title: Applicability of DPI formulations for novel neurokinin receptor antagonist.
abstract: A novel triple neurokinin receptor antagonist (TNRA) could have pharmaceutical efficacy for asthma and/or chronic obstructive pulmonary disease. TNRA is potentially developed as inhalation medicine. The aim of this investigation was to evaluate the applicability of dry powder inhaler (DPI) formulation for TNRA. DPI formulation containing lactose was used for this feasibility study. Mechanofusion process for surface modification was applied on lactose particles to prepare four different DPI formulations. The mixture of TNRA and lactose was administered to rats intratracheally using an insufflator. The deposition pattern and blood concentration profile of TNRA were evaluated. Although there was no significant difference in deposition on deep lungs between the four formulations, DPI formulations containing mechanofusion-processed lactose showed longer T(max) and t(1/2) and higher AUC(0-infinity) and MRT compared to that containing intact lactose. On the other hand, the contact angle measurement showed that the mechanofusion process decreased the polar part of the surface energy of the lactose. Therefore, the prolongation of the wetting of the formulated powder mixture seemed to delay the dissolution of TNRA deposited in respiratory tract. It was concluded that DPI formulation containing mechanofusion-processed lactose could be suitable for inhalation of TNRA.
authors.affiliation: Formulation Technology Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. kumon.michiko.c8@daiichisankyo.co.jp
authors.forename: M
authors.initials: M
authors.lastname: Kumon
authors.forename: Y
authors.initials: Y
authors.lastname: Yabe
authors.forename: Y
authors.initials: Y
authors.lastname: Kasuya
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: A
authors.initials: A
authors.lastname: Kusai
authors.forename: E
authors.initials: E
authors.lastname: Yonemochi
authors.forename: K
authors.initials: K
authors.lastname: Terada
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical; D003499:Cyclic S-Oxides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D005079:Excipients / Q000737:chemistry*; D006207:Half-Life; D007785:Lactose / Q000737:chemistry; D008297:Male; D009025:Morpholines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D009330:Nebulizers and Vaporizers; D011208:Powders; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*
chemical_list: C530698:1-(2-(2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl)ethyl)spiro(benzo(c)thiophene-1(3H),4'-piperidine)-2-oxide; D003499:Cyclic S-Oxides; D005079:Excipients; D009025:Morpholines; D011208:Powders; D018041:Receptors, Neurokinin-2; D007785:Lactose