hb Fe values were used to estimate Fe bioavailability from the diets. DMT-1, DcytB and ferroportin expressions were higher (P<0.05) in the "Low Fe" group than in the "High Fe" group (no added Fe), indicating lower Fe status and adaptation to less Fe-bioavailability. At times, Hb concentrations (d 21,28,35), HME (d 21), Hb-Fe (as from d 14) and liver ferritin were higher in the "High Fe" than in the "Low Fe" groups (P<0.05), indicating greater Fe absorption from the diet and improved Fe status. We conclude that the High Fe-bioavailability maize contains more bioavailable Fe than the Low Fe-bioavailability maize, presumably due to a more favorable matrix for absorption. Maize shows promise for Fe biofortification; therefore, human trials should be conducted to determine the efficacy of consuming the high bioavailable Fe maize to reduce Fe deficiency.

In vivo evaluation of a nasal insulin delivery system based on thiolated chitosan.

PubMed

Krauland, Alexander H; Leitner, Verena M; Grabovac, Vjera; Bernkop-Schnürch, Andreas

2006-11-01

The aim of this study was the preparation and in vivo evaluation of a nasal insulin delivery system based on thiolated chitosan. 2-Iminothiolane was covalently attached to chitosan. The resulting conjugate (chitosan-TBA) exhibited 304.9 +/- 63.5 micromol thiol groups per gram polymer. Microparticles were prepared via a new precipitation-micronization technique. The microparticulate delivery system comprised insulin, reduced glutathione and chitosan-TBA (Chito-TBA/Ins) or unmodified chitosan (Chito/Ins) and control microparticles were composed of insulin and mannitol (Mannitol/Ins). Due to a hydration process the size of Chito-TBA/Ins and Chito/Ins microparticles increased in phosphate buffer pH 6.8 2.6- and 2.2-fold, respectively. Fluorescent-labeled insulin-loaded chitosan-TBA microparticles showed a controlled release over 4 h. Chito-TBA/Ins administered nasally to rats led to an absolute bioavailability of 6.9 +/- 1.5%. The blood glucose level decreased for more than 2 h and the calculated absolute pharmacological efficacy was 4.9 +/- 1.4%. Chito/Ins, in comparison, displayed a bioavailability of 4.2 +/- 1.8% and a pharmacological efficacy of 0.7 +/- 0.6%. Mannitol/Ins showed a bioavailability of 1.6 +/- 0.4% and no reduction of the blood glucose level at all. According to these findings microparticles comprising chitosan-TBA seem to have substantial higher potential for nasal insulin administration than unmodified chitosan. Copyright 2006 Wiley-Liss, Inc. and the American Pharmacists Association

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.

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.

Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation

PubMed Central

El-Nabarawi, Mohamed A; Ali, Adel A; Aboud, Heba M; Hassan, Amira H; Godah, Amany H

2016-01-01

Objective Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Ménière’s disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance. Methods A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc® 24 mg tablet in six healthy male volunteers. Results Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl-optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%. Conclusion The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl. PMID:28008227

Surface modification of solid lipid nanoparticles for oral delivery of curcumin: Improvement of bioavailability through enhanced cellular uptake, and lymphatic uptake.

PubMed

Baek, Jong-Suep; Cho, Cheong-Weon

2017-08-01

Curcumin has been reported to exhibit potent anticancer effects. However, poor solubility, bioavailability and stability of curcumin limit its in vivo efficacy for the cancer treatment. Solid lipid nanoparticles (SLN) are a promising delivery system for the enhancement of bioavailability of hydrophobic drugs. However, burst release of drug from SLN in acidic environment limits its usage as oral delivery system. Hence, we prepared N-carboxymethyl chitosan (NCC) coated curcumin-loaded SLN (NCC-SLN) to inhibit the rapid release of curcumin in acidic environment and enhance the bioavailability. The NCC-SLN exhibited suppressed burst release in simulated gastric fluid while sustained release was observed in simulated intestinal fluid. Furthermore, NCC-SLN exhibited increased cytotoxicity and cellular uptake on MCF-7 cells. The lymphatic uptake and oral bioavailability of NCC-SLN were found to be 6.3-fold and 9.5-fold higher than that of curcumin solution, respectively. These results suggest that NCC-SLN could be an efficient oral delivery system for curcumin. Copyright © 2017 Elsevier B.V. All rights reserved.

Bilayer mucoadhesive microparticles for the delivery of metoprolol succinate: Formulation and evaluation.

PubMed

Kumar, Krishan; Dhawan, Neha; Sharma, Harshita; Patwal, Pramod S; Vaidya, Shubha; Vaidya, Bhuvaneshwar

2015-01-01

Metoprolol succinate is a very potent drug for the treatment of hypertension but suffers from poor bioavailability due to its erratic absorption in lower GI tract. Therefore, in the present study, it was hypothesized that by formulating mucoadhesive particles, the residence time in the GIT and release of drug may be prolonged that will enhance the bioavailability of metoprolol succinate. Metoprolol succinate loaded chitosan microparticles were prepared by ionic gelation method. The optimized microparticles were coated with sodium alginate to form a layer over chitosan microparticles to increase the mucoadhesive strength and to release the drug in controlled manner. Coated and uncoated microparticles were evaluated for particle size, zeta potential, morphology, entrapment efficiency, drug loading and in vitro drug release. The coated microparticles showed comparatively less drug release in the 0.1 N HCl while sustained release in PBS (pH 6.8) as compared to uncoated microparticles. The in vivo study on albino rats demonstrated an increase in bioavailability of the coated microparticles as compared to marketed formulation. From the study it can be concluded that alginate coated chitosan microparticles could be a useful carrier for the oral delivery of metoprolol succinate.

Novel Curcumin Diclofenac Conjugate Enhanced Curcumin Bioavailability and Efficacy in Streptococcal Cell Wall-induced Arthritis.

PubMed

Jain, S K; Gill, M S; Pawar, H S; Suresh, Sarasija

2014-09-01

Curcumin-diclofenac conjugate as been synthesized by esterification of phenolic group of curcumin with the acid moiety of diclofenac, and characterized by mass spectrometry, NMR, FTIR, DSC, thermogravimetric analysis and X-ray diffraction analysis. The relative solubility of curcumin-diclofenac conjugate, curcumin and diclofenac; stability of curcumin-diclofenac conjugate in intestinal extract; permeability study of curcumin-diclofenac conjugate using the everted rat intestinal sac method; stability of curcumin-diclofenac conjugate in gastrointestinal fluids and in vitro efficacy have been evaluated. In vivo bioavailability of curcumin-diclofenac conjugate and curcumin in Sprague-Dawley rats, and antiarthritic activity of curcumin-diclofenac conjugate, curcumin and diclofenac in modified streptococcal cell wall-induced arthritis model in Balb/c mice to mimic rheumatoid arthritis in humans have also been studied. In all of the above studies, curcumin-diclofenac conjugate exhibited enhanced stability as compared to curcumin; its activity was twice that of diclofenac in inhibiting thermal protein denaturation taken as a measure of in vitro antiinflammatory activity; it enhanced the bioavailability of curcumin by more than five folds, and significantly (P<0.01) alleviated the symptoms of arthritis in streptococcal cell wall-induced arthritis model as compared to both diclofenac and curcumin.

Characteristics of Artemether-Loaded Poly(lactic-co-glycolic) Acid Microparticles Fabricated by Coaxial Electrospray: Validation of Enhanced Encapsulation Efficiency and Bioavailability.

PubMed

Mangrio, Farhana Akbar; Dwivedi, Pankaj; Han, Shuya; Zhao, Gang; Gao, Dayong; Si, Ting; Xu, Ronald X

2017-12-04

Artemether is one of the most effective drugs for the treatment of chloroquine-resistant and Plasmodium falciparum strains of malaria. However, its therapeutic potency is hindered by its poor bioavailability. To overcome this limitation, we have encapsulated artemether in poly(lactic-co-glycolic) acid (PLGA) core-shell microparticles (MPs) using the coaxial electrospray method. With optimized process parameters including liquid flow rates and applied electric voltages, experiments are systematically carried out to generate a stable cone-jet mode to produce artemether-loaded PLGA-MPs with an average size of 2 μm, an encapsulation efficiency of 78 ± 5.6%, and a loading efficiency of 11.7%. The in vitro release study demonstrates the sustained release of artemether from the core-shell structure in comparison with that of plain artemether and that of MPs produced by single-axial electrospray without any relevant cytotoxicity. The in vivo studies are performed to evaluate the pharmacokinetic characteristics of the artemether-loaded PLGA-MPs. Our study implies that artemether can be effectively encapsulated in a protective shell of PLGA for controlled release kinetics and enhanced oral bioavailability.

Interactions between active pharmaceutical ingredients and excipients affecting bioavailability: impact on bioequivalence.

PubMed

García-Arieta, Alfredo

2014-12-18

The aim of the present paper is to illustrate the impact that excipients may have on the bioavailability of drugs and to review existing US-FDA, WHO and EMA regulatory guidelines on this topic. The first examples illustrate that small amounts of sorbitol (7, 50 or 60mg) affect the bioavailability of risperidone, a class I drug, oral solution, in contrast to what is stated in the US-FDA guidance. Another example suggests, in contrast to what is stated in the US-FDA BCS biowaivers guideline, that a small amount of sodium lauryl sulphate (SLS) (3.64mg) affects the bioavailability of risperidone tablets, although the reference product also includes SLS in an amount within the normal range for that type of dosage form. These factors are considered sufficient to ensure that excipients do not affect bioavailability according to the WHO guideline. The alternative criterion, defined in the WHO guideline and used in the FIP BCS biowaivers monographs, that asserts that excipients present in generic products of the ICH countries do not affect bioavailability if used in normal amounts, is shown to be incorrect with an example of alendronate (a class III drug) tablets, where 4mg of SLS increases bioavailability more than 5-fold, although a generic product in the USA contains SLS. Finally, another example illustrates that a 2mg difference in SLS may affect bioavailability of a generic product of a class II drug, even if SLS is contained in the comparator product, and in all cases its amount was within the normal range. Therefore, waivers of in vivo bioequivalence studies (e.g., BCS biowaivers, waivers of certain dosage forms in solution at the time of administration and variations in the excipient composition) should be assessed more cautiously. Copyright © 2014 Elsevier B.V. All rights reserved.

Ex vivo and in vivo diffusion of ropivacaine through spinal meninges: influence of absorption enhancers.

PubMed

Brandhonneur, Nolwenn; Dollo, Gilles; Ratajczak-Enselme, Maja; Deniau, Anne Laure; Chevanne, François; Estèbe, Jean Pierre; Legrand, Alain; Le Corre, Pascal

2011-02-14

Following epidural administration, cerebrospinal fluid bioavailability of local anesthetics is low, one major limiting factor being diffusion across the arachnoid mater barrier. The aim of this study was to evaluate the influence of absorption enhancers on the meningeal permeability of epidurally administered ropivacaine. Five enhancers known for their ability to increase drug permeability via transcellular and/or paracellular pathways, i.e. palmitoyl carnitine, ethylenediaminetetraacetic acid, sodium caprate, dodecylphosphocholine and pentylglycerol, were tested ex vivo on fresh specimen of meninges removed from cervical to lumbar level of rabbit spine following laminectomy and placed in diffusion chambers. Among them, sodium caprate lead to the best permeability improvement for both marker and drug (440% and 112% for mannitol and ropivacaine, respectively) and was therefore selected for in vivo study in a sheep model using microdialysis technique to evaluate epidural and intrathecal ropivacaine concentrations following epidural administration. Resulting dialysate and plasma concentrations were used to calculate pharmacokinetic parameters. Following sodium caprate pre-treatment, ropivacaine intrathecal maximal concentration (Cmax) was 1.6 times higher (78 ± 16 μg ml(-1) vs 129 ± 26 μg ml(-1), p<0.05) but the influence of the absorption enhancer was only effective the first 30 min following ropivacaine injection, as seen with the significantly increase of intrathecal AUC(0-30 min) (1629 ± 437 μg min ml(-1) vs 2477 ± 559 μg min ml(-1), p<0.05) resulting in a bioavailable fraction 130% higher 30 min after ropivavaine administration. Co-administration of local anesthetics with sodium caprate seems to allow a transient and reversible improvement of transmeningeal passage into intrathecal space. Copyright © 2010 Elsevier B.V. All rights reserved.

In vitro and in vivo studies on the complexes of glipizide with water-soluble β-cyclodextrin-epichlorohydrin polymers.

PubMed

Nie, Shufang; Zhang, Shu; Pan, Weisan; Liu, Yanli

2011-05-01

The purpose of this study was to evaluate the potential of a newly modified cyclodextrin derivative, water-soluble β-cyclodextrin-epichlorohydrin polymer (β-CDP), as an effective drug carrier to enhance the dissolution rate and oral bioavailability of glipizide as a poorly water-soluble model drug. Inclusion complexes of glipizide with β-CDP were prepared by the co-evaporation method and characterized by phase solubility, dissolution, and differential scanning calorimetry. The solubility curve was classified as type A(L), which indicated the formation of 1:1 complex between glipizide and β-CDP. β-CDP had better properties of increasing the aqueous solubility of glipizide compared with HP-β-CD. The dissolution rate of drug from the β-CDP complexes was significantly greater than that of the corresponding physical mixtures indicating that the formation of amorphous complex increased the solubility of glipizide. Moreover, the increment in drug dissolution rate from the glipizide/β-CDP systems was higher than that from the corresponding ones with HP-β-CD, which indicated that β-CDP could provide greater capability of solubilization for poorly soluble drugs. Furthermore, in vivo study revealed that the bioavailability of glipizide was significantly improved by glipizide /β-CDP inclusion complex after oral administration to beagle dogs.

Curcumin-loaded self-nanomicellizing solid dispersion system: part I: development, optimization, characterization, and oral bioavailability.

PubMed

Parikh, Ankit; Kathawala, Krishna; Song, Yunmei; Zhou, Xin-Fu; Garg, Sanjay

2018-05-29

Curcumin (CUR) is considered as one of the most bioactive molecules ever discovered from nature due to its proven anti-inflammatory and antioxidant in both preclinical and clinical studies. Despite its proven safety and efficacy, the clinical translation of CUR into a useful therapeutic agent is still limited due to its poor oral bioavailability. To overcome its limitation and enhance oral bioavailability by improving its aqueous solubility, stability, and intestinal permeability, a novel CUR formulation (NCF) was developed using the self-nanomicellizing solid dispersion strategy. From the initial screening of polymers for their potential to improve the solubility and stability, Soluplus (SOL) was selected. The optimized NCF demonstrated over 20,000-fold improvement in aqueous solubility as a result of amorphization, hydrogen bonding interaction, and micellization determined using differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, nuclear magnetic resonance, dynamic light scattering, and transmission electron microscopy. Moreover, the greater stabilizing effect in alkaline pH and light was observed. Furthermore, significant enhancement of dissolution and permeability of CUR across everted sacs of rat small intestine were noticed. Pharmacokinetic studies demonstrated that the oral bioavailability of CUR was increased 117 and 17-fold in case of NCF and physical mixture of CUR and SOL compared to CUR suspension. These results suggest NCF identified as a promising new approach for repositioning of CUR for pharmaceutical application by enhancing the oral bioavailability of CUR. The findings herein stimulate further in vivo evaluations and clinical tests of NCF.

Curcumin-loaded lipid nanocarrier for improving bioavailability, stability and cytotoxicity against malignant glioma cells.

PubMed

Kumar, Anil; Ahuja, Alka; Ali, Javed; Baboota, Sanjula

2016-01-01

In the present study, Curcumin (CU)-loaded nanocarrier (NC) such as nanoemulsion (NE) was developed with the objective of increasing its cytotoxicity and bioavailability through lymphatic transport by enhancing its solubility and intestinal permeability. Based on the area obtained in pseudoternary phase diagram, various % combination of Labrafac Lipophile WL 1349, Solutol HS 15, Transcutol HP and distilled water were selected. Formulations which passed physical stability studies were selected for further studies such as globule size, zeta potential, in vitro release, ex vivo permeation, in vitro lipolysis studies, bioavailability studies and cytotoxicity against glioblastoma cells (U-87). The optimized NC (NE-SB1) had small average globule diameter of 67 ± 6 nm with zeta potential of -37 ± 2.5 mv which indicated long-term dispersion stability. During in vitro lipolysis study, the digestion rate of medium chain triglycerides increased with decreased globule diameter. Statistically significant difference was found in AUC0-inf of NC formulation (p < 0.05) compared to CU suspension. The relative bioavailability of NC was found 11.88 ± 0.47 with respect to CU suspension. During cytotoxicity studies, IC50 of CU solution on U87 cells was found 24.23 µM, while for the NE- SB1 it was 16.41 µM. The optimized formulation was found to be stable during 6 months of accelerated stability. The overall results revealed that the CU-loaded NC is a very effective approach for enhancing the oral absorption of poorly water-soluble drug CU and have great potential for future clinical application.

Hot Melt Extruded Amorphous Solid Dispersion of Posaconazole with Improved Bioavailability: Investigating Drug-Polymer Miscibility with Advanced Characterisation

PubMed Central

Amin, Purnima

2014-01-01

Invasive antifungal infections are reasons for morbidity and mortality in immunogenic patients worldwide. Posaconazole is a most promising antifungal agent against all types of invasive infections with high % of cure rate. The marketed suspension formulation has low bioavailability and is needed to be taken with food. In this paper, PCZ hot melt extruded amorphous solid dispersion (SD) with immediate release and improved bioavailability was prepared using Soluplus (Sol) as primary carrier for solubilization. Surfactants such as PEG 400, Lutrol F27, Lutrol F68, and TPGS are also used in combination with Soluplus to improve the physicochemical performance of the formulation when it comes in contact with GI (gastrointestinal) fluid. Drug-polymer miscibility of SD was investigated using advanced techniques. In the in vivo study, the AUC(0–72) and Cmax of PCZ/Soluplus were 11.5 and 11.74 time higher than those of pure PCZ. The formulation of the extrudate SD had an AUC(0–72) and Cmax higher than those with the commercial capsule (Noxafil). Molecular dynamic (MD) simulation studies were carried out using in silico molecular modelling to understand the drug-polymer intermolecular behaviour. The results of this research ensure enhanced dissolution and bioavailability of the solid dispersion of PCZ prepared by HME compared with the PCZ suspension. PMID:25143935

Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs.

PubMed

De Smet, Lieselotte; Saerens, Lien; De Beer, Thomas; Carleer, Robert; Adriaensens, Peter; Van Bocxlaer, Jan; Vervaet, Chris; Remon, Jean Paul

2014-05-01

The aim of the study is to increase the bioavailability of itraconazole (ITRA) using nanosized cocrystals prepared via wet milling of ITRA in combination with dicarboxylic acids. Wet milling was used in order to create a nanosuspension of ITRA in combination with dicarboxylic acids. After spray-drying and bead layering, solid state was characterized by MDSC, XRD, Raman and FT-IR. The release profiles and bioavailability of the nanococrystalline suspension, the spray-dried and bead layered formulation were evaluated. A monodisperse nanosuspension (549±51nm) of ITRA was developed using adipic acid and Tween®80. Solid state characterization indicated the formation of nanococrystals by hydrogen bounds between the triazole group of ITRA and the carboxyl group of adipic acid. A bioavailability study was performed in dogs. The faster drug release from the nanocrystal-based formulation was reflected in the in vivo results since Tmax of the formulations was obtained 3h after administration, while Tmax of the reference formulation was observed only 6h after administration. This fast release of ITRA was obtained by a dual concept: manufacturing of nanosized cocrystals of ITRA and adipic acid via wet milling. Formation of stable nanosized cocrystals via this approach seems a good alternative for amorphous systems to increase the solubility and obtain a fast drug release of BCS class II drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Evaluation of Intestinal Absorption and Bioavailability of a Bergenin-Phospholipid Complex Solid Dispersion in Rats.

PubMed

Gao, Haoshi; Wei, Yue; Xi, Long; Sun, Yuanyuan; Zhang, Tianhong

2018-05-01

Bergenin (BN) is a Biopharmaceutics Classification System class IV (BCS IV) drug with poor hydrophilicity and lipophilicity and is potentially eliminated by the efflux function of P-glycoprotein (P-gp). These factors may explain its low oral bioavailability. In the present study, a BN-phospholipid complex solid dispersion (BNPC-SD) was prepared by solvent evaporation and characterized based on differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, infrared diffraction, solubility, octanol-water partition coefficient, and in vitro dissolution. To investigate how P-gp can inhibit BN absorption in vivo, the P-gp inhibitor verapamil was co-administered with BNPC-SD to Sprague Dawley rats. By in situ single-pass intestinal perfusion, the membrane permeability of BN from BNPC-SD was higher than that of BN given alone and was improved further by co-administered verapamil. A pharmacokinetics study was done in Sprague Dawley rats, with plasma BN levels estimated by high-performance liquid chromatography. C max and AUC 0 → t values for BN were significantly higher for BNPC-SD than for BN given alone and were increased further by verapamil. Thus, the relative oral bioavailability of BNPC-SD as well as BNPC-SD co-administered with verapamil was 156.33 and 202.46%, respectively, compared with the value for BN given alone. These results showed that BNPC-SD can increase the oral bioavailability of BCS IV drugs.

Sugar-based novel niosomal nanocarrier system for enhanced oral bioavailability of levofloxacin.

PubMed

Imran, Muhammad; Shah, Muhammad Raza; Ullah, Farhat; Ullah, Shafi; Elhissi, Abdelbary M A; Nawaz, Waqas; Ahmad, Farid; Sadiq, Abdul; Ali, Imdad

2016-11-01

Vesicular systems have attracted great attention in drug delivery because of their amphiphilicity, biodegradability, non-toxicity and potential for increasing drug bioavailability. A novel sugar-based double-tailed surfactant containing renewable block was synthesized for preparing niosomal vesicles that could be exploited for Levofloxacin encapsulation, aiming to increase its oral bioavailability. The surfactant was characterized by 1 H NMR, mass spectroscopy and Fourier transform infrared spectroscopy (FT-IR). Its biocompatibility was studied against cell cultures and human blood hemolysis. In vivo acute toxicity was evaluated in mice. The vesicle morphology, size, drug-excipients interaction and entrapment efficiency (EE) were examined using atomic force microscope (AFM), dynamic light scattering (DLS), FT-IR and HPLC. Oral bioavailability studies of Levofloxacin in surfactant-based niosomal formulation were carried out using rabbits and plasma samples were analyzed using HPLC. Vesicles were spherical in shape and the size was 190.31 ± 4.51 nm with a polydispersity index (PDI) of 0.29 ± 0.03. The drug EE in niosomes was 68.28 ± 3.45%. When applied on cell lines, high cell viability was observed even after prolonged exposure at high concentrations. It caused 5.77 ± 1.34% hemolysis at 1000 μg/mL and was found to be safe up to 2000 mg/kg. Elevated Levofloxacin plasma concentration was achieved when delivered with novel vesicles. The surfactant was demonstrated to be safe and effective as carrier of Levofloxacin. The study suggests that this sugar-based double-tailed nonionic surfactant could be promising nano-vesicular system for delivery and enhancing oral bioavailability of the hydrophobic Levofloxacin.

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics

PubMed Central

Ahmed, Osama AA; Hosny, Khaled M; Al-Sawahli, Majid M; Fahmy, Usama A

2015-01-01

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid–liquid phase separation method, according to the Box–Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance. PMID:25670883

Review of the Evidence from Epidemiology, Toxicology, and Lung Bioavailability on the Carcinogenicity of Inhaled Iron Oxide Particulates.

PubMed

Pease, Camilla; Rücker, Thomas; Birk, Thomas

2016-03-21

Since the iron-age and throughout the industrial age, humans have been exposed to iron oxides. Here, we review the evidence from epidemiology, toxicology, and lung bioavailability as to whether iron oxides are likely to act as human lung carcinogens. Current evidence suggests that observed lung tumors in rats result from a generic particle overload effect and local inflammation that is rat-specific under the dosing conditions of intratracheal instillation. This mode of action therefore, is not relevant to human exposure. However, there are emerging differences seen in vitro, in cell uptake and cell bioavailability between "bulk" iron oxides and "nano" iron oxides. "Bulk" particulates, as defined here, are those where greater than 70% are >100 nm in diameter. Similarly, "nano" iron oxides are defined in this context as particulates where the majority, usually >95% for pure engineered forms of primary particulates (not agglomerates), fall in the range 1-100 nm in diameter. From the weight of scientific evidence, "bulk" iron oxides are not genotoxic/mutagenic. Recent evidence for "nano" iron oxide is conflicting regarding genotoxic potential, albeit genotoxicity was not observed in an in vivo acute oral dose study, and "nano" iron oxides are considered safe and are being investigated for biomedical uses; there is no specific in vivo genotoxicity study on "nano" iron oxides via inhalation. Some evidence is available that suggests, hypothetically due to the larger surface area of "nano" iron oxide particulates, that toxicity could be exerted via the generation of reactive oxygen species (ROS) in the cell. However, the potential for ROS generation as a basis for explaining rodent tumorigenicity is only apparent if free iron from intracellular "nano" scale iron oxide becomes bioavailable at significant levels inside the cell. This would not be expected from "bulk" iron oxide particulates. Furthermore, human epidemiological evidence from a number of studies suggests that iron oxide is not a human carcinogen, and therefore, based upon the complete weight of evidence, we conclude that "bulk" iron oxides are not human carcinogens.

Improved oral bioavailability in rats of SR13668, a novel anti-cancer agent.

PubMed

Green, Carol E; Swezey, Robert; Bakke, James; Shinn, Walter; Furimsky, Anna; Bejugam, Naveen; Shankar, Gita N; Jong, Ling; Kapetanovic, Izet M

2011-05-01

SR13668, a bis-indole with potent activity in vitro and in vivo against various cancers and promising cancer chemopreventive activity, was found to have very low oral bioavailability, <1%, in rats during pilot pharmacokinetic studies. The objective of these studies was to better understand the source of low oral exposure and to develop a formulation that could be used in preclinical development studies. An automated screening system for determining solubility in lipid-based vehicles, singly and in combination, was used to identify formulations that might enhance absorption by improving solubility of SR13668, and these results were confirmed in vivo using Sprague-Dawley rats. Pharmacokinetics of SR13668 was then determined in male and female Sprague-Dawley rats administered 1 mg/kg iv, 1, 10, and 30 mg/kg po formulated in PEG400:Labrasol (1:1 v/v). Blood was collected at time points through 24 h and the concentration of SR13668 determined using HPLC with UV and fluorescence detection. SR13668 was found to be resistant to plasma esterases in vitro and relatively stable to rat and human liver microsomal metabolism. SR13668 concentrates in tissues as indicated by significantly higher levels in lung compared to blood, blood concentrations ~2.5-fold higher than plasma levels, and apparent volume of distribution (V) of ~5 l/kg. A marked sex difference was observed in exposure to SR13668 with area under the curve (AUC) significantly higher and clearance (CL) lower for female compared to male rats, after both iv and oral administration. The oral bioavailability (F) of SR13668 was 25.4 ± 3.8 and 27.7 ± 3.9% (30 mg/kg), for males and females, respectively. A putative metabolite (M1), molecular weight of 445 in the negative ion mode (i.e., SR13668 + 16), was identified in blood samples from both the iv and po routes, as well as in vitro microsomal samples. In summary, while SR13668 does undergo metabolism, probably by the liver, the oral bioavailability of SR13668 in rats was dramatically improved by the use of formulation that contained permeation enhancers and promoted better solubilization of the drug.

Review on Prescription Compatibility of Shaoyao Gancao Decoction and Reflection on Pharmacokinetic Compatibility Mechanism of Traditional Chinese Medicine Prescription Based on In Vivo Drug Interaction of Main Efficacious Components

PubMed Central

Bi, Xiaolin; Gong, Meirong; Di, Liuqing

2014-01-01

Shaoyao Gancao Decoction (SGD) derived from Zhang Zhongjing's “Typhoid Theory” is composed of peony and licorice, having the efficacy of nourishing liver, relaxing spasm, and relieving pain. Modern compatibility studies of SGD on chemistry, pharmacology, and pharmacokinetics all demonstrate the reasonable compatibility of peony and licorice. However, the present research on pharmacokinetics is only descriptive and limited to the influence on in vivo dynamic process of certain ingredients; correspondingly, there is lack of studies on the essence of these efficacious substances' in vivo changes; that is, whether it is because there exists in vivo drug interaction in absorption, distribution, metabolism, and excretion (ADME) of active ingredients that leads to the improvement of bioavailability. We herein take SGD as an example and suggest that it is necessary to study in vivo drug interaction of main efficacious components mediated by metabolic enzymes, transport proteins, or plasma protein binding in the course of ADME, which is helpful to illustrate the principle of pharmacokinetic compatibility from the essence leading to the changes of effective substances in vivo. PMID:25147573

Improving In Vivo Efficacy of Bioactive Molecules: An Overview of Potentially Antitumor Phytochemicals and Currently Available Lipid-Based Delivery Systems

PubMed Central

Torres, Carlos; Vázquez, Luis; Reglero, Guillermo; Fornari, Tiziana

2017-01-01

Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association. PMID:28555156

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.

Enhanced oral bioavailability of docetaxel by lecithin nanoparticles: preparation, in vitro, and in vivo evaluation

PubMed Central

Hu, Kaili; Cao, Shan; Hu, Fuqiang; Feng, Jianfang

2012-01-01

The aim of this research work was to investigate the potential of lecithin nanoparticles (LNs) in improving the oral bioavailability of docetaxel. Docetaxel-loaded LNs (DTX-LNs) were prepared from oil-in-water emulsions and characterized in terms of morphology, size, zeta potential, and encapsulation efficiency. The in vitro release of docetaxel from the nanoparticles was studied by using dialysis bag method. Caco-2 cell monolayer was used for the in vitro permeation study of DTX-LNs. Bioavailability studies were conducted in rats and different pharmacokinetic parameters were evaluated after oral administration of DTX-LNs. The results showed that DTX-LNs had a mean diameter of 360 ± 8 nm and exhibited spherical shape with smooth surface under transmission electron microscopy. The DTX-LNs showed a sustained-release profile, with about 80% of docetaxel released within 72 hours. The apical to basolateral transport of docetaxel across the Caco-2 cell monolayer from the DTX-LNs was 2.14 times compared to that of the docetaxel solution (0.15 × 10−5 ± 0.016 × 10−5 cm/second versus 0.07 × 10−5 ± 0.003 × 10−5 cm/second). The oral bioavailability of the DTX-LNs was 3.65 times that of docetaxel solution (8.75% versus 2.40%). These results indicate that DTX-LNs were valuable as an oral drug delivery system to enhance the absorption of docetaxel. PMID:22848177

Characterization, pharmacokinetics and tissue distribution of chlorogenic acid-loaded self-microemulsifying drug delivery system.

PubMed

Chen, Li; Liu, Chang-Shun; Chen, Qing-Zhen; Wang, Sen; Xiong, Yong-Ai; Jing, Jing; Lv, Jia-Jia

2017-03-30

The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Chlorogenic acid (CA), an important bioactive compound from Lonicerae Japonicae Flos with poor permeability. SMEDDS was prepared and characterized by self-emulsifying rate, morphological observation, droplet size determination, stability, in vitro release, in vivo bioavailability and tissue distribution experiments. Results shown that the SMEDDS of CA has a high self-emulsifying rate (>98%) in the dissolution media, and its microemulsion exhibits small droplet size (16.37nm) and good stability. In vitro release test showed a complete release of CA from SMEDDS in 480min. After oral administration in mice, significantly enhanced bioavailability of CA was achieved through SMEDDS (249.4% relative to the CA suspension). Interestingly, SMEDDS significantly changed the tissue distribution of CA and showed a better targeting property to the kidney (2.79 of the relative intake efficiency). It is suggested that SMEDDS improves the oral bioavailability of CA may mainly through increasing its absorption and slowing the metabolism of absorbed CA via changing its distribution from the liver to the kidney. In conclusion, it is indicated that SMEDDS is a promising carrier for the oral delivery of CA. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity.

PubMed

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M

2016-07-20

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (sc) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. Their ease and efficiency make double-click helix stabilization chemistries a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control sc absorption and clearance rates to customize plasma pharmacokinetics.

A selective androgen receptor modulator for hormonal male contraception.

PubMed

Chen, Jiyun; Hwang, Dong Jin; Bohl, Casey E; Miller, Duane D; Dalton, James T

2005-02-01

The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies, including hormonal male contraception. The identification of an orally bioavailable SARM with the ability to mimic the central and peripheral androgenic and anabolic effects of testosterone would represent an important step toward the "male pill". We characterized the in vitro and in vivo pharmacologic activity of (S)-3-(4-chloro-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (C-6), a novel SARM developed in our laboratories. C-6 was identified as an androgen receptor (AR) agonist with high AR binding affinity (K(i) = 4.9 nM). C-6 showed tissue-selective pharmacologic activity with higher anabolic activity than androgenic activity in male rats. The doses required to maintain the weight of the prostate, seminal vesicles, and levator ani muscle to half the size of the maximum effects (i.e., ED(50)) were 0.78 +/- 0.06, 0.88 +/- 0.1, and 0.17 +/- 0.04 mg/day, respectively. As opposed to other SARMs, gonadotropin levels in C-6-treated groups were significantly lower than control values. C-6 also significantly decreased serum testosterone concentration in intact rats after 2 weeks of treatment. Marked suppression of spermatogenesis was observed after 10 weeks of treatment with C-6 in intact male rats. Pharmacokinetic studies of C-6 in male rats revealed that C-6 was well absorbed after oral administration (bioavailability 76%), with a long (6.3 h) half-life at a dose of 10 mg/kg. These studies show that C-6 mimicked the in vivo pharmacologic and endocrine effects of testosterone while maintaining the oral bioavailability and tissue-selective actions of nonsteroidal SARMs.

Improving maraviroc oral bioavailability by formation of solid drug nanoparticles.

PubMed

Savage, Alison C; Tatham, Lee M; Siccardi, Marco; Scott, Trevor; Vourvahis, Manoli; Clark, Andrew; Rannard, Steve P; Owen, Andrew

2018-05-17

Oral drug administration remains the preferred approach for treatment of HIV in most patients. Maraviroc (MVC) is the first in class co-receptor antagonist, which blocks HIV entry into host cells. MVC has an oral bioavailability of approximately 33%, which is limited by poor permeability as well as affinity for CYP3A and several drug transporters. While once-daily doses are now the favoured option for HIV therapy, dose-limiting postural hypotension has been of theoretical concern when administering doses high enough to achieve this for MVC (particularly during coadministration of enzyme inhibitors). To overcome low bioavailability and modify the pharmacokinetic profile, a series of 70 wt% MVC solid drug nanoparticle (SDN) formulations (containing 30 wt% of various polymer/surfactant excipients) were generated using emulsion templated freeze-drying. The lead formulation contained PVA and AOT excipients ( MVC SDN PVA/AOT ), and was demonstrated to be fully water-dispersible to release drug nanoparticles with z-average diameter of 728 nm and polydispersity index of 0.3. In vitro and in vivo studies of MVC SDN PVA/AOT showed increased apparent permeability of MVC, compared to a conventional MVC preparation, with in vivo studies in rats showing a 2.5-fold increase in AUC (145.33 vs. 58.71 ng h ml -1 ). MVC tissue distribution was similar or slightly increased in tissues examined compared to the conventional MVC preparation, with the exception of the liver, spleen and kidneys, which showed statistically significant increases in MVC for MVC SDN PVA/AOT . These data support a novel oral format with the potential for dose reduction while maintaining therapeutic MVC exposure and potentially enabling a once-daily fixed dose combination product. Copyright © 2018. Published by Elsevier B.V.

High bioavailablilty iron maize (Zea mays L.) developed through molecular breeding provides more absorbable iron in vitro (Caco-2 model) and in vivo (Gallus gallus)

PubMed Central

2013-01-01

Background Iron (Fe) deficiency is the most common micronutrient deficiency worldwide. Iron biofortification is a preventative strategy that alleviates Fe deficiency by improving the amount of absorbable Fe in crops. In the present study, we used an in vitro digestion/Caco 2 cell culture model as the guiding tool for breeding and development of two maize (Zea mays L.) lines with contrasting Fe bioavailability (ie. Low and High). Our objective was to confirm and validate the in vitro results and approach. Also, to compare the capacities of our two maize hybrid varieties to deliver Fe for hemoglobin (Hb) synthesis and to improve the Fe status of Fe deficient broiler chickens. Methods We compared the Fe-bioavailability between these two maize varieties with the presence or absence of added Fe in the maize based-diets. Diets were made with 75% (w/w) maize of either low or high Fe-bioavailability maize, with or without Fe (ferric citrate). Chicks (Gallus gallus) were fed the diets for 6 wk. Hb, liver ferritin and Fe related transporter/enzyme gene-expression were measured. Hemoglobin maintenance efficiency (HME) and total body Hb Fe values were used to estimate Fe bioavailability from the diets. Results DMT-1, DcytB and ferroportin expressions were higher (P < 0.05) in the "Low Fe" group than in the "High Fe" group (no added Fe), indicating lower Fe status and adaptation to less Fe-bioavailability. At times, Hb concentrations (d 21,28,35), HME (d 21), Hb-Fe (as from d 14) and liver ferritin were higher in the "High Fe" than in the "Low Fe" groups (P < 0.05), indicating greater Fe absorption from the diet and improved Fe status. Conclusions We conclude that the High Fe-bioavailability maize contains more bioavailable Fe than the Low Fe-bioavailability maize, presumably due to a more favorable matrix for absorption. Maize shows promise for Fe biofortification; therefore, human trials should be conducted to determine the efficacy of consuming the high bioavailable Fe maize to reduce Fe deficiency. PMID:23286295

Vehicle effects in ophthalmic bioavailability: an evaluation of polymeric inserts containing pilocarpine.

PubMed

Saettone, M F; Giannaccini, B; Chetoni, P; Galli, G; Chiellini, E

1984-04-01

A series of polymeric ophthalmic inserts containing pilocarpine were formulated with four different types of polyvinyl alcohol, PVA, and two types of hydroxypropylcellulose. Pilocarpine was present as the nitrate, or as the salt with polyacrylic acid, PAA. In-vivo miosis vs time experiments on albino rabbits, showed that all inserts increased significantly the bioavailability of pilocarpine, with respect to a standard solution of pilocarpine nitrate. Two PVA inserts, containing the PAA-salt of pilocarpine, were particularly effective. The preparations were also submitted to in-vitro release tests and to differential scanning calorimetry, to ascertain the release mechanism, and to verify, via the thermal behaviour, possible interactions between drug and polymers. The chemical and physiochemical factors, most likely to influence the ophthalmic bioavailability of pilocarpine from the present preparations, are briefly reviewed.

High bioavailability curcumin: an anti-inflammatory and neurosupportive bioactive nutrient for neurodegenerative diseases characterized by chronic neuroinflammation.

PubMed

Ullah, Faheem; Liang, Andy; Rangel, Alejandra; Gyengesi, Erika; Niedermayer, Garry; Münch, Gerald

2017-04-01

Neuroinflammation is a pathophysiological process present in a number of neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, traumatic brain injury including chronic traumatic encephalopathy and other age-related CNS disorders. Although there is still much debate about the initial trigger for some of these neurodegenerative disorders, during the progression of disease, broad range anti-inflammatory drugs including cytokine suppressive anti-inflammatory drugs (CSAIDs) might be promising therapeutic options to limit neuroinflammation and improve the clinical outcome. One of the most promising CSAIDs is curcumin, which modulates the activity of several transcription factors (e.g., STAT, NF-κB, AP-1) and their pro-inflammatory molecular signaling pathways. However, normal curcumin preparations demonstrate low bioavailability in vivo. To increase bioavailability, preparations of high bioavailability curcumin have been introduced to achieve therapeutically relevant concentrations in target tissues. This literature review aims to summarize the pharmacokinetic and toxicity profile of different curcumin formulations.

Novel delivery system for natural products: Nano-curcumin formulations

PubMed Central

Rahimi, Hamid Reza; Nedaeinia, Reza; Sepehri Shamloo, Alireza; Nikdoust, Shima; Kazemi Oskuee, Reza

2016-01-01

Objective: Curcumin is extracted from Curcuma longa and regulates the intracellular signal pathways which control the growth of cancerous cell, inflammation, invasion and apoptosis. Curcumin molecules have special intrinsic features that can target the intracellular enzymes, genome (DNA) and messengers (RNA). A wide range of studies have been conducted on the physicochemical traits and pharmacological effects of curcumin on different diseases like cardiovascular diseases, diabetes, cancer, rheumatoid arthritis, Alzheimer’s, inflammatory bowel disease (IBD), and even it has wound healing. Oral bioavailability of curcumin is rather poor, which would certainly put some boundaries in the employment of this drug. Materials and Methods: Bibliographical searches were performed using MEDLINE/ScienceDirect/OVID up to February 2015 using the following keywords (all fields): (“Curcumin” OR “Curcuma longa”) AND [(nanoparticles) OR (Nanomicelles) OR (micro emulsions) OR (liposome) OR (phospholipid). Results: Consequently, for any developments of curcumin in the future, analogues of curcumin that have better bioavailability or substitute formulations are needed crucially. Conclusion: These studies indicated that nanotechnology can formulate curcumin effectively, and this nano-formulated curcumin with a potent ability against various cancer cells, were represented to have better efficacy and bioavailability under in vivo conditions. PMID:27516979

Nanoemulsion of atovaquone as a promising approach for treatment of acute and chronic toxoplasmosis.

PubMed

Azami, Sanaz Jafarpour; Amani, Amir; Keshavarz, Hossein; Najafi-Taher, Roqya; Mohebali, Mehdi; Faramarzi, Mohammad Ali; Mahmoudi, Mahmood; Shojaee, Saeedeh

2018-05-30

Treatment of toxoplasmosis is necessary in congenital form and immunocompromised patients. Atovaquone is a powerful suppressor of protozoan parasites with a broad-spectrum activity, but an extremely low water solubility and bioavailability. In this study, nanoemulsion of this drug was prepared with grape seed oil using spontaneous emulsification method to increase bioavailability and efficacy of atovaquone for treatment of toxoplasmosis. In vitro activity of atovaquone nanoemulsion against T. gondii, RH and Tehran strains, was assessed in HeLa cell culture. For in vivo assessment, BALB/c mice were infected with RH and Tehran strains and then treated with nanoemulsion of atovaquone, compared to that treated with free atovaquone. Concentration of atovaquone nanoemulsion showed in vitro anti-parasitic effects in both strains of T. gondii. Furthermore, oral administration of atovaquone nanoemulsion increased oral bioavailability, tissue distribution and mice survival time and reduced parasitemia and number and size of the brain cysts. Decrease of cyst numbers was verified by down regulation of BAG1 using real-time polymerase chain reaction (real-time PCR) assay. Effective therapeutic activity of atovaquone at a reduced dose is the major achievement of this study. Copyright © 2018 Elsevier B.V. All rights reserved.

Linking Suspension Nasal Spray Drug Deposition Patterns to Pharmacokinetic Profiles: A Proof of Concept Study using Computational Fluid Dynamics

PubMed Central

Rygg, Alex; Hindle, Michael; Longest, P. Worth

2016-01-01

The objective of this study is to link regional nasal spray deposition patterns of suspension formulations, predicted with computational fluid dynamics (CFD), to in vivo human pharmacokinetic (PK) plasma concentration profiles. This is accomplished through the use of CFD simulations coupled with compartmental PK modeling. Results showed a rapid initial rise in plasma concentration that is due to the absorption of drug particles deposited in the nasal middle passages, followed by a slower increase in plasma concentration that is governed by the transport of drug particles from the nasal vestibule to the middle passages. Although drug deposition locations in the nasal cavity had a significant effect on the shape of the concentration profile, the absolute bioavailability remained constant provided that all of the drug remained in the nose over the course of the simulation. Loss of drug through the nostrils even after long time periods resulted in a significant decrease in bioavailability and increased variability. The results of this study quantify how differences in nasal drug deposition affect transient plasma concentrations and overall bioavailability. These findings are potentially useful for establishing bioequivalence for nasal spray devices and reducing the burden of in vitro testing, pharmacodynamics and clinical studies. PMID:27238495

Role of folic acid in nitric oxide bioavailability and vascular endothelial function

PubMed Central

Kenney, W. Larry

2017-01-01

Folic acid is a member of the B-vitamin family and is essential for amino acid metabolism. Adequate intake of folic acid is vital for metabolism, cellular homeostasis, and DNA synthesis. Since the initial discovery of folic acid in the 1940s, folate deficiency has been implicated in numerous disease states, primarily those associated with neural tube defects in utero and neurological degeneration later in life. However, in the past decade, epidemiological studies have identified an inverse relation between both folic acid intake and blood folate concentration and cardiovascular health. This association inspired a number of clinical studies that suggested that folic acid supplementation could reverse endothelial dysfunction in patients with cardiovascular disease (CVD). Recently, in vitro and in vivo studies have begun to elucidate the mechanism(s) through which folic acid improves vascular endothelial function. These studies, which are the focus of this review, suggest that folic acid and its active metabolite 5-methyl tetrahydrofolate improve nitric oxide (NO) bioavailability by increasing endothelial NO synthase coupling and NO production as well as by directly scavenging superoxide radicals. By improving NO bioavailability, folic acid may protect or improve endothelial function, thereby preventing or reversing the progression of CVD in those with overt disease or elevated CVD risk. PMID:27974600

Nimodipine nanocrystals for oral bioavailability improvement: preparation, characterization and pharmacokinetic studies.

PubMed

Fu, Qiang; Sun, Jin; Zhang, Dong; Li, Mo; Wang, Yongjun; Ling, Guixia; Liu, Xiaohong; Sun, Yinghua; Sui, Xiaofan; Luo, Cong; Sun, Le; Han, Xiaopeng; Lian, He; Zhu, Meng; Wang, Siling; He, Zhonggui

2013-09-01

This study intended to develop nimodipine (NMD) nanocrystals with different sizes for oral administration and to investigate the relationship between dissolution and pharmacokinetics for NMD nanocrystals and Nimotop(®). NMD nanocrystals were prepared by combination of microprecipitation and high pressure homogenization and were further lyophilized. The particle size, morphology and aqueous solubility of the NMD nanocrystals were determined. With Nimotop(®) as the control, the dissolution rate was evaluated and the pharmacokinetic study was undertaken in beagle dogs. NMD nanocrystals with mean diameters of about 159.0, 503.0 and 833.3 nm were prepared, respectively. The lyophilization didn't affect the particle sizes of the redispersed nanocrystals. The aqueous solubility was significantly improved and displayed a size-dependent manner. The nanocrystals exhibited lower dissolution patterns than Nimotop(®) under non-sink condition, but bioavailability of the two nanocrystals (159.0 and 833.3 nm) was equivalent, about 2.6-fold higher than Nimotop(®). In conclusion, oral nanocrystal drug delivery system was a promising strategy in improving the oral bioavailability of poorly soluble or insoluble drugs. But we could not establish a favorable in vitro in vivo correlation for NMD nanocrystals and Nimotop(®) and thus the oral absorption mechanism of the NMD nanocrystals required further study. Copyright © 2013 Elsevier B.V. All rights reserved.

Potentiation of the bioavailability of blueberry phenolic compounds by co-ingested grape phenolic compounds in mice, revealed by targeted metabolomic profiling in plasma and feces.

PubMed

Dudonné, Stéphanie; Dal-Pan, Alexandre; Dubé, Pascal; Varin, Thibault V; Calon, Frédéric; Desjardins, Yves

2016-08-10

The low bioavailability of dietary phenolic compounds, resulting from poor absorption and high rates of metabolism and excretion, is a concern as it can limit their potential beneficial effects on health. Targeted metabolomic profiling in plasma and feces of mice supplemented for 15 days with a blueberry extract, a grape extract or their combination revealed significantly increased plasma concentrations (3-5 fold) of blueberry phenolic metabolites in the presence of a co-ingested grape extract, associated with an equivalent decrease in their appearance in feces. Additionally, the repeated daily administration of the blueberry-grape combination significantly increased plasma phenolic concentrations (2-3-fold) compared to animals receiving only a single acute dose, with no such increase being observed with individual extracts. These findings highlight a positive interaction between blueberry and grape constituents, in which the grape extract enhanced the absorption of blueberry phenolic compounds. This study provides for the first time in vivo evidence of such an interaction occurring between co-ingested phenolic compounds from fruit extracts leading to their improved bioavailability.

Characterization and evaluation of an oral microemulsion containing the antitumor diterpenoid compound ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid.

PubMed

Lu, Yingnian; Wu, Kefeng; Li, Li; He, Yuhui; Cui, Liao; Liang, Nianci; Mu, Bozhong

2013-01-01

The objective of this study was to develop an oral microemulsion formulation of the antitumor diterpenoid agent, ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (henceforth referred to as 5F), to enhance its bioavailability and evaluate its hepatotoxicity. Pseudoternary phase diagrams showed that the optimal microemulsion formulation contained 45% water, 10% castor oil as the oil phase, 15% Cremophor EL as the surfactant, and 30% as a cosurfactant mixture of 1,2-propanediol and polyethylene glycol (PEG)-400 (2:1, w/w). The microemulsion preparation was characterized and its droplet diameter was within 50 nm. Release of 5F in vitro from the microemulsion was slightly increased compared with a suspension containing the same amount of active drug. Pharmacokinetic parameters in vivo indicated that bioavailability was markedly improved, with the relative bioavailability being 616.15% higher for the microemulsion than for the suspension. Toxicity tests showed that the microemulsion had no hepatotoxicity in mice. These results suggest the potential for 5F microemulsion to be administered by the oral route.

Lack of Exposure in a First-in-Man Study Due to Aldehyde Oxidase Metabolism: Investigated by Use of 14C-microdose, Humanized Mice, Monkey Pharmacokinetics, and In Vitro Methods.

PubMed

Jensen, Klaus Gjervig; Jacobsen, Anne-Marie; Bundgaard, Christoffer; Nilausen, Dorrit Østergaard; Thale, Zia; Chandrasena, Gamini; Jørgensen, Martin

2017-01-01

Inclusion of a microdose of 14 C-labeled drug in the first-in-man study of new investigational drugs and subsequent analysis by accelerator mass spectrometry has become an integrated part of drug development at Lundbeck. It has been found to be highly informative with regard to investigations of the routes and rates of excretion of the drug and the human metabolite profiles according to metabolites in safety testing guidance and also when additional metabolism-related issues needed to be addressed. In the first-in-man study with the NCE Lu AF09535, contrary to anticipated, surprisingly low exposure was observed when measuring the parent compound using conventional bioanalysis. Parallel accelerator mass spectrometry analysis revealed that the low exposure was almost exclusively attributable to extensive metabolism. The metabolism observed in humans was mediated via a human specific metabolic pathway, whereas an equivalent extent of metabolism was not observed in preclinical species. In vitro, incubation studies in human liver cytosol revealed involvement of aldehyde oxidase (AO) in the biotransformation of Lu AF09535. In vivo, substantially lower plasma exposure of Lu AF09535 was observed in chimeric mice with humanized livers compared with control animals. In addition, Lu AF09535 exhibited very low oral bioavailability in monkeys despite relatively low clearance after intravenous administration in contrast to the pharmacokinetics in rats and dogs, both showing low clearance and high bioavailability. The in vitro and in vivo methods applied were proved useful for identifying and evaluating AO-dependent metabolism. Different strategies to integrate these methods for prediction of in vivo human clearance of AO substrates were evaluated. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

PLGA nanoparticles for the oral delivery of 5-Fluorouracil using high pressure homogenization-emulsification as the preparation method and in vitro/in vivo studies.

PubMed

Li, XueMing; Xu, YuanLong; Chen, GuoGuang; Wei, Ping; Ping, QiNeng

2008-01-01

The objective of the present study was to incorporate the hydrophilic anti-cancer drug 5-Fluorouracil(5-FU) into poly(lactide-co-glycolide) (PLGA) nanoparticles(NP) to improve the oral bioavailability. Owing to the high solubility of 5-FU in basic water, the water-in-oil-in-water (w/o/w) emulsification process has been chosen as one of the most appropriate method for the encapsulation of 5-FU, and the ammonia solution was used as the inner aqueous phase solvent to increase the solubility of 5-FU. In order to reach submicron size as well as increasing the grade of monodispersity compared to previous preparation techniques, we prepared 5-FU loaded PLGA-NP by a high-pressure emulsification-solvent evaporation process. The PLGA-NPs were characterized with respect to their morphology, particle size, size distribution, 5-FU encapsulation efficiency, in vitro and in vivo studies in rats. In vitro release of 5-FU from nanoparticles appeared to have two components with an initial rapid release due to the surface associated drug and followed by a slower exponential release of 5-FU, which was dissolved in the core. The in vivo research was studied in male Sprague-Dawley rats after an oral 5-FU dose of 45 mg/kg. Single oral administration of 5-FU loaded PLGA-NP to rats produced bioavailability, which was statistically higher than 5-FU solution as negative control. And the MRT (mean residence time) of 5-FU loaded PLGA-NP was significantly (P < 0.05) modified. Thus, it is possible to design a controlled drug delivery system for oral 5-FU delivery, improving therapy efficiency by possible reduction of time intervals between peroral administrations and reduction of local gastrointestinal side effects.

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.

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement

PubMed Central

Ali, Rashid; Ali, Raisuddin; Jaimini, Abhinav; Nishad, Dhruv Kumar; Mittal, Gaurav; Chaurasia, Om Prakash; Kumar, Raj; Bhatnagar, Aseem; Singh, Shashi Bala

2012-01-01

Objectives: Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). Materials and Methods: In vivo toxicity studies were performed in male balb ‘C’ mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. Results: No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. Conclusion: The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement. PMID:23087514

[Effect of Radix euphorbiae pekinensis extract on bioavailability of paclitaxel after their oral co-administration].

PubMed

Li, Minghua; Peng, Li; Yang, Fuheng; Liu, Sijia; Wang, Shengqi

2015-06-01

To evaluate the effect of Radix euphorbiae pekinensis extract on the permeability and bioavailability of paclitaxel co-administered orally. Based on Ussing Chamber and in vivo experiment, the permeability and bioavailability of paclitaxel were evaluated after oral co-administration with radix euphorbiae pekinensis in rats. The contents of paclitaxel in the permeates and the blood samples were determined using HPLC and LC-MS/MS method, respectively. In Radix euphorbiae pekinensis co-administration group, the Papp of the mucosal-to-serosal (M-S) transport or serosal-to-mucosal transport (S-M) of paclitaxel in the jejunum or ileum segment differed significantly from those in verapamil co-administration group and blank control group (P<0.05), but the Papp of S-M transport in the colon showed no significant difference from that in the blank control group. In the blank group, the average absolute bioavailability (AB%) of orally administered paclitaxel was only 2.81%, compared to that of 7.63% in radix euphorbiae pekinensis group. The average AB% in verapamil group was about 1.5 times that of the blank group. Co-administration of Radix euphorbiae pekinensis extract can increase the bioavailability of orally administered paclitaxel.

Potential applications of ferrocene as a structural feature in antioxidants.

PubMed

Liu, Zai-Qun

2011-04-01

Comparing with the wide usage of ferrocene in novel materials, ferrocene was unusually applied to be a structural feature in designing drugs even though some researchers pointed out that ferrocene and its derivatives possessed potential pharmacological applications. This was due to that low polarity limited bioavailability of ferrocene in vivo. Since ferrocene was inert to the oxidation at atmosphere, it was deduced that synthetic derivatives of ferrocene may be a novel kind of antioxidant, in which other organic groups may enhance the bioavailability of ferrocene, or large conjugated system formed among ferrocenyl and other organic groups may increase the antioxidant effectiveness. Thus, synthetic derivatives of ferrocene were divided into nonconjugated and conjugated ones in this review. For nonconjugated ferrocenyl derivatives, carbon chain or simple group attached one or two cyclopentadienyl rings in ferrocene to form a novel molecule with ferrocenyl group. The aim of synthesis of nonconjugated ferrocenyl compounds was to increase the bioavailability of ferrocene in vivo. On the other hand, the conjugated ferrocenyl derivatives referred to introduce other group to form a conjugated system with the cyclopentadienyl ring in ferrocene. The large conjugated system was beneficial for the single electron to dispense among the whole molecule while forming radicals, and enhanced the antioxidant capacity of the whole molecule. This review summarized the potential usage of ferrocene in antioxidants.

Solubility and bioavailability improvement of pazopanib hydrochloride.

PubMed

Herbrink, Maikel; Groenland, Stefanie L; Huitema, Alwin D R; Schellens, Jan H M; Beijnen, Jos H; Steeghs, Neeltje; Nuijen, Bastiaan

2018-06-10

The anti-cancer drug pazopanib hydrochloride (PZH) has a very low aqueous solubility and a variable oral bioavailability. A new pharmaceutical formulation with an improved solubility may enhance the bioavailability and reduce the variability. A broad selection of polymer excipients was tested for their compatibility and solubilizing properties by conventional microscopic, thermal and spectrometric techniques. A wet milling and mixing technique was used to produce homogenous powder mixtures. The dissolution properties of the formulation were tested by a pH-switch dissolution model. The final formulation was tested in vivo in cancer patient following a dose escalation design. Of the tested mixture formulations, the one containing the co-block polymer Soluplus® in a 8:1 ratio with PZH performed best in terms of in vitro dissolution properties. The in vivo results indicated that 300 mg of the developed formulation yields similar exposure and a lower variability (379 μg/mL∗h (36.7% CV)) than previously reported values for the standard PZH formulation (Votrient®) at the approved dose of 800 mg. Furthermore, the expected plasma-C through levels (27.2 μg/mL) exceeds the defined therapeutic efficacy threshold of 20 μg/mL. Copyright © 2018 Elsevier B.V. All rights reserved.

Curcumin Cocrystal Micelles-Multifunctional Nanocomposites for Management of Neurodegenerative Ailments.

PubMed

Desai, Preshita P; Patravale, Vandana B

2018-04-01

Curcumin, a potent antioxidant polyphenol with neuroprotective and antiamyloid activities, has significant potential in the treatment of neurodegenerative disorders such as Alzheimer's disease. However, its clinical translation is delayed due to poor bioavailability. For effective use of curcumin in Alzheimer's disease, it is imperative to increase its bioavailability with enhanced delivery at a therapeutic site that is, brain. With this objective, pharmaceutical cocrystals of curcumin were developed and incorporated in micellar nanocarriers for nose-to-brain delivery. For cocrystals, an antioxidant hydrophilic coformer was strategically selected using molecular modeling approach. The cocrystals were formulated using a planetary ball mill, and the process was optimized using 3 2 factorial design followed by characterization using differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy analysis. The cocrystal micelles exhibited globule size of 28.79 ± 0.86 nm. Further, curcumin cocrystal and co-crystal micelles exhibited a significantly low (p value <0.01) IC 50 concentration for antioxidant activity as compared to curcumin corroborating superior antioxidant performance. In vivo studies revealed about 1.7-fold absolute bioavailability of curcumin cocrystal micelles with C max of 1218.38 ± 58.11 ng/mL and showed significantly high brain distribution even beyond 6 hours of dosing. Thus, the studies confirmed enhanced bioavailability, higher brain uptake, retention, and delayed clearance with curcumin cocrystal micellar nanocarriers. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Self nanoemulsifying drug delivery system of stabilized ellagic acid-phospholipid complex with improved dissolution and permeability.

PubMed

Avachat, Amelia M; Patel, Vijay G

2015-07-01

Ellagic acid (EA), a plant polyphenol known for its wide-range of health benefits has limited use due to its low oral bioavailability. In this study, a new self-nanoemulsifying drug delivery system (SNEDDS), based on the phospholipid complex technique, was developed to improve the oral bioavailability of ellagic acid. Ellagic acid-phospholipid complex was prepared by an anti-solvent method and characterized. Enhanced lipophilicity after the formation of ellagic acid-phospholipid complex was verified through solubility studies. Preliminary screening was carried out to select oil, surfactant and co-surfactant. Ternary phase diagrams were constructed to identify the area of nanoemulsification. Formulations were optimized on the basis of globule size, cloud point and robustness to dilution. The optimized SNEDDS of ellagic acid-phospholipid complex showed mean globule size of 106 ± 0.198 nm and cloud point at 83-85 °C. The in vitro drug release from SNEDDS was found to be higher compared to EA suspension and complex, while ex vivo studies showed increased permeation from SNEDDS compared to EA suspension. Moreover, SNEDDS overcome the food effect which was shown by EA suspension. Thus, SNEDDS were found to be influential in improving the release performance of EA, indicating their potential to improve the oral bioavailability of EA.

The effect of wheat prebiotics on the gut bacterial population and iron status of iron deficient broiler chickens

PubMed Central

2014-01-01

Background Currently, there is a lot of interest in improving gut health, and consequently increasing Fe absorption, by managing the colonic microbial population. This is traditionally done by the consumption of probiotics, live microbial food supplements. However, an alternative, and often very effective approach, is the consumption of food ingredients known as prebiotics. Fructans and arabinoxylans are naturally occurring non-digestible oligosaccharides in wheat that exhibit prebiotic properties and may enhance intestinal iron (Fe) absorption. The aim of this study was to assess the effect of prebiotics from wheat on Fe bioavailability in vitro (Caco-2 cells) and in vivo (broiler chickens, Gallus gallus). Methods In the current study, the effect of intra-amniotic administration of wheat samples extracts at 17 d of embryonic incubation on the Fe status and possible changes in the bacterial population in intestinal content of broiler hatchlings were investigated. A group of 144 eggs were injected with the specified solution (1 ml per egg) into the amniotic fluid. Immediately after hatch (21 d) and from each treatment group, 10 chicks were euthanized and their small intestine, liver and cecum were removed for relative mRNA abundance of intestinal Fe related transporters, relative liver ferritin amounts and bacterial analysis of cecal content, respectively. Results The in vivo results are in agreement with the in vitro observations, showing no differences in the hatchling Fe status between the treatment groups, as Fe bioavailability was not increased in vitro and no significant differences were measured in the intestinal expression of DMT1, Ferroportin and DcytB in vivo. However, there was significant variation in relative amounts of bifidobacteria and lactobacilli in the intestinal content between the treatments groups, with generally more bifidobacteria being produced with increased prebiotic content. Conclusions In this study we showed that prebiotics naturally found in wheat grains/bread products significantly increased intestinal beneficial bacterial population in Fe deficient broiler chickens. With this short-term feeding trial we were not able to show differences in the Fe-status of broilers. Nevertheless, the increase in relative amounts of bifidobacteria and lactobacilli in the presence of wheat prebiotics is an important finding as these bacterial populations may affect Fe bioavailability in long-term studies. PMID:24924421

The effect of wheat prebiotics on the gut bacterial population and iron status of iron deficient broiler chickens.

PubMed

Tako, Elad; Glahn, Raymond P; Knez, Marija; Stangoulis, James Cr

2014-06-13

Currently, there is a lot of interest in improving gut health, and consequently increasing Fe absorption, by managing the colonic microbial population. This is traditionally done by the consumption of probiotics, live microbial food supplements. However, an alternative, and often very effective approach, is the consumption of food ingredients known as prebiotics. Fructans and arabinoxylans are naturally occurring non-digestible oligosaccharides in wheat that exhibit prebiotic properties and may enhance intestinal iron (Fe) absorption. The aim of this study was to assess the effect of prebiotics from wheat on Fe bioavailability in vitro (Caco-2 cells) and in vivo (broiler chickens, Gallus gallus). In the current study, the effect of intra-amniotic administration of wheat samples extracts at 17 d of embryonic incubation on the Fe status and possible changes in the bacterial population in intestinal content of broiler hatchlings were investigated. A group of 144 eggs were injected with the specified solution (1 ml per egg) into the amniotic fluid. Immediately after hatch (21 d) and from each treatment group, 10 chicks were euthanized and their small intestine, liver and cecum were removed for relative mRNA abundance of intestinal Fe related transporters, relative liver ferritin amounts and bacterial analysis of cecal content, respectively. The in vivo results are in agreement with the in vitro observations, showing no differences in the hatchling Fe status between the treatment groups, as Fe bioavailability was not increased in vitro and no significant differences were measured in the intestinal expression of DMT1, Ferroportin and DcytB in vivo. However, there was significant variation in relative amounts of bifidobacteria and lactobacilli in the intestinal content between the treatments groups, with generally more bifidobacteria being produced with increased prebiotic content. In this study we showed that prebiotics naturally found in wheat grains/bread products significantly increased intestinal beneficial bacterial population in Fe deficient broiler chickens. With this short-term feeding trial we were not able to show differences in the Fe-status of broilers. Nevertheless, the increase in relative amounts of bifidobacteria and lactobacilli in the presence of wheat prebiotics is an important finding as these bacterial populations may affect Fe bioavailability in long-term studies.

An update on Curcuma as a functional food in the control of cancer and inflammation.

PubMed

Schaffer, Moshe; Schaffer, Pamela M; Bar-Sela, Gil

2015-11-01

Curcumin, commonly known as turmeric, is a spice that comes from the root Curcuma longa. The present article presents an update of new studies of curcumin activities as tested in anticancer models from 2011 to 2015. Evidence from in-vitro and in-vivo research, together with clinical trials conducted over the past few decades, substantiates the potential of curcumin as an anticancer and anti-inflammatory agent. The development of formulations of curcumin in the form of nanoparticles, liposomes, micelles, or phospholipid complexes to enhance its bioavailability and efficacy are still in the early stages. Clinical trials with curcumin indicate safety, tolerability, and nontoxicity. However, the efficacy is questionable, based on the small numbers of patients in each study. The laboratory and the clinical studies until 2011 were summarized in a review published in this journal. An update of the new studies and knowledge from 2011 to March 2015 focuses on new ways to overcome its low bioavailability and data from clinical trials.

Isolation and determination of ivermectin in post-mortem and in vivo tissues of dung beetles using a continuous solid phase extraction method followed by LC-ESI+-MS/MS

PubMed Central

Ortiz, Antonio J.; Cortez, Vieyle; Azzouz, Abdelmonaim

2017-01-01

A new analytical method based on solvent extraction, followed by continuous solid-phase extraction (SPE) clean-up using a polymeric sorbent, was demonstrated to be applicable for the detection of ivermectin in complex biological matrices of dung beetles (hemolymph, excreta or dry tissues) using liquid chromatography combined with positive electrospray ionization tandem mass spectrometry (LC/ESI+–MS/MS). Using a signal-to-noise ratio of 3:1, the limit of detection (LOD) in the insect matrices at trace levels was 0.01 ng g–1 and the limit of quantification (LOQ) was 0.1 ng g–1. The proposed method was successfully used to quantitatively determine the levels of ivermectin in the analysis of small samples in in vivo and post mortem samples, demonstrating the usefulness for quantitative analyses that are focused on future pharmacokinetic and bioavailability studies in insects and the establishment of a new protocol to study the impact of ivermectin on non-target arthropods such as dung beetles and other insects that are related with the “dung community”. Because satisfactory precision and accuracy values were obtained in both in vivo matrices, we suggest that the method can be consistently used for quantitative determinations that are focused on future pharmacokinetic and bioavailability studies in insects. Furthermore, this new analytical method was successfully applied to biological samples of dead dung beetles from the field suggesting that the method can be used to establish a new routine analysis of ivermectin residues in insect carcasses that is applied to complement typical mortality tests. PMID:28207908

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.

Supersaturation of Calcipotriene and Betamethasone Dipropionate in a Novel Aerosol Foam Formulation for Topical Treatment of Psoriasis Provides Enhanced Bioavailability of the Active Ingredients.

PubMed

Lind, Marianne; Nielsen, Kim Troensegaard; Schefe, Line Hollesen; Nørremark, Kasper; Eriksson, André Huss; Norsgaard, Hanne; Pedersen, Brian Thoning; Petersson, Karsten

2016-09-01

Previous studies have demonstrated the superior efficacy of a novel aerosol foam formulation of fixed combination calcipotriene 0.005% (Cal) and betamethasone dipropionate 0.064% (BD), compared with the ointment formulation. The aim of this study is to ascertain whether enhanced bioavailability of the active ingredients due to supersaturation and/or occlusive properties can explain the observed greater clinical efficacy. Solubility and evaporation experiments were conducted to examine the abilities of Cal/BD aerosol foam ingredients to create a supersaturated environment. Optical microscopy, Raman imaging and X-ray powder diffraction were used to examine the physical state of Cal and BD in the formulations after application, and determine whether a supersaturated state remained stable for clinically relevant time periods. In vitro skin penetration and ex vivo biomarker assays were conducted to compare the skin penetration and bioavailability of Cal and BD from the aerosol foam and ointment formulations, respectively. Occlusive properties were examined via transepidermal water loss. Solubility studies showed that Cal and BD solubility increased with increasing dimethyl ether (DME) content. Both active ingredients are completely dissolved in the final aerosol foam formulation. DME rapidly evaporates after spraying, and the amount was reduced to 0.5% of the initial amount after 2 min. This led to the formation of a supersaturated environment, where Cal and BD crystals were absent for at least 26 h after application. Cal/BD aerosol foam had significantly greater in vitro skin penetration and had increased bioavailability compared with Cal/BD ointment. Both formulations effectively occluded the skin. A stable supersaturated solution of Cal/BD in the aerosol foam leads to increased bioavailability and explains the improved clinical effect when compared to the Cal/BD ointment. The studies included in the paper are all conducted by LEO Pharma A/S or CROs on behalf of LEO Pharma A/S.

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity

PubMed Central

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M.

2016-01-01

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (SC) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. The ease and efficiency of double-click helix stabilization chemistries is a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control SC absorption and clearance rates to customize plasma pharmacokinetics. PMID:27327034

Discovery of an Orally Bioavailable Gonadotropin-Releasing Hormone Receptor Antagonist.

PubMed

Kim, Seon-Mi; Lee, Minhee; Lee, So Young; Park, Euisun; Lee, Soo-Min; Kim, Eun Jeong; Han, Min Young; Yoo, Taekyung; Ann, Jihyae; Yoon, Suyoung; Lee, Jiyoun; Lee, Jeewoo

2016-10-13

We developed a compound library for orally available gonadotropin-releasing hormone (GnRH) receptor antagonists that were based on a uracil scaffold. On the basis of in vitro activity and CYP inhibition profile, we selected 18a (SKI2496) for further in vivo studies. Compound 18a exhibited more selective antagonistic activity toward the human GnRH receptors over the GnRHRs in monkeys and rats, and this compound also showed inhibitory effects on GnRH-mediated signaling pathways. Pharmacokinetic and pharmacodynamic evaluations of 18a revealed improved bioavailability and superior gonadotropic suppression activity compared with Elagolix, the most clinically advanced compound. Considering that 18a exhibited highly potent and selective antagonistic activity toward the hGnRHRs along with favorable pharmacokinetic profiles, we believe that 18a may represent a promising candidate for an orally available hormonal therapy.

Therapeutic modulation of cannabinoid lipid signaling: metabolic profiling of a novel antinociceptive cannabinoid-2 receptor agonist

PubMed Central

Wood, JodiAnne T.; Smith, Dustin M.; Janero, David R.; Zvonok, Alexander M.; Makriyannis, Alexandros

2012-01-01

Aims AM-1241, a novel, racemic cannabinoid-2 receptor (CB2) ligand, is the primary experimental agonist used to characterize the role of CB2-mediated lipid signaling in health and disease, including substance abuse disorders. In vivo pharmacological effects have been used as indirect proxies for AM-1241 biotransformation processes that could modulate activity. We report the initial pre-clinical characterization of AM-1241 biotransformation and in vivo distribution. Main methods AM-1241 metabolism was characterized in a variety of predictive in vitro systems (Caco-2 cells, mouse, rat and human microsomes) and in the mouse in vivo. Liquid chromatography and mass spectrometry techniques were used to quantify AM-1241 tissue distribution and metabolic conversion. Key findings AM-1241 bound extensively to plasma protein/albumin. A pharmacological AM-1241 dose (25 mg/kg, i.v.) was administered to mice for direct determination of its plasma half-life (37 min), following which AM-1241 was quantified in brain, spleen, liver, and kidney. After p.o. administration, AM-1241 was detected in plasma, spleen, and kidney; its oral bioavailability was ~21%. From Caco-2 permeability studies and microsomal-based hepatic clearance estimates, in vivo AM-1241 absorption was moderate. Hepatic microsomal metabolism of AM-1241 in vitro generated hydroxylation and demethylation metabolites. Species-dependent differences were discovered in AM-1241’s predicted hepatic clearance. Our data demonstrate that AM-1241 has the following characteristics: a) short plasma half-life; b) limited oral bioavailability; c) extensive plasma/albumin binding; d) metabolic substrate for hepatic hydroxylation and demethylation; e) moderate hepatic clearance. Significance These results should help inform the design, optimization, and pre-clinical profiling of CB2 ligands as pharmacological tools and medicines. PMID:22749867

Pharmacokinetics of Curcumin Diethyl Disuccinate, a Prodrug of Curcumin, in Wistar Rats.

PubMed

Bangphumi, Kunan; Kittiviriyakul, Chuleeporn; Towiwat, Pasarapa; Rojsitthisak, Pornchai; Khemawoot, Phisit

2016-12-01

Curcumin is the major bioactive component of turmeric, but has poor oral bioavailability that limits its clinical applications. To improve the in vitro solubility and alkaline stability, we developed a prodrug of curcumin by succinylation to obtain curcumin diethyl disuccinate, with the goal of improving the oral bioavailability of curcumin. The in vivo pharmacokinetic profile of curcumin diethyl disuccinate was compared with that of curcumin in male Wistar rats. Doses of curcumin 20 mg/kg intravenous or 40 mg/kg oral were used as standard regimens for comparison with the prodrug at equivalent doses in healthy adult rats. Blood, tissues, urine, and faeces were collected from time zero to 48 h after dosing to determine the prodrug level, curcumin level and a major metabolite by liquid chromatography-tandem spectrometry. The absolute oral bioavailability of curcumin diethyl disuccinate was not significantly improved compared with curcumin, with both compounds having oral bioavailability of curcumin less than 1 %. The major metabolic pathway of the prodrug was rapid hydrolysis to obtain curcumin, followed by glucuronidation. Interestingly, curcumin diethyl disuccinate gave superior tissue distribution with higher tissue to plasma ratio of curcumin and curcumin glucuronide in several organs after intravenous dosing at 1 and 4 h. The primary elimination route of curcumin glucuronide occurred via biliary and faecal excretion, with evidence of an entry into the enterohepatic circulation. Curcumin diethyl disuccinate did not significantly improve the oral bioavailability of curcumin due to first pass metabolism in the gastrointestinal tract. Further studies on reduction of first pass metabolism are required to optimise delivery of curcumin using a prodrug approach.

Rumen Microorganisms Decrease Bioavailability of Inorganic Selenium Supplements.

PubMed

Galbraith, M L; Vorachek, W R; Estill, C T; Whanger, P D; Bobe, G; Davis, T Z; Hall, J A

2016-06-01

Despite the availability of selenium (Se)-enriched trace mineral supplements, we have observed low Se status in cattle and sheep offered traditional inorganic Se supplements. Reasons for this may include inadequate intake or low bioavailability of inorganic Se sources. The objective of this study was to determine whether rumen microorganisms (RMO) alter the bioavailability of Se sources commonly used in Se supplements. Rumen microorganisms were isolated from ewes (n = 4) and incubated ex vivo with no Se (control), with inorganic Na selenite or Na selenate, or with organic selenomethionine (SeMet). Total Se incorporated into RMO and the amount of elemental Se formed were determined under equivalent conditions. Incorporation of Se from Na selenite, Na selenate, or SeMet into RMO was measured as fold change compared with control (no added Se). Incorporation of Se into microbial mass was greater for SeMet (13.2-fold greater than no-Se control) compared with inorganic Se supplements (P = 0.02); no differences were observed between inorganic Na selenate (3.3-fold greater than no-Se control) and Na selenite (3.5-fold greater than no-Se control; P = 0.97). Formation of non-bioavailable, elemental Se was less for RMO incubated with SeMet compared with inorganic Se sources (P = 0.01); no differences were observed between Na selenate and Na selenite (P = 0.09). The clinical importance of these results is that the oral bioavailability of organic SeMet should be greater compared with inorganic Se sources because of greater RMO incorporation of Se and decreased formation of elemental Se by RMO.

Resveratrol-sulfates provide an intracellular reservoir for generation of parent resveratrol, which induces autophagy in cancer cells.

PubMed

Andreadi, Catherine; Britton, Robert G; Patel, Ketan R; Brown, Karen

2014-03-01

Resveratrol has many proposed health benefits, including the prevention of cancers, but its low bioavailability is considered a limiting factor in translating these effects to humans. Based on in vivo and clinical studies we have shown that resveratrol is indeed rapidly metabolized by phase II enzymes, and that resveratrol sulfates are deconjugated by steroid sulfatases to afford free resveratrol in vitro and in vivo and hence act as an intracellular reservoir for resveratrol. Further, we have demonstrated that at clinically achievable concentrations of resveratrol sulfate, parent resveratrol is regenerated within human colorectal cancer, but not normal epithelial cells, and is responsible for inducing autophagy with senescence selectively in cancer cells.

[Silica-coated ethosome as a novel oral delivery system for enhanced oral bioavailability of curcumin].

PubMed

Li, Chong; Deng, Li; Zhang, Yan; Su, Ting-Ting; Jiang, Yin; Chen, Zhang-Bao

2012-11-01

The aim of this study is to investigate the feasibility of silica-coated ethosome as a novel oral delivery system for the poorly water-soluble curcumin (as a model drug). The silica-coated ethosomes loading curcumin (CU-SE) were prepared by alcohol injection method with homogenization, followed by the precipitation of silica by sol-gel process. The physical and chemical features of CU-SEs, and curcumin release were determined in vitro. The pharmacodynamics and bioavailability measurements were sequentially performed. The mean diameter of CU-SE was (478.5 +/- 80.3) nm and the polydispersity index was 0.285 +/- 0.042, while the mean value of apparent drug entrapment efficiency was 80.77%. In vitro assays demonstrated that CU-SEs were significantly stable with improved release properties when compared with curcumin-loaded ethosomes (CU-ETs) without silica-coatings. The bioavailability of CU-SEs and CU-ETs was 11.86- and 5.25-fold higher, respectively, than that of curcumin suspensions (CU-SUs) in in vivo assays. The silica coatings significantly promoted the stability of ethosomes and CU-SEs exhibited 2.26-fold increase in bioavailablity relative to CU-ETs, indicating that the silica-coated ethosomes might be a potential approach for oral delivery of poorly water-soluble drugs especially the active ingredients of traditional Chinese medicine with improved bioavailability.

Determination of the potential bioavailability of plant microRNAs using a simulated human digestion process.

PubMed

Philip, Anna; Ferro, Valerie A; Tate, Rothwelle J

2015-10-01

The "dietary xenomiR hypothesis" proposes that microRNAs (miRNAs) in foodstuffs survive transit through the mammalian gastrointestinal tract and pass into cells intact to affect gene regulation. However, debate continues as to whether dietary intake poses a feasible route for such exogenous gene regulators. Understanding on miRNA levels during pretreatments of human diet is essential to test their bioavailability during digestion. This study makes the novel first use of an in vitro method to eliminate the inherent complexities and variability of in vivo approaches used to test this hypothesis. Plant miRNA levels in soybean and rice were measured during storage, processing, cooking, and early digestion using real-time PCR. We have demonstrated for the first time that storage, processing, and cooking does not abolish the plant miRNAs present in the foodstuffs. In addition, utilizing a simulated human digestion system revealed significant plant miRNA bioavailability after early stage digestion for 75 min. Attenuation of plant messenger RNA and synthetic miRNA was observed under these conditions. Even after an extensive pretreatment, plant-derived miRNA, delivered by typical dietary ingestion, has a robustness that could make them bioavailable for uptake during early digestion. The potential benefit of these regulatory molecules in pharma nutrition could be explored further. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Oral Bioavailability of Trans-Resveratrol from a Grapevine-Shoot Extract in Healthy Humans is Significantly Increased by Micellar Solubilization.

PubMed

Calvo-Castro, Laura A; Schiborr, Christina; David, Franziska; Ehrt, Heidi; Voggel, Jenny; Sus, Nadine; Behnam, Dariush; Bosy-Westphal, Anja; Frank, Jan

2018-05-01

Grapevine-shoot extract Vineatrol30 contains abundant resveratrol monomers and oligomers with health-promoting potential. However, the oral bioavailability of these compounds in humans is low (˂1-2%). The aim of this study was to improve the oral bioavailability of resveratrol from vineatrol by micellar solubilization. Twelve healthy volunteers (six women, six men) randomly ingested a single dose of 500 mg vineatrol (30 mg trans-resveratrol, 75 mg trans-ε-viniferin) as native powder or liquid micelles. Plasma and urine were collected at baseline and over 24 h after intake. Resveratrol and viniferin were analyzed by HPLC. The area under the plasma concentration-time curve (AUC) and mean maximum plasma trans-resveratrol concentrations were 5.0-fold and 10.6-fold higher, respectively, after micellar supplementation relative to the native powder. However, no detectable amounts of trans-ε-viniferin were found in either plasma or urine. The transepithelial permeability of trans-resveratrol and trans-ε-viniferin across differentiated Caco-2 monolayers was consistent to the absorbed fractions in vivo. The oral bioavailability of trans-resveratrol from the grapevine-shoot extract Vineatrol30 was significantly increased using a liquid micellar formulation, without any treatment-related adverse effects, making it a suitable system for improved supplementation of trans-resveratrol. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study.

PubMed

Chen, Ling-Chun; Chen, Ying-Chen; Su, Chia-Yu; Hong, Chung-Shu; Ho, Hsiu-O; Sheu, Ming-Thau

2016-01-01

Quercetin (Que) is known to have biological benefits including an anticancer effect, but low water solubility limits its clinical application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the solubility and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic(®) P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (w/w), was prepared by a thin-film method. The average size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60 ± 5.02 nm, 0.589 ± 0.198, 96.87% ± 9.04%, and 12.18% ± 1.11%, respectively. The solubility of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17-7.7 μg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concentration values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 μM, respectively, indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concentration-time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core-shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its solubility and bioavailability.

Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study

PubMed Central

Chen, Ling-Chun; Chen, Ying-Chen; Su, Chia-Yu; Hong, Chung-Shu; Ho, Hsiu-O; Sheu, Ming-Thau

2016-01-01

Quercetin (Que) is known to have biological benefits including an anticancer effect, but low water solubility limits its clinical application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the solubility and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic® P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (w/w), was prepared by a thin-film method. The average size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60±5.02 nm, 0.589±0.198, 96.87%±9.04%, and 12.18%±1.11%, respectively. The solubility of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17–7.7 μg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concentration values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 μM, respectively, indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concentration–time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core–shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its solubility and bioavailability. PMID:27143878

Synergistic antioxidant action of vitamin E and rutin SNEDDS in ameliorating oxidative stress in a Parkinson’s disease model

NASA Astrophysics Data System (ADS)

Sharma, Shrestha; Narang, Jasjeet K.; Ali, Javed; Baboota, Sanjula

2016-09-01

Purpose. Oxidative stress is the leading cause in the pathogenesis of Parkinson’s disease. Rutin is a naturally occurring strong antioxidant molecule with wide therapeutic applications. It suffers from the problem of low oral bioavailability which is due to its poor aqueous solubility. Methods. In order to increase the solubility self-nanoemulsifying drug delivery systems (SNEDDS) of rutin were prepared. The oil, surfactant and co-surfactant were selected based on solubility/miscibility studies. Optimization was done by a three-factor, four-level (34) Box-Behnken design. The independent factors were oil, surfactant and co-surfactant concentration and the dependent variables were globule size, self-emulsification time, % transmittance and cumulative percentage of drug release. The optimized SNEDDS formulation (RSE6) was evaluated for various release studies. Antioxidant activity was assessed by various in vitro tests such as 2,2-diphenyl-1-picrylhydrazyl and reducing power assay. Oxidative stress models which had Parkinson’s-type symptoms were used to determine the antioxidant potential of rutin SNEDDS in vivo. Permeation was assessed through confocal laser scanning microscopy. Results. An optimized SNEDDS formulation consisting of Sefsol + vitamin E-Solutol HS 15-Transcutol P at proportions of 25:35:17.5 (w/w) was prepared and characterized. The globule size and polydispersity index of the optimized formulation was found to be 16.08 ± 0.02 nm and 0.124 ± 0.01, respectively. A significant (p < 0.05) increase in the percentage of drug release was achieved in the case of the optimized formulation as compared to rutin suspension. Pharmacokinetic study showed a 2.3-fold increase in relative oral bioavailability. The optimized formulation had significant in vitro and in vivo antioxidant activity. Conclusion. Rutin SNEDDS have been successfully prepared and they can serve as an effective tool in enhancing the oral bioavailability and efficacy of rutin, thus helping in ameliorating oxidative stress in neurodegenerative disorders like Parkinson’s disease.

Pterostilbene induces apoptosis through caspase activation in ovarian cancer cells.

PubMed

Dong, J; Guo, H; Chen, Y

2016-01-01

Pterostilbene, an analog of resveratrol increasing bioavailability has shown to offer antioxidant and anticancer properties in vitro and in vivo. Dietary compounds with anti-oxidant properties have been shown to gain importance due to therapeutic applications. In addition, compounds with higher bioavailability levels show great interest in present scenario. Thus, the present study aimed at investigating the cytotoxic role of pterostilbene and its mechanism of cell death in ovarian cancer cells line. The effect of pterostilbene was determined on SKOV-3 cells, by cytotoxicity assays, oxidative stress levels, [Ca2+]i levels, mitochondrial depolarization, cell cycle analysis and caspase 3, 8, and 9 activities. The study revealed that pterostilbene offered cytotoxic effect at a concentration of IC50-55 uM. Further, pterostilbene induced reactive oxygen species (ROS) mediated intrinsic pathway of apoptosis through enhancing oxidative stress, [Ca2+]i levels, mitochondrial depolarization, Sub G1 accumulation, and activation of caspase 3 and 9. The study demonstrates for the first time the cytotoxic potential of pterostilbene against ovarian cancer cells.

Pharmaceutical cocrystals: a novel approach for oral bioavailability enhancement of drugs.

PubMed

Chadha, Renu; Saini, Anupam; Arora, Poonam; Bhandari, Swati

2012-01-01

Solid dosage forms are by far the preferred drug delivery systems. However, these often face the problem of poor and erratic bioavailability during the drug development process. Numerous formulation strategies for drug delivery are currently under development, among which the solid forms such as polymorphs, solvates, salts, and cocrystals have been considered to be the most important for improving dissolution rate and bioavailability. Cocrystallization is a fairly new approach in pharmaceutical industry that can improve the solubility and, consequently, the bioactivity of the active pharmaceutical ingredient (API) without compromising its structural integrity. Pharmaceutical cocrystals have found their place in drug delivery, primarily due to their ability to produce alternative, viable solid forms when a more standard approach of salt and polymorph formation fails to deliver the desired objectives. Over the past few years, a number of papers have been published focusing on a broad range of subjects, from traditional crystal engineering to structure-property relationships of cocrystals. The present review, however, illustrates how the cocrystalline forms of APIs have improved their in vitro dissolution rate and in vivo bioavailability, often correlating well with their improved solubility as well.

Improved oral bioavailability in rats of SR13668, a novel anti-cancer agent

PubMed Central

Green, Carol E.; Swezey, Robert; Bakke, James; Shinn, Walter; Furimsky, Anna; Bejugam, Naveen; Shankar, Gita N.; Jong, Ling; Kapetanovic, Izet M.

2010-01-01

Purpose SR13668, a bis-indole with potent activity in vitro and in vivo against various cancers and promising cancer chemopreventive activity, was found to have very low oral bioavailability, <1%, in rats during pilot pharmacokinetic studies. The objective of these studies was to better understand the source of low oral exposure and to develop a formulation that could be used in preclinical development studies. Methods An automated screening system for determining solubility in lipid-based vehicles, singly and in combination, was used to identify formulations that might enhance absorption by improving solubility of SR13668, and these results were confirmed in vivo using Sprague–Dawley rats. Pharmacokinetics of SR13668 was then determined in male and female Sprague–Dawley rats administered 1 mg/kg iv, 1, 10, and 30 mg/kg po formulated in PEG400:Labrasol® (1:1 v/v). Blood was collected at time points through 24 h and the concentration of SR13668 determined using HPLC with UV and fluorescence detection. Results SR13668 was found to be resistant to plasma esterases in vitro and relatively stable to rat and human liver microsomal metabolism. SR13668 concentrates in tissues as indicated by significantly higher levels in lung compared to blood, blood concentrations ~2.5-fold higher than plasma levels, and apparent volume of distribution (V) of ~5 l/kg. A marked sex difference was observed in exposure to SR13668 with area under the curve (AUC) significantly higher and clearance (CL) lower for female compared to male rats, after both iv and oral administration. The oral bioavailability (F) of SR13668 was 25.4 ± 3.8 and 27.7 ± 3.9% (30 mg/kg), for males and females, respectively. A putative metabolite (M1), molecular weight of 445 in the negative ion mode (i.e., SR13668 + 16), was identified in blood samples from both the iv and po routes, as well as in vitro microsomal samples. Conclusions In summary, while SR13668 does undergo metabolism, probably by the liver, the oral bioavailability of SR13668 in rats was dramatically improved by the use of formulation that contained permeation enhancers and promoted better solubilization of the drug. PMID:20623225

Linking Suspension Nasal Spray Drug Deposition Patterns to Pharmacokinetic Profiles: A Proof-of-Concept Study Using Computational Fluid Dynamics.

PubMed

Rygg, Alex; Hindle, Michael; Longest, P Worth

2016-06-01

The objective of this study was to link regional nasal spray deposition patterns of suspension formulations, predicted with computational fluid dynamics, to in vivo human pharmacokinetic plasma concentration profiles. This is accomplished through the use of computational fluid dynamics simulations coupled with compartmental pharmacokinetic modeling. Results showed a rapid initial rise in plasma concentration that is due to the absorption of drug particles deposited in the nasal middle passages, followed by a slower increase in plasma concentration that is governed by the transport of drug particles from the nasal vestibule to the middle passages. Although drug deposition locations in the nasal cavity had a significant effect on the shape of the concentration profile, the absolute bioavailability remained constant provided that all the drug remained in the nose over the course of the simulation. Loss of drug through the nostrils even after long periods resulted in a significant decrease in bioavailability and increased variability. The results of this study quantify how differences in nasal drug deposition affect transient plasma concentrations and overall bioavailability. These findings are potentially useful for establishing bioequivalence for nasal spray devices and reducing the burden of in vitro testing, pharmacodynamics, and clinical studies. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Solution or suspension - Does it matter for lipid based systems? In vivo studies of chase dosing lipid vehicles with aqueous suspensions of a poorly soluble drug.

PubMed

Larsen, A T; Holm, R; Müllertz, A

2017-08-01

In this study, the potential of co-administering an aqueous suspension with a placebo lipid vehicle, i.e. chase dosing, was investigated in rats relative to the aqueous suspension alone or a solution of the drug in the lipid vehicle. The lipid investigated in the present study was Labrafil M2125CS and three evaluated poorly soluble model compounds, danazol, cinnarizine and halofantrine. For cinnarizine and danazol the oral bioavailability in rats after chase dosing or dosing the compound dissolved in Labrafil M21515CS was similar and significantly higher than for the aqueous suspension. For halofantrine the chase dosed group had a tendency towards a low bioavailability relative to the Labrafil M2125CS solution, but still a significant higher bioavailability relative to the aqueous suspension. This could be due to factors such as a slower dissolution rate in the intestinal phase of halofantrine or a lower solubility in the colloidal structures formed during digestion, but other mechanisms may also be involved. The study thereby supported the potential of chase dosing as a potential dosing regimen in situations where it is beneficial to have a drug in the solid state, e.g. due to chemical stability issues in the lipid vehicle. Copyright © 2017 Elsevier B.V. All rights reserved.

A selenium-deficient Caco-2 cell model for assessing differential incorporation of chemical or food selenium into glutathione peroxidase.

PubMed

Zeng, Huawei; Botnen, James H; Johnson, Luann K

2008-01-01

Assessing the ability of a selenium (Se) sample to induce cellular glutathione peroxidase (GPx) activity in Se-deficient animals is the most commonly used method to determine Se bioavailability. Our goal is to establish a Se-deficient cell culture model with differential incorporation of Se chemical forms into GPx, which may complement the in vivo studies. In the present study, we developed a Se-deficient Caco-2 cell model with a serum gradual reduction method. It is well recognized that selenomethionine (SeMet) is the major nutritional source of Se; therefore, SeMet, selenite, or methylselenocysteine (SeMSC) was added to cell culture media with different concentrations and treatment time points. We found that selenite and SeMSC induced GPx more rapidly than SeMet. However, SeMet was better retained as it is incorporated into proteins in place of methionine; compared with 8-, 24-, or 48-h treatment, 72-h Se treatment was a more sensitive time point to measure the potential of GPx induction in all tested concentrations. Based on induction of GPx activity, the cellular bioavailability of Se from an extract of selenobroccoli after a simulated gastrointestinal digestion was comparable with that of SeMSC and SeMet. These in vitro data are, for the first time, consistent with previous published data regarding selenite and SeMet bioavailability in animal models and Se chemical speciation studies with broccoli. Thus, Se-deficient Caco-2 cell model with differential incorporation of chemical or food forms of Se into GPx provides a new tool to study the cellular mechanisms of Se bioavailability.

Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition.

PubMed

Athukuri, Bhargavi Latha; Neerati, Prasad

2016-12-01

Cytochrome P450-2D6 (CYP2D6), a member of the CYP450 mixed function oxidase system, is an important CYP isoform with regard to herbal-drug interactions and is responsible for the metabolism of nearly 25% of drugs. Until now, studies on the effects of various phytochemicals on CYP2D6 activity in vivo have been very rare. Gallic acid and ellagic acid are natural polyphenols which are widely distributed in fruits and medicinal plants. In the present study, the effects of gallic acid and ellagic acid pretreatment on intestinal transport and oral bioavailability of metoprolol were investigated. The intestinal transport of metoprolol was assessed by conducting an in situ single pass intestinal perfusion (SPIP) study. The bioavailability study was conducted to evaluate the pharmacokinetic parameters of orally administered metoprolol in rats. After pretreatment with gallic acid and ellagic acid, no significant change in effective permeability of metoprolol was observed at the ileum part of rat intestine. A significant improvement in the peak plasma concentration (Cmax) and area under the serum concentration-time profile (AUC) and decrease in clearance were observed in rats pretreated with gallic acid and ellagic acid. Gallic acid and ellagic acid significantly enhanced the oral bioavailability of metoprolol by inhibiting CYP2D6-mediated metabolism in the rat liver. Hence, adverse herbal-drug interactions may result with concomitant ingestion of gallic acid and ellagic acid supplements and drugs that are CYP2D6 substrates. The clinical assessment of these interactions should be further investigated in human volunteers.

Pharmacological attempts to improve the bioavailability of oral etoposide.

PubMed

Joel, S P; Clark, P I; Heap, L; Webster, L; Robbins, S; Craft, H; Slevin, M L

1995-01-01

Etoposide demonstrates incomplete and variable bioavailability after oral dosing, which may be due to its concentration and pH-dependent stability in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a number of clinical studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absorption, did not significantly alter the etoposide area under the concentration-time curve (AUC) or bioavailability. Specifically, metoclopramide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4 +/- 20.3 micrograms ml-1 h, versus 74.3 +/- 25.9 micrograms ml-1 h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effect on etoposide absorption, delaying the time of maximal concentration tmax from 1.1 to 3.5 h (P < 0.01), but again without a significant improvement in drug AUC or bioavailability across the 24-h study period (AUC with etoposide alone 78.3 +/- 19.1 micrograms ml-1 h, versus 88.1 +/- 23.6 micrograms ml-1 h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for etoposide, with no change in AUC being observed after metoclopramide or propantheline administration but a significant delay in tmax being seen on co-administration with etoposide and propantheline. The co-administration of ethanol or bile salts (agents that significantly improved the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or reducing the variability in AUC, suggesting that drug stability in vivo was not affected by these agents. In the third study the co-administration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that etoposide stability was markedly improved at pH 3-5 as compared with pH 1 in artificial gastric fluid. This series of studies, designed to investigate factors that improved etoposide stability in laboratory studies, failed to demonstrate any potentially useful improvement in AUC or bioavailability in the clinical setting.

Development and characterisation of levosulpiride-loaded suppositories with improved bioavailability in vivo.

PubMed

Fakhar-Ud-Din; Khan, Gul Majid

2017-12-28

The purpose of this study was to develop and characterize levosulpiride loaded liquid suppository with improved bioavailability. The content of levosulpiride-loaded liquid suppositories were optimized in a series of experiments using various weight ratios of P188, P407, Tween 80, and drug. The suppositories were liquid at room temperature, however, when rectally administered, they became gel at body temperature. Their rheological properties and release characteristics were determined in vitro while pharmacokinetic study was performed after its rectal administration in rats and compared with drug suspension. Poloxamer 188 and Twee 80 decreased the gelation temperature and gelation time, but increased the gel strength and mucoadhesive force of liquid suppositories. Liquid suppository composed of [Levosulpiride/P 188/P 407/Tween 80 (1/15/17/3%)] with a gelation temperature of about 30.7 °C remained liquid at 25 °C, but converted to gel at 30-36.5 °C, resulting in easy administration and rapid gelation inside the body. This liquid suppository gave a considerably increased dissolution rate reflected in a meaningfully higher plasma concentration and 7.1-fold AUC values of levosulpiride in rats as compared to the drug suspension. Hence, liquid suppository system could be used for enhanced bioavailability of levosulpiride-loaded pharmaceutical products.

Systematic Approach for the Formulation and Optimization of Solid Lipid Nanoparticles of Efavirenz by High Pressure Homogenization Using Design of Experiments for Brain Targeting and Enhanced Bioavailability

PubMed Central

Gupta, Shweta; Kesarla, Rajesh; Chotai, Narendra; Misra, Ambikanandan

2017-01-01

The nonnucleoside reverse transcriptase inhibitors, used for the treatment of HIV infections, are reported to have low bioavailability pertaining to high first-pass metabolism, high protein binding, and enzymatic metabolism. They also show low permeability across blood brain barrier. The CNS is reported to be the most important HIV reservoir site. In the present study, solid lipid nanoparticles of efavirenz were prepared with the objective of providing increased permeability and protection of drug due to biocompatible lipidic content and nanoscale size and thus developing formulation having potential for enhanced bioavailability and brain targeting. Solid lipid nanoparticles were prepared by high pressure homogenization technique using a systematic approach of design of experiments (DoE) and evaluated for particle size, polydispersity index, zeta potential, and entrapment efficiency. Particles of average size 108.5 nm having PDI of 0.172 with 64.9% entrapment efficiency were produced. Zeta potential was found to be −21.2 mV and the formulation was found stable. The in-vivo pharmacokinetic studies revealed increased concentration of the drug in brain, as desired, when administered through intranasal route indicating its potential for an attempt towards complete eradication of HIV and cure of HIV-infected patients. PMID:28243600

Development and in-vivo assessment of the bioavailability of oridonin solid dispersions by the gas anti-solvent technique.

PubMed

Li, Songming; Liu, Ying; Liu, Tao; Zhao, Ling; Zhao, Jihui; Feng, Nianping

2011-06-15

We developed solid dispersions, using the gas anti-solvent technique (GAS), to improve the oral bioavailability of the poorly water-soluble active component oridonin. The solubility of oridonin in supercritical carbon dioxide was measured under various pressures and temperatures. To prepare oridonin solid dispersions using the GAS technique, ethanol was used as the solvent, CO(2) was used as the anti-solvent and the hydrophilic polymer polyvinylpyrrolidone K17 (PVP K17) was used as the drug carrier matrix. Characterization of the obtained preparations was undertaken using scanning electron microscopy (SEM), X-ray diffraction (XRD) analyses and a drug release study. Oridonin solid dispersions were formed and oridonin was present in an amorphous form in these dispersions. Oridonin solid dispersions significantly increased the drug dissolution rate compared with that of oridonin powder, primarily through drug amorphization. Compared with the physical mixture of oridonin and PVP K17, oridonin solid dispersions gave higher values of AUC and C(max), and the absorption of oridonin from solid dispersions resulted in 26.4-fold improvement in bioavailability. The present study illustrated the feasibility of applying the GAS technique to prepare oridonin solid dispersions, and of using them for the delivery of oridonin via the oral route. Copyright © 2011 Elsevier B.V. All rights reserved.

Integration of Dosimetry, Exposure and High-Throughput Screening Data in Chemical Toxicity Assessment

EPA Science Inventory

High-throughput in vitro toxicity screening can provide an efficient way to identify potential biological targets for chemicals. However, relying on nominal assay concentrations may misrepresent potential in vivo effects of these chemicals due to differences in bioavailability, c...

Factors influencing micronutrient bioavailability in biofortified crops.

PubMed

Bechoff, Aurélie; Dhuique-Mayer, Claudie

2017-02-01

Dietary and human factors have been found to be the major factors influencing the bioavailability of micronutrients, such as provitamin A carotenoid (pVAC), iron, and zinc, in biofortified crops. Dietary factors are related to food matrix structure and composition. Processing can improve pVAC bioavailability by disrupting the food matrix but can also result in carotenoid losses. By degrading antinutrients, such as phytate, processing can also enhance mineral bioavailability. In in vivo interventions, biofortified crops have been shown to be overall efficacious in reducing micronutrient deficiency, with bioconversion factors varying between 2.3:1 and 10.4:1 for trans-β-carotene and amounts of iron and zinc absorbed varying between 0.7 and 1.1 mg/day and 1.1 and 2.1 mg/day, respectively. Micronutrient bioavailability was dependent on the crop type and the presence of fat for pVACs and on antinutrients for minerals. In addition to dietary factors, human factors, such as inflammation and disease, can affect micronutrient status. Understanding the interactions between micronutrients is also essential, for example, the synergic effect of iron and pVACs or the competitive effect of iron and zinc. Future efficacy trials should consider human status and genetic polymorphisms linked to interindividual variations. © 2016 New York Academy of Sciences.

Impact of physiological, physicochemical and biopharmaceutical factors in absorption and metabolism mechanisms on the drug oral bioavailability of rats and humans.

PubMed

Hurst, Susan; Loi, Cho-Ming; Brodfuehrer, Joanne; El-Kattan, Ayman

2007-08-01

The onset, intensity and duration of therapeutic response to a compound depend on the intrinsic pharmacological activity of the drug and pharmacokinetic factors related to its absorption, distribution, metabolism and elimination that are inherent to the biological system. The process of drug transfer from the site of administration to the systemic circulation and the interspecies factors that impact this process are the scope of this review. In general, the factors that influence oral drug bioavailability via absorption and metabolism can be divided into physicochemical/biopharmaceutical and physiological factors. Physicochemical and biopharmaceutical factors that influence permeability and solubility tend to be species independent. Although there are significant differences in the anatomy and physiology of the gastrointestinal tract, these are not associated with significant differences in the rate and extent of drug absorption between rats and humans. However, species differences in drug metabolism in rats and humans did result in significant species differences in bioavailability. Overall, this review provides a better understanding of the interplay between drug physicochemical/biopharmaceutical factors and species differences/similarities in the absorption and metabolism mechanisms that affect oral bioavailability in rats and humans. This will enable a more rational approach to perform projection of oral bioavailability in human using available rat in vivo data.

Effect of polacrilin potassium as disintegrant on bioavailability of diclofenac potassium in tablets : a technical note.

PubMed

Bele, Mrudula H; Derle, Diliprao V

2012-09-01

Polacrilin potassium is an ion exchange resin used in oral pharmaceutical formulations as a tablet disintegrant. It is a weakly acidic cation exchange resin. Chemically, it is a partial potassium salt of a copolymer of methacrylic acid with divinyl benzene. It ionizes to an anionic polymer chain and potassium cations. It was hypothesized that polacrilin potassium may be able to improve the permeability of anionic drugs according to the Donnan membrane phenomenon. The effect of polacrilin potassium on the permeability of diclofenac potassium, used as a model anionic drug, was tested in vitro using diffusion cells and in vivo by monitoring serum levels in rats. The amount of drug permeated across a dialysis membrane in vitro was significantly more in the presence of polacrilin potassium. Significant improvement was found in the extent of drug absorption in vivo. It could be concluded that polacrilin potassium may be used as a high-functionality excipient for improving the bioavailability of anionic drugs having poor gastrointestinal permeability.

Application of a radiotelemetric system to evaluate the performance of enteric coated and plain aspirin tablets.

PubMed

Lui, C Y; Oberle, R; Fleisher, D; Amidon, G L

1986-05-01

The bioavailability of enteric coated and plain aspirin tablets was studied in four beagle dogs. Blood sampling for enteric coated tablets was planned with the aid of a radiotelemetric system. The release of aspirin from its dosage form was detected by monitoring the change in intestinal pH. Aspirin and salicylic acid levels in plasma obtained from the enteric coated dosage form exhibited familiar concentration versus time absorption profiles. Variation in the plasma concentrations of these two compounds within each dog studied (four runs each) was relatively small when time zero was adjusted to the commencement of tablet dissolution. The plasma levels obtained from plain aspirin (three runs each), however, show atypical absorption. The estimated absolute bioavailability was 0.432 +/- 0.0213 and 0.527 +/- 0.0260 for enteric coated and plain aspirin, respectively. Other pharmacokinetic parameters for these two dosage forms such as the highest observed plasma concentration (Cmax) (10.9 +/- 0.535 microgram/mL versus 13.6 +/- 1.88 micrograms/mL) and the time to reach Cmax (tmax) (26.6 +/- 1.94 min versus 31.0 +/- 7.04 min) agree well. The mean values for gastric emptying time, in vivo coating dissolution time, and in vivo disintegration/dissolution time of the tablet core for enteric coated aspirin are 48.7 +/- 7.23 min, 44.3 +/- 3.80 min, and 34.7 +/- 2.04 min, respectively.

Composition, Stability, and Bioavailability of Garlic Products Being Used in a Clinical Trial

PubMed Central

Lawson, Larry D.; Gardner, Christopher D.

2008-01-01

In support of a new clinical trial designed to compare the effects of crushed fresh garlic and two types of garlic supplement tablets (enteric-coated dried fresh garlic and dried aged garlic extract) on serum lipids, the three garlic products have been characterized for (a) composition (14 sulfur and 2 non-sulfur compounds), (b) stability of suspected active compounds, and (c) availability of allyl thiosulfinates (mainly allicin) under both simulated gastrointestinal (tablet dissolution) conditions and in vivo. The allyl thiosulfinates of blended fresh garlic were stable for at least two years when stored at −80 °C. The dissolution release of thiosulfinates from the enteric-coated garlic tablets was found to be >95%. The bioavailability of allyl thiosulfinates from these tablets, measured as breath allyl methyl sulfide, was found to be complete and equivalent to that of crushed fresh garlic. S-allylcysteine was stable for 12 months at ambient temperature. The stability of the suspected active compounds under the conditions of the study and the bioavailability of allyl thiosulfinates from the dried garlic supplement have validated the use of these preparations for comparison in a clinical trial. PMID:16076102

Characterization and evaluation of an oral microemulsion containing the antitumor diterpenoid compound ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid

PubMed Central

Lu, Yingnian; Wu, Kefeng; Li, Li; He, Yuhui; Cui, Liao; Liang, Nianci; Mu, Bozhong

2013-01-01

The objective of this study was to develop an oral microemulsion formulation of the antitumor diterpenoid agent, ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (henceforth referred to as 5F), to enhance its bioavailability and evaluate its hepatotoxicity. Pseudoternary phase diagrams showed that the optimal microemulsion formulation contained 45% water, 10% castor oil as the oil phase, 15% Cremophor EL as the surfactant, and 30% as a cosurfactant mixture of 1,2-propanediol and polyethylene glycol (PEG)-400 (2:1, w/w). The microemulsion preparation was characterized and its droplet diameter was within 50 nm. Release of 5F in vitro from the microemulsion was slightly increased compared with a suspension containing the same amount of active drug. Pharmacokinetic parameters in vivo indicated that bioavailability was markedly improved, with the relative bioavailability being 616.15% higher for the microemulsion than for the suspension. Toxicity tests showed that the microemulsion had no hepatotoxicity in mice. These results suggest the potential for 5F microemulsion to be administered by the oral route. PMID:23690685

Fabrication and evaluation of valsartan–polymer– surfactant composite nanoparticles by using the supercritical antisolvent process

PubMed Central

Kim, Min-Soo; Baek, In-hwan

2014-01-01

The aim of this study was to fabricate valsartan composite nanoparticles by using the supercritical antisolvent (SAS) process, and to evaluate the correlation between in vitro dissolution and in vivo pharmacokinetic parameters for the poorly water-soluble drug valsartan. Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process. X-ray diffraction and thermal analyses indicated that valsartan was present in an amorphous form within the composite nanoparticles. The in vitro dissolution and oral bioavailability of valsartan were dramatically enhanced by the composite nanoparticles. Valsartan–hydroxypropyl methylcellulose–poloxamer 407 nanoparticles exhibited faster drug release (up to 90% within 10 minutes under all dissolution conditions) and higher oral bioavailability than the raw material, with an approximately 7.2-fold higher maximum plasma concentration. In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency. Therefore, the preparation of composite nanoparticles with valsartan–hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability. PMID:25404856

Gut feedback mechanisms and food intake: a physiological approach to slow carbohydrate bioavailability.

PubMed

Zhang, Genyi; Hasek, Like Y; Lee, Byung-Hoo; Hamaker, Bruce R

2015-04-01

Glycemic carbohydrates in foods are an important macronutrient providing the biological fuel of glucose for a variety of physiological processes. A classification of glycemic carbohydrates into rapidly digestible carbohydrate (RDC) and slowly digestible carbohydrate (SDC) has been used to specify their nutritional quality related to glucose homeostasis that is essential to normal functioning of the brain and critical to life. Although there have been many studies and reviews on slowly digestible starch (SDS) and SDC, the mechanisms of their slow digestion and absorption were mostly investigated from the material side without considering the physiological processes of their in vivo digestion, absorption, and most importantly interactions with other food components and the gastrointestinal tract. In this article, the physiological processes modulating the bioavailability of carbohydrates, specifically the rate and extent of their digestion and absorption as well as the related locations, in a whole food context, will be discussed by focusing on the activities of the gastrointestinal tract including glycolytic enzymes and glucose release, sugar sensing, gut hormones, and neurohormonal negative feedback mechanisms. It is hoped that a deep understanding of these physiological processes will facilitate the development of innovative dietary approaches to achieve desired carbohydrate or glucose bioavailability for improved health.

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.

Highly potent growth hormone secretagogues: hybrids of NN703 and ipamorelin.

PubMed

Hansen, T K; Ankersen, M; Raun, K; Hansen, B S

2001-07-23

A series of NN703 analogues with lysine mimetics combined with naphthyl- or biphenylalanine in the core has been prepared and tested in vitro in a rat pituitary cell based assay and subsequently in vivo in pigs in a single dose at 50 nmol/kg. Re-introduction of certain pharmacophores in the C-terminal of NN703, which were originally removed during optimisation for oral bioavailability, led to unexpectedly potent compounds in vitro as well as in vivo.

Arylimidamide-Azole Combinations against Leishmaniasis

DTIC Science & Technology

2016-09-01

This compound will be selected for further in vivo testing in Q1 of Year 3. 3. Accomplishments: The efficacy of 3 arylimidamide compounds was...of this compound will take place in Q1 of Year 3. 4. IMPACT: The search for an orally bioavailable arylimidamide analogue with efficacy against...macrophage assay2 against L. major. One of the 4 compounds tested, AA2- 160, showed potency in this assay. This compound will be selected for toxicity testing and in vivo efficacy testing in Q1 of Year 3.

Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

PubMed Central

Wang, Piwen; Solorzano, Walter; Diaz, Tanya; Magyar, Clara E.; Henning, Susanne M.; Vadgama, Jaydutt V.

2017-01-01

The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (< 2μM) significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30-50% at 48h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID) mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo, which provides a high promise in its translation to human application. PMID:29062885

Arctigenin inhibits prostate tumor cell growth in vitro and in vivo.

PubMed

Wang, Piwen; Solorzano, Walter; Diaz, Tanya; Magyar, Clara E; Henning, Susanne M; Vadgama, Jaydutt V

2017-06-01

The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa , has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (< 2μM) significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30-50% at 48h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID) mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo , which provides a high promise in its translation to human application.

In Vitro and In Vivo Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs.

PubMed

Tahara, Kohei; Nishikawa, Masahiro; Matsui, Ko; Hisazumi, Koji; Onodera, Risako; Tozuka, Yuichi; Takeuchi, Hirofumi

2016-09-01

The aim of this study was to enhance the dissolution and oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs) using nanoparticle suspensions prepared with a PureNano™ continuous crystallizer (PCC). Nanoparticle suspensions were prepared with a PCC, which is based on microfluidics reaction technology and solvent-antisolvent crystallization. Phenytoin, bezafibrate, flurbiprofen, and miconazole were used as model APIs. These APIs were dissolved in ethanol and precipitated by the addition of water and polyvinyl alcohol. Batch crystallization (BC) using a beaker was also performed to prepare the suspensions. Both PCC and BC formulations were freeze-dried before being characterized in vitro and in vivo. The particle sizes of the nanoparticle suspensions prepared with the PCC were smaller than those prepared by BC. The dissolution rate of each API in vitro significantly increased after crystallization. Reducing the particle size of either the BC or PCC formulation led to increased API flux across Caco-2 cell monolayers. PCC preparations showed higher plasma concentrations after oral administration, demonstrating the advantages of a fast dissolution rate and increased interaction with the gastrointestinal tract owing to the smaller particle size. PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability.

Formulation of Convenient, Easily Scalable, and Efficient Granisetron HCl Intranasal Droppable Gels.

PubMed

Ibrahim, Howida K; Abdel Malak, Nevine S; Abdel Halim, Sally A

2015-06-01

Deacetylated gellan gum and two sodium alginate polymer types were used each at three concentrations in the suitable range for their sol-gel transition. The prepared nine droppable gels were evaluated in vitro, ex vivo through sheep nasal mucosa, as well as in vivo in comparison to drug solution given intravenously and orally at the same dose. The prepared formulas gelled instantaneously in simulated nasal fluid and the obtained gels sustained their shear thinning and thixotropic behavior up to 48 h. Polymer type and concentration had significant effects on the apparent viscosities and the in vitro release profile of granisetron from the prepared gels. The drug release data best fitted a modified Higuchi equation with initial burst and followed Fickian diffusion mechanism. A 0.5% gellan-gum-based formula sustained the in vitro drug release up to 3 h and enhanced the drug permeation without need for an enhancer. The histopatholgical study revealed the safety of the tested formula. Intranasal delivery recorded double the drug bioavailabilty in comparison to the oral route. It had an absolute bioavailability of 0.6539 and the maximum plasma drug concentration reached after 1.5 h. The developed formula could be promising for the management of chemotherapy-induced nausea and vomiting regarding its improved bioavailability, patient acceptability, and ease of production.

Mucoadhesive buccal tablets containing silymarin Eudragit-loaded nanoparticles: formulation, characterisation and ex vivo permeation.

PubMed

El-Nahas, Amira E; Allam, Ahmed N; El-Kamel, Amal H

2017-08-01

Eudragit-loaded silymarin nanoparticles (SNPs) and their formulation into buccal mucoadhesive tablets were investigated to improve the low bioavailability of silymarin through buccal delivery. Characterisation of SNPs and silymarin buccal tablets (SBTs) containing the optimised NPs were performed. Ex vivo permeability of nominated SBTs were assessed using chicken pouch mucosa compared to SNPs and drug suspension followed by histopathological examination. Selected SNPs had a small size (<150 nm), encapsulation effciency (>77%) with drug release of about 90% after 6 h. For STBs, all physicochemical parameters were satisfactory for different polymers used. DSC and FT-IR studies suggested the presence of silymarin in an amorphous state. Ex vivo permeation significantly emphasised the great enhancement of silymarin permeation after NPs formation and much more increase after formulating into BTs relative to the corresponding drug dispersion with confirmed membrane integrity. Incorporation of SNPs into BTs could be an efficient vehicle for delivery of silymarin.

Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity

PubMed Central

2017-01-01

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs. PMID:28968083

Nanoparticulation improves bioavailability of Erlotinib.

PubMed

Yang, Kyung Mi; Shin, In Chul; Park, Joo Won; Kim, Kab-Sig; Kim, Dae Kyong; Park, Kyungmoon; Kim, Kunhong

2017-09-01

Nanoparticulation using fat and supercritical fluid (NUFS TM ) is a drug delivery platform technology enabling efficient and effective formulation of poorly soluble drugs. We performed experiments to examine whether NUFS™ could improve poor bioavailability and reduce fed-fasted bioavailability variances of erlotinib (Ert). NUFS-Ert was prepared using NUFS™ technology; its physical properties were characterized, and drug release was measured. Furthermore, in vitro and in vivo efficacy tests and pharmacokinetic analysis were performed. NUFS-Ert nanoparticles had an average size of 250 nm and were stable for 2 months at 40 °C, 4 °C, and room temperature. The dissolution rate of NUFS-Ert increased in bio-relevant dissolution media. NUFS-Ert was more potent in inhibiting EGF signaling and in suppressing the proliferation of A549, a human non-small cell lung cancer cell line. Furthermore, A549 xenografts in BALB/c nude mice treated with NUFS-Ert regressed more efficiently than those in the mice treated with vehicle or Tarceva ® . In addition, experimental lung metastasis was more efficiently inhibited by NUFS-Ert than by Tarceva ® . The relative bioavailability of NUFS-Ert compared with that of Tarceva ® was 550% and the ratio of the area under the concentration-time curve (AUC) of fed state to the AUC of fasted state was 1.8 for NUFS-Ert and 5.8 for Tarceva ® . NUFS-Ert could improve poor bioavailability and reduce fed-fasted bioavailability variances of Ert. NUFS-Ert was more efficacious than Tarceva ® .

Optimized self nano-emulsifying systems of ezetimibe with enhanced bioavailability potential using long chain and medium chain triglycerides.

PubMed

Bandyopadhyay, Shantanu; Katare, O P; Singh, Bhupinder

2012-12-01

The objective of the current work is to develop systematically optimized self-nanoemulsifying drug delivery systems (SNEDDS) using long chain triglycerides (LCT's) and medium chain triglycerides (MCT's) of ezetimibe employing Formulation by Design (FbD), and evaluate their in vitro and in vivo performance. Equilibrium solubility studies indicated the choice of Maisine 35-1 and Capryol 90 as lipids, and of Labrasol and Tween 80 as emulgents for formulating the LCT and MCT systems, respectively. Ternary phase diagrams were constructed to select the areas of nanoemulsion, and the amounts of lipid (X(1)) and emulgent (X(2)) as the critical factor variables. The SNEDDS were systematically optimized using 3(2) central composite design and the optimized formulations located using overlay plot. TEM studies on reconstituted SNEDDS demonstrated uniform shape and size of globules. The nanometer size range and high negative values of zeta potential depicted non-coalescent nature of the optimized SNEDDS. Thermodynamic studies, cloud point determination and accelerated stability studies ascertained the stability of optimized formulations. In situ perfusion (SPIP) studies in Sprague Dawley (SD) rats construed remarkable enhancement in the absorptivity and permeability parameters of SNEDDS vis-à-vis the conventional marketed product. In vivo pharmacodynamic studies in SD rats indicated significantly superior modification in plasma lipid levels of optimized SNEDDS vis-à-vis marketed product, inclusion complex and pure drug. The studies, therefore, indicate the successful formulation development of self-nanoemulsifying systems with distinctly improved bioavailability potential of ezetimibe. Copyright © 2012 Elsevier B.V. All rights reserved.

Oral administration of amphotericin B nanoparticles: antifungal activity, bioavailability and toxicity in rats.

PubMed

Radwan, Mahasen A; AlQuadeib, Bushra T; Šiller, Lidija; Wright, Matthew C; Horrocks, Benjamin

2017-11-01

Amphotericin B (AMB) is used most commonly in severe systemic life-threatening fungal infections. There is currently an unmet need for an efficacious (AMB) formulation amenable to oral administration with better bioavailability and lower nephrotoxicity. Novel PEGylated polylactic-polyglycolic acid copolymer (PLGA-PEG) nanoparticles (NPs) formulations of AMB were therefore studied for their ability to kill Candida albicans (C. albicans). The antifungal activity of AMB formulations was assessed in C. albicans. Its bioavalability was investigated in nine groups of rats (n = 6). Toxicity was examined by an in vitro blood hemolysis assay, and in vivo nephrotoxicity after single and multiple dosing for a week by blood urea nitrogen (BUN) and plasma creatinine (PCr) measurements. The MIC of AMB loaded to PLGA-PEG NPs against C. albicans was reduced two to threefold compared with free AMB. Novel oral AMB delivery loaded to PLGA-PEG NPs was markedly systemically available compared to Fungizone® in rats. The addition of 2% of GA to the AMB formulation significantly (p < 0.05) improved the bioavailability from 1.5 to 10.5% and the relative bioavailability was > 790% that of Fungizone®. The novel AMB formulations showed minimal toxicity and better efficacy compared to Fungizone®. No nephrotoxicity in rats was detected after a week of multiple dosing of AMB NPs based on BUN and PCr, which remained at normal levels. An oral delivery system of AMB-loaded to PLGA-PEG NPs with better efficacy and minimal toxicity was formulated. The addition of glycyrrhizic acid (GA) to AMB NPs formulation resulted in a significant oral absorption and improved bioavailability in rats.

Comparative preclinical pharmacokinetics study of 3,3′-diindolylmethane formulations: is personalized treatment and targeted chemoprevention in the horizon?

PubMed Central

2013-01-01

Background 3,3′-Diindolylmethane (DIM) is known as an agent of natural origin that provides protection against different cancers due to the broad spectrum of its biological activities in vivo. However, this substance has a very poor biodistribution and absorption in animal tissues. This preclinical trial was conducted to evaluate the pharmacokinetics and bioavailability of various DIM formulations in animal model. Materials and methods The pharmacokinetic parameters of one crystalline DIM formulation and one liquid DIM formulation (oil solution) compared to non-formulated crystalline DIM (control) were tested in 200 rats. The formulations were orally administered to animals by gavage at doses of 200 mg/kg per DIM (crystalline DIM formulation and non-formulated crystalline DIM) and 0.1 mg/kg per DIM (DIM in oil solution). DIM plasma elimination was measured using HPLC method; after that, the area under the curve (AUC), relative bioavailability, and absolute bioavailability were estimated for two formulations in relation to non-formulated crystalline DIM. Results and conclusion The highest bioavailability was achieved by administering liquid DIM (oil solution), containing cod liver oil and polysorbate. The level of DIM in rat blood plasma was about fivefold higher, though the 2,000-fold lower dose was administered compared to crystalline DIM forms. The novel pharmacological DIM substance with high bioavailability may be considered as a promising targeted antitumor chemopreventive agent. It could be used to prevent breast and ovarian cancer development in patients with heterozygous inherited and sporadic BRCA1 gene mutations. Further preclinical and clinical trials are needed to prove this concept. PMID:24325835

Comparison of (-)-epigallocatechin-3-O-gallate (EGCG) and O-methyl EGCG bioavailability in rats.

PubMed

Oritani, Yukihiro; Setoguchi, Yuko; Ito, Ryouichi; Maruki-Uchida, Hiroko; Ichiyanagi, Takashi; Ito, Tatsuhiko

2013-01-01

(-)-Epigallocatechin-3-O-(3-O-methyl)gallate (EGCG3″Me) and (-)-epigallocatechin-3-O-(4-O-methyl)gallate (EGCG4″Me) are O-methyl derivatives of (-)-epigallocatechin-3-O-gallate (EGCG) present in tea cultivars such as Benifuuki. Although O-methyl EGCGs have various bioactivities, their bioavailabilities have not been determined. In this study, we compared the bioavailability of EGCG and O-methyl EGCGs in rats, and clarified the pharmacokinetics of O-methyl EGCGs. Following oral administration (100 mg/kg), the areas under the concentration-time curves (AUCs) for EGCG, EGCG3″Me, and EGCG4″Me were 39.6 ± 14.2 µg·h/L, 317.2 ± 43.7 µg·h/L, and 51.9 ± 11.0 µg·h/L, respectively. The AUC after intravenous administration (10 mg/kg) was 2772 ± 480 µg·h/L for EGCG, 8209 ± 549 µg·h/L for EGCG3″Me, and 2465 ± 262 µg·h/L for EGCG4″Me. The bioavailability of EGCG3″Me (0.38%) was the highest (EGCG: 0.14% and EGCG4″Me: 0.21%). The distribution volume of EGCG3″Me (0.26 ± 0.02 L/kg) was the lowest (EGCG: 0.94 ± 0.16 L/kg and EGCG4″Me: 0.93 ± 0.14 L/kg). These results suggested that the higher AUC of EGCG3″Me after oral administration was related to its high bioavailability and low distribution volume. These findings supported the stronger bioactivity of EGCG3″Me in vivo.

Role of tangeretin as a potential bioavailability enhancer for silybin: Pharmacokinetic and pharmacological studies.

PubMed

Yuan, Zhong-Wen; Li, Ya-Zhuo; Liu, Zhong-Qiu; Feng, Sen-Ling; Zhou, Hua; Liu, Chang-Xiao; Liu, Liang; Xie, Ying

2018-02-01

Biological responses of a variety of naturally occurring compounds in vivo were restrained by their poor oral bioavailability. Silybin, as one of the active ingredients of silymarin, has presented promising bioactivity for the treatment of chronic liver diseases and cancer. However, its exposure in body was limited. In this study, silybin was demonstrated to be substrates of both BCRP and MRP2 by utilizing monolayer Caco-2 cell model and confirmed in MDCK cells overexpressing specific efflux transporter. Of all compounds screened, tangeretin, a potent inhibitor of efflux transporters of BCRP, MRP2 and P-gp, was able to enhance exposure of silybin by inhibiting functions of the barriers mediating transcellular transport. Moreover, study carried out in sandwich-cultured rat hepatocyte (SCH) model showed that the biliary excretion index (BEI) and in vitro biliary clearance of silybin decreased as levels of tangeretin increased, indicating efflux transporters mediating biliary excretion of silybin might be involved. Pharmacokinetic behaviors of silybin in rats were altered by co-administration of tangeretin, in terms of increased AUC and Cmax of silybin by comparing with that of silybin given alone. In addition, results coming from CCl 4 -induced acute liver injury rat model revealed that protection effect of silybin against liver damage in the presence of tangeretin was significantly enhanced. All these data were evident that efflux transporters play a critical role in transcellular transport of silybin and account for its low bioavailability. Enhanced bioavailability of silybin with co-administration of tangeretin by significantly inhibiting the efflux transporters further boost its bioactivity which is of particular importance in clinical use. Copyright © 2017. Published by Elsevier Ltd.

Resveratrol-sulfates provide an intracellular reservoir for generation of parent resveratrol, which induces autophagy in cancer cells

PubMed Central

Andreadi, Catherine; Britton, Robert G; Patel, Ketan R; Brown, Karen

2014-01-01

Resveratrol has many proposed health benefits, including the prevention of cancers, but its low bioavailability is considered a limiting factor in translating these effects to humans. Based on in vivo and clinical studies we have shown that resveratrol is indeed rapidly metabolized by phase II enzymes, and that resveratrol sulfates are deconjugated by steroid sulfatases to afford free resveratrol in vitro and in vivo and hence act as an intracellular reservoir for resveratrol. Further, we have demonstrated that at clinically achievable concentrations of resveratrol sulfate, parent resveratrol is regenerated within human colorectal cancer, but not normal epithelial cells, and is responsible for inducing autophagy with senescence selectively in cancer cells. PMID:24419144

Construction and characterization of curcumin nanoparticles system

NASA Astrophysics Data System (ADS)

Sun, Weitong; Zou, Yu; Guo, Yaping; Wang, Lu; Xiao, Xue; Sun, Rui; Zhao, Kun

2014-03-01

This study was aimed at developing a nanoparticles system for curcumin, a widely used traditional Chinese medicine, but with the disadvantage of poor aqueous solubility. The objective was intended to improve in vitro release characteristics, enhance blood and gastrointestinal stability, increase bioavailability and pharmacological activities. Curcumin nanoparticles system (Cur-NS) was prepared by ionotropic gelation technique. Cur-NS was characterized by particle size, zeta potential, drug entrapment efficiency, drug loading, and physical stability, respectively. Cur-NS presented controlled release properties, and the release properties of Cur from NS were fit non-Fickian mechanism, controlled by the expected diffusional release and the erosion or solubilization from the crosslink layer of polymer carrier. In addition, the pharmacokinetic study in rats revealed a notable improved oral bioavailability of Cur, and the anti-tumor activity in vivo of Cur-NS on tumor growth was investigated. Cur-NS significantly inhibited tumor effect compared with non-vehicle group, thus making it a potential candidate for cancer therapy.

Lead Optimization Studies on FimH Antagonists: Discovery of Potent and Orally Bioavailable Ortho-substituted Biphenyl Mannosides

PubMed Central

Han, Zhenfu; Pinkner, Jerome S.; Ford, Bradley; Chorell, Erik; Crowley, Jan M.; Cusumano, Corinne K.; Campbell, Scott; Henderson, Jeffrey P.; Hultgren, Scott J.; Janetka, James W.

2012-01-01

Herein, we describe the X-ray structure-based design and optimization of biaryl mannoside FimH inhibitors. Diverse modifications to the biaryl ring to improve drug-like physical and pharmacokinetic properties of mannosides were assessed for FimH binding affinity based on their effects on hemagglutination and biofilm formation along with direct FimH binding assays. Substitution on the mannoside phenyl ring ortho to the glycosidic bond results in large potency enhancements of several-fold higher than corresponding unsubstituted matched pairs and can be rationalized from increased hydrophobic interactions with the FimH hydrophobic ridge (Ile13) or “tyrosine gate” (Tyr137 and Tyr48) also lined by Ile52. The lead mannosides have increased metabolic stability and oral bioavailability as determined from in vitro PAMPA predictive model of cellular permeability and in vivo pharmacokinetic studies in mice, thereby representing advanced preclinical candidates with promising potential as novel therapeutics for the clinical treatment and prevention of recurring urinary tract infections. PMID:22449031

Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation.

PubMed

Sambaraj, Swapna; Ammula, Divya; Nagabandi, Vijaykumar

2015-09-01

The main objective of the current research work was to formulate and evaluate furosemide loaded silica lipid hybrid microparticles for improved oral delivery. A novel silica-lipid hybrid microparticulate system is used for enhancing the oral absorption of low solubility and low permeability of (BCS Class IV) drugs. Silica-lipid hybrid microparticles include the drug solubilising effect of dispersed lipids and stabilizing effect of hydrophilic silica particles to increase drug solubilisation, which leads to enhanced oral bioavailability. The slica lipid hybrid (SLH) microparticles were composed of poorly soluble drug (furosemide), dispersion of oil phase (Soya bean oil and miglyol) in lecithin (Phospholipoid 90H), non-ionic surfactant (Polysorbate 80) and adsorbent (Aerosol 380). Saturation solubility studies were performed in different oils and surfactants with increased concentration of drug revealed increased solubility of furosemide. In vitro dissolution studies conducted under simulated gastric medium revealed 2-4 fold increase in dissolution efficiencies for SLH microparticles compared to that of pure drug (furosemide) and marketed formulation Lasix®. Ex vivo studies showed enhanced lipid digestibility, which improved drug permeability. Solid-state characterization of SLH microparticles by X-ray powder diffraction and Fourier transform infrared spectroscopic analysis confirmed non-crystalline nature and more compatibility of furosemide in silica-lipid hybrid microparticles. It can be concluded that the role of lipids and hydrophilic silica based carrier highlighted in enhancing solubility and permeability, and hence the oral bioavailability of poorly soluble drugs.

Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation

PubMed Central

Sambaraj, Swapna; Ammula, Divya; Nagabandi, Vijaykumar

2015-01-01

Purpose: The main objective of the current research work was to formulate and evaluate furosemide loaded silica lipid hybrid microparticles for improved oral delivery. A novel silica-lipid hybrid microparticulate system is used for enhancing the oral absorption of low solubility and low permeability of (BCS Class IV) drugs. Silica-lipid hybrid microparticles include the drug solubilising effect of dispersed lipids and stabilizing effect of hydrophilic silica particles to increase drug solubilisation, which leads to enhanced oral bioavailability. Methods: The slica lipid hybrid (SLH) microparticles were composed of poorly soluble drug (furosemide), dispersion of oil phase (Soya bean oil and miglyol) in lecithin (Phospholipoid 90H), non-ionic surfactant (Polysorbate 80) and adsorbent (Aerosol 380). Saturation solubility studies were performed in different oils and surfactants with increased concentration of drug revealed increased solubility of furosemide. Results: In vitro dissolution studies conducted under simulated gastric medium revealed 2-4 fold increase in dissolution efficiencies for SLH microparticles compared to that of pure drug (furosemide) and marketed formulation Lasix®. Ex vivo studies showed enhanced lipid digestibility, which improved drug permeability. Solid-state characterization of SLH microparticles by X-ray powder diffraction and Fourier transform infrared spectroscopic analysis confirmed non-crystalline nature and more compatibility of furosemide in silica-lipid hybrid microparticles. Conclusion: It can be concluded that the role of lipids and hydrophilic silica based carrier highlighted in enhancing solubility and permeability, and hence the oral bioavailability of poorly soluble drugs. PMID:26504763

In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis.

PubMed

Upton, A M; Cho, S; Yang, T J; Kim, Y; Wang, Y; Lu, Y; Wang, B; Xu, J; Mdluli, K; Ma, Z; Franzblau, S G

2015-01-01

Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10(-7). In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

PubMed Central

Cho, S.; Yang, T. J.; Kim, Y.; Wang, Y.; Lu, Y.; Wang, B.; Xu, J.; Mdluli, K.; Ma, Z.; Franzblau, S. G.

2014-01-01

Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10−7. In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole. PMID:25331696

Preclinical Bioavailability Strategy for Decisions on Clinical Drug Formulation Development: An In Depth Analysis.

PubMed

Van den Bergh, An; Van Hemelryck, Sandy; Bevernage, Jan; Van Peer, Achiel; Brewster, Marcus; Mackie, Claire; Mannaert, Erik

2018-06-11

The aim of the presented retrospective analysis was to verify whether a previously proposed Janssen Biopharmaceutical Classification System (BCS)-like decision tree, based on preclinical bioavailability data of a solution and suspension formulation, would facilitate informed decision making on the clinical formulation development strategy. In addition, the predictive value of (in vitro) selection criteria, such as solubility, human permeability, and/or a clinical dose number (Do), were evaluated, potentially reducing additional supporting formulation bioavailability studies in animals. The absolute ( F abs,sol ) and relative ( F rel, susp/sol ) bioavailability of an oral solution and suspension, respectively, in rat or dog and the anticipated BCS classification were analyzed for 89 Janssen compounds with 28 of these having F rel,susp/sol and F abs,sol in both rat and dog at doses around 10 and 5 mg/kg, respectively. The bioavailability outcomes in the dog aligned well with a BCS-like classification based upon the solubility of the active pharmaceutical ingredient (API) in biorelevant media, while the alignment was less clear for the bioavailability data in the rat. A retrospective analysis on the clinically tested formulations for a set of 12 Janssen compounds confirmed that the previously proposed animal bioavailability-based decision tree facilitated decisions on the oral formulation type, with the dog as the most discriminative species. Furthermore, the analysis showed that based on a Do for a standard human dose of 100 mg in aqueous and/or biorelevant media, a similar formulation type would have been selected compared to the one suggested by the animal data. However, the concept of a Do did not distinguish between solubility enhancing or enabling formulations and does not consider the API permeability, and hence, it produces the risk of slow and potentially incomplete oral absorption of an API with poor intestinal permeability. In cases where clinical dose estimations are available early in development, the preclinical bioavailability studies and dose number calculations, used to guide formulation selection, may be performed at more relevant doses instead of the proposed standard human dose. It should be noted, however, that unlike in late development, there is uncertainty on the clinical dose estimated in the early clinical phases because that dose is usually only based on in vitro and/or in vivo animal pharmacology models, or early clinical biomarker information. Therefore, formulation strategies may be adjusted based on emerging data supporting clinical doses. In summary, combined early information on in vitro-assessed API solubility and permeability, preclinical suspension/solution bioavailability data in relation to the intravenous clearance, and metabolic pathways of the API can strengthen formulation decisions. However, these data may not always fully distinguish between conventional (e.g., to be taken with food), enhancing, and enabling formulations. Therefore, to avoid overinvestment in complex and expensive enabling technologies, it is useful to evaluate a conventional and solubility (and/or permeability) enhancing formulation under fasted and fed conditions, as part of a first-in-human study or in a subsequent early human bioavailability study, for compounds with high Do, a low animal F rel,susp/sol , or low F abs,sol caused by precipitation of the solubilized API.

Bioavailability of antioxidants in extruded products prepared from purple potato and dry pea flours

USDA-ARS?s Scientific Manuscript database

Measuring antioxidant activity using biological relevant assay is unique to understand the role of phytochemicals in vivo than common chemical assays. Cellular antioxidant activity assay could provide more biological relevant information on bioactive compounds in the raw as well as processed food pr...

Subcutaneous adipose tissue from obese and lean adults does not release hepcidin, in vivo

USDA-ARS?s Scientific Manuscript database

Hepcidin is a small peptide that functions as the both the main regulator of systemic iron homeostasis, and as the link between host defense and iron metabolism. Elevated hepcidin is associated with reduced iron bioavailability, while low hepcidin concentrations are associated with increased dietary...

PRELIMINARY ASSESSMENTS OF IN VITRO PHARMACOKINETIC DATA AND EXPOSURE INFORMATION FOR THE TOXCAST PHASE II CHEMICALS

EPA Science Inventory

Momentum has been growing in Toxicology to assess the utility of high-throughput screening (HTS) assays in the determination of chemical testing priorities. However, in vitro potencies determined in these assays do not consider in vivo bioavailability, clearance or exposure estim...

Preserving viability of Lactobacillus rhamnosus GG in vitro and in vivo by a new encapsulation system

USDA-ARS?s Scientific Manuscript database

Probiotics have shown beneficial effects on human health. To increase the efficacy of probiotic applications, we used Lactobacillus rhamnosus GG (LGG) as a probiotic model to investigate approaches to enhance the bioavailability of probiotics. LGG was encapsulated in hydrogel beads containing pectin...

In situ formation of pyromorphite is not required for the reduction of in vivo pb relative bioavailability in contaminated soils.

PubMed

Juhasz, Albert L; Gancarz, Dorota; Herde, Carina; McClure, Stuart; Scheckel, Kirk G; Smith, Euan

2014-06-17

The effect of phosphate treatment on lead relative bioavailability (Pb RBA) was assessed in three distinct Pb-contaminated soils. Phosphoric acid (PA) or rock phosphate were added to smelter (PP2), nonferrous slag (SH15), and shooting range (SR01) impacted soils at a P:Pb molar ratio of 5:1. In all of the phosphate amended soils, Pb RBA decreased compared to that in untreated soils when assessed using an in vivo mouse model. Treatment effect ratios (i.e., the ratio of Pb RBA in treated soil divided by Pb RBA in untreated soil) ranged from 0.39 to 0.67, 0.48 to 0.90, and 0.03 to 0.19 for PP2, SH15, and SR01, respectively. The decrease in Pb RBA following phosphate amendment was attributed to the formation of poorly soluble Pb phosphates (i.e., chloropyromorphite, hydroxypyromorphite, and Pb phosphate) that were identified by X-ray absorption spectroscopy (XAS). However, a similar decrease in Pb RBA was also observed in untreated soils following the sequential gavage of phosphate amendments. This suggests that in vivo processes may also facilitate the formation of poorly soluble Pb phosphates, which decreases Pb absorption. Furthermore, XAS analysis of PA-treated PP2 indicated further in vivo changes in Pb speciation as it moved through the gastrointestinal tract, which resulted in the transformation of hydroxypyromorphite to chloropyromorphite.

Intranasal agomelatine solid lipid nanoparticles to enhance brain delivery: formulation, optimization and in vivo pharmacokinetics

PubMed Central

Fatouh, Ahmed M; Elshafeey, Ahmed H; Abdelbary, Ahmed

2017-01-01

Purpose Agomelatine is a novel antidepressant drug suffering from an extensive first-pass metabolism leading to a diminished absolute bioavailability. The aim of the study is: first to enhance its absolute bioavailability, and second to increase its brain delivery. Methods To achieve these aims, the nasal route was adopted to exploit first its avoidance of the hepatic first-pass metabolism to increase the absolute bioavailability, and second the direct nose-to-brain pathway to enhance the brain drug delivery. Solid lipid nanoparticles were selected as a drug delivery system to enhance agomelatine permeability across the blood–brain barrier and therefore its brain delivery. Results The optimum solid lipid nanoparticles have a particle size of 167.70 nm ±0.42, zeta potential of −17.90 mV ±2.70, polydispersity index of 0.12±0.10, entrapment efficiency % of 91.25%±1.70%, the percentage released after 1 h of 35.40%±1.13% and the percentage released after 8 h of 80.87%±5.16%. The pharmacokinetic study of the optimized solid lipid nanoparticles revealed a significant increase in each of the plasma peak concentration, the AUC(0–360 min) and the absolute bioavailability compared to that of the oral suspension of Valdoxan® with the values of 759.00 ng/mL, 7,805.69 ng⋅min/mL and 44.44%, respectively. The optimized solid lipid nanoparticles gave a drug-targeting efficiency of 190.02, which revealed more successful brain targeting by the intranasal route compared with the intravenous route. The optimized solid lipid nanoparticles had a direct transport percentage of 47.37, which indicates a significant contribution of the direct nose-to-brain pathway in the brain drug delivery. Conclusion The intranasal administration of agomelatine solid lipid nanoparticles has effectively enhanced both the absolute bioavailability and the brain delivery of agomelatine. PMID:28684900

Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients

PubMed Central

Wang, Conan K.; Northfield, Susan E.; Colless, Barbara; Chaousis, Stephanie; Hamernig, Ingrid; Lohman, Rink-Jan; Nielsen, Daniel S.; Schroeder, Christina I.; Liras, Spiros; Price, David A.; Fairlie, David P.; Craik, David J.

2014-01-01

Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed amides in cyclic peptides. N-methylation effectively caps these amides, modifying the overall solvation properties of the peptides and making them more membrane permeable. The approach for identifying sites for N-methylation is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Five leucine-rich peptide scaffolds are reported with selectively designed N-methylated derivatives. In vitro membrane permeability was assessed by parallel artificial membrane permeability assay and Caco-2 assay. The most promising N-methylated peptide was then tested in vivo. Here we report a novel peptide (15), which displayed an oral bioavailability of 33% in a rat model, thus validating the design approach. We show that this approach can also be used to explain the notable increase in oral bioavailability of a somatostatin analog. PMID:25416591

A Critical Appraisal of Solubility Enhancement Techniques of Polyphenols

PubMed Central

Kaur, Harkiran; Kaur, Gurpreet

2014-01-01

Polyphenols constitute a family of natural substances distributed widely in plant kingdom. These are produced as secondary metabolites by plants and so far 8000 representatives of this family have been identified. Recently, there is an increased interest in the polyphenols because of the evidence of their role in prevention of degenerative diseases such as neurodegenerative diseases, cancer, and cardiovascular diseases. Although a large number of drugs are available in the market for treatment of these diseases, however, the emphasis these days is on the exploitation of natural principles derived from plants. Most polyphenols show low in vivo bioavailability thus limiting their application for oral drug delivery. This low bioavailability could be associated with low aqueous solubility, first pass effect, metabolism in GIT, or irreversible binding to cellular DNA and proteins. Therefore, there is a need to devise strategies to improve oral bioavailability of polyphenols. Various approaches like nanosizing, self-microemulsifying drug delivery systems (SMEDDS), microencapsulation, complexation, and solid dispersion can be used to increase the bioavailability. This paper will highlight the various methods that have been employed till date for the solubility enhancement of various polyphenols so that a suitable drug delivery system can be formulated. PMID:26556188

Bioavailability and stability of erythromycin delayed release tablets.

PubMed

Ogwal, S; Xide, T U

2001-12-01

Erythromycin is available as the free base, ethylsuccinate, estolate, stearate, gluceptate, and lactobionate derivatives. When given orally erythromycin and its derivatives except the estolate are inactivated to some extent by the gastric acid and poor absorption may result. To establish whether delayed release erythromycin tablets meet the bioequivalent requirement for the market. Sectrophotometric analysis was used to determine the dissolution percentage of the tablets in vitro. High performance liquid chromatography and IBM/XT microcomputer was used to determine the bioavailability and pharmacokinetic parameters in vivo. Dissolution percentage in thirty minutes reached 28.9% and in sixty minutes erythromycin was completely released. The parameters of the delayed release tablets were Tlag 2.3 hr, Tmax.4.5 hr, and Cmax 2.123 g/ml Ka 0.38048 hr(-1) T (1/2) 1.8 hr, V*C/F 49.721 AUC 12.9155. The relative bioavailability of erythromycin delayed release tablet to erythromycin capsules was 105.31% The content, appearance, and dissolution bioavailability of delayed release erythromycin tablets conforms to the United States pharmacopoeia standards. The tablets should be stored in a cool and dry place in airtight containers and the shelf life is temporarily assigned two years.

Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.

PubMed

Wang, Conan K; Northfield, Susan E; Colless, Barbara; Chaousis, Stephanie; Hamernig, Ingrid; Lohman, Rink-Jan; Nielsen, Daniel S; Schroeder, Christina I; Liras, Spiros; Price, David A; Fairlie, David P; Craik, David J

2014-12-09

Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed amides in cyclic peptides. N-methylation effectively caps these amides, modifying the overall solvation properties of the peptides and making them more membrane permeable. The approach for identifying sites for N-methylation is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Five leucine-rich peptide scaffolds are reported with selectively designed N-methylated derivatives. In vitro membrane permeability was assessed by parallel artificial membrane permeability assay and Caco-2 assay. The most promising N-methylated peptide was then tested in vivo. Here we report a novel peptide (15), which displayed an oral bioavailability of 33% in a rat model, thus validating the design approach. We show that this approach can also be used to explain the notable increase in oral bioavailability of a somatostatin analog.

Lack of dose dependent kinetics of methyl salicylate-2-O-β-D-lactoside in rhesus monkeys after oral administration.

PubMed

He, Yangyang; Yan, Yu; Zhang, Tiantai; Ma, Yinzhong; Zhang, Wen; Wu, Ping; Song, Junke; Wang, Shuang; Du, Guanhua

2015-04-22

Methyl salicylate-2-O-β-d-lactoside (MSL) is one of the main active components isolated from Gaultheria yunnanensis, which is a traditional Chinese medicine used to treat arthritis and various aches and pains. Pharmacological researches showed that MSL had various effective activities in both in vivo and in vitro experiments. However, the pharmacokinetics features and oral bioavailability of MSL in primates were not studied up to now. To study the pharmacokinetics of different doses of MSL in rhesus monkeys and investigate the absolute bioavailability of MSL after oral administration. Male and female rhesus monkeys were either orally administrated with MSL 200, 400 and 800 mg/kg or received an intravenous dose of 20mg/kg randomly. The levels of MSL and salicylic acid (SA) in plasma were simultaneous measured by a simple, sensitive and reproducible high performance liquid chromatography method. Mean peak plasma concentration values for groups treated with 200, 400 and 800 mg/kg doses ranged from 48.79 to 171.83 μg/mL after single-dose oral administration of MSL, and mean area under the concentration-time curve values ranged from 195.16 to 1107.76 μg/mL h. Poor linearity of the kinetics of SA after oral administration of MSL was observed in the regression analysis of the Cmax-dose plot (r(2)=0.812), CL-dose plot (r(2)=0.225) and AUC(0-t)-dose plot (r(2)=0.938). Absolute bioavailability of MSL was assessed to be 118.89 ± 57.50, 213.54 ± 58.98 and 168.72 ± 76.58%, respectively. Bioavailability of MSL after oral administration in rhesus monkeys was measured for the first time. Pharmacokinetics parameters did not appear to be dose proportional among the three oral doses of treatments, and MSL showed an apparent absolute bioavailability in excess of 100% in rhesus monkeys based on the present study. In addition, a rapid, sensitive and reliable HPLC method was established and demonstrated for the research of traditional Chinese medicine in this study. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

G5 PAMAM dendrimer versus liposome: a comparison study on the in vitro transepithelial transport and in vivo oral absorption of simvastatin.

PubMed

Qi, Rong; Zhang, Heran; Xu, Lu; Shen, Wenwen; Chen, Cong; Wang, Chao; Cao, Yini; Wang, Yunan; van Dongen, Mallory A; He, Bing; Wang, Siling; Liu, George; Banaszak Holl, Mark M; Zhang, Qiang

2015-07-01

This study compared formulation effects of a dendrimer and a liposome preparation on the water solubility, transepithelial transport, and oral bioavailability of simvastatin (SMV). Amine-terminated G5 PAMAM dendrimer (G5-NH2) was chosen to form SMV/G5-NH2 molecular complexes, and SMV-liposomes were prepared by using a thin film dispersion method. The effects of these preparations on the transepithelial transport were investigated in vitro using Caco-2 cell monolayers. Results indicated that the solubility and transepithelial transport of SMV were significantly improved by both formulations. Pharmacokinetic studies in rats also revealed that both the SMV/G5-NH2 molecular complexes and the SMV-liposomes significantly improved the oral bioavailability of SMV with the liposomes being more effective than the G5-NH2. The overall better oral absorption of SMV-liposomes as compared to SMV/G5-NH2 molecular complexes appeared to arise from better liposomal solubilization and encapsulation of SMV and more efficient intracellular SMV delivery. Various carrier systems have been designed to enhance drug delivery via the oral route. In this study, the authors compared G5 PAMAM dendrimers to liposome preparations in terms of solubility, transepithelial transport, and oral bioavailability of this poorly water-soluble drug. This understanding has improved our knowledge in the further development of drug carrier systems. Copyright © 2015 Elsevier Inc. All rights reserved.

Role of folic acid in nitric oxide bioavailability and vascular endothelial function.

PubMed

Stanhewicz, Anna E; Kenney, W Larry

2017-01-01

Folic acid is a member of the B-vitamin family and is essential for amino acid metabolism. Adequate intake of folic acid is vital for metabolism, cellular homeostasis, and DNA synthesis. Since the initial discovery of folic acid in the 1940s, folate deficiency has been implicated in numerous disease states, primarily those associated with neural tube defects in utero and neurological degeneration later in life. However, in the past decade, epidemiological studies have identified an inverse relation between both folic acid intake and blood folate concentration and cardiovascular health. This association inspired a number of clinical studies that suggested that folic acid supplementation could reverse endothelial dysfunction in patients with cardiovascular disease (CVD). Recently, in vitro and in vivo studies have begun to elucidate the mechanism(s) through which folic acid improves vascular endothelial function. These studies, which are the focus of this review, suggest that folic acid and its active metabolite 5-methyl tetrahydrofolate improve nitric oxide (NO) bioavailability by increasing endothelial NO synthase coupling and NO production as well as by directly scavenging superoxide radicals. By improving NO bioavailability, folic acid may protect or improve endothelial function, thereby preventing or reversing the progression of CVD in those with overt disease or elevated CVD risk. © The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Benznidazole Extended-Release Tablets for Improved Treatment of Chagas Disease: Preclinical Pharmacokinetic Study

PubMed Central

Campos, Michel Leandro; Rosa, Talita Atanazio; Padilha, Elias Carvalho; Alzate, Alejandro Henao; Rolim, Larissa Araújo; Rolim-Neto, Pedro José

2016-01-01

Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediate-release tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentration in vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease. PMID:26883698

Solid lipid nanoparticles as an efficient drug delivery system of olmesartan medoxomil for the treatment of hypertension.

PubMed

Pandya, Nilima T; Jani, Parva; Vanza, Jigar; Tandel, Hemal

2018-05-01

The aim of the current investigation was to develop solid lipid nanoparticles of olmesartan medoxomil using hot homogenization method to improve its oral bioavailability. Central composite design was applied to optimize the formulation variables; lipid X1 (Glyceryl monostearate) and surfactant X2 (Poloxamer: Tween 80). The particle sizes were in the nanometer range and spherical shaped for all prepared solid lipid nanoparticles formulations and the zeta potential absolute values were high, predicting good long-term stability. In vitro study of olmesartan loaded solid lipid nanoparticle exhibited controlled release profile for at least 24 h. The rate and extent of drug diffusion was studied using dialysis sac, rat's stomach and intestine tissues; study demonstrated that drug release from the solid lipid nanoparticles was significantly higher than drug suspension. In vivo pharmacokinetic study of olmesartan loaded solid lipid nanoparticles revealed higher Cmax of 1610 ng/mL, higher AUC of 15492.50 ng/mL and increased relative bioavailability by almost 2.3 folds compared to marketed formulation. These results clearly indicate that olmesartan loaded solid lipid nanoparticles are shown to have enhanced bioavailability and effective therapeutic result and thus would be an excellent way to treat hypertension. Hence, these solid lipid nanoparticles could represent as a great potential for a possible alternative to conventional oral formulation in the treatment of hypertension. Copyright © 2018 Elsevier B.V. All rights reserved.

[Nutrition and health--favorable effect of wine and wine flavonoids on cardiovascular diseases].

PubMed

van de Wiel, A

2002-12-21

Epidemiological studies have shown a favourable effect of moderate alcohol consumption with regard to atherosclerotic disorders. In addition to alcohol, wine contains a large number of other components including polyphenols. These polyphenols mainly originate from the skins and seeds of grapes and, because of differences in vinification, their variety and concentration is higher in red wine than in white wine. In vitro and ex vivo studies have shown that some of these polyphenols are able to slow down LDL-cholesterol oxidation, stimulate NO production, influence prostaglandin synthesis and inhibit platelet aggregation. However, little is known about their resorption, bioavailability and effectiveness in vivo. Since data from intervention studies with wine polyphenols are also lacking, no statement can yet be made about any clinically relevant effect of these components, in either red or white wine, in terms of cardiovascular diseases.

Chlorogenic acid stabilized nanostructured lipid carriers (NLC) of atorvastatin: formulation, design and in vivo evaluation.

PubMed

Khan, Saba; Baboota, Sanjula; Ali, Javed; Narang, R S; Narang, Jasjeet K

2016-01-01

The present work was aimed at developing an optimized oral nanostructured lipid carrier (NLC) formulation of poorly soluble atorvastatin Ca (AT Ca) and assessing its in vitro release, oral bioavailability and pharmacodynamic activity. In this study, chlorogenic acid, a novel excipient having synergistic cholesterol lowering activity was utilized and explored in NLC formulation development. The drug-loaded NLC formulations were prepared using a high pressure homogenization technique and optimized by the Box-Behnken statistical design using the Design-Expert software. The optimized NLC formulation was composed of oleic acid and stearic acid as lipid phase (0.9% w/v), poloxamer 188 as surfactant (1% w/v) and chlorogenic acid (0.05% w/v). The mean particle size, polydispersity index (PDI) and % drug entrapment efficiency of optimized NLC were 203.56 ± 8.57 nm, 0.27 ± 0.028 and 83.66 ± 5.69, respectively. In vitro release studies showed that the release of drug from optimized NLC formulations were markedly enhanced as compared to solid lipid nanoparticles (SLN) and drug suspension. The plasma concentration time profile of AT Ca in rats showed 3.08- and 4.89-fold increase in relative bioavailability of developed NLC with respect to marketed preparation (ATORVA® tablet) and drug suspension, respectively. Pharmacodynamic study suggested highly significant (**p < 0.01) reduction in the cholesterol and triglyceride values by NLC in comparison with ATORVA® tablet. Therefore, the results of in vivo studies demonstrated promising prospects for successful oral delivery of AT Ca by means of its chlorogenic acid integrated NLC.

Novel dipeptide nanoparticles for effective curcumin delivery

PubMed Central

Alam, Shadab; Panda, Jiban J; Chauhan, Virander S

2012-01-01

Background: Curcumin, the principal curcuminoid of the popular Indian spice turmeric, has a wide spectrum of pharmaceutical properties such as antitumor, antioxidant, antiamyloid, and anti-inflammatory activity. However, poor aqueous solubility and low bioavailability of curcumin is a major challenge in its development as a useful drug. To enhance the aqueous solubility and bioavailability of curcumin, attempts have been made to encapsulate it in liposomes, polymeric nanoparticles (NPs), lipid-based NPs, biodegradable microspheres, cyclodextrin, and hydrogels. Methods: In this work, we attempted to entrap curcumin in novel self-assembled dipeptide NPs containing a nonprotein amino acid, α, β-dehydrophenylalanine, and investigated the biological activity of dipeptide-curcumin NPs in cancer models both in vitro and in vivo. Results: Of the several dehydrodipeptides tested, methionine-dehydrophenylalanine was the most suitable one for loading and release of curcumin. Loading of curcumin in the dipeptide NPs increased its solubility, improved cellular availability, enhanced its toxicity towards different cancerous cell lines, and enhanced curcumin’s efficacy towards inhibiting tumor growth in Balb/c mice bearing a B6F10 melanoma tumor. Conclusion: These novel, highly biocompatible, and easy to construct dipeptide NPs with a capacity to load and release curcumin in a sustained manner significantly improved curcumin’s cellular uptake without altering its anticancer or other therapeutic properties. Curcumin-dipeptide NPs also showed improved in vitro and in vivo chemotherapeutic efficacy compared to curcumin alone. Such dipeptide-NPs may also improve the delivery of other potent hydrophobic drug molecules that show poor cellular uptake, bioavailability, and efficacy. PMID:22915849

Enhanced antitumor immunity of nanoliposome-encapsulated heat shock protein 70 peptide complex derived from dendritic tumor fusion cells.

PubMed

Zhang, Yunfei; Luo, Wen; Wang, Yucai; Chen, Jun; Liu, Yunyan; Zhang, Yong

2015-06-01

Tumor-derived heat shock proteins peptide complex (HSP.PC-Tu) has been regarded as a promising antitumor agent. However, inadequate immunogenicity and low bioavailability limit the clinical uses of this agent. In a previous study, we first produced an improved HSP70.PC-based vaccine purified from dendritic cell (DC)-tumor fusion cells (HSP70.PC-Fc) which had increased immunogenicity due to enhanced antigenic tumor peptides compared to HSP70.PC-Tu. In order to increase the bioavailability of HSP70.PC-Fc, the peptide complex was encapsulated with nanoliposomes (NL-HSP70.PC-Fc) in this study. After encapsulation, the tumor immunogenicity was observed using various assays. It was demonstrated that the NL-HSP70.PC-Fc has acceptable stability. The in vivo antitumor immune response was increased with regard to T-cell activation, CTL response and tumor therapy efficiency compared to that of HSP70.PC-Fc. In addition, it was shown that DC maturation was improved by NL-HSP70.PC-Fc, which added to the antitumor immunity. The results obtained for NL-HSP70.PC-Fc, which improved immunogenicity and increases the bioavailability of HSP70.PC, may represent superior heat shock proteins (HSPs)-based tumor vaccines. Such vaccines deserve further investigation and may provide a preclinical rationale to translate findings into early phase trials for patients with breast tumors.

Enhancement of the bioavailability of an antihypertensive drug by transdermal protransfersomal system: formulation and in vivo study.

PubMed

Morsi, Nadia M; Aboelwafa, Ahmed A; Dawoud, Marwa H S

2018-06-01

Timolol Maleate (TiM), a nonselective β-adrenergic blocker, is a potent highly effective agent for management of hypertension. The drug suffers from poor oral bioavailability (50%) due to its first pass effect and a short elimination half-life of 4 h; resulting in its frequent administration. Transdermal formulation may circumvent these problems in the form of protransfersomes. The aim of this study is to develop and optimize transdermal protransfersomal system of Timolol Maleate by film deposition on carrier method where protransfersomes were converted to transfersomes upon skin hydration following transdermal application under occlusive conditions. Two 2 3 full factorial designs were employed to investigate the influence of three formulation variables which were; phosphatidyl choline: surfactant molar ratio, carrier: mixture and the type of SAA each on particle size, drug entrapment efficiency and release rate. The optimized formulation was evaluated regarding permeation through hairless rat skin and compared with oral administration of aqueous solution on male Wistar rats. Optimized protransfersomal system had excellent permeation rate through shaved rat skin (780.69 μg/cm 2 /h) and showed six times increase in relative bioavailability with prolonged plasma profile up to 72 h. A potential protransfresomal transdermal system was successfully developed and factorial design was found to be a smart tool in its optimization.

Concomitant ingestion of lactic acid bacteria and black tea synergistically enhances flavonoid bioavailability and attenuates d-galactose-induced oxidative stress in mice via modulating glutathione antioxidant system.

PubMed

Zhao, Danyue; Shah, Nagendra P

2016-12-01

Black tea (BT) has been positively linked to improved redox status, while its efficacy is limited due to the low bioavailability of BT flavonoids. In addition to the direct antioxidant activity, flavonoids regulate redox balance via inducing endogenous antioxidants, particularly glutathione (GSH) and GSH-dependent antioxidant enzymes. This work first examined the effect of lactic acid bacteria (LAB) and BT alone or in combination on flavonoid bioavailability and metabolism; next, the effect of LAB-fermented BT diet in attenuating oxidative stress in mice and the underlying mechanisms were studied. Phenolic profiles of plasma, urine and feces from healthy mice consuming plain yogurt, BT milk (BTM) or BT yogurt (BTY) were acquired using LC-MS/MS. Plasma antioxidant capacity, lipid peroxidation level, content of nonprotein thiols and expression of GSH-related antioxidant enzymes and Nrf2 were examined in d-galactose-treated mice. Total flavonoid content in plasma following a single dose of BTY attained 0.657 μmol/l, increased by 50% compared with the BTM group. Increased excretion of phenolic metabolite and hippuric acid in urine and feces indicated enhanced metabolism of flavonoids in BTY-fed mice. In the second study, 8-week concomitant LAB-BT treatment of oxidatively stressed mice effectively restored plasma antioxidant capacity and GSH levels, and mitigated lipid peroxidation, which were associated with significant induction of GSH-dependent antioxidant enzymes and nuclear accumulation of Nrf2. Our results demonstrated the effect of LAB fermentation in enhancing BT flavonoid bioavailability in vivo. The synergistic antioxidant efficacy of LAB-BT diet implied its therapeutic potential in enhancing antioxidant defenses and protecting organisms from oxidative damage. Copyright © 2016. Published by Elsevier Inc.

Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease

PubMed Central

Nixon, Gemma L.; McEntee, Laura; Johnson, Adam; Farrington, Nicola; Whalley, Sarah; Livermore, Joanne; Natal, Cristien; Washbourn, Gina; Bibby, Jaclyn; Berry, Neil; Lestner, Jodi; Truong, Megan; Owen, Andrew; Lalloo, David; Charles, Ian

2018-01-01

ABSTRACT Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply, and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The benzimidazoles have broad-spectrum antiparasitic activity but also have in vitro antifungal activity that includes Cryptococcus neoformans. Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships, and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans, with a modal MIC of 0.125 mg/liter using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal β-tubulin. Rapid fungicidal activity was evident in a hollow-fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg of body weight/day) orally resulted in an ∼2 log10CFU/g reduction in fungal burden compared with that in vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the cerebrospinal fluid (CSF) or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal meningitis. PMID:29311092

Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP

PubMed Central

Kusuhara, Hiroyuki; Furuie, Hidetoshi; Inano, Akihiro; Sunagawa, Akihiro; Yamada, Saiko; Wu, Chunyong; Fukizawa, Shinya; Morimoto, Nozomi; Ieiri, Ichiro; Morishita, Mariko; Sumita, Kiminobu; Mayahara, Hiroshi; Fujita, Takuya; Maeda, Kazuya; Sugiyama, Yuichi

2012-01-01

BACKGROUND AND PURPOSE An ATP-binding cassette (ABC) transporter, breast cancer resistance protein (BCRP)/ABCG2, limits oral bioavailability of sulphasalazine. Here we examined the effect of curcumin, the principal curcuminoid of turmeric, on oral bioavailability of microdoses and therapeutic doses of sulphasalazine in humans. EXPERIMENTAL APPROACH Effects of curcumin were measured on the ATP-dependent sulphasalazine uptake by hBCRP-expressing membrane vesicles and on oral bioavailability of sulphasalazine in wild-type and Bcrp(–/–) mice. Eight healthy Japanese subjects received an oral dose of sulphasalazine suspension (100 µg) or tablets (2 g) alone or after curcumin tablets (2 g). Uptake of sulphasalazine was studied in HEK293 cells transfected with the influx transporter (OATP)2B1. KEY RESULTS Curcumin was a potent hBCRP inhibitor in vitro (Ki 0.70 ± 0.41 µM). Curcumin increased the area under the curve (AUC)0–8 of plasma sulphasalazine eightfold in wild-type mice at 300 and 400 mg·kg−1, but not in Bcrp(–/–) mice. Curcumin increased AUC0–24 of plasma sulphasalazine 2.0-fold at microdoses and 3.2-fold at therapeutic doses in humans. Non-linearity of the dose–exposure relationship was observed between microdoses and therapeutic doses of sulphasalazine. Sulphasalazine was a substrate for OATP2B1 (Km 1.7 ± 0.3 µM). Its linear index (dose/Km) at the therapeutic dose was high and may saturate OATP2B1. CONCLUSIONS AND IMPLICATIONS Curcumin can be used to investigate effects of BCRP on oral bioavailability of drugs in humans. Besides the limited dissolution, OATP2B1 saturation is a possible mechanism underlying non-linearity in the dose–exposure relationship of sulphasalazine. PMID:22300367

Stable isotope methodology in the pharmacokinetic studies of androgenic steroids in humans.

PubMed

Shinohara, Y; Baba, S

1990-04-01

The use of stable isotopically labeled steroids combined with gas chromatography/mass spectrometry (GC/MS) has found a broad application in pharmacologic studies. Initially, stable isotopically labeled steroids served as the ideal analytic internal standard for GC/MS analysis; however, their in vivo use has expanded and has proven to be a powerful pharmacokinetic tool. We have successfully used stable isotope methodology to study the pharmacokinetic/bioavailability of androgens. The primary advantage of the technique is that endogenous and exogenous steroids with the same basic structure can be differentiated by using stable isotopically labeled analogs. The method was used to examine the pharmacokinetics of testosterone and testosterone propionate, and to clarify the influence of endogenous testosterone. Another advantage of the isotope methods is that steroidal drugs can be administered concomitantly in two formulations (e.g., solution and solid dosage). A single set of blood samples serves to describe the time course of the formulations being compared. This stable isotope coadministration technique was used to estimate the relative bioavailability of 17 alpha-methyltestosterone.

The plasma free amino acid dose-response technique: A proposed methodology for determining lysine relative bioavailability of rumen-protected lysine supplements.

PubMed

Whitehouse, N L; Schwab, C G; Brito, A F

2017-12-01

Estimates of Lys bioavailability of rumen-protected Lys (RP-Lys) supplements are often obtained using in vitro or 2-step in situ techniques, with little to no data determining efficacy and bioavailability in vivo. The objective of this study was to further evaluate and refine the use of the plasma free AA dose-response technique as a method for determining Lys relative bioavailability of RP-Lys supplements. Thirteen dose-response Latin square studies using 87 lactating, ruminally cannulated multiparous Holstein cows (days in milk from 55 to 315 and milk yield from 12 to 62 kg/d at the start of the studies) were conducted to measure the relative bioavailability of RP-Lys supplements. Intestinal (1 study) and abomasal (12 studies) infusions of Lys ranged from 0 to 84 g/d, and experimental periods ranged from 4 to 21 d. Basal diets were formulated to be adequate in metabolizable Met, but varied in predicted metabolizable Lys (5.04 to 6.81% of metabolizable protein). One to 4 daily blood samples were taken from the coccygeal vessels for 1 to 3 consecutive days in each period. Plasma Lys concentration in cows assigned to the control treatment (0 g/d Lys) ranged from 1.83 to 5.21% of total plasma AA, whereas that from cows duodenally or abomasally infused with Lys ranged from 2.53 to 7.51% of total plasma AA. Results from studies involving more than 2 amounts of infused Lys confirmed linearity of response. The following variables were regressed against the plasma Lys dose-response slopes generated from the Lys infusion treatments to examine their effects on the magnitude of the slopes: plasma Lys concentration of the control diet, plasma Lys concentration at the greatest amount of infused Lys, net energy of lactation and metabolizable protein balances, metabolizable protein supply, days in milk, milk yield, milk concentrations of fat, true protein, and lactose, milk true protein yield, and dry matter intake. The variable having the greatest effect on the magnitude of the dose-response slope was the plasma Lys concentration at the greatest amount infused. The relative bioavailability of evaluated RP-Lys supplements using the plasma free AA dose-response technique ranged from 5 to 87%. It was concluded that plasma free Lys increases in a linear fashion to increasing amounts of absorbed Lys and that the dose-response technique is an appropriate technique for evaluating RP-Lys supplements. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

COMPARISON OF IN VITRO DIGESTIVE FLUID EXTRACTION AND TRADITIONAL IN VIVO APPROACHES AS MEASURES OF POLYCYCLIC AROMATIC HYDROCARBON BIOAVAILABILITY FROM SEDIMENTS. (R825353)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

In vivo and in vitro methods for evaluating soil arsenic bioavailability: relevant to human health risk assessment

EPA Science Inventory

Arsenic (As) is the most frequently occurring contaminant on the priority list of hazardous substances, which lists substances of greatest public health concern to people living at or near U.S. National Priorities List site. Accurate assessment of human health risks from exposure...

Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development.

PubMed

Conover, Cheryl A; Bale, Laurie K; Overgaard, Michael T; Johnstone, Edward W; Laursen, Ulla H; Füchtbauer, Ernst-Martin; Oxvig, Claus; van Deursen, Jan

2004-03-01

Pregnancy-associated plasma protein A (PAPPA) is a metzincin superfamily metalloproteinase in the insulin-like growth factor (IGF) system. PAPPA increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGF-binding protein 4 (IGFBP4). To determine its function in vivo, we generated PAPPA-null mice by gene targeting. Mice homozygous for targeted disruption of the PAPPA gene were viable but 60% the size of wild-type littermates at birth. The impact of the mutation was exerted during the early embryonic period prior to organogenesis, resulting in proportional dwarfism. PAPPA, IGF2 and IGFBP4 transcripts co-localized in wild-type embryos, and expression of IGF2 and IGFBP4 mRNA was not altered in PAPPA-deficient embryos. However, IGFBP4 proteolytic activity was completely lacking in fibroblasts derived from PAPPA-deficient embryos, and IGFBP4 effectively inhibited IGF-stimulated mitogenesis in these cells. These results provide the first direct evidence that PAPPA is an essential growth regulatory factor in vivo, and suggest a novel mechanism for regulated IGF bioavailability during early fetal development.

Iron oxide core oil-in-water emulsions as a multifunctional nanoparticle platform for tumor targeting and imaging

PubMed Central

Jarzyna, Peter A.; Skajaa, Torjus; Gianella, Anita; Cormode, David P.; Samber, Dan D.; Dickson, Stephen D.; Chen, Wei; Griffioen, Arjan W.; Fayad, Zahi A.; Mulder, Willem J. M.

2009-01-01

Nanoemulsions are increasingly investigated for the delivery of hydrophobic drugs to improve their bioavailability or make their administration possible. In the current study, oil-in-water emulsions with three different mean diameters (30, 60, and 95 nm) were developed as a new multimodality nanoparticle platform for tumor targeting and imaging. To that aim, hydrophobically coated iron oxide particles were included in the soybean oil core of the nanoemulsions to enable their detection with magnetic resonance imaging (MRI), while the conjugation of a near infrared fluorophore allowed optical imaging. The accumulation of this novel nanocomposite in subcutaneous human tumors in nude mice was demonstrated with MRI and fluorescence imaging in vivo, and with Perl’s staining of histological tumor sections ex vivo. PMID:19783295

In vivo evaluation of a self-nanoemulsifying drug delivery system for curcumin.

PubMed

Nazari-Vanani, R; Moezi, L; Heli, H

2017-04-01

Curcumin has attracted particular attention in recent years due to its great variety of beneficial biological and pharmacological activities. However, its efficacy has been limited due to its low bioavailability, and this limitation can be overcome by novel drug delivery systems. Self-nanoemulsifying drug delivery system (SNEDDS) is a novel route to improve oral bioavailability of lipophilic drugs. SNEDDS spontaneously forms fine oil-in-water nanoemulsion by mild agitation. An optimal formula for a SNEDDS comprised ethyl oleate:tween 80:PEG 600 (50:40:10% w/w) with 11.2-nm uniform droplets was developed for curcumin delivery. The SNEDDS was characterized and its loading properties for curcumin were orally evaluated in rat. The results showed a significant increment of 3.95 times in C max , and the curcumin bioavailability was enhanced by 194.2%, compared to the curcumin suspension in water. The development of the SNEDDS formulation had a great potential as a possible alternative for curcumin administration. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Rifampicin-loaded 'flower-like' polymeric micelles for enhanced oral bioavailability in an extemporaneous liquid fixed-dose combination with isoniazid.

PubMed

Moretton, Marcela A; Hocht, Christian; Taira, Carlos; Sosnik, Alejandro

2014-08-01

Coadministration of rifampicin (RIF)/isoniazid (INH) is clinically recommended to improve the treatment of tuberculosis. Under gastric conditions, RIF undergoes fast hydrolysis (a pathway hastened by INH) and oral bioavailability loss. We aimed to assess the chemical stabilization and the oral pharmacokinetics of RIF nanoencapsulated within poly(ε-caprolactone)-b-PEG-b-poly(ε-caprolactone) 'flower-like' polymeric micelles. The chemical stability of RIF was evaluated in vitro under acid conditions with and without INH, and the oral pharmacokinetics of RIF-loaded micelles in rats was compared with those of a suspension coded by the US Pharmacopeia. Nanoencapsulation decreased the degradation rate of RIF with respect to the free drug. Moreover, in vivo data showed a statistically significant increase of RIF oral bioavailability (up to 3.3-times) with respect to the free drug in the presence of INH. Overall results highlight the potential of this nanotechnology platform to develop an extemporaneous liquid RIF/INH fixed-dose combination suitable for pediatric administration.

Solid lipid nanoparticles for pulmonary delivery of insulin.

PubMed

Liu, Jie; Gong, Tao; Fu, Hualin; Wang, Changguang; Wang, Xiuli; Chen, Qian; Zhang, Qin; He, Qin; Zhang, Zhirong

2008-05-22

Growing attention has been given to the potential of pulmonary route as an alternative for non-invasive systemic delivery of therapeutic agents. In this study, novel nebulizer-compatible solid lipid nanoparticles (SLNs) for pulmonary drug delivery of insulin were developed by reverse micelle-double emulsion method. The influences of the amount of sodium cholate (SC) and soybean phosphatidylcholine (SPC) on the deposition properties of the nanoparticles were investigated. Under optimal conditions, the entrapment delivery (ED), respirable fraction (RF) and nebulization efficiency (NE) of SLNs could reach 96.53, 82.11 and 63.28%, respectively, and Ins-SLNs remained stable during nebulization. Fasting plasma glucose level was reduced to 39.41% and insulin level was increased to approximately 170 microIU/ml 4h after pulmonary administration of 20 IU/kg Ins-SLNs. A pharmacological bioavailability of 24.33% and a relative bioavailability of 22.33% were obtained using subcutaneous injection as a reference. Incorporating fluorescent-labelled insulin into SLNs, we found that the SLNs were effectively and homogeneously distributed in the lung alveoli. These findings suggested that SLNs could be used as a potential carrier for pulmonary delivery of insulin by improving both in vitro and in vivo stability as well as prolonging hypoglycemic effect, which inevitably resulted in enhanced bioavailability.

An update on the potential role of intestinal first-pass metabolism for the prediction of drug-drug interactions: the role of PBPK modeling.

PubMed

Alqahtani, Saeed; Bukhari, Ishfaq; Albassam, Ahmed; Alenazi, Maha

2018-05-28

The intestinal absorption process is a combination of several events that are governed by various factors. Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes. The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs. Many studies have provided clear evidence on the significant role of intestinal first-pass metabolism on drug bioavailability and degree of drug-drug interactions (DDIs). Areas covered: This review provides an update on the role of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of drug-drug interactions. It also provides a comprehensive overview and summary of the latest update in the role of PBPK modeling in prediction of intestinal metabolism and DDIs in humans. Expert opinion: The contribution of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs has become more evident over the last few years. Several in vitro, in situ, and in vivo models have been developed to evaluate the role of first-pass metabolism and to predict DDIs. Currently, physiologically based pharmacokinetic modeling is considered the most valuable tool for the prediction of intestinal first-pass metabolism and DDIs.

Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation, optimization and in vivo evaluation.

PubMed

Nooli, Mounika; Chella, Naveen; Kulhari, Hitesh; Shastri, Nalini R; Sistla, Ramakrishna

2017-04-01

Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery. Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug-excipients interactions, powder X-ray diffraction analysis and drug release in vitro. The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100 nm, PDI 0.291, zeta potential of -23.4 mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration. In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.

Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure

PubMed Central

Cooper, Jason P; Hwang, Kyunghwa; Singh, Hardeep; Wang, Dong; Reynolds, C Patrick; Curley, Robert W; Williams, Simon C; Maurer, Barry J; Kang, Min H

2011-01-01

BACKGROUND AND PURPOSE High plasma levels of fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] were associated with improved outcome in a phase II clinical trial. Low bioavailability of 4-HPR has been limiting its therapeutic applications. This study characterized metabolism of 4-HPR in humans and mice, and to explore the effects of ketoconazole, an inhibitor of CYP3A4, as a modulator to increase 4-HPR plasma levels in mice and to increase the low bioavailability of 4-HPR. EXPERIMENTAL APPROACH 4-HPR metabolites were identified by mass spectrometric analysis and levels of 4-HPR and its metabolites [N-(4-methoxyphenyl)retinamide (4-MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR)] were quantified by high-performance liquid chromatography (HPLC). Kinetic analysis of enzyme activities and the effects of enzyme inhibitors were performed in pooled human and pooled mouse liver microsomes, and in human cytochrome P450 (CYP) 3A4 isoenzyme microsomes. In vivo metabolism of 4-HPR was inhibited in mice. KEY RESULTS Six 4-HPR metabolites were identified in the plasma of patients and mice. 4-HPR was oxidized to 4-oxo-4-HPR, at least in part via human CYP3A4. The CYP3A4 inhibitor ketoconazole significantly reduced 4-oxo-4-HPR formation in both human and mouse liver microsomes. In two strains of mice, co-administration of ketoconazole with 4-HPR in vivo significantly increased 4-HPR plasma concentrations by > twofold over 4-HPR alone and also increased 4-oxo-4-HPR levels. CONCLUSIONS AND IMPLICATIONS Mice may serve as an in vivo model of human 4-HPR pharmacokinetics. In vivo data suggest that the co-administration of ketoconazole at normal clinical doses with 4-HPR may increase systemic exposure to 4-HPR in humans. PMID:21391977

Experimental design and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application.

PubMed

Mahmood, Syed; Taher, Muhammad; Mandal, Uttam Kumar

2014-01-01

Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability of 2%. The aim of this study was to develop, statistically optimize, and characterize raloxifene hydrochloride-loaded transfersomes for transdermal delivery, in order to overcome the poor bioavailability issue with the drug. A response surface methodology experimental design was applied for the optimization of transfersomes, using Box-Behnken experimental design. Phospholipon(®) 90G, sodium deoxycholate, and sonication time, each at three levels, were selected as independent variables, while entrapment efficiency, vesicle size, and transdermal flux were identified as dependent variables. The formulation was characterized by surface morphology and shape, particle size, and zeta potential. Ex vivo transdermal flux was determined using a Hanson diffusion cell assembly, with rat skin as a barrier medium. Transfersomes from the optimized formulation were found to have spherical, unilamellar structures, with a homogeneous distribution and low polydispersity index (0.08). They had a particle size of 134±9 nM, with an entrapment efficiency of 91.00%±4.90%, and transdermal flux of 6.5±1.1 μg/cm(2)/hour. Raloxifene hydrochloride-loaded transfersomes proved significantly superior in terms of amount of drug permeated and deposited in the skin, with enhancement ratios of 6.25±1.50 and 9.25±2.40, respectively, when compared with drug-loaded conventional liposomes, and an ethanolic phosphate buffer saline. Differential scanning calorimetry study revealed a greater change in skin structure, compared with a control sample, during the ex vivo drug diffusion study. Further, confocal laser scanning microscopy proved an enhanced permeation of coumarin-6-loaded transfersomes, to a depth of approximately160 μM, as compared with rigid liposomes. These ex vivo findings proved that a raloxifene hydrochloride-loaded transfersome formulation could be a superior alternative to oral delivery of the drug.

Experimental design and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application

PubMed Central

Mahmood, Syed; Taher, Muhammad; Mandal, Uttam Kumar

2014-01-01

Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability of 2%. The aim of this study was to develop, statistically optimize, and characterize raloxifene hydrochloride-loaded transfersomes for transdermal delivery, in order to overcome the poor bioavailability issue with the drug. A response surface methodology experimental design was applied for the optimization of transfersomes, using Box-Behnken experimental design. Phospholipon® 90G, sodium deoxycholate, and sonication time, each at three levels, were selected as independent variables, while entrapment efficiency, vesicle size, and transdermal flux were identified as dependent variables. The formulation was characterized by surface morphology and shape, particle size, and zeta potential. Ex vivo transdermal flux was determined using a Hanson diffusion cell assembly, with rat skin as a barrier medium. Transfersomes from the optimized formulation were found to have spherical, unilamellar structures, with a homogeneous distribution and low polydispersity index (0.08). They had a particle size of 134±9 nM, with an entrapment efficiency of 91.00%±4.90%, and transdermal flux of 6.5±1.1 μg/cm2/hour. Raloxifene hydrochloride-loaded transfersomes proved significantly superior in terms of amount of drug permeated and deposited in the skin, with enhancement ratios of 6.25±1.50 and 9.25±2.40, respectively, when compared with drug-loaded conventional liposomes, and an ethanolic phosphate buffer saline. Differential scanning calorimetry study revealed a greater change in skin structure, compared with a control sample, during the ex vivo drug diffusion study. Further, confocal laser scanning microscopy proved an enhanced permeation of coumarin-6-loaded transfersomes, to a depth of approximately160 μM, as compared with rigid liposomes. These ex vivo findings proved that a raloxifene hydrochloride-loaded transfersome formulation could be a superior alternative to oral delivery of the drug. PMID:25246789

Intestinal absorption and activation of decitabine amino acid ester prodrugs mediated by peptide transporter PEPT1 and enterocyte enzymes.

PubMed

Tao, Wenhui; Zhao, Dongyang; Sun, Mengchi; Wang, Ziyu; Lin, Bin; Bao, Yu; Li, Yingying; He, Zhonggui; Sun, Yinghua; Sun, Jin

2018-04-25

Decitabine (DAC), a potent DNA methyltransferase (DNMT) inhibitor, has a limited oral bioavailability. Its 5'-amino acid ester prodrugs could improve its oral delivery but the specific absorption mechanism is not yet fully understood. The aim of this present study was to investigate the in vivo absorption and activation mechanism of these prodrugs using in situ intestinal perfusion and pharmacokinetics studies in rats. Although PEPT1 transporter is pH dependent, there appeared to be no proton cotransport in the perfusion experiment with a preferable transport at pH 7.4 rather than pH 6.5. This suggested that the transport was mostly dependent on the dissociated state of the prodrugs and the proton gradient might play only a limited role. In pH 7.4 HEPES buffer, an increase in P eff was observed for L-val-DAC, D-val-DAC, L-phe-DAC and L-trp-DAC (2.89-fold, 1.2-fold, 2.73-fold, and 1.90-fold, respectively), compared with the parent drug. When co-perfusing the prodrug with Glysar, a known substrate of PEPT1, the permeabilities of the prodrugs were significantly inhibited compared with the control. To further investigate the absorption of the prodrugs, L-val-DAC was selected and found to be concentration-dependent and saturable, suggesting a carrier-mediated process (intrinsic K m : 7.80 ± 2.61 mM) along with passive transport. Determination of drug in intestinal homogenate after perfusion further confirmed that the metabolic activation mainly involved an intestinal first-pass effect. In a pharmacokinetic evaluation, the oral bioavailability of L-val-DAC, L-phe-DAC and L-trp-DAC were nearly 1.74-fold, 1.69-fold and 1.49-fold greater than that of DAC. The differences in membrane permeability and oral bioavailability might be due to the different stability in the intestinal lumen and the distinct PEPT1 affinity which is mainly caused by the stereochemistry, hydrophobicity and steric hindrance of the side chains. In summary, the detailed investigation of the absorption mechanism by in vivo intestinal perfusion and pharmacokinetic studies showed that the prodrugs of DAC exhibited excellent permeability and oral bioavailability, which might be attributed to a hybrid (partly PEPT1-mediated and partly passive) transport mode and a rapid activation process in enterocytes. Copyright © 2018 Elsevier B.V. All rights reserved.

Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view.

PubMed

Chatterjee, Bappaditya; Hamed Almurisi, Samah; Ahmed Mahdi Dukhan, Ather; Mandal, Uttam Kumar; Sengupta, Pinaki

2016-11-01

Self-emulsifying drug delivery system (SEDDS) is an isotropic mixture of lipid, surfactant and co-surfactant, which forms a fine emulsion when comes in contact of an aqueous medium with mild agitation. SEDDS is considered as a potential platform for oral delivery of hydrophobic drug in order to overcome their poor and irregular bioavailability challenges. In spite of fewer advantages like improved solubility of drug, bypassing lymphatic transport etc., SEDDS faces different controversial issues such as the use of appropriate terminology (self-microemulsifying drug delivery system; SMEDDS or self-nanoemulsifying drug delivery system; SNEDDS), presence of high amount of surfactant, correlation of in vitro model to in vivo studies, lack of human volunteer study and effect of conversion of SEDDS to final administrable dosage form on pharmacokinetic behavior of the drug. In this review, potential issues or questions on SEDDS are identified and summarized from the pharmacokinetic point of view. Primarily this review includes the conflict between the influences of droplet size, variation in correlation between in vitro lipolysis or ex-vivo intestinal permeation and pharmacokinetic parameters, variation in in vivo results of solid and liquid SEDDS, and potential challenges or limitation of pharmacokinetic studies on human volunteers with orally administered SEDDS. In the past decades, hundreds of in vivo studies on SEDDS have been published. In the present study, only the relevant article on in vivo pharmacokinetic studies with orally administered SEDDS published in past 5-6 years are analyzed for an up to date compilation.

Preparation and In Vivo Pharmacokinetics of the Tongshu Suppository.

PubMed

Liu, Guoqiang; Dong, Leilei; Lu, Kuan; Liu, Sisi; Zheng, Yingying

2016-01-01

Astragalus polysaccharide (APS) (used for intestinal protection) was added to formulate the Tongshu suppository to improve the pharmacokinetics of Aceclofenac, which were assessed in New Zealand rabbits using an orthogonal experimental design. The single-agent Aceclofenac was taken as the control formulation. The concentration-time and drug release curves were drawn, and T max (min), C max (μg·mL(-1)), AUC0→∞ , and MRT were compared using a pharmacokinetic systems program. The formulated Tongshu suppository had moderate hardness, a smooth surface with uniform color, and theoretical drug-loading rate of 8%. Its release rate was in accordance with the drug preparation requirements. The concentration-time curves and drug release curves revealed that the maximum concentrations (C max) were 4.18 ± 1.03 μg·mL(-1) and 3.34 ± 0.41 μg·mL(-1) for the Tongshu and Aceclofenac suppositories, respectively, showing statistically insignificant difference, while the peak times were 34.87 ± 4.69 min and 34.76 ± 6.34 min, respectively, also showing statistically insignificant difference. Compared with the Aceclofenac suppository, the relative bioavailability of the Tongshu suppository was 104.4%, and the difference between them was statistically insignificant. In this experiment, the Tongshu suppository was prepared using the hot-melt method. In vivo pharmacokinetic studies confirmed it had higher bioavailability than the Aceclofenac suppository.

Preparation and In Vivo Pharmacokinetics of the Tongshu Suppository

PubMed Central

Dong, Leilei; Lu, Kuan; Liu, Sisi; Zheng, Yingying

2016-01-01

Astragalus polysaccharide (APS) (used for intestinal protection) was added to formulate the Tongshu suppository to improve the pharmacokinetics of Aceclofenac, which were assessed in New Zealand rabbits using an orthogonal experimental design. The single-agent Aceclofenac was taken as the control formulation. The concentration-time and drug release curves were drawn, and T max (min), C max (μg·mL−1), AUC0→∞, and MRT were compared using a pharmacokinetic systems program. The formulated Tongshu suppository had moderate hardness, a smooth surface with uniform color, and theoretical drug-loading rate of 8%. Its release rate was in accordance with the drug preparation requirements. The concentration-time curves and drug release curves revealed that the maximum concentrations (C max) were 4.18 ± 1.03 μg·mL−1 and 3.34 ± 0.41 μg·mL−1 for the Tongshu and Aceclofenac suppositories, respectively, showing statistically insignificant difference, while the peak times were 34.87 ± 4.69 min and 34.76 ± 6.34 min, respectively, also showing statistically insignificant difference. Compared with the Aceclofenac suppository, the relative bioavailability of the Tongshu suppository was 104.4%, and the difference between them was statistically insignificant. In this experiment, the Tongshu suppository was prepared using the hot-melt method. In vivo pharmacokinetic studies confirmed it had higher bioavailability than the Aceclofenac suppository. PMID:27610366

Development and in vivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbophil.

PubMed

Kast, Constantia E; Guggi, Davide; Langoth, Nina; Bernkop-Schnürch, Andreas

2003-06-01

It was the purpose of this study to develop a new oral drug delivery system for low molecular weight heparin (LMWH) providing an improved bioavailability and a prolonged therapeutic effect. The permeation enhancing polycarbophil-cysteine conjugate (PCP-Cys) used in this study displayed 111.4 +/- 6.4 microM thiol groups per gram polymer. Permeation studies on freshly excised intestinal mucosa were performed in Ussing chambers demonstrating a 2-fold improved uptake of heparin as a result of the addition of 0.5% (w/v) PCP-Cys and the permeation mediator glutathione (GSH). Tablets containing PCP-Cys, GSH, and 279 IU of LMWH showed a sustained drug release over 4 h. To guarantee the swelling of the polymeric carrier matrix in the small intestine tablets were enteric coated. They were orally given to rats. For tablets being based on the thiomer/GSH system an absolute bioavailability of 19.9 +/- 9.3% (means +/- SD; n = 5) vs. intravenous injection could be achieved. whereas tablets comprising unmodified PCP did not lead to a significant (p < 0.01) heparin concentration in plasma. The permeation enhancing effect and subsequently a therapeutic heparin level was maintained for 24 h after a single dose. Because of the strong and prolonged lasting permeation enhancing effect of the thiomer/GSH system, the oral bioavailability of LMWH could be significantly improved. This new delivery system represents therefore a promising tool for the oral administration of heparin.

Bioavailability of plant pigment phytochemicals in Angelica keiskei in older adults: A pilot absorption kinetic study

PubMed Central

Correa, Camila R; Chen, C-Y. Oliver; Aldini, Giancarlo; Rasmussen, Helen; Ronchi, Carlos F; Berchieri-Ronchi, Carolina; Cho, Soo-Muk; Blumberg, Jeffrey B

2014-01-01

BACKGROUND/OBJECTIVES Angelica keiskei is a green leafy vegetable rich in plant pigment phytochemicals such as flavonoids and carotenoids. This study examined bioavailability of flavonoids and carotenoids in Angelica keiskei and the alteration of the antioxidant performance in vivo. SUBJECTS AND MATERIALS Absorption kinetics of phytochemicals in Angelica keiskei were determined in healthy older adults (> 60 y, n = 5) and subjects with metabolic syndrome (n = 5). Subjects consumed 5 g dry Angelica keiskei powder encapsulated in gelatin capsules with a low flavonoid and carotenoid liquid meal. Plasma samples were collected at baseline, 0.5, 1, 2, 3, 4, 5, 6, 7, and 8 h. Samples were analyzed for flavonoids and carotenoids using HPLC systems with electrochemical and UV detection, respectively, and for total antioxidant performance by fluorometry. RESULTS After ingestion of Angelica keiskei increases in plasma quercetin concentrations were observed at 1-3 and 6-8 hr in the healthy group and at all time points in the metabolic syndrome group compared to baseline (P < 0.05). Plasma lutein concentrations were significantly elevated in both the healthy and metabolic syndrome groups at 8 hr (P < 0.05). Significant increases in total antioxidant performance were also observed in both the healthy and the metabolic syndrome groups compared to baseline (P < 0.05). CONCLUSIONS Findings of this study clearly demonstrate the bioavailability of phytonutrients of Angelica keiskei and their ability to increase antioxidant status in humans. PMID:25324936

Bioavailability of Bergamot (Citrus bergamia) Flavanones and Biological Activity of Their Circulating Metabolites in Human Pro-Angiogenic Cells

PubMed Central

Spigoni, Valentina; Fantuzzi, Federica; Tassotti, Michele; Brighenti, Furio; Bonadonna, Riccardo C.; Dei Cas, Alessandra

2017-01-01

Myeloid angiogenic cells (MACs) play a key role in endothelial repairing processes and functionality but their activity may be impaired by the lipotoxic effects of some molecules like stearic acid (SA). Among the dietary components potentially able to modulate endothelial function in vivo, (poly)phenolic compounds represent serious candidates. Here, we apply a comprehensive multidisciplinary approach to shed light on the prospects of Bergamot (Citrus bergamia), a citrus fruit rich in flavanones and other phenolic compounds, in the framework of lipotoxicity-induced MACs impairment. The flavanone profile of bergamot juice was characterized and 16 compounds were identified, with a new 3-hydroxy-3-methylglutaryl (HMG) flavanone, isosakuranetin-7-O-neohesperidoside-6″-O-HMG, described for the first time. Then, a pilot bioavailability study was conducted in healthy volunteers to assess the circulating flavanone metabolites in plasma and urine after consumption of bergamot juice. Up to 12 flavanone phase II conjugates (sulfates and glucuronides of hesperetin, naringenin and eriodyctiol) were detected and quantified. Finally, the effect of some of the metabolites identified in vivo, namely hesperetin-7-O-glucuronide, hesperetin-3′-O-glucuronide, naringenin-7-O-glucuronide and naringenin-4′-O-glucuronide, was tested, at physiological concentrations, on gene expression of inflammatory markers and apoptosis in MACs exposed to SA. Under these conditions, naringenin-4′-O-glucuronide and hesperetin-7-O-glucuronide were able to modulate inflammation, while no flavanone glucuronide was effective in curbing stearate-induced lipoapoptosis. These results demonstrate that some flavanone metabolites, derived from the in vivo transformation of bergamot juice phenolics in humans, may mitigate stearate-induced inflammation in MACs. PMID:29211032

Bioavailability of Bergamot (Citrus bergamia) Flavanones and Biological Activity of Their Circulating Metabolites in Human Pro-Angiogenic Cells.

PubMed

Spigoni, Valentina; Mena, Pedro; Fantuzzi, Federica; Tassotti, Michele; Brighenti, Furio; Bonadonna, Riccardo C; Del Rio, Daniele; Dei Cas, Alessandra

2017-12-06

Myeloid angiogenic cells (MACs) play a key role in endothelial repairing processes and functionality but their activity may be impaired by the lipotoxic effects of some molecules like stearic acid (SA). Among the dietary components potentially able to modulate endothelial function in vivo, (poly)phenolic compounds represent serious candidates. Here, we apply a comprehensive multidisciplinary approach to shed light on the prospects of Bergamot ( Citrus bergamia ), a citrus fruit rich in flavanones and other phenolic compounds, in the framework of lipotoxicity-induced MACs impairment. The flavanone profile of bergamot juice was characterized and 16 compounds were identified, with a new 3-hydroxy-3-methylglutaryl (HMG) flavanone, isosakuranetin-7- O -neohesperidoside-6″- O -HMG, described for the first time. Then, a pilot bioavailability study was conducted in healthy volunteers to assess the circulating flavanone metabolites in plasma and urine after consumption of bergamot juice. Up to 12 flavanone phase II conjugates (sulfates and glucuronides of hesperetin, naringenin and eriodyctiol) were detected and quantified. Finally, the effect of some of the metabolites identified in vivo, namely hesperetin-7- O -glucuronide, hesperetin-3'- O -glucuronide, naringenin-7- O -glucuronide and naringenin-4'- O -glucuronide, was tested, at physiological concentrations, on gene expression of inflammatory markers and apoptosis in MACs exposed to SA. Under these conditions, naringenin-4'- O -glucuronide and hesperetin-7- O -glucuronide were able to modulate inflammation, while no flavanone glucuronide was effective in curbing stearate-induced lipoapoptosis. These results demonstrate that some flavanone metabolites, derived from the in vivo transformation of bergamot juice phenolics in humans, may mitigate stearate-induced inflammation in MACs.

[Curcumin in chemoprevention of breast cancer].

PubMed

Terlikowska, Katarzyna; Witkowska, Anna; Terlikowski, Sławomir

2014-01-02

Breast cancer is the most common malignant cancer among women, both in Poland and worldwide. Due to the constantly increasing number of breast cancer cases, it is vital to develop effective activities in primary and secondary prevention. One of the promising methods of best value, connecting both types of cancer prevention, appears to be chemoprevention. Chemoprevention uses natural or synthetic compounds to inhibit, delay or reverse the process of carcinogenesis. Among ingredients of natural origin, great attention is paid to curcumin - a broad-spectrum anti-cancer polyphenol derivative, extracted from the rhizome of Curcuma longa L. Curcumin has a number of chemopreventive properties such as anti-inflammatory activity, induction of apoptosis, inhibition of angiogenesis as well as tumor metastasis. Numerous in vitro and in vivo studies have demonstrated the mentioned anti-cancer effect in the epithelial breast cell line MCF-10A and in the epithelial breast cell lines MCF-7, BT-474, SK-BR-3-hr and MDA-MB-231. The main problem associated with the use of curcumin as a chemopreventive agent in humans is its low absorption from the gastrointestinal tract, poor solubility in body fluids and low bioavailability. Current studies are underway to increase the bioavailability and effectiveness of curcumin in vivo. Good results in the prevention and the treatment of breast cancer could be ensured by curcumin nanoparticles coated with albumin, known as nanocurcumin. The studies using nanocurcumin, however, are still in the preclinical stage, which is why there is a need to conduct extensive long-term randomized clinical trials to determine its effectiveness.

Improved oral bioavailability of poorly water-soluble glimepiride by utilizing microemulsion technique

PubMed Central

Li, Haiying; Pan, Tingting; Cui, Ying; Li, Xiaxia; Gao, Jiefang; Yang, Wenzhi; Shen, Shigang

2016-01-01

The objective of this work was to prepare an oil/water glimepiride (GM) microemulsion (ME) for oral administration to improve its solubility and enhance its bioavailability. Based on a solubility study, pseudoternary phase diagrams, and Box–Behnken design, the oil/water GMME formulation was optimized and prepared. GMME was characterized by dynamic laser light scattering, zeta potential, transmission electron microscopy, and viscosity. The in vitro drug release, storage stability, pharmacodynamics, and pharmacokinetics of GMME were investigated. The optimized GMME was composed of Capryol 90 (oil), Cremophor RH40 (surfactant), and Transcutol (cosurfactant), and increased GM solubility up to 544.6±4.91 µg/mL. The GMME was spherical in shape. The particle size and its polydispersity index were 38.9±17.46 nm and 0.266±0.057, respectively. Meanwhile, the GMME was physicochemically stable at 4°C for at least 3 months. The short-term efficacy in diabetic mice provided the proof that blood glucose had a consistent and significant reduction at a dose of 375 µg/kg whether via IP injection or IG administration of GMME. Compared with the glimepiride suspensions or glimepiride-meglumine complex solution, the pharmacokinetics of GMME in Wistar rats via IG administration exhibited higher plasma drug concentration, larger area under the curve, and more enhanced oral bioavailability. There was a good correlation of GMME between the in vitro release values and the in vivo oral absorption. ME could be an effective oral drug delivery system to improve bioavailability of GM. PMID:27540291

Interactions of polyphenols with carbohydrates, lipids and proteins.

PubMed

Jakobek, Lidija

2015-05-15

Polyphenols are secondary metabolites in plants, investigated intensively because of their potential positive effects on human health. Their bioavailability and mechanism of positive effects have been studied, in vitro and in vivo. Lately, a high number of studies takes into account the interactions of polyphenols with compounds present in foods, like carbohydrates, proteins or lipids, because these food constituents can have significant effects on the activity of phenolic compounds. This paper reviews the interactions between phenolic compounds and lipids, carbohydrates and proteins and their impact on polyphenol activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model.

PubMed

Bichell, Terry Jo V; Wegrzynowicz, Michal; Tipps, K Grace; Bradley, Emma M; Uhouse, Michael A; Bryan, Miles; Horning, Kyle; Fisher, Nicole; Dudek, Karrie; Halbesma, Timothy; Umashanker, Preethi; Stubbs, Andrew D; Holt, Hunter K; Kwakye, Gunnar F; Tidball, Andrew M; Colbran, Roger J; Aschner, Michael; Neely, M Diana; Di Pardo, Alba; Maglione, Vittorio; Osmand, Alexander; Bowman, Aaron B

2017-06-01

Huntington's disease (HD) is caused by a mutation in the huntingtin gene (HTT), resulting in profound striatal neurodegeneration through an unknown mechanism. Perturbations in the urea cycle have been reported in HD models and in HD patient blood and brain. In neurons, arginase is a central urea cycle enzyme, and the metal manganese (Mn) is an essential cofactor. Deficient biological responses to Mn, and reduced Mn accumulation have been observed in HD striatal mouse and cell models. Here we report in vivo and ex vivo evidence of a urea cycle metabolic phenotype in a prodromal HD mouse model. Further, either in vivo or in vitro Mn supplementation reverses the urea-cycle pathology by restoring arginase activity. We show that Arginase 2 (ARG2) is the arginase enzyme present in these mouse brain models, with ARG2 protein levels directly increased by Mn exposure. ARG2 protein is not reduced in the prodromal stage, though enzyme activity is reduced, indicating that altered Mn bioavailability as a cofactor leads to the deficient enzymatic activity. These data support a hypothesis that mutant HTT leads to a selective deficiency of neuronal Mn at an early disease stage, contributing to HD striatal urea-cycle pathophysiology through an effect on arginase activity. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

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.

Improving the biopharmaceutical attributes of mangiferin using vitamin E-TPGS co-loaded self-assembled phosholipidic nano-mixed micellar systems.

PubMed

Khurana, Rajneet Kaur; Gaspar, Balan Louis; Welsby, Gail; Katare, O P; Singh, Kamalinder K; Singh, Bhupinder

2018-06-01

The current research work encompasses the development, characterization, and evaluation of self-assembled phospholipidic nano-mixed miceller system (SPNMS) of a poorly soluble BCS Class IV xanthone bioactive, mangiferin (Mgf) functionalized with co-delivery of vitamin E TPGS. Systematic optimization using I-optimal design yielded self-assembled phospholipidic nano-micelles with a particle size of < 60 nm and > 80% of drug release in 15 min. The cytotoxicity and cellular uptake studies performed using MCF-7 and MDA-MB-231 cell lines demonstrated greater kill and faster cellular uptake. The ex vivo intestinal permeability revealed higher lymphatic uptake, while in situ perfusion and in vivo pharmacokinetic studies indicated nearly 6.6- and 3.0-folds augmentation in permeability and bioavailability of Mgf. In a nutshell, vitamin E functionalized SPNMS of Mgf improved the biopharmaceutical performance of Mgf in rats for enhanced anticancer potency.

Digestibility of starches isolated from stem and root tubers of arracacha, cassava, cush-cush yam, potato and taro.

PubMed

Lovera, Mighay; Pérez, Elevina; Laurentin, Alexander

2017-11-15

Digestibility of arracacha, cassava, cush-cush yam, potato and taro starches was evaluated. In vitro (potentially-available starch and total resistant starch) and in vivo digestibility in the rice weevil (Sitophilus oryzae) bioassay (survival, weight variation, α-amylase like activity [ALA], and uric acid excretion [UAE] as biomarkers) were estimated. In in vitro assays, all starches presented high resistant starch content (14-56%, dry basis), except for cassava starch. In in vivo assays, cush-cush yam and potato starches promoted higher ALA (>3 times) and UAE (>4 times) compare to a reference diet (cornstarch), in agreement to their low digestibility. These two biomarkers were related with resistant starch (r>0.81) and could be used to predict the starch bioavailability. This study demonstrates that the use of both in vitro and in vivo assays allows a better evaluation of starch digestibility, and may help to elucidate the final metabolic fate of starch digestion products. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunochemical detection of food-derived polyphenols in the aorta: macrophages as a major target underlying the anti-atherosclerotic activity of polyphenols.

PubMed

Kawai, Yoshichika

2011-01-01

It has been suggested that polyphenol-rich diets decrease the risk of cardiovascular diseases. Although studies of the bioavailability of polyphenols, particularly their absorption and metabolism, have been reported recently, the tissue and cellular distributions underlying their biological mechanisms remain unknown. It is difficult to evaluate the specific localization of tissue and/or cellular polyphenols, because the method is limited to chromatography. To overcome these difficulties, we have developed anti-polyphenol antibodies to characterize immunohistochemically the localization of polyphenols and their metabolites in vivo. Two novel monoclonal antibodies were raised against quercetin and tea catechins, which represent flavonoid-type polyphenols distributed in foods and beverages, and are expected to exhibit anti-oxidative and anti-inflammatory activities in vivo. Using these antibodies, we identified activated macrophages as a specific target of these flavonoids during the development of atherosclerotic lesions. This review describes recent findings on the molecular actions of flavonoids that underly their anti-atherosclerotic activity in vivo.

Nanosizing of drugs: Effect on dissolution rate

PubMed Central

Dizaj, S. Maleki; Vazifehasl, Zh.; Salatin, S.; Adibkia, Kh.; Javadzadeh, Y.

2015-01-01

The solubility, bioavailability and dissolution rate of drugs are important parameters for achieving in vivo efficiency. The bioavailability of orally administered drugs depends on their ability to be absorbed via gastrointestinal tract. For drugs belonging to Class II of pharmaceutical classification, the absorption process is limited by drug dissolution rate in gastrointestinal media. Therefore, enhancement of the dissolution rate of these drugs will present improved bioavailability. So far several techniques such as physical and chemical modifications, changing in crystal habits, solid dispersion, complexation, solubilization and liquisolid method have been used to enhance the dissolution rate of poorly water soluble drugs. It seems that improvement of the solubility properties ofpoorly water soluble drugscan translate to an increase in their bioavailability. Nowadays nanotechnology offers various approaches in the area of dissolution enhancement of low aqueous soluble drugs. Nanosizing of drugs in the form of nanoparticles, nanocrystals or nanosuspensions not requiring expensive facilities and equipment or complicated processes may be applied as simple methods to increase the dissolution rate of poorly water soluble drugs. In this article, we attempted to review the effects of nanosizing on improving the dissolution rate of poorly aqueous soluble drugs. According to the reviewed literature, by reduction of drug particle size into nanometer size the total effective surface area is increased and thereby dissolution rate would be enhanced. Additionally, reduction of particle size leads to reduction of the diffusion layer thickness surrounding the drug particles resulting in the increment of the concentration gradient. Each of these process leads to improved bioavailability. PMID:26487886

Imprinted-like biopolymeric micelles as efficient nanovehicles for curcumin delivery.

PubMed

Zhang, Lili; Qi, Zeyou; Huang, Qiyu; Zeng, Ke; Sun, Xiaoyi; Li, Juan; Liu, You-Nian

2014-11-01

To enhance the solubility and improve the bioavailability of hydrophobic curcumin, a new kind of imprinted-like biopolymeric micelles (IBMs) was designed. The IBMs were prepared via co-assembly of gelatin-dextran conjugates with hydrophilic tea polyphenol, then crosslinking the assembled micelles and finally removing the template tea polyphenol by dialysis. The obtained IBMs show selective binding for polyphenol analogous drugs over other drugs. Furthermore, curcumin can be effectively encapsulated into the IBMs with 5×10(4)-fold enhancement of aqueous solubility. We observed the sustained drug release behavior from the curcumin-loaded IBMs (CUR@IBMs) in typical biological buffers. In addition, we found the cell uptake of CUR@IBMs is much higher than that of free curcumin. The cell cytotoxicity results illustrated that CUR@IBMs can improve the growth inhibition of HeLa cells compared with free curcumin, while the blank IBMs have little cytotoxicity. The in vivo animal study demonstrated that the IBMs could significantly improve the oral bioavailability of curcumin. Copyright © 2014 Elsevier B.V. All rights reserved.

Chemotherapeutic potential of curcumin-bearing microcells against hepatocellular carcinoma in model animals

PubMed Central

Farazuddin, Mohammad; Dua, Bhavyata; Zia, Qamar; Khan, Aijaz Ahmad; Joshi, Beenu; Owais, Mohammad

2014-01-01

Curcumin (diferuloylmethane) is found in large quantities in the roots of Curcuma longa. It possesses strong antioxidant and anti-inflammatory properties, and inhibits chemically-induced carcinogenesis in the skin, forestomach, colon, and liver. Unfortunately, the poor bioavailability and hydrophobicity of curcumin pose a major hurdle to its use as a potent anticancer agent. To circumvent some of these problems, we developed a novel, dual-core microcell formulation of curcumin. The encapsulation of curcumin in microcells increases its solubility and bioavailability, and facilitates slow release kinetics over extended periods. Besides being safe, these formulations do not bear any toxicity constraints, as revealed by in vitro and in vivo studies. Histopathological analysis revealed that curcumin-bearing microcells helped in regression of hepatocellular carcinoma and the maintenance of cellular architecture in liver tissue. Free curcumin had a very mild effect on cancer suppression. Empty (sham) microcells and microparticles failed to inhibit cancer cells. The novel curcumin formulation was found to suppress hepatocellular carcinoma efficiently in Swiss albino mice. PMID:24627632

Enhanced oral bioavailability and anticancer activity of novel curcumin loaded mixed micelles in human lung cancer cells.

PubMed

Patil, Sharvil; Choudhary, Bhavana; Rathore, Atul; Roy, Krishtey; Mahadik, Kakasaheb

2015-11-15

Curcumin has a wide range of pharmacological activities including antioxidant, anti-inflammatory, antidiabetic, antibacterial, wound healing, antiatherosclerotic, hepatoprotective and anti-carcinogenic. However, its clinical applications are limited owing to its poor aqueous solubility, multidrug pump P-gp efflux, extensive in vivo metabolism and rapid elimination due to glucuronidation/sulfation. The objective of the current work was to prepare novel curcumin loaded mixed micelles (CUR-MM) of Pluronic F-127 (PF127) and Gelucire® 44/14 (GL44) in order to enhance its oral bioavailability and cytotoxicity in human lung cancer cell line A549. 3(2) Factorial design was used to assess the effect of formulation variables for optimization of mixed micelle batch. CUR-MM was prepared by a solvent evaporation method. The optimized CUR-MM was evaluated for size, entrapment efficiency (EE), in vitro curcumin release, cytotoxicity and oral bioavailability in rats. The average size of CUR-MM was found to be around 188 ± 3 nm with an EE of about 76.45 ± 1.18% w/w. In vitro dissolution profile of CUR-MM revealed controlled release of curcumin. Additionally, CUR-MM showed significant improvement in cytotoxic activity (3-folds) and oral bioavailability (around 55-folds) of curcumin as compared to curcumin alone. Such significant improvement in cytotoxic activity and oral bioavailability of curcumin when formulated into mixed micelles could be attributed to solubilization of hydrophobic curcumin into micelle core along with P-gp inhibition effect of both, PF127 and GL44. Thus the present work propose the formulation of mixed micelles of PF127 and GL44 which can act as promising carrier systems for hydrophobic drugs such as curcumin with significant improvement in their oral bioavailability. Copyright © 2015 Elsevier GmbH. All rights reserved.

Comparison of in vitro digestive fluid extraction and traditional in vivo approaches as measures of polycyclic aromatic hydrocarbon bioavailability from sediments

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

Weston, D.P.; Mayer, L.M.

1998-05-01

The bioavailability of particle-associated contaminants was measured by a new approach that employs the digestive fluid of deposit feeders to solubilize contaminants in vitro. The proportion of contaminant solubilized by digestive fluid of the polychaete Arenicola brasiliensis was considered a measure of bioavailability and was contrasted with other, more traditional measures (i.e., uptake clearance, bioaccumulation factor, and absorption efficiency). There was generally good agreement among the four methods on the relative bioavailability of benzo[a]pyrene from six sandy sediments. Measures of phenanthrene bioavailability did not show strong correlations due to both a more limited data set and perhaps greater importance ofmore » uptake from the dissolved phase. The bioavailability of spiked polycyclic aromatic hydrocarbons (PAHs) differed from that of equivalent in situ-contaminated PAH but not in a predictable and consistent manner. By direct measurement of PAH content of recently ingested sediments collected from the foregut the authors were able to quantify the importance of particle-selective feeding in increasing PAH content of ingested material relative to the bulk, ambient sediments. In most instances, the effect of selective feeding by A. brasiliensis was minimal, increasing PAH content of ingested material <20% above the ambient sediments. Absorption efficiencies of PAH during gut passage were determined by direct measurement of PAH concentration in sediments at various points along the digestive tract. Overall digestive absorption efficiencies were similar to the extent of in vitro solubilization by digestive fluids from the same sediments. These data suggest that extent of solubilization of sediment-bound contaminants during gut passage is a critical constraint on uptake and that absorption efficiency, with respect to the solubilized fraction, approaches 100%.« less

Advantages and limitations of in vitro and in vivo methods of iron and zinc bioavailability evaluation in the assessment of biofortification program effectiveness

USDA-ARS?s Scientific Manuscript database

Biofortification aims to improve the micronutrient concentration of staple food crops through the best practices of breeding and modern biotechnology. However, increased zinc and iron concentrations in food crops may not always translate into proportional increases in absorbed zinc (Zn) and iron (Fe...

Resveratrol and cancer: focus on in vivo evidence

PubMed Central

Carter, Lindsay G; D'Orazio, John A; Pearson, Kevin J

2014-01-01

Resveratrol is a naturally occurring polyphenol that provides a number of anti-aging health benefits including improved metabolism, cardioprotection, and cancer prevention. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are, however, comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo, perhaps limited by its poor bioavailability when taken orally. Although research in cell culture has shown promising and positive effects of resveratrol, evidence from rodents and humans is inconsistent. This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers. Resveratrol supplementation in animal models of cancer has shown positive, neutral as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors. Within a specific cancer type, there is variability between studies with respect to strain, age, and sex of animal used, timing and method of resveratrol supplementation, and dose of resveratrol used to study cancer endpoints. Together, the data suggest that many factors need to be considered before resveratrol can be used for human cancer prevention or therapy. PMID:24500760