title: Effect of lipophilicity on the bioavailability of drugs after percutaneous administration by dissolving microneedles.
abstract: To elucidate drug lipophilicity effects on the bioavailability (BA) of drugs from skin after administration by dissolving microneedles, nine compounds with different lipophilicity indexes (log p value) were formulated into two-layered dissolving microneedles and administered percutaneously to rat skin: desmopressin (DDAVP), sumatriptan (ST), fluorescein (FL), granisetron (GRN), pindolol (PDL), pravastatin (PRV), rhodamine 123 (Rho), rifampicin (RFP), and salmeterol (SLM). Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry and spectrofluorometry. In vivo dissolution and diffusion in both horizontal and vertical directions of FL and RH in the skin were studied using fluorescence microscopy. Respective BAs were 95.1 ± 7.9% (DDAVP), 84.2 ± 2.7% (ST), 82.3 ± 7.2% (FL), 82.7 ± 6.7% (GRN), 71.6 ± 3.8% (PDL), 63.6 ± 7.5% (PRV), 53.7 ± 8.3% (Rho), 46.2 ± 6.1% (RFP), and 38.4 ± 2.7% (SM). BA decreased as the lipophilicity index, log p value, of the drug increased from-1.95 to 1.73. The respective remaining percentages in skin tissue were 1.4 ± 0.7% (DDAVP), 0.9 ± 0.1% (ST), 1.0 ± 0.2% (FL), 3.4 ± 1.2% (GRN), 14.5 ± 3.7% (PDL), 23.4 ± 5.2% (PRV), 32.2 ± 6.0% (Rho), 40.7 ± 4.9% (RFP), and 40.6 ± 5.1% (SLM), dependent on log p. Fluorescence microscopy showed no FL or Rho in skin tissue within 4 and 24 h after administration, respectively. The BA of drugs delivered by dissolving microneedles depends on the drug solubility in the skin epidermis and dermis.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. yukako@mb.kyoto-phu.ac.jp
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001682:Biological Availability; D016503:Drug Delivery Systems / Q000295:instrumentation*; D008055:Lipids / Q000737:chemistry*; D008297:Male; D009339:Needles; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D012995:Solubility
chemical_list: D008055:Lipids; D004364:Pharmaceutical Preparations