title: Inhibition mechanism of hydroxypropyl methylcellulose acetate succinate on drug crystallization in gastrointestinal fluid and drug permeability from a supersaturated solution.
abstract: The effects of drug-crystallization inhibitor in bile acid/lipid micelles solution on drug permeation was evaluated during the drug crystallization process. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was used as a drug-crystallization inhibitor, which efficiently suppressed dexamethasone (DEX) crystallization in a gastrointestinal fluid model containing sodium taurocholate (NaTC) and egg-phosphatidylcholine (egg-PC). Changes of molecular state of supersaturated DEX during the DEX crystallization process was monitored in real time using proton nuclear magnetic resonance (1H NMR). It revealed that DEX distribution to bulk water and micellar phases formed by NaTC and egg-PC was not changed during the DEX crystallization process even in the presence of HPMC-AS. DEX permeation during DEX crystallization was evaluated using dissolution/permeability system. The combination of crystallization inhibition by HPMC-AS and micellar encapsulation by NaTC and egg-PC led to considerably higher DEX concentrations and improvement of DEX permeation at the beginning of the DEX crystallization process. Crystallization inhibition by HPMC-AS can efficiently work even in the micellar solution, where NaTC/egg-PC micelles encapsulates some DEX. It was concluded that a crystallization inhibitor contributed to improvement of permeation of a poorly water-soluble drug in gastrointestinal fluid.
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan; Research Fellow of Japan Society for the Promotion of Science, Japan.
authors: Keisuke
authors: K
authors: Ueda
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Kenjirou
authors: K
authors: Higashi
authors: Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors: Makoto
authors: M
authors: Kataoka
authors: Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors: Shinji
authors: S
authors: Yamashita
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Keiji
authors: K
authors: Yamamoto
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. Electronic address: moribe@faculty.chiba-u.jp.
authors: Kunikazu
authors: K
authors: Moribe
mesh_terms: D018938:Caco-2 Cells; D003460:Crystallization; D003907:Dexamethasone / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007419:Intestinal Secretions / Q000737:chemistry*; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D010539:Permeability; D012996:Solutions
chemical_list: D012996:Solutions; C048331:hydroxypropylmethylcellulose acetate succinate; D003907:Dexamethasone; D008747:Methylcellulose
keywords: Caco-2 monolayer; Crystallization inhibition; Dissolution/permeation system; HPMC-AS; Supersaturated solution