JPH09124462A - Transdermal patch material and transdermal patch preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a transdermal patch material having excellent moisture permeability and suppressed skin irritation (rash) and capable of exhibiting excellent percutaneous absorption by forming a specific spaced part in an adhesive layer. SOLUTION: This transdermal patch material is obtained by forming an adhesive layer directly or indirectly on one side of a supporting body. In the adhesive layer, a space continuous in a plane direction is formed in such a state as to reach to the edge of the transdermal patch material and to have the thickness of 30-20μm in a part where the space is formed. The space is preferably formed by a space-forming material of one kind selected from a woven cloth, a nonwoven cloth and a knit cloth made of monofilaments or fiber bundles. Further, it is preferable that, in the transdermal patch material, a substantial moisture permeability from the back side is <=160g/m<2> .24hr, and an apparent moisture permeability is 150-400g/m<2> .24hr. The transdermal patch material is used as a transdermal patch preparation by containing a percutaneous absorption drug (e.g. a coronary vascular agonist a hormone or an analgesic) in the adhesive layer.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a patch and a patch preparation, and more particularly to a patch for medical use for covering and protecting a skin injury site and a continuous transdermal administration of a transdermal drug. It relates to a patch preparation.

[0002]

2. Description of the Related Art A medical patch such as a plaster or a bandage for fixing gauze or the like on the skin surface, a dressing for protecting damaged skin, or a drug for transdermal absorption is passed through the skin surface. Various patch preparations for transdermal administration have been conventionally proposed and developed. As these shapes, a non-woven fabric or various plastic films are generally used as a support, and an adhesive layer is formed on one surface of the support.

Products such as medical patches and patch preparations which are applied to the skin surface by utilizing adhesive strength must always be aware of the problem of skin rash during the development process. The cause of this skin rash is usually
The following three factors are considered.

Chemical irritation due to allergies and the like. Physical irritation during peeling caused by strong adhesion to the skin. Mules (maceration) due to insufficient moisture permeability of the patch or patch preparation itself.

The above can be prevented by removing substances that cause chemical irritation as much as possible.
In the case of a patch preparation containing a drug for percutaneous absorption, if the drug itself has skin irritation, a fatal problem that cannot be solved and a development is often stopped.

Further, in the case of skin rash caused by the above adhesive force, as described in JP-A-3-220120, the skin adhesive force is adjusted by using an adhesive layer having a specific composition. It is possible to solve.

Further, in the case of skin irritation due to insufficient moisture permeability as described above, it is possible to prevent stuffiness to some extent by improving the moisture permeability of the patch or patch preparation itself. Regarding this point, as proposed by Hosaka et al., The inflection point is around 400 g / m ² · 24 hr, and the skin irritation increases at moisture permeability below that and the skin irritation decreases above that. It is known (Abstracts of the Polymer Materials Forum, p. 149, Society of Polymer Science, December 1992).

On the other hand, in the case of a patch preparation containing a drug for percutaneous absorption, the relationship between moisture permeability and percutaneous absorption of the drug (skin transfer) has been investigated along with improvement of the skin rash. As a result, the transdermal absorbability of many drugs tends to decrease as the moisture permeability of the patch preparation increases. That is,
Prevention of skin rash (improvement of moisture permeability) and improvement of percutaneous absorption are contradictory, and in developing a patch preparation, it is an important problem to balance both of them.

As a result of examining the balance between such skin rash prevention and transdermal absorbability, Kinoshita et al. Empirically found that the moisture permeability of the preparation itself was set to about 100 to 400 g / m ² · 24 hr. It is said that it is possible to take a balance ("Formulation design and basic pharmaceutical knowledge of percutaneous absorption preparation", clinical practice and new drug, 30 (4), 166-175, 1
993).

[0010]

Therefore, in view of the above-mentioned relationship between transdermal absorbability and moisture permeability, the present inventors have applied a patch having a good balance with skin irritation (fogging) that occurs when applied to the skin surface. Studies have been repeated to develop agents and patches.

As a result, the inventors have found that the object of the present invention can be achieved by forming specific voids in the pressure-sensitive adhesive layer constituting the patch or patch preparation, and completed the present invention.

[0012]

That is, the present invention relates to a patch comprising an adhesive layer indirectly or directly formed on one surface of a support, which is continuous in the planar direction. The patch is characterized in that the void is formed so as to reach the edge of the patch, and the thickness of the void forming portion is 30 to 200 µm.

In particular, it is preferable to form the voids by a void forming member such as a single fiber such as a woven fabric or a non-woven fabric or a fiber bundle. Moreover, the amount of moisture permeation that substantially permeates from the back surface of the patch (JISL1099 moisture permeability test method for textiles A-1
According to the law. Hereinafter, referred to as a substantial moisture permeability) is 160
An apparent moisture permeability of g / m ² · 24 hr or less and also including the amount of water adsorbed in the patch (in accordance with JIS L1099, the moisture permeability test method A-2 of a textile product. Wet amount) is 150-400 g / m ² · 2
The preferred embodiment is 4 hours.

Furthermore, the present invention also provides a patch preparation in which a transdermal drug is contained in the adhesive layer of the above patch. As a preferable drug for transdermal absorption,
Examples include one selected from coronary vasoactive agents, hormonal agents, analgesics, bronchodilators, and antihypertensive agents.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The support used for the patch or patch preparation of the present invention is required to have moisture permeability to prevent stuffiness of the skin surface and to have a suitable barrier property for percutaneous absorption. Becomes Specifically, a single film such as polyester, nylon, saran, polyethylene, polypropylene, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, Surlyn, metal foil, or a laminated film thereof may be used. it can. Among these supports, film strength, price, thickness uniformity,
A polyester film is preferably used in terms of quality stability.

Even if the support is made of a material having relatively low moisture permeability such as polyester, it is possible to impart appropriate moisture permeability by reducing the film thickness. Therefore, the thickness of the support of the present invention is 0.5 to 25 μm.
m, preferably about 1.0 to 12 μm.

For example, the moisture permeability of a polyester film, which is said to have low comparative moisture permeability, and a polytetrafluoroethylene porous film (PTFE, manufactured by Nitto Denko Corporation, trade name NTF-DDS), which has extremely high moisture permeability. Table 1 shows the results of examination. The moisture permeability was measured according to JIS A1099 method A-1.

[0018]

[Table 1]

As is clear from the results shown in Table 1, the smaller the thickness of the polyester film, the higher the moisture vapor transmission rate. However, compared with the porous film having high moisture permeability, the polyester film has a low moisture vapor permeability at any thickness. It can be said that it is breathable.

However, in the patches and patch preparations actually used, since the pressure-sensitive adhesive layer is formed on one surface of the above-mentioned support film, the water vapor transmission rate is further lowered. Therefore, an acrylic pressure-sensitive adhesive obtained by polymerizing an acrylic acid alkyl ester, which is generally used as a medical pressure-sensitive adhesive, as a main component monomer is laminated on one side of the above-mentioned support film, and the transparency at that time is laminated. Moisture (JIS L1099 A-1
According to the law). Table 2 shows the results. The pressure-sensitive adhesive composition used in Example 1 of the present invention described later was 90 parts by weight of 2-ethylhexyl acrylate / 9.9 parts by weight of methyl methacrylate / 0.1 parts of glycidyl dimethacrylate.
An internally crosslinked acrylic copolymer obtained by polymerizing parts by weight was used to form a pressure-sensitive adhesive layer having a thickness of 40 μm.

[0021]

[Table 2]

As is clear from the comparison with Table 2 and Table 1 above, when the thickness of the polyester film exceeds 6 μm, even if the pressure-sensitive adhesive layer is laminated, the moisture permeation amount does not change as compared with that before lamination. When the pressure-sensitive adhesive layer is formed on one side of the support, the moisture permeability is generally low, and when the pressure-sensitive adhesive layer is laminated in the case of a polyester film, the total thickness is 200 g / m.
It becomes a value of ² · 24 hours or less, which is substantially equal to having no moisture permeability. On the other hand, the thicker the film, the harder it becomes and the stronger the physical irritation during application, so the thinner the film, the better. However, considering that the thinner the film thickness, the lower the mechanical strength of the film and the higher the price, and further that it is impossible to expect a practically useful improvement in moisture permeability when the pressure-sensitive adhesive layer is laminated as described above. In the case of a polyester film, the thickness is preferably 6 μm or less, preferably about 2 to 4 μm.

When the film thickness of the support used in the present invention is as thin as 6 μm or less, the mechanical strength is insufficient, the film is broken during production or use, and the self-supporting property is poor. Since it will be inferior in sticking operability, in order to supplement the mechanical strength and operability, non-woven fabric or woven fabric,
It is preferable to use a knitted cloth or the like as a backing material and stack it on the back surface of the support using a binder or the like. The backing material to be laminated at this time is preferably selected from a material having air permeability that does not impair the moisture permeability.

In the patch or patch preparation of the present invention, the pressure-sensitive adhesive layer formed on one surface of the support is a pressure-sensitive adhesive which has adhesiveness to the skin surface and is non-sensitizing to the skin. The pressure-sensitive adhesive that has been conventionally used as a medical pressure-sensitive adhesive can be used. Specifically, an acrylic, rubber-based, silicone-based, vinyl ether-based pressure-sensitive adhesive can be used. Among these adhesives, hydrophobic adhesives are preferable from the viewpoint of excellent adhesion to the skin surface, and those having relatively easy adjustment of adhesive physical properties include those made of acrylic polymers, particularly acrylic acid. It is preferable to use an adhesive obtained by copolymerizing alkyl ester or methacrylic acid alkyl ester (hereinafter referred to as (meth) acrylic acid alkyl ester) as a main component monomer and copolymerizing with other copolymerizable monomer.

As the above-mentioned (meth) acrylic acid alkyl ester, specifically, the alkyl group is butyl, pentyl,
Having a linear alkyl group or a branched alkyl group having 4 to 13 carbon atoms such as hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, etc. (meth)
Acrylic acid alkyl esters can be used, and these can be used alone or in combination of two or more.

The above-mentioned (meth) acrylic acid alkyl ester is not limited to the above-exemplified ones, and may have 1 to 10 carbon atoms as long as the adhesive property is not significantly deteriorated.
A (meth) acrylic acid alkyl ester having a lower alkyl group of 3 or a (meth) acrylic acid alkyl ester having a higher alkyl group having 14 or more carbon atoms may be used in combination.

The copolymerizable monomer which can be copolymerized with the above-mentioned (meth) acrylic acid alkyl ester has at least one unsaturated double bond involved in the copolymerization reaction in the molecule, and also has a carboxyl group. Groups (eg (meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride, etc.), hydroxyl groups (eg (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester etc.), sulfoxyl groups (eg styrene Sulfonic acid, allylsulfonic acid, (meth) acrylic acid sulfopropyl ester, (meth) acryloyloxynaphthalenesulfonic acid, acrylamidomethylpropanesulfonic acid, etc.), amino group (for example, (meth) acrylic acid aminoethyl ester, (meth) acrylic) Acid dimethylamino Chiruesuteru, (meth) acrylic acid tert- butylaminoethyl ester),
Amide group (for example, (meth) acrylamide, dimethyl (meth) acrylamide, N-butylacrylamide,
N-methylol (meth) acrylamide, N-methylolpropane (meth) acrylamide, etc., an alkoxyl group (for example, methoxyethyl (meth) acrylate, ethoxyethyl (meth) acrylate, methoxyethylene glycol (meth) acrylate) ,
(Meth) acrylic acid methoxydiethylene glycol ester, (meth) acrylic acid methoxypolyethylene glycol ester, (meth) acrylic acid methoxypolyethylene glycol ester, (meth) acrylic acid tetrahydrofurfuryl ester, etc.) A mer can be used. Examples of other copolymerizable monomers include (meth) acrylonitrile, vinyl acetate, vinyl propionate, and N-vinyl-2.
-Pyrrolidone, methylvinylpyrrolidone, vinylpyridine, vinylpiperidone, vinylpyrimidine, vinylpiperazine, vinylpyrazine, vinylpyrrole, vinylimidazole, vinylcaprolactam, vinyloxazole, vinylmorpholine and the like can be used.

These copolymerizable monomers can be copolymerized with one kind or two or more kinds, but the adhesive property is adhesiveness or cohesiveness, and the release property of the drug for transdermal absorption contained in the adhesive layer. From the viewpoint of reactivity at the time of cross-linking the pressure-sensitive adhesive layer, at least one of a carboxyl group-containing monomer and a hydroxyl group-containing monomer is an essential component, and if necessary, other unit amounts exemplified above. It is particularly preferred to copolymerize the body. The copolymerization amount of the above-mentioned copolymerizable monomer is 50% by weight or less, preferably 2 to 40, in all monomers depending on the purpose.
It can be arbitrarily set so as to fall within the range of weight%.

In the adhesive layer of the patch or patch preparation of the present invention, by adjusting the adhesive strength, it is possible to prevent keratin damage caused by peeling from the skin surface to reduce skin irritation, or for transdermal absorption. For the purpose of improving diffusion mobility (or drug release) and drug solubility of the drug in a patch preparation containing the drug, various auxiliaries which are liquid at room temperature are contained in the adhesive layer in an amount of 0 to 70% by weight, preferably It can be contained in the range of 20 to 60% by weight.

Examples of such auxiliaries include C _{6 to} C
₂₂ fatty acids such as hexylic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, behenic acid, hydrogenated rapeseed oil, these fatty acids and C ₁ -C ₄ methyl alcohol, Fatty acid esters obtained from alcohols such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol and isobutyl alcohol, monoglycerides obtained from the above fatty acids, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol , Glycols such as polypropylene glycol, olive oil, castor oil, squalene, oils and fats such as lanolin, ethyl alcohol, 1,3-butanediol, dimethyldecyl sulfoxide , Organic solvents such as methyl octyl sulfoxide, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dodecylpyrrolidone and isosorbitol, liquid surfactants, hydrocarbons such as liquid paraffin and the like.

The adhesive layer of the patch or patch preparation of the present invention has about 30 to 50 voids continuous in the plane direction.
It is formed so as to reach the edge of the patch with a thickness of 200 μm, preferably 50 to 200 μm. Since the voids are thus formed in the pressure-sensitive adhesive layer, the cohesiveness of the pressure-sensitive adhesive layer is inferior to that in which a dense pressure-sensitive adhesive layer having no voids is formed. When peeled off, there is a risk of cohesive failure. Therefore, in order to improve the mechanical strength of the pressure-sensitive adhesive layer, crosslinking treatment is preferably performed. Cross-linking methods include physical cross-linking by irradiation with radiation such as ultraviolet irradiation or electron beam irradiation, polyisocyanate compounds, organic peroxides, organic metal salts, metal alcoholates, metal chelate compounds, polyfunctional compounds (polyfunctional external cross-linking). Chemical crosslinking treatment using a crosslinking agent such as an agent or a polyfunctional internal crosslinking agent such as diacrylate or dimethacrylate. Of these cross-linking treatments, from the viewpoint of ease of adjustment of cross-linking reactivity and degree of cross-linking, and handleability, trifunctional isocyanate, metal alcoholate made of titanium or aluminum, or external cross-linking treatment using a metal chelate compound, An internal crosslinking treatment in which a polyfunctional monomer is copolymerized is preferable. These cross-linking agents do not cause a thickening phenomenon of the solution until coating and drying and are extremely excellent in workability, and the compounding amount is 0.01 with respect to 100 parts by weight of the solid content of the pressure-sensitive adhesive layer. It is about 1.0 part by weight.

The void in the present invention may be a simple space such as a bubble, but in order to surely reach the edge of the patch continuously, the void forming member is placed in the adhesive layer. It is preferable to intervene. As the void forming member, specifically, inert particles, glass beads, filler, woven fabric, non-woven fabric, knitted fabric and the like can be used. As a preferable void forming member, a woven fabric, a non-woven fabric, a knitted fabric, or the like formed from single fibers or fiber bundles is used. It is possible to easily adjust the size of the voids by adjusting the basis weight (basis weight) of these, and it is also easy to adjust the thickness of the void forming portion. Among these, when a woven fabric is used as the void forming member, a mesh-like one having relatively coarse mesh is preferable, and the mesh interval is 0.05
Approximately 1 mm. A woven fabric having a roughness of more than 1 mm is not preferable because the adhesive is densely embedded in the woven fabric and the voids are reduced. Further, as the material, polyester, polyethylene, polypropylene, rayon, cotton and the like, which are easily available and relatively inexpensive, are preferable.

By forming the void forming portion in the pressure-sensitive adhesive layer, a part of the water secreted from the skin surface of the application site can be stored and accumulated in the void forming portion. Then, the apparent moisture permeability in the present invention can be improved. As a result, it is possible to suppress skin irritation when the patch or patch preparation of the present invention is applied to the skin surface. That is, since the void forming portion reaches the edge of the patch or patch preparation, the moisture permeability of the patch or patch preparation as a whole is not only the moisture permeability utilizing the surface of the support but also the side surface of the adhesive layer. It also contributes to the moisture permeability by utilizing.

Therefore, in the patch or patch preparation of the present invention,
Substantial amount of moisture permeation from the back of the patch or patch preparation (JIS
L1099 textile product moisture permeability test method A-1 method), 160 g / m ² · 24 hr or less, preferably 6
It is desirable to set it to 0 to 160 g / m ² · 24 hr.
Further, the apparent moisture permeability including the amount of adsorbed water in the patch and patch preparation (according to JIS A1099 moisture permeability test method A-2 method for textile products) is 150 to 400 g / m ² ·
24 hr, preferably 200-400 g / m ² · 24 h
It is desirable to adjust to the range of r. When the substantial moisture permeability exceeds 160 g / m ² · 24 hr, the percutaneous absorption of the drug is apt to decrease. Also, the apparent moisture permeability is 150
When it is less than g / m ² · 24 hr, it does not show much effect on improving skin irritation, and 400 g / m ² · 2
If it exceeds 4 hours, the physical stability and transdermal absorbability of the patch or patch preparation may be adversely affected. Therefore, the best mode is a patch or patch preparation that satisfies the above-described substantial moisture permeability and apparent moisture permeability.

On the other hand, as a technique similar to the technique of the present invention, a method using a foamed pressure-sensitive adhesive obtained by foaming a pressure-sensitive adhesive layer,
There is a method of dispersing water-absorbing polymer particles in the pressure-sensitive adhesive layer. However, the former method has a problem that it is very difficult to uniformly and accurately foam the pressure-sensitive adhesive layer, and the pressure-sensitive adhesive property is not constant for each production lot. Further, in the method of containing water-absorbing polymer particles like the latter,
When the temperature is high and the humidity is high, the amount of perspiration at the application site increases, the water-absorbent polymer particles absorb the perspiration and the degree of swelling increases, and the adhesive properties decrease, and the volume of the adhesive layer itself increases due to the swelling particles. Then, it is deformed and a warp phenomenon occurs, resulting in a decrease in skin adhesiveness due to a decrease in adhesion area. However, in the present invention, by using the void-forming member, the support, the pressure-sensitive adhesive layer, and the void-forming member can be accurately formed, respectively, and by laminating these, a uniform patch and patch preparation can be produced.
In addition, moisture such as sweat is once adsorbed and stored in the void forming member and gradually diffused not only from the back surface of the support but also from the edge portion of the void forming member, so that the adhesive force is less likely to decrease.

Further, when the above-mentioned void forming member formed in the pressure-sensitive adhesive layer in the present invention is laminated on the side of the pressure-sensitive adhesive layer which is in contact with the support, the anchoring property between the pressure-sensitive adhesive layer and the support may be poor. Therefore, it is preferably provided in the pressure-sensitive adhesive layer. That is, the support, the pressure-sensitive adhesive layer A, the void forming member, and the pressure-sensitive adhesive layer B are laminated in this order. The pressure-sensitive adhesive layer A and the pressure-sensitive adhesive layer B may be the same pressure-sensitive adhesive or different pressure-sensitive adhesives. The pressure-sensitive adhesive layer A does not need to be a pressure-sensitive adhesive layer because it does not contact the skin surface, and may be a so-called known adhesive. When the adhesive is used as described above, the adhesive may bond the support and the void forming member, and thus the thickness of the adhesive layer may be about several μm. However, when the pressure-sensitive adhesive layer A is formed of a so-called pressure-sensitive adhesive, the pressure-sensitive adhesive is appropriately embedded in the void-forming member and bonded by the anchor effect. 10 to
About 50 μm is required. If the thickness is less than 10 μm, the support and the void-forming member may not be sufficiently joined to each other, causing anchor failure. Further, when the thickness is 50 μm or more, the anchoring effect is sufficiently exhibited, but there is almost no difference in effect from the case where the thickness is 50 μm or less.

As described above, since the pressure-sensitive adhesive layer in the present invention has the void-forming member and the like laminated and formed therein, the voids formed in the pressure-sensitive adhesive layer are deformed under pressure. Therefore, the thickness of the entire surface (whole area) of the obtained patch or patch preparation is not strictly constant, but in order to impart the preferable moisture permeability in the present invention, it is about 30 to 2 as described above.
Since the thickness of the void forming portion is required to be about 00 μm, preferably about 50 to 200 μm, the thickness of the void forming portion before lamination is required to be about 60 to 250 μm.

Further, the thickness of the pressure-sensitive adhesive layer in the present invention is, in order to maintain sufficient adhesiveness to the skin surface, a pressure-sensitive adhesive layer located below the void forming portion (skin surface-side pressure-sensitive adhesive layer). Has a thickness of 20 to 100 μm, preferably 40 to
The thickness is about 80 μm. If the thickness is less than 20 μm, the shape of the void-forming member in the pressure-sensitive adhesive layer may affect the smoothness of the surface of the pressure-sensitive adhesive on the skin-bonding surface side, and sufficient skin-bonding property may not be exhibited. On the other hand, when it exceeds 100 μm, the skin adhesive force becomes too large, which may cause skin irritation during peeling after application.

The patch preparation of the present invention comprises a drug for transdermal absorption in the adhesive layer of the patch having the above-mentioned constitution, particularly the adhesive layer located on the skin surface side. The drug for percutaneous absorption that can be used in the present invention is not particularly limited as long as it can be used for percutaneous absorption, and can be arbitrarily selected according to its therapeutic purpose. For example, corticosteroids, analgesic and anti-inflammatory agents, hypnotics, tranquilizers, antihypertensives, antihypertensive agents, antihypertensive diuretics, antibiotics, anesthetics, antibacterial agents, antifungal agents, vitamins, coronary vasodilators, antihistamines, antitussives. , Drugs such as sex hormones, antidepressants, cerebral circulation improvers, antiemetics, antitumor agents, biomedicals, etc., which do not stay on the skin surface but penetrate subcutaneously or into the blood A transdermally absorbable drug that exerts a local action or a systemic action can be used. Two or more of these drugs may be used in combination, if necessary. From the viewpoint of uniform dispersibility in the pressure-sensitive adhesive layer and transdermal absorbability, among these drugs, fat-soluble drugs (dissolved amount 0.4 g or less / water 1
It is preferable to use (00 ml / room temperature). Among the above-mentioned drugs for transdermal absorption, as drugs particularly suitable for transdermal administration, coronary vasoactive drugs such as isosorbide dinitrate and nitroglycerin, estradiol and estrone, their esters, hormonal drugs such as steroids, Examples include analgesics such as buprenorphine and morphines, ketoprofen, bronchodilators such as salbutamol and tulobute, and antihypertensive agents such as clonidine and bendroflumethiazide.

The content of these drugs for percutaneous absorption can be appropriately set depending on the drug species and the purpose of administration, but it is usually 1 to 40% by weight, preferably 2 to 30% in the total adhesive.
It is contained in the range of about wt%. If the content is less than 1% by weight, it may not be possible to expect an effective amount for treatment or prevention, and if it exceeds 40% by weight, the effect cannot be expected to increase due to an increase in the amount, which is economically disadvantageous. In addition, the adhesiveness to the skin tends to be poor. In the present invention, it is not necessary that all of the drug is dissolved in the pressure-sensitive adhesive, and the drug in the undissolved state may be contained by containing the drug having the solubility or higher in the pressure-sensitive adhesive. . In this case, the undissolved drug needs to be homogeneously dispersed in the patch preparation so that the content does not vary.

However, from the viewpoints of imparting sustained release over a long period of time, increasing the release amount by increasing the content per unit area, and miniaturizing the preparation for reducing skin irritation, etc. It goes without saying that it may be contained regardless of the weight range.

[0042]

EFFECT OF THE INVENTION The patch and patch preparation of the present invention are constituted as described above, and have excellent moisture permeability by forming a void forming part in a specific state in the adhesive layer. In addition, the apparent moisture permeability can be kept relatively high, and the substantial moisture permeability can be kept relatively low to suppress skin irritation that causes maceration. Moreover, since the water vapor transmission rate is substantially suppressed, the patch preparation containing a drug for transdermal absorption also has an effect of exhibiting excellent transdermal absorbability.

[0043]

EXAMPLES Examples of the present invention will be described below in more detail, but the present invention is not limited thereto, and various applications can be made without departing from the technical concept of the present invention. It is possible. In the following text, "parts" means "parts by weight".

<Example 1> 90 parts of 2-ethylhexyl acrylate, 9.9 parts of methyl methacrylate, and 0.1 part of glycidyl dimethacrylate were copolymerized in ethyl acetate under an inert gas atmosphere. To prepare a solution of acrylic copolymer.

20 parts of isosorbide dinitrate was mixed with 80 parts of the solid content of the resulting acrylic copolymer solution, and ethyl acetate was added to adjust the viscosity.
5 μm thick polyester separator and 3.8 μm
The thickness after drying is 60μ on a thick polyester film.
m and 30 μm, and dried to prepare pressure-sensitive adhesive layers containing a drug for transdermal absorption.

Next, a polyester non-woven fabric (manufactured by Nippon Vilene Co., Ltd., basis weight 20 g / m 2) is provided between the two adhesive layers.
⁽² , thickness of about 60 μm) were laminated, and pressure-bonded with a laminator of a mirror-finished stainless steel roll to obtain a patch preparation of the present invention.

<Second Embodiment> In the first embodiment, 3.8 μ
Instead of the m-thick polyester film, a 6 μm-thick polyester film is used, and the isosorbide dinitrate-containing pressure-sensitive adhesive layer coated on the polyester film has a thickness of 50 μm. Asahi Kasei Corporation, trade name ELTAS N
3030, thickness about 200 μm) was obtained in the same manner as in Example 1 to obtain a patch preparation of the present invention.

Example 3 2.5 parts of estradiol was mixed with 97.5 parts of the solid content of the acrylic copolymer solution obtained in Example 1, and tetrahydrofuran was added to adjust the viscosity. Then, in the same manner as in Example 1, a pressure-sensitive adhesive layer containing a drug for transdermal absorption was prepared.

Next, between the two adhesive layers, gauze (manufactured by Kawamoto Bandai Co., Ltd., trade name Kapine, thickness about 200 μm) is used.
m) was interposed and laminated by pressure bonding with a laminator of a mirror-finished stainless steel roll to obtain the adhesive preparation of the present invention.

<Example 4> In Example 3, the thickness of the estradiol-containing pressure-sensitive adhesive layer coated on the polyester separator was 40 μm, and the gauze to be interposed in the pressure-sensitive adhesive layer was used in Example 1. A patch preparation of the present invention was obtained in the same manner as in Example 3 except that the polyester non-woven fabric (manufactured by Japan Vilene Co., Ltd., basis weight 20 g / m ² , thickness about 60 μm) was used.

Example 5 In an inert gas atmosphere, 75 parts of acrylic acid 2-ethylhexyl ester, 22 parts of N-methylpyrrolidone and 3 parts of acrylic acid were copolymerized in ethyl acetate to prepare an acrylic copolymer. A combined solution was prepared.

2 μm thick polyester film and 12 g
The acrylic copolymer solution obtained as described above is included in the non-woven fabric layer on the non-woven fabric side of the laminated film made of a polyester non-woven fabric having a thickness of / m ² (the adhesive layer is impregnated in the non-woven fabric layer). (2) was coated to a thickness of 60 μm and dried to form a pressure-sensitive adhesive layer on one surface of the support.

Next, 5 parts of isopropyl myristate was added to 44.25 parts of solid content of the acrylic copolymer solution.
5 parts, 3.25 parts of estradiol and 2 parts of polyvinylpyrrolidone (K-90, manufactured by GAF) are dissolved in tetrahydrofuran and added, and polyisocyanate (Coronate HL, manufactured by Nippon Polyurethane Co.) is further added. After adding 0.4% to the solid content of the polymer and adjusting the viscosity with ethyl acetate, it was applied onto a polyester separator having a thickness of 75 μm so that the thickness after drying would be 60 μm, and dried. An adhesive layer containing a drug for percutaneous absorption was prepared.

Then, a nylon non-woven fabric (trade name ELTAS N3030, manufactured by Asahi Kasei Co., Ltd.) is provided between the pressure-sensitive adhesive layer formed on the support and the pressure-sensitive adhesive layer containing a drug for transdermal absorption formed on the separator. Were laminated in the state of interposing, and the patch preparation of the present invention was obtained in the same manner as in Example 2. The obtained patch preparation was used after being heat-treated at 60 ° C. for 48 hours immediately after preparation.

<Comparative Example 1> In Example 1, a polyester non-woven fabric (manufactured by Nippon Vilene Co., Ltd., basis weight 20 g / m 2)
^{2. A} patch preparation was prepared by laminating an adhesive layer (60 μm) containing isosorbide dinitrate on a 3.8 μm-thick polyester film without interposing a thickness of about 60 μm).

<Comparative Example 2> In Example 1, a polyester non-woven fabric (manufactured by Nippon Vilene Co., Ltd., basis weight 8 g / m ² ,
A patch preparation was prepared in the same manner as in Example 1 except that a thickness of about 30 μm was interposed.

<Comparative Example 3> In Example 4, nylon non-woven fabric (trade name ELTAS N1130, manufactured by Asahi Kasei Corp.,
A patch preparation was prepared in the same manner as in Example 4, except that a thickness of about 300 μm was interposed.

The following characteristics were examined with respect to each of the above Examples and Comparative Examples, and the results are shown in Table 3.

<Thickness of Void Forming Portion> The patch preparations obtained in each Example and Comparative Example were cut in the thickness direction and the cross section was observed with an optical microscope to measure the thickness of the void forming portion.

<Substantial Moisture Permeation Amount> The moisture permeation amount was measured according to the A-1 method of the moisture permeability test method (L1099) for JIS standard textile products. The test sample was placed with the exposed surface of the adhesive layer facing the moisture absorbent side.

<Amount of Apparent Moisture Permeability> The amount of moisture permeation was measured according to the A-2 method of the moisture permeability test method (L1099) of JIS standard textile products. The test sample was placed with the exposed surface of the adhesive layer facing the moisture absorbent side. After the completion of the measurement, the test sample was collected, water drops on the surface of the adhesive layer were carefully wiped off, and the weight was measured. Then, the change in the weight of the test sample before and after the measurement was obtained, and this weight increase amount was added to the above-mentioned substantial moisture permeability to obtain an apparent moisture permeability.

<Transdermal Absorption of Drug (Amount Transferred to Skin)> The patch preparations obtained in each of the Examples and Comparative Examples were cut into a size of 25 cm ² and applied to the back of a previously hair-removed rabbit. The application time was 24 hours for the isosorbide dinitrate-containing preparation and 48 hours for the estradiol-containing preparation. Then, the amount of drug contained before and after application was quantified by high performance liquid chromatography, and the difference was used as the amount transferred to the skin to evaluate the transdermal absorbability.

<Skin irritation> The patch preparations obtained in each of the Examples and Comparative Examples were cut into a size of 5 cm ² , and the cut patch was applied to the chest of 5 volunteers. After sticking for 24 hours, each patch preparation was peeled off, and the degree of skin irritation at the patched site (skin) 1 hour after peeling was judged by the following judgment criteria (Patch Test Study Group criteria), and the average I asked for a grade.

−: No reaction Score 0 ±: Light erythema 0.5 +: Erythema 1.0 ++: Erythema and edema 2.0 ++++: Erythema and edema and papules (or blisters) 3.0 ++++: Blisters 4. 0

[0065]

[Table 3]

Claims (8)

[Claims] 1. A patch comprising an adhesive layer indirectly or directly formed on one surface of a support, wherein the adhesive layer has voids continuous in the plane direction up to the edge of the patch. And the thickness of the void forming portion is 30
The patch is characterized in that it is ˜200 μm. 2. The patch according to claim 1, wherein the void is formed by a void forming member. 3. The patch according to claim 2, wherein the void-forming member is one selected from woven fabrics, non-woven fabrics, and knitted fabrics formed from single fibers or fiber bundles. 4. The patch according to claim 1, wherein voids are formed at or near the interface between the pressure-sensitive adhesive layer and the support. 5. A moisture permeation amount that substantially permeates from the back surface of the patch (JISL1099 moisture permeability test method A-1 for textiles).
The patch according to claim 1, which is 160 g / m ² · 24 hr or less. 6. (according to moisture permeability test method A-2 method of textile products JISL1099) moisture permeation amount of apparent also contained adsorbed water content into the adhesive patch, 150~400g / m ² · ²
The patch according to claim 1, which has a duration of 4 hours. 7. A patch preparation comprising the adhesive layer of the patch according to claim 1 containing a drug for transdermal absorption. 8. The patch preparation according to claim 7, wherein the drug for percutaneous absorption is one selected from coronary vasoactive drugs, hormone drugs, analgesics, bronchodilators, and antihypertensive drugs.