Chemical instability of pharmaceutical peptides in polymeric controlled release systems

Peptide and protein drugs are presently an important class of pharmaceuticals due to their favorable properties, i.e. high and selective activity. However, peptides and proteins are relatively sensitive for degradation and therefore there is need for investigation of the chemical stability of these biotherapeutics during formulation, storage and use. Stability evaluation of a drug substance or drug product is the key to drug quality as it determines the efficacy and safety of any drug dosage form. The objective of this work was to increase understanding of peptide integrity in hydrogels and polyester matrices. We showed that the N,N,N,N-tetramethylethylenediamine (TEMED) radical used to synthesis peptide loaded hydrogels also induced methyleneation (Δm +12) on peptides containing lysine residues depending on its neighboring amino acid. Avoiding the use of TEMED is recommended to prevent methyleneation of peptides during in situ polymerization. Acylation is a major problem in delivery of peptide drugs using polyester matrixes. It has been shown that acylation takes place to a lesser extent in more hydrophilic matrices and the acylation products were characterized in great detail using LC-MS/MS. Moreover besides to the known sites of acylation that are lysine and a free N-terminus, we now discovered that acylation also occurs on arginine in a model peptide . Finally, a new method was proposed to inhibit acylation of peptides in poly(D,L-lactic-co-glycolic acid) PLGA formulations by reversely blocking the amino groups of a model peptide (octreotide) with a novel self immolative protecting group.