In vivo evaluation of lipid-based formulations for oral delivery of apomorphine and its diester prodrugs.
In the present study, the differences in oral absorption of apomorphine and its diester prodrugs and the effect of lipid-based formulations on the absorption of apomorphine or its prodrugs were investigated. Apomorphine, dilauroyl apomorphine (DLA) and dipalmitoyl apomorphine (DPA) were orally administered (0.24mmol/kg) to rats as: DLA-o/w emulsion, DPA-o/w emulsion, apomorphine-o/w emulsion, apomorphine aqueous suspension, DLA-Maisine, DLA-soybean oil, DLA-self-emulsifying drug delivery systems (SEDDS), and DLA-w/o emulsion. The o/w and w/o emulsion consisted of Maisine 35-1 emulsified with water in 1:3 and 4:1 ratio, respectively. Tmaxof diesters was significantly increased (p≤0.05) compared to apomorphine in o/w emulsion, suggesting that esterification yielded prolonged drug absorption. Cmax, AUC and the relative bioavailability of apomorphine after DLA-SEDDS administration was higher (p≤0.05) than after DLA-w/o administration, indicating that triglycerides and surfactants improved the oral absorption of DLA. Similarly, Cmaxand AUC after dosing apomorphine-o/w were significantly higher (p≤0.05) than that of aqueous suspension. This suggested that lipids and lipolysis products possibly aided apomorphine micellar solubilization in intestinal fluids. A combination of prodrug strategy and lipid-based formulations facilitated a higher and prolonged absorption of apomorphine from its diester prodrugs.
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: nrupa.borkar@sund.ku.dk.
Nrupa
N
Borkar
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark. Electronic address: mrreneholm@hotmail.com.
René
R
Holm
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Department of Pharmaceutics, Shenyang Pharmaceutical University, 110016, China. Electronic address: mingshi.yang@sund.ku.dk.
Mingshi
M
Yang
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Bioneer: FARMA, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: anette.mullertz@sund.ku.dk.
Anette
A
Müllertz
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: huiling.mu@sund.ku.dk.
Huiling
H
Mu
D000284:Administration, Oral; D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D004655:Emulsions; D004952:Esters; D008055:Lipids / Q000737:chemistry; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley
D004655:Emulsions; D004952:Esters; D008055:Lipids; D011355:Prodrugs; D001058:Apomorphine
Apomorphine; In vivo absorption; Lipid-based formulation; Lipophilic diester prodrug; SEDDS