JPH08165240A - Ketotifen-containing percutaneously administering preparation - Google Patents

Abstract

PURPOSE: To provide the subject preparation markedly greater in percutaneous permeation rate, excellent in medicinal stability, with mitigated skin irritancy, and also excellent in physical properties. CONSTITUTION: This preparation contains as active ingredient pref. 0.1-10 (esp. 1.0-5.0)wt.% of ketotifen acetate. This preparation is pref. a non-aqueous-based one, and its formulation is pref. plaster or ointment. This preparation is not subjected to metabolism by a medicine due to its initial passing effect through the liver observed following its oral administration, can secure sustained effective blood levels, and also avoid side effects of digestive system and various other side effects which may be developed in association with the rise in its rapid blood levels. The formation of this preparation is e.g. a plaster with the tack layer composed of 0.1-10wt.% of the active ingredient and a base comprising 0.1-99wt.% of a liposoluble polymer, 0.1-70wt.% of a tackifier, 1.0-70wt.% of a softening agent and 0.01-20wt.% of an absorption promoter, or an ointment with the base containing a hydrocarbon, fatty acid ester, wax, surfactant and/or absorption promoter.

Description

Detailed Description of the Invention

[0001]

The present invention relates to ketotifen acetate (chemical name: 4- (1-methyl-4-piperidylidene) -4H.
-Benzo [4,5] cyclohepta [1,2-b] thiophen-10 (9H) one.acetate) as an active ingredient.

[0002]

2. Description of the Related Art Ketotifen is a compound having excellent antihistamine action, anti-SRS-A action and broad anti-allergic action. In particular, ketotifen fumarate is used in an oral dosage form as a preventive or therapeutic drug for bronchial asthma, allergic rhinitis, eczema, dermatitis and the like. However, when ketotifen or a salt thereof is orally administered, there are problems such as side effects such as gastrointestinal disorders, decrease in utilization rate due to hepatic first-pass effect, decrease in patient compliance due to long-term continuous use, etc. in order to solve these problems. Various dosage forms have been investigated.

For example, JP-A-62-164624 discloses an external gel preparation in which ketotifen or a salt thereof is contained in a gel base. In addition, JP-A-6
JP-A-2-223119 discloses an external cream preparation containing ketotifen or a salt thereof. Further, JP-A-1-102024 discloses a therapeutic agent for external skin diseases, which is an ointment or a solution containing a salt of ketotifen. In addition, Japanese Patent Laid-Open No. 1-106820
The publication discloses a transdermal preparation containing ketotifen or a salt of ketotifen in an aqueous gel matrix containing polyvinyl alcohol. Also,
Japanese Unexamined Patent Publication No. 4-91022 discloses a plaster preparation containing ketotifen or a salt thereof and an aliphatic monohydric alcohol as an absorption promoter. Further, JP-A-4-182425 discloses an external patch containing ketotifen or a salt thereof, a lower alcohol and a highly hydrophilic nonionic surfactant. Further, JP-A-5-946 discloses a transdermal preparation in which ketotifen is mixed with a fatty acid or an aliphatic alcohol and a divalent or higher valent alcohol. Furthermore, JP-A-5
No. 947 discloses an external preparation patch in which ketotifen is contained in a polymer water-absorbent copolymer and the pH of the drug layer is in the range of 6.7 to 8.5.

However, although these transdermal preparations have solved problems peculiar to orally administered preparations such as side effects such as gastrointestinal disorders and reduction of utilization rate due to first pass effect in liver, their skin permeation rate is slow. Moreover, there are problems in terms of drug stability, skin irritation, and physical properties of the preparation, and it has not been actually used clinically. Therefore, there is a demand for the development of a transdermal preparation containing ketotifen which has a fast skin penetration rate and is excellent in drug stability, skin irritation, and physical properties of the preparation.

[0005]

The object of the present invention is to contain ketotifen, which has a fast skin penetration rate, that is, is excellent in transdermal absorbability, and is also excellent in drug stability, skin irritation, and physical properties of preparations. It is to provide a preparation for transdermal administration.
As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that a transdermal preparation containing ketotifen acetate as an active ingredient is a transdermal preparation containing an acid addition salt of ketotifen as an active ingredient. It was found that the skin permeation rate is remarkably faster than that of the administration preparation, and that it is also excellent in terms of drug stability, skin irritation, and physical properties of the preparation, and completed the present invention.

[0006]

[Means for Solving the Problems] That is, the present invention comprises a transdermal preparation containing ketotifen acetate as an active ingredient. The present invention also comprises a transdermal preparation containing 0.1 to 10% by weight of ketotifen acetate as an active ingredient.
The present invention also comprises the above-mentioned transdermal preparation wherein the base is a non-aqueous system. The present invention also comprises the above-mentioned transdermal preparation which is a plaster. The present invention also comprises the above-mentioned percutaneous preparation which is a plaster containing a fat-soluble polymer, a tackifier and a softening agent in a base. In the present invention, the adhesive layer further comprises 0.1 to 10% by weight of ketotifen acetate and 0.1% by weight of the fat-soluble polymer.
1-99 wt%, tackifier 0.1-70 wt%, softener 1.0-70 wt% and / or absorption promoter 0.01-
The transdermal preparation is a plaster consisting of a base containing 20% by weight.

The present invention also comprises the above-mentioned transdermal preparation which is an ointment. The present invention also includes hydrocarbons in the base,
The transdermal preparation is an ointment containing a fatty acid ester, a wax, a surfactant and / or an absorption enhancer. The present invention also comprises ketotifen acetate 0.1 to 10% by weight, hydrocarbons 55 to 90% by weight, fatty acid ester 5
~ 15 wt%, waxes 4-10 wt%, surfactant 1 ~
5% by weight and / or absorption promoter 0.01-20% by weight
The above-mentioned transdermal preparation, which is an ointment comprising a base containing The present invention also comprises the above-mentioned transdermal preparation containing an aliphatic alcohol and glycols in a base.

The present invention will be described in detail below. The transdermal preparation of the present invention is preferably non-aqueous,
The dosage form is not particularly limited, but a plaster or an ointment is preferable.

First, the case where the transdermal preparation of the present invention is a plaster will be described. The plaster of the present invention is preferably non-aqueous. Further, the plaster of the present invention contains ketotifen acetate as a medicinal component in an amount of 0.1 to 10% by weight, particularly 1.0 to 10% by weight, based on the weight of the entire composition of the adhesive layer.
It is preferably contained in an amount of 5.0% by weight. When the content of ketotifen acetate is less than 0.1% by weight, a sufficient permeation amount as a transdermal preparation cannot be obtained, and when it exceeds 10% by weight, the physical properties of the preparation itself are adversely affected.
Not preferred.

The plaster of the present invention preferably contains a fat-soluble polymer, a tackifier and a softening agent and / or an absorption promoter in its base. Examples of the fat-soluble polymer include polyisobutylene (PIB), styrene-isoprene block copolymer (SIS), isoprene rubber, styrene-butadiene block copolymer (SBS), acrylic polymer (2-ethylhexyl acrylate, vinyl acetate, methacrylate). , Methoxyethyl acrylate and at least two copolymers of acrylic acid) and the like can be mentioned as preferred examples. The blending amount of such a fat-soluble polymer based on the total weight of the adhesive layer is preferably 0.1.
To 99% by weight, more preferably 0.1 to 70% by weight,
Particularly preferably, it can be 0.1 to 50% by weight. When the content of the fat-soluble polymer is less than 0.1% by weight, the cohesive force of the preparation is poor and the physical properties are adversely affected, and when it exceeds 99% by weight, the processability of the preparation is deteriorated and the adhesive strength is poor. Therefore, it is not preferable.

Since the tackifier is poor in tackiness of the fat-soluble polymer, it is desirable to add it in order to impart tackiness to the whole preparation. Preferable examples of the tackifier include polyterpene resin-based, petroleum resin-based, rosin-based, rosin ester-based, oil-soluble phenol resin-based and the like. The compounding amount of the tackifier based on the weight of the entire pressure-sensitive adhesive layer can be preferably 0.1 to 70% by weight, more preferably 5 to 50% by weight, and particularly preferably 10 to 35% by weight. If the blending amount of the tackifier is less than 0.1% by weight, the tackiness will be poor, and if it exceeds 70% by weight, problems such as stringing and cohesive force of the preparation will occur, which is not preferable.

It is desirable that the softening agent is blended in order to improve the processability of the plaster and adjust the tackiness. As the softening agent, fats and oils, particularly liquid paraffin, squalane, olive oil, camellia oil, bar shock oil, peanut oil and the like can be mentioned as preferable examples, and among them, liquid paraffin is particularly preferable. The blending amount of the softening agent based on the total weight of the adhesive layer is preferably 1.0 to 70% by weight,
It may be more preferably 10 to 60% by weight, and particularly preferably 20 to 50% by weight. If the compounding amount of the emollient is less than 1.0% by weight, the drug release is lowered and the skin permeability is inferior, and if it exceeds 70% by weight, exudation from the formulation occurs and the physical properties of the formulation are adversely affected. It is not preferable because it causes

The plaster of the present invention may also contain an absorption enhancer, if necessary. As the absorption enhancer, any compound can be used as long as it is a compound which is recognized to have an absorption promoting action on the skin. As the absorption promoter, fatty acids having 6 to 20 carbon chains, aliphatic alcohols, fatty acid esters or ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers, lactic acid esters, acetic acid esters , Monoterpene-based compounds, sesquiterpene-based compounds, Azone or its derivatives, glycerin fatty acid esters, sorbitan fatty acid esters, polysorbate-based, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil-based, sucrose fatty acid Esters and the like can be mentioned as preferred examples.

Specifically, caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid,
Stearic acid, oleic acid, linoleic acid, linolenic acid,
Lauryl alcohol, myristyl alcohol, oleyl alcohol, cetyl alcohol, methyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, salicylic acid, methyl salicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate , Cresol, cetyl lactate, ethyl acetate, propyl acetate, geraniol, thymol, eugenol, terpineol, 1-menthol, peppermint oil, borneolol, d-limonene, isoeugenol, isoborneol, nerol, dl-camphor, glycerin monolaurate , Glycerin monooleate, sorbitan monolaurate, sucrose monolaurate, polysorbate 20, polyethylene glycol monolaurate, po Ethylene glycol monostearate, polyoxyethylene (60) hardened castor oil, 1-
[2- (decylthio) ethyl] azacyclopentane-2
-One (hereinafter abbreviated as "pyrothiodecane") is preferable, and lauryl alcohol, myristyl alcohol, ethylene glycol salicylate, and pyrothiodecane are particularly preferable. The content of the absorption promoter based on the total weight of the adhesive layer is preferably 0.01 to 20% by weight, more preferably 0.1 to 10% by weight, and particularly preferably 0.5 to 5% by weight. You can If the content of the absorption enhancer exceeds 20% by weight, irritation to the skin such as redness and edema is observed, which is not preferable.

The plaster of the present invention may contain a hydrophilic polymer, if necessary, in order to prevent absorption of an aqueous component such as sweat from the skin and decomposition by moisture during storage. As the hydrophilic polymer, light anhydrous silicic acid, a cellulose derivative (carboxymethyl cellulose (CMC),
Carboxymethyl cellulose sodium (CMCN
a), methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (H
EC)), starch derivative (pullulan), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PV
P), vinyl acetate (VA), carboxy vinyl polymer (CVP), ethyl vinyl acetate (EVA), Eudragit, gelatin, polyacrylic acid, sodium polyacrylate, polyisobutylene maleic anhydride copolymer, alginic acid, sodium alginate, Carrageenan, gum arabic, tragacanth, karaya gum, polyvinyl methacrylate can be mentioned as preferred examples, and in particular,
Light anhydrous silicic acid, cellulose derivative (CMCNa, HP
MC, HPC, MC), Eudragit. The blending amount based on the weight of the entire adhesive layer of the hydrophilic polymer is
It is preferably about 0.5 to 5.0% by weight.

The plaster of the present invention may further contain a cross-linking agent, a preservative, an antioxidant and the like, if desired.
Examples of the cross-linking agent include amino resins, phenol resins, epoxy resins, alkyd resins, thermosetting resins such as unsaturated polyester, isocyanate compounds, blocked isocyanate compounds, organic cross-linking agents, and inorganic cross-linking agents such as metals or metal compounds. , Can be mentioned as a preferable example.
The compounding amount of the crosslinking agent based on the weight of the entire adhesive layer is 0.05.
It is preferably about 2% by weight.

Preferred preservatives include parabens such as methylparaben, ethylparaben, propylparaben or butylparaben, phenols such as thymol, chlorcresol, orthophenylphenol, isopropylmethylphenol, and pionine. You can The content of the preservative based on the total weight of the adhesive layer is preferably about 0.01 to 1% by weight. Examples of the antioxidant include tocopherol and its ester derivative, ascorbic acid and its ester derivative, nordihydroguaretinic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole (B
HA) and the like can be mentioned as preferred examples. The amount of the antioxidant based on the total weight of the adhesive layer is 0.01.
It is preferably about 5% by weight.

The adhesive layer of the plaster of the present invention having such a composition can be produced by any method. For example, in the case of producing by a solvent method, other components are added to an organic solvent solution of a fat-soluble polymer, stirred, and then spread on a support and dried to obtain a preparation. When the fat-soluble polymer can be applied by the hot melt method, after dissolving the polymer component at high temperature, adding other components, stirring, and then spreading on a support to obtain a preparation. You can

The plaster of the present invention may have any constitution and material other than the adhesive layer having the above composition. For example, the plaster of the present invention can be composed of the above-mentioned adhesive layer, a support layer supporting the adhesive layer, a release liner layer provided on the adhesive layer, and the like. The support layer is, for example, a film or sheet of polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane, etc., or a porous material, foamed material and paper, cloth, non-woven fabric thereof. And the like.

Next, the case where the transdermal preparation of the present invention is an ointment will be described. The blending amount of ketotifen acetate as a medicinal component to be blended in the ointment of the present invention is
It is desirable that the amount is the same as that described for the plaster. The ointment of the present invention is also preferably non-aqueous. As the ointment, for example, an oily ointment using a higher alcohol or paraffin hydrocarbon as a base, a macrogol ointment using polyethylene glycol, an FA in which an aliphatic alcohol is dispersed in glycols
Examples thereof include PG ointments, and the ointment of the present invention may be of any type, but oily and fat ointments and FAPG ointments are particularly preferable.

First, the case where the ointment is an oily ointment will be described. In that case, the ointment of the present invention preferably contains a hydrocarbon, a fatty acid ester, a wax, a surfactant and / or an absorption promoter in the base. Preferred examples of hydrocarbons include white petrolatum, petrolatum, paraffin, squalane, microcrystalline wax, pristane, and α-olefin oligomer. The blending amount of hydrocarbons is preferably 55 to 90% by weight based on the weight of the ointment. When the content of hydrocarbons is less than 55% by weight, the plaster becomes too hard, which makes it difficult to apply to the skin, and when it exceeds 90% by weight, separation of the preparation occurs, which adversely affects the physical properties. Absent.

As the fatty acid ester, diisopropyl adipate, isopropyl myristate, cetyl lactate,
Preferred examples include myristyl lactate, isopropyl palmitate, diethyl sebacate, hexyl larophosphate, and cetyl isooctanoate. The amount of the fatty acid ester is 5 to 15 based on the weight of the ointment.
It is preferably in the weight%. If the content of the fatty acid ester is less than 5% by weight, the penetration of the preparation into the skin will be reduced, and if it exceeds 15% by weight, the skin irritation will be high, which is not preferable.

As waxes, whale wax (natural and synthetic),
Beeswax and the like can be mentioned as a preferable example.
The wax content is 4 to 10 based on the weight of the ointment.
It is preferably in the weight%. When the content of waxes is less than 4% by weight, the gloss of the ointment is insufficient and the viscosity is lowered, and when it exceeds 10% by weight, the viscosity becomes too high and the usability becomes unfavorable.

Examples of the surfactant include nonionic surfactants, anionic surfactants, cationic surfactants,
Although amphoteric surfactants can be mentioned, non-ionic surfactants having low skin irritation are preferable, and sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, poly Preferred examples include oxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and the like. The content of the surfactant is preferably 1 to 5% by weight based on the weight of the ointment. When the content of the surfactant is less than 1% by weight, separation of the preparation is caused, and when it exceeds 5% by weight,
It is not preferable because it causes high skin irritation.

It is desirable that the absorption promoter optionally added be of the same type and amount as described for the plaster. The ointment of the present invention can also contain a preservative, if necessary. The preservative is preferably the same as that described for the plaster. The preservative content is 0.01 to 1 based on the weight of the ointment.
It is preferable to set the weight%. The ointment of the present invention may also contain, as other components, essential oil components such as menthol, camphor, peppermint oil, and thymol, and stabilizers such as butylhydroxytoluene and tocopherol derivatives.

The ointment of the present invention having such a composition can be produced by any known method. For example, a fatty acid ester and a surfactant are mixed with ketotifen fumarate and sodium acetate, waxes and hydrocarbons are added thereto, and the mixture is heated and melted, and kept at 70 ° C.
It can be obtained by uniformly mixing the base components with a homomixer or the like after forming a transparent solution, and then cooling to 30 ° C. with stirring.

Next, the case where the ointment of the present invention is a FAPG ointment will be described. In that case, the ointment of the present invention preferably contains aliphatic alcohol and glycols as essential base components. The FAPG ointment of the present invention contains ketotifen fumarate as an active ingredient, an aliphatic alcohol and a glycol as a base ingredient, and if necessary, an absorption promoter, a preservative, a plasticizer, and a coupling agent. be able to. Examples of the aliphatic alcohol include any of saturated fatty alcohols having 16 to 24 carbon atoms or a mixture thereof, and particularly cetyl alcohol, stearyl alcohol, oleyl alcohol, hexadecyl alcohol, behenyl alcohol and the like are preferable. The aliphatic alcohol is preferably blended in an amount of 20 to 40% by weight based on the total weight of the FAPG ointment.

Examples of glycols include 1,2-
Propylene glycol, such as propylene diol
1,3-propylene diol, polyethylene glycol having a molecular weight of 100 to 800, dipropylene glycol and the like can be mentioned. The glycols are preferably added in an amount of 60 to 80% by weight based on the weight of the whole FAPG ointment.

The optionally added absorption enhancer is preferably of the same type as described for the plaster, and is mixed in an amount of 20% by weight or less based on the total weight of the FAPG ointment. It is preferable. The plasticizer is optionally blended for the purpose of maintaining homogeneity in a solvent mixture of an aliphatic alcohol and glycols, and polyethylene glycol, 1,2,6-hexanetriol, sorbitol, glycerol and the like are mentioned as preferred examples. be able to. The plasticizer is preferably added in an amount of 0 to 15% by weight, based on the total weight of the FAPG ointment.

The coupling agent is arbitrarily blended for the purpose of maintaining the homogeneity of the base material and preventing the exudation of the liquid component of the base material stored at high temperature for a long period of time, and the stearic acid, palmitic acid, and behenic acid are added. Saturated fatty acids having 16 to 24 carbon atoms,
Fatty acid amides such as oleamide, palmitoamide, stearamide, behenamide, carbon number 16 such as sorbitan monostearate, polyethylene glycol monostearate, propylene glycol monostearate
-24 fatty acid esters and the corresponding monoesters of other fatty acids such as oleic acid and palmitic acid can be mentioned as preferred examples. The amount of the coupling agent compounded is preferably 0 to 10% by weight based on the weight of the FAPG ointment as a whole.

The FAPG ointment of the present invention can also be produced by any known method. For example, several kinds of aliphatic alcohol and glycols are mixed with ketotifen acetate and other components, heated and melted, and kept at 70 ° C.,
Then, it can be obtained by cooling to 30 ° C. with stirring. The ointment of the present invention can be obtained even if the mixing order of these components is changed. In the case of a topical preparation, the ointment of the present invention can be directly applied to a diseased part such as dermatitis. Further, in the case of a systemically administered preparation, it can be used in the reservoir layer of a reservoir-type preparation in order to clarify the dose.

[0032]

INDUSTRIAL APPLICABILITY The transdermal preparation of the present invention contains ketotifen acetate as an active ingredient, so that it is more effective than other conventional ketotifen-containing transdermal preparations using an acid addition salt of ketotifen as an active ingredient. It has a feature that the permeation rate is remarkably high, that is, the transdermal absorbability is remarkably excellent. The transdermal preparation of the present invention has good drug stability, reduced skin irritation, and excellent physical properties. Further, when the transdermal preparation of the present invention is a systemic preparation, ketotifen acetate is continuously absorbed directly into the circulating blood through the skin, and therefore, the first time in the liver observed during oral administration. A sustained effective blood concentration can be obtained without being metabolized by the drug due to the passage effect. Furthermore, it is possible to avoid the side effects of the digestive system that may occur during oral administration and the side effects that may occur as a result of a rapid increase in blood concentration.

[0033]

EXAMPLES The present invention will be described in more detail below with reference to examples. Reference Example 1 (Production of ketotifen acetate) Ketotifen fumarate 1
3.8 g was dispersed in 30 ml of water, and a saturated Na ₂ CO ₃ aqueous solution (or 1N NaOH aqueous solution) was added to adjust the pH to about 7-8. This solution was extracted with diethyl ether 2-3 times using a separating funnel, the obtained diethyl ether solution was washed with water, and dehydrated with anhydrous magnesium sulfate,
After filtering to remove anhydrous magnesium sulfate, diethyl ether was dried to dryness using an evaporator to obtain a solid residue. This residue was recrystallized using n-hexane to obtain a ketotifen-free body. This free form was dissolved in an aqueous solution containing an equal amount of acetic acid and dried using an evaporator to obtain 10 g of ketotifen acetate (theoretical value: 11.96 g).

Example 1 Liquid paraffin 28.5% by weight Petroleum resin tackifier 35.5% by weight (YS resin 75 manufactured by Yasuhara Jushi Kogyo Co., Ltd.) Light silicic acid 2.5% by weight SBS 25.0% by weight Oxidizing agent 1.5% by weight Ketotifen acetate 6.9% by weight Butyl paraoxybenzoate 0.1% by weight ----------------------------------. --- Total amount 100% by weight In the above components, components other than ketotifen acetate were added at 180 ° C.
After dissolving and mixing in, after adding the remaining components and dispersing until uniform, on a PET film 30 μm,
The adhesive layer was extended so as to have a thickness of 100 μm to obtain the preparation for transdermal administration (plaster) of the present invention.

Example 2 Liquid paraffin 41.62% by weight Rosin-based tackifier 29.5% by weight (KR-610 manufactured by Arakawa Chemical Industry Co., Ltd.) PIB 7.5% by weight SIS 16.5% by weight Antioxidant 1. 5% by weight Pyrothiodecane 2.0% by weight Ketotifen acetate 1.38% by weight ------------------ Total amount 100% by weight Above Among the components, components other than pyrothiodecane and ketotifen acetate were dissolved and mixed at 180 ° C., then the remaining components were added and dispersed until uniform, followed by PET film 3
The adhesive layer was extended to 0 μm so that the adhesive layer was 100 μm to obtain the transdermal preparation (plaster) of the present invention.

Example 3 Isopropyl myristate 10.0 wt% Whale wax 5.0 wt% Sodium polyoxyethylene cetyl ether phosphate 5.0 wt% White petrolatum 77.45 wt% Butylparaben 0.05 wt% Ketotifen acetate 2.5% by weight ------------------------------------------- Total amount 100% by weight The above ingredients are melted by heating and kept at 70 ° C. After the components other than ketotifen acetate became a transparent melt, they were uniformly mixed using a homomixer. Then, while stirring, 30
After cooling to 0 ° C., the transdermal preparation (ointment) of the present invention was obtained.

Example 4 Stearyl alcohol 10.0% by weight Cetyl alcohol 8.0% by weight Hexadecyl alcohol 12.0% by weight Propylene glycol 68.9% by weight Butylparaben 0.1% by weight Ketotifen acetate 1.0% by weight- --------------------------------- Total amount 100% by weight Total of 100% by weight The above components are mixed, melted by heating and kept at 60 ° C, except ketotifen acetate. After becoming a transparent melt, the components were mixed uniformly using a homomixer. Then, it cooled to 30 degreeC, stirring, and the percutaneous administration formulation (ointment) of this invention was obtained.

Comparative Examples 1 and 2 Comparative Examples 1 and 2 are the same as Examples 1 and 2, respectively.
A transdermal preparation (plaster) was obtained in the same manner except that ketotifen acetate was used instead of ketotifen acetate.

Comparative Examples 3 and 4 Comparative Examples 3 and 4 are the same as Examples 1 and 2, respectively.
A transdermal preparation (plaster) was obtained in the same manner except that ketotifen hydrochloride was used instead of ketotifen acetate.

Comparative Examples 5 and 6 Comparative Examples 5 and 6 are the same as Examples 1 and 2, respectively.
A transdermal preparation (plaster) was obtained in the same manner except that ketotifen citrate was used instead of ketotifen acetate.

Comparative Examples 7 and 8 Comparative Examples 7 and 8 are the same as Examples 1 and 2, respectively.
A transdermal preparation (plaster) was obtained in the same manner except that ketotifen tartrate was used instead of ketotifen acetate.

Comparative Examples 9 and 10 Comparative Examples 9 and 10 were prepared in the same manner as in Examples 3 and 4, except that ketotifen fumarate was used in place of ketotifen acetate. Got

Comparative Examples 11 and 12 In Comparative Examples 11 and 12, transdermal preparations (ointments) were prepared in the same manner as in Examples 3 and 4, except that ketotifen hydrochloride was used in place of ketotifen acetate. Obtained.

Comparative Examples 13 and 14 Comparative Examples 13 and 14 were prepared in the same manner as in Examples 3 and 4, except that ketotifen citrate was used in place of ketotifen acetate. Got

Comparative Examples 15 and 16 Comparative Examples 15 and 16 were prepared in the same manner as in Examples 3 and 4, except that ketotifen tartrate was used in place of ketotifen acetate.
I got

Comparative Example 17 0.3M acetate buffer (pH 5.0) 55% by weight Pyrothiodecane 2.5% by weight Glycerin 12% by weight Polyethylene glycol 400 5% by weight Zinc oxide 8% by weight Gelatin 3% by weight Polyvinyl alcohol 5% by weight Sodium polyacrylate 1% by weight Sodium carboxymethyl cellulose 3.5% by weight Ketotifen fumarate 5% by weight ----------------------------------------------------------------------------------------------- 100% by weight of total amount The above components were mixed, mixed and melted, and then spread on a non-woven fabric so that the adhesive layer had a thickness of 1 mm to obtain a poultice preparation.

Test Example 1 In Vitro Skin Permeation Test After excising the dorsal skin of hairless mice (weeks: 6-9), fat on the dermis side was carefully removed, and the temperature was kept at 37 ° C. so that the dermis side became the receptor layer. It was mounted in a flow-through cell in which water was circulated around the outer periphery of the receptor layer. The plasters, ointments and poultice preparations obtained in Examples 1 to 3 and Comparative Examples 1 to 4 were attached or applied to the stratum corneum side, and the receptor layer was treated with physiological saline at 5 ml / hour. Sampling was performed every hour for up to 24 hours. Then, the flow rate per hour was accurately measured, the drug concentration was measured by high performance liquid chromatography, the permeation rate per hour was calculated, and the skin permeation rate in a steady state was determined according to the following formula. The results are shown in Table 2 below. Skin permeation rate (μg / cm ² / hour) = (drug concentration (μg / ml) × flow rate (ml)) / application area of the formulation (cm ² )

Test Example 2 Drug Stability Test Each of the preparations obtained in Examples 1 to 3 and Comparative Examples 1 to 4 was stored at 40 ° C. for 6 months. Using the chromatographic method,
It was calculated according to the following formula. The results are shown in Table 2 below. Drug residual rate (%) = (drug content after 6 months / drug content at the time of production) × 100

Test Example 3 Human Skin Irritation Test Of the preparations obtained in Examples 1 to 3 and Comparative Examples 1 to 4,
For plasters and poultice preparations, a preparation having an area of 10 cm ² was applied to human dorsal skin for 24 hours, and then peeled off. The skin condition immediately after peeling and 24 hours after peeling was evaluated by the judgment method shown in Table 1 below. It was judged and the skin irritation index was calculated according to the following formula. As for ointment, the ointment should be applied to the skin at about 0.5.
After applying g and placing gauze on the applied part, the part was fixed with a Japanese bandage plaster, and after applying for 24 hours, only the ointment applied part was judged and the skin irritation index was calculated according to the following formula. The results are shown in Table 2 below.

[0050]

[Table 1] Judgment method Skin condition Score −−−−−−−−−−−−−−−−−−−−−−−−−−−− No reaction 0 ± Light erythema (redness) 0 .5 + erythema 1.0 ++ erythema + edema 2.0 +++ erythema + edema + papules, small blisters 3.0 ++++ large blisters 4.0 ------------- −−−−−−−−−−−−−−−−−−−

Skin irritation index = (sum of high values of irritation in each judgment immediately after peeling and after 24 hours / number of test subjects) × 10
0

Test Example 4 Physical Properties Test of Preparations Among the preparations obtained in Examples 1 to 3 and Comparative Examples 1 to 4,
For plasters and poultice preparations, the adhesive force was measured with a probe tack tester and a peel measuring device, and the cohesive force was measured with a creep measuring device. In addition, stringiness, bleeding of solution components, etc. were visually judged. As a result, those having no problem in the physical properties of the preparation were evaluated as ◯, and those having a problem were evaluated as x.
Further, regarding the ointment, the feeling of use of the preparation, the separation of the base and the like were evaluated, and those having no problem in the physical properties of the preparation were evaluated as ◯, and those having a problem were evaluated as ×. The results are shown in Table 2 below.

[0053]

[Table 2] Skin permeation rate Drug stability Skin irritation index Physical properties Example (μg / cm ² / hour) (%) −−−−−−−−−−−−−−−−−−−−−−−−− ------------- Example 1 7.3 97.6 11 ○ Example 2 9.0 98.2 8 ○ Example 3 5.8 98.7 13 ○ Example 4 4.1 98. 0 8 − −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Comparative Example 1 0.1 99.0 10 ○ Comparative Example 2 0.7 98.3 12 ○ Comparative Example 3 0.2 97.6 18 ○ Comparative Example 4 0.6 98.1 20 ○ Comparative Example 5 0.2 99.2 12 ○ Comparative Example 6 0.1 99.0 8 ○ Comparative Example 7 0.5 98.4 13 ○ Comparative Example 8 0.2 98.1 10 ○ Comparative Example 9 0.1 98.8 9 ○ Comparative Example 10 0.3 99.2 13 ○ Comparative Example 11 0 .7 97.4 17 ○ Comparative Example 12 0.4 98.0 18 ○ Comparative Example 13 0.1 99.1 11 ○ Comparative Example 14 0.2 98.7 10 ○ Comparative Example 15 0.4 97.7 9 ○ Comparative Example 16 0.5 98.5 14 ○ Comparative Example 17 12.3 25.0 30 − −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−

As is clear from the results shown in Table 2, the preparations obtained in the respective examples of the present invention have a significantly higher skin permeation rate and drug stability than the preparations obtained in the respective comparative examples. It was also superior or superior in terms of sex, skin irritation index and physical properties.

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Claims (10)

[Claims] 1. A transdermal preparation containing ketotifen acetate as an active ingredient. 2. Ketotifen acetate is used as an active ingredient in an amount of 0.1.
A transdermal preparation containing 1 to 10% by weight. 3. The base material according to claim 1, which is a non-aqueous base material.
The transdermal preparation according to. 4. The transdermal preparation according to any one of claims 1 to 3, which is a plaster. 5. The transdermal preparation according to claim 4, which is a plaster containing a fat-soluble polymer, a tackifier and a softening agent in the base. 6. The adhesive layer comprises ketotifen acetate 0.1 to 1
0% by weight, fat-soluble polymer 0.1-99% by weight, tackifier 0.1-70% by weight, softener 1.0-70% by weight and / or absorption promoter 0.01-20% by weight. The transdermal preparation according to claim 4, which is a plaster consisting of a base material contained therein. 7. The transdermal preparation according to any one of claims 1 to 3, which is an ointment. 8. The transdermal preparation according to claim 7, which is an ointment containing a hydrocarbon, a fatty acid ester, a wax, a surfactant and / or an absorption enhancer in the base. 9. Ketotifen acetate 0.1 to 10% by weight
And hydrocarbons 55 to 90% by weight, fatty acid ester 5 to
15% by weight, waxes 4 to 10% by weight, surfactants 1 to 5
The percutaneous preparation according to claim 7, which is an ointment comprising a base containing 10% by weight and / or 0.01 to 20% by weight of an absorption enhancer. 10. The transdermal preparation according to claim 7, which contains an aliphatic alcohol and a glycol in the base.