Effect of excipients on PLGA film degradation and the stability of an incorporated peptide

Abstract

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.

Reversible Blocking of Amino Groups of Octreotide for the Inhibition of Formation of Acylated Peptide Impurities in Poly(Lactide-co-Glycolide) Delivery Systems

“…Since the formation of acylated peptide impurities in PLGA delivery systems was found by mass spectrometric techniques, several strategies for inhibition of peptide acylation have been proposed (9,(16)(17)(18)(19)21,22). As the acylated peptide impurities can affect the pharmacological effect and toxicity of products, the prevention and evaluation are very important for securing the efficacy and safety of drug products (12).…”

“…PLGA films were prepared as described in the previous publications (17,24,25) by dissolving 500 μg of octreotide or di-MA-octreotide with 10 mg of PLGA in 0.2 mL of acetone and sonicating for 30 min. The solution was then pipetted into eppendorf tubes and allowed to dry for 2 days.…”

“…Lucke et al proposed that the use of block copolymer of poly(lactic acid) and polyethylene glycol (PEG) would prevent peptide acylation in PLGA microspheres, however, the block copolymer did not show favorable effect on inhibition of the peptide acylation (16 proton sponge, magnesium hydroxide, ammonium acetate, and magnesium acetate, on the chemical stability and acylation of peptides in PLGA films (17). Recently, the efficacy of water-soluble divalent cationic salts was proposed for inhibition of acylation of octreotide in PLGA microspheres (18,19).…”

Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

“…Indeed, the solubility of a peptide as a function of pH is one of the key considerations that should be evaluated at the lead optimization stage to ensure solubility at a physiologically relevant pH. The final pH of the dosing formulation can be precisely controlled through the use of buffered vehicle; however, the buffer components and their relative concentrations can also impact the solubility of the peptide (11)(12)(13)(14). Additionally, the choice of counter-ion for the ionized peptide can also affect its solubility.…”

Effect of Peptide Charge on the Formation of Acylated Peptide Impurities in PLGA Formulations

“…The peptide acylation reaction has been shown to be affected by several factors, such as polymer structure and medium pH (Murty et al, 2005a and2005b;Na, 2010). Several strategies for minimizing and preventing the peptide acylation in PLGA formulations have been proposed, including incorporation of pH modifying excipients or divalent cationic salts into PLGA formulations and chemical modification of peptide with polyethylene glycol (PEG) (Houchin et al, 2007;Na et al, 2003b andPark et al, 2010;Sophocleous et al, 2009;Zhang et al, 2009).…”