title: Setting accelerated dissolution test for PLGA microspheres containing peptide, investigation of critical parameters affecting drug release rate and mechanism.
abstract: The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45°C, in phosphate buffer saline (PBS) 0.02M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45°C to 40°C, release rate showed three-fold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01M (200 mOsm/kg) and PBS 0.01M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation.
authors.affiliation: Novartis Pharma AG, Analytical Research and Development, CH-4002 Basel, Switzerland; University of Auvergne, Department of Biopharmacy, EA 4678, 63001 Clermont-Ferrand, France. Electronic address: ivana.tomic@novartis.com.
authors.forename: I
authors.initials: I
authors.lastname: Tomic
authors.affiliation: Novartis Pharma AG, Analytical Research and Development, CH-4002 Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Vidis-Millward
authors.affiliation: Novartis Pharma AG, Analytical Research and Development, CH-4002 Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Mueller-Zsigmondy
authors.affiliation: University of Auvergne, Department of Biopharmacy, EA 4678, 63001 Clermont-Ferrand, France.
authors.forename: J-M
authors.initials: JM
authors.lastname: Cardot
mesh_terms: D002021:Buffers; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D065546:Drug Liberation; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000737:chemistry*; D008863:Microspheres; D009994:Osmolar Concentration; D010455:Peptides / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012995:Solubility; D013696:Temperature
chemical_list: D002021:Buffers; D010455:Peptides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Accelerated in vitro release; Degradation; Diffusion; Drug release mechanism; PLGA microspheres