title: Enhanced pulmonary absorption of poorly soluble itraconazole by micronized cocrystal dry powder formulations.
abstract: Micronized cocrystal powders and amorphous spray-dried formulations were prepared and evaluated in vivo and in vitro as pulmonary absorption enhancement formulations of poorly soluble itraconazole (ITZ). ITZ cocrystals with succinic acid (SA) or l-tartaric acid (TA) with a particle size diameter of <2μm were successfully micronized using the jet-milling system. The cocrystal crystalline morphologies observed using scanning electron microscopy (SEM) suggested particle shapes that differed from those of the crystalline or spray-dried amorphous ITZ. The micronized ITZ cocrystal powders showed better intrinsic dissolution rate (IDR) and pulmonary absorption profile in rats than that of the amorphous spray-dried formulation and crystalline ITZ with comparable particle sizes. Specifically, in rat pharmacokinetic studies following pulmonary administration, micronized ITZ-SA and ITZ-TA cocrystals showed area under the curve from 0 to 8h (AUC0-8h) values approximately 24- and 19-fold higher than those of the crystalline ITZ and 2.0- and 1.6-fold higher than the spray-dried ITZ amorphous values, respectively. The amorphous formulation appeared physically instable during the studies due to rapid crystallization of ITZ, which was its disadvantage compared to the crystalline formulations. Therefore, this study demonstrated that micronized cocrystals are promising formulations for enhancing the pulmonary absorption of poorly soluble compounds.
authors.affiliation: Takeda Pharmaceutical Company Ltd., Analytical Development, Pharmaceutical Sciences, Kanagawa 251-8555, Japan. Electronic address: masatoshi.karashima@takeda.com.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Karashima
authors.affiliation: Takeda Pharmaceutical Company Ltd., Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Kanagawa 251-8555, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Sano
authors.affiliation: Takeda Pharmaceutical Company Ltd., Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Kanagawa 251-8555, Japan.
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Takeda Pharmaceutical Company Ltd., Analytical Development, Pharmaceutical Sciences, Kanagawa 251-8555, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Takeda Pharmaceutical Company Ltd., Analytical Development, Pharmaceutical Sciences, Kanagawa 251-8555, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Takeda Pharmaceutical Company Ltd., Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Kanagawa 251-8555, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amano
authors.affiliation: Takeda Pharmaceutical Company Ltd., Analytical Development, Pharmaceutical Sciences, Kanagawa 251-8555, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D004339:Drug Compounding / Q000379:methods; D017964:Itraconazole / Q000737:chemistry*; D008297:Male; D008855:Microscopy, Electron, Scanning / Q000379:methods; D010316:Particle Size; D011208:Powders / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D065589:Respiratory Tract Absorption / Q000187:drug effects*; D012995:Solubility / Q000187:drug effects*; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D011208:Powders; D017964:Itraconazole
keywords: Amorphous; Cocrystals; Crystal engineering; Dissolution rate; Dry powder formulation; Itraconazole (PubChem CID: 3793); Micronized particles; Pulmonary absorption