title: In vitro permeation of a pegylated naltrexone prodrug across microneedle-treated skin.
abstract: Microneedles (MN) are a useful tool for increasing skin permeability to xenobiotics. Previous research showed marked improvement in the percutaneous flux of naltrexone (NTX) hydrochloride by the use of MN skin pretreatment alone; however, for better therapeutic effect, further enhancement is desired. The goal of this in vitro study was to combine microneedle skin pretreatment with the use of a highly water-soluble PEGylated naltrexone prodrug (polyethyleneglycol-NTX, PEG-NTX) to investigate its transdermal transport at varying concentrations. Solubility and stability of the prodrug were investigated. In vitro diffusion experiments employing MN-treated minipig skin were used to evaluate the performance of the PEGylated prodrug. The results revealed substantial deviation from ideal behavior, with the flux through MN-treated skin having a nonlinear relationship to the prodrug concentration in the donor solution. While in the lower concentration range tested the prodrug flux increase was proportional to the concentration increase, at high concentrations it showed no such dependence. Accounting for the decrease in the effective prodrug diffusivity accompanying the increase in viscosity, as predicted by the Stokes-Einstein equation, provided a rationale for the observed flux values. Increasing the viscosity of the donor solution is hypothesized to afford a curvilinear permeation profile for the PEGylated NTX prodrug.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
authors.forename: Mikolaj
authors.initials: M
authors.lastname: Milewski
authors.forename: Thirupathi Reddy
authors.initials: TR
authors.lastname: Yerramreddy
authors.forename: Priyanka
authors.initials: P
authors.lastname: Ghosh
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Audra L
authors.initials: AL
authors.lastname: Stinchcomb
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D066298:In Vitro Techniques; D008954:Models, Biological; D009271:Naltrexone / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D009339:Needles; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D012995:Solubility; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution; D014783:Viscosity
chemical_list: D004337:Drug Carriers; D011355:Prodrugs; D011092:Polyethylene Glycols; D009271:Naltrexone