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.

Q4 · MEDICINE

Article

Author: Osawa, Takashi ; Takashima, Kohki ; Kubo, Hiroaki ; Mizobe, Masakazu

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.

01 Jun 1994·AtherosclerosisQ2 · MEDICINE

The hypocholesterolemic action of TA-7552 and its effects on cholesterol metabolism in the rat

Q2 · MEDICINE

Article

Author: Takeo Kohno ; Shigeyuki Takeyama ; Akio Ohtani ; Kazuyuki Hirakoso ; Kohki Takashima ; Tetsuji Mori

The hypocholesterolemic property of 1-(3,4-dimethoxyphenyl)-2,3- bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene (TA-7552) and its effects on cholesterol metabolism were investigated in the rat. TA-7552 incorporated into a hypercholesterolemic diet at a concentration of 0.2% and administered for 7 days reduced serum cholesterol by 72% and liver cholesterol by 90%, and its minimal effective dose was 0.01% in the diet. Its hypocholesterolemic effect was associated with an elevation of serum HDL-cholesterol. Inclusion of 0.1% TA-7552 in the normal laboratory chow accelerated fecal excretion of 14C derived from orally administered 4-[14C]cholesterol or carbonyl-[14C]taurocholate. The net amounts of fecal neutral sterols and bile acids were markedly increased by the same treatment. Hepatic bile acid production and hepatic and intestinal cholesterol biosynthesis as measured by cholesterol 7 alpha-hydroxylase activity and 1-[14C]acetate incorporation into tissue cholesterol, respectively, were both stimulated by the drug treatment. All these data indicate that this hypocholesterolemic agent inhibits intestinal absorption of both cholesterol and bile acids and compensatorily stimulates hepatic production of bile acids and cholesterol.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypercholesterolemia	Phase 2	JP	Mitsubishi Tanabe Pharma Corp.	-

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