JPH0959153A - Production of isosorbide dinitrate-containing plaster - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a plaster containing an isosorbide dinitrate (hereinafter referred to as ISDN) capable of suppressing the occurrence of skin rash and excellent in pereutaneous absorption and tackiness and having good sustained release property. SOLUTION: This plaster is obtained by forming a tacky composition containing ISDN on a flexible carrier. The tacky composition comprises (A) a silicone based tacky agent of the formula [Me is CH3 or O-Si(Me)3 ; R' is OH or CH3 ; (x) and (y) are each 50-50000], (B) a polyvinyl acetate-based tacky agent and (C) ISDN. The weight ratio of each component is shown as follows. A:B=(85:15) to (15:85); (A+B):C=(90:10) to (60:40). A tacky agent layer of a mixture-based tacky agent not containing ISDN is obtained and a solution containing ISDN is attached to the tacky agent layer and then, the tacky agent layer to which ISDN is attached is heated or aged and ISDN is incorporated into the tacky agent layer to provide a tacky composition. A carrier obtained by laminating a polyester film, an adhesive layer and a polyester fabric is used as the carrier.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a patch containing isosorbide dinitrate. More specifically, an adhesive composition containing isosorbide dinitrate in a mixed adhesive composed of a silicone-based adhesive and a polyvinyl acetate-based adhesive in a specific mixing ratio is formed on a flexible carrier, and is gradually released. The present invention relates to a method for producing a patch having excellent properties and having good transdermal absorbability.

[0002]

2. Description of the Related Art It is known that drugs such as isosorbide dinitrate are percutaneously absorbed, and a number of products have already been developed as patches containing these drugs. It is shown in, for example, JP-A-57-116011 that a silicone-based, rubber-based, or acrylic-based pressure sensitive adhesive having a specific glass transition temperature is preferable as the pressure sensitive adhesive used in the patch. In addition, the 5th Annual Meeting of the Pharmaceutical Society of Japan (1989
(October 26-28th) Oguni et al. Compared acrylic, silicone and rubber adhesive patches containing isosorbide dinitrate (ISDN), and reported that the three had almost the same transdermal absorbability. There is. JP-A-57-
In Japanese Laid-Open Patent Publication No. 116011, it has been publicly disclosed that the acrylic pressure-sensitive adhesive is particularly preferable among the various pressure-sensitive adhesives and the amendment is carried out thereafter (Japanese Patent Publication No. 4-74329). That is,
Conventional ISD in patches containing isosorbide dinitrate
From the viewpoint of the relationship between the transdermal absorbability of N and the pressure-sensitive adhesive, it has been considered that the acrylic pressure-sensitive adhesive is preferable, or the acrylic or rubber-based pressure-sensitive adhesive is equivalent.

By the way, one of the drawbacks of patches is the occurrence of skin irritation, and various proposals have been made as methods for reducing the occurrence of skin irritation. One of them is to reduce the area where skin irritation occurs by reducing the size of the preparation. For this purpose, it is necessary to enhance the transdermal absorbability per unit area. Therefore, various absorption enhancers have been proposed in order to enhance the transdermal absorbability. However, many of the absorption enhancers are generally found to have skin irritation due to their low molecular weight. There is also a problem that the adhesive strength of the pressure-sensitive adhesive composition obtained by adding a large amount of an absorption enhancer decreases, and a patch having less occurrence of skin irritation and having excellent transdermal absorbability or adhesive strength is also provided. It is not always successful in providing.

[0004]

Accordingly, the present invention provides a method for producing a patch having less skin irritation and good transdermal absorbability by designing an adhesive having excellent compatibility with isosorbide dinitrate. It is intended to be provided. Another object of the present invention is to provide a method for producing a patch having low skin irritation, good transdermal absorbability, and sustained release. Still another object of the present invention is to provide a method for producing a patch having low skin irritation, good transdermal absorbability without using a transdermal absorption enhancer, and good adhesive strength. The present inventors have arrived at the present invention as a result of earnest research to solve such problems.

[0005]

Means for Solving the Problems That is, the present invention provides an adhesive patch comprising an adhesive layer comprising an adhesive composition containing an adhesive and isosorbide dinitrate formed on a flexible carrier. The agent comprises a silicone-based pressure-sensitive adhesive (A) and a polyvinyl acetate-based pressure-sensitive adhesive (B), and their weight ratio is A: B = 85: 15 to 15:85, which is a mixed pressure-sensitive adhesive. The weight ratio of isosorbide dinitrate (C) to (A + B) is (A + B): C = 90: 10-6.
A method for producing an isosorbide dinitrate-containing patch, which is 0:40, comprising: (1) obtaining an adhesive layer of the mixed adhesive which does not contain the isosorbide dinitrate (C); A solution containing the isosorbide nitrate (C) is directly or indirectly attached to the adhesive layer, and (3) the adhesive layer of the mixed adhesive to which the isosorbide nitrate (C) is attached is heated. The method for producing an isosorbide dinitrate-containing patch is characterized in that a therapeutically effective amount of the isosorbide dinitrate (C) is present in the adhesive layer of the mixed adhesive by aging or aging.

In the present invention, the silicone adhesive (A) is represented by the following formula [I]

[0007]

Embedded image

A terminal silanol-functional linear dimethylpolysiloxane having a two-dimensional structure (for example, a viscosity of about 100,000 to 3,000,000 cp (25 ° C.) as polysiloxane)
Which is a condensation reaction product of a silicate resin having a three-dimensional structure, and which has excellent properties as an adhesive for a transdermal preparation in Farm Tech Japan 7 (7), 51-55 (1991). It is possible to cite those that are introduced to have. Of course, in the above general formula, a part or all of R and / or R ′ may be replaced by other alkyl groups within a range that hardly affects the adhesive property.
It may be substituted with a vinyl group, an alkoxy group, an aryl group or the like. Specific examples of the silicone adhesive (A) of the present invention represented by the above formula [I] include, for example, Bio-PSA (registered trademark) 355 and Bio-PSA manufactured by Dow Corning.
(Registered trademark) Q7-2920, Bio-PSA (registered trademark) Q7-4501, Toshiba Silicone PSA657
There are 4 etc.

As the silicone-based pressure-sensitive adhesive (A) of the present invention, the chemical structure of the skeleton and the substituent in the above formula [I] is partially changed by a conventionally known carboxyl group, alkyl group, vinyl group or phenyl group. However, the transdermal absorbability and the adhesive property are practically not affected. Therefore, such a silicone-based pressure-sensitive adhesive, for example, one commonly used in medical applications can be used. The silicone-based adhesive may be used alone or in combination of two or more.
As the silicone-based adhesive (A) in the present invention, among these, the adhesive represented by the above formula [I], for example, Bio-PSA355, Bio-PSAQ7-29.
20, the same Q7-4501, PSA6574 and the like, more preferably Bio-PSA Q7-4501 and the same Q7-292.
No. 0 is preferable because it is difficult to peel off, there is little pain when removing the drug, and it has moderate tack.

In the present invention, the polyvinyl acetate adhesive (B) is, for example, a homopolymer of vinyl acetate; a copolymer of vinyl acetate and a (meth) acrylic acid alkyl ester and / or (meth) acrylic acid. A copolymer of vinyl acetate and vinyl ethers such as vinyl butyl ether, and the like, and a polymer having a copolymerization ratio of at least 50% by weight of vinyl acetate. Here, as the (meth) acrylic acid alkyl ester,
An alkyl ester of (meth) acrylic acid having an average carbon number of 3 to 14 is preferable, and examples of these include butyl (meth) acrylate, amyl (meth) acrylate,
Hexyl (meth) acrylate, heptyl (meth) acrylate, octyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth) acrylate, 2-
Examples thereof include ethylhexyl (meth) acrylate.

As the polyvinyl acetate-based pressure-sensitive adhesive (B) of the present invention, among the above, a copolymer of vinyl acetate and a (meth) acrylic acid alkyl ester and / or (meth) acrylic acid is preferable, and above all, it is particularly preferable. Alkyl ester of vinyl acetate and (meth) acrylic acid having an average carbon number of 3 to 14, especially 2-ethylhexyl (meth)
A copolymer of acrylate and (meth) acrylic acid is preferred. In this case, the copolymerization ratio is at least 50% by weight of vinyl acetate, and the copolymerization ratio is vinyl acetate: (meth) acrylic acid alkyl ester and / or (meth) acrylic acid = 50: 5.
A preferable range is 0 to 90:10, and particularly a range of 60:40 to 80:20. Especially about 7
0:30 is preferred.

In the present invention, a mixed system of such a silicone adhesive (A) and a polyvinyl acetate adhesive (B) is used. The advantage of this combination is that ISD
The point is that N has a very high transdermal absorbability and causes little skin irritation. As described above, it is known to use a silicone-based pressure-sensitive adhesive for ISDN-containing patches. However, with regard to mixed systems of different types of adhesives, exceptions are made in the case of rubber-based adhesives where the properties are difficult to obtain unless originally mixed.
Very little has actually been done. In particular, a patch obtained by mixing a mixed system of a silicone adhesive and a polyvinyl acetate adhesive is not known. It is considered that this is because the pressure-sensitive adhesives of both are different from each other in the solvent used, and the chemical structures are also very different, so that it is not necessary to mix them.

The patch using the mixed pressure-sensitive adhesive of the silicone-based pressure-sensitive adhesive (A) and the polyvinyl acetate-based pressure-sensitive adhesive (B) of the present invention is prepared by using another preferable pressure-sensitive adhesive such as an acrylic pressure-sensitive adhesive. It shows good transdermal absorbability equivalent to or higher than that of the obtained patch. It also has good adhesion to the skin. Regarding this, it is considered that the mixed adhesive obtained by mixing different kinds of adhesives has a so-called sea-island structure, and the adhesiveness to the skin and the release of ISDN have specificity.

In particular, when ISDN is added to a mixture of the silicone-based adhesive (A) and the polyvinyl acetate-based adhesive (B), the transdermal absorbability is specifically changed, and the transdermal absorbability is maximized. The mixing ratio (weight ratio) of A and B is about 30:70.
It has a surprising effect that its transdermal absorbability is up to 3 times that of the case of a single system. Even if it is not this maximum value, A: B is 85:15 to 15:85.
Even in this case, the transdermal absorbability is increased to such an extent that the benefits of mixing can be fully enjoyed. A: B exceeds 85:15 A
If the ratio of A is increased, the transdermal absorbability of the drug will be reduced. If the ratio of A: B exceeds 15:85 and the ratio of B is increased, the adhesive strength of the patch will be decreased, and stable application for a long time is required. Concerns arise. That is, in the present invention, A: B = 85: 15
The weight ratio is up to 15:80, but among them A: B = 2
0:80 to 40:60 is preferable, and A: B is about 3 in particular.
0:70 is preferred.

A preferred combination of both adhesives (A) and (B) in the mixed adhesive of the silicone adhesive (A) and the polyvinyl acetate adhesive (B) is a silicone adhesive. (A) is an adhesive represented by the above formula [I], and more specifically, Bio-PSA (registered trademark) 355 and Bio-PSA manufactured by Dow Corning Co., Ltd.
(Registered trademark) Q7-2920, Bio-PSA (registered trademark) Q7-4501, Toshiba Silicone PSA657
And the like, the polyvinyl acetate-based adhesive (B) is a homopolymer of vinyl acetate; a copolymer of vinyl acetate and a (meth) acrylic acid alkyl ester and / or (meth) acrylic acid; A copolymer with vinyl ethers such as vinyl butyl ether, which has a copolymerization ratio of at least 50% by weight of vinyl acetate, especially vinyl acetate, (meth) acrylic acid alkyl ester and / or (meth) acrylic A polymer which is a copolymer with an acid and has a copolymerization ratio of at least 50% by weight of vinyl acetate, especially vinyl acetate and (meth) acrylic acid having an average carbon number of 3 to
14 alkyl ester and (meth) acrylic acid, specifically, 2-ethylhexyl (meth) acrylate and (meth) acrylic acid in which at least vinyl acetate has a copolymerization ratio of 50% or more, particularly a copolymerization ratio of 60. : 40
The case of up to 80:20 can be mentioned as a preferable example.

In the adhesive composition for patch of the present invention, the ratio of ISDN (C) to the mixed adhesive is the total weight of the silicone adhesive (A) and the polyvinyl acetate adhesive (B). On the other hand, ISDN (C) is compounded or contained so that the weight of ISDN (C) satisfies the relationship of (A + B): C = 90: 10 to 60:40. If the ISDN (C) ratio is less than 10, the effect as a drug is insufficient, while if it exceeds 40, the ISDN crystallized in the adhesive increases, but the adhesive strength of the resulting adhesive decreases. However, the flexibility of the patch will decrease. In addition, 4
Even if the ISDN is increased beyond 0, the percutaneous absorption rate of ISDN per unit area does not increase, and the drug utilization rate also decreases.

The manufacturing method of the present invention will be described below.

In the first step of the present invention, an adhesive layer of a mixed adhesive containing no isosorbide dinitrate (C) is obtained. That is, the silicone-based adhesive (A) and the polyvinyl acetate-based adhesive (B) are obtained by dissolving or dispersing them in a single solvent or a mixed solvent such as ethyl acetate, hexane, chloroform, xylene, toluene, hexane, acetone, and methanol. The adhesive solution or dispersion to be applied is coated on a release paper or a release film so that the thickness after drying becomes a predetermined thickness, for example, 5 to 100 μm, dried, and the solvent is sufficiently removed by evaporation. To obtain an adhesive layer containing no ISDN (C). Here, the mixed pressure-sensitive adhesive containing no isosorbide nitrate (C) means a mixed pressure-sensitive adhesive which does not contain isosorbide nitrate (C) or does not contain a therapeutically effective amount of a sufficient amount of isosorbide nitrate (C). .

That is, as is known, the less residual solvent in the final patch, specifically, 100 ppm or less,
Preferably, the residual solvent amount of 50 ppm or less reduces the skin irritation of the patch. Therefore, in order to obtain such a patch with less residual solvent, a solution or dispersion of an adhesive is applied onto a release film or the like, and when dried,
It is desirable to reduce the residual solution by applying sufficient heat, and / or taking a sufficient drying time, or by heating the obtained adhesive layer or placing it under reduced pressure. I
Since SDN is a sublimable drug, if the adhesive layer does not contain ISDN or does not contain enough ISDN, I
There is no need to worry about sublimation of SDN,
It is possible to easily form an adhesive layer with a sufficiently small residual solvent.

In the second step of the present invention, the adhesive layer is
Directly or indirectly, a solution containing the isosorbide nitrate (C) (ISDN-containing solution) is attached. Examples of the solvent for such a solution include highly volatile solvents such as acetone, methanol, ethanol, and ethyl acetate. Among them, acetone can be mentioned as a preferable solvent. As the ISDN-containing solution used in this case, for example, a solution in which 5 to 65% by weight of ISDN is dissolved at a high concentration is preferable. Solvent used for coating and drying in the first step to form an adhesive layer and ISDN in the second step
If the solvent used for dissolving the same is the same, a method of producing an adhesive layer using a solution or dispersion in which a mixed adhesive and ISDN are mixed in advance is also conceivable, but according to the production method of the present invention, It is possible to easily reduce the residual solvent of the patch.

In the second step, the ISDN-containing solution is directly applied to the adhesive layer, or indirectly through a film; a fabric such as a knitted fabric, a woven fabric or a non-woven fabric; Or by dipping etc., the desired IS
Although the DN is attached, the spray is indirectly applied via a cloth such as a knitted fabric, a woven fabric, or a non-woven fabric laminated on the adhesive layer.
It is preferable to attach them by means such as.

In the case of the mixed pressure-sensitive adhesive of the present invention, surprisingly, acetone is used as a solvent for such ISDN-containing solution, and it is indirectly bonded through a fabric such as a knitted fabric, a woven fabric or a non-woven fabric laminated on the pressure-sensitive adhesive layer. When applied by a spray or the like, about 60% by weight of the therapeutically effective amount of ISDN to be finally contained in the adhesive layer can be transferred to the adhesive layer in the step of this second step. .

In the third step of the present invention, a therapeutically effective amount of isosorbide dinitrate (C) is mixed by heating or aging the adhesive layer of the mixed adhesive to which isosorbide dinitrate (C) is adhered. It is contained in the adhesive layer of the system adhesive.

A preferred method in this step is
The adhesive layer is laminated on a release paper or a release film, and for example, such a laminate is wound up in a roll form alone, or a laminate obtained by laminating a softer support on the adhesive layer is formed into a roll form. It can be mentioned a method in which it is rolled up and the obtained roll-shaped material is heated or aged. Above all, the method of winding the laminate alone in a roll and heating it, or aging it is particularly preferable because it is suitable to continuously produce the patch of the present invention with high productivity.

Here, heating means 50-80 ° C., 4
It is said that a therapeutically effective amount of isosorbide dinitrate (C) is contained in the adhesive layer of the mixed adhesive by heating for ~ 70 hours, and heating at 65-75 ° C for 5-12 hours is preferable. Also, aging means that a therapeutically effective amount of isosorbide dinitrate (C) is contained in the adhesive layer of the mixed adhesive under mild conditions, for example, at room temperature to 50 ° C. for a long time.

If a flexible carrier is not previously laminated on the adhesive layer of the mixed adhesive containing the therapeutically effective amount of isosorbide dinitrate (C) thus obtained, this flexible carrier is laminated. As a result, the isosorbide dinitrate-containing patch of the present invention can be obtained.

When a cloth or the like is used in the second step of the present invention, a flexible carrier having a pressure-sensitive adhesive laminated on the side of the carrier on which the cloth is laminated is used. However, the pressure-sensitive adhesive layer of the mixed pressure-sensitive adhesive and the carrier can be sufficiently strongly pressure-bonded via a cloth or the like, which is preferable. Further, as a method of indirectly adhering the ISDN-containing solution or the like to the adhesive layer of the mixed adhesive in the second step, for example, I
A preferable method is also one in which an SDN-containing solution or the like is dropped, sprayed, coated, dipped or the like to hold ISDN, and a cloth or the like holding such ISDN is pressure-bonded to the pressure-sensitive adhesive layer.

Furthermore, in the third step of the present invention, when heating is carried out in a state where the flexible carrier is not pressure-bonded to the pressure-sensitive adhesive layer of the mixed pressure-sensitive adhesive, the adhesion of the mixed pressure-sensitive adhesive is carried out by this heating step. It is particularly preferable because the residual solvent remaining in the layer can be easily removed.

In the present invention, the pressure-sensitive adhesive composition contains, in addition to the components A to C, other pressure-sensitive adhesives such as natural rubber: SI within a range not practically affecting the characteristics of these compositions.
Rubber-based adhesives such as synthetic rubbers such as S elastomer and vinyl ether-based adhesives may be used alone or in combination, and if necessary, known absorption promoters, dissolution aids, diffusion aids, fillers and the like may be added. You may contain it individually or in mixture.

When an absorption enhancer is used, isopropyl myristate is particularly preferable as the absorption enhancer, and when isopropyl myristate is used, ISDN (C)
It is preferable to use 0.01 to 5 parts by weight with respect to 1 part by weight.
Further, as other absorption promoters or diffusion aids, for example, sodium lauryl sulfate, sodium dodecylbenzene sulfonate, sodium alkyldiphenyl ether disulphonate, dioctyl sulfosuccinate, polyoxyalkyl phenyl ether sulfate ammonium salt and other surface active agents. Agents; alcohols such as glycerin, diethylene glycol, propylene glycol, polyethylene glycol, and higher aliphatic alcohols; dimethyl sulfoxide and alkylmethyl derivatives; salicylic acid, urea, dimethylacetamide, dimethylformamide, lanolin, allantoin, squalene, carbopol, diisopropyl adipate, Pyroglutamic acid lauryl ester, ethyl laurate, methyl nicotinate, sorbitol and Pyrrolidone derivatives such as dodecylpyrrolidone, olive oil, castor oil, liquid paraffin, petrolatum, gelatin, amino acids, lactic acid, ethyl lactate, benzyl nicotinate, L-menthol, camphor, dodecylazacycloheptan-2-one can be used. it can. It is preferable to use such an additive in an amount of 0.05 to 5 parts by weight per 1 part by weight of ISDN.

In the patch of the present invention, the silicone adhesive (A), the polyvinyl acetate adhesive (B) and the ISD
An adhesive layer made of an adhesive composition containing N (C) is formed on a flexible carrier, and examples of such a flexible carrier include a film; a fabric such as a woven fabric, a knitted fabric, and a nonwoven fabric; or A composite of film and cloth is used.
As a material for such a film or cloth, polyester such as polyethylene terephthalate; polyolefin such as polyethylene or polypropylene; polyamide such as nylon 6; ethylene-vinyl acetate copolymer can be used. Among these materials, polyester is preferable in terms of stability and safety.

In particular, when a film is used on the outer surface of the patch as a flexible carrier that makes it difficult for ISDN to escape from the patch and has high stability, the film of the film may be used for the purpose of improving the handleability of the patch. When a fabric such as a woven fabric, a knitted fabric or a non-woven fabric is attached via an adhesive or a pressure-sensitive adhesive to the inner or outer surface, the obtained patch has high stability and good handleability. As described above, in order to have high stability and good handleability, the film thickness is preferably 0.5 to 10 μm, and the fabric weight is preferably 8 to 100 g / m 2, and particularly, the film thickness is 0.5. ~ 4.9μ
m polyester film with a fabric weight of 8 to 60 g /
Preferred is m2 polyester.

A particularly preferred embodiment of the patch is shown below.
That is, the patch comprises (a) film layer, (b) adhesive layer, (c) cloth, (d) adhesive layer, (e) release film layer, and the outermost layer is (a), and (a), (b) ),
(C), (d) and (e) are laminated in this order, and (e) is discarded when used.

(A) is a polyester film layer having a thickness of 0.5 to 4.9 μm. As the film, for example, an extremely thin polyester film (trade name, Teijin Tetoron film F type) is particularly preferable. (B) is an adhesive layer having a thickness of 5 to 40 μm, which is a known adhesive such as the above-mentioned silicone adhesive, acrylic adhesive, rubber adhesive, polyvinyl acetate adhesive or ethylene- (C) is a polyester cloth having a weight per unit area of 8 to 60 g / m @ 2, which is composed of a vinyl acetate copolymer adhesive or the like alone or in a mixed system. (D) is an adhesive layer composed of a mixture of the silicone adhesive (A) of the present invention and the polyvinyl acetate adhesive (B) as described above, and the weight ratio of A and B is 85:15.
˜15: 85 and a thickness of 10 to 60 μm, and (e) is a fluororesin-coated thickness of 30˜.
It is a polyester film-based release film layer having a thickness of 100 μm. ISDN (C) is mainly present in the (d) adhesive layer, but may be present in the (b) adhesive layer and (c) fabric.

In such a particularly preferred patch, the polyester film of the (a) film layer is
Those having a range of 0.5 to 4.0 μm are preferable in terms of strength, handleability, skin rash, and sealing property. If it is less than 0.5 μm, the strength and handleability may be insufficient, and 4.
If it exceeds 9 μm, there may be a problem with respect to skin followability and skin rash.

The fabric (c) has a basis weight of 10 to 4
0 g / m @ 2 is preferable from the viewpoint of skin rash and handleability, and a basis weight of 10 to 25 g / m @ 2 is more preferable because it is excellent in drug diffusion and absorption.

Among these, preferred combinations of (a) to (d) include, for example, about 1.0 to (a).
3.5 μm polyester film, (b) about 5-2
5 μm adhesive layer, (c) polyester fabric having a basis weight of 10 to 40 g / m 2, and especially 10 to 25 g / m 2, (d)
Is an adhesive layer having a thickness of about 25 to 45 μm. When an adhesive or a pressure-sensitive adhesive having a property that the saturated solubility of ISDN is extremely smaller than that of the (d) adhesive layer in the (b) adhesive layer, the ISDN concentration in the (d) adhesive layer can be increased. It is particularly preferable because the transdermal absorbability can be maintained at a high level. In particular, when the ISDN saturated solubility of (b) the adhesive layer is set to 1/2 or less, preferably 1/3 or less of the ISDN saturated solubility of the (d) adhesive layer, ISDN effectively used for transdermal absorption is From the fact that the amount is less than 1/3 to 1/2, (d) only ISDN in the adhesive layer is used for transdermal absorption and wasted (b) IS in the adhesive layer.
The amount of DN is extremely small, which is preferable. further,
By making the thickness of the (b) adhesive layer smaller than the thickness of the (d) adhesive layer, it is possible to further reduce this wasted ISDN amount, which is preferable. A rubber-based pressure-sensitive adhesive can be given as a specific example of the adhesive of the (b) adhesive layer.

In the production of the patch of such a preferred embodiment, a laminate of (b) an adhesive layer, (e) a release film layer and (d) an adhesive layer, which does not contain ISDN or does not contain ISDN sufficiently, is produced. Then, (c) cloth is laminated on the free surface of the (d) adhesive layer of this laminate to obtain a composite layer, and ISDN dissolved in a solvent such as acetone is added to the cloth portion of the composite layer. It is applied by dripping, spraying, dipping, etc., and then heated or aged to give a therapeutically effective amount of IS.
DN is included in (d). Next, the separately prepared composite layer in which the (a) film layer and the (b) adhesive layer are laminated is pressure-bonded to the above composite layer so that the (b) adhesive layer and the (c) fabric are in contact with each other to obtain a target. A patch containing isosorbide dinitrate is obtained. In addition, when the (b) adhesive layer has ISDN transferability, by heating or aging the preparation after pressure bonding,
(B) the adhesive layer contains a predetermined amount of ISDN, and (d) the adhesive layer contains a therapeutically effective amount of ISDN,
It is also possible to have a constant quality formulation. The ISDN-containing patch is usually used after being cut into a size of 10 to 100 cm @ 2, but such cutting may be performed before heating or after heating.

[0039]

The present invention will be described in more detail with reference to the following examples. All parts, percentages and ratios in the examples are by weight. The method for measuring the blood ISDN concentration used in the examples, the preparation of the polyvinyl acetate adhesive and the fabric sample are as follows.

(1) Method for measuring blood ISDN concentration, that is, after separating plasma from 1 ml of blood sampled,
The ISDN was extracted with 4 ml of n-hexane, concentrated, and the concentrate was mixed with 100 μl of ethyl acetate and 10 μl of ethyl acetate.
A sample was obtained by adding 0 μl, and ISDN in this sample was analyzed by GC.
-Quantified by ECD method.

(2) Polyvinyl acetate adhesive (PVA-
Preparation of 1) A copolymer with 2-ethylhexyl acrylate was synthesized by the following method. That is, vinyl acetate 70
Parts, 2-ethylhexyl acrylate 27 parts, acrylic acid 3 parts, benzoyl peroxide 1 part and ethyl acetate 150
Part was charged into a reaction vessel equipped with a reflux condenser and an agitator, and stirred at 60 ° C. under a nitrogen atmosphere while slowly stirring 12
The polymerization was continued for hours. The polymerization conversion was 99.9%.
250 parts of ethyl acetate was added to the obtained polymer solution to adjust the solid content concentration to about 20%. This is called an acrylic ester copolymerized polyvinyl acetate pressure-sensitive adhesive sample (PVA-1). The weight average molecular weight of this product (in terms of polystyrene) is 35.
6,000.

(3) Fabric sample preparation 297 parts of dimethyl terephthalate, ethylene glycol 2
65 parts, sodium 3,5-di (carbomethoxy) benzenesulfonate 53 parts (11.7 mol% based on dimethyl terephthalate), manganese acetate tetrahydrate 0.084 parts and sodium acetate trihydrate 1.22 Part into a glass flask equipped with a rectification column, and transesterification is performed according to a conventional method.After the theoretical amount of methanol is distilled off, the reaction product is put into a polycondensation flask equipped with a rectification column. Add 0.090 parts of a 56% aqueous solution of acid and 0.135 parts of antimony trioxide as a polycondensation catalyst at a temperature of 275 ° C.
After reacting under normal pressure for 20 minutes and under reduced pressure of 30 mmHg for 15 minutes, they were reacted under high vacuum for 100 minutes. The final internal pressure was 0.39 mmHg, the intrinsic viscosity of the obtained copolymer was 0.402, and the softening point was about 200 ° C. After completion of the reaction, the copolymerized polymer was made into chips according to a conventional method.

15 parts of this copolymerized polymer chip and 85 parts of polyethylene terephthalate chip having an intrinsic viscosity of 0.640 were mixed in a Nauta mixer (manufactured by Hosokawa Iron Works) for 5 minutes, and then 110 ° C. in a nitrogen stream. After drying for 2 hours and further at 150 ° C. for 7 hours, the mixture was melt-kneaded at 285 ° C. using a twin-screw extruder to form chips. This chip had an intrinsic viscosity of 0.535 and a softening point of 261 ° C.

This chip was dried by a conventional method, and a spinning spinneret having a circular slit having a width of 0.05 mm and a diameter of 0.6 mm having two arc-shaped openings closed at two positions was used, and spinning was carried out according to a conventional method. Then, a hollow fiber (hollow ratio 25%) having an outer diameter to inner diameter ratio of 2: 1 was produced. The obtained hollow fibers were scattered over the entire cross section of the hollow fibers and had fine pores arranged in the fiber direction, and at least a part of the fine pores communicated with the hollow portion. This yarn is 150 denier / 12 filaments, and using this yarn, a draw ratio of 5.
The filament was drawn at 1 time to obtain a multifilament of 20 denier / 12 filament. The diameter of the single yarn of the present multifilament was 11 μm in diameter.

This multifilament was formed into a knitted fabric, scoured and dried by a conventional method, and then treated with a 1% caustic soda aqueous solution and at a boiling temperature for 2 hours to reduce the alkali reduction ratio to 2
A 0% knit was obtained. The obtained knitted fabric was stretched 1.5 times in the machine direction and heated at 100 ° C. for 1 minute to heat set to obtain a knitted fabric having a basis weight of 13 g / m 2, that is, a fabric sample.

[Examples 1, 3, 4 and Comparative Examples 2, 3] (1) Preparation of (b) Adhesive Layer and (d) Adhesive Layer As a silicone-based adhesive (A), Bio-PSA manufactured by Dow Corning Co. (Registered trademark) 355 (solid content 18.5
%) As the polyvinyl acetate adhesive (B)
-1 was used. The mixing ratio of the silicone-based adhesive (A) and the polyvinyl acetate-based adhesive (B) was changed as shown in Table 1, and both were sufficiently stirred to obtain a mixed dope. The thickness after drying is 15 μm ((b) adhesive layer) and 30 μm for each level.
Two types of pressure-sensitive adhesive layers ((d) pressure-sensitive adhesive layer) were obtained. (2) Preparation of Composite Layer of (a) Film Layer and (b) Adhesive Layer As the (a) film, a polyethylene terephthalate film (Teijin Tetoron film F type) having a thickness of 2.0 μm is used. An adhesive layer (b) was pressure-bonded onto the above. (3) Preparation of (e) Release Film, (d) Adhesive Layer, and (c) Cloth Composite Layer and Adhesion of ISDN-Containing Solution To (e) Release Film Coated with Fluorine-Based Release Agent , (D) The pressure-sensitive adhesive layer was pressure-bonded to obtain a laminate.
(D) The cloth sample (c) was pressed onto the free surface of the adhesive layer. Next, an ISDN (C) acetone solution was applied to the free surface of this cloth sample per 1 m 2 of IS.
It was continuously added dropwise so that DN (C) was 10 g. At this stage, HP indicates that 5.8 g (about 60% by weight) of ISDN (C) per 1 m2 is transferred to the (d) adhesive layer.
It was confirmed by measuring by LC. (4) Heating of the adhesive layer to which ISDN is adhered and lamination with the composite layers ((a), (b)) Then, the laminate is rolled and heated at 65 ° C. for 7 hours. , Evaporate acetone, and at the same time ISDN
(C) was almost completely transferred to the (d) adhesive layer to obtain a (d) adhesive layer containing a therapeutically effective amount of ISDN (C).

Thereafter, (d) through the free surface of the cloth (c) to the free surface of the adhesive layer (b) of the composite layer comprising (a) film and (b) adhesive layer. The pressure-sensitive adhesive layer and (e) the release film layer were pressure-bonded to obtain a laminate. The obtained laminate was cut into a size of 6.3 cm × 6.3 cm, and then this was heated at 65 ° C. for 120 minutes. (5) Pharmacological test From the thus-obtained preparation, a preparation for animal testing having a size of 10 cm2 was prepared and applied to the back of a hairless rat (n = 3) having an average body weight of 200 g, before and after application.
Time, 24 hours after application, ISD in blood
The N concentration was measured, and Cmax and A were determined from the obtained blood concentration.
UC was calculated. Also, the state of adhesion to the skin was examined. The results are shown in Table 1. In Table 1, the polyvinyl acetate adhesive is P
Displayed as VA-1.

[Examples 2 and 5] (b) Examples except that a 15 μm thick SIS rubber adhesive layer (SIS elastomer: about 40%, hydrogenated rosin: about 60%) was used as the adhesive layer. Formulations as in 1, 3, 4 (Example 2,
5) was obtained, and then the same test was performed. The results are shown in Table 1. In Table 1, Examples 2 and 5 using the SIS rubber-based pressure-sensitive adhesive are marked with *.

[Comparative Example 1] (d) Completely the same as Examples 1, 3, and 4 except that a polyvinyl acetate-based pressure-sensitive adhesive (PVA-1) (B) was not mixed as the pressure-sensitive adhesive layer. A preparation was obtained in the same manner (Comparative Example 1), and the preparation was tested. The results are shown in Table 1.

[Comparative Example 4] (d) A preparation was obtained in exactly the same manner as in Examples 1, 3 and 4, except that a pressure-sensitive adhesive containing no silicone-based pressure-sensitive adhesive (A) was used as the pressure-sensitive adhesive layer. (Comparative Example 4) The formulation was tested. The results are shown in Table 1.

[Comparative Example 5] Example 1, except that acrylic acid-based pressure-sensitive adhesive layers having thicknesses of 15 μm and 30 μm were used as (b) adhesive layer and (d) pressure-sensitive adhesive layer, respectively.
A formulation was obtained in exactly the same manner as 3 and 4 (Comparative Example 5), and the formulation was tested. The results are shown in Table 1.

The acrylic acid type pressure-sensitive adhesive was synthesized by the following method.

90 parts of 2-ethylhexyl acrylate,
A reflux condenser containing 7 parts of methyl methacrylate, 3 parts of acrylic acid, 1 part of benzoyl peroxide and 100 parts of ethyl acetate,
Charge in a reaction vessel equipped with a stirrer, and under a nitrogen atmosphere 6
Polymerization was continued for 12 hours with slow stirring at 0 ° C.
The polymerization conversion was 99.9%. 300 parts of ethyl acetate was added to the obtained polymer solution to adjust the solid content concentration to about 20%.

[0054]

[Table 1]

From Table 1, patches (Examples 1 to 5) using mixed adhesives according to the production method of the present invention, particularly silicone adhesives (A) and polyvinyl acetate adhesives (B)
It is understood that when the ratio is about 50:50 to 30:70 (Examples 3 to 5), the adhesiveness is good, skin irritation does not occur, and excellent blood kinetics are exhibited. On the other hand, the preparations of Comparative Examples all have insufficient blood kinetics as compared with the preparations of the present invention, and further have weak adhesiveness (Comparative Examples 3 and 4) and slightly strong skin irritation (Comparative Example). It turns out that there are problems such as 5).

Front page continued (72) Inventor Tsutsusuke Oe, 5-5-3 Midorigaoka, Hamura-shi, Tokyo 5 Sansan Pharmaceutical Co., Ltd. (72) Inventor Shubun Hidaka 5-5-3 Midorigaoka, Hamura-shi, Tokyo Pharmaceutical Co., Ltd.

Claims (14)

[Claims] 1. A patch comprising an adhesive composition comprising an adhesive composition containing an adhesive and isosorbide dinitrate formed on a flexible carrier, wherein the adhesive is a silicone adhesive (A). And a polyvinyl acetate adhesive (B),
They are mixed adhesives having a weight ratio of A: B = 85: 15 to 15:85, and the weight ratio of isosorbide dinitrate (C) to the adhesive (A + B) is (A + B): C = 9.
A method for producing an isosorbide dinitrate-containing patch, which is 0:10 to 60:40, wherein (1) an adhesive layer of the mixed adhesive which does not contain the isosorbide dinitrate (C) is obtained,
(2) A solution containing the isosorbide dinitrate (C) is directly or indirectly attached to the adhesive layer of the mixed adhesive, and (3) the isosorbide dinitrate (C) is then attached. An adhesive patch containing isosorbide nitrate, characterized in that a therapeutically effective amount of the isosorbide nitrate (C) is contained in the adhesive layer of the mixed adhesive by heating or aging the adhesive layer of the mixed adhesive. Manufacturing method. 2. The weight ratio of the adhesive is A: B = 20:
The isosorbide dinitrate-containing patch according to claim 1, which is 80 to 40:60. 3. The silicone-based pressure-sensitive adhesive (A) has the following formula [I]: The isosorbide dinitrate-containing patch according to claim 1, which is an adhesive represented by 4. The polyvinyl acetate-based pressure-sensitive adhesive (B) is a copolymer of vinyl acetate and a (meth) acrylic acid alkyl ester and / or (meth) acrylic acid, and is a copolymer of at least vinyl acetate. The method for producing an isosorbide dinitrate-containing patch according to claim 1, which is an adhesive having a ratio of 50% by weight or more. 5. The polyvinyl acetate pressure-sensitive adhesive (B) has a copolymerization ratio of vinyl acetate with 2-ethylhexyl (meth) acrylate and (meth) acrylic acid of 60:40 to.
The method for producing an isosorbide dinitrate-containing patch according to any one of claims 1 to 3, which is an 80:20 adhesive. 6. The flexible carrier comprises (a) a film layer,
It consists of (b) adhesive layer and (c) cloth, the outermost layer is (a), and it is laminated | stacked in order of (a), (b), (c). The method for producing an isosorbide dinitrate-containing patch according to item 1. 7. The method for producing an isosorbide dinitrate-containing patch according to claim 1, wherein the adhesive layer has a thickness of 10 to 60 μm. 8. The production of an isosorbide dinitrate-containing patch according to claim 6, wherein the film layer has a thickness of 0.5 to 10 μm and is made of polyester, polyolefin, polyamide and / or ethylene-vinyl acetate copolymer. Method. 9. The film layer has a thickness of 0.5 to 4.9 μm.
The method for producing an isosorbide dinitrate-containing patch according to claim 6, which is a polyester film of m. 10. The adhesive layer has a thickness of 5 to 40 μm and has a silicone-based adhesive, an acrylic-based adhesive, a rubber-based adhesive, a polyvinyl acetate-based adhesive, an ethylene-vinyl acetate-based adhesive. The method for producing an isosorbide dinitrate-containing patch according to claim 6, which comprises and / or a combination thereof. 11. The method for producing an isosorbide dinitrate-containing patch according to claim 6, wherein the adhesive layer is a rubber-based adhesive having a thickness of 10 to 25 μm. 12. The production of an isosorbide nitrate-containing patch according to claim 6, wherein the fabric layer has a basis weight of 8 to 100 g / m 2 and is made of polyester, polyolefin, polyamide and / or ethylene-vinyl acetate copolymer. Method. 13. The method for producing an isosorbide dinitrate-containing patch according to claim 6, wherein the fabric layer is a polyester having a basis weight of 5 to 60 g / m 2. 14. The adhesive layer has a thickness of 10 to 60 μm, the film layer is a polyester film having a thickness of 0.5 to 4.9 μm, and the adhesive layer has a thickness of 10 to 25 μm.
Of the rubber-based adhesive, and the fabric layer has a basis weight of 5 to 60.
7. The method for producing an isosorbide dinitrate-containing patch according to claim 6, which is a polyester of g / m @ 2.