title: Biophysical elucidation of the mechanism of enhanced drug release and topical delivery from polymeric film-forming systems.
abstract: The effect of incorporating the lipidic medium-chain triglyceride (MCT) into polymeric film-forming systems (FFS) for topical drug delivery has been evaluated. First, the in vitro release of betamethasone-17-valerate (BMV), a representative dermatological drug, was determined from FFS comprising either hydrophobic polyacrylate co-polymers, or hydrophilic hydroxypropyl cellulose, with and without MCT. Release was enhanced from both polymers in the presence of MCT. Atomic force microscopy imaging and nanoindentation of FFS with MCT revealed two-phase structured films with softer inclusions (0.5 to 4μm in diameter) surrounded by a more rigid structure. Chemical mapping with Raman micro-spectroscopy showed that MCT was primarily confined to the inclusions within the polymer, which predominated in the surrounding film. BMV was distributed throughout the film but was more concentrated outside the inclusions. Furthermore, while BMV dissolved better into the hydrophobic films, it was more soluble in the MCT inclusions in hydrophilic films, suggesting its increased availability for diffusion from these softer regions of the polymer and explaining the release enhancement observed. Second, ex vivo skin penetration studies clearly revealed that uptake of BMV was higher from hydrophobic FFS than that from the more hydrophilic polymer due, at least in part, to the superior anti-nucleation efficiency of the former. Drug was quickly taken up into the SC from which it then diffused continuously over a sustained period into the lower, viable skin layers. In the presence of MCT, the overall uptake of BMV was increased and provides the basis for further optimisation of FFS as simple, convenient and sustained formulations for topical therapy.
authors.affiliation: University of Bath, Department of Physics, Bath, BA2 7AY, UK; University of Bath, Department of Pharmacy & Pharmacology, Bath, BA2 7AY, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Garvie-Cook
authors.affiliation: University of Bath, Department of Pharmacy & Pharmacology, Bath, BA2 7AY, UK; LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
authors.forename: Kit
authors.initials: K
authors.lastname: Frederiksen
authors.affiliation: LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Petersson
authors.affiliation: University of Bath, Department of Pharmacy & Pharmacology, Bath, BA2 7AY, UK. Electronic address: r.h.guy@bath.ac.uk.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Guy
authors.affiliation: University of Bath, Department of Physics, Bath, BA2 7AY, UK.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Gordeev
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001624:Betamethasone Valerate / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D065546:Drug Liberation; D004423:Ear; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine; D014280:Triglycerides / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D011108:Polymers; D014280:Triglycerides; C022834:miglyol 812; D001624:Betamethasone Valerate
keywords: Anti-nucleation; Atomic force microscopy; Polymeric film-forming systems; Raman chemical mapping; Supersaturation; Topical drug delivery