Reduction in burst release after coating poly(D,L-lactide-co-glycolide) (PLGA) microparticles with a drug-free PLGA layer.

The high initial burst release of a highly water-soluble drug from poly (D,L-lactide-co-glycolide) (PLGA) microparticles prepared by the multiple emulsion (w/o/w) solvent extraction/evaporation method was reduced by coating with an additional polymeric PLGA layer. Coating with high encapsulation efficiency was performed by dispersing the core microparticles in peanut oil and subsequently in an organic polymer solution, followed by emulsification in the aqueous solution. Hardening of an additional polymeric layer occurred by oil/solvent extraction. Peanut oil was used to cover the surface of core microparticles and, therefore, reduced or prevented the rapid erosion of core microparticles surface. A low initial burst was obtained, accompanied by high encapsulation efficiency and continuous sustained release over several weeks. Reduction in burst release after coating was independent of the amount of oil. Either freshly prepared (wet) or dried (dry) core microparticles were used. A significant initial burst was reduced when ethyl acetate was used as a solvent instead of methylene chloride for polymer coating. Multiparticle encapsulation within the polymeric layer increased as the size of the core microparticles decreased (< 50 µm), resulting in lowest the initial burst. The initial burst could be controlled well by the coating level, which could be varied by varying the amount of polymer solution, used for coating.

Encapsulation of water-soluble drugs by an o/o/o-solvent extraction microencapsulation method.

A new o/o/o-solvent extraction microencapsulation method based on less toxic solvents is presented in this study. The drug is dissolved/dispersed into a poly(D,L-lactide)/or poly (D,L-lactide-co-glycolide) (PLGA) solution in a water-miscible organic solvent (e.g., dimethylsulfoxide or 2-pyrrolidone) (o(1)), followed by emulsification into an oil phase (o(2)) (e.g., peanut oil). This emulsion is added to the external phase (o(3)) to solidify the drug-containing polymer droplets. The polymer solvent and the oil are extracted in an external phase (o(3)) (e.g., ethanol), which is a nonsolvent for the polymer and miscible with both the polymer solvent and the oil. One major advantage of this method is the reduced amount of solvent/nonsolvent volumes. In addition, very high encapsulation efficiencies were achieved at polymer concentration of 20%, w/w for all investigated polymers and o(1)/o(2) phase ratios with ethanol as the external (o(3)) phase. The encapsulation efficiency was very low (<20%) with water as external phase. The particle size of the microparticles increased with increasing polymer concentration and o(1)/o(2) phase ratio and larger microparticles were obtained with 2-pyrrolidone compared to dimethylsulfoxide as polymer solvent (o(1)). After an initial burst, in vitro drug release from the microparticles increased for the investigated polymer as follows: Resomer(®) RG 506>RG 756>R 206. A third more rapid release phase was observed after 6 weeks with Resomer(®) RG 506 due to polymer degradation. Similar drug release patterns were obtained with the o/o/o and w/o/w multiple emulsion methods because of similar porous structures. This new method has the advantages of less toxic solvents, much lower preparation volume and solvent consumption and high encapsulation efficiencies when compared to the classical w/o/w method.

How autocatalysis accelerates drug release from PLGA-based microparticles: a quantitative treatment.

The major aim of this study was to better understand the importance of autocatalysis in poly(lactic-co-glycolic acid) (PLGA)-based microparticles used as controlled drug delivery systems. Upon contact with biological fluids, PLGA is degraded into shorter chain alcohols and acids. An accumulation of the latter can lead to significant drops in micro-pH and subsequent accelerated polymer degradation. The system size, determining the diffusion path lengths, plays a crucial role for the occurrence/absence of autocatalytic effects. Using an oil-in-water solvent-extraction/evaporation process, different-sized drug-free and drug-loaded, PLGA-based microparticles were prepared and physicochemically characterized (SEM, DSC, SEC, optical microscopy, and UV-spectrophotometry) before and upon exposure to simulated biological fluids. Based on these experimental results, an adequate mathematical theory was developed describing the dominating mass transfer processes and chemical reactions. Importantly, a quantitative relationship could be established between the dimension of the device and the resulting drug release patterns, taking the effects of autocatalysis into account.