Lipophilic prodrugs of apomorphine I: preparation, characterisation, and in vitro enzymatic hydrolysis in biorelevant media.

Nrupa Borkar, Boyang Li, René Holm, Anders E Håkansson, Anette Müllertz, Mingshi Yang, Huiling Mu

文献索引：Eur. J. Pharm. Biopharm. 89 , 216-23, (2015)

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摘要

Apomorphine, a subcutaneously administered drug for Parkinson's disease with short half-life requires frequent administration leading to patient non-compliance. This study aimed at synthesising and purifying lipophilic diesters of apomorphine, and investigating their in vitro degradation in biorelevant media before and after incorporating them into self-emulsifying drug delivery systems (SEDDS) for oral delivery. Two apomorphine diester prodrugs were synthesised: dilauroyl apomorphine (DLA) and dipalmitoyl apomorphine (DPA). The in vitro enzymatic hydrolysis of diesters was performed using biorelevant media with pancreatin to catalyse the diester degradation. The synthesised and purified diesters were found to be free from reactants as impurities confirmed by LC/MS and NMR. DLA and DPA were degraded into corresponding monoesters and free apomorphine within 5 min after adding pancreatin, leaving about 4% and 28% of the intact diester, respectively. The incorporation of the diesters into SEDDS reduced the enzymatic degradation of diesters. In addition, the chain length of diester and the type of oil used in formulations affected diester hydrolysis. The lipophilic apomorphine diesters were substrates of lipases present in pancreatin, and the degree of diester degradation can be controlled by selecting suitable lipid excipients. Therefore, diesters of apomorphine are promising prodrugs for oral delivery aiming at lymphatic transport.Copyright © 2014 Elsevier B.V. All rights reserved.