Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ortho-hydroxybenzoic acid or derivative doai
Reexamination Certificate
1999-04-26
2001-07-31
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ortho-hydroxybenzoic acid or derivative doai
C514S546000, C514S547000, C514S557000
Reexamination Certificate
active
06268355
ABSTRACT:
DESCRIPTION
A stable external preparation containing Aspirin
TECHNICAL FIELD
The present invention relates to a stable external preparation containing Aspirin (acetyl salicylic acid).
More specifically, the present invention relates to a technique to store stably an external preparation containing Aspirin for a long term which is characterized in mixing Aspirin together with at least one substance selected from an ester of an organic acid having 2 to 20 carbon atoms, a glycerol fatty acid ester, silicon oil, hydrocarbon oil and crotamiton.
BACKGROUND ART
Aspirin has been used as an anti-inflammatoric antipyretic analgesics from of old. It is in general orally administered in form of tablets, granules and so on.
However, due to the intestinal injury by Aspirin, its external application has been recently studied. The results are reported in Japanese Patent Pub. No. 3-72426, in Japanese Patent Pub. No. 6-72879, in Japanese Patent Pub. 6-183980, in Japanese Patent Pub. No. (Tokuhyo Hei) 9-503755, etc.
These techniques are; one which makes weight on transdermal absorption and does not take care of stability of Aspirin; one which secures stability of Aspirin for a short term, but was not necessarily satisfied for a long term stability; a method characterized in patches to be consumed once and very difficult to apply to preparations consisting of a pack which are often opened and closed, for example creams, solutions, etc.; such a case as in application to preparations, such as ointments, due to the presence of crystals the feeling on use is extremely bad and there is irritation by roughness and therefore, it is very difficult to apply to the region of injured skin like heat injuries. There are many points to be improved in these techniques.
Furthermore, there are disclosed techniques of patches containing Aspirin in Japanese Patent Pub. Nos. 8-104624, 8-104625 and 8-113531, but there are not disclosed techniques to stabilize Aspirin in the patches for a long term.
The literatures which describe methods for stabilization of Aspirin in preparations except for external preparations, are Japanese Patent Pub. No.
56-32425
, Japanese Patent Pub. No.
62-89619
, Japanese Patent Pub. No.
4-346930
and so on.
Because Aspirin is readily hydrolyzed even in the presence of small amount of water and furthermore, by depending on a kind of additives the hydrolysis is accelerated, in these literatures in order to avoid to contact with the additive, it is disclosed to use the protective layer consisting of sucrose, or to use binders in which water was excluded as much as possible and to add a hydrogenated oil as a lubricant. However, it is hardly possible to apply such a technique to external preparations. For example, it is very difficult to make a protective layer between Aspirin and a base in ointments.
As such, in external preparations of Aspirin, the technique to avoid water to the possible extent in preparations and store in the package in which water is eliminated as much as possible in order to secure stability of Aspirin in preparing external preparations are found, but the technique to be applied to all external preparations and to secure the satisfied stability has not been shown.
DISCLOSURE OF INVENTION
The present invention was made in considering of the above problems and the object of the present invention is to provide an external preparation containing Aspirin which is superior in stability and transdermal absorption and can be stored for a long term.
That is, by mixing Aspirin together with at least one substance selected from an ester of an organic acid having 2 to 20 carbon atoms, a glycerol fatty acid ester, silicon oil and hydrocarbon oil, it was found to solve the above problems and thus, the present invention was completed.
The amount of Aspirin as an active ingredient in an external preparation of the present invention is 0.001 to 30% by weight per total amount, preferably 0.01 to 20% by weight, more preferably 0.05 to 15% by weight. In case of more than 30% by weight of Aspirin, it causes hydrolysis of Aspirin due to increase of stabilization effect by the stabilizing agent. On the other hand, in case of less than 0.001 percent by weight of Aspirin it is hardly to exhibit the pharmacological activities of Aspirin. Each case is not preferable.
The stabilizing agents of the present invention are selected from substances having ability to dissolve Aspirin, too and for example, an ester of an organic acid having 2 to 20 carbon atoms, a glycerol fatty acid ester, silicon oil, hydrocarbon oil and crotamiton are used, and in general one substance or more selected from them are used.
Examples of the organic acids of esters of organic acids having 2 to 20 carbon atoms are myristic acid, lauric acid, oleic acid, sebacic acid, palmitic acid, caprylic acid, isooctanoic acid, stearic acid, isostearic acid, acetic acid, propionic acid, isopalmitic acid, undecylic acid, linoleic acid, linolenic acid, adipic acid, salicylic acid, benzoic acid, lactic acid, caproic acid, eicosanic acid, etc., preferably myristic acid, oleic acid, sebacic acid, palmitic acid, isooctanoic acid, isostearic acid and adipic acid, more preferably myristic acid, oleic acid, sebacic acid and adipic acid. Examples of the esters of the organic acids are esters with an aliphatic monoalcohol, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, hexyl ester, octyl ester, decyl ester, cetyl ester, isocetyl ester, stearyl ester, isostearyl ester, oleyl ester, etc.
Examples of the glycerol fatty acid esters are a plant oil, such as soy bean oil, almond oil, sesame oil, olive oil, camellia oil, corn oil, coconuts oil, etc., an animal oil, such as whale oil, lard, beef tallow, lever oil, etc., triacetin(glycerol triacetate), a middle chain-fatty acid triglyceride, glycerol triisooctanoate, etc., preferably soy bean oil, almond oil, sesame oil, triacetin, a middle chain-fatty acid triglyceride and glycerol triisooctanoate, more preferably soy bean oil, almond oil and a middle chain-fatty acid triglyceride.
Examples of the hydrocarbon oils are liquid paraffin, squalane, squalene, etc., preferably liquid paraffin and squalane.
The stabilizing agents of the present invention do not only stabilize Aspirin, but also dissolve Aspirin. Therefore, in mixing the stabilizing agent in external preparations, it has enhancing effect of absorption of Aspirin from skin and it is very preferable.
The amount of the stabilizing agent is preferably 0.1 to 20 times as much as the amount of Aspirin, more preferably 0.5 to 15 times. In case of less than 0.1 time, Aspirin can not dissolve thoroughly and as a result, transdermal absorption enhancing activity is prohibited. On the other hand in case of more than 20 times irritation against skin etc. occurs. The amount of the stabilizing agent per total weight depends on form of the preparations, but is preferably 0.01 to 50% by weight. When using the stabilizing agent more than 50% by weight in plasters it is difficult to keep their form, and in cataplasms or creams the separation from hydrophilic substances etc. and skin irritation occur and it is not desirable. In case of less than 0.01% by weight especially in the preparation in which water is added, it is difficult to secure stability of Aspirin.
In order to avoid hydrolysis of Aspirin to the possible extent in the preparation of the present invention, it should be taken care for water contents. For example it is desirable not to add water, or even in case of addition of water the amount of water per total weight is desirably less than 10%, more desirably less than 5%. Within this range the stabilization effect of Aspirin by the stabilizing agent is exhibited and it is possible to avoid hydrolysis of Aspirin. When the amount of water to be added is beyond 10% by weight, the stabilization effect of Aspirin by the stabilization agent is not exhibited enough and hydrolysis of Aspirin is accelerated and therefore, it is not desirable. Kinds of the preparations containing Aspirin of the present invention are not limited if
Hasegawa Yuichi
Hisaichi Shin-ichi
Kawada Mitsuhiro
Mizobuchi Noriko
Birch & Stewart Kolasch & Birch, LLP
Teikoku Seiyaku Co., Ltd.
Weddington Kevin E.
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