Improved physical stability and injectability of non-aqueous in situ PLGA microparticle forming emulsions.
The goal of this study was to obtain physically stable non-aqueous in situ forming microparticle (ISM) emulsions capable of forming biodegradable microparticles upon injection. ISM emulsions consist of a biocompatible organic PLGA solution dispersed in a continuous oil phase prepared in a two-syringe/connector system prior to administration. A variety of parenteral approved excipients were tested for a stability-enhancing effect and possible stabilization mechanisms evaluated. Glycerol monostearate (GMS) showed superior stabilizing potential prolonging the emulsion stability from a few minutes to more than 12h. Flow behavior analysis, differential scanning calorimetry, polarized light- and Cryo-electron microscopy revealed, that the stabilization was caused by an immediate, more than 5-fold viscosity increase in the continuous phase after emulsification and by a stabilized interface through a liquid crystalline GMS layer around the polymer solution droplets. Despite the viscosity increase the injectability of the stabilized ISM emulsion was improved by about 30% compared to the corresponding highly viscous PLGA solution (in situ implant) due to a pronounced shear thinning of the GMS containing oil phase. The injectability improvement allows a faster administration or enables the use of thinner needles and hence reduced patient discomfort.
College of Pharmacy, Freie Universitaet Berlin, Kelchstrasse 31, 12169 Berlin, Germany.
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Voigt
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Koerber
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Bodmeier
D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D020285:Cryoelectron Microscopy; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004355:Drug Stability; D004655:Emulsions; D005079:Excipients / Q000737:chemistry*; D005989:Glycerides / Q000737:chemistry*; D007267:Injections; D019344:Lactic Acid / Q000737:chemistry*; D050866:Liquid Crystals / Q000737:chemistry; D008859:Microscopy, Polarization; D008863:Microspheres; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013997:Time Factors; D014783:Viscosity
D004337:Drug Carriers; D004655:Emulsions; D005079:Excipients; D005989:Glycerides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; C048159:glyceryl monostearate; D011100:Polyglycolic Acid; D019344:Lactic Acid