Deamidation, acylation and proteolysis of a model peptide in PLGA films.
The relative rates of deamidation, acylation and proteolysis (i.e. amide bond cleavage) were determined for a model peptide (VYPNGA) in poly (dl-lactide-co-glycolide) films. Films were stored at 70 degrees C and either 95%, 75%, 60%, 45%, 28%, or approximately 0% relative humidity and at 37 degrees C and 95% relative humidity. Peptide degradation products were identified by ESI+MS/MS and quantitated by LC/MS/MS. Extensive overlap of degradation mechanisms occurred, producing a complex mixture of products. Acylation was the dominant peptide degradation reaction (10-20% of total peptide) at early stages of PLGA hydrolysis and at intermediate relative humidity (60-45% RH). Deamidation and proteolysis were dominant (25-50% and 20-40% of total peptide, respectively) at later stages and at high relative humidity (95-75% RH). Understanding the relative rates of each peptide degradation reaction will allow for improved design of PLGA formulations that preserve the stability of peptide and protein drugs.
Houchin
M L
ML
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA.
Heppert
K
K
Topp
E M
EM
D000215:Acylation; D000577:Amides / Q000737:chemistry; D003692:Delayed-Action Preparations; D006813:Humidity; D006868:Hydrolysis; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry*; D008956:Models, Chemical; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011489:Protein Denaturation; D013696:Temperature; D013997:Time Factors
D000577:Amides; D003692:Delayed-Action Preparations; D009842:Oligopeptides; D010446:Peptide Fragments; D011108:Polymers; C089005:valyl-tyrosyl-prolyl-asparaginyl-glycyl-alanine; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid