JPH05294832A - Dermal plaster - Google Patents

Abstract

PURPOSE:To obtain the subject plaster by forming a plaster layer composed of (+ or -)-4-[2-hydroxy-3-[3-(2-methoxyphenoxy)-2-propylamino]propoxy]-2(2H)- isoquinoline as a medicine for improving hypertension and an adhesive base material on a substrate. CONSTITUTION:This invented dermal plaster is obtained by forming a sticky layer containing a tacky base material (especially a synthetic resin, natural rubber, etc., exhibiting -70 to -10 deg.C glass transition temperature) and (+ or -)-4-[2- hydroxy-3-[3-(2-methoxy)-2-propylamino]propoxy]-2(2H)-isoquinoline as a hypertensive drug or further a p-hydroxybenzoic acid ester on a substrate and useful for percutaneous administration of the drug to the circulation system in the body by putting it on the skin. As the substrate, e.g. a laminated film of polyethylene terephthalate and an ethylene vinyl acetate copolymer is preferably used and the thickness is 5 to 150mum. This plaster can mildly increase the concentration of the medicine in blood at the initial stage and the effective concentration in blood can be maintained over a long period during an administration period.

Description

Detailed Description of the Invention

[0001]

The present invention relates to (±) -4- [2-hydroxy-3-] recently developed as a therapeutic drug for hypertension.
Regarding a novel dosage form of (3- (2-methoxyphenoxy) -2-propylamino) propoxy] -1 (2H) -isoquinolinone (hereinafter abbreviated as Compound A), more specifically, it is applied to the skin. Then, it relates to a percutaneous absorption patch used for administering the drug through the skin to the circulatory system in the body.

[0002]

2. Description of the Related Art As therapeutic drugs for hypertension, that is, antihypertensive agents, antihypertensive diuretics, sympathetic nerve inhibitors, vasodilators, etc. are known, and various new antihypertensive agents have been developed in recent years. Among these antihypertensive agents, Compound A is one of those recently developed, is a new antihypertensive agent having both α-blocking action and β-blocking action, and exerts remarkable drug effect (JP-A-59-59). 116269).

[0003]

The antihypertensive agent is generally provided in the form of a tablet and is generally administered orally. The α-blocker and the β-blocker exert a reliable blood pressure lowering effect by oral administration, but on the other hand, there is a problem that side effects such as dizziness and dizziness cannot be avoided. In addition, once a side effect occurs, it is very difficult to remove the side effect. Therefore, as an α-blocker and a β-blocker, the blood concentration thereof is gradually increased after administration, and a pharmaceutical preparation that can be removed at a certain concentration for a long time and when side effects occur can be removed. It was expected to appear.

In order to achieve the above-mentioned demand, various attempts have conventionally been made to control the disintegration property of tablets. However, the method of controlling the disintegration property of the tablet has a problem that the pH in the gastrointestinal tract is
The disintegration / absorption of the drug greatly varies depending on the condition of the contents, contents, etc., and it has been difficult to maintain a constant blood concentration of the drug. Not only that, even if the disintegration property of the tablet can be controlled, the side effect cannot be removed once the side effect once appears.

Therefore, the object of the present invention is to gradually increase the blood level of Compound A after administration, and then to gradually supply Compound A so as to maintain a constant blood level. An object of the present invention is to provide a compound A preparation capable of promptly eliminating the side effect when the above-mentioned symptoms occur.

[0006]

Means and Actions for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention can achieve the above-mentioned problems if a compound A is used to form a transdermal patch. It was found that the present invention has been accomplished. That is, the first invention of the present application is a transdermal absorption patch obtained by forming a patch layer containing an adhesive base and compound A on a support. A second invention of the present application is a transdermal absorption patch formed by forming a patch layer containing an adhesive base, compound A and p-hydroxybenzoic acid ester on a support.

In the first and second inventions of the present application, since the preparation containing the compound A as an essential component is in the form of a transdermal patch, the above-mentioned drawbacks of the conventional compound A-containing tablets can be solved. You can That is, when a side effect occurs, the side effect can be suppressed by removing it from the skin. In addition, various transdermal absorption type drugs, for example, various effects such as variations in the dose or stains on clothes due to the method of spray application of drug-containing solution or application of ointment The problem can be solved.

The inventors of the present application have paid attention to the above advantages in the case of being configured as a percutaneous absorption patch as described above,
Furthermore, as a result of a study on a transdermal absorption patch capable of reliably absorbing Compound A from the skin and gradually increasing the blood concentration after administration, and further maintaining a constant blood concentration, the adhesive layer was found to be on the skin. Suitable conditions are that they are firmly adhered for a predetermined period of time, that the saturated solubility of the drug in the adhesive base layer is moderately large, that they have appropriate Compound A release properties from the adhesive base to the skin, etc. I found that.
Hereinafter, each constitution and manufacturing method of the percutaneous absorption patch according to the first and second inventions of the present application will be described in detail.

Adhesive bases which can be combined with the adhesive base compound A and which satisfy the above-mentioned preferable conditions 1 to 3 have a glass transition temperature Tg of -70 ° C to -10 ° C and are synthesized or Natural polymer compounds and compositions containing these polymer compounds are preferred. When a pressure-sensitive adhesive base having a Tg lower than -70 ° C is used, the shape retention of the pressure-sensitive adhesive base layer is deteriorated and a residue on the skin is generated during peeling, which is not preferable, and Tg is higher than -10 ° C. In that case, it is not preferable because the adhesion to the skin is lowered.

The most preferable Tg as an adhesive base is-
It is 60 ° C to -20 ° C. However, some copolymers and mixtures of two or more polymer compounds have several Tg's. In this case, all Tg's are within the above range.
That is, it is not necessary to be in the range of -70 ° C to -10 ° C.
The pressure-sensitive adhesive base having Tg in the range of -70 ° C to -10 ° C and exhibiting pressure-sensitive adhesiveness at room temperature may be composed of, for example, one selected from the group of the following synthetic and / or natural resins. it can.

As the synthetic resin, polyvinyl alkyl ether, poly (meth) acrylate, polyurethane, polyester, polyamide, ethylene-vinyl acetate copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, polybutene, poly Examples of the natural resin include isoprene rubber, butyl rubber, silicone rubber, and the like. Preferred are styrene-isoprene-styrene block copolymers and acrylic copolymers. When the Tg in the above range cannot be obtained when the above polymer compound is used alone, other polymer compounds may be used in combination or a known compounding agent may be added to obtain the required Tg. You may adjust.

Among the acrylic copolymers, preferred are those in which the average carbon number of the alkyl group is 2 or more, preferably 2 to
It is an acrylic copolymer containing at least 50% by weight of 18 (meth) acrylic acid alkyl ester. This acrylic copolymer has good adhesion to the skin and good solubility with respect to the drug, is less irritating to the skin, and can hold the drug stably. The acrylic copolymer includes a copolymer of (meth) acrylic acid alkyl ester and another copolymerizable monomer,
The copolymerizable monomer is copolymerized in an amount of 40% by weight or less, preferably 0.5 to 30% by weight.

By adjusting the type of the copolymerizable monomer and the copolymerization ratio, the cohesiveness, drug solubility and drug release of the acrylic copolymer can be controlled. Therefore, the acrylic copolymer or a mixture of the acrylic copolymers is suitable as a polymer carrying the compound A. Examples of the (meth) acrylic acid alkyl ester monomer used for constituting the acrylic copolymer include ethyl (meth) acrylate,
n-butyl acrylate, n-butyl methacrylate,
Hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate and the like can be exemplified.

Examples of the monomer copolymerizable with the (meth) acrylic acid alkyl ester monomer include (meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride,
Examples include hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl (meth) acrylate, t-butylaminoethyl (meth) acrylate, vinyl acetate, vinyl propionate, and vinylpyrrolidone. You can

If necessary, a polyfunctional monomer may be added to the acrylic copolymer. The addition of this polyfunctional monomer causes only slight cross-linking between the resulting polymers, which increases the internal cohesive strength of the adhesive base. Therefore, the so-called adhesive residue phenomenon at the time of peeling off the patch is almost eliminated regardless of the property of the applied skin and the amount of perspiration. Moreover, the addition of this polyfunctional monomer does not have any adverse effect on the drug release property and the low skin irritation property.
Examples of such polyfunctional monomers include, but are not limited to, di (meth) acrylate, tri (meth) acrylate, tetra (meth) acrylate, and the like. More specifically, di (meth) acrylate obtained by combining polymethylene glycol such as hexamethylene glycol or octamethylene glycol with (meth) acrylic acid; polyalkylene glycols such as polyethylene glycol and polypropylene glycol When,
Di (meth) obtained by combining with (meth) acrylic acid
There are acrylates; tri (meth) acrylates such as trimethylolpropane tri (meth) acrylate and glycerin tri (meth) acrylate; and tetra (meth) acrylates such as pentaerythritol tetra (meth) acrylate. You may use these polyfunctional monomers in combination of 2 or more types. The polyfunctional monomer is used in an amount of 0.5% by weight or less based on the total amount of the monomers used for producing the adhesive base. When the amount of the polyfunctional monomer used is more than 0.5% by weight, the adhesive base obtained by the polymerization is apt to cause gelation and the diffusion and release of the drug are affected.

The adhesive base may be a filler, an absorption aid or a dissolution aid in order to maintain its shape-retaining property, to enhance the drug absorption capacity of the skin, or to enhance the drug solubility. Etc. can be blended. Examples of the filler include fine powder silica, titanium white, calcium carbonate and the like, and examples of the absorption aid include propylene glycol, polyethylene glycol, 1,3-butanediol, isopropyl myristate, palmitic acid. Examples thereof include isopropyl and polyoxyethylene aliphatic ester / ether, and examples of the dissolution aid include lactic acid. Usually, the above filler is used in an amount of 20% by weight or less in the adhesive layer, and the absorption aid is 30%.
It is used in an amount up to wt%. Further, the tackifying base may be added with a general tackifying resin, a softening agent, a compounding agent such as an antioxidant, and / or another drug such as an irritation reducing agent such as an anti-itch agent. Good.

Compound A In the transdermal patch of the first and second inventions of the present application, Compound A is contained in the patch layer as a drug. Compound A
As mentioned above, has been conventionally used as a hypotensive agent for treating hypertension and the like. The content of the compound A is preferably in the range of 0.1 to 30% by weight in the adhesive layer. 0.
If it is less than 1% by weight, it is difficult to achieve the desired drug effect, and it is necessary to significantly increase the size of the patch and increase the patch area. However, such a large patch is not easy to use. In addition, the feeling of use during application is poor, and it becomes difficult to apply for a long time. On the other hand, when the content exceeds 30% by weight, the compound A becomes supersaturated in the adhesive base, and the drug crystals are deposited on the surface of the adhesive base, which deteriorates the sticking property,
After all, sticking for a long time becomes difficult. The particularly preferable content of the compound A is in the range of 0.5 to 25% by weight in the adhesive layer.

Support The support is flexible, but serves to impart self-supporting property to the transdermal patch and prevent volatilization and migration of the drug in the patch, and the non-drug It may be composed of a transparent sheet or film, a laminate thereof, a metal vapor-deposited of these, a woven or non-woven fabric, a metal foil, or the like. Examples of the material of the support include cellulose acetate,
Examples thereof include ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride, aluminum and the like. Of these materials, materials that have sufficient followability to the skin surface are preferably used. In particular, polyethylene terephthalate, a laminated film with an ethylene-vinyl acetate copolymer, and the like are preferable. The thickness of the support is 500 μm or less, preferably 5 to 150 μm.

The support increases the amount of water in the keratin of the skin,
In order to promote percutaneous absorption without irritation, it is preferably composed of a material having low breathability or low moisture permeability. Further, in order to prevent the patch from peeling off or reduce the discomfort caused by the patch, 10% by weight or more, preferably 50% by weight or more of the support is made of a ductile material, or stretchable. It is preferable to use a support provided with.

P-Hydroxybenzoic Acid Ester In the second invention of the present application, the adhesive layer contains p-hydroxybenzoic acid ester as an absorption aid in addition to the compound A described above. The content of p-hydroxybenzoic acid ester is preferably 0.5 to 15% by weight in the patch layer.
The range is. If it is less than 0.5% by weight, a sufficient absorption aid effect is not expressed, while if it exceeds 15% by weight, the p-hydroxybenzoic acid ester becomes supersaturated in the adhesive base and crystallizes on the surface of the adhesive base. As a result, the sticking property is deteriorated and sticking for a long time becomes difficult. Particularly preferred content of p-hydroxybenzoic acid ester is 1 to
It is in the range of 10% by weight. Examples of p-hydroxybenzoic acid ester include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, isopropyl p-hydroxybenzoate, n-butyl p-hydroxybenzoate, and p-hydroxybenzoic acid. Acid t
-Butyl and the like can be mentioned.

In addition to the p-hydroxybenzoic acid ester, it is also possible to use other absorption aids in combination. Examples of such other absorption aids include propylene glycol, polyethylene glycol, 1,3-butanediol, isopropyl myristate, isopropyl palmitate, polyoxyethylene aliphatic ester ether and the like.

Release Paper In the percutaneous absorption patch of the first and second inventions of the present application, usually,
A release paper is laminated on the sticking surface. The release paper is provided so as not to reduce the sticking ability of the surface of the patch layer before using the patch and to prevent the surface of the patch layer from being contaminated. As the release paper, any suitable release paper can be used as long as it can be easily peeled off from the adhesive layer. For example, a polyethylene terephthalate film treated with silicone is often used. The thickness of the release paper is selected to be 500 μm or less, preferably 20 to 200 μm.

The first production method the present application, transdermal patches agent according to the second invention can be manufactured by the method of conventional adhesive tape.
For example, a solvent coating method is mentioned as a typical manufacturing method.
Further, as other methods, an emulsion coating method, a hot melt method, a method by electronic cross-linking and the like are used. To produce the transdermal patch according to the first and second inventions of the present application by a solvent coating method, for example, an adhesive base, a drug and an absorption aid, and if necessary, a compounding agent is dissolved in a suitable solvent. Alternatively, it is dispersed, and the obtained solution or dispersion is directly applied on the surface of the support and dried to form a patch layer having a thickness of 5 to 300 μm. Alternatively, this solution or dispersion may be applied onto a protective release paper and the adhesive layer obtained after drying may be brought into close contact with the support. The adhesive layer may be formed on the entire one main surface of the support, or may be partially formed, for example, in a stripe shape, a lattice shape, or a corrugated shape.

As a preferable modification of the patch of the present invention,
Two or more different adhesive layers having different compositions, thicknesses and / or drug contents are sequentially formed on one support from one end to the other end with a predetermined width or alternately with a predetermined width. It is also possible to form a sea-island shape. In such a mixed pattern type patch, since the release rate or release amount of the drug can be made different by using different kinds of patch layers, it is possible to release the drug as a whole as compared with a patch having a single patch layer. The advantage is that the time can be extended.

Another preferred variant is that on one support,
The adhesive layer may be formed by laminating two or more adhesive substances having different compositions, thicknesses and / or drug contents in layers. In this case, if the adhesive layer is formed by stacking different kinds of adhesives so that the amount of the drug in the adhesive layer increases from the outside to the inside, the drug is gradually supplied from the inside of the adhesive layer to the outside. It can be possible.
Such a laminated-type patch has an effect of preventing transdermal absorption of a large amount of drug at once immediately after the formulation is brought into close contact with the skin.

[0026]

According to the first and second inventions of the present application, the compound A
Is constituted in the form of a transdermal patch, it is possible to solve the problems of the conventional oral administration type compound A preparations, that is, the blood concentration of compound A is gently increased in the initial stage of administration. The effective blood concentration can be maintained for a long time during administration, and when a side effect occurs, the side effect can be effectively suppressed by peeling off from the skin surface. Furthermore, since it is a transdermal patch, it is extremely easy to handle.

In the second invention, compound A which is a drug is used.
In addition, since the p-hydroxybenzoic acid ester which is an absorption aid is contained in the adhesive layer, the absorption ability of Compound A via the skin surface is further enhanced, and therefore the drug efficacy of Compound A is further enhanced. It can be used effectively. Furthermore, in other percutaneous absorption type pharmaceutical preparations, for example, a method of spray-applying a drug-containing solution onto the skin or a method of applying an ointment, the dose may vary, and the spray solution or ointment may adhere to clothes. Although there are various problems of soiling clothes, the transdermal patch of the first and second inventions of the present application has no possibility of causing such problems.

[0028]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be made clear by describing non-limiting and specific embodiments of the present invention. Example 1 1) Rubber-based adhesive-Styrene-isoprene-styrene block copolymer (manufactured by Shell Chemical Co., trade name: Califlex TR1107) ... 14.6 g-Polybutene (manufactured by Nippon Oil Co., trade name: HV-300) ) ... 4.9 g-Alicyclic saturated hydrocarbon (Arakawa Chemical Co., Ltd., trade name: Alcon P-70) ... 41.9 g-Liquid paraffin ... 36.9 g

A rubber-based pressure-sensitive adhesive base having a Tg of −49 ° C. was prepared by blending the above composition. 2) Compound A was added to 233.3 g of tetrahydrofuran.
g and 99 g of a rubber-based pressure-sensitive adhesive base were mixed and uniformly mixed by a dissolver to obtain a pressure-sensitive adhesive solution having a solid content of 30% by weight. 3) After coating the coating liquid obtained in step 2) on a polyethylene terephthalate release liner having a thickness of 48 μm,
Dry in a gear oven at 60 ℃ for 30 minutes and have a thickness of 80 μm
The adhesive layer of was formed. Then, a 20 μm-thick support made of a polyethylene film was brought into close contact with the patch layer to prepare a transdermal absorption patch.

Example 2 1) 65% 2-ethylhexyl acrylate (30 mol%)
2.0 g), vinylpyrrolidone 35 mol% (98.0
g) and 0.02 mol% (40.0 mg) of 1,6-hexamethylene glycol dimethacrylate were charged into a separable flask, and 400 g of ethyl acetate was further added.
The monomer concentration was adjusted to 50% by weight. This solution was heated to a temperature of 60 ° C. under a nitrogen atmosphere, then 2 g of lauroyl peroxide was added to 100 g of cyclohexane and 240 g of ethyl acetate.
A polymerization initiator solution prepared by dissolving it in a mixed solvent of g was added little by little, and the polymerization reaction was carried out for 12 hours to obtain an ethyl acetate-cyclohexane mixed solution of an acrylic adhesive base having a solid content concentration of 35% by weight. Then, the obtained solution is added to 10
After drying at 5 ° C. for 3 hours, ethyl acetate and cyclohexane were evaporated to obtain 400 g of an acrylic pressure-sensitive adhesive.

2) 233.3 g of tetrahydrofuran in the same manner as in step 2) of Example 1 using the acrylic adhesive base obtained in step 1) instead of the rubber adhesive base.
To 3 g of compound A and 97 g of the above acrylic adhesive base
And were dissolved to prepare a coating solution containing a patch formulation having a solid content concentration of 30% by weight. 3) By the same operation as in step 3) of Example 1, an adhesive layer is formed on a release liner made of a PET film treated with silicon, and a support made of a polyethylene film is adhered to this layer to give a transdermal patch. Prepared.

Example 3 1) 2-Ethylhexyl acrylate 10 mol% (3
5.0 g), 2-ethylhexyl methacrylate 80 mol% (301.0 g), dodecyl methacrylate 10 mol% (48.2 g), dimethacrylate 1,6-hexamethylene glycol 0.02 mol% (50 mg) Was charged in a separable flask, and 165 g of ethyl acetate was further added to adjust the monomer concentration to 70% by weight. This solution is heated to a temperature of 80 ° C. under a nitrogen atmosphere, then 4 g of lauroyl peroxide are added to 50 g of cyclohexane and 36 g of ethyl acetate.
A polymerization initiator solution prepared by dissolving it in 0 g of a mixed solvent was added little by little, and the polymerization reaction was carried out for 24 hours to obtain an ethyl acetate-cyclohexane mixed solution of an acrylic adhesive base having a solid content concentration of 40% by weight. This is the step 1 of Example 2)
In the same manner as above, ethyl acetate and cyclohexane were evaporated to obtain 384 g of an acrylic adhesive.

2) As in Example 2, using the acrylic pressure sensitive adhesive base obtained in the above step 1), 3 g of compound A and 97 g of the acrylic pressure sensitive adhesive base were dissolved in 233.3 g of tetrahydrofuran. Then, a coating solution containing a patch formulation having a solid content concentration of 30% by weight was prepared. 3) By the same operation as in step 3) of Example 1, an adhesive layer was formed on a release liner made of a silicon-treated PET film, and a support made of a polyethylene film was adhered to this layer to give a transdermal patch. Prepared.

Example 4 1) Using the acrylic pressure-sensitive adhesive base obtained in the step 1) of Example 2, to 233.3 g of tetrahydrofuran, compound A was added.
25 g, 5 g of lactic acid as a dissolution aid, and 70 g of an acrylic pressure-sensitive adhesive base were dissolved to prepare a coating solution containing a patch formulation having a solid content concentration of 30% by weight. 2) By the same operation as in step 3) of Example 1, an adhesive layer is formed on a release liner made of a silicon-treated PET film, and a support made of a polyethylene film is adhered to this layer to give a transdermal patch. Prepared.

Example 5 Example 1 was repeated except that 233.3 g of tetrohydrofuran was mixed with 1 g of compound A, 3 g of methyl p-hydroxybenzoate and 96 g of a rubber-based adhesive base.
A transdermal patch was prepared in the same manner as in.

Example 6 To 233.3 g of tetrahydrofuran was added 3 g of the compound A.
And 10 g of n-butyl p-hydroxybenzoate and 87 g of an acrylic pressure sensitive adhesive base were dissolved in the same manner as in Example 2 except that a patch formulation having a solid concentration of 30% by weight was used. To prepare a transdermal absorption patch.

Example 7 25 g of compound A was added to 233.3 g of tetrahydrofuran.
Except that 10 g of n-butyl p-hydroxybenzoate, 5 g of lactic acid as a solubilizing agent and 60 g of an acrylic adhesive base were dissolved, and a patch formulation having a solid content concentration of 30% by weight was used. A transdermal patch was prepared in the same manner as in Example 4.

Example 8 33.3 g of Compound A was added to 233.3 g of tetrahydrofuran.
10 g of n-butyl p-hydroxybenzoate, 5 g of isopropyl myristate, and acrylic adhesive base 82
A transdermal patch was prepared in the same manner as in Example 3, except that the patch formulation having a solid content concentration of 30% by weight obtained by dissolving g. As is clear from the above, Examples 5 to 7 are the same as Examples 1, 2, and 4, respectively.
The only difference is whether or not it contains p-hydroxybenzoate.

Evaluation An evaluation experiment was conducted on each transdermal patch of the example obtained as described above in the following manner. Experiment 1 For Examples 1 to 8, the following rabbit sticking test was conducted. When the hair of a rabbit is clipped with a hair clipper and a shaver, a diameter of 2
A 0 mm circular patch (area: 3.14 cm ² ) was applied for 24 hours, and the adhesiveness at the time of application and after 24 hours and the skin irritation after 1 hour from peeling were observed. This experiment was carried out in three cases for each transdermal patch.

Experiment 2 For Examples 1 to 8, the following hairless mouse skin permeability test was conducted. First, a Franz type diffusion cell 1 shown in FIG. 1 was prepared. The diffusion cell 1 is composed of a bottomed cylindrical receptor tank 2 having a bottom, and a cylindrical bottomed donor tank 3 arranged thereon. An opening 4 is provided at the center of the bottom wall of the donor tank 3, and an upper flange 5 and a lower flange 6 are provided at the lower end of the donor tank 3 and the upper end of the receptor tank 2, respectively. And the upper flange 5
By stacking the lower flange 6 and the lower flange 6 so as to face each other, the donor tank 3 and the receptor tank 2 are stacked airtightly and concentrically. A laterally projecting sampling port 7 is attached to the side of the receptor tank 2, and a magnetic stirrer 9 is placed inside the receptor tank 2.

A hairless mouse (6 weeks old, male) was sacrificed by cervical dislocation, and immediately the back skin was peeled off to remove subcutaneous fat and muscle layer, and a skin piece of about 5 cm × 5 cm was obtained. The skin piece 8 is sandwiched between the upper flange 5 and the lower flange 6 of the diffusion cell 1, and the opening 4 of the donor tank 3 is inserted into the skin piece 8.
I tried to close it completely. On the upper surface of the skin piece 8, a percutaneous absorption patch is circular with a diameter of 20 mm (area 3.14 cm ² ).
The test piece 10 obtained by punching was attached. The receptor tank 2 was filled with a receptor solution prepared according to the preparation method described below.

Then, the diffusion cell 1 was kept at a temperature of 37.degree.
Installed in a constant temperature bath, with a magnetic stirrer
The stirring solution was stirred. Sampling port 7 after a predetermined time
1 ml of receptor solution was collected from After collecting, an equal amount of
The Scepter solution was replenished. Drug to this collected receptor fluid
Was measured by high performance liquid chromatography.
The number of each test piece is three for each transdermal patch.
did. Receptor solution preparation method: NaH₂PO_Four(5 x 1
0^-Fourmol), Na₂HPO _Four(2 x 10^-Fourmol),
NaCl (1.5 x 10^-1mol), gentamicin 1
Dissolve 0 mg in 500 ml of distilled water and add 0.1 N-Na.
After adjusting the pH to 7.2 with an aqueous OH solution, add 100 to 100 with distilled water.
It was set to 0 ml.

Experiment 3 The hairless rat percutaneous absorbency test shown below for Examples 2 and 6 and the following SHR for Example 2
A rat pharmacological test was performed. Percutaneous Absorption Test of Hairless Rats An adhesive patch having a size of about 5 cm × about 4 cm (the four corners were partially cut off, the area is 18.75 cm ² ) was applied to the abdomen of the hairless rats, and blood was applied at predetermined intervals of 0. Collect 6 ml each, centrifuge the obtained blood, and equal volume of 1N with plasma.
NaOH was added to extract 5% (V / V) methanol / chloroform solution and dried under reduced pressure to dissolve the dry solid in the mobile phase.
The concentration of Compound A in plasma was measured by HPLC.

SHR Rat Pharmacological Test Only in Example 2, SHR subjected to hair removal similar to that of rabbits
A patch of about 5 cm × about 4 cm (the four corners were partly cut away so that the area is 18.75 cm ² ) was applied to the rat, and blood pressure was measured at predetermined intervals. The results of Experiment 1 to Experiment 3 are
The results are shown in Tables 1 to 4.

[0045]

[Table 1]

In Table 1, the evaluation criteria shown in the table are:
It is as follows. [Skin adhesion] At the time of application ... Excellent: Skin application area is 100% Good: Skin application area is 70% to less than 100% Possible: Skin application area is less than 70% Not possible: No adhesion to skin after 24 hours… Excellent: Skin application Area 100% and no adhesive residue Good: Skin application area 70% to less than 100% and no adhesive residue Acceptable: Skin application area less than 70% and no adhesive residue Not possible: No adhesion to skin or adhesive residue

[Irritation] 1) Erythema and crusting 0: No erythema 1: Very slight (finally recognized) erythema 2: Clear erythema 3: Moderate to strong erythema 4: Strong deep erythema Light crusting

2) Edema formation 0: No edema 1: Very slight (barely noticeable) edema 2: Edema clearly distinguishable from the surroundings 3: Moderate edema 4: Strong edema 1) and 2) and Was added. The evaluation of irritation was carried out by applying after peeling for 24 hours and evaluating the irritation 1 hour after peeling.

[0049]

[Table 2]

However, in Table 2, N. D shows that it was below the detection limit.

[0051]

[Table 3]

[0052]

[Table 4]

In Tables 3 and 4, -indicates that no data was measured. Further, the compound A concentrations shown in Tables 3 and 4 are average values of 3 cases, and blood pressure changes of SHR rats are average values of 4 cases. As is clear from Tables 3 and 4, in the transdermal absorption patch according to Example 2 and Example 6, the plasma concentration of Compound A was gently increased immediately after administration, and then maintained at a constant concentration. It can be seen that it is possible to exert a pharmacological effect for a long time.

[Brief description of drawings]

FIG. 1 is a schematic view of a test device used for a skin permeability test in the present invention.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 ... Diffusion cell 2 ... Receptor tank 3 ... Donor tank 4 ... Opening 5 ... Upper flange 6 ... Lower flange 7 ... Sampling port 8 ... Skin piece 10 ... Test piece

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kiyoshi Sato 1-19-5 Isehara-cho, Kawagoe City, Saitama Prefecture (72) Inventor Toyohiro Tadokoro 1-13-23 Nishi, Kamifukuoka City, Saitama Prefecture

Claims (2)

[Claims] 1. An adhesive base and a drug (±) -4- [2-hydroxy-3- (3- (2-methoxyphenoxy) -2].
-Propylamino) propoxy] -1 (2H) -isoquinolinone, a percutaneously absorbable patch comprising an adhesive layer formed on a support. 2. An adhesive base and a drug (±) -4- [2-hydroxy-3- (3- (2-methoxyphenoxy) -2].
-Propylamino) propoxy] -1 (2H) -isoquinolinone and p-hydroxybenzoic acid ester. A percutaneously absorbable patch comprising an adhesive patch formed on a support.