Effect of excipients on PLGA film degradation and the stability of an incorporated peptide.
The effect of pH modifying excipients on the chemical stability of a model peptide (VYPNGA) and the degradation of poly(dl-lactide-co-glycolide)(PLGA) was studied in PLGA films under accelerated storage conditions. pH modifiers included a basic amine (proton sponge), a basic salt (magnesium hydroxide) and two pH buffers (ammonium acetate and magnesium acetate). Changes in film pH were monitored using (13)C NMR, peptide degradation products were quantified by LC/MS/MS and PLGA degradation was analyzed by TGA, DSC and SEC. Inclusion of pH modifiers had little impact on PLGA degradation. The proton sponge affected an initial decrease in pH but reduced peptide deamidation and chain cleavage relative to an unbuffered control. Magnesium hydroxide produced an initial increase in pH but also showed increased peptide deamidation. Ammonium acetate decreased pH and increased peptide chain cleavage, presumably due to increased PLGA hydrolysis. Magnesium acetate buffer increased the initial pH but resulted in increased peptide loss. The extent of peptide acylation increased in all formulations, most notably in the proton sponge modified films. The effectiveness of pH modifiers in PLGA formulations under storage conditions is dependant on both the mechanism of pH alteration and the peptide degradation reaction of interest.
Houchin
M L
ML
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., Lawrence, KS 66047, USA.
Neuenswander
S A
SA
Topp
E M
EM
D000215:Acylation; D002021:Buffers; D002138:Calibration; D002152:Calorimetry, Differential Scanning; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000737:chemistry*; D008276:Magnesium Hydroxide; D009682:Magnetic Resonance Spectroscopy; D008970:Molecular Weight; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D013818:Thermogravimetry; D014867:Water / Q000737:chemistry
D002021:Buffers; D005079:Excipients; D010455:Peptides; D011108:Polymers; D014867:Water; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D008276:Magnesium Hydroxide