title: Novel oral formulation approach for poorly water-soluble drug using lipocalin-type prostaglandin D synthase.
abstract: Lipocalin-type prostaglandin D synthase (L-PGDS), a member of the lipocalin superfamily, possesses the function of forming complexes together with various small lipophilic molecules. In this study, we chose telmisartan as a model drug due to its pH dependent poor water solubility, and developed and characterized a novel solubilized formulation of telmisartan using a complex formulation with L-PGDS. The solid state of the complex formulation was prepared using a spray-drying process. The spray-dried formulation of telmisartan/L-PGDS powder showed a typical spray-dried particle without any change in the secondary and tertiary structures of L-PGDS. Furthermore, the complex formulation showed a high rate and level of drug release in pH 1.2, 5.0, and 6.8 solutions in comparison with the active pharmaceutical ingredient (API) and commercial product. To validate the potential for oral administration of the telmisartan/L-PGDS complex in vivo, the pharmacokinetic and pharmacodynamic profiles were assessed in spontaneous hypertensive rats. An animal study revealed that the complex formulation led to a significant improvement of AUC and Cmax as compared with API, and the prolonged pharmacologic effect on blood pressure reduction was comparable with the commercial product. These results, taken together, demonstrate that this novel approach is feasible for the solubilized solid oral formulation and it can be applied to poorly water-soluble drugs to enhance oral bioavailability.
authors.affiliation: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, 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.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizoguchi
authors.affiliation: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nakatsuji
authors.affiliation: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Pharmacokinetics and Nonclinical Safety, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sakamoto
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: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan. Electronic address: inuit@bioinfo.osakafu-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Inui
mesh_terms: D000284:Administration, Oral; D019943:Amino Acid Substitution; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001565:Benzoates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004063:Digestion; D016503:Drug Delivery Systems; D065546:Drug Liberation; D004795:Enzyme Stability; D005079:Excipients / Q000737:chemistry* / Q000378:metabolism; D005240:Feasibility Studies; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008297:Male; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011208:Powders; D011487:Protein Conformation; D011897:Random Allocation; D011918:Rats, Inbred SHR; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D005079:Excipients; D054834:Lipocalins; D050505:Mutant Proteins; D011208:Powders; D011994:Recombinant Proteins; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D000077333:Telmisartan
keywords: Drug-delivery carrier; L-PGDS; Oral absorption; Poorly water-soluble drug; Solubility; Spray drying; Telmisartan (PubChem CID: 65999)