title: Practical method for preparing nanosuspension formulations for toxicology studies in the discovery stage: formulation optimization and in vitro/in vivo evaluation of nanosized poorly water-soluble compounds.
abstract: The present study aimed to develop a practical method for preparing nanosuspension formulations of poorly water-soluble compounds for enhancing oral absorption in toxicology studies in the discovery stage. To obtain a suitable nanosuspension formulation for the intended purpose, formulations were optimized with a focus on the following characteristics: i) containing a high drug concentration, ii) consisting of commonly used excipient types in proper quantities for toxicology studies, iii) having long-term stability, and iv) having versatility for use with diverse compounds. Test compounds were milled with various excipients by wet media milling methods using a mixer mill (10 mg/batch) and a rotation/revolution mixer (0.5 g/batch). As a result, 100 mg/mL nanosuspensions of all 11 test compounds could be prepared with an optimized dispersing agent, 0.5% hydroxypropyl methylcellulose (HPMC) (3 cP)-0.5% Tween 80. Notably, it was found that the molecular weight of HPMC influenced not only particle size but also the stability of nanosuspensions and they were stable for 4 weeks at 5°C. The nanosuspensions increased in vitro dissolution rates and provided 3.9 and 3.0 times higher Cmax and 4.4 and 1.6 times higher area under the concentration-time curve from 0-24 h (AUC0-24 h) in rats (oral dose of 300 mg/kg) for cilostazol and danazol, respectively. In conclusion, applying a wet media milling method with the combination of HPMC of a small molecular weight and Tween 80 as a dispersing agent, nanosuspensions can be practically prepared and conveniently utilized for enhancing the oral absorption of poorly water-soluble compounds in toxicology studies in the discovery stage.
authors.affiliation: Medicinal Chemistry Research Laboratories I, Mitsubishi Tanabe Pharma Corporation.
authors.forename: Takao
authors.initials: T
authors.lastname: Komasaka
authors.forename: Hisako
authors.initials: H
authors.lastname: Fujimura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tagawa
authors.forename: Akio
authors.initials: A
authors.lastname: Sugiyama
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kitano
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004339:Drug Compounding / Q000379:methods*; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013535:Suspensions; D018675:Toxicity Tests
chemical_list: D004364:Pharmaceutical Preparations; D013535:Suspensions