Water-soluble betamethasone-loaded poly(lactide-co-glycolide) hollow microparticles as a sustained release dosage form

In this study, betamethasone disodium phosphate-loaded microparticles were fabricated for sustained release using poly(lactide-co-glycolide) (PLGA) by spray drying and emulsion solvent evaporation/extraction techniques. Encapsulation efficiencies ranged from 59–80% using a water-in-oil-in-oil (W/O/O) double emulsion technique and more than 90% for a spray-drying method were obtained. This was a significant improvement compared to fabrication by a water-in-oil-in-water (W/O/W) double emulsion process, which had an encapsulation efficiency of less than 15%. Multiple-phase and biphasic release profiles were observed for microparticles of PLGA 50/50 and PLGA of higher lactide contents, respectively. The PLGA 50/50 hollow microparticles fabricated using the W/O/O double emulsion technique provided a sustained release of betamethasone disodium phosphate over 3 weeks.     

Water-soluble betamethasone-loaded poly(lactide-co-glycolide) hollow microparticles as a sustained release dosage form

In this study, betamethasone disodium phosphate-loaded microparticles were fabricated for sustained release using poly(lactide-co-glycolide) (PLGA) by spray drying and emulsion solvent evaporation/extraction techniques. Encapsulation efficiencies ranged from 59-80% using a water-in-oil-in-oil (W/O/O) double emulsion technique and more than 90% for a spray-drying method were obtained. This was a significant improvement compared to fabrication by a water-in-oil-in-water (W/O/W) double emulsion process, which had an encapsulation efficiency of less than 15%. Multiple-phase and biphasic release profiles were observed for microparticles of PLGA 50/50 and PLGA of higher lactide contents, respectively. The PLGA 50/50 hollow microparticles fabricated using the W/O/O double emulsion technique provided a sustained release of betamethasone disodium phosphate over 3 weeks.     

Modification of the tri-phasic drug release pattern of leuprolide acetate-loaded poly(lactide-co-glycolide) microparticles.

Leuprolide acetate-loaded poly(lactide-co-glycolide) (PLGA RG503H) microparticles prepared by the solvent evaporation method had a tri-phasic drug release pattern over a duration of up to 2 months. An initial release was followed by a slow drug release phase and a final rapid drug release. The objective of this study was to identify parameters, which shift the release profile from the tri-phasic to a more continuous release profile. Varying formulation and processing parameters (e.g., drug loading, volume of the external aqueous phase, using low molecular weight PLGA, different microparticle drying methods) affected the initial release (burst) but did not influence the drug release thereafter. The addition of the hydrophilic polymer polyvinylpyrrolidone (PVP) led to the formation of more porous microparticles. This influenced the initial release but did not change the tri-phasic drug release pattern. The inclusion of medium chain triglycerides (MCT) successfully shifted the tri-phasic pattern to a continuous release profile. MCT accelerated the leuprolide release in the second, slow release phase and reduced it in the final rapid release phase. MCT led to the formation of microparticles with an irregular surface and a highly porous inner structure. Differential scanning calorimetry (DSC) revealed a high encapsulation efficiency of MCT (88-105%) in the microparticles and an unchanged glass transition temperature (Tg) of PLGA.     

Hydrophilic versus hydrophobic porogens for engineering of poly(lactide-co-glycolide) microparticles containing risedronate sodium

Objective: The aim of this study was to investigate the effect of two mechanistically different porogens, namely: the hydrophilic hydroxy-propyl-β-cyclodextrin and the hydrophobic porogens (mineral oil and corn oil) in producing open/closed pored engineered polylactide-co-glycolic-acid microspheres suitable for pulmonary delivery of risedronate sodium (RS).

Materials and methods: Surface morphology of the microspheres was studied and they were characterized for entrapment efficiency (%EE), particle size, and porosity as well as aerodynamic and flow properties. Selected formulae were investigated for in vitro drug release and deposition behavior using next generation impactor. Furthermore, the safety of the free drug and the selected prepared systems was assessed by MTT viability test performed on Calu-3 cell line.

Results and discussion: The current work revealed that HP-β-CD produced open-pored microspheres, while oils produced closed pored microspheres. Modulation of preparation parameters generated porous RS microspheres with high %EE, sustained drug release profile up to 15 days, suitable geometric and aerodynamic particle sizes and excellent flow properties. The safety of HP-β-CD systems was higher than the systems utilizing oil as porogen.

Conclusion: Porogen type affected the behavior of the microspheres as demonstrated by the various characterization experiments, with microspheres prepared using HP-β-CD being superior to those prepared using oils as porogens.     

Key parameters affecting the initial release (burst) and encapsulation efficiency of peptide-containing poly(lactide-co-glycolide) microparticles

The objective of this study was to identify key variables affecting the initial release (burst) and the encapsulation of leuprolide acetate-containing poly(lactide-co-glycolide) (PLGA) microparticles, which were prepared by the cosolvent evaporation method. Adjusting parameters, which affected the PLGA precipitation kinetics, provided efficient ways to increase the encapsulation efficiency and to control the initial release. Addition of 0.05M NaCl to the external aqueous phase increased the encapsulation efficiency and the initial release; in contrast, NaCl at high concentration (0.5M) delayed polymer precipitation and resulted in non-porous microparticles with a low initial release. The presence of ethanol in the external phase led to porous microparticles with an increased initial release but a decreased encapsulation efficiency. The initial release also decreased with decreasing volume of the external phase and homogenization speed, as well as with covering the preparation apparatus; however, these variations had no significant effect on the encapsulation efficiency. Scale-up of the laboratory size by a factor of 5 and 25 showed insignificant influence on the encapsulation efficiency, particle size, and drug release.     

Effect of poly(lactide-co-glycolide) molecular weight on the release of dexamethasone sodium phosphate from microparticles

The objective of this study was to investigate the effect of poly(lactide-co-glycolide) (PLGA) molecular weight (Resomer RG 502H, RG 503H, and RG 504H) on the release behavior of dexamethasone sodium phosphate-loaded microparticles. The microparticles were prepared by three modifications of the solvent evaporation method (O/W-cosolvent, O/W-dispersion, and W/O/W-methods). The encapsulation efficiency of microparticles prepared by the cosolvent- and W/O/W-methods increased from approximately 50% to >90% upon addition of NaCl to the external aqueous phase, while the dispersion method resulted in lower encapsulation efficiencies. The release of dexamethasone sodium phosphate from PLGA microparticles (>50 microm) was biphasic. The initial burst release correlated well with the porosity of the microparticles, both of which increased with increasing polymer molecular weight (RG 504H > 503H > 502H). The burst was also dependent on the method of preparation and was in the order of dispersion method > WOW method > consolvent method. In contrast to the higher molecular weight PLGA microparticles, the release from RG 502H microparticles prepared by cosolvent method was not affected by volume of organic solvent (1.5-3.0 ml) and drug loading (4-13%). An initial burst of approximately 10% followed by a 5-week sustained release phase was obtained. Microparticles with a size <50 microm released in a triphasic manner; an initial burst was followed by a slow release phase and then by a second burst.     

Poly(lactide-co-glycolide) microparticles for the development of single-dose controlled-release vaccines

With the exception of the provision of clean water supplies, vaccination remains the most successful public health intervention strategy for the control of infectious diseases. However, the logistics of delivering at least two to three doses of vaccines to achieve protective immunity are complex and compliance is frequently inadequate, particularly in developing countries. In addition, newly developed purified subunit and synthetic vaccines are often poorly immunogenic and need to be administered with potent vaccine adjuvants. Microparticles prepared from the biodegradable and biocompatible polymers, the poly(lactide-co-glycolides) or (PLG), have been shown to be effective adjuvants for a number of antigens. Moreover, PLG microparticles can control the rate of release of entrapped antigens and therefore, offer potential for the development of single-dose vaccines. To prepare single-dose vaccines, microparticles with different antigen release rates may be combined as a single formulation to mimic the timing of the administration of booster doses of vaccine. If necessary, adjuvants may also be entrapped within the microparticles or, alternatively, they may be co-administered. The major problems which may restrict the development of microparticles as single-dose vaccines include the instability of vaccine antigens during microencapsulation, during storage of the microparticles and during hydration of the microparticles following in vivo administration. In the present review, we discuss the adjuvant effect of PLG microparticles, and also their potential for the development of single-dose vaccines through the use of controlled-release technology.     

Poly(lactide-co-glycolide) microparticles as systems for controlled release of proteins -- preparation and characterization

Poly(DL-lactide-co-glycolide) (PDLLGA) and poly(L-lactide-co-glycolide) (PLLGA) copolymers were prepared by bulk ring opening polymerization of lactide and glycolide and characterized by GPC, FTIR, 1H NMR and DSC. Copolymers with different molar masses at a constant lactide/glycolide ratio were used for preparation of bovine serum albumin (BSA)-loaded microparticles by the double emulsion w/o/w method. The influence of the copolymer molar mass and composition on the microparticle morphology, size, yield, degradation rate, BSA-loading efficiency and BSA release profile were studied. For microparticles prepared from PDLLGA copolymers, a biphasic profile for BSA release was found and for those made from PLLGA copolymers the release profile was typically triphasic; both of them were characterized by high initial burst release. Possible reasons for such behavior are discussed.     

Determination of water-soluble acid distribution in poly(lactide-co-glycolide)

Determination of the kinetics of water-soluble degradation products inside poly(lactide-co-glycolide) (PLGA) delivery systems during polymer degradation is important to evaluate the polymer microclimate conditions, particularly microclimate pH changes for optimization of encapsulated drug stability. A pre-derivatization high-performance liquid chromatography (HPLC) method was developed for separation and quantification of water-soluble acid impurities and degradation products in PLGA. Thin PLGA films (approximately 200 microm) were incubated in PBS/0.02% Tween 80, pH 7.4, for 6 weeks. Water-soluble monomers and oligomers were obtained from polymer films after repeated CHCl(3)/H(2)O extraction and then derivatized into bromophenacyl esters. With the common chromophore, the esters were separated and quantified by HPLC with increased ultraviolet (UV) sensitivity at 254 nm. The total amount of water-soluble acids in the extract was validated by potentiometric titration with tetrabutyl ammonium hydroxide. During the first 3 weeks of incubation of PLGA 50:50 (inherent viscosity = 0.63 dL/g), the principal water-soluble acids in the polymer were glycolic, lactic, and lactoyllactic acids, and an unknown oligomer. After 4 weeks of incubation, a large fraction of higher molecular weight oligomers was observed. Pre-derivatization HPLC can be used to accurately measure water-soluble acid distribution, and may be invaluable to examine the degradation behavior of PLGAs, including the underlying mechanism of polymer microclimate pH development.     

Analysis of residual solvents in poly(lactide-co-glycolide) nanoparticles

Biodegradable nanoparticles formulated from poly(lactide-co-glycolide) (PLGA) have been extensively investigated for drug delivery. The emulsification-solvent evaporation method for manufacturing PLGA nanoparticles is simple and reproducible, but the organic solvent, dichloromethane, has undesirable environmental and safety risks. Dichloromethane is also a suspected carcinogen and mutagen, so has to be completely removed from the nanoparticles. The International Committee for Harmonization suggests a limit of residual dichloromethane of no more than 600?ppm. Here, we evaluate the residual quantity of volatile dichloromethane after the manufacturing process of nanoparticles. We developed a simple, fast, and reliable method by gas chromatography with a flame ionization detector to determine dichloromethane levels. This method was validated according to regulatory requirements and produced acceptable results with respect to specificity, linearity, sensitivity, precision, and accuracy. We also tested the effects of various parameters in the preparation of the nanoparticles such as surfactant concentration, organic phase volume, and washing frequency. This study provides a useful method for manufacturing PLGA nanoparticles with minimal residual solvent by decreasing surfactant concentration or increasing washing frequency.     

Development of mass transport resistance in poly(lactide-co-glycolide) films and particles--a mechanistic study

Poly(D,L-lactide-co-glycolide) (PLG) is the most frequently used biodegradable polymer in the controlled release of an encapsulated drug. The purpose of this work was to explain the surprisingly slow diffusion through this polymer, and locate the major source of mass transport resistance. Diffusion of human growth hormone (hGH) and glucose through PLG films was undetectable (using a diffusion cell), although the degraded polymer contained several times more water than polymer mass. In vitro release of hGH from PLG-coated particles also showed a surprisingly slow rate of release. Non-porous regions inside the PLG films were detected after three weeks of degradation using dextran-coupled fluorescent probes and confocal microscopy. The findings were supported by scanning electron microscopy. Diffusion through PLG films degraded for five weeks was significantly increased when the porosity of both surfaces was increased due to the presence of ZnCl(2) in the buffer the last 3 days of the degradation period. The results indicated high mass transport resistance inside the films after three weeks of degradation, and at the surfaces after five weeks of degradation. These results should also be applicable to microparticles of different sizes. Knowledge of the reason for transport resistance is important in the development of pharmaceuticals and when modifying the rate of drug release.     

Vancomycin release from poly(D,L-lactide) and poly(lactide-co-glycolide) disks

A biodegradable and biocompatible polymeric system was developed for the controlled release of vancomycin for the treatment of brain abscesses. Poly(D,L-lactic acid) (PLA) and its copolymers poly(lactide-co-glycolide) PLGA 90:10 and PLGA 70:30, were prepared. Polymer disks containing vancomycin (VN) were prepared by solvent casting from methylene chloride solutions. Degradation of the polymer disk was studied by scanning electron microscopy, NMR and GPC. SEM revealed an increasing degree of degradation with time with both PLGAs, the effect being more distinct in the PLGA with the higher glycolide content (PLGA 70:30), which was confirmed with GPC, which showed both a decrease in the molecular weights of PLGA and a decrease in the heterogeneity index (chain length distribution) upon incubation in isotonic phosphate buffer at 37#176;C for up to 5 weeks. NMR showed a decrease in the CH 2 contents of the copolymers, implying that the glycolide component of the copolymers is being preferentially degraded. In situ, vancomycin release behaviour of the disks in pH 7.4 phosphate buffer saline (PBS) was followed for ~2 months in a static system. It was observed that release was according to Higuchi kinetics (Q vs. t 1/2) , and introduction of low molecular weight PLA or hydrophilic compounds like PEG increased the release rate.     

Glycol chitosan as a stabilizer for protein encapsulated into poly(lactide-co-glycolide) microparticle

Glycol chitosan (GC), a chitosan derivative conjugated with ethylene glycol, is soluble in water at a neutral/acidic pH and is viscous. This GC was incorporated into poly(lactide-co-glycolide) (PLGA) microparticles (prepared by the multi-emulsion W(1)/O/W(2) (water-in-oil-in-water) method) to stabilize lysozyme (Lys) used as a model protein. Herein, GC's viscous property helped to improve Lys encapsulation efficacy and reduce Lys denaturaton at the water/organic solvent interface. When the GC concentration in the W(1) phase increased, the formation of non-covalent Lys aggregates decreased. This may be because the aqueous microdroplets surrounded by the firm viscous interface protect Lys from the degrading environment formed by the water/organic solvent interface. In an in vitro Lys release test, 40mg incorporation of GC led to continuous Lys release of up to 78wt.% for 1 month and presented bioactivity of more than 95% for Lys released from microparticles. In addition, there was negligible immune response in the tissue treated with the GC-incorporated PLGA microparticles, whereas there was a moderate foreign body reaction in the muscle layer and many configurations of neutrophils in the tissue treated with the PLGA microparticles without GC. It is expected that GC facilitates a decrease in immune responses exacerbated as a consequence of PLGA degradation.     

Drug delivery into the brain using poly(lactide-co-glycolide) microspheres

Among the strategies developed for drug delivery into the CNS, locally controlled drug release by the way of an implantable polymeric device has been developed in recent years. The first polymeric devices developed were macroscopic implants needing open surgery for implantation. Over the last few years, poly(lactide-co-glycolide) microspheres have been shown to be safe and promising for drug delivery into the brain. Poly(lactide-co-glycolide) is biodegradable and biocompatible with brain tissue. Due to their size, these microspheres can be easily implanted by stereotaxy in discrete, precise and functional areas of the brain without causing damage to the surrounding -tissue. Brain tumour treatments have been developed using this approach and clinical trials have been performed. Potential applications in neurodegenerative diseases have also been explored, particularly neurotrophic factor delivery and cell therapy.     

聚氨基酯作为基因载体的研究进展

随着基因治疗研究的不断深入,寻求一种高效、安全、靶向表达的载体已成为了基因治疗的核心问题之一。聚氨基酯(poly amino ester,PAE)作为一种新型的阳离子聚合物基因载体,具有原料廉价、合成简单、结构多样、可降解、细胞毒性低和转染效率高等优点,已越来越受到人们的关注。本文将从聚氨基酯的合成途径、理化性质、聚氨基酯/DNA纳米粒的制备及聚氨基酯/DNA纳米粒转染效率和影响因素等方面详细阐述了近年来聚氨基酯作为基因载体的研究进展。     

Sustained release of ganciclovir from poly(lactide-co-glycolide) microspheres

Biodegradable poly(lactide-co-glycolide) microspheres loaded with ganciclovir were produced using the emulsification/solvent evaporation technique. The effects of drug-to-polymer ratio and dispersion time on the drug content in the microspheres were investigated. The release rate of the drug was studied for 20 weeks in a phosphate buffered solution of pH 7 at 37°C. Data revealed that lower drug content was obtained with increasing drug-to-polymer ratio and decreasing dispersion time. The release of the drug followed a triphasic release pattern, i.e. an initial burst, a diffusive phase and a second burst. The initial burst occurred within the first 2 days of immersion. After the burst, the release was by diffusion for up to 13 weeks, followed by another burst release, which signals the onset of bulk degradation of the polymer. Gel permeation chromatography (GPC), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and ultraviolet spectroscopy (UV) were used to follow the hydrolytic degradation and drug release rate of the microspheres.     

Drug delivery into the brain using poly(lactide-co-glycolide) microspheres

Among the strategies developed for drug delivery into the CNS, locally controlled drug release by the way of an implantable polymeric device has been developed in recent years. The first polymeric devices developed were macroscopic implants needing open surgery for implantation. Over the last few years, poly(lactide-co-glycolide) microspheres have been shown to be safe and promising for drug delivery into the brain. Poly(lactide-co-glycolide) is biodegradable and biocompatible with brain tissue. Due to their size, these microspheres can be easily implanted by stereotaxy in discrete, precise and functional areas of the brain without causing damage to the surrounding -tissue. Brain tumour treatments have been developed using this approach and clinical trials have been performed. Potential applications in neurodegenerative diseases have also been explored, particularly neurotrophic factor delivery and cell therapy.     

Sustained release of ganciclovir from poly(lactide-co-glycolide) microspheres

Biodegradable poly(lactide-co-glycolide) microspheres loaded with ganciclovir were produced using the emulsification/solvent evaporation technique. The effects of drug-to-polymer ratio and dispersion time on the drug content in the microspheres were investigated. The release rate of the drug was studied for 20 weeks in a phosphate buffered solution of pH 7 at 37 degrees C. Data revealed that lower drug content was obtained with increasing drug-to-polymer ratio and decreasing dispersion time. The release of the drug followed a triphasic release pattern, i.e. an initial burst, a diffusive phase and a second burst. The initial burst occurred within the first 2 days of immersion. After the burst, the release was by diffusion for up to 13 weeks, followed by another burst release, which signals the onset of bulk degradation of the polymer. Gel permeation chromatography (GPC), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and ultraviolet spectroscopy (UV) were used to follow the hydrolytic degradation and drug release rate of the microspheres.     

Vancomycin release from poly(D,L-lactide) and poly(lactide-co-glycolide) disks.

A biodegradable and biocompatible polymeric system was developed for the controlled release of vancomycin for the treatment of brain abscesses. Poly(D,L-lactic acid) (PLA) and its copolymers poly(lactide-co-glycolide) PLGA 90:10 and PLGA 70:30, were prepared. Polymer disks containing vancomycin (VN) were prepared by solvent casting from methylene chloride solutions. Degradation of the polymer disk was studied by scanning electron microscopy, NMR and GPC. SEM revealed an increasing degree of degradation with time with both PLGAs, the effect being more distinct in the PLGA with the higher glycolide content (PLGA 70:30), which was confirmed with GPC, which showed both a decrease in the molecular weights of PLGA and a decrease in the heterogeneity index (chain length distribution) upon incubation in isotonic phosphate buffer at 37 degrees C for up to 5 weeks. NMR showed a decrease in the CH2 contents of the copolymers, implying that the glycolide component of the copolymers is being preferentially degraded. In situ, vancomycin release behaviour of the disks in pH 7.4 phosphate buffer saline (PBS) was followed for approximately 2 months in a static system. It was observed that release was according to Higuchi kinetics (Q vs. t(1/2)), and introduction of low molecular weight PLA or hydrophilic compounds like PEG increased the release rate.     

Formulating poly(lactide-co-glycolide) particles for plasmid DNA delivery

Biodegradable poly(lactide-co-glycolide) (PLGA) particles have shown significant potential for sustained and targeted delivery of several pharmaceutical agents, including plasmid DNA (pDNA). Here, we survey current approaches to PLGA particle preparation for pDNA delivery and discuss recent progress on optimizing formulation development.