title: Preparation of extended release solid dispersion formulations of tacrolimus using ethylcellulose and hydroxypropylmethylcellulose by solvent evaporation method.
abstract: OBJECTIVE
  Tacrolimus is a poorly water-soluble compound that is used to prevent allograft rejection. We aimed to prepare an extended release formulation of tacrolimus to achieve both an extended release profile and improved solubility of tacrolimus.
  
  
  METHODS
  Extended release granules (ERG) of tacrolimus were prepared with lactose, ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) via the solvent evaporation method.
  
  
  RESULTS
  In an in vitro release study, ERG had an extended release profile, and the release rate of tacrolimus was regulated by the quantity of lactose, EC and HPMC in the formulation. HPMC-containing ERG successfully enhanced and maintained supersaturation of tacrolimus even after 24 h in a supersaturated release study. In contrast, the extent of supersaturation rapidly decreased after 4 h and the concentration nearly reached the same level as that of crystalline tacrolimus at 24 h for ERG without HPMC. In vivo absorption characteristics were compared between ERGs and immediate release (IR) formulation of tacrolimus. Successful and sustained absorption of tacrolimus without reducing bioavailability compared with IR formulation was observed for ERG.
  
  
  CONCLUSIONS
  These results suggest the feasibility of combining an EC-based formulation with solid dispersion utilizing HPMC for the extended release of oral formulations and sustained absorption of tacrolimus.
authors.affiliation: Pharmaceutical Research and Technology Labs., Astellas Pharma Inc., Yaizu, Shizuoka, Japan.|Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsunashima
authors.affiliation: Pharmaceutical Research and Technology Labs., Astellas Pharma Inc., Yaizu, Shizuoka, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Ogawara
authors.affiliation: Astellas Ireland Co., Ltd., Mulhuddart, Dublin 15, Ireland.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sako
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Higaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002482:Cellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D065347:Hypromellose Derivatives / Q000737:chemistry*; D007785:Lactose / Q000737:chemistry; D008252:Macaca fascicularis; D008297:Male; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D016559:Tacrolimus / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D012997:Solvents; D014867:Water; D065347:Hypromellose Derivatives; C013517:ethyl cellulose; D002482:Cellulose; D007785:Lactose; D016559:Tacrolimus
keywords: controlled release; dissolution; oral absorption; pharmacokinetics; solid dispersion