title: Enhanced supersaturation and oral absorption of sirolimus using an amorphous solid dispersion based on Eudragit® e.
abstract: The present study aimed to investigate the effect of Eudragit® E/HCl (E-SD) on the degradation of sirolimus in simulated gastric fluid (pH 1.2) and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid dispersions were fabricated by a spray drying process. A kinetic solubility test demonstrated that the sirolimus/E-SD/TPGS (1/8/1) solid dispersion had a maximum solubility of 196.7 μg/mL within 0.5 h that gradually decreased to 173.4 μg/mL after 12 h. According to the dissolution study, the most suitable formulation was the sirolimus/E-SD/TPGS (1/8/1) solid dispersion in simulated gastric fluid (pH 1.2), owing to enhanced stability and degree of supersaturation of E-SD and TPGS. Furthermore, pharmacokinetic studies in rats indicated that compared to the physical mixture and sirolimus/HPMC/TPGS (1/8/1) solid dispersion, the sirolimus/E-SD/TPGS (1/8/1) solid dispersion significantly improved oral absorption of sirolimus. E-SD significantly inhibited the degradation of sirolimus in a dose-dependent manner. E-SD also significantly inhibited the precipitation of sirolimus compared to hydroxypropylmethyl cellulose (HPMC). Therefore, the results from the present study suggest that the sirolimus-loaded E-SD/TPGS solid dispersion has great potential in clinical applications.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea. yscho@yuyu.co.kr.
authors.forename: Youngseok
authors.initials: Y
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Korea. edel@pusan.ac.kr.
authors.forename: Eun-Sol
authors.initials: ES
authors.lastname: Ha
authors.affiliation: College of Pharmacy, Kyungsung University, Busan 608-736, Korea. baek@ks.ac.kr.
authors.forename: In-Hwan
authors.initials: IH
authors.lastname: Baek
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Korea. minsookim@pusan.ac.kr.
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea. chocw@cnu.ac.kr.
authors.forename: Cheong-Weon
authors.initials: CW
authors.lastname: Cho
authors.affiliation: College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Korea. sjh11@yonsei.ac.kr.
authors.forename: Sung-Joo
authors.initials: SJ
authors.lastname: Hwang
mesh_terms: D000818:Animals; D001682:Biological Availability; D040761:Biomimetic Materials / Q000737:chemistry*; D004337:Drug Carriers; D004355:Drug Stability; D005079:Excipients; D005750:Gastric Juice / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis / Q000187:drug effects; D065347:Hypromellose Derivatives / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D065568:Oral Mucosal Absorption / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D011109:Polymethacrylic Acids / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D012995:Solubility; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004337:Drug Carriers; D005079:Excipients; D011109:Polymethacrylic Acids; D014810:Vitamin E; C038300:methylmethacrylate-methacrylic acid copolymer; D065347:Hypromellose Derivatives; D011092:Polyethylene Glycols; C014225:tocophersolan; D020123:Sirolimus
keywords: Eudragit® E; bioavailability; sirolimus; solid dispersion; supersaturation