Porcine insulin biodegradable polyester microspheres: stability and in vitro release characteristics.
The stability of porcine insulin in biodegradable polymers, i.e., poly(DL-lactide-co-glycolide) 50:50 (50:50 DL-PLGA) and poly(L-lactide) (L-PLA) was investigated. Insulin encapsulated microspheres were fabricated from both polymers using double-emulsion-solvent evaporation and emulsion-solvent evaporation techniques and subjected to accelerated stability studies at 40 degrees C and 75% relative humidity. Porcine insulin was found to degrade in all microsphere formulations with an average of < 50% of the initial loading amount remaining intact at the end of 4 weeks. The two major degradation products observed in these formulations were determined to be A-21 desamido insulin and covalent insulin dimer with trace amounts of high molecular weight transformation products. In vitro release studies in phosphate buffered saline at 37 degrees C resulted in very slow and incomplete (< 30% in 30 days) release kinetics for all microsphere formulations. Extraction and analyses of the unreleased insulin within the microspheres revealed that an average of approximately 11% of the encapsulated insulin remained intact. The degradation products observed consisted of approximately 15% of three distinct deamidated hydrolysis products including A-21 desamido insulin, approximately 22% covalent insulin dimer, and trace amounts of high molecular weight transformation products. The degradation of porcine insulin within biodegradable polyester microspheres during stability and release studies can be attributed to the gradual decrease in the pH within the microspheres due to progressive polymer hydrolysis resulting in the production of DL-lactic and glycolic acids. The encapsulation of an acid-base indicator, bromophenol blue, in 50:50 PLGA microspheres (as a probe to estimate pH within the microspheres during accelerated stability studies) indicated that the pH decreased to approximately 3.8 after 3 weeks.
Shao
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Warner-Lambert Research Division, Morris Plains, New Jersey 07950, USA.
Bailey
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LC
D000818:Animals; D001672:Biocompatible Materials; D001978:Bromphenol Blue / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006358:Hot Temperature; D006813:Humidity; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007202:Indicators and Reagents / Q000737:chemistry; D007328:Insulin / Q000737:chemistry*; D019344:Lactic Acid / Q000737:chemistry*; D008863:Microspheres; D011091:Polyesters / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D013552:Swine
D001672:Biocompatible Materials; D007202:Indicators and Reagents; D007328:Insulin; D011091:Polyesters; D011108:Polymers; D001978:Bromphenol Blue; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide)