JP2886020B2 - Patch with minimal skin irritation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release medicated patch for transdermal administration, and more particularly, the present invention relates to a low-pressure patch comprising a specific cloth, a pressure-sensitive adhesive layer containing a drug, and a film. The present invention relates to an easy-to-handle patch that is irritating, highly safe, and excellent in sustained release.

[0002] The present invention relates to a patch containing nitrates which is useful for preventing and improving cardiovascular diseases, in particular, heart diseases such as angina and arrhythmia.

[0003] The present invention also relates to an estradiol-containing patch which is useful for preventing and ameliorating disorders often observed in postmenopausal women such as menopause, osteoporosis, and Alzheimer's dementia.

[0004] The present invention further relates to buprenorphine-containing, which is useful for analgesia after surgery, various cancers, myocardial infarction, anesthesia assistance, low back pain, rheumatoid arthritis, trauma, tooth extraction, etc. It relates to a patch.

[0005]

2. Description of the Related Art In the development of pharmaceuticals, at the same time as developing new compounds with excellent medicinal properties, the dosage form has been changed to further enhance the effects of these new compounds and those already used as pharmaceuticals. Various studies have been made to optimize the dosage form. For example, in order to extend the duration of a drug with a short half-life, which is also a parameter of the effective duration of the drug in the body, the drug must be at a concentration above the minimum effective concentration and below the maximum safe concentration, i.e., at a reduced effective blood concentration. Active development of so-called sustained-release preparations in which components are absorbed into the human body over a long period of time has been actively conducted.

Examples of sustained release preparations include preparations for percutaneous absorption such as ointment and spray application. Since these preparations are applied to the skin in the amount of eye, there is a problem that the dosage is not constant, and that the ointment or the like adheres to clothes and stains.

[0007] As a measure for remedying such drawbacks, there are tapes and patches which contain a certain amount of drug in an adhesive and are formed into a certain size (for example, JP-A-57-116011, JP-A-58-1983). -134020).

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

It has also been found that when a drug is administered transdermally, the rate of so-called hepatic metabolism, in which the drug is metabolized in the liver and the drug efficacy is lost, 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 a property of transdermal absorption.

However, as such patches have been used more and more, it has become clear that there are some problems with the conventional patches.

[0011] Among these problems, the most frequent occurrence is skin rash occurring at the site where the patch is applied to the patient. In general, sustained-release preparations are often administered to patients with chronic diseases.Therefore, skin patches are liable to occur because patches are repeatedly applied over a long period of time, and once skin rash occurs, the affected area expands. There is a problem that it is easy. According to certain statistics, the occurrence of skin irritation due to the patch is 20-50% of all patients.

[0012] Another problem of patches is fluctuation of drug blood concentration. Factors of the blood concentration fluctuation are complicated with factors on the patch side, factors on the human skin side, factors of the human metabolic function, and the like, so that it is not easy to stabilize the drug blood concentration.

Another problem relates to handling. That is, in order to reduce the skin fogging in the patch, the support of the patch was made as thin as possible, the flexibility was increased, and the skin fogging could be somewhat reduced by contriving to reduce the patch. There is also a problem that it is very difficult to correctly affix to a predetermined position on a patient. For example, in recent years, patches containing nitrates as an active ingredient have been widely used as a therapeutic agent for circulatory diseases such as angina pectoris. There is a demand for a patch that can stably maintain the blood concentration of the drug and does not have such a problem.

Although this problem has been avoided in the past from the occurrence of uterine cancer as a side effect, it has been found that this problem can be solved by transdermal administration. In recent years, it has been spotlighted as a therapeutic drug for menopause and osteoporosis in women. The situation is the same in the case of estradiol, progesterone and derivatives thereof, which are on the rise. Since the estradiol-containing patch compensates for the decrease in estrogen that occurs with menopause, and the treatment period extends for several months to several years, high patient compliance is also an essential requirement.
Particularly, in the case of a patch, although the unpleasant sensation at the time of sticking and the occurrence of skin rash are the most serious problems, the conventional techniques have insufficiently considered this point.

As described above, in the prior art, in the case of an oral preparation having relatively high patient compliance, BA
A transdermal patch having low (Bio Availability), serious side effects, high BA, and stable drug concentration in blood has a problem that it causes discomfort and causes skin irritation.

In order to improve the feeling of discomfort, which is one of the disadvantages of the prior art, it is desirable to increase the flexibility of the patch and reduce its size. However, if the flexibility is too high, the handling of the patch becomes extremely difficult, and the utility is lacking. In addition, since the size of the patch is proportional to the amount of drug absorbed, that is, the blood concentration of the drug, if the required degree of drug in blood is determined, in order to reduce the size of the patch, some drug must be used. Means for increasing transdermal absorption are essential. When an absorption enhancer is used for the purpose of enhancing the transdermal absorbability of a drug, there is a problem in that skin fogging is often promoted. On the other hand, in order to improve skin irritation, it has been studied to appropriately select the type of adhesive from the past, and to reduce residual monomers and residual solvents in the adhesive.
Fundamentally, it is desirable to increase the moisture transpiration of the patch and the permeability of oxygen, carbon dioxide and the like. However, simply increasing the moisture transpiration or the gas permeability of oxygen or the like may also decrease the hermeticity of the patch and, as a result, decrease the transdermal absorbability of the drug.

The same is true for morphine, fentanyl, buprenorphine, and the like, which are considered to be used as analgesics for cancer and the like that require long-term medical treatment.

[0018]

Therefore, the present invention eliminates the above-mentioned problems of the prior art, has a stable drug blood concentration, has no uncomfortable feeling, and has remarkably improved skin fogging. Another object of the present invention is to provide a patch which is easy to handle. Other objects and advantages of the present invention will be apparent from the following description.

According to the present invention, a film (layer a) having a semi-permeation of water and a fabric (layer b) having a single yarn thickness of 1 to 30 μm and a basis weight of 8 to 100 g / m ² are provided. A patch having a size of 10 to 150 cm ² containing a pressure-sensitive adhesive layer (c layer) containing a drug and having a thickness of 10 to 100 μm as an essential component, and having the following water vapor transpiration properties (A) to (C) Satisfied patch (a) 1.0 to 30 mg / day · c from the plane direction of the adhesive layer (c layer) of the patch to the plane direction of the film layer (a layer)
m ^2, and is 25～180Mg / day to (ii) a cross-sectional direction of the patch. (C) The total water transpiration in the directions (a) and (b) is ^{2 to} 40 mg / day · cm ² . Is obtained.

[0020]

As described above, in the present invention, the object of the present invention is to use a cloth, a pressure-sensitive adhesive layer containing a drug, and a film having semi-permeation of water, and skillfully utilizing them. It has been found that this can be achieved, and the present invention has been achieved.

That is, in order to prevent skin irritation, which is the most problematic in the use of a patch, at least the organic solvent used in the production process does not remain in the patch, or at least hardly remains. In addition to being less irritating, it is important that the application site does not become excessively humid, and that the application site is appropriately supplied with oxygen to allow the carbon dioxide and ammonia gas generated at the application site to permeate through skin physiology. It is necessary. In particular, it is important to prevent excessive stuffiness at the sticking 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 and to give appropriate stuffiness. There are difficulties in achieving the goal.

The inventors of the present invention have made intensive studies on the humid state in which skin irritation occurs and the humid state required for percutaneous absorption of the drug. Even if the layer is more humid than the saturated water content (excessive water becomes droplets at the interface between the skin and the patch), it does not become faster. The fact was found that it increased when the saturation point was exceeded. From these facts, it was considered that the preferable sealing property as a patch means that the stratum corneum of the skin at the sticking site was always maintained near the saturated moisture content, and the drug form of the sticking portion was studied diligently.

[0024] By changing the preparation in this way, the drawbacks of the conventional patches can be improved. However, further improvements are desired.

Therefore, further studies have been made. One of the objectives of keeping transdermal absorption constant at a sufficient level is to determine the amount of water evaporating from the patch by an amount sufficient to saturate the water content of the stratum corneum. It ca n’t be higher,
Either the most of this moisture evaporation is evaporated in the plane direction of the patch and released through the semi-permeable film surface of the patch, or the part with this moisture evaporation is evaporated and released in the cross-sectional direction of the patch. It was found that there was a difference in the occurrence of skin irritation of the resulting patches.

A semipermeable film can change the amount of water permeation by changing the material of the film, the thickness of the film, and the like. However, the change in the amount of water permeation depends on the amount of oxygen or carbon dioxide from the film. The film is not necessarily in a proportional relationship with the amount of change in gas permeation, and in general, the film is used for the adhesive layer used for the patch of the present invention,
It is much harder to transmit gases such as oxygen and carbon dioxide gas than cloth. Therefore, even when the amount of moisture evaporation from the patch as a whole is the same, the amount of moisture evaporation from the pressure-sensitive adhesive layer or fabric is mainly in the cross-sectional direction compared to when the amount of moisture evaporation is increased in the planar direction. It is considered that when the amount of water evaporation is increased, the difference in the air permeability, which is another factor of the skin irritation, occurs.

That is, the present invention relates to a film (layer a) having a semi-permeation of moisture and a fabric (layer b) having a single yarn thickness of 1 to 30 μm and a basis weight of 8 to 100 g / m ² . A patch having a size of 10 to 150 cm ² containing a pressure-sensitive adhesive layer (c layer) containing a drug and having a thickness of 10 to 100 μm as an essential component, and having the following water vapor transpiration properties (A) to (C) Satisfied patch (a) 1.0 to 30 mg / day · c from the plane direction of the adhesive layer (c layer) of the patch to the plane direction of the film layer (a layer)
a m ^2, (b) is the cross-sectional direction of the adhesive patch 25 to 180
mg / day, and the total water transpiration in the (c), (a) and (b) directions is ^{2 to} 40 mg / day · cm ² . It is.

Surprisingly, with the patch of the present invention,
Even if the degree of skin sweating was slightly changed due to the external environment and the exercise condition of the patient to which the patch was applied, the water content of the stratum corneum at the application site could be kept almost the same value.

In order to prevent skin irritation, the residual solvent in the patch must be reduced as much as possible. Specifically, the residual amount of all solvents used in the step of preparing the patch is 100 to the weight of the adhesive.
It is desirable that the content be not more than 50 ppm, preferably not more than 50 ppm. In adhesive patches, most of these residual solvents remain when the pressure-sensitive adhesive solution is used to form the pressure-sensitive adhesive layer. A method of suctioning, 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 a method of heating at a high temperature is most often used industrially. 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 such a thickness as to be used as a pressure-sensitive adhesive layer of a patch, it is necessary to employ considerably strict drying conditions.

When a drug is mixed in the pressure-sensitive adhesive layer,
Adopting such severe drying conditions often causes a problem accompanied by deterioration and decomposition of the drug, and when using an evaporative drug as the drug, the drug evaporates at high temperatures, so the conditions are milder than normal drying conditions. I have to adopt
It is difficult to obtain a highly safe patch with little residual solvent.

However, it has also been found that the patch of the present invention has an effect that the residual solvent is easily reduced by heating, vacuum suction, or the like because the patch has air permeability also in the cross-sectional direction of the patch.

The semipermeable film used in the present invention is a flexible film. When the film is tested for water permeability alone, the water permeability at 37 ° C. is 1%.
１０００1000 mg / day ・ cm ² , and a film having a thickness of 0.5〜4.9 μm is preferred. Particularly preferred are those having a thickness of 0.5 to 4.9 μm, a strength in two substantially perpendicular directions of 8 to 85 g / mm, and an elongation in two substantially perpendicular directions of 30 to 150%. And a film whose elongation ratio in the two directions is 1.0 to 5.0 (however, when the elongation ratio in the two directions is not the same, the smaller elongation is the denominator). Film. 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 preferably 4.9 μm or less, more preferably 4.0 μm or less, especially 3.5 μm or less, because this tendency becomes remarkable. On the other hand, since the patch is used by attaching it to human skin, it is necessary that the patch can follow the stretching movement of human skin accompanying human activity to some extent. When the film is too thin, the film breaks, or when the film hardly follows the stretching movement of the skin, skin irritation increases. Even if the thickness is reduced to less than 0.5 μm, the physical stimulus does not change much and the disadvantage that it tends to be inconvenient to manufacture increases.

The purpose of providing a film layer as a support on the patch is to enhance the sealing property of the sticking site to promote percutaneous absorption, and to cover the adhesive surface to adhere the adhesive to clothing and other places on the skin. This is to prevent the situation. As the thickness of the film decreases, the sealing property also decreases. If the thickness is less than 5 μm, the sealing property tends to decrease. However, if it is less than 1 μm and less than 0.5 μm, it becomes difficult to obtain sufficient sealing properties as a patch.

Regarding the strength of the film, if the strength in two directions substantially perpendicular to each other exceeds 85 g / mm, the physical irritation is not sufficiently small no matter how thin the thickness is, while it is less than 8 g / mm. The preparation is apt to be damaged at the time of application or during use after application, and tends to be difficult to use with confidence.

Regarding the elongation of the film, when the elongation in two directions substantially perpendicular to each other exceeds 150%, the handleability is poor. On the other hand, when the elongation is less than 30%, the physical irritation increases, Breakage at the time of sticking is likely to occur.

According to the results of the study by the present inventors, the ratio of the elongation in the two directions is 1.0 to 5.0 (however, when the elongation is the same, the smaller elongation is regarded as the denominator. Do), but especially 1.
It is preferable to use a film having a thickness of 0 to 3.0 because the film has good sticking comfort when stuck. When the ratio exceeds 5.0, that is, when a film having an 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 sense of tightness. This is not suitable because it tends to cause problems such as poor sticking feeling, easy peeling, and easy breakage.

Accordingly, the film of the present invention has a thickness of 0.5 to 4.9 μm, a strength in each of two substantially perpendicular directions of 8 to 85 g / mm, and an elongation of two substantially perpendicular directions. It is preferably 30 to 150%, and the elongation ratio in the two directions is preferably 1.0 to 5.0 (however, when the 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, the strength is 8 to 85 g / mm, and the elongation is 45 to 150%.
And a film having an elongation ratio of 1.0 to 3.0 is preferable.

The strength referred to in the present invention is a value obtained by calculating the maximum load up to cutting in accordance with the method for measuring the tensile strength of "Plaster" of the Japanese Pharmacopoeia and converting it to the load per unit mm (g / m).
m), and the elongation indicates the elongation (%) of the length before tension and the length at the time of cutting. The two orthogonal directions mean a so-called vertical direction and a horizontal direction.

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

Of these films, polyester films are preferred. Polyester films generally have good stability to heat and light, have low drug adsorption and interaction with drugs, and have high safety to humans. Among the polyester films, a film made of polyethylene terephthalate is preferable.

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

In the present invention, it is particularly preferable to use a polyester film as the above-mentioned film layer, but a small percentage of solid fine particles may be present in the polyester film for the purpose of improving its slipperiness. However, heretofore, there has been no sufficient knowledge as to how such solid fine particles exert an influence on the patch as in the present invention.

The inventor of the present invention has conducted intensive studies on this point, and found that the amount of solid fine particles present in the polyester film layer was 0.01 to 1% by weight, and the average particle size was 0.0 to 1%.
It is important that the average particle diameter is from 1 to 3.0 μm and the average particle diameter does not substantially exceed 1.5 times the thickness of the polyester film, while reducing the skin rash while absorbing a clinically effective amount of the drug. Was found.

As such solid fine particles, for example,
(1) silicon dioxide, (2) alumina, (3) silicates and aluminosilicate compounds containing 30% by weight or more of silicon dioxide, (4) one or more metals selected from magnesium, zinc, zirconium, and titanium Oxides, (5) sulfates of one or more metals selected from calcium and barium, (6) phosphates of one or more metals selected from lithium, sodium, and calcium, (7) calcium sulfate, barium, zinc, and manganese One or more metal terephthalates selected, (8) one or more metal titanates selected from magnesium, calcium, barium, iron, cobalt, manganese, nickel, etc., (9) one selected from calcium and magnesium , (10) carbon, (11)
Inorganic or organic solid fine particles such as glass and (12) cross-linked polystyrene can be exemplified. Of course, these uses may be one kind or a mixture of two or more kinds.

When the amount of the solid fine particles is less than 0.01% by weight, the effect of reducing skin fogging tends to be insufficient, so that it is not preferable. In some cases, the transdermal absorbability of the drug may not be sufficiently satisfied, which may be undesirable as a patch. When the average particle size is less than 0.01 μm, the effect of reducing skin fogging is insufficient, and the handling property may not be sufficiently satisfied. If it exceeds 1.5 times, the transdermal absorbability of the drug may not be sufficiently satisfied as described above. In such a case, it is conceivable that the moisture transpiration and air permeability become too large due to 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 for using the fabric in the present invention is that 25 to 180 mg / patch is applied in the cross-sectional direction of the patch.
It is to give the day moisture transpiration. The second reason for using a fabric is to improve the handling of a patch using a soft and thin film. The third reason for using a fabric is that the thickness of the film containing the flexible thin film and the drug is 10 to 10
A patch consisting only of a 0 μm pressure-sensitive adhesive layer can be prevented from being broken or deformed by a slight stress, which facilitates the production of the patch.

In particular, the first and second reasons are important.
If the basis weight of the fabric is 8 g / m ² or less, it tends to be difficult to achieve the desired moisture transpiration in the cross-sectional direction, no matter how much the pressure-sensitive adhesive layer and the manufacturing method described below are optimized.
In addition, the handleability may not be sufficient.

On the other hand, if the basis weight of the fabric is 100 g / m ² or more, it is not preferable because the water evaporation in the cross-sectional direction becomes too large. In addition, when the basis weight of the fabric is 100 g / m ² or more, the thickness of the patch becomes large, so that the patch is easily peeled off from the portion to be adhered at the time of sticking and is likely to fall off.
It is considered that the cause of peeling when the basis weight of the fabric is increased is that the end face, particularly the corner, of the patch is rubbed against clothing or the like and is taken up by the clothing or the like. A particularly preferred fabric weight is 10 to 60 g / m ² .

In such a fabric, the thickness of a single yarn of the fibers constituting the fabric is important. In general, a fibrous material can be arbitrarily manufactured from a small one having a size of 0.5 μm or less to a large one having a size exceeding 1000 μm.
It is used properly depending on the application.

According to the studies by the present inventors so far, it has been found that the thickness of this single thread has an effect on skin irritation even when it is used for a patch, and the preferred thickness of the single thread is 1%.
１７17 μm. When the thickness of the single yarn is less than 1 μm,
When the basis weight of the fabric is 8 g / m ² in order to ensure the handleability of the patch of the present invention, there is a tendency that the transpiration of moisture from the cross-sectional direction tends to be too large, and the fibers are too thin. Cuts and the like frequently occur, causing difficulty in the manufacturing process of the patch.

On the other hand, when the thickness of the single yarn is larger than 30 μm, the skin irritation becomes large no matter how small the basis weight of the fabric is. Particularly preferred single yarn thickness range is 5 to 25 μm.
m.

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, it is less irritating to the skin than a fabric having the same basis weight using the same single yarn. 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. The single yarn used may be a mixture of different types of single yarns.
In this case, most of the single yarns constituting the fabric are preferably in the above-described range.

In the present invention, it is possible to use other than hollow fibers, in which most of the single yarns of the fibers constituting the fabric have holes penetrating in the outer peripheral direction, ie, solid fibers and hollow fibers. Alternatively, in the present invention, it is preferable to use a hollow fiber having a hole in which most of the single yarn of the fiber constituting the fabric penetrates in the outer peripheral direction, although there is an economic problem, but a preferred embodiment for achieving the object of the present invention. It is. Such hollow fibers are disclosed in, for example, JP-A-56-20612 and JP-A-5-20612.
It can be produced by the methods described in JP-A-6-20613 and JP-A-56-43420.

The fibers used in the present invention include, for example, polyesters such as polyethylene terephthalate; polyolefins such as polyethylene and polypropylene; polyamides such as nylon 6 and nylon 66; polyurethane, cellulose acetate, polyacrylonitrile, polyvinyl chloride, and polyvinyl acetate. Arbitrary things such as vinyl can be selected. Of these, polyesters are preferred, and polyethylene terephthalate is particularly safe for humans, has excellent stability to heat, light, and temperature, has no interaction with drugs, and impregnates hollow fibers with drug solutions. This is preferred because it is difficult to be denatured by the solvent used.

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

Examples of the drug used in the present invention include nitrates used in coronary vasodilators such as isosorbide dinitrate and nitroglycerin; menthol, camphor,
Salicylic esters such as methyl salicylate; hormonal agents such as estradiol, norethisterone, progesterone and derivatives thereof; morphine, fentanyl,
An analgesic such as buprenorphine hydrochloride or a derivative thereof; a heart disease drug such as clonidine, nifedipine, captolyl or a derivative thereof can be exemplified, but not limited thereto.

The amount of the drug used is appropriately determined depending on the strength of the pharmacological action of the drug used, the absorbability to the skin, and the like.
Usually, it is 0.1 to 20% by weight based on the total amount of the pressure-sensitive adhesive. Such a drug may be present in the pressure-sensitive adhesive layer in a state compatible with the pressure-sensitive adhesive, and may be partially precipitated as a crystal as long as it does not affect the drug effect.

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 medicine are administered orally or as an injection, and in that case, a clinically effective drug dose is described in many literatures (for example, Pharmaceutical Handbook, 4th edition, Pharmaceutical Handbook). Tokihosha (1988)). Therefore, 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, the amount remaining in the preparation increases, so that the dosage tends to be larger than that of an oral preparation or the like. However, in the case of a nitrate drug having a large hepatic metabolism, the amount of the drug used for the patch may be smaller than that of the oral drug. Therefore, the amount of drug in one patch is 1/5 or more to 10 times or less the daily dose of oral preparations and injections.

As the pressure-sensitive adhesive used in the present invention, a normal 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. Viscous composition;
Vinyl-based viscous compositions such as polyvinyl alcohol and ethylene-vinyl acetate copolymer; viscous compositions mainly composed of silicone-based adhesives, polyurethane elastic, polyester elastic, polybutadiene elastic; and acrylic resins You can choose from. Among them, acrylic resins are preferred, and from the viewpoint of less skin irritation, moderate tackiness, adhesiveness, high internal concentration, and excellent solvent resistance, (1) an alkyl group having 4 or more carbon atoms (Meth) acrylic acid alkyl ester of at least 80 to 9
An acrylic resin obtained by copolymerizing 8 mol% and (2) 2 to 20 mol% of acrylic acid and / or methacrylic acid is particularly preferable. Examples of (meth) acrylates of alkyl groups having 4 or more carbon atoms include, for example, butyl (meth) acrylate, amyl (meth) acrylate, hexyl (meth)
Examples include acrylate, heptyl (meth) acrylate, octyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth) acrylate, and 2-ethylhexyl (meth) acrylate. These adhesives may be used alone or in combination of two or more.

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

In the present invention, these adhesives can be combined according to the type of the drug. For example, an adhesive having high compatibility is provided near the film layer of the backing, and the compatibility with the drug is much lower. By using a pressure-sensitive adhesive that is not high but has low skin irritation on the surface in contact with the skin, a patch with low skin irritation and excellent sustained release can be obtained.

The preferred thickness of the pressure-sensitive adhesive layer of the present invention is 5 to 1
00 μm. When the thickness of the pressure-sensitive adhesive layer is large, the amount of the residual solvent tends to be extremely high, so that the thickness is particularly preferably 60 μm or less. Conversely, when the pressure-sensitive adhesive layer becomes thinner, the adhesive strength to human skin decreases, and the stability during use of the patch decreases.

The first method of the method for producing a patch of the present invention is as follows: a film and a fabric are adhered by applying pressure under heating to obtain a laminate of the film and the fabric, and then a drug-containing adhesive is prepared. This is a method in which an agent solution is applied onto the fabric surface of a laminate and dried.

A second method of the production method is to apply a pressure-sensitive adhesive solution containing a drug in advance on a release film to obtain a drug-containing pressure-sensitive adhesive layer having a thickness of 10 to 100 μm after drying. In this method, the drug-containing adhesive layer is pressure-bonded to the fabric surface of a laminate of the film and the fabric obtained by the first method of the production method.

A third method of the production method is to apply a drug-containing pressure-sensitive adhesive solution on a release film in advance and to form two drug-containing pressure-sensitive adhesive layers having a thickness after drying of 10 to 100 μm ( Thus, drug-containing adhesive layers A and B) are obtained. At this time, different pressure-sensitive adhesives may be used for the drug-containing pressure-sensitive adhesive layers A and B, the thickness may be different, the content of the drug may be different, the type of the contained drug may be different, and the drug-containing Any one of the adhesive layers A and B may not substantially contain a drug. One of the two drug-containing pressure-sensitive adhesive layers (layer A) thus obtained is pressure-bonded to a film, and then a fabric is pressure-bonded to the surface of the layer A where the film is not pressure-bonded to form a three-layer laminate ( C layer) and then the drug-containing layer (B layer) may be pressed on the free surface of the C layer fabric.

The fourth method of the manufacturing method is the third method of the manufacturing method.
This is the method described in the first method, but a drug is contained when the adhesive layer is formed, or two adhesive layers (A layer and B layer) are formed without containing a drug, and these are laminated and manufactured. A three-layer laminate (layer C) described in the third method is obtained, and thereafter, a drug dissolved in a solvent is dropped, immersed, and contacted on the fabric of the three-layer laminate to form a coating. The solvent is removed by evaporation to obtain a three-layer laminate (D layer) containing the drug, and the pressure-sensitive adhesive layer B containing or not containing the drug is pressed on the fabric of the D layer. The patch thus obtained may be homogenized in quality before or after cutting, if necessary, by heating, vacuum suction or the like.

As a person skilled in the art can easily imagine, a solution of a drug-containing pressure-sensitive adhesive is applied onto the cloth of the D layer obtained by the fourth method of the manufacturing method, heated and the solvent is removed directly. It is also possible to form an adhesive layer corresponding to the adhesive layer B. Further, it is also possible to adopt a multilayer lamination of the pressure-sensitive adhesive layer by the above-mentioned production method as required.

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

The patch of the present invention is based on the finding that the moisture transpiration, especially the water transpiration in the cross-sectional direction in addition to the planar direction, is important.

The patch of the present invention comprises the above-mentioned moisture-permeable film and cloth. Even if the cloth has the above-mentioned range, the greater the basis weight, the better the handleability. Further, if the thickness of the adhesive layer to be used is the same and the pressing conditions are the same, the greater the basis weight, the greater the moisture evaporation in the cross-sectional direction. Therefore, when the basis weight of the fabric is determined from the viewpoint of handleability, the thickness of the adhesive layer to be used is increased in order to maintain the transdermal absorbability and to keep the moisture transpiration in the cross-sectional direction in a preferable range. It is preferable to increase the conditions for pressure bonding with the fabric. Especially when adopting a method of applying a pressure-sensitive adhesive solution obtained by dissolving a pressure-sensitive adhesive layer on a cloth,
Since the pressure-sensitive adhesive layer is formed in a state in which the pressure-sensitive adhesive has penetrated into the cloth, the water evaporation in the cross-sectional direction tends to be smaller than when the pressure-sensitive adhesive layer having the same thickness is pressed.

On the other hand, from the viewpoint of preventing the preparation from peeling off at the time of application, it is preferable that the cloth is thin. Therefore, when the basis weight is reduced as long as the handleability of the obtained patch is not impaired, the adhesive layer becomes thin. Or / and weakening the pressure bonding conditions between the fabric and the adhesive layer.

The percutaneous absorbability of the obtained patch largely depends on the water transpiration property of the entire patch. When the size of a usual preparation is 10 to 150 cm ² , the value is 2%.
４０40 mg / day · cm ² . 40 mg / day · cm ²
When it is larger, it is difficult to obtain sufficient transdermal absorbability. Conversely, if it is less than ² mg / day · cm ² , it will not be a formulation with low skin irritation.

From the viewpoint of preventing skin irritation, the greater the water transpiration property is, the better it is at least 40 mg / day · cm ² . However, in the present invention, it is intended to reduce skin fogging while maintaining sufficient transdermal absorbability. For this purpose, oxygen or carbon dioxide gas is used as an adhesive, and gas permeability is reduced through a fabric layer. Attachment along a pressure-sensitive adhesive layer or a fabric layer that evaporates moisture in the direction of the outer surface above the film (that is, in the plane direction) through a relatively low film, and has good oxygen or carbon dioxide permeability in the plane direction or more. It is preferable to evaporate the water in the direction of the side surface of the agent (that is, in the cross-sectional direction). It can be easily imagined that the pressure-sensitive adhesive layer or the porous cloth, in which the solvent is simply removed from the amorphous polymer, rather than the film produced by stretching and orientation, has a remarkably large air permeability.

[0074] Therefore, in the patch of the present invention, as the size of the patch is 1.0～30Mg / day · cm ² is the patch per one planar direction of 10～150Cm ^2, and patch The water vapor transpiration in the cross-sectional direction per patch having a size of 10 to 150 cm ² is adjusted to 25 to 180 mg / day. In conventional patches, the idea of increasing the moisture transpiration and air permeability to reduce skin irritation is known (for example, JP-A-4-77419). In the patch of the present invention, as long as the object of the present invention can be achieved, micropores or cuts (cutting lines) can be provided as many as necessary on the film surface or the like.
In such a case, the water vapor transpiration of the patch of the present invention may be such that there are no such micropores or cuts satisfying the water transpiration.

Since the patch of the present invention has such water transpiration, air permeability is also ensured. As a result, skin rash is extremely reduced, and sufficient transdermal absorption of the contained transdermally absorbable drug is achieved. Absorbency can be ensured.

One of the main production conditions for producing the patch of the present invention is a known laminator pressurizing condition used for laminating and pressurizing a film.

In the case of the present invention, the present invention is controlled by controlling conditions such as 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, and the temperature when passing through the roll. Can be obtained.

In particular, in the case of the patch of the present invention, a thin film which is more easily broken than a normal film is used, a specific cloth is used, and a specific adhesive is used. By having a specific quality standard, which is one of the properties required for pharmaceutical formulations,
A patch with less variation in quality, that is, a balance between the characteristics of high transdermal absorbability, low skin irritation, and good handleability, and almost no peeling trouble when applied. It is possible to provide a patch with little variation that can prevent a predetermined drug from being absorbed at a predetermined absorption rate.

In order to eliminate troubles, the peeling force between the film and the fabric is preferably 10 g / mm or more.

The patch of the present invention may contain, if necessary, other absorption promoters, dissolution aids, diffusion aids, fillers and the like. As the absorption promoter or diffusion aid used in the present invention, in addition to those exemplified above, for example, sodium lauryl sulfate, sodium dodecylbenzene sulfonate, sodium alkyldiphenyl ether disulfonate, dioctyl sulfosuccinate, polyoxyalkylphenyl ether Surfactants such as sulfate ammonium salts; glycerin, diethylene glycol,
Alcohols such as propylene glycol, polyethylene glycol and higher fatty acid alcohols; dimethyl sulfoxide and alkylmethyl derivatives; salicylic acid, urea,
Dimethylacetamide, dimethylformamide, lanolin, allantoin, squalene, carbopol, diisopropyl adipate, lauryl pyroglutamate, isopropyl myristate, 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, dodecylazacycloheptane-2-one and the like can be used.

The absorption enhancer or the nucleic acid auxiliary may be in a range that does not impair the adhesiveness.
It can be used in the range of up to 30% by weight.

In the patch, as a filler,
Water, titanium oxide, calcium carbonate, masonry, calcium silicate, aluminum silicate, diatomaceous earth, carbon black, redwood, various dyes and pigments, liquid paraffin, vaseline, lactose, fragrances, deodorants, coloring agents, polyethylene, A powder or a molded product of a synthetic resin such as polypropylene, polyester, or polystyrene may be contained in an amount of 0.1 to 30% by weight.

[0083]

INDUSTRIAL APPLICABILITY As described above, the patch according to the present invention has a desired percutaneous absorbability (sustained release) and is used for transdermal administration in which the occurrence of skin rash is significantly prevented. It can be used as a patch. In addition, the patch according to the present invention is a patch which is very flexible, has little skin irritation, and maintains a required hermeticity, has a small amount of residual solvent, has excellent handleability, and has enhanced safety. It will be widely used as an agent.

[0084]

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

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

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

Next, the glass plate with the patch was adhered to 37
The glass plate was placed in a hot-air constant-temperature bath at 24 ° C. and weighed 24 hours later, and was measured as W ₂ (mg). The water transpiration in the planar direction is obtained from W ₁ and W ₂ and W ₃ and W ₄ below.

Next, an aluminum foil was closely adhered to the film surface (outside) of the patch using an adhesive having a thickness of about 30 μm, the release film of the patch backed with this aluminum foil was peeled off, and 3 ml of water was removed. Is bonded so as to cover the depression of the glass plate in which is placed, and its weight W ₃ (mg) is measured. This product was put in a 37 ° C. warm air bath for 24 hours and weighed W ₄
(Mg). From these W ₃ and W ₄ , the moisture transpiration in the sectional direction is obtained.

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

[0090]

(Equation 1)

The size of the patch to be tested is 50 mm
When the diameter 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 there is a cut line or the like in the film (layer a) of the patch, the test is performed on the patch without the cut line or the like, or the cut line or the like is not affected on the test results. Repair and test.

(Ii) Standard method for delamination force Adhesion test method for "adhesive plaster" of the Japanese Pharmacopoeia Law. A commercially available cloth tape (for example, Terraoka tape) is previously adhered to the outer surface of the patch film, and then the width 20
A test piece cut into a strip of mm is used. After the adhesive surface of the patch as a test piece is adhered on the phenolic resin plate, the interface (interlayer) between the film and the fabric is peeled off by about 5 mm. The test piece having a slight delamination between the layers is tested according to the adhesion test method to determine the delamination force.

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

The hollow fiber and the pressure-sensitive 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, sodium 3,5-di (carbomethoxy) benzenesulfonate 53 parts (11.7 mol% based on dimethyl terephthalate), manganese acetate tetrahydrate 0.084 part and sodium acetate trihydrate 1.22 Part into a glass flask with a rectification tower, and transesterified according to a conventional method,
After the theoretical amount of methanol was distilled off, the reaction product was placed in a polycondensation flask equipped with a rectifying column, and 56% of orthophosphoric acid was used as a stabilizer.
% Of an aqueous solution and 0.135 part of antimony trioxide as a polycondensation catalyst were added at a temperature of 275 ° C. under atmospheric pressure.
The reaction was performed for 15 minutes under a reduced pressure of 30 mmHg for 0 minutes, and then the reaction was performed for 100 minutes under a high vacuum. Final internal pressure is 0.39mm
Hg, and the intrinsic viscosity of the obtained copolymer is 0.1.
402, the softening point was about 200 ° C. After completion of the reaction, the copolymer was formed into chips according to a conventional method.

15 parts of this copolymer tip and 8 chips of polyethylene terephthalate having an intrinsic viscosity of 0.640
5 parts in a Nauta mixer (manufactured by Hosokawa Iron Works) for 5 minutes, and then at 110 ° C. for 2 hours in a nitrogen stream, and further 1 hour.
After drying at 50 ° 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.

The chip is dried by a conventional method, and a spinneret having a circular slit having a width of 0.05 mm and a diameter of 0.6 mm and having two closed circular slits is used. Then, a hollow fiber having a ratio of outer diameter to inner diameter of 2: 1 (hollow ratio: 25%) was produced. The original yarn was 300 denier / 24 filaments, and the original yarn was drawn at a draw ratio of 4.2 times according to a conventional method to obtain a multifilament of 71 denier / 24 filaments. The single yarn of this multifilament had a diameter of 18 μm. The multifilament is knitted into a knitted fabric, scoured and dried by a conventional method, and then treated with a 1% aqueous sodium hydroxide solution at a boiling temperature for 2 hours to reduce the alkali loss by 20% and the water absorption rate to 3%.
In seconds, a knitted fabric having a water absorption of 84% was obtained. The obtained knitted fabric was stretched 1.5 times in the longitudinal direction, heated at 100 ° C. for 1 minute and heat-set to obtain a knitted fabric having a basis weight of 17 g / m ² .

The obtained hollow fiber was a hollow fiber scattered throughout the cross section of the hollow fiber and arranged in the fiber direction, and at least a part of the hollow fiber had fine pores communicating with the hollow portion.

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

This hollow fiber has no 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 were equipped with a reflux condenser and a stirrer. The polymerization was continued for 9 hours while charging the reaction vessel at 60 ° C under a nitrogen atmosphere while slowly expanding sales. The polymerization conversion was 99.9%.

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

[0104]

Example 1 An 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) is dried on a silicone-coated release film to have a thickness of 15 μm after drying. 90 ° C for 1 minute at 80 ° C
For 1 minute and 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 content of ISDN was 2.3 g / m ² .

Further, 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 was 40 μm, and the coating was performed at 80 ° C. for 2 minutes. Dried at 90 ° C for 2 minutes and 130 ° C for 4 minutes. The residual amount of ethyl acetate in the obtained pressure-sensitive adhesive layer (pressure-sensitive adhesive layer b) is 25.
ppm, and the content of ISDN was 6.0 g / m ² .

Next, synthetic silica having a thickness of 2.5 μm, strengths of 35 g / mm and 41 g / mm in two orthogonal directions, elongations of 37% and 81%, and an average particle size of 0.45 μm, respectively. A pressure-sensitive adhesive layer a was pressed against one surface of a polyethylene terephthalate film (PET film) containing 0.1% by weight and 0.05% by weight of talc having an average particle size of 0.75 μm.
A laminate (laminate c) of the ET film and the adhesive layer a was obtained.

Next, the hollow fiber sample (1) was pressed onto the free adhesive layer surface of the laminate c to obtain a laminate (laminate d).

Next, a laminator in which a nip pressure is applied 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, and The PET film surface (film direction) of the laminate d is between the rolls in which the pressure (pressurizing pressure P) is 6 kg / cm ² · G, and the hollow fiber sample (1 ) Was passed through the free surface so that the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer b could be pressed, to obtain a laminate (laminate e) of the laminate d and the laminate b.

At this time, the speed of passing between the rolls (pressing speed)
Was 3 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 adhesive surface of the adhesive layer b to prevent the adhesive surface from sticking to the metal roll.

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

The patch was measured for water transpiration, and found to be 14.3 mg / day · cm ² in the horizontal direction and 45 mg / day in the cross-sectional direction, and the water transpiration rate of the whole preparation was 16.7 mg / day · cm ² .

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

[0113]

Comparative Examples 1-4 Patches were obtained using the materials shown in Example 1 except that the direction of the film, the pressing pressure P and the pressing speed were changed, and patches were obtained in the same manner. The results are shown in Table 1.

The patch of Comparative Example 1 was harder and stiffer than the preparation of Example 1. Comparative Example 3
In the patch of Comparative Example 4, the interface between the film surface and the adhesive layer was easily peeled in the latter half of the sticking time. This proved to be unsuitable for human clinical trials.

[0115]

Comparative Example 5 Instead of the hollow fiber sample (1), the basis weight was 112 g.
/ M ² , a patch was obtained in the same manner as in Example 1 except that a polyester knitted fabric was used.
It was shown to. In this case, skin irritation was small, but transdermal absorption was poor.

[0116]

Comparative Example 6 Instead of the film of Example 1, the thickness was 10 μm.
A patch was obtained in the same manner as in Example 1 except that the polyethylene film of Example 1 was used.
It was shown to.

[0117]

Comparative Example 7 A patch was obtained in the same manner as in Example 1 except that a polyester nonwoven fabric having a basis weight of 9 g / m ² was used in place of the hollow fiber sample (1) in Example 1, and the results of the test performed on the patch were obtained. The results are shown in Table 1.

[0118]

[Table 1]

[0119]

[Test Examples 1 to 8] A so-called placebo patch containing no ISDN was produced in the patch production method shown in Example 1 and Comparative Examples 1 to 7, and the size was set to 3 cm x 3 cm. Table 2 shows the results of examining skin irritation, peeling of the preparation from the skin (peeling) and delamination between the film and the fabric (film peeling) after 48 hours of application.

The evaluation of skin irritation was defined as 0 when no reaction was observed, 1 for slight erythema, 2 for evident erythema, and 3 for hill examination etc., for a total of 10 evaluation points. Was determined.

[0121]

Test Example 9 The placebo preparation obtained using a fabric having a basis weight of 17 g / m ² made by using a polyester yarn having a denier of 35 μm in place of the hollow fiber sample (1) of the test example was tested. Are also shown in Table 2.

[0122]

[Table 2]

It is clear from Test Examples 2 and 8 that the skin fogging increases when the transpiring property in the cross-sectional direction decreases. Considering that the transdermal absorbability of the preparation of Test Example 2 is good as shown in Comparative Example 1, it becomes clear how difficult a balance is required for a medical patch.

Test Examples 3, 4, 5, 6, and 7 have little skin irritation, but all have the disadvantage of poor transdermal absorbability. Furthermore, the patch of Test Example 6 has a serious drawback that peeling is likely to occur during the application because the fabric weight is large.

In Test Example 9 using a fabric in which the thickness of a single yarn was large, the skin rash was particularly large.

[0126]

Test Examples 10 to 14 In Test Example 9, the effect of the thickness of the single yarn was remarkable, so that a single yarn of various thicknesses made of ordinary polyethylene terephthalate was used with a basis weight of 17 ± 1 g / m ^2. Table 3 shows the results obtained by making a knitted fabric, making the same placebo as in Test Example 1, and performing a human sticking test in the same manner as in Test Example 1.

[0127]

[Table 3]

[0128]

Example 2 The adhesive layer a, the adhesive layer b obtained in Example 1 and PE
A laminate c was obtained using a T film.

On the free adhesive layer surface of the laminate c,
To obtain a fabric consisting of basis weight 17 g / m ² made of polyethylene terephthalate not hollow with an average diameter 18μm single yarn knitted (fabric 2) Crimp the laminate (laminate d _2).

Next, a laminator in which a nip pressure is applied 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, is used. pressure (applied pressure P) is 6 kg / cm PET film surface of the laminate d ₂ between the rolls so as to be ² · G (direction of the film) is located towards the EPT Gomuromu,
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 (pressing speed)
Was 3 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 adhesive surface of the adhesive layer b to prevent the adhesive surface from sticking to the metal roll.

Thus, the obtained laminate e ₂ has 7.1 c
The patch was cut into a size of mx 7.1 cm to obtain a patch for angina pectoris containing 40 mg of ISDN per sheet.

The water-evaporation property of the patch was measured to be 14.0 mg / day · cm ² in the plane direction and 28 mg / day in the cross-sectional direction, and the water evaporation amount of the whole preparation was 16.2 mg / day. - it was cm ^2.

The patch was cut into a circle having a diameter of 30 mm.
The hairless rat with an average weight of 17.7 g was stuck to the back of a hairless rat, blood was collected at a predetermined time, and ISDN in plasma was measured. As a result, 0 ng / ml before application and 82 hours after application 1 hour
mg / ml, 133 ng / ml after 3 hours from application, 141 mg / ml after 8 hours from application, 106 ng / m after 24 hours from application
l.

[0135]

Example 3 Example 2 was repeated except that the fabric 2 of Example 2 was replaced with a knitted fabric (fabric 3) having a single yarn average diameter of 7 μm and a solid weight of 34 g / m ^{2 made} of solid polyethylene terephthalate. 7.1cm x in the same way as 2
ISDN with a size of 7.1 cm, 4
A patch containing 0 mg was obtained.

When the water loss of the patch was measured, it was 14.5 mg / day · cm ² in the plane direction and 68 mg / day in the cross-sectional direction, and the water loss of the whole preparation was 19.9 mg / day · cm. ^{Was 2} .

The patch was cut into a circle having a diameter of 30 mm,
The hairless rat with an average weight of 17.7 g was stuck to the back of a hairless rat, blood was collected at a predetermined time, and ISDN in plasma was measured. The results were 0 ng / ml before application and 67 hours after application.
mg / ml, 102 ng / ml after 3 hours from application, 93 mg / ml after 8 hours from application, and 90 ng / ml after 24 hours from application.

[0138]

Test Examples 15 and 16 The placebo preparations of Examples 2 and 3 were prepared and tested as in Test Example 1. The results are shown in Table 4.

[0139]

[Table 4]

When the results of Test Example 1 (the placebo preparation of Example 1) and Test Example 15 (the placebo preparation of Example 2) were compared, Test Example 1 showed good skin rash.
Test Example 15 was also within the allowable range. In Test Example 16, the skin rash was comparable to Test Example 1. However, peeling tended to increase slightly.

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 9/70

Claims (13)

(57) [Claims] 1. A film (a layer) having a semi-permeation of water, a single yarn having a thickness of 1 to 30 μm, and a basis weight of 8 to 10
0 g / m ² fabric (layer b) and a drug-containing thickness of 1
A patch having a pressure-sensitive adhesive layer (c layer) of 0 to 100 [mu] m as an essential component and a size of 10 to 150 cm < ² >, wherein the water vapor transpiration satisfies the following (A) to (C). (B) 1.0 to 30 mg / day · c from the plane direction of the adhesive layer (c layer) of the patch to the plane direction of the film layer (a layer).
a m ^2, (b) is the cross-sectional direction of the adhesive patch 25 to 180
mg / day, and the total water transpiration in the (c), (a) and (b) directions is ^{2 to} 40 mg / day · cm ² . 2. The patch according to claim 1, wherein the film is a film having a thickness of 0.5 to 4.9 μm. 3. The film has a strength in two directions substantially perpendicular to each other of 8 to 85 g / mm, and an elongation in two directions substantially perpendicular to each other of 30 to 150%. 3. The patch according to claim 2, wherein the patch has a degree ratio of 1.0 to 5.0 (however, if the elongation ratios in the two directions are not the same, the smaller elongation is the denominator). . 4. The patch according to claim 4, wherein the film is a polyester film. 5. A polyester film comprising (1) solid fine particles having an average particle diameter of 0.001 to 3.0 μm and (2) an average particle diameter substantially not exceeding 1.5 times the thickness of the polyester film. The patch according to claim 4, which is a film containing 0.01 to 1.0% by weight based on the total amount of the polyester film. 6. The patch according to claim 1, wherein the fabric is a knit or a non-woven fabric. 7. The patch according to claim 6, wherein the knitted fabric has a structure in which the total number of loops in the vertical and horizontal directions is 15 to 37 / cm. 8. The patch according to claim 1, wherein the single yarn of the fibers occupying most of the fibers constituting the fabric has an average diameter of 1 to 30 μm. 9. The patch according to claim 8, wherein most of the fibers constituting the fabric are not hollow fibers having holes penetrating in the outer peripheral direction. 10. The adhesive preparation according to claim 1, wherein the majority of the adhesive constituting the adhesive layer comprises one of a rubber-based adhesive, a silicone-based adhesive, and an acrylic-based adhesive. 11. The patch according to claim 1, wherein the pressure-sensitive adhesive layer comprises two or more layers, and most of the respective pressure-sensitive adhesive layers are composed of the same or different pressure-sensitive adhesives. 12. The patch according to claim 1, wherein the drug is at least one drug selected from coronary vasoactive drugs, hormonal drugs, analgesics, and antiallergic drugs. 13. A delamination force between a fabric and a film is 10
The patch according to claim 1, which is not less than g / mm.