title: Release mechanisms of tacrolimus-loaded PLGA and PLA microspheres and immunosuppressive effects of the microspheres in a rat heart transplantation model.
abstract: The objective of this study was to elucidate the release and absorption mechanisms of tacrolimus loaded into microspheres composed of poly(lactic-co-glycolic acid) (PLGA) and/or polylactic acid (PLA). Tacrolimus-loaded microspheres were prepared by the o/w emulsion solvent evaporation method. The entrapment efficiency correlated with the molecular weight of PLGA, and the glass transition temperature of PLGA microspheres was not decreased by the addition of tacrolimus. These results indicate that intermolecular interaction between tacrolimus and the polymer would affect the entrapment of tacrolimus in the microspheres. Tacrolimus was released with weight loss of the microspheres, and the dominant release mechanism of tacrolimus was considered to be erosion of the polymer rather than diffusion of the drug. The whole-blood concentration of tacrolimus in rats was maintained for at least 2 weeks after a single subcutaneous administration of the microspheres. The pharmacokinetic profile of tacrolimus following subcutaneous administration was similar to that following intramuscular administration, suggesting that the release and dissolution of tacrolimus, rather than the absorption of the dissolved tacrolimus, were rate-limiting steps. Graft-survival time in a heart transplantation rat model was prolonged by the administration of tacrolimus-loaded microspheres. The microsphere formulation of tacrolimus would be expected to precisely control the blood concentration while maintaining the immunosuppressive effect of the drug.
authors.affiliation: Pharmaceutical Research & Technology Labs., Astellas Pharma Inc., 180, Ozumi, Yaizu-shi, Shizuoka 425-0072, Japan; Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: ryo.kojima@astellas.com.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kojima
authors.affiliation: Pharmaceutical Research & Technology Labs., Astellas Pharma Inc., 180, Ozumi, Yaizu-shi, Shizuoka 425-0072, Japan.
authors.forename: Takatsune
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Pharmaceutical Research & Technology Labs., Astellas Pharma Inc., 180, Ozumi, Yaizu-shi, Shizuoka 425-0072, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tasaki
authors.affiliation: Pharmaceutical Research & Technology Labs., Astellas Pharma Inc., 180, Ozumi, Yaizu-shi, Shizuoka 425-0072, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Umejima
authors.affiliation: Research Portfolio & Science, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Research Portfolio & Science, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Pharmaceutical Research & Technology Labs., Astellas Pharma Inc., 180, Ozumi, Yaizu-shi, Shizuoka 425-0072, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D065546:Drug Liberation; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D008863:Microspheres; D011091:Polyesters; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D011091:Polyesters; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); D016559:Tacrolimus
keywords: Controlled release; Heart transplantation; Microsphere; PLA; PLGA; Tacrolimus