Enhancement of oral bioavailability and pharmacological effect of 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8- trimethoxynaphthalene (TA-7552), a new hypocholesterolemic agent, by micronization in co-ground mixture with D-mannitol.
To improve the bioavailability of the sparingly water-soluble drug, 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8- trimethoxynaphthalene (TA-7552), the usefulness of the co-grinding method with D-mannitol was investigated. The co-grinding was performed at various weight ratios of TA-7552 and D-mannitol using a ball mill. The particle size was markedly reduced with increasing amount of D-mannitol. A mixture ratio greater than or equal to 1:3 of the drug and D-mannitol produced submicron-sized particles. In dogs, bioavailability increased with increasing amount of D-mannitol. The 1:9 co-ground mixture gave complete absorption, as did a lecithin solution of the drug. Even co-ground powders with lower amounts of D-mannitol provided relatively high bioavailability in comparison with ground drug powder alone of a similar particle size. Further, pharmacological examination using rats indicated that the inhibition of cholesterol absorption was intestified with the reduction of particle size. These findings suggest that the co-grinding method with D-mannitol is useful for enhancing the bioavailability and pharmacological effectiveness of this sparingly water-soluble drug.
Kubo
H
H
Pharmaceutics Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Osawa
T
T
Takashima
K
K
Mizobe
M
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D004285:Dogs; D007408:Intestinal Absorption; D008297:Male; D008353:Mannitol / Q000737:chemistry / Q000494:pharmacology*; D009284:Naphthols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles; D011208:Powders; D012995:Solubility
D000924:Anticholesteremic Agents; D009284:Naphthols; D014677:Pharmaceutical Vehicles; D011208:Powders; C090176:TA 7552; D008353:Mannitol