JPH0348621A - Percutaneously absorbable preparation of ketotifen - Google Patents

Abstract

PURPOSE:To provide the subject preparation capable of maintaining a high blood concentration of the subject drug for a long time despite the application within a small area by adding the drug and liquid paraffin and/or silicon oil as absorption-accelerating agents in specific amounts, respectively, to a specific tackifier layer on a support. CONSTITUTION:A tackifier layer containing 1-42wt.% of 4-(1-methyl-4- peperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-10(9H)-on and/or a salt thereof useful as a treating agent of allergic diseases and further containing (A) liquid paraffin and/or (B) a silicone oil in a ratio of A=1-300 pts.wt. : B=1-200 pts.wt. based on 100 pts.wt. of the tackifier base material is disposed on a drug-impermeable, flexible support to provide a percutaneous absorbable preparation of ketotifen having high skin permeability of the drug, sustained releasing property, high treating ability, excellent safety and good adhesivity.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention provides 4-(l-methyl-4-piperidylidene)-4-day-benzo(4,5)cyclohebut[1,
2b] This invention relates to a transdermal patch containing thiophen-10(9+1)-one and/or a salt thereof, which is capable of achieving a stable drug blood concentration over time by supplying the drug through transdermal absorption.

(Prior art) 4-(1-Methyl-4-biperidylidene)-411-benzo(4,5]cyclohepta[1,2-b:lthiophen-10(9B)-one (hereinafter referred to as ketotifen; Publication No. 6,139,287) and/or its salts are effective as therapeutic agents for allergic diseases such as bronchial asthma, allergic rhinitis, eczema, dermatitis, hives, and pruritus cutaneous. , capsules, syrups, etc. However, when this drug is administered orally.

- Drowsiness due to a temporary increase in drug concentration in the blood.

Side effects such as diarrhea may occur. moreover.

The effects only last for about 12 hours after administration, and the drug must be taken multiple times a day. Therefore, it is desired to use sustained-release preparations, and for example, transdermal absorption-type preparations are considered appropriate. However, since the skin has a biological defense function that prevents foreign substances from entering the body, it is generally difficult to administer a sufficient amount of a drug through the skin.

British Patent Publication No. 2098865A discloses formulations for facilitating transdermal absorption of drugs that are difficult to absorb through the stratum corneum of the skin.1 For example, a cream containing a microemulsion containing ketotifen is disclosed. ing. In such a cream formulation, the area of application to the skin is largely related to the amount of drug absorbed into the body. However, such cream-like preparations, after being applied to the skin, are removed from the skin surface when they come into contact with clothing, etc., and do not exhibit the expected medicinal efficacy. Furthermore, if the area of application to the skin is too large, the amount of drug absorbed into the body will temporarily increase, potentially causing serious side effects.

As a transdermal absorption type sustained release preparation, Japanese Patent Publication No. 615013
No. 24 discloses a patch in which a reservoir layer is provided between a support and an adhesive layer. The reservoir layer is composed of a hydrophilic polymer containing a drug (for example, a (meth)acrylate polymer containing various functional groups).9 For example, ketotifen is disclosed as the drug. However, such formulations have low drug release properties and
In order to obtain a satisfactory medicinal effect, it is necessary to enlarge the size of the preparation, which causes a great discomfort due to the adhesion of the preparation, making it difficult to apply it for a long period of time. JP-A-63-8
Publication No. 332 discloses a sustained-release oral preparation containing ketotifen and/or a salt thereof, and states that this preparation provides an effective blood concentration over a 24-hour period. However, in the case of oral administration, it is generally known that the amount of drug absorbed differs depending on the influence of meals before and after taking the drug, and therefore, depending on the above formulation,
A certain level of medicinal efficacy cannot be expected. Furthermore, in order to obtain a long-acting formulation, it is necessary to increase the dosage. Therefore, when side effects occur, more serious symptoms occur.

(Problems to be Solved by the Invention) The present invention is intended to solve the above-mentioned conventional problems, and its purpose is to provide a drug containing ketotifen and/or a salt thereof, which has high skin permeability. The object of the present invention is to provide a sustained-release transdermal absorption preparation that can supply a sufficient amount of a drug even in a small amount or area. Another object of the present invention is to have the above-mentioned excellent properties, not cause any damage to the skin, and even in the event that side effects occur, the formulation can be peeled off from the skin to reduce or avoid side effects. The purpose of the present invention is to provide a transdermal absorption preparation that can be absorbed by the skin.

(Means for Solving the Problems) The transdermal absorption preparation of the present invention is a transdermal absorption preparation in which an adhesive layer containing a drug and an absorption enhancer for the drug is provided on a drug-impermeable flexible support. A formulation wherein the drug is 4-(1
-methyl-4-biperidylidene)-4H-benzo(4,
5] Cyclohepta[1,2-b)thiophene-10 (
9H)-one and/or a salt thereof; and the absorption enhancer contains liquid paraffin and/or silicone oil; the content of the liquid paraffin based on 100 parts by weight of the adhesive base of the adhesive layer is 1 to 300 parts by weight, and the content of silicone oil is 1 to 200 parts by weight; and the drug is present in the adhesive layer in an amount of 1 to 42 parts by weight.
The above object is thereby achieved.

The medicinal ingredient of the transdermal absorption preparation of the present invention is 4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)
cyclohepta[1,2-b)thiophene-10(9H
)-one (hereinafter referred to as ketotifen) and/or a salt thereof, and examples of the salt of ketotifen include acid addition salts.

2 usually when ketotifen is used in salt form.

An alkaline substance is added to the adhesive base. The addition of alkaline substances converts the ketotifen salt into a free base form, improving skin permeability. As an alkaline substance,
Potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide.

Sodium carbonate, sodium bicarbonate, phosphate.

Examples include borates, ammonia, dialkylamines, and trialkylamines.

Ketotifen is added in an amount of 1% to the total weight of the adhesive layer (total weight of adhesive base, drug, transdermal absorption enhancer, etc.) as described below.
It is contained in a proportion of ~42% by weight, preferably 3-20% by weight. When the content of ketotifen and/or its salt is less than 1% by weight, the medicinal efficacy is insufficient, and a large-area patch preparation is required to ensure the required dosage. Such preparations have a poor application window and are not suitable for long-term application. If the amount is more than 42% by weight, the drug will precipitate as crystals on the surface of the adhesive base, reducing the adhesion properties.

Liquid paraffin and/or silicone oil are used as the transdermal absorption enhancer contained in the transdermal absorption preparation of the present invention. Liquid paraffin is a highly refined colorless hydrocarbon oil. The liquid paraffin is contained in an amount of 1 to 300 parts by weight, preferably 1 to 150 parts by weight, based on 100 parts by weight of the adhesive base. Examples of silicone oils include dimethylpolysiloxane, methylvinylpolysiloxane, and methylphenylvinylpolysiloxane. This silicone oil is adhesive base 100%
1 to 200 parts by weight, preferably.

It is contained in a proportion of 1 to 150 parts by weight. If there is too little liquid paraffin and/or silicone oil, the skin permeability of the drug will be insufficient, and if it is too much, a so-called "residue residue" phenomenon will occur when the preparation is peeled off.

As the adhesive base used in the formulation of the present invention, an adhesive base that is pressure sensitive at room temperature can be used. For example, an acrylic adhesive base or a rubber adhesive base is used.

As the acrylic adhesive base, in particular (
Co)polymers and/or (co)polymers of the above (meth)acrylic acid alkyl ester and other functional monomers are preferably used.

The above (meth)acrylic esters include butyl (meth)acrylate, isobutyl (meth)acrylate,
Hexyl (meth)acrylate, Octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, (
isooctyl meth)acrylate.

Examples include decyl (meth)acrylate, isodecyl (meth)acrylate, lauryl (meth)acrylate, stearyl (meth)acrylate, methyl methacrylate, and ethyl methacrylate.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and the like. Examples of monomers having a hydroxyl group include hydroxyalkyl (meth)acrylates such as 2-hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate. As a hexamer having a carboxyl group.

Examples include α-β unsaturated carboxylic acids such as acrylic acid and methacrylic acid; maleic acid monoalkyl esters such as butyl maleate; maleic acid; fumaric acid; and crotonic acid. Maleic anhydride also provides the same (co)polymerization component as maleic acid. Examples of monomers having an amide group include acrylamide, alkyl (meth)acrylamides such as dimethylacrylamide and diethylacrylamide; alkyl ether methylol (meth)acrylamides such as butoxymethylacrylamide and ethoxymethylacrylamide, diaseptone acrylamide; vinylpyrrolidone, etc. . Examples of monomers having an amino group include dimethylamino acrylate.

Polymerizable monomers other than the above may be copolymerized,
Such polymerizable monomers include vinyl acetate, styrene 1 α-methylstyrene, and vinyl chloride. Acrylonitrile, ethylene, propylene.

Examples include butadiene.

The rubber adhesive base mainly contains a rubber elastic body, a tackifier resin, and if necessary, a modifier such as a softener, an antiaging agent, and the like. The rubber elastic material is natural rubber (cis-
1,4-isoprene) 1 synthetic rubber (trans-1,4-
isoprene), styrene-isoprene-styrene block copolymer, polyisobutylene. polyvinyl ether,
Polyurethane.

Polybutadiene, styrene-butadiene copolymer.

Suitable examples include styrene-isoprene copolymer, styrene-isoprene-butylene block copolymer, and silicone rubber. Examples of tackifier resins include rosin resins such as rosin and rosin derivatives (obtained by hydrogenation, disproportionate dipolymerization, esterification, etc.); terpene resins such as α-pinene 1 β-pinene; terpene phenol resins; fats. family-based, aromatic-based.

Alicyclic or copolymerized petroleum resins; alkylphenol resins; xylene resins and the like are used.

These tackifying resins are used in an amount of 20 to 200 parts by weight per 100 parts by weight of the rubber elastic body. As the softening agent, polybutene, process oil, liquid isobutylene, liquid polyacrylate, castor oil, cottonseed oil, palm oil, beeswax, carnauba wax, lanolin, etc. are used.

More preferably, the adhesive base used is a rubber adhesive base or a hydrophobic adhesive base made of a (meth)acrylic acid ester monomer (co)polymer having 7 or more carbon atoms. When liquid paraffin and/or silicone oil is added to these adhesive bases, the amount of drug permeation is significantly improved, and the adhesive properties are not impaired.

As the support for the patch preparation, a drug-impermeable support commonly used for patch preparations is used. Materials for such supports include cellulose acetate, ethyl cellulose, polyethylene terephthalate plasticized vinyl acetate-vinyl chloride copolymer, nylon ethylene-vinyl acetate copolymer,
Plasticized polyvinyl chloride, polyurethane, polyethylene,
Examples include polyvinylidene chloride and aluminum. These materials are used, for example, as a single-layer sheet (film) or a laminate of two or more sheets.

An adhesive layer made of a mixture of an adhesive base containing ketotifen and/or its salt, liquid paraffin and/or silicone oil 1, and optionally the above alkaline substance and other additives is formed on the surface of the support. and the preparation is obtained.

To form the adhesive layer, various coating methods such as a solvent coating method and a hot melt coating method can be used.

Among these, the solvent coating method is suitable. To form an adhesive layer using the solvent coating method 1. For example, dilute the adhesive base with an appropriate solvent, add the above drug, and absorption enhancers and other additives as necessary, and mix uniformly. Then, the obtained solution is applied to the surface of the support and dried. When adding alkaline substances.

Conveniently, the alkaline substance is added after being dissolved in a suitable solvent, such as an alcohol. Instead of applying the solution directly to the surface of the support, it may be applied onto a release paper coated with silicone resin or the like, and after drying, the solution may be brought into close contact with the support. Although the thickness of the adhesive layer is not particularly limited, it is usually 30 to 200 μm.

(Function) According to the present invention, by containing a predetermined absorption enhancer, a transdermal absorption patch containing ketotifen is obtained which can maintain a high blood concentration over a long period of time in a small area. It will be done. Therefore, sufficient medicinal efficacy can be obtained even with a small area. The absorption enhancer used in the present invention has no irritation to the skin and is highly safe. Therefore, occurrence of erythema is avoided even in people who are sensitive to skin irritation. Since the patch preparation of the present invention can be prepared into a patch preparation with a small area, it is easy to apply it over and over again, and there is little discomfort during application. Since the adhesive layer has a single and simple structure, it is easy to manufacture and can be manufactured into a thin shape. Such formulations, like the cream formulations disclosed in the prior art section, are removed from the skin surface through clothing, resulting in inconsistent absorption of the drug into the body; The absorption amount of the drug is not affected by food or other factors, and a predetermined blood concentration of the drug can be maintained for a long period of time.

(Example) The present invention will be described below with reference to Examples.

Preparation of formulation> Ura-tane-mau 1 2-ethylhexyl acrylate (hereinafter referred to as EIIA) 36.4 g (10 mol%), 2-methacrylic acid
Ethylhexyl 313.2 g (80 mol%), dodecyl methacrylate 50.4 g (to mol%) and L6-hexamethylene glycol dimethacrylate 80
0.02% by weight based on Kaneko Zuma) was added to the ethyl acetate solution, lauroyl peroxide (polymerization initiator) was added to conduct a polymerization reaction, and the ethyl acetate solution of the adhesive (solid content 43%) was added to the ethyl acetate solution.
97% by weight). 18.71 g of the obtained polymer (adhesive base) solution (solid content 8.2268 g)
1.24 g of liquid paraffin (15 parts by weight per 100 parts by weight of adhesive base), 1.44 g of ketothiphen fumarate
65g (13.3% by weight based on total solids) and 1m
Potassium hydroxide-isopropanol solution in mol/relative 6
A coating solution was prepared by adding ゜8 relative and mixing uniformly. Thickness 48
μm polyethylene terephthalate (hereinafter referred to as PET
Prepare a release paper with a silicone-treated sheet,
The above-mentioned coating liquid was applied to this so that the thickness after drying would be 80 μm, and it was dried in a gear oven at 60° C. for 30 minutes. This was followed by a 38 μm thick support (laminated with PET and ethylene-vinyl acetate copolymer; hereinafter referred to as PE).
T-EV^) were bonded together to obtain a patch.

Solid line ±1 As the rubber elastic body, 49.18 g (100 parts by weight) of styrene-isoprene-styrene block copolymer was used as the tackifying resin, and alicyclic hydrogenated petroleum resin (Alcon-P90 manufactured by Kanyo Kagaku Co., Ltd.) 68 .71 g (140 parts by weight) and polybutene (weight HV-30) as a softening agent.
0) 12.25g (25 parts by weight) was dissolved in 232.91g of cyclohexane to obtain an adhesive base solution with a solid content of 35.85% by weight. 5.71 g of liquid paraffin was added to 21.24 g of the obtained solution (solid content 7.6124 g).
(75 parts by weight based on 100 parts by weight of adhesive base), 2.0357 g of ketotifen fumarate (1% based on total solid content)
3.3% by weight), and 9.6% of potassium hydroxide-isopropanol/ml were uniformly mixed to obtain a coating solution. Using this, a patch was obtained in the same manner as in Example 1.

E) IA 302.0 g (65 mol%), vinylpyrrolidone 98.0 g (35 mol%), and 1.6-hexamethylene glycol dimethacrylate 80.0+ng
(0.02% by weight based on the total monomers), a polymerization reaction was carried out in the same manner as in Example 1, and the solid content was 36.50% by weight.
An ethyl acetate solution of the adhesive was obtained. This polymer? Liquid volume 30.31 g (solid content 11.0631 g),
Liquid paraffin 1.66g (15 parts by weight per 100 parts by weight of adhesive base), Ketotifen fumarate 1.945
2g (13.3% by weight based on total solids), and 1
A 9.1 mmol/ml potassium hydroxide isopropanol solution was added and mixed uniformly to prepare a coating solution. This coating solution was applied to a 48 μm thick PET sheet on release paper treated with silicone.

The patch was coated to a thickness of 100 μm after drying, and a patch was obtained in the same manner as in Example 1.

To 19.24 g of the polymer solution obtained in Example 1 (solid content 8.4598 g), 36
0 medical fluid 1.27g (15 parts by weight per 100 parts by weight of adhesive base), ketotiphen fumarate 1.4
923 g (13.3% by weight based on the total solid content) and 7.0 d of a 1 mmol/Fn1 hydroxyl potassium-isopropanol solution were added and mixed uniformly to prepare a coating liquid. A patch was obtained in the same manner as in Example 1 using this coating liquid.

To 20.05 g of the polymer solution obtained in Example 1 (solid content 8.8159 g) was added 1 liter of ketothiphene fumarate on carbon.
．． 3472 g (13.3% by weight based on the total solid content) and 6.3 ml of l mmol/d of potassium hydroxide-isopropanol were added and mixed uniformly to obtain a coating liquid. Using this, a patch was obtained in the same manner as in Example 1.

For comparison, 21.33 g (solid content 7.6468 g) of the adhesive base solution obtained in Example 2 was added with 1 1 g of ketothiphene fumarate.
．． 1685 g (13.3% by weight based on the total solid content) and 5.5 d of l mmol Z-related potassium hydroxide-isopropanol were added and mixed uniformly to obtain a coating liquid. Using this, a patch was obtained in the same manner as in Example 1.

Comparative ± 48.41 g of the polymer solution obtained in Main Example 3 (solid content 17.6697 g) was added with 2.7021 g of ketotifen fumarate (13.3% by weight based on the total solid content) and 1 mmol/d. 12.7 m of potassium hydroxide-isopropanol were added and mixed uniformly to obtain a coating solution. Using this, a patch was obtained in the same manner as in Example 1.

Examples 1 to 3 above. A drug permeability test through the skin was conducted using the patches obtained in Comparative Examples 1 to 3.

A diffusion cell 10 shown in FIG. 1 was prepared. This diffusion cell 1
0 has a receptor tank 1 having a cylindrical shape with a bottom and a donor tank 2 having a cylindrical shape with a bottom and an opening 21 at the bottom. The donor tank 2 has a pair of O-rings 31 above the receptor tank l.
and 32 are stacked airtightly and concentrically.

The receptor tank l has a sampling port 11 projecting laterally on its side. Between the 0 rings 31 and 32,
The skin 4 used for the test is sandwiched, and the opening 2 of the donor tank 2
1 is entirely covered by the skin 4.

Hairless mice (tli, 6 weeks old) were sacrificed by cervical dislocation, the skin was peeled off, and its subcutaneous fat composition was removed to obtain skin pieces. The adhesive patch (3, 14c4) was applied to this and set between both O-rings 31 and 32 of the diffusion cell 10. The receptor tank 1 was filled with the following receptor liquid, and the receptor liquid was stirred using a stirrer 12.

Receptor wave preparation method: NaH2PO45XI in distilled water
O-'M, NaH2PO42Xl0-'M, N
aC11,5x10-'M and gentamicin 10m
Dissolve 0.g in 500 ml of distilled water. lNNaNN
Adjust the pH to 7.2 for 3 times using an aqueous solution, add 100 ml of polyethylene glycol 400, and further add distilled water to make 1000 ml.

The entire diffusion cell 10 was placed in a constant temperature bath maintained at 37°C. 24 hours after the start of the test, sample port 1
1 ml of receptor fluid was collected from No. 1 and supplemented with 1 mR of new receptor fluid. The concentration of ketotifen in the collected receptor fluid was measured by high performance liquid chromatography. The results are shown in Table 1.

Table 1 vinegar.

Table 2 From Table 1, when liquid paraffin is added.

It can be seen that the amount of skin permeation is extremely large.

Sadatan I Above Examples 1 to 3. The adhesion properties of the patch obtained in Comparative Example 3 were evaluated according to the method of JIS Z-0237. In this experimental example, the holding power of each patch was measured under the conditions of a test temperature of 40° C., a test time of 20 minutes, and a load of 1000 g. Furthermore, the residual adhesive base (adhesive residue) after peeling was evaluated. The results are shown in Table 2. From Table 2, Example 1. It can be seen that patches Nos. 2 and 4 have high adhesiveness, and no adhesive residue is observed when they are used.

The patch of Example 3 is as follows.

Since it is an adhesive base made by copolymerizing a hydrophilic monomer such as vinylpyrrolidone, the addition of an absorption enhancer causes adhesive residue to occur, resulting in a slight decrease in adhesion.

(Effects of the Invention) According to the present invention, the transdermal skin contains ketotifen and/or its salt, has high skin permeability of the drug, and can supply a sufficient amount of the drug even in a small area. Absorbent patch formulations are provided. moreover.

The drug is also recognized to have an excellent effect in that it is released in a predetermined amount over a long period of time. Therefore, the therapeutic effect is high,
It has a good feeling of application and can be applied for a long time. Such preparations can be widely used as sustained release preparations for allergic diseases and the like.

Figure 1 is a perspective view of a diffusion cell for testing the skin permeability of drugs contained in formulations.

that's all

Claims (1)

[Scope of Claims] 1. A transdermal absorption preparation in which an adhesive layer containing a drug and an absorption enhancer for the drug is provided on a drug-impermeable flexible support, wherein the drug is 4- (1-methyl-4-piperidylidene)-4
H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one and/or a salt thereof, and the absorption enhancer contains liquid paraffin and/or silicone oil, The content of the liquid paraffin is 1 to 300 parts by weight and the content of silicone oil is 1 to 200 parts by weight based on 100 parts by weight of the adhesive base of the adhesive layer, and the drug is A transdermal absorption preparation containing 1 to 42% by weight in the drug layer. 2. The transdermal absorption preparation according to claim 1, wherein the adhesive base is a (co)polymer of a (meth)acrylic acid ester monomer having 7 or more carbon atoms, or a rubber-based adhesive base.