JPS62164624A - Gel preparation for external use - Google Patents

Abstract

PURPOSE:A gel preparation for external use that is obtained by allowing the gel base to include ketotifen or its salt as an active ingredient. CONSTITUTION:The gel base is composed of 5-60wt% of a lower alcohol such as ethanol, 3-45wt% of a polyhydric alcohol such as glycerol or propylene glycol, 0.1-5wt% of a solubilizer such as crotamiton or benzyl alcohol, 30-60wt% of water, 0.1-5wt% of a gelling agent of hydrophilic polymer such as a carboxyvinyl polymer and 0.1-5.0wt% of a neutralizer such as inorganic base, e.g., sodium or potassium hydroxide. The gel base is combined with 0.01-5.0wt% of ketotifen as an active ingredient to give the objective gel preparation for external use with increase percutaneous absorption. The preparation has suitably 5-9, preferably 6-8pH. Ketotifen has antihistamic, anti-SRS-A and antiallergic actions and may be combined with an antioxidant, when needed, in the preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Industrial application field The present invention uses ketotifen (-ship name) [chemical name: 4-(1-methyl-4-piveridylidene)-4H-] as a medicinal ingredient.
The present invention relates to an external gel preparation containing benzo(4,5)cyclohepta (1<2-b]thiophene-10(9H)-one).

More specifically, the present invention relates to an external gel preparation intended for topical application of ketotifen, which has antihistamine and anti-5R3-A effects as well as a wide range of antiallergic effects.

(b) Conventional technology Ketotifen has excellent antihistamine action and anti-5R3-A
It is an oral drug that has a wide range of antiallergic effects and is used as a therapeutic agent for diseases such as bronchial asthma and nasal allergies in the form of a salt obtained by adding fumaric acid to ketotifen.

Also, JP-A-51-32724 and JP-A-51
JP-A-142543 describes cream preparations and spray preparations containing ketotifen. However, it goes without saying that these have not yet been put to practical use, and the above-mentioned known documents do not describe anything regarding the gel preparation of the present invention, nor do they contain any description that suggests it.

(c) Problems to be solved by the invention The oral formulation of ketotifen [trade name: Sagiten] currently on the market has been shown to cause side effects on the nervous system such as drowsiness and fatigue, and side effects on the liver. is,
It is said that particular care must be taken when taking the drug for a long period of time. Therefore, the present inventors began research into an external preparation of this drug with the aim of alleviating the above-mentioned side effects.

Furthermore, the known cream formulation containing this drug has the following characteristics: (1) transdermal absorption, (n) thermal stability of the formulation, (I[r) feeling of use, (rV) solubility of the medicinal ingredient, and (V) Since it is difficult to say that this is a satisfactory external preparation in terms of sustainability of drug efficacy, (VI) drug release from the base, etc., the next object of the present invention is to solve these problems. The causes of the problems with the above-mentioned known cream formulations are speculated by the present inventors as follows.

In other words, the physicochemical properties of ketotyphen, which is a medicinal ingredient,
In other words, because it is not easily soluble in water and organic solvent systems, it exists in an incompletely dissolved form in the base, and the medicinal ingredients are not sufficiently released from the base and absorbed through the skin. .

Therefore, in order to promote the transdermal absorption of ketotifen, which has poor transdermal absorption, various studies were conducted from the viewpoint of formulation, and it was found that by making it into a gel formulation, an external preparation with reduced side effects could be obtained. , and further the above (I) to (V
The present invention was completed based on the discovery that an external preparation can be obtained that satisfies the requirements of item I). The ketotifen-containing gel preparation of the present invention and its composition are completely new findings that have not been published in any literature, and were discovered for the first time as a result of intensive research by the present inventors.

(d). For fortune-telling.

The present invention relates to a gel preparation for external use, which contains 0.01 to 5.0% by weight of ketotifen or a pharmaceutically acceptable salt thereof as a medicinal ingredient in a gel base.

Pharmaceutically acceptable salts of ketotifen include, for example, inorganic salts such as hydrochloride and sulfate, and fumarate.

Examples include organic salts such as maleic acid and tartrate.

Ketotifen or a pharmaceutically acceptable salt thereof is blended in an amount of 0.01 to 5.0% by weight based on the weight of the gel formulation. In addition, as the gel base used in the external preparation of the present invention, a gel base is selected that can stably retain the medicinal ingredient in terms of formulation and can sufficiently release the medicinal ingredient when applied transdermally, It is a formulated composition consisting of lower alcohol, polyhydric alcohol, solubilizer, water, gelling agent and neutralizing agent.

Next, the formulation of the present invention will be explained in detail. A preferred formulation of the present invention is that the gel base contains 5 to 5 lower alcohols.
60% by weight, polyhydric alcohol 3-45% by weight, solubilizing agent 0.1-25% by weight, water 30-60% by weight, gelling agent 0.1-5% by weight, and neutralizing agent 0.1-5%. The composition is 0.0% by weight, and 0.01 to 5.0% by weight of ketotifen, which is a medicinal ingredient, is blended therein. In addition, the pH value of this type agent is 5 to 9, preferably 6 to 8,
It is appropriate to do so.

Next, the base component of the present invention will be explained in more detail.

Specific examples of the lower alcohol include ethanol, propatool, isopropanol, etc. Among them, ethanol is the most preferable, and its final concentration is 5 to 6.
It is blended in an amount of 0% by weight, preferably 10 to 50% by weight.

Examples of polyhydric alcohols include glycerin, 1-propylene glycol, ethylene glycol, 1,3-phthylene gelicol, and triethylene glycol.

Examples include polyethylene glycol, but glycerin, propylene glycol and 1,3-butylene glycol are preferred. These have a final concentration of 3 to 45% by weight,
Preferably, the purpose is achieved by blending 5 to 40% by weight.

As a solubilizing agent, specifically crotamiton.

Benzyl alcohol, benzoic acid, salicylic acid, methyl salicylate, glycol salicylate, peppermint oil, l-menthol, lower alcohol esters with a carbon number of CI to C1 of monocarboxylic acids with a carbon number of 04 to CI4, such as isopropyl palmitate, isopropyl myristate, etc. , or carbon number CI of dicarboxylic acid with carbon number 04 to C3°
diesters of C3 alcohols, such as diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, etc., or esters of mono-, di- or tricarboxylic acids of glycerin or propylene glycol, such as glyceryl monocaprate, glyceryl capriate, propylene glycol capriate, Glycerin tricaprate, etc., higher alcohols such as 2-octyldodecanol, 2-hexyldecanol, etc., Eisin (trade name), urea, etc. are used. These solubilizers have a final concentration of O, 1 to 25% by weight.
, preferably 0.5 to 20% by weight, to promote transdermal absorption of medicinal ingredients.

Gelling agents include lower alcohols and wood-philic polymers that gel in water systems, such as carboxyvinyl polymers, hydroxypropylene, and cellulose.

Hydroxyethyl cellulose, polyvinyl alcohol,
Examples include carboxymethyl cellulose, alginate propylene glycol ester, and the like.

These gelling agents may be used alone or in combination of two or more to give a final concentration of 0.1 to 5, preferably 0.3.
It is preferable to mix up to 3% by weight.

The neutralizing agent is used in a range of 0.1 to 5% by weight to neutralize the gelling agent, and examples of the neutralizing agent include inorganic bases such as potassium hydroxide, sodium hydroxide, and aqueous ammonia; Examples include organic bases such as triethylamine, arginine, triethanolamine, triisopropanolamine, jetanolamine, and diisopropanolamine, and it is particularly preferable to use an organic base in the present invention. In addition, this neutralizing agent has a pH value of the entire gel preparation near neutrality, that is, a PTT value of 5 to 9, preferably a pH value of 6 to 8.
From the viewpoint of transdermal absorption of the medicinal ingredients, it is most preferable to add the medicinal ingredients so that the amount of the medicinal ingredients is set at

In addition to these base components, nonionic surfactants such as polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene alkyl ether, and dibutyl hydroxytoluene may be added as necessary. Antioxidants such as di-α-tocopherol can be added.

Next, an example of the method for producing the external gel preparation of the present invention will be explained.

To produce the gel preparation of the present invention, ketotifen is dissolved in a lower alcohol, a solubilizing agent and a polyhydric alcohol are added thereto, an aqueous solution of a gelling agent is added and stirred, and then a neutralizing agent is added to this. Add the solution dissolved in water, p
The gel preparation of the present invention can be produced by adjusting the H value to 5 to 9 and stirring until a uniform gel preparation is obtained.

] 1" mouth 1 square Example 1 Add 40 g of ethanol to 1 g of ketotifen and dissolve.

15 g of propylene glycol and 3 g of diisopropyl adipate are added to this solution and stirred. Next, add 1.1 g of carboxyvinyl polymer to this solution and add 29.4 g of water.
Add the solution dissolved in g and stir. Next, a solution of 1.5 g of diisopropanolamine dissolved in 10 g of water was added to this and stirred until the mixture became homogeneous to obtain a gel preparation.

Example 2 A solution of 0.7 g of carboxyvinyl polymer dissolved in 30.29 g of water is added to a solution of 35 g of ethanol, 10 g of propylene glycol, and 3 g of diisopropyl sebacate, and the mixture is stirred. A solution of 1 g of diisopropanolamine dissolved in 5 g of water is added to this solution and stirred. Next, a solution of 0.01 g of ketotifen fumarate dissolved in 15 g of water was added to the mixture and stirred until the mixture became homogeneous to obtain a gel preparation.

Example 3 Add 35g of ethanol to 0.01g of ketotifen? Understand. 10 g of propylene glycol and 2 g of diisopropyl adipate are added to this solution and stirred. Add 0.8 g of carboxyvinyl polymer to this solution and 41.1 g of water.
Add the solution dissolved in 9 g and stir. Next, a solution of 1 g of diisopropanolamine dissolved in 10 g of water was added to the mixture and stirred until the mixture became homogeneous to obtain a gel preparation.

Example 4 Add 40 g of ethanol to 0.1 g of ketotifen and dissolve. 10 g of glycerin and 3 g of diisopropyl adipate are added to this solution and stirred. A solution of 0.8 g of carboxyvinyl polymer dissolved in 35 g of water is added to this solution and stirred. Next, add 1. diisopropanolamine to this.
1g to 10g of water? The dissolved solution was added and stirred until homogeneous to obtain a gel formulation.

Example 5 Ketotifen 0.3g and ethanol 40g and 1.3g
- Add and dissolve 15 g of butylene glycol and 5 g of oleyl alcohol. A solution of 0.8 g of carboxyvinyl polymer in 27.8 g of water was added to this solution and stirred. Next, add 1. diisopropanolamine to this.
A solution of 1 g dissolved in water Log was added and stirred until homogeneous to obtain a gel preparation.

Example 6 Ketotiphen 2g ethanol 35g 1 crotamiton 2
g and 10 g of 1,3-butylene glycol were added and dissolved. Add 1 g of carboxyvinyl polymer to this solution and 3 ml of water.
Add the solution dissolved in 9 g and stir. Next, a solution of 1 g of diisopropanolamine dissolved in Log of water was added to this and stirred until it became homogeneous to obtain a gel preparation.

Example 7 35 g of ethanol, 15 g of propylene glycol, and 2 g of glycerin caprylate are added and dissolved in 1 g of ketotifen. Add 1g of carboxyvinyl polymer to this solution.
Add a solution of 34.5 g of water and stir. Next, a solution of 1.5 g of triethanolamine dissolved in 10 g of water was added to this and stirred until it became homogeneous to obtain a gel preparation.

Example 8 35 g of ethanol is added to 1 g of ketotifen and dissolved. A solution of hydroxypropyl cellulose in 15 g of propylene glycol was added to this solution and stirred. Next, a solution of 4 g of diisopropyl adipate and 1 g of carboxyvinyl polymer dissolved in 31.5 g of water is added to this solution and stirred. A solution of 1.5 g of diisopropanolamine dissolved in Log of water was added to this and stirred until homogeneous to obtain a gel preparation.

Example 9 1 g of carboxyvinyl polymer to 2 2 parts of water 7. A solution of 1.5 g of diisopropanolamine dissolved in 10 g of water was added to the solution to form a gel. Next, 3 g of ketotifen was added to 40 g of ethanol, polyoxyethylene (6
0) 2 g and l hydrogenated castor oil.

It was dissolved in 15 g of 3-butylene glycol, and this solution was added to the previous gel and stirred until it became homogeneous to obtain a gel preparation.

Reference example 1 63g of wool wax and 15g of liquid paraffin at 75℃
It was heated to dissolve. On the other hand, ketotifen fumarate 0
．． 21.994 g of water was added to 006 g and heated to 75°C. Next, the aqueous phase was added to the oil phase while stirring, and then emulsified with a homogenizer, and cooled to room temperature while stirring to obtain a cream formulation.

Reference Example 2 Lauryl lactate 1 9. 5 g, 2-hexyldecanol 8 g, 1,2-propylene glycol 3 g, 2-ethylcaproic acid cetyl ester and isopropyl myristate 2 g, 3 g polyethylene glycol stearate DAB? and 3 g of colloidal magnesium aluminum silicate were dissolved in Example 5 g of ketotiphen with heating to 40°C, and 15 g of fatty acid amidopropyl-dimethylaminoacetic acid betaine (average chain length of fatty acid groups - 14 carbon atoms) was added to this solution. A solution dissolved in 46 g of water was added, emulsified using a homogenizer, and then cooled to room temperature to obtain a cream formulation.

Test Example 1 Thermal Stability Test The gel formulation of the present invention and the cream formulation of Reference Example 1 were heated at 60°C.
Table 1 shows the changes in appearance when stored.

Table 1: Thermal Stability Test under Storage Conditions at 60° C. As is clear from the above results, the gel formulation of the present invention was found to have much better thermal stability than the cream formulation of the reference example.

Test Example 2 Percutaneous absorption test [Test method] Wistar male rats (5 weeks old, body weight 115-125
A group of 4 animals (g) was prepared, and 90 μg of the gel preparation prepared in Example 1 was applied to the shaved backs of the animals, which was then covered with aluminum foil and fixed with tape. The rats were shackled and housed one by one in a breeding cage. After application 0.5.2.4.6.
After 8 hours, blood was collected by cutting the femoral artery and vein, and the blood was collected for 3000 r.
Serum was obtained by centrifugation at pm. The content of ketotiphen in this serum was determined by liquid chromatography.

The results are shown in Table 2.

Table 2 As is clear from the above results, the gel formulation of the present invention showed a higher blood concentration than the cream formulation of the reference example. This sufficiently suggests the release and transdermal absorbability of ketotifen from the gel base.

(f) Actions and Effects of the Invention The gel preparation of the present invention can be used locally on the skin, oral cavity, nasal cavity, rectum, etc. of the human body, and can be used to treat gastrointestinal allergies,
It is medically useful as a local or systemic therapeutic agent for allergic diseases such as swine measles, atopic dermatitis, rhinitis, bronchial asthma, hay fever, eczema, and skin pruritus, and it also has an oral formulation. It has the effect of being completely free of various side effects.

Furthermore, the gel preparation of the present invention has excellent effects on physicochemical stability, thermal stability of the medicinal ingredient in the base, and release of the medicinal ingredient from the base. Since the polymer inside forms a film, it produces a sealing therapeutic effect on the site of use, giving good results in promoting transdermal absorption, etc. Furthermore, since the formulation of the present invention volatilizes immediately after application, it provides a refreshing feeling to the skin and has the effect of being a non-sticky formulation that is pleasant to use. or,
The gel preparation of the present invention has very good transdermal absorption of medicinal ingredients and can be expected to have significant pharmacological effects.

Furthermore, since the pH value of the formulation of the present invention is adjusted to 5 to 9, it also has the effect of promoting transdermal absorption without irritating the skin and other areas of use. Furthermore,
As is clear from the test results of Test Examples 1 and 2, the gel formulation of the present invention has superior thermal stability compared to known cream formulations, and is particularly superior in release of medicinal ingredients from the gel base and transdermal absorption. This shows the effect that

Procedural amendment 0. ) April 14, 1986 Commissioner of the Patent Office Kuro 1) Akio Tono 421
, Indication of the case 1985 Patent Application No. 7641 2 Name of the invention Topical gel preparation 3 Person making the amendment 4 Date of amendment order Voluntary (1) In the description, "3. Detailed description of the invention" In the column 9th line from the top of page 5, the phrase "in the weight of the gel preparation" is corrected to "in the total weight of the gel preparation."

(2) In the same book, from the 6th line to the 8th line from directly above No. 16, the phrase ``applying Wistar male rats...'' was replaced with ``Wistar male rats (5 unions, weight 115
~125 g) were made into a group of 4 animals, and 90 cm of the gel preparation prepared in Example 1 and Reference Examples 1 and 2 was applied to the shaved backs of the animals.

Claims (2)

[Claims] (1) Ketotifen or its salt 0.0 as a medicinal ingredient
An external gel preparation containing 1 to 5% by weight in a gel base. (2) 5 to 60% by weight of lower alcohol as a gel base;
Polyhydric alcohol 3-45% by weight, solubilizer 0.1-2
5% by weight of water, 30-60% by weight of water, 0.1-5% by weight of gelling agent and 0.1-5% by weight of neutralizing agent, according to claim 1. .