Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-05-17
2001-07-17
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C424S449000
Reexamination Certificate
active
06262121
ABSTRACT:
TECHNICAL FIELD
The present invention relates to external oil patches containing diclofenac sodium which hardly show skin irritation and which do not decrease of release of the said drug.
BACKGROUND ART
Diclofenac sodium is sold as non-steroidal anti-inflamatoric antipyretic analgesics in the form of tablets, capsules or suppositories for the purpose of systemic action. When diclofenac sodium is orally administered, side effects on the stomach, such as stomach unpleasant feelings, occur. To reduce such side effects, therefore, preparations for transdermal absorption of diclofenac sodium have been studied.
Because diclofenac sodium hardly dissolves in water and an oil base, external preparations containing diclofenac sodium are prepared in the state of dispersion of diclofenac sodium. However, transdermal absorption of diclofenac sodium is not good in the state of dispersion preparations. Accordingly, techniques to dissolve diclofenac sodium in external preparations by additives have been developed.
There are, for instance, known external preparations, such as oil ointments characterized in using propylene glycol etc. as a solubilizing agent in order to solve the problem on insolubility of diclofenac sodium in an oil base (Japanese Patent Publication No. 59-33211), gel preparations characterized in using a definite amount of an alcohol, considering that diclofenac sodium dissolves well in an alcohol (Japanese Patent Publication No. 59-76013), emulsion preparations characterized in using a fatty acid and a carboxylic acid dialkyl ester (Japanese Patent Publication No. 64-13020).
Furthermore, following preparations are proposed: poultices characterized in using ethanol/water as a solvent, poultices characterized in using an alkylene glycol having 3 to 4 carbon atoms as a solvent with maintaining moisture (Japanese Patent Publication No. 61-60608), patches containing styrene-isoprene-styrene block copolymer and crotamiton (Japanese Patent Publication No. 4-321624), preparations for transdermal administration characterized in using a base consisting of a fatty acid ester, an alcohol and water (Japanese Patent Publication No. 6-321771), transdermal preparations containing urea or sodium edetate (Japanese Patent Publication No. 6-48939) and so on.
DISCLOSURE OF INVENTION
In the above oil ointments, solubility of diclofenac sodium is improved, but its transdermal absorption is not necessarily satisfied.
In case of the above gel preparations, it is difficult to control the amount of administration of diclofenac sodium and it is necessary to wrap with a bandage and the like, due to being afraid of adhesion on clothes and it is troublesome. Furthermore, in case of preparations in which an alcohol is used, diclofenac sodium is crystallized owing to volatility of the alcohol and by contacting skin with the alcohol for a long term, there is a possibility to cause skin irritation.
In the above emulsion preparations, it is difficult to control the amount of administration of diclofenac sodium and there is afraid of adhesion on clothes as in the gel preparations. Further, regarding a surfactant for emulsification, depending on its amount in the preparations or its kind, there is a possibility of occurrence of skin irritation.
In case of the above poultices, owing to using ethanol there is afraid of generation of crystals of diclofenac sodium and skin irritation as in the above gel preparations. In case of using an alkylene glycol, transdermal absorption of diclofenac sodium is not necessarily satisfied. In case of the above patches containing styrene-isoprene-styrene block copolymer and crotamiton, solubility of diclorofenac sodium is improved, but they are not necessarily satisfied.
In case of the above preparations for transdermal administration containing a fatty acid ester, an alcohol and water, there is a possibility of occurrence of skin irritation owing to using the alcohol.
The above preparations containing urea or sodium edetate are creams and therefore, it is difficult to control the amount of the drug.
Furthermore, in order to improve transdermal absorption of diclofenac sodium, it is tried to combine a fatty acid, such as oleic acid, linoleic acid, linolenic acid, etc. in diclofenac sodium and make the fatty acid capture sodium ion to produce the free acid and as a result to improve transdermal absorption of diclofenac sodium. However, because in this case, sodium salt of the fatty acid is produced at the same time, there is a possibility to cause skin irritation by its salt.
As mentioned above, regarding to known external preparations containing diclofenac sodium, there is a problem on its transdermal absorption and even if the problem is solved, there is still another problem on skin irritation.
Therefore, it has been desired to develop external preparations without skin irritation in which diclofenac sodium is effectively percutaneously absorbed.
The present inventors engaged in extensively in solving above problems, and found to make external oil patches containing diclofenac sodium which show hardly irritation to skin without decrease of release of the said drug by combining a fatty acid having 10 to 18 carbon atoms which is liquid at ordinary temperature and isostearic acid in an adhesive.
More specifically, diclofenac sodium is dissolved in a mixture (oil base) of isostearic acid, a fatty acid having 10 to 18 carbon atoms which is liquid at ordinary temperature and a liquid oil, such as crotamiton, diethyl sebacate, isopropyl myristate, etc., and the resulting solution (drug solution) is admixed in a solution of styrene-isoprene-styrene block copolymer (abbreviated as SIS) and a tackifier resin, and then the mixture is spread on the silicon treated liner and after drying, is stuck on the soft backing to prepare transdermal patches, which patches have excellent adhesiveness and drug release and show hardly skin irritation. Thus, the present invention was completed.
The present invention was explained more in detail as follows.
The amount of diclofenac sodium which is a main ingredient of the patches related to the present invention (it may be abbreviated as the drug) is 0.5 to 6% by weight per total adhesive base material, preferably 2 to 5%, and more preferably 2.5 to 4.5%. In case of less than 0.5%, owing to the less of the drug release, the effect of the drug is not expected. On the other hand, in case of beyond 6%, it becomes hardly to dissolve the drug in the preparation. Either case is not preferable.
The amount of the oil base is 8 to 30% by weight per total adhesive base material, preferably 10 to 25% and more preferably 17 to 22%. In case of less than 8%, release of the drug from the preparation is not enough and the effect of the drug is not expected. On the other hand, in case of beyond 30%, adhesive power especially decreases and therefore, it is impossible to adhere to the skin for long hours.
The ratio of a fatty acid and a liquid oil, such as crotamiton, isopropyl myristate, etc. which are used as an oil base is preferably 1:2 to 2:1.
Examples of fatty acids having 10 to 18 carbon atoms which are liquid at ordinary temperature used in the patches of the present invention are capric acid, 2-undecylenic acid, 10-undecylenic acid, undecylic acid, trans-2-dodecenic acid, 2-hexyl decanoic acid, licinolic acid, linolenic acid, oleic acid, cis-6-octadecenoic acid, linoleic acid, petroselinic acid, etc., preferably capric acid, oleic acid, linoleic acid, linolenic acid and more preferably oleic acid and linolenic acid.
The ratio of isostearic acid and a fatty acid having 10 to 18 carbon atoms which is liquid at ordinary temperature is 8:2 to 4:6, preferably 15:5 to 9:11, and more preferably 7:3 to 5:5. In case of beyond 80% in the amount of isostearic acid, it is impossible to dissolve the drug and release of the drug from the preparation become less. Therefore, it is not preferable. On the other hand, in case of beyond 60% in the amount of a liquid fatty acid, skin irritation on application occurs and therefore, it is not also preferable.
The amount of the mixture of
Kawaji Toshikuni
Yamaji Masahiro
Birch & Stewart Kolasch & Birch, LLP
Jarvis William R. A.
Kim Vickie
Teikoku Seiyaku Co., Ltd.
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