Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 297, Issue 1-2, Pages 50-61Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2005.02.035
Keywords
somatostatin analogues; octreotide acetate; PLA microspheres; PLGA microspheres; peptide acylation; peptide stability
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The purpose of the present investigation was to assess the peptide related substances or impurities formed during incubation of drug loaded poly-(D,L-lactide-co-glycolide) (PLGA) and poly-(D,L-lactide) (PLA) microspheres under in vivo conditions. Sprague-Dawley rats were injected with separate batches of octreotide microspheres prepared by either an oil/water or oil/oil dispersion technique. At specified time points (days 14, 22, 30, and 41), animals were sacrificed and microsphere particles were recovered from the subcutaneous injection sites. The recovered particles were further extracted with 1:1 mixture of dimethylsulfoxide:dichloromethane for subsequent impurity analysis by HPLC and mass spectrometry. During incubation, the percentage purity of parent compound depended on the PLGA co-monomer ratio (e.g. 50:50, 85:15, and 100:0 glycolide:lactide ratios). After 41 days of incubation, for instance, octreotide area percentage by HPLC was determined to be similar to 47% for PLGA 50:50 microspheres, similar to 75% for PLGA 85:15 microspheres, and similar to 87% for PLA microspheres. Spectral analysis of particle extracts revealed the presence of peptide related substances with 58 m/z and 72 m/z units higher than the parent peptide m/z value. This indicated the presence of glycoyl and lactoyl covalent substitutions on the drug compound, resulting from chemical interaction between peptide amine groups and PLGA or PLA ester groups. (c) 2005 Elsevier B.V. All rights reserved.
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