title: Application of hydrotropy to transdermal formulations: hydrotropic solubilization of polyol fatty acid monoesters in water and enhancement effect on skin permeation of 5-FU.
abstract: OBJECTIVE
  A hydrotropic formulation containing a percutaneous enhancer was developed for the transdermal formulation of a water-soluble drug and the solubilizing mechanisms of a percutaneous enhancer in water by a hydrotropic agent were investigated. The enhancement effect was also compared with the hydrotropic formulation and the other formulations using ethanol, propylene glycol or mixed micelles.
  
  
  METHODS
  Sodium salicylate (SA) and sodium benzoate (BA) were selected as hydrotropic agents, and polyol fatty acid ester (POFE) and 5-fluorouracil (5-FU) were selected as a percutaneous enhancer and a water-soluble drug, respectively. Near-infrared (NIR) spectrophotometric and ¹H NMR spectroscopic studies were carried out to investigate the solubilizing mechanisms. The mean particle size in the hydrotropic formulation was measured. The in-vitro skin permeation of 5-FU and the accumulation in the skin of propylene glycol monocaprylate (PGMC), one of the monoesters of POFE, from the hydrotropic formulation or the other formulations were investigated by using Franz-type diffusion cell.
  
  
  RESULTS
  The presence of SA and BA had a visible effect on the O-H stretching band of water in the NIR region. The surface tension of SA and BA aqueous solutions was found to decrease with an increase in SA or BA concentration. Although SA interacted with PGMC in the presence of water, it did not interact with PGMC in the absence of water. Mean particle size in a solution consisting of 5% (v/v) PGMC and 30% SA aqueous solution was approximately 14 nm. ¹H NMR spectroscopic studies indicated that the hydrotropic salts formed aggregates with which PGMC interacted from the outside. The hydrotropic formulation prepared in this study enhanced skin permeation of 5-FU when compared with the other formulations.
  
  
  CONCLUSIONS
  SA and BA solubilized monoesters of POFE in water, and SA interacted with PGMC in water. The hydrotropic formulation prepared in this study significantly enhanced skin permeation of 5-FU compared with the other formulations. The results suggest that a hydrotropic formulation containing PGMC may be a useful transdermal formulation for water-soluble drugs.
authors: Department of Pharmaceutics, School of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Shiga, Japan. koichi@mukogawa-u.ac.jp
authors: Koichi
authors: K
authors: Takahashi
authors: Megumi
authors: M
authors: Komai
authors: Natsumi
authors: N
authors: Kinoshita
authors: Emi
authors: E
authors: Nakamura
authors: Xiao-Long
authors: XL
authors: Hou
authors: Tomoka
authors: T
authors: Takatani-Nakase
authors: Masaya
authors: M
authors: Kawase
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D002210:Caprylates / Q000737:chemistry* / Q000494:pharmacology; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D010316:Particle Size; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology; D019946:Propylene Glycol / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D054772:Rats, Hairless; D012867:Skin; D012869:Skin Absorption / Q000187:drug effects*; D020160:Sodium Benzoate / Q000737:chemistry* / Q000494:pharmacology; D012980:Sodium Salicylate / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D013500:Surface Tension; D017155:Wettability
chemical_list: D002210:Caprylates; D004952:Esters; D011108:Polymers; C024617:polyol; D019946:Propylene Glycol; D020160:Sodium Benzoate; D005472:Fluorouracil; D012980:Sodium Salicylate