Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds
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- Komasaka Takao
- Medicinal Chemistry Research Laboratories I, Mitsubishi Tanabe Pharma Corporation
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- Fujimura Hisako
- Safety Research Laboratories, Mitsubishi Tanabe Pharma Corporation
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- Tagawa Toshiaki
- Safety Research Laboratories, Mitsubishi Tanabe Pharma Corporation
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- Sugiyama Akio
- Safety Research Laboratories, Mitsubishi Tanabe Pharma Corporation
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- Kitano Yasunori
- Medicinal Chemistry Research Laboratories I, Mitsubishi Tanabe Pharma Corporation
Bibliographic Information
- Other Title
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- 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
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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.
Journal
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- Chemical and Pharmaceutical Bulletin
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Chemical and Pharmaceutical Bulletin 62 (11), 1073-1082, 2014
The Pharmaceutical Society of Japan
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Details 詳細情報について
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- CRID
- 1390282679155121024
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- NII Article ID
- 130004712901
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- NII Book ID
- AA00602100
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- ISSN
- 13475223
- 00092363
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- NDL BIB ID
- 025880457
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- PubMed
- 25366311
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- Abstract License Flag
- Disallowed