标题：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
摘要：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 coground 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, pharamacological 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.
