title: Solid dispersions of efonidipine hydrochloride ethanolate with improved physicochemical and pharmacokinetic properties prepared with microwave treatment.
abstract: Drug absorption into the body is known to be greatly affected by the solubility of the drug itself. The active pharmaceutical ingredient efonidipine hydrochloride ethanolate (NZ-105) is a novel 1,4-dihydropyridine calcium antagonist that has a very low solubility in water. It is classified as a poorly soluble drug, and improvements in its solubility and higher bioavailability with oral administration are needed. In this study, employing microwave technology as a new means to improve solubility, we established a method for preparing solid dispersions using hydroxypropyl methylcellulose acetate succinate as a polymeric carrier and urea as a third component. This effective method has a treatment time of several minutes (simple) and does not require the use of organic solvents (low environmental impact). The third component, urea, acts to lower the melting point of NZ-105, which promotes amorphization. This greatly improves the solubility compared with the microwave-treated product of NZ-105/HPMC-AS binary system. The solid dispersion prepared with this method, in addition to evaluation in vitro, was tested in vivo using beagle dogs and shown to be effective from the eightfold improvement in absorption compared with NZ-105 alone based on the area under the curve.
authors.affiliation: Analysis Research Department, Nissan Chemical Industries, Ltd., 2-10-1 Tsuboi-nishi, Funabashi, Chiba 274-8507, Japan. Electronic address: otsukam@nissanchem.co.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Otsuka
authors.affiliation: Analysis Research Department, Nissan Chemical Industries, Ltd., 2-10-1 Tsuboi-nishi, Funabashi, Chiba 274-8507, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Maeno
authors.affiliation: Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fukami
authors.affiliation: Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Aichi 467-8603, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tagami
authors.affiliation: Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Aichi 467-8603, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ozeki
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002152:Calorimetry, Differential Scanning; D004095:Dihydropyridines / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D006358:Hot Temperature; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D008872:Microwaves; D009596:Nitrophenols / Q000737:chemistry* / Q000493:pharmacokinetics; D009930:Organic Chemicals; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D014508:Urea / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D004095:Dihydropyridines; D004337:Drug Carriers; D009596:Nitrophenols; D009930:Organic Chemicals; D009943:Organophosphorus Compounds; D012997:Solvents; C066425:efonidipine; C048331:hydroxypropylmethylcellulose acetate succinate; C038806:1,4-dihydropyridine; D014508:Urea; D008747:Methylcellulose
keywords: Efonidipine (PubChem CID: 119171); Efonidipine hydrochloride ethanolate (PubChem CID: 163838); Fusing agent; Microwave irradiation; NZ-105; Solid dispersion; Solubility improvement; Urea