JPH01102024A - External remedy for skin disease - Google Patents

Abstract

PURPOSE:To obtain an external remedy for skin diseases directly applicable to affected sites, having excellent action with a small amount free from skin irritation and systemic side effects, containing a salt of ketotifen, a fat-soluble basic substance and a glycol. CONSTITUTION:A salt of ketotifen (e.g. ketotifen fumarate) is dissolved in a glycol (e.g. propylene glycol), a fat-soluble basic substance (e.g. alkylamine) is added to the prepared amine, which is optionally mixed with another additive and stirred to give the aimed substance. This external remedy for skin diseases contains 0.01-5wt.% salt of ketotifen, 0.008-15wt.% fat-soluble basic substance and 3-90wt.% glycol. The remedy is preferably prepared into a dosage form such as ointment or solution. The remedy is effective for humid tetter, dermatitis, urticaria, atopic dermatitis and insect bite and further has inhibitory action on liberation of chemical mediator of ketotifen and anti-histamine action.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides ketotifen (chemical name: 4-, (1-methyl-4-piperizidene')-4H-benzo[4°5]cyclohebuta(1 ,2-b]thiophene-10(9H)-
This is an ointment or liquid preparation containing a salt of 100% of the skin, and is used externally as a therapeutic agent for skin diseases.

More specifically, it is a topical skin disease treatment agent that has almost no skin irritation and can be applied directly to skin disease areas, has no systemic side effects, and can exhibit excellent therapeutic effects with a small amount. It is related to.

[Conventional technology]

External agents currently used for the treatment of skin diseases are broadly classified into steroids, nonsteroids, and antihistamines. However, for allergic diseases such as atopic dermatitis, there are currently no external preparations that are fully satisfactory in terms of therapeutic efficacy and action.

On the other hand, one of the oral drugs effective for allergic diseases is ketotifen. Ketotifen was developed by Sandoz, Switzerland, and has an anti-allergic effect based on its effect of inhibiting the release of chemical mediators such as histamine and 5R3-A. Ketotifen fumarate (chemical name: 4-(1-methyl-4-piperizidene)-4H-benzoC4,5)cyclohepta(1,2-b)thiophene-10(9H)-
Hydrogen fumarate) has been confirmed to be useful in treating bronchial asthma, allergic rhinitis, eczema, dermatitis, hives, etc. in various countries since 1978, and is commercially available as tablets and syrup.

[Problem that the invention seeks to solve]

However, when ketotifen is orally administered, side effects on the neuropsychiatric system, such as drowsiness, and side effects on the gastrointestinal tract and liver are observed. This is a problem considering that this drug is taken prophylactically for a long period of time and is also administered to children. Additionally, orally administered drugs generally have the disadvantage that it is difficult to maintain a constant effect due to fluctuations in gastrointestinal absorption in the recipient.

Therefore, in order to avoid these disadvantages caused by oral administration, preparations have been proposed in which drugs are administered transdermally to reduce systemic side effects.

For example, creams made of microemulsions (British Patent Publication No. 2098865A), examples containing them in reservoirs made of hydrophilic polymers (Japanese Patent Publication No. 61-501)
324 Publication) and an example of blending as a gel agent (Japanese Unexamined Patent Publication No. 6
2-164624) is known. However,
In these cases, although the administration site is different, ketotifen is distributed throughout the body via the blood, which is the same as in oral preparations, and it is questionable whether systemic side effects can be completely avoided.

As mentioned above, preparations are known that are administered transdermally and, like oral preparations, exhibit effects by being distributed throughout the body. However, there are no known therapeutic agents that exert efficacy only locally on skin diseases when administered transdermally. Furthermore, it has not been elucidated whether the antiallergic effect of ketotifen, which is based on its effect of inhibiting the release of various chemical mediators, is exerted locally on the skin.

In addition, in skin diseases, unlike in healthy skin, the selection of a base for external preparations is also important. For example, in the case of a disease that produces a lot of secretions, emulsion bases such as creams cannot be used because the secretions from the inflamed area will be reabsorbed, worsening the lesion and spreading to various parts of the body. In addition, formulations that contain a large amount of surfactants (Japanese Unexamined Patent Publication No. 51-32724, British Patent Publication No. 2098865A) or preservatives may cause secondary irritation or allergens, which is a problem. be. Furthermore, surfactants may interact with ketotifen, which is undesirable from the viewpoint of drug stability.

Furthermore, preparations containing acetone, lower alcohols, etc. to increase transdermal absorption are highly irritating, worsen symptoms on wet and erosive surfaces, and cannot be used on areas with skin diseases. On the other hand, ointments using oily bases are said to have excellent skin protection effects and cause very little irritation or rash. However, ointments using oleaginous bases are generally considered to have inferior percutaneous absorption compared to emulsion bases, gel bases, etc.
Particularly in cases of skin diseases such as thickened and mossy lesions, it is difficult to put into practical use formulations with poor absorption.

Regarding improving the transdermal absorption of ketotifen,
- In Publication No. 164624, the pif value of the gel agent is 5
~9 is considered appropriate. However, the gel's p
The H value is usually in this range, and the publication does not describe any test examples or reasons why this pH is preferable for transdermal absorption of ketotifen.

As mentioned above, with conventional technology, drug absorption and safety (
There is no known formulation that is both hypoallergenic.

SUMMARY OF THE INVENTION An object of the present invention is to provide a topical skin disease treatment agent that is less irritating to the skin, has excellent transdermal absorption, and exhibits the medicinal efficacy of ketotifen in localized areas where skin If relapse occurs.

The present inventors have made extensive studies to achieve the above objective,
Various studies were conducted focusing on the pharmacological effects of ketotifen on skin diseases.

As a result, the salt of ketotifen was dissolved in glycols,
A preparation that is easy to prepare by mixing with an external base containing a basic substance to form an ointment or liquid formulation, does not contain water or lower alcohol, and has little skin irritation, and can be administered directly to the diseased area as a base. I found that.

Recent research has revealed the involvement of contact allergy in atopic dermatitis based on its clinical and histological images, and topical products with skin protective effects have been used to prevent allergens from entering through the skin surface. The usefulness of the agent is great.

Furthermore, by adding a fat-soluble basic substance as a release improving agent, it becomes a topical preparation with good release properties from the base, and transdermal administration of this preparation can suppress the release of various chemical mediators of ketotifen. The anti-allergic and anti-histamine effects are exerted locally on the skin,
As a result, systemic side effects can be avoided, and by administering directly to the diseased area, it acts directly on the allergen that causes the skin disease, compared to indirect administration such as oral administration or systemic transdermal administration. Excellent effects can be obtained with a smaller amount, and it also has a strong direct antagonistic effect against released histamine, so it is effective against local itching on the skin such as insect bites, for which conventional oral preparations have been insufficiently effective. The present invention was completed based on the discovery that it is also effective.

[Means for solving problems]

The present invention relates to an external skin disease therapeutic agent containing a ketotifen salt, a fat-soluble basic substance, and glycols.

Examples of the salt of ketotifen used in the present invention include inorganic salts of ketotifen, such as hydrochloride, and organic salts such as fumarate and citrate, with ketotifen fumarate being preferred.

The content of the ketotifen salt is suitably 0.01 to 5% by weight, preferably 0.1 to 1%, based on the total weight of the therapeutic agent of the present invention.

As the fat-soluble basic substance, the following structural formula (I) or (I
t) (In the formula, R8 and R2 are hydrogen, an alkyl group having 1 to 20 carbon atoms, or a hydroxyalkyl group having 1 to 6 carbon atoms, and R5 is an alkyl group having 1 to 20 carbon atoms or a hydroxyalkyl group having 1 to 6 carbon atoms.
is a phenyl group substituted with a hydroxyalkyl group or an alkyloxycarbonyl group having 1 to 6 carbon atoms, and R
1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and
is a carbon atom, an oxygen atom, a nitrogen atom, or a carbon number of 1 to 6
is a nitrogen atom substituted with an alkyl group, and m and n are integers of 1 to 3).

Examples of the organic amine include alkylamines such as ethylamine, diisopropylamine, di(2-ethylhexyl)amine, triethylamine, stearylamine, dimethyloctylamine, dimethylaminoethanol,
Examples include alkanolamines such as diisopropanolamine and triethanolamine, cyclic amines such as piperidine, piperidine, morpholine, and N-methylpiperidine, and aniline derivatives such as ethyl aminobenzoate and butyl aminobenzoate. These fat-soluble basic substances are known compounds, and may be used alone or in combination of two or more.

The content of the fat-soluble basic substance may be any amount necessary to approximately neutralize the acidic substance forming the salt with ketotifen, and for example, the content is preferably 0.8 to 3 times the amount of the ketotifetin salt; ~2 times the amount is suitable. The blending amount is 0.
0.008 to 15% by weight, preferably 0.01 to 10%, more preferably 0.01 to 5%.

In addition, if the fat-soluble basic substance is added in excess of the above,
It may have an adverse effect on the pH balance of the skin surface, which is naturally weakly acidic, and may cause skin irritation.

In the external preparation of ketotifen of the present invention, the fat-soluble basic substance is a glycol which is thought to have the effect of increasing the amount of the base of ketotifen in the preparation, as well as the effect of increasing the release of ketotifen from the base as a common ion. Examples of the glycol include propylene glycol, 1,3-butylene glycol, polyethylene glycol, etc. Propylene glycol is particularly preferred.The blending amount of glycols varies depending on the dosage form, etc., but for oily ointments, it is 3 to 20% by weight, macrogol ointment, FAPG
The external preparation of the present invention, which preferably contains 40% by weight or more in ointments and liquids, contains, in addition to the above three components, at least one nonaqueous group selected from the group consisting of higher alcohols, paraffinic hydrocarbons, and silicone oils. The composition may further contain an agent component.

Examples of higher alcohols include cetanol, stearyl alcohol, behenyl alcohol, 2-hexyldecanol, instearyl alcohol, 2-octyldecanol, and the like. The content of higher alcohol is preferably 5 to 50% by weight in oleaginous ointments and FAPG ointments.

Examples of paraffinic hydrocarbons include petrolatum, paraffin, squalane, microcrystalline wax, blistane, and alpha-olefin oligomers. The content of paraffinic hydrocarbons is 20 to 20% in oil-based ointments.
It is preferably 70% by weight.

Examples of silicone oils include methylpolysiloxane,
Examples include methylphenylpolysiloxane. The silicone oil content in oily ointments is 20 to 70.
Preferably, it is expressed as % by weight.

In the external preparation of the present invention, other pharmaceutically acceptable additives may be added as necessary. Examples of such additives include polyhydric alcohols, higher fatty acids, esters of higher fatty acids, essential oil components, stabilizers, humectants, and the like. These ingredients are added to improve the appearance and properties of the preparation.

Examples of polyhydric alcohols include glycerin, 1°2.6
- Examples include hexandriol.

Examples of higher fatty acids include stearic acid and palmitic acid.

Examples of higher fatty acid esters include isopropyl adipate diisopropinopemiristate, cetyl lactate, and myristyl lactate.

Essential oil ingredients include menthol, camphor, peppermint oil,
Examples include thymol. Stabilizers include organic antioxidants such as TEHA, methyl hydroxytoluene, and tocopherol derivatives. Examples of moisturizers include cholesterol derivatives.

Furthermore, the formulation may contain anti-inflammatory agents such as guaiazulene, glycyrrhetinic acid, and methyl salicylate, steroids such as prednisolone, eisin (1-dodecyl azacyclohebutan-2-one), phospholipids, and irritating agents. It is also possible to contain small amounts of surfactants.

Examples of the surfactant include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. Nonionic surfactants are preferred from the viewpoint of low skin irritation, such as sorbitan. Examples include fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbicun fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and the like.

The external preparation of the present invention is preferably in the form of an ointment or a liquid.

Here, ointment does not contain water or lower alcohol,
It is a semi-solid external preparation with an appropriate consistency and a gold medal, such as oil-based ointments using higher alcohols or paraffin hydrocarbons as a base, macrogol ointments using polyethylene glycol, and aliphatic alcohols dispersed in glycols. Examples include FAPG ointment and the like.

The oil-based ointment is made by adding one or more types selected from the group consisting of fat-soluble basic substances, higher alcohols, paraffinic hydrocarbons, and silicone oils to a solution obtained by heating and dissolving ketotifen salt in a mixture of glycols, etc. It is prepared by adding and stirring a solution obtained by heating and dissolving the base components and other additives as necessary.

Macrogol ointment is made by adding a solution obtained by heating and dissolving a fat-soluble basic substance and other additives as necessary to a solution prepared by heating and dissolving ketotifen salt in a mixture of glycols, etc., and stirring the mixture. be done.

FAPG ointment is prepared by heating and dissolving ketotifen salt in a mixed solution of glycols, etc., adding a solution containing a fat-soluble basic substance, higher alcohol, and other additives as necessary, and stirring. be done.

In the present invention, the liquid preparation is a liquid preparation for external use that does not contain water or lower alcohol. The liquid preparation is prepared by adding a solution obtained by heating and dissolving a fat-soluble basic substance and other additives as necessary to a solution obtained by heating and dissolving a ketotifen salt in a mixed solution of glycols, etc., and stirring the mixture.

In preparing the preparation of the present invention, when the salt of ketotifen is not dissolved in glycols but mixed with a base containing a fat-soluble basic substance, etc., the salt of ketotifen or the acidic substance forming the salt with ketotifen and the fat The salt formed by the reaction of the soluble basic substance may not dissolve in the base component, making it impossible to obtain a uniform preparation.

In addition, since the external preparation of the present invention does not contain water or lower alcohol, the pH of the preparation cannot be directly measured. For convenience, the pH is 5 to 9 when diluted 10 times with distilled water. However, the relationship between pH at 10-fold dilution and drug release properties varies greatly depending on the formulation of the ointment and liquid, and there were cases where good release properties were shown at pH 6 or lower or 8 or higher.

Examples of skin diseases for which the external preparation of the present invention can be used include eczema, dermatitis, hives, pruritus, atopic dermatitis, heat rash, rash, frostbite, and insect bites. Furthermore, it is also effective against other skin diseases in which the chemical mesoieter release inhibiting effect and antihistamine effect of ketotifen are exhibited.

The present invention will be specifically described below with reference to test examples and examples.

Test Example 1 Ketotifen Release Test from Preparations In order to compare the release properties of ketotifen from preparations, a test was conducted using a release tester as shown in FIG. 1. A silicone membrane was used as the test membrane, about 1 g of the preparation was placed on it, and about 22 - of the 0, IN hydrochloric acid aqueous solution, which was the release liquid, was stirred in a constant temperature bath at 37°C, and after 3 hours it was released into the release liquid through the silicone membrane. The amount of ketotiphen produced was quantified.

A formulation prepared by adjusting the amount of diisopropanolamine in the formulation of Example 1.7.10 was used.

The formulations of Comparative Examples 3 to 6 were used as comparative examples. In addition, since the drug concentration affects the release properties, the drug concentration is Ketotifen fumarate o, 13 a% or Ketotifen 0.1%.
And so.

The results are shown in Table 1 and FIGS. 2 and 3. As is clear from the results, the distribution and release of drugs into the silicone membrane, which is a distribution membrane and does not pass through ionic molecules and is said to exhibit permeability similar to that of the skin, greatly depends on the amount of basic substance in the preparation. shown to be affected.

In other words, as shown in Figure 2, no fumaric acid is released in the formulation prepared as it is, and the amount of basic substance reaches its maximum when the amount is 1 to 3 times the amount required to neutralize fumaric acid. ,
This was almost constant regardless of the formulation.

Furthermore, as shown in FIG. 3, the pH and release properties of the formulations vary greatly depending on the formulation, and it was shown that good release properties may be exhibited even when the pH is 6 or lower or 8 or higher.

Example 1 (ointment), 1, 5.8
150 Example 1 (Ointment), Amine increase 1.25 5.9 180 Example 7 (Ointment) 1 8.2 9
0 Example 7 (ointment), Amine increase 2.5 9.0 110 Comparative example 3 (ointment) 0 4.15 Comparative example 4 (ointment)
0 4.5 10 Comparative example 5 (liquid)
0 4.2 0 The amount of basic substance is expressed with the amount necessary to neutralize fumaric acid being 1. pH was measured by diluting the formulation 10 times with distilled water.

Test Example 2 Effect of Compound 48/80 on suppressing increased vascular permeability The ointment of Example 1 was used as a sample and compared with oral administration.

30 mg of the sample was injected into one of the two places (area 5 cm') on the back of male Wistar rats (weight 134-151 g), which had been dehaired with clippers 2-4 hours before (6 rats per group).
It was applied over a period of seconds, and the other side was left untreated. In addition, for oral administration, 0.2 mg of ketotifen fumarate dissolved in distilled water was administered.
/kg or 0.6 kg/kg. 1 hour later
Physiological saline in which 1 μg of compound 48/80 was dissolved was injected intradermally. Immediately, 2% Evans blue saline solution was injected, and 30 minutes later, the animals were sacrificed by exsanguination. The skin at the site of dye leakage was cut out, and extracted using the acetone method to measure the amount of dye leakage.

The results are shown in Table 3. The ointment showed stronger suppression than oral administration at the same drug dose, and it did not suppress pigment leakage in untreated areas, indicating that the effect of ketotifen is exerted locally on the skin. confirmed. This confirmed that a sufficient amount of ketotifen was absorbed intradermally from the ointment applied to the skin surface, and that ketotifen had excellent intradermal retention without being distributed throughout the body via the blood.

Test Example 3 Stability Test Each formulation was packed into an aluminum tube whose inner surface was coated with epoxy resin, and after storage at 55°C and 60% relative humidity for 70 days, the ketotifen content was determined by property observation and liquid chromatography. Quantitated. The results are shown in Table 3, and the formulation of the present invention showed no change in properties.
The content was stable with only a slight decrease. On the other hand, a change in appearance and a decrease in content were observed in the comparative formulation.

Table 3 Stability of formulation 55°C relative humidity 60% 70 days storage Cream of Comparative Example 6 Separation (not implemented) [Effects of the invention] The external preparation of the present invention utilizes the effect on skin diseases among the antiallergic effects of ketotifen. This formulation is effective by suppressing the release of chemical mesoieters, making it an excellent topical preparation that is closer to treating the cause of skin diseases than conventional topical preparations for skin diseases. In addition, it has a strong antihistamine effect.

In addition, since the effect of ketotifen is exerted locally on the skin, it is effective in a smaller amount than oral administration, and there is no unnecessary distribution of the drug throughout the body via the blood, which has the advantage of avoiding side effects.

Furthermore, it is a non-irritating formulation that can be used directly on diseased areas, has a skin protective effect, is easy to manufacture, has good release properties and transdermal retention, and has excellent drug stability. There is.

As described above, the external preparation of the present invention is a practically very useful preparation.

Examples will be described below, but the present invention is not limited thereto.

Example 1 (a) Ketotifen fumarate 0.138% by weight propylene glycol 5. O〃(B)Diisopropanolamine 0.088 ``Stearyl alcohol 20.0'' Hexyldecanol 30.0 〃Microcrystalline wax 10.0 〃White petrolatum
34.774 After each of the above components was heated and dissolved, component (0) was added to component (A), mixed, and then cooled to obtain a white ointment.

Example 2 Example 1 except that 0.2 g of ethyl aminobenzoate was used instead of diisopropanolamine.
A white ointment was obtained in the same manner as above.

Example 3 Example 1 except that 0.1 g of triethanolamine was used instead of diisopropanolamine.
A white ointment was obtained in the same manner as above.

Example 4 (a) Ketotifen fumarate 0.2% by weight
Propylene glycol 8.0〃(B) Triethanolamine 0.14〃Polyethylene glycol 400 42.0〃Polyethylene glycol 4000 49.66 After heating and dissolving each of the above components, add the component (B) to the component (B). Add
After mixing, the mixture was cooled to obtain a white ointment.

Example 5 (a) Ketotifen fumarate 0.1% by weight
Propylene glycol 8.0//(12)
,) Reethanolamine 0.07 Guaiazulene 0.02 Cetyl lactate 1.0 Crotamiton 3.O Stearyl alcohol
20.0” isosetanol
20.0 Microcrystalline wax
10.0” White Vaseline 3
7.61 ``After heating and dissolving the above components, (
Component (b) was added to component (a), mixed and cooled to obtain a white ointment.

Example 6 (a) Ketotifen fumarate 0.138% by weight 1.3-butylene glycol 8.0 (b) N-
Methylpiperidine 0.07 Prednisolone 0.25 Dibutylhydroxytoluene 0.1 Tocopherol acetate
0.5〃Glyceryl monostearate 1.5〃
Crotamiton 5.0 White beeswax 14.0 Hexyldecanol 39.0 Microcrystalline wax 4.5 White petrolatum
26.942 After each of the above components was heated and dissolved, component (0) was added to component (A), mixed, and then cooled to obtain a white ointment.

Example 7 (a) Ketotifen fumarate 0.138% by weight Propylene glycol 74,774
(b) Diisopropanolamine 0.088
〃Cetyl alcohol 12.0
〃Stearyl alcohol 8.0〃1, 2.6
-Hexandriol 5.0 After heating and dissolving each of the above components, add component (B) to component (A),
After mixing, the mixture was cooled to obtain a white ointment.

Example 8 Example 8 except that 0.2 g of ethyl aminobenzoate was used instead of diisopropanolamine in Example 7.
A white ointment was obtained in the same manner as above.

Example 9 (a) Ketotifen fumarate 1.38 1% propylene glycol 59.74
〃1.3-Butylene glycol 5.0〃(b) Diisopropanolamine 0.88〃1,2.6-
Hexandriol 5.0 Diisopropyl adipate 5.0 Cetyl alcohol 8
．． 0〃Stearyl alcohol 15.0〃After heating and dissolving each of the above components, add (B) to component (A).
The following ingredients were added, mixed and cooled to obtain a white ointment.

Example 10 (a) Ketotifen fumarate 0.138% by weight Propylene glycol 70.0 (
0) Diisopropaturamine 0.11
"Propylene glycol 29.752
〃After heating and dissolving the ingredients in (a), the components were heated and dissolved (mouth)
After adding and mixing the components, the mixture was cooled to obtain a liquid.

Example 11 (a) Ketotifen fumarate 0.138% by weight Propylene glycol 69.662
(rl) Ethyl aminobenzoate 0.2 Isopropyl myristate 5.0 Crotamiton
5.0 Polyethylene glycol
20.0 After heating and dissolving the component (A), the heated and dissolved component (0) was added, mixed, and then cooled to obtain a liquid.

Example 12 (a) Ketotiphine fumarate 0.5% by weight Propylene glycol 69.18 (
b) Diisopropanolamine 0.32
〃Dimethylphenylpolysiloxane 10.0 〃1
．． 3-Butylene glycol 20.0 After heating and dissolving the component (a), the heated and dissolved component (1) was added and mixed, and then cooled to obtain a liquid.

Comparative Example 1 (a) Ketotifen fumarate 0.5% by weight Hexyldecanol 75.0 Isopropyl myristate 2.5 (c) Aerosil 200?, 0 The ingredients in (a) were heated and mixed, but ketotifen fumarate It did not dissolve, and even after adding component (0) obtained by spray drying an aqueous solution and mixing with heat, it did not dissolve, and a uniform ointment could not be obtained.

, Comparative Example 2 In Example 1, ketotifen fumarate was heated and mixed with the remaining base components, but the crystals did not dissolve and a uniform ointment was not obtained.

Comparative Example 3 A white ointment was obtained in the same manner as in Example 1 except that diisopropanolamine was not used.

Comparative Example 4 A white ointment was obtained in the same manner as in Example 7 except that diisopropanolamine was not used.

Comparative Example 5 A liquid was obtained in the same manner as in Example 10 except that diisopropanolamine was not used.

Comparative Example 6 (A) Ketotifen fumarate 0.138% by weight Purified water 21.6 (B) Wool wax 62.9 Liquid paraffin 15.6 Components (A) were dissolved by heating and mixed by heating (rl ) were added and emulsified to obtain cream.

[Brief explanation of the drawing]

Figure 1 shows a release tester, in which 1 is the tester body, 2 is a silicone membrane that is a test membrane, 3 is a drug preparation, 4 is a release test liquid,
5 is a rotor, and 6 is a constant temperature layer. FIG. 2 shows the relationship between the amount of diisopropanolamine and the release property of ketotifen. The horizontal axis shows the amount ratio of diisopropanolamine, with the amount necessary to neutralize fumaric acid being 1, and the vertical axis shows the released amount (mg) of ketotifen. Figure 3 shows the amount of diisopropanolamine and the pH of the formulation.
shows the relationship between The horizontal axis shows the pH measured after diluting the formulation 10 times with purified water, and the vertical axis shows the amount of ketotifen released (m
g). Figure 1 Figure 2 Amount of diisopropanolamine Figure 3 H

Claims (12)

[Claims] (1) An external skin disease treatment agent containing a ketotifen salt, a fat-soluble basic substance, and glycols. (2) Ketotifen salt content is 0.01 to 5% by weight
and the content of fat-soluble basic substances is 0.008 to 15
% by weight, and the content of glycols is 3 to 90% by weight.
The external skin disease therapeutic agent according to claim (1). (3) Claim (1) further contains at least one nonaqueous base component selected from the group consisting of higher alcohols, paraffinic hydrocarbons, and silicone oils.
External skin disease treatment agent described in Section 1. (4) Ketotifen salt content is 0.01 to 5% by weight
, the content of the fat-soluble basic substance is 0.05 to 5% by weight, the content of glycols is 3 to 20% by weight, the content of higher alcohol is 5 to 50% by weight,
The external skin disease therapeutic agent according to claim (3), wherein the paraffinic hydrocarbon content is 20 to 70% by weight. (5) The external skin disease therapeutic agent according to claim (1), further comprising a pharmaceutically acceptable additive. (6) The external skin disease therapeutic agent according to claim (1), wherein the ketotifen salt is ketotifen fumarate. (7) Lipid-soluble basic substances have the following formulas (I) and (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) is hydrogen, an alkyl group having 1 to 20 carbon atoms, or a hydroxyalkyl group having 1 to 6 carbon atoms, and R_3 is an alkyl group having 1 to 20 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, or a hydroxyalkyl group having 1 to 6 carbon atoms. A phenyl group substituted with an alkyloxycarbonyl group, R_4 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and X is a carbon atom, an oxygen atom, a nitrogen atom, or an alkyl group having 1 to 6 carbon atoms. is a substituted nitrogen atom, m
, n is an integer of 1 to 3). (8) Claim No. 1 in which the glycol is propylene glycol and/or 1,3-butylene glycol (
1) The topical skin disease treatment agent described in item 1). (9) The external skin disease therapeutic agent according to claim (1), wherein the pharmaceutically acceptable additives are polyhydric alcohols, higher fatty acids, higher fatty acid esters, essential oil components, stabilizers, and humectants. (10) Skin disease is eczema, dermatitis, hives, skin ■
The external skin disease treatment agent according to claim (1), which is for treating pruritus, atopic dermatitis, heat rash, rash, chilblains, or insect bites. (11) Claim No. (1) which is an ointment or a liquid preparation
External skin disease treatment agent described in Section 1. (12) A method for producing an external skin disease therapeutic agent, which comprises dissolving a ketotifen salt in glycols and adding a fat-soluble basic substance to the resulting solution.