title: Improved oral absorption and chemical stability of everolimus via preparation of solid dispersion using solvent wetting technique.
abstract: The aim of this study was to improve the physicochemical properties and oral absorption of poorly water-soluble everolimus via preparation of a solid dispersion (SD) system using a solvent wetting (SW) technique. The physicochemical properties, drug release profile, and bioavailability of SD prepared by SW process were also compared to SD prepared by the conventional co-precipitation method. Solid state characterizations using scanning electron microscopy, particle size analysis and X-ray powder diffraction indicated that drug homogeneously dispersed and existed in an amorphous state within the intact polymeric carrier. Whereas, a film-like mass was obtained by a co-precipitation method and further pulverization step was needed for tabletization. The drug release from the SD tablet prepared by SW process at a ratio of drug to hydroxypropyl methylcellulose of 1:15 was markedly higher than the drug alone and equivalent to the marketed product (Afinitor(®), Novartis Pharmaceuticals), a SD tablet prepared by co-precipitation method, archiving over 75% the drug release after 30 min. At the accelerated (40°C/75% R.H.) and stress (80°C) stability tests, the novel formula was more stable than drug powder and provided comparable drug stability with the commercially available product, which contains a potentially risky antioxidant, butylated hydroxyl toluene. The pharmacokinetic parameters after single oral administration in beagles showed no significant difference (P>0.01) between the novel SD-based tablet and the marketed product. The results of this study, therefore, suggest that the novel SD system prepared by the solvent wetting process may be a promising approach for improving the physicochemical stability and oral absorption of the sirolimus derivatives.
authors.affiliation: Dong-A Pharmaceutical Co. Ltd., Giheung-gu, Yongin, Gyeonggi 446-905, South Korea.
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Jang
authors.affiliation: College of Pharmacy, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan, Chungnam 330-714, South Korea. Electronic address: kangmj@dankook.ac.kr.
authors.forename: Myung Joo
authors.initials: MJ
authors.lastname: Kang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D004355:Drug Stability; D000431:Ethanol / Q000737:chemistry; D000068338:Everolimus; D065347:Hypromellose Derivatives / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D008752:Methylene Chloride / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D033362:Powder Diffraction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D012997:Solvents / Q000737:chemistry; D013607:Tablets; D014961:X-Ray Diffraction
chemical_list: D007166:Immunosuppressive Agents; D012997:Solvents; D013607:Tablets; D000431:Ethanol; D065347:Hypromellose Derivatives; D008752:Methylene Chloride; D000068338:Everolimus; D020123:Sirolimus
keywords: Everolimus; Oral absorption; Solid dispersion; Solvent wetting technique; Stability