Manabu Nakatani
Boehringer Ingelheim
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Featured researches published by Manabu Nakatani.
International Journal of Pharmaceutics | 2011
Yohei Kawabata; Koichi Wada; Manabu Nakatani; Shizuo Yamada; Satomi Onoue
The poor oral bioavailability arising from poor aqueous solubility should make drug research and development more difficult. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. To complete development works within a limited amount of time, the establishment of a suitable formulation strategy should be a key consideration for the pharmaceutical development of poorly water-soluble drugs. In this article, viable formulation options are reviewed on the basis of the biopharmaceutics classification system of drug substances. The article describes the basic approaches for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Literature-based examples of the formulation options for poorly water-soluble compounds and their practical application to marketed products are also provided. Classification of drug candidates based on their biopharmaceutical properties can provide an indication of the difficulty of drug development works. A better understanding of the physicochemical and biopharmaceutical properties of drug substances and the limitations of each delivery option should lead to efficient formulation development for poorly water-soluble drugs.
Journal of Chromatography A | 1994
Manabu Nakatani; Akimasa Shibukawa; Terumichi Nakagawa
Sodium dodecyl sulphate (SDS) capillary electrophoresis using pullulan solution as a separation matrix was developed for the separation and molecular mass determination of proteins. The silanol functions on the inner surface of a fused-silica capillary were deactivated by coating with linear polyacrylamide through Si-C linkages, into which the pullulan solution was filled. The stability of the coating was examined by exposure to an alkaline buffer solution (pH 9.2) for up to 30 days. Compared with conventional coatings with linear polyacrylamide through siloxane linkages, the present capillary was more stable even under alkaline conditions and markedly reduced electroosmotic flow. Thus, polymer solutions of low viscosity such as pullulan solution could be stabilized in the capillary, resulting in a prolonged life-span of the capillary and improved reproducibility of separations. An excellent linear relationship was obtained between the mobility and the logarithm of the molecular mass of SDS-proteins. The relative standard deviation of migration times was below 0.5% when the pullulan solution was refilled in each analysis (n = 10). The calibration plots of the integrated peak areas at 214 nm vs. concentration of standard proteins were linear in the range 5 micrograms/ml-0.1 mg/ml.
Journal of Chromatography A | 1994
Manabu Nakatani; Akimasa Skibukawa; Terumichi Nakagawa
A stable sieving matrix of polyacrylamide filled in a capillary was developed. The inner wall of a fused-silica capillary was covalently bonded with a linear polyacrylamide through Si-C linkages, in which cross-linked polyacrylamide gel or linear polyacrylamide solution was filled. The stability of the coating was examined by exposure of the capillaries to alkaline buffer (pH 8) for up to 30 days. Compared with the coatings with linear polyacrylamide bonded through siloxane linkages, the present capillary markedly reduced the electroosmotic flow. Thus, the sieving matrix in the capillary was stabilized, resulting in a prolonged lifetime of the capillary and good reproducibility of separations. The migration behaviours of oligonucleotides were compared for the cross-linked gel and linear polyacrylamide solution at the same concentration.
European Journal of Pharmaceutical Sciences | 2015
Masashi Adachi; Yuta Hinatsu; Kosuke Kusamori; Hidemasa Katsumi; Toshiyasu Sakane; Manabu Nakatani; Koichi Wada; Akira Yamamoto
Formulation development of poorly water-soluble compounds can be challenging because of incomplete dissolution that causes low and variable bioavailability. Enhancing compound solubility is important and many techniques have been investigated to that end, but they require specific materials and machinery. This study investigates the incorporation of a pH-modifier as a method to increase compound solubility and uses ketoconazole (KZ), which is weakly basic (pKa: 6.5), as a model compound. Organic acids are effective pH-modifiers and are generally used in pharmaceutical industries. We successfully obtained granules containing variable organic acids (KZ/acid granule) using a high-shear mixer. Dissolution tests of the KZ/acid granule resulted in highly enhanced solubility under non-sink conditions. Adding water-soluble acids, such as citric acid (CA) and tartaric acid, resulted in more than 8-fold higher dissolution at pH 6.0 compared to that of KZ only. The granules containing citric acid (KZ/CA granule) improved the dissolution of KZ after oral administration to rats under low gastric acid conditions, where the bioavailability of the KZ/CA granules at elevated gastric pH was comparable with that of KZ only at gastric acidic pH. The incorporation of organic acids would result in effective therapeutic outcomes independent of gastric pH in patients. In addition, higher bioavailability of KZ was observed after oral administration of KZ/CA granules under gastric acidic pH conditions than that of KZ alone. Thus, CA improved the dissolution and absorption rate of KZ after oral administration.
Aaps Pharmscitech | 2017
Masashi Adachi; Yuta Hinatsu; Kosuke Kusamori; Hidemasa Katsumi; Toshiyasu Sakane; Manabu Nakatani; Koichi Wada; Akira Yamamoto
Poorly water-soluble compounds have a potential risk of low and variable bioavailability caused by incomplete dissolution. Incorporation of organic acids as pH modifiers is effective method for solubility enhancement of basic compounds and requires no special technique and equipment. The purpose of this study was to evaluate the effect of manufacturing method on the extent of drug solubility enhancement. We successfully prepared the granules and tablets containing ketoconazole (KZ), which is weakly basic, as a model compound and citric acid as a pH modifier using conventional wet and dry granulations. KZ solubility under non-sink condition was enhanced with supersaturation using both wet and dry granulations. High-shear granulation was the most effective method in terms of KZ dissolution enhancement, because both an intimate contact and strong bonding between KZ and incorporated acid were achieved. KZ dissolved amount from the granules prepared by high-shear granulation was about eight times higher than that from the granules without the acid. The granulation involved to suppress a diffusion of acid dissolved, leading to the effectively maintained supersaturation state. The bioavailability of KZ after oral administration to rats was improved by applying high-shear granulation with citric acid independent of gastrointestinal pH. The granules prepared by high-shear granulation showed the bioavailability about 1.7-fold higher than that of the physical mixture in rats with and without neutralization of stomach. As a result, both the dissolution and absorption rates of KZ after oral administration were enhanced using conventional manufacturing technology.
Archive | 2003
Manabu Nakatani; Toshimitsu Ohki; Sawada Takeshi; Kenzo Toyoshima
Electrophoresis | 1995
Manabu Nakatani; Akimasa Shibukawa; Terumichi Nakagawa
Archive | 2003
Manabu Nakatani; Sawada Takeshi; Toshimitsu Ohki; Kenzo Toyoshima
Biological & Pharmaceutical Bulletin | 1993
Manabu Nakatani; Akimasa Shibukawa; Terumichi Nakagawa
Electrophoresis | 1996
Manabu Nakatani; Akimasa Shibukawa; Terumichi Nakagawa