title: Development of pH-Independent Drug Release Formulation Using Lipocalin-Type Prostaglandin D Synthase.
abstract: The purpose of this study was to develop a pH-independent drug release formulation using lipocalin-type prostaglandin D synthase, a member of the lipocalin superfamily, with the function of forming complexes together with various small lipophilic molecules. Dipyridamole, a poorly water-soluble drug, showing a pH-dependent solubility profile, was used as the model drug. The solubilization of dipyridamole was achieved by a simple complex formulation method with lipocalin-type prostaglandin D synthase. The complex formulation was produced successfully by spray drying, and the obtained powder formulation showed complete dissolution in fasted-state simulated gastric fluid (pH, 1.6) and phosphate-buffered solution (pH, 6.8). In addition, the potential stability of the complex formulation was assessed, and the dissolution profile of the produced powder at pH 6.8 was maintained after 4-week storage under several storage conditions. Furthermore, a pharmacokinetic study using hypochlorhydria model rats was performed to verify the improvement of the intestinal absorption behavior, and eventually the complex formulation overcame the problematic absorption profile of dipyridamole in the elevated gastric pH conditions. These results, taken together, demonstrate that the use of this well-designed drug-delivery carrier is feasible for the development of pH-independent drug release formulations.
authors.affiliation: Department of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan; Department of Chemistry, Manufacturing and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizoguchi
authors.affiliation: Department of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nakatsuji
authors.affiliation: Department of Chemistry, Manufacturing and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Takano
authors.affiliation: Department of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishibashi
authors.affiliation: Department of Chemistry, Manufacturing and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan. Electronic address: inuit@bioinfo.osakafu-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Inui
mesh_terms: D000818:Animals; D004176:Dipyridamole / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D004339:Drug Compounding; D065546:Drug Liberation; D004355:Drug Stability; D005079:Excipients; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D019746:Intramolecular Oxidoreductases / Q000737:chemistry*; D054834:Lipocalins / Q000737:chemistry*; D008297:Male; D008958:Models, Molecular; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D012995:Solubility
chemical_list: D005079:Excipients; D054834:Lipocalins; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D004176:Dipyridamole; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase
keywords: absorption enhancer; dissolution; formulation vehicle; oral absorption; oral drug delivery; proteins; solubility; spray drying