JPH06271462A - Stable patch - Google Patents

Abstract

PURPOSE:To obtain a stable patch minimized in rash action. CONSTITUTION:A patch comprises a water semi-permeable film (layer (a)) having 0.5-4.9mum thickness, a fabric (layer (b)) having 1-17mum average diameter of single yarn and 8-100g/m<2> weight and a tacky agent layer (layer (c)) containing a medicine and has (1) 10-40g/mm or 3-30g/mm interlaminar peel strength between the layer (a) and the layer (b) depending upon the kind of fabric and (2) 2-40mg/day.cm<2> water transpiration from the patch.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release pharmaceutical patch for transdermal administration. More specifically, the present invention comprises a specific cloth, an adhesive layer containing a drug, and a film. The present invention relates to a patch having high property, excellent release property, and easy to handle.

The present invention relates to a patch containing a nitrate ester which is useful for the prevention and amelioration of cardiovascular diseases, in particular, heart diseases such as angina and arrhythmia.

The present invention also relates to an estradiol-containing patch useful for the prevention and amelioration of the disorders often observed in postmenopausal women such as menopausal disorder, osteoporosis and Alzheimer's dementia.

The present invention further comprises buprenorphine, which is useful for postoperative various cancers, myocardial infarction, anesthesia support, lumbago, rheumatoid arthritis, trauma, tooth extraction, etc., and especially for pain relief associated with various cancers. Regarding patches.

[0005]

2. Description of the Related Art In the development of pharmaceuticals, at the same time as developing new compounds with excellent drug efficacy, the dosage form is changed to further enhance the effects of these new compounds and those already used as pharmaceuticals. And various optimization of the dosage form has been studied.

For example, for the purpose of prolonging the duration of a drug having a short half-life, which is also a parameter of the effective duration of the drug in the body, the concentration of the drug is above the minimum effective concentration and below the maximum safe concentration, that is, the effective blood concentration. So-called sustained-release preparations are being actively developed in which the active ingredients are absorbed into the human body over a long period of time.

Examples of sustained-release preparations include percutaneous absorption preparations such as ointments and spray coatings. Since these formulations are applied to the skin in a metered amount, there is a problem that the dose is not constant and that ointment or the like adheres to clothes and stains.

[0008] As a measure for remedying such a drawback, there are tapes and patches in which a certain amount of a drug is contained in an adhesive and molded into a certain size (for example, JP-A-57-116011 and JP-A-58). -1340020).

According to the method using a tape or patch,
Many problems that occur with methods such as ointment and spray application can be solved.

It has also been found that when a drug is transdermally administered, the rate of so-called hepatic metabolism in which the drug is metabolized in the liver and loses its efficacy can be significantly reduced as compared with the case of oral administration. Therefore, tapes and patches (hereinafter referred to as patches) are very excellent drug administration forms when the drug has the property of being transdermally absorbed.

However, it has become clear that there are some problems with the conventional patches as the patches are frequently used.

[0012] Of these problems, the most frequently occurring problem is skin rash occurring at the application site of a patient who has applied the patch. Generally, sustained-release preparations are often administered to patients with chronic diseases, and therefore the patch is repeatedly applied over a long period of time, so that skin irritation is likely to occur, and once skin irritation occurs, the affected area expands. There is a problem that it is easy. According to one statistic, the skin irritation caused by the patch is 20 to 50% of all patients.

Another problem with patches is the variation in blood drug concentration. The factors of blood concentration fluctuation are complicated with factors of patch side, human skin side, human metabolic function factor, etc. Therefore, it is not easy to stabilize drug blood concentration.

Another problem relates to handling. That is, in order to reduce the skin rash caused by the patch, the support of the patch was made as thin as possible, the flexibility was increased, and the skin rash was somewhat reduced by devising a smaller patch. There is also a problem that it is very difficult to correctly attach the to the predetermined position of the patient. For example, in recent years, a patch containing a nitrate ester as an active ingredient has been widely used as a therapeutic agent for cardiovascular diseases such as angina, but the above-mentioned problems, especially the problem of skin rash, There is a demand for a patch that maintains a stable blood concentration of the drug and does not have such a problem.

This problem has been conventionally avoided from the occurrence of uterine cancer as a side effect, but it has been found that transdermal administration can solve this problem, and in recent years, it has been highlighted as a therapeutic drug for menopausal disorders and osteoporosis in women. The situation is the same in the case of estradiol, progesterone and their derivatives which are being developed. Since the estradiol-containing patch supplements the decrease in estrogen that occurs with menopause, and the treatment period extends from several months to several years, high patient compliance is also an essential requirement.
In particular, in the case of patches, although the most serious problems are the discomfort at the time of application and the occurrence of skin irritation, the conventional techniques have not sufficiently considered this point.

Furthermore, the present inventors have discovered that in the course of studying such a patch, it has practically important characteristics. That is, it is the stability when the patch is applied, more specifically, the shape retention property. The fact that the shape is not retained
The transdermal absorbability also varies, and patients cannot use such patches with peace of mind.

As described above, in the prior art, BA is used in the case of oral preparations which have relatively high patient compliance.
(Bio Availability) is low, side effects are serious, BA is high, and drug concentration in the blood is stable. Therefore, the transdermal patch has a problem that it causes discomfort and skin irritation.

In order to improve the uncomfortable feeling, which is one of the drawbacks of the prior art, it is desirable to increase the flexibility of the patch and reduce its size. However, if the flexibility is too large, the patch will be extremely difficult to handle and will be impractical. Since the size of the patch is proportional to the amount of drug absorbed, that is, the drug concentration in blood, if the required drug concentration in the blood is fixed, in order to reduce the size of the patch, some kind of drug Means for enhancing skin absorbability are essential. Therefore, when an absorption enhancer is used for the purpose of enhancing the transdermal absorbability of a drug, there is a problem that skin irritation is often promoted. On the other hand, in order to improve skin irritation, it has been conventionally considered to appropriately select the type of the adhesive and reduce the residual monomer and the residual solvent in the adhesive,
Fundamentally, it is desirable to enhance the moisture vaporization property of the patch and the air permeability of oxygen, carbon dioxide gas and the like. However, simply increasing the water vapor permeable property or the gas permeability of oxygen or the like may reduce the sealing property of the patch, resulting in a decrease in the transdermal absorbability of the drug.

The same circumstance applies to morphine, fentanyl, buprenorphine and the like, which are considered to be used as analgesics for cancers requiring long-term treatment.

[0020]

Therefore, the object of the present invention is to eliminate the above-mentioned problems of the prior art, to stabilize the blood concentration of the drug, to give no discomfort, and to significantly improve skin rash. And to provide a patch that is easy to handle.

As a result of intensive studies conducted by the present inventors in order to solve the above problems, most of the problems are solved by a laminated type patch in which a specific film, a specific cloth and a specific adhesive layer are combined. I found that I could do it.

However, as a result of further testing and evaluation of such a laminated patch, depending on the mode in which such a laminated patch is used, the interface between the film and the fabric,
It has also been found that delamination may occur at the interface between the fabric and / or the pressure-sensitive adhesive layer, and the commercial value of the drug may be significantly impaired.

Therefore, another object of the present invention is to provide a stable patch. Other objects and advantages of the present invention will be apparent from the following description.

According to the invention, a patch applied to the outer skin
Yes, (a) Semi-permeable to water, and the film is substantially perpendicular to the 2
8-85g / mm each direction strength, and substantially orthogonal
The elongation in each of the two directions is 30 to 150%,
The ratio of the elongation in the directions is 1.0 to 5.0 (however, the elongation in the two directions is
If the degrees are not the same, the smaller elongation is used as the denominator.
Film having a thickness of 0.5 to 4.9 μm (a
Layer) (b) The average diameter of the single yarn is 1 to 30 μm, and
Basis weight is 8 to 100 g / m ²Cloth (layer b) (c) Adhesive layer containing drug and having a thickness of 5 to 100 μm
(C layer) as an essential ingredient, and from the top of the patch a layer, b
Layers are laminated in this order on the layer c, and the following (1) and
And a patch satisfying the characteristics of (2) (1) Delamination force between layers a and b is 10 to 40 g / m when the fabric of layer b is a knitted fabric.
m is 3 to 30 when the b-layer fabric is a non-woven fabric or a woven fabric.
g / mm, (2) Moisture transpiration from the patch is 2-40 mg / day.c
m²It can be obtained.

[0025]

As described above, according to the present invention, a cloth, an adhesive layer containing a drug, and a water semi-permeable film are used, and the objects of the present invention are achieved by skillfully utilizing them. The inventors have found that the above can be achieved and arrived at the present invention.

That is, in order to prevent skin rash which is the most problematic problem in using the patch, at least the organic solvent used in the manufacturing process does not remain in the patch and / or hardly remains, and the skin of the adhesive used. In addition to being less irritating, it is important that the application site does not become excessively stuffy. Further, it is necessary that oxygen is appropriately supplied to the application site and that carbon dioxide gas and ammonia gas generated at the application site due to skin physiology be permeated. In particular, it is important to prevent excessive stuffiness of the application site, which is considered to be related to the difficulty of permeation of oxygen, carbon dioxide, ammonia and the like.

However, from the viewpoint of percutaneously absorbing a sufficient amount of the drug, which is the original purpose of the patch, it is an essential condition to seal the patch site to give a proper amount of stuffiness. There is difficulty achieving the purpose.

The present inventors have made diligent studies on the stuffy state causing skin rash and the stuffy state required for percutaneous absorption of a drug, and as a result, the stratum corneum of the skin at the site of application has a saturated moisture content. Even if the amount of stuffiness increases, the transdermal absorption of the drug will not be accelerated even if the excess moisture becomes droplets at the interface between the skin and the patch, and conversely the moisture content of the stratum corneum will reach the saturation point. It was found that the skin irritation increases when it exceeds the limit. From this, it was thought that the preferable sealing property as a patch is to keep the stratum corneum of the skin at the site of application so that it is always in the vicinity of the saturated moisture content, and the inventors studied the dosage form of the application site diligently.

As a result, excessive sealing for increasing skin irritation does not occur, and the transdermal absorbability is semipermeable to water and has a thickness of 0.
It is important to use a film of 5 to 4.9 μm, and it does not promote skin irritation, does not deteriorate water transpiration property, maintains the flexibility of the patch, and makes the patch easy to handle. To improve, the average diameter of single yarn is 1 ~ 30μm
It is preferable that a cloth having a basis weight of 8 to 100 g / m ² be laminated and used, and that a pressure-sensitive adhesive layer containing a drug and having a thickness of 5 to 100 μm be laminated and used on this cloth. I found that.

Moreover, by not just simply laminating such materials, but also by setting the delamination force between the respective layers within a predetermined range, there is less skin irritation than ever before and sufficient transdermal absorbability is secured, It has a good handleability and has reached a stable patch in which the preparation form does not collapse even when it is applied for a long time.

That is, the present invention is a patch applied to the outer skin.
Yes, (a) Semi-permeable to water, and the film is substantially perpendicular to the 2
8-85g / mm each direction strength, and substantially orthogonal
The elongation in each of the two directions is 30 to 150%,
The ratio of the elongation in the directions is 1.0 to 5.0 (however, the elongation in the two directions is
If the degrees are not the same, the smaller elongation is used as the denominator.
Film having a thickness of 0.5 to 4.9 μm (a
Layer) (b) The average diameter of the single yarn is 1 to 30 μm, and
Basis weight is 8 to 100 g / m ²Cloth (layer b) (c) Adhesive layer containing drug and having a thickness of 5 to 100 μm
(C layer) as an essential ingredient, and from the top of the patch a layer, b
Layers are laminated in this order on the layer c, and the following (1) and
(2) (1) Delamination force between layers a and b is 10 to 40 g / m when the fabric of layer b is a knitted fabric.
m is 3 to 30 when the b-layer fabric is a non-woven fabric or a woven fabric.
g / mm (2) Moisture transpiration from the patch is 2-40 mg / day · c
m²It is a patch that satisfies the following characteristics.

Surprisingly, with the patch of the present invention,
Even if the degree of skin perspiration changed to some extent depending on the external environment in which the patch was applied and the exercise condition of the patient, it was possible to maintain the water content of the stratum corneum at the application site at almost the same value.

In order to prevent skin rash, the residual solvent in the patch should be minimized. Specifically, the residual amount of all the solvents used in the process of producing the patch should be 100 relative to the weight of the adhesive.
It is desirable that the content is ppm or less, preferably 50 ppm or less. In the patch, most of these residual solvents remain when forming the pressure-sensitive adhesive layer from the pressure-sensitive adhesive solution, but methods to reduce the residual solvent in the pressure-sensitive adhesive layer are by heating at high temperature and by vacuuming under heating. A method of sucking, a method of washing and extracting the obtained pressure-sensitive adhesive layer with a solvent such as water, methanol, ethanol and the like are used, and industrially, a method of heating at a high temperature is most often used. However, in order to obtain a pressure-sensitive adhesive layer having a residual solvent of 100 ppm or less from a pressure-sensitive adhesive layer (polymer layer) having a thickness that can be used as a pressure-sensitive adhesive layer of a patch, it is necessary to employ quite severe drying conditions.

When a drug is mixed in the adhesive layer,
Adopting such severe drying conditions is often accompanied by deterioration and decomposition of the drug, and when an evaporative drug is used as the drug, the drug evaporates at high temperatures, so mild conditions rather than normal drying conditions are used. I have no choice but to adopt
It is difficult to obtain a highly safe patch with little residual solvent.

Moreover, the patch of the present invention can be used regardless of the season.
Even if you take normal everyday actions and do bending and stretching exercises, or sweating, there is almost no delamination between the film surface and the fabric surface or the fabric surface and the adhesive layer surface. It is a patch that can be expected to have high patient compliance.

The semi-moisture permeable film used in the present invention is a flexible film and has a moisture permeability of 1 at 37 ° C. when tested independently for moisture permeability of the film.
˜1000 mg / day · cm ² and the thickness of the film is preferably 0.5 to 4.9 μm. Particularly preferred is a thickness of 0.5 to 4.9 μm, a strength in two substantially orthogonal directions of 8 to 85 g / mm, and an elongation in two substantially orthogonal directions of 30 to 150%. The ratio of the elongations in the two directions is 1.0 to 5.0 (however, if the ratios of the elongations in the two directions are not the same, the smaller elongation is the denominator). In order to reduce skin irritation, it is first of all important to reduce the physical irritation of the formulation. For this purpose, the smaller the thickness of the film used, the less the irritation. Therefore, the thickness is 4.9 μm or less, preferably 4.0 μm or less, and more preferably 3.5 μm or less, since this tendency becomes remarkable. On the other hand, since the patch is used by being applied to human skin, it is necessary to be able to follow the expansion and contraction movement of human skin due to human activity to some extent. If it is too thin, the film may break, or if it does not follow the stretching movement of the skin, skin irritation may increase. Even if the thickness is reduced to less than 0.5 μm, the physical irritation is not changed so much, and the inconvenience that it tends to be inconvenient for manufacturing increases.

The purpose of providing a film layer as a support on the patch is to enhance the sealing property of the patch site to promote percutaneous absorption, and to coat the adhesive surface to attach the adhesive to other places on clothes or skin. This is to prevent the The smaller the thickness of the film is, the smaller the sealing property becomes. When the film thickness is less than 5 μm, the sealing property tends to decrease. However, when it is less than 1 μm and less than 0.5 μm, it becomes difficult to obtain sufficient sealing property as a patch.

Regarding the strength of the film, when the strength in the two directions substantially orthogonal to each other exceeds 85 g / mm, the physical irritation is not sufficiently small, however thin, but it is less than 8 g / mm. The formulation tends to be damaged during application or during application, which makes it difficult to use with confidence.

Regarding the elongation of the film, if the elongations in the two directions which are substantially orthogonal to each other exceed 150%, the handleability is poor. On the other hand, if the elongation is less than 30%, the physical irritation increases. Fracture during sticking is likely to occur.

Further, according to the results of examination by the present inventor, the ratio of the elongations in the two directions is 1.0 to 5.0 (however, when the elongations are the same, the smaller elongation is the denominator. Yes, especially 1.
When a film having a thickness of 0 to 3.0 is used, it is preferable because it gives a good feeling of sticking. When this ratio exceeds 5.0, that is, when a film having extremely small elongation in a certain direction is used, the film cannot sufficiently follow the expansion and contraction of the skin in that direction, resulting in a tight feeling. It is not appropriate because it tends to come out and feel uncomfortable to stick to, easy to peel off, and easy to break.

Therefore, the film of the present invention is semipermeable to water and has a thickness of 0.5 to 4.9 μm, strengths in two directions which are substantially orthogonal to each other of 8 to 85 g / mm, and 2 which are substantially orthogonal to each other. The elongation in each direction is 30 to 150%,
The ratio of the elongations in the two directions is preferably 1.0 to 5.0 (however, when the respective elongations are not the same, the smaller elongation is the denominator). Above all, the thickness is 3.5 μm or less, particularly 0.5 to
2.0 μm, strength 8-85 g / mm, and elongation 4
A film having an elongation ratio of 5 to 150% and an elongation ratio of 1.0 to 3.0 is preferable.

The term "strength" as used in the present invention means the maximum load until cutting according to the tensile strength measurement method of the Japanese Pharmacopoeia "Band plaster" and converted into a load per unit mm (g / m).
m), and the elongation indicates the length before pulling and the elongation rate (%) of the length at the time of cutting. Further, the two directions orthogonal to each other mean so-called vertical direction and horizontal direction.

In the present invention, it is more preferable that such a film has good stability over time and is highly safe such that it does not cause an allergic reaction when applied to human skin. As such a film, a film made of polyolefin such as polyethylene or polypropylene; polyester such as polyethylene terephthalate or polyethylene naphthalate; polyamide such as nylon 6 or nylon 66; ethylene-vinyl acetate copolymer or the like can be used. These films may be used alone, or may be combined or laminated.

Of these films, polyester film is preferred. Polyester film is generally stable to heat and light, has low drug adsorption and interaction with the drug, and is highly safe for humans. Among the polyester films, a film made of polyethylene terephthalate is preferable.

In the present invention, when an ultrathin film having a thickness of 3.5 μm or less, a strength of 8 to 85 g / mm and an elongation of 45 to 150% is used, the patch is long. Can be attached stably for a long time.

In the present invention, it is particularly preferable to use a polyester film as the above-mentioned film layer, but a small proportion of solid fine particles may be present in this polyester film for the purpose of improving its slipperiness. However, hitherto, there has not been sufficient knowledge as to what kind of effects such solid fine particles have on the patch of the present invention.

As a result of diligent studies on the above points, the present inventors have found that the amount of solid fine particles present in the polyester film layer is 0.01 to 1% by weight, and the average particle diameter thereof is 0.
It is important that the average particle size is 01 to 3.0 μm and does not substantially exceed 1.5 times the thickness of the polyester film in order to absorb a clinically effective amount of the drug and particularly to reduce skin rash. I found that.

Examples of such solid fine particles include:
(1) silicon dioxide, (2) alumina, (3) silicate containing 30% by weight or more of silicon dioxide, an aluminosilicate compound, (4) one or more metals selected from magnesium, zinc, zirconium, and titanium. Oxides, (5) one or more metal sulfates selected from calcium and barium, (6) one or more metal phosphates selected from lithium, sodium and calcium, (7) calcium, barium, zinc and manganese Terephthalate of one or more metals selected, (8) Titanate of one or more metals selected from magnesium, calcium, barium, iron, cobalt, manganese, nickel, etc. (9) One selected from calcium, magnesium , (10) carbon, (11)
Inorganic or organic solid fine particles such as glass and (12) crosslinked polystyrene can be exemplified. Of course, these may be used alone or as a mixture of two or more.

When the amount of the solid fine particles is less than 0.01% by weight, the effect of reducing skin rash tends to be insufficient, which is not preferable, and when it exceeds 1% by weight. In some cases, the transdermal absorbability of a drug may not be sufficiently satisfied, which is not preferable as a patch. If the average particle size is less than 0.01 μm, the effect of reducing skin rash may be insufficient and the handling may not be sufficiently satisfied. Further, if it exceeds 3.0 μm or the film thickness is If it exceeds 1.5 times, the transdermal absorbability of the drug may not be sufficiently satisfied as described above. In this case, it is considered that this is because the water vaporization property and the air permeability become too large due to the voids between the solid fine particles and the film layer.

The fabric used in the present invention has a basis weight of 8 to 100 g.
/ M ² . One of the reasons why the cloth is used in the present invention is that it is easy to secure the moisture transpiration property of the patch at ² to 40 mg / day · cm ² . That is, since the cloth hardly resists the water vapor transpiration property, the water vapor transpiration property of the preparation can be easily designed. The second reason to use cloth is
It is to improve the handleability of a patch using a soft and thin film. The third reason for using the cloth is that a patch consisting only of a flexible thin film and a pressure-sensitive adhesive layer containing a drug and having a thickness of 5 to 100 μm easily breaks or deforms with a slight stress. And that the production of the patch is easy.

Particularly, the first and second reasons are important.
This is because if the fabric weight is less than 8 g / m ² , it tends to be difficult to achieve the desired moisture transpiration property and the handleability tends to be insufficient.

On the other hand, when the fabric weight is more than 100 g / m ² , the moisture transpiration property becomes too large, which is not preferable.
This is because moisture escapes through the cloth in the cross-sectional direction (side surface) of the preparation. In addition, when the fabric weight exceeds 100 g / m ² , the thickness of the patch becomes large and the patch is liable to peel off from the application site during peeling (peeling). The cause of peeling when the fabric weight is large is
It is considered that this is because the end face of the patch, particularly the corners, are rubbed against clothes and the like and taken off by the clothes and the like. A particularly preferable fabric weight is 10 to 60 g / m ² .

In such a cloth, the thickness of the single yarn of the fibers constituting the cloth is important. Generally, the average diameter of fibrous substances can be arbitrarily made from small ones of 0.5 μm or less to large ones of more than 1000 μm, and they are properly used depending on the application.

According to the studies conducted by the present inventors so far, it has been found that the thickness of the single yarn has an effect on skin irritation even when it is used in a patch, and the fibers constituting the fabric of the present invention are known. The average diameter of the single yarn is 1 to 30 μm. When it is less than 1 μm, when the fabric weight of the fabric is set to 8 g / m ² in order to ensure the handleability of the patch of the present invention, the evaporation of water from the cross-sectional direction tends to be too large, and too much. Since the fibers are thin, fiber breakage and the like occur frequently, which causes difficulties in the patch manufacturing process.

On the other hand, when the average diameter of the single yarn is larger than 30 μm, the skin irritation becomes large no matter how small the fabric weight is. Particularly preferable range of average diameter of single yarn is 5
Is about 25 μm.

In the present invention, such a fabric can be used in the form of a woven fabric, a knitted fabric, a non-woven fabric or the like. However, the stretchability of the fabric itself becomes large due to the known knitted fabric or non-woven fabric structure. This is considered to be due to the fact that it is less skin irritating than the case where a woven fabric having the same basis weight is formed by using the same single yarn, which is preferable. In the present invention,
Such a fabric may have a structure of one woven fabric, knitted fabric, or non-woven fabric, but such a fabric may be laminated and used. Further, the single yarns to be used can also be used by mixing different types of single yarns. In this case, most of the single yarns that make up the fabric must be in the above range.

As the single yarn constituting the cloth of the present invention, non-hollow fiber having a hole penetrating most of the outer periphery thereof, for example, deformed, solid or hollow fiber can be used.

When most of the single yarns used in the present invention are hollow fibers having pores penetrating in the outer peripheral direction (microporous hollow fibers), the object of the present invention can be achieved more easily, though there is an economical problem. it can.

Such hollow fibers are disclosed, for example, in JP-A-56-56.
It can be produced by the method described in JP-A-20612, JP-A-56-20613, JP-A-56-43420 or the like.

Examples of the material of the fibers constituting the cloth of the present invention include polyester such as polyethylene terephthalate; polyolefin such as polyethylene and polypropylene; polyamide such as nylon 6 and nylon 66; polyurethane, cellulose acetate, polyacrylonitrile,
Any material such as polyvinyl chloride and polyvinyl acetate can be selected. Among these, polyester is preferable, and particularly polyethylene terephthalate is highly safe for humans, has excellent stability to heat, light and temperature, has no interaction with a drug, and impregnates hollow fiber with a drug solution. It is preferable because it is less likely to be modified by the solvent used.

Such fibers may be used alone or in a plurality of two or more.

Examples of the drug used in the present invention include nitrate esters used in coronary vasodilators such as isosorbide dinitrate and nitroglycerin; menthol, camphor,
Salicylates such as methyl salicylate; hormonal agents such as estradiol, norethisterone, progesterone and its derivatives; morphine, fentanyl,
Examples thereof include, but are not limited to, analgesics such as buprenorphine hydrochloride and its derivatives; and heart disease drugs such as clonidine, nifedipine, captoril and its derivatives.

The amount of the drug used is appropriately determined depending on the strength of the pharmacological action of the drug used, absorbability into the skin, etc.
Usually, it is 0.1 to 20% by weight with respect to the total amount of the adhesive. Such a drug may be present in the pressure-sensitive adhesive layer in a state of being compatible with the pressure-sensitive adhesive, or a part thereof may be precipitated as crystals unless the drug efficacy is affected.

The amount of the drug to be contained in one patch can be arbitrarily changed from 1 μg to 200 mg. That is, generally, drugs used in pharmaceuticals are administered orally or as injections, and the doses of the drugs that are clinically effective in that case are shown in many literatures (eg, Pharmaceuticals Manual, 4th Edition, Drugs). Kogyohosha (1988)). Therefore, also in the case of patches, the amount of drug to be contained in one patch can be estimated from the amount used in oral preparations and injections. Usually, in the case of a patch, since the amount remaining in the preparation is large, the dose tends to be larger than that of an oral preparation or the like. However, in the case of nitric acid drugs, which have large liver metabolism, the amount of drug used in the patch may be smaller than that of the oral drug. Therefore, the amount of the drug in one patch is 1/5 to 10 times the daily dose of the oral preparation or injection. As a specific example of the content of the drug to be contained in one patch, in the case of isosorbide dinitrate, the size of the patch is 20 to 60 cm ² and isosorbide dinitrate is 5 to 100 mg per sheet. In the case of nitroglycerin, the size of the patch is 5
50 cm ² with 1-2 nitroglycerin per sheet
Contains 0 mg. In the case of estradiol, the size of the preparation is 10 to 60 cm ² , and 0.2 to 10 per sheet.
mg contained. In the case of buprenorphine hydrochloride, the size of the preparation is 10 to 100 cm ² , and 1 to 1 preparation
Contains 10 mg. Of course, the amount of drug may be larger than that of the reference example shown above as long as the drug efficacy is not hindered.

From the above, the amount of the drug contained in the patch of the present invention and the size of the patch will be more apparent.

As the pressure-sensitive adhesive used in the present invention, an ordinary pressure-sensitive pressure-sensitive adhesive is used, for example, a rubber containing silicon rubber, polyisoprene rubber, styrene-butadiene copolymer rubber, acrylic rubber, natural rubber or the like as a main component. System viscous composition;
Vinyl-based viscous compositions such as polyvinyl alcohol and ethylene-vinyl acetate copolymers; viscous compositions containing silicone-based adhesives, polyurethane elastic bodies, polyester elastic bodies, polybutadiene elastic bodies, etc. as main components; acrylic resins, etc. You can choose from. Among them, acrylic resins are preferable, and particularly (1) an alkyl group having 4 or more carbon atoms, from the viewpoint of less skin irritation, moderate tackiness, adhesiveness and high internal force, and excellent solvent resistance. Of (meth) acrylic acid alkyl ester of at least 80-9
An acrylic resin in which 8 mol% and (2) 2 to 20 mol% of acrylic acid and / or methacrylic acid are copolymerized is particularly preferable. Examples of the (meth) acrylic acid ester of an alkyl group having 4 or more carbon atoms include, for example, butyl (meth) acrylate, amyl (meth) acrylate, and hexyl (meth).
Examples thereof include acrylate, heptyl (meth) acrylate, octyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth) acrylate, and 2-ethylhexyl (meth) acrylate. These pressure-sensitive adhesives may be used alone or in combination of two or more.

The acrylic pressure-sensitive adhesive may contain a known organic or inorganic crosslinking agent in an amount of 0.01 to 10% by weight.

In the present invention, these adhesives may be combined depending on the kind of drug. For example, an adhesive having a high compatibility is provided near the film layer of the backing, and the compatibility with the drug is not shown. As a combination of using an adhesive which is not so high but has low skin irritation on the surface in contact with the skin, a patch having low skin irritation and excellent sustained release can be obtained.

The thickness of the pressure-sensitive adhesive layer of the present invention is 5 to 100 μm.
Is. When the thickness of the pressure-sensitive adhesive layer is large, the amount of residual solvent tends to be extremely high, and therefore the thickness is particularly preferably 60 μm.
It is the following. On the contrary, when the pressure-sensitive adhesive layer becomes thin, the adhesive force to human skin also decreases, and the stability of the patch when used decreases, so that it is preferably 10 μm or more.

The first method of manufacturing the patch of the present invention is to bond the film and the cloth under pressure at room temperature or under heating to obtain a laminate of the film and the cloth, after which the drug is added. In this method, the adhesive solution contained is applied onto the fabric surface of the laminate and dried.

An adhesion aid such as a liquid material, a solid material or a film material may be used to assist the adhesiveness between the film and the cloth when they are adhered under pressure. It may be contained.

The second manufacturing method is to apply a pressure-sensitive adhesive solution containing a drug in advance onto the release film to obtain a drug-containing pressure-sensitive adhesive layer having a thickness after drying of 5 to 100 μm. This is a method in which this drug-containing pressure-sensitive adhesive layer is pressure-bonded to the fabric surface of the laminate of the film and the fabric obtained by the first method of the production method.

The third method of production is a two-layered drug-containing pressure-sensitive adhesive layer in which a pressure-sensitive adhesive solution containing a drug is previously applied onto a release film and the thickness after drying is 5 to 100 μm. (Drug-containing pressure-sensitive adhesive layers A and B) are obtained. At this time, different adhesives may be used for the drug-containing adhesive layers A and B,
The thickness may be different, the content of the drug may be different, the kind of the contained drug may be different, and any one of the drug-containing pressure-sensitive adhesive layers A and B substantially contains the drug. You don't have to. Drug-containing pressure-sensitive adhesive layer 2 thus obtained
One of the layers (A layer) and the film are pressure-bonded, and then the fabric is pressure-bonded on the surface of the A layer which is not pressure-bonded to obtain a three-layer laminate (C layer), and then C The drug-containing adhesive layer (B layer) may be pressure-bonded onto the free surface of the layer fabric.

The fourth method of the production method is the method described in the third method of the production method. However, when the pressure-sensitive adhesive layer is prepared, a drug is contained or the drug layer is not contained. Two layers (A layer and B layer) are prepared, and these are laminated to obtain the three-layer laminate (C layer) described in the third method of the production method, and then three layers of the drug dissolved in the solvent are prepared. A three-layer laminate (D layer) containing a drug is obtained by coating the laminate fabric by dripping, dipping, contacting, etc., and removing the solvent by evaporation to obtain the drug on the D layer fabric. This is a method of pressure-bonding the adhesive layer B layer that contains or does not contain. The patch thus obtained may be homogenized in quality by heating, vacuum suction or the like as needed before or after cutting.

As can be easily assumed by those skilled in the art, the solution of the adhesive containing the drug is applied on the fabric of the D layer obtained by the fourth method of the production method, and the solution is heated to remove the solvent and directly removed. It is also possible to form an adhesive layer corresponding to the adhesive layer B layer.
Further, it is also possible to employ a multilayer structure of the pressure-sensitive adhesive layer by the above-mentioned manufacturing method, if necessary.

Further, it is not necessary that the film, the cloth and the pressure-sensitive adhesive layer used in the present invention all have almost the same plane area, and any one of them may form a part of the preparation, and the discontinuity may be discontinuous. It may be a plurality of layers.

As expected, the method for producing the patch of the present invention is not limited to the above.

The patch of the present invention has a water vaporization property of 2 to 40 mg / day · cm ² from the patch.

Since a cloth is used in the case of the patch of the present invention, in order to bring the moisture transpiration property from the patch to this range, the adhesive layer, cloth and film of the patch usually considered are used. In addition to the moisture transpiration property from the outer surface of the film, that is, the plane direction, it is necessary to take into consideration the moisture transpiration property from the adhesive layer of the patch to the side surface of the patch, that is, from the cross-sectional direction through the cloth.

In the patch of the present invention, even if the fabric weight is within the above range, the larger the weight is, the better the handleability is. Further, if the pressure-sensitive adhesive layers used have the same thickness and the same pressurizing condition, the larger the basis weight, the greater the water evaporation property in the cross-sectional direction. Therefore, when determining the fabric weight of the fabric from the viewpoint of handleability, increase the thickness of the pressure-sensitive adhesive layer in order to ensure that the moisture transmissibility in the cross-sectional direction does not become excessive in order to ensure transdermal absorbability. It is preferable to increase the pressure bonding condition between the pressure-sensitive adhesive layer and the cloth. In particular, when the method of applying the pressure-sensitive adhesive solution in which the pressure-sensitive adhesive layer is dissolved onto the cloth is adopted, the pressure-sensitive adhesive layer is formed in a state where the pressure-sensitive adhesive enters the cloth. The moisture transpiration property becomes smaller than that when the pressure-sensitive adhesive layer having the same thickness is pressure-bonded.

On the other hand, it is preferable that the cloth is thin from the viewpoint of preventing the preparation from peeling off at the time of application. Therefore, when the fabric weight is reduced within a range that does not impair the handleability of the obtained patch, a preferable moisture transpiration property is obtained. In order to ensure the above, it is preferable to make the pressure-sensitive adhesive layer thin and / or to weaken the pressure adhesion condition between the cloth and the pressure-sensitive adhesive layer.

The patch of the present invention also greatly depends on the water transpiration property of the patch as a whole in terms of percutaneous absorption, and when the size of a usual preparation is 10 to 150 cm ² , the water transpiration property is low. Is ^{2 to} 40 mg / day · cm ² . 40 mg
If it exceeds / day · cm ² , it is difficult to obtain sufficient transdermal absorbability. On the other hand, if the amount is less than ² mg / day · cm ² , the preparation does not have a low skin irritation.

Micropores and cutting lines can be provided in the film layer of the patch of the present invention, if necessary. In such a case, the value measured by the moisture transpiration test method described below is It should be in the range.

From the viewpoint of preventing skin irritation, the greater the water transpiration property is, the better it is at 40 mg / day · cm ² or more. However, in order to reduce skin irritation while maintaining sufficient transdermal absorbability, oxygen and In addition to evaporating water through a film with relatively low gas permeability such as carbon dioxide (that is, in the planar direction), through a pressure-sensitive adhesive layer or fabric layer that has good oxygen and carbon dioxide permeability (that is, in the cross-sectional direction) Based on the finding that it is more preferable to evaporate water, it is preferable that a considerable portion of the water evaporative property from the patch is also allowed to escape in the cross-sectional direction.

Therefore, in the patch of the present invention, it is more preferable that the moisture transpiration property in the cross-sectional direction is 25 to 180 mg / day for each patch having a size of 10 to 150 cm ² . In the present invention, the film (a layer) and the cloth (a layer) in the patch of the present invention are further secured in order to secure the stability after the patch is applied for a long time, which is the main characteristic targeted by the present invention. The delamination force between the b layer) is 10 to 40 g / mm when the b layer fabric is a knitted fabric, and 3 to 30 g / mm when the b layer fabric is a non-woven fabric or a woven fabric.
And

The delamination force between the a layer and the b layer is brought about by controlling the conditions as described below, for example, in the production of the patch of the present invention.

One of the main manufacturing conditions is the pressing condition of a known laminator used when laminating and pressing film-shaped products.

For example, by controlling the hardness of the roll used for the laminator, the diameter of the roll, the speed of passing through the roll, the pressing pressure applied to the roll, the temperature when passing through the roll, etc., the above-mentioned delamination can be achieved. A patch can be obtained.

In particular, in the case of the patch of the present invention, a thin film which is easily broken is used, a specific cloth is used, and a specific adhesive is used, but nevertheless, the transdermal absorbability is high,
A patch that is hypoallergenic, easy to handle, and within the specific quality standards required for pharmaceutical preparations, and that has less variation in quality, that is, they are balanced and then applied. It is characterized by being a stable, sustained-release patch that is less likely to delaminate than before.

In the patch of the present invention, the peeling force between the film and the cloth is preferably 10 g / mm or more.

In the case of a medical patch, the film, the cloth, and the adhesive must have high safety. Moreover, these materials must have no adverse effect on the drug used.

Further, a strict constraint condition such as a soft base material which does not cause skin irritation is applied.

After satisfying all of these constraints,
The first object of the present invention is to provide an adhesive patch, which satisfies the requirements of low skin rash, high transdermal absorbability, and good handleability, and which does not cause delamination even when applied for an extremely long time. To do was a very difficult examination.

Surprisingly, in the present invention, the specific film (a), the specific cloth (b), the pressure-sensitive adhesive layer (c) and (1) the peeling force between the film and the cloth and (2) the patch It has become possible to provide such a patch by setting the moisture transpiration property from the above into a specific numerical range.

The following findings are greatly involved in reaching the present invention.

That is, regarding the inter-layer peeling force required as the inter-layer peeling force between the film and the cloth, the first one is to complete the measuring method. It is also known in the literature to measure the peeling force of an adhesive surface. However, the difficulty in the case of the present invention is that when considering the delamination force of a very thin film having a thickness of 0.5 to 4.9 μm, a weak film is used instead of a sufficiently strong film for this value.
It could not be measured by the usual method. For this, a simple and highly reproducible method described later was completed. The second was the problem of what the peeling force should be when the formulation is applied to the patient. What the present inventors have found in the process of examination is the fact that the conditions under which the patch is received when the patch is applied to a patient (particularly in the case of a human patient) for 1 to 3 days are extremely severe.

In many of these cases, the problem becomes apparent only when the formulation composition of the present invention is used for a long time. For example, a patch has a temperature of 32 to
At 37 ° C, the humidity is almost 100%, sometimes water accumulates on the inner surface of the patch due to perspiration, and due to bathing or showering, the temperature exceeds 40 ° C and the humidity is 100%, and these conditions There are repeated stresses due to movements, and some parts of the body are subject to strong tensile tension due to expansion and contraction of that part of the body, especially elongation, and clothes are subjected to rubbing stress on the surface and corners of the patch. Is there.

Most of these stresses are problems that should hardly be considered when the patch is a simple and thin film type which is the most common type. Further, even thick preparations, if they do not play a delicate role, if the adhesive force to the patient's skin is sufficient, there will be almost no problem.

In particular, in the case of the patch of the present invention, when a stress due to a certain strong stretching is applied, it is easy for the fabric to be repeatedly stressed if the stress elongation of the film is large even though the stress elongation of the film is small. It means that the interface between the film and the fabric is peeled off. Here is one of the difficulties of combining fabrics and films.

From a practical point of view, it is easy to manufacture, and the film, the cloth and the adhesive are easily selected only from the viewpoints of safety, percutaneous absorption and handling.
The weaker the inter-layer peeling force between the film and the fabric and between the fabric and the pressure-sensitive adhesive, the better. Therefore, it is extremely important to know where these inter-layer peeling forces are in order to make and manage a practical patch. Moreover, since it is an important factor that the patch is stable even if the patient uses it for a long time, it is thought that the delamination force should be increased as much as possible.

The patch of the constitution of the present invention is a new dosage form of a specific film, a specific cloth, and a specific pressure-sensitive adhesive layer, and therefore, the inventors of the present invention need to make diligent studies on solving the problem. There was.

As a result, the following preferable range of delamination force was found and the present invention was completed.

That is, the film thickness is 0.5 to 4.9 μm.
m, the strength of the film in the two directions substantially orthogonal to each other is 8 to 85 g / mm, and the elongation in the two directions substantially orthogonal to each other is 30 to 150%, and the elongation in the two directions is Is 1.0 to 5.0 (however, when the elongation ratios in the two directions are not the same, the smaller elongation is used as the denominator), (1) the fabric is In the case of a knitted fabric having an average diameter of single yarn of 1 to 30 μm and a basis weight of 8 to 100 g / m ² ,
Delamination force between film and fabric is 10-40g / mm
Becomes More preferably, it is 17-40 g / mm. (2) When the fabric is a non-woven fabric or a woven fabric having an average diameter of a single yarn of 1 to 30 μm and a basis weight of 8 to 100 g / m ² , the interlayer peeling force between the film and the fabric is 3 to 30.
It becomes g / mm.

The reason why the required delamination force is smaller when the cloth is a non-woven fabric or a woven cloth than when it is a knitted cloth is as follows.
It is considered that the non-woven fabric and the woven fabric are less stretchable than the knitted fabric. Therefore, a non-woven fabric or a woven fabric is more advantageous than a knitted fabric for a patch that is stable for a longer period of time when applied for a long time.

However, from the viewpoint of skin irritation of the patch, it is recognized that the greater the stretchability of the fabric, the better. Therefore, the patch is selected from the overall balance.

The patch of the present invention having such a delamination force is tested under the delamination force test method of the present invention for the patch prepared by the above-mentioned method using the above-mentioned materials, and the appropriate conditions are obtained. It can be obtained by setting, for example, the one obtained in the embodiment.

The significance of setting the delamination force between the cloth and the film as described above will become clearer if the findings are explained in another comparison. That is, when the composition of the preparation is laminated in the order of the cloth (b layer), the film (a layer), and the adhesive layer (c layer), the interlayer peeling force between the b layer and the a layer is 4 even though the cloth is a knitted fabric. Even if it is 10 g / mm, the interlaminar peeling force hardly causes a problem.

The patch of the present invention may contain other absorption promoters, dissolution aids, diffusion aids, fillers and the like, if necessary.

Examples of the absorption enhancer or diffusion aid used in the present invention include, in addition to those exemplified above, sodium lauryl sulfate, sodium dodecylbenzene sulfonate, sodium alkyldiphenyl ether disulphonate, dioctyl sulfosuccinate, polyoxy. Surfactants such as alkyl phenyl ether sulfate ammonium salts; alcohols such as glycerin, diethylene glycol, propylene glycol, polyethylene glycol, higher fatty acid alcohols; dimethyl sulfoxide and alkylmethyl derivatives; salicylic acid, urea, dimethylacetamide, dimethylformamide, lanolin, allantoin , Squalene, carbopol, diisopropyl adipate, pyroglutamic acid lauryl ester, myristic acid Propyl, ethyl laurate, methyl nicotinate, sorbitol and dodecyl pyrrolidone, pyrrolidone derivatives, such as methyl pyrrolidone, olive oil, castor oil, liquid paraffin, vaseline, gelatin, amino acids, benzyl nicotinate, L- menthol,
Camphor, dodecylazacycloheptan-2-one and the like can be used.

The absorption promoter or diffusion aid may be used within a range that does not impair the tackiness, and is 0.1% with respect to the tackiness agent.
It can be used in the range of ˜30 wt%.

In the patch, as a filler,
Water, titanium oxide, calcium carbonate, gypsum, calcium silicate, aluminum silicate, diatomaceous earth, carbon black, red iron oxide, various dyes and pigments, liquid paraffin, vaseline, lactose, fragrance, deodorant, colorant, polyethylene, Powder of a synthetic resin such as polypropylene, polyester, polystyrene or the like, a molded product, or the like may be contained in an amount of 0.1 to 30% by weight. Two or more of these absorption promoters, diffusion aids, fillers and the like may be used in combination.

[0112]

INDUSTRIAL APPLICABILITY As described above, the patch according to the present invention has the desired transdermal absorbability (sustained release) and is intended for transdermal administration in which skin irritation is significantly prevented. It can be used as a patch. Further, the patch according to the present invention is a patch whose patch itself is very flexible, has almost no skin irritation, and has a small residual solvent, excellent handleability and improved safety while maintaining the necessary sealing property. It will be widely used as an adhesive patch that is highly stable even when used for a long time.

[0113]

The present invention will be described in more detail with reference to the following examples. Parts in the examples indicate parts by weight, and the characteristics appearing in the examples were measured by the following methods.

(I) Test Method for Moisture Evaporation Property A glass plate having a thickness of about 10 mm and a size of about 150 mm × 150 mm has a diameter of 40 mm (area 12.56 cm).
² ) Make a depression with a depth of 6 mm. Put 3 ml of distilled water in the depression.

One patch is taken, the release film is peeled off, and the patch is applied to this glass plate so that the adhesive surface completely covers the depression. The weight at this time is W ₁ (mg).

Next, the glass plate with the patch applied is
The glass plate is placed in a warm air type constant temperature bath at ℃, and after 24 hours, the glass plate is weighed to obtain W ₂ (mg).

Next, an aluminum foil was adhered and adhered to the film surface (outside) of the patch using an adhesive having a thickness of about 30 μm, and the release film of the patch backed with this aluminum foil was peeled off, and 3 ml of water was used. Laminate the glass plates containing the so as to cover the depressions, and measure the weight W ₃ (mg). After placing this in a 37 ° C warm air bath for 24 hours, weigh it W ₄
(Mg).

The moisture transpiration property of the side surface (cross-sectional direction) of the patch is determined through the pressure-sensitive adhesive layer or the fabric layer of the patch by means of W ₃ and W ₄ . Further, the water transpiration property of the outer surface (planar direction) of the film passing through the pressure-sensitive adhesive layer of the patch, the cloth and the film layer is determined by these W _{1 to} W ₄ .

At this time, the water evaporation amount is calculated by the following formula.

[0120]

[Equation 1]

The size of the patch to be tested is 50 mm.
When the size is smaller than × 50 mm, the diameter of the hollow at the center of the glass plate is about 10 mm smaller than the length of one short side of the preparation.

When the film (a layer) of the patch has a cutting line or the like, the test should be carried out on the part of the patch without the cutting line or the cutting line should not affect the test results. It shall be repaired and tested.

(Ii) Determining Method of Delamination Force Adhering to the adhesive test method of "Band plaster" of the Japanese Pharmacopoeia. A commercially available cloth tape (for example, Teraoka tape) is adhered to the outer surface of the patch film in advance, and the width is 20.
A test piece is cut into a strip of mm. After the adhesive surface of the patch, which has become a test piece, is adhered onto the phenol resin plate, the interface between the film and the cloth (interlayer) is peeled off by about 5 mm. A test piece in which the layers are slightly peeled off is tested according to the adhesive strength test method, and the interlayer peeling force is obtained.

When the adhesive strength of the adhesive surface of the patch does not adhere sufficiently strongly to the phenolic resin plate, other adhesives or adhesives may be supplementarily used so as not to affect the test.

(Iii) Measurement of isosorbide dinitrate in blood
Than collecting blood of the law 3ml, after separation of the plasma, 4ml of N
-Extract with hexane, concentrate, and add ethyl acetate to add 10
The volume was set to 0 μl and quantified by GC-ECD.

Further, the hollow fiber and adhesive solution used in the examples were prepared by the following method.

(1) Hollow fiber sample (1) 297 parts of dimethyl terephthalate, ethylene glycol 2
65 parts, 53 parts of sodium 3,5-di (carbomethoxy) benzenesulfonate (11.7 mol% with respect to 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 conduct a transesterification reaction according to a conventional method,
After the theoretical amount of methanol had been distilled off, the reaction product was placed in a polycondensation flask equipped with a rectification column, and 56% of orthophosphoric acid was added as a stabilizer.
% Aqueous solution 0.090 parts and 0.135 parts of antimony trioxide as a polycondensation catalyst are added, and the temperature is 275 ° C. and normal pressure is 2
After reacting for 15 minutes under a reduced pressure of 0 mm and 30 mmHg for 100 minutes under high vacuum. Final internal pressure is 0.39mm
Hg, and the intrinsic viscosity of the obtained copolymer is 0.
402, the softening point was about 200 ° C. After completion of the reaction, the copolymerized polymer was made into chips by 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 in a nitrogen stream at 110 ° C. 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 spinneret having a circular slit with 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 performed 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. This raw yarn was 300 denier / 24 filament, and this raw yarn was drawn at a draw ratio of 4.2 times according to a conventional method to obtain a 71 denier / 24 filament multifilament. The average diameter of the single yarn of the present multifilament was 18 μm. This multifilament is 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 obtain an alkali weight loss rate of 20% and a water absorption rate of 3
Second, a knitted fabric having a water absorption rate of 84% 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 17 g / m ² .

The obtained hollow fiber was a hollow fiber having fine pores scattered throughout the cross section of the hollow fiber and arranged in the fiber direction, and at least a part of the hollow fiber was communicated to the hollow part.

(2) Hollow fiber sample (2) The knitted fabric obtained in the preparation of the hollow fiber sample (1) was not subjected to alkali treatment and had a water absorption rate of 23.
It is a knitted fabric having an absorption rate of 38% for 0 seconds. Hollow fiber sample (1)
The fabric weight obtained by heat setting in the same manner as in Example ² was 25 g / m ² .

This hollow fiber does not have a hole penetrating in the outer peripheral direction.

(3) Adhesive solution (1) 97.5 parts of 2-ethylhexyl acrylate, 2.5 parts of methacrylic acid, 1.0 part of benzoyl peroxide and 100 parts of ethyl acetate are equipped with a reflux condenser and an agitator. Polymerization was continued for 9 hours while charging in a reaction vessel and slowly expanding sales at 60 ° C. in a nitrogen atmosphere. The polymerization conversion rate was 99.9%.

500 parts of ethyl acetate was added to the obtained polymer solution to adjust the solid content concentration to about 20%.

[0135]

Example 1 Adhesive solution (1) 50 having a solid content of 20%
After adding 13 parts of isosorbide dinitrate (ISDN) to 0 parts, a part of this mixed solution (M-1) was used to form a silicone-coated release film on which the thickness of the adhesive layer after drying was 15 μm. Coating at 80 ℃ for 1 minute, 90
It was dried at 1 ° C. for 1 minute and at 130 ° C. for 2 minutes. The residual amount of ethyl acetate in the obtained pressure-sensitive adhesive layer (pressure-sensitive adhesive layer a) was 11 ppm.
And the ISDN content was 2.3 g / m ² .

Furthermore, a part of the mixed solution (M-1) was applied onto a silicone-coated release film so that the thickness of the adhesive layer after drying would be 40 μm, and the mixture was dried at 80 ° C. for 2 minutes.
It was dried at 90 ° C. for 2 minutes and at 130 ° C. for 4 minutes. The residual amount of ethyl acetate in the obtained pressure-sensitive adhesive layer (pressure-sensitive adhesive layer b) was 25 ppm, and the ISDN content was 6.0 g / m ² .

Next, a synthetic silica having a thickness of 2.5 μm, a strength in each of two orthogonal directions of 35 g / mm and 41 g / mm, an elongation of 37% and 81%, and an average diameter of 0.45 μm was used. 1% by weight of polyethylene terephthalate film (PET film) containing 1% by weight and 0.05% by weight of talc having an average particle size of 0.75 μm, the adhesive layer a is pressure-bonded to one surface of the PET film and the adhesive layer a (laminate The product c) was obtained.

Then, the hollow fiber sample (1) was pressure bonded to the free adhesive layer surface of the laminate c to obtain a laminate (laminate d).

Next, the hollow fiber sample (1) was pressure bonded to the free pressure-sensitive adhesive layer surface of the laminate c to obtain a laminate (laminate d).
Got Next, there is a laminator that applies a nip pressure between a roll made of ethylene / propylene tetramer (EPT) rubber having a roll diameter of 150 mm and a chrome-plated metal roll having a roll diameter of 150 mm. The PET film surface (in the film direction) of the laminate d is on the EPT rubber roll between the rolls whose pressure P) is 6 kg / cm ² · G.
The hollow fiber sample (1) was passed through the free surface of the hollow fiber sample (1) so that the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer b could be pressure bonded to obtain a laminate of the laminate d and the laminate b (laminate e).

At this time, the speed of passing between the rolls (pressurizing speed)
Was 1.5 m / min. When passing between the rolls, a release film made of polyethylene terephthalate having a thickness of 75 μm was placed on the other side of the pressure-sensitive adhesive layer b to prevent the pressure-sensitive adhesive surface from sticking to the metal roll.

The laminate e thus obtained has a size of 7.1 cm ×
Cut ISDN to a size of 7.1 cm and 40 ISDN per sheet
It was a patch for angina containing mg.

When the water transpiration property of the patch was measured, it was 14.0 mg / day · cm ² in the plane direction and 42 mg / day in the cross-sectional direction, and the water transpiration amount of the whole preparation was 17.3 mg / day · It was cm ² .

The peeling force between the film and the cloth of the obtained patch was 23 g / mm.

The patch was cut into a circle with a diameter of 30 mm,
The hairless rat having an average body weight of 1.77 g was attached to the back of the hairless rat, and blood was collected at a predetermined time to measure ISDN in plasma. The results are shown in Table 1.

[0145]

[Comparative Examples 1 to 3] Patches were obtained in the same manner using the materials shown in Example 1 except that the direction of the film, the pressurizing pressure P and the pressurizing speed were changed, and the results of the tests were conducted on them. Table 1
It was shown to.

The patches of Comparative Examples 1 and 2 were partially unpeeled at the interface between the film surface and the cloth after being applied for 24 hours, and it was determined that they were not suitable for human clinical tests. . Further, it was found that Comparative Example 2 having a large water evaporation property was inferior in transdermal contraction property.

In Comparative Example 3, the peeling phenomenon was the largest.
The transdermal absorbability was also poor.

[0148]

Comparative Example 4 Adhesive Solution (1) 50 with 20% Solids Concentration
A mixed solution (M-2) was prepared by adding 8.9 parts of isosorbide dinitrate (ISDN) to 0 parts, and the thickness after drying was 40 μm on 50 μm thick polyethylene terephthalate coated with M-2 by silicone. Coating 8
It was dried at 0 ° C. for 2 minutes, 90 ° C. for 2 minutes, and 130 ° C. for 4 minutes. The residual amount of ethyl acetate in the obtained adhesive layer is 29 pp.
m, and the ISDN content was 4.2 g / m ² .

The pressure-sensitive adhesive layer was divided into two equal parts, one of which was used as the pressure-sensitive adhesive layer a and the other was used as the pressure-sensitive adhesive layer b.

Next, the thickness is 2.5 μm, the strength in each of two orthogonal directions is 35 g / mm and 41 g / mm, and the elongation is 37% and 81%. One side of a polyethylene terephthalate film (PET film) is used. A laminate of the PET film and the pressure-sensitive adhesive layer a by pressure-bonding the pressure-sensitive adhesive layer a (laminate c)
Got

Next, the hollow fiber sample (1) was pressure-bonded to the free pressure-sensitive adhesive layer surface of the laminate c to obtain a laminate (laminate d). Next, there is a laminator that applies a nip pressure between a roll made of ethylene / propylene tetramer (EPT) rubber having a roll diameter of 150 mm and a chrome-plated metal roll having a roll diameter of 150 mm. The PET film surface of the laminate d (the direction of the film) is on the PET rubber roll between the rolls whose pressurization pressure P) is 6 kg / cm ² · G, and the hollow fiber sample of the laminate d (1) The free surface was passed through so that the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer b could be pressure bonded to obtain a laminate of the laminate d and the laminate b (laminate e).

At this time, the speed of passing between the rolls (pressurizing speed)
Was 1.5 m / min. When passing between the rolls, a release film made of polyethylene terephthalate having a thickness of 75 μm was provided on the other side of the pressure-sensitive adhesive layer b to prevent the pressure-sensitive adhesive surface from sticking to the metal roll.

Thus, the obtained laminate e has a size of 7.1 cm.
Cut into a size of 7.1 cm x 4 ISDN per sheet
It was a patch for angina containing 0 mg.

The moisture transpiration property of the patch was measured and found to be 6.5 mg / day · cm ² in the plane direction and 20 mg / day in the cross-sectional direction, and the moisture transpiration amount of the entire preparation was 8.1 kg / day.・ It was cm ² .

The delamination force between the film and the cloth of the obtained patch was 41 g / mm.

The patch was cut into a circle having a diameter of 30 mm,
The hairless rat having an average body weight of 1.77 g was attached to the back of the hairless rat, and blood was collected at a predetermined time to measure ISDN in plasma. The results are shown in Table 1.

[0157]

Comparative Example 5 Instead of the hollow fiber sample (1), a fabric weight of 112 g /
A patch was obtained in the same manner as in Example 1 except that the polyester knitted fabric of m ² was used, and the results of the test thereof are shown in Table 1. In this case, skin irritation was small, but transdermal absorbability was poor.

[0158]

[Comparative Example 6] 10 μm thick instead of the film of Example 1
A patch was obtained in the same manner as in Example 1 except that the polyethylene film of Example 1 was used, and the results of testing the same were shown in Table 1.

[0159]

[Table 1]

[0160]

[Test Examples 1 to 7] A so-called placebo patch containing no ISDN was prepared in the method for manufacturing the patch shown in Example 1 and Comparative Examples 1 to 7, and the size was 3 cm x 3 c.
It is a skin irritation when applied to the back of a healthy person for 48 hours as m.
Table 2 shows the results obtained by examining the peeling of the formulation from the skin (peeling) and the delamination between the film and the fabric (film peeling).

The skin irritation was judged as 0 for no reaction, 1 for slight erythema, 2 for obvious erythema, 3 for hill examination, and 3 for 10 subjects. It was judged by.

[0162]

[Test Example 8] A placebo preparation obtained by using a fabric having a basis weight of 17 g / m ² prepared by using a yarn made of polyester having an average diameter of 35 μm of a single yarn instead of the hollow fiber sample (1) of the Test Example. The test results are also shown in Table 2.

[0163]

[Table 2]

When the interlaminar peeling force from Test Examples 2, 3 and 4 was increased, the film peeling (the surface of the film peeled off from the cloth,
The film floats or peels off from the patch). In most of these patches, there was no problem up to 12 hours after application, and the problem became serious after application for a long time. In addition, such a film strip was obviously awful in summer and winter.

As shown in Test Example 5, when the delamination force was focused on and increased, a problem occurred with the object of skin irritation which was the first object of the present invention.

In Test Example 6, skin irritation was good, but transdermal absorbability was low, and the patch was dropped from the site of application and peeling occurred.

The film is thickened as in Test Example 7,
The skin irritation increased when the average diameter of the single yarn was increased.

[0168]

[Test Examples 9 to 12] In Test Example 8, the influence of the average diameter of the single yarns was remarkable. Therefore, the single yarns of various thicknesses made of ordinary polyethylene terephthalate were restricted to a basis weight of 17 ± 1 g / m ^2. The knitted fabric used was made, the same placebo patch as in Test Example 1 was made, and a human patch test was conducted in the same manner as in Test Example 1. The results are shown in Table 3.

However, in the trial production of this placebo patch, the pressing speed was 3 m / min. The delamination force of each patch is 1
0-40g / mm, moisture transpiration is 2-40mg /
The day was cm ² .

[0170]

[Table 3]

[0171]

Instead of Test Example 13] basis weight 17 g / m ² of the hollow fiber sample (1), except that the average diameter of the single yarn with basis weight 20 g / m ² nonwoven fabric made mainly of polyethylene terephthalate with 15μm Test Example 2 A placebo formulation was obtained by the method of 1. and tested.

The delamination force of this placebo patch was 6 g /
It was mm. The skin irritation of this patch was 5 and the peeling was 0. Compared with the 30% peeling in the case of knitting, the peeling was significantly reduced.

[0173]

TEST EXAMPLE 14 TEST EXAMPLE 1 (placebo patch of Example 1)
In place of the hollow fiber sample (1), the basis weight is 20 g /
A placebo patch was obtained by the method of Test Example 1 except that a non-woven fabric made of polyethylene terephthalate having an average diameter of m ² and a single yarn of 15 μm was used, and the thickness of the pressure-sensitive adhesive layer a was 5 μm. The peeling force between the film of this patch and the cloth was 4 g / mm.

The skin rash was 5 and peeling was 10%. Regarding peeling, it was still within the acceptable range.

[0175]

Example 2 The pressure-sensitive adhesive layer a, the pressure-sensitive adhesive layer b, obtained in Example 1,
A laminate c was obtained using a PET film.

On the free pressure-sensitive adhesive layer surface of the laminate c, a fabric (fabric 2) made of a knitted fabric having an average diameter of 18 μm and a solid weight of polyethylene terephthalate having a basis weight of 17 g / m ² was pressure-bonded to the laminate c. was obtained (laminate d _2).

Next, there is a laminator for applying a nip pressure between a roll made of ethylene / propylene tetramer (EPT) rubber having a roll diameter of 150 mm and a chrome-plated metal roll having a roll diameter of 150 mm. The PET film surface (direction of the film) of the laminate d ₂ is on the EPT rubber loam between the rolls whose pressure (pressurization pressure P) is 6 kg / cm ² · G.
The free surface of the fabric laminate d ₂ is in communication as the adhesive surface of the adhesive layer b can be crimped to obtain a laminate d ₂ stack of laminates b (the laminate e _2).

At this time, the speed of passing between the rolls (pressurizing speed)
Was 3 m / min. Further, when passing between the rolls, a release film made of polyethylene terephthalate having a thickness of 75 μm was provided on the other side of the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer b so that the pressure-sensitive adhesive surface did not adhere to the metal roll.

Thus, the obtained laminate e ₂ was 7.1c.
The patch was cut into a size of m × 7.1 cm to prepare an angina patch containing 40 mg of ISDN per sheet.

Moisture transpiration of the patch was measured and found to be 14.0 mg / day · cm ² in the plane direction and 28 mg / day in the cross-sectional direction, and the water transpiration amount of the entire preparation was 16.2 mg / day.・ It was cm ² .

The delamination force between the film and the cloth of the obtained patch was 19 g / mm.

The patch was cut into a circle having a diameter of 30 mm,
The hairless rat having an average body weight of 17.7 g was applied to the back of the hairless rat, and blood was collected at a predetermined time, and ISDN in plasma was measured. As a result, 0 ng / ml before application and 60 mg / hour after application
ml, 3 hours after application 140 ng / ml, 8 hours after application 1
28 mg / ml and 115 ng / ml 24 hours after application.

[0183]

TEST EXAMPLE 15 When the placebo patch of Example 2 was prepared and tested in the same manner as in Test Example 1, the skin rash was 7, peeling was 3%, and film peeling was 10%.

Compared with Test Example 1, this preparation tended to cause more skin irritation, but it was judged to be in an acceptable range.

It was found that the manufacturing cost of Test Example 15 (Example 1) was lower than that of Test Example 1 (Example 1).

Claims (10)

[Claims] 1. A patch applied to the outer skin, comprising: (a) semipermeable to water and substantially perpendicular to the film.
8-85g / mm each direction strength, and substantially orthogonal
The elongation in each of the two directions is 30 to 150%,
The ratio of the elongation in the directions is 1.0 to 5.0 (however, the elongation in the two directions is
If the degrees are not the same, the smaller elongation is used as the denominator.
Film having a thickness of 0.5 to 4.9 μm (a
Layer) (b) The average diameter of the single yarn is 1 to 30 μm, and
Basis weight is 8 to 100 g / m ²Cloth (layer b) (c) Adhesive layer containing drug and having a thickness of 5 to 100 μm
(C layer) as an essential ingredient, and from the top of the patch a layer, b
Layers are laminated in this order on the layer c, and the following (1) and
And a patch satisfying the characteristics of (2). (1) Delamination force between the a layer and the b layer is 10 to 40 g / m when the fabric of the b layer is a knitted fabric.
m is 3 to 30 when the b-layer fabric is a non-woven fabric or a woven fabric.
It is g / mm. (2) Moisture transpiration from the patch is 2-40 mg / day.c
m²Is. 2. The patch according to claim 1, wherein the film is a polyester film. 3. A polyester film comprising (1) solid fine particles having an average particle size of 0.001 to 3.0 μm, and (2) a solid fine particle whose average particle size does not substantially exceed 1.5 times the thickness of the polyester film. The patch according to claim 2, which is a film containing 0.01 to 1.0% by weight relative to the total amount of the polyester film. 4. The patch according to claim 1, wherein the cloth is a knitted fabric, and the knitted fabric has a structure in which the sum of the number of loops in the longitudinal and transverse directions is 15 to 37 pieces / cm. 5. The cloth is a non-woven fabric or a woven fabric, and its eyes
With 8 to 30 g / m ²The patch according to claim 1, which is 6. The patch according to claim 1, wherein the single yarn has an average diameter of 5 to 25 μm. 7. The patch according to claim 1, wherein most of the fibers constituting the cloth are not hollow fibers having holes penetrating in the outer peripheral direction. 8. The patch according to claim 1, wherein most of the pressure-sensitive adhesives constituting the pressure-sensitive adhesive layer are selected from rubber-based pressure-sensitive adhesives, silicone-based pressure-sensitive adhesives, and acrylic pressure-sensitive adhesives. 9. The adhesive layer comprises two or more layers,
The patch according to claim 1, wherein the respective pressure-sensitive adhesive layers are composed of the same or different pressure-sensitive adhesives. 10. The patch according to claim 1, wherein the drug is at least one drug selected from coronary vasoactive drugs, hormones, analgesics, and antiallergic drugs.