Conventional PLGA Microspheres Research Articles

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

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 ± 0.39μm (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.

Preparation of uniform-sized colloidosomes based on chitosan-coated alginate particles and its application for oral insulin delivery.

Colloidosomes are microcapsules that consist of a hollow core coated by a shell composed of self-assembled colloidal particles. In recent years, they have attracted significant attention as potential vehicles for the controlled delivery of active ingredients. A key challenge in such applications is the production of uniform-sized colloidosomes for the encapsulation of active ingredients such that the actual delivery amount can be well controlled. Based on our previous study on an ethyl acetate-in-water emulsion stabilized by chitosan-coated alginate particles, we further prepared monodisperse colloidosomes with a high yield and low permeability by combining the premix membrane emulsification technique and polymer deposition method. The potential application of the formed colloidosomes as oral insulin delivery vehicles was investigated. Our results revealed that in comparison to conventional PLGA microspheres, the formulated colloidosomes showed high drug encapsulation efficiency (up to 96.7%) and an obvious pH sensitive release profile. Moreover, in animal testing, the colloidosomes formulation achieved a long-term hypoglycemic effect up to 6 h, which confirmed its application as an oral drug delivery system.

Succinylated Pullulan Acetate Microspheres for Protein Delivery

【In order to develop new protein carrier replacing poly(DL-lactic acid-co-glycolic acid) (PLGA) microspheres, succinylated pullulan acetate (SPA) was investigated to fabricate a long term protein delivery carrier. SPA microspheres loaded with lysozyme (Lys) as a model protein drug were prepared by a water/oil/water (W/O/W) double emulsion method. An acidity test of SPA copolymers after hydrolysis was performed to estimate the change of protein stability during releasing proteins from the microspheres. There was no pH change of SPA copolymers, but pH of PLGA polymers after hydrolysis was significantly decreased to around pH 2, indicating that the long-term stability of proteins released from SPA microspheres can be guaranteed. Loading efficiency of proteins into SPA microspheres was three times higher than those into conventional PLGA microspheres, indication of inducing stronger charge interaction between proteins and succinyl groups in SPA microspheres. Although initial burst behaviors were monitored in Lys-loaded SPA microspheres due to relatively strong hydrophilic succinyl segments in SPA microspheres, initial burst issues would be circumvented if the ratio of charge density of succinyl moieties and hydrophobic acetate groups is harmonically controlled. Therefore, in this study, a new attempt of protein delivery system was made and functional SPA was successfully confirmed as a new protein carrier.】

Alginate–Chitosan–PLGA Composite Microspheres Enabling Single-Shot Hepatitis B Vaccination

Hepatitis B vaccination typically requires a multi-dose administration protocol over a course of 3-6 months. Aiming at developing a single-shot formulation for hepatitis B vaccine (hepatitis B surface antigen (HBsAg)), a novel vaccine delivery system, the composite microspheres of alginate-chitosan-poly(lactic-co-glycolic acid) (PLGA), was synthesized by a two-step preparation. The composite microspheres showed distinct advantages over the conventional PLGA microspheres in aspects of the high loading capacity and the elimination of lyophilizing process. The loading capacity of the composite microspheres was about seven times higher than those in the conventional PLGA microspheres, due to the protein-friendly microenvironment created by the hydrophilic alginate-chitosan cores of the composite microspheres. This vaccine delivery system was shown to be able to induce robust immune responses by single injection and display no significant difference in HBsAg-specific antibody levels compared to the double-injection method.

In vitro and in vivo studies of cyclosporin A-loaded microspheres based on copolymers of lactide and ɛ-caprolactone: Comparison with conventional PLGA microspheres

A hydrophobic peptide, cyclosporin A (CyA), was incorporated in microspheres based on poly(lactide- b-ɛ-caprolactone) (P(LA- b-CL), LA/CL (in molar ratio): 78.7/21.3 and 48.1/51.9) and poly(lactide-co-glycolide) (PLGA, LA/GA: 80/20) using oil-in-water (O/W) emulsion solvent evaporation method. The microspheres were characterized by SEM, DSC and X-ray diffraction, and CyA release rate was determined by HPLC. It was revealed that CyA can be efficiently loaded into all the microspheres (exceed 96%). Compared to PLGA microspheres, P(LA- b-CL) microspheres liberated CyA more rapidly. Within the first day, about 75, 50 and 12% of CyA released from P(LA- b-CL) (48.1/51.9), P(LA- b-CL) (78.7/21.3) and PLGA microspheres, respectively, which can be attributed to the partial crystallization occurring in P(LA- b-CL) microspheres. CyA levels in whole blood were also tested. In comparison with PLGA microspheres, P(LA- b-CL) microspheres provided a higher blood level of CyA. The maximum CyA concentration in whole blood (∼520, 450 and 400 ng ml −1 for P(LA- b-CL) (48.1/51.9) P(LA- b-CL) (78.7/21.3) and PLGA microspheres, respectively) was reached at the second day post administration. And then P(LA- b-CL) microspheres showed a constant CyA level (about 100–200 ng ml −1) for extended periods of time (several weeks). Such CyA-loaded P(LA- b-CL) microspheres displaying higher CyA concentration during the first few days and similar constant blood CyA level thereafter showed more advantages than those prepared with PLGA and could meet clinical needs more efficiently.

Sustained release of PEG-g-chitosan complexed DNA from poly(lactide-co-glycolide)

Chitosan and its derivatives have emerged as promising gene-delivery vehicles because of their capability to form polyplexes with plasmid DNA and enhance its transport across cellular membranes through endocytosis. Evidently, polyplexes of chitosan and DNA significantly improve transfection efficiency; however, these polyplexes are not capable of sustained DNA release and, thus, prolong gene transfer. In order to achieve prolonged delivery of DNA/chitosan polyplexes, we have formulated microspheres by physically combining poly(ethylene glycol)-grafted chitosan (PEG-g-CHN) with poly(lactide-co-glycolide) (PLGA) using a modified conventional in-emulsion solvent evaporation method. Electrophoretic analysis of materials released from these microspheres suggests the presence of PEG-g-CHN complexed DNA and these microspheres are capable of sustained release of DNA/PEG-g-CHN for at least 9 weeks. The rate of DNA release can be modulated by varying the amount of PEG-g-CHN. The release products from these microspheres are bioactive and show enhanced transfection in vitro over DNA released from conventional PLGA microspheres containing no PEG-g-CHN. In vivo experiments also show that these microspheres are capable of achieving gene transfer in a rat hind limb muscle model.

A protein delivery system: biodegradable alginate–chitosan–poly(lactic-co-glycolic acid) composite microspheres

In the present study we developed alginate–chitosan–poly(lactic-co-glycolic acid) (PLGA) composite microspheres to elevate protein entrapment efficiency and decrease its burst release. Bovine serum albumin (BSA), which used as the model protein, was entrapped into the alginate microcapsules by a modified emulsification method in an isopropyl alcohol-washed way. The rapid drug releases were sustained by chitosan coating. To obtain the desired release properties, the alginate–chitosan microcapsules were further incorporated in the PLGA to form the composite microspheres. The average diameter of the composite microcapsules was 31 ± 9 μm and the encapsulation efficiency was 81–87%, while that of conventional PLGA microspheres was just 61–65%. Furthermore, the burst releases at 1 h of BSA entrapped in composite microspheres which containing PLGA (50:50) and PLGA (70:30) decreased to 24% and 8% in PBS, and further decreased to 5% and 2% in saline. On the contrary, the burst releases of conventional PLGA microspheres were 48% and 52% in PBS, respectively. Moreover, the release profiles could be manipulated by regulating the ratios of poly(lactic acid) to poly(glycolic acid) in the composite microspheres.

Development of biodegradable poly(propylene fumarate)/poly(lactic-co-glycolic acid) blend microspheres. I. Preparation and characterization.

We developed poly(propylene fumarate)/poly(lactic-co-glycolic acid) (PPF/PLGA) blend microspheres and investigated the effects of various processing parameters on the characteristics of these microspheres. The advantage of these blend microspheres is that the carbon-carbon double bonds along the PPF backbone could be used for their immobilization in a PPF scaffold. Microspheres containing the model drug Texas red dextran were fabricated using a double emulsion-solvent extraction technique. The effects of the following six processing parameters on the microsphere characteristics were investigated: PPF/PLGA ratio, polymer viscosity, vortex speed during emulsification, amount of internal aqueous phase, use of poly(vinyl alcohol) (PVA) in the internal aqueous phase, and PVA concentration in the external aqueous phase. Our results showed that the microsphere surface morphology was affected most by the viscosity of the polymer solution. Microspheres fabricated with a kinematic viscosity of 39 centistokes had a smooth, nonporous surface. In most microsphere formulations, the model drug was dispersed uniformly in the polymer matrix. For all fabricated formulations, the average microsphere diameter ranged between 19.0 and 76.9 microm. The external PVA concentration and vortex speed had most effect on the size distribution. Entrapment efficiencies varied from 60 to 98% and were most affected by the amount of internal aqueous phase, vortex speed, and polymer viscosity. Overall, we demonstrated the ability to fabricate PPF/PLGA blend microspheres with similar surface morphology, entrapment efficiency, and size distribution as conventional PLGA microspheres.

Preparation and characterization of a composite PLGA and poly(acryloyl hydroxyethyl starch) microsphere system for protein delivery.

To prepare and characterize a novel composite microsphere system based on poly(D,L-lactide-co-glycolide) (PLGA) and poly(acryloyl hydroxyethyl starch) (acHES) hydrogel for controlled protein delivery. Model proteins, bovine serum albumin, and horseradish peroxidase were encapsulated in the acHES hydrogel, and then the protein-containing acHES hydrogel particles were fabricated in the PLGA matrix by a solvent extraction or evaporation method. The protein-loaded PLGA-acHES composite microspheres were characterized for protein loading efficiency, particle size, and in vitro protein release. Protein stability was examined by size-exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and monitoring the enzymatic activity. Scanning electron microscopy showed discrete PLGA microspheres containing many acHES particles. The composite microspheres were spherical and smooth in size range of 39-93 microm. The drug loading efficiency ranged from 51 to 101%. The composite microspheres showed more favorable in vitro release than conventional PLGA microspheres. The composite microspheres showed 20% less initial with a gradual sustained release compared to high burst (approximately 60%) followed by a very slow release with the conventional PLGA microspheres. The composite microspheres also stabilized encapsulated proteins from the loss of activity during the microsphere preparation and release. Proteins extracted from the composite microspheres showed good stability without protein degradation products and structural integrity changes in the size-exclusion chromatography and SDS-PAGE analyses. Horseradish peroxidase extracted from microspheres retained more than 81% enzymatic activity. The PLGA-acHES composite microsphere system could be useful for the controlled delivery of protein drugs.

A novel approach to stabilization of protein drugs in poly(lactic-co-glycolic acid) microspheres using agarose hydrogel

A novel approach has been taken to stabilize protein drugs in poly(lactic-co-glycolic acid) (PLGA) microspheres. This approach creates a new protein drug delivery system, which is based on the combination of agarose hydrogel particles and PLGA microspheres. This combination produces a heterogeneously structured polymeric composite. The protein drug molecules are encapsulated in the agarose hydrogel particles and the drug-containing agarose hydrogel particles are further dispersed in the PLGA microspheres. One PLGA microsphere may contain many agarose hydrogel particles to form a PLGA–agarose composite microsphere. The PLGA–agarose composite microspheres have spherical shape and a smooth surface. They possess a normal or Gaussian size distribution and an average diameter of 150 μm. The PLGA–agarose composite microspheres have higher protein loading efficiency than that of the conventional PLGA microspheres. The hydration of the PLGA–agarose composite microsphere matrix is faster than that of the conventional PLGA microspheres. Protein drugs can be slowly released from the PLGA–agarose composite microspheres. The agarose hydrogel particles can stabilize protein drugs in the PLGA matrix, which is the major advantage of this novel protein drug delivery system over the conventional PLGA microspheres.