title: Lipophilic prodrugs of apomorphine I: preparation, characterisation, and in vitro enzymatic hydrolysis in biorelevant media.
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.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: nrupa.borkar@sund.ku.dk.
authors.forename: Nrupa
authors.initials: N
authors.lastname: Borkar
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: liboyang555@gmail.com.
authors.forename: Boyang
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Biologics and Pharmaceutical Science, H. Lundbeck A/S, Valby, Denmark. Electronic address: rhol@lundbeck.com.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: Process Chemistry, H. Lundbeck A/S, Valby, Denmark. Electronic address: aeh@lundbeck.com.
authors.forename: Anders E
authors.initials: AE
authors.lastname: Håkansson
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Bioneer: FARMA, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: anette.mullertz@sund.ku.dk.
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: mingshi.yang@sund.ku.dk.
authors.forename: Mingshi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: huiling.mu@sund.ku.dk.
authors.forename: Huiling
authors.initials: H
authors.lastname: Mu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001058:Apomorphine / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D004655:Emulsions / Q000737:chemistry; D004952:Esters / Q000737:chemistry; D006868:Hydrolysis; D008055:Lipids / Q000737:chemistry; D010184:Pancreatic Extracts / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry*; D013552:Swine
chemical_list: D004655:Emulsions; D004952:Esters; D008055:Lipids; D010184:Pancreatic Extracts; D011355:Prodrugs; D001058:Apomorphine
keywords: Apomorphine; Apomorphine diester; In vitro degradation; Lipid based drug delivery; Lipophilic prodrug; Purification; SEDDS