Skip to Content
Merck
  • Lipophilic prodrugs of apomorphine I: preparation, characterisation, and in vitro enzymatic hydrolysis in biorelevant media.

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

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (2014-12-17)
Nrupa Borkar, Boyang Li, René Holm, Anders E Håkansson, Anette Müllertz, Mingshi Yang, Huiling Mu
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Acetonitrile, HPLC Plus, ≥99.9%, poly-coated bottles
Sigma-Aldrich
Sodium hydroxide-16O solution, 20 wt. % in H216O, 99.9 atom % 16O
Sigma-Aldrich
Methanol-12C, 99.95 atom % 12C
Sigma-Aldrich
Ethyl acetate, ≥99%, FCC, FG
Sigma-Aldrich
Ethyl acetate, natural, ≥99%, FCC, FG
Sigma-Aldrich
Lauroyl chloride, 98%
Supelco
Maleic acid, Standard for quantitative NMR, TraceCERT®, Manufactured by: Sigma-Aldrich Production GmbH, Switzerland
Supelco
Acetonitrile, suitable for HPLC, gradient grade, ≥99.9% (GC)
Supelco
Acetonitrile, analytical standard
Sigma-Aldrich
Sodium bicarbonate-12C, 99.9 atom % 12C
Sigma-Aldrich
Acetonitrile, ≥99.5%, ACS reagent
Sigma-Aldrich
Ethyl acetate, ACS reagent, ≥99.5%
Supelco
Trifluoroacetic acid, analytical standard
Supelco
Ethyl acetate, analytical standard
Sigma-Aldrich
Acetonitrile, anhydrous, 99.8%
Sigma-Aldrich
Ethyl acetate, anhydrous, 99.8%
Sigma-Aldrich
Ethyl acetate, ReagentPlus®, ≥99.8%
Sigma-Aldrich
Maleic acid, ReagentPlus®, ≥99% (HPLC)
Sigma-Aldrich
Acetonitrile, electronic grade, 99.999% trace metals basis
Supelco
Residual Solvent - Chloroform, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Methanol solution, contains 0.10 % (v/v) formic acid, UHPLC, suitable for mass spectrometry (MS), ≥99.5%
Sigma-Aldrich
Acetonitrile, ACS reagent, ≥99.5%
Sigma-Aldrich
Ethyl acetate, ACS reagent, ≥99.5%
Sigma-Aldrich
Acetonitrile, ReagentPlus®, 99%
Sigma-Aldrich
Trifluoroacetic acid, ReagentPlus®, 99%
USP
Maleic acid, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Ethyl acetate
Sigma-Aldrich
Ethyl acetate
Supelco
Ethyl Acetate, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Trifluoroacetic acid, puriss. p.a., suitable for HPLC, ≥99.0% (GC)