JPH0735332B2 - Cream formulation for external use - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention uses ketotifen (generic name) [chemical name: 4- (1-methyl-4-piperididene) -4H-benzo [4,5] as a medicinal ingredient. Cyclohepta [1,2-b] thiophene-10 (9H)-
ON].

More specifically, antihistamine action and anti-SRS-A action,
It also relates to a cream preparation for external use intended for topical application of ketotifen having a wide range of antiallergic effects.

(B) Conventional technology Ketotifen has excellent antihistamine activity, anti-SRS-A activity and wide-ranging antiallergic activity, and is used for the treatment of diseases such as bronchial asthma and nasal allergy in the form of a salt in which fumaric acid is added to ketotifen. It is an oral drug used as a drug.

Further, as a prior art relating to a cream preparation containing ketotifen and a salt thereof, JP-A-51-32724 discloses a cream preparation comprising an aliphatic alcohol, an anionic surfactant, an amphoteric surfactant and water, and Showa 51-14254
Japanese Patent Publication No. 3 discloses a cream preparation consisting of wax, hydrocarbon and water. However, it goes without saying that these have not been put to practical use yet, and the above-mentioned publicly known documents do not describe anything about the cream preparation of the present invention, nor do they suggest any description thereof.

(C) Problems to be Solved by the Invention Currently, the oral preparations of ketotifen [trade name: Zaditen] which are commercially available have some adverse effects on the nervous system such as drowsiness and malaise, or side effects on the liver. Therefore, it is said that it is necessary to pay particular attention to long-term use. Therefore, the present inventors set out to study the external preparation of this drug for the purpose of reducing the above-mentioned side effects. Furthermore, a known cream preparation containing the drug is (1) heat-stable on the preparation (2) percutaneous absorption (3) feeling of use (stickiness, spread or dryness, etc.) (4) persistence of medicinal effect (5) ) It is difficult to say that a satisfactory external preparation in terms of drug release from the base, etc. Therefore, it is the next object of the present invention to solve this problem. The present inventors presume the cause of the problem of the above-mentioned known cream preparation as follows. That is, it is judged that the cause is due to the cream base itself.

More specifically, since the known cream base uses a base containing a large amount of wax, a higher alcohol, and a hydrocarbon, which are solid at room temperature, long-term storage stability in the preparation, severe conditions at 40 to 70 ° C. It is considered that there are problems in physicochemical heat stability under the following, release of medicinal components from the base, transdermal absorbability, persistence of medicinal effect, and feeling of use. Therefore, various studies were made from the viewpoint of the cream preparations that can satisfy the above requirements (1) to (5). As a result, it was found that the conventional wax component, which is the base component, and the solid hydrocarbons at room temperature were mixed. The present invention has been completed by finding out a new cream formulation having a novel composition.

The present invention is a hydrophilic polymer, a nonionic surfactant,
A cream base consisting of solubilizer, neutralizer and water,
It has a novel composition in which a medicinal ingredient, ketotifen, is added, and overcomes the above-mentioned drawbacks of conventional cream preparations. In particular, it can be argued that the cream preparation of the present invention is a preparation excellent in heat stability remarkably by incorporating a hydrophilic polymer as a base.

The cream preparation of the present invention and the composition thereof are new findings that have not been published in any literature, and have been discovered for the first time as a result of intensive studies by the present inventors.

(D) Means for Solving the Problem The present invention relates to a cream preparation for external use, which comprises ketotifen or a pharmaceutically acceptable salt thereof as a medicinal component in a cream base.

Examples of the pharmaceutically acceptable salt of ketotifen include inorganic salts such as hydrochloride and sulfate, and organic salts such as fumarate, maleate and tartrate.

The pharmacologically acceptable salt of ketotifen or a salt thereof is blended in an amount of 0.01 to 5% by weight in the total amount of the cream preparation. Further, as the cream base used in the external preparation of the present invention, a cream base is selected which can stably maintain the medicinal component in the formulation and which can sufficiently release the medicinal component in transdermal application. The base is a compounding composition characterized by comprising a hydrophilic polymer, a nonionic surfactant, a solubilizing agent, a neutralizing agent and water, and not blending a wax and a solid hydrocarbon at room temperature. Further, as the composition ratio of the present invention, the hydrophilic polymer is 0.1 to 3% by weight,
Nonionic surfactant 0.5-10% by weight, solubilizer 5-4
0.01% of ketotifen as a medicinal component is contained in a cream base consisting of 0% by weight, 0.2 to 3% by weight of a neutralizing agent and 50 to 90% by weight of water.
-5% by weight of the formulation.

Next, the base component of the present invention will be described more specifically.

As the hydrophilic polymer, carboxyvinyl polymer (for example, Carbopol 93 manufactured by Goodrich Chemical Co., Ltd.
4, 940, 941 or Hibis Wako 103 manufactured by Wako Pure Chemical Industries,
104, 105, etc.), hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, carboxymethyl cellulose, polyvinylpyrrolidone methyl cellulose, alginic acid propylene glycol ester, etc., among which carboxyvinyl polymer is most suitable. In addition, these hydrophilic polymers are blended in one or two or more kinds, and the blending amount is 0.1 to 3 in consideration of the conditions such as the consistency and the feeling of use of the cream, or the physical thermal stability. It is preferable that the composition is blended by weight, preferably 0.2 to 1.5 weight%.

As the nonionic surfactant, an ester type nonionic surfactant, for example, sorbitan fatty acid ester, glycerin fatty acid ester, decaglycerin fatty acid ester,
Propylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and the like can be mentioned. Further, examples of the ether-based nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, and polyoxyethylene alkylphenyl ether. These nonionic surfactants are compounded in one or more kinds, and are compounded in such a manner that drug release, feeling of use or emulsification conditions are sufficiently taken into consideration, that is, 0.5 to 10% by weight, preferably 1
~ 5% by weight.

Examples of the solubilizing agent include crotamiton, benzyl alcohol, phenylethyl alcohol, methyl salicylate, glycol salicylate, peppermint oil, l-menthol, and C _{1 to} C ₅ alcohol esters of monocarboxylic acids having C _{4 to} C ₁₄ carbon atoms (for example, , Isopropyl palmitate, isopropyl myristate, etc.), or diesters of C _{1 to} C ₃ alcohols of dicarboxylic acids having ₄ to ₁₀ carbon atoms (for example, diisopropyl adipate, diisopropyl sebacate, etc.), glycerin or propylene glycol mono,
Di- or tri-fatty acid ester (eg, glycerin monocaprate, propylene glycol dicaprate, glycerin tricaprylate, etc.) or higher fatty acid ethanolamide (eg, coconut oil fatty acid diethanolamide, coconut oil fatty acid monoethanolamide, lauric acid monoethanolamide) , Lauric acid diethanolamide,
Myristic acid diethanolamide, myristic acid monoethanolamide, stearic acid diethanolamide, oleic acid diethanolamide, etc.) or higher alcohols (eg, 2-octyldodecanol, oleyl alcohol, 2-hexyldecanol, etc.), or polyhydric alcohols (eg, , Glycerin, propylene glycol, ethylene glycol, 1,3-butylene glycol, etc.), or squalane or liquid paraffin which is liquid at room temperature. These solubilizers are used alone or in combination of two or more kinds, and after taking into consideration the transdermal absorbability of the medicinal ingredient, the thermal stability of the preparation, the feeling of use, the solubility of the medicinal ingredient, etc. 5 to 40% by weight, preferably 10 to 20% by weight.

Neutralizer is 0.2 ~ 3 to adjust the pH value of the cream formulation
It is used within the range of% by weight, and examples thereof include inorganic bases such as potassium hydroxide, sodium hydroxide and aqueous ammonia, and organic bases such as triethylamine, arginine, triethanolamine, triisopropanolamine, diethanolamine and diisopropanolamine. In addition, this neutralizing agent has a pH value near neutral in the cream formulation, that is, a pH value of 5
~ 9, preferably added to adjust to a pH value of 6-8.5, from the viewpoint of stability of the medicinal component in the base, release from the base, transdermal absorption, or skin irritation. It is preferable.

In addition, an antiseptic agent is added if necessary. For example, parabens such as methylparaben, ethylparaben, propylparaben or butylparaben, phenols such as thymol, chlorcresol, orthophenylphenol, isopropylmethylphenol, or pionine are added in an amount of 3% by weight or less. Further, if necessary, an antioxidant such as dibutylhydroxytoluene or dl-α-tocopherol can be added.

Next, an example of the method for producing the cream preparation of the present invention will be described.

To produce the cream preparation of the present invention, first, (A) ketotifen, a solubilizing agent, a nonionic surfactant, or an antiseptic agent is added, and the mixture is heated and dissolved. Meanwhile (B)
The hydrophilic polymer is dissolved in water, the oil phase of (A) is added thereto, and the mixture is emulsified while stirring at an appropriate speed.
A neutralizer-water solution was gradually added to this, and the pH value was adjusted to fall within the range of 5 to 9, and the mixture was stirred so as to obtain a uniform cream formulation. It can be manufactured. Further, in the above-mentioned production method, it can be produced by the reverse method such as adding the aqueous phase of (B) into the oil phase of (A), and the order of the production steps is not particularly limited, It can be manufactured by other methods.

(E) Examples Hereinafter, the present invention will be described more specifically with reference to Examples, but of course the present invention is not limited to these Examples.

Example 1 1 g of ketotifen, 2 g of crotamiton, 10 g of isopropyl myristate, 5 g of oleyl alcohol, 5 g of polyoxyethylene (20) sorbitan monostearate, methylparaben
Add 0.1 g and 0.1 g of propylparaben and heat to 70 ° C to dissolve. Meanwhile, 0.8 g of carboxyvinyl polymer is mixed with 65
dissolve in g. The above oil phase is added to this carboxyvinyl polymer aqueous solution with stirring to emulsify. Next, a solution prepared by dissolving 1 g of diisopropanolamine in 10 g of water was added thereto, and the mixture was stirred until it was uniform to obtain a cream preparation.

Example 2 0.01 g of ketotifen, 2 g of diisopropyl adipate, 3 g of polyoxyethylene (45) monostearate, 10 g of propylene glycol dicaprylate and 5 g of propylene glycol
Add 0.002 g of pionine and heat to 70 ° C to dissolve. On the other hand, 0.8 g of carboxyvinyl polymer is dissolved in 68.2 g of water. The above oil phase is added to this carboxyvinyl polymer aqueous solution with stirring to emulsify. Next, a solution prepared by dissolving 1 g of triethanolamine in 10 g of water was added thereto, and the mixture was stirred until it became uniform to obtain a cream preparation.

Example 3 To 0.1 g of ketotifen, 2 g of diisopropyl adipate, 10 g of isopropyl myristate, 5 g of oleyl alcohol, 5 g of polyoxyethylene (20) sorbitan monostearate and 0.2 g of methylparaben were added and dissolved at 70 ° C. On the other hand, 0.8 g of carboxyvinyl polymer is dissolved in 65.7 g of water. The above oil phase is added to this carboxyvinyl polymer aqueous solution with stirring to emulsify. Next, a solution prepared by dissolving 1.2 g of diisopropanolamine in 10 g of water was added thereto, and the mixture was stirred until it became uniform to obtain a cream preparation.

Example 4 To 0.3 g of ketotifen, 5 g of diisopropyl sebacate, 5 g of propylene glycol dicaprylate, 5 g of 2-octyldodecanol, 3 g of polyoxyethylene (60) hydrogenated castor oil, and 0.1 g of isopropylmethylphenol were added and heated to 70 ° C. Dissolve. On the other hand, carboxyvinyl polymer 0.8g
Is dissolved in 70 g of water. The above oil phase is added to this carboxyvinyl polymer aqueous solution with stirring to emulsify. Next, a solution prepared by dissolving 0.8 g of triethanolamine in 10 g of water was added thereto, and the mixture was stirred until it became uniform to obtain a cream preparation.

Example 5 To 0.01 g of ketotifen, 2 g of benzyl alcohol, 10 g of glycerin tricaprylate, 5 g of propylene glycol and 3 g of polyoxyethylene (20) sorbitan monolaurate were added and dissolved by heating at 70 ° C. On the other hand, 1.3 g of carboxyvinyl polymer is dissolved in 67.7 g of water. The above oil phase is added to this carboxyvinyl polymer aqueous solution with stirring to emulsify. Next, add 1 g of diisopropanolamine to 10 g of water.
The solution dissolved in g was added, and the mixture was stirred until it became uniform to obtain a cream preparation.

Example 6 To 0.1 g of ketotifen, 2 g of crotamiton, 5 g of isopropyl myristate, 3 g of polyoxyethylene (20) sorbitan monostearate, 5 g of squalane, 0.18 g of methylparaben and 0.02 g of propylparaben are added and dissolved by heating at 70 ° C. Meanwhile, 0.7 g of carboxyvinyl polymer is 73 g of water.
Dissolve in. The above oil phase is added to this carboxyvinyl polymer aqueous solution with stirring to emulsify. Next, a solution prepared by dissolving 1 g of triisopropanolamine in 10 g of water was added thereto, and the mixture was stirred until it became uniform to obtain a cream preparation.

Example 7 0.5 g of ketotifen, 3 g of crotamiton, 5 g of diisopropyl sebacate, and polyoxyethylene (23) cetyl ether 2
Add g and 0.2 g of methylparaben and heat to 70 ° C to dissolve. On the other hand, 0.6 g of carboxyvinyl polymer is added to water of 77.6
dissolve in g. This carboxyvinyl polymer aqueous solution is added to the above oil phase while stirring and emulsified. Next, a solution prepared by dissolving 1.1 g of diisopropanolamine in 10 g of water was added thereto, and the mixture was stirred until it became uniform to obtain a cream preparation.

Example 8 0.5 g of carboxyvinyl polymer is dissolved in 47.6 g of water.
A solution of 0.7 g of diisopropanolamine dissolved in 10 g of water is added to this carboxyvinyl polymer aqueous solution, and the mixture is stirred. On the other hand, 3 g of ketotifen, 3 g of crotamiton, 10 g of isopropyl myristate, 2-hexyldecanol 4 g, 1,3-
Add 15 g of butylene glycol, 6 g of polyoxyethylene (20) sorbitan monostearate and 0.2 g of methylparaben, and dissolve by heating to 70 ° C. This oil phase was added to the above aqueous phase while stirring, and further stirred until uniform to obtain a cream preparation.

Reference Example 1 63 g of wool wax and 15 g of liquid paraffin were heated to 75 ° C. and dissolved. On the other hand, 0.006 g of ketotifen fumarate in water
22 g was added and heated to 75 ° C. to dissolve. Next, the aqueous phase was added to the above oil phase with stirring to emulsify, and the mixture was cooled to room temperature with stirring to obtain a cream preparation.

Test Example 1 Thermal Stability Test [Experimental Method]: 3 g of the cream preparation drug of Example 1 and Reference Example 1 was filled in a 4 ml transparent sample bottle, tightly stoppered, and stored in a thermostat at 60 ° C. to observe appearance changes.

[Experimental results]: Table 1 shows the appearance changes when the cream preparations of Example 1 and Reference Example 1 were stored at 60 ° C.

As is clear from the above test results, it was found that the cream preparation of the present invention has very excellent thermal stability over a long period of time.

Test Example 2 Percutaneous Absorption Test [Test Method] Male Wistar rats (5-week-old, body weight 110 to 125 g) were set to 4 per group, and 90 mg of the cream preparation prepared in Example 1 and Reference Example 1 was placed on the back of the shaved back. It was applied, covered with aluminum foil and fixed with tape. The rat wears a neck shackle,
Each animal was housed in a cage.

0.5, 1, 2, 4, 6, 8, 8 and 12 hours after the application, blood was collected by cutting the femoral artery and vein and centrifuged at 3000 rpm to obtain serum. The content of ketotifen in this serum was quantified by liquid chromatography.

The results are shown in Table 2.

As is clear from the above results, the cream preparation of the present invention showed higher blood concentration than the cream preparation of Reference Example.

This sufficiently suggests that the cream preparation of the present invention has excellent ketotifen release and transdermal absorbability.

(F) Actions / Effects of the Invention The cream preparation of the present invention has the best physicochemical stability of the preparation itself, especially the heat stability, and the releasability of the medicinal component from the base is remarkable. Moreover, since the hydrophilic polymer used as the base has the ability to form a film, it exerts the effect of a sealing therapy (ODT therapy) on the site of use, transferring the medicinal ingredient to the skin, that is, transdermal absorption. It has a useful effect as an external preparation such as remarkably promoting the effect. Furthermore, this formulation spreads well on the skin, and
It is also non-greasy, has a quick-drying effect, and is extremely excellent in use. In addition, since the pH value of this formulation is adjusted to around neutral, it also has the effect that the medicinal components are sufficiently released from the base without causing skin irritation, and that transdermal absorption can be expected sufficiently. It is a thing.

Further, since the percutaneous absorbability of the medicinal component is very excellent in this preparation, remarkable pharmacological action and therapeutic effect can be expected sufficiently.

In addition, this preparation can be used locally on the human body such as skin, oral cavity, nasal cavity, and rectum, and has gastrointestinal allergy, urticaria, atopic dermatitis, rhinitis, bronchial asthma, hay fever,
It is medically useful as a local or systemic therapeutic agent for allergic diseases such as eczema and pruritus dermatitis, and has the effect of remarkably reducing various side effects of the oral preparation.

 ─────────────────────────────────────────────────── --- Continuation of the front page (56) Reference JP-A-51-32724 (JP, A) JP-A-51-142543 (JP, A) JP-A-58-185514 (JP, A) JP-A-54- 119024 (JP, A)

Claims (4)

[Claims] 1. A ketotifen or a salt thereof as an active ingredient, a hydrophilic polymer as a base, a nonionic surfactant, a solubilizer, a neutralizing agent and water, and a wax and a solid hydrocarbon at room temperature. A cream for external use characterized by not doing. 2. The external cream preparation according to claim 1, wherein the hydrophilic polymer is a carboxyvinyl polymer. 3. The method according to claim 1, further comprising one or more of methylparaben, ethylparaben, propylparaben, butylparaben, isopropylmethylphenol, or pionine. The external cream preparation described in. 4. Ketotifen or a salt thereof as an active ingredient.
0.01-5 wt%, hydrophilic polymer 0.1-3 wt% as a base, nonionic surfactant 0.5-10 wt%, solubilizer 5-40 wt%, neutralizing agent 0.2-3 wt% and water 50 The external cream preparation according to any one of claims 1, 2 and 3, which is a composition consisting of ˜90% by weight.