Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-29
2001-03-13
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S372000
Reexamination Certificate
active
06201009
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to an absorption-enhancing composition for a pantothenic acid derivative, which comprises a pantothenic acid derivative represented by the following general formula (I), a neutral or alcoholic ester, and a nonionic surfactant:
wherein
R
1
and R
2
are the same or different and each independently represents a hydrogen atom or a hydroxyl-protective group or R
1
and R
2
together represent a hydroxyl-protective group;
R
3
represents a saturated or unsaturated, linear, branched or cyclic C
5-25
monovalent aliphatic hydrocarbon group optionally substituted by an aromatic group, or an amino group represented by the formula —N(R
4
)R
5
(wherein R
4
represents a saturated or unsaturated, linear, branched or cyclic C
3-25
monovalent aliphatic hydrocarbon group; and R
5
represents a hydrogen atom or a saturated or unsaturated, linear, branched or cyclic monovalent aliphatic hydrocarbon group optionally substituted by an aromatic group);
A represents a saturated or unsaturated, linear, branched or cyclic C
2-16
divalent aliphatic hydrocarbon group, divalent aromatic hydrocarbon group or divalent heteroaryl group optionally substituted by an aromatic group;
one of X and Y represents an amino group represented by the formula —N(R
6
)— while the other represents —O—, —S— or an amino group represented by the formula —N(R
7
)— (wherein R
6
and R
7
represent each a hydrogen atom or a lower alkyl group); and
n is an integer of from 1 to 4.
BACKGROUND ART
The pantothenic acid derivatives represented by the above general formula (I) were found out as compounds having an inhibitory effect on acyl CoA-cholesterol-acyltransferase (ACAT) (JP-A-3-218340; the term “JP-A” as used herein means an “unexamined published Japanese patent application”). It is known that ACAT is contained in a large amount in intracellular microsomes in the liver and small intestine and participates in the intestinal absorption of cholesterol and the accumulation of cholesterol ester in cells. Accordingly, it is expected that compounds capable of inhibiting ACAT are usable as drugs having a blood lipid-lowering effect as well as an antiarteriosclerotic effect.
It has been confirmed that the pantothenic acid derivatives represented by the above general formula (I) have excellent inhibitory effect on ACAT. When orally administered, however, these compounds are scarcely absorbed via the digestive tracts and thus fail to establish any satisfactory effects.
Therefore, it has been required to develop compositions whereby the absorbability of the pantothenic acid derivatives represented by the above general formula (I) in vivo can be elevated and thus the bioavailability thereof can be improved. It has been also required to prepare the thus produced compositions into preparations in which the active compounds contained therein can be stabilized and stored over a long period of time.
SUMMARY OF THE INVENTION
The present inventors have conducted extensive studies to solve the above-mentioned problems. As a result, they have successfully found out that the pantothenic acid derivatives represented by the above general formula (I) can be improved in absorbability in vivo and can be stored over a long period of time by preparing compositions containing these pantothenic acid derivatives together with a neutral or alcoholic ester and a nonionic surfactant, thus completing the present invention.
Accordingly, the present invention provides absorption-enhancing compositions for pantothenic acid derivatives represented by the above general formula (I) prepared by dissolving the pantothenic acid derivative of the general formula (I) in a neutral or alcoholic ester or a solvent mixture thereof (i.e., a carbonic acid diester, an oxy-acid ester or a mixture thereof) and adding thereto a nonionic surfactant or a mixture thereof, thus enlarging the application range of the compound as a drug.
DETAILED DESCRIPTION OF THE INVENTION
Examples of the neutral or alcoholic ester to be used in the present invention include carbonic acid diesters and oxy-acid esters. The neutral or alcoholic ester can be used in an amount of 0.05 parts by weight or above, preferably from 0.1 to 40.0 parts by weight and still preferably 0.5 to 10.0 parts by weight, per 1 part by weight of the pantothenic acid derivative represented by the general formula (I). Either one of these neutral or alcoholic esters or a mixture thereof may be used in the present invention.
The carbonic acid diesters as described above have been employed as cosmetic components or, in the field of medicines, as solvents, plasticizers or gelling agents in oral preparations, general preparations for external use and preparations to be administered to the oral cavity. They may be classified into linear diesters and cyclic diesters. Examples of the linear diesters include dimethyl carbonate, diethyl carbonate and diisopropyl carbonate, while examples of the cyclic diesters include ethylene carbonate, propylene carbonate, etc. Either one of these esters or a mixture thereof may be employed. These carbonates or cyclic diesters are commercially available or can be easily obtained.
The oxy-acid esters to be used in the present invention have been employed as plasticizers for film-coating compositions for oral preparations in the field of medicines. Examples of these esters include triethyl citrate and tributyl citrate. Either one of these esters or a mixture thereof may be employed.
The nonionic surfactants to be used in the present invention have been commonly employed as emulsifiers, dispersants, etc. in the field of medicines. They may be classified into the ether type, the ether ester type, the ester type and the nitrogen-containing type. These nonionic surfactants can be used in an amount of from 0.5 to 50 parts by weight, preferably from 1 to 25 parts by weight, per 1 part by weight of the pantothenic acid derivative represented by the above general formula (I). Either one of these nonionic surfactants or a mixture thereof may be employed.
The nonionic surfactants of the ether type as described above can be further classified into, for example, polyoxyethylene alkyl ethers, polyoxyethylene alkyl aryl ethers, etc. The nonionic surfactants of the ether ester type as described above can be further classified into, for example, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, etc. The nonionic surfactants of the ester type as described above can be further classified into, for example, sorbitan fatty acid esters, propylene glycol fatty acid esters, ethylene glycol fatty acid esters, ester glycerin fatty acid esters, etc. The nonionic surfactants of the nitrogen-containing type as described above can be further classified into, for example, polyoxyethylene fatty acid amides, polyoxyethylene alkylamines, etc.
Examples of the polyoxyethylene alkyl ethers include polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, etc. Examples of the polyoxyethylene alkyl aryl ethers include polyoxyethylene nonylphenyl ether, etc. Examples of the polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, etc. Examples of the polyoxyethylene glycerin fatty acid esters include polyoxyethylene glycerin monostearate, polyoxyethylene glycerin triisostearate, etc. Examples of the hardened castor oil derivatives include polyoxyethylene-hardened castor oil 40, polyoxyethylene-hardened castor oil 50, polyoxyethylene-hardened castor oil 60, etc. Examples of the sorbitan fatty acid esters include polyoxyethylene fatty acid esters, sorbitan trioleate, sorbitan monooleate, sorbitan monostearate, sorbitan monocaprylate, etc. Examples of the propylene glycol fatty acid esters include propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monoisooctanoate, propylene glycol diisooctanoate, propylene glycol dicaprylate, etc. Examples of the ethylene
Hagiuda Miwako
Ozaki Masahiro
Watanabe Daiichi
Arent Fox Kintner & Plotkin & Kahn, PLLC
Fujirebio Inc.
Lambkin Deborah C.
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