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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 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

  12. 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

  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

    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

  19. 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

  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

    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

  13. 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

  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. 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

  19. 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

  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. 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.

  18. 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

  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. 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

  14. 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

  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. 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

  19. 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

  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. 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

  17. 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

  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

    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

  3. 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

  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. 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

  10. 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

  11. 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

  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. 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

  14. 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

  15. 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

  16. 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

  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. 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

  8. 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

  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

    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

  11. 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

  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. 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

  14. 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

  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. 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

  18. 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

  19. 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

  20. 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

  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. 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

  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. 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

  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. 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

  19. 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

  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. 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

  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. 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

  9. 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…

  10. 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...

  11. 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 ...

  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. 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

  14. 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

  15. 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

  16. 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

  17. 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

  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. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  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. 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

  18. 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

  19. 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

  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. 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

  7. 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

  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. 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