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Sample records for long-acting plga microspheres

  1. Development of Risperidone PLGA Microspheres

    PubMed Central

    D'Souza, Susan; Faraj, Jabar A.; Giovagnoli, Stefano; DeLuca, Patrick P.

    2014-01-01

    The aim of this study was to design and evaluate biodegradable PLGA microspheres for sustained delivery of Risperidone, with an eventual goal of avoiding combination therapy for the treatment of schizophrenia. Two PLGA copolymers (50 : 50 and 75 : 25) were used to prepare four microsphere formulations of Risperidone. The microspheres were characterized by several in vitro techniques. In vivo studies in male Sprague-Dawley rats at 20 and 40 mg/kg doses revealed that all formulations exhibited an initial burst followed by sustained release of the active moiety. Additionally, formulations prepared with 50 : 50 PLGA had a shorter duration of action and lower cumulative AUC levels than the 75 : 25 PLGA microspheres. A simulation of multiple dosing at weekly or 15-day regimen revealed pulsatile behavior for all formulations with steady state being achieved by the second dose. Overall, the clinical use of Formulations A, B, C, or D will eliminate the need for combination oral therapy and reduce time to achieve steady state, with a smaller washout period upon cessation of therapy. Results of this study prove the suitability of using PLGA copolymers of varying composition and molecular weight to develop sustained release formulations that can tailor in vivo behavior and enhance pharmacological effectiveness of the drug. PMID:24616812

  2. PLGA/alginate composite microspheres for hydrophilic protein delivery.

    PubMed

    Zhai, Peng; Chen, X B; Schreyer, David J

    2015-11-01

    Poly(lactic-co-glycolic acid) (PLGA) microspheres and PLGA/alginate composite microspheres were prepared by a novel double emulsion and solvent evaporation technique and loaded with bovine serum albumin (BSA) or rabbit anti-laminin antibody protein. The addition of alginate and the use of a surfactant during microsphere preparation increased the encapsulation efficiency and reduced the initial burst release of hydrophilic BSA. Confocal laser scanning microcopy (CLSM) of BSA-loaded PLGA/alginate composite microspheres showed that PLGA, alginate, and BSA were distributed throughout the depths of microspheres; no core/shell structure was observed. Scanning electron microscopy revealed that PLGA microspheres erode and degrade more quickly than PLGA/alginate composite microspheres. When loaded with anti-laminin antibody, the function of released antibody was well preserved in both PLGA and PLGA/alginate composite microspheres. The biocompatibility of PLGA and PLGA/alginate microspheres were examined using four types of cultured cell lines, representing different tissue types. Cell survival was variably affected by the inclusion of alginate in composite microspheres, possibly due to the sensitivity of different cell types to excess calcium that may be released from the calcium cross-linked alginate. PMID:26249587

  3. Size matters: effects of PLGA-microsphere size in injectable CPC/PLGA on bone formation.

    PubMed

    Liao, Hongbing; Félix Lanao, Rosa P; van den Beucken, Jeroen J J P; Zhou, Nuo; Both, Sanne K; Wolke, Joop G C; Jansen, John A

    2016-08-01

    The aim of this study was to evaluate the effect of PLGA microsphere dimensions on bone formation after injection of calcium phosphate cement (CPC)/PLGA in a guinea pig tibial intramedullarly model. To this end, injectable CPC/PLGA formulations were prepared using PLGA microspheres with either a small (~25 µm) or large (~100 µm) diameter, which were incorporated at a 20:80 ratio (wt%) within apatite CPC. Both CPC/PLGA formulations were injected into a marrow-ablated tibial intramedullary cavity and, after an implantation period of 12 weeks, histology and histomorphometry were used to address bone formation. The results demonstrated bone ingrowth throughout the entire scaffold material for both CPC/PLGA formulations upon PLGA microsphere degradation. More importantly, bone formation within the CPC matrix was > two-fold higher for CPC-PLGA with 25 µm PLGA microspheres. Additionally, the pattern of bone and marrow formation showed distinct differences related to PLGA microsphere dimension. In general, this study demonstrates that PLGA microsphere dimensions of ~25 µm, leading to pores of ~25 µm within CPC, are sufficient for bone ingrowth and allow substantial bone formation. Further, the results demonstrate that PLGA microsphere dimensions provide a tool to control bone formation for injectable CPC/PLGA bone substitutes. Copyright © 2013 John Wiley & Sons, Ltd. PMID:24170734

  4. Seeing is believing, PLGA microsphere degradation revealed in PLGA microsphere/PVA hydrogel composites.

    PubMed

    Gu, Bing; Sun, Xuanhao; Papadimitrakopoulos, Fotios; Burgess, Diane J

    2016-04-28

    The aim of this study was to understand the polymer degradation and drug release mechanism from PLGA microspheres embedded in a PVA hydrogel. Two types of microspheres were prepared with different molecular weight PLGA polymers (approximately 25 and 7kDa) to achieve different drug release profiles, with a 9-day lag phase and without a lag phase, respectively. The kinetics of water uptake into the microspheres coincided with the drug release profiles for both formulations. For the 25kDa microspheres, minimal water uptake was observed in the early part of the lag phase followed by substantial water uptake at the later stages and in the drug release phase. For the 7kDa microspheres, water uptake occurred simultaneously with drug release. Water uptake was approximately 2-3 times that of the initial microsphere weight for both formulations. The internal structure of the PLGA microspheres was evaluated using low temperature scanning electron microscopy (cryo-SEM). Burst drug release occurred followed by pore forming from the exterior to the core of both microspheres. A well-defined hydrogel/microsphere interface was observed. For the 25kDa microspheres, internal pore formation and swelling occurred before the second drug release phase. The surface layer of the microspheres remained intact whereas swelling, and degradation of the core continued throughout the drug release period. In addition, microsphere swelling reduced glucose transport through the coatings in PBS media and this was considered to be a as a consequence of the increased thickness of the coatings. The combination of the swelling and microdialysis results provides a fresh understanding on the competing processes affecting molecular transport of bioanalytes (i.e. glucose) through these composite coatings during prolonged exposure in PBS. PMID:26965956

  5. Effects of formulation parameters on encapsulation efficiency and release behavior of thienorphine loaded PLGA microspheres.

    PubMed

    Yang, Yang; Gao, Yongliang; Mei, Xingguo

    2013-01-01

    To develop a long-acting injectable thienorphine biodegradable poly (d, l-lactide-co-glycolide) (PLGA) microsphere for the therapy of opioid addiction, the effects of formulation parameters on encapsulation efficiency and release behavior were studied. The thienorphine loaded PLGA microspheres were prepared by o/w solvent evaporation method and characterized by HPLC, SEM, laser particle size analysis, residual solvent content and sterility testing. The microspheres were sterilized by gamma irradiation (2.5 kGy). The results indicated that the morphology of the thienorphine PLGA microspheres presented a spherical shape with smooth surface, the particle size was distributed from 30.19 ± 1.17 to 59.15 ± 0.67 μm and the drug encapsulation efficiency was influenced by drug/polymer ratio, homogeneous rotation speed, PVA concentration in the water phase and the polymer concentration in the oil phase. These changes were also reflected in drug release. The plasma drug concentration vs. time profiles were relatively smooth for about 25 days after injection of the thienorphine loaded PLGA microspheres to beagle dogs. In vitro and in vivo correlation was established. PMID:21967467

  6. In Vitro and In Vivo Evaluations of PLGA Microspheres Containing Nalmefene

    PubMed Central

    Xie, Xiangyang; Lin, Wen; Xing, Chuanfeng; Yang, Yanfang; Chi, Qiang; Zhang, Hui; Li, Ying; Li, Zhiping; Yang, Yang; Yang, Zhenbo; Li, Mingyuang

    2015-01-01

    Poor patient compliance, untoward reactions and unstable blood drug levels after the bolus administration are impeding the pharmacotherapy for insobriety. A long-acting preparation may address these limitations. The aim of this paper was to further investigate the in vitro characteristics and in vivo performances of nalmefene microspheres. Nalmefene was blended with poly (lactide-co-glycolide) (PLGA) to prepare the target microspheres by an O/O emulsification solvent evaporation method. The prepared microspheres exhibited a controlled release profile of nalmefene in vitro over 4 weeks, which was well fitted with a first-order model. In vitro degradation study showed that the drug release in vitro was dominated by both drug diffusion and polymer degradation mechanisms. Pharmacokinetics study indicated that the prepared microspheres could provide a relatively constant of nalmefene plasma concentration for at least one month in rats. The in vivo pharmacokinetics profile was well correlated with the in vitro drug release. Pharmacodynamics studies revealed that the drug loaded microspheres could produce a long-acting antagonism efficacy on rats. These results demonstrated the promising application of injectable PLGA microspheres containing nalmefene for the long-term treatment of alcohol dependence. PMID:25938514

  7. Prediction of dexamethasone release from PLGA microspheres prepared with polymer blends using a design of experiment approach.

    PubMed

    Gu, Bing; Burgess, Diane J

    2015-11-10

    Hydrophobic drug release from poly (lactic-co-glycolic acid) (PLGA) microspheres typically exhibits a tri-phasic profile with a burst release phase followed by a lag phase and a secondary release phase. High burst release can be associated with adverse effects and the efficacy of the formulation cannot be ensured during a long lag phase. Accordingly, the development of a long-acting microsphere product requires optimization of all drug release phases. The purpose of the current study was to investigate whether a blend of low and high molecular weight polymers can be used to reduce the burst release and eliminate/minimize the lag phase. A single emulsion solvent evaporation method was used to prepare microspheres using blends of two PLGA polymers (PLGA5050 (25 kDa) and PLGA9010 (113 kDa)). A central composite design approach was applied to investigate the effect of formulation composition on dexamethasone release from these microspheres. Mathematical models obtained from this design of experiments study were utilized to generate a design space with maximized microsphere drug loading and reduced burst release. Specifically, a drug loading close to 15% can be achieved and a burst release less than 10% when a composition of 80% PLGA9010 and 90 mg of dexamethasone is used. In order to better describe the lag phase, a heat map was generated based on dexamethasone release from the PLGA microsphere/PVA hydrogel composite coatings. Using the heat map an optimized formulation with minimum lag phase was selected. The microspheres were also characterized for particle size/size distribution, thermal properties and morphology. The particle size was demonstrated to be related to the polymer concentration and the ratio of the two polymers but not to the dexamethasone concentration. PMID:26325309

  8. The in vivo performance of CaP/PLGA composites with varied PLGA microsphere sizes and inorganic compositions.

    PubMed

    Hoekstra, Jan Willem M; Ma, Jinling; Plachokova, Adelina S; Bronkhorst, Ewald M; Bohner, Marc; Pan, Juli; Meijer, Gert J; Jansen, John A; van den Beucken, Jeroen J J P

    2013-07-01

    Enrichment of calcium phosphate (CaP) bone substitutes with poly(lactic-co-glycolic acid) (PLGA) microspheres to create porosity overcomes the problem of poor CaP degradation. The degradation of CaP-PLGA composites can be customized by changing the physical and chemical properties of PLGA and/or CaP. However, the effect of the size of dense (solid rather than hollow) PLGA microspheres in CaP has not previously been described. The present study aimed at determining the effect of different dense (i.e. solid) PLGA microsphere sizes (small (S) ~20μm vs. large (L) ~130μm) and of CaP composition (CaP with either anhydrous dicalcium phosphate (DCP) or calcium sulphate dihydrate (CSD)) on CaP scaffold biodegradability and subsequent bone in-growth. To this end mandibular defects in minipigs were filled with pre-set CaP-PLGA implants, with autologous bone being used as a control. After 4weeks the autologous bone group outperformed all CaP-PLGA groups in terms of the amount of bone present at the defect site. On the other hand, at 12weeks substantial bone formation was observed for all CaP-PLGA groups (ranging from 47±25% to 62±15%), showing equal amounts of bone compared with the autologous bone group (82±9%), except for CaP with DCP and large PLGA microspheres (47±25%). It was concluded that in the current study design the difference in PLGA microsphere size and CaP composition led to similar results with respect to scaffold degradation and subsequent bone in-growth. Further, after 12weeks all CaP-PLGA composites proved to be effective for bone substitution. PMID:23511808

  9. Design of Controlled Release PLGA Microspheres for Hydrophobic Fenretinide.

    PubMed

    Zhang, Ying; Wischke, Christian; Mittal, Sachin; Mitra, Amitava; Schwendeman, Steven P

    2016-08-01

    Fenretinide, a chemotherapeutic agent for cancer, is water-insoluble and has a very low oral bioavailability. Hence, the objective was to deliver it as an injectable depot and improve the drug solubility and release behavior from poly(lactide-co-glycolide) (PLGA) microspheres by incorporating nonionic surfactants with fenretinide. Enhancement of drug solubilization was observed with Brij 35 or 98, Tween 20, and Pluronic F127, but not Pluronic F68. Co-incorporation of Brij 98 with fenretinide significantly changed the microsphere morphology and improved the fenretinide release profile. The most optimal microsphere formulation, with 20% Brij 98 as excipient, showed an initial in vitro burst around 20% and a sustained release over 28 days in a solubilizing release medium at 37 °C. The effect of addition of MgCO3, drug loading, and polymer blending on the release of fenretinide from PLGA microspheres was also investigated and observed to enhance the drug release. Two sustained release formulations, one incorporating 20% Brij 98 and the other incorporating 3% MgCO3 in the oil phase, were selected for dosing in Sprague-Dawley rats and compared to a single injection of an equivalent dose of fenretinide drug suspension. These two formulations were chosen due to their high encapsulation efficiency, high cumulative release, and desirable in vitro release profile. The drug suspension resulted in a higher initial release in rats compared to the polymeric formulations, however, sustained release was also observed beyond 2 weeks, which may be attributed to the physiological disposition of the drug in vivo. The two PLGA based test formulations provided the desired low initial burst of fenretinide followed by 4 weeks of in vivo sustained release. PMID:27144450

  10. Formulation and in vitro/in vivo evaluation of terbutaline sulphate incorporated in PLGA (25/75) and L-PLA microspheres.

    PubMed

    Selek, H; Sahin, S; Ercan, M T; Sargon, M; Hincal, A A; Kas, H S

    2003-01-01

    Terbutaline sulphate (TBS) is widely used in the treatment of bronchial asthma, chronic bronchitis and emphysema. Because of its short biological half life and dosing schedule, a long acting TBS formulation is required to improve patient compliance. The objective of this study was to develop a TBS containing biodegradable microsphere formulation. Poly(D,L-lactide-co-glycolide) (PLGA) and poly(L-lactic acid) (L-PLA) were chosen as matrix materials. A solvent evaporation method was used for preparation of microspheres. Surface morphology, particle size distribution and encapsulation efficiency were investigated. In vitro release studies were performed in pH 7.4 phosphate buffer. In vitro distribution of microspheres were studied in the Swiss albino male mice. All microspheres were spherical in shape and had a porous surface with mean diameters of 9-21 microm. The encapsulation efficiency was influenced by the polymer type, but not the molecular weight. About 90% of the initial amount was trapped in PLGA microspheres, and the remainder was on the surface. In the case of L-PLA, 50% of the total drug was associated with the surface of microspheres. The In vitro release pattern was biphasic characterized by an initial burst phase followed by a slower phase. The L-PLA microspheres released approximately 92% of the initial payload in 72 h. On the other hand, TBS release was increased with an increase in the molecular weight of PLGA. Biodistribution of L-PLA microspheres was characterized by an initially high uptake (35%) by the lungs. All these results suggest that L-PLA and PLGA microspheres have the potential to be used for passive lung targeting. PMID:12554379

  11. Heuristic modeling of macromolecule release from PLGA microspheres.

    PubMed

    Szlęk, Jakub; Pacławski, Adam; Lau, Raymond; Jachowicz, Renata; Mendyk, Aleksander

    2013-01-01

    Dissolution of protein macromolecules from poly(lactic-co-glycolic acid) (PLGA) particles is a complex process and still not fully understood. As such, there are difficulties in obtaining a predictive model that could be of fundamental significance in design, development, and optimization for medical applications and toxicity evaluation of PLGA-based multiparticulate dosage form. In the present study, two models with comparable goodness of fit were proposed for the prediction of the macromolecule dissolution profile from PLGA micro- and nanoparticles. In both cases, heuristic techniques, such as artificial neural networks (ANNs), feature selection, and genetic programming were employed. Feature selection provided by fscaret package and sensitivity analysis performed by ANNs reduced the original input vector from a total of 300 input variables to 21, 17, 16, and eleven; to achieve a better insight into generalization error, two cut-off points for every method was proposed. The best ANNs model results were obtained by monotone multi-layer perceptron neural network (MON-MLP) networks with a root-mean-square error (RMSE) of 15.4, and the input vector consisted of eleven inputs. The complicated classical equation derived from a database consisting of 17 inputs was able to yield a better generalization error (RMSE) of 14.3. The equation was characterized by four parameters, thus feasible (applicable) to standard nonlinear regression techniques. Heuristic modeling led to the ANN model describing macromolecules release profiles from PLGA microspheres with good predictive efficiency. Moreover genetic programming technique resulted in classical equation with comparable predictability to the ANN model. PMID:24348037

  12. Heuristic modeling of macromolecule release from PLGA microspheres

    PubMed Central

    Szlęk, Jakub; Pacławski, Adam; Lau, Raymond; Jachowicz, Renata; Mendyk, Aleksander

    2013-01-01

    Dissolution of protein macromolecules from poly(lactic-co-glycolic acid) (PLGA) particles is a complex process and still not fully understood. As such, there are difficulties in obtaining a predictive model that could be of fundamental significance in design, development, and optimization for medical applications and toxicity evaluation of PLGA-based multiparticulate dosage form. In the present study, two models with comparable goodness of fit were proposed for the prediction of the macromolecule dissolution profile from PLGA micro- and nanoparticles. In both cases, heuristic techniques, such as artificial neural networks (ANNs), feature selection, and genetic programming were employed. Feature selection provided by fscaret package and sensitivity analysis performed by ANNs reduced the original input vector from a total of 300 input variables to 21, 17, 16, and eleven; to achieve a better insight into generalization error, two cut-off points for every method was proposed. The best ANNs model results were obtained by monotone multi-layer perceptron neural network (MON-MLP) networks with a root-mean-square error (RMSE) of 15.4, and the input vector consisted of eleven inputs. The complicated classical equation derived from a database consisting of 17 inputs was able to yield a better generalization error (RMSE) of 14.3. The equation was characterized by four parameters, thus feasible (applicable) to standard nonlinear regression techniques. Heuristic modeling led to the ANN model describing macromolecules release profiles from PLGA microspheres with good predictive efficiency. Moreover genetic programming technique resulted in classical equation with comparable predictability to the ANN model. PMID:24348037

  13. Development of new reverse micellar microencapsulation technique to load water-soluble drug into PLGA microspheres.

    PubMed

    Kim, Hyunjoo; Cho, Mihyun; Sah, Hongkee

    2005-03-01

    The objective of this study was to develop a new reverse micelle-based microencapsulation technique to load tetracycline hydrochloride into PLGA microspheres. To do so, a reverse micellar system was formulated to dissolve tetracycline hydrochloride and water in ethyl formate with the aid of cetyltrimethylammonium bromide. The resultant micellar solution was used to dissolve 0.3 to 0.75 g of PLGA, and microspheres were prepared following a modified solvent quenching technique. As a control experiment, the drug was encapsulated into PLGA microspheres via a conventional methylene chloride-based emulsion procedure. The microspheres were then characterized with regard to drug loading efficiency, their size distribution and morphology. The reverse micellar procedure led to the formation of free-flowing, spherical microspheres with the size mode of 88 microm. When PLGA microspheres were prepared following the conventional methylene chloride-based procedure, most of tetracycline hydrochloride leached to the aqueous external phase: A maximal loading efficiency observed our experimental conditions was below 5%. Their surfaces had numerous pores, while their internal architecture was honey-combed. In sharp contrast, the new reverse micellar encapsulation technique permitted the attainment of a maximal loading efficiency of 63.19 +/- 0.64%. Also, the microspheres had smooth and pore-free surfaces, and hollow cavities were absent from their internal matrices. The results of this study demonstrated that PLGA microspheres could be successfully prepared following the new reverse micellar encapsulation technique. PMID:15832828

  14. Fabrication of PLGA polymer microspheres for U. S. mediated gene delivery

    NASA Astrophysics Data System (ADS)

    Williamson, Rene G.; Saltzman, William M.; Brandsma, Janet L.

    2001-05-01

    The promises of gene therapy remain unfulfilled because of the lack of a safe and efficient method for transfecting DNA into cells. PLGA has been used as a vehicle for protein, drug, and gene delivery applications because of its biocompatibility and sustained release properties. PLGA polymer microspheres offer advantages of safety and the possibility of sustained intracytoplasmic delivery. The PLGA also protects the plasmid from degradation. Using the double-emulsion microsphere fabrication technique, a new DNA delivery vehicle, comprising of plasmid DNA and octafluoropropane gas encapsulated in PLGA polymer and PVA stabilizer (Sonospheres) was made. The encapsulated gas offers acoustic activity to the microspheres, which enables them to undergo cavitation in an acoustic field. The goal is to lead to increased DNA transfection when these Sonospheres are subjected to an acoustic field in the MHz frequency range. A summary of the fabrication methods and some initial in vitro studies will be presented.

  15. Gelatin/chitosan/hyaluronan scaffold integrated with PLGA microspheres for cartilage tissue engineering.

    PubMed

    Tan, Huaping; Wu, Jindan; Lao, Lihong; Gao, Changyou

    2009-01-01

    Poly(lactide-co-glycotide) (PLGA) microspheres integrated into gelatin/chitosan/hyaluronan scaffolds were fabricated by freeze-drying and crosslinking with 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide. The effects of the microspheres on porosity, density, compressive modulus, phosphate-buffered saline uptake ratio and weight loss of the scaffolds were evaluated. Generally, a scaffold with a higher PLGA content had a lower porosity and weight loss, and a medium uptake ratio, but a larger apparent density and compressive modulus. When the PLGA content was lower than 50%, the PLGA-integrated scaffolds had a similar pore size (approximately 200microm) as that of the control, and as much as 90% of their porosity could be preserved. In vitro chondrocyte culture in the 50% PLGA-integrated scaffold demonstrated that the cells could proliferate and secrete extracellular matrix at the same level as in the control gelatin/chitosan/hyaluronan scaffold. PMID:18723417

  16. Facile fabrication of biocompatible PLGA drug-carrying microspheres by O/W pickering emulsions.

    PubMed

    Wei, Zengjiang; Wang, Chaoyang; Liu, Hao; Zou, Shengwen; Tong, Zhen

    2012-03-01

    This study is focused on the preparation of Ibuprofen (IBU) loaded micrometer-sized poly(lactic-co-glycolic acid) (PLGA) microspheres and process variables on the size, drug loading and release during preparation of formulation. Silicon dioxide (SiO(2)) nanoparticle-coated PLGA microspheres were fabricated via a combined system of "Pickering-type" emulsion route and solvent volatilization method in the absence of any molecular surfactants. Stable oil-in-water emulsions were prepared using SiO(2) nanoparticles as a particulate emulsifier and a dichloromethane (CH(2)Cl(2)) solution of PLGA as an oil phase. The SiO(2) nanoparticle-coated PLGA microspheres were fabricated by the evaporation of CH(2)Cl(2) in situ, and then bare-PLGA microspheres were prepared by removal of the SiO(2) nanoparticles using HF aqueous solution. The two types of microspheres were characterized in terms of size, component and morphology using scanning electronic microscope (SEM), Fourier-transform infrared, optical microscope, and so on. Moreover, IBU was encapsulated into the hybrid beads by dispersing them in the CH(2)Cl(2) solution of PLGA in the fabrication process. The sustained release could be obtained due to the barrier of the polymeric matrix (PLGA). More over, the release curves were nicely fitted by the Weibull equation and the release followed Fickian diffusion. The combined system of Pickering emulsion and solvent volatilization opens up a new route to fabricate a variety of microspheres. The resulting microspheres may find applications as delivery vehicles for biomolecules, drugs, cosmetics and living cells. PMID:22088755

  17. Porous silicon oxide-PLGA composite microspheres for sustained ocular delivery of daunorubicin

    PubMed Central

    Nan, Kaihui; Ma, Feiyan; Hou, Huiyuan; Freeman, William R.; Sailor, Michael J.; Cheng, Lingyun

    2014-01-01

    A water-soluble anthracycline antibiotic drug (daunorubicin, DNR) was loaded into oxidized porous silicon (pSiO2) microparticles and then encapsulated with a layer of polymer (poly lactide-co-glycolide, PLGA) to investigate their synergistic effects in control of DNR release. Similarly fabricated PLGA-DNR microspheres without pSiO2, and pSiO2 microparticles without PLGA were used as control particles. The composite microparticles synthesized by a solid-in-oil-in-water (S/O/W) emulsion method have mean diameters of 52.33±16.37 μm for PLGA-pSiO2_21/40-DNR and the mean diameter of 49.31±8.87 μm for PLGA-pSiO2_6/20-DNR. The mean size, 26.00±8 μm, of PLGA-DNR was significantly smaller, compared with the other two (p<0.0001). Optical microscopy revealed that PLGA-pSiO2-DNR microsphere contained multiple pSiO2 particles. In vitro release experiments determined that control PLGA-DNR microspheres completely released DNR within 38 days and control pSiO2-DNR microparticles (with no PLGA coating) released DNR within 14 days, while the PLGA-pSiO2-DNR microspheres released DNR for 74 days. Temporal release profiles of DNR from PLGA-pSiO2 composite particles indicated that both PLGA and pSiO2 contribute to the sustained release of the payload. The PLGA-pSiO2 composite displayed a more constant rate of DNR release than the pSiO2 control formulation, and it displayed a significantly slower release of DNR than either the PLGA or pSiO2 formulations. We conclude that this system may be useful in managing unwanted ocular proliferation when formulated with anti-proliferation compounds such as DNR. PMID:24793657

  18. Active self-healing encapsulation of vaccine antigens in PLGA microspheres

    PubMed Central

    Desai, Kashappa-Goud H.; Schwendeman, Steven P.

    2013-01-01

    Herein, we describe the detailed development of a simple and effective method to microencapsulate vaccine antigens in poly(lactic-co-glycolic acid) (PLGA) by simple mixing of preformed active self-microencapsulating (SM) PLGA microspheres in a low concentration aqueous antigen solution at modest temperature (10-38 °C). Co-encapsulating protein-sorbing vaccine adjuvants and polymer plasticizers were used to “actively” load the protein in the polymer pores and facilitate polymer self-healing at temperature > hydrated polymer glass transition temperature, respectively. The microsphere formulation parameters and loading conditions to provide optimal active self-healing microencapsulation of vaccine antigen in PLGA was investigated. Active self-healing encapsulation of two vaccine antigens, ovalbumin and tetanus toxoid (TT), in PLGA microspheres was adjusted by preparing blank microspheres containing different vaccine adjuvant (aluminum hydroxide (Al(OH)3) or calcium phosphate). Active loading of vaccine antigen in Al(OH)3-PLGA microspheres was found to: a) increase proportionally with an increasing loading of Al(OH)3 (0.88-3 wt%) and addition of porosigen, b) decrease when the inner Al(OH)3/trehalose phase to 1 mL outer oil phase and size of microspheres was respectively > 0.2 mL and 63 μm, and c) change negligibly by PLGA concentration and initial incubation (loading) temperature. Encapsulation of protein sorbing Al(OH)3 in PLGA microspheres resulted in suppression of self-healing of PLGA pores, which was then overcome by improving polymer chain mobility, which in turn was accomplished by coincorporating hydrophobic plasticizers in PLGA. Active self-healing microencapsulation of manufacturing process-labile TT in PLGA was found to: a) obviate micronization- and organic solvent-induced TT degradation, b) improve antigen loading (1.4-1.8 wt% TT) and encapsulation efficiency (~ 97%), c) provide nearly homogeneous distribution and stabilization of antigen in polymer

  19. Active self-healing encapsulation of vaccine antigens in PLGA microspheres.

    PubMed

    Desai, Kashappa-Goud H; Schwendeman, Steven P

    2013-01-10

    Herein, we describe the detailed development of a simple and effective method to microencapsulate vaccine antigens in poly(lactic-co-glycolic acid) (PLGA) by simple mixing of preformed active self-microencapsulating (SM) PLGA microspheres in a low concentration aqueous antigen solution at modest temperature (10-38 °C). Co-encapsulating protein-sorbing vaccine adjuvants and polymer plasticizers were used to "actively" load the protein in the polymer pores and facilitate polymer self-healing at a temperature>the hydrated polymer glass transition temperature, respectively. The microsphere formulation parameters and loading conditions to provide optimal active self-healing microencapsulation of vaccine antigens in PLGA was investigated. Active self-healing encapsulation of two antigens, ovalbumin and tetanus toxoid (TT), in PLGA microspheres was adjusted by preparing blank microspheres containing different vaccine adjuvants (aluminum hydroxide (Al(OH)₃) or calcium phosphate). Active loading of vaccine antigen in Al(OH)₃-PLGA microspheres was found to: a) increase with an increasing loading of Al(OH)₃ (0.88-3 wt.%) and addition of porosigen, b) decrease when the inner Al(OH)₃/trehalose phase to 1 mL outer oil phase and size of microspheres was respectively >0.2 mL and 63 μm, and c) change negligibly by PLGA concentration and initial incubation (loading) temperature. Encapsulation of protein sorbing Al(OH)₃ in PLGA microspheres resulted in suppression of self-healing of PLGA pores, which was then overcome by improving polymer chain mobility, which in turn was accomplished by coincorporating hydrophobic plasticizers in PLGA. Active self-healing microencapsulation of manufacturing process-labile TT in PLGA was found to: a) obviate micronization- and organic solvent-induced TT degradation, b) improve antigen loading (1.4-1.8 wt.% TT) and encapsulation efficiency (~97%), c) provide nearly homogeneous distribution and stabilization of antigen in polymer, and d

  20. PLGA-Mesoporous Silicon Microspheres for the in Vivo Controlled Temporospatial Delivery of Proteins.

    PubMed

    Minardi, Silvia; Pandolfi, Laura; Taraballi, Francesca; De Rosa, Enrica; Yazdi, Iman K; Liu, Xeuwu; Ferrari, Mauro; Tasciotti, Ennio

    2015-08-01

    In regenerative medicine, the temporospatially controlled delivery of growth factors (GFs) is crucial to trigger the desired healing mechanisms in the target tissues. The uncontrolled release of GFs has been demonstrated to cause severe side effects in the surrounding tissues. The aim of this study was to optimize a translational approach for the fine temporal and spatial control over the release of proteins, in vivo. Hence, we proposed a newly developed multiscale composite microsphere based on a core consisting of the nanostructured silicon multistage vector (MSV) and a poly(dl-lactide-co-glycolide) acid (PLGA) outer shell. Both of the two components of the resulting composite microspheres (PLGA-MSV) can be independently tailored to achieve multiple release kinetics contributing to the control of the release profile of a reporter protein in vitro. The influence of MSV shape (hemispherical or discoidal) and size (1, 3, or 7 μm) on PLGA-MSV's morphology and size distribution was investigated. Second, the copolymer ratio of the PLGA used to fabricate the outer shell of PLGA-MSV was varied. The composites were fully characterized by optical microscopy, scanning electron microscopy, ζ potential, Fourier transform infrared spectroscopy, and thermogravimetric analysis-differential scanning calorimetry, and their release kinetics over 30 days. PLGA-MSV's biocompatibility was assessed in vitro with J774 macrophages. Finally, the formulation of PLGA-MSV was selected, which concurrently provided the most consistent microsphere size and allowed for a zero-order release kinetic. The selected PLGA-MSVs were injected in a subcutaneous model in mice, and the in vivo release of the reporter protein was followed over 2 weeks by intravital microscopy, to assess if the zero-order release was preserved. PLGA-MSV was able to retain the payload over 2 weeks, avoiding the initial burst release typical of most drug delivery systems. Finally, histological evaluation assessed the

  1. Hollow superparamagnetic PLGA/Fe 3O 4 composite microspheres for lysozyme adsorption

    NASA Astrophysics Data System (ADS)

    Yang, Qi; Wu, Yao; Lan, Fang; Ma, Shaohua; Xie, Liqin; He, Bin; Gu, Zhongwei

    2014-02-01

    Uniform hollow superparamagnetic poly(lactic-co-glycolic acid) (PLGA)/Fe3O4 composite microspheres composed of an inner cavity, PLGA inner shell and Fe3O4 outer shell have been synthesized by a modified oil-in-water (O/W) emulsion-solvent evaporation method using Fe3O4 nanoparticles as a particulate emulsifier. The obtained composite microspheres with an average diameter of 2.5 μm showed excellent monodispersity and stability in aqueous medium, strong magnetic responsiveness, high magnetite content (>68%), high saturation magnetization (58 emu g-1) and high efficiency in lysozyme adsorption.

  2. Hollow superparamagnetic PLGA/Fe3O4 composite microspheres for lysozyme adsorption.

    PubMed

    Yang, Qi; Wu, Yao; Lan, Fang; Ma, Shaohua; Xie, Liqin; He, Bin; Gu, Zhongwei

    2014-02-28

    Uniform hollow superparamagnetic poly(lactic-co-glycolic acid) (PLGA)/Fe(3)O(4) composite microspheres composed of an inner cavity, PLGA inner shell and Fe(3)O(4) outer shell have been synthesized by a modified oil-in-water (O/W) emulsion-solvent evaporation method using Fe(3)O(4) nanoparticles as a particulate emulsifier. The obtained composite microspheres with an average diameter of 2.5 μm showed excellent monodispersity and stability in aqueous medium, strong magnetic responsiveness, high magnetite content (>68%), high saturation magnetization (58 emu g(-1)) and high efficiency in lysozyme adsorption. PMID:24492410

  3. Injectable long-acting systems for Radix Ophiopogonis polysaccharide based on mono-PEGylation and in situ formation of a PLGA depot

    PubMed Central

    Shi, XiaoLi; Lin, Xiao; Zheng, XiangWei; Feng, Yi; Shen, Lan

    2014-01-01

    Background Radix Ophiopogonis polysaccharide (ROP), a highly hydrophilic macromolecule, has a unique anti-ischemic action in the myocardium. One of the main problems with its use is its relatively short half-life in vivo. To solve this problem, injectable long-acting drug delivery systems, which combine mono-PEGylation (PEG, polyethylene glycol) with the in situ formation of poly(d,l-lactide-co-glycolide) copolymer (PLGA) depots, were tested in this study. Methods Through a moderate coupling reaction between 20 kDa amino-terminated methoxy-PEG and excessive ROP with activated hydroxyls, a long-circulating and bioactive mono-PEGylated ROP was prepared and characterized. A reasonable and applicable range of PLGA formulations loaded with the mono-PEGylated ROP were prepared, characterized, and evaluated in vivo. Results Relative to ROP, the half-life of which was only 0.5 hours, the conjugate alone, following subcutaneous administration, showed markedly prolonged retention in the systemic circulation, with a mean residence time in vivo of approximately 2.76 days. In combination with in situ-forming PLGA depots, the residence time of the conjugate in vivo was prolonged further. In particular, a long-lasting and steady plasma exposure for nearly a month was achieved by the formulation comprising 40% 30 kDa PLGA in N-methyl-2-pyrrolidone. Conclusion Long-lasting and steady drug exposure could be achieved using mono-PEGylation in combination with in situ formation of PLGA depots. Such a combination with ROP would be promising for long-term prophylaxis and/or treatment of myocardial ischemia. For high-dose and highly hydrophilic macromolecular drugs like ROP, more than one preparation technology might be needed to achieve week-long or month-long delivery per dosing. PMID:25489243

  4. Effect of different sintering methods on bioactivity and release of proteins from PLGA microspheres.

    PubMed

    Dormer, Nathan H; Gupta, Vineet; Scurto, Aaron M; Berkland, Cory J; Detamore, Michael S

    2013-10-01

    Macromolecule release from poly(d,l-lactide-co-glycolide) (PLGA) microspheres has been well-characterized, and is a popular approach for delivering bioactive signals from tissue-engineered scaffolds. However, the effect of some processing solvents, sterilization, and mineral incorporation (when used in concert) on long-term release and bioactivity has seldom been addressed. Understanding these effects is of significant importance for microsphere-based scaffolds, given that these scaffolds are becoming increasingly more popular, yet growth factor activity following sintering and/or sterilization is heretofore unknown. The current study evaluated the 6-week release of transforming growth factor (TGF)-β3 and bone morphogenetic protein (BMP)-2 from PLGA and PLGA/hydroxyapatite (HAp) microspheres following exposure to ethanol (EtOH), dense phase carbon dioxide (CO2), or ethylene oxide (EtO). EtO was chosen based on its common use in scaffold sterilization, whereas EtOH and CO2 were chosen given their importance in sintering microspheres together to create scaffolds. Release supernatants were then used in an accelerated cell stimulation study with human bone marrow stromal cells (hBMSCs) with monitoring of gene expression for major chondrogenic and osteogenic markers. Results indicated that in microspheres without HAp, EtOH exposure led to the greatest amount of delivery, while those treated with CO2 delivered the least growth factor. In contrast, formulations with HAp released almost half as much protein, regardless of EtOH or CO2 exposure. Notably, EtO exposure was not found to significantly affect the amount of protein released. Cell stimulation studies demonstrated that eluted protein samples performed similarly to positive controls in PLGA-only formulations, and ambiguously in PLGA/HAp composites. In conclusion, the use of EtOH, subcritical CO2, and EtO in microsphere-based scaffolds may have only slight adverse effects, and possibly even desirable effects in some

  5. Stability study of full-length antibody (anti-TNF alpha) loaded PLGA microspheres.

    PubMed

    Marquette, S; Peerboom, C; Yates, A; Denis, L; Langer, I; Amighi, K; Goole, J

    2014-08-15

    Antibodies (Abs) require the development of stable formulations and specific delivery strategies given their susceptibility to a variety of physical and chemical degradation pathways. In this study, the encapsulation of an antibody into polylactide-co-glycolide (PLGA) based microspheres was explored to obtain a controlled-release of the incorporated drug. In order to avoid stability issues, a solid-in-oil-in-water (s/o/w) method was preferred. The solid phase was made of anti-TNF alpha monoclonal antibody (MAb) spray-dried microparticles, and the PLGA microspheres were produced using two different polymers (i.e., Resomer(®) RG505 and Resomer(®) RG755S). The stability of the MAb incorporated into the microspheres was investigated under three conditions (5 ± 3°C, 25 ± 2°C/60% RH and 40 ± 2°C/75% RH) for 12 weeks. During this stability study, it was demonstrated that the MAb loaded PLGA microspheres were stable when stored at 5 ± 3°C and that the Resomer(®) RG755S, composed of 75%(w/w) lactic acid as PLGA, was preferred to preserve the stability of the system. Storage at temperatures higher than 5°C led to antibody stability issues such as aggregation, fragmentation and loss of activity. The release profiles were also altered. Physical ageing of the system associated with changes in the glass transition temperature and enthalpy of relaxation was noticed during the storage of the MAb loaded PLGA microspheres. PMID:24792974

  6. Factors affecting the loading efficiency of water-soluble drugs in PLGA microspheres.

    PubMed

    Ito, Fuminori; Fujimori, Hiroyuki; Makino, Kimiko

    2008-01-15

    Poly(lactide-co-glycolide), PLGA, microspheres containing blue dextran as a hydrophilic model drug were prepared by a solvent evaporation method from w/o/w emulsions using a micro homogenizer. Effects of surfactant concentration in oil phase, stirring time period and stirring rate in the preparation procedure of primary emulsion (w/o) upon drug-loading efficiency were evaluated. Stirring rate during preparation of primary emulsion and surfactant concentration in oil phase affected drug-loading efficiency and the particle size of primary emulsion. Microspheres having the higher drug-loading efficiency were obtained when size differences between the primary emulsions and the secondary ones were large. That is, when the diameter of the primary emulsion is much smaller than that of the secondary emulsion, PLGA microspheres with high-loading efficiency of blue dextran were obtained. PMID:17719753

  7. Studies on the preparation, characterization and pharmacological evaluation of tolterodine PLGA microspheres.

    PubMed

    Sun, Fengying; Sui, Cheng; Teng, Lesheng; Liu, Ximing; Teng, Lirong; Meng, Qingfan; Li, Youxin

    2010-09-15

    In this study, poly(d,l-lactide-co-glycolide) (PLGA) microspheres of tolterodine depot formulation were prepared using oil in water (o/w) method to investigate their potential pharmacokinetic and pharmacodynamic advantages over tolterodine l-tartrate tablets. Morphological studies of the microspheres showed a spherical shape and smooth surface with mean size of 50.69-83.01 microm, and the encapsulation efficiency was improved from 62.55 to 79.10% when the polymer concentration increased from 180 to 230 mg/ml. The addition of stearic or palmitic acids could significantly raise the drug entrapment efficiency but only slightly affected the in vitro release. A low initial burst followed by a proximately constant release of tolterodine was noticed in the in vitro release profiles. The in vivo study was carried out by intramuscular (i.m.) administration of tolterodine-loaded microspheres on beagle dogs, and a sustained release of drug from the PLGA microspheres was achieved until the 18th day with a low initial burst. Since the absence of hepatic first pass metabolism, only a single active compound-tolterodine was detected in the plasma. This avoided the coexistence of two active compounds in plasma in the case of oral administration of tolterodine, which may lead to a difficulty in dose control due to the different metabolic capacity of patients. In the pharmacodynamic study, the influence of tolterodine PLGA microspheres on the inhibition of carbachol-induced rat urinary bladder contraction was more significant than that of tolterodine l-tartrate tablets. There were invisible changes in rat bladder slices between tolterodine-loaded PLGA microspheres group and tolterodine l-tartrate tablets group. These results indicate that the continuous inhibition of muscarinic receptor may offer an alternative therapy of urge incontinence. PMID:20600717

  8. Pharmacokinetics and distributions of bevacizumab by intravitreal injection of bevacizumab-PLGA microspheres in rabbits

    PubMed Central

    Ye, Zhuo; Ji, Yan-Li; Ma, Xiang; Wen, Jian-Guo; Wei, Wei; Huang, Shu-Man

    2015-01-01

    AIM To investigate the pharmacokinetics and distributions of bevacizumab by intravitreal injection of prepared bevacizumab-poly (L-lactic-co-glycolic acid) (PLGA) microspheres in rabbits, to provide evidence for clinical application of this kind of bevacizumab sustained release dosage form. METHODS Bevacizumab was encapsulated into PLGA microsphere via the solid-in-oil-in-hydrophilic oil (S/O/hO) method. Fifteen healthy New Zealand albino-rabbits were used in experiments. The eyes of each rabbit received an intravitreal injection. The left eyes were injected with prepared bevacizumab-PLGA microspheres and the right eyes were injected with bevacizumab solution. After intravitreal injection, rabbits were randomly selected at days 3, 7, 14, 28 and 42 respectively, three animals each day. Then we used immunofluorescence staining to observe the distribution and duration of bevacizumab in rabbit eye tissues, and used the sandwich ELISA to quantify the concentration of free bevacizumab from the rabbit aqueous humor and vitreous after intravitreal injection. RESULTS The results show that the concentration of bevacizumab in vitreous and aqueous humor after administration of PLGA formulation was higher than that of bevacizumab solution. The T1/2 of intravitreal injection of bevacizumab-PLGA microspheres is 9.6d in vitreous and 10.2d in aqueous humor, and the T1/2 of intravitreal injection of soluble bevacizumab is 3.91d in vitreous and 4.1d in aqueous humor. There were statistical significant difference for comparison the results of the bevacizumab in vitreous and aqueous humor between the left and right eyes (P<0.05). The AUC0-t of the sustained release dosage form was 1-fold higher than that of the soluble form. The relative bioavailability was raised significantly. The immunofluorescence staining of PLGA-encapsulated bevacizumab (b-PLGA) in rabbit eye tissues was still observed up to 42d. It was longer than that of the soluble form. CONCLUSION The result of this study

  9. Phagostimulatory effect of uptake of PLGA microspheres loaded with rifampicin on alveolar macrophages.

    PubMed

    Hirota, Keiji; Hasegawa, Taizo; Nakajima, Takehisa; Makino, Kimiko; Terada, Hiroshi

    2011-10-15

    Our previous results on the phagocytic activity of alveolar macrophages (Mϕs) toward poly(lactic-co-glycolic) acid microspheres (PLGA MS) loaded with the anti-tuberculosis agent rifampicin (R-PLGA MS) suggest that the phagocytosis of R-PLGA MS enhances the phagocytic activity of Mϕ cells. To confirm this possibility, we examined the effect of phagocytosis of R-PLGA MS and polystyrene latex (PSL) MS on the phagocytic uptake of fluorescent PSL (F-PSL) MS by cells of the rat alveolar macrophage cell line NR8383 at 37°C. Phagocytic activity was examined in terms of the population of Mϕ cells that had phagocytosed MS (N(total)) and the total number of MS phagocytosed (n(total)) by counting the phagocytic Mϕ cells and the MS ingested in optical microscopic fields. Phagocytosis of R-PLGA MS enhanced about 1.5 times the values of N(total) and n(total) of the phagocytosis of F-PSL MS under the conditions where the phagocytosis of F-PSL MS did not attain the saturated level. In contrast, the phagocytosis of PSL MS did not enhance the phagocytic activity of Mϕ cells toward F-PSL MS. In conclusion, R-PLGA MS are favorable for drug delivery of anti-tuberculosis agents into alveolar Mϕs due to their ability to up-regulate the phagocytosis of MS. PMID:21700434

  10. Local delivery of controlled-release simvastatin/PLGA/HAp microspheres enhances bone repair

    PubMed Central

    Tai, I-Chun; Fu, Yin-Chih; Wang, Chih-Kuang; Chang, Je-Ken; Ho, Mei-Ling

    2013-01-01

    Statins are used clinically for reduction of cholesterol synthesis to prevent cardiovascular disease. Previous in vitro and in vivo studies have shown that statins stimulate bone formation. However, orally administered statins may be degraded during first-pass metabolism in the liver. This study aimed to prevent this degradation by developing a locally administered formulation of simvastatin that is encapsulated in poly(lactic-co-glycolic acid)/hydroxyapatite (SIM/PLGA/HAp) microspheres with controlled-release properties. The effect of this formulation of simvastatin on bone repair was tested using a mouse model of gap fracture bridging with a graft of necrotic bone. The simvastatin released over 12 days from 3 mg and 5 mg of SIM/PLGA/HAp was 0.03–1.6 μg/day and 0.05–2.6 μg/day, respectively. SIM/PLGA/HAp significantly stimulated callus formation around the repaired area and increased neovascularization and cell ingrowth in the grafted necrotic bone at week 2 after surgery. At week 4, both 3 mg and 5 mg of SIM/PLGA/HAp increased neovascularization, but only 5 mg SIM/PLGA/HAp enhanced cell ingrowth into the necrotic bone. The low dose of simvastatin released from SIM/PLGA/HAp enhanced initial callus formation, neovascularization, and cell ingrowth in the grafted bone, indicating that SIM/PLGA/HAp facilitates bone regeneration. We suggest that SIM/PLGA/HAp should be developed as an osteoinductive agent to treat osteonecrosis or in combination with an osteoconductive scaffold to treat severe bone defects. PMID:24143094

  11. Biocompatibility and osteogenesis of calcium phosphate composite scaffolds containing simvastatin-loaded PLGA microspheres for bone tissue engineering.

    PubMed

    Zhang, Hao-Xuan; Xiao, Gui-Yong; Wang, Xia; Dong, Zhao-Gang; Ma, Zhi-Yong; Li, Lei; Li, Yu-Hua; Pan, Xin; Nie, Lin

    2015-10-01

    By utilizing a modified solid/oil/water (s/o/w) emulsion solvent evaporation technique, calcium phosphate composite scaffolds containing simvastatin-loaded PLGA microspheres (SIM-PLGA-CPC) were prepared in this study. We characterized the morphology, encapsulation efficiency and in vitro drug release of SIM-loaded PLGA microspheres as well as the macrostructure, pore size, porosity and mechanical strength of the scaffolds. Rabbit bone mesenchymal stem cells (BMSCs) were seeded onto SIM-PLGA-CPC scaffolds, and the proliferation, morphology, cell cycle and differentiation of BMSCs were investigated using the cell counting kit-8 (CCK-8) assay, scanning electron microscopy (SEM), flow cytometry, alkaline phosphatase (ALP) activity and alizarin red S staining, respectively. The results revealed that SIM-PLGA-CPC scaffolds were biocompatible and osteogenic in vitro. To determine the in vivo biocompatibility and osteogenesis of the scaffolds, both pure PLGA-CPC scaffolds and SIM-PLGA-CPC scaffolds were implanted in rabbit femoral condyles and microradiographically and histologically investigated. SIM-PLGA-CPC scaffolds exhibited good biocompatibility and could improve the efficiency of new bone formation. All these results suggested that the SIM-PLGA-CPC scaffolds fulfilled the basic requirements of bone tissue engineering scaffold and possessed application potentials in orthopedic surgery. PMID:25809455

  12. Injectable and porous PLGA microspheres that form highly porous scaffolds at body temperature

    PubMed Central

    Qutachi, Omar; Vetsch, Jolanda R.; Gill, Daniel; Cox, Helen; Scurr, David J.; Hofmann, Sandra; Müller, Ralph; Quirk, Robin A.; Shakesheff, Kevin M.; Rahman, Cheryl V.

    2014-01-01

    Injectable scaffolds are of interest in the field of regenerative medicine because of their minimally invasive mode of delivery. For tissue repair applications, it is essential that such scaffolds have the mechanical properties, porosity and pore diameter to support the formation of new tissue. In the current study, porous poly(dl-lactic acid-co-glycolic acid) (PLGA) microspheres were fabricated with an average size of 84 ± 24 μm for use as injectable cell carriers. Treatment with ethanolic sodium hydroxide for 2 min was observed to increase surface porosity without causing the microsphere structure to disintegrate. This surface treatment also enabled the microspheres to fuse together at 37 °C to form scaffold structures. The average compressive strength of the scaffolds after 24 h at 37 °C was 0.9 ± 0.1 MPa, and the average Young’s modulus was 9.4 ± 1.2 MPa. Scaffold porosity levels were 81.6% on average, with a mean pore diameter of 54 ± 38 μm. This study demonstrates a method for fabricating porous PLGA microspheres that form solid porous scaffolds at body temperature, creating an injectable system capable of supporting NIH-3T3 cell attachment and proliferation in vitro. PMID:25152354

  13. Injectable and porous PLGA microspheres that form highly porous scaffolds at body temperature.

    PubMed

    Qutachi, Omar; Vetsch, Jolanda R; Gill, Daniel; Cox, Helen; Scurr, David J; Hofmann, Sandra; Müller, Ralph; Quirk, Robin A; Shakesheff, Kevin M; Rahman, Cheryl V

    2014-12-01

    Injectable scaffolds are of interest in the field of regenerative medicine because of their minimally invasive mode of delivery. For tissue repair applications, it is essential that such scaffolds have the mechanical properties, porosity and pore diameter to support the formation of new tissue. In the current study, porous poly(dl-lactic acid-co-glycolic acid) (PLGA) microspheres were fabricated with an average size of 84±24μm for use as injectable cell carriers. Treatment with ethanolic sodium hydroxide for 2min was observed to increase surface porosity without causing the microsphere structure to disintegrate. This surface treatment also enabled the microspheres to fuse together at 37°C to form scaffold structures. The average compressive strength of the scaffolds after 24h at 37°C was 0.9±0.1MPa, and the average Young's modulus was 9.4±1.2MPa. Scaffold porosity levels were 81.6% on average, with a mean pore diameter of 54±38μm. This study demonstrates a method for fabricating porous PLGA microspheres that form solid porous scaffolds at body temperature, creating an injectable system capable of supporting NIH-3T3 cell attachment and proliferation in vitro. PMID:25152354

  14. Fabrication and evaluation of a sustained-release chitosan-based scaffold embedded with PLGA microspheres.

    PubMed

    Song, Kedong; Liu, Yingchao; Macedo, Hugo M; Jiang, Lili; Li, Chao; Mei, Guanyu; Liu, Tianqing

    2013-04-01

    Nutrient depletion within three-dimensional (3D) scaffolds is one of the major hurdles in the use of this technology to grow cells for applications in tissue engineering. In order to help in addressing it, we herein propose to use the controlled release of encapsulated nutrients within polymer microspheres into chitosan-based 3D scaffolds, wherein the microspheres are embedded. This method has allowed maintaining a stable concentration of nutrients within the scaffolds over the long term. The polymer microspheres were prepared using multiple emulsions (w/o/w), in which bovine serum albumin (BSA) and poly (lactic-co-glycolic) acid (PLGA) were regarded as the protein pattern and the exoperidium material, respectively. These were then mixed with a chitosan solution in order to form the scaffolds by cryo-desiccation. The release of BSA, entrapped within the embedded microspheres, was monitored with time using a BCA kit. The morphology and structure of the PLGA microspheres containing BSA before and after embedding within the scaffold were observed under a scanning electron microscope (SEM). These had a round shape with diameters in the range of 27-55 μm, whereas the chitosan-based scaffolds had a uniform porous structure with the microspheres uniformly dispersed within their 3D structure and without any morphological change. In addition, the porosity, water absorption and degradation rate at 37 °C in an aqueous environment of 1% chitosan-based scaffolds were (92.99±2.51) %, (89.66±0.66) % and (73.77±3.21) %, respectively. The studies of BSA release from the embedded microspheres have shown a sustained and cumulative tendency with little initial burst, with (20.24±0.83) % of the initial amount released after 168 h (an average rate of 0.12%/h). The protein concentration within the chitosan-based scaffolds after 168 h was found to be (11.44±1.81)×10(-2) mg/mL. This novel chitosan-based scaffold embedded with PLGA microspheres has proven to be a promising technique

  15. Computational Intelligence Modeling of the Macromolecules Release from PLGA Microspheres-Focus on Feature Selection.

    PubMed

    Zawbaa, Hossam M; Szlȩk, Jakub; Grosan, Crina; Jachowicz, Renata; Mendyk, Aleksander

    2016-01-01

    Poly-lactide-co-glycolide (PLGA) is a copolymer of lactic and glycolic acid. Drug release from PLGA microspheres depends not only on polymer properties but also on drug type, particle size, morphology of microspheres, release conditions, etc. Selecting a subset of relevant properties for PLGA is a challenging machine learning task as there are over three hundred features to consider. In this work, we formulate the selection of critical attributes for PLGA as a multiobjective optimization problem with the aim of minimizing the error of predicting the dissolution profile while reducing the number of attributes selected. Four bio-inspired optimization algorithms: antlion optimization, binary version of antlion optimization, grey wolf optimization, and social spider optimization are used to select the optimal feature set for predicting the dissolution profile of PLGA. Besides these, LASSO algorithm is also used for comparisons. Selection of crucial variables is performed under the assumption that both predictability and model simplicity are of equal importance to the final result. During the feature selection process, a set of input variables is employed to find minimum generalization error across different predictive models and their settings/architectures. The methodology is evaluated using predictive modeling for which various tools are chosen, such as Cubist, random forests, artificial neural networks (monotonic MLP, deep learning MLP), multivariate adaptive regression splines, classification and regression tree, and hybrid systems of fuzzy logic and evolutionary computations (fugeR). The experimental results are compared with the results reported by Szlȩk. We obtain a normalized root mean square error (NRMSE) of 15.97% versus 15.4%, and the number of selected input features is smaller, nine versus eleven. PMID:27315205

  16. Release mechanisms of tacrolimus-loaded PLGA and PLA microspheres and immunosuppressive effects of the microspheres in a rat heart transplantation model.

    PubMed

    Kojima, Ryo; Yoshida, Takatsune; Tasaki, Hiroaki; Umejima, Hiroyuki; Maeda, Masashi; Higashi, Yasuyuki; Watanabe, Shunsuke; Oku, Naoto

    2015-08-15

    The objective of this study was to elucidate the release and absorption mechanisms of tacrolimus loaded into microspheres composed of poly(lactic-co-glycolic acid) (PLGA) and/or polylactic acid (PLA). Tacrolimus-loaded microspheres were prepared by the o/w emulsion solvent evaporation method. The entrapment efficiency correlated with the molecular weight of PLGA, and the glass transition temperature of PLGA microspheres was not decreased by the addition of tacrolimus. These results indicate that intermolecular interaction between tacrolimus and the polymer would affect the entrapment of tacrolimus in the microspheres. Tacrolimus was released with weight loss of the microspheres, and the dominant release mechanism of tacrolimus was considered to be erosion of the polymer rather than diffusion of the drug. The whole-blood concentration of tacrolimus in rats was maintained for at least 2 weeks after a single subcutaneous administration of the microspheres. The pharmacokinetic profile of tacrolimus following subcutaneous administration was similar to that following intramuscular administration, suggesting that the release and dissolution of tacrolimus, rather than the absorption of the dissolved tacrolimus, were rate-limiting steps. Graft-survival time in a heart transplantation rat model was prolonged by the administration of tacrolimus-loaded microspheres. The microsphere formulation of tacrolimus would be expected to precisely control the blood concentration while maintaining the immunosuppressive effect of the drug. PMID:26160668

  17. Effect of osmotic pressure in the solvent extraction phase on BSA release profile from PLGA microspheres.

    PubMed

    Jiang, Ge; Thanoo, B C; DeLuca, Patrick P

    2002-11-01

    This study investigated the influence of osmotic pressure in the organic solvent extraction phase on release profile of bovine serum albumin (BSA) from poly(lactide-co-glycolide) (PLGA) microspheres. BSA-loaded PLGA microspheres with a target load of 10% were prepared by a double emulsion phase separation method. All the microsphere batches were fabricated in the same conditions except that in the organic solvent (CH2Cl2) evaporation step. Different concentrations of NaCl (0, 1.8, and 3.6%) or sucrose (20%) were used to generate a range of osmotic pressures in the extraction aqueous phase. These microspheres were characterized for incorporation efficiency, surface and internal morphology, particle size, protein stability, and in vitro release. The microspheres were spherical with particle size ranging from 16.8 to 27.8 microns. Higher osmotic pressure resulted in a denser internal structure although similar nonporous surface morphology was observed with all batches. No significant difference in encapsulation efficiency existed from batch to batch (87-94%). Sodium dodecyl sulfate-polyamide gel electrophoresis showed that BSA integrity was well retained. The release profile of the batch prepared with only water as the continuous (solvent extraction) phase exhibited a 79% burst release in the first 24 hr followed by a plateau and then a little release after 21 days. In the presence of NaCl or sucrose, the burst effect significantly decreased with increase in osmotic pressure in the extraction aqueous phase, which was then followed by sustained release for 35 days. A mass balance was made when the release terminated. Therefore, in the organic solvent extraction and evaporation step, increasing the osmotic pressure in the aqueous phase both reduced the burst release from the microspheres and improved the subsequent sustained release profile. PMID:12503521

  18. Preparation and properties of PLGA microspheres containing hydrophilic drugs by the SPG (shirasu porous glass) membrane emulsification technique.

    PubMed

    Ito, Fuminori; Honnami, Hiroyuki; Kawakami, Hiroyoshi; Kanamura, Kiyoshi; Makino, Kimiko

    2008-11-15

    In the present paper, monodisperse poly (lactide-co-glycolide) (PLGA) microspheres containing the hydrophilic model drug, blue dextran (BLD), were manufactured by the solvent evaporation method and the shirasu porous glass (SPG) membrane emulsification technique. In order to prepare PLGA microspheres with a higher drug loading efficiency by the membrane emulsification technique, the test of stability and productivity of the primary emulsion (w(1)/o emulsion) was preliminary examined by change species or concentration of the oil-soluble surfactant and the ratio of water and organic solvent. The primary emulsion (w(1)/o) composed of the BLD aqueous solution and dichloromethane (DCM) dissolved PLGA was prepared with the micro homogenizer. The secondary emulsion (w(1)/o/w(2)) was prepared by the SPG membrane emulsification technique. BLD/PLGA microspheres of various micro level sizes of 2.0-10 microm prepared by variation of pore size of the using SPG membrane. The highly monodisperse BLD/PLGA microspheres were also manufactured by added polyethylene glycol (PEG) into the water phase, as reported in a previous paper. The initial release rate of the drug from such microspheres controlled than the sample manufactured without an additive. PMID:18774278

  19. Localized and Sustained Delivery of Erythropoietin from PLGA Microspheres Promotes Functional Recovery and Nerve Regeneration in Peripheral Nerve Injury

    PubMed Central

    Zhang, Wei; Gao, Yuan; Zhou, Yan; Liu, Jianheng; Zhang, Licheng; Long, Anhua; Zhang, Lihai; Tang, Peifu

    2015-01-01

    Erythropoietin (EPO) has been demonstrated to exert neuroprotective effects on peripheral nerve injury recovery. Though daily intraperitoneal injection of EPO during a long period of time was effective, it was a tedious procedure. In addition, only limited amount of EPO could reach the injury sites by general administration, and free EPO is easily degraded in vivo. In this study, we encapsulated EPO in poly(lactide-co-glycolide) (PLGA) microspheres. Both in vitro and in vivo release assays showed that the EPO-PLGA microspheres allowed sustained release of EPO within a period of two weeks. After administration of such EPO-PLGA microspheres, the peripheral nerve injured rats had significantly better recovery compared with those which received daily intraperitoneal injection of EPO, empty PLGA microspheres, or saline treatments. This was supported by the functional, electrophysiological, and histological evaluations of the recovery done at week 8 postoperatively. We conclude that sustained delivery of EPO could be achieved by using EPO-PLGA microspheres, and such delivery method could further enhance the recovery function of EPO in nerve injury recovery. PMID:25821803

  20. Electrospray synthesis and properties of hierarchically structured PLGA TIPS microspheres for use as controlled release technologies.

    PubMed

    Malik, Salman A; Ng, Wing H; Bowen, James; Tang, Justin; Gomez, Alessandro; Kenyon, Anthony J; Day, Richard M

    2016-04-01

    Microsphere-based controlled release technologies have been utilized for the long-term delivery of proteins, peptides and antibiotics, although their synthesis poses substantial challenges owing to formulation complexities, lack of scalability, and cost. To address these shortcomings, we used the electrospray process as a reproducible, synthesis technique to manufacture highly porous (>94%) microspheres while maintaining control over particle structure and size. Here we report a successful formulation recipe used to generate spherical poly(lactic-co-glycolic) acid (PLGA) microspheres using the electrospray (ES) coupled with a novel thermally induced phase separation (TIPS) process with a tailored Liquid Nitrogen (LN2) collection scheme. We show how size, shape and porosity of resulting microspheres can be controlled by judiciously varying electrospray processing parameters and we demonstrate examples in which the particle size (and porosity) affect release kinetics. The effect of electrospray treatment on the particles and their physicochemical properties are characterized by scanning electron microscopy, confocal Raman microscopy, thermogravimetric analysis and mercury intrusion porosimetry. The microspheres manufactured here have successfully demonstrated long-term delivery (i.e. 1week) of an active agent, enabling sustained release of a dye with minimal physical degradation and have verified the potential of scalable electrospray technologies for an innovative TIPS-based microsphere production protocol. PMID:26803601

  1. Mechanistic studies for monodisperse exenatide-loaded PLGA microspheres prepared by different methods based on SPG membrane emulsification.

    PubMed

    Qi, Feng; Wu, Jie; Yang, Tingyuan; Ma, Guanghui; Su, Zhiguo

    2014-10-01

    Poly(DL-lactic-co-glycolic acid) (PLGA) microspheres have been widely prepared by many methods, including solvent evaporation, solvent extraction and the co-solvent method. However, very few studies have compared the properties of microspheres fabricated by these methods. This is partly because the broad size distribution of the resultant particles severely complicates the analysis and affects the reliability of the comparison. To this end, uniform-sized PLGA microspheres have been prepared by Shirasu porous glass premix membrane emulsification and used to encapsulate exenatide, a drug for treating Type 2 diabetes. Based on this technique, the influences on the properties of microspheres fabricated by the aforementioned three methods were intensively investigated, including in vitro release, degradation and pharmacology. We found that these microspheres presented totally different release behaviors in vitro and in vivo, but exhibited a similar trend of PLGA degradation. Moreover, the internal structural evolution visually demonstrated these release behaviors. We selected for further examination the microsphere prepared by solvent evaporation because of its constant release rate, and explored its pharmacodynamics, histology, etc., in more detail. This microsphere when injected once showed equivalent efficacy to that of twice-daily injections of exenatide with no inflammatory response. PMID:24952071

  2. Magnetic field activated drug release system based on magnetic PLGA microspheres for chemo-thermal therapy.

    PubMed

    Fang, Kun; Song, Lina; Gu, Zhuxiao; Yang, Fang; Zhang, Yu; Gu, Ning

    2015-12-01

    Controlled drug delivery systems have been extensively investigated for cancer therapy in order to obtain better specific targeting and therapeutic efficiency. Herein, we developed doxorubicin-loaded magnetic PLGA microspheres (DOX-MMS), in which DOX was encapsulated in the core and high contents (28.3 wt%) of γ-Fe2O3 nanoparticles (IOs) were electrostatically assembled on the surface of microsphere to ensure the high sensitivity to response of an external alternating current magnetic field (ACMF). The IOs in PLGA shell can both induce the heat effect and trigger shell permeability enhancement to release drugs when DOX-MMs was activated by ACMF. Results show that the cumulative drug release from DOX-MMs exposed to ACMF for 30 min (21.6%) was significantly higher (approximately 7 times higher) than that not exposed to ACMF (2.8%). The combination of hyperthermia and enhanced DOX release from DOX-MMS is beneficial for in vitro 4T1 breast cancer cell apoptosis as well as effective inhibition of tumor growth in 4T1 tumor xenografts. Therefore, the DOX-MMS can be optimized as powerful delivery system for efficient magnetic responsive drug release and chemo-thermal therapy. PMID:26513754

  3. Immunogenicity of single-dose diphtheria vaccines based on PLA/PLGA microspheres in guinea pigs.

    PubMed

    Johansen, P; Moon, L; Tamber, H; Merkle, H P; Gander, B; Sesardic, D

    1999-09-01

    Biodegradable polyester microspheres (MS) have shown potential for single-dose vaccines. This study examined the immunogenicity of diphtheria toxoid (Dtxd) microencapsulated in different types of poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) MS prepared by the methods of spray-drying and coacervation. We investigated the influence of polymer type (PLGA 50:50 of low M(w); PLA of high M(w); end-group stearylated PLAs of low M(w)) and co-encapsulated excipients (BSA and/or trehalose) on Dtxd content, in vitro release and immunogenicity in guinea pigs. The co-encapsulated trehalose lowered the Dtxd entrapment efficiency in the spray-dried particles from 75 to 56%, whereas albumin alone had no effect in the spray-drying, but improved the encapsulation in the coacervation process. With the hydrophobic, end-group stearylated PLAs, Dtxd could only be encapsulated in the presence of albumin. Guinea pigs immunised with Dtxd-MS made with the relatively hydrophilic PLGA 50:50 exhibited specific and sustained antibody responses over 40 weeks, comparable to the responses to alum-adjuvanted toxoid. In contrast, undetectable or very low antibody responses were determined after immunisation with MS made with hydrophobic polymers. Surprisingly, large (15-60 microm) and small (1-5 microm) MS gave comparable primary antibody responses. In conclusion, the data presented confirm the feasibility of MS vaccines to induce strong, long-lasting protective antibody responses after a single immunisation. PMID:10506644

  4. Anti-VEGFR2-conjugated PLGA microspheres as an x-ray phase contrast agent for assessing the VEGFR2 expression

    NASA Astrophysics Data System (ADS)

    Tang, Rongbiao; Chai, Wei-Min; Ying, Weihai; Yang, Guo-Yuan; Xie, Honglan; Liu, Hui-Qiang; Chen, Ke-Min

    2012-05-01

    The primary goal of this study was to evaluate the feasibility of using anti-vascular endothelial growth factor receptor 2 (VEGFR2)-conjugated poly(lactic-co-glycolic acid) (PLGA) microspheres as an x-ray phase contrast agent to assess the VEGFR2 expression in cell cultures. The cell lines, mouse LLC (Lewis lung carcinoma) and HUVEC (human umbilical vein endothelial cell), were selected for cell adhesion studies. The bound PLGA microspheres were found to better adhere to LLC cells or HUVECs than unbound ones. Absorption and phase contrast images of PLGA microspheres were acquired and compared in vitro. Phase contrast imaging (PCI) greatly improves the detection of the microspheres as compared to absorption contrast imaging. The cells incubated with PLGA microspheres were imaged by PCI, which provided clear 3D visualization of the beads, indicating the feasibility of using PLGA microspheres as a contrast agent for phase contrast CT. In addition, the microspheres could be clearly distinguished from the wall of the vessel on phase contrast CT images. Therefore, the approach holds promise for assessing the VEGFR2 expression on endothelial cells of tumor-associated vessels. We conclude that PLGA microsphere-based PCI of the VEGFR2 expression might be a novel, promising biomarker for future studies of tumor angiogenesis.

  5. Tissue Engineering: Biomimetic Concealing of PLGA Microspheres in a 3D Scaffold to Prevent Macrophage Uptake (Small 11/2016).

    PubMed

    Minardi, Silvia; Corradetti, Bruna; Taraballi, Francesca; Sandri, Monica; Martinez, Jonathan O; Powell, Sebastian T; Tampieri, Anna; Weiner, Bradley K; Tasciotti, Ennio

    2016-03-01

    Avoiding the clearance of drug delivery systems from 3D scaffolds is crucial to preserve the bioactivity of their therapeutic payload. This is accomplished on page 1479, by E. Tasciotti and co-workers, through a "concealing" strategy: cloaking PLGA microspheres with the type I collagen matrix of a biomimetic scaffold, which enables the control of the production of inflammatory mediators. PMID:26970527

  6. Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: in vitro and in vivo studies.

    PubMed

    Sun, Yi; Wang, Jiancheng; Zhang, Xuan; Zhang, Zhijun; Zheng, Yan; Chen, Dawei; Zhang, Qiang

    2008-08-01

    A controlled drug release system based on the injectable PLGA microspheres loaded with gestodene and ethinyl estradiol was prepared and evaluated for the feasibility of monthly synchronic delivery of the two hormonal contraceptives. The scanning electron microscopy, light-scattering analyzer and gel permeation chromatography were used to study the morphology, particle size and molecular weight of the polymer microspheres, respectively. HPLC was utilized to determine the drug loading and the drug released, while a LC-MS-MS system was employed to analyze the plasma drug concentration. Result indicated that the PLGA particles obtained were spherical and appropriate in size. The formulation was stable during the test period. In vitro drug release from the microspheres for both drugs was sustained for about 30 days mostly by the diffusion mechanism. The plasma drug concentration-time profiles of the drug-loaded microspheres were relatively smooth after subcutaneous injection to rats for about 1-month, compared with that for drug suspension. In vitro and in vivo correlation was established. One of the most important facts is the synchronicity of the two contraceptives both in the release kinetics in vitro and the pharmacokinetic behaviors in vivo. Therefore, the synchronic delivery of two contraceptives is achieved for about 1 month by using the injectable PLGA-based microspheres. PMID:18539353

  7. Use of biodegradable PLGA microspheres as a slow release delivery system for the Boophilus microplus synthetic vaccine SBm7462.

    PubMed

    Sales-Junior, P A; Guzman, F; Vargas, M I; Sossai, S; Patarroyo V, A M; González, C Z L; Patarroyo, J H

    2005-09-15

    The synthetic anti-Boophilus microplus vaccine SBm7462 derived from the tick intestinal protein, Bm86, induced a protective immune response when emulsified in saponin and used in cattle. Using a mice model, and with the objective of improving the vaccine by continual peptide release, it was encapsulated in PLGA 50:50 microspheres and inoculated in BALB/c mice to assess the immunological response by detection of anti-peptide IgGs. Comparative studies were made with the peptide emulsified in saponin and with another synthetic vaccine, and the microsphere/peptide was characterized for efficiency of encapsulation, in vitro release profile, morphology, size, peptide integrity after encapsulation and stability in different pHs. The findings showed that saponin enhances a better immune response from SBm7462 and that the PLGA 50:50 microspheres are suitable for use with this peptide. PMID:16002149

  8. Mapping microclimate pH distribution inside protein-encapsulated PLGA microspheres using confocal laser scanning microscopy

    PubMed Central

    Liu, Yajun; Schwendeman, Steven P.

    2012-01-01

    The pH in the aqueous pores of poly(lactide-co-glycolide) (PLGA) matrix, also referred to microclimate pH (μpH), is often uncontrolled ranging from highly acidic to neutral pH range. The μpH distribution inside protein-encapsulated PLGA microspheres was quantitatively evaluated using confocal laser scanning microscopy. The fluorescent response of Lysosensor yellow/blue® dextran used to map μpH in PLGA was influenced by the presence of encapsulated protein. The nonprotonated form of pyridyl group on the fluorescence probe at neutral pH was responsible for the interference, which was dependent on the type and concentration of protein. A method for correction of this interference based on estimating protein concentration inside the microspheres was established and validated. After correction of the influence, the μpH distribution kinetics inside microspheres was evaluated for different PLGA 50/50 microsphere formulations under physiological conditions for 4 weeks. Generally, the μpH acidity increased with the progression of incubation time. The co-incorporation of poorly soluble base, magnesium carbonate, in the microspheres prolonged the appearance of detectable acidity for up to 3 weeks. Co-addition of an acetate buffer was able to control the μpH over a slightly acidic range (around pH 4.7) after two weeks incubation. Microspheres prepared from a lower polymer concentration exhibited a higher μpH, likely owing to reduced diffusional resistance to acidic degradation products. The stability of protein was enhanced by addition of MgCO3, acetate buffer, or by reduced polymer concentration in the preparation, as evidenced by more soluble protein recovered after incubation. Hence, the μpH imaging technique developed can be employed in the future for optimization of formulation strategies for controlling μpH and stabilizing encapsulated proteins. PMID:22428586

  9. Mapping microclimate pH distribution inside protein-encapsulated PLGA microspheres using confocal laser scanning microscopy.

    PubMed

    Liu, Yajun; Schwendeman, Steven P

    2012-05-01

    The pH in the aqueous pores of poly(lactide-co-glycolide) (PLGA) matrix, also referred to as microclimate pH (μpH), is often uncontrolled, ranging from highly acidic to neutral pH range. The μpH distribution inside protein-encapsulated PLGA microspheres was quantitatively evaluated using confocal laser scanning microscopy. The fluorescent response of Lysosensor yellow/blue dextran used to map μpH in PLGA was influenced by the presence of encapsulated protein. The nonprotonated form of pyridyl group on the fluorescence probe at neutral pH was responsible for the interference, which was dependent on the type and concentration of protein. A method for correction of this interference based on estimating protein concentration inside the microspheres was established and validated. After correction of the influence, the μpH distribution kinetics inside microspheres was evaluated for different PLGA 50/50 microsphere formulations under physiological conditions for 4 weeks. Generally, the μpH acidity increased with the progression of incubation time. The coincorporation of poorly soluble base, magnesium carbonate, in the microspheres prolonged the appearance of detectable acidity for up to 3 weeks. Co-addition of an acetate buffer was able to control the μpH over a slightly acidic range (around pH 4.7) after two week incubation. Microspheres prepared from a lower polymer concentration exhibited a higher μpH, likely owing to reduced diffusional resistance to acidic degradation products. The stability of protein was enhanced by addition of MgCO(3), acetate buffer, or by reduced polymer concentration in the preparation, as evidenced by more soluble protein recovered after incubation. Hence, the μpH imaging technique developed can be employed in the future for optimization of formulation strategies for controlling μpH and stabilizing encapsulated proteins. PMID:22428586

  10. Bone regeneration using a freeze-dried 3D gradient-structured scaffold incorporating OIC-A006-loaded PLGA microspheres based on β-TCP/PLGA.

    PubMed

    Lin, Liulan; Gao, Haitao; Dong, Yangyang

    2015-01-01

    To reveal the latent capacity of the growth factor-like low-molecular-weight material OIC-A006 in tissue regeneration, it is essential to design a porous scaffold in order to concurrently accommodate cells and drug release in a controlled manner. Consequently, we fabricated poly (L-lactide-co-glycolide) (PLGA)-based microspheres with an OIC-A006-loaded gradient-structured β-TCP/PLGA scaffold by freeze-drying which could then be used for drug delivery and bone regeneration. The OIC-A006-loaded β-TCP/PLGA scaffold consisted of two parts which loaded different doses of OIC-A006 (6.25 μM, outside; 12.5 μM, inside). The porosity, compressive strength, SEM, degradation, and cumulative amount of drug release in vitro were characterized. Furthermore, we confirmed the incorporation of OIC-A006 into the PLGA-based microspheres within the scaffolds using UV-spectrophotometry, and the amount of drug remaining in the scaffold was maintained by 10 % for up to 28 days. The drug release was slower in the normal-structured drug-loaded scaffold. The OIC-A006 released action from the OIC-A006-loaded β-TCP/PLGA scaffold with ideal therapeutic prospects in tissue regeneration. In vitro cell culture results showed that this gradient-structured composite scaffold can induce the adhesion and proliferation of rat bone marrow stromal cells towards osteoblasts. These results showed that the newly developed OIC-A006-loaded scaffolds with gradient structure can be potentially applied to bone regeneration in clinical applications. PMID:25577209

  11. Sustained delivery of rhBMP-2 via PLGA microspheres: cranial bone regeneration without heterotopic ossification or craniosynostosis

    PubMed Central

    Wink, Jason D.; Gerety, Patrick A.; Sherif, Rami D.; Lim, Youngshin; A.Clarke, Nadya; Rajapakse, Chamith S.; Nah, Hyun-Duck; Taylor, Jesse A.

    2014-01-01

    Background Commercially available recombinant human bone morphogenetic protein 2 (rhBMP2) has demonstrated efficacy in bone regeneration, but not without significant side effects. In this study, we utilize rhBMP2 encapsulated in PLGA microspheres (PLGA-rhBMP2) placed in a rabbit cranial defect model to test whether low-dose, sustained, delivery can effectively induce bone regeneration. Methods rhBMP2 was encapsulated in 15% poly (lactic-co-glycolic acid), using a double emulsion, solvent extraction/evaporation technique, and its release kinetics and bioactivity were tested. Two critical-size defects (10mm) were created in the calvarium of New Zealand White rabbits (5-7 mos of age, M/F) and filled with a collagen scaffold containing one of four groups: 1) no implant, 2) collagen scaffold only, 3) PLGA-rhBMP2(0.1ug/implant), or 4) free rhBMP2 (0.1ug/implant). After 6 weeks, the rabbits were sacrificed and defects were analyzed by μCT, histology, and finite element analysis. Results RhBMP2 delivered via bioactive PLGA microspheres resulted in higher volumes and surface area coverage of new bone than an equal dose of free rhBMP2 by μCT and histology (p=0.025, 0.025). FEA indicated that the mechanical competence using the regional elastic modulus did not differ with rhBMP2 exposure (p=0.70). PLGA-rhBMP2 did not demonstrate heterotopic ossification, craniosynostosis, or seroma formation. Conclusions Sustained delivery via PLGA microspheres can significantly reduce the rhBMP2 dose required for de novo bone formation. Optimization of the delivery system may be a key to reduce the risk for recently reported rhBMP2 related adverse effects. Level of Evidence Animal Study PMID:24622573

  12. A novel study on the mechanisms of drug release in PLGA-mPEG microspheres with fluorescent drug.

    PubMed

    Shi, Chen; Feng, Shuibin; Liu, Ping; Liu, Xianzhe; Feng, Xiaobo; Fu, Dehao

    2016-06-01

    The purpose of this research was to proof the microspheres release mechanism by a novel method-detecting and comparing the drugs fluorescent changes on the microspheres surface. Fluorescein sodium (FS, 0.4 kDa) and fluorescein isothiocyanate-bovine serum albumin (FITC-BSA, 66.8 kDa) were employed as model drugs. FS and FITC-BSA were encapsulated into PLGA-mPEG microspheres through double emulsion evaporation method, and the drug-loaded microspheres in vitro degradation and release behaviors were evaluated by scanning electron microscope, gel permeation chromatography, confocal laser scanning microscopy (CLSM), BCA assay kit, and UV-vis spectrophotometry. FS-loaded microspheres revealed a severe initial burst release, followed by a sustained release, and we could observe a bright fluorescent on the microspheres surface during the early release period under the CLSM. The bright fluorescent gradually faded out in the later period as only 1~2% FS was remained after 14 days release. FITC-BSA-loaded microspheres revealed a typical tri-phase release profile, and we observed a weak fluorescent on the microspheres surface after the initial burst release, and the fluorescent came bright again after an obvious erosion appeared on the microspheres surface. In the later release stage, the fluorescent gradually faded out as the fast release of FITC-BSA. PMID:26980344

  13. Control of drug loading efficiency and drug release behavior in preparation of hydrophilic-drug-containing monodisperse PLGA microspheres.

    PubMed

    Ito, Fuminori; Fujimori, Hiroyuki; Honnami, Hiroyuki; Kawakami, Hiroyoshi; Kanamura, Kiyoshi; Makino, Kimiko

    2010-05-01

    We prepared monodisperse poly(lactide-co-glycolide) (PLGA) microspheres containing blue dextran (BLD)--a hydrophilic drug--by membrane emulsification technique. The effects of electrolyte addition to the w(2) phase and significance of the droplet size ratio between primary (w(1)/o) and secondary (w(1)/o/w(2)) emulsions during the preparation of these microspheres was examined. The droplet size ratio was evaluated from the effect of stirring rate of the homogenizer when preparing the primary emulsion. The drug loading efficiency of BLD in these microspheres increased with stirring rate. It increased to approximately 90% when 2.0% NaCl was added to the w(2) phase. Drug release from these microspheres was slower than that when they were prepared without electrolyte addition. Despite the very high efficiency drug release was gradual because BLD was distributed at the microspheres core. Relatively monodisperse hydrophilic-drug-containing PLGA microspheres with controlled drug loading efficiency and drug release behavior were prepared. PMID:20221788

  14. A novel and simple preparative method for uniform-sized PLGA microspheres: Preliminary application in antitubercular drug delivery.

    PubMed

    Liu, Zhiqiang; Li, Xia; Xiu, Bingshui; Duan, Cuimi; Li, Jiangxue; Zhang, Xuhui; Yang, Xiqin; Dai, Wenhao; Johnson, Heather; Zhang, Heqiu; Feng, Xiaoyan

    2016-09-01

    Particle size has been demonstrated as a key parameter influencing the phagocytosis of drug-loaded PLGA microspheres (MS) by the target cells. However, the current preparative methods were either insufficient in controlling the homogeneity of the produced MS, or requires sophisticated and costly equipment. This study aimed to explore a simple and economical method for uniform PLGA MS preparation. Based on the heterogeneous emulsification of routine mechanical stirring, we designed an adjuvant strategy to enhance the homogeneity of MS. By using glass beads as adjutant, the dispersion produced during mechanical stirring was much more homogeneous in the solution. The particles produced were much smaller and the size distribution was much narrower as compared with those produced using the routine mechanical stirring method under the same condition. After enrichment by selective centrifugation, about 60% of the particles of similar size were obtained, providing further evidence for the efficiency of the novel method in controlling particle homogeneity. Further, the method was applied to prepare rifampicin-loaded PLGA MS of the optimized size for macrophage uptake. The functional evaluation showed that the prepared PLGA MS could efficiently deliver an antitubercular drug into macrophages and maintain a higher intracellular concentration by controlled release, suggesting the potential application of the method in PLGA MS-based drug delivery. Collectively, the study provided a simple and economical method for preparing uniform-sized PLGA MS with potential of widespread applications. PMID:27289309

  15. Design and evaluation of surface and adjuvant modified PLGA microspheres for uptake by dendritic cells to improve vaccine responses.

    PubMed

    Salvador, Aiala; Sandgren, Kerrie J; Liang, Frank; Thompson, Elizabeth A; Koup, Richard A; Pedraz, José Luis; Hernandez, Rosa Maria; Loré, Karin; Igartua, Manoli

    2015-12-30

    Designing strategies for targeting antigens to dendritic cells is a major goal in vaccinology. Here, PLGA (poly lactic-co-glycolic acid) microspheres and with several surface modifications that affect to their uptake by human blood primary dendritic cells and monocytes have been evaluated. Higher uptake was found by all the cell types when cationic microspheres (PLGA modified with polyethylene imine) were used. These cationic particles were in vivo evaluated in mice. In addition, MPLA(1) or poly(I:C)(2) and α-GalCer(3) were also encapsulated to address their adjuvant effect. All the microspheres were able to produce humoral immune responses, albeit they were higher for cationic microspheres. Moreover, surface charge seemed to have a role on biasing the immune response; cationic microspheres induced higher IFN-γ levels, indicative of Th1 activation, while unmodified ones mainly triggered IL4 and IL17A release, showing Th2 activation. Thus, we have shown here the potential and versatility of these MS, which may be tailored to needs. PMID:26475970

  16. Injectable long acting chitosan/tripolyphosphate microspheres for the intra-articular delivery of lornoxicam: Optimization and in vivo evaluation.

    PubMed

    Abd-Allah, Hend; Kamel, Amany O; Sammour, Omaima A

    2016-09-20

    Chitosan microspheres were formulated for the intra-articular delivery of lornoxicam in knee osteoarthritis, to minimize associated side-effects after prolonged oral administration. Ionotropic-gelation technique was employed using tripolyphosphate as anionic cross-linker. Full-factorial design experiment was conducted to optimize lornoxicam entrapment-efficiency%. Formulations were assessed for their particle size, in-vitro drug release, Scanning electron microscopy, Differential-scanning-calorimetry and Fourier transform infra-red spectroscopy studies. Changing independent variables, chitosan pH, TPP pH and lornoxicam concentration resulted in different values of entrapment-efficiency% ranging from 13.5%±0.35 to 59.5%±2.2. Particle size ranged from 3.57μm±0.02 to 6.12μm±0.00 and lornoxicam%release was prolonged for up to 8days. SEM results showed spherical shape of the microspheres. FTIR and DSC studies confirmed the crosslinking of chitosan with tripolyphosphate. In-vivo therapeutic effect of lornoxicam microspheres was investigated using Monosodiumiodoacetate (MIA) induced osteoarthritis model in rats. Optimized formula showed long-term in-vivo anti-inflammatory effect relative to lornoxicam solution injected intra-articularly with significant reduction of histological, inflammatory and biochemical parameters of osteoarthritis. PMID:27261750

  17. Release of a Wound-Healing Agent from PLGA Microspheres in a Thermosensitive Gel

    PubMed Central

    Machado, H. A.; Abercrombie, J. J.; You, T.; DeLuca, P. P.; Leung, K. P.

    2013-01-01

    The purpose of this research was to develop a topical microsphere delivery system in a thermosensitive 20% poloxamer 407 gel (Pluronic F127) to control release of KSL-W, a cationic antimicrobial decapeptide, for a period of 4–7 days for potential application in combat related injuries. KSL-W loaded microsphere formulations were prepared by a solvent extraction-evaporation method (water-oil-water), with poly (D,L-lactic-co-glycolic acid) (PLGA) (50 : 50, low-weight, and hydrophilic end) as the polymeric system. After optimization of the process, three formulations (A, B, and C) were prepared with different organic to water ratio of the primary emulsion while maintaining other components and manufacturing parameters constant. Formulations were characterized for surface morphology, porous nature, drug loading, in vitro drug release, and antimicrobial activity. Microspheres containing 20% peptide with porous surfaces and internal structure were prepared in satisfactory yields and in sizes varying from 25 to 50 μm. Gels of 20% Pluronic F127, which were liquid at or below 24.6°C and formed transparent films at body temperature, were used as carriers for the microspheres. Rheological studies showed a gelation temperature of 24.6°C for the 20% Pluronic F127 gel alone. Gelation temperature and viscosity of formulations A, B, and C as a function of temperature were very close to those of the carrier. A Franz diffusion cell system was used to study the release of peptide from the microspheres suspended in both, phosphate-buffered saline (PBS) and a 20% Pluronic F127 gel. In vitro release of greater than 50% peptide was found in all formulations in both PBS and the gel, and in one formulation there was a release of 75% in both PBS and the gel. Fractions collected from the release process were also tested for bactericidal activity against Staphylococcus epidermidis using the broth microdilution method and found to provide effective antimicrobial activity to warrant

  18. Development of porous PLGA/PEI1.8k biodegradable microspheres for the delivery of Mesenchymal Stem Cells (MSCs)

    PubMed Central

    Lee, Young Sook; Lim, Kwang Suk; Oh, Jung-Eun; Yun, Arum; Joo, Wan Seok; Kim, Hyun Soo; Yun, Chae-Ok; Kim, Sung Wan

    2015-01-01

    Multipotent mesenchymal stem cells (MSCs) promise a therapeutic alternative for many debilitating and incurable diseases. However, one of the major limitations for the therapeutic application of human MSC (hMSC) is the lengthy ex vivo expansion time for preparing a sufficient amount of cells due to the low engraftment rate after transplantation. To solve this conundrum, a porous biodegradable polymeric microsphere was investigated as a potential scaffold for the delivery of MSCs. The modified water/oil/water (W1/O/W2) double emulsion solvent evaporation method was used for the construction of porous microspheres. PEI1.8k was blended with Poly(lactic-co-glycolic acid) (PLGA) to enhance electrostatic cellular attachment to the microspheres. The porous PLGA/PEI1.8k (PPP) particles demonstrated an average particle size of 290 µm and an average pore size of 14.3 µm, providing a micro-carrier for the MSC delivery. PPP particles allowed for better attachment of rMSCs than nonporous PLGA/PEI1.8k (NPP) particles and non-porous (NP) and porous PLGA (PP) microspheres. rMSC successfully grew on the PPP particles for 2 weeks in vitro. Next, PPP particles loaded with 3 different amounts of hMSC showed increased in vivo engraftment rates and maintained the stemness characteristics of hMSC compared with hMSCs-alone group in rats 2 weeks after intramyocardial administration. These customized PPP particles for MSC delivery are a biodegradable and injectable scaffold that can be used for clinical applications. PMID:25575866

  19. Controllable promotion of chondrocyte adhesion and growth on PVA hydrogels by controlled release of TGF-β1 from porous PLGA microspheres.

    PubMed

    Nie, Lei; Zhang, Guohua; Hou, Ruixia; Xu, Haiping; Li, Yaping; Fu, Jun

    2015-01-01

    Poly(vinyl alcohol) (PVA) hydrogels have been candidate materials for cartilage tissue engineering. However, the cell non-adhesive nature of PVA hydrogels has been a limit. In this paper, the cell adhesion and growth on PVA hydrogels were promoted by compositing with transform growth factor-β1 (TGF-β1) loaded porous poly(D,L-lactide-co-glycolide) (PLGA) microspheres. The porous microspheres were fabricated by a modified double emulsion method with bovine serum albumin (BSA) as porogen. The average pore size of microspheres was manipulated by changing the BSA/PLGA ratio. Such controllable porous structures effectively influenced the encapsulation efficiency (Eencaps) and release profile of TGF-β1. By compositing PVA hydrogels with such TGF-β1-loaded PLGA microspheres, chondrocyte adhesion and proliferation were significantly promoted in a controllable manner, as confirmed by fluorescent imaging and quantitative CCK-8 assay. That is, the chondrocyte proliferation was favored by using PLGA microspheres with high Eencaps of TGF-β1 or by increasing the PLGA microsphere content in the hydrogels. These results demonstrated a facile method to improve the cell adhesion and growth on the intrinsically cell non-adhesive PVA hydrogels, which may find applications in cartilage substitution. PMID:25437063

  20. Stem cell differentiation-related protein-loaded PLGA microspheres as a novel platform micro-typed scaffold for chondrogenesis.

    PubMed

    Park, Ji Sun; Lim, Hye-Jin; Yi, Se Won; Park, Keun-Hong

    2016-01-01

    During cell differentiation for tissue regeneration, several factors, including growth factors and proteins, influence cascades in stem cells such as embryonic stem cells and mesenchymal stem cells (MSCs). In this study, transforming growth factor (TGF)-β3 and SOX9, which is an important protein in chondrocytes, were used to generate mature chondrocytes from human MSCs (hMSCs). For safe and effective delivery of bioactive molecules into hMSCs, biodegradable poly-(d,l-lactide-co-glycolide) (PLGA) microspheres (MSs) were coated with TGF-β3 and loaded with SOX9. Instead of SOX9 protein, release of the model protein FITC-bovine serum albumin (BSA) from PLGA MS was evaluated in vitro and in vivo by confocal laser microscopy and Kodak imaging. The bioactivities of TGF-β3 and SOX9 were evaluated by assessing α-helical formation using circular dichroism. PLGA MS loaded with FITC-BSA easily entered hMSCs without causing cytotoxicity. To confirm that internalization of PLGA MSs harboring TGF-β3 and SOX9 induced chondrogenesis of hMSCs, we performed several molecular analyses. By analysis, the specific marker gene expression levels in hMSCs adhered onto PLGA MSs coated with TGF-β3 and loaded with SOX9 were more than 3-5 times that of the control group both in vitro and in vivo. This result revealed that PLGA MS uptake and subsequent release of SOX9 induced chondrogenesis of hMSCs was enhanced by coating PLGA MSs with TGF-β3. PMID:27586647

  1. Thermostabilization of inactivated polio vaccine in PLGA-based microspheres for pulsatile release.

    PubMed

    Tzeng, Stephany Y; Guarecuco, Rohiverth; McHugh, Kevin J; Rose, Sviatlana; Rosenberg, Evan M; Zeng, Yingying; Langer, Robert; Jaklenec, Ana

    2016-07-10

    Vaccines are a critical clinical tool in preventing illness and death due to infectious diseases and are regularly administered to children and adults across the globe. In order to obtain full protection from many vaccines, an individual needs to receive multiple doses over the course of months. However, vaccine administration in developing countries is limited by the difficulty in consistently delivering a second or third dose, and some vaccines, including the inactivated polio vaccine (IPV), must be injected more than once for efficacy. In addition, IPV does not remain stable over time at elevated temperatures, such as those it would encounter over time in the body if it were to be injected as a single-administration vaccine. In this manuscript, we describe microspheres composed of poly(lactic-co-glycolic acid) (PLGA) that can encapsulate IPV along with stabilizing excipients and release immunogenic IPV over the course of several weeks. Additionally, pH-sensitive, cationic dopants such as Eudragit E polymer caused clinically relevant amounts of stable IPV release upon degradation of the PLGA matrix. Specifically, IPV was released in two separate bursts, mimicking the delivery of two boluses approximately one month apart. In one of our top formulations, 1.4, 1.1, and 1.2 doses of the IPV serotype 1, 2, and 3, respectively, were released within the first few days from 50mg of particles. During the delayed, second burst, 0.5, 0.8, and 0.6 doses of each serotype, respectively, were released; thus, 50mg of these particles released approximately two clinical doses spaced a month apart. Immunization of rats with the leading microsphere formulation showed more robust and long-lasting humoral immune response compared to a single bolus injection and was statistically non-inferior from two bolus injections spaced 1 month apart. By minimizing the number of administrations of a vaccine, such as IPV, this technology can serve as a tool to aid in the eradication of polio and

  2. [Studies on preparation by SPG membrane emulsification method and in vitro characterization of tetradrine-tashionone II(A)-PLGA composite microspheres].

    PubMed

    Lu, Jin; Zhang, Meng; Zhu, Hua-xu; Guo, Li-wei; Pan, Lin-mei; Fu, Ting-ming

    2015-03-01

    Tetradrine-tashionone II(A)-PLGA composite microspheres were prepared by the SPG membrane emulsification method, and the characterization of tetradrine-tashionone II(A) -PLGA composite microspheres were studied in this experiment. The results of IR, DSC and XRD showed that teradrine and tashionone II(A) in composite microspheres were highly dispersed in the PLGA with amorphous form. The results of tetradrine-tashionone II(A) -PLGA composite microspheres in vitro release experiment showed that the cumulative release amounts of tetradrine and tashionone II(A) were 6.44% and 3.60% in 24 h, and the cumulative release amounts of tetradrine and tashionone II(A) were 89.02% and 21.24% in 17 d. The process of drug in vitro release accorded with the model of Riger-Peppas. Tetradrine-tashionone II(A) -PLGA composite microspheres had slow-release effect, and it could significantly reduce the burst release, prolong the therapeutic time, decrease the dosage of drugs and provide a new idea and method to prepare traditional Chinese medicine compound. PMID:26226751

  3. Encapsulation of Exenatide in Poly-(d,l-Lactide-Co-Glycolide) Microspheres Produced an Investigational Long-Acting Once-Weekly Formulation for Type 2 Diabetes

    PubMed Central

    MacConell, Leigh; Sarin, Viren; Trautmann, Michael; Herbert, Paul

    2011-01-01

    Abstract Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet and exercise or as a combination therapy with an oral antidiabetes drug(s) in adults with type 2 diabetes. This long-acting formulation contains the active ingredient of the original exenatide twice-daily (EBID) formulation encapsulated in 0.06-mm-diameter microspheres of medical-grade poly-(d,l-lactide-co-glycolide) (PLG). After mechanical suspension and subcutaneous injection by the patient, EQW microspheres hydrate in situ and adhere to one another to form an amalgam. A small amount of loosely bound surface exenatide, typically less than 1%, releases in the first few hours, whereas drug located in deeper interstices diffuses out more slowly (time to maximum, ∼2 weeks). Fully encapsulated exenatide (i.e., drug initially inaccessible to diffusion) releases over a still longer period (time to maximum, ∼7 weeks) as the PLG matrix hydrolyzes into lactic acid and glycolic acid, which are subsequently eliminated as carbon dioxide and water. For EQW, plasma exenatide concentrations reach the therapeutic range by 2 weeks and steady state by 6–7 weeks. This gradual approach to steady state seems to improve tolerability, as nausea is less frequent with EQW than EBID. EQW administrations may be associated with palpable skin nodules that generally resolve without further medical intervention. In comparative trials, EQW improved hemoglobin A1c more than EBID, sitagliptin, pioglitazone, or insulin glargine and reduced fasting plasma glucose more than EBID. Weight loss due to EQW or EBID was similar. EQW is the first glucose-lowering agent that is administered once weekly. PMID:21751887

  4. Conformational stability of a model protein (bovine serum albumin) during primary emulsification process of PLGA microspheres synthesis.

    PubMed

    Kang, Feirong; Singh, Jagdish

    2003-07-01

    The goal of this study was to investigate the conformational stability of a model protein, bovine serum albumin (BSA), during the primary emulsification process of poly(D,L-lactide-co-glycolide) (PLGA) microspheres preparation. Differential scanning calorimeter (DSC) was utilized to assess the conformational structure of BSA during primary emulsification in the presence and absence of PLGA. Three excipients [i.e. mannitol, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and sodium dodecyl sulfate (SDS)] were investigated for their stabilizing effect on BSA during emulsification process. The DSC profile of intact BSA was best fitted by a non-2-state model with two peaks, which have midpoint temperatures (T(m1), 60.9 +/- 0.4 degrees C and T(m2), 66.4 +/- 1.0 degrees C), respectively, and a total calorimetric enthalpy Delta H(tot) of 599 +/- 42 kJ/mol. After emulsifying BSA aqueous solution with methylene chloride, an additional apparent peak at a higher temperature was observed. The T(m) of this peak was 77.4 +/- 0.8 degrees C. HP-beta-CD was able to suppress the occurrence of an additional peak, whereas mannitol failed. SDS increased the thermal stability of BSA dramatically. Furthermore, HP-beta-CD increased BSA recovery from 72 +/- 8% to 89 +/- 7% after extraction from w/o in the presence of PLGA. These results provided evidence that HP-beta-CD could be a promising excipient for conformational stability of BSA during synthesis of PLGA microspheres. PMID:12818819

  5. Sustained release of TGFbeta3 from PLGA microspheres and its effect on early osteogenic differentiation of human mesenchymal stem cells.

    PubMed

    Moioli, Eduardo K; Hong, Liu; Guardado, Jesse; Clark, Paul A; Mao, Jeremy J

    2006-03-01

    Despite the widespread role of transforming growth factor-beta3 (TGFbeta3) in wound healing and tissue regeneration, its long-term controlled release has not been demonstrated. Here, we report microencapsulation of TGFbeta3 in poly-d-l-lactic-co-glycolic acid (PLGA) microspheres and determine its bioactivity. The release profiles of PLGA-encapsulated TGFbeta3 with 50:50 and 75:25 PLA:PGA ratios differed throughout the experimental period. To compare sterilization modalities of microspheres, bFGF was encapsulated in 50:50 PLGA microspheres and subjected to ethylene oxide (EO) gas, radio-frequency glow discharge (RFGD), or ultraviolet (UV) light. The release of bFGF was significantly attenuated by UV light, but not significantly altered by either EO or RFGD. To verify its bioactivity, TGFbeta3 (1.35 ng/mL) was control-released to the culture of human mesenchymal stem cells (hMSC) under induced osteogenic differentiation. Alkaline phosphatase staining intensity was markedly reduced 1 week after exposing hMSC-derived osteogenic cells to TGFbeta3. This was confirmed by lower alkaline phosphatase activity (2.25 +/- 0.57 mU/mL/ng DNA) than controls (TGFbeta3- free) at 5.8 +/- 0.9 mU/mL/ng DNA (p < 0.05). Control-released TGFbeta3 bioactivity was further confirmed by lack of significant differences in alkaline phosphatase upon direct addition of 1.35 ng/mL TGFbeta3 to cell culture (p > 0.05). These findings provide baseline data for potential uses of microencapsulated TGFbeta3 in wound healing and tissue-engineering applications. PMID:16579687

  6. Ultrasound-modulated shape memory and payload release effects in a biodegradable cylindrical rod made of chitosan-functionalized PLGA microspheres.

    PubMed

    Bao, Min; Zhou, Qihui; Dong, Wen; Lou, Xiangxin; Zhang, Yanzhong

    2013-06-10

    Minimally invasive implants and/or scaffolds integrated with multiple functionalities are of interest in the clinical settings. In this paper, chitosan (CTS) functionalized poly(lactic-co-glycolic acid) (PLGA) microspheres containing a model payload, lysozyme (Lyz), were prepared by a water-in-oil-in-water emulsion method, from which cylindrical shaped rod (5 mm in diameter) was fabricated by sintering the composite microspheres in a mold. High-intensity focused ultrasound (HIFU) was then employed as a unique technique to enable shape memory and payload release effects of the three-dimensional (3-D) structure. It was found that incorporation of CTS into PLGA microspheres could regulate the transition temperature Ttrans of the microsphere from 45 to 50 °C and affect shape memory ratio of the fabricated cylindrical rod to some extent. Shape memory test and drug release assay proved that HIFU could modulate the shape recovery process and synchronize the release kinetics of the encapsulated Lyz in the rod in a switchable manner. Moreover, the two processes could be manipulated by varying the acoustic power and insonation duration. Mechanical tests of the microspheres-based rod before and after ultrasound irradiation revealed its compressive properties in the range of trabecular bone. Examination of the degradation behavior indicated that the introduction of CTS into the PLGA microspheres also alleviated acidic degradation characteristic of the PLGA-dominant cylindrical rod. With HIFU, this study thus demonstrated the desired capabilities of shape recovery and payload release effects integrated in one microspheres-based biodegradable cylindrical structure. PMID:23675980

  7. Gas-generating TPGS-PLGA microspheres loaded with nanoparticles (NIMPS) for co-delivery of minicircle DNA and anti-tumoral drugs.

    PubMed

    Gaspar, Vítor M; Moreira, André F; Costa, Elisabete C; Queiroz, João A; Sousa, Fani; Pichon, Chantal; Correia, Ilídio J

    2015-10-01

    Drug-DNA combination therapies are receiving an ever growing focus due to their potential for improving cancer treatment. However, such approaches are still limited by the lack of multipurpose delivery systems that encapsulate drugs and condense DNA simultaneously. In this study, we describe the successful formulation of gas-generating pH-responsive D-α-tocopherol PEG succinate-poly(D,L-lactic-co-glycolic acid) (TPGS-PLGA) hollow microspheres loaded with both Doxorubicin (Dox) and minicircle DNA (mcDNA) nanoparticles as a strategy to co-deliver these therapeutics. For this study mcDNA vectors were chosen due to their increased therapeutic efficiency in comparison to standard plasmid DNA. The results demonstrate that TPGS-PLGA microcarriers can encapsulate Dox and chitosan nanoparticles completely condense mcDNA. The loading of mcDNA-nanoparticles into microspheres was confirmed by 3D confocal microscopy and co-localization analysis. The resulting TPGS-PLGA-Dox-mcDNA nanoparticle-in-microsphere hybrid carriers exhibit a well-defined spherical shape and neutral surface charge. Microcarriers incubation in acidic pH produced a gas-mediated Dox release, corroborating the microcarriers stimuli-responsive character. Also, the dual-loaded TPGS-PLGA particles achieved 5.2-fold higher cellular internalization in comparison with non-pegylated microspheres. This increased intracellular concentration resulted in a higher cytotoxic effect. Successful transgene expression was obtained after nanoparticle-mcDNA co-delivery in the microspheres. Overall these findings support the concept of using nanoparticle-microsphere multipart systems to achieve efficient co-delivery of various drug-mcDNA combinations. PMID:26209779

  8. Preparation and property of a novel bone graft composite consisting of rhBMP-2 loaded PLGA microspheres and calcium phosphate cement.

    PubMed

    Fei, Zhengqi; Hu, Yunyu; Wu, Daocheng; Wu, Hong; Lu, Rong; Bai, Jianping; Song, Hongxun

    2008-03-01

    Calcium phosphate cement (CPC) is a highly promising bone substitute and an excellent carrier for delivering growth factors. Yet, the lack of macro-porosity and osteoinductive ability, limit its use. This study is aimed at developing a novel biodegradable biomaterial for bone repair with both highly osteoconductive and osteoinductive properties. RhBMP-2 loaded PLGA microspheres were incorporated into rhBMP-2/CPC for macropores for bone ingrowth. The compressive strength, crystallinity, microscopic structure, and bioactivity of the composites were investigated. The results showed that with the incorporation of rhBMP-2 loaded PLGA microspheres, the compressive strength was decreased from (29.48+/-6.42) MPa to (8.26+/-3.58) MPa. X-ray diffraction revealed that the crystallinity pattern of HA formed by CPC had no significant change. Inside the composite, the microspheres distributed homogeneously and contacted intimately with the HA matrix, as observed by scanning electron microscopy (SEM). When the PLGA microspheres dissolved after having been emerged in PBS for 56 days, macropores were created within the CPC. The rhBMP-2/PLGA/CPC composite, showing a 4.9% initial release of rhBMP-2 in 24 h, followed by a prolonged release for 28 days, should have a greater amount of rhBMP-2 released compared to the CPC delivery system. When rabbit marrow stromal cells were cocultured with the composite, the alkaline phosphatase (ALP) and osteocalcin (OC) showed a dose response to the rhBMP-2 released from the composite, indicating that the activity of rhBMP-2 was retained. This study shows that the new composite reveals more rhBMP-2 release and osteogenic activity. This novel BMP/PLGA/CPC composite could be a promising synthetic bone graft in craniofacial and orthopedic repairs. PMID:17701313

  9. Cytotoxic T cell vaccination with PLGA microspheres interferes with influenza A virus replication in the lung and suppresses the infectious disease.

    PubMed

    Herrmann, Valerie L; Hartmayer, Carmen; Planz, Oliver; Groettrup, Marcus

    2015-10-28

    Current influenza virus vaccines aim to elicit antibodies directed toward viral surface glycoproteins, which however are prone to antigenic drift. Cytotoxic T lymphocytes (CTLs) can exhibit heterosubtypic immunity against most influenza A viruses. In our study, we encapsulated the highly conserved, immunodominant, HLA-A*0201 restricted epitope from the influenza virus matrix protein M158-66 together with TLR ligands in biodegradable poly(d,l-lactide-co-glycolide) (PLGA) microspheres. Subcutaneous immunization of transgenic mice expressing chimeric HLA-A*0201 molecules with these microspheres induced a strong and sustained CTL response which sufficed to prevent replication of a recombinant vaccinia virus expressing the influenza A virus (IAV) matrix protein but not the replication of IAV in the lung. However, subcutaneous priming followed by intranasal boosting with M158-66 bearing PLGA microspheres was able to induce vigorous CTL responses both in the lung and spleen of mice which interfered with IAV replication, weight loss, and infection-related death. Taken together, vaccination with well-defined and highly conserved IAV-derived CTL epitopes encapsulated into clinically compatible PLGA microspheres contribute to the control of influenza A virus infections. The promptitude and broad reactivity of the CTL response may help to attenuate pandemic outbreaks of influenza viruses. PMID:26276509

  10. Effect of lecithin and MgCO3 as additives on the enzymatic activity of carbonic anhydrase encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres.

    PubMed

    Sandor, Maryellen; Riechel, Alex; Kaplan, Ian; Mathiowitz, Edith

    2002-02-15

    A model enzyme, carbonic anhydrase, was encapsulated and released from poly(lactide-co-glycolide) (PLGA) microspheres (1-3 microm) made by a novel phase inversion technique. Lecithin was used as a surfactant in the encapsulation process and was incorporated in either the organic phase, aqueous phase, both phases, or not at all. Additional microspheres were also made with lecithin incorporated in the aqueous phase and a basic salt, MgCO3, in the polymeric phase. Released carbonic anhydrase, protein extracted from microspheres, or enzyme incubated with lecithin and PLGA were analyzed via HPLC and activity assay to determine the effect of these additives on protein integrity and activity. Lecithin in the aqueous phase appeared to increase the fraction of enzyme in monomeric form as well as its activity for both extracted protein and released protein as compared to the other formulations without MgCO3. Incubation of enzyme with PLGA degradation products indicated that the acidic environment within the microspheres aids in the irreversible inactivation of the encapsulated protein. Addition of MgCO3 further increased the amount of monomer in both the extracted and released protein by decreasing the amount of acid-induced cleavage and noncovalent aggregation, but still greatly decreased the activity of the enzyme. PMID:11960690

  11. Spinal cord injury repair by implantation of structured hyaluronic acid scaffold with PLGA microspheres in the rat.

    PubMed

    Wen, Yujun; Yu, Shukui; Wu, Yanhong; Ju, Rongkai; Wang, Hao; Liu, Yujun; Wang, Ying; Xu, Qunyuan

    2016-04-01

    In order to create an optimal microenvironment for neural regeneration in the lesion area after spinal cord injury (SCI), we fabricated a novel scaffold composed of a hyaluronic acid (HA) hydrogel with a longitudinal multi-tubular conformation. The scaffold was modified by binding with an anti-Nogo receptor antibody (antiNgR) and mixed further with poly(lactic-co-glycolic acid) (PLGA) microspheres containing brain-derived neurotrophic factor and vascular endothelial growth factor (HA+PLGA). In the rat, after implantation of this composite into an injured area created by a dorsal hemisection at T9-10 of the spinal cord, favorable effects were seen with regard to the promotion of spinal repair, including excellent integration of the implants with host tissue, inhibition of inflammation, and gliosis. In particular, large numbers of new blood vessels and regenerated nerve fibers were found within and around the implants. Simultaneously, the implanted rats exhibited improved locomotor recovery. Thus, this novel composite material might provide a suitable microenvironment for neural regeneration following SCI. PMID:26463048

  12. Quantitative multi-agent models for simulating protein release from PLGA bioerodible nano- and microspheres.

    PubMed

    Barat, Ana; Crane, Martin; Ruskin, Heather J

    2008-09-29

    Using poly(lactide-co-glycolide) (PLGA) particles for drug encapsulation and delivery has recently gained considerable popularity for a number of reasons. An advantage in one sense, but a drawback of PLGA use in another, is that drug delivery systems made of this material can provide a wide range of dissolution profiles, due to their internal structure and properties related to particles' manufacture. The advantages of enriching particulate drug design experimentation with computer models, are evident with simulations used to predict and optimize design, as well as indicate choice of best manufacturing parameters. In the present work, we seek to understand the phenomena observed for PLGA micro- and nanospheres, through Cellular Automata (CA) agent-based Monte Carlo (MC) models. Systems are studied both over large temporal scales (capturing slow erosion of PLGA) and for various spatial configurations (capturing initial as well as dynamic morphology). The major strength of this multi-agent approach is to observe dissolution directly, by monitoring the emergent behaviour: the dissolution profile manifested, as a sphere erodes. Different problematic aspects of the modelling process are discussed in details in this paper. The models were tested on experimental data from literature, demonstrating very good performance. Quantitative discussion is provided throughout the text in order to make a demonstration of the use in practice of the proposed model. PMID:18436414

  13. Controlled release of imatinib mesylate from PLGA microspheres inhibit craniopharyngioma mediated angiogenesis.

    PubMed

    Karal-Yilmaz, Oksan; Ozkan, Abdulkadir; Akgun, Emel; Kukut, Manolya; Baysal, Kemal; Avsar, Timucin; Kilic, Turker

    2013-01-01

    Poly(lactic-co-glycolic acid) microspheres loaded with imatinib mesylate has been developed as a new therapeutic strategy to prevent craniopharyngioma recurrence. Microspheres composed of different lactic/glycolic acid ratios, molecular weights and drug compositions were synthesized and loaded with imatinib mesylate by modified double-emulsion/solvent evaporation technique and subsequently characterized by particle-size distribution, scanning electron microscopy, encapsulation efficiency and in vitro drug release. Inhibitory potential of imatinib containing microspheres on tumor neovascularization was investigated on craniopharyngioma tumor samples by rat cornea angiogenesis assay. Results showed that microspheres in different LA:GA ratios [LA:GA 50:50 (G50), 75:25 (G25), 85:15 (G15)] considerably reduced neovascularization induced by recurrent tumor samples in an in vivo angiogenesis assay (P < 0.01). Our data indicate that local delivery of imatinib mesylate to the post-surgical tumoral cavity using biodegradable microspheres may be a promising biologically selective approach to prevent the recurrence of craniopharyngiomas, via inhibition of neovascularization. PMID:23053813

  14. PLGA microspheres for the delivery of a novel subunit TB vaccine.

    PubMed

    Kirby, Daniel J; Rosenkrands, Ida; Agger, Else M; Andersen, Peter; Coombes, Allan G A; Perrie, Yvonne

    2008-05-01

    Biodegradable poly(dl-lactide-co-glycolide) microspheres were prepared using a modified double emulsion solvent evaporation method for the delivery of the subunit tuberculosis vaccine (Ag85B-ESAT-6), a fusion protein of the immunodominant antigens 6-kDa early secretory antigenic target (ESAT-6) and antigen 85B (Ag85B). Addition of the cationic lipid dimethyl dioctadecylammonium bromide (DDA) and the immunostimulatory trehalose 6,6'-dibehenate (TDB), either separately or in combination, was investigated for the effect on particle size and distribution, antigen entrapment efficiency, in vitro release profiles and in vivo performance. Optimised formulation parameters yielded microspheres within the desired sub-10 microm range (1.50 +/- 0.13 microm), whilst exhibiting a high antigen entrapment efficiency (95 +/- 1.2%) and prolonged release profiles. Although the microsphere formulations induced a cell-mediated immune response and raised specific antibodies after immunisation, this was inferior to the levels achieved with liposomes composed of the same adjuvants (DDA-TDB), demonstrating that liposomes are more effective vaccine delivery systems compared with microspheres. PMID:18446607

  15. Optimising the controlled release of dexamethasone from a new generation of PLGA-based microspheres intended for intravitreal administration.

    PubMed

    Rodríguez Villanueva, Javier; Bravo-Osuna, Irene; Herrero-Vanrell, Rocío; Molina Martínez, Irene Teresa; Guzmán Navarro, Manuel

    2016-09-20

    Successful therapy for chronic diseases affecting the posterior segment of the eye requires sustained drug concentrations at the site of action for extended periods of time. To achieve this, it is necessary to use high systemic doses or frequent intraocular injections, both associated with serious adverse effects. In order to avoid these complications and improve patient's quality of life, an experimental study has been conducted on the preparation of a new generation of biodegradable poly(D,L-lactide-co-glycolide) (50:50) (PLGA) polymer microspheres (MSs) loaded with Dxm, vitamin E and/or human serum albumin (HSA). Particles were prepared according to a S/O/W encapsulation method and the 20-40μm fraction was selected. This narrow size distribution is suitable for minimally invasive intravitreal injection by small calibre needles. Characterisation of the MSs showed high Dxm loading and encapsulation efficiency (> 90%) without a strong interaction with the polymer matrix, as revealed by DSC analysis. MSs drug release studies indicated a small burst effect (lower than 5%) during the first five hours and subsequently, drug release was sustained for at least 30days, led by diffusion and erosion mechanisms. Dxm release rate was modulated when solid state HSA was incorporated into MSs formulation. SDS-PAGE analysis showed that the protein maintained its integrity during the encapsulation process, as well as for the release study. MSs presented good tolerance and lack of cytotoxicity in macrophages and HeLa cultured cells. After 12months of storage under standard refrigerated conditions (4±1°C), MSs retained appropriate physical and chemical properties and analogous drug release kinetics. Therefore, we conclude that these microspheres are promising pharmaceutical systems for intraocular administration, allowing controlled release of the drug. PMID:26987610

  16. Setting accelerated dissolution test for PLGA microspheres containing peptide, investigation of critical parameters affecting drug release rate and mechanism.

    PubMed

    Tomic, I; Vidis-Millward, A; Mueller-Zsigmondy, M; Cardot, J-M

    2016-05-30

    The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45°C, in phosphate buffer saline (PBS) 0.02M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45°C to 40°C, release rate showed three-fold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01M (200 mOsm/kg) and PBS 0.01M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation. PMID:27025293

  17. Microspheres prepared with different co-polymers of poly(lactic-glycolic acid) (PLGA) or with chitosan cause distinct effects on macrophages.

    PubMed

    Bitencourt, Claudia da Silva; Silva, Letícia Bueno da; Pereira, Priscilla Aparecida Tartari; Gelfuso, Guilherme Martins; Faccioli, Lúcia Helena

    2015-12-01

    Microencapsulation of bioactive molecules for modulating the immune response during infectious or inflammatory events is a promising approach, since microspheres (MS) protect these labile biomolecules against fast degradation, prolong the delivery over longer periods of time and, in many situations, target their delivery to site of action, avoiding toxic side effects. Little is known, however, about the influence of different polymers used to prepare MS on macrophages. This paper aims to address this issue by evaluating in vitro cytotoxicity, phagocytosis profile and cytokines release from alveolar macrophages (J-774.1) treated with MS prepared with chitosan, and four different co-polymers of PLGA [poly (lactic-co-glycolic acid)]. The five MS prepared presented similar diameter and zeta potential each other. Chitosan-MS showed to be cytotoxic to J-774.1 cells, in contrast to PLGA-MS, which were all innocuous to this cell linage. PLGA 5000-MS was more efficiently phagocytized by macrophages compared to the other MS tested. PLGA 5000-MS and 5002-MS induced significant production of TNF-α, while 5000-MS, 5004-MS and 7502-MS decreased spontaneous IL-6 release. Nevertheless, only PLGA 5002-MS induced significant NFkB/SEAP activation. These findings together show that MS prepared with distinct PLGA co-polymers are differently recognized by macrophages, depending on proportion of lactic and glycolic acid in polymeric chain, and on molecular weight of the co-polymer used. Selection of the most adequate polymer to prepare a microparticulate drug delivery system to modulate immunologic system may take into account, therefore, which kind of immunomodulatory response is more adequate for the required treatment. PMID:26497115

  18. Inhibition of Octreotide Acylation Inside PLGA Microspheres by Derivatization of the Amines of the Peptide with a Self-Immolative Protecting Group.

    PubMed

    Shirangi, Mehrnoosh; Najafi, Marzieh; Rijkers, Dirk T S; Kok, Robbert Jan; Hennink, Wim E; van Nostrum, Cornelus F

    2016-03-16

    Acylation of biopharmaceuticals such as peptides has been identified as a major obstacle for the successful development of PLGA controlled release formulations. The purpose of this study was to develop a method to inhibit peptide acylation in poly(d,l-lactide-co-glycolide) (PLGA) formulations by reversibly and temporarily blocking the amine groups of a model peptide (octreotide) with a self-immolative protecting group (SIP), O-4-nitrophenyl-O'-4-acetoxybenzyl carbonate. The octreotide with two self-immolative protecting groups (OctdiSIP) on the N-terminus and lysine side chain was synthesized by reaction of the peptide with O-4-nitrophenyl-O'-4-acetoxybenzyl carbonate, purified by preparative RP-HPLC and characterized by mass spectrometry. Degradation studies of OctdiSIP in aqueous solutions of different pH values showed that protected octreotide was stable at low pH (pH 5) whereas the protecting group was eliminated at physiological pH, especially in the presence of an esterase, to generate native octreotide. OctdiSIP encapsulated in PLGA microspheres, prepared using a double emulsion solvent evaporation method, showed substantial inhibition of acylation as compared to the unprotected octreotide: 52.5% of unprotected octreotide was acylated after 50 days incubation of microspheres in PBS pH 7.4 at 37 °C, whereas OctdiSIP showed only 5.0% acylation in the same time frame. In conclusion, the incorporation of self-immolative protection groups provides a viable approach for inhibition of acylation of peptides in PLGA delivery systems. PMID:26726953

  19. Release of PLGA-encapsulated dexamethasone from microsphere loaded porous surfaces.

    PubMed

    Dawes, G J S; Fratila-Apachitei, L E; Necula, B S; Apachitei, I; Witkamp, G J; Duszczyk, J

    2010-01-01

    The aim of the present study was to investigate the morphology and function of a drug eluting metallic porous surface produced by the immobilization of poly lactide-co-glycolide microspheres bearing dexamethasone onto plasma electrolytically oxidized Ti-6Al-7Nb medical alloy. Spheres of 20 microm diameter were produced by an oil-in-water emulsion/solvent evaporation method and thermally immobilized onto titanium discs. The scanning electron microscopy investigations revealed that the size distribution and morphology of the attached spheres had not changed significantly. The drug release profiles following degradation in phosphate buffered saline for 1000 h showed that, upon immobilisation, the spheres maintained a sustained release, with a triphasic profile similar to the non-attached system. The only significant change was an increased release rate during the first 100 h. This difference was attributed to the effect of thermal attachment of the spheres to the surface. PMID:19669866

  20. Modeling the Time Course of the Tissue Responses to Intramuscular Long-acting Paliperidone Palmitate Nano-/Microcrystals and Polystyrene Microspheres in the Rat.

    PubMed

    Darville, Nicolas; van Heerden, Marjolein; Erkens, Tim; De Jonghe, Sandra; Vynckier, An; De Meulder, Marc; Vermeulen, An; Sterkens, Patrick; Annaert, Pieter; Van den Mooter, Guy

    2016-02-01

    Long-acting injectable (LAI) drug suspensions consist of drug nano-/microcrystals suspended in an aqueous vehicle and enable prolonged therapeutic drug exposure up to several months. The examination of injection site reactions (ISRs) to the intramuscular (IM) injection of LAI suspensions is relevant not only from a safety perspective but also for the understanding of the pharmacokinetics. The aim of this study was to perform a multilevel temporal characterization of the local and lymphatic histopathological/immunological alterations triggered by the IM injection of an LAI paliperidone palmitate suspension and an analog polystyrene suspension in rats and identify critical time points and parameters with regard to the host response. The ISRs showed a moderate to marked chronic granulomatous inflammation, which was mediated by multiple cyto-/chemokines, including interleukin-1β, monocyte Chemoattractant Protein-1, and vascular endothelial growth factor. Lymphatic uptake and lymph node retention of nano-/microparticles were observed, but the contribution to the drug absorption was negligible. A simple image analysis procedure and empirical model were proposed for the accurate evaluation of the depot geometry, cell infiltration, and vascularization. This study was designed as a reference for the evaluation and comparison of future LAIs and to support the mechanistic modeling of the formulation-physiology interplay regulating the drug absorption from LAIs. PMID:26698322

  1. Biomimetic Concealing of PLGA Microspheres in a 3D Scaffold to Prevent Macrophage Uptake.

    PubMed

    Minardi, Silvia; Corradetti, Bruna; Taraballi, Francesca; Sandri, Monica; Martinez, Jonathan O; Powell, Sebastian T; Tampieri, Anna; Weiner, Bradley K; Tasciotti, Ennio

    2016-03-01

    Scaffolds functionalized with delivery systems for the release of growth factors is a robust strategy to enhance tissue regeneration. However, after implantation, macrophages infiltrate the scaffold, eventually initiating the degradation and clearance of the delivery systems. Herein, it is hypothesized that fully embedding the poly(d,l-lactide-co-glycolide acid) microspheres (MS) in a highly structured collagen-based scaffold (concealing) can prevent their detection, preserving the integrity of the payload. Confocal laser microscopy reveals that non-embedded MS are easily internalized; when concealed, J774 and bone marrow-derived macrophages (BMDM) cannot detect them. This is further demonstrated by flow cytometry, as a tenfold decrease is found in the number of MS engulfed by the cells, suggesting that collagen can cloak the MS. This correlates with the amount of nitric oxide and tumor necrosis factor-α produced by J774 and BMDM in response to the concealed MS, comparable to that found for non-functionalized collagen scaffolds. Finally, the release kinetics of a reporter protein is preserved in the presence of macrophages, only when MS are concealed. The data provide detailed strategies for fabricating three dimensional (3D) biomimetic scaffolds able to conceal delivery systems and preserve the therapeutic molecules for release. PMID:26797709

  2. Porous nano-hydroxyapatite/collagen scaffold containing drug-loaded ADM-PLGA microspheres for bone cancer treatment.

    PubMed

    Rong, Zi-Jie; Yang, Lian-Jun; Cai, Bao-Ta; Zhu, Li-Xin; Cao, Yan-Lin; Wu, Guo-Feng; Zhang, Zan-Jie

    2016-05-01

    To develop adriamycin (ADM)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles in a porous nano-hydroxyapatite/collagen scaffold (ADM-PLGA-NHAC). To provide novel strategies for future treatment of osteosarcoma, the properties of the scaffold, including its in vitro extended-release properties, the inhibition effects of ADM-PLGA-NHAC on the osteosarcoma MG63 cells, and its bone repair capacity, were investigated in vivo and in vitro. The PLGA copolymer was utilized as a drug carrier to deliver ADM-PLGA nanoparticles (ADM-PLGA-NP). Porous nano-hydroxyapatite and collagen were used to materials to produce the porous nano-hydroxyapatite/collagen scaffold (NHAC), into which the ADM-PLGA-NP was loaded. The performance of the drug-carrying scaffold was assessed using multiple techniques, including scanning electron microscopy and in vitro extended release. The antineoplastic activities of scaffold extracts on the human osteosarcoma MG63 cell line were evaluated in vitro using the cell counting kit-8 (CCK8) method and live-dead cell staining. The bone repair ability of the scaffold was assessed based on the establishment of a femoral condyle defect model in rabbits. ADM-PLGA-NHAC and NHAC were implanted into the rat muscle bag for immune response experiments. A tumor-bearing nude mice model was created, and the TUNEL and HE staining results were observed under optical microscopy to evaluate the antineoplastic activity and toxic side effects of the scaffold. The composite scaffold demonstrated extraordinary extended-release properties, and its extracts also exhibited significant inhibition of the growth of osteosarcoma MG63 cells. In the bone repair experiment, no significant difference was observed between ADM-PLGA-NHAC and NHAC by itself. In the immune response experiments, ADM-PLGA-NHAC exhibited remarkable biocompatibility. The in vivo antitumor experiment revealed that the implantation of ADM-PLGA-NHAC in the tumor resulted in a improved antineoplastic

  3. Modified composite microspheres of hydroxyapatite and poly(lactide-co-glycolide) as an injectable scaffold

    NASA Astrophysics Data System (ADS)

    Hu, Xixue; Shen, Hong; Yang, Fei; Liang, Xinjie; Wang, Shenguo; Wu, Decheng

    2014-02-01

    The compound of hydroxyapatite-poly(lactide-co-glycolide) (HA-PLGA) was prepared by ionic bond between HA and PLGA. HA-PLGA was more stable than the simple physical blend of hydroxyapatite and poly(lactide-co-glycolide) (HA/PLGA). The surface of HA-PLGA microsphere fabricated by an emulsion-solvent evaporation method was rougher than that of HA/PLGA microspheres. Moreover, surface HA content of HA-PLGA microspheres was more than that of HA/PLGA microspheres. In vitro mouse OCT-1 osteoblast-like cell culture results showed that the HA-PLGA microspheres clearly promoted osteoblast attachment, proliferation and alkaline phosphatase activity. It was considered that surface rich HA component and rough surface of HA-PLGA microsphere enhanced cell growth and differentiation. The good cell affinity of the HA-PLGA microspheres indicated that they could be used as an injectable scaffold for bone tissue engineering.

  4. PLGA-PEG-PLGA microspheres as a delivery vehicle for antisense oligonucleotides to CTGF: Implications on post-surgical peritoneal adhesion prevention

    NASA Astrophysics Data System (ADS)

    Azeke, John Imuetinyan-Jesu, Jr.

    , while both cytokines are over-expressed within the first day following injury, CTGF protein levels could not be correlated with observed adhesion development. In addition, we synthesized linear triblock copolymers of polyethylene glycol (PEG) and poly(D,L-lactide-co-glycolide) (PLGA), two of the most widely studied biodegradable polymers in use today. Bulk gels and microparticles of the copolymers were then evaluated for gelling behavior, temperature stability, and drug loading and release kinetics in order assess their suitability as potential carriers of antisense therapeutics. A novel approach to affecting the antisense oligonucleotide release kinetics by varying the relative concentrations of co-encapsulated cationic lipid transfection agents was also presented.

  5. Physicochemical and mechanical properties of freeze cast hydroxyapatite-gelatin scaffolds with dexamethasone loaded PLGA microspheres for hard tissue engineering applications.

    PubMed

    Ghorbani, Farnaz; Nojehdehian, Hanieh; Zamanian, Ali

    2016-12-01

    Hydroxyapatite (HA)-gelatin scaffolds incorporated with dexamethasone-loaded polylactic-co-glycolic acid (PLGA) microspheres were synthesized by freeze casting technique. Scanning electron microscopy (SEM) micrographs demonstrated a unidirectional microstructure and a decrease in the pore size as a function of temperature gradient. Higher amounts of HA resulted in a decrease in the pore size. According to the results, at lower cooling rates, the formation of a lamellar structure decreased the mechanical strength, but at the same time, enhanced the swelling ratio, biodegradation rate and drug release level. On the other hand, higher weight ratios of HA increased the compressive strength, and reduced the swelling ratio, biodegradation rate and drug release level. The results obtained by furrier transform infrared spectroscopy (FTIR) and bioactivity analysis illustrated that the interactions of the materials support the apatite formation in the simulated body fluid (SBF) solution. Based on the obtained results, the synthesized composite scaffolds have the necessary mechanical and physicochemical features to support the regeneration of defects and to maintain their stability during the neo-tissue formation. PMID:27612706

  6. Microspheres

    NASA Technical Reports Server (NTRS)

    1990-01-01

    Vital information on a person's physical condition can be obtained by identifying and counting the population of T-cells and B-cells, lymphocytes of the same shape and size that help the immune system protect the body from the invasion of disease. The late Dr. Alan Rembaum developed a method for identifying the cells. The method involved tagging the T-cells and B-cells with microspheres of different fluorescent color. Microspheres, which have fluorescent dye embedded in them, are chemically treated so that they can link with antibodies. With the help of a complex antibody/antigen reaction, the microspheres bind themselves to specific 'targets,' in this case the T-cells or B-cells. Each group of cells can then be analyzed by a photoelectronic instrument at different wavelengths emitted by the fluorescent dyes. Same concept was applied to the separation of cancer cells from normal cells. Microspheres were also used to conduct many other research projects. Under a patent license Magsphere, Inc. is producing a wide spectrum of microspheres on a large scale and selling them worldwide for various applications.

  7. Influence of PEI as a Core Modifying Agent on PLGA Microspheres of PGE1, A Pulmonary Selective Vasodilator

    PubMed Central

    Gupta, Vivek; Ahsan, Fakhrul

    2011-01-01

    This study tests the hypothesis that large porous poly (lactic-co-glycolic acid) (PLGA) microparticles modified with polyethyleneimine (PEI) are viable carriers for pulmonary delivery of prostaglandin E1 (PGE1) used in the treatment of pulmonary arterial hypertension (PAH), a pulmonary vascular disorder. The particles were prepared by a double-emulsion solvent evaporation method with PEI-25 kDa in the internal aqueous phase to produce an osmotic pressure gradient. Polyvinyl alcohol (PVA) was used for external coating of the particles. The particles were examined for morphology, size, aerodynamic diameter, surface area, pore volume and in-vitro release profiles. Particles with optimal properties for inhalation were tested for in-vivo pulmonary absorption, metabolic stability in rat lung homogenates, and acute toxicity in rat bronchoalveolar lavage fluid and respiratory epithelial cells, Calu-3. The micromeritic data indicated that the PEI-modified particles of PGE1 are optimal for inhalation. Incorporation of PEI in the formulations resulted in an increased entrapment efficiency–83.26±3.04% for particles with 1% PVA and 95.48±0.46% for particles with 2% PVA. The amount of cumulative drug released into the simulated interstitial lung fluid was between 50.8±0.76% and 55.36±0.06%. A remarkable extension of the circulation half-life up to 6.0–6.5 hours was observed when the formulations were administered via the lungs. The metabolic stability and toxicity studies showed that the optimized formulations were stable at physiological conditions and relatively safe to the lungs and respiratory epithelium. Overall, this study demonstrates that large porous inhalable polymeric microparticles can be a feasible option for non-invasive and controlled release of PGE1 for treatment of PAH. PMID:21530623

  8. Long-acting muscarinic antagonists.

    PubMed

    Melani, Andrea S

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Inhaled bronchodilators are the mainstay of COPD pharmacological treatment. Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators. Some LAMA/device systems with different characteristics and dosing schedules are currently approved for maintenance therapy of COPD and a range of other products are being developed. They improve lung function and patient-reported outcomes and reduce acute bronchial exacerbations with good safety. LAMAs are used either alone or associated with long-acting β₂-agonists, eventually in fixed dose combinations. Long-acting β₂-agonist/LAMA combinations assure additional benefits over the individual components alone. The reader will obtain a view of the safety and efficacy of the different LAMA/device systems in COPD patients. PMID:26109098

  9. Long-acting injectable hormonal dosage forms for contraception.

    PubMed

    Wu, Linfeng; Janagam, Dileep R; Mandrell, Timothy D; Johnson, James R; Lowe, Tao L

    2015-07-01

    Although great efforts have been made to develop long-acting injectable hormonal contraceptives for more than four decades, few long-acting injectable contraceptives have reached the pharmaceutical market or even entered clinical trials. On the other hand, in clinical practice there is an urgent need for injectable long-acting reversible contraceptives which can provide contraceptive protection for more than 3 months after one single injection. Availability of such products will offer great flexibility to women and resolve certain continuation issues currently occurring in clinics. Herein, we reviewed the strategies exploited in the past to develop injectable hormonal contraceptive dosages including drug microcrystal suspensions, drug-loaded microsphere suspensions and in situ forming depot systems for long-term contraception and discussed the potential solutions for remaining issues met in the previous development. PMID:25899076

  10. Long-acting hormonal contraception.

    PubMed

    Benagiano, Giuseppe; Gabelnick, Henry; Brosens, Ivo

    2015-11-01

    Today, a new category of fertility-regulating agents has been created: long-acting, reversible hormonal contraceptives; they minimize compliance, while maximize effectiveness. They comprise subdermal implants and intrauterine devices. Other long-acting agents exist, such as Depo Provera and Noristerat. Use of Depo Provera and Noristerat carries great effectiveness, good clinical safety and usefulness in developing countries. They cause no significant increase in breast cancer risk, but they may carry an increased risk of HIV. Subcutaneous delivery systems have two common features: prolongation of effect is obtained by a drug reservoir and for most of their duration of action they provide a continuous, sustained release of the active hormone. Finally, the intrauterine system Mirena represents both a very effective contraceptive and a specific treatment for menorrhagia. PMID:26626534

  11. A 12-week intramuscular toxicity study of risperidone-loaded microspheres in Beagle dogs.

    PubMed

    Tian, J; Wang, W; Ye, L; Cen, X; Guan, X; Zhang, J; Yu, P; Du, G; Liu, W; Li, Y

    2014-05-01

    Long-acting formulations of antipsychotics are important treatment options to increase the compliance of schizophrenic patients. Risperidone, a 5-HT2 and dopaminergic D2 receptor antagonist, was developed as long-acting sustained-release microspheres with poly(lactide-co-glycolide) (PLGA) as a drug carrier for the treatment of schizophrenia. In the present study, the main objective is to determine the nonclinical safety profile of risperidone-loaded microspheres (RM) in Beagle dogs after intramuscular administration for 3 months, once in 2 weeks, followed by 8-week recovery phase. No animal death was found and no special toxicological findings were observed. The findings, such as hypoactivity, ptosis, increased heart rate, and elevated serum and pituitary prolactin levels, were observed and related to the pharmacological effects of risperidone. The changes in the reproductive system (uterus, ovary, vagina, cervix, and mammary gland) were considered secondary to the prolactin elevation, and the congestion of spleen was related to risperidone. The foreign body granulomas at injection sites might be caused by PLGA. At the end of recovery phase, the above changes mostly recovered to normal, and on administering 3 mg/kg dose level once in 2 weeks on Beagle dogs showed no observed adverse effect. Taken together, RM had exhibited the acceptable safety. PMID:23925946

  12. Caffeic Acid-PLGA Conjugate to Design Protein Drug Delivery Systems Stable to Irradiation

    PubMed Central

    Selmin, Francesca; Puoci, Francesco; Parisi, Ortensia I.; Franzé, Silvia; Musazzi, Umberto M.; Cilurzo, Francesco

    2015-01-01

    This work reports the feasibility of caffeic acid grafted PLGA (g-CA-PLGA) to design biodegradable sterile microspheres for the delivery of proteins. Ovalbumin (OVA) was selected as model compound because of its sensitiveness of γ-radiation. The adopted grafting procedure allowed us to obtain a material with good free radical scavenging properties, without a significant modification of Mw and Tg of the starting PLGA (Mw PLGA = 26.3 ± 1.3 kDa vs. Mw g-CA-PLGA = 22.8 ± 0.7 kDa; Tg PLGA = 47.7 ± 0.8 °C vs. Tg g-CA-PLGA = 47.4 ± 0.2 °C). By using a W1/O/W2 technique, g-CA-PLGA improved the encapsulation efficiency (EE), suggesting that the presence of caffeic residues improved the compatibility between components (EEPLGA = 35.0% ± 0.7% vs. EEg-CA-PLGA = 95.6% ± 2.7%). Microspheres particle size distribution ranged from 15 to 50 µm. The zeta-potential values of placebo and loaded microspheres were −25 mV and −15 mV, respectively. The irradiation of g-CA-PLGA at the dose of 25 kGy caused a less than 1% variation of Mw and the degradation patterns of the non-irradiated and irradiated microspheres were superimposable. The OVA content in g-CA-PLGA microspheres decreased to a lower extent with respect to PLGA microspheres. These results suggest that g-CA-PLGA is a promising biodegradable material to microencapsulate biological drugs. PMID:25569163

  13. Long-acting contraceptive options.

    PubMed

    Kaunitz, A M

    1996-01-01

    Long-acting contraceptive methods are appropriate choices for women who prefer the convenience and high contraceptive efficacy of methods not requiring frequent compliance, and women for whom contraceptive doses of estrogen are either medically contraindicated or associated with persistent intolerable side effects. Annual pregnancy rates for the three methods described below are less than 1 per 100 woman-years. As currently formulated, levonorgestrel implants (Norplant) consist of six 34 x 2.4 mm soft plastic implants, each filled with 36 mg of crystalline levonorgestrel. Irregular and often persistent menstrual bleeding and spotting constitute the most important side effects experienced by and leading to method discontinuation in implant users. Implant removal is technically more difficult and time-consuming than insertion. Depot-medroxyprogesterone acetate (DMPA or Depo-Provera) is injected as an aqueous suspension of microcrystals. Intramuscular injection of 150 mg of DMPA results in more than 3 months of contraception. Irregular bleeding and spotting followed by amenorrhea, constitute the most importance side effects experienced by DMPA users. Because DMPA use can result in prolonged (but not permanent) infertility, DMPA is not an optimum contraceptive choice for women who may want to conceive in the next one or two years. The Copper T380A intrauterine device (IUD) provides reversible contraception for up to 10 years. IUDs act as contraceptives, not early abortafacients. Recent epidemiologic data indicate that long-term IUD use does not increase the occurrence of pelvic inflammatory disease. Heavier menstrual flow and cramps constitute the main side effects experienced by women using the copper IUD. Intrauterine device insertion and removal are accomplished during brief office-based procedures. PMID:8829701

  14. Long-acting local anesthetics in dentistry.

    PubMed Central

    Sisk, A. L.

    1992-01-01

    Long-acting local anesthetics have proved to be effective for the suppression of both intraoperative and postoperative pain. They are useful for lengthy dental treatments and for prevention of severe pain following many types of surgical procedures. Although the currently available long-acting local anesthetics for dentistry have minimal side effects in the doses usually employed, there are potential problems. Bupivacaine, for example, can cause significant cardiac depressant and dysrhythmogenic responses. Etidocaine has less pronounced effects on the cardiovascular system, but its use may be associated with inadequate control of intraoperative bleeding. A new long-acting local anesthetic, ropivacaine, appears to offer advantages over either of the currently used long-acting agents. PMID:1308373

  15. Synthesis and Characterization of PLGA Shell Microcapsules Containing Aqueous Cores Prepared by Internal Phase Separation.

    PubMed

    Abulateefeh, Samer R; Alkilany, Alaaldin M

    2016-08-01

    The preparation of microcapsules consisting of poly(D,L-lactide-co-glycolide) (PLGA) polymer shell and aqueous core is a clear challenge and hence has been rarely addressed in literature. Herein, aqueous core-PLGA shell microcapsules have been prepared by internal phase separation from acetone-water in oil emulsion. The resulting microcapsules exhibited mean particle size of 1.1 ± 0.39 μm (PDI = 0.35) with spherical surface morphology and internal poly-nuclear core morphology as indicated by scanning electron microscopy (SEM). The incorporation of water molecules into PLGA microcapsules was confirmed by differential scanning calorimetry (DSC). Aqueous core-PLGA shell microcapsules and the corresponding conventional PLGA microspheres were prepared and loaded with risedronate sodium as a model drug. Interestingly, aqueous core-PLGA shell microcapsules illustrated 2.5-fold increase in drug encapsulation in comparison to the classical PLGA microspheres (i.e., 31.6 vs. 12.7%), while exhibiting sustained release behavior following diffusion-controlled Higuchi model. The reported method could be extrapolated to encapsulate other water soluble drugs and hydrophilic macromolecules into PLGA microcapsules, which should overcome various drawbacks correlated with conventional PLGA microspheres in terms of drug loading and release. PMID:26416284

  16. Surface studies of coated polymer microspheres and protein release from tissue-engineered scaffolds.

    PubMed

    Meese, Thomas M; Hu, Yunhua; Nowak, Richard W; Marra, Kacey G

    2002-01-01

    The controlled release of growth factors from porous, polymer scaffolds is being studied for potential use as tissue-engineered scaffolds. Biodegradable polymer microspheres were coated with a biocompatible polymer membrane to permit the incorporation of the microspheres into tissue-engineered scaffolds. Surface studies with poly(D,L-lactic-co-glycolic acid) [PLGA], and poly(vinyl alcohol) [PVA] were conducted. Polymer films were dip-coated onto glass slides and water contact angles were measured. The contact angles revealed an initially hydrophobic PLGA film, which became hydrophilic after PVA coating. After immersion in water, the PVA coating was removed and a hydrophobic PLGA film remained. Following optimization using these 2D contact angle studies, biodegradable PLGA microspheres were prepared, characterized, and coated with PVA. X-ray photoelectron spectroscopy was used to further characterize coated slides and microspheres. The release of the model protein bovine serum albumin from PVA-coated PLGA microspheres was studied over 8 days. The release of BSA from PVA-coated PLGA microspheres embedded in porous PLGA scaffolds over 24 days was also examined. Coating of the PLGA microspheres with PVA permitted their incorporation into tissue-engineered scaffolds and resulted in a controlled release of BSA. PMID:12022746

  17. Long-acting preparations of exenatide

    PubMed Central

    Cai, Yunpeng; Wei, Liangming; Ma, Liuqing; Huang, Xiwen; Tao, Anqi; Liu, Zhenguo; Yuan, Weien

    2013-01-01

    Exenatide has been widely used for the treatment of type 2 diabetes mellitus. However, its short plasma half-life of 2.4 hours has limited its clinical application. The exenatide products on the market, twice-daily Byetta™ and once-weekly Bydureon™ (both Amylin Pharmaceuticals, San Diego, CA, USA), are still not perfect. Many researchers have attempted to prolong the acting time of exenatide by preparing sustained-release dosage forms, modifying its structure, gene therapies, and other means. This review summarizes recent advances in long-acting exenatide preparations. PMID:24039406

  18. Polymeric microspheres

    DOEpatents

    Walt, David R.; Mandal, Tarun K.; Fleming, Michael S.

    2004-04-13

    The invention features core-shell microsphere compositions, hollow polymeric microspheres, and methods for making the microspheres. The microspheres are characterized as having a polymeric shell with consistent shell thickness.

  19. Synthesis of uniform poly(d,l-lactide) and poly(d,l-lactide-co-glycolide) microspheres using a microfluidic chip for comparison.

    PubMed

    Yang, Chih-Hui; Huang, Keng-Shiang; Grumezescu, Alexandru Mihai; Wang, Chih-Yu; Tzeng, Shian-Chiuan; Chen, Szu-Yu; Lin, Yu-Hsin; Lin, Yung-Sheng

    2014-02-01

    Applications of poly(l-lactide) (PLA) and poly(d,l-lactide-co-glycolide) (PLGA) microspheres are widely used in the biomedical and pharmaceutical fields. The effects of PLA/PLGA on microsphere properties when using conventional particulate preparation methods are not easily defined due to the uncontrollable particle size and size distribution. This study was aimed to synthesize uniform PLA and PLGA microspheres using a phenol formaldehyde resin-based microfluidic chip, which has the advantage of being solvent-resistant, flexible, and is readily disassembled for cleaning. The proposed chip can rapidly fabricate reproducible PLA and PLGA microspheres. Uniform emulsion droplets can be achieved by hydrodynamic flow focusing. After solvent evaporation, the free-flowing PLA and PLGA microspheres have a high level of morphological uniformity and size, allowing for a clear comparison of material effects. The results indicate that the sizes of the PLA and PLGA microspheres for the various flow rates of dispersed/continuous phases are very similar. The PLA/PLGA materials do not have a significant effect on particle size, but the particle surface indicates a different morphology. The result of the cytotoxicity evaluation shows no difference between PLA and PLGA and ensures the biocompatibility of both prepared PLA and PLGA microspheres for biomedical and pharmaceutical applications in the future. PMID:23857679

  20. Preparation, characterization, and in vitro release studies of insulin-loaded double-walled poly(lactide-co-glycolide) microspheres.

    PubMed

    Ansary, Rezaul H; Rahman, Mokhlesur M; Awang, Mohamed B; Katas, Haliza; Hadi, Hazrina; Doolaanea, Abd Almonen

    2016-06-01

    The purpose of this study was to fabricate insulin-loaded double-walled and single-polymer poly(lactide-co-glycolide) (PLGA) microspheres using a fast degrading glucose core, hydroxyl-terminated poly(lactide-co-glycolide) (Glu-PLGA), and a moderate degrading carboxyl-terminated PLGA polymers. A modified water-in-oil-in-oil-in-water (w/o/o/w) emulsion solvent evaporation technique was employed to prepare double-walled microspheres, whereas single-polymer microspheres were fabricated by a conventional water-in-oil-in-water (w/o/w) emulsion solvent evaporation method. The effect of fabrication techniques and polymer characteristics on microspheres size, morphology, encapsulation efficiency, in vitro release, and insulin stability was evaluated. The prepared double-walled microspheres were essentially non-porous, smooth surfaced, and spherical in shape, whereas single-polymer microspheres were highly porous. Double-walled microspheres exhibited a significantly reduced initial burst followed by sustained and almost complete release of insulin compared to single-polymer microspheres. Initial burst release was further suppressed from double-walled microspheres when the mass ratio of the component polymers was increased. In conclusion, double-walled microspheres made of Glu-PLGA and PLGA can be a potential delivery system of therapeutic insulin. PMID:26817478

  1. A novel strategy for the preparation of porous microspheres and its application in peptide drug loading.

    PubMed

    Wei, Yi; Wang, Yuxia; Zhang, Huixia; Zhou, Weiqing; Ma, Guanghui

    2016-09-15

    A new strategy is developed to prepare porous microspheres with narrow size distribution for peptides controlled release, involving a fabrication of porous microspheres without any porogens followed by a pore closing process. Amphiphilic polymers with different hydrophobic segments (poly(monomethoxypolyethylene glycol-co-d,l-lactide) (mPEG-PLA), poly(monomethoxypolyethylene glycol-co-d,l-lactic-co-glycolic acid) (mPEG-PLGA)) are employed as microspheres matrix to prepare porous microspheres based on a double emulsion-premix membrane emulsification technique combined with a solvent evaporation method. Both microspheres possess narrow size distribution and porous surface, which are mainly caused by (a) hydrophilic polyethylene glycol (PEG) segments absorbing water molecules followed by a water evaporation process and (b) local explosion of microspheres due to fast evaporation of dichloromethane (MC). Importantly, mPEG-PLGA microspheres have a honeycomb like structure while mPEG-PLA microspheres have a solid structure internally, illustrating that the different hydrophobic segments could modulate the affinity between solvent and matrix polymer and influence the phase separation rate of microspheres matrix. Long term release patterns are demonstrated with pore-closed microspheres, which are prepared from mPEG-PLGA microspheres loading salmon calcitonin (SCT). These results suggest that it is potential to construct porous microspheres for drug sustained release using permanent geometric templates as new porogens. PMID:27285778

  2. [Relation between drug release and the drug status within curcumin-loaded microsphere].

    PubMed

    Chen, De; Liu, Yi; Fan, Kai-yan; Xie, Yi-qiao; Yu, An-an; Xia, Zi-hua; Yang, Fan

    2016-01-01

    To study the relation between drug release and the drug status within curcumin-loaded microsphere, SPG (shirasu porous glass) membrane emulsification was used to prepare the curcumin-PLGA (polylactic-co-glycolic acid) microspheres with three levels of drug loading respectively, and the in vitro release was studied with high-performance liquid chromatography (HPLC). The morphology of microspheres was observed with scanning electron microscopy (SEM), and the drug status was studied with X-ray diffraction (XRD), differential scanning calorimetry (DSC) and infrared analysis (IR). The drug loading of microspheres was (5.85 ± 0.21)%, (11.71 ± 0.39)%, (15.41 ± 0.40)%, respectively. No chemical connection was found between curcumin and PLGA. According to the results of XRD, curcumin dispersed in PLGA as amorphous form within the microspheres of the lowest drug loading, while (2.12 ± 0.64)% and (5.66 ± 0.07)% curcumin crystals was detected in the other two kinds of microspheres, respectively, indicating that the drug status was different within three kinds of microspheres. In the data analysis, we found that PLGA had a limited capacity of dissolving curcumin. When the drug loading exceeded the limit, the excess curcumin would exist in the form of crystals in microspheres independently. Meanwhile, this factor contributes to the difference in drug release behavior of the three groups of microspheres. PMID:27405176

  3. Preparation and Analysis of Co-precipitated, Biodegradable Poly-(Lactide-co-Glycolide) and Polyethylene Glycol Microspheres Prepared by Spray Drying

    NASA Astrophysics Data System (ADS)

    Javiya, Curie

    Biodegradable poly-(d,l-lactide-co-glycolide) (PLGA) based microspheres are commonly used for numerous clinical applications. PEG is a widely used polymer due to its hydrophilic, biocompatible, and nontoxic nature. In this study, different blends of PLGA/PEG microspheres were prepared using a spray drying technique. The microspheres were spherical with maximum yield found to be 60.3% and average particle size in the range of 2.4 to 3.1 microm. Under the spray drying processing conditions, the polymers showed full miscibility slightly below 15% w/w and partial miscibility up to 20% w/w of PEG in the blended microspheres. At higher temperatures, PLGA and PEG were miscible in all proportions used for the blended microspheres. Blending 10% w/w PEG in PLGA membranes showed significant reduction in attachment of macrophages compared to PLGA membranes. The in-vitro response of macrophage towards the miscible blends of PLGA/PEG microspheres was further characterized. Results showed some reduction in macrophage viability and activation, however, significant effects with PLGA/PEG microspheres were not observed.

  4. Preparation and characterization of negatively charged poly(lactic-co-glycolic acid) microspheres.

    PubMed

    Xu, Qingguo; Crossley, Alison; Czernuszka, Jan

    2009-07-01

    Negatively charged poly(lactic-co-glycolic acid) (PLGA) microspheres encapsulated with hydrophilic drugs have been successfully prepared by a solid-in-oil-in-water (s/o/w) solvent evaporation method in the presence of anionic surfactants, sodium dodecyl sulfate (SDS), and dioctyl sodium sulfosuccinate (DSS), and nonionic surfactant polyvinyl alcohol (PVA). The effects of microencapsulation methods, surfactants types, and surfactant concentrations on the properties of microspheres were studied. Amoxicillin (AMX) was chosen as a hydrophilic model drug, and its encapsulation efficiency (EE) and in vitro release profiles were measured. The s/o/w method achieved higher EE of 40% in PLGA microspheres using surfactant SDS compared with the conventional water-in-oil-in-water (w/o/w) method (about 2%). Triphasic release profiles were observed for all PLGA microspheres (s/o/w) with slight drug burst, a slow diffusion-controlled release within the period of about 7 days and followed by the degradation-controlled sustained release for further 30 days. Smaller particle size and surface charge were achieved for s/o/w method than w/o/w method using the same anionic surfactants, and smooth surface and less porous interior matrix. The s/o/w method effectively encapsulated AMX into anionic PLGA microspheres using anionic surfactants, and these negatively charged PLGA microspheres represented an attractive approach for the controlled release of hydrophilic drugs. PMID:19009589

  5. [Aripiprazole long-acting for the maintenance treatment of schizophrenia.

    PubMed

    Samalin, L; Charpeaud, T; Llorca, P-M

    2014-11-13

    Antipsychotics are the cornerstone for the maintenance treatment of schizophrenia patients. Their long-acting formulations are helpful for preventing relapses through improvement of adherence to medication and a better pharmacokinetic coverage. However, their use is often reserved for refractory or non-observant clinical forms because of limitations among both clinicians and patients. The development of a new formulation of long-acting injectable aripiprazole administered every 4 weeks is a new option. Two randomized controlled trials vs. placebo and vs. oral aripiprazole respectively show a superiority and non-inferiority in terms of relapse prevention. Meanwhile, a mirror-image study demonstrates fewer hospitalizations. The safety profile is comparable to the oral formulation, particularly in terms of metabolic and neurological side-effects. As mentioned in various professional recommendations, long-acting injectable antipsychotics, so long-acting injectable aripiprazole, are one of the major strategies of the maintenance treatment for patients with schizophrenia. PMID:25453734

  6. A Systemic Review and Experts' Consensus for Long-acting Injectable Antipsychotics in Bipolar Disorder.

    PubMed

    Chou, Yuan Hwa; Chu, Po-Chung; Wu, Szu-Wei; Lee, Jen-Chin; Lee, Yi-Hsuan; Sun, I-Wen; Chang, Chen-Lin; Huang, Chien-Liang; Liu, I-Chao; Tsai, Chia-Fen; Yen, Yung-Chieh

    2015-08-31

    Bipolar disorder (BD) is a major psychiatric disorder that is easily misdiagnosed. Patient adherence to a treatment regimen is of utmost importance for successful outcomes in BD. Several trials of antipsychotics suggested that depot antipsychotics, including long-acting first- and second-generation agents, are effective in preventing non-adherence, partial adherence, and in reducing relapse in BD. Various long-acting injectable (LAI) antipsychotics are available, including fluphenazine decanoate, haloperidol decanoate, olanzapine pamoate, risperidone microspheres, paliperidone palmitate, and aripiprazole monohydrate. Due to the increasing number of BD patients receiving LAI antipsychotics, treatment guidelines have been developed. However, the clinical applicability of LAI antipsychotics remains a global cause for concern, particularly in Asian countries. Expert physicians from Taiwan participated in a consensus meeting, which was held to review key areas based on both current literature and clinical practice. The purpose of this meeting was to generate a practical and implementable set of recommendations for LAI antipsychotic use to treat BD; target patient groups, dosage, administration, and adverse effects were considered. Experts recommended using LAI antipsychotics in patients with schizophrenia, rapid cycling BD, BD I, and bipolar-type schizoaffective disorder. LAI antipsychotic use was recommended in BD patients with the following characteristics: multiple episodes and low adherence; seldom yet serious episodes; low adherence potential per a physician's clinical judgment; preference for injectable agents over oral agents; and multiple oral agent users still experiencing residual symptoms. PMID:26243837

  7. A Systemic Review and Experts’ Consensus for Long-acting Injectable Antipsychotics in Bipolar Disorder

    PubMed Central

    Chou, Yuan Hwa; Chu, Po-Chung; Wu, Szu-Wei; Lee, Jen-Chin; Lee, Yi-Hsuan; Sun, I-Wen; Chang, Chen-Lin; Huang, Chien-Liang; Liu, I-Chao; Tsai, Chia-Fen; Yen, Yung-Chieh

    2015-01-01

    Bipolar disorder (BD) is a major psychiatric disorder that is easily misdiagnosed. Patient adherence to a treatment regimen is of utmost importance for successful outcomes in BD. Several trials of antipsychotics suggested that depot antipsychotics, including long-acting first- and second-generation agents, are effective in preventing non-adherence, partial adherence, and in reducing relapse in BD. Various long-acting injectable (LAI) antipsychotics are available, including fluphenazine decanoate, haloperidol decanoate, olanzapine pamoate, risperidone microspheres, paliperidone palmitate, and aripiprazole monohydrate. Due to the increasing number of BD patients receiving LAI antipsychotics, treatment guidelines have been developed. However, the clinical applicability of LAI antipsychotics remains a global cause for concern, particularly in Asian countries. Expert physicians from Taiwan participated in a consensus meeting, which was held to review key areas based on both current literature and clinical practice. The purpose of this meeting was to generate a practical and implementable set of recommendations for LAI antipsychotic use to treat BD; target patient groups, dosage, administration, and adverse effects were considered. Experts recommended using LAI antipsychotics in patients with schizophrenia, rapid cycling BD, BD I, and bipolar-type schizoaffective disorder. LAI antipsychotic use was recommended in BD patients with the following characteristics: multiple episodes and low adherence; seldom yet serious episodes; low adherence potential per a physician’s clinical judgment; preference for injectable agents over oral agents; and multiple oral agent users still experiencing residual symptoms. PMID:26243837

  8. Raloxifene-/raloxifene-poly(ethylene glycol) conjugate-loaded microspheres: A novel strategy for drug delivery to bone forming cells.

    PubMed

    Kavas, Ayşegül; Keskin, Dilek; Altunbaş, Korhan; Tezcaner, Ayşen

    2016-08-20

    Raloxifene (Ral)- or Ral-poly(ethylene glycol) (PEG) conjugate-loaded microspheres were prepared with poly(ε-caprolactone) (PCL) alone or with the blend of PCL and poly(D,L-lactide-co-glycolide) (PLGA) to provide controlled and sustained Ral release systems. Benefits of these formulations were evaluated on bone regeneration. Ral-loaded PCL microspheres had the highest encapsulation efficiency (70.7±5.0%) among all groups owing to high hydrophobic natures of both Ral and PCL. Cumulative amount of Ral released from Ral-PEG (1:2) conjugate-loaded PCL:PLGA (1:1) microspheres (26.9±8.8%) after 60days was significantly higher relative to other microsphere groups. This finding can be ascribed to two factors: i) Ral-PEG conjugation, resulting in increased water-solubility of Ral and increased degradation rates of PCL and PLGA with enhanced water penetration into the polymer matrix, and ii) usage of PLGA besides PCL in the carrier composition to benefit from less hydrophobic and faster degradable nature of PLGA in comparison to PCL. In vitro cytotoxicity studies performed using adipose-derived mesenchymal stem cells (ASCs) demonstrated that all microspheres were non-toxic. Evaluation of intensities of Alizarin red S staining conducted after 7 and 14days of incubation of ASCs in the release media of the different microsphere groups was performed with Image J analysis software. At day 7, it was observed that the matrix deposited by the cells cultivated in the release medium of Ral-PEG (1:2) conjugate-loaded PCL:PLGA (1:1) microspheres had significantly higher mineral content (26.78±6.23%) than that of the matrix deposited by the cells cultivated in the release media of the other microsphere groups except Ral-loaded PCL:PLGA (1:1) microsphere group. At day 14, Ral release from Ral-PEG (1:2) conjugate-loaded PCL:PLGA (1:1) microsphere group resulted with significantly higher mineralization of the matrix (32.31±1.85%) deposited by ASCs in comparison to all other microsphere

  9. Exendin-4-loaded PLGA microspheres relieve cerebral ischemia/reperfusion injury and neurologic deficits through long-lasting bioactivity-mediated phosphorylated Akt/eNOS signaling in rats.

    PubMed

    Chien, Chiang-Ting; Jou, Ming-Jia; Cheng, Tai-Yu; Yang, Chih-Hui; Yu, Tzu-Ying; Li, Ping-Chia

    2015-11-01

    Glucagon-like peptide-1 (GLP-1) receptor activation in the brain provides neuroprotection. Exendin-4 (Ex-4), a GLP-1 analog, has seen limited clinical usage because of its short half-life. We developed long-lasting Ex-4-loaded poly(D,L-lactide-co-glycolide) microspheres (PEx-4) and explored its neuroprotective potential against cerebral ischemia in diabetic rats. Compared with Ex-4, PEx-4 in the gradually degraded microspheres sustained higher Ex-4 levels in the plasma and cerebrospinal fluid for at least 2 weeks and improved diabetes-induced glycemia after a single subcutaneous administration (20 μg/day). Ten minutes of bilateral carotid artery occlusion (CAO) combined with hemorrhage-induced hypotension (around 30 mm Hg) significantly decreased cerebral blood flow and microcirculation in male Wistar rats subjected to streptozotocin-induced diabetes. CAO increased cortical O2(-) levels by chemiluminescence amplification and prefrontal cortex edema by T2-weighted magnetic resonance imaging analysis. CAO significantly increased aquaporin 4 and glial fibrillary acidic protein expression and led to cognition deficits. CAO downregulated phosphorylated Akt/endothelial nitric oxide synthase (p-Akt/p-eNOS) signaling and enhanced nuclear factor (NF)-κBp65/intercellular adhesion molecule-1 (ICAM-1) expression, endoplasmic reticulum (ER) stress, and apoptosis in the cerebral cortex. PEx-4 was more effective than Ex-4 to improve CAO-induced oxidative injury and cognitive deficits. The neuroprotection provided by PEx-4 was through p-Akt/p-eNOS pathways, which suppressed CAO-enhanced NF-κB/ICAM-1 signaling, ER stress, and apoptosis. PMID:26058696

  10. Subcutaneously Administered Self-Cleaving Hydrogel-Octreotide Conjugates Provide Very Long-Acting Octreotide.

    PubMed

    Schneider, Eric L; Henise, Jeff; Reid, Ralph; Ashley, Gary W; Santi, Daniel V

    2016-07-20

    We developed a long-acting drug-delivery system that supports subcutaneous administration of the peptidic somatostatin agonist octreotide-a blockbuster drug used to treat acromegaly and neuroendocrine tumors. The current once-a-month polymer-encapsulated octreotide, Sandostatin LAR, requires a painful intragluteal injection through a large needle by a health-care professional. To overcome such shortcomings, Tetra-PEG hydrogel microspheres were covalently attached to the α-amine of d-Phe(1) or the ε-amine of Lys(5) of octreotide by a self-cleaving β-eliminative linker; upon subcutaneous injection in the rat using a small-bore needle, octreotide was slowly released. The released drug from the ε-octreotide conjugate showed a remarkably long serum half-life that exceeded two months. The α-octreotide conjugate had a half-life of ∼2 weeks, and showed an excellent correlation of in vitro and in vivo drug release. Pharmacokinetic models indicate these microspheres should support once-weekly to once-monthly self-administered subcutaneous dosing in humans. The hydrogel-octreotide conjugate shows the favorable pharmacokinetics of Sandostatin LAR without its drawbacks. PMID:27253622

  11. PLGA microdevices for retinoids sustained release produced by supercritical emulsion extraction: continuous versus batch operation layouts.

    PubMed

    Porta, Giovanna Della; Campardelli, Roberta; Falco, Nunzia; Reverchon, Ernesto

    2011-10-01

    Retinyl acetate (RA) was selected as a model compound to be entrapped in poly(lactic-co-glycolic)acid (PLGA) microspheres using supercritical emulsion extraction (SEE). Several oil-in-water emulsions prepared using acetone and aqueous glycerol (80% glycerol, 20% water) were processed using supercritical carbon dioxide (SC-CO2 ) to extract the oily phase and to induce microspheres formation. The characteristics of the microspheres obtained by conventional liquid emulsion extraction and SEE were also compared: SEE produced spherical and free flowing microspheres, whereas the conventional liquid-liquid extraction showed large intraparticles aggregation. Emulsion extraction by SC-CO2 technology was tested using two different operation layouts: batch (SEE-B) and continuous (SEE-C). SEE-C was performed using a packed tower to produce emulsion/SC-CO2 contact in countercurrent mode, allowing higher microsphere recovery and process efficiencies. Operating at 80 bar and 36°C, SEE-C produced PLGA/RA microspheres with mean sizes between 3.3 and 4.5 μm with an excellent encapsulation efficiency of 80%-90%. Almost all the drug was released in about 6 days when charged at 2.7% (w/w), whereas only 40% and 10% of RA were released in the same period of time when the charge was 5.2% and 8.8% (w/w), respectively. Release kinetics constants calculated from the experimental data, using a mathematical model, were also proposed and discussed. PMID:21638283

  12. Clinical blood chemistry values and long acting phenothiazines.

    PubMed

    Schneider, S J; Kirby, E J; Itil, T M

    1981-05-01

    Fifty-nine chronic schizophrenic patients received one year of treatment with either fluphenazine enanthate or pipothiazine palmitate IM. Both long acting neuroleptics significantly decreased serum albumin, total protein and creatinine values. Triglycerides were decreased only early in treatment. Pretreatment findings from therapy responders, as compared with those who failed to respond to treatment, included higher albumin values and to a lesser extent, lower lactic dehydrogenase values and greater height. These results were discussed with an eye toward the hepatocellular effects of long acting phenothiazines and the effect of liver function on the pharmacokinetics of these medications. PMID:6114503

  13. Reverse micelle-based microencapsulation of oxytetracycline hydrochloride into poly-d,l-lactide-co-glycolide microspheres.

    PubMed

    Kim, Hyunjoo; Lee, Beom-Jin; Sah, Hongkee

    2007-02-01

    The objectives of this study were to solubilize oxytetracycline hydrochloride (HCl) in reverse micelles to prepare poly-d,l-lactide-co-glycolide (PLGA) microspheres and to explore parameters affecting its encapsulation efficiency. Oxytetracycline HCl was dissolved in the reverse micelles consisting of cetyltrimethylammonium bromide, water, and ethyl formate. A PLGA polymer was then dissolved in the reverse micellar solution, and a modified solvent quenching procedure was carried out to prepare PLGA microspheres. Encapsulation efficiencies of oxytetracycline HCl ranged from 2.3 +/- 0.2 to 24.9 +/- 4.6%, depending on experimental conditions. Important parameters affecting its encapsulation efficiency included the amounts of water used to prepare the reverse micelles and PLGA polymer. With regard to microsphere morphology, the reverse micellar process produced the microspheres with smooth and pore-free surfaces. In particular, their internal matrices did not possess hollow cavities that were frequently observed when a typical double emulsion technique was used to make microspheres. In summary, it was possible to encapsulate oxytetracycline HCl into PLGA microspheres via the ethyl formate-based reverse micellar technique. We also anticipate that the use of ethyl formate could avoid environmental and human toxicity issues associated with methylene chloride. PMID:17364873

  14. Safety evaluation of poly(lactic-co-glycolic acid)/poly(lactic-acid) microspheres through intravitreal injection in rabbits

    PubMed Central

    Rong, Xianfang; Yuan, Weien; Lu, Yi; Mo, Xiaofen

    2014-01-01

    Poly(lactic-co-glycolic acid) (PLGA) and/or poly(lactic-acid) (PLA) microspheres are important drug delivery systems. This study investigated eye biocompatibility and safety of PLGA/PLA microspheres through intravitreal injection in rabbits. Normal New Zealand rabbits were randomly selected and received intravitreal administration of different doses (low, medium, or high) of PLGA/PLA microspheres and erythropoietin-loaded PLGA/PLA microspheres. The animals were clinically examined and sacrificed at 1, 2, 4, 8, and 12 weeks postadministration, and retinal tissues were prepared for analysis. Retinal reactions to the microspheres were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end staining and glial fibrillary acidic protein immunohistochemistry. Retinal structure changes were assessed by hematoxylin and eosin staining and transmission electron microscopy. Finally, retinal function influences were explored by the electroretinography test. Terminal deoxynucleotidyl transferase-mediated dUTP nick end staining revealed no apoptotic cells in the injected retinas; immunohistochemistry did not detect any increased glial fibrillary acidic protein expression. Hematoxylin and eosin staining and transmission electron microscopy revealed no micro- or ultrastructure changes in the retinas at different time points postintravitreal injection. The electroretinography test showed no significant influence of scotopic or photopic amplitudes. The results demonstrated that PLGA/PLA microspheres did not cause retinal histological changes or functional damage and were biocompatible and safe enough for intravitreal injection in rabbits for controlled drug delivery. PMID:25028546

  15. A biomimetic approach to active self-microencapsulation of proteins in PLGA.

    PubMed

    Shah, Ronak B; Schwendeman, Steven P

    2014-12-28

    A biomimetic approach to organic solvent-free microencapsulation of proteins based on the self-healing capacity of poly (DL)-lactic-co-glycolic acid (PLGA) microspheres containing glycosaminoglycan-like biopolymers (BPs), was examined. To screen BPs, aqueous solutions of BP [high molecular weight dextran sulfate (HDS), low molecular weight dextran sulfate (LDS), chondroitin sulfate (CS), heparin (HP), hyaluronic acid (HA), chitosan (CH)] and model protein lysozyme (LYZ) were combined in different molar and mass ratios, at 37 °C and pH7. The BP-PLGA microspheres (20-63 μm) were prepared by a double water-oil-water emulsion method with a range of BP content, and trehalose and MgCO3 to control microclimate pH and to create percolating pores for protein. Biomimetic active self-encapsulation (ASE) of proteins [LYZ, vascular endothelial growth factor165 (VEGF) and fibroblast growth factor (FgF-20)] was accomplished by incubating blank BP-PLGA microspheres in low concentration protein solutions at ~24 °C, for 48 h. Pore closure was induced at 42.5 °C under mild agitation for 42h. Formulation parameters of BP-PLGA microspheres and loading conditions were studied to optimize protein loading and subsequent release. LDS and HP were found to bind >95% LYZ at BP:LYZ>0.125 w/w, whereas HDS and CS bound >80% LYZ at BP:LYZ of 0.25-1 and <0.33, respectively. HA-PLGA microspheres were found to be not ideal for obtaining high protein loading (>2% w/w of LYZ). Sulfated BP-PLGA microspheres were capable of loading LYZ (~2-7% w/w), VEGF (~4% w/w), and FgF-20 (~2% w/w) with high efficiency. Protein loading was found to be dependent on the loading solution concentration, with higher protein loading obtained at higher loading solution concentration within the range investigated. Loading also increased with content of sulfated BP in microspheres. Release kinetics of proteins was evaluated in-vitro with complete release media replacement. Rate and extent of release were found to depend

  16. A Biomimetic Approach to Active Self-Microencapsulation of Proteins in PLGA

    PubMed Central

    Shah, Ronak B.; Schwendeman, Steven P.

    2014-01-01

    A biomimetic approach to organic solvent-free microencapsulation of proteins based on the self-healing capacity of poly (DL)-lactic-co-glycolic acid (PLGA) microspheres containing glycosaminoglycan-like biopolymers (BPs), was examined. To screen BPs, aqueous solutions of BP [high molecular weight dextran sulfate (HDS), low molecular weight dextran sulfate (LDS), chondroitin sulfate (CS), heparin (HP), hyaluronic acid (HA), chitosan (CH)] and model protein lysozyme (LYZ) were combined in different molar and mass ratios, at 37 °C and pH 7. The BP-PLGA microspheres (20–63 µm) were prepared by a double water-oil-water emulsion method with a range of BP content, and trehalose and MgCO3 to control microclimate pH and to create percolating pores for protein. Biomimetic active self-encapsulation (ASE) of proteins [LYZ, vascular endothelial growth factor165 (VEGF) and fibroblast growth factor (FgF-20)] was accomplished by incubating blank BP-PLGA microspheres in low concentration protein solutions at ~24 °C, for 48 h. Pore closure was induced at 42.5 °C under mild agitation for 42 h. Formulation parameters of BP-PLGA microspheres and loading conditions were studied to optimize protein loading and subsequent release. LDS and HP were found to bind >95% LYZ at BP:LYZ >0.125 w/w, whereas HDS and CS bound > 80% LYZ at BP:LYZ of 0.25–1 and < 0.33, respectively. HA-PLGA microspheres were found to be not ideal for obtaining high protein loading (>2% w/w of LYZ). Sulfated BP-PLGA microspheres were capable of loading LYZ (~2–7 % w/w), VEGF (~ 4% w/w), and FgF-20 (~2% w/w) with high efficiency. Protein loading was found to be dependent on the loading solution concentration, with higher protein loading obtained at higher loading solution concentration within the range investigated. Loading also increased with content of sulfated BP in microspheres. Release kinetics of proteins was evaluated in-vitro with complete release media replacement. Rate and extent of release were

  17. In vitro drug release behavior, mechanism and antimicrobial activity of rifampicin loaded low molecular weight PLGA-PEG-PLGA triblock copolymeric nanospheres.

    PubMed

    Gajendiran, M; Divakar, S; Raaman, N; Balasubramanian, S

    2013-12-01

    Poly (lactic-co-glycolic acid) (PLGA (92:8)) and a series of PLGA-PEG-PLGA tri block copolymers were synthesized by direct melt polycondensation. The copolymers were characterized by FTIR, and 1HNMR spectroscopic techniques, viscosity, gel permeation chromatography (GPC) and powder x-ray diffraction (XRD). The rifampicin (RIF) loaded polymeric nanospheres (NPs) were prepared by ultrasonication-W/O emulsification technique. The NPs have been characterized by field emission scanning electron microscopy (FESEM), TEM, powder X-ray diffraction (XRD), UVvisible spectroscopy and DLS measurements. The drug loaded triblock copolymeric NPs have five folds higher drug content and drug loading efficiency than that of PLGA microspheres (MPs). The in vitro drug release study shows that the drug loaded NPs showed an initial burst release after that sustained release up to 72 h. All the triblock copolymeric NPs follow anomalous drug diffusion mechanism while the PLGA MPs follow non-Fickian super case-II mechanism up to 12 h. The overall in-vitro release follows second order polynomial kinetics up to 72 h. The antimicrobial activity of the RIF loaded polymer NPs was compared with that of pure RIF and tetracycline (TA). The RIF loaded triblock copolymeric NPs inhibited the bacterial growth more effectively than the pure RIF and TA. PMID:23701139

  18. Two cases of long-acting paliperidone in adolescence

    PubMed Central

    Fàbrega, Marina; Sugranyes, Gisela; Baeza, Inmaculada

    2015-01-01

    Paliperidone palmitate long-acting injection (PPLAI) is an atypical antipsychotic agent currently approved by the European Medicine Agency for the acute and maintenance treatment of schizophrenia in adults. However, there is no information so far on safety and effectiveness in patients under 18 years of age. We report on two clinical cases of adolescents with a psychotic spectrum disorder treated with PPLAI in an inpatient setting. The cases illustrate that PPLAI may hold potential as an effective and acceptably tolerated antipsychotic drug in adolescents with psychotic spectrum disorders. Given the lack of approved long acting injectable antipsychotics in patients under 18 years of age, reports on the effectiveness and safety of such medications in children and adolescent patients are of importance. PMID:26557986

  19. Status of long-acting-growth hormone preparations--2015.

    PubMed

    Høybye, Charlotte; Cohen, Pinchas; Hoffman, Andrew R; Ross, Richard; Biller, Beverly M K; Christiansen, Jens Sandahl

    2015-10-01

    Growth hormone (GH) treatment has been an established therapy for GH deficiency (GHD) in children and adults for more than three decades. Numerous studies have shown that GH treatment improves height, body composition, bone density, cardiovascular risk factors, physical fitness and quality of life and that the treatment has few side effects. Initially GH was given as intramuscular injections three times per week, but daily subcutaneous injections were shown to be more effective and less inconvenient and the daily administration has been used since its introduction in the 1980s. However, despite ongoing improvements in injection device design, daily subcutaneous injections remain inconvenient, painful and distressing for many patients, leading to noncompliance, reduced efficacy and increased health care costs. To address these issues a variety of long-acting formulations of GH have been developed. In this review we present the current status of long-acting GH preparations and discuss the specific issues related to their development. PMID:26187188

  20. Comparative effectiveness of long-acting antipsychotics: issues and challenges from a pragmatic randomised study.

    PubMed

    Ostuzzi, G; Barbui, C

    2016-02-01

    Although long-acting antipsychotics are widely used in individuals with psychotic disorders, it is unclear which long-acting preparation should be considered as first-line treatment in clinical practice. In this commentary, the main strengths and weaknesses of a recently published pragmatic randomised study comparing long-acting paliperidone palmitate v. long-acting haloperidol decanoate are briefly analysed. PMID:26515607

  1. The pharmacokinetics of long-acting antipsychotic medications.

    PubMed

    Spanarello, Stefano; La Ferla, Teresa

    2014-01-01

    The depot antipsychotics are synthesized by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil, with the exception of some molecules of new generation characterized by microcrystalline technologies. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate. The pharmacokinetics of depot antipsychotic medications are such that an intramuscular injection given at intervals from 1 to 4 weeks will produce adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot formulations of antipsychotic drugs have been extensively studied. The clinical pharmacokinetics of the depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, bromperidol decanoate, clopenthixol decanoate, flupenthixol decanoate, perphenazine onanthat, pipotiazine undecylenate, pipotiazine palmitate, fluspirilene, long-acting injectable risperidone, olanzapine pamoate, paliperidone palmitate, long-acting iloperidone, long-acting injectable aripiprazole) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed. PMID:23343447

  2. Sustained release of risperidone from biodegradable microspheres prepared by in-situ suspension-evaporation process.

    PubMed

    An, Taekun; Choi, Juhyuen; Kim, Aram; Lee, Jin Ho; Nam, Yoonjin; Park, Junsung; Sun, Bo Kyung; Suh, Hearan; Kim, Cherng-Ju; Hwang, Sung-Joo

    2016-04-30

    Risperidone-loaded poly (d,l-lactide-co-glycolide) (PLGA) microspheres were prepared with a suspension-evaporation process with an aqueous suspension containing an in situ-formed aluminum hydroxide inorganic gel (SEP-AL process) and evaluated for encapsulation efficiency, particle size, surface morphology, glass transition temperature, in vitro drug release profile, and in vivo behavior. The SEP-AL microspheres were compared with conventional oil-in-water (O/W) emulsion solvent evaporation method using polyvinylalcohol (PVA) as an emulsifier (CP-PVA process). The microspheres were spherical in shape. DSC measurements showed that risperidone crystallinity was greatly reduced due to the homogeneous distribution of risperidone in PLGA microspheres. In vitro drug release profile from the microspheres showed a sigmoidal pattern of negligible initial burst up to 24h and minimal release (time-lag) for 7days. After the lag phase, slow release took a place up to 25days and then rapid release occurred sharply for 1 week. In vivo rat pharmacokinetic profile from the microspheres showed very low blood concentration level at the initial phase (up to 24h) followed by the latent phase up to 21days. At the 3rd week, main phase started and the blood concentration of the drug increased up to the 5th week, and then gradually decreased. The risperidone-loaded PLGA microspheres produced by SEP-AL process showed excellent controlled release characteristics for the effective treatment of schizophrenia patients. PMID:26899975

  3. Derivation of an Analytical Solution to a Reaction-Diffusion Model for Autocatalytic Degradation and Erosion in Polymer Microspheres

    PubMed Central

    Ford Versypt, Ashlee N.; Arendt, Paul D.; Pack, Daniel W.; Braatz, Richard D.

    2015-01-01

    A mathematical reaction-diffusion model is defined to describe the gradual decomposition of polymer microspheres composed of poly(D,L-lactic-co-glycolic acid) (PLGA) that are used for pharmaceutical drug delivery over extended periods of time. The partial differential equation (PDE) model treats simultaneous first-order generation due to chemical reaction and diffusion of reaction products in spherical geometry to capture the microsphere-size-dependent effects of autocatalysis on PLGA erosion that occurs when the microspheres are exposed to aqueous media such as biological fluids. The model is solved analytically for the concentration of the autocatalytic carboxylic acid end groups of the polymer chains that comprise the microspheres as a function of radial position and time. The analytical solution for the reaction and transport of the autocatalytic chemical species is useful for predicting the conditions under which drug release from PLGA microspheres transitions from diffusion-controlled to erosion-controlled release, for understanding the dynamic coupling between the PLGA degradation and erosion mechanisms, and for designing drug release particles. The model is the first to provide an analytical prediction for the dynamics and spatial heterogeneities of PLGA degradation and erosion within a spherical particle. The analytical solution is applicable to other spherical systems with simultaneous diffusive transport and first-order generation by reaction. PMID:26284787

  4. Derivation of an Analytical Solution to a Reaction-Diffusion Model for Autocatalytic Degradation and Erosion in Polymer Microspheres.

    PubMed

    Ford Versypt, Ashlee N; Arendt, Paul D; Pack, Daniel W; Braatz, Richard D

    2015-01-01

    A mathematical reaction-diffusion model is defined to describe the gradual decomposition of polymer microspheres composed of poly(D,L-lactic-co-glycolic acid) (PLGA) that are used for pharmaceutical drug delivery over extended periods of time. The partial differential equation (PDE) model treats simultaneous first-order generation due to chemical reaction and diffusion of reaction products in spherical geometry to capture the microsphere-size-dependent effects of autocatalysis on PLGA erosion that occurs when the microspheres are exposed to aqueous media such as biological fluids. The model is solved analytically for the concentration of the autocatalytic carboxylic acid end groups of the polymer chains that comprise the microspheres as a function of radial position and time. The analytical solution for the reaction and transport of the autocatalytic chemical species is useful for predicting the conditions under which drug release from PLGA microspheres transitions from diffusion-controlled to erosion-controlled release, for understanding the dynamic coupling between the PLGA degradation and erosion mechanisms, and for designing drug release particles. The model is the first to provide an analytical prediction for the dynamics and spatial heterogeneities of PLGA degradation and erosion within a spherical particle. The analytical solution is applicable to other spherical systems with simultaneous diffusive transport and first-order generation by reaction. PMID:26284787

  5. Doxorubicin-loaded porous PLGA microparticles with surface attached TRAIL for the inhalation treatment of metastatic lung cancer.

    PubMed

    Kim, Insoo; Byeon, Hyeong Jun; Kim, Tae Hyung; Lee, Eun Seong; Oh, Kyung Taek; Shin, Beom Soo; Lee, Kang Choon; Youn, Yu Seok

    2013-09-01

    Inhalable highly porous large PLGA microparticles with incorporated doxorubicin and surface-attached with TRAIL (TRAIL/Dox PLGA MP) were fabricated using a w/o/w double emulsification method using ammonium bicarbonate as a gas-foaming agent for the treatment of lung cancer. The TRAIL/Dox PLGA MP produced were highly porous and 11.5 ± 0.4 μm in diameter, and the loading efficiencies of Dox and TRAIL were 86.5 ± 6.5% and 91.8 ± 2.4%, respectively. TRAIL and doxorubicin were gradually released by TRAIL/Dox PLGA over 7 days, and pulmonary administration resulted in the deposition of TRAIL/Dox PLGA MP in mouse lungs, and they remained in situ for up to a week. The anti-tumor efficacy of pulmonary administered TRAIL/Dox PLGA MP was evaluated in a BALB/c nu/nu mice mouse model of H226 cell metastasis. Tumors in H226-implanted mice treated with TRAIL/Dox PLGA MP were markedly smaller and fewer in number than mice treated with TRAIL or Dox PLGA MP alone. Furthermore, this improved performance was found to be due to the synergistic apoptotic effects of the two drugs. We believe that TRAIL/Dox PLGA MP offer a promise of a sustained-release, long-acting, inhalable anti-lung cancer agent. Furthermore, the synergism observed between TRAIL and doxorubicin suggests that the doxorubicin dosage could be substantially reduced and its side effects minimized. PMID:23755831

  6. Polyacrolein microspheres

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor)

    1986-01-01

    Microspheres of acrolein homopolymers and copolymer with hydrophillic comonomers such as methacrylic acid and/or hydroxyethylmethacrylate are prepared by cobalt gamma irradiation of dilute aqueous solutions of the monomers in presence of suspending agents, especially alkyl sulfates such as sodium dodecyl sulfate. Amine or hydroxyl modification is achieved by forming adducts with diamines or alkanol amines. Carboxyl modification is effected by oxidation with peroxides. Pharmaceuticals or other aldehyde reactive materials can be coupled to the microspheres. The microspheres directly form antibody adducts without agglomeration.

  7. Polyacrolein microspheres

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor)

    1983-01-01

    Microspheres of acrolein homopolymers and co-polymer with hydrophillic comonomers such as methacrylic acid and/or hydroxyethylmethacrylate are prepared by cobalt gamma irradiation of dilute aqueous solutions of the monomers in presence of suspending agents, especially alkyl sulfates such as sodium dodecyl sulfate. Amine or hydroxyl modification is achieved by forming adducts with diamines or alkanol amines. Carboxyl modification is effected by oxidation with peroxides. Pharmaceuticals or other aldehyde reactive materials can be coupled to the microspheres. The microspheres directly form antibody adducts without agglomeration.

  8. Polyacrolein microspheres

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor)

    1987-01-01

    Microspheres of acrolein homopolymers and copolymer with hydrophillic comonomers such as methacrylic acid and/or hydroxyethylmethacrylate are prepared by cobalt gamma irradiation of dilute aqueous solutions of the monomers in presence of suspending agents, especially alkyl sulfates such as sodium dodecyl sulfate. Amine or hydroxyl modification is achieved by forming adducts with diamines or alkanol amines. Carboxyl modification is effected by oxidation with peroxides. Pharmaceuticals or other aldehyde reactive materials can be coupled to the microspheres. The microspheres directly form antibody adducts without agglomeration.

  9. Biodegradable Polymeric Microsphere-Based Drug Delivery for Inductive Browning of Fat

    PubMed Central

    Jiang, Chunhui; Kuang, Liangju; Merkel, Madeline P.; Yue, Feng; Cano-Vega, Mario Alberto; Narayanan, Naagarajan; Kuang, Shihuan; Deng, Meng

    2015-01-01

    Brown and beige adipocytes are potent therapeutic agents to increase energy expenditure and reduce risks of obesity and its affiliated metabolic symptoms. One strategy to increase beige adipocyte content is through inhibition of the evolutionarily conserved Notch signaling pathway. However, systemic delivery of Notch inhibitors is associated with off-target effects and multiple dosages of application further faces technical and translational challenges. Here, we report the development of a biodegradable polymeric microsphere-based drug delivery system for sustained, local release of a Notch inhibitor, DBZ. The microsphere-based delivery system was fabricated and optimized using an emulsion/solvent evaporation technique to encapsulate DBZ into poly(lactide-co-glycolide) (PLGA), a commonly used biodegradable polymer for controlled drug release. Release studies revealed the ability of PLGA microspheres to release DBZ in a sustained manner. Co-culture of white adipocytes with and without DBZ-loaded PLGA microspheres demonstrated that the released DBZ retained its bioactivity, and effectively inhibited Notch and promoted browning of white adipocytes. Injection of these DBZ-loaded PLGA microspheres into mouse inguinal white adipose tissue depots resulted in browning in vivo. Our results provide the encouraging proof-of-principle evidence for the application of biodegradable polymers as a controlled release platform for delivery of browning factors, and pave the way for development of new translational therapeutic strategies for treatment of obesity. PMID:26617571

  10. Biodegradable Polymeric Microsphere-Based Drug Delivery for Inductive Browning of Fat.

    PubMed

    Jiang, Chunhui; Kuang, Liangju; Merkel, Madeline P; Yue, Feng; Cano-Vega, Mario Alberto; Narayanan, Naagarajan; Kuang, Shihuan; Deng, Meng

    2015-01-01

    Brown and beige adipocytes are potent therapeutic agents to increase energy expenditure and reduce risks of obesity and its affiliated metabolic symptoms. One strategy to increase beige adipocyte content is through inhibition of the evolutionarily conserved Notch signaling pathway. However, systemic delivery of Notch inhibitors is associated with off-target effects and multiple dosages of application further faces technical and translational challenges. Here, we report the development of a biodegradable polymeric microsphere-based drug delivery system for sustained, local release of a Notch inhibitor, DBZ. The microsphere-based delivery system was fabricated and optimized using an emulsion/solvent evaporation technique to encapsulate DBZ into poly(lactide-co-glycolide) (PLGA), a commonly used biodegradable polymer for controlled drug release. Release studies revealed the ability of PLGA microspheres to release DBZ in a sustained manner. Co-culture of white adipocytes with and without DBZ-loaded PLGA microspheres demonstrated that the released DBZ retained its bioactivity, and effectively inhibited Notch and promoted browning of white adipocytes. Injection of these DBZ-loaded PLGA microspheres into mouse inguinal white adipose tissue depots resulted in browning in vivo. Our results provide the encouraging proof-of-principle evidence for the application of biodegradable polymers as a controlled release platform for delivery of browning factors, and pave the way for development of new translational therapeutic strategies for treatment of obesity. PMID:26617571

  11. A qualitative analysis of long-acting reversible contraception.

    PubMed

    Sundstrom, Beth; Baker-Whitcomb, Annalise; DeMaria, Andrea L

    2015-07-01

    Increasing access to long-acting reversible contraception (LARC), including the intrauterine device and the implant is a public health and clinical imperative to reduce rates of unintended pregnancy. In 2012, the American College of Obstetricians and Gynecologists recommended these methods for all women, including adolescents. Little research explores why young women reject these safe, effective contraceptive methods. A total of 53 women aged 18-24 years completed in-depth interviews. Analytical techniques from the grounded theory approach were used to identify patterns and themes across the data. Participants initiated hormonal contraception for "the pill's" beneficial side effects and believed a myth of perfect use, which constructed a false choice of LARC methods. Barriers to LARC options included access, medical resistance, and cost. Participants described a sense of unease about methods perceived as "alien." These women underestimated the risks of oral contraceptive pills and overestimated the risks of long-acting reversible contraception, including infertility. The myth of perfect use emerged as participants wanted to be in control by taking "the pill" every day; however, many described imperfect adherence. Findings include strategies for public health professionals and health care providers to distribute satisfactory and effective contraception for young women. Effective health communication campaigns will emphasize the desirable side effects, safety and increased effectiveness of LARC methods. PMID:25424456

  12. Long-acting antituberculous therapeutic nanoparticles target macrophage endosomes

    PubMed Central

    Edagwa, Benson J.; Guo, Dongwei; Puligujja, Pavan; Chen, Han; McMillan, JoEllyn; Liu, Xinming; Gendelman, Howard E.; Narayanasamy, Prabagaran

    2014-01-01

    Eradication of Mycobacterium tuberculosis (MTB) infection requires daily administration of combinations of rifampin (RIF), isoniazid [isonicotinylhydrazine (INH)], pyrazinamide, and ethambutol, among other drug therapies. To facilitate and optimize MTB therapeutic selections, a mononuclear phagocyte (MP; monocyte, macrophage, and dendritic cell)-targeted drug delivery strategy was developed. Long-acting nanoformulations of RIF and an INH derivative, pentenyl-INH (INHP), were prepared, and their physicochemical properties were evaluated. This included the evaluation of MP particle uptake and retention, cell viability, and antimicrobial efficacy. Drug levels reached 6 μg/106 cells in human monocyte-derived macrophages (MDMs) for nanoparticle treatments compared with 0.1 μg/106 cells for native drugs. High RIF and INHP levels were retained in MDM for >15 d following nanoparticle loading. Rapid loss of native drugs was observed in cells and culture fluids within 24 h. Antimicrobial activities were determined against Mycobacterium smegmatis (M. smegmatis). Coadministration of nanoformulated RIF and INHP provided a 6-fold increase in therapeutic efficacy compared with equivalent concentrations of native drugs. Notably, nanoformulated RIF and INHP were found to be localized in recycling and late MDM endosomal compartments. These were the same compartments that contained the pathogen. Our results demonstrate the potential of antimicrobial nanomedicines to simplify MTB drug regimens.—Edagwa, B. J., Guo, D., Puligujja, P., Chen, H., McMillan, J., Liu, X., Gendelman, H. E., Narayanasamy, P. Long-acting antituberculous therapeutic nanoparticles target macrophage endosomes. PMID:25122556

  13. Access Barriers to Long-Acting Reversible Contraceptives for Adolescents.

    PubMed

    Kumar, Natasha; Brown, Joanna D

    2016-09-01

    The United States continues to have the highest adolescent birth rate of any industrialized country. Recently published guidelines by the American Academy of Pediatrics create a new consensus among professional organizations around the suitability of long-acting reversible contraceptives as first-line contraception for adolescents. Through a narrative review of U.S. studies published after 2000, this study seeks to summarize existing access barriers to long-acting reversible contraceptives for adolescents and highlight areas that warrant further intervention so that the recommendations of these professional organizations can be effectively integrated into clinical practice. Existing barriers include costs for institutions providing contraceptive care and for recipients; consent and confidentiality for adolescent patients; providers' attitudes, misconceptions and limited training; and patients' lack of awareness or misconceptions. Systemic policy interventions are required to address cost and confidentiality, such as the Affordable Care Act's mandate that contraceptive coverage be a part of essential health benefits for all insurance providers. Individual-level access barriers such as providers' misconceptions and gaps in technical training as well as patients' lack of awareness can be addressed directly by professional medical organizations, health care training programs, and other interventions. PMID:27247239

  14. One-step fabrication of inorganic/organic hybrid microspheres with tunable surface texture for controlled drug release application.

    PubMed

    Dong, Hua; Tang, Guannan; Ma, Ting; Cao, Xiaodong

    2016-01-01

    In this paper, we report one-step fabrication of poly(lactide-co-glycolic acid)/titanium oxide (PLGA/TiO2) hybrid microspheres with tunable surface texture via droplet-based microfluidics. Surface texture of microspheres can be continuously tuned by changing the mass ratio between titanium tetraisopropoxide (TTIP) and PLGA in the dispersed phase. The fast hydrolysis of TTIP on the droplet surface can generate a thin shell membrane, resulting in a wrinkled surface after extraction of organic solvent. In vitro drug release monitoring of tanshinone IIA-loaded PLGA/TiO2 hybrid microsphere reveals that surface texture can affect the drug release rate to a large extent without sacrificing the drug encapsulation efficiency. Our finding might benefit the sustained drug delivery where variable drug release rate and high drug encapsulation efficiency are both required. PMID:26610930

  15. Effect of Dexamethasone-Loaded Poly(Lactic-Co-Glycolic Acid) Microsphere/Poly(Vinyl Alcohol) Hydrogel Composite Coatings on the Basic Characteristics of Implantable Glucose Sensors

    PubMed Central

    Wang, Yan; Vaddiraju, Santhisagar; Qiang, Liangliang; Xu, Xiaoming; Papadimitrakopoulos, Fotios; Burgess, Diane J.

    2012-01-01

    Background Hydrogels alone and in combination with microsphere drug delivery systems are being considered as biocompatible coatings for implantable glucose biosensors to prevent/minimize the foreign body response. Previously, our group has demonstrated that continuous release of dexamethasone from poly(lactic-co-glycolic acid) (PLGA) microsphere/poly(vinyl alcohol) (PVA) hydrogel composites can successfully prevent foreign body response at the implantation site. The objective of this study was to investigate the effect of this composite coating on sensor functionality. Methods The PLGA microsphere/PVA hydrogel coatings were prepared and applied to glucose biosensors. The swelling properties of the composite coatings and their diffusivity to glucose were evaluated as a function of microsphere loading. Sensor linearity, response time, and sensitivity were also evaluated as a function of coating composition. Results The PLGA microsphere/PVA hydrogel composite coating did not compromise sensor linearity (sensors were linear up to 30 mM), which is well beyond the physiological glucose range (2 to 22 mM). The sensor response time did increase in the presence of the coating (from 10 to 19 s); however, this response time was still less than the average reported values. Although the sensitivity of the sensors decreased from 73 to 62 nA/mM glucose when the PLGA microsphere loading in the PVA hydrogel changed from 0 to 100 mg/ml, this reduced sensitivity is acceptable for sensor functionality. The changes in sensor response time and sensitivity were due to changes in glucose permeability as a result of the coatings. The embedded PLGA microspheres reduced the fraction of bulk water present in the hydrogel matrix and consequently reduced glucose diffusion. Conclusions This study demonstrates that the PLGA microsphere/PVA hydrogel composite coatings allow sufficient glucose diffusion and sensor functionality and therefore may be utilized as a smart coating for implantable

  16. In vitro-in vivo correlation of parenteral risperidone polymeric microspheres.

    PubMed

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

    2015-11-28

    The objective of the present study was to determine whether an in vitro-in vivo correlation (IVIVC) can be established for polymeric microspheres that are equivalent in formulation composition but prepared with different manufacturing processes. Risperidone was chosen as a model therapeutic and poly(lactic-co-glycolic acid) (PLGA) with similar molecular weight as that used in the commercial product Risperdal® Consta® was used to prepare risperidone microspheres. Various manufacturing processes were investigated to produce the risperidone microspheres with similar drug loading (approx. 37%) but distinctly different physicochemical properties (e.g. porosity, particle size and particle size distribution). In vitro release of the risperidone microspheres was investigated using different release testing methods (such as sample-and-separate and USP apparatus 4). In vivo pharmacokinetic profiles of the risperidone microsphere formulations following intramuscular administration were determined using a rabbit model. Furthermore, the obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method and the calculated in vivo release was compared with the in vitro release of these microspheres. Level A IVIVCs were established and validated for the compositionally equivalent risperidone microspheres based on the in vitro release data obtained using USP apparatus 4. The developed IVIVCs demonstrated good predictability and were robust. These results showed that the developed USP apparatus 4 method was capable of discriminating PLGA microspheres that are equivalent in formulation composition but with manufacturing differences and predicting their in vivo performance in the investigated animal model. PMID:26423236

  17. Process and formulation variables in the preparation of injectable and biodegradable magnetic microspheres

    PubMed Central

    Zhao, Hong; Gagnon, Jeffrey; Häfeli, Urs O

    2007-01-01

    The aim of this study was to prepare biodegradable sustained release magnetite microspheres sized between 1 to 2 μm. The microspheres with or without magnetic materials were prepared by a W/O/W double emulsion solvent evaporation technique using poly(lactide-co-glycolide) (PLGA) as the biodegradable matrix forming polymer. Effects of manufacturing and formulation variables on particle size were investigated with non-magnetic microspheres. Microsphere size could be controlled by modification of homogenization speed, PLGA concentration in the oil phase, oil phase volume, solvent composition, and polyvinyl alcohol (PVA) concentration in the outer water phase. Most influential were the agitation velocity and all parameters that influence the kinematic viscosity of oil and outer water phase, specifically the type and concentration of the oil phase. The magnetic component yielding homogeneous magnetic microspheres consisted of magnetite nanoparticles of 8 nm diameter stabilized with a polyethylene glycole/polyacrylic acid (PEG/PAA) coating and a saturation magnetization of 47.8 emu/g. Non-magnetic and magnetic microspheres had very similar size, morphology, and size distribution, as shown by scanning electron microscopy. The optimized conditions yielded microspheres with 13.7 weight% of magnetite and an average diameter of 1.37 μm. Such biodegradable magnetic microspheres seem appropriate for vascular administration followed by magnetic drug targeting. PMID:17407608

  18. Computational Intelligence Modeling of the Macromolecules Release from PLGA Microspheres—Focus on Feature Selection

    PubMed Central

    Zawbaa, Hossam M.; Szlȩk, Jakub; Grosan, Crina; Jachowicz, Renata; Mendyk, Aleksander

    2016-01-01

    Poly-lactide-co-glycolide (PLGA) is a copolymer of lactic and glycolic acid. Drug release from PLGA microspheres depends not only on polymer properties but also on drug type, particle size, morphology of microspheres, release conditions, etc. Selecting a subset of relevant properties for PLGA is a challenging machine learning task as there are over three hundred features to consider. In this work, we formulate the selection of critical attributes for PLGA as a multiobjective optimization problem with the aim of minimizing the error of predicting the dissolution profile while reducing the number of attributes selected. Four bio-inspired optimization algorithms: antlion optimization, binary version of antlion optimization, grey wolf optimization, and social spider optimization are used to select the optimal feature set for predicting the dissolution profile of PLGA. Besides these, LASSO algorithm is also used for comparisons. Selection of crucial variables is performed under the assumption that both predictability and model simplicity are of equal importance to the final result. During the feature selection process, a set of input variables is employed to find minimum generalization error across different predictive models and their settings/architectures. The methodology is evaluated using predictive modeling for which various tools are chosen, such as Cubist, random forests, artificial neural networks (monotonic MLP, deep learning MLP), multivariate adaptive regression splines, classification and regression tree, and hybrid systems of fuzzy logic and evolutionary computations (fugeR). The experimental results are compared with the results reported by Szlȩk. We obtain a normalized root mean square error (NRMSE) of 15.97% versus 15.4%, and the number of selected input features is smaller, nine versus eleven. PMID:27315205

  19. Electrospun aligned PLGA and PLGA/gelatin nanofibers embedded with silica nanoparticles for tissue engineering.

    PubMed

    Mehrasa, Mohammad; Asadollahi, Mohammad Ali; Ghaedi, Kamran; Salehi, Hossein; Arpanaei, Ayyoob

    2015-08-01

    Aligned poly lactic-co-glycolic acid (PLGA) and PLGA/gelatin nanofibrous scaffolds embedded with mesoporous silica nanoparticles (MSNPs) were fabricated using electrospinning method. The mean diameters of nanofibers were 641±24 nm for the pure PLGA scaffolds vs 418±85 nm and 267±58 nm for the PLGA/10 wt% MSNPs and the PLGA/gelatin/10 wt% MSNPs scaffolds, respectively. The contact angle measurement results (102°±6.7 for the pure PLGA scaffold vs 81°±6.8 and 18°±8.7 for the PLGA/10 wt% MSNPs and the PLGA/gelatin/10 wt% MSNPs scaffolds, respectively) revealed enhanced hydrophilicity of scaffolds upon incorporation of gelatin and MSNPs. Besides, embedding the scaffolds with MSNPs resulted in improved tensile mechanical properties. Cultivation of PC12 cells on the scaffolds demonstrated that introduction of MSNPs into PLGA and PLGA/gelatin matrices leads to the improved cell attachment and proliferation as well as long cellular processes. DAPI staining results indicated that cell proliferations on the PLGA/10 wt% MSNPs and the PLGA/gelatin/10 wt% MSNPs scaffolds were strikingly (nearly 2.5 and 3 folds, respectively) higher than that on the aligned pure PLGA scaffolds. These results suggest superior properties of silica nanoparticles-incorporated PLGA/gelatin eletrospun nanofibrous scaffolds for the stem cell culture and tissue engineering applications. PMID:26045092

  20. Injectable polymer microspheres enhance immunogenicity of a contraceptive peptide vaccine.

    PubMed

    Cui, Chengji; Stevens, Vernon C; Schwendeman, Steven P

    2007-01-01

    Advanced contraceptive peptide vaccines suffer from the unavailability of adjuvants capable of enhancing the antibody response with acceptable safety. We sought to overcome this limitation by employing two novel poly(lactic-co-glycolic acid) (PLGA) microsphere formulations to deliver a synthetic human chorionic gonadotropin (hCG) peptide antigen co-synthesized with a T-cell epitope from tetanus toxoid (TT), C-TT2-CTP35: surface-conjugated immunogen to induce phagocytosis; and encapsulated peptide to provide a depot effect, with MgCO(3) co-encapsulated in the polymer to neutralize acidity from the biodegrading PLGA polyester. A single immunization of encapsulated peptide in rabbits elicited a stronger antibody response with equivalent duration relative to a positive control--three injections of the peptide administered in a squalene-based water-in-oil emulsion. Surface-conjugated peptide was less effective but enhanced antibody levels at 1/5 the dose, relative to soluble antigen. Most remarkable and unexpected was the finding that co-encapsulation of base was essential to attain the powerful adjuvant effect of the PLGA-MgCO(3) system, as the MgCO(3)-free microspheres were completely ineffective. A promising contraceptive hCG peptide vaccine with acceptable side effects (i.e., local tissue reactions) was achieved by minimizing PLGA and MgCO(3) doses, without significantly affecting antibody response. PMID:16996662

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

    PubMed Central

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

    2014-01-01

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

  2. Synchrotron radiation-based Fourier-transform infrared spectromicroscopy for characterization of the protein/peptide distribution in single microspheres

    PubMed Central

    Wang, Manli; Lu, Xiaolong; Yin, Xianzhen; Tong, Yajun; Peng, Weiwei; Wu, Li; Li, Haiyan; Yang, Yan; Gu, Jingkai; Xiao, Tiqiao; Chen, Min; Zhang, Jiwen

    2015-01-01

    The present study establishes a visualization method for the measurement of the distribution and localization of protein/peptide constituents within a single poly-lactide-co-glycolide (PLGA) microsphere using synchrotron radiation–based Fourier-transform infrared spectromicroscopy (SR-FTIR). The representative infrared wavenumbers specific for protein/peptide (Exenatide) and excipient (PLGA) were identified and chemical maps at the single microsphere level were generated by measuring and plotting the intensity of these specific bands. For quantitative analysis of the distribution within microspheres, Matlab software was used to transform the map file into a 3D matrix and the matrix values specific for the drug and excipient were extracted. Comparison of the normalized SR-FTIR maps of PLGA and Exenatide indicated that PLGA was uniformly distributed, while Exenatide was relatively non-uniformly distributed in the microspheres. In conclusion, SR-FTIR is a rapid, nondestructive and sensitive detection technology to provide the distribution of chemical constituents and functional groups in microparticles and microspheres. PMID:26579456

  3. Synchrotron radiation-based Fourier-transform infrared spectromicroscopy for characterization of the protein/peptide distribution in single microspheres.

    PubMed

    Wang, Manli; Lu, Xiaolong; Yin, Xianzhen; Tong, Yajun; Peng, Weiwei; Wu, Li; Li, Haiyan; Yang, Yan; Gu, Jingkai; Xiao, Tiqiao; Chen, Min; Zhang, Jiwen

    2015-05-01

    The present study establishes a visualization method for the measurement of the distribution and localization of protein/peptide constituents within a single poly-lactide-co-glycolide (PLGA) microsphere using synchrotron radiation-based Fourier-transform infrared spectromicroscopy (SR-FTIR). The representative infrared wavenumbers specific for protein/peptide (Exenatide) and excipient (PLGA) were identified and chemical maps at the single microsphere level were generated by measuring and plotting the intensity of these specific bands. For quantitative analysis of the distribution within microspheres, Matlab software was used to transform the map file into a 3D matrix and the matrix values specific for the drug and excipient were extracted. Comparison of the normalized SR-FTIR maps of PLGA and Exenatide indicated that PLGA was uniformly distributed, while Exenatide was relatively non-uniformly distributed in the microspheres. In conclusion, SR-FTIR is a rapid, nondestructive and sensitive detection technology to provide the distribution of chemical constituents and functional groups in microparticles and microspheres. PMID:26579456

  4. Liraglutide-loaded poly(lactic-co-glycolic acid) microspheres: Preparation and in vivo evaluation.

    PubMed

    Wu, Junzi; Williams, Gareth R; Branford-White, Christopher; Li, Heyu; Li, Yan; Zhu, Li-Min

    2016-09-20

    In this work, we sought to generate sustained-release injectable microspheres loaded with the GLP-1 analogue liraglutide. Using water-in-oil-in-water double emulsion methods, poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with liraglutide were prepared. The microspheres gave sustained drug release over 30days, with cumulative release of up to 90% reached in vitro. The microspheres were further studied in a rat model of diabetes, and their performance compared with a group given daily liraglutide injections. Reduced blood sugar levels were seen in the microsphere treatment groups, with the results being similar to those obtained with conventional injections between 10 and 25days after the commencement of treatment. After 5 and 30days of treatment, the microspheres seem a little slower to act than the injections. The pathology of the rats' spleen, heart, kidney and lungs was probed after the 30-day treatment period, and the results indicated that the microspheres were safe and had beneficial effects on the liver, reducing the occurrence of fatty deposits seen in untreated diabetic rats. Moreover, in terms of liver, renal and cardiac functions, and blood lipid and antioxidant levels, the microspheres were as effective as the injections. The expression of several proteases linked to the metabolism of aliphatic acids and homocysteine was promoted by the microsphere formulations. Inflammatory markers in the microsphere treatment groups were somewhat higher than the injection group, however. The liraglutide/PLGA microspheres prepared in this work are overall shown to be efficacious in a rat model of diabetes, and we thus believe they have strong potential for clinical use. PMID:27343696

  5. Long-Acting Reversible Contraception (LARC) for Adolescent

    PubMed Central

    McNicholas, Colleen; Peipert, Jeffrey F

    2014-01-01

    Purpose of review Teen pregnancy continues to plague the United States. This review will discuss long-acting reversible contraceptive (LARC) method use in teens. It will specifically address the myths about appropriate candidates as well as continuation and satisfaction among teen users. Recent findings The American College of Obstetrics and Gynecology along with the American Academy of Pediatrics, the Centers for Disease Control, and the World health Organization have recognized the potential impact of LARC (comprising intrauterine contraception and subdermal implants) to reduce unintended pregnancies. They have affirmed the safety of such devices, and no effects on long-term fertility have been identified. Teen users of these methods have been shown to have high continuation and satisfaction rates. On the other hand, oral contraceptive pills, the patch, and the contraceptive vaginal ring have significantly higher contraceptive failure rates, and these rates are magnified in young women. Summary LARC methods should be considered first-line options for teens seeking contraception. PMID:22781078

  6. Efficacy and Safety of Long-Acting Reversible Contraception

    PubMed Central

    Stoddard, Amy; McNicholas, Colleen; Peipert, Jeffrey F.

    2013-01-01

    Long-acting reversible contraception (LARC) includes intrauterine devices (IUDs) and the subdermal implant. These methods are the most effective reversible methods of contraception, and have the additional advantages of being long-lasting, convenient, well liked by users and cost effective. Compared with other user-dependent methods that increase the risk of noncompliance-related method failure, LARC methods can bring ‘typical use’ failure rates more in line with ‘perfect use’ failure rates. LARC methods are ‘forgettable’; they are not dependent on compliance with a pill-taking regimen, remembering to change a patch or ring, or coming back to the clinician for an injection. LARC method failure rates rival that of tubal sterilization at <1% for IUDs and the subdermal implant. For these reasons, we believe that IUDs and implants should be offered as first-line contraception for most women. This article provides a review of the LARC methods that are currently available in the US, including their effectiveness, advantages, disadvantages and contraindications. Additionally, we dispel myths and misconceptions regarding IUDs, and address the barriers to LARC use. PMID:21668037

  7. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

    Knight, John M.; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O.; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A.; Milner, Joshua D.; Zhang, Yuan; Mandal, Pijus K.; Luong, Amber; Kheradmand, Farrah

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  8. Long-Acting Beta Agonists Enhance Allergic Airway Disease.

    PubMed

    Knight, John M; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A; Milner, Joshua D; Zhang, Yuan; Mandal, Pijus K; Luong, Amber; Kheradmand, Farrah; McMurray, John S; Corry, David B

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  9. Bacterial protease triggered release of biocides from microspheres with an oily core.

    PubMed

    Craig, Marina; Amiri, Mona; Holmberg, Krister

    2015-03-01

    This study deals with controlled release of drugs to a Staphylococcus aureus infected site from microspheres with an oily core and a polymeric shell. The intended use of the microspheres is for chronic wounds and the microspheres may be administered in the form of a wash liquid or incorporated in a gel. Chronic wounds often carry infection, and the use of microspheres with drug release triggered by the bacterial infection is therefore of interest. A lipophilic drug or a model of the drug was dissolved in an oil and the oil phase was dispersed into an o/w emulsion. A nanofilm shell was then assembled around the oil droplets with the layer-by-layer technique using the two biodegradable polypeptides anionic poly-L-glutamic acid (PLGA) and cationic poly-L-lysine (PLL). Since S. aureus exudes proteases such as glutamyl endopeptidase (V8) during colonization and infection, its substrate specificity was key when assembling the nanofilm. Since V8 is known to be substrate specific to the Glu-X bond, PLGA was chosen as the terminating layer of the nanofilm. Crosslinking the nanofilm after assembly lead to increased stability of the microspheres. It was shown that in a non-infectious environment, i.e. when a human wound enzyme, HNE (human neutrophile elastase), was present, the microspheres remained intact. The staphylococcal protease V8, on the other hand, readily catalyzed degradation of the microspheres, thus releasing the drug when triggered by the infectious environment. PMID:25679492

  10. The Pharmacokinetics and Pharmacodynamics of Lidocaine-Loaded Biodegradable Poly(lactic-co-glycolic acid) Microspheres

    PubMed Central

    Liu, Jianming; Lv, Xin

    2014-01-01

    The purpose of this study was to develop novel lidocaine microspheres. Microspheres were prepared by the oil-in-water (o/w) emulsion technique using poly(d,l-lactide-co-glycolide acid) (PLGA) for the controlled delivery of lidocaine. The average diameter of lidocaine PLGA microspheres was 2.34 ± 0.3 μm. The poly disperse index was 0.21 ± 0.03, and the zeta potential was +0.34 ± 0.02 mV. The encapsulation efficiency and drug loading of the prepared microspheres were 90.5% ± 4.3% and 11.2% ± 1.4%. In vitro release indicated that the lidocaine microspheres had a well-sustained release efficacy, and in vivo studies showed that the area under the curve of lidocaine in microspheres was 2.02–2.06-fold that of lidocaine injection (p < 0.05). The pharmacodynamics results showed that lidocaine microspheres showed a significant release effect in rats, that the process to achieve efficacy was calm and lasting and that the analgesic effect had a significant dose-dependency. PMID:25268618

  11. Biodegradable polymeric microspheres with "open/closed" pores for sustained release of human growth hormone.

    PubMed

    Kim, Hong Kee; Chung, Hyun Jung; Park, Tae Gwan

    2006-05-15

    A new approach for attaining sustained release of protein is introduced, involving a pore-closing process of preformed porous PLGA microspheres. Highly porous biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres were fabricated by a single water-in-oil emulsion solvent evaporation technique using Pluronic F127 as an extractable porogen. Recombinant human growth hormone (rhGH) was incorporated into porous microspheres by a simple solution dipping method. For their controlled release, porous microspheres containing hGH were treated with water-miscible solvents in aqueous phase for production of pore-closed microspheres. These microspheres showed sustained release patterns over an extended period; however, the drug loading efficiency was extremely low. To overcome the drug loading problem, the pore-closing process was performed in an ethanol vapor phase using a fluidized bed reactor. The resultant pore-closed microspheres exhibited high protein loading amount as well as sustained rhGH release profiles. Also, the released rhGH exhibited structural integrity after the treatment. PMID:16542746

  12. In vitro stress effect on degradation and drug release behaviors of basic fibroblast growth factor – poly(lactic-co-glycolic-acid) microsphere

    PubMed Central

    Xiong, Yan; Yu, Zeping; Lang, Yun; Hu, Juanyu; Li, Hong; Yan, Yonggang; Tu, Chongqi; Yang, Tianfu; Song, Yueming; Duan, Hong; Pei, Fuxing

    2016-01-01

    Objective To study the degradation and basic fibroblast growth factor (bFGF) release activity of bFGF – poly(lactic-co-glycolic-acid) microsphere (bFGF-PLGA MS) under stress in vitro, including the static pressure and shearing force-simulating mechanical environment of the joint cavity. Method First, bFGF-PLGA MSs were created. Meanwhile, two self-made experimental instruments (static pressure and shearing force loading instruments) were initially explored to provide stress-simulating mechanical environment of the joint cavity. Then, bFGF-PLGA MSs were loaded into the two instruments respectively, to study microsphere degradation and drug release experiments. In the static pressure loading experiment, normal atmospheric pressure loading (approximately 0.1 MPa), 0.35 MPa, and 4.0 MPa pressure loading and shaking flask oscillation groups were designed to study bFGF-PLGA MS degradation and bFGF release. In the shearing force loading experiment, a pulsating pump was used to give the experimental group an output of 1,000 mL/min and the control group an output of 10 mL/min to carry out bFGF-PLGA MS degradation and drug release experiments. Changes of bFGF-PLGA MSs, including microsphere morphology, quality, weight-average molecular weight of polymer, and microsphere degradation and bFGF release, were analyzed respectively. Results In the static pressure loading experiment, bFGF-PLGA MSs at different pressure were stable initially. The trend of molecular weight change, quality loss, and bFGF release was consistent. Meanwhile, microsphere degradation and bFGF release rates in the 4.0 MPa pressure loading group were faster than those in the normal and 0.35 MPa pressure loading groups. It was the fastest in the shaking flask group, showing a statistically significant difference (P<0.0001). In the shearing force loading experiment, there were no distinctive differences in the rates of microsphere degradation and bFGF release between experimental and control group. Meanwhile

  13. Aripiprazole Lauroxil Long-Acting Injectable: The Latest Addition to Second-Generation Long-Acting Agents.

    PubMed

    Aggarwal, Arpit; Gopalakrishna, Ganesh; Lauriello, John

    2016-01-01

    Antipsychotics have long been the mainstay for the treatment of schizophrenia and other psychotic disorders. Long-acting injectables (LAI) of antipsychotics-provided once every two weeks to once every three months-promise to reduce the incidence of nonadherence. ARISTADA(™) (aripiprazole lauroxil; ALLAI) extended-release injectable suspension was approved by the U.S. Food and Drug Administration in October 2015 for the treatment of schizophrenia, and is the newest entrant in the LAI market. ALLAI is available as a single-use, pre-filled syringe, can be started in three different dosages, and also has the option of every six-week dosing. Treatment with oral aripiprazole is recommended for the first twenty-one days after the first ALLAI injection, which is a potential disadvantage. Adverse effects include sensitivity to extrapyramidal symptoms, especially akathisia, which is well documented in other aripiprazole preparations. There is no available data comparing ALLAI to other antipsychotics, and more head-to-head trials comparing different LAI formulations are needed. Based on the available data, ALLAI is an effective and safe option for treatment of schizophrenia. Further studies and post-marketing data will provide better understanding of this formulation. PMID:27074333

  14. Preparation, characterization, and in vitro testing of poly(lactide-co-glycolide) and dextran magnetic microspheres for in vivo applications

    NASA Astrophysics Data System (ADS)

    Leamy, Patrick J.

    Many research groups are investigating degradable magnetic particles for magnetic resonance imaging (MRI) contrast agents and as carriers for magnetic drug guidance. These particles are composite materials with a degradable polymer matrix and iron oxide nanoparticles for magnetic properties. The degradable polymer matrix acts to provide colloidal stability and, for drug delivery applications, provides a reservoir for the storage and release of drugs. Natural polymers, like albumin and dextran, which degrade by the action of enzymes; have been used for the polymer matrix. Iron oxide nanoparticles are used for magnetic properties since they can be digested in vivo and have low toxicities. Polylactic acid (PLA) and its copolymers with polyglycolic acid (PLGA) are versatile polymers that degrade by simple hydrolysis without the aid of enzymes. Microspheres are easily formed using the solvent extraction/evaporation method and a wide range of drugs can be encapsulated in them. Magnetic PLGA microspheres suitable for applications were synthesized for the first time in this dissertation. This was accomplished by coating iron oxide nanoparticles with oleic acid to make them dispersible in the organic solvents used in the extraction/evaporation microsphere preparation method. In addition to the magnetic PLGA microspheres, a novel all-aqueous method for preparing crosslinked dextran magnetic microspheres was developed in this dissertation. This method uses free radical polymerization for crosslinking and does not require the use of flammable and harmful solvents. For efficient MRI contrast and magnetic drug guidance, maximized iron oxide content of microspheres is desirable. The two different microsphere preparation methods were optimized for iron oxide content. The effect of iron oxide content on microsphere size and morphology was studied. In addition, an in vitro circulation model was used to evaluate the ability of magnetic microspheres to be guided at physiologic blood

  15. Coaxial electrohydrodynamic atomization process for production of polymeric composite microspheres.

    PubMed

    Xu, Qingxing; Qin, Hao; Yin, Zhenyuan; Hua, Jinsong; Pack, Daniel W; Wang, Chi-Hwa

    2013-12-18

    Polymeric composite microspheres consisting of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(D,L-lactic acid) (PDLLA) shell layer were successfully fabricated by coaxial electrohydrodynamic atomization (CEHDA) process. Process conditions, including nozzle voltage and polymer solution flow rates, as well as solution parameters, such as polymer concentrations, were investigated to ensure the formation of composite microspheres with a doxorubicin-loaded PLGA core surrounded by a relatively drug-free PDLLA shell layer. Various microsphere formulations were fabricated and characterized in terms of their drug distribution, encapsulation efficiency and in vitro release. Numerical simulation of CEHDA process was performed based on a computational fluid dynamics (CFD) model in Fluent by employing the process conditions and fluid properties used in the experiments. The simulation results were compared with the experimental work to illustrate the capability of the CFD model to predict the production of consistent compound droplets, and hence, the expected core-shell structured microspheres. PMID:24347672

  16. Coaxial electrohydrodynamic atomization process for production of polymeric composite microspheres

    PubMed Central

    Xu, Qingxing; Qin, Hao; Yin, Zhenyuan; Hua, Jinsong; Pack, Daniel W.; Wang, Chi-Hwa

    2013-01-01

    Polymeric composite microspheres consisting of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(D,L-lactic acid) (PDLLA) shell layer were successfully fabricated by coaxial electrohydrodynamic atomization (CEHDA) process. Process conditions, including nozzle voltage and polymer solution flow rates, as well as solution parameters, such as polymer concentrations, were investigated to ensure the formation of composite microspheres with a doxorubicin-loaded PLGA core surrounded by a relatively drug-free PDLLA shell layer. Various microsphere formulations were fabricated and characterized in terms of their drug distribution, encapsulation efficiency and in vitro release. Numerical simulation of CEHDA process was performed based on a computational fluid dynamics (CFD) model in Fluent by employing the process conditions and fluid properties used in the experiments. The simulation results were compared with the experimental work to illustrate the capability of the CFD model to predict the production of consistent compound droplets, and hence, the expected core-shell structured microspheres. PMID:24347672

  17. Reconstructing jaw defects with MSCs and PLGA-encapsulated growth factors.

    PubMed

    Tee, Boon Ching; Desai, Kashappa Goud H; Kennedy, Kelly S; Sonnichsen, Brittany; Kim, Do-Gyoon; Fields, Henry W; Mallery, Susan R; Schwendeman, Steven P; Sun, Zongyang

    2016-01-01

    Cell and growth factor-based tissue engineering has shown great potentials for skeletal regeneration. This study tested its feasibility in reconstructing large mandibular defects and compared the efficacy of varied construction materials and sealing methods. Bilateral mandibular critical-size (5-cm(3)) defects were created on six 4-month-old domestic pigs, and grafted with β-tricalcium phosphate (βTCP) only (Group-A), βTCP with autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) (Group-B), and βTCP with BM-MSCs and biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres containing bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) (Group-C). The buccal sides of Groups-B/-C were either sealed by fibrin sealant or by a biodegradable PLGA barrier membrane before soft-tissue closure. Computed tomography (CT), microCT and histology analyses were performed 12 weeks postoperatively. In vitro data demonstrated that BM-MSCs, with MSC properties confirmed, remained vital after integration with βTCP; and PLGA microspheres exhibited an initial burst followed by slow and continuous release of growth factors over a period of 28 days. In vivo data demonstrated that Group-B/-C sites had significantly greater gap obliteration, higher tissue mineral densities and more residual βTCP granules (p<0.05, Kruskal-Wallis tests). Qualitatively, Group-B/-C defect sites had started remodeling while Group-A sites were mainly forming new bone to bridge the gaps. Furthermore, βTCP degradation was not mediated by macrophages or osteoclasts, and was significantly slowed down by sealing the defects with barrier membrane. Combined, these data present a promising formulation composed of βTCP granules, autologous MSCs, controlled-release growth factors and biodegradable PLGA barrier membrane for the reconstruction of critical-size mandibular defects. PMID:27398152

  18. Reconstructing jaw defects with MSCs and PLGA-encapsulated growth factors

    PubMed Central

    Tee, Boon Ching; Desai, Kashappa Goud H; Kennedy, Kelly S; Sonnichsen, Brittany; Kim, Do-Gyoon; Fields, Henry W; Mallery, Susan R; Schwendeman, Steven P; Sun, Zongyang

    2016-01-01

    Cell and growth factor-based tissue engineering has shown great potentials for skeletal regeneration. This study tested its feasibility in reconstructing large mandibular defects and compared the efficacy of varied construction materials and sealing methods. Bilateral mandibular critical-size (5-cm3) defects were created on six 4-month-old domestic pigs, and grafted with β-tricalcium phosphate (βTCP) only (Group-A), βTCP with autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) (Group-B), and βTCP with BM-MSCs and biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres containing bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) (Group-C). The buccal sides of Groups-B/-C were either sealed by fibrin sealant or by a biodegradable PLGA barrier membrane before soft-tissue closure. Computed tomography (CT), microCT and histology analyses were performed 12 weeks postoperatively. In vitro data demonstrated that BM-MSCs, with MSC properties confirmed, remained vital after integration with βTCP; and PLGA microspheres exhibited an initial burst followed by slow and continuous release of growth factors over a period of 28 days. In vivo data demonstrated that Group-B/-C sites had significantly greater gap obliteration, higher tissue mineral densities and more residual βTCP granules (p<0.05, Kruskal-Wallis tests). Qualitatively, Group-B/-C defect sites had started remodeling while Group-A sites were mainly forming new bone to bridge the gaps. Furthermore, βTCP degradation was not mediated by macrophages or osteoclasts, and was significantly slowed down by sealing the defects with barrier membrane. Combined, these data present a promising formulation composed of βTCP granules, autologous MSCs, controlled-release growth factors and biodegradable PLGA barrier membrane for the reconstruction of critical-size mandibular defects. PMID:27398152

  19. Ondansetron-loaded biodegradable microspheres as a nasal sustained delivery system: in vitro/in vivo studies.

    PubMed

    Gungor, Sevgi; Okyar, Alper; Erturk-Toker, Sidika; Baktir, Gul; Ozsoy, Yildiz

    2010-06-01

    The aim of this study was to prepare ondansetron-loaded biodegradable microspheres as a nasal delivery system. Microspheres were prepared with emulsification/spray-drying technique using poly(d,l-lactide) (PLA) and two different types of poly(d,l-lactide-co-glycolide) (PLGA). The effect of the type of organic solvent (dichloromethane (DCM) or a mixture of DCM and ethyl acetate) on the microsphere characteristics was also examined. The prepared microspheres were evaluated with respect to the morphological properties, particle size, zeta potential, drug loading efficiency, and in vitro drug release. The mean particle size (d(50)) of microsphere formulations was ranged from 11.67-25.54 μm, indicating suitable particle size for nasal administration. All microspheres had low drug loading efficiency in the range of 12.28-21.04%. The results indicated that particle size of microspheres were affected by both type of polymer and organic solvent, however drug loading efficiency of microspheres were affected by only the type of organic solvent used. All microspheres were negatively charged due to the polymers (PLA or PLGA) used. A prolonged in vitro drug release profile was observed for 96 h. Based on in vitro data, the selected microsphere formulation has been applied via nasal route to rats in vivo. Following nasal administration of ondansetron-loaded microsphere to rats, ondansetron plasma levels were within a range of 30-48 ng/mL during 96 h, indicating a sustained drug delivery pattern and relatively a constant plasma drug concentration level. The results suggested that biodegradable microspheres prepared with emulsification/spray-drying technique could be considered to deliver ondansetron via nasal route to obtain a prolonged release. PMID:22716466

  20. Synthesis and characterization of UPPE-PLGA-rhBMP2 scaffolds for bone regeneration.

    PubMed

    Tian, Zhichao; Zhu, Yuanli; Qiu, Jinjun; Guan, Hanfeng; Li, Liangyu; Zheng, Shouchao; Dong, Xuehai; Xiao, Jun

    2012-08-01

    A novel unsaturated polyphosphoester (UPPE) was devised in our previous research, which is a kind of promising scaffold for improving bone regeneration. However, the polymerization process of UPPE scaffolds was unfavorable, which may adversely affect the bioactivity of osteoinductive molecules added if necessary, such as recombinant human bone morphogenetic protein-2 (rhBMP2). The purpose of this study was to build a kind of optimal scaffold named UPPE-PLGA-rhBMP2 (UPB) and to investigate the bioactivity of rhBMP2 in this scaffold. Furthermore, the cytotoxicity and biocompatibility of UPB scaffold was assessed in vitro. A W1/O/W2 method was used to fabricate PLGA-rhBMP2 microspheres, and then the microspheres were added to UPPE for synthesizing UPB scaffold. The morphological characters of PLGA-rhBMP2 microspheres and UPB scaffolds were observed under the scanning electron microscopy and laser scanning confocal microscopy. The cumulative release of UPB scaffolds was detected by using ELISA. The cytotoxicity and biocompatibility of UPB scaffolds were evaluated through examining the adsorption and apoptosis of bone marrow stromal cells (bMSCs) seeded on the surface of UPB scaffolds. The bioactivity of rhBMP2 in UPB scaffolds was assessed through measuring the alkaline phosphates (ALP) activity in bMSCs seeded. The results showed that UPB scaffolds sequentially exhibited burst and sustained release of rhBMP2. The cytotoxicity was greatly reduced when the scaffolds were immersed in buffer solution for 2 h. bMSCs attached and grew on the surface of soaked UPB scaffolds, exerting well biocompatibility. The ALP activity of bMSCs seeded was significantly enhanced, indicating that the bioactivity of rhBMP2 remained and still took effect after the unfavorable polymerization process of scaffolds. It was concluded that UPB scaffolds have low cytotoxicity, good biocompatibility and preserve bioactivity of rhBMP2. UPB scaffolds are promising in improving bone regeneration. PMID

  1. Poly(D,L-lactic-co-glycolic acid) microspheres for sustained delivery and stabilization of camptothecin.

    PubMed

    Ertl, B; Platzer, P; Wirth, M; Gabor, F

    1999-09-20

    Camptothecin (CPT) and its water-insoluble derivatives are known as topoisomerase-I inhibitors exhibiting high antitumoral activity against a wide spectrum of human malignancies. Until now clinical application of CPT is restricted by insolubility and instability of the drug in its active lactone form resulting in less antitumor potency and poor bioavailability. For these reasons CPT-loaded-microspheres were prepared by the solvent evaporation method using the H-series of poly(D,L-lactide-co-glycolide) (H-PLGA), which contain more carboxylic acid end chains and hydrate faster than the non-H-series. At 1.2% CPT-payload the drug was molecular dispersed throughout the matrix whereas at higher CPT-payload the amount of crystalline CPT-islets increased with the CPT content. The release pattern of CPT was biphasic comprising a first burst effect delivering 20-35% of the payload and increasing with drug-loading. This phase was followed by sustained delivery of CPT releasing 40-75% of the payload within 160 h. In comparison to PLGA-microspheres, the CPT-release rate from H-PLGA was twofold higher and accelerated. The active CPT-lactone was maintained during preparation, storage and release due to hindered diffusion of acidic oligomers among other mechanisms. Thus stabilization and sustained release of CPT from PLGA-microspheres might reduce local toxicity combined with prolonged efficacy offering new perspectives in CPT chemotherapy. PMID:10477803

  2. Microradiographic microsphere manipulator

    DOEpatents

    Singleton, Russell M.

    1980-01-01

    A method and apparatus for radiographic characterization of small hollow spherical members (microspheres), constructed of either optically transparent or opaque materials. The apparatus involves a microsphere manipulator which holds a batch of microspheres between two parallel thin plastic films for contact microradiographic characterization or projection microradiography thereof. One plastic film is translated to relative to and parallel to the other to roll the microspheres through any desired angle to allow different views of the microspheres.

  3. Microradiographic microsphere manipulator

    DOEpatents

    Singleton, R.M.

    A method and apparatus is disclosed for radiographic characterization of small hollow spherical members (microspheres), constructed of either optically transparent or opaque materials. The apparatus involves a microsphere manipulator which holds a batch of microspheres between two parallel thin plastic films for contact microradiographic characterization or projection microradiography thereof. One plastic film is translated relative to and parallel to the other to roll the microspheres through any desired angle to allow different views of the microspheres.

  4. Evaluation of PEGylated exendin-4 released from poly (lactic-co-glycolic acid) microspheres for antidiabetic therapy.

    PubMed

    Lim, Sung Mook; Eom, Ha Na; Jiang, Hai Hua; Sohn, Minji; Lee, Kang Choon

    2015-01-01

    Peptide-based therapies have the potential to induce antibody formation if the molecules differ from a native human peptide. Several reports have disclosed the occurrence of antibody generation in a patient treated with exenatide. The immune response can be problematic from a clinical stand point, particularly if the antibodies neutralize the efficacy of the biotherapeutic agent or cause a general immune reaction. To overcome this limit, PEGylated exendin-4 analogs were designed and examined for metabolic stability and biological activity. To develop an extended release delivery system for exendin-4 for the safe and effective delivery of bioactive exendin-4 without peptide acylation and immunogenicity, PEGylated exendin-4 was encapsulated into poly (lactic-co-glycolic acid) (PLGA) microspheres by w/o/w double emulsion solvent evaporation method. Peptide-loaded microspheres were characterized in terms of morphology, particle diameter, and peptide encapsulation efficiency. Then, the release profile of the peptide from PLGA microspheres and the acylated products from PLGA polymer degradation was determined. The results obtained showed that the stability of exendin-4 was greatly improved by PEGylation. Moreover, eliminated acylation during PLGA polymer degradation in vitro and reduced immunogenicity in vivo were observed. The findings demonstrate that PEGylated exendin-4-loaded microspheres may be a safe and biocompatible system for clinical development. PMID:25407390

  5. Metabolic microspheres

    NASA Astrophysics Data System (ADS)

    Fox, Sidney W.

    1980-08-01

    A systematic review of catalytic activities in thermal proteinoids and microspheres aggregated therefrom yields some new inferences on the origins and evolution of metabolism. Experiments suggest that, instead of being inert, protocells were already biochemically and cytophysically competent. The emergence and refinement of metabolism ab initio is thus partly traced conceptually. When the principle of molecular self-instruction, as of amino acids in peptide synthesis, is taken into account as a concomitant of natural selection, an expanded theory of organismic evolution, including saltations, emerges.

  6. Hybrid microspheres

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor); Yen, Richard C. K. (Inventor)

    1985-01-01

    Substrates, particularly inert synthetic organic resin beads (10) or sheet (12) such as polystyrene are coated with a covalently bound layer (24) of polyacrolein by irradiation a solution (14) of acrolein or other aldehyde with high intensity radiation. Individual microspheres (22) are formed which attach to the surface to form the aldehyde containing layer (24). The aldehyde groups can be converted to other functional groups by reaction with materials such as hydroxylamine. Adducts of proteins such as antibodies or enzymes can be formed by direct reaction with the surface aldehyde groups.

  7. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease

    PubMed Central

    Karner, Charlotta; Cates, Christopher J

    2014-01-01

    Background Long-acting bronchodilators comprising long-acting beta2-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta2-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear. Objectives To assess the relative effects of treatment with tiotropium in addition to long-acting beta2-agonist compared to tiotropium or long-acting beta2-agonist alone in patients with chronic obstructive pulmonary disease. Search methods We searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012. Selection criteria We included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta2-agonist against tiotropium or long-acting beta2-agonist alone for patients with chronic obstructive pulmonary disease. Data collection and analysis Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. Main results Five trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta2-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta2-agonist (formoterol) alone. Two studies used the long-acting beta2-agonist indacaterol, two used formoterol and one used salmeterol. Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long-acting

  8. Preparation and In-vitro Evaluation of Controlled Release PLGA Microparticles Containing Triptoreline.

    PubMed

    Mahboubian, Alireza; Hashemein, Seyyed Kazem; Moghadam, Shadi; Atyabi, Fatemeh; Dinarvand, Rassoul

    2010-01-01

    Triptoreline is a potent agonist of luteinizing hormone-releasing hormone, currently used in the treatment of prostatic cancer where therapy may be required over months or years. Frequent injection of drug decreases patients' compliance. The present study describes the formulation of a sustained release microparticulate drug delivery system containing triptoreline acetate, using poly (D,L lactide-co-glycolide) (PLGA). Biodegradable microspheres were prepared using 50 : 50 PLGA by a water in-oil-in-water (w/o/w) double emulsion-solvent evaporation procedure and characterized for drug content and drug release rate using the a HPLC method, particle size distribution using the laser diffraction method, and surface morphology using scanning electron microscopy and drug release rate. Effect of critical process parameters and formulation variables; i.e. volume of inner water phase, addition of NaCl to the outer aqueous phase (W2), addition of different types and amounts of emulsifying agents on microsphere characteristics; were investigated. Microspheres prepared were spherical with a smooth surface, but addition of poloxamer to the first emulsion produced microspheres with large pores. Size of microparticles was dependent on the type, as well as the amount of co-encapsulated surfactants. Increasing the inner water phase volume resulted in larger particles with a lower encapsulation efficiency. Low concentrations of Span 20 decreased triptoreline release rate, whereas the addition of poloxamer or high concentrations of Span 20 increased the drug release rateit. In conclusion, by selecting an appropriate level of the investigated parameters, spherical microparticles with encapsulation efficiencies higher than 90% and a prolonged triptoreline release over 45 days were obtained. PMID:24381601

  9. Pitch carbon microsphere composite

    NASA Technical Reports Server (NTRS)

    Price, H. L.; Nelson, J. B.

    1977-01-01

    Petroleum pitch carbon microspheres were prepared by flash heating emulsified pitch and carbonizing the resulting microspheres in an inert atmosphere. Microsphere composites were obtained from a mixture of microspheres and tetraester precursor pyrrone powder. Scanning electron micrographs of the composite showed that it was an aggregate of microspheres bonded together by the pyrrone at the sphere contact points, with voids in and among the microspheres. Physical, thermal, and sorption properties of the composite are described. Composite applications could include use as a honeycomb filler in elevated-temperature load-bearing sandwich boards or in patient-treatment tables for radiation treatment of tumors.

  10. Evaluation of protective efficacy using a nonstructural protein NS1 in DNA vaccine–loaded microspheres against dengue 2 virus

    PubMed Central

    Huang, Shih-Shiung; Li, I-Hsun; Hong, Po-da; Yeh, Ming-kung

    2013-01-01

    Dengue virus results in dengue fever or severe dengue hemorrhagic fever/dengue shock syndrome in humans. The purpose of this work was to develop an effective antidengue virus delivery system, by designing poly (dl-lactic-co-glycolic) acid/polyethylene glycol (PLGA/PEG) microspheres using a double-emulsion solvent extraction method, for vaccination therapy based on locally and continuously sustained biological activity. Nonstructural protein 1 (NS1) in deoxyribonucleic acid (DNA) vaccine–loaded PLGA/PEG microspheres exhibited a high loading capacity (4.5% w/w), yield (85.2%), and entrapment efficiency (39%), the mean particle size 4.8 μm, and a controlled in vitro release profile with a low initial burst (18.5%), lag time (4 days), and continued released protein over 70 days. The distribution of protein on the microspheres surface, outer layer, and core were 3.0%, 28.5%, and 60.7%, respectively. A release rate was noticed to be 1.07 μg protein/mg microspheres/day of protein release, maintained for 42 days. The cumulative release amount at Days 1, 28, and 42 was 18.5, 53.7, and 62.66 μg protein/mg microspheres, respectively. The dengue virus challenge in mice test, in which mice received one dose of 20 μg NS1 protein content of microspheres, in comparison with NS1 protein in Al(OH)3 or PBS solution, was evaluated after intramuscular immunization of BALB/c mice. The study results show that the greatest survival was observed in the group of mice immunized with NS1 protein–loaded PLGA/PEG microspheres (100%). In vivo vaccination studies also demonstrated that NS1 protein–loaded PLGA/PEG microspheres had a protective ability; its steady-state immune protection in rat plasma changed from 4,443 ± 1,384 pg/mL to 10,697 ± 3,197 pg/mL, which was 2.5-fold higher than that observed for dengue virus in Al(OH)3 at 21 days. These findings strongly suggest that NS1 protein–loaded PLGA/PEG microspheres offer a new therapeutic strategy in optimizing the vaccine

  11. Evaluation of protective efficacy using a nonstructural protein NS1 in DNA vaccine-loaded microspheres against dengue 2 virus.

    PubMed

    Huang, Shih-shiung; Li, I-Hsun; Hong, Po-da; Yeh, Ming-kung

    2013-01-01

    Dengue virus results in dengue fever or severe dengue hemorrhagic fever/dengue shock syndrome in humans. The purpose of this work was to develop an effective antidengue virus delivery system, by designing poly (dl-lactic-co-glycolic) acid/polyethylene glycol (PLGA/PEG) microspheres using a double-emulsion solvent extraction method, for vaccination therapy based on locally and continuously sustained biological activity. Nonstructural protein 1 (NS1) in deoxyribonucleic acid (DNA) vaccine-loaded PLGA/PEG microspheres exhibited a high loading capacity (4.5% w/w), yield (85.2%), and entrapment efficiency (39%), the mean particle size 4.8 μm, and a controlled in vitro release profile with a low initial burst (18.5%), lag time (4 days), and continued released protein over 70 days. The distribution of protein on the microspheres surface, outer layer, and core were 3.0%, 28.5%, and 60.7%, respectively. A release rate was noticed to be 1.07 μg protein/mg microspheres/day of protein release, maintained for 42 days. The cumulative release amount at Days 1, 28, and 42 was 18.5, 53.7, and 62.66 μg protein/mg microspheres, respectively. The dengue virus challenge in mice test, in which mice received one dose of 20 μg NS1 protein content of microspheres, in comparison with NS1 protein in Al(OH)3 or PBS solution, was evaluated after intramuscular immunization of BALB/c mice. The study results show that the greatest survival was observed in the group of mice immunized with NS1 protein-loaded PLGA/PEG microspheres (100%). In vivo vaccination studies also demonstrated that NS1 protein-loaded PLGA/PEG microspheres had a protective ability; its steady-state immune protection in rat plasma changed from 4,443 ± 1,384 pg/mL to 10,697 ± 3,197 pg/mL, which was 2.5-fold higher than that observed for dengue virus in Al(OH)3 at 21 days. These findings strongly suggest that NS1 protein-loaded PLGA/PEG microspheres offer a new therapeutic strategy in optimizing the vaccine incorporation

  12. Functional motor recovery is improved due to local placement of GDNF microspheres after delayed nerve repair.

    PubMed

    Wood, Matthew D; Gordon, Tessa; Kemp, Stephen W P; Liu, Edward H; Kim, Howard; Shoichet, Molly S; Borschel, Gregory H

    2013-05-01

    The majority of bioengineering strategies to promote peripheral nerve regeneration after injury have focused on therapies to bridge large nerve defects while fewer therapies are being developed to treat other nerve injuries, such as nerve transection. We constructed delivery systems using fibrin gels containing either free GDNF or polylactide-glycolic acid (PLGA) microspheres with GDNF to treat delayed nerve repair, where ELISA verified GDNF release. We determined the formulation of microspheres containing GDNF that optimized nerve regeneration and functional recovery in a rat model of delayed nerve repair. Experimental groups underwent delayed nerve repair and treatment with GDNF microspheres in fibrin glue at the repair site or control treatments (empty microspheres or free GDNF without microspheres). Contractile muscle force, muscle mass, and MUNE were measured 12 weeks following treatment, where GDNF microspheres (2 weeks formulation) were superior compared to either no GDNF or short-term release of free GDNF to nerve. Nerve histology distal to the repair site demonstrated increased axon counts and fiber diameters due to GDNF microspheres (2 weeks formulation). GDNF microspheres partially reversed the deleterious effects of chronic nerve injury, and recovery was slightly favored with the 2 weeks formulation compared to the 4 weeks formulation. PMID:23239194

  13. Release of paclitaxel from polylactide-co-glycolide (PLGA) microparticles and discs under irradiation.

    PubMed

    Wang, J; Ng, C W; Win, K Y; Shoemakers, P; Lee, T K Y; Feng, S S; Wang, C H

    2003-01-01

    Paclitaxel is a promising anti-cancer drug as well as a radiosensitizer for chemotherapy and radiotherapy applications. Because of the poor solubility of paclitaxel in water and most pharmaceutical reagents, it is usually formulated with an adjuvant called Cremophor EL, which causes severe side effects. This work develops new dosage forms of paclitaxel for controlled release application, which do not require the adjuvant and, thus, can avoid its associated side effects. Paclitaxel was encapsulated into the PLGA matrix with various additives such as polyethylene glycol (PEG), isopropyl myristate (IPM) and d-alpha tocopheryl polyethylene glycol (Vitamin E TPGS). These additives were used to enhance the release rate of paclitaxel from the polymer matrix. Spray-drying and an hydraulic press were used to prepare paclitaxel-PLGA microspheres and discs. The microspheres and discs were given different irradiation doses to investigate their effects on the surface morphology (characterized by SEM, AFM and XPS) and in vitro release properties. There seems to be a small effect of the ionizing radiation on various formulations. Although the irradiation did not cause observable changes on the morphology of the polymer matrix, the release rate can be enhanced by a few per cent. It was found that PEG has the highest enhancement effect for release rate among all the additives investigated in this study. PMID:12881113

  14. Injectable PLGA/hydrocortisone formulation produced by continuous supercritical emulsion extraction.

    PubMed

    Falco, Nunzia; Reverchon, Ernesto; Della Porta, Giovanna

    2013-01-30

    The objective of the present study was to develop an anti-inflammatory prolonged action formulation for local injection in prefilled syringes. Hydrocortisone acetate (HA) was selected as a model corticosteroid drug to be incorporated in poly(lactic-co-glycolic) (PLGA) microspheres. The formulation was obtained by supercritical emulsion extraction in continuous operation layout (SEE-C) to test the process robustness for a continuous industrial production. PLGA/HA microspheres with mean sizes between 1 μm (SD±0.20) and 5 μm (SD±1.45) were obtained when operating at 80 bar and 38 °C with a L/G ratio of 0.1 in the counter-current tower. The produced microdevices showed excellent encapsulation efficiencies between 75% and 80%, depending on the emulsion formulations tested, and different sustained release in the range of 6-15 days. In dependence of the different emulsion (single or double) processed by SEE-C, different products can be obtained according to the therapeutic requests. SEE-C confirms to be an innovative and flexible technology for biopolymer microdevices production, coupling the efficiency of continuous operation to the easy process scalability. PMID:23124104

  15. Ketoprofen-poly(D,L-lactic-co-glycolic acid) microspheres: influence of manufacturing parameters and type of polymer on the release characteristics.

    PubMed

    Gabor, F; Ertl, B; Wirth, M; Mallinger, R

    1999-01-01

    The effect of manufacturing parameters on the size and drug-loading of ketoprofen-containing biodegradable and biocompatible poly(DL-lactic-co-glycolic acid) (PLGA) microspheres prepared by the solvent evaporation method was investigated. For both drug-free and drug-loaded microspheres, smaller microspheres with a narrower size distribution were obtained when the stirring rate or the volume of the organic phase was increased. Incorporation of ketoprofen was found to increase with increasing volume of the organic phase and decreasing pH of the aqueous phase, but was independent of the acidity and the inherent viscosity of the PLGA used. The biphasic release profile of ketoprofen from the microspheres was dependent on the type of PLGA as well as the size and drug-loading, two parameters governed by the manufacturing process. The first burst effect was found to increase with the drug content, reduction of size of the microspheres and increasing inherent viscosity of the matrix, whereas acidity of the PLGA had no effect on the release of this acidic drug. A vigorous first burst effect was associated with reduced sustained delivery of ketoprofen, the rate of the delayed release phase being dependent on the inherent viscosity of the matrix, the size, the payload and the pH during preparation of the microspheres. Thus, by selection of the manufacturing parameters and the type of PLGA, it is possible to design a controlled drug delivery system for the prolonged release of ketoprofen, improving therapy by possible reduction of time intervals between peroral administration and reduction of local gastrointestinal side effects. PMID:9972498

  16. Biodegradable poly(lactic-co-glycolic acid) microspheres loaded with S-nitroso-N-acetyl-D-penicillamine for controlled nitric oxide delivery.

    PubMed

    Lautner, Gergely; Meyerhoff, Mark E; Schwendeman, Steven P

    2016-03-10

    Nitric oxide (NO) is a fascinating and important endogenous free-radical gas with potent antimicrobial, vasodilating, smooth muscle relaxant, and growth factor stimulating effects. However, its wider biomedical applicability is hindered by its cumbersome administration, since NO is unstable especially in biological environments. In this work, to ultimately develop site-specific controlled release vehicles for NO, the NO donor S-nitroso-N-acetyl-D-penicillamine (SNAP) was encapsulated within poly(lactic-co-glycolic acid) 50:50 (PLGA) microspheres by using a solid-in-oil-in-water emulsion solvent evaporation method. The highest payload was 0.56(±0.01) μmol SNAP/mg microspheres. The in vitro release kinetics of the donor were controlled by the bioerosion of the PLGA microspheres. By using an uncapped PLGA (Mw=24,000-38,000) SNAP was slowly released for over 10days, whereas by using the ester capped PLGA (Mw=38,000-54,000) the release lasted for over 4weeks. The presence of copper ions and/or ascorbate in solution was necessary to efficiently decompose the released NO donor and obtain sustained NO release. It was also demonstrated that light can be used to induce rapid NO release from the microspheres over several hours. SNAP exhibited excellent storage stability when encapsulated in the PLGA microspheres. These new microsphere formulations may be useful for site-specific administration and treatment of pathologies associated with dysfunction in endogenous NO production, e.g. treatment of diabetic wounds, or in diseases involving other biological functions of NO including vasodilation, antimicrobial, anticancer, and neurotransmission. PMID:26763376

  17. Long-Acting Injectable Naltrexone for the Management of Patients with Opioid Dependence

    PubMed Central

    Kjome, Kimberly L.; Moeller, F. Gerard

    2011-01-01

    Opioid dependence is a condition with serious clinical ramifications. Treatment has focused on detoxification, agonist therapy with methadone or buprenorphine, or remission maintenance with the opioid antagonist, naltrexone. Treatment with oral naltrexone has been limited by poor treatment adherence and relapse. Studies with long-acting formulations have shown increased treatment adherence. Extended-release injectable naltrexone has been used for the treatment of alcohol dependence, and has recently received an indication for treatment of opioid dependence from the US Food and Drug Administration. Dosing occurs once monthly and existing data with long-acting naltrexone supports efficacy of treatment for opioid dependence; however published data is sparse. Treatment with long-acting naltrexone should be monitored for hepatotoxicity, and patients should be made aware of increased risk of overdose with administration of opioids during and immediately after discontinuation of long-acting naltrexone. PMID:22879745

  18. Self-Assembly of pH-Responsive Microspheres for Intestinal Delivery of Diverse Lipophilic Therapeutics.

    PubMed

    Zhou, Xing; Zhao, Yang; Chen, Siyu; Han, Songling; Xu, Xiaoqiu; Guo, Jiawei; Liu, Mengyu; Che, Ling; Li, Xiaohui; Zhang, Jianxiang

    2016-08-01

    Targeted delivery of therapeutics to the intestine is preferred for the management of many diseases due to its diverse advantages. Currently, there are still challenges in creating cost-effective and translational pH-responsive microspheres for intestinal delivery of various hydrophobic drugs. Herein we report a multiple noncovalent interactions-mediated assembly strategy in which carboxyl-bearing compounds (CBCs) are guest molecules, while poly(N-isopropylacrylamide) (PNIPAm) serves as a host polymer. Formation of microparticles and therapeutic packaging can be achieved simultaneously by this assembly approach, leading to well-shaped microspheres with extremely higher drug loading capacity as compared to microspheres based on two FDA-approved materials of poly(d,l-lactide-co-glycolide) (PLGA) and an enteric coating polymer EudragitS 100 (S100). Also, carboxyl-deficient hydrophobic drugs can be effectively entrapped. These assembled microspheres, with excellent reconstitution capability as well as desirable scalability, could selectively release drug molecules under intestinal conditions. By significantly enhancing drug dissolution/release in the intestine, these pH-responsive assemblies may notably improve the oral bioavailability of loaded therapeutics. Moreover, the assembled microspheres possessed superior therapeutic performance in rodent models of inflammation and tumor over the control microspheres derived from PLGA and S100. Therapy with newly developed microspheres did not cause undesirable side effects. Furthermore, in vivo evaluation in mice revealed the carrier material PNIPAm was safe for oral delivery at doses as high as 10 g/kg. Collectively, our findings demonstrated that this type of pH-responsive microsphere may function as superior and translational intestine-directed delivery systems for a diverse array of therapeutics. PMID:27398635

  19. Selective delivery of rifampicin incorporated into poly(DL-lactic-co-glycolic) acid microspheres after phagocytotic uptake by alveolar macrophages, and the killing effect against intracellular Mycobacterium bovis Calmette-Guérin.

    PubMed

    Yoshida, Aya; Matumoto, Makoto; Hshizume, Hiroyuki; Oba, Yoshiro; Tomishige, Tatuo; Inagawa, Hiroyuki; Kohchi, Chie; Hino, Mami; Ito, Fuminori; Tomoda, Keishiro; Nakajima, Takehisa; Makino, Kimiko; Terada, Hiroshi; Hori, Hitoshi; Soma, Gen-Ichiro

    2006-08-01

    Macrophages and their phagocytotic abilities play a dominant role for defense against infected organisms. However, Mycobacterium tuberculosis can survive in the phagosomes of macrophages. In this study, the effective delivery of a drug and the killing effect of tubercle bacilli within macrophages were investigated utilizing the phagocytotic uptake of rifampicin (RFP) that had been incorporated into poly(DL-lactic-co-glycolic) acid (PLGA) microspheres. The microspheres were composed of PLGA that had a monomer ratio (lactic acid/glycolic acid) of either 50/50 or 75/25. They had molecular weights from 5000 to 20,000, and diameters of 1.5, 3.5, 6.2 and 8.9 microm. The most significant factor for phagocytotic activity of macrophages was the diameter of the microspheres. By contrast, molecular weight and monomer ratio of PLGA did not influence phagocytosis. The amount of RFP delivered into cells was also investigated. RFP-PLGA microspheres composed of PLGA with a molecular weight of 20,000 and monomer ratio of 75/25 showed the highest amount of delivery (4 microg/1 x 10(6) cells). Fourteen days after infection, the survival rate of treated intracellular bacilli was 1% when compared with untreated cells. There was almost no killing effect of free RFP (4 or 15 microg/ml) on intracellular bacilli. In vivo efficacy of RFP-PLGA was also examined in rats infected with M. tuberculosis Kurono. Intratracheal administration of RFP-PLGA microspheres was shown to be superior to free RFP for killing of intracellular bacilli and preventing granuloma formation in some lobes. These results suggest that phagocytotic activity could be part of a new drug delivery system that selectively targeted macrophages. PMID:16879999

  20. Biodegradable, Tethered Lipid Bilayer-Microsphere Systems with Membrane-Integrated α-Helical Peptide Anchors.

    PubMed

    Fried, Eric S; Luchan, Joshua; Gilchrist, M Lane

    2016-04-12

    Supported lipid bilayers (SLBs) are ideally suited for the study of biomembrane-biomembrane interactions and for the biomimicry of cell-to-cell communication, allowing for surface ligand displays that contain laterally mobile elements. However, the SLB paradigm does not include three-dimensionality and biocompatibility. As a way to bypass these limitations, we have developed a biodegradable form of microsphere SLBs, also known as proteolipobeads (PLBs), using PLGA microspheres. Microspheres were synthesized using solvent evaporation and size selected with fluorescence activated cell sorting (FACS). Biomembranes were covalently tethered upon fusion to microsphere supports via short-chain PEG spacers connecting membrane-integrated α-helical peptides and the microsphere surface, affecting membrane diffusivity and mobility as indicated by confocal FRAP analysis. Membrane heterogeneities, which are attributed to PLGA hydrophobicity and rough surface topography, are curtailed by the addition of PEG tethers. This method allows for the presentation of tethered, laterally mobile biomembranes in three dimensions with functionally embedded attachment peptides for mobile ligand displays. PMID:26972467

  1. Cationic poly(lactic-co-glycolic acid) iron oxide microspheres for nucleic acid detection

    NASA Astrophysics Data System (ADS)

    Pandey, Chandra Mouli; Sharma, Aditya; Sumana, Gajjala; Tiwari, Ida; Malhotra, Bansi Dhar

    2013-04-01

    Herein, we envisage the possibility of preparing stable cationic poly(lactic-co-glycolic acid) (PLGA) microspheres encapsulating the iron oxide nanoparticles (IONPs; 8-12 nm). The IONPs are incorporated into PLGA in organic phase followed by microsphere formation and chitosan coating in aqueous medium via nano-emulsion technique. The average size of the microspheres, as determined by dynamic light scattering are about 310 nm, while the zeta potential for the composite remains near 35 mV at pH 4.0. These microspheres are electrophoretically deposited onto indium tin oxide (ITO)-coated glass substrate used as cathode and parallel platinum plate as the counter electrode. This platform is utilized to fabricate a DNA biosensor, by immobilizing a probe sequence specific to Escherichia coli. The bioelectrode shows a surface-controlled electrode reaction with the electron transfer coefficient (α) of 0.64 and charge transfer rate constant (ks) of 61.73 s-1. Under the optimal conditions, this biosensor shows a detection limit of 8.7 × 10-14 M and is found to retain about 81% of the initial activity after 9 cycles of use.Herein, we envisage the possibility of preparing stable cationic poly(lactic-co-glycolic acid) (PLGA) microspheres encapsulating the iron oxide nanoparticles (IONPs; 8-12 nm). The IONPs are incorporated into PLGA in organic phase followed by microsphere formation and chitosan coating in aqueous medium via nano-emulsion technique. The average size of the microspheres, as determined by dynamic light scattering are about 310 nm, while the zeta potential for the composite remains near 35 mV at pH 4.0. These microspheres are electrophoretically deposited onto indium tin oxide (ITO)-coated glass substrate used as cathode and parallel platinum plate as the counter electrode. This platform is utilized to fabricate a DNA biosensor, by immobilizing a probe sequence specific to Escherichia coli. The bioelectrode shows a surface-controlled electrode reaction with the

  2. Committee Opinion No 672 Summary Clinical Challenges of Long-Acting Reversible Contraceptive Methods.

    PubMed

    2016-09-01

    Long-acting reversible contraceptive methods are the most effective reversible contraceptives and have an excellent safety record. Although uncommon, possible long-acting reversible contraceptive complications should be included in the informed consent process. Obstetrician-gynecologists and other gynecologic care providers should understand the diagnosis and management of common clinical challenges. The American College of Obstetricians and Gynecologists recommends the algorithms included in this document for management of the most common clinical challenges. PMID:27548551

  3. Committee Opinion No 672: Clinical Challenges of Long-Acting Reversible Contraceptive Methods.

    PubMed

    2016-09-01

    Long-acting reversible contraceptive methods are the most effective reversible contraceptives and have an excellent safety record. Although uncommon, possible long-acting reversible contraceptive complications should be included in the informed consent process. Obstetrician-gynecologists and other gynecologic care providers should understand the diagnosis and management of common clinical challenges. The American College of Obstetricians and Gynecologists recommends the algorithms included in this document for management of the most common clinical challenges. PMID:27548557

  4. Recent advances in COPD disease management with fixed-dose long-acting combination therapies.

    PubMed

    Bateman, Eric D; Mahler, Donald A; Vogelmeier, Claus F; Wedzicha, Jadwiga A; Patalano, Francesco; Banerji, Donald

    2014-06-01

    Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled corticosteroids (ICS) are recommended therapies in the management of chronic obstructive pulmonary disease (COPD). Three fixed-dose combination products have recently been approved for the treatment of COPD (the long-acting β2-agonist plus long-acting muscarinic antagonist [LABA/LAMA] combinations glycopyrronium/indacaterol [QVA149] and umeclidinium/vilanterol, and the LABA/ICS fluticasone furoate/vilanterol), with others currently in late-stage development. LABA/LAMA and LABA/ICS combination therapies demonstrate positive effects on both lung function and patient-reported outcomes, with significant improvements observed with LABA/LAMA combinations compared with placebo, each component alone and other comparators in current use. No new safety concerns have been observed with combinations of long-acting bronchodilators. Combinations of two long-acting bronchodilators represent a new and convenient treatment option in COPD. This review summarizes published efficacy and safety data from clinical trials of both LABA/LAMA and novel LABA/ICS combinations in patients with COPD. PMID:24802656

  5. Cartilage Regeneration of Adipose-Derived Stem Cells in the TGF-β1-Immobilized PLGA-Gelatin Scaffold.

    PubMed

    Yin, Feng; Cai, Junfeng; Zen, Wen; Wei, Yanhui; Zhou, Wei; Yuan, Feng; Singh, Shree Ram; Wei, Yiyong

    2015-06-01

    Articular cartilage has restricted self-regenerative capacity; therefore, treatment of cartilage lesions is a great challenge in the field of orthopedics. In the present study, we evaluate the enhancing effect of a transforming growth factor-beta 1 (TGF-β1)-immobilized scaffold, fabricated by incorporating TGF-β1-loaded gelatin microspheres into PLGA framework, on the differentiation of adipose-derived stem cells (ASCs) into chondrocytes. Significant increase in cell proliferation was observed in the TGF-β1-immobilized PLGA-gelatin scaffold, as compared with the ASC-seeded non-TGF-β1-immobilized PLGA-gelatin scaffold. When chondrogenic differentiation of ASCs was evaluated for both constructs, sulfated glycosaminoglycan (sGAG) content was significantly higher in the TGF-β1-immobilized scaffold. This study showed that ASCs containing the TGF-β1-immobilized scaffold better promoted cartilage regeneration in defective articular cartilage, which is assessed by histological observation. Based on the above results, we conclude that TGF-β1-immobilized PLGA-gelatin scaffold seeded with ASCs considerably enhances the quality of the tissue-engineered cartilage, therefore, advancing the field of cartilage tissue engineering. PMID:25267436

  6. Hydrogel-PLGA delivery system prolongs 2-methoxyestradiol-mediated anti-tumor effects in osteosarcoma cells.

    PubMed

    Maran, Avudaiappan; Dadsetan, Mahrokh; Buenz, Colleen M; Shogren, Kristen L; Lu, Lichun; Yaszemski, Michael J

    2013-09-01

    Osteosarcoma is a bone tumor that affects children and young adults. 2-Methoxyestradiol (2-ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2-ME, we have encapsulated 2-ME in a composite of oligo-(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic-co-glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2-ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2-ME can be released in a controlled manner over 21-days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2-ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2-ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2-ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer-mediated delivery produces anti-tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2-ME and could be further explored in the treatment of osteosarcoma. PMID:23355512

  7. microsphere assemblies

    NASA Astrophysics Data System (ADS)

    Peña-Flores, Jesús I.; Palomec-Garfias, Abraham F.; Márquez-Beltrán, César; Sánchez-Mora, Enrique; Gómez-Barojas, Estela; Pérez-Rodríguez, Felipe

    2014-09-01

    The effect of Fe ion concentration on the morphological, structural, and optical properties of TiO2 films supported on silica (SiO2) opals has been studied. TiO2:Fe2O3 films were prepared by the sol-gel method in combination with a vertical dip coating procedure; precursor solutions of Ti and Fe were deposited on a monolayer of SiO2 opals previously deposited on a glass substrate by the same procedure. After the dip coating process has been carried out, the samples were thermally treated to obtain the TiO2:Fe2O3/SiO2 composites at the Fe ion concentrations of 1, 3, and 5 wt%. Scanning electron microscopy (SEM) micrographs show the formation of colloidal silica microspheres of about 50 nm diameter autoensembled in a hexagonal close-packed fashion. Although the X-ray diffractograms show no significant effect of Fe ion concentration on the crystal structure of TiO2, the μ-Raman and reflectance spectra do show that the intensity of a phonon vibration mode and the energy bandgap of TiO2 decrease as the Fe+3 ion concentration increases.

  8. Microsphere size influences the foreign body reaction.

    PubMed

    Zandstra, J; Hiemstra, C; Petersen, A H; Zuidema, J; van Beuge, M M; Rodriguez, S; Lathuile, A A; Veldhuis, G J; Steendam, R; Bank, R A; Popa, E R

    2014-01-01

    Biodegradable poly-(DL-lactide-co-glycolide) (PLGA) microspheres (MSP) are attractive candidate vehicles for site-specific or systemic sustained release of therapeutic compounds. This release may be altered by the host's foreign body reaction (FBR), which is dependent on the characteristics of the implant, e.g. chemistry, shape or size. In this study, we focused on the characterisation of the influence of MSP size on the FBR. To this end we injected monodisperse MSP of defined size (small 5.8 µm, coefficient of variance (CV) 14 % and large 29.8 µm, CV 4 %) and polydisperse MSP (average diameter 34.1 µm, CV 51 %) under the skin of rats. MSP implants were retrieved at day 7, 14 and 28 after transplantation. The FBR was studied in terms of macrophage infiltration, implant encapsulation, vascularisation and extracellular matrix deposition. Although PLGA MSP of all different sizes demonstrated excellent in vitro and in vivo biocompatibility, significant differences were found in the characteristics of the FBR. Small MSP were phagocytosed, while large MSP were not. Large MSP occasionally elicited giant cell formation, which was not observed after implantation of small MSP. Cellular and macrophage influx and collagen deposition were increased in small MSP implants compared to large MSP. We conclude that the MSP size influences the FBR and thus might influence clinical outcome when using MSP as a drug delivery device. We propose that a rational choice of MSP size can aid in optimising the therapeutic efficacy of microsphere-based therapies in vivo. PMID:25350249

  9. Long-acting insulins alter milk composition and metabolism of lactating dairy cows.

    PubMed

    Winkelman, L A; Overton, T R

    2013-01-01

    This study investigated the effect of 2 different types of long-acting insulin on milk production, milk composition, and metabolism in lactating dairy cows. Multiparous cows (n=30) averaging 88 d in milk were assigned to one of 3 treatments in a completely randomized design. Treatments consisted of control (C), Humulin-N (H; Eli Lilly and Company, Indianapolis, IN), and insulin glargine (L). The H and L treatments were administered twice daily at 12-h intervals via subcutaneous injection for 10d. Cows were milked twice daily, and milk composition was determined every other day. Mammary biopsies were conducted on d 11, and mammary proteins extracted from the biopsies were analyzed by Western blot for components of insulin and mammalian target of rapamycin signaling pathways. Treatment had no effect on dry matter intake or milk yield. Treatment with both forms of long-acting insulin increased milk protein content and tended to increase milk protein yield over the 10-d treatment period. Analysis of milk N fractions from samples collected on d 10 of treatment suggested that cows administered L tended to have higher yields of milk protein fractions than cows administered H. Milk fat content and yield tended to be increased for cows administered long-acting insulins. Lactose content and yields were decreased by treatment with long-acting insulins. Administration of long-acting insulins, particularly L, tended to shift milk fatty acid composition toward increased short- and medium-chain fatty acids and decreased long-chain fatty acids. Plasma concentrations of glucose and urea N were lower for cows administered long-acting insulins; interactions of treatment and sampling time were indicative of more pronounced effects of L than H on these metabolites. Concentrations of nonesterified fatty acids and insulin were increased in cows administered long-acting insulins. Decreased concentrations of urea N in both plasma and milk suggested more efficient use of N in cows

  10. Characterization of ciclosporin A loaded poly (D,L lactide-co-glycolide) microspheres using modulated temperature differential scanning calorimetry.

    PubMed

    Passerini, N; Craig, D Q M

    2002-07-01

    The aim of this study was to investigate the physical structure of poly (D,L lactide-co-glycolide) (PLGA) microspheres loaded with ciclosporin A in terms of the amorphous properties of the individual components and the phase separation characteristics of the binary systems. Microspheres were prepared using a standard oil-in-water emulsion technique. The thermal properties of the PLGA, ciclosporin A and loaded spheres were investigated using modulated temperature differential scanning calorimetry (MTDSC) using a TA Instruments MTDSC 2920, with scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and high-performance liquid chromatography used as supportive techniques. MTDSC indicated a glass transition for ciclosporin A in the reversing heat flow signal at 107 degrees C, supported by temperature cycling studies, while XRD showed clear evidence for diffraction peaks, thereby indicating that the material as received is semi-crystalline. The unloaded PLGA spheres showed a glass transition (Tg) at 43 degrees C, with no reduction in Tg being observed on loading the peptide up to 50%, w/w. Similarly, no evidence for diffraction peaks were seen for the drug-loaded systems, although the glass transition corresponding to the peptide was observed for the loaded microspheres, suggesting that the drug is present as a separate amorphous phase. Similarly, SEM studies showed the appearance of distinct "islands" on the surface of the spheres that are suggested to correspond to the drug phase, with the size of the islands increasing with drug loading. Evidence is therefore presented that ciclosporin A may exist in a range of solid states, with the degree of crystallinity being altered by processing. In addition, there appears to be little or no miscibility between the drug and PLGA using the manufacturing protocol employed here. These findings may have implications for the choice of manufacturing protocol, the release of peptide drugs from PLGA microspheres and the

  11. Comparison of Subjective Experiences and Effectiveness of First-Generation Long-Acting Injectable Antipsychotics and Risperidone Long-Acting Injectables in Patients With Schizophrenia.

    PubMed

    Chen, Wen-Yin; Lin, Shih-Ku

    2016-10-01

    We conducted a cross-sectional study to compare the subjective experiences and clinical effects of first-generation long-acting injectable (FGA-LAI) antipsychotics with those of risperidone long-acting injectables (RIS-LAIs) in 434 schizophrenia patients. Compared with the RIS-LAI group, the patients treated with FGA-LAIs had a significantly longer duration of illness and LAI treatment and were older. Our results suggest that patients treated with FGA-LAI have more satisfactory subjective experiences compared with patients treated with RIS-LAI and that both FGA-LAI and RIS-LAI treatments can prevent relapses and hospitalization. Additional longitudinal studies determining the long-term benefits of RIS-LAI are warranted. PMID:27580495

  12. Development of Yersinia pestis F1 antigen-loaded microspheres vaccine against plague

    PubMed Central

    Huang, Shih-shiung; Li, I-Hsun; Hong, Po-da; Yeh, Ming-kung

    2014-01-01

    Yersinia pestis F1 antigen-loaded poly(DL-lactide-co-glycolide)/polyethylene glycol (PEG) (PLGA/PEG) microspheres were produced using a water-in-oil-in-water emulsion/solvent extraction technique and assayed for their percent yield, entrapment efficiency, surface morphology, particle size, zeta potential, in vitro release properties, and in vivo animal protect efficacy. The Y. pestis F1 antigen-loaded microspheres (mean particle size 3.8 μm) exhibited a high loading capacity (4.5% w/w), yield (85.2%), and entrapment efficiency (38.1%), and presented a controlled in vitro release profile with a low initial burst (18.5%), then continued to release Y. pestis F1 antigen over 70 days. The distribution (%) of Y. pestis F1 on the microspheres surface, outer layer, and core was 3.1%, 28.9%, and 60.7%, respectively. A steady release rate was noticed to be 0.55 μg Y. pestis F1 antigen/mg microspheres/day of Y. pestis F1 antigen release maintained for 42 days. The cumulative release amount at the 1st, 28th, and 42nd days was 8.2, 26.7, and 31.0 μg Y. pestis F1 antigen/mg microspheres, respectively. The 100 times median lethal dose 50% (LD50) of Y. pestis Yokohama-R strain by intraperitoneal injection challenge in mice test, in which mice received one dose of 40 μg F1 antigen content of PLGA/PEG microspheres, F1 antigen in Al(OH)3, and in comparison with F1 antigen in Al(OH)3 vaccine in two doses, was evaluated after given by subcutaneous immunization of BALB/c mice. The study results show that the greatest survival was observed in the group of mice immunized with one dose of F1 antigen-loaded PLGA/PEG microspheres, and two doses of F1 antigen in Al(OH)3 vaccine (100%). In vivo vaccination studies also demonstrated that F1 vaccines microspheres had a protective ability; its steady-state IgG immune protection in mice plasma dramatic increased from 2 weeks (18,764±3,124) to 7 weeks (126,468±19,176) after vaccination. These findings strongly suggest that F1-antigen loaded

  13. Development of Yersinia pestis F1 antigen-loaded microspheres vaccine against plague.

    PubMed

    Huang, Shih-shiung; Li, I-Hsun; Hong, Po-da; Yeh, Ming-kung

    2014-01-01

    Yersinia pestis F1 antigen-loaded poly(DL-lactide-co-glycolide)/polyethylene glycol (PEG) (PLGA/PEG) microspheres were produced using a water-in-oil-in-water emulsion/solvent extraction technique and assayed for their percent yield, entrapment efficiency, surface morphology, particle size, zeta potential, in vitro release properties, and in vivo animal protect efficacy. The Y. pestis F1 antigen-loaded microspheres (mean particle size 3.8 μm) exhibited a high loading capacity (4.5% w/w), yield (85.2%), and entrapment efficiency (38.1%), and presented a controlled in vitro release profile with a low initial burst (18.5%), then continued to release Y. pestis F1 antigen over 70 days. The distribution (%) of Y. pestis F1 on the microspheres surface, outer layer, and core was 3.1%, 28.9%, and 60.7%, respectively. A steady release rate was noticed to be 0.55 μg Y. pestis F1 antigen/mg microspheres/day of Y. pestis F1 antigen release maintained for 42 days. The cumulative release amount at the 1st, 28th, and 42nd days was 8.2, 26.7, and 31.0 μg Y. pestis F1 antigen/mg microspheres, respectively. The 100 times median lethal dose 50% (LD50) of Y. pestis Yokohama-R strain by intraperitoneal injection challenge in mice test, in which mice received one dose of 40 μg F1 antigen content of PLGA/PEG microspheres, F1 antigen in Al(OH)3, and in comparison with F1 antigen in Al(OH)3 vaccine in two doses, was evaluated after given by subcutaneous immunization of BALB/c mice. The study results show that the greatest survival was observed in the group of mice immunized with one dose of F1 antigen-loaded PLGA/PEG microspheres, and two doses of F1 antigen in Al(OH)3 vaccine (100%). In vivo vaccination studies also demonstrated that F1 vaccines microspheres had a protective ability; its steady-state IgG immune protection in mice plasma dramatic increased from 2 weeks (18,764 ± 3,124) to 7 weeks (126,468 ± 19,176) after vaccination. These findings strongly suggest that F1-antigen

  14. Nasal absorption of mixtures of fast-acting and long-acting insulins

    PubMed Central

    Pillion, Dennis J.; Fyrberg, Michael D.; Meezan, Elias

    2010-01-01

    Mixtures of fast-acting and long-acting insulins were administered nasally to anesthetized, hyperglycemic rats in the presence and absence of tetradecyl-β-D-maltoside (TDM). The fast-acting analogs, aspart insulin, lispro insulin, and glulisine insulin, were all rapidly absorbed from the nose when applied individually with 0.125% TDM (Tmax = 15 minutes). One long-acting insulin analog, glargine insulin, was also absorbed from the nose when applied individually in the presence of 0.125% TDM (Tmax = 60 minutes). The other long-acting insulin analog, detemir insulin, was not soluble when formulated with 0.125% TDM. A series of mixtures (1:1) of the three rapid-acting insulins and long-acting glargine insulin were formulated with 0.125% TDM and applied nasally. The pharmacokinetic and pharmacodynamic profiles of the insulin mixtures reflected the additive contributions of both the rapid-acting and the long-acting insulin. These results support the possibility of formulating certain insulin mixtures in tandem to provide nasal insulin products that match the needs of patients with diabetes mellitus better than those currently available. PMID:20080164

  15. Biodegradable polylactide microspheres enhance specific immune response induced by Hepatitis B surface antigen

    PubMed Central

    Qiu, Shaohui; Wei, Qiang; Liang, Zhenglun; Ma, Guanghui; Wang, Lianyan; An, Wenqi; Ma, Xiaowei; Fang, Xin; He, Peng; Li, Hemin; Hu, Zhongyu

    2014-01-01

    Hepatitis B (HB) infection caused by Hepatitis B virus (HBV) is the most common liver disease in the world. HB vaccine, when administered in conjunction with alum adjuvants, induces Th2 immunity that confers protection against HBV. However, currently available vaccine formulations and adjuvants do not elicit adequate Th1 and CTL responses that are important for prevention of maternal transmission of the virus. Microspheres synthesized from poly (D, L-lactide-co-glycolide) (PLGA) or poly (D, L-lactide) (PLA) polymers have been considered as promising tools for in vivo delivery of antigens and drugs. Here we describe PLA microspheres synthesized by premix membrane emulsification method and their application in formulating a new microsphere based HB vaccine. To evaluate the immunogenicity of this microsphere vaccine, BALB/c mice were immunized with microsphere vaccine and a series of immunological assays were conducted. Results of Enzyme-linked ImmunoSpot (ELISPOT) assays revealed that the number of interferon-gamma (IFN-γ)-producing splenocytes and CD8+ T cells increased significantly in the microsphere vaccine group. Microsphere vaccine group showed enhanced specific cell lysis when compared with HB surface antigen (HBsAg) only group in 51Cr cytotoxicity assays. Moreover, microsphere vaccine elicited a comparable level of antibody production as that of HB vaccine administered with alum adjuvant. We show that phagocytosis of HBsAg by dendritic cells is more pronounced in microsphere vaccine group when compared with other control groups. These results clearly demonstrate the potential of using PLA microspheres as effective HB vaccine adjuvants for an enhanced Th1 immune response. PMID:25424942

  16. Biodegradable polylactide microspheres enhance specific immune response induced by Hepatitis B surface antigen.

    PubMed

    Qiu, Shaohui; Wei, Qiang; Liang, Zhenglun; Ma, Guanghui; Wang, Lianyan; An, Wenqi; Ma, Xiaowei; Fang, Xin; He, Peng; Li, Hemin; Hu, Zhongyu

    2014-01-01

    Hepatitis B (HB) infection caused by Hepatitis B virus (HBV) is the most common liver disease in the world. HB vaccine, when administered in conjunction with alum adjuvants, induces Th2 immunity that confers protection against HBV. However, currently available vaccine formulations and adjuvants do not elicit adequate Th1 and CTL responses that are important for prevention of maternal transmission of the virus. Microspheres synthesized from poly (D, L-lactide-co-glycolide) (PLGA) or poly (D, L-lactide) (PLA) polymers have been considered as promising tools for in vivo delivery of antigens and drugs. Here we describe PLA microspheres synthesized by premix membrane emulsification method and their application in formulating a new microsphere based HB vaccine. To evaluate the immunogenicity of this microsphere vaccine, BALB/c mice were immunized with microsphere vaccine and a series of immunological assays were conducted. Results of Enzyme-linked ImmunoSpot (ELISPOT) assays revealed that the number of interferon-gamma (IFN-γ)-producing splenocytes and CD8(+) T cells increased significantly in the microsphere vaccine group. Microsphere vaccine group showed enhanced specific cell lysis when compared with HB surface antigen (HBsAg) only group in (51)Cr cytotoxicity assays. Moreover, microsphere vaccine elicited a comparable level of antibody production as that of HB vaccine administered with alum adjuvant. We show that phagocytosis of HBsAg by dendritic cells is more pronounced in microsphere vaccine group when compared with other control groups. These results clearly demonstrate the potential of using PLA microspheres as effective HB vaccine adjuvants for an enhanced Th1 immune response. PMID:25424942

  17. The Impact of Long-Acting Medications on Attention-Deficit/Hyperactivity Disorder Treatment Disparities

    PubMed Central

    Fullerton, Catherine; McGuire, Thomas

    2013-01-01

    Abstract Objective Long-acting stimulants have increased medication adherence for many children diagnosed with attention deficit/hyperactivity disorder (ADHD), but it is unknown whether the increase has been similar across racial/ethnic groups. Our objective was to determine whether differences in medication utilization and adherence among white, black, and Hispanic ADHD-diagnosed children and adolescents narrowed following the introduction of long-acting stimulants in the 1990s. Methods We conducted a retrospective analysis of Florida Medicaid claims data from fiscal years 1996–2005. At each of three cross sections, we identified children and adolescents 3–17 years of age with at least two claims with an ADHD diagnosis. We used linear regression to model disparities over the study period in utilization of any ADHD medications (utilization of long-acting medication specifically) and medication adherence, and identified patient level, treatment setting, and geographic contributors to disparities. Results Although ADHD medication utilization was lower for ADHD-diagnosed minorities than whites in all years, minorities were as likely as whites to switch to long-acting medications. The increase in prescribed days following long-acting medication diffusion was comparable for white and black medication users (40 and 43 days, respectively), but lower for Hispanics (27 days). Geography and provider setting helped to explain disparities in medication utilization overall, but disparities in adherence were not explained by any of the covariates. Conclusions Despite equivalent switching to long-acting medications in the study period, minorities continued to utilize all ADHD medications less than did whites, and for shorter periods. Provider setting helps explain the ADHD medication utilization gap. High-volume, minority-serving providers are potential targets for future interventions related to improved communication about medication and follow-up after medication

  18. Use of Aripiprazole Long Acting Injection in Negative Symptoms of Schizophrenia.

    PubMed

    James, Suneeta; Kapugama, Chaya; Al-Uzri, Mohammed

    2016-01-01

    Background. Evidence for the efficacious use of second-generation antipsychotics for the treatment of negative symptoms in schizophrenia is scant. Case Presentation. We report the case of a 34-year-old female of Afro-Caribbean origin, who presented with prominent negative symptoms of schizophrenia and was successfully treated with aripiprazole long acting injection. Within a period of six to nine months, the patient returned to her premorbid level of functioning. Conclusion. Aripiprazole long acting injection promises benefits in the treatment of negative symptoms of schizophrenia. Further research needs to be conducted on the use of this drug. PMID:26981301

  19. Long-acting Preparations in Substance Abuse Management: A Review and Update

    PubMed Central

    Hegde, Aditya; Singh, Shubh Mohan; Sarkar, Siddharth

    2013-01-01

    Many pharmacological approaches have been used in managing substance use disorders. Conventional pharmacological agents have relatively short durations of action which make them vulnerable to non-adherence and relapse to substance use disorder. To overcome this problem, long-acting preparations have been developed with the aim of reducing the frequency of use and hence improving adherence. This review takes a broad overview of the long-acting preparations available for the management of substance use disorders. The pharmacology, advantages and disadvantages of these preparations are discussed. Many of these preparations hold promise for improving patient outcomes. PMID:23833336

  20. Use of Aripiprazole Long Acting Injection in Negative Symptoms of Schizophrenia

    PubMed Central

    James, Suneeta; Kapugama, Chaya; Al-Uzri, Mohammed

    2016-01-01

    Background. Evidence for the efficacious use of second-generation antipsychotics for the treatment of negative symptoms in schizophrenia is scant. Case Presentation. We report the case of a 34-year-old female of Afro-Caribbean origin, who presented with prominent negative symptoms of schizophrenia and was successfully treated with aripiprazole long acting injection. Within a period of six to nine months, the patient returned to her premorbid level of functioning. Conclusion. Aripiprazole long acting injection promises benefits in the treatment of negative symptoms of schizophrenia. Further research needs to be conducted on the use of this drug. PMID:26981301

  1. A short term quality control tool for biodegradable microspheres.

    PubMed

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

    2014-06-01

    Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C. PMID:24519488

  2. Metallic coating of microspheres

    SciTech Connect

    Meyer, S.F.

    1980-08-15

    Extremely smooth, uniform metal coatings of micrometer thicknesses on microscopic glass spheres (microspheres) are often needed as targets for inertial confinement fusion (ICF) experiments. The first part of this paper reviews those methods used successfully to provide metal coated microspheres for ICF targets, including magnetron sputtering, electro- and electroless plating, and chemical vapor pyrolysis. The second part of this paper discusses some of the critical aspects of magnetron sputter coating of microspheres, including substrate requirements, the sticking of microspheres during coating (preventing a uniform coating), and the difficulties in growing the desired dense, smooth, uniform microstructure on continuously moving spherical substrates.

  3. Sustained release poly (lactic-co-glycolic acid) microspheres of bone morphogenetic protein 2 plasmid/calcium phosphate to promote in vitro bone formation and in vivo ectopic osteogenesis

    PubMed Central

    Qiao, Chunyan; Zhang, Kai; Sun, Bin; Liu, Jinzhong; Song, Jiyu; Hu, Yue; Yang, Shihui; Sun, Hongchen; Yang, Bai

    2015-01-01

    Bone regeneration often requires continuous stimulation to promote local bone formation. In the present study, calcium phosphate (CaPi) was used to promote transfection of human bone morphogenetic protein 2 (BMP-2) cDNA plasmid, and poly (lactic-co-glycolic acid) (PLGA) was used to prepare microspheres of pBMP-2/CaPi (i.e., PLGA@pBMP-2/CaPi) using W/O/W double emulsion solvent evaporation method. We showed that PLGA@pBMP-2/CaPi microspheres were spherical with smooth surface, and the particle size ranged from 0.5 to 35 μm. Encapsulation efficiency was up to 30~50%. The release of BMP-2 cDNA from microspheres continued more than 30 days and constituted, less than 7.5% of total plasmid amount within the first 24 h. Real-time PCR results showed that co-culturing of PLGA@pBMP-2/CaPi with bone marrow-derived mesenchymal stem cells (BMSCs) increased calcium deposition and gene expressions of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), SP7, and collagen type I (COLL I) in a time-dependent manner. Finally, X-ray analysis demonstrated that in vivo delivery of PLGA@pBMP-2/CaPi microspheres into the tibialis anterior muscles of rats promoted the generation of osteoblasts, bone tissue, and bone structure. The findings suggested that PLGA@pBMP-2/CaPi microspheres can promote ectopic osteogenesis in non-bone tissues, with strong prospects in promoting bone regeneration. PMID:26885257

  4. Bioactive Microsphere-Based Scaffolds Containing Decellularized Cartilage.

    PubMed

    Sutherland, Amanda J; Detamore, Michael S

    2015-07-01

    The aim of this study was to fabricate mechanically functional microsphere-based scaffolds containing decellularized cartilage (DCC), with the hypothesis that this approach would induce chondrogenesis of rat bone marrow-derived mesenchymal stem cells (rBMSCs) in vitro. The DCC was derived from porcine articular cartilage and decellularized using a combination of physical and chemical methods. Four types of scaffolds were fabricated: poly(d,l-lactic-co-glycolic acid) (PLGA) only (negative control), TGF-β-encapsulated (positive control), PLGA surface coated with DCC, and DCC-encapsulated. These scaffolds were seeded with rBMSCs and cultured up to 6 weeks. The compressive modulus of the DCC-coated scaffolds prior to cell seeding was significantly lower than all other scaffold types. Gene expression was comparable between DCC-encapsulated and TGF-β-encapsulated groups. Notably, DCC-encapsulated scaffolds contained 70% higher glycosaminoglyan (GAG) content and 85% more hydroxyproline compared to the TGF-β group at week 3 (with baseline levels subtracted out from acellular DCC scaffolds). Certainly, bioactivity was demonstrated in eliciting a biosynthetic response from the cells with DCC, although true demonstration of chondrogenesis remained elusive under the prescribed conditions. Encapsulation of DCC appeared to lead to improved cell performance relative to coating with DCC, although this finding may be a dose-dependent observation. Overall, DCC introduced via microsphere-based scaffolds appears to be promising as a bioactive approach to cartilage regeneration, although additional studies will be required to conclusively demonstrate chondroinductivity. PMID:25821206

  5. A method to tune the shape of protein-encapsulated polymeric microspheres

    PubMed Central

    Alteriis, Renato de; Vecchione, Raffaele; Attanasio, Chiara; Gregorio, Maria De; Porzio, Massimiliano; Battista, Edmondo; Netti, Paolo A.

    2015-01-01

    Protein encapsulation technologies of polymeric microspheres currently in use have been optimized to effectively protect their “protein cargo” from inactivation occurring in biological environments, preserving its bioactivity during release up to several weeks. The scenario of protein delivery would greatly benefit by strategies enabling the production of non-spherical particles. Herein we report an easy and effective stamp-based method to produce poly-lactic-glycolic-acid (PLGA) microparticles encapsulating Vascular Endothelial Growth Factor (VEGF) of different shapes. We demonstrate that PLGA microspheres can be deformed at room temperature exploiting solvent/non-solvent plasticization in order to preserve the properties of the starting microspheres. This gentle method allows the production of shaped particles that provide a prolonged release of VEGF in active form, as verified by an angiogenic assay. The retention of the biological activity of an extremely labile molecule, i.e. VEGF, lets us hypothesize that a wide variety of drug and protein encapsulated polymeric microspheres can be processed using this method. PMID:26224659

  6. Peptide/protein vaccine delivery system based on PLGA particles.

    PubMed

    Allahyari, Mojgan; Mohit, Elham

    2016-03-01

    Due to the excellent safety profile of poly (D,L-lactide-co-glycolide) (PLGA) particles in human, and their biodegradability, many studies have focused on the application of PLGA particles as a controlled-release vaccine delivery system. Antigenic proteins/peptides can be encapsulated into or adsorbed to the surface of PLGA particles. The gradual release of loaded antigens from PLGA particles is necessary for the induction of efficient immunity. Various factors can influence protein release rates from PLGA particles, which can be defined intrinsic features of the polymer, particle characteristics as well as protein and environmental related factors. The use of PLGA particles encapsulating antigens of different diseases such as hepatitis B, tuberculosis, chlamydia, malaria, leishmania, toxoplasma and allergy antigens will be described herein. The co-delivery of antigens and immunostimulants (IS) with PLGA particles can prevent the systemic adverse effects of immunopotentiators and activate both dendritic cells (DCs) and natural killer (NKs) cells, consequently enhancing the therapeutic efficacy of antigen-loaded PLGA particles. We will review co-delivery of different TLR ligands with antigens in various models, highlighting the specific strengths and weaknesses of the system. Strategies to enhance the immunotherapeutic effect of DC-based vaccine using PLGA particles can be designed to target DCs by functionalized PLGA particle encapsulating siRNAs of suppressive gene, and disease specific antigens. Finally, specific examples of cellular targeting where decorating the surface of PLGA particles target orally administrated vaccine to M-cells will be highlighted. PMID:26513024

  7. Possibility for the development of cosmetics with PLGA nanospheres.

    PubMed

    Ito, Fuminori; Takahashi, Tadahito; Kanamura, Kiyoshi; Kawakami, Hiroyoshi

    2013-05-01

    The optimized preparation of Poly-(lactide-co-glycolic acid) (PLGA) nanospheres containing ubiquinone (UQ) for cosmetic products was pursued. By investigating various conditions for the preparation of UQ/PLGA nanospheres such as the molecular weight of PLGA, PLGA concentration, and UQ concentration, UQ/PLGA nanospheres with increased stability and slower drug release at a higher drug loading efficiency were prepared. Permeation tests on the prepared nanospheres using iontophoresis via electric dermal administration on membrane filters (200 nm pore size) and hairless mouse skin samples were also carried out. After iontophoresis, the nanospheres choked the membrane filter and remained on the horny layer of the hairless mouse skin, even after washing. Therefore, the prepared UQ/PLGA nanospheres and the established iontophoresis technique with the PLGA nanospheres in the present study can be applied to the future development of cosmetics. PMID:22725249

  8. Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of ...

  9. Pharmacokinetics of Short- and Long-acting Formulations of Oxytetracycline After Intramuscular Administration in Chickens.

    PubMed

    Gberindyer, Aondover F; Okpeh, Ene R; Semaka, Asaaga A

    2015-12-01

    Both short- and long-acting formulations of oxytetracycline are commonly used in veterinary medicine to treat animals infected with gram-negative and gram-positive bacteria, rickettsiae, mycoplasma, and chlamydiae. To compare pharmacokinetics of short- and long-acting oxytetracycline in chickens, injectable formulations from the same pharmaceutical company were administered to healthy 6-week-old broiler chickens in accordance to the labeled instructions. Fourteen chickens were separated into 2 groups: chickens in group A (n = 7) were administered the short-acting formulation (10 mg/kg IM q24h) for 4 consecutive days, whereas those in group B (n = 7) were treated with a single dose (20 mg/kg IM) of the long-acting formulation. Blood samples were collected into heparinized tubes before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 24 hours after initial treatment. Thereafter, blood samples were taken every 24 hours up to 120 hours. Plasma concentrations of oxytetracycline were determined by competitive enzyme-linked immunoabsorbent assay, and pharmacokinetic parameters were obtained. Both formulations delivered therapeutic plasma concentrations of oxytetracycline for approximately 100% of their respective dosing intervals as recommended. However, considering the additional labor, patient stress, and mortalities associated with handling, in addition to rejection of the carcass due to tissue necrosis resulting from multiple injections, we recommend use of the long-acting instead of the short-acting injectable formulation in broiler chickens. PMID:26771319

  10. Does Prolonged Therapy with a Long-Acting Stimulant Suppress Growth in Children with ADHD?

    ERIC Educational Resources Information Center

    Spencer, Thomas J.; Faraone, Stephen V.; Biederman, Joseph; Lerner, Marc; Cooper, Kimberly M.; Zimmerman, Brenda

    2006-01-01

    Objective: To investigate whether prolonged therapy with a long-acting stimulant affects growth in children with attention-deficit/hyperactivity disorder (ADHD). Method: One hundred seventy-eight children ages 6 to 13 years received OROS methylphenidate (OROS MPH, CONCERTA) for at least 21 months. Height and weight were measured monthly during the…

  11. Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH). A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrino...

  12. Long-acting muscarinic antagonist + long-acting beta agonist versus long-acting beta agonist + inhaled corticosteroid for COPD: A systematic review and meta-analysis.

    PubMed

    Horita, Nobuyuki; Miyazawa, Naoki; Tomaru, Koji; Inoue, Miyo; Kaneko, Takeshi

    2015-11-01

    Some trials have been conducted to compare long-acting muscarinic antagonist (LAMA) + long-acting beta agonist (LABA) versus LABA + inhaled corticosteroids (ICS) for chronic obstructive pulmonary disease (COPD), but no meta-analysis were reported. Two investigators independently searched for eligible articles using the PubMed, Web of Science and Cochrane databases. Articles in authors' reference files were also regarded as candidates. The eligibility criteria for the current meta-analysis were original trials written in English comparing the impact of LAMA + LABA and LABA + ICS for COPD patients. A pooled value for the continuous value was calculated using the genetic inverse variance method for mean difference. Incidence of events was evaluated using the odds ratio (OR). Minimal clinically important difference were 50 mL for forced expiratory volume in 1 s (FEV1 ), four points for St George Respiratory Questionnaire (SGRQ) and one point for transition dyspnoea index (TDI). We included seven randomized controlled trials and one cross-over trial with follow-up period of 6-26 weeks. Compared with LABA + ICS, LAMA + LABA led to significantly greater improvements of trough FEV1 by 71 (95% CI: 48-95) mL, TDI by 0.38 points (95% CI: 0.17-0.58), less exacerbations with an OR of 0.77 (95% CI: 0.62-0.96) and less pneumonia with an OR of 0.28 (95% CI: 0.12-0.68). Frequencies of any adverse event, serious adverse event, adverse event leading to discontinuation, all-cause death and change of total score of SGRQ were not different in both arms. LAMA + LABA might be a better option for treating COPD than LABA + ICS. PMID:26235837

  13. Patient perspectives in the development and use of long-acting antipsychotics in schizophrenia: focus on olanzapine long-acting injection.

    PubMed

    Citrome, Leslie

    2009-01-01

    Schizophrenia is a chronic mental disorder generally treated with antipsychotic medication. However, non-adherence and partial adherence to antipsychotic medication treatment is common and long-acting injectable "depot" preparations of antipsychotic medications have been used as an alternative to oral medication therapy for patients for whom adherence is a clinically significant problem, as well as for the sake of convenience and in response to patient preference. Olanzapine long-acting injection (OLAI) is a new treatment option and has been approved by several regulatory agencies for the treatment of schizophrenia. OLAI is a crystalline salt formulation of olanzapine and pamoic acid. Efficacy was established in 2 double-blind randomized clinical trials of OLAI for the treatment of acute schizophrenia and for the maintenance of response. The therapeutic OLAI dosages are 150 mg q2 weeks, 210 mg q2 weeks, 300 mg q2 weeks or q4 weeks, and 405 mg q4 weeks, administered by deep intramuscular gluteal injection with a 19-gauge needle. Injection volume ranges from 1 to 2.7 mL. OLAI has essentially the same general tolerability as that of oral olanzapine; however with the depot there is the additional risk of a post-injection delirium sedation syndrome occurring at a rate of 0.07% of injections, requiring a risk management plan that includes observing the patient for 3 hours post injection. PMID:20016798

  14. Switching from risperidone long-acting injectable to paliperidone long-acting injectable or oral antipsychotics: analysis of a Medicaid claims database

    PubMed Central

    Ryan, Patrick B.; Stang, Paul E.; Hough, David; Alphs, Larry

    2015-01-01

    This report examines relapse risk following a switch from risperidone long-acting injectable (RLAI) to another long-acting injectable antipsychotic [paliperidone palmitate (PP)] versus a switch to oral antipsychotics (APs). Truven Health’s MarketScan Multistate Medicaid Database compared relapses following switches from RLAI. New user cohorts for these two groups were created on the basis of first incidence of exposure to the ‘switched to’ drug. Groups were balanced using 1:1 propensity score matching. Time-to-event analysis assessed schizophrenia-related hospital/emergency department visits. A total of 188 patients switched from RLAI to PP, and 131 patients switched from RLAI to oral AP. Propensity score-matched cohort included 109 patients who switched to PP and 109 patients who switched to an oral AP. Patients who switched from RLAI to PP had fewer events (26 vs. 32), longer time to an event (mean 70 vs. 47 days), and lower risk of relapse (hazard ratio, 0.54; 95% confidence interval, 0.32–0.92; P=0.024) compared with those who switched from RLAI to oral AP. Switching from RLAI to PP may be associated with a lower risk for relapse and longer duration of therapy compared with switching to oral AP. Given the limitations of observational studies, these results should be confirmed by other prospective evaluations. PMID:25730525

  15. Patient perspectives in the development and use of long-acting antipsychotics in schizophrenia: focus on olanzapine long-acting injection

    PubMed Central

    Citrome, Leslie

    2009-01-01

    Schizophrenia is a chronic mental disorder generally treated with antipsychotic medication. However, non-adherence and partial adherence to antipsychotic medication treatment is common and long-acting injectable “depot” preparations of antipsychotic medications have been used as an alternative to oral medication therapy for patients for whom adherence is a clinically significant problem, as well as for the sake of convenience and in response to patient preference. Olanzapine long-acting injection (OLAI) is a new treatment option and has been approved by several regulatory agencies for the treatment of schizophrenia. OLAI is a crystalline salt formulation of olanzapine and pamoic acid. Efficacy was established in 2 double-blind randomized clinical trials of OLAI for the treatment of acute schizophrenia and for the maintenance of response. The therapeutic OLAI dosages are 150 mg q2 weeks, 210 mg q2 weeks, 300 mg q2 weeks or q4 weeks, and 405 mg q4 weeks, administered by deep intramuscular gluteal injection with a 19-gauge needle. Injection volume ranges from 1 to 2.7 mL. OLAI has essentially the same general tolerability as that of oral olanzapine; however with the depot there is the additional risk of a post-injection delirium sedation syndrome occurring at a rate of 0.07% of injections, requiring a risk management plan that includes observing the patient for 3 hours post injection. PMID:20016798

  16. Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma?

    PubMed Central

    Price, David; Fromer, Leonard; Kaplan, Alan; van der Molen, Thys; Román-Rodríguez, Miguel

    2014-01-01

    Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long-acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of ‘cholinergic tone’. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations. PMID:25030457

  17. RhBMP-2 microspheres-loaded chitosan/collagen scaffold enhanced osseointegration: an experiment in dog.

    PubMed

    Shi, Shanshan; Cheng, Xiangrong; Wang, Jiawei; Zhang, Wei; Peng, Lin; Zhang, Yufeng

    2009-01-01

    The purpose of this study is to develop a novel recombinant human bone morphogenetic protein-2 (rhBMP-2) sustained release scaffold for dental implant osseointegration, and to evaluate the effect of this scaffold on promoting bone formation. RhBMP-2 was encapsulated in the poly-D,L-lactide-co-glycolide (PLGA) biodegradable microspheres, which were subsequently dispersed in a chitosan/collagen composite scaffold. This rhBMP-2 microspheres-loaded scaffold (S-MB) was compared with a chitosan/collagen scaffold without microspheres that directly encapsulated rhBMP-2 (S-B) in vitro and in vivo. The microstructure of the new scaffold was examined with scanning electron microscopy. The release profile of rhBMP-2 in vitro was measured at interval periods. The effect of rhBMP-2 encapsulated scaffolds on enhancing bone formation through implantation in dogs' mandibles was identified by histological examination of the regenerated bone after 4 weeks of implantation. Due to PLGA microspheres being loaded, the S-MB exhibited lower values at porosity and swelling rate, as well as a higher effective release dose than that of the S-B. Bone density, bone-implant contact, and bone-fill values measured from dog experiments demonstrated that the S-MB induced bone regeneration more quickly and was timely substituted by new bone. It was concluded that this sustained carrier scaffold based on microspheres was more effective to induce implant osseointegration. PMID:18667455

  18. Production of hollow aerogel microspheres

    SciTech Connect

    Upadhye, R.S.; Henning, S.A.

    1990-12-31

    A method is described for making hollow aerogel microspheres of 800--1200{mu} diameter and 100--300{mu} wall thickness by forming hollow alcogel microspheres during the sol/gel process in a catalytic atmosphere and capturing them on a foam surface containing catalyst. Supercritical drying of the formed hollow alcogel microspheres yields hollow aerogel microspheres which are suitable for ICF targets.

  19. Production of hollow aerogel microspheres

    DOEpatents

    Upadhye, Ravindra S.; Henning, Sten A.

    1993-01-01

    A method is described for making hollow aerogel microspheres of 800-1200 .mu. diameter and 100-300 .mu. wall thickness by forming hollow alcogel microspheres during the sol/gel process in a catalytic atmosphere and capturing them on a foam surface containing catalyst. Supercritical drying of the formed hollow alcogel microspheres yields hollow aerogel microspheres which are suitable for ICF targets.

  20. Evaluation of Orntide microspheres in a rat animal model and correlation to in vitro release profiles.

    PubMed

    Kostanski, J W; Dani, B A; Reynolds, G A; Bowers, C Y; DeLuca, P P

    2000-01-01

    Orntide acetate, a novel luteinizing hormone-releasing hormone (LHRH) antagonist, was prepared and evaluated in vivo in 30-day and 120-day sustained delivery formulations using a rat animal model. Orntide poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l- lactide) (PLA) microspheres were prepared by a dispersion method and administered subcutaneously in a liquid vehicle to rats at 2.2 mg Orntide/kg of body weight (30-day forms) or 8.8 mg Orntide/kg (120-day forms). Serum levels of Orntide and testosterone were monitored by radioimmunoassays, and a dose-response study at 4 doses (3, 2.25, 1.5, and 1.75 mg Orntide/kg) was conducted to determine the effective dose of Orntide. Microspheres with diameters between 3.9 and 14 micron were prepared. The onset and duration of testosterone suppression varied for different microsphere formulations and were influenced both by polymer properties and by microsphere characteristics. Microspheres prepared with 50:50 and 75:25 copolymers effectively sustained peptide release for 14 to 28 days, whereas an 85:15 copolymer and the PLA microspheres extended the pharmacological response for more than 120 days. Increase in drug load generally accelerated peptide release from the microspheres, resulting in higher initial serum levels of Orntide and shorter duration of the release. In general, apparent release was faster in vivo than under in vitro conditions. Orntide microspheres effectively suppressed testosterone in rats, providing rapid onset of release and extended periods of chemical castration. Testosterone suppression occurred immediately after microsphere administration without the initial elevation seen with LHRH superagonists. PMID:14727892

  1. Metabolism of proteinoid microspheres

    NASA Technical Reports Server (NTRS)

    Nakashima, T.; Fox, S. W. (Principal Investigator)

    1987-01-01

    The literature of metabolism in proteinoids and proteinoid microspheres is reviewed and criticized from a biochemical and experimental point of view. Closely related literature is also reviewed in order to understand the function of proteinoids and proteinoid microspheres. Proteinoids or proteinoid microspheres have many activities. Esterolysis, decarboxylation, amination, deamination, and oxidoreduction are catabolic enzyme activities. The formation of ATP, peptides or oligonucleotides is synthetic enzyme activities. Additional activities are hormonal and inhibitory. Selective formation of peptides is an activity of nucleoproteinoid microspheres; these are a model for ribosomes. Mechanisms of peptide and oligonucleotide syntheses from amino acids and nucleotide triphosphate by proteinoid microspheres are tentatively proposed as an integrative consequence of reviewing the literature.

  2. Metabolism of proteinoid microspheres

    NASA Technical Reports Server (NTRS)

    Nakashima, T.; Fox, S. W. (Principal Investigator)

    1987-01-01

    The literature of metabolism in proteinoids and proteinoid microspheres is reviewed and criticized from a biochemical and experimental point of view. Closely related literature is also reviewed in order to understand the function of proteinoids and proteinoid microspheres. Proteinoids or proteinoid microspheres have many activities. Esterolyis, decarboxylation, amination, deamination, and oxidoreduction are catabolic enzyme activities. The formation of ATP, peptides or oligonucleotides is synthetic enzyme activities. Additional activities are hormonal and inhibitory. Selective formation of peptides is an activity of nucleoproteinoid microspheres; these are a model for ribosomes. Mechanisms of peptide and oligonucleotide syntheses from amino acids and nucleotide triphosphate by proteinoid microspheres are tentatively proposed as an integrative consequence of reviewing the literature.

  3. Preparation of porous microsphere-scaffolds by electrohydrodynamic forming and thermally induced phase separation.

    PubMed

    Ghanbar, Hanif; Luo, C J; Bakhshi, Poonam; Day, Richard; Edirisinghe, Mohan

    2013-07-01

    The availability of forming technologies able to mass produce porous polymeric microspheres with diameters ranging from 150 to 300 μm is significant for some biomedical applications where tissue augmentation is required. Moreover, appropriate assembly of microspheres into scaffolds is an important challenge to enable direct usage of the as-formed structures in treatments. This work reports the production of poly (glycolic-co-lactic acid) and poly (ε-caprolactone) microspheres under ambient conditions using one-step electrohydrodynamic jetting (traditionally known as atomisation) and thermally induced phase separation (TIPS). To ensure robust production for practical uses, this work presents 12 comprehensive parametric mode mappings of the diameter distribution profiles of the microspheres obtained over a broad range of key processing parameters and correlating of this with the material parameters of 5 different polymer solutions of various concentrations. Poly (glycolic-co-lactic acid) (PLGA) in Dimethyl carbonate (DMC), a low toxicity solvent with moderate conductivity and low dielectric constant, generated microspheres within the targeted diameter range of 150-300 μm. The fabrication of the microspheres suitable for formation of the scaffold structure is achieved by changing the collection method from distilled water to liquid nitrogen and lyophilisation in a freeze dryer. PMID:23623059

  4. Tracking the effect of microspheres size on the drug release from a microsphere/sucrose acetate isobutyrate (SAIB) hybrid depot in vitro and in vivo.

    PubMed

    Lin, Xia; Wang, Jing; Xu, Yuhong; Tang, Xing; Chen, Jian; Zhang, Yu; Zhang, Yan; Yang, Ziyi

    2016-09-01

    The effects of particle size of microspheres on the drug release from a microsphere/sucrose acetate isobutyrate (SAIB) hybrid depot (m-SAIB) was investigated to develop a long-term sustained release drug delivery system with low burst release both in vitro and in vivo. A model drug, risperidone, was first encapsulated into PLGA microspheres with different particle sizes using conventional emulsification and membrane emulsification methods. The m-SAIB was prepared by dispersing the risperidone-microspheres in the SAIB depot. The drug release from m-SAIB was double controlled by the drug diffusion from the microspheres into SAIB matrix and the drug diffusion from the SAIB matrix into the medium. Large microspheres (18.95 ± 18.88 µm) prepared by the conventional homogenization method exhibited porous interior structure, which contributed to the increased drug diffusion rate from microspheres into SAIB matrix. Consequently, m-SAIB containing such microspheres showed rapid initial drug release (Cmax = 110.1 ±54.2 ng/ml) and subsequent slow drug release (Cs(4-54d)= 2.7 ± 0.8 ng/ml) in vivo. Small microspheres (5.91 ± 2.24 µm) showed dense interior structure with a decreased drug diffusion rate from microspheres into SAIB matrix. The initial drug release from the corresponding m-SAIB was significantly decreased (Cmax = 40.9 ± 13.7 ng/ml), whereas the drug release rate from 4 to 54 d was increased (Cs(4-54d)=4.1 ± 1.0 ng/ml). By further decreasing the size of microspheres to 3.38 ± 0.70 µm, the drug diffusion surface area was increased, which subsequently increased the drug release from the m-SAIB. These results demonstrate that drug release from the m-SAIB can be tailored by varying the size of microspheres to reduce the in vivo burst release of SAIB system alone. PMID:26790718

  5. Long-acting injectable antipsychotics in the elderly: guidelines for effective use.

    PubMed

    Masand, Prakash S; Gupta, Sanjay

    2003-01-01

    The elderly are at increased risk for psychosis because of age-related deterioration of cortical areas and neurochemical changes, comorbid physical illnesses, social isolation, sensory deficits and polypharmacy. The prevalence of psychiatric and neuropsychiatric disorders requiring treatment with an antipsychotic agent is expected to increase dramatically among people aged >64 years. Antipsychotic agents are effective in the treatment of schizophrenia, schizoaffective disorder, behavioural symptoms in patients with dementia, and mood disorders with psychosis. However, failure to adhere to a prescribed medication regimen by patients with psychosis is one of the most frustrating problems faced by mental healthcare providers, because of the high risk of relapse associated with partial compliance. For patients with psychosis who will not or cannot take oral medications on a regular daily basis or have other characteristics, such as memory, vision or auditory impairment, which contribute to partial compliance, long-acting injectable antipsychotic medication offers a solution. Older patients are especially at risk of adverse effects associated with traditional antipsychotic agents, such as motor effects, postural hypotension, excessive sedation, and anticholinergic effects because of age-related pharmacokinetic and pharmacodynamic factors, coexisting medical illnesses and concomitant medications. Therefore, drug dosage recommendations in the elderly are much more conservative than in younger patients. The appropriate starting dose of an antipsychotic in older individuals is 25% of the usual adult dose; total daily maintenance doses ranges from 25-50% of the adult dose. There are few studies regarding the use of depot antipsychotics in elderly patients. Studies that are available indicate that traditional antipsychotic agents given as depot injections are associated with positive outcomes in the elderly. Because the risks for extrapyramidal symptoms and tardive dyskinesia

  6. Serial follow-up of presurgical treatment using pasireotide long-acting release with or without octreotide long-acting release for naïve active acromegaly.

    PubMed

    Chang, Jan-Shun; Tseng, Ham-Min; Chang, Tien-Chun

    2016-06-01

    The aim of the present study was to evaluate the serial changes of GH and IGF-1 in seven patients with naïve, active acromegaly following presurgical treatment of the somatostatin analog pasireotide long-acting release (LAR) and octreotide LAR. The patients were treated with pasireotide LAR with or without octreotide LAR for two years and underwent transsphenoidal adenomectomy. After treatment with the somatostatin analogs, the surgical cure rate was similar to that in patients who underwent transsphenoidal surgery alone. Diabetes insipidus was not identified in any patients after the operation. Pasireotide LAR was effective on GH as well as IGF-1 suppression and tumor size decreasing when used as the primary therapy. Future large-population studies to investigate the surgical curative rate after presurgical treatment with somatostatin analogs in patients with acromegaly and macroadenomas close to the cavernous sinus are warranted. However, that hyperglycemia developed following pre-surgical treatment with pasireotide should take into consideration. PMID:27117887

  7. Effectiveness of long-acting antipsychotics in clinical practice: 2. Effects of antipsychotic polypharmacy on risperidone long-acting injection and zuclopenthixol decanoate

    PubMed Central

    Cordiner, Matthew; Shajahan, Polash; McAvoy, Sarah; Bashir, Muhammad; Taylor, Mark

    2016-01-01

    Objectives: Antipsychotic polypharmacy (APP) is common clinical practice. Theoretically, APP runs the risk of additional side effects, drug interactions, adherence and cost. A limited evidence base is emerging to support the effectiveness of APP in clinical practice. Our companion paper highlighted the extent of APP alongside commonly prescribed long-acting antipsychotic injections (LAIs). We aimed to examine the effects of APP on discontinuation rates and Clinical Global Impression (CGI) outcomes in patients commenced on risperidone long-acting injection (RLAI) and zuclopenthixol decanoate. Method: LAI-naïve patients commenced on RLAI (n = 102) and zuclopenthixol decanoate(n = 105) were identified using our electronic patient record (running from 2002) within NHS Lanarkshire, Scotland, UK. This was a retrospective, electronic case note review with an 18-month follow up. Patient groups were divided into those receiving the LAI as the sole antipsychotic and those who were receiving additional oral antipsychotic polypharmacy (APP) for at least 50% of the duration of the treatment with their LAI. Kaplan–Meier statistics were calculated for discontinuation rates. CGI severity and improvement scores were retrospectively assigned by the investigating team. Results: Antipsychotic polypharmacy occurred with RLAI (37%) and zuclopenthixol decanoate (46%) and was associated with lower discontinuation rates (statistical significant with zuclopenthixol for any cause and adverse effects discontinuation). APP had no adverse outcomes on hospital admissions or CGI ratings. Patients on APP did not have more severe, chronic or treatment resistant illnesses. Conclusions: For RLAI and zuclopenthixol decanoate, APP had some favourable outcomes when examining discontinuation rates for any cause, and adverse effects. This was unexpected as we had considered APP would signal illness chronicity and severity and be associated with increased adverse effects resulting in early

  8. Nocturnal Hypoglycemia: Answering the Challenge With Long-acting Insulin Analogs

    PubMed Central

    Brunton, Stephen A.

    2007-01-01

    Background Nocturnal hypoglycemia may be the most common type of hypoglycemia in individuals with diabetes using insulin and is particularly worrisome because it often goes undetected and may lead to unconsciousness and even death in severe cases. Objectives The prevalence, causes, and consequences of nocturnal hypoglycemia as well as detection and prevention strategies are reviewed, including the use of long-acting insulin analogs, which offer more physiologic and predictable time-action profiles than traditional human basal insulin. Data Sources A total of 307 publications (151 PubMed; 104 Adis; 52 BIOSIS) were reviewed. Review Methods Relevant trials were found by searching for “(detemir OR glargine) AND nocturnal AND (hypoglycemia OR hypoglycaemia) AND diabetes.” To capture trials that may not have specified “nocturnal” in the title or abstract text but still reported nocturnal hypoglycemia data, a supplemental search of PubMed using “(detemir OR glargine) AND (nocturnal OR hypoglycemia OR hypoglycaemia) AND diabetes” was undertaken. Results A review of these trials found that patients with type 1 and type 2 diabetes mellitus have a lower risk for nocturnal hypoglycemia when receiving long-acting insulin analogs (insulin detemir or insulin glargine), provided that glycemic control is comparable to that provided by traditional human basal insulin. Long-acting insulin analogs may be the best option to provide basal insulin coverage in patients who do not choose or require continuous subcutaneous insulin infusion. Conclusions Randomized clinical trials suggest that the long-acting insulin analogs are associated with a lower risk for nocturnal hypoglycemia than neutral protamine Hagedorn without sacrificing glycemic control. PMID:17955093

  9. Microsphere Insulation Panels

    NASA Technical Reports Server (NTRS)

    Mohling, R.; Allen, M.; Baumgartner, R.

    2006-01-01

    Microsphere insulation panels (MIPs) have been developed as lightweight, longlasting replacements for the foam and vacuum-jacketed systems heretofore used for thermally insulating cryogenic vessels and transfer ducts. The microsphere core material of a typical MIP consists of hollow glass bubbles, which have a combination of advantageous mechanical, chemical, and thermal-insulation properties heretofore available only separately in different materials. In particular, a core filling of glass microspheres has high crush strength and low density, is noncombustible, and performs well in soft vacuum.

  10. Repair of rat cranial bone defect by using bone morphogenetic protein-2-related peptide combined with microspheres composed of polylactic acid/polyglycolic acid copolymer and chitosan.

    PubMed

    Li, Jingfeng; Jin, Lin; Wang, Mingbo; Zhu, Shaobo; Xu, Shuyun

    2015-08-01

    The effects of the transplanted bone morphogenetic protein-2 (BMP2) -related peptide P24 and rhBMP2 combined with poly(lactic-co-glycolic acid) (PLGA)/chitosan (CS) microspheres were investigated in promoting the repair of rat cranial bone defect. Forty white rats were selected and equally divided into four groups (group A: 1 μg of rhBMP2/PLGA/CS composite; group B: 3 mg of P24/PLGA/CS composite; group C: 0.5 μg of rhBMP2 + 1.5 mg of P24/PLGA/CS composite; group D: blank PLGA/CS material), and rat cranial bone defect models with a diameter of 5 mm were established. The materials were transplanted to the cranial bone defects. The animals were sacrificed on weeks 6 and 12 post-operation. Radiographic examinations (x-ray imaging and 3D CT scanning) and histological evaluations were performed. The repaired areas of cranial bone defects were measured, and the osteogenetic abilities of various materials were compared. Cranial histology, imaging, and repaired area measurements showed that the osteogenetic effects at two time points (weeks 6 and 12) in group C were better than those in groups A and B. The effects in groups A and B were similar. Group D achieved the worst repair effect of cranial bone defects, where a large number of fibrous connective tissues were observed. The PLGA/CS composite microspheres loaded with rhBMP2 and P24 had optimal concrescence and could mutually increase their osteogenesis capability. rhBMP2 + P24/PLGA/CS composite is a novel material for bone defect repair with stable activity to induce bone formation. PMID:26154695

  11. Risks versus benefits of different types of long-acting injectable antipsychotics.

    PubMed

    McEvoy, Joseph P

    2006-01-01

    Since their introduction into clinical practice in the early 1960s, long-acting depot antipsychotics have been widely used as maintenance therapy for patients with schizophrenia. The improved pharmacokinetics of injectable long-acting antipsychotic therapies have provided more reliable drug delivery and reduced differences in peak and trough plasma levels of the drug. Studies that have compared short-acting oral antipsychotics with long-acting injectable antipsychotics, although imperfect, support injectable antipsychotics as having real benefit over oral antipsychotics on patient outcome owing largely to improved adherence. If patients forget or refuse to take their prescribed oral medications, weeks or months may go by before they experience an exacerbation; the effects of nonadherence become apparent too late to preempt the problem. On the other hand, if a patient fails to show up for an injection, the problem of nonadherence can be immediately addressed. When injectable medication is combined with an active psychosocial treatment program that will respond assertively to nonadherence, relapse rates may be reduced. By preventing or delaying relapse, consistent treatment can improve the patient's quality of life and lead to an overall reduction in the cost of care. PMID:16822092

  12. Long-acting muscarinic antagonists: a potential add-on therapy in the treatment of asthma?

    PubMed

    Busse, William W; Dahl, Ronald; Jenkins, Christine; Cruz, Alvaro A

    2016-03-01

    Asthma is a chronic inflammatory disorder of the airways that is a major global burden on both individuals and healthcare systems. Despite guideline-directed treatment, a significant proportion of patients with asthma do not achieve control. This review focuses on the potential use of long-acting anticholinergics as bronchodilators in the treatment of asthma, with results published from clinical trials of glycopyrrolate, umeclidinium and tiotropium. The tiotropium clinical trial programme is the most advanced, with data available from a number of phase II and III studies of tiotropium as an add-on to inhaled corticosteroid maintenance therapy, with or without a long-acting β2-agonist, in patients across asthma severities. Recent studies using the Respimat Soft Mist inhaler have identified 5 µg once daily as the preferred dosing regimen, which has shown promising results in adults, adolescents and children with asthma. Tiotropium Respimat has recently been incorporated into the Global Initiative for Asthma 2015 treatment strategy as a recommended alternative therapy at steps 4 and 5 in adult patients with a history of exacerbations. The increasing availability of evidence from ongoing and future clinical trials will be beneficial in determining where long-acting anticholinergic agents fit in future treatment guidelines across a variety of patient populations and disease severities. PMID:26929422

  13. Factors associated with relapse in schizophrenia despite adherence to long-acting injectable antipsychotic therapy.

    PubMed

    Alphs, Larry; Nasrallah, Henry A; Bossie, Cynthia A; Fu, Dong-Jing; Gopal, Srihari; Hough, David; Turkoz, Ibrahim

    2016-07-01

    Many patients with schizophrenia will relapse despite uninterrupted antipsychotic (AP) long-acting therapy (LAT). This exploratory analysis examined variables associated with relapse despite ensured adherence to LAT. This was a post-hoc exploratory analysis of a 1-year study of risperidone long-acting injection in patients with stable schizophrenia or schizoaffective disorder (NCT00297388; N=323). Patients were discontinued from previous oral APs and randomly assigned to biweekly intramuscular injections of risperidone long-acting injectable 50 (n=163) or 25 mg (n=161) for 52 weeks. Cox proportional hazards regression models examined variables putatively associated with relapse. A total of 59/323 (18.3%) patients relapsed over 12 months despite continuous AP LAT. Variables associated with the risk of relapse included illness duration (6.0% increase each year; P=0.0003) and country (Canada vs. USA, 4.7-fold risk increase; P=0.0008). When illness duration was further categorized as ≤5, 6-10, and >10 years, patients with an illness duration of >10 versus ≤5 years were at greatest risk of relapse (>10 vs. ≤5 years associated with a 4.4-fold increase in the risk of relapse; P=0.0181). Findings suggest that patients with more chronic illness have a greater risk of relapse despite ensured treatment adherence, supporting the need for early intervention to prevent the deleterious effects of chronicity. PMID:26974214

  14. Organic aerogel microspheres

    DOEpatents

    Mayer, Steven T.; Kong, Fung-Ming; Pekala, Richard W.; Kaschmitter, James L.

    1999-01-01

    Organic aerogel microspheres which can be used in capacitors, batteries, thermal insulation, adsorption/filtration media, and chromatographic packings, having diameters ranging from about 1 micron to about 3 mm. The microspheres can be pyrolyzed to form carbon aerogel microspheres. This method involves stirring the aqueous organic phase in mineral oil at elevated temperature until the dispersed organic phase polymerizes and forms nonsticky gel spheres. The size of the microspheres depends on the collision rate of the liquid droplets and the reaction rate of the monomers from which the aqueous solution is formed. The collision rate is governed by the volume ratio of the aqueous solution to the mineral oil and the shear rate, while the reaction rate is governed by the chemical formulation and the curing temperature.

  15. Organic aerogel microspheres

    DOEpatents

    Mayer, S.T.; Kong, F.M.; Pekala, R.W.; Kaschmitter, J.L.

    1999-06-01

    Organic aerogel microspheres are disclosed which can be used in capacitors, batteries, thermal insulation, adsorption/filtration media, and chromatographic packings, having diameters ranging from about 1 micron to about 3 mm. The microspheres can be pyrolyzed to form carbon aerogel microspheres. This method involves stirring the aqueous organic phase in mineral oil at elevated temperature until the dispersed organic phase polymerizes and forms nonstick gel spheres. The size of the microspheres depends on the collision rate of the liquid droplets and the reaction rate of the monomers from which the aqueous solution is formed. The collision rate is governed by the volume ratio of the aqueous solution to the mineral oil and the shear rate, while the reaction rate is governed by the chemical formulation and the curing temperature.

  16. Calcium phosphate cement scaffolds with PLGA fibers.

    PubMed

    Vasconcellos, Letícia Araújo; dos Santos, Luís Alberto

    2013-04-01

    The use of calcium phosphate-based biomaterials has revolutionized current orthopedics and dentistry in repairing damaged parts of the skeletal system. Among those biomaterials, the cement made of hydraulic grip calcium phosphate has attracted great interest due to its biocompatibility and hardening "in situ". However, these cements have low mechanical strength compared with the bones of the human body. In the present work, we have studied the attainment of calcium phosphate cement powders and their addition to poly (co-glycolide) (PLGA) fibers to increase mechanical properties of those cements. We have used a new method that obtains fibers by dripping different reagents. PLGA fibers were frozen after lyophilized. With this new method, which was patented, it was possible to obtain fibers and reinforcing matrix which furthered the increase of mechanical properties, thus allowing the attainment of more resistant materials. The obtained materials were used in the construction of composites and scaffolds for tissue growth, keeping a higher mechanical integrity. PMID:23827539

  17. A New Level A Type IVIVC for the Rational Design of Clinical Trials Toward Regulatory Approval of Generic Polymeric Long-Acting Injectables.

    PubMed

    Somayaji, Mahadevabharath R; Das, Debarun; Przekwas, Andrzej

    2016-10-01

    Chronic neuropsychiatric disorders and diabetes mellitus affect millions of patients and require long-term supervision and expensive medical care. Although repeated drug administration can help manage these diseases, relapses and re-hospitalization owing to patient non-adherence and reduced therapeutic efficacy remain challenging. In response, long-acting injectables, which provide sustained drug release over longer periods at concentrations close to therapeutic ranges, have been proposed. Recent advancements include polymeric long-acting injectables (pLAIs), in which the active pharmaceutical ingredient (API) is encapsulated within U.S. Food and Drug Administration (FDA)-approved biocompatible polymers, such as poly(lactic-co-glycolic acid), or PLGA. Despite significant progress and development in the global pLAI market, FDA guidance for the approval of complex drug products, such as generic pLAIs, is not clearly defined. Although in vitro to in vivo correlation (IVIVC) can facilitate the identification of critical quality attributes (CQAs), drug formulations, and in vitro test platforms for evaluating drug performance in vivo, the application of IVIVC in order to shortlist time- and resource-intensive clinical trials for generic pLAIs has not been reported. Here, we propose a new Level A Type IVIVC that directly correlates the in vitro outcomes, such as drug dissolution, of candidate generic formulations with the clinical characteristics, such as drug absorption, of a reference listed drug (RLD), to help identify the specific generic pLAI formulations with clinical absorptions that are likely to be similar to that of the RLD, thereby reducing the number of clinical trials required for evaluation of clinical bioequivalence (BE). Therefore, the scope of the proposed method is intended only for the rational design of clinical trials, i.e., to shortlist the specific pLAI generic formulations for clinical BE evaluation, and not necessarily to analyze drug performances

  18. Bone Regeneration from PLGA Micro-Nanoparticles.

    PubMed

    Ortega-Oller, Inmaculada; Padial-Molina, Miguel; Galindo-Moreno, Pablo; O'Valle, Francisco; Jódar-Reyes, Ana Belén; Peula-García, Jose Manuel

    2015-01-01

    Poly-lactic-co-glycolic acid (PLGA) is one of the most widely used synthetic polymers for development of delivery systems for drugs and therapeutic biomolecules and as component of tissue engineering applications. Its properties and versatility allow it to be a reference polymer in manufacturing of nano- and microparticles to encapsulate and deliver a wide variety of hydrophobic and hydrophilic molecules. It additionally facilitates and extends its use to encapsulate biomolecules such as proteins or nucleic acids that can be released in a controlled way. This review focuses on the use of nano/microparticles of PLGA as a delivery system of one of the most commonly used growth factors in bone tissue engineering, the bone morphogenetic protein 2 (BMP2). Thus, all the needed requirements to reach a controlled delivery of BMP2 using PLGA particles as a main component have been examined. The problems and solutions for the adequate development of this system with a great potential in cell differentiation and proliferation processes under a bone regenerative point of view are discussed. PMID:26509156

  19. Bone Regeneration from PLGA Micro-Nanoparticles

    PubMed Central

    Ortega-Oller, Inmaculada; Padial-Molina, Miguel; Galindo-Moreno, Pablo; O'Valle, Francisco; Jódar-Reyes, Ana Belén; Peula-García, Jose Manuel

    2015-01-01

    Poly-lactic-co-glycolic acid (PLGA) is one of the most widely used synthetic polymers for development of delivery systems for drugs and therapeutic biomolecules and as component of tissue engineering applications. Its properties and versatility allow it to be a reference polymer in manufacturing of nano- and microparticles to encapsulate and deliver a wide variety of hydrophobic and hydrophilic molecules. It additionally facilitates and extends its use to encapsulate biomolecules such as proteins or nucleic acids that can be released in a controlled way. This review focuses on the use of nano/microparticles of PLGA as a delivery system of one of the most commonly used growth factors in bone tissue engineering, the bone morphogenetic protein 2 (BMP2). Thus, all the needed requirements to reach a controlled delivery of BMP2 using PLGA particles as a main component have been examined. The problems and solutions for the adequate development of this system with a great potential in cell differentiation and proliferation processes under a bone regenerative point of view are discussed. PMID:26509156

  20. Cross-sectional comparison of first-generation antipsychotic long-acting injections vs risperidone long-acting injection: patient-rated attitudes, satisfaction and tolerability

    PubMed Central

    Singh, Sourabh Moti; Haddad, Peter M.; Husain, Nusrat; Heaney, Eamonn; Tomenson, Barbara; Chaudhry, Imran B.

    2016-01-01

    Objectives: The objective of this study was to compare patients’ attitudes and satisfaction with medication and patient-rated tolerability between those prescribed a first-generation antipsychotic long-acting injection (FGA-LAI) and those prescribed risperidone long-acting injection (RLAI). Method: A cross-sectional study of a representative sample of outpatients prescribed an FGA-LAI or RLAI for a minimum of 6 months and attending a depot clinic. Attitudes to medication were assessed by the Drug Attitude Inventory (DAI-30), tolerability was measured by the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) and satisfaction with antipsychotic medication was assessed by the Satisfaction with Antipsychotic Medication (SWAM) scale. Results: The RLAI (n = 28) and FGA-LAI (n = 39) groups did not differ in terms of mean age, sex, diagnosis and ethnicity. All individual LAIs were prescribed within British National Formulary limits. The most commonly prescribed FGA-LAI was flupentixol decanoate (n = 22). There was no significant difference between the RLAI and FGA-LAI groups in terms of mean total scores on the DAI-30, LUNSERS and SWAM or the tolerability subscales of the LUNSERS or the two subscales (treatment acceptability and medication insight) of the SWAM. In both LAI groups there was a low level of side effects (LUNSERS) and a generally positive attitude (DAI-30) and reasonable satisfaction (SWAM) with medication. Conclusions: Patients treated with FGA-LAI and RLAI for at least 6 months did not differ in terms of patient-rated tolerability, attitudes and satisfaction with medication. The current design cannot determine whether differences would have been evident earlier on during treatment. These results should be regarded as preliminary and are subject to prescribing bias. Randomized studies avoid prescribing bias and are a superior way to compare specific LAIs. Ideally randomized studies should include patient-rated outcome measures including

  1. Microencapsulation of Streptococcus equi antigens in biodegradable microspheres and preliminary immunisation studies.

    PubMed

    Azevedo, Ana F; Galhardas, Jorge; Cunha, António; Cruz, Patrícia; Gonçalves, Lídia M D; Almeida, António J

    2006-10-01

    Streptococcus equi subspecies equi is the causative agent of strangles, a bacterial infection of the respiratory tract of equidae. Current strategies to prevent strangles rely on antimicrobial therapy or immunisation with inactivated bacteria, S. equi bacterin, or M-like protein (SeM) extract. The aim of this work was to investigate whether immunisation with whole killed S. equi or a bacterial lysate entrapped in poly(lactide-co-glycolide) (PLGA) microspheres might induce protective immunity to mice. Animals were treated with a dose of antigen equivalent to 25 microg of SeM. For intranasal route animals were primed on days 1, 2 and 3 and were boosted on day 29. For intramuscular route, primary immunisation was carried out with a single injection on day 1 and animals were boosted on day 29. On day 43 animals were submitted to a challenge with a virulent strain of S. equi. Vaccination with antigen-containing microspheres induced higher serum antibody levels in mice treated by the intranasal route, whereas intramuscular immunisation did not reveal any difference between control and treatment groups. Microencapsulated antigens achieved to fully protect mice against experimental infection irrespective of the route of administration used. Following intranasal or intramuscular administration soluble antigen failed to protect mice against challenge. These studies indicate that PLGA microspheres are a potential carrier system for the delivery of S. equi antigens. PMID:16846728

  2. Microsphere-based scaffolds encapsulating tricalcium phosphate and hydroxyapatite for bone regeneration.

    PubMed

    Gupta, Vineet; Lyne, Dina V; Barragan, Marilyn; Berkland, Cory J; Detamore, Michael S

    2016-07-01

    Bioceramic mixtures of tricalcium phosphate (TCP) and hydroxyapatite (HAp) are widely used for bone regeneration because of their excellent cytocompatibility, osteoconduction, and osteoinduction. Therefore, we hypothesized that incorporation of a mixture of TCP and HAp in microsphere-based scaffolds would enhance osteogenesis of rat bone marrow stromal cells (rBMSCs) compared to a positive control of scaffolds with encapsulated bone-morphogenic protein-2 (BMP-2). Poly(D,L-lactic-co-glycolic acid) (PLGA) microsphere-based scaffolds encapsulating TCP and HAp mixtures in two different ratios (7:3 and 1:1) were fabricated with the same net ceramic content (30 wt%) to evaluate how incorporation of these ceramic mixtures would affect the osteogenesis in rBMSCs. Encapsulation of TCP/HAp mixtures impacted microsphere morphologies and the compressive moduli of the scaffolds. Additionally, TCP/HAp mixtures enhanced the end-point secretion of extracellular matrix components relevant to bone tissue compared to the "blank" (PLGA-only) microsphere-based scaffolds as evidenced by the biochemical, gene expression, histology, and immunohistochemical characterization. Moreover, the TCP/HAp mixture groups even surpassed the BMP-2 positive control group in some instances in terms of matrix synthesis and gene expression. Lastly, gene expression data suggested that the rBMSCs responded differently to different TCP/HAp ratios presented to them. Altogether, it can be concluded that TCP/HAp mixtures stimulated the differentiation of rBMSCs toward an osteoblastic phenotype, and therefore may be beneficial in gradient microsphere-based scaffolds for osteochondral regeneration. PMID:27272903

  3. Multifunctional PLGA particles containing poly(l-glutamic acid)-capped silver nanoparticles and ascorbic acid with simultaneous antioxidative and prolonged antimicrobial activity.

    PubMed

    Stevanović, Magdalena; Bračko, Ines; Milenković, Marina; Filipović, Nenad; Nunić, Jana; Filipič, Metka; Uskoković, Dragan P

    2014-01-01

    A water-soluble antioxidant (ascorbic acid, vitamin C) was encapsulated together with poly(l-glutamic acid)-capped silver nanoparticles (AgNpPGA) within a poly(lactide-co-glycolide) (PLGA) polymeric matrix and their synergistic effects were studied. The PLGA/AgNpPGA/ascorbic acid particles synthesized by a physicochemical method with solvent/non-solvent systems are spherical, have a mean diameter of 775 nm and a narrow size distribution with a polydispersity index of 0.158. The encapsulation efficiency of AgNpPGA/ascorbic acid within PLGA was determined to be >90%. The entire amount of encapsulated ascorbic acid was released in 68 days, and the entire amount of AgNpPGAs was released in 87 days of degradation. The influence of PLGA/AgNpPGA/ascorbic acid on cell viability, generation of reactive oxygen species (ROS) in HepG2 cells, as well as antimicrobial activity against seven different pathogens was investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated good biocompatibility of these PLGA/AgNpPGA/ascorbic acid particles. We measured the kinetics of ROS formation in HepG2 cells by a DCFH-DA assay, and found that PLGA/AgNpPGA/ascorbic acid caused a significant decrease in DCF fluorescence intensity, which was 2-fold lower than that in control cells after a 5h exposure. This indicates that the PLGA/AgNpPGA/ascorbic acid microspheres either act as scavengers of intracellular ROS and/or reduce their formation. Also, the results of antimicrobial activity of PLGA/AgNpPGA/ascorbic acid obtained by the broth microdilution method showed superior and extended activity of these particles. The samples were characterized using Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, transmission electron microscopy, zeta potential and particle size analysis. This paper presents a new approach to the treatment of infection that at the same time offers a very pronounced antioxidant effect. PMID:23988864

  4. Preparation and characterization of poly(lactic-co-glycolic acid) microspheres loaded with a labile antiparkinson prodrug.

    PubMed

    D'Aurizio, E; van Nostrum, C F; van Steenbergen, M J; Sozio, P; Siepmann, F; Siepmann, J; Hennink, W E; Di Stefano, A

    2011-05-16

    L-dopa-α-lipoic acid (LD-LA) is a new multifunctional prodrug for the treatment of Parkinson's disease. In human plasma, LD-LA catechol esters and amide bonds are chemically and enzymatically cleaved, respectively, resulting in a half-life time of about fifty minutes. In the present work, the unstable LD-LA was entrapped into biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres designed as depot systems to protect this prodrug against degradation and to obtain a sustained release of the intact compound. The microspheres were prepared by an oil-in-water emulsion/solvent evaporation technique and the effect of formulation and processing parameters (polymer concentration in the organic solvent, volumes ratio of the phases, rate of the organic solvent evaporation) on microspheres characteristics (size, loading, morphology, release) was investigated. Also emphasis was given on the stability of the drug before and after release as well as on the underlying mass transport mechanisms controlling LD-LA release. Interestingly, when encapsulated in appropriate conditions into PLGA microspheres, the labile prodrug was stabilized and released via Fickian diffusion up to more than one week. PMID:21356295

  5. Method for sizing hollow microspheres

    DOEpatents

    Farnum, E.H.; Fries, R.J.

    1975-10-29

    Hollow Microspheres may be effectively sized by placing them beneath a screen stack completely immersed in an ultrasonic bath containing a liquid having a density at which the microspheres float and ultrasonically agitating the bath.

  6. Increasing Use of Long-Acting Reversible Contraception to Decrease Unplanned Pregnancy.

    PubMed

    Lotke, Pamela S

    2015-12-01

    Unintended pregnancy remains high in the United States, accounting for one-half of pregnancies. Both contraceptive nonuse and imperfect use contribute to unplanned pregnancies. Long-acting reversible contraception (LARC) have greater efficacy than shorter acting methods. Data from large studies show that unplanned pregnancy rates are lower among women using LARC. However, overall use of LARC is low; of the reproductive age women using contraception, less than 10% are LARC users. Barriers include lack of knowledge and high up-front cost, and prevent more widespread use. Overcoming these barriers and increasing the number of women using LARC will decrease unplanned pregnancies and abortions. PMID:26598299

  7. Prevention of unintended pregnancy: a focus on long-acting reversible contraception.

    PubMed

    Pickle, Sarah; Wu, Justine; Burbank-Schmitt, Edith

    2014-06-01

    This article summarizes the literature regarding the epidemiology and prevention of unintended pregnancy in the United States. Because of the Affordable Care Act and its accompanying contraceptive provision, there is a need for more primary care clinicians to provide family planning services. Office-based interventions to incorporate family planning services in primary care are presented, including clinical tools and electronic health record use. Special attention is paid to long-acting reversible contraceptive methods (the subdermal implant and intrauterine devices); these highly effective and safe methods have the greatest potential to decrease the rate of unintended pregnancy, but have been underused. PMID:24830607

  8. [Guidelines on long-acting injectable atypical antipsychotics for first-episode schizophrenia].

    PubMed

    Azorin, J-M

    2013-09-01

    The current review raises the question of the place of long-acting injectable (LAI) atypical antipsychotics for the treatment of first-episode schizophrenia in current and future guidelines. After exposing the different points of view adopted in the former, the author presents the clinical trials conducted with LAI atypicals in this indication, as well as the surveys related to psychiatrists'opinion regarding the use of these drugs in early schizophrenia. Pros and cons of this therapeutic option are discussed and suggestions are made for further guidelines. PMID:24084422

  9. Controlled release of vascular endothelial growth factor using poly-lactic-co-glycolic acid microspheres: In vitro characterization and application in polycaprolactone fumarate nerve conduits

    PubMed Central

    Rui, Jing; Dadsetan, Mahrokh; Runge, M. Brett; Spinner, Robert J.; Yaszemski, Michael J.; Windebank, Anthony J.; Wang, Huan

    2014-01-01

    Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulator. Controlled release of such stimulators may enhance and guide the vascularization process, and when applied in a nerve conduit may play a role in nerve regeneration. We report the fabrication and in vitro characterization of VEGF encapsulating poly-lactic-co-glycolic acid (PLGA) microspheres and the in vivo application of nerve conduits supplemented with VEGF-containing microspheres. PLGA microspheres containing VEGF were prepared by the double emulsion-solvent evaporation technique. This yielded 83.16% of the microspheres with a diameter < 53 µm. VEGF content measured by ELISA indicated 93.79 ±10.64% encapsulation efficiency. Release kinetics were characterized by an initial burst release of 67.6±8.25% within the first 24 hours, followed by consistent release of approximately 0.34% per day for 4 weeks. Bioactivity of the released VEGF was tested by human umbilical vein endothelial cell (HUVEC) proliferation assay. VEGF released at all time points enhanced HUVEC proliferation confirming that VEGF retained its bioactivity through the 4-week time period. When the microsphere delivery system was placed in a biosynthetic nerve scaffold, robust nerve regeneration was observed. This study established a novel system for controlled release of growth factors and enables in vivo studies of nerve conduits conditioned with this system. PMID:22019759

  10. Cost and carbon burden of long-acting injections: a sustainable evaluation.

    PubMed

    Maughan, Daniel L; Lillywhite, Rob; Cooke, Matthew

    2016-06-01

    Aims and method This study explores the economic cost and carbon footprint associated with current patterns of prescribing long-term flupentixol decanoate long-acting injections. We conducted an analysis of prescription data from a mental health trust followed by economic and carbon cost projections using local and national data. Results A reduction of £300 000 could be achieved across England by improving prescribing behaviour, which equates to £250 per patient per year and 170 000 kg CO2e. These savings are unlikely to be released as cash from the service, but will lead to higher-value service provision at the same or lower cost. Most of these carbon emissions are attributable to the carbon footprint of the appointment - 88 000 kg CO2e (including energy use and materials used) and the overprescribing of medication - 66 000 kg CO2e. Clinical implications Psychiatrists need to review their prescribing practice of long-acting injections to reduce their impact on the National Health Service financial budget and the environment. PMID:27280033

  11. Cost and carbon burden of long-acting injections: a sustainable evaluation

    PubMed Central

    Maughan, Daniel L.; Lillywhite, Rob; Cooke, Matthew

    2016-01-01

    Aims and method This study explores the economic cost and carbon footprint associated with current patterns of prescribing long-term flupentixol decanoate long-acting injections. We conducted an analysis of prescription data from a mental health trust followed by economic and carbon cost projections using local and national data. Results A reduction of £300 000 could be achieved across England by improving prescribing behaviour, which equates to £250 per patient per year and 170 000 kg CO2e. These savings are unlikely to be released as cash from the service, but will lead to higher-value service provision at the same or lower cost. Most of these carbon emissions are attributable to the carbon footprint of the appointment – 88 000 kg CO2e (including energy use and materials used) and the overprescribing of medication – 66 000 kg CO2e. Clinical implications Psychiatrists need to review their prescribing practice of long-acting injections to reduce their impact on the National Health Service financial budget and the environment. PMID:27280033

  12. The Contraceptive CHOICE Project: Reducing Barriers to Long-Acting Reversible Contraception

    PubMed Central

    Secura, Gina M.; Allsworth, Jenifer E.; Madden, Tessa; Mullersman, Jennifer L.; Peipert, Jeffrey F.

    2010-01-01

    OBJECTIVE To introduce and promote the use of long-acting reversible methods of contraception (LARC; intrauterine contraceptives and subdermal implant) by removing financial and knowledge barriers. STUDY DESIGN The Contraceptive CHOICE Project is a prospective cohort study of 10,000 women 14-45 years who want to avoid pregnancy for at least one year and are initiating a new form of reversible contraception. Women screened for this study are read a script regarding LARC to increase awareness of these options. Participants choose their contraceptive method that is provided at no cost. We report the contraceptive choice and baseline characteristics of the first 2,500 women enrolled August 2007 through December 2008. RESULTS Sixty-seven percent of women enrolled (95% confidence interval: 65.3, 69.0) chose long-acting methods. Fifty-six percent selected intrauterine contraception and 11% selected the subdermal implant. CONCLUSION Once financial barriers were removed and LARC methods were introduced to all potential participants as a first-line contraceptive option, two-thirds chose LARC. PMID:20541171

  13. Acceptance of long-acting reversible contraceptive methods by adolescent participants in the Contraceptive CHOICE Project

    PubMed Central

    Mestad, Renee; Secura, Gina; Allsworth, Jenifer E; Madden, Tessa; Zhao, Qiuhong; Peipert, Jeffrey F

    2012-01-01

    Background Adolescent women have a high risk of unintended pregnancy. Currently, there are little data about their choice to initiate long-acting reversible contraception (LARC). Study Design We evaluated the association of age and preference for a LARC vs. a non-LARC method among adolescent participants in the Contraceptive CHOICE Project, comparing those aged 14–17 years to adolescents aged 18–20 years. We then analyzed the association between age and choice of the implant vs. the intrauterine device (IUD) among adolescents. Results Of the 5086 women enrolled, 70% (n=3557) of participants chose a LARC method. Among adolescents aged 14–20 years, 69% of 14–17-year-olds chose LARC, while 61% of 18–20-year-olds chose LARC (relative risk 1.16, 95% confidence interval 1.03–1.30). Among adolescents choosing a LARC method, 63% (n=93/148) of the 14–17-year-olds chose the implant, whereas 71% (n=364/510) of the 18–20-year-olds chose the IUD. Conclusion Long-acting reversible contraception use is clearly acceptable and common among adolescents enrolled in the Contraceptive CHOICE Project, with the younger group being most interested in the implant. PMID:22018123

  14. Risperidone long-acting injection: a review of its long term safety and efficacy

    PubMed Central

    Rainer, Michael K

    2008-01-01

    A long-acting form of the second-generation antipsychotic drug risperidone is now broadly available for the treatment of schizophrenia and closely related psychiatric conditions. It combines the advantage of previously available depot formulations for first-generation drugs with the favorable characteristics of the modern “atypical” antipsychotics, namely higher efficacy in the treatment of the negative symptoms of schizophrenia and reduced motor disturbances. Published clinical studies show an objective clinical efficacy (as per psychiatric symptom scores and relapse data) that exceeds that of oral atypical antipsychotics when patients are switched to the long-acting injectable form, a low incidence of treatment-emergent extrapyramidal side effects, and very good acceptance by patients. Available data for maintenance treatment of bipolar disorder show equivalence with the oral form instead of superiority, but are still limited. As it seems likely that efficacy benefits are mostly due to the fact that the injectable form reduces the demand for patient compliance to one physician visit every 2 weeks instead of self-administration on a daily or twice-daily basis, additional potential could exist in other psychiatric disorders where atypical antipsychotic drugs are of benefit but where patient adherence to treatment schedules is typically low. PMID:19183782

  15. Long-acting medications for the hyperkinetic disorders. A note on cost-effectiveness.

    PubMed

    Schlander, Michael

    2007-10-01

    New long-acting medications for attention-deficit/ hyperactivity disorder (ADHD) have become available, which combine certain advantages over conventional short-acting drugs with higher acquisition costs. Choices between these drugs should thus be driven by their clinical profiles and by an acceptable balance of increased costs and additional benefits. Accordingly, the notion of relative cost-effectiveness should be central to recommendations about the use of these drugs in practice. A recent technology assessment on behalf of the National Institute for Health and Clinical Excellence (NICE) did not identify differences between compounds in terms of clinical efficacy and described drug cost as the major driver of cost-effectiveness. The underlying economic model was restricted to a cost-utility analysis that used only a fraction of the available clinical evidence base and did not address the distinction between efficacy and effectiveness. Cost-effectiveness evaluations including the potential impact of improved treatment compliance indicate a relatively more attractive cost-effectiveness of long-acting medications than suggested by the NICE assessment. These evaluations provide health economic support to treatment recommendations recently published by the European Network for Hyperkinetic Disorders. Limitations of currently available economic evaluations include their short time horizon, and future research should assess treatment effects on long-term sequelae associated with ADHD. PMID:17401606

  16. Adjunctive and Long-Acting Nanoformulated Antiretroviral Therapies for HIV-associated neurocognitive disorders

    PubMed Central

    Gendelman, Howard E.; Gelbard, Harris A.

    2014-01-01

    Purpose of review This review focuses on current and future strategies to modulate neuroinflammation while reducing residual viral burden in the central nervous system (CNS). This has been realized by targeted long acting antiretroviral nano- and adjunctive therapies being developed for HIV infected people. Our ultimate goal is to eliminate virus from its CNS reservoirs and, in so doing, reverse the cognitive and motor dysfunctions seen in HIV-associated neurocognitive disorders (HAND). Recent findings Herein, we highlight our laboratories development of adjunctive and nanomedicine therapies for HAND. An emphasis is placed on drug-drug interactions that target both the viral life cycle and secretory pro-inflammatory neurotoxic factors and signaling pathways. Summary Antiretroviral therapy (ART) has improved the quality and duration of life for people living with HIV-1. A significant long-term comorbid illness is HAND. Symptoms, while reduced in severity, are common. Disease occurs, in part, through continued low-level viral replication inducing secondary glial neuroinflammatory activities. Our recent works and those of others have seen disease attenuated in animal models through the use of adjunctive and long-acting reservoir targeted nanoformulated ART. The translation of these inventions from animals to humans is the focus of this review. PMID:25226025

  17. Effectiveness of long-acting risperidone in a patient with comorbid intellectual disability, catatonic schizophrenia, and oneiroid syndrome.

    PubMed

    Serata, Daniele; Rapinesi, Chiara; Kotzalidis, Georgios Demetrios; Alessi, Maria Chiara; Janiri, Delfina; Massolo, Anna Claudia; Ferri, Vittoria Rachele; Criscuolo, Silvia; Callovini, Gemma; Angeletti, Gloria; Girardi, Paolo; Del Casale, Antonio

    2015-01-01

    A patient with comorbid intellectual disability, catatonic schizophrenia, and recurrent oneiroid state of consciousness improved on long-acting risperidone and remains well at the three-year follow-up. We report a case treated with 50 mg long-acting risperidone administered every 14 days, who has been followed-up for three years. We studied his regional cerebral blood flow through technetium-99 m hexamethylpropyleneamine oxime single-photon emission computed tomography after two years of treatment. Symptoms of catatonic schizophrenia improved after two months of treatment, followed suit by oneiroid syndrome remission. Two years later, his brain perfusion was normal. No side effect has occurred since the patient was started on long-acting risperidone. Long-acting risperidone proved to be safe and effective in treating symptoms of catatonia and oneiroid syndrome. PMID:26443711

  18. Long-term safety and tolerability of long-acting injectable risperidone in patients with schizophrenia or schizoaffective disorder.

    PubMed

    Lindenmayer, Jean-Pierre; Khan, Akbar; Eerdekens, Mariëlle; Van Hove, Ilse; Kushner, Stuart

    2007-01-15

    Subjects were patients with schizophrenia or schizoaffective disorder enrolled in extension studies (Study A and Study B) after participating in 12-week studies of long-acting injectable risperidone [Kane, J.M., Eerdekens, M., Lindenmayer, J.-P., Keith, S.J., Lesem, M., Karcher, K., 2003. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am. J. Psychiatry 160, 1125-1132; Lindenmayer, J.-P., Eerdekens, L., Berry, S., Eerdekens, M., 2004. Safety and efficacy of long-acting risperidone in schizophrenia: a 12-week, multicenter, open-label study in stable patients switched from typical and atypical oral antipsychotics. J. Clin. Psychiatry 65, 1084-1089]. Twelve months of treatment were completed by 55% of Study A patients and 52% of Study B patients. The median modal dose of long-acting injectable risperidone was 50 mg/14 days in both studies. Most frequent adverse events were psychosis, headache, insomnia, agitation, and rhinitis. EPS-related adverse events were reported in 33% of patients in Study A and 22% in Study B. Patients with Clinical Global Impressions ratings of "not ill" and "mild" increased from 14% at baseline to 54% at endpoint in Study A and from 42% to 65% in Study B. It is concluded that treatment with long-acting injectable risperidone for 1 year or longer appeared to be safe and well tolerated in patients with schizophrenia or schizoaffective disorder. PMID:17049818

  19. Method for preparing hollow metal oxide microsphere

    DOEpatents

    Schmitt, C.R.

    1974-02-12

    Hollow refractory metal oxide microspheres are prepared by impregnating resinous microspheres with a metallic compound, drying the impregnated microspheres, heating the microspheres slowly to carbonize the resin, and igniting the microspheres to remove the carbon and to produce the metal oxide. Zirconium oxide is given as an example. (Official Gazette)

  20. Comparative Effectiveness of Risperidone Long-Acting Injectable vs First-Generation Antipsychotic Long-Acting Injectables in Schizophrenia: Results From a Nationwide, Retrospective Inception Cohort Study

    PubMed Central

    Nielsen, Jimmi; Jensen, Signe O. W.; Friis, Rasmus B.; Valentin, Jan B.; Correll, Christoph U.

    2015-01-01

    Objective: To compare in a generalizable sample/setting objective outcomes in patients receiving first-generation antipsychotic long-acting injectables (FGA-LAIs) or risperidone-LAI (RIS-LAI). Methods: Nationwide, retrospective inception cohort study of adults with International Classification of Diseases-10 schizophrenia using Danish registers from 1995 to 2009 comparing outcomes between clinician’s/patient’s choice treatment with FGA-LAIs or RIS-LAI. Primary outcome was time to psychiatric hospitalization using Cox-regression adjusting for relevant covariates. Secondary outcomes included time to all-cause discontinuation and psychiatric hospitalization in patients without LAI possession gap >28 days, and number of bed-days after psychiatric hospitalization. Results: Among 4532 patients followed for 2700 patient-years, 2078 received RIS-LAI and 2454 received FGA-LAIs (zuclopenthixol decanoate = 52.2%, perphenazine decanoate = 37.2%, haloperidol decanoate = 5.0%, flupenthixol decanoate = 4.4%, fluphenazine decanoate = 1.3%). RIS-LAI was similar to FGA-LAIs regarding time to hospitalization (RIS-LAI = 246.2±323.7 days vs FGA-LAIs = 276.6±383.3 days; HR = 0.95, 95% confidence interval (CI) = 0.87–1.03, P = 0.199) and time to all-cause discontinuation (RIS-LAI = 245.8±324.0 days vs FGA-LAIs = 287.0±390.9 days; HR = 0.93, 95% CI = 0.86–1.02, P = 0.116). Similarly, in patients without LAI discontinuation, RIS-LAI and FGA-LAIs did not differ regarding time to hospitalization (RIS-LAI = 175.0±268.1 days vs FGA-LAIs = 210.7±325.3 days; HR = 0.95, 95% CI = 0.86–1.04, P = 0.254). Finally, duration of hospitalization was also similar (incidence rate ratio = 0.97, 95% CI = 0.78–1.19, P = 0.744). Results were unchanged when analyzing only patients treated after introduction of RIS-LAI. Conclusions: In this nationwide cohort study, RIS-LAI was not superior to FGA-LAIs regarding time to psychiatric hospitalization, all-cause discontinuation, and duration of

  1. Safety of long acting muscarinic antagonists: are all these drugs always and equally safe?

    PubMed

    Melani, Andrea S; Sestini, Piersante

    2016-05-01

    Inhaled bronchodilators - such as long-acting muscarinic receptor antagonists (LAMAs) - are central to the pharmacological management of symptomatic chronic obstructive pulmonary disease. LAMAs are considered to be safe drugs at recommended dosages. In the present issue of the Journal safety of umeclidinium, a recently marketed LAMA, at twice the recommended dosage, has been evaluated with good results in a Japanese, COPD population. However, because muscarinic receptors are expressed not only in the lungs but also at the level of heart, digestive and urinary apparatus, the potential exists for LAMAs to cause adverse events related to stimulation of receptors in these organs. Head-to-head and post-marketing vigilance studies are required to determine the profile risk of these drugs, ultimately, and whether differences exist between currently available LAMAs. PMID:26789695

  2. Committee Opinion No. 670 Summary: Immediate Postpartum Long-Acting Reversible Contraception.

    PubMed

    2016-08-01

    Immediate postpartum long-acting reversible contraception (LARC) has the potential to reduce unintended and short-interval pregnancy. Women should be counseled about all forms of postpartum contraception in a context that allows informed decision making. Immediate postpartum LARC should be offered as an effective option for postpartum contraception; there are few contraindications to postpartum intrauterine devices and implants. Obstetrician-gynecologists and other obstetric care providers should discuss LARC during the antepartum period and counsel all pregnant women about options for immediate postpartum initiation. Education and institutional protocols are needed to raise clinician awareness and to improve access to immediate postpartum LARC insertion. Obstetrician-gynecologists and other obstetric care providers should incorporate immediate postpartum LARC into their practices, counsel women appropriately about advantages and risks, and advocate for institutional and payment policy changes to support provision. PMID:27454730

  3. Committee Opinion No. 670: Immediate Postpartum Long-Acting Reversible Contraception.

    PubMed

    2016-08-01

    Immediate postpartum long-acting reversible contraception (LARC) has the potential to reduce unintended and short-interval pregnancy. Women should be counseled about all forms of postpartum contraception in a context that allows informed decision making. Immediate postpartum LARC should be offered as an effective option for postpartum contraception; there are few contraindications to postpartum intrauterine devices and implants. Obstetrician-gynecologists and other obstetric care providers should discuss LARC during the antepartum period and counsel all pregnant women about options for immediate postpartum initiation. Education and institutional protocols are needed to raise clinician awareness and to improve access to immediate postpartum LARC insertion. Obstetrician-gynecologists and other obstetric care providers should incorporate immediate postpartum LARC into their practices, counsel women appropriately about advantages and risks, and advocate for institutional and payment policy changes to support provision. PMID:27454734

  4. Long-Acting Muscarinic Antagonists for Difficult-to-Treat Asthma: Emerging Evidence and Future Directions.

    PubMed

    Bulkhi, Adeeb; Tabatabaian, Farnaz; Casale, Thomas B

    2016-07-01

    Asthma is a complex disease where many patients remain symptomatic despite guideline-directed therapy. This suggests an unmet need for alternative treatment approaches. Understanding the physiological role of muscarinic receptors and the parasympathetic nervous system in the respiratory tract will provide a foundation of alternative therapeutics in asthma. Currently, several long-acting muscarinic antagonists (LAMAs) are on the market for the treatment of respiratory diseases. Many studies have shown the effectiveness of tiotropium, a LAMA, as add-on therapy in uncontrolled asthma. These studies led to FDA approval for tiotropium use in asthma. In this review, we discuss how the neurotransmitter acetylcholine itself contributes to inflammation, bronchoconstriction, and remodeling in asthma. We further describe the current clinical studies evaluating LAMAs in adult and adolescent patients with asthma, providing a comprehensive review of the current known physiological benefits of LAMAs in respiratory disease. PMID:27289376

  5. Shared Decision Aids: Increasing Patient Acceptance of Long-Acting Reversible Contraception

    PubMed Central

    George, Tracy P.; DeCristofaro, Claire; Dumas, Bonnie P.; Murphy, Pamela F.

    2015-01-01

    Unintended pregnancies are an important public health issue. Long-acting reversible contraceptive methods (LARCs) are reliable, safe, highly effective methods for most women; however they are underutilized in the United States. Shared decision aids were added to usual care in five public health family planning clinics in the Southeastern United States, staffed by advance practice nurses and registered nurses. All five sites showed an increase in the use of LARCs during the time period that shared decision aids were used (results statistically significant to p < 0.001). It is important for women to make informed choices about contraception, and shared decision aids can be utilized to support this decision making. This resource has been adopted for statewide use in all public health clinics, and implications for practice suggest that the use of shared decision aids is an effective method to support informed patient decision making and acceptance of LARC methods of contraception. PMID:27417757

  6. Reversible Contraception Update: The Importance of Long-Acting Reversible Contraception

    PubMed Central

    Mestad, Renee E.; Kenerson, Jessica; Peipert, Jeffrey F.

    2011-01-01

    The past several years have seen an expansion in contraception options. Emerging data support the use of long-acting reversible contraception (LARC) such as the intrauterine device and subdermal implant as the most effective methods of contraception with the highest continuation rates and very high levels of patient satisfaction. In addition, the appropriate target population for the use of the intrauterine device now includes nulliparous women and adolescents. When a patient considers initiating a new contraceptive method, it is important to consider the characteristics of each method, including the side effects, effectiveness, and patient acceptability. Additionally, medical comorbidities must also be evaluated prior to choosing a method. In this article, we provide a brief overview of available reversible contraceptive methods, with an emphasis on LARC. PMID:19641264

  7. [Long-acting injectable antipsychotics. Overview and advice for daily routine care].

    PubMed

    Köhler, S; Heinz, A; Sterzer, P

    2014-09-01

    Recent investigations have demonstrated a significant reduction of relapse and hospitalization rates associated with the use of long-acting injectable antipsychotics (LAIs) in the treatment of schizophrenia. There are only marginal differences in the effectiveness of different specific LAIs. Furthermore, LAIs are comparable to the oral equivalents with respect to effectiveness and side effects. The occurrence of extrapyramidal motor disorders (EPD) is less frequent in second generation (SG) LAIs than in first generation (FG) LAIs. Moreover, specific characteristics of some substances should be considered: In SG-LAIs immediate onset of action is only applicable for olanzapine and paliperidone and FG-LAIs should always be given as a test dose first to assure a general tolerance. All LAIs have a high variability of plasma levels which complicates the dose titration. Last but not least, current research concerning long-term consequences of continuous treatment with antipsychotics and the potentially poorer response to antipsychotics should be considered. PMID:24113854

  8. Standard and long-acting depot neuroleptics in chronic schizophrenics: an 18-month open multicentric study.

    PubMed

    Simon, P; Fermanian, J; Ginestet, D; Goujet, M A; Péron-Magnan, P

    1978-07-01

    The overall objective of this 18-month open study was to compare standard neuroleptics and long-acting depot neuroleptics following the current psychiatric practice in order to determine the best therapy. Thirty French psychiatrists from 15 different wards participated in this experiment. One hundred eighty-one chronic schizophrenic patients were randomly assigned to receive one of the following three treatments: standard neuroleptics, pipotiazine palmitate, or fluphenazine decanoate. Criteria used for evaluation were an overall clinical evaluation by a psychiatrist, a Brief Psychiatric Rating Scale, and a Nurse's Observation Scale for Inpatient Evaluation. No significant difference (P greater than .05) was observed between the three groups in drug effectiveness or tolerance. PMID:28102

  9. Plasma corticosteroid levels in rats maintained on a long-acting naltrexone delivery system.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1978-04-01

    A long-acting delivery system for naltrexone has been described, which blocked the antinociceptive action of 10 mg kg-1 s.c. dose of morphine in rats for a period of 2 to 3 months. Male Wistar rats implanted s.c. with such a delivery system showed highly significant depression of plasma corticosteroid levels (40.2% in one week and 22.4 to 27.2% in 3 months) as compared to placebo pellet-implanted animals. Morphine-dependent male rats implanted with 75 mg morphine pellets showed a small (17.5%) but significant increase in plasma corticosteroid levels as compared to the placebo controls 72 hr. after pellet implantation. PMID:663407

  10. Long-Acting Integrase Inhibitor Protects Macaques from Intrarectal Simian/Human Immunodeficiency Virus

    PubMed Central

    Andrews, Chasity D.; Spreen, William R.; Mohri, Hiroshi; Moss, Lee; Ford, Susan; Gettie, Agegnehu; Russell-Lodrigue, Kasi; Bohm, Rudolf P.; Cheng-Mayer, Cecilia; Hong, Zhi; Markowitz, Martin; Ho, David D.

    2015-01-01

    GSK1265744 (GSK744) is an integrase strand-transfer inhibitor that has been formulated as a long-acting (LA) injectable suitable for monthly to quarterly clinical administration. GSK744 LA was administered at two time points 4 weeks apart beginning 1 week before virus administration, and macaques were challenged weekly for 8 weeks. GSK744 LA, at plasma concentrations achievable with quarterly injections in humans, protected all animals against repeated low-dose challenges. In a second experiment, macaques were given GSK744 LA 1 week before virus administration and challenged repeatedly until infection occurred. Protection decreased over time and correlated with the plasma drug levels. With a quarterly dosing schedule in humans, our results suggest that GSK744 LA could potentially decrease adherence problems associated with daily preexposure prophylaxis (PrEP). PMID:24594934

  11. Affective and Neuroendocrine Effects of Withdrawal from Chronic, Long-Acting Opiate Administration

    PubMed Central

    Hamilton, Kathryn L.; Harris, Andrew C.; Gewirtz, Jonathan C.

    2013-01-01

    Although the long-acting opiate methadone is commonly used to treat drug addiction, relatively little is known about effects of withdrawal from this drug in preclinical models. The current study examined affective, neuroendocrine, and somatic signs of withdrawal from the longer-acting methadone derivative l-alpha-acetylmethydol (LAAM) in rats. Anxiety-like behavior during both spontaneous and antagonist-precipitated withdrawal was measured by potentiation of the startle reflex. Withdrawal elevated corticosterone and somatic signs and blunted circadian variations in baseline startle responding. In addition, fear to an explicit, Pavlovian conditioned stimulus (fear-potentiated startle) was enhanced. These data suggest that anxiety-like behavior as measured using potentiated startle responding does not emerge spontaneously during withdrawal from chronic opiate exposure – in contrast to withdrawal from acute drug exposure – but rather is manifested as exaggerated fear in response to explicit threat cues. PMID:24076207

  12. Surface characteristics of PLA and PLGA films

    NASA Astrophysics Data System (ADS)

    Paragkumar N, Thanki; Edith, Dellacherie; Six, Jean-Luc

    2006-12-01

    Surface segregation and restructuring in polylactides (poly( D, L-lactide) and poly( L-lactide)) and poly( D,L-lactide-co-glycolide) (PLGA) films of various thicknesses were investigated using both attenuated total reflection FTIR (ATR-FTIR) and contact angle relaxation measurements. In case of poly( D,L-lactide) (DLPLA), it was observed that the surface segregation and the surface restructuring of methyl side groups are influenced by the polymer film thickness. This result has been confirmed by X-ray photoelectron spectroscopy (XPS). In the same way, PLGA thick films were also characterized by an extensive surface segregation of methyl side groups. Finally, surface restructuring was investigated by dynamic contact angle measurements and it was observed when film surface comes into contact with water. In parallel, we also found that poly( L-lactide) (PLLA) thin and clear films with thickness ˜15 μm undergo conformational changes on the surface upon solvent treatment with certain solvents. The solvent treated surface of PLLA becomes hazy and milky white and its hydrophobicity increases compared to untreated surface. FTIR spectroscopic analysis indicated that polymer chains at the surface undergo certain conformational changes upon solvent treatment. These changes are identified as the restricted motions of C-O-C segments and more intense and specific vibrations of methyl side groups. During solvent treatment, the change in water contact angle and FTIR spectrum of PLLA is well correlated.

  13. The long-acting β2-adrenoceptor agonist olodaterol attenuates pulmonary inflammation

    PubMed Central

    Wex, Eva; Kollak, Ines; Duechs, Matthias J; Naline, Emmanuel; Wollin, Lutz; Devillier, Philippe

    2015-01-01

    Background and Purpose β2-adrenoceptor agonists are widely used in the management of obstructive airway diseases. Besides their bronchodilatory effect, several studies suggest inhibitory effects on various aspects of inflammation. The aim of our study was to determine the efficacy of the long-acting β2-adrenoceptor agonist olodaterol to inhibit pulmonary inflammation and to elucidate mechanism(s) underlying its anti-inflammatory actions. Experimental Approach Olodaterol was tested in murine and guinea pig models of cigarette smoke- and LPS-induced lung inflammation. Furthermore, effects of olodaterol on the LPS-induced pro-inflammatory mediator release from human parenchymal explants, CD11b adhesion molecule expression on human granulocytes TNF-α release from human whole blood and on the IL-8-induced migration of human peripheral blood neutrophils were investigated. Key Results Olodaterol dose-dependently attenuated cell influx and pro-inflammatory mediator release in murine and guinea pig models of pulmonary inflammation. These anti-inflammatory effects were observed at doses relevant to their bronchodilatory efficacy. Mechanistically, olodaterol attenuated pro-inflammatory mediator release from human parenchymal explants and whole blood and reduced expression of CD11b adhesion molecules on granulocytes, but without direct effects on IL-8-induced neutrophil transwell migration. Conclusions and Implications This is the first evidence for the anti-inflammatory efficacy of a β2-adrenoceptor agonist in models of lung inflammation induced by cigarette smoke. The long-acting β2-adrenoceptor agonist olodaterol attenuated pulmonary inflammation through mechanisms that are separate from direct inhibition of bronchoconstriction. Furthermore, the in vivo data suggest that the anti-inflammatory properties of olodaterol are maintained after repeated dosing for 4 days. PMID:25824824

  14. Second-generation long-acting injectable antipsychotics in schizophrenia: patient functioning and quality of life

    PubMed Central

    Montemagni, Cristiana; Frieri, Tiziana; Rocca, Paola

    2016-01-01

    Long-acting injectable antipsychotics (LAIs) were developed to make treatment easier, improve adherence, and/or signal the clinician when nonadherence occurs. Second-generation antipsychotic LAIs (SGA-LAIs) combine the advantages of SGA with a long-acting formulation. The purpose of this review is to evaluate the available literature concerning the impact of SGA-LAIs on patient functioning and quality of life (QOL). Although several studies regarding schizophrenia patients’ functioning and QOL have been performed, the quantity of available data still varies greatly depending on the SGA-LAI under investigation. After reviewing the literature, it seems that SGA-LAIs are effective in ameliorating patient functioning and/or QOL of patients with schizophrenia, as compared with placebo. However, while methodological design controversy exists regarding the superiority of risperidone LAI versus oral antipsychotics, the significant amount of evidence in recently published research demonstrates the beneficial influence of risperidone LAI on patient functioning and QOL in stable patients and no benefit over oral treatment in unstable patients. However, the status of the research on SGA-LAIs is lacking in several aspects that may help physicians in choosing the correct drug therapy. Meaningful differences have been observed between SGA-LAIs in the onset of their clinical efficacy and in the relationships between symptoms and functioning scores. Moreover, head-to-head studies comparing the effects of SGA-LAIs on classical measures of psychopathology and functioning are available mainly on risperidone LAI, while those comparing olanzapine LAI with other SGA-LAIs are still lacking. Lastly, some data on their use, especially in first-episode or recent-onset schizophrenia and in refractory or treatment-resistant schizophrenia, is available. PMID:27143893

  15. A critical appraisal of paliperidone long-acting injection in the treatment of schizoaffective disorder.

    PubMed

    Chue, Pierre; Chue, James

    2016-01-01

    Schizoaffective disorder (SCA) is a chronic and disabling mental illness that presents with mixed symptoms of schizophrenia and affective disorders. SCA is recognized as a discrete disorder, but with greater heterogeneity and symptom overlap, leading to difficulty and delay in diagnosis. Although the overall prognosis is intermediate between schizophrenia and mood disorders, SCA is associated with higher rates of suicide and hospitalization than schizophrenia. No treatment guidelines exist for SCA, and treatment is frequently complex, involving off-label use and polypharmacy (typically combinations of antipsychotics, mood stabilizers, and antidepressants). Oral paliperidone extended-release was the first agent to be approved for the treatment of SCA. As in schizophrenia and bipolar disorder, adherence to oral medications is poor, further contributing to suboptimal outcomes. The use of an antipsychotic in a long-acting injection (LAI) addresses adherence issues, thus potentially reducing relapse. Paliperidone palmitate represents the LAI formulation of paliperidone. In a long-term, double-blind, randomized, controlled trial of adult patients (n=334; intent-to-treat [ITT]) with SCA, paliperidone long-acting injection (PLAI) significantly delayed risk of relapse compared to placebo (hazard ratio 2.49, 95% confidence interval, 1.55-3.99; P<0.001). This study demonstrated the efficacy and safety of PLAI when used as either monotherapy or adjunctive therapy for the maintenance treatment of SCA. The results are consistent with a similarly designed study conducted in patients with schizophrenia, which suggests a benefit in the long-term control of not only psychotic but also affective symptoms. No new safety signals were observed. When used in monotherapy, PLAI simplifies treatment by reducing complex pharmacotherapy and obviating the necessity for daily oral medications. PLAI is the second agent, and the first LAI, to be approved for the treatment of SCA; as an LAI

  16. Differential pharmacology and clinical utility of long-acting bronchodilators in COPD - focus on olodaterol.

    PubMed

    Matera, Maria Gabriella; Ora, Josuel; Cazzola, Mario

    2015-01-01

    Olodaterol (BI 1744 CL) is a novel, once-daily long-acting β2-agonist (LABA) designed with the aim of improving β2-adrenoreceptor selectivity and intrinsic activity. Phase III pivotal trials have documented that olodaterol Respimat Soft Mist inhaler 5 μg induces fast onset of bronchodilation, comparable with formoterol at day 1. Moreover, significant lung function improvements have been documented up to 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Olodaterol was generally well tolerated and had an acceptable cardiovascular and respiratory adverse event profile. Regrettably, the clinical development of olodaterol is however still too partial to draw any firm conclusions on the positioning of this ultra-LABA as monotherapy in the management of COPD. Waiting for further data on the impact of olodaterol on different patient-reported outcomes, which however are widely available for indacaterol, and mainly for a head-to-head comparison between these two ultra-LABAs and between olodaterol long-acting antimuscarinic antagonists other than tiotropium, we believe it is correct to follow the clinical indications of indacaterol also for olodaterol. In any case, the parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The results from the ongoing large TOviTO Phase III trial program have documented the efficacy and safety of olodaterol/tiotropium fixed-dose combination as maintenance therapy in patients with moderate to very severe COPD. In particular, olodaterol/tiotropium fixed-dose combination provides a convincing alternative for patients remaining symptomatic with olodaterol monotherapy. PMID:26676161

  17. Differential pharmacology and clinical utility of long-acting bronchodilators in COPD – focus on olodaterol

    PubMed Central

    Matera, Maria Gabriella; Ora, Josuel; Cazzola, Mario

    2015-01-01

    Olodaterol (BI 1744 CL) is a novel, once-daily long-acting β2-agonist (LABA) designed with the aim of improving β2-adrenoreceptor selectivity and intrinsic activity. Phase III pivotal trials have documented that olodaterol Respimat Soft Mist inhaler 5 μg induces fast onset of bronchodilation, comparable with formoterol at day 1. Moreover, significant lung function improvements have been documented up to 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Olodaterol was generally well tolerated and had an acceptable cardiovascular and respiratory adverse event profile. Regrettably, the clinical development of olodaterol is however still too partial to draw any firm conclusions on the positioning of this ultra-LABA as monotherapy in the management of COPD. Waiting for further data on the impact of olodaterol on different patient-reported outcomes, which however are widely available for indacaterol, and mainly for a head-to-head comparison between these two ultra-LABAs and between olodaterol long-acting antimuscarinic antagonists other than tiotropium, we believe it is correct to follow the clinical indications of indacaterol also for olodaterol. In any case, the parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The results from the ongoing large TOviTO Phase III trial program have documented the efficacy and safety of olodaterol/tiotropium fixed-dose combination as maintenance therapy in patients with moderate to very severe COPD. In particular, olodaterol/tiotropium fixed-dose combination provides a convincing alternative for patients remaining symptomatic with olodaterol monotherapy. PMID:26676161

  18. A critical appraisal of paliperidone long-acting injection in the treatment of schizoaffective disorder

    PubMed Central

    Chue, Pierre; Chue, James

    2016-01-01

    Schizoaffective disorder (SCA) is a chronic and disabling mental illness that presents with mixed symptoms of schizophrenia and affective disorders. SCA is recognized as a discrete disorder, but with greater heterogeneity and symptom overlap, leading to difficulty and delay in diagnosis. Although the overall prognosis is intermediate between schizophrenia and mood disorders, SCA is associated with higher rates of suicide and hospitalization than schizophrenia. No treatment guidelines exist for SCA, and treatment is frequently complex, involving off-label use and polypharmacy (typically combinations of antipsychotics, mood stabilizers, and antidepressants). Oral paliperidone extended-release was the first agent to be approved for the treatment of SCA. As in schizophrenia and bipolar disorder, adherence to oral medications is poor, further contributing to suboptimal outcomes. The use of an antipsychotic in a long-acting injection (LAI) addresses adherence issues, thus potentially reducing relapse. Paliperidone palmitate represents the LAI formulation of paliperidone. In a long-term, double-blind, randomized, controlled trial of adult patients (n=334; intent-to-treat [ITT]) with SCA, paliperidone long-acting injection (PLAI) significantly delayed risk of relapse compared to placebo (hazard ratio 2.49, 95% confidence interval, 1.55–3.99; P<0.001). This study demonstrated the efficacy and safety of PLAI when used as either monotherapy or adjunctive therapy for the maintenance treatment of SCA. The results are consistent with a similarly designed study conducted in patients with schizophrenia, which suggests a benefit in the long-term control of not only psychotic but also affective symptoms. No new safety signals were observed. When used in monotherapy, PLAI simplifies treatment by reducing complex pharmacotherapy and obviating the necessity for daily oral medications. PLAI is the second agent, and the first LAI, to be approved for the treatment of SCA; as an LAI

  19. Biocompatible riboflavin laurate long-acting injectable nanosuspensions allowing sterile filtration.

    PubMed

    Hu, Xi; Lin, Xia; Gu, Yuechen; Liu, Zitong; Tang, Yilin; Zhang, Yu; Chen, Xi; Wang, Yanjiao; Tang, Xing

    2014-08-01

    The aim of this research was to prepare biocompatible riboflavin laurate (RFL) long-acting injectable nanosuspensions for intramuscular injection with a small particle size allowing sterile filtration. RFL nanosuspensions were manufactured by a precipitation-combined high-pressure homogenization method. Three kinds of mixed stabilizers-d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a primary stabilizer, and egg lecithin (PL-100M), Kollidon VA64, Kollidon S-630 as a secondary stabilizer, were separately applied to avoid further aggregation. In the three optimized formulations, the mean particle size of the RFL nanosuspensions was about 170 nm allowing sterilization by filtration. Results from transmission electron microscopy, differential scanning calorimeter, powder X-ray diffraction and Fourier transform infrared reflectance spectroscopy revealed that RFL existed as rod-like crystals. However, a few nano-spheres under 100 nm were found only when PL-100 was used as a secondary stabilizer, possibly due to TPGS and PL-100, which inserted into RFL during the process of crystallization and homogenization. In irritation testing, RFL long-acting injection (LAI) stabilized by TPGS and PL-100 led to mild paw-licking responses and a slight inflammatory reaction, which returned to normal by 14 d after administration. The endogenous PL-100 and nano-spheres with a small size may have contributed to the excellent biocompatibility. As a result, TPGS and PL-100 were selected as blended stabilizers to prepare the irritation-free RFL-LAI that could be sterilized by passage through a 0.22 μm millipore membrane filter. PMID:24188474

  20. [A history of antipsychotic long-acting injections in the treatment of schizophrenia].

    PubMed

    Crocq, M-A

    2015-02-01

    From a historical perspective, this article describes the use of antipsychotic long-acting injections (LAI) in the treatment of schizophrenia, a disorder that was defined in the final years of the 19th century. An efficient treatment for schizophrenia was discovered only in 1952 with the introduction of chlorpromazine, a phenothiazine derivative. Fairly soon, antipsychotics became available as LAI. The first compounds were fluphenazine enanthate (1966) and decanoate (1968) whose development is attributed to G.R. Daniel, a medical director at Squibb & Sons. Other first-generation antipsychotics long-acting injections (FGA-LAIs) were introduced in a rapid succession in the 1960s and 1970s. FGA-LAIs made a key contribution to the development of community psychiatry. As neuroleptics emptied psychiatric hospitals, it was important to ensure that patients could be taken care of in outpatient facilities. FGA-LAIs prevented covert non-compliance. Compliance was further reinforced by the social and psychological support of patients. The introduction of second-generation antipsychotics (SGA) led to a loss of interest in FGA-LAIs. This is evidenced by a drop in the number of papers published on this topic. The interest in LAI was revived with the introduction of the first SGA-LAI in 2003. Four different preparations have been approved in the decade between 2003 and 2013. SGA-LAIs differ from FGA-LAIs in the technology that is used to produce the depot effect, and also in the treatment objectives. The rationale for using SGA-LAIs is not only to prevent relapses due to treatment interruption, but also to achieve more constant plasma levels in order to reduce side effects due to excessive plasma levels and loss of efficacy due to insufficient plasma levels. Also, treatment objectives are no longer limited to controlling acute symptoms. Treatment objectives now include the alleviation of negative symptoms and cognitive deficits that are key prognostic factors. PMID:25598520

  1. Effects of Nano-hydroxyapatite/Poly(DL-lactic-co-glycolic acid) Microsphere-Based Composite Scaffolds on Repair of Bone Defects: Evaluating the Role of Nano-hydroxyapatite Content.

    PubMed

    He, Shu; Lin, Kai-Feng; Sun, Zhen; Song, Yue; Zhao, Yi-Nan; Wang, Zheng; Bi, Long; Liu, Jian

    2016-07-01

    The aim of the current study was to prepare microsphere-based composite scaffolds made of nano-hydroxyapatite (nHA)/poly (DL-lactic-co-glycolic acid) (PLGA) at different ratios and evaluate the effects of nHA on the characteristics of scaffolds for tissue engineering application. First, microsphere-based composite scaffolds made of two ratios of nHA/PLGA (nHA/PLGA = 20/80 and nHA/PLGA = 50/50) were prepared. Then, the effects of nHA on the wettability, mechanical strength, and degradation of scaffolds were investigated. Second, the biocompatibility and osteoinductivity were evaluated and compared by co-culture of scaffolds with bone marrow stromal stem cells (BMSCs). The results showed that the adhesion, proliferation, and osteogenic differentiation of BMSCs with nHA/PLGA (50/50) were better than those with nHA/PLGA (20/80). Finally, we implanted the scaffolds into femur bone defects in a rabbit model, then the capacity of guiding bone regeneration as well as the in vivo degradation were observed by micro-CT and histological examinations. After 4 weeks' implantation, there was no significant difference on the repair of bone defects. However, after 8 and 12 weeks' implantation, the nHA/PLGA (20/80) exhibited better bone formation than nHA/PLGA (50/50). These results suggested that a proper concentration of nHA in the nHA/PLGA composite should be taken into account when the composite scaffolds were prepared, which plays an important role in the biocompatibility, degradation rate and osteoconductivity. PMID:27378617

  2. Polyvinyl pyridine microspheres

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor); Gupta, Amitava (Inventor); Volksen, Willi (Inventor)

    1980-01-01

    Microspheres are produced by cobalt gamma radiation initiated polymerization of a dilute aqueous vinyl pyridine solution. Addition of cross-linking agent provides higher surface area beads. Addition of monomers such as hydroxyethylmethacrylate acrylamide or methacrylamide increases hydrophilic properties and surface area of the beads. High surface area catalytic supports are formed in the presence of controlled pore glass substrate.

  3. Doped zinc oxide microspheres

    DOEpatents

    Arnold, Jr., Wesley D.; Bond, Walter D.; Lauf, Robert J.

    1993-01-01

    A new composition and method of making same for a doped zinc oxide microsphere and articles made therefrom for use in an electrical surge arrestor which has increased solid content, uniform grain size and is in the form of a gel.

  4. Doped zinc oxide microspheres

    DOEpatents

    Arnold, W.D. Jr.; Bond, W.D.; Lauf, R.J.

    1993-12-14

    A new composition and method of making same for a doped zinc oxide microsphere and articles made therefrom for use in an electrical surge arrestor which has increased solid content, uniform grain size and is in the form of a gel. 4 figures.

  5. Fusion microsphere targets

    SciTech Connect

    Koo, J.C.

    1980-07-28

    It was shown that a microsphere within the structure limitations is hydrodynamically stable. To insure its perfect formation, the initial chemical compositions must have a blowing capability, more important, the resultant liquid compositions must also have sufficient surface tension and low viscosity.

  6. Microsphere insulation systems

    NASA Technical Reports Server (NTRS)

    Allen, Mark S. (Inventor); Willen, Gary S. (Inventor); Mohling, Robert A. (Inventor)

    2005-01-01

    A new insulation system is provided that contains microspheres. This insulation system can be used to provide insulated panels and clamshells, and to insulate annular spaces around objects used to transfer, store, or transport cryogens and other temperature-sensitive materials. This insulation system provides better performance with reduced maintenance than current insulation systems.

  7. Polyvinyl pyridine microspheres

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor); Gupta, Amitava (Inventor); Volksen, Willi (Inventor)

    1979-01-01

    Microspheres are produced by cobalt gamma radiation initiated polymerization of a dilute aqueous vinyl pyridine solution. Addition of cross-linking agent provides higher surface area beads. Addition of monomers such as hydroxyethylmethacrylate acrylamide or methacrylamide increases hydrophilic properties and surface area of the beads. High surface area catalytic supports are formed in the presence of controlled pore glass substrate.

  8. Cellular uptake, antioxidant and antiproliferative activity of entrapped α-tocopherol and γ-tocotrienol in poly (lactic-co-glycolic) acid (PLGA) and chitosan covered PLGA nanoparticles (PLGA-Chi).

    PubMed

    Alqahtani, Saeed; Simon, Lacey; Astete, Carlos E; Alayoubi, Alaadin; Sylvester, Paul W; Nazzal, Sami; Shen, Yixiao; Xu, Zhimin; Kaddoumi, Amal; Sabliov, Cristina M

    2015-05-01

    The aim of this study was to formulate and characterize α-tocopherol (α-T) and tocotrienol-rich fraction (TRF) entrapped in poly (lactide-co-glycolide) (PLGA) and chitosan covered PLGA (PLGA-Chi) based nanoparticles. The resultant nanoparticles were characterized and the effect of nanoparticles entrapment on the cellular uptake, antioxidant, and antiproliferative activity of α-T and TRF were tested. In vitro uptake studies in Caco2 cells showed that PLGA and PLGA-Chi nanoparticles displayed a greater enhancement in the cellular uptake of α-T and TRF when compared with the control without causing toxicity to the cells (p<0.0001). Furthermore, the cellular internalization of both PLGA and PLGA-Chi nanoparticles labeled with FITC was investigated by fluorescence microscopy; both types of nanoparticles were able to get internalized into the cells with reasonable amounts. However, PLGA-Chi nanoparticles showed significantly higher (3.5-fold) cellular uptake compared to PLGA nanoparticles. The antioxidant activity studies demonstrated that entrapment of α-T and TRF in PLGA and PLGA-Chi nanoparticles exhibited greater ability in inhibiting cholesterol oxidation at 48 h compared to the control. In vitro antiproliferative studies confirmed marked cytotoxicity of TRF on MCF-7 and MDA-MB-231 cell lines when delivered by PLGA and PLGA-Chi nanoparticles after 48 h incubation compared to control. In summary, PLGA and PLGA-Chi nanoparticles may be considered as an attractive and promising approach to enhance the bioavailability and activity of poorly water soluble compounds such as α-tocopherol and tocotrienols. PMID:25622049

  9. Combination of calcium sulfate and simvastatin-controlled release microspheres enhances bone repair in critical-sized rat calvarial bone defects

    PubMed Central

    Fu, Yin-Chih; Wang, Yan-Hsiung; Chen, Chung-Hwan; Wang, Chih-Kuang; Wang, Gwo-Jaw; Ho, Mei-Ling

    2015-01-01

    Most allogenic bone graft substitutes have only osteoconductive properties. Developing new strategies to improve the osteoinductive activity of bone graft substitutes is both critical and practical for clinical application. Previously, we developed novel simvastatin-encapsulating poly(lactic-co-glycolic acid) microspheres (SIM/PLGA) that slowly release simvastatin and enhance fracture healing. In this study, we combined SIM/PLGA with a rapidly absorbable calcium sulfate (CS) bone substitute and studied the effect on bone healing in critical-sized calvarial bone defects in a rat model. The cytotoxicity and cytocompatibility of this combination was tested in vitro using lactate dehydrogenase leakage and a cell attachment assay, respectively. Combination treatment with SIM/PLGA and the CS bone substitute had no cytotoxic effect on bone marrow stem cells. Compared with the control, cell adhesion was substantially enhanced following combination treatment with SIM/PLGA and the CS bone substitute. In vivo, implantation of the combination bone substitute promoted healing of critical-sized calvarial bone defects in rats; furthermore, production of bone morphogenetic protein-2 and neovascularization were enhanced in the area of the defect. In summary, the combination of SIM/PLGA and a CS bone substitute has osteoconductive and osteoinductive properties, indicating that it could be used for regeneration of bone in the clinical setting. PMID:26664114

  10. Electrospinning Growth Factor Releasing Microspheres into Fibrous Scaffolds

    PubMed Central

    Whitehead, Tonya J.; Sundararaghavan, Harini G.

    2014-01-01

    This procedure describes a method to fabricate a multifaceted substrate to direct nerve cell growth. This system incorporates mechanical, topographical, adhesive and chemical signals. Mechanical properties are controlled by the type of material used to fabricate the electrospun fibers. In this protocol we use 30% methacrylated Hyaluronic Acid (HA), which has a tensile modulus of ~500 Pa, to produce a soft fibrous scaffold. Electrospinning on to a rotating mandrel produces aligned fibers to create a topographical cue. Adhesion is achieved by coating the scaffold with fibronectin. The primary challenge addressed herein is providing a chemical signal throughout the depth of the scaffold for extended periods. This procedure describes fabricating poly(lactic-co-glycolic acid) (PLGA) microspheres that contain Nerve Growth Factor (NGF) and directly impregnating the scaffold with these microspheres during the electrospinning process. Due to the harsh production environment, including high sheer forces and electrical charges, protein viability is measured after production. The system provides protein release for over 60 days and has been shown to promote primary nerve cell growth. PMID:25178038

  11. Porous microsphere and its applications

    PubMed Central

    Cai, Yunpeng; Chen, Yinghui; Hong, Xiaoyun; Liu, Zhenguo; Yuan, Weien

    2013-01-01

    Porous microspheres have drawn great attention in the last two decades for their potential applications in many fields, such as carriers for drugs, absorption and desorption of substances, pulmonary drug delivery, and tissue regeneration. The application of porous microspheres has become a feasible way to address existing problems. In this essay, we give a brief introduction of the porous microsphere, its characteristics, preparation methods, applications, and a brief summary of existing problems and research tendencies. PMID:23515359

  12. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease

    PubMed Central

    Nannini, Luis Javier; Lasserson, Toby J; Poole, Phillippa

    2014-01-01

    Background Both inhaled steroids (ICS) and long-acting beta2-agonists (LABA) are used in the management of chronic obstructive pulmonary disease (COPD). This updated review compared compound LABA plus ICS therapy (LABA/ICS) with the LABA component drug given alone. Objectives To assess the efficacy of ICS and LABA in a single inhaler with mono-component LABA alone in adults with COPD. Search methods We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search was November 2011. Selection criteria We included randomised, double-blind controlled trials. We included trials comparing compound ICS and LABA preparations with their component LABA preparations in people with COPD. Data collection and analysis Two authors independently assessed study risk of bias and extracted data. The primary outcomes were exacerbations, mortality and pneumonia, while secondary outcomes were health-related quality of life (measured by validated scales), lung function, withdrawals due to lack of efficacy, withdrawals due to adverse events and side-effects. Dichotomous data were analysed as random-effects model odds ratios or rate ratios with 95% confidence intervals (CIs), and continuous data as mean differences and 95% CIs. We rated the quality of evidence for exacerbations, mortality and pneumonia according to recommendations made by the GRADE working group. Main results Fourteen studies met the inclusion criteria, randomising 11,794 people with severe COPD. We looked at any LABA plus ICS inhaler (LABA/ICS) versus the same LABA component alone, and then we looked at the 10 studies which assessed fluticasone plus salmeterol (FPS) and the four studies assessing budesonide plus formoterol (BDF) separately. The studies were well-designed with low risk of bias for randomisation and blinding but they had high rates of attrition, which reduced our confidence in the results for outcomes other than mortality. Primary outcomes There was low quality

  13. “Set it and forget it”: Women’s perceptions and opinions of long-acting topical vaginal gels

    PubMed Central

    van den Berg, Jacob J.; Rosen, Rochelle K.; Bregman, Dana E.; Thompson, Lara A.; Jensen, Kathleen M.; Kiser, Patrick F.; Katz, David F.; Buckheit, Karen; Buckheit, Robert W.; Morrow, Kathleen M.

    2014-01-01

    Women’s initial understandings and anticipated acceptability of long-acting vaginal gels as potential anti-HIV microbicides was investigated by exploring the perceptibility variables associated with prototype formulations. Four focus groups with 29 women, aged 18–45, were conducted to consider gel prototypes with varied physicochemical and rheological properties. Participants responded favorably to the concept of long-acting vaginal gels as microbicides. Distinctions in understandings and stated needs regarding product dosing, characteristics, and effectiveness offer valuable insights into product design. Long-acting vaginal gels capable of protecting against HIV/STIs will be a viable option among potential users, with dosing frequency being an important factor in willingness to use. PMID:24248674

  14. Synthesis and characterization of magnetite/PLGA/chitosan nanoparticles

    NASA Astrophysics Data System (ADS)

    Ibarra, Jaime; Melendres, Julio; Almada, Mario; Burboa, María G.; Taboada, Pablo; Juárez, Josué; Valdez, Miguel A.

    2015-09-01

    In this work, we report the synthesis and characterization of a new hybrid nanoparticles system performed by magnetite nanoparticles, loaded in a PLGA matrix, and stabilized by different concentrations of chitosan. Magnetite nanoparticles were hydrophobized with oleic acid and entrapped in a PLGA matrix by the emulsion solvent evaporation method, after that, magnetite/PLGA/chitosan nanoparticles were obtained by adding dropwise magnetite/PLGA nanoparticles in chitosan solutions. Magnetite/PLGA nanoparticles produced with different molar ratios did not show significant differences in size and the 3:1 molar ratio showed best spherical shapes as well as uniform particle size. Isothermal titration calorimetry studies demonstrated that the first stage of PLGA-chitosan interaction is mostly regulated by electrostatic forces. Based on a single set of identical sites model, we obtained for the average number of binding sites a value of 3.4, which can be considered as the number of chitosan chains per nanoparticle. This value was confirmed by using a model based on the DLVO theory and fitting zeta potential measurements of magnetite/PLGA/chitosan nanoparticles. From the adjusted parameters, we found that an average number of chitosan molecules of 3.6 per nanoparticle are attached onto the surface of the PLGA matrix. Finally, we evaluated the effect of surface charge of nanoparticles on a membrane model of endothelial cells performed by a mixture of three phospholipids at the air-water interface. Different isotherms and adsorption curves show that cationic surface of charged nanoparticles strongly interact with the phospholipids mixture and these results can be the basis of future experiments to understand the nanoparticles- cell membrane interaction.

  15. Influence of storage temperature and moisture on the performance of microsphere/hydrogel composites.

    PubMed

    Wang, Yan; Burgess, Diane J

    2013-09-15

    The current study involved investigation of the effect of storage temperature and moisture on the performance of poly(lactide-co-glycolide) (PLGA) microsphere/poly(vinyl-alcohol) (PVA) hydrogel composites. Physical aging occurred in composites stored at 25°C due to structural relaxation. The glass transition temperature (Tg) and enthalpy of relaxation of the composites increased leading to a slower cumulative % release. The Tg of composites incubated at 40°C, 75% RH decreased significantly due to the plasticization effect of absorbed water, whereas no change was observed in the Tg of microspheres alone; indicating that the hydrogel component enhanced water absorption. PLGA degradation occurred leading to significantly faster dexamethasone release following incubation at 40°C, 75% RH for 1 month. No significant change was observed in the in vitro release profiles of composites after 6 months storage at 25°C, 60% RH, however, release was accelerated following 12 months storage. Accordingly, exposure of the composites to ambient temperature/moisture during storage, shipping or handling may cause physical aging, plasticization, and degradation and hence, their performance may be affected. The extent to which the performance of the composite is affected by storage temperature and moisture is a net effect of physical aging and moisture induced plasticization/hydrolytic degradation. PMID:23811131

  16. Biomimetic mucin modified PLGA nanoparticles for enhanced blood compatibility.

    PubMed

    Thasneem, Y M; Rekha, M R; Sajeesh, S; Sharma, Chandra P

    2013-11-01

    Efforts to develop long circulating polymeric nanoparticles have propelled many strategies in nanoparticle surface modification to bypass immune surveillance and systemic clearance. In this context, our present study reports on the preparation and evaluation of mucin functionalized poly lactic-co-glycolic acid (PLGA) nanoparticles as hemocompatible, cell penetrating nanoparticulate drug delivery system. Amino groups of mucin were conjugated to the terminal carboxylic acid groups on PLGA to be followed by nanoparticle synthesis via standard solvent evaporation technique. Detailed in vitro experiments were performed to illustrate the significance of alternating copolymer structured mucin modified PLGA nanoparticles in terms of enhanced hemocompatibility and cellular uptake. Mucylation proved promising in controlling PLGA nanoparticle- interaction with plasma proteins (opsonins) and blood components via hemolysis, thrombogenecity and complement activation. Besides hemocompatibility, the modified and unmodified nanoparticles were also found to be cytocompatible with L929 and C6 cell lines. The fluorescent and confocal image analysis evaluated the extent of cellular uptake of nanoparticles into C6 cells. Specifically the combination of stealth properties and cellular internalization capacity of mucin modified PLGA nanoparticle (PLGA-Mucin) lead us to propose it as a safe, efficient and multifunctional nanoplatform for disease specific intravenous drug delivery applications as far as in vitro experiments are concerned. PMID:23978287

  17. Systemic delivery to central nervous system by engineered PLGA nanoparticles.

    PubMed

    Cai, Qiang; Wang, Long; Deng, Gang; Liu, Junhui; Chen, Qianxue; Chen, Zhibiao

    2016-01-01

    Neurological disorders are an important global public health problem, but pharmaceutical treatments are limited due to drug access to the central nervous system being restricted by the blood-brain barrier (BBB). Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are one of the most promising drug and gene delivery systems for crossing the BBB. While these systems offer great promise, PLGA NPs also have some intrinsic drawbacks and require further engineering for clinical and research applications. Multiple strategies have been developed for using PLGA NPs to deliver compounds across the BBB. We classify these strategies into three categories according to the adaptations made to the PLGA NPs (1) to facilitate travel from the injection site (pre-transcytosis strategies); (2) to enhance passage across the brain endothelial cells (BBB transcytosis strategies) and (3) to achieve targeting of the impaired nervous system cells (post-transcytosis strategies). PLGA NPs modified according to these three strategies are denoted first, second, and third generation NPs, respectively. We believe that fusing these three strategies to engineer multifunctional PLGA NPs is the only way to achieve translational applications. PMID:27158367

  18. Systemic delivery to central nervous system by engineered PLGA nanoparticles

    PubMed Central

    Cai, Qiang; Wang, Long; Deng, Gang; Liu, Junhui; Chen, Qianxue; Chen, Zhibiao

    2016-01-01

    Neurological disorders are an important global public health problem, but pharmaceutical treatments are limited due to drug access to the central nervous system being restricted by the blood-brain barrier (BBB). Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are one of the most promising drug and gene delivery systems for crossing the BBB. While these systems offer great promise, PLGA NPs also have some intrinsic drawbacks and require further engineering for clinical and research applications. Multiple strategies have been developed for using PLGA NPs to deliver compounds across the BBB. We classify these strategies into three categories according to the adaptations made to the PLGA NPs (1) to facilitate travel from the injection site (pre-transcytosis strategies); (2) to enhance passage across the brain endothelial cells (BBB transcytosis strategies) and (3) to achieve targeting of the impaired nervous system cells (post-transcytosis strategies). PLGA NPs modified according to these three strategies are denoted first, second, and third generation NPs, respectively. We believe that fusing these three strategies to engineer multifunctional PLGA NPs is the only way to achieve translational applications. PMID:27158367

  19. New platform for controlled and sustained delivery of the EGF receptor tyrosine kinase inhibitor AG1478 using poly(lactic-co-glycolic acid) microspheres

    PubMed Central

    Robinson, Rebecca; Bertram, James P.; Reiter, Jill L.; Lavik, Erin B.

    2015-01-01

    Inhibition of the epidermal growth factor receptor (EGFR) has been shown to reduce tumor growth and metastases and promote axon regeneration in the central nervous system. Current strategies for inhibiting EGFR include the administration of reversible or irreversible small-molecule tyrosine kinase inhibitors (TKIs). However, to be effective in vivo constant and sustained delivery is required. This study explored the feasibility of encapsulating the tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) in poly(lactic-co-glycolic acid) (PLGA) microspheres to achieve sustained delivery of the TKI. We characterized microspheres prepared using three different emulsion methods: solid-in-oil-in-water, oil-in-water, and oil-in-water with co-solvent. Addition of a co-solvent increased the loading and release of AG1478, and significantly (P<0.001) decreased the size of the microspheres which facilitates administration of the spheres. On average, sustained delivery of AG1478 from microspheres was achieved for six months. However, the addition of a co-solvent prolonged release for over nine months (266 days). In addition, AG1478 retained its bioactivity upon delivery, and inhibited EGFR in both immortalized rat fibroblasts and in EGFR-amplified human carcinoma cells. These results demonstrate that AG1478 can be encapsulated in PLGA and retain bioactivity; thereby providing a new platform for controlled administration of EGFR TKIs. PMID:20055747

  20. The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge.

    PubMed

    Radzio, Jessica; Spreen, William; Yueh, Yun Lan; Mitchell, James; Jenkins, Leecresia; García-Lerma, J Gerardo; Heneine, Walid

    2015-01-14

    Daily preexposure prophylaxis (PrEP) with Truvada is a proven HIV prevention strategy; however, its effectiveness is limited by low adherence. Antiretroviral drug formulations that require infrequent dosing may increase adherence and thus PrEP effectiveness. We investigated whether monthly injections of a long-acting formulation of the HIV integrase inhibitor GSK1265744 (GSK744 LA) prevented simian/human immunodeficiency virus (SHIV) infection by vaginal challenge in macaques. Female pigtail macaques (n = 12) were exposed to intravaginal inoculations of SHIV twice a week for up to 11 weeks. Half of the animals received a GSK744 LA injection every 4 weeks, and half received placebo. GSK744 LA, at plasma concentrations achievable with quarterly injections in humans, protected all six macaques from infection. Placebo controls were all infected after a median of 4 (range, 2 to 20) vaginal challenges with SHIV. Efficacy was related to high and sustained vaginal and plasma drug concentrations that remained above the protein-adjusted 90% inhibitory concentration during the dosing cycles. These data support advancement of GSK744 LA as a potential PrEP candidate for women. PMID:25589631

  1. Treatment effectiveness and adherence in patients with schizophrenia treated with risperidone long-acting injection.

    PubMed

    Chang, Chen-Lin; Tzeng, Dong-Sheng; Lung, For-Wey

    2010-11-30

    This study investigated the variables related to the effectiveness and adherence to treatment with risperidone long-acting injection (RLAI) in patients with schizophrenia. We performed a retrospective medical chart review of 137 patients with schizophrenia who were prescribed RLAI between July 2004 and December 2006. Cox regression analysis showed that the effectiveness of treatment in patients treated with RLAI was affected significantly by the provision of home care and the use of illicit drugs. The adherence of patients to treatment with RLAI was affected most by the provision of home care. Bayesian analysis showed that patients who received the provision of home care or who had no history of illicit drug use continued treatment for, on average, 15.27 and 17.14days longer, respectively, than those who did not receive such care or take illicit drugs. Patients who received the provision of home care adhered to treatment for 343.98 more days than those who did not. Even though patients taking RLAI show better adherence than those taking oral risperidone, home care services can have a significant additional effect on adherence. Randomized clinical follow-up trial studies are necessary to explore the risk factors for nonadherence in more detail. PMID:20488552

  2. Plasma bioavailability of 2 long-acting oxytetracycline formulations in the pig.

    PubMed

    Archimbault, P; Navetat, H; Vidal, R; Douin, M J; Mignot, A

    1994-01-01

    Two commercially available long-acting oxytetracycline (OTC-LA) formulations were administered by intramuscular injection in 2 groups of 10 clinically healthy pigs at the recommended dose level of 20 mg/kg. Plasma concentrations were analysed by high-performance liquid chromatography (HPLC) of a period of 0 to 84 h. The limit of quantification of the assay was 0.125 microgram/ml. The comparison of the CMAX did not reveal any significant differences (4.45 +/- 1.30 and 4.40 +/- 0.9 micrograms/ml). The results were similar for the TMAX (3.60 +/- 1.58 and 4.00 +/- 2.67 h). The areas under the curve were also similar. The AUC0-84 h results were respectively 92.8 +/- 14.1 and 96.3 +/- 11.3 mg.h/l and the AUC0-infinity results were 99.5 +/- 14.7 and 106.7 +/- 15.4 mg.h/l. No significant difference was found. This may be considered as a preliminary study to demonstrate the bioequivalence of the 2 preparations. On the basis of the statistical analysis of the results obtained, a cross-over study using 2 groups of 20 animals is theoretically necessary for such a demonstration. PMID:8087147

  3. Demand for long-acting and permanent contraceptive methods among Kurdish women in Mahabad, Iran.

    PubMed

    Hosseini, Hatam; Torabi, Fatemeh; Bagi, Balal

    2014-11-01

    It is anticipated that the demand for contraceptives in Iran will increase in the near future as the number of women of reproductive age increases and with women wanting smaller families. The aim of this paper was to study the demand for long-acting and permanent contraceptive methods (LAPCMs), and its determinants, among Kurdish women in Mahabad city, Iran. Data were taken from the Mahabad Fertility Survey (MFS) conducted on a sample of over 700 households in April 2012. The results show that the demand for LAPCMs was 71.35% at the time of survey, although only 27.7% of women were using these methods. Thus, the number of unintended pregnancies is likely to increase in the future if this gap is not reduced. The multivariate analysis showed significant impacts on the dependent variables of the number of children ever born, perceived contraceptive costs and childbearing intentions. Moreover, women at the end of their reproductive lives and those with higher education were more likely to desire LAPCMs. It is concluded that despite a growing use of contraceptive methods in Iran in recent decades, the development of reproductive health services and promotion of the quality of family planning services remains a necessity. PMID:24406051

  4. Comparison of attitudes toward long-acting injectable antipsychotics among psychiatrists and patients.

    PubMed

    Kim, Sung-Wan; Lee, Yo-Han; Jang, Ji-Eun; Yoo, Taeyoung; Kim, Jae-Min; Shin, Il-Seon; Yoon, Jin-Sang

    2013-03-01

    The current prescription rate of long-acting injectable antipsychotics (LAI) is less than 1% in Korea. This study aimed to investigate the reason for LAI underuse by surveying the attitudes toward LAI among psychiatrists and patients receiving LAI. A total of 173 psychiatrists and 99 patients receiving LAI participated in the survey. Participating psychiatrists were divided into two groups according to experience with prescribing LAI to at least 10 patients. The two psychiatrist groups did not differ significantly in terms of sociodemographic characteristics and clinical practice patterns. However, the group with higher experience more frequently provided explanations of LAI to their patients and was more satisfied with the use of LAI than the group with less experience. Acceptance rates of patients to the recommendation for LAI treatment and satisfaction of psychiatrists with the outcome of LAI were also significantly higher in the group with higher experience. Psychiatrists with less experience with LAI were more negative toward LAI than patients receiving LAI as well as psychiatrists with higher experience. In conclusion, attitudes of psychiatrists toward LAI were closely related to the use of LAI. The negative attitude and reluctance of psychiatrists, rather than patient resistance, may contribute toward the underuse of LAI. PMID:23325306

  5. Thienorphine is a potent long-acting partial opioid agonist: a comparative study with buprenorphine.

    PubMed

    Yu, Gang; Yue, Yong-Juan; Cui, Meng-Xun; Gong, Ze-Hui

    2006-07-01

    A strategy in the development of new treatment for opioid addiction is to find partial opioid agonists with properties of long duration of action and high oral bioavailability. In a search for such compounds, thienorphine, a novel analog of buprenorphine, was synthesized. Here, we reported that, like buprenorphine, thienorphine bound potently and nonselectively to mu-, delta-, and kappa-opioid receptors stably expressed in CHO (Chinese hamster ovary) cells and behaved as a partial agonist at mu-opioid receptor. However, some differences were observed between the pharmacological profiles of thienorphine and buprenorphine. In vitro, thienorphine was more potent than buprenorphine in inhibiting [3H]diprenorphine and stimulating guanosine 5'-O-(3-[35S]thio)triphosphate binding to rat mu-opioid receptor stably expressed in CHO cells. In vivo, thienorphine exhibited a less potent but more efficacious antinociceptive effect with an ED50 value of 0.25 mg/kg s.c. and more potent antimorphine effect with an ED50 value of 0.64 mg/kg intragastric, compared with buprenorphine. Additionally, the bioavailability of thienorphine was greatly higher than that of buprenorphine after oral administration. Moreover, compared with buprenorphine, thienorphine showed a similar long-lasting antinociceptive effect but a much longer antagonism of morphine-induced lethality (more than 15 days). These results indicate that thienorphine is a potent, long-acting partial opioid agonist with high oral bioavailability and may have possible application in treating addiction. PMID:16569757

  6. Femoral Nerve Block Versus Long-Acting Wound Infiltration in Total Knee Arthroplasty.

    PubMed

    Emerson, Roger H; Barrington, John W; Olugbode, Oluseun; Lovald, Scott; Watson, Heather; Ong, Kevin

    2016-05-01

    Multimodal wound infiltration analgesic techniques have attracted growing interest for applications in total knee arthroplasty (TKA). A benefit of using wound infiltration instead of femoral nerve block (FNB) in a multimodal pain control regimen is the limitation of muscle strength impairment to the surgical area, which will focus the pain control effort and may provide the opportunity for easier rehabilitation and earlier discharge from the hospital. The current study directly compares patients undergoing TKA who are given a continuous FNB with those who were administered an injection of liposomal bupivacaine infiltration. The study cohort included 36 patients with osteoarthritis who were treated with a continuous FNB (OnQ pump; I-Flow, Lake Forest, California), and 36 patients who were administered an injection for liposome bupivacaine infiltration (EXPAREL; Pacira Pharmaceuticals, Inc, Parsippany, New Jersey) for postoperative pain analgesia. The average number of narcotic doses and the total number of narcotics consumed was greater in the FNB group (P<.001). Average visual analog scale pain scores trended higher for patients in the FNB group (2.29 vs 1.93) overall and for each day postoperatively up to day 5, although the overall difference was not significant in this study sample (P=.115). The results of the current study support the conclusion that long-acting liposome bupivacaine infiltration gives comparable postoperative analgesia compared with a continuous FNB, but with significantly less narcotic medication. [Orthopedics. 2016; 39(3):e449-e455.]. PMID:27018607

  7. Permanent Sterilisation to Long-Acting Reversible Contraception: Is a Paradigm Shift Necessary?

    PubMed

    Shantha Kumari, S

    2016-06-01

    The concept of family planning originated as birth control in 1912 to control the size of the family and prevent unplanned pregnancies transformed to family welfare and later on expanded its horizons to reproductive and child health (RCH). A wide spectrum of choices both for male and female, temporary and permanent, have been developed and offered. Developed world having stabilised population faces problem with teenage and adolescent pregnancies. Developing nations are still struggling to stabilise population and traditionally depend on permanent female sterilisation as a major method of contraception. Lot of unmet need is seen in young recently married women, post-delivery, post-abortal states. Long-acting reversible contraception which includes intrauterine device, IUD, and implants has re-emerged strongly as a first choice of contraception for women of all ages including unmarried teenage pregnancies. They are highly efficient with failure rates equivalent or better than permanent methods, cost-effective, reversible, and have the potential to replace permanent sterilisation. PMID:27298522

  8. Planning ahead for implementation of long acting HIV prevention: challenges and opportunities

    PubMed Central

    Meyers, Kathrine

    2015-01-01

    Purpose of Review Broad-based access, uptake, and dissemination of daily oral HIV pre-exposure prophylaxis (PrEP) have been slow, despite strong evidence for efficacy. Effective and efficient implementation of long-acting (LA) HIV prevention products will require both analysis of the dynamics and determinants of daily oral PrEP implementation and identification of the distinct challenges and opportunities inherent in emerging technologies. Recent Findings Evidence suggests the importance of addressing implementation issues at three levels: patient, provider, and system. Patient-level factors include targeted education and messaging, tailored supports to enhance acceptability and uptake, and effective strategies for promoting adherence/persistence and retention in care. Provider-level factors include engaging a broad mix of providers, while ensuring adequate training and support for patient assessment, counseling, and follow-up. Systems-level factors include optimal delivery modalities, resource allocation, and ensuring access to populations most in need of new prevention options. Summary Formative social/behavioral research must be undertaken proactively in order to prepare for and address future implementation challenges and reduce the gap between proving efficacy in clinical trials and assuring real-world effectiveness. Conceptualizing new HIV prevention technologies as behavioral interventions at the level of the patient, provider, and system will be paramount to effective and efficient implementation. PMID:26049956

  9. Contraception for Adolescents: Focusing on Long-Acting Reversible Contraceptives (LARC) to Improve Reproductive Health Outcomes

    PubMed Central

    Salcedo, Jennifer

    2015-01-01

    Adolescent pregnancy rates in the U.S. have reached an all-time low from their peak in the 1980s and 1990s. However, the U.S. maintains the highest rate of teenage pregnancy among developed nations. Adolescents experience higher typical use failure rates for user-dependent contraceptives compared to their adult counterparts. Long-acting reversible contraception (LARC), IUDs and implants, have failure rates that are both very low and independent of user age. In settings where the most effective methods are prioritized and access barriers are removed, the majority of adolescents initiate LARC. Use of LARC by adolescents significantly reduces rates of overall and repeat teen pregnancy. All methods of contraception are safe for use in teens, including IUDs and DMPA. Dual use of LARC and barrier methods to reduce risk of sexually transmitted infection, is the optimal contraceptive strategy for most adolescents. Adolescent access to evidence-based and confidential contraceptive services, provided in a manner that respects autonomy, is a vital public health goal.

  10. Pharmacokinetics and bioavailability of a long-acting formulation of cephalexin after intramuscular administration to cats.

    PubMed

    Albarellos, G A; Montoya, L; Quaine, P C; Landoni, M F

    2011-08-01

    The pharmacokinetic profile and bioavailability of a long-acting formulation of cephalexin after intramuscular administration to cats was investigated. Single intravenous (cephalexin lysine salt) and intramuscular (20% cephalexin monohydrate suspension) were administered to five cats at a dose rate of 10 mg/kg. Serum disposition curves were analyzed by noncompartmental approaches. After intravenous administration, volume of distribution (V(z)), total body clearance (Cl(t)), elimination constant (λ(z)), elimination half-life (t(½)(λ)) and mean residence time (MRT) were: 0.33±0.03 L/kg; 0.14±0.02 L/hkg, 0.42±0.05 h(-1), 1.68±0.20 h and 2.11±0.25 h, respectively. Peak serum concentration (C(max)), time to peak serum concentration (T(max)) and bioavailability after intramuscular administration were 15.67±1.95 μg/mL, 2.00±0.61 h and 83.33±8.74%, respectively. PMID:20800248

  11. Subcutaneous implants for long-acting drug therapy in laboratory animals may generate unintended drug reservoirs

    PubMed Central

    Guarnieri, Michael; Tyler, Betty M.; DeTolla, Louis; Zhao, Ming; Kobrin, Barry

    2014-01-01

    Background: Long-acting therapy in laboratory animals offers advantages over the current practice of 2-3 daily drug injections. Yet little is known about the disintegration of biodegradable drug implants in rodents. Objective: Compare bioavailability of buprenorphine with the biodegradation of lipid-encapsulated subcutaneous drug pellets. Methods: Pharmacokinetic and histopathology studies were conducted in BALB/c female mice implanted with cholesterol-buprenorphine drug pellets. Results: Drug levels are below the level of detection (0.5 ng/mL plasma) within 4-5 days of implant. However, necroscopy revealed that interstitial tissues begin to seal implants within a week. Visual inspection of the implant site revealed no evidence of inflammation or edema associated with the cholesterol-drug residue. Chemical analyses demonstrated that the residues contained 10-13% of the initial opiate dose for at least two weeks post implant. Discussion: The results demonstrate that biodegradable scaffolds can become sequestered in the subcutaneous space. Conclusion: Drug implants can retain significant and unintended reservoirs of drugs. PMID:24459402

  12. Eliminating health disparities in unintended pregnancy with long-acting reversible contraception (LARC).

    PubMed

    Parks, Caitlin; Peipert, Jeffrey F

    2016-06-01

    Significant public health disparities exist surrounding teen and unplanned pregnancy in the United States. Women of color and those with lower education and socioeconomic status are at much greater risk of unplanned pregnancy and the resulting adverse outcomes. Unplanned pregnancies reduce educational and career opportunities and may contribute to socioeconomic deprivation and widening income disparities. Long-acting reversible contraception (LARC), including intrauterine devices and implants, offer the opportunity to change the default from drifting into parenthood to planned conception. LARC methods are forgettable; once placed, they offer highly effective, long-term pregnancy prevention. Increasing evidence in the medical literature demonstrates the population benefits of use of these methods. However, barriers to more widespread use of LARC methods persist and include educational, access, and cost barriers. With increasing insurance coverage under the Affordable Care Act and more widespread, no-cost coverage of methods, more and more women are choosing intrauterine devices and the contraceptive implant. Increasing the use of highly effective contraceptive methods may provide one solution to the persistent problem of the health disparities of unplanned and teen pregnancies in the United States and improve women's and children's health. PMID:26875950

  13. Effectiveness of long-acting paliperidone palmitate in borderline personality disorder.

    PubMed

    Palomares, Nerea; Montes, Ana; Díaz-Marsá, Marina; Carrasco, José L

    2015-11-01

    The aim of the present study is to test the efficacy of palmitate paliperidone long-acting injection for patients with borderline personality disorder (BPD). A total of 16 patients with BPD were treated with intramuscular paliperidone palmitate (IMPP) over 12 weeks. Effectiveness measures included the CGI-BPD, HARS, MADRS, BIS-11, and STAXI-2. Functional improvement was assessed using the Global Assessment of Functioning scale. A list of adverse events was provided to clinicians and patients. Treatment with IMPP was associated with a significant average reduction of 1.6 (95% confidence interval: 1192-2008; P>0.01) in CGI-BPD scores and an average increase of psychosocial functioning as scored by the Global Assessment of Functioning scale of 13.3 (95% confidence interval: 8.35-18.31; P>0.01) was obtained. The treatment decreased impulsive-disruptive behaviors and improved general functioning. An acceptable tolerance was observed. The average weight gain was clinically irrelevant despite being statistically significant. No other relevant adverse side effects were reported, with the exception of galactorrhea, which required suspension of treatment in three patients. IMPP seems to be a well-tolerated alternative to other second-generation antipsychotics in the treatment of BPD. More controlled studies replicating these results should be proposed in the future. PMID:26230268

  14. Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application.

    PubMed

    Kesteleyn, Bart; Amssoms, Katie; Schepens, Wim; Hache, Geerwin; Verschueren, Wim; Van De Vreken, Wim; Rombauts, Klara; Meurs, Greet; Sterkens, Patrick; Stoops, Bart; Baert, Lieven; Austin, Nigel; Wegner, Jörg; Masungi, Chantal; Dierynck, Inge; Lundgren, Stina; Jönsson, Daniel; Parkes, Kevin; Kalayanov, Genadiy; Wallberg, Hans; Rosenquist, Asa; Samuelsson, Bertil; Van Emelen, Kristof; Thuring, Jan Willem

    2013-01-01

    The design and synthesis of novel HIV-1 protease inhibitors (PIs) (1-22), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was initiated from compound 1, a Phe-Phe hydroxyethylene peptidomimetic PI, and was directed towards the discovery of new PIs suitable for a long-acting (LA) injectable drug application. Introducing a heterocyclic 6-methoxy-3-pyridinyl or a 6-(dimethylamino)-3-pyridinyl moiety (R(3)) at the para-position of the P1' benzyl fragment generated compounds with antiviral potency in the low single digit nanomolar range. Halogenation or alkylation of the metabolic hot spots on the various aromatic rings resulted in PIs with high stability against degradation in human liver microsomes and low plasma clearance in rats. Replacing the chromanolamine moiety (R(1)) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16-22) with EC(50)s on wild-type HIV-1 in the range of 0.8-1.8 nM. PIs 18 and 22, formulated as nanosuspensions, showed gradual but sustained and complete release from the injection site over two months in rats, and were therefore identified as interesting candidates for a LA injectable drug application for treating HIV/AIDS. PMID:23177258

  15. Profile of olanzapine long-acting injection for the maintenance treatment of adult patients with schizophrenia.

    PubMed

    Di Lorenzo, Rosaria; Brogli, Alice

    2010-01-01

    Olanzapine long-acting injection (OLAI) is a crystalline salt composed of olanzapine and pamoic acid, which permits a depot intramuscular formulation of olanzapine. The half-life of olanzapine pamoate is 30 days, and its steady state is reached approximately at 12 weeks. Oral supplementation of olanzapine is not required during OLAI initiation, according to Eli Lilly recommendations, although a study indicated that ≥60% of D(2) receptor occupancy was reached only by the fifth injection cycle. To date, a short-term, placebo-controlled study of 8 weeks in acutely ill patients and a long-term, controlled trial of 24 weeks in stabilized patients have been conducted. In both the studies, efficacy and safety were similar to those of oral olanzapine, with the exception of an acute adverse effect, the so-called inadvertent intravascular injection event, which occurred 1-3 hours after the injection with an incidence rate of 0.07% per injection. It consisted of symptoms that are similar to those reported in cases of oral olanzapine overdose. The most significant studies published to date, on the use of olanzapine pamoate in schizophrenia, are reviewed in this article. The pharmacodynamic and pharmacokinetic profile and related side effects of OLAI are reported. PMID:20856920

  16. Corifollitropin alfa, a long-acting follicle-stimulating hormone agonist for the treatment of infertility.

    PubMed

    Loutradis, Dimitris; Drakakis, Petros; Vlismas, Antonis; Antsaklis, Aristidis

    2009-04-01

    Corifollitropin alfa is being developed by Schering-Plough Corp as an injectable, long-acting follicle-stimulating hormone (FSH) agonist for the treatment of infertility. A single dose of corifollitropin alfa could initiate and sustain multifollicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection. The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH. Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing. The drug was well tolerated and does not appear to be associated with any serious adverse events or the formation of antibodies. The initial results from a large, phase III, double-blind clinical trial indicated that the ongoing pregnancy rate achieved with corifollitropin alfa treatment was high and similar to the rate established with daily treatment of recombinant FSH. The number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment. Thus, corifollitropin alfa has the potential to serve as a viable fertility agent and to gain a place in the infertility market. PMID:19337959

  17. Safety of long-acting beta agonists and inhaled corticosteroids in children and adolescents with asthma

    PubMed Central

    Xia, Ying; Kelton, Christina M. L.; Xue, Liang; Bian, Boyang; Wigle, Patricia R.

    2013-01-01

    The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy for adult, as well as pediatric, patients with asthma. However, the use of LABAs has raised safety concerns, especially the potential for severe asthma exacerbations (SAEs) resulting in hospitalizations or even death. Meanwhile, the use of inhaled corticosteroids (ICSs), a cornerstone in the treatment of mild-to-severe persistent asthma, has been associated with growth suppression in children. The purpose of this review was to identify and discuss the major published safety studies surrounding LABA, ICS, and combined LABA/ICS usage in children. By way of a critical search for influential published clinical trials, meta-analyses, and observational studies, six studies relevant to the safety of LABA monotherapy, seven studies relevant to ICS monotherapy, and four studies on the subject of LABA/ICS combination usage were identified and reviewed. Based on the reviewed literature, the controversy surrounding these anti-asthma medications was clearly exposed. On the one hand, there is some evidence that LABA monotherapy may be associated with SAEs and asthma-related death, while ICS monotherapy may be associated with a higher risk of growth suppression. On the other hand, the concurrent use of a LABA with an ICS has been associated with positive outcomes including symptom reduction and reduced rate and severity of exacerbations. Further clinical research is warranted and has been called for by the US Food and Drug Administration. PMID:25114786

  18. Profile of olanzapine long-acting injection for the maintenance treatment of adult patients with schizophrenia

    PubMed Central

    Di Lorenzo, Rosaria; Brogli, Alice

    2010-01-01

    Olanzapine long-acting injection (OLAI) is a crystalline salt composed of olanzapine and pamoic acid, which permits a depot intramuscular formulation of olanzapine. The half-life of olanzapine pamoate is 30 days, and its steady state is reached approximately at 12 weeks. Oral supplementation of olanzapine is not required during OLAI initiation, according to Eli Lilly recommendations, although a study indicated that ≥60% of D2 receptor occupancy was reached only by the fifth injection cycle. To date, a short-term, placebo-controlled study of 8 weeks in acutely ill patients and a long-term, controlled trial of 24 weeks in stabilized patients have been conducted. In both the studies, efficacy and safety were similar to those of oral olanzapine, with the exception of an acute adverse effect, the so-called inadvertent intravascular injection event, which occurred 1–3 hours after the injection with an incidence rate of 0.07% per injection. It consisted of symptoms that are similar to those reported in cases of oral olanzapine overdose. The most significant studies published to date, on the use of olanzapine pamoate in schizophrenia, are reviewed in this article. The pharmacodynamic and pharmacokinetic profile and related side effects of OLAI are reported. PMID:20856920

  19. Functional magnetic microspheres

    NASA Technical Reports Server (NTRS)

    Yen, Shiao-Ping S. (Inventor); Rembaum, Alan (Inventor); Landel, Robert F. (Inventor)

    1981-01-01

    Functional magnetic particles are formed by dissolving a mucopolysaccharide such as chitosan in acidified aqueous solution containing a mixture of ferrous chloride and ferric chloride. As the pH of the solution is raised magnetite is formed in situ in the solution by raising the pH. The dissolved chitosan is a polyelectrolyte and forms micelles surrounding the granules at pH of 8-9. The chitosan precipitates on the granules to form microspheres containing the magnetic granules. On addition of the microspheres to waste aqueous streams containing dissolved ions, the hydroxyl and amine functionality of the chitosan forms chelates binding heavy metal cations such as lead, copper, and mercury and the chelates in turn bind anions such as nitrate, fluoride, phosphate and borate.

  20. Global trends in use of long-acting reversible and permanent methods of contraception: Seeking a balance.

    PubMed

    Joshi, Ritu; Khadilkar, Suvarna; Patel, Madhuri

    2015-10-01

    The global trend shows that the use of permanent contraception to prevent unintended pregnancy is high. Although the trend also shows a rise in the use of long-acting reversible methods, these are still underutilized despite having contraceptive as well as non-contraceptive benefits. Lack of knowledge among women, dependence on the provider for information, and provider bias for permanent contraception are cited as reasons for this reduced uptake. Training of healthcare providers and increased patient awareness about the effectiveness of long-acting reversible contraceptive methods will increase their uptake and help prevent unintended pregnancies. PMID:26433510

  1. Trading polymeric microspheres: exchanging DNA molecules via microsphere interaction.

    PubMed

    Morimoto, Nobuyuki; Muramatsu, Kanna; Nomura, Shin-ichiro M; Suzuki, Makoto

    2015-04-01

    A new class of artificial molecular transport system is constructed by polymeric microspheres. The microspheres are prepared by self-assembly of poly(ethylene glycol)-block-poly(3-dimethyl(methacryloyloxyethyl)ammonium propane sulfonate), PEG-b-PDMAPS, by intermolecular dipole-dipole interaction of sulfobetaine side chains in water. Below the upper critical solution temperature (UCST) of PEG-b-PDMAPS, the microspheres (∼1μm) interact with other microspheres by partial and transit fusion. In order to apply the interaction between microspheres, a 3'-TAMRA-labeled single-stranded DNA oligomer (ssDNA) is encapsulated into a PEG-b-PDMAPS microsphere by thermal treatment. The exchange of ssDNA between microspheres is confirmed by fluorescence resonance energy transfer (FRET) quenching derived from double-stranded formation with complementary 5'-BHQ-2-labeled ssDNA encapsulated in PEG-b-PDMAPS microspheres. The exchange rate of ssDNA is controllable by tuning the composition of the polymer. The contact-dependent transport of molecules can be applied in the areas of microreactors, sensor devices, etc. PMID:25731098

  2. Tetracycline-HCl-loaded poly(DL-lactide-co-glycolide) microspheres prepared by a spray drying technique: influence of gamma-irradiation on radical formation and polymer degradation.

    PubMed

    Bittner, B; Mäder, K; Kroll, C; Borchert, H H; Kissel, T

    1999-05-01

    Tetracycline-HCl (TCH)-loaded microspheres were prepared from poly(lactide-co-glycolide) (PLGA) by spray drying. The drug was incorporated in the polymer matrix either in solid state or as w/o emulsion. The spin probe 4-hydroxy-2,2,6, 6-tetramethyl-piperidine-1-oxyl (TEMPOL) and the spin trap tert-butyl-phenyl-nitrone (PBN) were co-encapsulated into the TCH-loaded and placebo particles. We investigated the effects of gamma-irradiation on the formation of free radicals in polymer and drug and the mechanism of chain scission after sterilization. Gamma-Irradiation was performed at 26.9 and 54.9 kGy using a 60Co source. The microspheres were characterized especially with respect to the formation of radicals and in vitro polymer degradation. Electron paramagnetic resonance (EPR) spectroscopy, gel permeation chromatography (GPC), differential scanning calorimetry (DSC), high-performance liquid chromatography (HPLC), gas chromatography-mass spectroscopy (GC-MS), and scanning electron microscopy (SEM) were used for characterization of the microspheres. Using EPR spectroscopy, we successfully detected gamma-irradiation induced free radicals within the TCH-loaded microspheres, while unloaded PLGA did not contain radicals under the same conditions. The relatively low glass transition temperature of the poly(dl-lactide-co-glycolide) (37-39 degrees C) seems to favor subsequent reactions of free radicals due to the high mobility of the polymeric chains. Because of the high melting point of TCH (214 degrees C), the radicals can only be stabilized in drug loaded microspheres. In order to determine the mechanism of polymer degradation after exposure to gamma-rays, the spin trap PBN and the spin probe TEMPOL were encapsulated in the microspheres. gamma-Irradiation of microspheres containing PBN resulted in the formation of a lipophilic spin adduct, indicating that a polymeric radical was generated by random chain scission. Polymer degradation by an unzipping mechanism would have

  3. CO2-assisted high pressure homogenization: a solvent-free process for polymeric microspheres and drug-polymer composites.

    PubMed

    Kluge, Johannes; Mazzotti, Marco

    2012-10-15

    The study explores the enabling role of near-critical CO(2) as a reversible plasticizer in the high pressure homogenization of polymer particles, aiming at their comminution as well as at the formation of drug-polymer composites. First, the effect of near-critical CO(2) on the homogenization of aqueous suspensions of poly lactic-co-glycolic acid (PLGA) was investigated. Applying a pressure drop of 900 bar and up to 150 passes across the homogenizer, it was found that particles processed in the presence of CO(2) were generally of microspherical morphology and at all times significantly smaller than those obtained in the absence of a plasticizer. The smallest particles, exhibiting a median x(50) of 1.3 μm, were obtained by adding a small quantity of ethyl acetate, which exerts on PLGA an additional plasticizing effect during the homogenization step. Further, the study concerns the possibility of forming drug-polymer composites through simultaneous high pressure homogenization of the two relevant solids, and particularly the effect of near-critical CO(2) on this process. Therefore, PLGA was homogenized together with crystalline S-ketoprofen (S-KET), a non-steroidal anti-inflammatory drug, at a drug to polymer ratio of 1:10, a pressure drop of 900 bar and up to 150 passes across the homogenizer. When the process was carried out in the presence of CO(2), an impregnation efficiency of 91% has been reached, corresponding to 8.3 wt.% of S-KET in PLGA; moreover, composite particles were of microspherical morphology and significantly smaller than those obtained in the absence of CO(2). The formation of drug-polymer composites through simultaneous homogenization of the two materials is thus greatly enhanced by the presence of CO(2), which increases the efficiency for both homogenization and impregnation. PMID:22750408

  4. Stem Cells Grown in Osteogenic Medium on PLGA, PLGA/HA, and Titanium Scaffolds for Surgical Applications

    PubMed Central

    Asti, Annalia; Gastaldi, Giulia; Dorati, Rossella; Saino, Enrica; Conti, Bice; Visai, Livia; Benazzo, Francesco

    2010-01-01

    Pluripotent adipose tissue-derived stem cells (hASCs) can differentiate into various mesodermal cell types such as osteoblasts, chondroblasts, and myoblasts. We isolated hASCs from subcutaneous adipose tissue during orthopaedic surgery and induced the osteogenic differentiation for 28 days on three different synthetic scaffolds such as polylactide-co-glycolide (PLGA), polylactide-co-glycolide/hydroxyapatite (PLGA/HA), and trabecular titanium scaffolds (Ti6Al4V). Pore size can influence certain criteria such as cell attachment, infiltration, and vascularization. The aim of this study was to investigate the performance of PLGA and PLGA/HA scaffolds with a higher porosity, ranging between 75% and 84%, with respect to Ti scaffolds but with smaller pore size, seeded with hASCs to develop a model that could be used in the treatment of bone defects and fractures. Osteogenesis was assessed by ELISA quantitation of extracellular matrix protein expression, von Kossa staining, X-ray microanalysis, and scanning electron microscopy. The higher amount of protein matrix on the Ti scaffold with respect to PLGA and PLGA/HA leads to the conclusion that not only the type of material but the structure significantly affects cell proliferation. PMID:21234383

  5. Incorporation of mesoporous silica nanoparticles into random electrospun PLGA and PLGA/gelatin nanofibrous scaffolds enhances mechanical and cell proliferation properties.

    PubMed

    Mehrasa, Mohammad; Asadollahi, Mohammad Ali; Nasri-Nasrabadi, Bijan; Ghaedi, Kamran; Salehi, Hossein; Dolatshahi-Pirouz, Alireza; Arpanaei, Ayyoob

    2016-09-01

    Poly(lactic-co-glycolic acid) (PLGA) and PLGA/gelatin random nanofibrous scaffolds embedded with different amounts of mesoporous silica nanoparticles (MSNPs) were fabricated using electrospinning method. To evaluate the effects of nanoparticles on the scaffolds, physical, chemical, and mechanical properties as well as in vitro degradation behavior of scaffolds were investigated. The mean diameters of nanofibers were 974±68nm for the pure PLGA scaffolds vs 832±70, 764±80, and 486±64 for the PLGA/gelatin, PLGA/10wt% MSNPs, and the PLGA/gelatin/10wt% MSNPs scaffolds, respectively. The results suggested that the incorporation of gelatin and MSNPs into PLGA-based scaffolds enhances the hydrophilicity of scaffolds due to an increase of hydrophilic functional groups on the surface of nanofibers. With porosity examination, it was concluded that the incorporation of MSNPs and gelatin decrease the porosity of scaffolds. Nanoparticles also improved the tensile mechanical properties of scaffolds. Using in vitro degradation analysis, it was shown that the addition of nanoparticles to the nanofibers matrix increases the weight loss percentage of PLGA-based samples, whereas it decreases the weight loss percentage in the PLGA/gelatin composites. Cultivation of rat pheochromocytoma cell line (PC12), as precursor cells of dopaminergic neural cells, on the scaffolds demonstrated that the introduction of MSNPs into PLGA and PLGA/gelatin matrix leads to improved cell attachment and proliferation and enhances cellular processes. PMID:27207035

  6. Encapsulation of immunoglobulin G by solid-in-oil-in-water: effect of process parameters on microsphere properties.

    PubMed

    Marquette, Sarah; Peerboom, Claude; Yates, Andrew; Denis, Laurence; Goole, Jonathan; Amighi, Karim

    2014-04-01

    Antibodies (Abs) are prone to a variety of physical and chemical degradation pathways, which require the development of stable formulations and specific delivery strategies. In this study, injectable biodegradable and biocompatible polymeric particles were employed for controlled-release dosage forms and the encapsulation of antibodies into polylactide-co-glycolide (PLGA) based microspheres was explored. In order to avoid stability issues which are commonly described when water-in-oil (w/o) emulsion is used, a solid-in-oil-in-water (s/o/w) method was developed and optimized. The solid phase was made of IgG microparticles and the s/o/w process was evaluated as an encapsulation method using a model Ab molecule (polyclonal bovine immunoglobulin G (IgG)). The methylene chloride (MC) commonly used for an encapsulation process was replaced by ethyl acetate (EtAc), which was considered as a more suitable organic solvent in terms of both environmental and human safety. The effects of several processes and formulation factors were evaluated on IgG:PLGA microsphere properties such as: particle size distribution, drug loading, IgG stability, and encapsulation efficiency (EE%). Several formulations and processing parameters were also statistically identified as critical to get reproducible process (e.g. the PLGA concentration, the volume of the external phase, the emulsification rate, and the quantity of IgG microparticles). The optimized encapsulation method has shown a drug loading of up to 6% (w/w) and an encapsulation efficiency of up to 60% (w/w) while preserving the integrity of the encapsulated antibody. The produced microspheres were characterized by a d(0.9) lower than 110 μm and showed burst effect lower than 50% (w/w). PMID:24184674

  7. Systems Approach to targeted and long-acting HIV/AIDS therapy.

    PubMed

    Ho, Rodney J Y; Yu, Jesse; Li, Bowen; Kraft, John C; Freeling, Jennifer P; Koehn, Josefin; Shao, Jingwei

    2015-12-01

    Medication adherence and insufficient drug levels are central to HIV/AIDS disease progression. Recently, Fletcher et al. confirmed that HIV patients on oral antiretroviral therapy had lower intracellular drug concentrations in lymph nodes than in blood. For instance, in the same patient, multiple lymph node drug concentrations were as much as 99 % lower than in blood. This study built upon our previous finding that HIV patients taking oral indinavir had 3-fold lower mononuclear cell drug concentrations in lymph nodes than in blood. As a result, an association between insufficient lymph node drug concentrations in cells and persistent viral replication has now been validated. Lymph node cells, particularly CD4 T lymphocytes, host HIV infection and persistence; CD4 T cell depletion in blood correlates with AIDS progression. With established drug targets to overcome drug insufficiency in lymphoid cells and tissues, we have developed and employed a "Systems Approach" to engineer multi-drug-incorporated particles for HIV treatment. The goal is to improve lymphatic HIV drug exposure to eliminate HIV drug insufficiency and disease progression. We found that nano-particulate drugs that absorb, transit, and retain in the lymphatic system after subcutaneous dosing improve intracellular lymphatic drug exposure and overcome HIV lymphatic drug insufficiency. The composition, physical properties, and stability of the drug nanoparticles contribute to the prolonged and enhanced drug exposure in lymphoid cells and tissues. In addition to overcoming lymphatic drug insufficiency and potentially reversing HIV infection, targeted drug nanoparticle properties may extend drug concentrations and enable the development of long-acting HIV drug therapy for enhanced patient compliance. PMID:26315144

  8. Combination treatment with risperidone long-acting injection and psychoeducational approaches for preventing relapse in schizophrenia

    PubMed Central

    Zhao, Yueren; Kishi, Taro; Iwata, Nakao; Ikeda, Manabu

    2013-01-01

    A recent meta-analysis showed that long-acting injectable (LAI) antipsychotics were not superior to oral antipsychotics for preventing relapse in patients with schizophrenia. We therefore designed a treatment strategy combining risperidone LAI and COMPASS (COMprehensive Psycho-educational Approach and Scheme Set), an original psychoeducational program supporting treatment with risperidone LAI and evaluating subjective treatment satisfaction, transition of symptoms, and effectiveness in preventing symptomatic relapse. The aim of this study was to examine whether addition of COMPASS to risperidone LAI was more effective in preventing relapse in schizophrenia patients than risperidone LAI alone, with the latter group consisting of patients enrolled in a Phase III trial of risperidone LAI in Japan. Patients were followed up for 6 months, with COMPASS continuously implemented from the transition to the observation phase. The primary efficacy measurements were relapse rate (rates of rehospitalization and discontinuation due to inefficacy). Secondary efficacy measurements were the Brief Psychiatric Rating Scale (BPRS) and Global Assessment of Functioning (GAF) scores. Of the 96 patients originally enrolled, 19 (19.8%) were discontinued from all causes. During the 6-month study period, ten of the 96 patients (10.4%) relapsed, compared with a 12.2% relapse rate in patients enrolled in a Phase III trial of risperidone LAI in Japan. Patients showed significant improvements in BPRS total scores (P = 0.0031), BPRS positive (P = 0.0451), BRPS negative (P < 0.0001), and general subscale scores (P = 0.0031), and GAF (P < 0.0001) from baseline to 6 months. In conclusion, the lower relapse rate observed in patients treated with COMPASS plus risperidone LAI than in patients treated with risperidone LAI alone suggests that COMPASS may have benefits in the treatment of schizophrenia, indicating a need for randomized, controlled trials in larger numbers of patients. PMID:24194642

  9. Long-acting reversible contraception: Findings from the Understanding Fertility Management in Contemporary Australia survey.

    PubMed

    Holton, Sara; Rowe, Heather; Kirkman, Maggie; Jordan, Lynne; McNamee, Kathy; Bayly, Chris; McBain, John; Sinnott, Vikki; Fisher, Jane

    2016-04-01

    Objectives The aim of this research was to investigate awareness, perceived reliability and consideration of use of long-acting reversible contraception (LARC) among Australians of reproductive age. Methods A sample of 18- to 50-year-old women and men (N = 2235) was randomly recruited from the Australian electoral roll in 2013. Respondents completed a self-administered, anonymous questionnaire. Data were weighted to reduce non-response bias. Factors associated with perceived reliability and consideration of use of LARC were identified in multivariable analyses. Results Most respondents had heard of implants (76.5%) and intrauterine contraception (63.7%). However, most did not think implants (56.3%) or IUDs (63.9%) were reliable and would not consider using implants (71.6%) or IUDs (77.5%). Those significantly more likely to perceive LARC as reliable were younger, did not regard religion as important in fertility choices, had private health insurance, had been pregnant and had had an abortion; and women who had a partner. Those more likely to consider using LARC were younger and did not regard religion as important in fertility choices; women who had private health insurance, lived in an area of socioeconomic advantage and had had an abortion; and men without a partner, born in Australia and comfortable talking to a health care provider about contraceptive matters. Conclusions Despite high awareness of LARC among Australian adults, its perceived reliability and willingness to use it remain low in certain groups. Targeted interventions that aim to increase knowledge of the benefits and reliability of LARC and allow informed use are recommended. PMID:26043118

  10. Long-acting Neuraminidase Inhibitor Laninamivir Octanoate as Post-exposure Prophylaxis for Influenza

    PubMed Central

    Kashiwagi, Seizaburo; Watanabe, Akira; Ikematsu, Hideyuki; Uemori, Mitsutoshi; Awamura, Shinichiro

    2016-01-01

    Background. A single administration of laninamivir octanoate, a long-acting neuraminidase inhibitor, has been proven to be effective in the treatment of influenza but not for post-exposure prophylaxis. Methods. We conducted a double-blind, multicenter, randomized, placebo-controlled study to determine if a single administration of laninamivir octanoate 40 mg was superior to placebo for post-exposure prophylaxis. Eligible participants who had cohabited with an influenza patient within 48 hours of symptom onset were randomly assigned (1:1:1) to 1 of 3 groups: 40 mg of laninamivir octanoate single administration (LO-40SD), 20 mg of laninamivir octanoate once daily for 2 days (LO-20TD), or placebo. The primary efficacy endpoint was the proportion of participants who developed clinical influenza (defined as influenza virus positive, an axillary temperature >37.5°C, and at least 2 symptoms) over a 10-day period. Results. A total of 803 participants were enrolled, with 801 included in the primary analysis. The proportions of participants with clinical influenza were 4.5% (12/267), 4.5% (13/269), and 12.1% (32/265) in the LO-40SD, LO-20TD, and placebo groups, respectively. A single administration of laninamivir octanoate 40 mg significantly reduced the development of influenza compared with placebo (P = .001). The relative risk reductions compared with the placebo group were 62.8% and 63.1% for the LO-40SD and LO-20TD groups, respectively. The incidence of adverse events in the LO-40SD group was similar to that of the LO-20TD and placebo groups. Conclusions. A single administration of laninamivir octanoate was effective and well tolerated as post-exposure prophylaxis to prevent the development of influenza. Clinical Trials Registration. JapicCTI-142679. PMID:27118785

  11. Relevance of dosage in adherence to treatment with long-acting anticholinergics in patients with COPD

    PubMed Central

    Izquierdo, José Luis; Paredero, José Manuel; Piedra, Raul

    2016-01-01

    Introduction The aim of this study was to assess the degree of adherence for two standard regimens for administrating anticholinergic drugs (12 and 24 hours) in patients with chronic obstruction of the airflow and to establish whether the use of a once-daily dose improves the level of treatment adherence. Methods We used long-acting anticholinergics (LAMAs) as a study variable, and included the entire health area of Castile-La Mancha, numbering 2,100,998 inhabitants, as the study population. We analyzed a total of 16,446 patients who had been prescribed a LAMA between January 1, 2013 and December 31, 2013. The follow-up period, based on a centralized system of electronic prescription management, was extended until December 2014. Results During 2013, the medication collected was 7.4%–10.7% higher than indicated by labeling. This was very similar for all LAMAs, irrespective of the patient’s sex, the molecule, the device, and the drug dosage. We did not observe seasonal variations in the consumption of LAMAs, nor did we detect differences between prescription drugs for once-daily (every 24 hours) versus twice-daily (every 12 hours) administration, between the different molecules, or between different types of inhalers for the same molecule. The results were similar in 2014. Conclusion The principal conclusion of this study is that, in an area with a centralized management system of pharmacological prescriptions, adherence to treatment with LAMAs is very high, irrespective of the molecules or inhalation device. We did not find that patients who used twice-daily medication had a lower adherence. PMID:26929614

  12. Long-acting muscarinic antagonists for the prevention of exacerbations of chronic obstructive pulmonary disease.

    PubMed

    Jones, Paul W

    2015-06-01

    Exacerbations of chronic obstructive pulmonary disease (COPD) have important consequences for lung function, health status and mortality. Furthermore, they are associated with high economic costs, predominantly related to hospitalization. They are managed acutely with short-acting bronchodilators, systemic corticosteroids or antibiotics; however, a large proportion of COPD exacerbations are unreported and therefore untreated or self-managed. There is evidence to suggest that these unreported exacerbations also have important consequences for health status; therefore, reducing exacerbation risk is an important goal in the management of COPD. Current guidelines recommend long-acting muscarinic antagonists (LAMAs) as first-line bronchodilator therapy in patients with stable COPD who have a high risk of exacerbation or increased symptoms. To date, three LAMAs, tiotropium bromide, aclidinium bromide and glycopyrronium bromide, have been approved as maintenance bronchodilator treatments for stable COPD. These all provide clinically significant improvements in lung function, reduce symptoms and improve health status compared with placebo in patients with COPD. This paper reviews evidence from randomized, controlled clinical trials demonstrating that tiotropium, aclidinium and glycopyrronium reduce exacerbation risk in patients with COPD. Reductions were seen irrespective of the exacerbation measure used, whether time to first event or annualized exacerbation rate. Furthermore, studies with aclidinium suggest LAMAs can reduce exacerbation risk irrespective of whether exacerbation events are assessed, using an event-based approach or a symptom-based method which includes unreported events. Together these results demonstrate that LAMAs have the potential to provide clinical benefit in the management of exacerbations in patients with stable COPD. PMID:25801643

  13. Knowledge and attitudes about long-acting reversible contraception among Latina women who desire sterilization

    PubMed Central

    White, Kari; Hopkins, Kristine; Potter, Joseph E.; Grossman, Daniel

    2013-01-01

    Background There is growing interest in increasing the use of long-acting reversible contraception (LARC), and suggestions that such methods may serve as an alternative to sterilization. However, there is little information about whether women who do not want more children would be interested in using LARC methods. Methods We conducted semi-structured interviews with 120 parous Latina women in El Paso, Texas who wanted a sterilization but had not obtained one. We assessed women’s awareness of and interest in using the copper intrauterine device (IUD), levonorgestrel intrauterine system (LNG-IUS), and etonogestrel implant. Findings Overall, 51%, 23% and 47% of women reported they had heard of the copper IUD, LNG-IUS and implant, respectively. More women stated they would use the copper IUD (24%) than the LNG-IUS (14%) or implant (9%). Among women interested in LARC, the most common reasons were that, relative to their current method, LARC methods were more convenient, effective, and provided longer-term protection against pregnancy. Those who had reservations about LARC were primarily concerned with menstrual changes. Women also had concerns about side effects and the methods' effectiveness in preventing pregnancy, preferring to use a familiar method. Conclusions Although these findings indicate many Latina women in this setting do not consider LARC an alternative to sterilization, they point to an existing demand among some who wish to end childbearing. Efforts are needed to improve women’s knowledge and access to a range of methods so they can achieve their childbearing goals. PMID:23816156

  14. Long-acting Reversible Contraception for Adolescents and Young Adults: Patient and Provider Perspectives

    PubMed Central

    Kavanaugh, Megan L.; Frohwirth, Lori; Jerman, Jenna; Popkin, Ronna; Ethier, Kathleen

    2013-01-01

    Study objective To describe and explore provider- and patient-level perspectives regarding long-acting reversible contraception (LARC) for teens and young adults (ages 16-24). Methods Data collection occurred between June – December 2011. We first conducted telephone interviews with administrative directors at 20 publicly funded facilities that provide family planning services. At six of these sites, we conducted a total of six focus group discussions (FGDs) with facility staff and forty-eight in-depth interviews (IDIs) with facility clients ages 16-24. Results Staff in the FGDs did not generally equate being a teen with ineligibility for IUDs. In contrast to staff, one quarter of the young women did perceive young age as rendering them ineligible. Clients and staff agreed that the “forgettable” nature of the methods and their duration were some of LARC’s most significant advantages. They also agreed that fear of pain associated with both insertion and removal and negative side effects were disadvantages. Some aspects of IUDs and implants were perceived as advantages by some clients but disadvantages by others. Common challenges to providing LARC-specific services to younger patients included extra time required to counsel young patients about LARC methods, outdated clinic policies requiring multiple visits to obtain IUDs, and a perceived higher removal rate among young women. The most commonly cited strategy for addressing many of these challenges was securing supplementary funding to support the provision of these services to young patients. Conclusion Incorporating young women’s perspectives on LARC methods into publicly funded family planning facilities’ efforts to provide these methods to a younger population may increase their use among young women. PMID:23287602

  15. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors

    PubMed Central

    Cives, M; Kunz, P L; Morse, B; Coppola, D; Schell, M J; Campos, T; Nguyen, P T; Nandoskar, P; Khandelwal, V; Strosberg, J R

    2015-01-01

    Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response. PMID:25376618

  16. Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

    PubMed Central

    Gunawardana, Manjula; Remedios-Chan, Mariana; Miller, Christine S.; Fanter, Rob; Yang, Flora; Marzinke, Mark A.; Hendrix, Craig W.; Beliveau, Martin; Moss, John A.; Smith, Thomas J.

    2015-01-01

    Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day−1 in vitro was evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml−1; interquartile range [IQR], 0.60 to 1.50 ng ml−1) and tenofovir (TFV; median, 15.0 ng ml−1; IQR, 8.8 to 23.3 ng ml−1), the product of in vivo TAF hydrolysis. High concentrations (median, 512 fmol/106 cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations. PMID:25896688

  17. Long-acting diltiazem HCl for the chronotherapeutic treatment of hypertension and chronic stable angina pectoris.

    PubMed

    Claas, Steven A; Glasser, Stephen P

    2005-05-01

    Hypertension is associated with increased cardio- and cerebrovascular morbidity and mortality; antihypertensive drugs have been shown to reduce the risk of adverse cardio- and cerebrovascular events. These events tend to be more common during the morning hours, a time when both normo- and hypertensives show a circadian peak in blood pressure (BP). Although clinicians have a number of safe and well-tolerated antihypertensive agents in various classes and formulations at their disposal, few are designed to specifically attenuate the morning BP surge while maintaining 24-h efficacy. A novel, once-daily, long-acting formulation of diltiazem HCl (DTZ-LA) has been developed with chronodynamics in harmony with diurnal BP variation. DTZ-LA effectively reduces BP in a dose-dependent fashion over a 24-h dosing interval in patients with moderate-to-severe essential hypertension. When compared with a morning dose, the evening dose is associated with significant and clinically meaningful greater reductions in BP during the morning hours, when adverse cardiovascular events tend to cluster. Evening-dosed DTZ-LA was more effective than morning-dosed amlodipine in reducing morning diastolic BP in African-Americans. Evening-dosed DTZ-LA was also more effective than evening-dosed ramipril in reducing morning BP. Evening dosing of DTZ-LA significantly increased exercise tolerance in patients with angina pectoris over the 24-h interval. DTZ-LA is associated with adverse effects consistent with other diltiazem formulations, and overall is safe and well tolerated, even when titrated to doses of 540 mg/day. PMID:15934903

  18. Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy.

    PubMed

    Owen, Andrew; Rannard, Steve

    2016-08-01

    Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥1week, ≥1month or ≥6months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits. PMID:26916628

  19. Antipsychotic-induced metabolic effects in the female rat: Direct comparison between long-acting injections of risperidone and olanzapine.

    PubMed

    Ersland, Kari M; Skrede, Silje; Røst, Therese H; Berge, Rolf K; Steen, Vidar M

    2015-12-01

    Several antipsychotics have well-known adverse metabolic effects. Studies uncovering molecular mechanisms of such drugs in patients are challenging due to high dropout rates, previous use of antipsychotics and restricted availability of biological samples. Rat experiments, where previously unexposed animals are treated with antipsychotics, allow for direct comparison of different drugs, but have been hampered by the short half-life of antipsychotics in rodents. The use of long-acting formulations of antipsychotics could significantly increase the value of rodent models in the molecular characterization of therapeutic and adverse effects of these agents. However, as long-acting formulations have rarely been used in rodents, there is a need to characterize the basic metabolic phenotype of different antipsychotics. Using long-acting olanzapine injections as a positive control, the metabolic effects of intramuscular long-acting risperidone in female rats were investigated for the first time. Like olanzapine, risperidone induced rapid, significant hyperphagia and weight gain, with concomitant increase in several plasma lipid species. Both drugs also induced weight-independent upregulation of several genes encoding enzymes involved in lipogenesis, but this activation was not confirmed at the protein level. Our findings shed light on the role of drug administration, drug dose and nutritional status in the development of rodent models for adverse metabolic effects of antipsychotic agents. PMID:26378122

  20. Metal containing polymeric functional microspheres

    NASA Technical Reports Server (NTRS)

    Yen, Shiao-Ping S. (Inventor); Rembaum, Alan (Inventor); Molday, Robert S. (Inventor)

    1979-01-01

    Polymeric functional microspheres containing metal or metal compounds are formed by addition polymerization of a covalently bondable olefinic monomer such as hydroxyethylmethacrylate in the presence of finely divided metal or metal oxide particles, such as iron, gold, platinum or magnetite, which are embedded in the resulting microspheres. The microspheres can be covalently bonded to chemotherapeutic agents, antibodies, or other proteins providing a means for labeling or separating labeled cells. Labeled cells or microspheres can be concentrated at a specific body location such as in the vicinity of a malignant tumor by applying a magnetic field to the location and then introducing the magnetically attractable microspheres or cells into the circulatory system of the subject. Labeled cells can be separated from a cell mixture by applying a predetermined magnetic field to a tube in which the mixture is flowing. After collection of the labeled cells, the magnetic field is discontinued and the labeled sub-cell population recovered.

  1. Immunofluorescence detection methods using microspheres

    NASA Astrophysics Data System (ADS)

    Szurdoki, Ferenc; Michael, Karri L.; Agrawal, Divya; Taylor, Laura C.; Schultz, Sandra L.; Walt, David R.

    1999-01-01

    Microsphere-based immunoassays were devised for compounds of agricultural and biomedical interest (e.g., digoxin, theophylline, and zearalenone). Commercially available microspheres with surface functional groups for chemical derivatization were used as solid carriers. After immobilizing the target substances, the surface of the haptenized microspheres was blocked by a protein to reduce aspecific binding. Competitive immunoassays were performed using the functionalized microspheres and antibodies labeled with horseradish peroxidase. Immunofluorescence signal amplification was achieved by enzyme-catalyzed reporter deposition (CARD). An epifluorescence microscope, a CCD camera interfaced with a computer, and microscopy image analysis software were employed for quantitative detection of fluorescent light emitted from individual microspheres. Integration of several such immunoassays and application of an optical encoding method enabled multianalyte determination. These immunoassays can also be utilized in an immunosensor array format. This immunoarray format could facilitate miniaturization and automation of multianalyte immunoassays.

  2. Janus nanogels of PEGylated Taxol and PLGA-PEG-PLGA copolymer for cancer therapy

    NASA Astrophysics Data System (ADS)

    Wei, Jun; Wang, Huaimin; Zhu, Meifeng; Ding, Dan; Li, Dongxia; Yin, Zhinan; Wang, Lianyong; Yang, Zhimou

    2013-09-01

    Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy.Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. Electronic supplementary information (ESI) available: Synthesis and characterization of compounds, dynamic time sweep, H

  3. Chalcogenide glass microsphere laser.

    PubMed

    Elliott, Gregor R; Murugan, G Senthil; Wilkinson, James S; Zervas, Michalis N; Hewak, Daniel W

    2010-12-01

    Laser action has been demonstrated in chalcogenide glass microsphere. A sub millimeter neodymium-doped gallium lanthanum sulphide glass sphere was pumped at 808 nm with a laser diode and single and multimode laser action demonstrated at wavelengths between 1075 and 1086 nm. The gallium lanthanum sulphide family of glass offer higher thermal stability compared to other chalcogenide glasses, and this, along with an optimized Q-factor for the microcavity allowed laser action to be achieved. When varying the pump power, changes in the output spectrum suggest nonlinear and/or thermal effects have a strong effect on laser action. PMID:21165022

  4. Photonic crystal microspheres

    NASA Astrophysics Data System (ADS)

    Zhokhov, A. A.; Masalov, V. M.; Sukhinina, N. S.; Matveev, D. V.; Dolganov, P. V.; Dolganov, V. K.; Emelchenko, G. A.

    2015-11-01

    Spherical samples of photonic crystals formed by colloidal SiO2 nanoparticles were synthesized. Synthesis of microspheres from 160 nm, 200 nm and 430 nm diameter colloidal nanoparticles was performed over a wide size range, from 5 μm to 50 μm. The mechanism of formation of void microparticles exceeding 50 μm is discussed. The spectral measurements verified the association of the spectra with the peaks of selective reflection from the cubic lattice planes. The microparticle morphology is characterized by scanning electron microscopy (SEM).

  5. In vivo biocompatibility of the PLGA microparticles in parotid gland

    PubMed Central

    Cantín, Mario; Miranda, Patricio; Suazo Galdames, Iván; Zavando, Daniela; Arenas, Patricia; Velásquez, Luis; Vilos, Cristian

    2013-01-01

    Poly(lactic-co-glycolic acid) (PLGA) microparticles are used in various disorders for the controlled or sustained release of drugs, with the management of salivary gland pathologies possible using this technology. There is no record of the response to such microparticles in the glandular parenchyma. The purpose of this study was to assess the morphological changes in the parotid gland when injected with a single dose of PLGA microparticles. We used 12 adult female Sprague Dawley rats (Rattus norvegicus) that were injected into their right parotid gland with sterile vehicle solution (G1, n=4), 0.5 mg PLGA microparticles (G2, n=4), and 0.75 mg PLGA microparticles (G3, n=4); the microparticles were dissolved in a sterile vehicle solution. The intercalar and striated ducts lumen, the thickness of the acini and the histology aspect in terms of the parenchyma organization, cell morphology of acini and duct system, the presence of polymeric residues, and inflammatory response were determined at 14 days post-injection. The administration of the compound in a single dose modified some of the morphometric parameters of parenchyma (intercalar duct lumen and thickness of the glandular acini) but did not induce tissue inflammatory response, despite the visible presence of polymer waste. This suggests that PLGA microparticles are biocompatible with the parotid tissue, making it possible to use intraglandular controlled drug administration. PMID:24228103

  6. Vouchers in Fragile States: Reducing Barriers to Long-Acting Reversible Contraception in Yemen and Pakistan.

    PubMed

    Boddam-Whetham, Luke; Gul, Xaher; Al-Kobati, Eman; Gorter, Anna C

    2016-08-11

    In conflict-affected states, vouchers have reduced barriers to reproductive health services and have enabled health programs to use targeted subsidies to increase uptake of specific health services. Vouchers can also be used to channel funds to public- and private-service providers and improve service quality. The Yamaan Foundation for Health and Social Development in Yemen and the Marie Stopes Society (MSS) in Pakistan-both working with Options Consultancy Services-have developed voucher programs that subsidize voluntary access to long-acting reversible contraceptives (LARCs) and permanent methods (PMs) of family planning in their respective fragile countries. The programs focus on LARCs and PMs because these methods are particularly difficult for poor women to access due to their cost and to provider biases against offering them. Using estimates of expected voluntary uptake of LARCs and PMs for 2014 based on contraceptive prevalence rates, and comparing these with uptake of LARCs and PMs through the voucher programs, we show the substantial increase in service utilization that vouchers can enable by contributing to an expanded method choice. In the governorate of Lahj, Yemen, vouchers for family planning led to an estimated 38% increase in 2014 over the expected use of LARCs and PMs (720 vs. 521 expected). We applied the same approach in 13 districts of Punjab, Khyber Pakhtunkhwa (KPK), and Sindh provinces in Pakistan. Our calculations suggest that vouchers enabled 10 times more women than expected to choose LARCs and PMs in 2014 in those areas of Pakistan (73,639 vs. 6,455 expected). Voucher programs can promote and maintain access to family planning services where existing health systems are hampered. Vouchers are a flexible financing approach that enable expansion of contraceptive choice and the inclusion of the private sector in service delivery to the poor. They can keep financial resources flowing where the public sector is prevented from offering services

  7. Attitudes towards the administration of long-acting antipsychotics: a survey of physicians and nurses

    PubMed Central

    2013-01-01

    Background Discontinuation of antipsychotic treatment for schizophrenia can interrupt improvement and exacerbate the illness. Reasons for discontinuing treatment are multifactorial and include adherence, efficacy and tolerability issues. Poor adherence may be addressed through non-pharmacological approaches as well as through pharmacological ones, ie ensured delivery of medication, such as that achieved with long-acting injectable (LAI) antipsychotics. However, attitudes of healthcare professionals (HCPs) towards LAI antipsychotics may influence their prescribing decisions and may influence medication choices offered to patients. We therefore conducted a survey to investigate factors driving LAI use as well as physician and nurse attitudes to LAI antipsychotics and to different injection sites. Methods An independent market research agency conducted the survey of HCPs across Europe. Participants were recruited by telephone and completed the survey online. Using conjoint analyses (a multivariate statistical technique analysing preferences on the basis of ranking a limited number of attributes which are presented repetitively), attitudes to oral versus LAI medication and gluteal versus deltoid injection routes were assessed. Results A total of 891 HCPs across Europe were surveyed. Of these, 40% would choose LAI antipsychotics for first episode patients whereas 90% would select LAI antipsychotics for chronic patients with two to five psychotic episodes. Dominant elements in antipsychotic choice were low sedation but no tardive dyskinesia, no or mild pain at injection and low risk of embarrassment or impact upon therapeutic alliance. Eighty-six per cent of respondents considered that having the choice of a deltoid as well as gluteal administration site was beneficial over not having that choice. Two thirds of respondents said they agreed that medication administration via the deltoid muscle may reduce social embarrassment associated with LAI antipsychotics and most

  8. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness

    PubMed Central

    2013-01-01

    Background Long-acting injectable (LAI) formulations are not widely used in routine practice even though they offer advantages in terms of relapse prevention. As part of a process to improve the quality of care, the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) elaborated guidelines for the use and management of antipsychotic depots in clinical practice. Methods Based on a literature review, a written survey was prepared that asked about 539 options in 32 specific clinical situations concerning 3 fields: target-population, prescription and use, and specific populations. We contacted 53 national experts, 42 of whom (79%) completed the survey. The options were scored using a 9-point scale derived from the Rand Corporation and the University of California in the USA. According to the answers, a categorical rank (first-line/preferred choice, second-line/alternate choice, third-line/usually inappropriate) was assigned to each option. The first-line option was defined as a strategy rated as 7–9 (extremely appropriate) by at least 50% of the experts. The following results summarize the key recommendations from the guidelines after data analysis and interpretation of the results of the survey by the scientific committee. Results LAI antipsychotics are indicated in patients with schizophrenia, schizoaffective disorder, delusional disorder and bipolar disorder. LAI second-generation antipsychotics are recommended as maintenance treatment after the first episode of schizophrenia. LAI first-generation antipsychotics are not recommended in the early course of schizophrenia and are not usually appropriate in bipolar disorder. LAI antipsychotics have long been viewed as a treatment that should only be used for a small subgroup of patients with non-compliance, frequent relapses or who pose a risk to others. The panel considers that LAI antipsychotics should be considered and systematically proposed to any patients for whom maintenance

  9. Vouchers in Fragile States: Reducing Barriers to Long-Acting Reversible Contraception in Yemen and Pakistan

    PubMed Central

    Boddam-Whetham, Luke; Gul, Xaher; Al-Kobati, Eman; Gorter, Anna C

    2016-01-01

    ABSTRACT In conflict-affected states, vouchers have reduced barriers to reproductive health services and have enabled health programs to use targeted subsidies to increase uptake of specific health services. Vouchers can also be used to channel funds to public- and private-service providers and improve service quality. The Yamaan Foundation for Health and Social Development in Yemen and the Marie Stopes Society (MSS) in Pakistan—both working with Options Consultancy Services—have developed voucher programs that subsidize voluntary access to long-acting reversible contraceptives (LARCs) and permanent methods (PMs) of family planning in their respective fragile countries. The programs focus on LARCs and PMs because these methods are particularly difficult for poor women to access due to their cost and to provider biases against offering them. Using estimates of expected voluntary uptake of LARCs and PMs for 2014 based on contraceptive prevalence rates, and comparing these with uptake of LARCs and PMs through the voucher programs, we show the substantial increase in service utilization that vouchers can enable by contributing to an expanded method choice. In the governorate of Lahj, Yemen, vouchers for family planning led to an estimated 38% increase in 2014 over the expected use of LARCs and PMs (720 vs. 521 expected). We applied the same approach in 13 districts of Punjab, Khyber Pakhtunkhwa (KPK), and Sindh provinces in Pakistan. Our calculations suggest that vouchers enabled 10 times more women than expected to choose LARCs and PMs in 2014 in those areas of Pakistan (73,639 vs. 6,455 expected). Voucher programs can promote and maintain access to family planning services where existing health systems are hampered. Vouchers are a flexible financing approach that enable expansion of contraceptive choice and the inclusion of the private sector in service delivery to the poor. They can keep financial resources flowing where the public sector is prevented from

  10. A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia.

    PubMed

    Li, Huafang; Rui, Qing; Ning, Xiaoping; Xu, Haiyan; Gu, Niufan

    2011-06-01

    This open-label, rater-blinded, parallel-group study was designed to evaluate noninferiority of paliperidone palmitate (PP), a once-monthly injectable atypical antipsychotic, to once-biweekly risperidone long-acting injectable (RIS-LAI) in adult Chinese patients with acute schizophrenia. Eligible Chinese adults (N=452) with schizophrenia were randomized (1:1) to either PP (N=229; deltoid injections on day 1 [150 mg eq.] and day 8 [100 mg eq.]; then once-monthly deltoid or gluteal injections, flexibly dosed [50, 100, or 150 mg eq.]), or RIS-LAI (N=223; once-biweekly gluteal injections, flexibly dosed [25, 37.5 or 50 mg]). RIS-LAI-treated patients received oral risperidone supplementation (1-6 mg/day) at initiation and with RIS-LAI dose increases. Mean (SD) Positive and Negative Syndrome Scale (PANSS) total score at baseline was 83.2 (12.44). Mean (SD) change from baseline to endpoint in PANSS total scores (primary efficacy measure) was: -23.6 (16.28) for PP group and -26.9 (15.43) for RIS-LAI group. PP was noninferior to RIS-LAI (least squares mean difference [95% CI]: -2.3 [-5.20; 0.63]; predetermined non-inferiority margin: -5.5). Mean (SD) change from baseline to endpoint in Clinical Global Impression-Severity scale score was: -1.5 (1.24; PP group), -1.7 (1.16; RIS-LAI group) and in Personal and Social Performance Scale scores was: 16.8 (14.76; PP group), 18.6 (13.92; RIS-LAI group). The incidence of treatment-emergent adverse events (TEAEs) was similar between the two groups (73% [PP]; 75% [RIS-LAI]). The most common TEAEs were akathisia, tremor, and insomnia. The study demonstrated the noninferiority of PP (50-150 mg eq., flexibly dosed, without oral paliperidone supplementation) to risperidone-LAI (25-50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population. PMID:21315787

  11. Bioequivalence Study of Two Long-Acting Formulations of Oxytetracycline Following Intramuscular Administration in Bovines

    PubMed Central

    Mestorino, Nora; Marchetti, María Laura; Lucas, Mariana Florencia; Modamio, Pilar; Zeinsteger, Pedro; Fernández Lastra, Cecilia; Segarra, Ignacio; Mariño, Eduardo Luis

    2016-01-01

    The aim of this study was to evaluate the bioequivalence of two commercial long-acting formulations based on oxytetracycline (OTC) hydrochloride between the reference formulation (Terramycin LA, Pfizer) and a test formulation (Cyamicin LA, Fort Dodge Saude Animal). Both formulations were administered in a single intramuscular route at a dose of 20 mg OTC/kg of body weight in clinically healthy bovines. The study was carried out according to a one-period parallel design. Plasma samples were analyzed by high-pressure liquid chromatography. The limit of quantitation was 0.050 μg/mL with an accuracy of 101.67% with a coefficient of variation of 13.15%. Analysis of variance and 90% confidence interval tests were used to compare the bioavailability parameters (maximum plasma concentration, Cmax, and the area under the concentration-versus-time curve extrapolated to infinity, AUC0–∞) of both products. In the case of the time to maximum concentration (Tmax), non-parametric tests based on Wilcoxon’s signed rank test were preferred. The comparison of the mean AUC0–∞ values did not reveal any significant differences (311.40 ± 93.05 μg h/mL and 287.71 ± 45.31 μg h/mL, respectively). The results were similar for the Tmax (3.58 ± 0.90 h versus 3.42 ± 0.51 h). However, when comparing the mean Cmax some significant differences were found (8.73 ± 3.66 μg/mL and 10.43 ± 3.84 μg/mL, respectively). The 90% confidence intervals for the ratio of AUC0–∞ and Tmax values for the reference and test product are within the interval 80–125%, but the 90% confidence intervals for the ratio of Cmax falls outside the proposed interval. It was concluded that Cmax of test product are not within the 20% of those of the reference, thus suggesting that test OTC is not bioequivalent to the reference formulation. PMID:27446938

  12. A novel, long-acting glucagon-like peptide receptor-agonist: dulaglutide

    PubMed Central

    Gurung, Tara; Shyangdan, Deepson S; O’Hare, Joseph Paul; Waugh, Norman

    2015-01-01

    Background Dulaglutide is a new, long-acting glucagon-like peptide analogue in the treatment of type 2 diabetes. It is available in two doses, 0.75 and 1.5 mg, given by injection once weekly. This systematic review reports the effectiveness and safety of dulaglutide in type 2 diabetes in dual and triple therapy. Methods MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, and conference abstracts were searched from 2005 to August 2014, and updated in January 2015. Company websites and references of included studies were checked for potentially relevant studies. European Medicines Agency and US Food and Drug Administration websites were searched. Results Four trials were included. All were manufacturer-funded randomized controlled trials from the Assessment of Weekly Administration of Dulaglutide in Diabetes (AWARD) program. AWARD-1 compared dulaglutide 1.5 mg against exenatide 10 µg twice daily and placebo, AWARD-2 compared dulaglutide 0.75 and 1.5 mg against insulin glargine, AWARD-5 compared dulaglutide 0.75 and 1.5 mg against sitagliptin 100 mg and placebo, and AWARD-6 compared dulaglutide 1.5 mg against liraglutide 1.8 mg. The duration of follow-up in the trials ranged from 26 to 104 weeks. The primary outcome of all the included trials was change in HbA1c. At 26 weeks, greater HbA1c reductions were seen with dulaglutide than with twice daily exenatide (dulaglutide 1.5/0.75 mg: −1.5%/−1.3%; exe: 0.99%) and sitagliptin (1.5/0.75 mg −1.22%/−1.01%; sitagliptin: −0.6%). HbA1c change was greater with dulaglutide 1.5 mg (−1.08%) than with glargine (−0.63%), but not with dulaglutide 0.75 mg (−0.76%). Dulaglutide 1.5 mg was found to be noninferior to liraglutide 1.8 mg. More patients treated with dulaglutide achieved HbA1c targets of <7% and ≤6.5%. Reduction in weight was greater with dulaglutide than with sitagliptin and exenatide. Hypoglycemia was infrequent. The main adverse events were nausea, diarrhea, and vomiting. Conclusion

  13. A simple and robust method for pre-wetting poly (lactic-co-glycolic) acid microspheres

    PubMed Central

    Wright, Bernice; Parmar, Nina; Bozec, Laurent; Aguayo, Sebastian D

    2015-01-01

    Poly (lactic-co-glycolic) acid microspheres are amenable to a number of biomedical procedures that support delivery of cells, drugs, peptides or genes. Hydrophilisation or wetting of poly (lactic-co-glycolic) acid are an important pre-requisites for attachment of cells and can be achieved via exposure to plasma oxygen or nitrogen, surface hydrolysis with NaOH or chloric acid, immersion in ethanol and water, or prolonged incubation in phosphate buffered saline or cell culture medium. The aim of this study is to develop a simple method for wetting poly (lactic-co-glycolic) acid microspheres for cell delivery applications. A one-step ethanol immersion process that involved addition of serum-supplemented medium and ethanol to PLGA microspheres over 30 min–24 h is described in the present study. This protocol presents a more efficient methodology than conventional two-step wetting procedures. Attachment of human skeletal myoblasts to poly (lactic-co-glycolic) acid microspheres was dependent on extent of wetting, changes in surface topography mediated by ethanol pre-wetting and serum protein adsorption. Ethanol, at 70% (v/v) and 100%, facilitated similar levels of wetting. Wetting with 35% (v/v) ethanol was only achieved after 24 h. Pre-wetting (over 3 h) with 70% (v/v) ethanol allowed significantly greater (p ≤ 0.01) serum protein adsorption to microspheres than wetting with 35% (v/v) ethanol. On serum protein-loaded microspheres, greater numbers of myoblasts attached to constructs wetted with 70% ethanol than those partially wetted with 35% (v/v) ethanol. Microspheres treated with 70% (v/v) ethanol presented a more rugose surface than those treated with 35% (v/v) ethanol, indicating that more efficient myoblast adhesion to the former may be at least partially attributed to differences in surface structure. We conclude that our novel protocol for pre-wetting poly (lactic-co-glycolic) acid microspheres that incorporates biochemical and structural features

  14. Particle Tracking of Fluorescent Microspheres

    NASA Astrophysics Data System (ADS)

    Kaminski, Zofia; Mueller, Joachim; Berk, Serkan

    2010-10-01

    In this research, the diffusion coefficients of the fluorescent microspheres and the relation of those coefficients to particle radius were investigated. An additional focus was to see how well the measured radius of the microspheres compared to the radius as reported by the manufacturer and to measure the distribution of radii in a sample. This study further developed the critical process of ensuring particle movement within the sample volume and made preliminary sample measurements.The methods developed for tracking microspheres will later be used to determine the radii of virus like particles (VLPs), which are a non-infectious model system of the HIV virus. Results from our measurements will be reported.

  15. Microsphere based saliva diagnostics

    NASA Astrophysics Data System (ADS)

    Rissin, David M.; DiCesare, Christopher; Hayman, Ryan B.; Blicharz, Timothy M.; Walt, David R.

    2005-11-01

    Saliva presents a minimally invasive alternative medium to blood for performing diagnostics1. Microsphere sensors for ions, small organic molecules, and proteins are currently being developed and optical microarrays containing thousands of these sensors will be used for simultaneous multi-analyte analysis. The fiber bundle platform in use is 1mm in diameter and contains approximately 50,000 individually addressable 3.1μm fibers, each with an etched well capable of housing a single 3.1μm microsphere sensor. Micron-sized bead-based chemistries are produced in house, followed by deposition onto a fiber-optic bundle platform, allowing for multiplexed analysis. The ultimate goal is to develop a universal diagnostic system using saliva as the diagnostic medium. This platform will permit multiplexed analysis of a sample by integrating microfluidics with the optical arrays loaded with sensors capable of detecting relevant biomarkers associated with a wide range of disease states. Disease states that are currently under investigation include end stage renal disease (ESRD) and Sjoegrens Syndrome (SS).

  16. Microencapsulation of curcumin in PLGA microcapsules by coaxial flow focusing

    NASA Astrophysics Data System (ADS)

    Lei, Fan; Si, Ting; Luo, Xisheng; Xu, Ronald X.

    2014-03-01

    Curcumin-loaded PLGA microcapsules are fabricated by a liquid-driving coaxial flow focusing device. In the process, a stable coaxial cone-jet configuration is formed under the action of a coflowing liquid stream and the coaxial liquid jet eventually breaks up into microcapsules because of flow instability. This process can be well controlled by adjusting the flow rates of three phases including the driving PVA water solution, the outer PLGA ethyl acetate solution and the inner curcumin propylene glycol solution. Confocal and SEM imaging methods clearly indicate the core-shell structure of the resultant microcapsules. The encapsulation rate of curcumin in PLGA is measured to be more than 70%, which is much higher than the tranditional methods such as emulsion. The size distribution of resultant microcapsules under different conditions is presented and compared. An in vitro release simulation platform is further developed to verify the feasibility and reliability of the method.

  17. Chemical Conjugation of Evans Blue Derivative: A Strategy to Develop Long-Acting Therapeutics through Albumin Binding

    PubMed Central

    Chen, Haojun; Wang, Guohao; Lang, Lixin; Jacobson, Orit; Kiesewetter, Dale O.; Liu, Yi; Ma, Ying; Zhang, Xianzhong; Wu, Hua; Zhu, Lei; Niu, Gang; Chen, Xiaoyuan

    2016-01-01

    The efficacy of therapeutic drugs is highly dependent on their optimal in vivo pharmacokinetics. Albumin conjugation is considered to be one of the most effective means of protracting the short lifespan of peptides and proteins. In this study, we proposed a novel platform for developing long lasting therapeutics by conjugating a small molecular albumin binding moiety, truncated Evans blue, to either peptides or proteins. Using the anti-diabetic peptide drug Exendin-4 as a model peptide, we synthesized a new long-acting Exendin-4 derivative (denoted as Abextide). Through complexation with albumin in situ, the biological half-life of Abextide was significantly extended. The hypoglycemic effect of Abextide was also improved remarkably over Exendin-4. Thus, Abextide has considerable potential to treat type 2 diabetes. This strategy as a general technology platform can be applied to other small molecules and biologics for the development of long-acting therapeutic drugs. PMID:26877782

  18. Costs and effects of long-acting risperidone compared with oral atypical and conventional depot formulations in Germany.

    PubMed

    Laux, Gerd; Heeg, Bart; van Hout, Ben A; Mehnert, Angelika

    2005-01-01

    Schizophrenia is one of the most expensive psychiatric conditions because of high direct and indirect costs associated with the nature of the illness, its resistance to treatment and the consequences of relapse. Long-acting risperidone is a new formulation of an atypical antipsychotic drug that also offers the improvements in compliance associated with haloperidol depot. The aim of this simulation study was to compare the benefits and costs of three pharmacological treatment strategies comprising first-line treatment with long-acting risperidone injection, a haloperidol depot or an oral atypical antipsychotic agent, over a 5-year period in Germany. A discrete event simulation model was developed to compare three treatment scenarios from the perspective of major third-party payers (sickness funds and social security 'Sozialversicherung'). The scenarios comprised first-line treatment with haloperidol depot (scenario 1), long-acting risperidone (scenario 2) and oral olanzapine (scenario 3). Switches to second or third-line options were allowed when side-effects occurred or a patient suffered more than a fixed number of relapses. The model accounted for fixed patient characteristics, and on the basis of these, simulated patient histories according to several time-dependent variables. The time horizon for this model was limited to 5 years, and in accordance with German guidelines, costs and effects were discounted by between 3 and 10%. Direct costs included medication, type of physician visits and treatment location. Indirect costs were not included. Information on treatment alternatives, transition probabilities, model structure and healthcare utilization were derived from the literature and an expert panel. Outcomes were expressed in terms of the number and duration of psychotic episodes, cumulative symptom scores, costs, and quality-adjusted life-years (QALY). Univariate sensitivity analyses were carried out, as were subgroup analyses based on disease severity and

  19. [Side effects of treatment with the long-acting gonadorelin agonist triptorelin in a case of paraphilia].

    PubMed

    Hoogeveen, J H; van der Veer, E

    2007-01-01

    A 35-year-old man with a paraphilia was treated with long-acting gonadorelin. The desired result was reduced preoccupation with sexuality, but there were various side effects including a serious amount of bone loss. We believe that more attention should be given to the adverse effects of long-term treatment with triptorelin. In our view the drug regimen needs to be revised. PMID:17290340

  20. Controlled Release of Dutasteride from Biodegradable Microspheres: In Vitro and In Vivo Studies

    PubMed Central

    Xie, Xiangyang; Yang, Yanfang; Chi, Qiang; Li, ZhiPing; Zhang, Hui; Li, Ying; Yang, Yang

    2014-01-01

    The aim of the present work was to study the in vitro/in vivo characteristics of dutasteride loaded biodegradable microspheres designed for sustained release of dutasteride over four weeks. An O/W emulsion-solvent evaporation method was used to incorporate dutasteride, which is of interest in the treatment of benign prostatic hyperplasia (BPH), into poly(lactide-co-glycolide) (PLGA). A response surface method (RSM) with central composite design (CCD) was employed to optimize the formulation variables. A prolonged in vitro drug release profile was observed, with a complete release of the entrapped drug within 28 days. The pharmacokinetics study showed sustained plasma drug concentration-time profile of dutasteride loaded microspheres after subcutaneous injection into rats. The in vitro drug release in rats correlated well with the in vivo pharmacokinetics profile. The pharmacodynamics evaluated by determination of the BPH inhibition in the rat models also showed a prolonged pharmacological response. These results suggest the potential use of dutasteride loaded biodegradable microspheres for the management of BPH over long periods. PMID:25541985

  1. Material characterization of microsphere-based scaffolds with encapsulated raw materials.

    PubMed

    Sridharan, BanuPriya; Mohan, Neethu; Berkland, Cory J; Detamore, Michael S

    2016-06-01

    "Raw materials," or materials capable of serving both as building blocks and as signals, which are often but not always natural materials, are taking center stage in biomaterials for contemporary regenerative medicine. In osteochondral tissue engineering, a field leveraging the underlying bone to facilitate cartilage regeneration, common raw materials include chondroitin sulfate (CS) for cartilage and β-tricalcium phosphate (TCP) for bone. Building on our previous work with gradient scaffolds based on microspheres, here we delved deeper into the characterization of individual components. In the current study, the release of CS and TCP from poly(d,l-lactic-co-glycolic acid) (PLGA) microsphere-based scaffolds was evaluated over a time period of 4weeks. Raw material encapsulated groups were compared to 'blank' groups and evaluated for surface topology, molecular weight, and mechanical performance as a function of time. The CS group may have led to increased surface porosity, and the addition of CS improved the mechanical performance of the scaffold. The finding that CS was completely released into the surrounding media by 4weeks has a significant impact on future in vivo studies, given rapid bioavailability. The addition of TCP seemed to contribute to the rough external appearance of the scaffold. The current study provides an introduction to degradation patterns of homogenous raw material encapsulated scaffolds, providing characterization data to advance the field of microsphere-based scaffolds in tissue engineering. PMID:27040236

  2. New insights into the pore structure of poly(d,l-lactide-co-glycolide) microspheres.

    PubMed

    Vay, Kerstin; Scheler, Stefan; Friess, Wolfgang

    2010-12-15

    The objective of this work was to develop a fast and significant method for the determination of the intraparticulate pore size distribution of microspheres. Poly(lactide-co-glycolide) (PLGA) microspheres prepared with a solvent extraction/evaporation process were studied. From the envelope and the skeletal volume of the microspheres the porosity was calculated. The skeletal volume was determined with nitrogen and helium pycnometry and mercury intrusion porosimetry. Based on single particle optical sensing (SPOS) a novel method was developed by which the envelope volume is calculated from the particle size distribution (PSD), provided that all particles have a spherical shape. The penetration capacity of the applied intrusion media is limited by their atomic or molecular diameter or by the surface tension and the pressure in case of mercury. A classification of the pore structure was obtained by comparing these different skeletal values with the values for the envelope volume. Two well separated pore fractions were found, a nanoporous fraction smaller than 0.36nm and a macroporous fraction larger than 3.9μm. The total porosity and the ratio between both fractions is controlled by the preparation process and was shown to depend on the solvent extraction temperature. PMID:20883760

  3. Controlled release of dutasteride from biodegradable microspheres: in vitro and in vivo studies.

    PubMed

    Xie, Xiangyang; Yang, Yanfang; Chi, Qiang; Li, ZhiPing; Zhang, Hui; Li, Ying; Yang, Yang

    2014-01-01

    The aim of the present work was to study the in vitro/in vivo characteristics of dutasteride loaded biodegradable microspheres designed for sustained release of dutasteride over four weeks. An O/W emulsion-solvent evaporation method was used to incorporate dutasteride, which is of interest in the treatment of benign prostatic hyperplasia (BPH), into poly(lactide-co-glycolide) (PLGA). A response surface method (RSM) with central composite design (CCD) was employed to optimize the formulation variables. A prolonged in vitro drug release profile was observed, with a complete release of the entrapped drug within 28 days. The pharmacokinetics study showed sustained plasma drug concentration-time profile of dutasteride loaded microspheres after subcutaneous injection into rats. The in vitro drug release in rats correlated well with the in vivo pharmacokinetics profile. The pharmacodynamics evaluated by determination of the BPH inhibition in the rat models also showed a prolonged pharmacological response. These results suggest the potential use of dutasteride loaded biodegradable microspheres for the management of BPH over long periods. PMID:25541985

  4. Knowledge and Perception on Long Acting and Permanent Contraceptive Methods in Adigrat Town, Tigray, Northern Ethiopia: A Qualitative Study

    PubMed Central

    Addissie, Adamu

    2014-01-01

    Background. Long acting and permanent contraceptive methods have the potential to reduce unintended pregnancies but the contraceptive choice and utilization in Ethiopia are highly dominated by short term contraceptives. Objective. To assess the knowledge and perception on long acting and permanent contraceptives of married women and men in Northern Ethiopia. Method. A qualitative method was conducted in Adigrat on January, 2012. Four focus group discussions with married women and men and six in-depth interviews with family planning providers were conducted. Content analysis was used to synthesize the data. Result. Participants' knowledge on long acting and permanent contraceptives is limited to recognizing the name of the methods. Most of the participants are not able to identify permanent methods as a method of contraception. They lack basic information on how these methods work and how they can use it. Women had fears and rumors about each of these methods. They prefer methods which do not require any procedure. Family planning providers stated as they have weakness on counseling of all contraceptive choices. Conclusion. There are personal barriers and knowledge gaps on these contraceptive methods. Improving the counseling service program can help women to increase knowledge and avoid misconceptions of each contraceptive choice. PMID:25140252

  5. Glass microsphere lubrication

    NASA Technical Reports Server (NTRS)

    Geiger, Michelle; Goode, Henry; Ohanlon, Sean; Pieloch, Stuart; Sorrells, Cindy; Willette, Chris

    1991-01-01

    The harsh lunar environment eliminated the consideration of most lubricants used on earth. Considering that the majority of the surface of the moon consists of sand, the elements that make up this mixture were analyzed. According to previous space missions, a large portion of the moon's surface is made up of fine grained crystalline rock, about 0.02 to 0.05 mm in size. These fine grained particles can be divided into four groups: lunar rock fragments, glasses, agglutinates (rock particles, crystals, or glasses), and fragments of meteorite material (rare). Analysis of the soil obtained from the missions has given chemical compositions of its materials. It is about 53 to 63 percent oxygen, 16 to 22 percent silicon, 10 to 16 percent sulfur, 5 to 9 percent aluminum, and has lesser amounts of magnesium, carbon, and sodium. To be self-supporting, the lubricant must utilize one or more of the above elements. Considering that the element must be easy to extract and readily manipulated, silicon or glass was the most logical choice. Being a ceramic, glass has a high strength and excellent resistance to temperature. The glass would also not contaminate the environment as it comes directly from it. If sand entered a bearing lubricated with grease, the lubricant would eventually fail and the shaft would bind, causing damage to the system. In a bearing lubricated with a solid glass lubricant, sand would be ground up and have little effect on the system. The next issue was what shape to form the glass in. Solid glass spheres was the only logical choice. The strength of the glass and its endurance would be optimal in this form. To behave as an effective lubricant, the diameter of the spheres would have to be very small, on the order of hundreds of microns or less. This would allow smaller clearances between the bearing and the shaft, and less material would be needed. The production of glass microspheres was divided into two parts, production and sorting. Production includes the

  6. Oral Delivery of DMAB-Modified Docetaxel-Loaded PLGA-TPGS Nanoparticles for Cancer Chemotherapy

    NASA Astrophysics Data System (ADS)

    Chen, Hongbo; Zheng, Yi; Tian, Ge; Tian, Yan; Zeng, Xiaowei; Liu, Gan; Liu, Kexin; Li, Lei; Li, Zhen; Mei, Lin; Huang, Laiqiang

    2011-12-01

    Three types of nanoparticle formulation from biodegradable PLGA-TPGS random copolymer were developed in this research for oral administration of anticancer drugs, which include DMAB-modified PLGA nanoparticles, unmodified PLGA-TPGS nanoparticles and DMAB-modified PLGA-TPGS nanoparticles. Firstly, the PLGA-TPGS random copolymer was synthesized and characterized. DMAB was used to increase retention time at the cell surface, thus increasing the chances of particle uptake and improving oral drug bioavailability. Nanoparticles were found to be of spherical shape with an average particle diameter of around 250 nm. The surface charge of PLGA-TPGS nanoparticles was changed to positive after DMAB modification. The results also showed that the DMAB-modified PLGA-TPGS nanoparticles have significantly higher level of the cellular uptake than that of DMAB-modified PLGA nanoparticles and unmodified PLGA-TPGS nanoparticles. In vitro, cytotoxicity experiment showed advantages of the DMAB-modified PLGA-TPGS nanoparticle formulation over commercial Taxotere® in terms of cytotoxicity against MCF-7 cells. In conclusion, oral chemotherapy by DMAB-modified PLGA-TPGS nanoparticle formulation is an attractive and promising treatment option for patients.

  7. Emulsion Electrospinning as an Approach to Fabricate PLGA/Chitosan Nanofibers for Biomedical Applications

    PubMed Central

    Tavanai, Hossein; Hilborn, Jöns; Donzel-Gargand, Olivier; Leifer, Klaus; Arpanaei, Ayyoob

    2014-01-01

    Novel nanofibers from blends of polylactic-co-glycolic acid (PLGA) and chitosan have been produced through an emulsion electrospinning process. The spinning solution employed polyvinyl alcohol (PVA) as the emulsifier. PVA was extracted from the electrospun nanofibers, resulting in a final scaffold consisting of a blend of PLGA and chitosan. The fraction of chitosan in the final electrospun mat was adjusted from 0 to 33%. Analyses by scanning and transmission electron microscopy show uniform nanofibers with homogenous distribution of PLGA and chitosan in their cross section. Infrared spectroscopy verifies that electrospun mats contain both PLGA and chitosan. Moreover, contact angle measurements show that the electrospun PLGA/chitosan mats are more hydrophilic than electrospun mats of pure PLGA. Tensile strengths of 4.94 MPa and 4.21 MPa for PLGA/chitosan in dry and wet conditions, respectively, illustrate that the polyblend mats of PLGA/chitosan are strong enough for many biomedical applications. Cell culture studies suggest that PLGA/chitosan nanofibers promote fibroblast attachment and proliferation compared to PLGA membranes. It can be assumed that the nanofibrous composite scaffold of PLGA/chitosan could be potentially used for skin tissue reconstruction. PMID:24689041

  8. Development of a methacrylate-terminated PLGA copolymer for potential use in craniomaxillofacial fracture plates.

    PubMed

    Upson, Sarah J; Partridge, Simon W; Tcacencu, Ion; Fulton, David A; Corbett, Ian; German, Matthew J; Dalgarno, Kenneth W

    2016-12-01

    We synthesised methacrylate-terminated PLGA (HT-PLGA, 85:15 LA:GA, 169kDa), for potential use as an adhesively attached craniomaxillofacial fracture fixation plate. The in vitro degradation of molecular weight, pH and flexural modulus were measured over 6weeks storage in PBS at 37°C, with commercially available high (225kDa, H-PLGA) and low (116kDa, L-PLGA) molecular weight 85:15 PLGAs used as comparators. Molecular weights of the materials reduced over 6weeks, HT-PLGA by 48%, H-PLGA by 23% and L-PLGA by 81%. HT-PLGA and H-PLGA exhibited a near constant pH (7.35) and had average flexural moduli in excess of 6GPa when produced, similar to that of the mandible. After 1week storage both exhibited a significant reduction in average modulus, however, from weeks 1-6 no further significant changes were observed, the average modulus never dropped significantly below 5.5GPa. In contrast, the L-PLGA caused a pH drop to below 7.3 by week 6 and an average modulus drop to 0.6 from an initial 4.6GPa. Cell culture using rat bone marrow stromal cells, revealed all materials were cytocompatible and exhibited no osteogenic potential. We conclude that our functionalised PLGA retains mechanical properties which are suitable for use in craniofacial fixation plates. PMID:27612737

  9. Monodisperse double-walled microspheres loaded with chitosan-p53 nanoparticles and doxorubicin for combined gene therapy and chemotherapy

    PubMed Central

    Xu, Qingxing; Xia, Yujie; Wang, Chi-Hwa; Pack, Daniel W.

    2012-01-01

    We have designed and evaluated a dual anticancer delivery system to provide combined gene therapy and chemotherapy. Double-walled microspheres consisting of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(lactic acid) (PLA) shell were fabricated via the precision particle fabrication (PPF) technique. We make use of the advantages of double-walled microspheres to deliver chitosan-DNA nanoparticles containing the gene encoding the p53 tumor suppressor protein (chi-p53) and/or doxorubicin (Dox), loaded in the shell and core phases, respectively. Different molecular weights of PLA were used to form the shell layer for each formulation. The microspheres were monodisperse with a mean diameter of 65 to 75 μm and uniform shell thickness of 8 to 17 μm. Blank and Dox-loaded microspheres typically exhibited a smooth surface with relatively few small pores, while chi-microspheres containing p53 nanoparticles, with and without Dox, presented rough and porous surfaces. The encapsulation efficiency of Dox was significantly higher when it was encapsulated alone compared to co-encapsulation with chi-p53 nanoparticles. The encapsulation efficiency of chi-p53 nanoparticles, on the other hand, was not affected by the presence of Dox. As desired, chi-p53 nanoparticles were released first, followed by simultaneous release of chi-p53 nanoparticles and Dox at a near zero-order rate. Thus, we have demonstrated that the PPF method is capable of producing double-walled microspheres and encapsulating dual agents for combined modality treatment, such as gene therapy and chemotherapy. PMID:22981564

  10. Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma in children

    PubMed Central

    Ni Chroinin, Muireann; Lasserson, Toby J; Greenstone, Ilana; Ducharme, Francine M

    2014-01-01

    Background Long-acting ß2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are increasingly prescribed in asthmatic children. Objectives To compare the safety and benefit of adding LABA to ICS with the same or an increased dose of ICS in children with persistent asthma. Search methods We searched the Cochrane Airways Group Asthma Trials Register (May 2008). Selection criteria We included randomised controlled trials testing the combination of LABA and ICS versus the same or an increased dose of ICS for minimum of at least 28 days in children and adolescents with asthma. The main outcome was the rate of exacerbations requiring rescue oral steroids. Secondary outcomes included pulmonary function, symptoms, adverse events, and withdrawals. Data collection and analysis Studies were assessed independently by two review authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible. Main results A total of 25 trials representing 31 control-intervention comparisons were included in the review randomising 5572 children. Most of the participants were inadequately controlled on current ICS dose. We assessed the addition of LABA to the same dose of ICS and to an increased dose of ICS: (1)The addition of LABA to ICS was compared to same dose ICS, namely 400 mcg/day of beclomethasone or less in 16 of the 24 studies. The mean age of participants was 10 years and males accounted for 64% of the study populations. The mean FEV1 at baseline was 80% of predicted or above in 10 studies; FEV1 61% to 79% of predicted in eight studies; and unreported in the remaining study. Participants were inadequately controlled before randomisation in all but seven studies. Compared to ICS alone, the addition of LABA to ICS was not associated with a significant reduction in exacerbations requiring oral steroids (seven studies, RR 0.92 95% CI 0.60 to 1.40). Compared to ICS alone, there was a significantly greater improvement in FEV1

  11. Aqueous Two Phase System Assisted Self-Assembled PLGA Microparticles

    NASA Astrophysics Data System (ADS)

    Yeredla, Nitish; Kojima, Taisuke; Yang, Yi; Takayama, Shuichi; Kanapathipillai, Mathumai

    2016-06-01

    Here, we produce poly(lactide-co-glycolide) (PLGA) based microparticles with varying morphologies, and temperature responsive properties utilizing a Pluronic F127/dextran aqueous two-phase system (ATPS) assisted self-assembly. The PLGA polymer, when emulsified in Pluronic F127/dextran ATPS, forms unique microparticle structures due to ATPS guided-self assembly. Depending on the PLGA concentration, the particles either formed a core-shell or a composite microparticle structure. The microparticles facilitate the simultaneous incorporation of both hydrophobic and hydrophilic molecules, due to their amphiphilic macromolecule composition. Further, due to the lower critical solution temperature (LCST) properties of Pluronic F127, the particles exhibit temperature responsiveness. The ATPS based microparticle formation demonstrated in this study, serves as a novel platform for PLGA/polymer based tunable micro/nano particle and polymersome development. The unique properties may be useful in applications such as theranostics, synthesis of complex structure particles, bioreaction/mineralization at the two-phase interface, and bioseparations.

  12. PLGA nanofibers improves the antitumoral effect of daunorubicin.

    PubMed

    Guimarães, Pedro P G; Oliveira, Michele F; Gomes, Alinne D M; Gontijo, Sávio M L; Cortés, Maria E; Campos, Paula P; Viana, Celso T R; Andrade, Silvia P; Sinisterra, Rubén D

    2015-12-01

    The objective of this study was to evaluate the in vivo anti-inflammatory angiogenesis activity and in vitro cytotoxicity on normal and cancer cell models of a drug delivery system consisting of poly(lactic-co-glycolic acid) nanofibers loaded with daunorubicin (PLGA-DNR) that were fabricated using an electrospinning process. The PLGA-DNR nanofibers were also characterized by thermogravimetric analysis (TGA), differential thermal analysis (DTA) and differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM) and confocal fluorescence microscopy. In vitro release of DNR from the nanofibers and its corresponding mechanism were also evaluated. Sixty-five percent of the DNR was released in an initial burst over 8h, and by 1224 h, eighty-five percent of the DNR had been released. The Higuchi model yielded the best fit to the DNR release profile over the first 8h, and the corresponding data from 24 to 1224 h could be modeled using zero-order kinetics. The PLGA-DNR nanofibers exhibited a higher cytotoxicity to A431 cells than free DNR but a cytotoxicity similar to free DNR against fibroblast cells. A higher antiangiogenic effect of PLGA nanofibers was observed in the in vivo data when compared to free DNR, and no inflammatory potential was observed for the nanofibers. PMID:26402423

  13. Aqueous Two Phase System Assisted Self-Assembled PLGA Microparticles.

    PubMed

    Yeredla, Nitish; Kojima, Taisuke; Yang, Yi; Takayama, Shuichi; Kanapathipillai, Mathumai

    2016-01-01

    Here, we produce poly(lactide-co-glycolide) (PLGA) based microparticles with varying morphologies, and temperature responsive properties utilizing a Pluronic F127/dextran aqueous two-phase system (ATPS) assisted self-assembly. The PLGA polymer, when emulsified in Pluronic F127/dextran ATPS, forms unique microparticle structures due to ATPS guided-self assembly. Depending on the PLGA concentration, the particles either formed a core-shell or a composite microparticle structure. The microparticles facilitate the simultaneous incorporation of both hydrophobic and hydrophilic molecules, due to their amphiphilic macromolecule composition. Further, due to the lower critical solution temperature (LCST) properties of Pluronic F127, the particles exhibit temperature responsiveness. The ATPS based microparticle formation demonstrated in this study, serves as a novel platform for PLGA/polymer based tunable micro/nano particle and polymersome development. The unique properties may be useful in applications such as theranostics, synthesis of complex structure particles, bioreaction/mineralization at the two-phase interface, and bioseparations. PMID:27279329

  14. Aqueous Two Phase System Assisted Self-Assembled PLGA Microparticles

    PubMed Central

    Yeredla, Nitish; Kojima, Taisuke; Yang, Yi; Takayama, Shuichi; Kanapathipillai, Mathumai

    2016-01-01

    Here, we produce poly(lactide-co-glycolide) (PLGA) based microparticles with varying morphologies, and temperature responsive properties utilizing a Pluronic F127/dextran aqueous two-phase system (ATPS) assisted self-assembly. The PLGA polymer, when emulsified in Pluronic F127/dextran ATPS, forms unique microparticle structures due to ATPS guided-self assembly. Depending on the PLGA concentration, the particles either formed a core-shell or a composite microparticle structure. The microparticles facilitate the simultaneous incorporation of both hydrophobic and hydrophilic molecules, due to their amphiphilic macromolecule composition. Further, due to the lower critical solution temperature (LCST) properties of Pluronic F127, the particles exhibit temperature responsiveness. The ATPS based microparticle formation demonstrated in this study, serves as a novel platform for PLGA/polymer based tunable micro/nano particle and polymersome development. The unique properties may be useful in applications such as theranostics, synthesis of complex structure particles, bioreaction/mineralization at the two-phase interface, and bioseparations. PMID:27279329

  15. Quantitative three-dimensional analysis of poly (lactic-co-glycolic acid) microsphere using hard X-ray nano-tomography revealed correlation between structural parameters and drug burst release.

    PubMed

    Huang, Xiaozhou; Li, Na; Wang, Dajiang; Luo, Yuyan; Wu, Ziyu; Guo, Zhefei; Jin, Qixing; Liu, Zhuying; Huang, Yafei; Zhang, Yongming; Wu, Chuanbin

    2015-08-10

    The objective of this study was to investigate the use of transmission hard X-ray nano-computed-tomography (nano-CT) for characterization of the pore structure and drug distribution in poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating bovine serum albumin and to study the correlation between drug distribution and burst release. The PLGA microspheres were fabricated using a double-emulsion method. The results of pore structure analysis accessed with nano-CT were compared with those acquired by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Surface pore interconnectivity and surface protein interconnectivity were obtained using combined nano-CT and pixel analysis. The correlation between surface protein interconnectivity with the initial burst release across various tested formulations was also analyzed. The size, shape, and distribution of the pores and protein could be clearly observed in the whole microsphere using nano-CT, whereas only the sectional information was observed using SEM or CLSM. Interconnected pores and surface connected pores could be clearly distinguished in nano-CT, which enables the quantitative analysis of surface pore interconnectivity and surface protein interconnectivity. The surface protein interconnectivity in different formulations correlated well with the burst release at 5-10h. Nano-CT provided a nondestructive, high-resolution, and three-dimensional analysis method to characterize the porous microsphere. PMID:25951620

  16. Effectiveness of long-acting antipsychotics in clinical practice : 1. A retrospective, 18-month follow up and comparison between paliperidone palmitate, risperidone long-acting injection and zuclopenthixol decanoate

    PubMed Central

    Cordiner, Matthew; Shajahan, Polash; McAvoy, Sarah; Bashir, Muhammad; Taylor, Mark

    2016-01-01

    Objectives: In the UK, nine different compounds are available as long-acting antipsychotic injections (LAIs). There are few clinical guidelines for determining which LAIs are most effective in specific patient groups. To measure the clinical effectiveness of LAIs we aimed to determine the now-established concept of antipsychotic discontinuation rates and measure Clinical Global Impression (CGI) outcomes. Method: The population (n was approximately 560,000) was a secondary care NHS adult mental health service in Lanarkshire, Scotland, UK. This was a retrospective, electronic case note search of LAI-naïve patients commenced on paliperidone palmitate (n = 31), risperidone long-acting injection (RLAI) (n = 102) or zuclopenthixol decanoate (n = 105), with an 18-month follow up. Kaplan–Meier survival statistics for discontinuation rates and hospital admission were calculated. CGI severity and improvement scores were retrospectively assigned by the investigating team. Results: Paliperidone palmitate performed less favourably than risperidone long-acting injection (RLAI) or zuclopenthixol decanoate. Paliperidone palmitate had higher discontinuation rates due to any cause, inefficacy and increased hospitalization risk. Paliperidone palmitate had the smallest proportion of patients assigned a clinically desirable CGI-I score of 1 (very much improved) or 2 (much improved). Conclusions: Paliperidone palmitate had less favourable discontinuation and CGI outcomes compared with RLAI and zuclopenthixol decanoate. This could not be adequately explained by patients in the paliperidone group being more chronically or severely unwell, nor by the presence of comorbidities such as alcohol or substance misuse, or by the use of lower mean dosages compared with RLAI or zuclopenthixol decanoate. We considered that prescribers are familiarizing themselves with paliperidone and outcomes may improve over time. PMID:26913175

  17. Fabrication of glass microspheres with conducting surfaces

    DOEpatents

    Elsholz, William E.

    1984-01-01

    A method for making hollow glass microspheres with conducting surfaces by adding a conducting vapor to a region of the glass fabrication furnace. As droplets or particles of glass forming material pass through multiple zones of different temperature in a glass fabrication furnace, and are transformed into hollow glass microspheres, the microspheres pass through a region of conducting vapor, forming a conducting coating on the surface of the microspheres.

  18. Fabrication of glass microspheres with conducting surfaces

    DOEpatents

    Elsholz, W.E.

    1982-09-30

    A method for making hollow glass microspheres with conducting surfaces by adding a conducting vapor to a region of the glass fabrication furnace. As droplets or particles of glass forming material pass through multiple zones of different temperature in a glass fabrication furnace, and are transformed into hollow glass microspheres, the microspheres pass through a region of conducting vapor, forming a conducting coating on the surface of the microspheres.

  19. Microspheres and their methods of preparation

    DOEpatents

    Bose, Anima B; Yang, Junbing

    2015-03-24

    Carbon microspheres are doped with boron to enhance the electrical and physical properties of the microspheres. The boron-doped carbon microspheres are formed by a CVD process in which a catalyst, carbon source and boron source are evaporated, heated and deposited onto an inert substrate.

  20. Preparation and properties of PLGA nanofiber membranes reinforced with cellulose nanocrystals.

    PubMed

    Mo, Yunfei; Guo, Rui; Liu, Jianghui; Lan, Yong; Zhang, Yi; Xue, Wei; Zhang, Yuanming

    2015-08-01

    Although extensively used in the fields of drug-carrier and tissue engineering, the biocompatibility and mechanical properties of polylactide-polyglycolide (PLGA) nanofiber membranes still limit their applications. The objective of this study was to improve their utility by introducing cellulose nanocrystals (CNCs) into PLGA nanofiber membranes. PLGA and PLGA/CNC composite nanofiber membranes were prepared via electrospinning, and the morphology and thermodynamic and mechanical properties of these nanofiber membranes were characterized by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). The cytocompatibility and cellular responses of the nanofiber membranes were also studied by WST-1 assay, SEM, and confocal laser scanning microscopy (CLSM). Incorporation of CNCs (1, 3, 5, and 7 wt.%) increased the average fiber diameter of the prepared nanofiber membranes from 100 nm (neat PLGA) to ∼400 nm (PLGA/7 wt.% CNC) and improved the thermal stability of the nanofiber membranes. Among the PLGA/CNC composite nanofiber membranes, those loaded with 7 wt.% CNC nanofiber membranes had the best mechanical properties, which were similar to those of human skin. Cell culture results showed that the PLGA/CNC composite nanofiber membranes had better cytocompatibility and facilitated fibroblast adhesion, spreading, and proliferation compared with neat PLGA nanofiber membranes. These preliminary results suggest that PLGA/CNC composite nanofiber membranes are promising new materials for the field of skin tissue engineering. PMID:26047881

  1. Development of sulfadiazine-decorated PLGA nanoparticles loaded with 5-fluorouracil and cell viability.

    PubMed

    Guimarães, Pedro Pires Goulart; Oliveira, Sheila Rodrigues; de Castro Rodrigues, Gabrielle; Gontijo, Savio Morato Lacerda; Lula, Ivana Silva; Cortés, Maria Esperanza; Denadai, Ângelo Márcio Leite; Sinisterra, Rubén Dario

    2015-01-01

    The aim of this work was to synthesize sulfadiazine-poly(lactide-co-glycolide) (SUL-PLGA) nanoparticles (NPs) for the efficient delivery of 5-fluorouracil to cancer cells. The SUL-PLGA conjugation was assessed using FTIR, 1H-NMR, 13C-NMR, elemental analysis and TG and DTA analysis. The SUL-PLGA NPs were characterized using transmission and scanning electron microscopy and dynamic light scattering. Additionally, the zeta potential, drug content, and in vitro 5-FU release were evaluated. We found that for the SUL-PLGA NPs, Dh = 114.0 nm, ZP = -32.1 mV and the encapsulation efficiency was 49%. The 5-FU was released for up to 7 days from the NPs. Cytotoxicity evaluations of 5-FU-loaded NPs (5-FU-SUL-PLGA and 5-FU-PLGA) on two cancer cell lines (Caco-2, A431) and two normal cell lines (fibroblast, osteoblast) were compared. Higher cytotoxicity of 5-FU-SUL-PLGA NPs were found to both cancer cell lines when compared to normal cell lines, demonstrating that the presence of SUL could significantly enhance the cytotoxicity of the 5-FU-SUL-PLGA NPs when compared with 5-FU-PLGA NPs. Thus, the development of 5-FU-SUL-PLGA NPs to cancer cells is a promising strategy for the 5-FU antitumor formulation in the future. PMID:25580685

  2. Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management.

    PubMed

    King, Nathan; Tran, Minh-Ha

    2015-10-01

    Long-acting anticoagulant rodenticides (LAARs) inhibit vitamin K epoxide reductase (VKOR). Related bleeding may present a diagnostic challenge and require administration of blood component therapy, hemostatic agents, and vitamin K. This article intends to provide the reader a comprehensive understanding of LAAR poisoning. An exhaustive literature search of PubMed, Science Direct, US National Library of Medicine Toxicology Data Network, and Google Scholar yielded 174 reported cases of LAAR poisoning from which clinical data were extracted and reviewed. In addition, 25 years of epidemiologic data from the American Association of Poison Control Centers was reviewed. In the United States, on average, there were 10413 exposures reported with 2750 patients treated annually. For 25 years, there were 315951 exposures reported with nearly 90% among children and more than 100000 patients treated in a health care facility. Fortunately, only 2% of all exposures result in morbidity or mortality. Inhalational, transcutaneous, and oral routes of exposure have been documented. Most exposures are unintentional. The most frequently reported bleeding sites are mucocutaneous, with hematuria being the most common feature. Deaths were most commonly associated with intracranial hemorrhage. Long-acting anticoagulant rodenticide-induced paradoxical thrombosis and thrombotic complications accompanying hemostatic therapy have also been observed. Most patients present with coagulation assay values beyond measurable limits. Long-acting anticoagulant rodenticides have an extremely high affinity for VKOR compared with warfarin, characterized by rebound coagulopathy and bleeding after initial treatment and the need for high-dose, long-term therapy with vitamin K1. Treatment of acute hemorrhagic symptoms often required intravenous vitamin K1 in excess of 50 to 100 mg; chronic maintenance with 100 mg PO vitamin K1 daily was the most frequently used dose required to suppress coagulopathy. Treatment

  3. [Experimental study on application recombinant human bone morphogenetic protein 2(rhBMP-2)/poly-lactide-co-glycolic acid (PLGA)/fibrin sealant(FS) on repair of rabbit radial bone defect].

    PubMed

    Fan, Zhongkai; Cao, Yang; Zhang, Zhe; Zhang, Mingchao; Lu, Wei; Tang, Lei; Yao, Qi; Lu, Gang

    2012-10-01

    This paper is aimed to investigate the repair of rabbit radial bone defect by the recombinant human bone morphogenetic protein 2/poly-lactideco-glycolic acid microsphere with fibrin sealant (rhBMP-2/PLGA/FS). The radial bone defect models were prepared using New Zealand white rabbits, which were randomly divided into 3 groups, experiment group which were injected with eMP-2/PLGA/FS at bone defect location, control group which were injected with FS at bone defect location, and blank control group without treatment. The ability of repairing bone defect was evaluated with X-ray radiograph. Bone mineral density in the defect regions was analysed using the level of ossification. The osteogenetic ability of repairing bone defect, the degradation of the material, the morphologic change and the bone formation were assessed by HE staining and Masson staining. The result showed that rhBMP-2/PLGA/FS had overwhelming superiority in the osteogenetic ability and quality of bone defect over the control group, and it could promote the repair of bone defect and could especially repair the radial bone defect of rabbit well. It may be a promising and efficient synthetic bone graft. PMID:23198432

  4. Potential long-acting anticonvulsants. 1; Synthesis and activity of succinimides containing an alkylating group at the 2 position.

    PubMed

    Kornet, M J; Crider, A M; Magarian, E O

    1977-03-01

    The synthesis of succinimide derivatives in which alkylating groups have been attached to the 2 positions of the ring or to the para position of the 2-phenyl substituent is described. The alkylating groups used were (a) alpha-haloacetyl, (b) alpha-haloacetamido, (c) maleimido, and (d) maleamyl. These compounds were prepared as potential long-acting anticonvulsants. Several of these derivatives exhibited activity against metrazole-induced seizures comparable to phensuximde, The maleimide 16 and the bromoacetamido derivative 23 exhibited a duration of action of at least 3.5 h. PMID:845873

  5. Pipotiazine palmitate: an evaluation of a new long acting intramuscular antipsychotic agent in severely ill schizophrenic patients.

    PubMed

    Gallant, D M; Mielke, D; Bishop, G; Oelsner, T; Guerrero-Figueroa, R

    1975-04-01

    Findings in this study support earlier investigations in attesting to the antipsychotic efficacy and relatively low toxicity of pipotiazine palmitate. Results with all efficacy measures utilized were consistent in indicating a high level of efficacy for this investigational compound. Pipotiazine palmitate apparently has an average duration of action that extends beyond 4 weeks in severely ill schizophrenic patients. This particular long acting IM antipsychotic preparation appears to have an even longer duration of activity than some of the other available standard long acting agents. The optimal dosage range for severely ill schizophrenic patients appears to be between 100 and 600 mg once monthly. While this type of drug (as is the case with many antipsychotic drugs) does reduce the psychotic symptomatology and improves the thought associations sufficient to enable the patient to leave the hospital, it should be re-emphasized that socioeconomic and guidance counseling services are necessary to maintain the patient in the community. The availability of this type of long acting preparation is not only economical in terms of nursing care and hospital cost but it should also increase the efficacy of psychopharmacologic treatment of schizophrenics by reducing both patient errors and staff errors in administration of medication. In addition, this IM preparation should prove to be of invaluable help in maintaining the schizophrenic patient in his community by reducing the relapse and the rehospitalization rates. It should be noted that there are schizophrenic patients who either absorb compounds from the gastrointestinal tract in a very poor manner or too rapidly metabolize the antipsychotic agents with resultant suboptimal blood levels and these subjects may be called "drug refractory." This type of long acting medication is an ideal preparation for the schizophrenic patient who has these types of absorption or metabolic problems since the "circulatory pass" through the

  6. Multilayered polymer microspheres by thermal imprinting during microsphere growth.

    PubMed

    Takekoh, Ryu; Li, Wen-Hui; Burke, Nicholas A D; Stöver, Harald D H

    2006-01-11

    Modulation of the polymerization temperature in precipitation polymerizations was used to form onion-type polymer microspheres consisting of multiple nested layers. Specifically, the copolymerization of chloromethylstyrene and divinylbenzene-55 in acetonitrile, at temperatures ramping between 65 and 75 degrees C, led to monodisperse, cross-linked microspheres of about 10 mum diameter that have radial density profiles closely reflecting the thermal profiles used. This thermal imprinting is attributed to the copolymer formed being close to its theta point during the polymerization. As the microspheres grow by continuously capturing oligomers from solution, the resulting transient surface gel layer expands and contracts with temperature, and thus records the reaction temperature profile in the form of a corresponding density profile, even as it cross-links. PMID:16390152

  7. Advances in Microsphere Insulation Systems

    NASA Astrophysics Data System (ADS)

    Allen, M. S.; Baumgartner, R. G.; Fesmire, J. E.; Augustynowicz, S. D.

    2004-06-01

    Microsphere insulation, typically consisting of hollow glass bubbles, combines in a single material the desirable properties that other insulations only have individually. The material has high crush strength, low density, is noncombustible, and performs well in soft vacuum. Microspheres provide robust, low-maintenance insulation systems for cryogenic transfer lines and dewars. They also do not suffer from compaction problems typical of perlite that result in the necessity to reinsulate dewars because of degraded thermal performance and potential damage to its support system. Since microspheres are load bearing, autonomous insulation panels enveloped with lightweight vacuum-barrier materials can be created. Comprehensive testing performed at the Cryogenics Test Laboratory located at the NASA Kennedy Space Center demonstrated competitive thermal performance with other bulk materials. Test conditions were representative of actual-use conditions and included cold vacuum pressure ranging from high vacuum to no vacuum and compression loads from 0 to 20 psi. While microspheres have been recognized as a legitimate insulation material for decades, actual implementation has not been pursued. Innovative microsphere insulation system configurations and applications are evaluated.

  8. Microsphere-Based Scaffolds Carrying Opposing Gradients of Chondroitin Sulfate and Tricalcium Phosphate

    PubMed Central

    Gupta, Vineet; Mohan, Neethu; Berkland, Cory J.; Detamore, Michael S.

    2015-01-01

    Extracellular matrix (ECM) components, such as chondroitin sulfate (CS) and tricalcium phosphate, serve as raw materials, and thus spatial patterning of these raw materials may be leveraged to mimic the smooth transition of physical, chemical, and mechanical properties at the bone-cartilage interface. We hypothesized that encapsulation of opposing gradients of these raw materials in high molecular weight poly(d,l-lactic-co-glycolic acid) (PLGA) microsphere-based scaffolds would enhance differentiation of rat bone marrow–derived stromal cells. The raw material encapsulation altered the microstructure of the microspheres and also influenced the cellular morphology that depended on the type of material encapsulated. Moreover, the mechanical properties of the raw material encapsulating microsphere-based scaffolds initially relied on the composition of the scaffolds and later on were primarily governed by the degradation of the polymer phase and newly synthesized ECM by the seeded cells. Furthermore, raw materials had a mitogenic effect on the seeded cells and led to increased glycosaminoglycan (GAG), collagen, and calcium content. Interestingly, the initial effects of raw material encapsulation on a per-cell basis might have been overshadowed by medium-regulated environment that appeared to favor osteogenesis. However, it is to be noted that in vivo, differentiation of the cells would be governed by the surrounding native environment. Thus, the results of this study demonstrated the potential of the raw materials in facilitating neo-tissue synthesis in microsphere-based scaffolds and perhaps in combination with bioactive signals, these raw materials may be able to achieve intricate cell differentiation profiles required for regenerating the osteochondral interface. PMID:26191526

  9. Effect of copolymer composition on the physicochemical characteristics, in vitro stability, and biodistribution of PLGA-mPEG nanoparticles.

    PubMed

    Avgoustakis, K; Beletsi, A; Panagi, Z; Klepetsanis, P; Livaniou, E; Evangelatos, G; Ithakissios, D S

    2003-06-18

    The physicochemical properties, the colloidal stability in vitro and the biodistribution properties in mice of different PLGA-mPEG nanoparticle compositions were investigated. The nanoparticles were prepared by a precipitation-solvent evaporation technique. The physical characteristics and the colloidal stability of the PLGA-mPEG nanoparticles were significantly influenced by the composition of the PLGA-mPEG copolymer used to prepare the nanoparticles. PLGA-mPEG nanoparticles prepared from copolymers having relatively high mPEG/PLGA ratios were smaller and less stable than those prepared from copolymers having relatively low mPEG/PLGA ratios. All PLGA-mPEG nanoparticle compositions exhibited prolonged residence in blood, compared to the conventional PLGA nanoparticles. The composition of the PLGA-mPEG copolymer affected significantly the blood residence time and the biodistribution of the PLGA-mPEG nanoparticles in liver, spleen and bones. The in vivo behavior of the different PLGA-mPEG nanoparticle compositions did not appear to correlate with their in vitro stability. Optimum mPEG/PLGA ratios appeared to exist leading to long blood circulation times of the PLGA-mPEG nanoparticles. This may be associated with the effects of the mPEG/PLGA ratio on the density of PEG on the surface of the nanoparticles and on the size of the nanoparticles. PMID:12787641

  10. Microsphere-based gradient implants for osteochondral regeneration: a long-term study in sheep

    PubMed Central

    Mohan, Neethu; Gupta, Vineet; Sridharan, Banu Priya; Mellott, Adam J; Easley, Jeremiah T; Palmer, Ross H; Galbraith, Richard A; Key, Vincent H; Berkland, Cory J; Detamore, Michael S

    2015-01-01

    Background: The microfracture technique for cartilage repair has limited ability to regenerate hyaline cartilage. Aim: The current study made a direct comparison between microfracture and an osteochondral approach with microsphere-based gradient plugs. Materials & methods: The PLGA-based scaffolds had opposing gradients of chondroitin sulfate and β-tricalcium phosphate. A 1-year repair study in sheep was conducted. Results: The repair tissues in the microfracture were mostly fibrous and had scattered fissures with degenerative changes. Cartilage regenerated with the gradient plugs had equal or superior mechanical properties; had lacunated cells and stable matrix as in hyaline cartilage. Conclusion: This first report of gradient scaffolds in a long-term, large animal, osteochondral defect demonstrated potential for equal or better cartilage repair than microfracture. PMID:26418471

  11. Development of 5-iodo-2'-deoxyuridine milling process to reduce initial burst release from PLGA microparticles.

    PubMed

    Gèze, A; Venier-Julienne, M C; Mathieu, D; Filmon, R; Phan-Tan-Luu, R; Benoit, J P

    1999-02-15

    The aim of this study was to prepare 5-iodo-2'-deoxyuridine (IdUrd) loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with a reduced initial burst in the in vitro release profile, by modifying the drug grinding conditions. IdUrd particle size reduction has been performed using spray-drying or ball milling. Spray-drying significantly reduced drug particle size with a change of the initial crystalline form to an amorphous one and led to a high initial burst. Conversely, ball milling did not affect the initial IdUrd crystallinity. Therefore, the grinding process was optimized to emphasize the initial burst reduction. A first step allowed us to set qualitative parameters such as ball number (7) and cooling with liquid nitrogen to obtain a mean size reduction and a narrow distribution. In a second step, three parameters including milling speed, drug amount and time were studied by a response surface analysis. The interrelationship between drug amount and milling speed was the most significant factor. To reduce particle size it should be necessary to use a moderate speed associated with a sufficient drug amount (400-500 mg). IdUrd release from microparticles prepared by the o/w emulsion/extraction solvent evaporation process with the lowest crystalline particle size (15.3 microns) was studied. Burst effect could be reduced significantly. Concerning the first phase of drug release, the burst was 8.7% for 15.3 microns compared to 19% for 19.5 microns milled drug particles. PMID:10205645

  12. Modeling the Formation of Polyimide Microspheres

    NASA Technical Reports Server (NTRS)

    Pipes, R. B.; Weiser, E. S.; Gonsoulin, B.; Hubert, P.

    2002-01-01

    High temperature polyimide microspheres have been developed from polyimide solid residuum by a simple inflation process. Microspheres have been fabricated from several polyimide precursors through the use of a circulating air oven. Microsphere formation and final physical property characterization have been limited to simple mechanical and thermal testing. The present paper focuses on developing an understanding of microsphere formation through simple geometric rules for an incompressible polymeric material and microscopic observations of precursor residuum inflation. Inflation kinematics of the hollow polyimide microspheres as a function of time and temperature is discussed.

  13. Polarization Dependent Whispering Gallery Modes in Microspheres

    NASA Technical Reports Server (NTRS)

    Adamovsky, Grigory (Inventor); Wrbanek, Susan Y. (Inventor)

    2016-01-01

    A tunable resonant system is provided and includes a microsphere that receives an incident portion of a light beam generated via a light source, the light beam having a fundamental mode, a waveguide medium that transmits the light beam from the light source to the microsphere, and a polarizer disposed in a path of the waveguide between the light source and the microsphere. The incident portion of the light beam creates a fundamental resonance inside the microsphere. A change in a normalized frequency of the wavelength creates a secondary mode in the waveguide and the secondary mode creates a secondary resonance inside the microsphere.

  14. Biocompatibility and characteristics of chitosan/cellulose acetate microspheres for drug delivery

    NASA Astrophysics Data System (ADS)

    Zhou, Hui-Yun; Zhou, Dong-Ju; Zhang, Wei-Fen; Jiang, Ling-Juan; Li, Jun-Bo; Chen, Xi-Guang

    2011-12-01

    In this work, chitosan/cellulose acetate microspheres (CCAM) were prepared by the method of W/O/W emulsion with no toxic reagents. The microspheres were spherical, free flowing, and non-aggregated, which had a narrow size distribution. More than 90% of the microspheres had the diameter ranging from 200 to 280 μm. The hemolytic analysis indicated that CCAM was safe and had no hemolytic effect. The implanted CCAM did not produce any significant changes in the hematology of Sprague-Dawley (SD) rats, such as white blood cell, red blood cell, platelet, and the volume of hemoglobin. In addition, the levels of serum alanine aminotransferase, blood urea nitrogen, and creatinine had no obvious changes in SD rats implanted with CCAM, surger thread, or normal SD rats without any implantation. Thus, the CCAM had good blood compatibility and had no hepatotoxicity or renal toxicity to SD rats. Furthermore, CCAM with or without the model drug had good tissue compatibility with respect to the inflammatory reaction in SD rats and showed no significant difference from that of SD rats implanted with surgery thread. CCAM shows promise as a long-acting delivery system, which had good biocompatibility and biodegradability.

  15. Pharmacokinetics of a long-acting oxytetracycline preparation in ring-necked pheasants, great horned owls, and Amazon parrots.

    PubMed

    Teare, J A; Schwark, W S; Shin, S J; Graham, D L

    1985-12-01

    After a single IV or IM dose of a long-acting oxytetracycline (OTC) preparation, serum concentrations were determined at various times in the ring-necked pheasant, great horned owl, and Amazon parrot. Pharmacokinetic parameters, including serum half-life (t1/2) and apparent volume of distribution (Vd) were calculated from the OTC concentration-time curves for each species and route of administration. Significant differences (P less than 0.05) were found in the t1/2 and Vd parameters between species and routes of administration. Dosage regimens to maintain minimum OTC concentration of 5 micrograms/ml of serum were calculated from the t 1/2 and Vd values obtained, using steady-state pharmacokinetics. In the pheasant, the calculated mean IV dose was 23 mg/kg of body weight every 6 hours, whereas the mean IM dose was 43 mg/kg every 24 hours. The mean IM dose was 16 mg/kg every 24 hours for the owl and 58 mg/kg every 24 hours for the parrot. The small volumes required for treatment, the long-dosing interval obtainable, and the broad spectrum of antimicrobial activity of the long-acting OTC preparation studied offered major advantages over other antibiotics commonly used in treating avian species. PMID:4083606

  16. Long-Acting Reversible Contraceptive Use in Urban Women From a Title X–Supported Boston Community Health Center

    PubMed Central

    Ricciotti, Hope A.; Dodge, Laura E.; Ramirez, Christina I.; Barnes, Katherine; Hacker, Michele R.

    2015-01-01

    Background Unintended and adolescent pregnancy disproportionately affects minority populations, but the effect of age, race and ethnicity on the use of long-acting reversible contraception (LARC) has not been well studied. Objective The objective of this pilot study was to examine LARC use over a 5-year period among women receiving care at a Boston community health center. Methods Retrospective cohort study of LARC method use among black, Hispanic, and white women receiving care at the Dimock Center from 2006 to 2010. Results This study included 276 women (60.1% black, 18.5% Hispanic, and 9.1% white). LARC was not used as a first-line method in the majority (96.0%), regardless of age, race, and ethnicity; yet nearly half identified a long-acting contraceptive as their method of choice. Conclusions The findings of this pilot study reveal opportunities to reduce unintended pregnancy through increased LARC use, which may be accomplished by provider and patient education. PMID:25301380

  17. Long-acting injectables and risk for rehospitalization among patients with schizophrenia in the home care program in Taiwan.

    PubMed

    Ju, Po-Chung; Chou, Frank Huang-Chih; Lai, Te-Jen; Chuang, Po-Ya; Lin, Yung-Jung; Yang, Ching-Wen Wendy; Tang, Chao-Hsiun

    2014-02-01

    We aimed at evaluating the relationship between medication and treatment effectiveness in a home care setting among patients with schizophrenia. Patients with schizophrenia hospitalized between 2004 and 2009 with a primary International Classification of Diseases, Ninth Revision, Clinical Modification code of 295 were identified from Psychiatric Inpatient Medical Claims Data released by the National Health Research Institute in Taiwan. Patients who joined the home care program after discharge and were prescribed long-acting injection (LAI) (the LAI group) or oral antipsychotic medications (the oral group) were included as study subjects. The final sample for the study included 810 participants in the LAI group and 945 in the oral group. Logistic regression was performed to examine the independent effect of LAI medication on the risk for rehospitalization within the 12-month observation window after controlling for patient and hospital characteristics and propensity score quintile adjustment. The unadjusted odds ratio for rehospitalization risk was 0.80 (confidence interval, 0.65-0.98) for the LAI group compared to the oral group. The adjusted odds ratio was further reduced to 0.78 (confidence interval, 0.63-0.97). Results remained unchanged when the propensity score quintiles were entered into the regression for further adjustment. In a home care setting, patients treated with long-acting antipsychotic agents are at a significantly lower risk for psychiatric rehospitalization than those treated with oral medication. Consequently, LAI home-based treatment for the prevention of schizophrenia relapse may lead to substantial clinical and economic benefits. PMID:24145217

  18. Rapid nongenomic actions of inhaled corticosteroids on long-acting β(2)-agonist transport in the airway.

    PubMed

    Horvath, Gabor; Mendes, Eliana S; Schmid, Nathalie; Schmid, Andreas; Conner, Gregory E; Fregien, Nevis L; Salathe, Matthias; Wanner, Adam

    2011-12-01

    Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting β(2)-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the non-charged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid-sensitive disposition mechanism for cationic long-acting β(2)-agonist bronchodilators in the airway. Potency rank order and other 'classical' features of anti-inflammatory effects do not apply to inhaled corticosteroids' rapid drug transport actions. PMID:21914487

  19. Production of monodisperse, polymeric microspheres

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor); Rhim, Won-Kyu (Inventor); Hyson, Michael T. (Inventor); Chang, Manchium (Inventor)

    1990-01-01

    Very small, individual polymeric microspheres with very precise size and a wide variation in monomer type and properties are produced by deploying a precisely formed liquid monomer droplet, suitably an acrylic compound such as hydroxyethyl methacrylate into a containerless environment. The droplet which assumes a spheroid shape is subjected to polymerizing radiation such as ultraviolet or gamma radiation as it travels through the environment. Polymeric microspheres having precise diameters varying no more than plus or minus 5 percent from an average size are recovered. Many types of fillers including magnetic fillers may be dispersed in the liquid droplet.

  20. Fabrication of Fucoxanthin-Loaded Microsphere(F-LM) By Two Steps Double-Emulsion Solvent Evaporation Method and Characterization of Fucoxanthin before and after Microencapsulation.

    PubMed

    Noviendri, Dedi; Jaswir, Irwandi; Taher, Muhammad; Mohamed, Farahidah; Salleh, Hamzah Mohd; Noorbatcha, Ibrahim Ali; Octavianti, Fitri; Lestari, Widya; Hendri, Ridar; Ahmad, Hasna; Miyashita, Kazuo; Abdullah, Alias

    2016-08-01

    Microencapsulation is a promising approach in drug delivery to protect the drug from degradation and allow controlled release of the drug in the body. Fucoxanthin-loaded microsphere (F-LM) was fabricated by two step w/o/w double emulsion solvent evaporation method with poly (L-lactic-coglycolic acid) (PLGA) as carrier. The effect of four types of surfactants (PVA, Tween-20, Span-20 and SDS), homogenization speed, and concentration of PLGA polymer and surfactant (PVA), respectively, on particle size and morphology of F-LM were investigated. Among the surfactants tested, PVA showed the best results with smallest particle size (9.18 µm) and a smooth spherical surface. Increasing the homogenization speed resulted in a smaller mean F-LM particle size [d(0.50)] from 17.12 to 9.18 µm. Best particle size results and good morphology were attained at homogenization speed of 20 500 rpm. Meanwhile, increased PLGA concentration from 1.5 to 11.0 (% w/v) resulted in increased F-LM particle size. The mean particle size [d(0.5)] of F-LM increased from 3.93 to 11.88 µm. At 6.0 (% w/v) PLGA, F-LM showed the best structure and external morphology. Finally, increasing PVA concentration from 0.5 to 3.5 (% w/v) resulted in decreased particle size from 9.18 to 4.86 µm. Fucoxanthin characterization before and after microencapsulation was carried out to assess the success of the microencapsulation procedure. Thermo gravimetry analysis (TGA), glass transition (Tg) temperature of F-LM and fucoxanthin measured using DSC, ATR-FTIR and XRD indicated that fucoxanthin was successfully encapsulated into the PLGA matrix, while maintaining the structural and chemical integrity of fucoxanthin. PMID:27430384

  1. Formulations for modulation of protein release from large-size PLGA microparticles for tissue engineering.

    PubMed

    Qodratnama, Roozbeh; Serino, Lorenzo Pio; Cox, Helen C; Qutachi, Omar; White, Lisa J

    2015-02-01

    In this study we present an approach to pre-program lysozyme release from large size (100-300 μm) poly(DL-lactic acid-co-glycolic acid) (PLGA) microparticles. This approach involved blending in-house synthesized triblock copolymers with a PLGA 85:15. In this work it is demonstrated that the lysozyme release rate and the total release are related to the mass of triblock copolymer present in polymer formulation. Two triblock copolymers (PLGA-PEG1500-PLGA and PLGA-PEG1000-PLGA) were synthesized and used in this study. In a like-for-like comparison, these two triblock copolymers appeared to have similar effects on the release of lysozyme. It was shown that blending resulted in the increase of the total lysozyme release and shortened the release period (70% release within 30 days). These results demonstrated that blending PLGA-PEG-PLGA triblock copolymer with PLGA 85:15 can be used as a method to pre-program protein release from microparticles. These microparticles with modulated protein release properties may be used to create microparticle-based tissue engineering constructs with pre-programmed release properties. PMID:25492193

  2. Initial Development and Characterization of PLGA Nanospheres Containing Ropivacaine

    PubMed Central

    Moraes, Carolina Morales; de Matos, Angélica Prado; de Lima, Renata; Rosa, André Henrique; de Paula, Eneida

    2008-01-01

    Local anesthetics are able to induce pain relief by binding to the sodium channels of excitable membranes, blocking the influx of sodium ions and the propagation of the nervous impulse. Ropivacaine (RVC) is an amino amide, enantiomerically pure, local anesthetic largely used in surgical procedures, which present physico-chemical and therapeutic properties similar to those of bupivacaine but decreased toxicity and motor blockade. The present work focuses on the preparation and characterization of nanospheres containing RVC; 0.25% and 0.50% RVC were incorporated in poly(d,l-lactide-co-glycolide (PLGA) 50:50) nanospheres (PLGA-NS), prepared by the nanoprecipitation method. Characterization of the nanospheres was conducted through the measurement of pH, particle size, and zeta potential. The pH of the nanoparticle system with RVC was 6.58. The average diameters of the RVC-containing nanospheres was 162.7 ± 1.5 nm, and their zeta potentials were negative, with values of about −10.81 ± 1.16 mV, which promoted good stabilization of the particles in solution. The cytotoxicity experiments show that RVC-loaded PLGA-NS generate a less toxic formulation as compared with plain RVC. Since this polymer drug-delivery system can effectively generate an even less toxic RVC formulation, this study is fundamental due to its characterization of a potentially novel pharmaceutical form for the treatment of pain with RVC. PMID:19669531

  3. HDL-Mimetic PLGA Nanoparticle To Target Atherosclerosis Plaque Macrophages

    PubMed Central

    Sanchez-Gaytan, Brenda L.; Fay, Francois; Lobatto, Mark E.; Tang, Jun; Ouimet, Mireille; Kim, YongTae; van der Staay, Susanne E. M.; van Rijs, Sarian M.; Priem, Bram; Zhang, Liangfang; Fisher, Edward A; Moore, Kathryn J.; Langer, Robert; Fayad, Zahi A.; Mulder, Willem J M

    2015-01-01

    High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA–HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA–HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers. PMID:25650634

  4. NanoCipro Encapsulation in Monodisperse Large Porous PLGA Microparticles

    PubMed Central

    Arnold, Matthew M.; Gorman, Eric M.; Schieber, Loren J.; Munson, Eric J.; Berland, Cory

    2007-01-01

    Pulmonary drug delivery of controlled release formulations may provide an effective adjunct approach to orally delivered antibiotics for clearing persistent lung infections. Dry powder formulations for this indication should possess characteristics including; effective deposition to infected lung compartments, persistence at the infection site, and steady release of antibiotic. Large porous particles (∼10-15 μm) have demonstrated effective lung deposition and enhanced lung residence as a result of their large diameter and reduced clearance by macrophages in comparison to small microparticles (∼1-5 μm). In this report, Precision Particle Fabrication technology was used to create monodisperse large porous particles of poly(D,L-lactic-co-glycolic acid) (PLGA) utilizing oils as extractable porogens. After extraction, the resulting large porous PLGA particles exhibited a low density and a web-like or hollow interior depending on porogen concentration and type, respectively. Ciprofloxacin nanoparticles (nanoCipro) created by homogenization in dichloromethane, possessed a polymorph with a decreased melting temperature. Encapsulating nanoCipro in large porous PLGA particles resulted in a steady release of ciprofloxacin that was extended for larger particle diameters and for the solid particle morphology in comparison to large porous particles. The encapsulation efficiency of nanoCipro was quite low and factors impacting the entrapment of nanoparticles during particle formation were elucidated. A dry powder formulation with the potential to control particle deposition and sustain release to the lung was developed and insight to improve nanoparticle encapsulation is discussed. PMID:17604870

  5. Microspheres and nanoparticles from ultrasound

    NASA Astrophysics Data System (ADS)

    Suh, Won Hyuk

    Improved preparations of various examples of monodispersed, porous, hollow, and core-shell metal and semiconductor nanoparticles or nanowires have been developed. Now titania microspheres and nanoparticles and silica microspheres can be synthesized using an inexpensive high frequency (1.7 MHz) ultrasonic generator (household humidifier; ultrasonic spray pyrolysis; USP). Morphology and pore size of titania microspheres were controlled by the silica to Ti(IV) ratio and silica particle size. Fine tuning the precursor ratio affords sub-50 nm titania nanoparticles as well. In terms of silica microspheres, morphology was controlled by the silica to organic monomer ratio. In liquids irradiated with high intensity ultrasound (20 kHz; HIUS), acoustic cavitation produces high energy chemistry through intense local heating inside the gas phase of collapsing bubbles in the liquid. HIUS and USP confine the chemical reactions to isolated sub-micron reaction zones, but sonochemistry does so in a heated gas phase within a liquid, while USP uses a hot liquid droplet carried by a gas flow. Thus, USP can be viewed as a method of phase-separated synthesis using submicron-sized droplets as isolated chemical reactors for nanomaterial synthesis. While USP has been used to create both titania and silica spheres separately, there are no prior reports of titania-silica composites. Such nanocomposites of metal oxides have been produced, and by further manipulation, various porous structures with fascinating morphologies were generated. Briefly, a precursor solution was nebulized using a commercially available household ultrasonic humidifier (1.7 MHz ultrasound generator), and the resulting mist was carried in a gas stream of air through a quartz glass tube in a hot furnace. After exiting the hot zone, these microspheres are porous or hollow and in certain cases magnetically responsive. In the case of titania microspheres, they are rapidly taken up into the cytoplasm of mammalian cells and

  6. FDA's recommendations on the use of long-acting {beta}2 agonists in the management of asthma.

    PubMed

    Robinson, Christie A

    2010-10-01

    The revised labeling for long-acting β(2) agonists (LABAs) by the Food and Drug Administration (FDA) is controversial and in part is inconsistent with the 2007 National Asthma Education and Prevention Program asthma guidelines. Two large randomized controlled studies, the Serevent Nationwide Surveillance (SNS) study and the Salmeterol Multicenter Asthma Research Trial (SMART), and a 2008 meta-analysis conducted by the FDA were the main sources of information used to determine the label changes. A paucity of large, well-designed, controlled, prospective studies evaluating the asthma-related risks associated with LABAs makes it difficult to reach a consensus regarding how best to use LABAs in patients with asthma. PMID:20841520

  7. Short- and long-term effect of a long-acting somatostatin analogue, lanreotide (SR-L) on metastatic gastrinoma.

    PubMed

    Gaztambide, S; Vazquez, J A

    1999-02-01

    Medical treatment is the elective therapy for patients with gastrinoma when the tumor is not found at surgery or is unresectable or when there is a metastatic disease. H2-blockers and omeprazol are able to control gastric acid secretion and, in addition, somatostatin analogues decrease gastrin levels. A new long-acting and slow release formulation of a somatostatin analogue (lanreotide, SR-L) has been developed. We treated two patients suffering from gastrinoma, total gastrectomy and hepatic metastases with 30 mg intramuscular injections of SR-L every 15 and 10 days, respectively, for a seven-month period. After the treatment, gastrin levels decreased from 35,494 and 15,086 ng/l to 3,211 and 167 ng/l (92 and 98% below pre-treatment levels) in case 1 and 2 respectively, with a relief of symptoms and no side effects. PMID:10195383

  8. Crimson carrier, a long-acting contrast agent for in vivo near-infrared imaging of injured and diseased muscle.

    PubMed

    Prajapati, Suresh I; Martinez, Carlo O; Abraham, Jinu; McCleish, Amanda T; Michalek, Joel E; McManus, Linda M; Rubin, Brian P; Shireman, Paula K; Keller, Charles

    2010-08-01

    The near-infrared wavelengths (700-900 nm) are the most suitable optical window for light penetration and deep tissue imaging in small animals. Herein we report a near-infrared fluorescent contrast agent, crimson carrier, which acts as a blood pool contrast agent to detect and quantify injury and disease in live animals. After determining the excitation-emission spectra and pharmacokinetics, crimson carrier was injected into myoinjured mice to monitor their recovery. Crimson carrier was also used to image transgenic mice with spontaneous tumors. Crimson carrier has maximal excitation and emission wavelengths of 745 nm and 820 nm, respectively. Elimination occurs predominantly via urinary excretion. We demonstrate the utility of this contrast agent for serial imaging of traumatized muscle as well as muscle tumors. The unique long-acting pharmacokinetics and urinary excretion route characteristics make crimson carrier a contrast agent of choice for the visualization of tumors and injured muscle or other tissues in live animal studies. PMID:20544935

  9. Improving Access to Long-Acting Contraceptive Methods and Reducing Unplanned Pregnancy Among Women with Substance Use Disorders

    PubMed Central

    Black, Kirsten I.; Day, Carolyn A.

    2016-01-01

    Much has been written about the consequences of substance use in pregnancy, but there has been far less focus on the prevention of unintended pregnancies in women with substance use disorders (SUDs). We examine the literature on pregnancy incidence for women with SUDs, the clinical and economic benefits of increasing access to long-acting reversible contraceptive (LARC) methods in this population, and the current hurdles to increased access and uptake. High rates of unintended pregnancies and poor physical and psychosocial outcomes among women with SUDs underscore the need for increased access to, and uptake of, LARC methods among these women. A small number of studies that focused on improving access to contraception, especially LARC, via integrated contraception services predominantly provided in drug treatment programs were identified. However, a number of barriers remain, highlighting that much more research is needed in this area. PMID:27199563

  10. PHARMACOKINETIC EVALUATION OF A LONG-ACTING FENTANYL SOLUTION AFTER TRANSDERMAL ADMINISTRATION IN HELMETED GUINEAFOWL (NUMIDA MELEAGRIS).

    PubMed

    Waugh, Lynnette; Knych, Heather; Cole, Gretchen; D'Agostino, Jennifer

    2016-06-01

    The objective of this study was to investigate the pharmacokinetics of a long-acting fentanyl solution in helmeted guineafowl ( Numida meleagris ) after transdermal administration. Twenty-one guineafowl received a single administration of 5 mg/kg of fentanyl transdermal solution. No adverse effects on behavior were appreciated. Plasma fentanyl concentrations were determined by liquid chromatography-mass spectrometry analysis of protein-precipitated samples. Mean maximum plasma concentration was 228.8 ng/ml at 4 hr. The mean plasma terminal half-life was 33.2 hr. At 168 hr the mean plasma concentration was 1.3 ng/ml. A single topical dose of 5 mg/kg appears to be safe for use in this species and maintained plasma concentrations above those reported to be analgesic in dogs for at least 7 days. PMID:27468018

  11. Improved fertility in suckled beef cows ovulating large follicles or supplemented with long-acting progesterone after timed-AI.

    PubMed

    Pugliesi, G; Santos, F B; Lopes, E; Nogueira, É; Maio, J R G; Binelli, M

    2016-04-15

    We aimed to evaluate the effects and the interaction of size of the preovulatory follicle (POF) and long-acting progesterone (P4) supplementation after timed-AI on CL function and pregnancy success in beef cows. In experiment 1, ovulations of beef cows were synchronized starting on Day -10, and cows were split to receive sodium cloprostenol (large follicle group; LF; n = 31) or nothing (small follicle group; SF; n = 35). Ovulations were induced on Day 0, and cows were inseminated. Ovulated cows were assigned to receive placebo (LF/control group, n = 14; and SF/control group, n = 9) or 150 mg of long-acting P4 on Day 4.5 (LF/P4 group, n = 13; and SF/P4 group, n = 12). Diameter of POF, blood flow in POF wall, ovulation rate, and size and vascularization of CL were greater (P < 0.05) in LF group. In experiments 2 (unknown cyclic status) and 4 (noncycling), ovulations were synchronized, and beef cows received placebo or 150 mg of long-acting P4 on Day 4 after timed-artificial insemination. In experiment 2, pregnancy/AI (P/AI) did not differ (P > 0.1) between P4-treated (53.2%; 209/393) and control cows (56.2%; 219/390), but P/AI was greater in cows with a CL < 0.9 cm(2) on Day 4 that were P4-treated (57.9%, 22/38) versus placebo-treated (40.4%, 21/52; P < 0.05). In Experiment 4, P/AI was greater (P < 0.05) in P4-treated cows (55.6%, 105/189 vs. 46.0%, 86/187). In Experiment 3, cyclic-suckled beef cows were treated as described in Experiment 1 to generate animals with small (SF; n = 111) or large POF (LF; n = 109), and subdivided to receive placebo or P4 on Day 4. POF size, ovulation rate, CL area, and P/AI were greater (P < 0.007) in the LF group. Pregnancy/AI in ovulated cows were lower (P = 0.05) in the SF/control group (41.5%, 17/41) compared to LF/control group (62%, 31/50) and were similar for the SF/P4 group (55.6%, 25/45) and LF/P4 group (57%, 28/49) compared to others. In summary, smaller and less vascularized POF results in

  12. [Efficiency of a pharmaceutical care program for long-acting parenteral antipsychotics in the health area of Santiago de Compostela].

    PubMed

    Vázquez-Mourelle, Raquel; Parrondo, Carmen Durán; López-Pardo Pardo, Estrella; Carracedo-Martínez, Eduardo

    2016-01-01

    In the healthcare area of Santiago de Compostela (Spain), the therapeutic subgroup "other antipsychotics" represented the fifth largest outpatient expenditure in 2013. More than half of this expenditure corresponded to long-acting parenteral forms of paliperidone and risperidone. Over a 12-month period, the implementation of a pharmaceutical care program based on process management and coordination of actions between health professionals in both levels of care represented savings of € 636,391.01 for the organization and a direct saving of € 16,767.36 and 9,008 trips to the pharmacy for patients. This study shows the efficiency of the program, which was facilitated by its situation in an area of integrated management and the use the unified medical records and electronic prescription, elements that will enable the future implementation of similar programmes. The new registries and healthcare interventions will allow reliable evaluation of their effectiveness in terms of treatment adherence, relapses and hospitalisations. PMID:26627381

  13. Barriers to, and strategies for, starting a long acting injection clinic in a community mental health center.

    PubMed

    Velligan, Dawn I; Medellin, Elisa; Draper, Meredith; Maples, Natalie; Dassori, Albana; Moore, Troy A; Lopez, Linda

    2011-12-01

    As many as 50% of patients with schizophrenia do not take oral antipsychotic medications as prescribed, yet long acting injections are rarely utilized. Community agencies that serve this population are often over-burdened and poorly funded. There are negative attitudes on the part of both physicians and consumers about injections. Transportation and logistics are often problematic. We describe the unique opportunity provided by the need for bi-weekly or monthly injections to establish a recovery-oriented group around injection visits. Our approach discusses methods and resources to help overcome some of the common barriers by establishing advocates within the agency, establishing necessary infrastructure, providing education for consumers, providers, and staff, sharing information about successful outcomes with clinic staff and working through billing issues. We also recommend public advocacy on the part of the clinic and consumers to work with state funding sources to change regulations that may limit appropriate clinical care. PMID:21253830

  14. Influence of the primary emulsification procedure on the characteristics of small protein-loaded PLGA microparticles for antigen delivery.

    PubMed

    Wischke, C; Borchert, H-H

    2006-06-01

    Microparticles prepared from poly(lactic-co-glycolic acid) (PLGA) using a W1/O/W2 double emulsion solvent evaporation method are suitable vehicles for the delivery of proteins to antigen presenting cells, e.g. dendritic cells. In this study, the influence of different techniques for the preparation of the primary W1/O emulsion was investigated with respect to the protein localization within the microparticles, morphological characteristics of these particles, protein burst release and the native state of the released protein. Bovine serum albumin bearing fluorescein isothiocyanate (FITC-BSA) was used as model protein. A static micromixer was applied for the preparation of the W1/O/W2 double emulsion. Employing a rotor-stator homogenizer (Ultra-Turrax) for primary emulsification, microcapsules with a high burst release were produced, because nearly all FITC-BSA was attached to the outside of the particle wall. Using a high pressure homogenizer or an ultrasonic procedure resulted in the formation of microspheres with homogeneous protein distribution and a reduced burst release. PMID:16854818

  15. The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy.

    PubMed

    Zhang, Gang; Guo, Dongwei; Dash, Prasanta K; Araínga, Mariluz; Wiederin, Jayme L; Haverland, Nicole A; Knibbe-Hollinger, Jaclyn; Martinez-Skinner, Andrea; Ciborowski, Pawel; Goodfellow, Val S; Wysocki, Tadeusz A; Wysocki, Beata J; Poluektova, Larisa Y; Liu, Xin-Ming; McMillan, JoEllyn M; Gorantla, Santhi; Gelbard, Harris A; Gendelman, Howard E

    2016-01-01

    During studies to extend the half-life of crystalline nanoformulated antiretroviral therapy (nanoART) the mixed lineage kinase-3 inhibitor URMC-099, developed as an adjunctive neuroprotective agent was shown to facilitate antiviral responses. Long-acting ritonavir-boosted atazanavir (nanoATV/r) nanoformulations co-administered with URMC-099 reduced viral load and the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues more than either drug alone in infected humanized NOD/SCID/IL2Rγc-/- mice. The drug effects were associated with sustained ART depots. Proteomics analyses demonstrated that the antiretroviral responses were linked to affected phagolysosomal storage pathways leading to sequestration of nanoATV/r in Rab-associated recycling and late endosomes; sites associated with viral maturation. URMC-099 administered with nanoATV induced a dose-dependent reduction in HIV-1p24 and reverse transcriptase activity. This drug combination offers a unique chemical marriage for cell-based viral clearance. From the Clinical Editor: Although successful in combating HIV-1 infection, the next improvement in antiretroviral therapy (nanoART) would be to devise long acting therapy, such as intra-cellular depots. In this report, the authors described the use of nanoformulated antiretroviral therapy given together with the mixed lineage kinase-3 inhibitor URMC-099, and showed that this combination not only prolonged drug half-life, but also had better efficacy. The findings are hoped to be translated into the clinical setting in the future. PMID:26472049

  16. Long-acting Inhaled Bronchodilator and Risk of Vascular Events in Patients With Chronic Obstructive Pulmonary Disease in Taiwan Population.

    PubMed

    Tsai, Ming-Jun; Chen, Chung-Yu; Huang, Yaw-Bin; Chao, Hsiao-Chung; Yang, Chih-Jen; Lin, Pei-Jin; Tsai, Yi-Hung

    2015-12-01

    A combination of long-acting anticholinergic agents (LAACs) and long-acting β2-adrenergic receptor agonist (LABA) is effective in improving lung function in chronic obstructive pulmonary disease (COPD) compared with monotherapy. However, evidence on whether this combination increases the incidence of stroke or other cardiac events remains sparse. The objective of the present study was to investigate the incidence of stroke and other cardiovascular diseases in COPD patients treated with LAAC, LABA, or a combination of the 2.We conducted this population-based study using the Taiwan National Health Insurance Research Database (1997-2008), identifying COPD patients and their prescribed medication from the International Classification of Disease, Ninth Revision codes 490-492 or 496. A multivariate Cox proportional-hazards model was used to compare the risk of stroke and other cardiovascular diseases over the 11-year period after treatment with LAAC or LABA only or in combination.Of the 596 COPD patients (mean age 70 y), 196 were treated with LAAC, 318 with LABA, and 82 were treated with a combination. The overall incidence of stroke (8.53%) significantly increased in the combination group compared with LAAC (2.04%) or LABA (1.26%) only. In the Cox regression analysis, the adjusted hazard ratio over the 11-year survey period for stroke in patients treated with the combination compared with LABA only was 1.04 (95% confidence interval, 1.06-2.99) and for LAAC, it was 0.31 (95% confidence interval, 0.02-2.32).This cohort study using a large health insurance database showed that treating patients with COPD, with a combination of LAAC and LABA, may be associated with an increased hazard of stroke compared with treatment with either agent alone. We should be particularly cautious about comedication of LAAC and LABA in patients with COPD. PMID:26705214

  17. Long-acting Inhaled Bronchodilator and Risk of Vascular Events in Patients With Chronic Obstructive Pulmonary Disease in Taiwan Population

    PubMed Central

    Tsai, Ming-Jun; Chen, Chung-Yu; Huang, Yaw-Bin; Chao, Hsiao-Chung; Yang, Chih-Jen; Lin, Pei-Jin; Tsai, Yi-Hung

    2015-01-01

    Abstract A combination of long-acting anticholinergic agents (LAACs) and long-acting β2-adrenergic receptor agonist (LABA) is effective in improving lung function in chronic obstructive pulmonary disease (COPD) compared with monotherapy. However, evidence on whether this combination increases the incidence of stroke or other cardiac events remains sparse. The objective of the present study was to investigate the incidence of stroke and other cardiovascular diseases in COPD patients treated with LAAC, LABA, or a combination of the 2. We conducted this population-based study using the Taiwan National Health Insurance Research Database (1997–2008), identifying COPD patients and their prescribed medication from the International Classification of Disease, Ninth Revision codes 490–492 or 496. A multivariate Cox proportional-hazards model was used to compare the risk of stroke and other cardiovascular diseases over the 11-year period after treatment with LAAC or LABA only or in combination. Of the 596 COPD patients (mean age 70 y), 196 were treated with LAAC, 318 with LABA, and 82 were treated with a combination. The overall incidence of stroke (8.53%) significantly increased in the combination group compared with LAAC (2.04%) or LABA (1.26%) only. In the Cox regression analysis, the adjusted hazard ratio over the 11-year survey period for stroke in patients treated with the combination compared with LABA only was 1.04 (95% confidence interval, 1.06–2.99) and for LAAC, it was 0.31 (95% confidence interval, 0.02–2.32). This cohort study using a large health insurance database showed that treating patients with COPD, with a combination of LAAC and LABA, may be associated with an increased hazard of stroke compared with treatment with either agent alone. We should be particularly cautious about comedication of LAAC and LABA in patients with COPD. PMID:26705214

  18. Pharmacodynamic actions of a long-acting PTH analog (LA-PTH) in thyroparathyroidectomized (TPTX) rats and normal monkeys

    PubMed Central

    Shimizu, Masaru; Joyashiki, Eri; Noda, Hiroshi; Watanabe, Tomoyuki; Okazaki, Makoto; Nagayasu, Miho; Adachi, Kenji; Tamura, Tatsuya; Potts, John T.; Gardella, Thomas J.; Kawabe, Yoshiki

    2016-01-01

    Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long-acting PTH analog, [Ala1,3,12,18,22, Gln10,Arg11,Trp14,Lys26]-PTH(1–14)/PTHrP(15–36) (LA–PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intra-venous administration of LA-PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near-normal levels for longer than 48 hours, while PTH(1–34) and PTH(1–84), each injected at a dose 80-fold higher than that used for LA-PTH, increased sCa and decreased sPi only modestly and transiently (< 6 hours). LA-PTH also exhibited enhanced and prolonged efficacy versus PTH(1–34) and PTH(1–84) for elevating sCa when administered subcutaneously (SC) into monkeys. Daily SC administration of LA-PTH (1.8 nmol/kg) into TPTX rats for 28-days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long-acting PTH analogs as potential therapies for patients with hypoparathyroidism. PMID:26865415

  19. N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption.

    PubMed

    Sheng, Jianyong; Han, Limei; Qin, Jing; Ru, Ge; Li, Ruixiang; Wu, Lihong; Cui, Dongqi; Yang, Pei; He, Yuwei; Wang, Jianxin

    2015-07-22

    Although several strategies have been applied for oral insulin delivery to improve insulin bioavailability, little success has been achieved. To overcome multiple barriers to oral insulin absorption simultaneously, insulin-loaded N-trimethyl chitosan chloride (TMC)-coated polylactide-co-glycoside (PLGA) nanoparticles (Ins TMC-PLGA NPs) were formulated in our study. The Ins TMC-PLGA NPs were prepared using the double-emulsion solvent evaporation method and were characterized to determine their size (247.6 ± 7.2 nm), ζ-potential (45.2 ± 4.6 mV), insulin-loading capacity (7.8 ± 0.5%) and encapsulation efficiency (47.0 ± 2.9%). The stability and insulin release of the nanoparticles in enzyme-containing simulated gastrointestinal fluids suggested that the TMC-PLGA NPs could partially protect insulin from enzymatic degradation. Compared with unmodified PLGA NPs, the positively charged TMC-PLGA NPs could improve the mucus penetration of insulin in mucus-secreting HT29-MTX cells, the cellular uptake of insulin via clathrin- or adsorption-mediated endocytosis in Caco-2 cells and the permeation of insulin across a Caco-2 cell monolayer through tight junction opening. After oral administration in mice, the TMC-PLGA NPs moved more slowly through the gastrointestinal tract compared with unmodified PLGA NPs, indicating the mucoadhesive property of the nanoparticles after TMC coating. Additionally, in pharmacological studies in diabetic rats, orally administered Ins TMC-PLGA NPs produced a stronger hypoglycemic effect, with 2-fold higher relative pharmacological availability compared with unmodified NPs. In conclusion, oral insulin absorption is improved by TMC-PLGA NPs with the multiple absorption barriers overcome simultaneously. TMC-PLGA NPs may be a promising drug delivery system for oral administration of macromolecular therapeutics. PMID:26111015

  20. Microsphere coated substrate containing reactive aldehyde groups

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor); Yen, Richard C. K. (Inventor)

    1984-01-01

    A synthetic organic resin is coated with a continuous layer of contiguous, tangential, individual microspheres having a uniform diameter preferably between 100 Angstroms and 2000 Angstroms. The microspheres are an addition polymerized polymer of an unsaturated aldehyde containing 4 to 20 carbon atoms and are covalently bonded to the substrate by means of high energy radiation grafting. The microspheres contain reactive aldehyde groups and can form conjugates with proteins such as enzymes or other aldehyde reactive materials.

  1. Monitoring model drug microencapsulation in PLGA scaffolds using X-ray powder diffraction

    PubMed Central

    Aina, Adeyinka; Gupta, Manish; Boukari, Yamina; Morris, Andrew; Billa, Nashiru; Doughty, Stephen

    2015-01-01

    The microencapsulation of three model drugs; metronidazole, paracetamol and sulphapyridine into Poly (dl-Lactide-Co-Glycolide) (PLGA) scaffolds were probed using X-ray Powder Diffraction (XRPD). Changes in the diffraction patterns of the PLGA scaffolds after encapsulation was suggestive of a chemical interaction between the pure drugs and the scaffolds and not a physical intermixture. PMID:27013917

  2. Concepts and practices used to develop functional PLGA-based nanoparticulate systems

    PubMed Central

    Sah, Hongkee; Thoma, Laura A; Desu, Hari R; Sah, Edel; Wood, George C

    2013-01-01

    The functionality of bare polylactide-co-glycolide (PLGA) nanoparticles is limited to drug depot or drug solubilization in their hard cores. They have inherent weaknesses as a drug-delivery system. For instance, when administered intravenously, the nanoparticles undergo rapid clearance from systemic circulation before reaching the site of action. Furthermore, plain PLGA nanoparticles cannot distinguish between different cell types. Recent research shows that surface functionalization of nanoparticles and development of new nanoparticulate dosage forms help overcome these delivery challenges and improve in vivo performance. Immense research efforts have propelled the development of diverse functional PLGA-based nanoparticulate delivery systems. Representative examples include PEGylated micelles/nanoparticles (PEG, polyethylene glycol), polyplexes, polymersomes, core-shell–type lipid-PLGA hybrids, cell-PLGA hybrids, receptor-specific ligand-PLGA conjugates, and theranostics. Each PLGA-based nanoparticulate dosage form has specific features that distinguish it from other nanoparticulate systems. This review focuses on fundamental concepts and practices that are used in the development of various functional nanoparticulate dosage forms. We describe how the attributes of these functional nanoparticulate forms might contribute to achievement of desired therapeutic effects that are not attainable using conventional therapies. Functional PLGA-based nanoparticulate systems are expected to deliver chemotherapeutic, diagnostic, and imaging agents in a highly selective and effective manner. PMID:23459088

  3. Tetraiodothyroacetic acid-conjugated PLGA nanoparticles: a nanomedicine approach to treat drug-resistant breast cancer

    PubMed Central

    Bharali, Dhruba J; Yalcin, Murat; Davis, Paul J; Mousa, Shaker A

    2013-01-01

    Aim The aim was to evaluate tetraiodothyroacetic acid (tetrac), a thyroid hormone analog of l-thyroxin, conjugated to poly(lactic-co-glycolic acid) nanoparticles (T-PLGA-NPs) both in vitro and in vivo for the treatment of drug-resistant breast cancer. Materials & methods The uptake of tetrac and T-PLGA-NPs in doxorubicin-resistant MCF7 (MCF7-Dx) cells was evaluated using confocal microscopy. Cell proliferation assays and a chick chorioallantoic membrane model of FGF2-induced angiogenesis were used to evaluate the anticancer effects of T-PLGA-NPs. In vivo efficacy was examined in a MCF7-Dx orthotopic tumor BALBc nude mouse model. Results T-PLGA-NPs were restricted from entering into the cell nucleus, and T-PLGA-NPs inhibited angiogenesis by 100% compared with 60% by free tetrac. T-PLGA-NPs enhanced inhibition of tumor-cell proliferation at a low-dose equivalent of free tetrac. In vivo treatment with either tetrac or T-PLGA-NPs resulted in a three- to five-fold inhibition of tumor weight. Conclusion T-PLGA-NPs have high potential as anticancer agents, with possible applications in the treatment of drug-resistant cancer. PMID:23448245

  4. Preclinical Development and In Vivo Efficacy of Ceftiofur-PLGA Microparticles

    PubMed Central

    Vilos, Cristian; Velasquez, Luis A.; Rodas, Paula I.; Zepeda, Katherine; Bong, Soung-Jae; Herrera, Natalia; Cantin, Mario; Simon, Felipe; Constandil, Luis

    2015-01-01

    Drug delivery systems based on polymeric microparticles represent an interesting field of development for the treatment of several infectious diseases for humans and animals. In this work, we developed PLGA microparticles loaded with ceftiofur (PLGA-cef), a third- generation cephalosporin that is used exclusively used in animals. PLGA-cef was prepared by the double emulsion w/o/w method, and exhibited a diameter in the range of 1.5–2.2 μm, and a negative ζ potential in the range of -35 to -55 mV. The loading yield of PLGA-cef was ~7% and encapsulation efficiency was approximately 40%. The pharmacokinetic study demonstrated a sustained release profile of ceftiofur for 20 days. PLGA-cef administrated in a single dose was more effective than ceftiofur non-encapsulated in rats challenged with S. Typhimurium. The in vivo toxicological evaluation showed that PLGA-cef did not affect the blood biochemical, hematological and hemostasis parameters. Overall, the PLGA-cef showed slow in vivo release profile, high antibacterial efficacy, and low toxicity. The results obtained supports the safe application of PLGA-cef as sustained release platform in the veterinary industry. PMID:25915043

  5. Biomimetic Porous PLGA Scaffolds Incorporating Decellularized Extracellular Matrix for Kidney Tissue Regeneration.

    PubMed

    Lih, Eugene; Park, Ki Wan; Chun, So Young; Kim, Hyuncheol; Kwon, Tae Gyun; Joung, Yoon Ki; Han, Dong Keun

    2016-08-24

    Chronic kidney disease is now recognized as a major health problem, but current therapies including dialysis and renal replacement have many limitations. Consequently, biodegradable scaffolds to help repairing injured tissue are emerging as a promising approach in the field of kidney tissue engineering. Poly(lactic-co-glycolic acid) (PLGA) is a useful biomedical material, but its insufficient biocompatibility caused a reduction in cell behavior and function. In this work, we developed the kidney-derived extracellular matrix (ECM) incorporated PLGA scaffolds as a cell supporting material for kidney tissue regeneration. Biomimetic PLGA scaffolds (PLGA/ECM) with different ECM concentrations were prepared by an ice particle leaching method, and their physicochemical and mechanical properties were characterized through various analyses. The proliferation of renal cortical epithelial cells on the PLGA/ECM scaffolds increased with an increase in ECM concentrations (0.2, 1, 5, and 10%) in scaffolds. The PLGA scaffold containing 10% of ECM has been shown to be an effective matrix for the repair and reconstitution of glomerulus and blood vessels in partially nephrectomized mice in vivo, compared with only PLGA control. These results suggest that not only can the tissue-engineering techniques be an effective alternative method for treatment of kidney diseases, but also the ECM incorporated PLGA scaffolds could be promising materials for biomedical applications including tissue engineered scaffolds and biodegradable implants. PMID:27456613

  6. Combined modality doxorubicin-based chemotherapy and chitosan-mediated p53 gene therapy using double-walled microspheres for treatment of human hepatocellular carcinoma

    PubMed Central

    Xu, Qingxing; Leong, Jiayu; Chua, Qi Yi; Chi, Yu Tse; Chow, Pierce Kah-Hoe; Pack, Daniel W.; Wang, Chi-Hwa

    2013-01-01

    The therapeutic efficiency of combined chemotherapy and gene therapy on human hepatocellular carcinoma HepG2 cells was investigated using double-walled microspheres that consisted of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(L-lactic acid) (PLLA) shell layer and fabricated via the precision particle fabrication (PPF) technique. Here, double-walled microspheres were used to deliver doxorubicin (Dox) and/or chitosan-DNA nanoparticles containing the gene encoding the p53 tumor suppressor protein (chi-p53), loaded in the core and shell phases, respectively. Preliminary studies on chi-DNA nanoparticles were performed to optimize gene transfer to HepG2 cells. The transfection efficiency of chi-DNA nanoparticles was optimal at an N/P ratio of 7. In comparison to the 25-kDa branched polyethylenimine (PEI), chitosan showed no inherent toxicity towards the cells. Next, the therapeutic efficiencies of Dox and/or chi-p53 in microsphere formulations were compared to free drug(s) and evaluated in terms of growth inhibition, and cellular expression of tumor suppressor p53 and apoptotic caspase 3 proteins. Overall, the combined Dox and chi-p53 treatment exhibited enhanced cytotoxicity as compared to either Dox or chi-p53 treatments alone. Moreover, the antiproliferative effect was more substantial when cells were treated with microspheres than those treated with free drugs. High p53 expression was maintained during a five-day period, and was largely due to the controlled and sustained release of the microspheres. Moreover, increased activation of caspase 3 was observed, and was likely to have been facilitated by high levels of p53 expression. Overall, double-walled microspheres present a promising dual anticancer delivery system for combined chemotherapy and gene therapy. PMID:23578555

  7. Combined modality doxorubicin-based chemotherapy and chitosan-mediated p53 gene therapy using double-walled microspheres for treatment of human hepatocellular carcinoma.

    PubMed

    Xu, Qingxing; Leong, Jiayu; Chua, Qi Yi; Chi, Yu Tse; Chow, Pierce Kah-Hoe; Pack, Daniel W; Wang, Chi-Hwa

    2013-07-01

    The therapeutic efficiency of combined chemotherapy and gene therapy on human hepatocellular carcinoma HepG2 cells was investigated using double-walled microspheres that consisted of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(L-lactic acid) (PLLA) shell layer and fabricated via the precision particle fabrication (PPF) technique. Here, double-walled microspheres were used to deliver doxorubicin (Dox) and/or chitosan-DNA nanoparticles containing the gene encoding the p53 tumor suppressor protein (chi-p53), loaded in the core and shell phases, respectively. Preliminary studies on chi-DNA nanoparticles were performed to optimize gene transfer to HepG2 cells. The transfection efficiency of chi-DNA nanoparticles was optimal at an N/P ratio of 7. In comparison to the 25-kDa branched polyethylenimine (PEI), chitosan showed no inherent toxicity towards the cells. Next, the therapeutic efficiencies of Dox and/or chi-p53 in microsphere formulations were compared to free drug(s) and evaluated in terms of growth inhibition, and cellular expression of tumor suppressor p53 and apoptotic caspase 3 proteins. Overall, the combined Dox and chi-p53 treatment exhibited enhanced cytotoxicity as compared to either Dox or chi-p53 treatments alone. Moreover, the antiproliferative effect was more substantial when cells were treated with microspheres than those treated with free drugs. High p53 expression was maintained during a five-day period, and was largely due to the controlled and sustained release of the microspheres. Moreover, increased activation of caspase 3 was observed, and was likely to have been facilitated by high levels of p53 expression. Overall, double-walled microspheres present a promising dual anticancer delivery system for combined chemotherapy and gene therapy. PMID:23578555

  8. Glass microspheres for medical applications

    NASA Astrophysics Data System (ADS)

    Conzone, Samuel David

    Radioactive dysprosium lithium borate glass microspheres have been developed as biodegradable radiation delivery vehicles for the radiation synovectomy treatment of rheumatoid arthritis. Once injected into a diseased joint, the microspheres deliver a potent dose of radiation to the diseased tissue, while a non-uniform chemical reaction converts the glass into an amorphous, porous, hydrated dysprosium phosphate reaction product. The non-radioactive, lithium-borate component is dissolved from the glass (up to 94% weight loss), while the radioactive 165Dy reacts with phosphate anions in the body fluids, and becomes "chemically" trapped in a solid, dysprosium phosphate reaction product that has the same size as the un-reacted glass microsphere. Ethylene diamine tetraacetate (EDTA) chelation therapy can be used to dissolve the dysprosium phosphate reaction product after the radiation delivery has subsided. The dysprosium phosphate reaction product, which formed in vivo in the joint of a Sprague-Dawley rat, was dissolved by EDTA chelation therapy in <1 week, without causing any detectable joint damage. The combination of dysprosium lithium borate glass microspheres and EDTA chelation therapy provides an unique "tool" for the medical community, which can deliver a large dose (>100 Gy) of localized beta radiation to a treatment site within the body, followed by complete biodegradability. The non-uniform reaction process is a desirable characteristic for a biodegradable radiation delivery vehicle, but it is also a novel material synthesis technique that can convert a glass to a highly porous materials with widely varying chemical composition by simple, low-temperature, glass/solution reaction. The reaction product formed by nonuniform reaction occupies the same volume as the un-reacted glass, and after drying for 1 h at 300°C, has a specific surface area of ≈200 m2/g, a pore size of ≈30 nm, and a nominal crushing strength of ≈10 MPa. Finally, rhenium glass

  9. Coupling system to a microsphere cavity

    NASA Technical Reports Server (NTRS)

    Iltchenko, Vladimir (Inventor); Maleki, Lute (Inventor); Yao, Steve (Inventor); Wu, Chi (Inventor)

    2002-01-01

    A system of coupling optical energy in a waveguide mode, into a resonator that operates in a whispering gallery mode. A first part of the operation uses a fiber in its waveguide mode to couple information into a resonator e.g. a microsphere. The fiber is cleaved at an angle .PHI. which causes total internal reflection within the fiber. The energy in the fiber then forms an evanescent field and a microsphere is placed in the area of the evanescent field. If the microsphere resonance is resonant with energy in the fiber, then the information in the fiber is effectively transferred to the microsphere.

  10. In vitro biocompatibility of polypyrrole/PLGA conductive nanofiber scaffold with cultured rat hepatocytes

    NASA Astrophysics Data System (ADS)

    Chu, Xue-Hui; Xu, Qian; Feng, Zhang-Qi; Xiao, Jiang-Qiang; Li, Qiang; Sun, Xi-Tai; Cao, Yang; Ding, Yi-Tao

    2014-09-01

    To intruduce conductive biomaterial into liver tissue engineering, a conductive nanofiber scaffold, polypyrrole/poly(lactic-co-glycolic)acid(PLGA), was designed and prepared via electro-spinning and oxidative polymerization. Effects of the scaffold on hepatocyte adhesion, viability and function were then investigated. SEM revealed pseudopodium formation and abundant extracellular matrix on the surface of PLGA membrane and polypyrrole/PLGA membrane. The adhesion rate, cellular activity, urea synthesis and albumin secretion of the hepatocytes cultured on polypyrrole/PLGA group were similar to those on the PLGA group, but were significantly higher than those on the control group. There were no significant differences in concentrations of LDH and TNF-α among three groups. These results suggested the potential application of this conductive nanofiber scaffold as a suitable substratum for hepatocyte culturing in liver tissue engineering.

  11. Compression molding of aerogel microspheres

    DOEpatents

    Pekala, R.W.; Hrubesh, L.W.

    1998-03-24

    An aerogel composite material produced by compression molding of aerogel microspheres (powders) mixed together with a small percentage of polymer binder to form monolithic shapes in a cost-effective manner is disclosed. The aerogel composites are formed by mixing aerogel microspheres with a polymer binder, placing the mixture in a mold and heating under pressure, which results in a composite with a density of 50--800 kg/m{sup 3} (0.05--0.80 g/cc). The thermal conductivity of the thus formed aerogel composite is below that of air, but higher than the thermal conductivity of monolithic aerogels. The resulting aerogel composites are attractive for applications such as thermal insulation since fabrication thereof does not require large and expensive processing equipment. In addition to thermal insulation, the aerogel composites may be utilized for filtration, ICF target, double layer capacitors, and capacitive deionization. 4 figs.

  12. Compression molding of aerogel microspheres

    DOEpatents

    Pekala, Richard W.; Hrubesh, Lawrence W.

    1998-03-24

    An aerogel composite material produced by compression molding of aerogel microspheres (powders) mixed together with a small percentage of polymer binder to form monolithic shapes in a cost-effective manner. The aerogel composites are formed by mixing aerogel microspheres with a polymer binder, placing the mixture in a mold and heating under pressure, which results in a composite with a density of 50-800 kg/m.sup.3 (0.05-0.80 g/cc). The thermal conductivity of the thus formed aerogel composite is below that of air, but higher than the thermal conductivity of monolithic aerogels. The resulting aerogel composites are attractive for applications such as thermal insulation since fabrication thereof does not require large and expensive processing equipment. In addition to thermal insulation, the aerogel composites may be utilized for filtration, ICF target, double layer capacitors, and capacitive deionization.

  13. Biodegradable microspheres for parenteral delivery.

    PubMed

    Sinha, V R; Trehan, A

    2005-01-01

    Nowadays, emphasis is being laid to development of controlled release dosage forms. Interest in this technology has increased steadily over the past few years. Although oral administration of drugs is a widely accepted route of drug delivery, bioavailability of drug often varies as a result of gastrointestinal absorption, degradation by first-pass effect, and hostile environment of gastrointestinal tract. Transdermal administration for percutaneous absorption of drug is limited by the impermeable nature of the stratum corneum. Ocular and nasal delivery is also unfavorable because of degradation by enzymes present in eye tissues and nasal mucosa. Hence, the parenteral route is the most viable approach in such cases. Of the various ways of achieving long-term parenteral drug delivery, biodegradable microspheres are one of the better means of controlling the release of drug over a long time. Because of the lipidic nature of liposomes, problems such as limited physical stability and difficulty of freeze-drying are encountered. Similarly, for emulsions, stability on long-term basis and in suspensions, rheological changes during filling, injecting, and storage poses limitation. Also, in all these systems, the release rate cannot be tailored to the needs of the patient. Parenteral controlled-release formulations based on biodegradable microspheres can overcome these problems and can control the release of drug over a predetermined time span, usually in the order of days to weeks to months. Various FDA-approved controlled-release parenteral formulations based on these biodegradable microspheres are available on the market, including Lupron Depot Nutropin Depot and Zoladex. This review covers various molecules encapsulated in biodegradable microspheres for parenteral delivery. PMID:16566705

  14. Microspheres in Plasma Display Panels

    NASA Technical Reports Server (NTRS)

    2006-01-01

    Filling small bubbles of molten glass with gases is just as difficult as it sounds, but the technical staff at NASA is not known to shy away from a difficult task. When Microsphere Systems, Inc. (MSI), of Ypsilanti, Michigan, and Imaging Systems Technology, Inc. (IST), of Toledo, Ohio, were trying to push the limits of plasma displays but were having difficulty with the designs, NASA s Glenn Garrett Morgan Commercialization Initiative (GMCI) assembled key personnel at Glenn Research Center and Ohio State University for a brainstorming session to come up with a solution for the companies. They needed a system that could produce hollow, glass micro-sized spheres (microspheres) that could be filled with a variety of gasses. But the extremely high temperature required to force the micro-sized glass bubbles to form at the tip of a metal nozzle resulted in severe discoloration of the microspheres. After countless experiments on various glass-metal combinations, they had turned to the GMCI for help. NASA experts in advanced metals, ceramics, and glass concluded that a new design approach was necessary. The team determined that what was needed was a phosphate glass composition that would remain transparent, and they went to work on a solution. Six weeks later, using the design tips from the NASA team, Tim Henderson, president of MSI, had designed a new system in which all surfaces in contact with the molten glass would be ceramic instead of metal. Meanwhile, IST was able to complete a Phase I Small Business Innovation Research (SBIR) grant supported by the National Science Foundation (NSF) and supply a potential customer with samples of the microspheres for evaluation as filler materials for high-performance insulations.

  15. Incidence, Predictors, and Clinical Implications of Discontinuing Therapy with Inhaled Long-Acting Bronchodilators among Patients with Chronic Obstructive Pulmonary Disease.

    PubMed

    Arfè, Andrea; Nicotra, Federica; Cerveri, Isa; de Marco, Roberto; Vaghi, Adriano; Merlino, Luca; Corrao, Giovanni

    2016-10-01

    Incidence, predictors and effect of discontinuation of long-acting bronchodilators on the risk of death or hospital admission among adults with Chronic Obstructive Pulmonary Disease (COPD) were assessed in a large population-based prospective study carried out by linking Italian healthcare utilization databases. Specifically, the cohort of 17,490 beneficiaries of the National Health Service in the Italian Region of Lombardy, aged 40 years or older, who started long-acting bronchodilators therapy during 2005-2008 was followed from first dispensation until 2012. During this period, patients who experienced discontinuation of long-acting bronchodilators were identified. Hospitalizations for COPD and deaths for any cause (composite clinical outcome) were also identified during follow-up. A Cox proportional hazards model was fitted to identify predictors of discontinuation. The case-crossover design was used to assess the implications of treatment discontinuation on the clinical outcome risk. Cumulative incidences of discontinuation were, respectively, 67%, 80%, and 92% at 6 months, 1 year, and 5 years since initial treatment. Significant predictors of discontinuation were female gender, younger age, starting treatment with fixed-dose combination of inhaled bronchodilators and corticosteroids, using antibiotics, inhaled long-acting bronchodilators and corticosteroids and not using short-acting bronchodilators, other respiratory drugs and systemic corticosteroids during follow-up. Odds ratios (95% confidence intervals) for the clinical outcome associated with not discontinuing long-acting bronchodilators was 0.64 (0.50 to 0.82). In conclusion, in the real-life setting, discontinuation of inhaled long-acting bronchodilators in adults with COPD is high even after just 6 months, even though persistence to these drugs reduces the risk of severe outcomes. PMID:26934569

  16. Pharmacokinetic and milk penetration of a difloxacin long-acting poloxamer gel formulation with carboxy-methylcellulose in lactating goats.

    PubMed

    Escudero, Elisa; Marín, Pedro; Cárceles, Carlos M; Ramírez, María J; Fernández-Varón, Emilio

    2011-04-01

    The single-dose disposition kinetics of difloxacin were determined in clinically normal lactating goats (n=6) after subcutaneous administration of a long-acting poloxamer 407 gel formulation with carboxy-methylcellulose (P407-CMC). Difloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. The concentration-time data were analysed by non-compartmental kinetic methods. Plasma and milk elimination half-lives after P407-CMC dosing were 35.19 h and 33.93 h, respectively. With this formulation, difloxacin achieved maximum plasma concentrations of 2.67±0.34 mg/L at 2.92±1.20 h and maximum milk concentrations of 2.31±0.35 mg/L at 4.00±0.00 h. The area under the curve (AUC) ratio AUC(milk)/AUC(plasma) was 0.89 after P407-CMC administration. It was concluded that a 15 mg/kg dose of difloxacin within P407-CMC would be effective against mastitis pathogens with a minimum inhibitory concentration (MIC)≤0.12 mg/L. PMID:20359917

  17. Pharmacokinetics and milk penetration of difloxacin after a long-acting formulation for subcutaneous administration to lactating goats.

    PubMed

    Marín, P; Escudero, E; Fernández-Varón, E; Ramírez, M J; Cárceles, C M

    2010-07-01

    The single-dose disposition kinetics of difloxacin were determined in clinically normal lactating goats (n=6) after intravenous (IV) and subcutaneous (SC) administration and subcutaneous administration of a long-acting poloxamer 407 gel formulation (P407). Difloxacin concentrations were determined by HPLC with fluorescence detection. Minimum inhibitory concentrations of difloxacin against 14 strains of Staphylococcus aureus isolated from mastitic goats' milk in Spain were determined to compute pharmacodynamic surrogate markers. The concentration-time data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Following SC and P407 administration, difloxacin achieved maximum milk concentrations of 1.34+/-0.12 and 2.97+/-1.18 mg/L, respectively, at 4.00+/-0.00 h (SC) and 3.60+/-0.89 h (P407) after administration. The absolute bioavailabilities after SC and P407 administration were 81.74+/-15.60% and 72.58+/-20.45%, respectively. Difloxacin penetration from the blood into the milk was good and high concentrations were found in milk secretions. From these data, a 15 mg/kg dose of difloxacin P407 would appear to be effective against Staphylococcus aureus isolated from mastitic goats' milk with minimum inhibitory concentrations

  18. Effectiveness and Predictors of Continuation of Paliperidone Palmitate Long-Acting Injection Treatment: A 12-Month Naturalistic Cohort Study.

    PubMed

    Whale, Richard; Pereira, Marco; Cuthbert, Sharon; Fialho, Renata

    2015-10-01

    Antipsychotic long-acting injectable (LAI) medication has an important place as a treatment option in schizophrenia with evolving evidence to support clinical benefit over oral medication. Paliperidone palmitate is recently licensed as an LAI. We studied a naturalistic cohort of all identifiable patients who initiated paliperidone LAI in a specific United Kingdom region (Sussex) from first availability up to January 2013 (n = 179). Favorably, 60% of the cohort continued paliperidone LAI beyond 12 months from initiation. Schizophrenia diagnosis was significantly associated with 12-month continuation on univariate analysis (65% continuation rate at 12 months in this diagnostic subgroup). No baseline variables were identified as independently associated with 12-month continuation. However, fewer inpatient days after initiation (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.003-1.011; P = 0.002), dose adjustment up or down (OR, 3.46; 95% CI, 1.26-9.51; P = 0.016), and a higher maintenance dose (OR, 8.31; 95% CI, 1.84-37.51; P = 0.006) during treatment course were all independently associated with continuation on multivariate analysis. Our findings support the importance of a collaborative approach with the LAI recipient in treatment decision making to enhance treatment effectiveness. PMID:26267419

  19. Within-drug benefit-risk evaluation of olanzapine long-acting injection at one and two years of treatment.

    PubMed

    Detke, Holland C; Lauriello, John; Landry, John; McDonnell, David P

    2014-12-01

    We sought to evaluate the within-drug benefit-risk of olanzapine long-acting injection (LAI) using both quantitative and qualitative methods. Subjects included 1192 adult patients with schizophrenia or schizoaffective disorder who participated in clinical trials with the opportunity for at least two years of continuous treatment with olanzapine LAI (45-405 mg every two to four weeks). Using the Benefit Risk Action Team (BRAT) framework, we evaluated frequency versus duration of benefits and risks commonly observed with atypical antipsychotics. We then used the Transparent Uniform Risk/Benefit Overview (TURBO) method, which weighs the drug's two most medically serious and/or frequent adverse events versus its primary benefit (effectiveness) and an ancillary benefit. The most frequent events among all patients were remaining free of relapse (91.4% for an average of 306 days at one year, 88.4% for 546 days at two years) and symptomatic remission (81.7% for an average of 239 days at one year, 84.1% for 438 days at two years). One- and two-year incidence of ≥7% weight gain was 33.3% and 41.7%. Incidences for sexual dysfunction, hyperprolactinemia, and post-injection delirium/sedation syndrome (PDSS) were <2%. TURBO ratings unanimously selected PDSS and weight gain as key risks and resulted in an average score in the acceptable benefit-risk balance range. PMID:24996038

  20. Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy

    PubMed Central

    Li, Tianyuzi; Gendelman, Howard E; Zhang, Gang; Puligujja, Pavan; McMillan, JoEllyn M; Bronich, Tatiana K; Edagwa, Benson; Liu, Xin-Ming; Boska, Michael D

    2015-01-01

    Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory’s development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery. PMID:26082630

  1. Can a new ultra-long-acting insulin analogue improve patient care? Investigating the potential role of insulin degludec.

    PubMed

    Robinson, Jennifer D; Neumiller, Joshua J; Campbell, R Keith

    2012-12-24

    The basal-bolus concept of delivering insulin to diabetic patients makes physiological sense, as it mimics normal insulin release in people without diabetes. In line with this concept, a major effort put forth by insulin manufacturers has been to develop the ideal exogenous basal insulin product. The perfect basal insulin product would be injected into subcutaneous tissue without causing irritation, release insulin continuously at a constant rate for at least 24 hours, be stable, not contribute to weight gain, have a low risk of allergic reactions and, very importantly, minimize the risk of hypoglycaemia. While the perfect insulin has not yet been discovered, advancements are still being made. Insulin degludec is an ultra-long-acting basal insulin analogue that possesses a flat, stable glucose-lowering effect in patients with type 1 or type 2 diabetes mellitus. Insulin degludec achieves these pharmacokinetic properties by forming soluble multihexamers upon subcutaneous injection, resulting in the formation of a depot in the subcutaneous tissue that is slowly released and absorbed into circulation. Insulin degludec has been associated with slightly less weight gain and fewer nocturnal hypoglycaemic episodes when compared with insulin glargine in some, but not all, clinical studies. This article briefly reviews current evidence for the use of insulin degludec in patients with type 1 or type 2 diabetes mellitus and discusses the potential impact of this new basal insulin on clinical practice. PMID:23145524

  2. Crimson Carrier, A Long-Acting Contrast Agent for In Vivo Near-Infrared Imaging of Injured and Diseased Muscle

    PubMed Central

    Prajapati, Suresh I.; Martinez, Carlo O.; Abraham, Jinu; McCleish, Amanda T.; Michalek, Joel E.; McManus, Linda M.; Rubin, Brian P.; Shireman, Paula K.; Keller, Charles

    2010-01-01

    Introduction The near-infrared wavelengths (700nm–900nm) are the most suitable optical window for light penetration and deep tissue imaging in small animals. Herein we report a near-infrared fluorescent contrast agent, crimson carrier, which acts as a blood pool contrast agent to detect and quantify injury and disease in live animals. Methods After determining the excitation-emission spectra and pharmacokinetics, crimson carrier was injected into myoinjured mice to monitor their recovery. Crimson carrier was also used to image transgenic mice with spontaneous tumors. Results Crimson carrier has maximal excitation and emission wavelengths of 745 nm and 820 nm, respectively. Elimination occurs predominantly via urinary excretion. Discussion We demonstrate the utility of this contrast agent for serial imaging of traumatized muscle as well as muscle tumors. The unique long-acting pharmacokinetics and urinary excretion route characteristics make crimson carrier a contrast agent of choice for the visualization of tumors and injured muscle or other tissues in live animal studies. PMID:20544935

  3. Modeling the budget impact of long-acting injectable paliperidone palmitate in the treatment of schizophrenia in Japan

    PubMed Central

    Mahlich, Jörg; Nishi, Masamichi; Saito, Yoshimichi

    2015-01-01

    Background The cost of schizophrenia in Japan is high and new long-acting injectable (LAI) antipsychotics might be able to reduce costs by causing a reduction of hospital stays. We aim to estimate budget effects of the introduction of a new 1-month LAI, paliperidone palmitate, in Japan. Methods A budget impact analysis was conducted from a payer perspective. The model took direct costs of illness into account (ie, costs for inpatient and outpatient services, as well as drug costs). The robustness of the model was checked using a sensitivity analysis. Results According to our calculations, direct total costs of schizophrenia reach 710,500 million yen a year (US$6 billion). These costs decrease to 691,000 million yen (US$5.9 billion) 3 years after the introduction of paliperidone palmitate. Conclusion From a payer point of view, the introduction of a new treatment for schizophrenia in Japan helps to save resources and is not associated with a higher financial burden. PMID:26045674

  4. Comparison of conventional and long-acting oxytetracyclines in prevention of induced Actinobacillus (Haemophilus) pleuropneumoniae infection of growing swine.

    PubMed Central

    Kiorpes, A L; Bäckström, L R; Collins, M T; Kruse, G O

    1989-01-01

    These experiments tested the hypothesis that long-acting oxytetracycline (oxytetracycline-LA) was more effective than regular oxytetracycline in preventing porcine pleuropneumonia when administered either 24 or 48 h prior to experimental challenge with virulent strains of Actinobacillus pleuropneumoniae. Two experiments (1 and 2) were conducted using growing pigs (average weight 12-15 kg). Antibiotic treatments were administered once intramuscularly at 20 mg/kg body weight; controls received an equivalent volume of saline. Clinical signs were recorded over seven days, and mortality rates and pathological lesions were analyzed using analysis of variance. Serum oxytetracycline levels were compared 48 and 72 h postinjection. All pigs developed clinical disease following experimental infection. Actinobacillus pleuropneumoniae was recovered from 42% of experiment 1 pigs and all of experiment 2 pigs. The data showed that both oxytetracycline and oxytetracycline-LA given at the same dose protected pigs against experimental infection when given 24 h prior to challenge, and there was no difference between the efficacy of the two drugs in this experiment. When administered 48 h prior to challenge, only oxytetracycline-LA reduced the clinical signs and pathological changes following A. pleuropneumoniae challenge. Between 48 and 72 h postinjection, oxytetracycline-LA blood levels were significantly greater compared to oxytetracycline-treated pigs. PMID:2531629

  5. Insulin degludec, a long-acting once-daily basal analogue for type 1 and type 2 diabetes mellitus.

    PubMed

    Berard, Lori; MacNeill, Gail

    2015-02-01

    Here, we discuss certain practical issues related to use of insulin degludec, a new long-acting basal insulin analogue. Degludec provides uniform ("peakless") action that extends over more than 24 hours and is highly consistent from dose to dose. Like the 2 previously available basal analogues (detemir and glargine), degludec is expected to simplify dose adjustment and enable patients to reach their glycemic targets with reduced risk of hypoglycemia. Phase 3 clinical trials involving type 1 and type 2 diabetes have demonstrated that degludec was noninferior to glargine in allowing patients to reach a target glycated hemoglobin (A1C) of 7%, and nocturnal hypoglycemia occurred significantly less frequently with degludec. In addition, when dosing intervals vary substantially from day to day, degludec continues to be effective and to maintain a low rate of nocturnal hypoglycemia. Degludec thus has the potential to reduce risk of nocturnal hypoglycemia, to enhance the flexibility of the dosing schedule and to improve patient and caregiver confidence in the stability of glycemic control. A dedicated injector, the FlexTouch prefilled pen, containing degludec 200 units/mL, will be recommended for most patients with type 2 diabetes. Degludec will also be available as 100 units/mL cartridges, to be used in the NovoPen 4 by patients requiring smaller basal insulin doses, including most patients with type 1 diabetes. PMID:25065475

  6. Counseling and provision of long-acting reversible contraception in the US: National survey of nurse practitioners

    PubMed Central

    Harper, Cynthia C.; Stratton, Laura; Raine, Tina R.; Thompson, Kirsten; Henderson, Jillian T.; Blum, Maya; Postlethwaite, Debbie; Speidel, J Joseph

    2013-01-01

    Objective Nurse practitioners (NPs) provide frontline care in women’s health, including contraception, an essential preventive service. Their importance for contraceptive care will grow, with healthcare reforms focused on affordable primary care. This study assessed practice and training needs to prepare NPs to offer high-efficacy contraceptives - IUDs and implants. Method A US nationally representative sample of nurse practitioners in primary care and women’s health was surveyed in 2009 (response rate 69%, n=586) to assess clinician knowledge and practices, guided by the CDC US Medical Eligibility Criteria for Contraceptive Use. Results Two-thirds of women’s health NPs (66%) were trained in IUD insertions, compared to 12% of primary care NPs. Contraceptive counseling that routinely included IUDs was low overall (43%). Nurse practitioners used overly restrictive patient eligibility criteria, inconsistent with CDC guidelines. Insertion training (aOR=2.4, 95%CI: 1.10 5.33) and knowledge of patient eligibility (aOR=2.9, 95%CI: 1.91 4.32) were associated with IUD provision. Contraceptive implant provision was low: 42% of NPs in women’s health and 10% in primary care . Half of NPs desired training in these methods. Conclusion Nurse practitioners have an increasingly important position in addressing high unintended pregnancy in the U.S., but require specific training in long-acting reversible contraceptives. PMID:24128950

  7. Changes in use of long-acting contraceptive methods in the U.S., 2007–2009

    PubMed Central

    Finer, Lawrence B.; Jerman, Jenna; Kavanaugh, Megan L.

    2012-01-01

    Objectives To examine trends in use of long-acting reversible contraceptive (LARC) methods — the IUD and implant — and the extent to which these methods have replaced permanent sterilization and less-effective short-acting methods. Design We tabulated data from female survey respondents overall and by demographic subgroups. We performed t-tests of the differences in the proportions of female contraceptors using LARC in 2007 and 2009. We also looked at use of LARC, sterilization, other methods and no method among women at risk of unintended pregnancy. Setting Secondary analysis of the 2002 and 2006–2010 National Survey of Family Growth, an in-home, nationally representative survey of women 15–44. Patients All female respondents to the surveys. Interventions None. Main outcome measures Current use of LARC methods in 2009, and change in use from 2007. Results The proportion of contraceptors using LARC increased significantly from 2.4% in 2002 to 3.7% in 2007 and 8.5% in 2009. The increase occurred among women in almost every age, race, education and income group. Among women at risk of unintended pregnancy, increases in LARC use more than offset decreases in sterilization. Conclusions LARC methods (primarily IUDs) are contributing to an increase in contraceptive effectiveness in the United States. PMID:22795639

  8. Long-acting progestin-only contraceptives impair endometrial vasculature by inhibiting uterine vascular smooth muscle cell survival

    PubMed Central

    Kayisli, Umit A.; Basar, Murat; Guzeloglu-Kayisli, Ozlem; Semerci, Nihan; Atkinson, Helen C.; Shapiro, John; Summerfield, Taryn; Huang, S. Joseph; Prelle, Katja; Schatz, Frederick; Lockwood, Charles J.

    2015-01-01

    Molecular mechanisms responsible for abnormal endometrial vasculature in women receiving long-acting progestin-only contraceptives (LAPCs) are unknown. We hypothesize that LAPCs impair vascular smooth muscle cell (VSMC) and pericyte proliferation and migration producing thin-walled hyperdilated fragile microvessels prone to bleeding. Proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (αSMA) double-immunostaining assessed VSMC differentiation and proliferation in endometria from women before and after DepoProvera (Depo) treatment and from oophorectomized guinea pigs (OVX-GPs) treated with vehicle, estradiol (E2), medroxyprogesterone acetate (MPA), or E2+MPA. Whole-genome profiling, proliferation, and migration assays were performed on cultured VSMCs treated with MPA or etonogestrel (ETO). Endometrial vessels of Depo-administered women displayed reduced αSMA immunoreactivity and fewer PCNA (+) nuclei among αSMA (+) cells (P < 0.008). Microarray analysis of VSMCs identified several MPA- and ETO-altered transcripts regulated by STAT1 signaling (P < 2.22 × 10−6), including chemokine (C-C motif) ligand 2 (CCL2). Both MPA and ETO reduce VSMC proliferation and migration (P < 0.001). Recombinant CCL2 reversed this progestin-mediated inhibition, whereas a STAT1 inhibitor abolished the CCL2 effect. Similarly, the endometria of MPA treated OVX-GPs displayed decreased αSMA staining and fewer PCNA (+) nuclei in VSMC (P < 0.005). In conclusion, LAPCs promote abnormal endometrial vessel formation by inhibiting VSMC proliferation and migration. PMID:25847994

  9. Introduction of postabortion contraception, prioritizing long-acting reversible contraceptives, in the principal maternity hospital of Gabon.

    PubMed

    Mayi-Tsonga, Sosthène; Obiang, Pamphile Assoumou; Minkobame, Ulysse; Ngouafo, Doris; Ambounda, Nathalie; de Souza, Maria Helena

    2014-07-01

    A prospective, descriptive, analytic study was conducted at the Centre Hospitalier de Libreville in Gabon between February and September 2013 to evaluate acceptance of long-acting reversible contraceptives (LARC) and depot-medroxyprogesterone acetate (DMPA) following abortion. Women received counseling on the combined oral pill, DMPA, copper intrauterine devices (IUDs), and implants. The association between sociodemographic and clinical characteristics, knowledge of contraceptives, and acceptance was analyzed. Of the 383 women admitted with abortion complications, 206 (53.7%) knew of no systemic contraceptives. The best-known method was the oral pill (42.0%). Only 14 women (3.6%) knew of a LARC method (IUD or implants) and only 2 (0.5%) said the injectable was their best-known method. Over 90% accepted a modern contraceptive method after abortion. Two-thirds (66.8%) chose the pill, 14.6% DMPA, and 9.3% a LARC method. Only 9.1% of the women refused to initiate use of any method. PMID:24745694

  10. Working with State Health Departments on Emerging Issues in Maternal and Child Health: Immediate Postpartum Long-Acting Reversible Contraceptives

    PubMed Central

    Kroelinger, Charlan D.; Waddell, Lisa F.; Goodman, David A.; Pliska, Ellen; Rudolph, Claire; Ahmed, Einas; Addison, Donna

    2016-01-01

    Background Immediate postpartum long-acting reversible contraceptives (LARC) are highly effective in preventing unintended pregnancy. State health departments are in the process of implementing a systems change approach to better apply policies supporting the use of immediate postpartum LARC. Methods Beginning in 2014, a group of national organizations, federal agencies, and six states have convened a LARC Learning Community to share strategies and best practices in immediate postpartum LARC policy development and implementation. Community activities consist of in-person meetings and a webinar series as forums to discuss systems change. Results The Learning Community identified eight domains for discussion and development of resources: training, pay streams, stocking and supply, consent, outreach, stakeholder partnerships, service location, and data and surveillance. The community is currently developing resource materials and guidance for use by other state health departments. Conclusions To effectively implement policies on immediate postpartum LARC, states must engage a number of stakeholders in the process, raise awareness of the challenges to implementation, and communicate strategies across agencies during policy development. PMID:26390378

  11. Why use long acting bronchodilators in chronic obstructive lung diseases? An extensive review on formoterol and salmeterol.

    PubMed

    Santus, P; Radovanovic, D; Paggiaro, P; Papi, A; Sanduzzi, A; Scichilone, N; Braido, F

    2015-07-01

    Long-acting β2-adrenoceptor agonists, formoterol and salmeterol, represent a milestone in the treatments of chronic obstructive lung diseases. Although no specific indications concerning the choice of one molecule rather than another are provided by asthma and COPD guidelines, they present different pharmacological properties resulting in distinct clinical employment possibilities. In particular, salmeterol has a low intrinsic efficacy working as a partial receptor agonist, while formoterol is a full agonist with high intrinsic efficacy. From a clinical perspective, in the presence of low β2-adrenoceptors availability, like in inflamed airways, a full agonist can maintain its bronchodilatory and non-smooth muscle activities while a partial agonist may be less effective. Furthermore, formoterol presents a faster onset of action than salmeterol. This phenomenon, combined with the molecule safety profile, leads to a prompt amelioration of the symptoms, and allows using this drug in asthma as an "as needed" treatment in patients already on regular treatment. The fast onset of action and the full agonism of formoterol need to be considered in order to select the best pharmacological treatment of asthma and COPD. PMID:26049917

  12. [Effect of a single dose of some long-acting neuroleptics on the estrus cycle and the mammary gland of the rat].

    PubMed

    Lanza, J P; Goude, F; Lanza, M

    1979-01-01

    The effects of two neuroleptics (pipotiazine and fluphenazine) and five long-acting neuroleptics (pipotiazine undecylenate and palmitate, fluphenazine enanthate and decanoate, fluopentixol decanoate) are tested in the rat, during an observation period of 20 to 40 days following only one injection of compound. The compounds administered at three different and non toxic doses, are showing effects, the intensity and duration of which are different according to the dose and the compound: diestrus of pseudo-gestation or more than 15 days, hypertrophy of mammary gland, decreasing of the uterine weight. Some long-acting neuroleptics are active during more than forty days. PMID:43191

  13. Prostaglandin D2-loaded microspheres effectively activate macrophage effector functions.

    PubMed

    Pereira, Priscilla Aparecida Tartari; Bitencourt, Claudia da Silva; dos Santos, Daiane Fernanda; Nicolete, Roberto; Gelfuso, Guilherme Martins; Faccioli, Lúcia Helena

    2015-10-12

    Biodegradable lactic-co-glycolic acid (PLGA) microspheres (MS) improve the stability of biomolecules stability and allow enable their sustained release. Lipid mediators represent a strategy for improving host defense; however, most of these mediators, such as prostaglandin D2 (PGD2), have low water solubility and are unstable. The present study aimed to develop and characterize MS loaded with PGD2 (PGD2-MS) to obtain an innovative tool to activate macrophages. PGD2-MS were prepared using an oil-in-water emulsion solvent extraction-evaporation process, and the size, zeta potential, surface morphology and encapsulation efficiency were determined. It was also evaluated in vitro the phagocytic index, NF-κB activation, as well as nitric oxide and cytokine production by alveolar macrophages (AMs) in response to PGD2-MS. PGD2-MS were spherical with a diameter of 5.0±3.3 μm and regular surface, zeta potential of -13.4±5.6 mV, and 36% of encapsulation efficiency, with 16-26% release of entrapped PGD2 at 4 and 48 h, respectively. PGD2-MS were more efficiently internalized by AMs than unloaded-MS, and activated NF-κB more than free PGD2. Moreover, PGD2-MS stimulated the production of nitric oxide, TNF-α, IL-1β, and TGF-β, more than free PGD2, indicating that microencapsulation increased the activating effect of PGD2 on cells. In LPS-pre-treated AMs, PGD2-MS decreased the release of IL-6 but increased the production of nitric oxide and IL-1β. These results show that the morphological characteristics of PGD2-MS facilitated interaction with, and activation of phagocytic cells; moreover, PGD2-MS retained the biological activities of PGD2 to trigger effector mechanisms in AMs. It is suggested that PGD2-MS represent a strategy for therapeutic intervention in the lungs of immunocompromised subjects. PMID:26143263

  14. POROUS WALL, HOLLOW GLASS MICROSPHERES

    SciTech Connect

    Sexton, W.

    2012-06-30

    Hollow Glass Microspheres (HGM) is not a new technology. All one has to do is go to the internet and Google{trademark} HGM. Anyone can buy HGM and they have a wide variety of uses. HGM are usually between 1 to 100 microns in diameter, although their size can range from 100 nanometers to 5 millimeters in diameter. HGM are used as lightweight filler in composite materials such as syntactic foam and lightweight concrete. In 1968 a patent was issued to W. Beck of the 3M{trademark} Company for 'Glass Bubbles Prepared by Reheating Solid Glass Particles'. In 1983 P. Howell was issued a patent for 'Glass Bubbles of Increased Collapse Strength' and in 1988 H. Marshall was issued a patent for 'Glass Microbubbles'. Now Google{trademark}, Porous Wall, Hollow Glass Microspheres (PW-HGMs), the key words here are Porous Wall. Almost every article has its beginning with the research done at the Savannah River National Laboratory (SRNL). The Savannah River Site (SRS) where SRNL is located has a long and successful history of working with hydrogen and its isotopes for national security, energy, waste management and environmental remediation applications. This includes more than 30 years of experience developing, processing, and implementing special ceramics, including glasses for a variety of Department of Energy (DOE) missions. In the case of glasses, SRS and SRNL have been involved in both the science and engineering of vitreous or glass based systems. As a part of this glass experience and expertise, SRNL has developed a number of niches in the glass arena, one of which is the development of porous glass systems for a variety of applications. These porous glass systems include sol gel glasses, which include both xerogels and aerogels, as well as phase separated glass compositions, that can be subsequently treated to produce another unique type of porosity within the glass forms. The porous glasses can increase the surface area compared to 'normal glasses of a 1 to 2 order of

  15. Hydrogels composed of cyclodextrin inclusion complexes with PLGA-PEG-PLGA triblock copolymers as drug delivery systems.

    PubMed

    Khodaverdi, Elham; Mirzazadeh Tekie, Farnaz Sadat; Hadizadeh, Farzin; Esmaeel, Haydar; Mohajeri, Seyed Ahmad; Sajadi Tabassi, Sayyed A; Zohuri, Gholamhossein

    2014-02-01

    Although conventional pharmaceuticals have many drug dosage forms on the market, the development of new therapeutic molecules and the low efficacy of instant release formulations for the treatment of some chronic diseases and specific conditions encourage scientists to invent different delivery systems. To this purpose, a supramolecular hydrogel consisting of the tri-block copolymer PLGA-PEGPLGA and α-cyclodextrin was fabricated for the first time and characterised in terms of rheological, morphological, and structural properties. Naltrexone hydrochloride and vitamin B12 were loaded, and their release profiles were determined. PMID:24234803

  16. Integrated Cryogenic Experiment (ICE) microsphere investigation

    NASA Technical Reports Server (NTRS)

    Spradley, I.; Read, D.

    1989-01-01

    The main objective is to determine the performance of microsphere insulation in a 0-g environment and compare its performance to reference insulations such as multilayer insulation. The Lockheed Helium Extended-Life Dewar (HELD) is used to provide superfluid-helium cold sink for the experiment. The use of HELD allows the low-g dynamic properties of Passive Orbital Disconnect Struts (PODS) to be characterized and provides a flight demonstration of the PODS system. The thermal performance of microspheres in 1 and 0 g was predicted, a flight experiment was designed to determine microsphere thermal performance, and the interface was also designed between the experimental package and the shuttle through HELD and the Hitchhiker-M carrier. A single test cell was designed and fabricated. The cell was filled with uncoated glass microspheres and tested with a liquid-nitrogen cold sink. The data were found to agree with predictions of microsphere performance in 1 g.

  17. Polymer microspheres carrying fluorescent DNA probes

    NASA Astrophysics Data System (ADS)

    Chen, Xiaoyu; Dai, Zhao; Zhang, Jimei; Xu, Shichao; Wu, Chunrong; Zheng, Guo

    2010-07-01

    A polymer microspheres carried DNA probe, which was based on resonance energy transfer, was presented in this paper when CdTe quantum dots(QDs) were as energy donors, Au nanoparticles were as energy accepters and poly(4- vinylpyrindine-co-ethylene glycol dimethacrylate) microspheres were as carriers. Polymer microspheres with functional group on surfaces were prepared by distillation-precipitation polymerization when ethylene glycol dimethacrylate was as crosslinker in acetonitrile. CdTe QDs were prepared when 3-mercaptopropionic acid(MPA) was as the stabilizer in aqueous solution. Because of the hydrogen-bonding between the carboxyl groups of MPA on QDs and the pyrindine groups on the microspheres, the QDs were self-assembled onto the surfaces of microspheres. Then, the other parts of DNA probe were finished according to the classic method. The DNA detection results indicated that this novel fluorescent DNA probe system could recognize the existence of complementary target DNA or not.

  18. Multiplexed Microsphere Suspension Array-Based Immunoassays.

    PubMed

    Lin, Andrew; Salvador, Alexandra; Carter, J Mark

    2015-01-01

    ELISA is an extremely powerful tool to detect analytes because of its sensitivity, selectivity, reproducibility and ease of use. Here we describe sandwich immunoassays performed in suspension on spectrally unique microspheres developed by Luminex. Luminex assays offer the benefit of multiplex analysis of large numbers of analytes in a single reaction. Because the microspheres are spectrally unique, many microspheres, each attached to various antibodies, can be added to a single sample. Luminex instruments can distinguish each microsphere and detect the intensity of a reporter signal for each microsphere. Results are reported in Median Fluorescent Intensities for each analyte. Luminex assays can be used to detect up to 500 analytes in a high-throughput format. Luminex refers to this technology as xMAP(®). Here we describe a routine protocol for a Luminex immunoassay. Other Luminex assays would have to be optimized for specific conditions according to their use. PMID:26160569

  19. Laser-Induced Spallation of Microsphere Monolayers.

    PubMed

    Hiraiwa, Morgan; Stossel, Melicent; Khanolkar, Amey; Wang, Junlan; Boechler, Nicholas

    2016-08-01

    The detachment of a semiordered monolayer of polystyrene microspheres adhered to an aluminum-coated glass substrate is studied using a laser-induced spallation technique. The microsphere-substrate adhesion force is estimated from substrate surface displacement measurements obtained using optical interferometry, and a rigid-body model that accounts for the inertia of the microspheres. The estimated adhesion force is compared with estimates obtained using an adhesive contact model together with interferometric measurements of the out-of-plane microsphere contact resonance, and with estimated work of adhesion values for the polystyrene-aluminum interface. Scanning electron microscope images of detached monolayer regions reveal a unique morphology, namely, partially detached monolayer flakes composed of single hexagonal close packed crystalline domains. This work contributes to the fields of microsphere adhesion and contact dynamics, and demonstrates a unique monolayer delamination morphology. PMID:27409715

  20. Integrated Cryogenic Experiment (ICE) microsphere investigation

    SciTech Connect

    Spradley, I.; Read, D.

    1989-09-01

    The main objective is to determine the performance of microsphere insulation in a 0-g environment and compare its performance to reference insulations such as multilayer insulation. The Lockheed Helium Extended-Life Dewar (HELD) is used to provide superfluid-helium cold sink for the experiment. The use of HELD allows the low-g dynamic properties of Passive Orbital Disconnect Struts (PODS) to be characterized and provides a flight demonstration of the PODS system. The thermal performance of microspheres in 1 and 0 g was predicted, a flight experiment was designed to determine microsphere thermal performance, and the interface was also designed between the experimental package and the shuttle through HELD and the Hitchhiker-M carrier. A single test cell was designed and fabricated. The cell was filled with uncoated glass microspheres and tested with a liquid-nitrogen cold sink. The data were found to agree with predictions of microsphere performance in 1 g.

  1. Gas foamed open porous biodegradable polymeric microspheres.

    PubMed

    Kim, Taek Kyoung; Yoon, Jun Jin; Lee, Doo Sung; Park, Tae Gwan

    2006-01-01

    Highly open porous biodegradable polymeric microspheres were fabricated for use as injectable scaffold microcarriers for cell delivery. A modified water-in-oil-in-water (W1/O/W2) double emulsion solvent evaporation method was employed for producing the microspheres. The incorporation of an effervescent salt, ammonium bicarbonate, in the primary W1 droplets spontaneously produced carbon dioxide and ammonia gas bubbles during the solvent evaporation process, which not only stabilized the primary emulsion, but also created well inter-connected pores in the resultant microspheres. The porous microspheres fabricated under various gas foaming conditions were characterized. The surface pores became as large as 20 microm in diameter with increasing the concentration of ammonium bicarbonate, being sufficient enough for cell infiltration and seeding. These porous scaffold microspheres could be potentially utilized for cultivating cells in a suspension manner and for delivering the seeded cells to the tissue defect site in an injectable manner. PMID:16023197

  2. Transdermal iontophoresis of flufenamic acid loaded PLGA nanoparticles.

    PubMed

    Malinovskaja-Gomez, K; Labouta, H I; Schneider, M; Hirvonen, J; Laaksonen, T

    2016-06-30

    The objective of this study was to test in vitro a drug delivery system that combines nanoencapsulation and iontophoresis for the transdermal delivery of lipophilic model drug using poly(lactic-co-glycolic acid) (PLGA) as the carrier polymer. Negatively charged fluorescent nanoparticles loaded with negatively charged flufenamic acid were prepared. The colloidal properties of the particles were stable under iontophoretic current (constant, pulsed and alternating) profiles and in contact with skin barrier. The release of the drug from the particles was not affected by iontophoresis and remained always limited (≈50%), leading to significantly lower transdermal fluxes across human epidermis and full thickness porcine skin compared to respective free drug formulation. From nanoparticles, pulsed current profile resulted in comparable or higher fluxes compared to constant current profile although fluorescence imaging was not able to confirm deeper distribution of nanoparticles in skin. Based on our results, there is no clear advantage with respect to drug permeation from nanoencapsulating flufenamic acid into PLGA nanoparticles compared to free drug formulation, either in passive or iontophoretic delivery regimens. However, pulsed current iontophoresis could be an effective alternative instead of traditional constant current iontophoresis to enhance transdermal permeation of drugs from nanoencapsulated formulations. PMID:27131608

  3. Development of hematin conjugated PLGA nanoparticle for selective cancer targeting.

    PubMed

    Amin, Md Lutful; Kim, Dami; Kim, SeJin

    2016-08-25

    Targeted nanomedicine for cancer therapy has gained widespread popularity and is being extensively explored. Porphyrins have intrinsic tumor localizing ability and have been studied for photodynamic therapy. However, they have not been used as cancer targeting agents for nanomedicines. In this study, PLGA nanoparticles were formulated and an iron-containing blood porphyrin, hematin was conjugated to the surface of the nanoparticles to investigate selectivity towards cancer cell and cellular internalization. Hematin was previously shown to facilitate growth and proliferation of cancer cells. PLGA nanoparticles were characterized by FE-SEM, AFM, DLS, and Zeta potential analyzer. The conjugation of hematin was confirmed by FTIR. HeLa cells were used to study tumor selectivity and uptake. Hematin conjugated particles (ζ potential: -15.19mV) showed higher affinity towards the cancer cells than the control particles. The result indicated that the particles were internalized by heme carrier protein-1. Together these data suggest that hematin is a promising cancer targeting material for nanotherapeutics. PMID:27260086

  4. PLGA Nanoparticles for Ultrasound-Mediated Gene Delivery to Solid Tumors

    PubMed Central

    Figueiredo, Marxa; Esenaliev, Rinat

    2012-01-01

    This paper focuses on novel approaches in the field of nanotechnology-based carriers utilizing ultrasound stimuli as a means to spatially target gene delivery in vivo, using nanoparticles made with either poly(lactic-co-glycolic acid) (PLGA) or other polymers. We specifically discuss the potential for gene delivery by particles that are echogenic (amenable to destruction by ultrasound) composed either of polymers (PLGA, polystyrene) or other contrast agent materials (Optison, SonoVue microbubbles). The use of ultrasound is an efficient tool to further enhance gene delivery by PLGA or other echogenic particles in vivo. Echogenic PLGA nanoparticles are an attractive strategy for ultrasound-mediated gene delivery since this polymer is currently approved by the US Food and Drug Administration for drug delivery and diagnostics in cancer, cardiovascular disease, and also other applications such as vaccines and tissue engineering. This paper will review recent successes and the potential of applying PLGA nanoparticles for gene delivery, which include (a) echogenic PLGA used with ultrasound to enhance local gene delivery in tumors or muscle and (b) PLGA nanoparticles currently under development, which could benefit in the future from ultrasound-enhanced tumor targeted gene delivery. PMID:22506124

  5. Osteointegration of PLGA implants with nanostructured or microsized β-TCP particles in a minipig model.

    PubMed

    Kulkova, Julia; Moritz, Niko; Suokas, Esa O; Strandberg, Niko; Leino, Kari A; Laitio, Timo T; Aro, Hannu T

    2014-12-01

    Bioresorbable suture anchors and interference screws have certain benefits over equivalent titanium-alloy implants. However, there is a need for compositional improvement of currently used bioresorbable implants. We hypothesized that implants made of poly(l-lactide-co-glycolide) (PLGA) compounded with nanostructured particles of beta-tricalcium phosphate (β-TCP) would induce stronger osteointegration than implants made of PLGA compounded with microsized β-TCP particles. The experimental nanostructured self-reinforced PLGA (85L:15G)/β-TCP composite was made by high-energy ball-milling. Self-reinforced microsized PLGA (95L:5G)/β-TCP composite was prepared by melt-compounding. The composites were characterized by gas chromatography, Ubbelohde viscometry, scanning electron microscopy, laser diffractometry, and standard mechanical tests. Four groups of implants were prepared for the controlled laboratory study employing a minipig animal model. Implants in the first two groups were prepared from nanostructured and microsized PLGA/β-TCP composites respectively. Microroughened titanium-alloy (Ti6Al4V) implants served as positive intra-animal control, and pure PLGA implants as negative control. Cone-shaped implants were inserted in a random order unilaterally in the anterior cortex of the femoral shaft. Eight weeks after surgery, the mechanical strength of osteointegration of the implants was measured by a push-out test. The quality of new bone surrounding the implant was assessed by microcomputed tomography and histology. Implants made of nanostructured PLGA/β-TCP composite did not show improved mechanical osteointegration compared with the implants made of microsized PLGA/β-TCP composite. In the intra-animal comparison, the push-out force of two PLGA/β-TCP composites was 35-60% of that obtained with Ti6Al4V implants. The implant materials did not result in distinct differences in quality of new bone surrounding the implant. PMID:25241283

  6. Surface modification of PLGA nanoparticles via human serum albumin conjugation for controlled delivery of docetaxel

    PubMed Central

    2013-01-01

    Background Poly lactic-co-glycolic acid (PLGA) based nanoparticles are considered to be a promising drug carrier in tumor targeting but suffer from the high level of opsonization by reticuloendothelial system due to their hydrophobic structure. As a result surface modification of these nanoparticles has been widely studied as an essential step in their development. Among various surface modifications, human serum albumin (HSA) possesses advantages including small size, hydrophilic surface and accumulation in leaky vasculature of tumors through passive targeting and a probable active transport into tumor tissues. Methods PLGA nanoparticles of docetaxel were prepared by emulsification evaporation method and were surface conjugated with human serum albumin. Fourier transform infrared spectrum was used to confirm the conjugation reaction where nuclear magnetic resonance was utilized for conjugation ratio determination. In addition, transmission electron microscopy showed two different contrast media in conjugated nanoparticles. Furthermore, cytotoxicity of free docetaxel, unconjugated and conjugated PLGA nanoparticles was studied in HepG2 cells. Results Size, zeta potential and drug loading of PLGA nanoparticles were about 199 nm, −11.07 mV, and 4%, respectively where size, zeta potential and drug loading of conjugated nanoparticles were found to be 204 nm, −5.6 mV and 3.6% respectively. Conjugated nanoparticles represented a three-phasic release pattern with a 20% burst effect for docetaxel on the first day. Cytotoxicity experiment showed that the IC50 of HSA conjugated PLGA nanoparticles (5.4 μg) was significantly lower than both free docetaxel (20.2 μg) and unconjugated PLGA nanoparticles (6.2 μg). Conclusion In conclusion surface modification of PLGA nanoparticles through HSA conjugation results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PLGA nanoparticles. Albumin conjugated PLGA nanoparticles may

  7. Porous magnesium/PLGA composite scaffolds for enhanced bone regeneration following tooth extraction.

    PubMed

    Brown, Andrew; Zaky, Samer; Ray, Herbert; Sfeir, Charles

    2015-01-01

    Sixty percent of implant-supported dental prostheses require bone grafting to enhance bone quantity and quality prior to implant placement. We have developed a metallic magnesium particle/PLGA composite scaffold to overcome the limitations of currently used dental bone grafting materials. This is the first report of porous metallic magnesium/PLGA scaffolds synthesized using a solvent casting, salt leaching method. We found that incorporation of varying amounts of magnesium into the PLGA scaffolds increased the compressive strength and modulus, as well as provided a porous structure suitable for cell infiltration, as measured by mercury intrusion porosimetry. Additionally, combining basic-degrading magnesium with acidic-degrading PLGA led to an overall pH buffering effect and long-term release of magnesium over the course of a 10-week degradation assay, as measured with inductively coupled plasma-atomic emission spectroscopy. Using an indirect proliferation assay adapted from ISO 10993:5, it was found that extracts of medium from degrading magnesium/PLGA scaffolds increased bone marrow stromal cell proliferation in vitro, a phenomenon observed by other groups investigating magnesium's impact on cells. Finally, magnesium/PLGA scaffold biocompatibility was assessed in a canine socket preservation model. Micro-computed tomography and histological analysis showed the magnesium/PLGA scaffolds to be safer and more effective at preserving bone height than empty controls. Three-dimensional magnesium/PLGA composite scaffolds show promise for dental socket preservation and also, potentially, orthopedic bone regeneration. These scaffolds could decrease inflammation observed with clinically used PLGA devices, as well as enhance osteogenesis, as observed with previously studied magnesium devices. PMID:25234156

  8. Effects of a long-acting, trace mineral, reticulorumen bolus on range cow productivity and trace mineral profiles.

    PubMed

    Sprinkle, J E; Cuneo, S P; Frederick, H M; Enns, R M; Schafer, D W; Carstens, G E; Daugherty, S B; Noon, T H; Rickert, B M; Reggiardo, C

    2006-06-01

    The objectives were to determine if strategic supplementation of range cows with a long-acting (6 mo), trace mineral, reticulorumen bolus containing Cu, Se, and Co would: (1) increase cow BCS and BW, and calf birth, weaning, and postweaning weights, or weight per day of age (WDA); (2) increase liver concentrations of Cu or Zn in cows, or blood Se, Cu, or Zn concentrations in cows and calves; and (3) vary by cow breed for any of these response variables. There were 192 control and 144 bolused Composite cows (C; 25% Hereford, Angus, Gelbevieh, and Senepol or Barzona); 236 control and 158 bolused Hereford (H) cows; and 208 control and 149 bolused Brahman cross (B) cows used in a 3-yr experiment. Cows were weighed and scored for body condition in January, May, and September, and all bolused cows received boluses in January. Each year, from among the 3 breed groups a subset of 15 control and 15 bolused cows (n = 90) had samples obtained in January and May for liver Cu and Zn, blood Se, and serum Cu and Zn. As for cows, blood and serum from the calves of these cows were sampled each year in May and September for Cu, Se, and Zn. There was a significant breed x year x treatment interaction (P = 0.001) for cow weight loss from January to May. Calf WDA, weaning, and postweaning weights did not differ (P > 0.40) between bolused and control cows, but there was a significant (P = 0.022) breed x year x treatment interaction for birth weight. Liver Cu was deficient (< 75 ppm; P < 0.001) in control cows and adequate (< 75 to 90 ppm) for bolused cows. Liver Cu differed by year (P < 0.001). Blood Se was adequate (< 0.1 ppm) for all cows except in January 2001 and 2002. There was no difference (P > 0.50) in blood Se between treatment groups in January, but bolused cows had greater (P < 0.01) blood Se in May. Breed differences for blood Se concentrations existed for bolused cows, with B having greater (P < 0.05) blood Se than either C or H cows. Breed differences also existed for

  9. Focal release of neurotrophic factors by biodegradable microspheres enhance motor and sensory axonal regeneration in vitro and in vivo.

    PubMed

    Santos, Daniel; Giudetti, Guido; Micera, Silvestro; Navarro, Xavier; Del Valle, Jaume

    2016-04-01

    Neurotrophic factors (NTFs) promote nerve regeneration and neuronal survival after peripheral nerve injury. However, drawbacks related with administration and bioactivity during long periods limit their therapeutic application. In this study, PLGA microspheres (MPs) were used to locally release different NTFs and evaluate whether they accelerate axonal regeneration in comparison with free NTFs or controls. ELISA, SEM, UV/visible light microscopy, organotypic cultures of DRG explants and spinal cord slices were used to characterize MP properties and the bioactivity of the released NTFs. Results of organotypic cultures showed that encapsulated NTFs maintain longer bioactivity and enhance neurite regeneration of both sensory and motor neurons compared with free NTFs. For in vivo assays, the rat sciatic nerve was transected and repaired with a silicone tube filled with collagen gel or collagen mixed with PBS encapsulated MPs (control groups) and with free or encapsulated NGF, BDNF, GDNF or FGF-2. After 20 days, a retrotracer was applied to the regenerated nerve to quantify motor and sensory axonal regeneration. NTF encapsulation in MPs improved regeneration of both motor and sensory axons, as evidenced by increased numbers of retrolabeled neurons. Hence, our results show that slow release of NTFs with PLGA MP enhance nerve regeneration. PMID:26854135

  10. A Long-Acting Integrase Inhibitor Protects Female Macaques from Repeated High-Dose Intravaginal SHIV Challenge

    PubMed Central

    Andrews, Chasity D.; Yueh, Yun Lan; Spreen, William R.; St. Bernard, Leslie; Boente-Carrera, Mar; Rodriguez, Kristina; Gettie, Agegnehu; Russell-Lodrigue, Kasi; Blanchard, James; Ford, Susan; Mohri, Hiroshi; Cheng-Mayer, Cecilia; Hong, Zhi; Ho, David D.; Markowitz, Martin

    2015-01-01

    GSK1265744 long-acting (GSK744 LA) is a strand-transfer inhibitor of HIV/SIV integrase and was shown to be an effective pre-exposure prophylaxis agent in a low-dose intrarectal SHIV rhesus macaque challenge model. Here, we examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with 50 mg/kg of GSK744 LA monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were 5-fold lower on average in cervical tissues than rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected 6 of 8 female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for pre-exposure prophylaxis. PMID:25589630

  11. Long-acting injectable versus daily oral antipsychotic trea