JPH09169636A - Plaster - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a plaster containing silicic anhydride as an irritation reducing agent, having high percutaneous absorption property of a medicine, simultaneously having extremely low skin irritation property and further, having good attaching property free from residue of paste and high safety. SOLUTION: This plaster is obtained by laminating a tacky agent layer containing (A) a tacky base, (B) a medicine, (C) 5-40wt.% higher fatty acid ester comprising a 10-18C fatty acid and a 1-20C alcohol, (D) 0.1-15wt.% at least one compound selected from the group consisting of an dicarboxylic acid, an oxycarboxylic acid, a polyoxy ethylenealkyl ether and an amide compound, (E) 1-20wt.% silicic anhydride and preferably further, (F) 0.1-30wt.% dialkanolamine and/or a trialkanolamine onto one surface of a support.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a patch for transdermal administration of drugs.

[0002]

2. Description of the Related Art In general, a transdermal patch is used to absorb a drug (physiologically active substance) through the skin in order to obtain a systemic or local drug effect. In contrast to the transdermal administration method using such a patch, in the conventional oral administration method, for example, when the drug is orally administered, the drug absorbed in the intestine is circulated and metabolized to the liver, so that the drug effect is exhibited. There was a defect that a considerable amount was decomposed before it was done.

On the other hand, in the case of transdermal administration, the absorbed drug does not pass through the liver during the initial circulation in the body, so that the drug effect is not significantly reduced by the metabolism of the liver and the drug absorbability is controlled. It becomes easy and it becomes possible to reduce side effects caused by a large amount of drug being absorbed in a short time. Furthermore, it becomes easy to maintain a constant blood concentration over a long period of time, and the number of drug administrations can be reduced. However, the stratum corneum on the skin surface
Since it has a barrier function of preventing foreign substances from entering the body, even if a drug is administered using a patch, it is difficult for the drug to penetrate the skin, and bioavailability is often low.

Therefore, a patch containing an absorption enhancer in order to weaken the barrier function of the stratum corneum and absorb a sufficient amount of a drug has been disclosed (US Pat. No. 19162, JP-A-4-342531). Issue). However, these skin acting absorption enhancers are often irritating to the skin. Further, in JP-A-3-291217, a hydrophilic silicic acid anhydride and a hydrophobic silicic acid anhydride are added in order to obtain an absorption promoting effect by adding a large amount of a fatty acid ester and further enhance the cohesive force of the pressure-sensitive adhesive layer. Techniques for combined use are disclosed. However, for hydrophobic drugs represented by estradiol, the fatty acid ester does not have a sufficient absorption promoting effect. Further, JP-A-62-240614 and JP-A-2-102656 disclose a technique in which a fatty acid ester and an absorption enhancer acting on the skin are used in combination. Although a promoting effect is observed, skin irritation increases depending on the effect.

[0005]

DISCLOSURE OF THE INVENTION The present invention is intended to solve the above problems, and its object is to have a high transdermal absorption effect of a drug, low skin irritation, and safe for living organisms.
Further, it is a point to provide an adhesive patch having good adhesive properties with no adhesive residue or the like.

[0006]

In the patch of the present invention, an adhesive layer is laminated on one side of a support, and the adhesive layer comprises an adhesive base, a drug, a higher fatty acid ester, a dicarboxylic acid, an oxycarboxylic acid. , At least one selected from the group consisting of polyoxyethylene alkyl ether and amide compounds, and an irritation reducing agent.

As the above-mentioned adhesive base, it is sufficient if the adhesive has an adhesive force capable of fixing the patch on the skin surface at room temperature for a long time,
There is no particular limitation. For example, an acrylic-based, rubber-based, silicone resin-based pressure-sensitive adhesive can be used, and an acrylic-based and rubber-based pressure-sensitive adhesive is usually used.

Acrylic pressure-sensitive adhesives are particularly advantageous because of their adhesiveness and the like, and (meth) aliphatic alcohols having 1 to 18 carbon atoms.
A (co) polymer of (meth) acrylic acid alkyl ester obtained from acrylic acid and / or a copolymer of the above (meth) acrylic acid alkyl ester and other functional monomer are preferable.

Examples of the alkyl (meth) acrylate ester include ethyl (meth) acrylate, butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, and octyl (meth) acrylate. , 2-ethylhexyl (meth) acrylate,
Isooctyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, and the like.

Examples of the other functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group and a monomer having an amino group.

Examples of the above-mentioned monomer having a hydroxyl group include 2-hydroxyethyl (meth) acrylate,
Hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate such as hydroxypropyl (meth), and polyoxyethylene (4)
Examples include lauryl ether and the like.

Examples of the monomer having a carboxyl group include α, β such as acrylic acid and methacrylic acid.
-Unsaturated carboxylic acids, maleic acid monoalkyl esters such as butyl maleate, (anhydrous) maleic acid, fumaric acid, crotonic acid and the like.

The monomers having an amide group include:
Examples thereof include alkyl (meth) acrylamides such as acrylamide, dimethyl acrylamide and diethyl acrylamide, alkyl ether methylol (meth) acrylamides such as butoxymethyl acrylamide and ethoxymethyl acrylamide, and diacetone acrylamide.

As the above-mentioned monomer having an amino group,
For example, dimethylaminoethyl acrylate and the like can be mentioned.

Further, as other functional monomers other than the above, vinyl acetate, N-vinyl-2-pyrrolidone,
Examples thereof include acrylonitrile and styrene.

In order to enhance the cohesiveness of the acrylic adhesive,
Further, it is preferable that a polyfunctional monomer is contained if necessary. The addition of this polyfunctional monomer causes only slight crosslinking between the resulting polymers, thereby increasing the internal cohesion of the adhesive. Therefore, the so-called glue residue phenomenon at the time of peeling the adhesive is almost eliminated irrespective of the properties of the attached skin and the amount of perspiration. Moreover, the addition of this polyfunctional monomer has no effect on the drug release or hypoallergenicity. The polyfunctional monomer is not particularly limited, and examples thereof include di (meth) acrylic acid ester, tri (meth) acrylic acid ester, and tetra (meth) acrylic acid ester.

Examples of the above di (meth) acrylic acid ester include polymethylene glycols such as hexamethylene glycol and octamethylene glycol, and (meth)
Di (meth) acrylic acid ester obtained by combining acrylic acid, di (meth) acrylic acid ester obtained by combining with acrylic acid, polyalkylene glycols such as polyethylene glycol and polypropylene glycol, and (meth) acrylic acid Can be mentioned.

Examples of the tri (meth) acrylic acid ester include trimethylolpropane tri (meth) acrylic acid ester and glycerin tri (meth) acrylic acid ester. Examples of the tetra (meth) acrylic acid ester include pentaerythritol tetra (meth) acrylic acid ester.

The above polyfunctional monomers may be used in combination of two or more kinds. If the amount of the polyfunctional monomer is small, the effect of improving the internal cohesive force by cross-linking is small, and if it is large, the adhesive obtained by the polymerization is apt to cause gelation, and the diffusion and release of the drug are also affected.
0.005 to 100% of all monomers used for production of adhesive base
It is preferably used in a proportion of 0.5% by weight.

If desired, a tackifier such as a rosin resin, a polyterpene resin, a coumarone-indene resin, a petroleum resin, or a terpene-phenol resin may be added to the acrylic pressure-sensitive adhesive.

The above-mentioned acrylic pressure-sensitive adhesive is polymerized by an ordinary known method, for example, prepared by blending the above-mentioned monomers in the presence of a polymerization initiator and carrying out solution polymerization. However, the polymerization conditions are appropriately selected mainly depending on the type of the monomer.

As the acrylic pressure-sensitive adhesive, in particular, 45 to 97% by weight of a (meth) acrylic acid alkyl ester having an alkyl group with 1 to 18 carbon atoms and 3 to 55% by weight of vinylpyrrolidone are polymerized. Copolymers or copolymers of (meth) acrylic acid alkyl esters having an alkyl group with 6 or more carbon atoms are preferably used.

Examples of the rubber-based pressure-sensitive adhesive include natural rubber, synthetic isoprene, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene,
Styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer rubber elastic body, for example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin,
Tackifiers such as terpene-phenolic resins and, if necessary, softening agents such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, liquid polyacrylate; fillers such as titanium oxide; aging prevention of butylhydroxytoluene, etc. A product obtained by adding an appropriate amount of the agent or the like is used. In particular, it is preferable to use 100 to 100 parts by weight of a styrene-isoprene-styrene copolymer to which 50 to 200 parts by weight of a tackifier such as a petroleum resin is added.

As the above silicone resin adhesive, one containing polyorganosiloxane as a main component is used.

The drug is not particularly limited as long as it can permeate the biological membrane transdermally, and examples thereof include antipyretic and analgesic anti-inflammatory agents such as indomethacin, piroxicam, indomethacin farnesyl, steroidal anti-inflammatory agents and isosorbide nitrate. Vasodilators, hypertension / arrhythmia agents, antihypertensive agents, antitussive expectorants, antitumor agents, local anesthetics, hormone agents,
Asthma / nasal allergy treatment agent, antihistamine, anticoagulant, antispasmodic agent, cerebral circulation / metabolic agent, antidepressant / anxiety agent,
Vitamin D preparations, hypoglycemic agents, anti-ulcer agents, hypnotics, antibiotics and the like can be mentioned.

The content of the above-mentioned drug varies depending on the kind of the drug and the purpose of use of the preparation, but when the content is low, sufficient permeability cannot be obtained and the therapeutic effect is lowered, and when it is high, crystals are deposited in the pressure-sensitive adhesive layer and sticking Since the adhesiveness of the adhesive layer is reduced,
1-40% by weight is preferred.

In the present invention, the higher fatty acid ester is an ester composed of a fatty acid having 10 to 18 carbon atoms and an alcohol having 1 to 20 carbon atoms.

The above-mentioned higher fatty acid ester is used in order to promote the distribution of the drug or the like to the skin and enhance the transdermal absorbability of the drug.
It is preferable that (octanol / water partition coefficient) = P is 4 to 16 as the value of logP. The higher fatty acid ester is not particularly limited, but is preferably liquid at 30 ° C. or higher.

As the above-mentioned fatty acid having 10 to 18 carbon atoms,
For example, saturated aliphatic monocarboxylic acids such as capric acid, lauric acid, myristic acid, palmitic acid and stearic acid; unsaturated aliphatic monocarboxylic acids such as palmitoleic acid, oleic acid, vaccenic acid, linoleic acid and linolenic acid;
Examples thereof include saturated aliphatic dicarboxylic acids such as sebacic acid.

Examples of the alcohol having 1 to 20 carbon atoms include methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, capryl alcohol and nonyl. Examples thereof include alcohols, decyl alcohol, lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, and other saturated aliphatic alcohols.

Examples of the higher fatty acid ester include isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, diethyl sebacate, etc. Of these, isopropyl myristate and isopropyl palmitate are particularly preferred.

When the content of the higher fatty acid ester is low, the plasticizing effect cannot be sufficiently obtained, and when it is high, the cohesive force of the pressure-sensitive adhesive layer cannot be obtained, and a paste residue is generated to reduce the pressure-sensitive adhesive layer. It is 5 to 40% by weight, preferably 8 to 30% by weight.

In the present invention, at least one selected from the group consisting of dicarboxylic acids, oxycarboxylic acids, polyoxyethylene alkyl ethers and amide compounds is used.

The dicarboxylic acid is not particularly limited, and examples thereof include fumaric acid and maleic acid. Of these, fumaric acid is particularly preferable. The oxycarboxylic acid is not particularly limited, and examples thereof include lactic acid and malic acid, and among these, lactic acid is particularly preferable.

The polyoxyethylene alkyl ether is not particularly limited, and examples thereof include polyoxyethylene lauryl ether and polyoxyethylene oleyl ether. The amide compound is not particularly limited as long as it has an amide group, and examples thereof include fatty acid ethanolamide and N-acyl sarcosine, and of these, lauric acid diethanolamide is particularly preferable.

The above dicarboxylic acid, oxycarboxylic acid, polyoxyethylene alkyl ether and amide compound may be used alone or in combination.

When the content of at least one selected from the above-mentioned dicarboxylic acid, oxycarboxylic acid, polyoxyethylene alkyl ether and amide compound is small, sufficient skin transfer amount, skin permeation amount, etc. cannot be obtained, and when it is large. Although the skin permeability is high, the skin irritation becomes a problem, so the content in the adhesive layer is 0.1 to 15% by weight, preferably 1 to 6% by weight.

In the present invention, at least one of the above dicarboxylic acid, oxycarboxylic acid, polyoxyethylene alkyl ether and amide compound is used in combination with dialkanolamine and / or trialkanolamine to enhance skin irritation. The absorption promoting effect can be further enhanced synergistically.

In the dialkanolamine and / or trialkanolamine, the structure of the alkanol group is not particularly limited and may be linear or branched. Examples of the dialkanolamine include diethanolamine, diisopropanolamine and di-n-.
Examples include propanolamine and dibutanolamine. Examples of the trialkanolamine include triethanolamine, triisopropanolamine, tri-n-propanolamine, tributanolamine, and the like. The dialkanolamine and / or trialkanolamine may be used alone or in combination of two or more kinds.

When the content of the above dialkanolamine and / or trialkanolamine is small, the sufficient effect cannot be obtained, and when it is large, the skin permeability is high, but the cohesive force of the pressure-sensitive adhesive layer is lowered and the skin is peeled off. Since the adhesive residue will occur in (3), it is 0.1 to 30% by weight, and preferably 1 to 20% by weight in the pressure-sensitive adhesive layer.

In the present invention, silicic acid anhydride is used as the irritation reducing agent. The above-mentioned silicic acid anhydride is amorphous silicon dioxide having a hydroxyl group on the surface, its primary particle diameter is about 5 to 100 nm, and primary particles are usually present in the form of agglomerated secondary particles. The degree of aggregation depends on the manufacturing method (eg, gas phase method, liquid phase method, gelation method, etc.). The specific surface area is generally 100 to 1,000 m ² / g, and the higher the specific surface area, the greater the cohesive force.

Examples of the silicic acid anhydride include hydrophilic silicic acid whose surface is entirely covered with hydroxyl groups, hydrophobic silicic acid anhydride in which alkylsilane is bonded to a part of the hydroxyl groups on the surface, or which is surface-treated with silicone oil. It is preferable to use hydrophilic silicic acid anhydride. Incidentally, when the content of the hydrophilic silicic acid anhydride becomes large, the thixotropic property becomes too high and cannot be applied depending on the type of the compounding liquid at the time of production of the pressure-sensitive adhesive, so that the hydrophobic silicic acid anhydride is used for the purpose of reducing the thixotropic property. It is preferable to use them in combination.

When the content of silicic acid anhydride is small, the skin irritation reducing effect becomes insufficient, and when it is large, the adhesive strength of the pressure-sensitive adhesive decreases, so that the content of the pressure-sensitive adhesive layer is 1 to 20% by weight, preferably 5 to 5. It is 15% by weight.

In the present invention, by containing the above-mentioned silicic acid anhydride, skin irritation is reduced, and further reduction of cohesive force of the pressure-sensitive adhesive due to the inclusion of the plasticizer is improved.

The support is not particularly limited as long as it has flexibility and drug transfer-preventing property.
Examples thereof include films of polyethylene, polyurethane, polyethylene terephthalate, vinyl acetate-ethylene copolymer and the like, or those obtained by subjecting these to a drug transfer preventing treatment. The thickness of the support is usually preferably 500 μm or less, more preferably 2 to 150 μm.

The patch of the present invention can be prepared according to a conventional method for producing an adhesive tape, and for example, a solvent coating method, a hot melt coating method, an electron beam curing emulsion coating method, etc. can be used. The coating method is preferred. The coating of the pressure-sensitive adhesive layer varies depending on the purpose of use, but is usually 20 to 2
The thickness is set to 00 μm.

In the patch of the present invention, after the pressure-sensitive adhesive layer is once formed on the release paper, this pressure-sensitive adhesive layer may be laminated on the support. The release paper may be laminated until use to protect the adhesive layer. The release paper is not particularly limited, and examples thereof include those obtained by subjecting a polyethylene terephthalate film to silicon treatment.

The patch of the present invention can reduce skin irritation by containing silicic acid anhydride. Due to this, in order to enhance the skin permeability of the drug, one or more kinds selected from the group consisting of dicarboxylic acids, oxycarboxylic acids, polyoxyethylene alkyl ethers and amide compounds, and higher fatty acid ester should be contained in the patch. Therefore, it is possible to achieve both the effectiveness of effectively absorbing the drug from the skin and the safety of reducing skin irritation.

When a dialkanolamine and / or a trialkanolamine is used in combination, the absorption promoting effect can be synergistically enhanced while the skin irritation is reduced. This also achieves both effectiveness and safety.

Further, the decrease in the cohesive force of the pressure-sensitive adhesive due to the inclusion of higher fatty acid and dialkanolamine and / or trialkanolamine is also improved by the inclusion of silicic anhydride, and good adhesiveness without adhesive residue is obtained. A patch having the same can be provided.

[0051]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

[Preparation of Adhesive Base Solution A] Acrylic Acid 2-
Ethylhexyl 10 mol% (36.4 g), dodecyl methacrylate 10 mol% (50.2 g), 2-ethylhexyl methacrylate 80 mol% (313.3).
g) and 52.0 mg of 1,6-hexamethylene glycol dimethacrylic acid ester were charged in a separable flask, and 400 g of ethyl acetate was further added to adjust the monomer concentration to 50% by weight. This solution was heated to a temperature of 60 ° C. under a nitrogen atmosphere, a solution of 2 g of lauroyl peroxide dissolved in 100 g of cyclohexane and 240 g of ethyl acetate were added little by little, and polymerization was carried out for 12 hours to obtain an acrylic resin having a solid content of 35% by weight. A system adhesive base solution A was obtained.

[Preparation of Adhesive Base Solution B] Acrylic Acid 2-
Ethylhexyl 65 mol% (302 g), N-vinyl-2-pyrrolidone 35 mol% (98 g), and 1,6
-Hexamethylene glycol dimethacrylic acid ester (40.0 mg) was charged into a separable flask, and 400 g of ethyl acetate was further added to adjust the monomer concentration to 50% by weight. This solution was heated to a temperature of 60 ° C. under a nitrogen atmosphere,
A solution prepared by dissolving 2 g of lauroyl peroxide in 100 g of cyclohexane and 240 g of ethyl acetate were added little by little,
Polymerization was performed for 12 hours to obtain an acrylic adhesive base solution B having a solid content of 35% by weight.

[Preparation of Adhesive Base Solution C] 200 g of ethyl acrylate, 180 g of octyl acrylate, and 20 g of N-vinyl-2-pyrrolidone were placed in a separable flask equipped with a stirrer and a cooling device, and 400 g of ethyl acetate was added. After adjusting the monomer concentration to 50% by weight, the temperature of this solution was raised to 80 ° C. under a nitrogen atmosphere, and a solution of 4 g of lauroyl peroxide in 100 g of cyclohexane and 243 g of ethyl acetate were added little by little, and after 12 hours. A polymerization reaction was performed to obtain an acrylic pressure-sensitive adhesive base solution C having a solid content of 35% by weight.

[Preparation of Adhesive Base Solution D] 38 parts by weight of a styrene-isoprene-styrene block copolymer (Califlex 1107P, Shell Chemical Co.) was dissolved in 260 parts by weight of cyclohexane, and the alicyclic group was added thereto. 58 parts by weight of saturated hydrocarbon resin (Alcon P85, manufactured by Arakawa Chemical Co., Ltd.),
And dibutylhydroxytoluene (Orient BHT,
1 part by weight (manufactured by Orient Chemical Co., Ltd.) was added, and the mixture was thoroughly stirred and completely dissolved to obtain adhesive base solution D.

(Examples 1 to 9 and Comparative Examples 1 to 5) Adhesive bases (numerical values in the table indicate weight% as solid content) and indomethacin (“IM” in the table) having the compositions shown in Table 1. ,), Silicic anhydride (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd., indicated by “ARS” in the table), isopropyl myristate (indicated by “IPM” in the table), and lauric acid diethanolamide (indicated by “LD” in the table). , Polyoxyethylene (2) lauryl ether (indicated by "BL" in the table), lactic acid, diethanolamine (indicated by "DEA" in the table) and diisopropanolamine (indicated by "DIA" in the table)
Were mixed, and ethyl acetate was added so that the final solid content was 25% by weight, to obtain a coating solution which was made uniform throughout.

This coating solution was applied onto a silicone-treated release paper having a thickness of 38 μm and a polyethylene terephthalate film (hereinafter referred to as “PET”) having a thickness of 80 μm after drying.
And was dried in a gear oven at 60 ° C. for 30 minutes to form an adhesive layer. This, thickness 31μ
m of PET and an ethylene-vinyl acetate copolymer laminated film were laminated to prepare a patch.

The following tests were conducted on the patch obtained above. [Skin Irritation Test] The abdomen of a guinea pig (5 weeks old, male) was shaved, and a sample obtained by punching out the patch of Examples 1 to 9 and Comparative Examples 1 to 5 to 3.14 cm 2 was applied. After 24 hours, the sample was peeled off, and after 30 minutes and 24 hours, skin irritation was determined according to the following criteria. The test is n = 6
The average value was taken. The results are shown in Table 1.

[Skin Permeability Test] Hairless mice (6 weeks old, male) were sacrificed by cervical dislocation, and then the skin was immediately peeled off to remove subcutaneous fat and set in Franz cells. 2. The patches of Examples 1 to 9 and Comparative Examples 1 to 5 were prepared as described in 3.
The sample punched out to 14 cm ² was applied on the skin excised from the hairless mouse. Sodium hydrogen phosphate (5 × 10 ^-4
mol), disodium hydrogen phosphate (2 × 10 ⁻⁴ mo
l), sodium chloride (1.5 × 10 ⁻¹ mol), and gentamicin 10 mg were dissolved in distilled water, the pH was adjusted to 7.2 with 0.1N sodium hydroxide aqueous solution, and distilled water was added. Receptor solution was prepared with 1000 ml.

The receptor solution described above was placed in the receptor layer below the Franz cell and placed in a constant temperature bath maintained at 37 ° C. from the start of the test. Twenty-four hours after the start of the test, a liquid was collected from the lower receptor layer, and the amount of indomethacin in the liquid (skin permeation amount) was measured by high performance liquid chromatography. The sample takes the average value with n = 3,
The value of the sample of Comparative Example 5 was set to 100%, and the transmission amount of other samples was obtained. The skin permeation amount of the sample of Comparative Example 5 was 0.0
11mg / cm was ² / 24hr. The results are shown in Table 1.

[0061]

[Table 1]

(Examples 10 to 19 and Comparative Examples 6 to 9) With the composition shown in Table 2, an adhesive base (numerical values in the table indicate weight% as solid content) and isosorbide dinitrate ("ISD" in the table).
N "), silicic anhydride (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd., indicated by" ARS "in the table), lauric acid diethanolamide (indicated by" LD "in the table), polyoxyethylene (2) lauryl ether (see table). Medium (indicated by “BL”), lactic acid, diethanolamine (indicated by “DEA” in the table), diisopropanolamine (indicated by “DIA” in the table) and triethanolamine (indicated by “TEA” in the table), Ethyl acetate was added so that the final solid content was 20% by weight, to obtain a coating solution which was uniform throughout.

This coating solution was applied to a release paper obtained by treating a 38 μm-thick PET film with silicon so that the thickness after drying was 1
It was applied so as to have a thickness of 00 μm and dried in a gear oven at 60 ° C. for 30 minutes to form an adhesive layer. This was laminated on the PET side of a laminate of PET and PET non-woven fabric (8 g / m ² ) having a thickness of 6 μm to prepare a patch.

The following tests were carried out on the patch obtained above. [Skin transfer amount test] Rats (7-week-old, male) were shaved on their backs, and the samples obtained by punching out the patches of Examples 10 to 19 and Comparative Examples 6 to 9 to 3.14 cm ² were attached. After 24 hours, the sample was peeled off, immersed in methanol, the amount of ISDN extracted in methanol was measured by high performance liquid chromatography, and the residual amount of ISDN after the test was determined. Also,
The patches of Examples 10 to 19 and Comparative Examples 6 to 9 were prepared as described in 3.
After the sample punched out to 14 cm ² was immersed in methanol, the amount of ISDN extracted in methanol was measured by high performance liquid chromatography to determine the initial ISDN content.
The amount transferred to the skin was determined from the obtained initial content of ISDN and the remaining ISDN content. The test took the average value as n = 6. The results are shown in Table 2.

[Skin Irritation Test] A sample was applied in the same manner as in Example 1, and after 48 hours, the sample was peeled off, and No. 3
The judgment was performed after 0 minutes and 24 hours. The test was n = 6, and the average value was taken. The results are shown in Table 2.

[0066]

[Table 2]

(Examples 20 to 26 and Comparative Examples 10 to 1)
3) Solvent the adhesive base B solution at 105 ° C (ethyl acetate)
It was dried to the odor and the formulation shown in Table 3 was added to the dried adhesive base B. Further, tetrahydrofuran was added so that the final solid content was 25% by weight, and the mixture was uniformly stirred to obtain a coating liquid. In the table, "PX" indicates piroxicam.

This coating solution was applied onto a release paper, which was obtained by treating a PET film having a thickness of 38 μm with silicon, with a thickness of 8 after drying.
It was applied so as to have a thickness of 0 μm and dried in a gear oven at 60 ° C. for 30 minutes to form an adhesive layer. This was attached to a laminated film of PET and an ethylene-vinyl acetate copolymer having a thickness of 31 μm to prepare a patch.

The following tests were carried out on the patches obtained above. [Skin Permeability Test] Hairless mice (6 weeks old, male) were sacrificed by cervical dislocation, the skin was immediately peeled off, subcutaneous fat was removed, and the cells were set in Franz cells. The patch of Examples 20-26 and Comparative Examples 10-13 was prepared as 3.14c.
The sample punched out to m ² was applied on the skin removed from the hairless mouse. Sodium hydrogen phosphate (5 × 10 ^-4 mo
l), disodium hydrogen phosphate (2 × 10 ⁻⁴ mol),
Sodium chloride (1.5 × 10 ⁻¹ mol) and gentamicin 10 mg were dissolved in distilled water, the pH was adjusted to 7.2 with 0.1N aqueous sodium hydroxide solution, and distilled water was added to make 1000 ml. A receptor solution was prepared.

The receptor liquid was put in the receptor layer below the Franz cell and placed in a constant temperature bath kept at 37 ° C. after the test was started. Twenty-four hours after the start of the test, a liquid was collected from the lower receptor layer, and the amount of piroxicam in the liquid (skin permeation amount) was measured by high performance liquid chromatography. For the sample, the average value was taken with n = 3, and the value of Comparative Example 10 was expressed as 100. Comparative Example 10
The amount of skin permeation was 4.2μg / cm ² / 24hr. The results are shown in Table 3.

[Skin Irritation Test] Guinea pigs (5 weeks old,
The male abdomen was shaved, and a patch obtained by punching out the patch of Examples 20 to 26 and Comparative Examples 10 to 13 to 3.14 cm ² was applied. After 24 hours, the sample was peeled off, and 24 hours later, skin irritation was evaluated according to the following criteria. The test was n = 6, and the average value was taken. The results are shown in Table 3.

[0072]

[Table 3]

(Examples 27 to 32 and Comparative Examples 14 to 1)
8) Adhesive base having the composition shown in Table 4 (numerical values in the table indicate% by weight as solid content), indomethacin farnesyl as a drug (indicated by “IF” in the table), silicic anhydride (Aerosil 200, Nippon Aerosil) Manufactured by the company, indicated by "ARS" in the table), isopropyl myristate (indicated by "IPM" in the table), lauric acid diethanolamide (indicated by "LD" in the table), polyoxyethylene (2) lauryl ether (in the table) (Denoted by “BL”), lactic acid and diethanolamine (denoted by “DEA” in the table), and the final solid content is 30.
Ethyl acetate was added so as to be a weight% to obtain a coating solution which was uniform throughout.

This coating solution was applied to a release paper obtained by treating a 38 μm-thick PET film with silicon so that the thickness after drying was 1
It was applied so as to have a thickness of 00 μm and dried in a gear oven at 60 ° C. for 30 minutes to form an adhesive layer. This was attached to a laminated film of PET and an ethylene-vinyl acetate copolymer having a thickness of 31 μm to prepare a patch.

The following test was conducted on the patch obtained above. [Skin transfer amount test] In the same manner as in Example 10, the skin transfer amount of indomethacin farnesyl was measured. The test is n = 4
Then, the average value was taken as the amount transferred to the skin. Table 4 shows the results
It was shown to.

[Skin Irritation Test] Skin irritation was determined in the same manner as in Example 1. The test was n = 6, and the average value was taken. The results are shown in Table 4.

[0077]

[Table 4]

(Examples 33 to 38 and Comparative Examples 19 to 2)
3) A composition prepared by dissolving an adhesive base (the numerical values in the table represent% by weight as a solid content) and indomethacin (indicated by "IM" in the table) as a drug with a small amount of ethyl acetate in the composition shown in Table 5 ( Numerical values in the table indicate the weight% of the drug itself), silicic anhydride (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd., indicated by "ARS" in the table), isopropyl myristate (indicated by "IPM" in the table), diethanolamine laurate. (Indicated by "LD" in the table), polyoxyethylene (2) lauryl ether (indicated by "BL" in the table), lactic acid and diethanolamine (indicated by "DEA" in the table) were mixed to give a final solid content of 20. Cyclohexane was added so as to be a weight% to obtain a coating liquid which is uniform throughout.

This coating solution was applied to a 38 μm-thick PET film siliconized release paper to give a dry thickness of 1
It was applied so as to have a thickness of 00 μm and dried in a gear oven at 60 ° C. for 30 minutes to form an adhesive layer. This was attached to a laminated film of PET and an ethylene-vinyl acetate copolymer having a thickness of 31 μm to prepare a patch.

The following test was performed on the patch obtained above.
Was done. [Skin Permeability Test] Indometasi in the same manner as in Example 1.
The amount of skin permeation of the skin was measured. The test is flat with n = 3
Take the average value and set the value of the sample of Comparative Example 23 as 100%
The transmission amount of the sample was determined. The skin of the sample of Comparative Example 23
Skin penetration is 0.013mg / cm ^Two/ 24 hr
Was. The results are shown in Table 5.

[Skin Irritation Test] Skin irritation was determined in the same manner as in Example 1. The test was n = 6, and the average value was taken. Table 5 shows the results.

[0082]

[Table 5]

[0083]

EFFECTS OF THE INVENTION The patch of the present invention is as described above and has not only high percutaneous absorption of a drug but also very low skin irritation and good adhesiveness with no adhesive residue. ,
It is possible to obtain a patch that is effective in treating various diseases and has high safety.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display area A61K 47/14 A61K 47/14 E 47/16 47/16 E (72) Inventor Kunio Yonedo Hyogo Sekisui Chemical Co., Ltd. 5-8-6 Shioe, Amagasaki City, Japan

Claims (2)

[Claims] 1. A patch comprising an adhesive layer laminated on one surface of a support, wherein the adhesive layer comprises an adhesive base, a drug, a fatty acid having 10 to 18 carbon atoms and an alcohol having 1 to 20 carbon atoms. 5 to 40% by weight of higher fatty acid ester consisting of, and 0.1 to 15% by weight of at least one selected from the group consisting of dicarboxylic acid, oxycarboxylic acid, polyoxyethylene alkyl ether and amide compound, and irritation reducing agent An adhesive patch containing 1 to 20% by weight of silicic acid anhydride as. 2. A patch comprising an adhesive layer laminated on one surface of a support, wherein the adhesive layer comprises an adhesive base, a drug, a fatty acid having 10 to 18 carbon atoms and an alcohol having 1 to 20 carbon atoms. 5 to 40% by weight of a higher fatty acid ester consisting of, and 0.1 to 15% by weight of at least one selected from the group consisting of dicarboxylic acids, oxycarboxylic acids, polyoxyethylene alkyl ethers and amide compounds, and anhydrous as an irritation reducing agent. 1 to 20% by weight of silicic acid and 0.1 to 30% by weight of dialkanolamine and / or trialkanolamine
An adhesive patch containing: