title: Oral apomorphine delivery from solid lipid nanoparticles with different monostearate emulsifiers: pharmacokinetic and behavioral evaluations.
abstract: Apomorphine, a dopamine receptor agonist for treating Parkinson's disease, has very poor oral bioavailability (<2%) due to the first-pass effect. The aim of this work was to investigate whether the oral bioavailability and brain regional distribution of apomorphine could be improved by utilizing solid lipid nanoparticles (SLNs). Glyceryl monostearate (GMS) and polyethylene glycol monostearate (PMS) were individually incorporated into SLNs as emulsifiers. It was found that variations in the emulsifiers had profound effects on the physicochemical characteristics. Mean diameters of the GMS and PMS systems were 155 and 63 nm, respectively. More than 90% of the apomorphine was entrapped in the SLNs. The interfacial film was the likely location for most of apomorphine molecules. The PMS system, when incubated in simulated intestinal medium, was found to be more stable in terms of particle size and encapsulation efficiency than the GMS system. Using the GMS and PMS systems to orally administer apomorphine (26 mg/kg) equally enhanced the bioavailability in rats. SLNs showed 12- to 13-fold higher bioavailability than the reference solution. The drug distribution in the striatum, the predominant site of therapeutic action, also increased when using the SLNs. The anti-Parkinsonian activity of apomorphine was evaluated in rats with 6-hydroxydopamine-induced lesions, a model of Parkinson's disease. The contralateral rotation behavior was examined after oral apomorphine delivery. The total number of rotations increased from 20 to 94 and from 20 to 115 when the drug was administered from SLNs containing GMS and PMS, respectively. The experimental results suggest that SLNs may offer a promising strategy for apomorphine delivery via oral ingestion.
authors.affiliation: Food and Drug Administration, Department of Health, Executive Yuan, Taipei, Taiwan.
authors.forename: Ming-Jun
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Yaw-Bin
authors.initials: YB
authors.lastname: Huang
authors.forename: Pao-Chu
authors.initials: PC
authors.lastname: Wu
authors.forename: Yaw-Syan
authors.initials: YS
authors.lastname: Fu
authors.forename: Yao-Ren
authors.initials: YR
authors.lastname: Kao
authors.forename: Jia-You
authors.initials: JY
authors.lastname: Fang
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Tsai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001058:Apomorphine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D045703:Emulsifying Agents / Q000737:chemistry; D005989:Glycerides / Q000737:chemistry; D008297:Male; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010300:Parkinson Disease / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000978:Antiparkinson Agents; D045703:Emulsifying Agents; D005989:Glycerides; C048159:glyceryl monostearate; D011092:Polyethylene Glycols; C009314:polyethylene glycol monostearate; D001058:Apomorphine