Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1999-07-29
2001-01-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S449000, C424S447000, C564S041000
Reexamination Certificate
active
06174543
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an antidiabetic external skin application composition and, more specifically relates to an antidiabetic external skin application composition containing glibenclamide formulated therein.
2. Description of the Related Art
Glibenclamide is a sulfonylurea type oral hypoglycemic drug developed by cooperative study of Boehringer Mannheim and Hoechst in 1966 and is now commercially available in the field of drugs in the form of tablets (Trade name: Euglucon tablet available from Yamanouchi Seiyaku K. K., Japan, Trade name: Daonil available from Japan Hoechst). Such tablets containing, as an effective ingredient, glibenclamide formulated therein are conventionally used because they provide a strong hypoglycemic action at a small dosage, as described in, for example, Arzneim Forsch, vol. 19(8a), 1363-1368 (1969); Therapiewoche, vol. 18, 11-20 (1968).
Nevertheless, the tablet containing, as an effective ingredient, glibenclamide formulated therein is a powerful drug, as described in, for example, the attached statement of the powers of Euglucon tablet (Yamanouchi Seiyaku K. K.) that, since the tablet sometimes causes, as a side effect, a significant and prolonged hypoglycemia, the dosage regimen should be specially attentioned. Furthermore, since numbers of diabetes mellitus of aged people are recently increasing, as pointed out in, for example, Gekkan Yakuji (Japanese), Vol. 31, No. 4, 663-667 (1989), the dosage is especially important in the administration of the oral hypoglycemic drug to aged people.
In order to reduce the danger of the side effect as mentioned above, it is convenient that, if the tablet can be made in the form of a percutaneously absorbable external skin treatment agent (or ointment), the application amount can be easily adjusted and, in addition, even if rapid hypoglycemic action occurs, the agent can be easily washed out, for example, and therefore, the danger can be avoided. As the form of drug other than the oral administration type tablets, the application type external skin treatment agent (e.g., ointment) is known in the art (e.g., JP-A-4-18023, JP-A-3-86828). However, because of the characteristics of glibenclamide mentioned below, the prior application type external skin treatment agents have not been satisfied from the viewpoints of stability and percutaneous absorbability.
Namely, since glibenclamide is not soluble in most of solvents, it is very difficult to prepare the external skin treatment type agent thereof. Furthermore, although it is known in the art that glibenclamide is soluble in dimethylsulfoxide, it is not usable in the form of the dimethylsulfoxide solution from the viewpoint of safety. Thus, although the external skin, application type agent is desired, it has not been yet developed from the practical point of view.
SUMMARY OF THE INVENTION
Accordingly, the objects of the present invention are to eliminate the above-mentioned problems of the prior art and to provide an antidiabetic external skin application composition capable of containing the effective ingredient, glibenclamide, formulated in the dissolved form and having excellent percutaneous absorption and stability.
The present inventors have found, as a result of the extensive study, that benzyl alcohol has an excellent solubility for glibenclamide and both benzyl alcohol and glibenclamide can be formulated to obtain the desired antidiabetic external skin application composition. The stability and the solubility are generally inconsistent with each other and, when the solubility is increased, the stability generally or often is decreased. However, benzyl alcohol has especially excellent solving power for glibenclamide, among the other various solvents, and provides good stability when compared with the use of the other solvents. Thus, the present invention has been completed based upon these findings.
In accordance with the present invention, there is provided an antidiabetic external skin application composition comprising glibenclamide and benzyl alcohol.
In the present invention, the composition is most stable when the pH thereof is within the range of 8-10 and preferably contains a nonionic surfactant to improve the stability.
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Bander et al. “Zur Pharmakologie von HB 419, enem neuen, start wirksmen oralen Antifiabeticum”, Arzneim Forsch, vol. 19(8a), pp. 1363-1368, 1969.
K. Schoffling, “Stand der Therapie mit Sulfonylharnstoffen und Biguaniden”, Therapiewoche, vol. 18, pp. 11-20 1968.
Gekkan Yakuji (Japanese), vol. 31, No. 4, pp.663-667 (1989).
T. Yamamoto et al., “Topical application of the hypoglycemic agent glibenclamide and changes in blood glucose, plasma insulin (IRI) levels and plasma concentration of glibenclamide in normal rats”, Diabetes Resrch. & Clinical Practice, 8, pp. 19-22 (1990).
N.M. Sanghavi et al., “Solubilization of Glibenclamide with B-Cycodextrin G its Derivatives”, Drug Dev. & Indus. Pharm. 20(7), pp. 1275-1283.
Takahashi et al., “Trial for Transdermal Administration of Sulfonylureas”, Yakugaku Zasshi, 117 (12), pp. 1022-1027 1997.
El-Massik et al, “Development of a dissolution medium for glibenclamide”, Inter'l J. of Pharm. 140, pp.69-76.
Kanayama Toshiji
Kiyota Yuko
Matsui Rakan
Nakashima Masaya
Foley & Lardner
McQueeney P. E.
Page Thurman K.
Shiseido Company Ltd.
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