Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-19
2004-04-20
Spivack, Phyllis (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06723732
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a percutaneously administrable preparation containing a cerebral function activator, specifically, a percutaneously administrable preparation containing an imidazopyridine derivative as a cerebral function activator.
BACKGROUND ART
A compound of the formula (I):
wherein R is optionally substituted aryl or optionally substituted heteroaryl, A ring is a 5- to 9-membered alicyclic group which may contain one or more of O, S, SO, SO
2
and/or NR
1
wherein R
1
is hydrogen, alkyl, esterified carboxy, carbamoyl or acyl, and which may be substituted with alkyl, pharmaceutically acceptable salt or hydrate thereof (hereinafter referred to as Compound (I)) is described in JP 5-286973 A and known to be useful as a psychotropic agent, an antianxiety agent, a narcotic antagonist and a cerebral function activator.
It has been reported that a pharmaceutical activity of a cerebral function activator was enhanced by being administered in a sustained release depot form (European Journal of Pharmacology, 271, 357-366, 1994), but it is not known that the effect of the cerebral function activator can be prolonged by being administered in a percutaneously administrable preparation.
The drug absorption rate from skin is generally slower than that at mucous membrane such as gastrointestinal tract etc., and a large number of studies have been conducted on absorption enhancing agents in order to increase the percutaneous absorption. Absorption enhancing agents, such as DMSO, various surface active agents, 1-dodecylazacycloheptan-2-one, fatty acids, terpenes, alcohols, and mixtures (e.g., 1-menthol-ethanol-water, lactic acid-ethanol-isopropyl myristate and the like), have been studied (Fragrance Journal 1996(4), 17-25). In these studies, however, a preparation containing a cerebral function activator or a condensed imidazopyridine derivative as an active ingredient has not been investigated.
DISCLOSURE OF INVENTION
An object of the present invention is to provide a percutaneously administrable preparation which contains a cerebral function activator, specifically, a condensed imidazopyridine derivative as an active ingredient and which can sustain an effective blood concentration and the efficacy of the active ingredient by suppressing an extreme raise of the blood concentration after the administration.
The present invention relates to
1) a percutaneously administrable preparation, which comprises either an aqueous base comprising 1-menthol, a lower alcohol and an acidic buffer or water, or an oily base comprising 1-menthol, a lower alcohol and isopropyl myristate, and a cerebral function activator therein,
2) the percutaneously administrable preparation described in 1) wherein the cerebral function activator is a compound of the formula (I):
wherein R is optionally substituted aryl or optionally substituted heteroaryl and A ring is a 5- to 9-membered alicyclic group which may contain one or more of O, S, SO, SO
2
and/or NR
1
wherein R
1
is hydrogen, alkyl, esterified carboxy, carbamoyl or acyl, and which may be substituted with alkyl, pharmaceutically acceptable salt or hydrate thereof,
3) the percutaneously administrable preparation described in 1) or 2) wherein the cerebral function activator is 2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine, pharmaceutically acceptable salt or hydrate thereof,
4) the percutaneously administrable preparation described in 3) wherein the cerebral function activator is 2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine phosphate or hydrate thereof,
5) the percutaneously administrable preparation described in 1) to 4) wherein the percentage of 1-menthol to all amount of the base is 1 to 3.5% by weight,
6) the percutaneously administrable preparation described in 1) to 5) wherein the percentage of the lower alcohol to all amount of the base is 10 to 35% by weight,
7) the percutaneously administrable preparation described in 1) to 6) wherein the lower alcohol is a lower alcohol having 1 to 3 carbon atoms,
8) the percutaneously administrable preparation described in 1) to 7) wherein the lower alcohol is ethanol,
9) the percutaneously administrable preparation described in 1) to 8) wherein the percentage of the acidic buffer, water or isopropyl myristate to all amount of the base is 55 to 90% by weight,
10) the percutaneously administrable preparation described in 1) to 9) wherein pH of the acidic buffer is 2 to 6,
11) the percutaneously administrable preparation described in 1) to 10) wherein the acidic buffer is a phosphate buffer,
12) the percutaneously administrable preparation described in 1) to 4), wherein each percentage to all amount of the base: 1-menthol is 2 to 3% by weight, ethanol is 15 to 35% by weight, the phosphate buffer, water or isopropyl myristate is 60 to 80% by weight, and pH of the acidic buffer is 3 to 5, and
13) the percutaneously administrable preparation described in 1) to 12) comprising 1 to 25 mg of the cerebral function activator per 1 g of the base.
An orally administrable preparation generally tends to lack the sustained efficacy due to the extreme raise of blood concentration. A preparation of the present invention overcomes such a problem and has the following advantages. The percutaneously administrable preparation of the present invention can reduce individual differences of the blood concentration by avoiding the hepatic first-pass effect. The preparation shows a continuously pharmacological efficacy because the plasma concentration of the active ingredient can be kept constant for a long duration by the sustained release to whole body blood circulation. Further, the preparation scarcely causes side effects, e.g., a gastrointestinal injury which often occurs upon oral administration.
REFERENCES:
patent: 5378848 (1995-01-01), Takada et al.
patent: 480054 (1992-04-01), None
patent: 556008 (1993-08-01), None
patent: 581587 (1994-02-01), None
patent: 682942 (1995-11-01), None
patent: 5-25046 (1993-02-01), None
Miyamoto et al., European Journal of Pharmacology, 271, pp. 357-366 (1994).
Sugibayashi et al., Fragrance Journal 1996-4, pp. 17-25.
Morimoto et al., International Journal of Pharmaceutics, 91, pp. 9-14 (1993).
Wada et al., Biol. Pharm. Bull. 16(6), pp. 600-603 (1993).
Nishihara Yoshitaka
Sugita Katsuji
Yoshikawa Takayoshi
Shionogi & Co. Ltd.
Spivack Phyllis
Wenderoth Lind & Ponack LLP
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