title: Development and in vitro-in vivo evaluation of fenretinide-loaded oral mucoadhesive patches for site-specific chemoprevention of oral cancer.
abstract: OBJECTIVE
  To develop fenretinide oral mucoadhesive patch formulations and evaluate their in vitro and in vivo release performance for future site-specific chemoprevention of oral cancer.
  
  
  METHODS
  Solubilization of fenretinide in simulated saliva (SS) was studied by incorporating nonionic surfactants (Tween® 20 and 80, and Brij® 35 and 98), bile salts (sodium salt of cholic, taurocholic, glycocholic, and deoxycholic acids), phospholipid (lecithin), and novel polymeric solubilizer (Souplus®). Adhesive (polycarbophil: hydroxypropyl methylcellulose 4KM) and drug release (Fenretinide/Eudragit® RL PO with or without solubilizers) layers were prepared by solvent casting. Oral mucoadhesive patches were formed by attaching drug and adhesive layers onto backing layer (Tegaderm™ film). Physical state of drug in Eudragit® films was examined by X-ray diffraction (XRD). Evaluation of in vitro and in vivo fenretinide release from the patch was conducted in SS containing 5%w/v sodium deoxycholate and rabbits, respectively. Fenretinide was quantified by HPLC.
  
  
  RESULTS
  Tween® 20 and 80, Brij® 98, and sodium deoxycholate exhibited the highest fenretinide solubilization potential among the solubilizers. Drug loading efficiency in Eudragit® films was 90%-97%. XRD suggested fenretinide was amorphous in solubilizer-free and solubilizer-loaded films. Solubilizer-free patch exhibited poor in vitro and in vivo controlled drug release behavior. Increases in drug loading (5-10 wt%) or changes in polymeric matrix permeability did not provide continuous drug release. Co-incorporation of either single or mixed solubilizers in fenretinide/Eudragit® patches, (20 wt% Tween® 20, Tween® 80 and sodium deoxycholate or 20 wt% Tween® 80 + 40 wt% sodium deoxycholate solubilizers) led to significantly improved continuous in vitro/in vivo fenretinide release.
  
  
  CONCLUSIONS
  Fenretinide/Eudragit® RL PO patches with 20 wt% Tween® 80 + 40 wt% sodium deoxycholate solubilizers exhibit excellent release behavior for further preclinical and/or clinical evaluation in oral cancer chemoprevention.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, 428 Church St., Ann Arbor, Michigan, USA.
authors.forename: Kashappa-Goud H
authors.initials: KG
authors.lastname: Desai
authors.forename: Susan R
authors.initials: SR
authors.lastname: Mallery
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Holpuch
authors.forename: Steven P
authors.initials: SP
authors.lastname: Schwendeman
mesh_terms: D000269:Adhesives / Q000737:chemistry; D000278:Administration, Buccal; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry; D018890:Chemoprevention / Q000379:methods; D004304:Dosage Forms; D015195:Drug Design; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage* / Q000737:chemistry*; D009061:Mouth Mucosa / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011817:Rabbits; D012463:Saliva / Q000187:drug effects; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000269:Adhesives; D001647:Bile Acids and Salts; D004304:Dosage Forms; D010743:Phospholipids; D011108:Polymers; D013501:Surface-Active Agents; D017313:Fenretinide