title: Improved dissolution and absorption of ketoconazole in the presence of organic acids as pH-modifiers.
abstract: 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.
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto 607-8414, Japan; Department of Chemistry, Manufacturing, and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: adachim@kaw.boehringer-ingelheim.com.
authors.forename: Masashi
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Hinatsu
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kusamori
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto 607-8414, Japan. Electronic address: sakane@mb.kyoto-phu.ac.jp.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sakane
authors.affiliation: Department of Chemistry, Manufacturing, and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Nakatani
authors.affiliation: Department of Chemistry, Manufacturing, and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D019343:Citric Acid / Q000008:administration & dosage* / Q000737:chemistry; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects*; D007654:Ketoconazole / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D017208:Rats, Wistar; D012995:Solubility; D013270:Stomach / Q000187:drug effects*; D013644:Tartrates / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D054328:Proton Pump Inhibitors; D013644:Tartrates; D019343:Citric Acid; D007654:Ketoconazole; C029768:tartaric acid
keywords: Bioavailability; Dissolution rate; Hypochlorhydria; Ketoconazole; Organic acid; pH-modifier