title: Reversible blocking of amino groups of octreotide for the inhibition of formation of acylated peptide impurities in poly(lactide-co-glycolide) delivery systems.
abstract: The purpose of this study was to develop a novel method to inhibit the formation of acylated peptide impurities in poly(D,L-lactide-co-glycolide) (PLGA) formulations by reversely blocking the amino groups of octreotide with maleic anhydride (MA). Two mono-MA conjugates with different modification sites (N terminus and Lys residue) and di-MA conjugate of octreotide were prepared and isolated by reversed-phase high-performance liquid chromatography (RP-HPLC). The polymer interaction of peptides and the formation of acylated peptides were monitored by RP-HPLC. The stability of MA-octreotide conjugates in PLGA films was studied in 0.1 M phosphate buffer (pH 7.4) at 37°C. The conjugation of MA to octreotide substantially inhibited the interaction of peptide with PLGA polymer and the subsequent formation of acylated peptide impurities. The MA-octreotides were successfully converted to intact octreotide as pH drops by PLGA hydrolysis. In PLGA films, MA-octreotide also showed complete inhibition of peptide acylation. In conclusion, MA conjugation provides a viable approach for stabilizing peptides in PLGA delivery systems.
authors.affiliation: College of Pharmacy, Kyungsung University, Busan, Republic of Korea.
authors.forename: Jae Hwa
authors.initials: JH
authors.lastname: Ahn
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Park
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
authors.forename: Dong Hee
authors.initials: DH
authors.lastname: Na
mesh_terms: D000215:Acylation; D002021:Buffers; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D004337:Drug Carriers; D004339:Drug Compounding; D004340:Drug Contamination; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008299:Maleic Anhydrides / Q000737:chemistry; D015282:Octreotide / Q000737:chemistry*; D011098:Polyglactin 910 / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
chemical_list: D002021:Buffers; D004337:Drug Carriers; D008299:Maleic Anhydrides; D011098:Polyglactin 910; D015282:Octreotide