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

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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.

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Acknowledgments

This work was financially supported by the Ministry of Knowledge Economy (MKE) and Korea Institute for Advancement in Technology (KIAT) through the Workforce Development Program in Strategic Technology.

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Authors and Affiliations

  1. College of Pharmacy, Kyungsung University, Busan, 608-736, Republic of Korea

    Jae Hwa Ahn, Eun Ji Park & Dong Hee Na

  2. College of Pharmacy, The Catholic University of Korea, Bucheon, 420-743, Republic of Korea

    Hye Suk Lee

  3. College of Pharmacy, SungKyunKwan University, Suwon, 440-746, Republic of Korea

    Kang Choon Lee

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  1. Jae Hwa Ahn
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  2. Eun Ji Park
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  3. Hye Suk Lee
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  4. Kang Choon Lee
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  5. Dong Hee Na
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Correspondence to Dong Hee Na.

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Ahn, J.H., Park, E.J., Lee, H.S. et al. Reversible Blocking of Amino Groups of Octreotide for the Inhibition of Formation of Acylated Peptide Impurities in Poly(Lactide-co-Glycolide) Delivery Systems. AAPS PharmSciTech 12, 1220–1226 (2011). https://doi.org/10.1208/s12249-011-9694-y

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  • DOI: https://doi.org/10.1208/s12249-011-9694-y

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