JPH0825871B2 - Patch and its manufacturing method - Google Patents

Description

TECHNICAL FIELD The present invention relates to a sustained-release pharmaceutical patch for transdermal administration and a method for producing the same, and more specifically, the present invention relates to a knitted fabric made of a specific hollow fiber, The present invention relates to a highly safe and easy-to-handle patch excellent in sustained release, which comprises a pressure-sensitive adhesive layer containing a drug and a film, and a method for efficiently producing the same.

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

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

The present invention further relates to post-treatment, various cancers, myocardial infarction, anesthesia support, low back pain, rheumatoid arthritis, trauma, analgesia such as after tooth extraction, and particularly to a buprenorphine-containing patch useful for analgesia of pain associated with various cancers. .

[Prior art] In the development of medical products, at the same time as developing new compounds having excellent medicinal properties, the dosage form is designed to further enhance the effects of these new compounds and compounds already used as medical products. Various studies have been conducted to change the dosage form and optimize the dosage form.

For example, for the purpose of prolonging 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 is effective at a concentration above the minimum effective concentration and below the maximum safe concentration, that is, the effective blood concentration decreases. Development of so-called sustained-release preparations, in which the components are absorbed by the human body over a long period of time, is being actively conducted.

Examples of sustained-release preparations include preparations for percutaneous absorption such as difficult flight and spray application. 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.

As a remedy for such drawbacks, there are tapes and patches prepared by incorporating a certain amount of a drug into an adhesive and molding it into a certain size (for example, JP-A-47-116011 and JP-A-58-134020).
(See the official gazette).

The method using a tape or patch can solve many problems caused by methods such as ointment and spray application.

It is also known that when a drug is administered transdermally, the rate of so-called hepatic metabolism, in which the drug is metabolized in the liver and loses its efficacy, can be significantly reduced compared to when it is orally administered. Tapes and patches (hereinafter referred to as patches) are excellent drug administration forms when the drug has a 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.

Of these problems, the most frequent occurrence is skin irritation occurring at the application site of the patient to whom the patch is applied. 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 variability in blood drug concentration. Factors of blood concentration fluctuation are factors on the patch side, factors on the human skin side,
Since it is complicated with factors such as human metabolic function, it is not easy to stabilize the drug blood concentration.

Another issue relates to handleability. That is,
In order to reduce skin rash on the patch, the skin of the patch can be reduced to some extent by making the patch support as thin as possible, making it more flexible, and making the patch smaller.
There is also a problem that it is very difficult to correctly apply the patch to a predetermined position on 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.

On the other hand, menopause, which is often observed in postmenopausal women, osteoporosis, reduction of estrogen associated with menopause as a cause of Alzheimer's dementia, etc. is regarded as important, and estradiol, estriol and their derivatives are mainly oral agents, It is clinically applied as an injection.

However, since the use of estrogen has side effects such as an increase in endometrial cancer when it is heavily used, the bioavailability (BA) is increased as much as possible with the minimum necessary dose, and the drug concentration in blood is high. Is desired to be maintained stably.

Among various clinically applied estrogen, estradiol is one of the so-called natural estrogen that is originally synthesized and used in the body, and is used as a drug because of its high pharmacological activity and safety. Though considered the most suitable estrogen to do, it is rarely used. The reason for this is that when estradiol is orally administered, it is rapidly metabolized in the digestive tract and liver, resulting in a low BA. A large amount of estradiol must be administered to maintain the required blood concentration of the drug, but in that case, it means that a large amount of harmful metabolites are simultaneously produced in the blood, which is not preferable.

By transdermal administration, estradiol can significantly improve BA and maintain a stable drug blood concentration.

It is known that estradiol and its esters and other derivatives are percutaneously absorbed, and JP-B-46-5427 discloses.
It is disclosed in JP-A-57-154122. In particular, the patch shown in JP-A-57-154122 is excellent in improving BA and stabilizing the drug blood concentration. However, estradiol-containing patches supplement the decrease in estrogen that occurs with menopause, and the treatment period extends from several months to several years. Therefore, 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.

As described above, in the prior art, in the case of an oral preparation having relatively high patient compliance, BA is low, side effects are serious, BA is high, and drug concentration in blood is stable. There was a problem in that the type patch had an uncomfortable feeling and skin irritation occurred.

In order to improve the discomfort, 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. In addition, the size of the patch is proportional to the amount of drug absorbed, that is, the concentration in the blood of the drug, so if the required drug level in the blood is fixed, in order to reduce the size of the patch, some kind of drug Means for enhancing transdermal 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, but basically,
It is desirable to enhance the water vapor permeable 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.

In addition, 80% of end-stage cancer patients have unbearable pain,
It is said that 50 to 80% of them do not currently receive treatment for pain relief.

However, recently, it has been considered that end-stage cancer patients who have little prospect of treatment should spend the rest with their families at home, which is why administration is easy, there is sufficient effect, and there are few side effects. Development of analgesics is desired.

Generally, treatment of cancer pain is based on WHO's three-stage cancer pain ladder. In other words, when Itami occurs, first, the Hi-Apart analgesic is used, and if it is not sufficient, a weak-acting opiate narcotic is used, and if it does not work, a strong opiate-type analgesic is used. The intolerable pain experienced by end-stage patients with cancer is the second and third stages, and opiates are used as the drug therapy for this treatment.

The representative drug as a weak opiate narcotic is codeine, and the substitute drug for strong opiate narcotic is morphine. Whether it is weak or strong opiate is related to the strength of action, but various side effects are also considered. Side effects of opiate narcotics include nausea, vomiting, drowsiness, constipation, and confusion, and there are so-called drug resistance and addiction that are less effective during use. The fact is that even if the analgesic effect of is significant, there is no choice but to hesitate to start using it.

In order to solve the problem of opiate narcotics, attempts have been made for many years to chemically modify opiate narcotics to enhance their analgesic effect and reduce side effects.

One of the synthetic analgesics developed from such studies is buprenorphine. Buprenorphine is 25 of morphine
It is known that it has a 50-fold analgesic effect and few side effects such as mental disorders. Buprenorphine is marketed in Japan as an injection, and suppositories are being developed. It is also marketed as a sublingual tablet in foreign countries. Development studies as an ointment are also under way.

However, conventional preparations have problems that the number of administrations is large and pain recurs unless they are administered at an accurate time, and the administration method is complicated. Moreover, the conventional administration method causes large fluctuations in the blood concentration of the drug.

Buprenorphine is a preferred drug with fewer side effects than morphine, but side effects similar to morphine occur due to long-term continuous use.

Although the mechanism of occurrence of side effects is not clear, it is not preferable to increase blood concentration more than necessary because it is dose-dependent. Continuous use for a long time with blood levels higher than necessary not only increases the possibility of causing serious side effects, but also may induce serious side effects such as respiratory depression in the short term.

[Problems to be Solved by the Invention] Accordingly, the present invention eliminates the above-mentioned problems of the prior art, and is a highly safe, excellent sustained-release, easy-to-handle patch, and efficiently manufactures the same. The purpose is to provide a method of doing.

Still another object of the present invention is to provide patients with high BA, stable drug blood concentration, and remarkably improved discomfort and skin rash which are the drawbacks of conventional transdermal patches of nitrates. To provide a highly compliant patch containing a nitrate ester.

Another object of the present invention is to have a high BA, a stable blood concentration of the drug, and a significant improvement in patient discomfort and skin irritation, which are the drawbacks of the conventional estradiol transdermal patch, and high patient compliance. It is to provide an estradiol-containing patch.

Still another object of the present invention is to provide a buprenorphine preparation having a simple administration method and a stable drug blood concentration.

Other objects and advantages of the present invention will be apparent from the following description.

According to the invention, a water-impermeable or water-semipermeable film (a layer), one pressure-sensitive adhesive layer (b layer) laminated on one surface of the a layer, and an outer periphery on the b layer. Another pressure-sensitive adhesive layer (d) laminated via a knitted fabric (c-layer) having a basis weight of 10 to 100 g / m ² and consisting of hollow fibers having pores penetrating in the direction and containing substantially no drug therein. And a layer), and at least one of the b layer and the d layer contains an evaporative or non-evaporable drug.

[Means for Solving the Problems] As described above, in the first aspect of the present invention, a knitted fabric made of hollow fibers having a hole penetrating in the outer peripheral direction and containing substantially no drug, and an adhesive containing the drug The inventors have found that the object of the present invention can be achieved by using an agent layer and a water-impermeable or water-semipermeable film and skillfully utilizing them, and arrived at the present invention.

That is, in order to prevent skin irritation, which is the most problematic problem in the use of patches, at least the organic solvent used in the manufacturing process does not remain in the patch or / or hardly remains, and the skin irritation of the adhesive used is In addition to the small number, it is important that the application site does not become excessively stuffy, and it is necessary to adequately supply oxygen to the application site and to permeate carbon dioxide gas and ammonia gas generated at the application site due to skin physiology. Is. 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 and give a proper amount of stuffiness, and the object of the present invention is achieved here. There is difficulty in doing so.

The present inventors diligently studied the stuffy state in which skin rash occurs and the stuffy state required for percutaneous absorption of a drug, and as a result, the transdermal absorption of the drug saturates the stratum corneum of the application site skin. Even if the amount of stuffiness exceeds that of the water content (the excess water becomes droplets at the interface between the skin and the patch at this time), it does not become faster, and conversely, skin irritation causes the water content of the stratum corneum to reach the saturation point. We have found the fact that it will increase when it exceeds. From this, it is considered that the preferable sealing property as a patch is to keep the stratum corneum of the patch site skin always close to the saturated moisture content, and as a result of diligent study on the dosage form of the patch, the present invention Arrived

That is, the present invention relates to a water-impermeable or water-semipermeable film (a layer), one pressure-sensitive adhesive layer (b layer) laminated on one side of the film, and an outer peripheral direction on the b layer. Another pressure-sensitive adhesive layer (d layer) laminated via a knitted fabric (c layer) having a basis weight of 10 to 100 g / m ² and comprising hollow fibers having through holes and substantially containing no drug therein. ) And b
It is a patch comprising an evaporative or non-evaporable drug in at least one of the layer and the d layer. Surprisingly, by the patch of the present invention, even if the degree of skin sweating slightly changes depending on the external environment or the exercise state in which the patient to whom the patch is applied is placed, the moisture content of the skin stratum corneum at the application site is almost the same. We could keep the same value.

In order to prevent skin irritation, minimize the residual solvent in the patch, specifically, the residual amount of all the solvents used in the process of producing the patch is 100 ppm or less, preferably 50 ppm or less, relative to the weight of the adhesive. Is desirable. In the patch, most of these residual solvents remain when forming the pressure-sensitive adhesive layer from the pressure-sensitive adhesive solution, but as a method of reducing the residual solvent of the pressure-sensitive adhesive layer, a method by heating at high temperature, a vacuum under heating is used. A method of absorption, 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, if such a severe drying condition is adopted, it often causes a problem due to deterioration and decomposition of the drug, and when an evaporative drug is used as the drug, the drug is not heated at a high temperature. Since it evaporates, it is unavoidable to adopt mild conditions rather than ordinary drying conditions, and it is difficult to obtain a highly safe patch with less residual solvent.

The rate of escape of the residual solvent from the pressure-sensitive adhesive layer becomes extremely poor as the thickness of the pressure-sensitive adhesive layer increases, and becomes relatively easy when the thickness of the pressure-sensitive adhesive layer is small. Therefore, in the present invention, the adhesive layer containing the drug is composed of two adhesive layers.

 The method for producing the patch of the present invention will be described below.

The first method for producing a patch of the present invention is that a water-impermeable or water-semipermeable film (layer a) has one adhesive layer (layer b) and a hole penetrating in the outer peripheral direction on one side. A knitted fabric (c layer) having a basis weight of 10 to 100 g / m ² and another pressure-sensitive adhesive layer (d) layer, which are made of hollow fibers substantially containing no drug, are then placed in the order of a, b, c, d layers. So that it becomes
And a method for producing a patch comprising using an adhesive layer containing an evaporative or non-evaporable drug as at least one of the b layer and the d layer, and the second production method is (1) ) Water-impermeable or semi-permeable film (a
Layer), one pressure-sensitive adhesive layer (b layer) laminated on one side of the a layer and containing substantially no or / or a small amount of the evaporative drug, and penetrates the b layer in the outer circumferential direction. Of a knitted fabric (c-layer) having a basis weight of 10 to 100 g / m ² which is composed of hollow fibers having substantially no pores therein and vaporized on the surface of the c-layer. A drug solution obtained by dissolving a volatile drug in a volatile solvent is impregnated, and (2) the laminate is then heated in a state where the surface of the c layer is not in contact with air to evaporate in the knitted portion. The drug of b
And (3) after that, another adhesive layer (d layer) optionally containing the evaporative drug is laminated on the c layer, which is a method for producing a patch. The third production method is (1) is substantially free from a water-impermeable or water-semipermeable film (a layer) and an evaporative drug laminated on one surface of the a layer, or / One adhesive layer (b layer) contained in a small amount, and hollow fibers having a hole penetrating in the outer peripheral direction on the b layer and having substantially no drug therein, having a basis weight of 10 to 100 g / The surface of the c layer of the laminate in which the knitted fabric (c layer) of m ² is laminated is impregnated with a drug solution obtained by dissolving an evaporative drug in a volatile solvent, and (2) then the c layer Another pressure-sensitive adhesive layer (d layer) which may contain the evaporative drug is laminated on the above to obtain a laminated body, and (3) after that It is a method for producing a patch, which comprises heating the laminate to cause the evaporative drug in the knitted portion to migrate to the b layer and / or the d layer.

The d layer and the b layer may have the same thickness or may have different thicknesses. Since both layers are thinner than the total pressure-sensitive adhesive layer of the final patch, it is easy to reduce the residual solvent, and if you do not contain an evaporative drug, it is possible to apply harsh impression conditions. It is more easily possible to make it below, or below 50 ppm. Further, if necessary, it is possible to reduce the residual solvent by applying a suitable method such as vacuum suction, extraction and washing. As another method for reducing the residual solvent, two or more thinner pressure-sensitive adhesive layers prepared in advance may be laminated to form the d-layer and the b-layer.

The first manufacturing method of the present invention is specifically as follows, for example.

First, layer b is laminated on one surface of a water-impermeable or water-semipermeable film. The layer b is laminated, for example, by coating the film with a pressure-sensitive adhesive solution to form the layer b, or by pressure-bonding the film to one surface of the layer b which is separately manufactured. Thus, a laminate composed of the film and the b layer is obtained.

Then, on the layer b, a knitted fabric made of hollow fibers having a hole penetrating in the outer peripheral direction and containing substantially no drug is laminated by pressure bonding or the like.

Thereafter, the d layer is laminated on the knitted fabric by pressure bonding or the like (this is referred to as a patch original fabric). When the d-layer and the b-layer are pressure-bonded to the knitted fabric sequentially, as described above, a patch having a more stable shape can be obtained.
Three layers may be laminated simultaneously.

In the first manufacturing method of the present invention, the d layer and b used
The layer contains a vaporizable or non-evaporable drug in at least one of the layers.

The second and third methods for producing the patch of the present invention are specifically as follows.

(1) In any of the second and third production methods, first, a laminated body composed of a film in which the surface of a knitted fabric is impregnated with a drug solution, an adhesive layer, and a knitted hollow fiber is produced.

First, a layer b containing substantially no or a small amount of an evaporative drug is laminated on one surface of a water-impermeable or water-semipermeable film. The laminating method is, for example, by coating or press-bonding the b layer separately manufactured as described above. The amount of the drug in the layer b may be substantially absent or a small amount in consideration of the transfer of the drug due to the subsequent heating.

Next, on this layer b, a knitted fabric made of hollow fibers having a hole penetrating in the outer peripheral direction and containing substantially no drug is laminated by pressure bonding or the like to obtain a laminate comprising a film, a layer b, and a knitted fabric. (Hereinafter, referred to as a hollow fiber knit laminate).

On the other hand, a drug solution (hereinafter referred to as a drug solution) is prepared by dissolving the evaporative drug of the present invention in a volatile solvent such as acetone, methanol, ethanol or chloroform.

Next, the knitted surface of the above-mentioned hollow fiber knitted laminate is impregnated with a predetermined amount of the drug solution. The volatile solvent is removed, for example, if the laminate is left standing at room temperature, but it may be removed if necessary under conditions such as heating and cooling.

In order to obtain a patch containing the drug uniformly, it is desirable to uniformly impregnate the knitted fabric with the drug solution. Examples of such methods include a method of measuring the drug solution and dropping it, and a predetermined amount of the drug. A method of immersing a hollow fiber knitted laminate of a predetermined area in a solution, a state in which the hollow fiber knitted laminate is moved at a constant speed, and a drug solution is continuously measured by a known method using a small scale or a pump. Then, it is possible to employ a method of bringing the knitted fabric into contact with the knitted fabric for transfer, dropping, or spraying.

The hollow fiber knitted fabric laminate used for impregnating the drug solution in the second and third production methods of the present invention is a laminate of films as described above. Of course, it is also possible to impregnate the single layer of the knitted fabric without laminating the film. However, in the case of using a laminated film, despite the stretchability and flexibility of the knit, in this case, the film gives the patch a proper sealing property and drug escape prevention property. In addition to contributing to maintaining the regularity of the knitted fabric, it becomes easy to stably and uniformly impregnate the knitted fabric with the drug solution, which is suitable for industrial production.

Furthermore, in order to improve this uniformity, among knits made of hollow fibers described below as knits, warp knits and / or knits
Alternatively, a knitted fabric reinforced to maintain the regularity can be used.

Thus, a hollow fiber knitted fabric laminate impregnated with the drug solution is obtained.

(2) In the second production method of the present invention, the thus obtained laminate is then heated in a state where the surface of the knitted fabric is not in contact with air, and the drug in the knitted part is added to layer b. Then, the d layer which may contain the drug is laminated on the knitted fabric.

Here, with the surface of the knitted fabric not in contact with air,
Specifically, the intention is to make the drug not escape to the outside of the laminate. Examples of such a state include a roll state and a folded state such that the film is on the outer side and the knitted material is on the inner side, or a method of covering or wrapping the laminate is exemplified.

Above all, it is particularly preferable to produce the laminated body in the form of a long strip having a width of 80 to 1000 mm, and roll it up so that the film is on the outside and tightly wind it, because the drug hardly escapes.

The heating condition is preferably at a temperature of 40 to 80 ° C. for several hours to several days. By this heating, the drug in the knitted part is transferred to the b layer, and the b layer containing the evaporative drug and the hollow fiber knit substantially containing no drug are obtained.

By this heating, the layer b is usually saturated with the drug in 1 to 2 days, and the amount of the drug in the layer b does not increase even if the heating time is further prolonged. Of course, the degree of transfer to the layer b can be increased by adjusting the heating conditions according to the type of drug and raising the temperature, for example.

(3) On the knitted fabric of the laminate thus obtained, the d layer which may contain the evaporative drug is laminated by pressure bonding or the like to obtain a patch original fabric.

As described above, the patch original fabric obtained by the first to third production methods of the present invention is cut as necessary and then hermetically packaged to obtain a patch as a preparation. When it is desired to accelerate percutaneous absorption of the drug in the patch immediately after being applied to a patient and increase the rise in the drug blood concentration to accelerate the onset of the effect, the patch packaged in a hermetically sealed package depending on the degree is 40- Heat at a temperature of 80 ° C for several hours to several days. If this heating condition is close to the heating condition of the drug-impregnated knitted fabric laminate, d
The drug concentrations in layers and b are almost the same. Further, as the heating condition is relaxed, the initial drug concentration in the d layer becomes lower than the drug concentration in the b layer, the blood concentration rises slowly, and there is a tendency for more sustained release. Therefore, the production method of the present invention facilitated the design of a preferable sustained-release preparation.

Instead of cutting the patch original fabric and then sealing and packaging and then heating it, it is also possible to heat the patch original fabric and transfer the drug in the layer b to the necessary amount of the adhesive layer d. .

(2) ′ On the other hand, in the third production method of the present invention, the d layer which may contain the evaporative drug is laminated on the hollow fiber knitted layer body obtained in the above (1). A laminate is obtained, and (3) ′ is then heated to transfer the drug in the knitted portion to the b layer and / or the d layer. In this way, a patch original fabric is similarly obtained.

The heating conditions in this case are the same as those in the second manufacturing method described above. Instead of transferring the drug in the knitted part to the b layer and the d layer by heating to obtain a patch original fabric, after cutting the patch original fabric, it is hermetically packaged and then heat-treated to remove the drug in the knitted part. You may transfer to b layer and / or d layer.

According to the second and third production methods of the present invention, for example, the transition to the d layer is the final stage of the production process, so that the sustained release of the evaporative drug can be easily controlled. Further, when the d layer is laminated after the drug in the knitted portion is transferred to the b layer, there is an advantage that it is easy to laminate because it is not affected by the drug.

In the present invention, the contents of the drug contained in the d layer and the b layer may be different, and their compositions and additives may be different.

Further, in the present invention, when using the d layer and the b layer of a specific thickness, or when the knitted hollow fiber has a specific basis weight, the hollow fiber knitted fabric provided around the center of the obtained patch is A suitable degree of void is created, and the interaction between this void and the hollow fiber itself having a hole penetrating in the outer circumferential direction prevents excessive stuffiness of the application site, which is the purpose of the present invention, and ensures sufficient drug absorption. It is more preferable because it is possible to provide a patch having a sealing property that can be absorbed into.

Further, by adjusting the number of ropes of the knitted hollow fiber, the d layer and the b layer are brought into proper contact with each other. For example, even when the drug is not contained in the d layer, the drug is transferred to the b layer and is released slowly. It is preferable because the effect can be obtained.

The patch original fabric of the present invention is cut into an arbitrary size such as a circle, a square or a rectangle with an arbitrary size of 3 to 100 cm ² and packaged by a known method to prepare a medical patch. You can

It is essential that the hollow fiber used in the present invention has a hole penetrating in the outer peripheral direction. Here, as the hollow fibers having holes penetrating in the outer peripheral direction, scattered throughout the hollow fiber cross section,
Hollow fibers having fine pores arranged in the fiber axis direction and at least a part of which are continuous to the hollow portion are preferred.

The hollow fiber of the present invention may have any shape in the cross section and the shape of the hollow portion. For example, when the outer shape and the hollow portion are both substantially circular, either one of the outer shape and the hollow portion is substantially circular and the other is deformed, and the outer shape and the hollow portion are both similar or dissimilar. . Also,
There is no particular limitation on the size of the outer shape.

The thickness of such hollow fibers is preferably 0.2 to 20 denier in diameter, particularly 1 to 5 denier. If the thickness is 20 denier or more, skin irritation is too great. If it is less than 0.2 denier, it is difficult to handle and the absorption rate of the drug solution is low.

The hollow ratio of the hollow fiber of the present invention may be arbitrary, but especially 5%
The above is preferable, the porosity due to both the hollow rate and the holes penetrating in the outer peripheral direction, and the ratio to the fiber cross-sectional area are preferably 0.01 to 70% of the fiber cross-sectional area excluding the hollow portion, and particularly 0.01 to 50. %, More preferably 1 to 50%.

In the present invention, such hollow fibers need to be in the form of a knit. The knitted fabric may be composed mainly of the hollow fibers described above, and may have some fibers other than the hollow fibers mixed therein as long as the effect of the present invention is not impaired.

By the way, the form of the fiber is roughly classified into a woven fabric, a knitted fabric and a non-woven fabric, and a base material such as a gauze and a plaster which has been conventionally used for clothing is a woven fabric. It is considered that this is mainly because the woven fabric has good dimensional stability and is easy to handle. However, the fabric causes great skin irritation when used as a patch.
On the other hand, the knitted fabric has less skin irritation, and the thin knitted fabric has less irritation. Particularly, the knitted fabric made of hollow fibers having holes penetrating in the outer peripheral direction is extremely soft and hardly causes skin irritation. Surprisingly, when this knitted fabric is laminated with a film having a small elasticity and an appropriate thickness, the flexibility at the time of application is hardly lost. It is considered that this is because the delicate margin in the fiber structure of the knit absorbs external stress.

The basis weight of the hollow fiber knitted fabric of the present invention is 10 g / m ² or more and 100 g / m ^2.
2 or less. If the basis weight is too large, the resulting patch will have poor sealing properties and poor transdermal absorbability of the drug, which is not preferable. On the contrary, if the basis weight becomes too small, some problems will occur. That is, if the fabric weight is too small, it may be difficult to handle the knitted fabric, and if the fabric weight is too small, it may give an excessive sealing property.

The hollow fiber knitted fabric of the present invention has a 1 cm × 1 cm square frame with an open central portion, and when the loops of the knitted fabric are counted, the number of loops in the longitudinal direction and the number of loops in the lateral direction are 3 to 22 pieces / cm, respectively.
And a knitted fabric whose sum is 15 to 37 pieces / cm is preferable.

For the knitting structure, for example, "Knitting technique must-have"
(Japanese Society of Textile Machinery, August 10, 1982) can be referred to. Figure 6.2 on page 199 and section 4.1 on page 109
Figure 7 is shown in Figures 2 and 3. In FIG. 2, the numbers of loops in the vertical and horizontal directions are 7 and 5, respectively. Further, in FIG. 3, there are four in the vertical direction and six in the horizontal direction. In the case of Figs. 2 and 3, the actual number of loops per unit length is unknown because the actual dimensions are not described.
If the vertical and horizontal lengths of the figure are 0.5 x 0.5 cm, the sum of the number of loops is 24 / cm and 20 / cm, respectively.

In the present invention, when the total number of loops of the knitted fabric is 37 pieces / cm or more, in addition to the problem that the sealing property of the obtained patch is not sufficient, the stability of the formulation when the patch is applied to a patient for a long time The property deteriorates, and delamination occurs between the pressure-sensitive adhesive layer and the knitted fabric.

Particularly preferably, the sum of the number of loops is 26 / cm or less. If the total number of loops is less than 15 / cm, the layer b jumps out of the knit when the basis weight of the knit is relatively small, and the sticking-out adhesive when handling the laminate sticks to facilities and workers, which is not preferable. Also, when the basis weight of the knitted fabric is relatively large, the voids around the hollow fiber knitted fabric in the patch become too large and the sealing property as the patch becomes insufficient. Even if the number of loops is the same, the unit weight can be freely changed by changing the number of hollow fibers used to make one loop, but in the present invention, the unit weight is preferably 10 to 100 g / m ² , and the number of loops is Sum of 1
5 to 37 pieces / cm is preferable, and particularly preferably, the basis weight is 20 to 60 g /
m ² and the sum of the number of loops is 15 to 26 / cm. In particular, the knitted fabric obtained by stretching the hollow fiber knitted fabric so that the number of the longitudinal loops is not the same and the number of the longitudinal loops is 1.5 times or more the number of the lateral loops is used. The handleability of the hollow fiber knitted fabric is improved step by step, and a patch having stable quality and excellent sustained release can be obtained.

Examples of the material of the hollow fiber used in 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, polyvinyl chloride,
Any material such as polyvinyl acetate can be selected. Among these, polyester is preferable, and polyethylene terephthalate is particularly safe for humans,
It is preferable because it has excellent stability against heat, light and temperature, has no interaction with a drug, and is not easily modified by the solvent used when the hollow fiber is impregnated with the drug solution.

Hollow fibers used in the present invention include, for example, JP-A-56-20612.
It can be produced by the methods described in JP-A Nos. 56-20613 and 56-43420.

In the present invention, the hollow fibers can be used in combination of a plurality of materials having different shapes and different hollow fibers.

In the present invention, the evaporative drug refers to a drug that has an evaporative property when applied to the human body. Therefore, it may be a solid that is originally evaporated when it is sublimated, or a liquid that is originally liquid and evaporates from that state. Typical examples of such a drug include nitrates such as isosorbide dinitrate and nitroglycerin, but guaiazulene, menthol, camphor and salicylates such as methyl salicylate can also be exemplified. The amount of drug used is
It is appropriately determined depending on the strength of the pharmacological action of the drug used, absorbability into the skin, etc.
It is 0% by weight. The total amount is the solid content of the pressure-sensitive adhesive excluding the solvent and the like. 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. When the drug is a nitrate ester, the content is more preferably 8 to 18% by weight. Further, as the method for producing a patch containing a nitrate ester, the second and third production methods, among which the third production method is particularly preferable. Is preferred.

A non-evaporable drug can also be used as the drug in the present invention. In the present invention, the non-evaporable drug refers to a drug having almost no evaporative property when applied to the human body. Among such drugs, transdermally absorbable drugs are preferable.

Examples of such drugs include hormones such as estradiol, progesterone and its derivatives; analgesics such as morphine, buprenorphine and its derivatives; heart disease drugs such as clonidine and nifedipine. However, it is not limited to these as long as they are non-evaporable, especially non-evaporable and transdermally absorbable drugs. 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., but is usually 0.1 to 20% by weight based on 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.

As the pressure-sensitive adhesive used in the present invention, a normal pressure-sensitive adhesive is used, for example, silicone rubber, polyisoprene rubber, styrene-butadiene copolymer rubber, acrylic rubber,
Rubber-based viscous composition containing natural rubber as a main component; vinyl-based viscous composition such as polyvinyl alcohol, ethylene-vinyl acetate copolymer, mainly silicone adhesive, polyurethane elastic body, polyester elastic body, polybutadiene elastic body, etc. A viscous composition as a component; it can be selected from acrylic resins and the like. 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. At least 80 to 98 mol% of (meth) acrylic acid alkyl ester,
(2) An acrylic resin obtained by copolymerizing 2 to 20 mol% of acrylic acid and / or methacrylic acid 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, hexyl (meth) acrylate, heptyl (meth) acrylate, octyl (meth).
Examples thereof include 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.

In the present invention, these pressure-sensitive adhesives may be combined depending on the kind of drug, for example, a pressure-sensitive adhesive having a high compatibility is used for the b layer, and the compatibility with the drug is not so high in the d layer. As a combination of using an adhesive having low skin irritation, a patch having low skin irritation and excellent sustained release can be obtained.

The preferred thickness of each of the d layer and the b layer of the present invention is 5
~ 100 μm. 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 50 μm or less. On the contrary, when the pressure-sensitive adhesive layer becomes thin, the adhesion to human skin also decreases, the adhesion to the knitting layer and the film layer also decreases, and the stability during use of the patch decreases, so that the thickness of the adhesive layer is 5 μm or more, and particularly preferable thickness of the adhesive layer. Is 10 μm or more. Regarding the relationship between the b layer and the d layer, the former is 10 to 50 μm.
The latter preferably has a thickness of 10 to 100 μm and the layer b is thin.

As the film used for the patch of the present invention, it is preferable to satisfy the requirements that the escape of the drug is prevented, the adhesion to the skin is not reduced, and the skin does not feel uncomfortable when attached to the skin, such as polyethylene and polypropylene. Polyolefins; polyesters such as polyethylene terephthalate; polyamides such as nylon 6 and nylon 66; films of polyvinyl alcohol, vinylidene chloride, polyurethane, ethylene-vinyl acetate copolymer, rubber and the like can be used. These films may be used alone, or may be compounded or laminated.

Among these films, ultrathin polyethylene terephthalate having a thickness of 4.9 μm or less is particularly preferable because it has good stability to heat and light and does not adsorb a drug or interact with a drug (hereinafter, the film according to the present invention will be described. Is called a backing film).

Further, in the present invention, a release sheet may be provided on the pressure-sensitive adhesive layer. The release sheet may be one normally used, and examples thereof include paper having a surface coated with a release layer.

When the patch of the present invention contains estradiol or a derivative thereof as a drug, it is preferable that 0.5 to 5% by weight of estradiol or a derivative thereof is contained in the acrylic pressure-sensitive adhesive layer.

Such an estradiol or a derivative thereof means a natural type estrogen, a synthetic estrogen and a derivative thereof, and examples thereof include estradiol, estradiol benzoate, estradiol dipropionate, estradiol valerate, ethinyl estradiol, etc. In, these estradiol
Referred to as E _2).

The concentration of E _{2 in} the acrylic adhesive layer is the last obtained E ₂
It is an important factor for the transdermal absorbability of the contained patch, and if it is less than 0.5% by weight, it is difficult to obtain a sufficiently high transdermal absorbability.
Percutaneous absorption increases almost proportionally as the concentration increases above 0.5% by weight. However, when the concentration is more than 10% by weight, the transdermal absorbability hardly increases, but rather the crystallization of E ₂ in the pressure-sensitive adhesive layer becomes prominent, and as a result, the transdermal absorbability tends to decrease. Yes, so 10% by weight
If it is larger, the transdermal absorbability is low, and the adhesive strength of the obtained preparation is insufficient, which is not preferable. Above all 1 to 5
A concentration of wt% is preferred.

Moreover, the present inventors have found that transdermal absorbability is obtained even when a patch having an E ₂ concentration in the pressure-sensitive adhesive layer of 0.5 to 5% by weight is stored as a packaging form of a known patch such as an aluminum bag. However, I have often experienced that the transdermal absorbability fluctuates significantly, and the more serious problem is that it is still insufficient.

As a result of intensive studies on means for enhancing the transdermal absorbability of E ₂ and preventing such aging, the present inventors have first found that the crystallization of E ₂ significantly changes depending on the humidity of the outside air. We have diligently studied ways to prevent this. as a result,
(1) The equilibrium moisture content of the acrylic adhesive changes depending on the temperature and humidity, but is 0.7 to 1.5% under normal room temperature conditions.
In addition, a small amount of water may be used as part of the process for producing an acrylic pressure-sensitive adhesive, in which case the drying conditions when applying the acrylic pressure-sensitive adhesive and drying to obtain a pressure-sensitive adhesive layer are relaxed. It was found that the water content in the obtained pressure-sensitive adhesive layer may exceed 20%. As long as the adhesive layer having such a moisture content is used, even if the obtained patch is double-folded or triple-moisture-proof packaged in aluminum packaging or the like, it is not possible to prevent E ₂ from being made into cosmetics. If the difference is different, the degree of crystallization and the rate differ depending on the degree, which causes variations in percutaneous absorption.

In the present invention, the water content in the pressure-sensitive adhesive layer can be lowered to 0.5% by weight or less to prevent crystallization of E ₂ from occurring, and the concentration of E _{2 in} the pressure-sensitive adhesive layer is also 5% by weight. Hereafter, it was made possible to reduce the content to 3.5% by weight or less, and it became possible to prevent the crystals from precipitating from the patch and the change in absorbency occurring with time.

However, when the concentration of E ₂ is 0.5% by weight or less, the transdermal absorbability becomes extremely low, and it becomes difficult to exert a medicinal effect.

Therefore E ₂ concentration in the present invention is 0.5 to 5 wt%, water content is to employ a 0.5 wt% or less, preferably E ₂
When the concentration (% by weight) is expressed by C _E and the water content (% by weight) is C _W , it is extremely important to use the water content expressed by C _W 0.6-0.1 × C _E (where C _W is 0.5 or less). A stable patch can be obtained.

The adhesive layer of the patch of the present invention has a water content of 0.5% by weight.
As the following method, in the drying step for producing the acrylic pressure-sensitive adhesive layer containing estradiol used in the present invention, the moisture content in the pressure-sensitive adhesive layer is adjusted to 0.5% by weight or less over a sufficient temperature and time. After that, in order to avoid moisture absorption, a method of quickly formulating and packaging in a moisture-proof bag such as an aluminum bag, or packaging in a moisture-proof bag such as an aluminum bag in a moisture-proof environment; once an adhesive obtained by a usual method The layer as it is or after processing, in a dehumidified environment, under mild heating of 40 ~ 80 ° C., or after reducing the water content to 0.5 wt% or less under reduced pressure,
A method of packaging in a moisture-proof bag such as an aluminum bag; after the formulated patch has a moisture content of 0.5% by weight or less under a dehumidified environment, under mild heating at 40 to 80 ° C, or under reduced pressure, A method of packaging in a moisture-proof bag such as an aluminum bag; a method of storing the formulated patch with a known desiccant such as silica gel, alumina, or a phosphorus compound in a moisture-proof bag such as an aluminum bag or a box can be adopted. When the above-mentioned methods, and are adopted, the water content in water is set to 0.5% by weight or less at the time of manufacture, but the medical patch is exposed to various temperature and humidity and stress, and therefore, it is slightly Permeability easily occurs and quality variation easily occurs.

As the moisture-proof packaging material, as is well known, is aluminum foil or a plastic packaging material on which aluminum is vapor-deposited, and as the plastic, Teflon, polyvinylidene chloride, polyethylene, high density polyethylene, polyisobutylene, butyl rubber, hydrochloric acid rubber or the like is preferable. According to the results of the study by the present inventors, the thickness of the aluminum foil or aluminum vapor-deposited used here was important. The packaging material is usually designed in consideration of economy in addition to its beautiful appearance and touch, and the thickness of aluminum is often 7 μm or less, but for the purpose of the present invention, the thickness of aluminum is 8 μm or more, more preferably 9 μm or more. It was good. Another form of moisture-proof packaging is tin packaging, but it is not recommended because it is inconvenient to carry and economically problematic.

The cause of skin irritation at the application site due to the patch is also the residual solvent remaining in the adhesive layer. That is, it is known that various organic solvents used for forming the pressure-sensitive adhesive layer remain in the obtained pressure-sensitive adhesive layer, but adjustment of the amount of the resident solvent is important for reducing skin rash. In the study by the present inventors, in order to significantly reduce skin rash, the amount of this residual solvent is 100 ppm or less with respect to the pressure-sensitive adhesive, preferably 50 ppm or less, but the water content of the present invention is reduced. It is preferable to use the above-mentioned methods for reducing the residual solvent at the same time.

In the acrylic pressure-sensitive adhesive layer containing E ₂ of the present invention,
It is desirable to use polyvinylpyrrolidone. That is,
Even if the E ₂ concentration in the acrylic pressure-sensitive adhesive layer is set to about 3% by weight, at which the transdermal absorbability is almost optimal, the transdermal absorbability may be insufficient. This is because E ₂ may be crystallized and deposited in the layer, which may change the transdermal absorbability. The present inventors have increased the transdermal absorbability of E ₂ , as a result of diligent study on means for preventing such a time-dependent change, polyvinylpyrrolidone 0.
It has been found that the inclusion of 5 to 15% by weight is effective.

The polyvinylpyrrolidone of the present invention has a molecular weight of about 100,00.
It means a polymer of 0 or more N-vinyl-2-pyrrolidone (hereinafter, abbreviated as PVP in the present invention).

When the degree of polymerization of PVP is smaller than this, when PVP is dissolved in a so-called dope (which is prepared by dissolving the adhesive in an organic solvent) to form an acrylic adhesive layer, the dope gels and the adhesive of uniform thickness is formed. It is difficult to make a layer, and the gel-like PVP in the resulting acrylic adhesive layer
Are present in large numbers as spots, and the effect of promoting transdermal absorption of E ₂ tends to be small.

The PVP of the present invention is included in the scope of the present invention as long as the effects of the present invention can be obtained even if a small amount of another monomer or polymer other than PVP is copolymerized.

Such PVP is for the adhesive in the acrylic adhesive layer
It is preferable to contain 0.5 to 15% by weight. If it exceeds 15% by weight, the adhesive force of the obtained pressure-sensitive adhesive layer tends to be insufficient. If it is less than 0.5% by weight, it is difficult to obtain a sufficient effect of promoting percutaneous absorption and an effect of preventing crystallization of E ₂ .

The effect of promoting transdermal absorption and the effect of preventing crystallization of E ₂ , that is, the effect of improving stability over time, are not related to the E ₂ concentration in the adhesive layer, but the higher the concentration of PVP, the greater the effect obtained. There is a tendency. When it is 10% by weight or more, the increasing tendency is small, and the preferable range is 0.5 to 5% by weight.

In the estradiol-containing patch of the present invention containing PVP in the adhesive layer, by incorporating a specific amount of PVP,
_Although crystallization of ₂ was prevented and excellent transdermal absorbability was obtained, the present inventors further found that by keeping the water content in this patch low below a certain level, stable patching for a longer period of time was achieved. It was found that a drug can be obtained.

Therefore, in the adhesive patch of the present invention, the water content in the adhesive patch is 1% by weight or less, preferably 0.7% with respect to the adhesive patch.
It is preferably not more than weight%. The moisture content of such a predetermined amount is made by controlling the drying temperature, time, etc. during the production of the patch, but in order to maintain it for a long period of time, the moisture content of the patch is 0.2% by weight or less. It is possible to obtain the water content of 1% by weight or less by producing the above-described product and sealing it in a moisture-proof packaging material so as to be in a dry state.

In such a case, interposing a desiccant such as silica gel is also effective.

In order for such a preparation of the present invention to give sufficient transdermal absorbability, the water content in the preparation is 0 when the preparation is applied to a patient.
It is desirable that the hermeticity is maintained at 9% or more, preferably 1.0% or more.

In the present invention, the E ₂ and the acrylic pressure-sensitive adhesive are mixed in the presence of a solvent, preferably containing PVP in this way, and the obtained acrylic pressure-sensitive adhesive dope is applied by a usual coating machine and dried. , Preferably 5 to 100 μm in thickness, excluding solvent, to have a prescribed water content
Then, an acrylic pressure-sensitive adhesive layer containing E ₂ is obtained.

Using the acrylic pressure-sensitive adhesive layer containing E ₂ thus obtained, according to the first production method described above,
Provided is an estradiol patch base material comprising an acrylic pressure-sensitive adhesive layer containing E ₂ .

Such an original patch material can be used as an E ₂ -containing adhesive agent by cutting it into an appropriate size and shape as described above.

In the patch containing the buprenorphine of the present invention, the administration method is simple in view of the above-mentioned drawbacks of the prior art,
Further, there is provided a preparation for administering buprenorphine in a highly safe manner with a stable drug blood concentration.

The buprenorphine of the present invention refers to free buprenorphine or a pharmaceutically acceptable salt of buprenorphine such as buprenorphine hydrochloride. Hereinafter, in the present invention, such buprenorphine is abbreviated as BN.

In the present invention, it is preferable that BN is contained in the adhesive in an amount of 1 to 20% by weight, more preferably 5 to 15% by weight, based on the total amount of the adhesive.

In general, the higher the drug concentration in the adhesive, the higher the drug release from the patch. However, in the case of BN, when the content in the pressure-sensitive adhesive is 1 to 10% by weight, the BN releasing property increases, but when it exceeds about 10% by weight, the BN releasing property decreases conversely. Especially when the content is less than 1% by weight or more than 20% by weight, in the former case, the area of application of the preparation for obtaining the blood concentration of BN in humans, which causes sufficient drug efficacy, becomes large, and in the latter case, skin irritation increases. In addition, the adhesiveness of buprenorphine is reduced due to crystallization, etc., and the superiority of BN over other administration forms is easily diminished.

On the other hand, the size of the patch is preferably about 100 cm ² or less in order to keep skin irritation small. Also, there is a problem with an extremely small preparation from the viewpoint of handling of the preparation, and the preferable size of the patch is 3 cm ² or more. It is preferably 20 to 100 cm ² .

In the patch of the present invention, two pressure-sensitive adhesive layers, d layer and b layer, are used as the pressure-sensitive adhesive layer, but BN is contained only in the d layer, or BN is contained in the d layer at a higher concentration than in the b layer. By doing so, it becomes possible to reduce the amount of BN used in the patch, and it is possible to provide a BN patch with few side effects even after long-term continuous use.

Examples of the method for producing the BN-containing patch of the present invention include the above-mentioned first production method.

The thickness of each pressure-sensitive adhesive layer of the present invention is preferably 10 to 100 μm. When the thickness of the pressure-sensitive adhesive layer becomes large, it becomes difficult to remove the solvent used when forming the pressure-sensitive adhesive layer, which causes a problem of residual solvent. That is, such residual solvent is a major cause of skin irritation, for example, skin rash. If the pressure-sensitive adhesive layer becomes too thick, the amount of the pressure-sensitive adhesive layer exposed on the cut surface of the obtained patch will increase, and external foreign matter will adhere to the patch when it is applied for a long time, resulting in a black and dirty state, which is unfriendly to the patient. It makes you feel good. The preferable thickness is 100 μm or less.
On the other hand, when the pressure-sensitive adhesive layer is smaller than 15 μm, the adhesive force to human skin is significantly reduced, and when it is 10 μm or less, it is difficult to stably adhere to human skin for a long time. A particularly preferable thickness is 10 to 60 μm.

As a method of reducing the residual solvent, it is generally performed to enhance the drying at the time of forming the pressure-sensitive adhesive layer, that is, to increase the drying temperature × the drying time, but in the case of BN, the thermal stability of BN is poor, so the drying temperature is low. It is not preferable to increase the. In order to make it easier for residual solvent to volatilize, the adhesive layer is 10-60 μm
It is preferable to reduce the thickness to m.

The total BN content in the patch is also important. The total BN content in the present invention refers to the total amount of the patch, and a total BN content of 0.6 mg or more is preferable in order to exert a pain-relieving effect in humans by sustained release for a sufficiently long time. On the other hand, the amount of 30 mg or more is not preferable from the viewpoint of safety and cost such as overdose. A particularly preferred range is 1 to 15 mg.

BN is a drug with a small clinical dose, and it is a drug that is relatively easily transdermally absorbed from the viewpoint of its dose. In particular, the free form, which is not a salt, is easily transdermally absorbed. It is thought that it can be achieved.

However, when this patch is used for pain relief especially in terminal cancer patients, it is always used and the period is a long period of several years, so it is smaller and sufficient as a patch. It must be a patch that gives a high blood level so that pain can be obtained.

 Therefore, an absorption enhancer may be used in the patch of the present invention.
Is also desirable. Examples of such absorption promoters include (1) polyoxyethylene hydrogenated castor oil 10 (hereinafter poly
Oxyethylene hydrogenated castor oil is abbreviated as HCO), HCO-4
0, HCO-50, HCO-60, Polysorbate 40 (hereinafter Polysol
Twin beets Abbreviated), twin ,twin -65,
twin -80, sorbitan trioleate, polyoxy
Ethylene (160) Polyoxypropylene (30) Glyco
Solubitan monostearate, sol monopalmitate
Bitan, sorbitan monolaurate, monostearic acid
Glycerin, sodium lauryl sulfate, lauromacrog
, Sorbitan sesquioleate, benzalkoni chloride
Non-ionic surfactants such as um and benzethonium chloride,
Amphoteric surfactant, anionic surfactant, cationic field
Surfactants such as surface active agents; (2) monoethanolamine, diethanolamine,
Triethanolamine, diisopropanolamine,
Amines such as lysopropanolamine; (3) Sodium hydroxide, potassium hydroxide, potassium hydroxide
Inorganic alkalization of lucium, sodium hydrogen carbonate, etc.
Compound; (4) Polyvinylpyrrolidone, propylene glycol
, Benzyl alcohol, menthol, isosorbi nitrate
Do, dodecylazacycloheptan-2-one, ethanol
There are such as Le.

It is preferable to use such an absorption promoter in an amount of 0.1 to 5% by weight based on the pressure-sensitive adhesive. If it is less than 0.1% by weight, a sufficient absorption promoting effect cannot be obtained, and if it exceeds 5% by weight, the adhesive force of the obtained patch tends to be lowered. Such absorption promoters may be used alone or in combination of two or more.

Of these absorption promoters, amines and / or inorganic alkaline compounds are particularly effective when BN is a hydrochloride of buprenorphine and is used in an amount of equimolar or less with respect to buprenorphine hydrochloride. When ethanol is used as an absorption enhancer, a transdermal absorption amount of BN can be controlled by providing an ethanol reservoir in the patch and making the dosage form such that ethanol is released from the reservoir at an almost constant rate. .

The patch of the present invention containing BN obtained as described above is excellent in handleability, and a stable BN blood concentration is obtained.
It is a highly safe patch.

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

As the absorption enhancer 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 disulphonate,
Surfactants such as dioctyl sulfosuccinate, ammonium polyoxyalkylphenyl ether sulfate; 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, ethyl laurate, methyl nicotinate, sorbitol and dodecylpyrrolidone, pyrrolidone derivatives such as methylpyrrolidone, olive oil, castor oil, liquid paraffin, Vaseline, gelatin, amino acid, benzyl nicotinate, l-
Menthol, camphor, dodecylazacycloheptan-2-one and the like can be used.

It is preferable that such a diffusion aid is put in a drug solution together with an evaporative drug and impregnated into the hollow fiber knitted laminate, since the transferability can be enhanced even in the case of a drug having insufficient transferability to adhesiveness.

As the 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, powder of synthetic resin such as polyethylene, polypropylene, polyester, polystyrene and Examples include molded products.

[Industrial Applicability] As described above, the patch according to the present invention has a pressure-sensitive adhesive layer (b layer and d layer) containing an evaporative or non-evaporable drug in at least one of the layers. A knitted fabric (c layer) having a unit weight of 10 to 100 g / m ² and having hollow holes penetrating in the outer peripheral direction between the hollow fibers and containing substantially no drug therein.
Since the patch is formed by providing the patch, when the patch is applied to the skin, it gives moderate roughness to the patch site but prevents excessive stuffiness, and thus has the desired transdermal absorbability (sustained release) and It can be used as a patch for transdermal administration in which the occurrence of skin rash is significantly prevented. Further, the patch according to the present invention is a very flexible patch itself because it uses a specific knitted fabric made of hollow fibers, there is almost no skin irritation, and while maintaining the necessary sealing property, residual solvent is It will be widely used as a patch that has few and excellent handleability and enhances safety.

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

(I) Water absorption rate test method (according to JIS-L 1018) A fiber is formed into a knitted fabric, and this knitted fabric is washed with a 0.3% aqueous solution of anionic detergent sub (manufactured by Kao Soap Co., Ltd.) at 40 ° C. for 30 minutes by a household electric washing machine Wash the sample for a predetermined number of times, then dry it and stretch the sample horizontally, and drop one drop (0.04 cc) from the height of 1 cm above the sample, and the water will be completely absorbed by the sample and no reflected light will be observed. Measure time until.

(Ii) Method of measuring water absorption rate A sample obtained by drying a knitted fabric is immersed in water for 30 minutes or more, and then dehydrated for 5 minutes with a dehydrator of a domestic electric washing machine. It was calculated from the weight of the dried sample and the weight of the sample after dehydration by the following formula.

(Iii) Method for measuring isosorbide dinitrate in blood After separating plasma from 3 ml of collected blood, extraction with 4 ml of N-hexane and concentration, and addition of ethyl acetate to 100 μl
And quantified by GC-ECD.

(Iv) BN blood concentration measurement method After separating plasma from 1 ml of collected blood, the literature (Journ
Al-Chromatography, 338 (1985) 89-98), and the amount was determined by the GC-MS method.

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

(1) Hollow fiber sample (1) Dimethyl terephthalate 297 parts, ethylene glycol 265
Parts, sodium 3,5-di (carbomethoxy) benzenesulfonate 53 parts (11.7 mol% based on dimethyl terephthalate), manganese acetate tetrahydrate 0.084 parts and sodium acetate trihydrate 1.22 parts Put in a flask, carry out transesterification reaction according to a conventional method, after the theoretical amount of methanol was distilled off, put the reaction product in a flask for polycondensation with a rectifying column, and 0.090 parts of a 56% aqueous solution of orthophosphoric acid as a stabilizer and 0.135 parts of antimony trioxide was added as a polycondensation catalyst at a temperature of 2
The reaction was carried out at 75 ° C. under normal pressure for 20 minutes and under reduced pressure of 30 mmHg for 15 minutes, and then under high vacuum for 100 minutes. Final internal pressure is 0.39mmHg
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 with an intrinsic viscosity of 0.640
After mixing for 5 minutes in a mixer (manufactured by Hosokawa Iron Works), after drying in a nitrogen stream at 110 ° C for 2 hours and further at 150 ° C for 7 hours, melt kneading at 285 ° C using a twin-screw extruder. And made into chips. This chip had an intrinsic viscosity of 0.535 and a softening point of 261 ° C.

The chips are dried by a conventional method, and the width of the spinneret is 0.05 m.
A hollow fiber with a circular slit of m and a diameter of 0.6 mm, which has two circular arc openings that are closed at two points, is spun according to a conventional method, and the ratio of the outer diameter to the inner diameter is 2: 1. %)made. This yarn is 300 denier / 24 filament, and this yarn is drawn at a draw ratio of 4.2 times according to a conventional method.
A multifilament of denier / 24 filament was obtained. This multifilament is knitted into a knitted fabric, refined by a conventional method, dried, and then treated with a 1% aqueous solution of caustic soda for 2 hours at a boiling temperature to obtain an alkali weight loss rate of 15%, a water absorption rate of 3 seconds, and a water absorption rate of 80%. I got a knit. 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 38 g / m ² . The number of loops in the longitudinal and transverse directions of this knitted fabric was 7 / cm and 14 / cm, respectively.

The obtained hollow fiber was a hollow fiber having fine pores scattered all over the cross section of the hollow fiber and arranged in the fiber direction, and at least a part of the hollow fiber communicates with 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.
The knitted fabric has a water absorption rate of 0% for 38 seconds. The basis weight of the knitted fabric obtained by heat setting in the same manner as in the case of the hollow fiber sample (1) is 45.
a g / cm ^2, the sum of the number of loops is the same as hollow sample (1).

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

(3) Adhesive solution (1) 2-ethylhexyl acrylate 97.4 parts, methacrylic acid 2.5 parts, polyethylene glycol (degree of polymerization 14) dimethacrylate 0.1 parts, benzoyl peroxide 1.0 part and ethyl acetate 100 parts are refluxed and stirred. Polymerization was continued for 9 hours while charging in a reaction vessel equipped with a machine and slowly expanding sales at 60 ° C. under 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%.

Example 1-1 After adding 13 parts of isosorbide dinitrate (ISDN) to 500 parts of the pressure-sensitive adhesive solution (1) having a solid content of 20%, the thickness of the pressure-sensitive adhesive layer after drying was applied onto the silicone-coated release film. 20
It was coated so as to have a thickness of μm and dried at 70 ° C. for 2 minutes and 110 ° C. for 3 minutes. The residual amount of ethyl acetate in the obtained adhesive layer is 49 pp.
m, ISDN pigment was 2.4 g / m ² . The pressure-sensitive adhesive layer containing the ISDN is divided into three, and three pressure-sensitive adhesive layers having the same composition (this are referred to as pressure-sensitive adhesive layer d1, pressure-sensitive adhesive layer d2, and pressure-sensitive adhesive layer b)
I got

Next, a 3.5 μm thick film of polyethylene terephthalate (a in FIG. 1) was pressure-bonded to one surface of the pressure-sensitive adhesive layer b. Next, the hollow fiber sample (1) (c in FIG. 1) was pressure-bonded to the free surface of the pressure-sensitive adhesive layer b. The pressure-sensitive adhesive layer d1 is pressure-bonded to the free surface of the hollow fiber sample (1), and the pressure-sensitive adhesive layer d2 is pressure-bonded to the free surface of the pressure-sensitive adhesive layer d1 to obtain ISDN of 8.4 g / An original patch material containing m ² and having a residual solvent of 45 ppm was obtained.

The thickness of the adhesive layer on the backing film side of this patch is 20
μm (b in FIG. 1), and the thickness of the adhesive layer on the human skin side was 40 μm (d in FIG. 1).

The patch original fabric was cut into 2 cm × 2 cm, attached to the back of a dehaired latch having a body weight of about 180 g, and blood was collected at a predetermined time to measure ISDN in plasma. The results are shown in Table 1-1.

Comparative Example 1-1 After adding 16 parts of ISDN to 500 parts of a pressure-sensitive adhesive solution having a solid content of 20%, it was coated on a silicone-coated release film so that the thickness of the pressure-sensitive adhesive layer after drying would be 60 μm. Then
It was dried at 70 ° C. for 1 minute and 90 ° C. for 3 minutes.

The remaining amount of ethyl acetate in the obtained adhesive is 153 ppm,
The ISDN content was 8.7 g / m ² . Drying temperature was 90 ° C for 1 minute and 130 ° C for 3 minutes to reduce the residual amount of ethyl acetate.
When the time was taken as minutes, the ISDN content was 8.1 g / m ² . The residual ethyl acetate at this time was 79 ppm.

A 3.5 μm-thick polyethylene terephthalate film was pressure-bonded to one surface of the pressure-sensitive adhesive, and then cut into a size of 2 cm × 2 cm, and a rat sticking test was conducted in the same manner as in Example 1.

The results are shown in Table 1-1. The formulation looked like a flaky film and was very difficult to handle.

Further, obvious erythema was observed on the skin of the rats after the test.

Comparative Example 1-2 A patch was obtained in the same manner as in Example 1-1, except that the hollow fiber sample (2) was used in place of the hollow fiber sample (1), and the patch test on rats was performed. The results are shown in Table 1-1.

In the texture test, this preparation was obviously harder than the patch of Example 1-1, and erythema was observed on the rat skin after the test.

Examples 1-2 to 1-3 and Comparative Examples 1-3 to 1-5 71 denier / 24 shown in the section of making hollow fiber sample (1)
A knitted fabric and a woven fabric having different basis weights are prepared by using multifilaments of filaments, and after scouring and drying by a conventional method, a 1% aqueous solution of casein soda and boiling temperature 2
It was treated for a period of time to obtain a knitted fabric and a woven fabric having an alkali weight loss of about 15%. Using this woven or knitted fabric, a rat sticking test was conducted in the same manner as in Example 1-1, and the results are shown in Table 1-2.

From Table 1-2, it is clear that the patch of the present invention exhibits excellent sustained release properties. On the other hand, in Comparative Example 1-3, a sufficient blood concentration was not obtained, and in Comparative Examples 1-4 and 1-5, erythema was observed on the skin of the rat after the test.

Test Example 1-1 Except that ISDN was not used and the production scale was set to 1/10, all other conditions were used in Example 1-1.
~ 1-3, a so-called placebo preparation containing no ISDN was prepared under the same conditions as Comparative Examples 1-1 to 1-5, and Comparative Example 1
-1 in which 6 μm polyethylene terephthalate was used in place of the 3.5 μm polyethylene terephthalate film as the placebo preparation of Comparative Example 1-6, which was cut and used as a patch of 3 cm × 3 cm, aged 20 to 30 years old, body weight 56-72
A total of 9 pieces of each patch, one piece of each patch, were randomly attached to the expert on the center of the backs of five healthy components (kg), and the skin rash condition was determined 2 days after application. Judgment is 0
Table 1-3 shows the results of judgment by the total of the judgment points of 5 people, with 1 showing slightly erythema, 2 showing obvious erythema, and 3 showing hill examination. Indicated.

From Table 1-3, it is clear that the patch of the present invention significantly reduces skin rash.

It should be noted that, as shown in Table 1-2, the samples of Comparative Example 1-3 could not obtain a sufficient blood concentration.

Example 1-4 After drying on a silicone-coated release film (the substrate of the film is polyethylene terephthalate having a thickness of 75 μm) of the ethyl acetate solution containing the adhesive prepared in the above “(3) Adhesive solution” Thickness is 20μm and 40
Coated to a thickness of μm, 90 ℃ for 1 minute, then 130 ℃
And dried for 3 minutes to obtain two types of pressure-sensitive adhesive layers, a pressure-sensitive adhesive layer (1) and a pressure-sensitive adhesive layer (2) having a thickness of 20 μm. The residual solvent in the pressure-sensitive adhesive layer was 20 ppm or less.

A polyethylene terephthalate film having a thickness of 3.5 μm, a width of 1000 mm and a length of 100 m is adhered to one side of a 980 mm width residual ethyl acetate 22 ppm, a thickness of 20 μm and a length of 100 m of the pressure-sensitive adhesive layer (1), and then the pressure-sensitive adhesive layer ( 1) 1000mm wide and long on top
A 100 m hollow fiber sample (1) was pressure bonded. The surface of the hollow fiber sample (1) was continuously contacted with an acetone solution containing 30% by weight of ISDN to uniformly impregnate almost the entire surface of the acetone solution. The acetone-impregnated laminate strip thus obtained was passed through room temperature air blast for 5 minutes to almost completely remove the acetone solvent and remove ISDN at 9 g / m 2.
A laminate containing ² was obtained. The ISDN impregnated laminate has an inner diameter
A paper tube with a width of 7.6 cm and a width of 1000 mm was used as a center and was rolled into a roll.

The roll-shaped ISDN-impregnated knitted fabric laminate thus obtained was wrapped with an aluminum foil having a thickness of about 100 μm, and then at a constant temperature of 70 ° C. 2
Heated for 4 hours. By this heating scan, I
It was confirmed by sampling that almost all SDN was transferred to the pressure-sensitive adhesive layer (1).

Residual ethyl acetate 38ppm, thickness 40μ on the free surface of the hollow fiber sample (1) of the heated IDSN-impregnated knitted fabric laminate.
A new adhesive layer (2) having a width of 980 mm and a length of 100 m was pressure-bonded to obtain a patch original fabric. The residual ethyl acetate in the raw fabric was 18 ppm with respect to the pressure-sensitive adhesive.

The original patch fabric was cut into 2 cm x 2 cm, and the patch was applied to the back of a hair-removed rat having a body weight of about 180 g, and blood was collected at a predetermined time to measure ISDN in plasma. The results are shown in Tables 1-4.

Example 1-5 The patch of the patch obtained in Example 1-4 was cut into 2 cm x 2 cm, heat-sealed in an aluminum bag, and then heated at 40 ° C for 2 days. Was attached to the back of the rat from which hair had been removed, and blood was collected at a predetermined time to measure ISDN in plasma. The results are shown in Table 1-4.

Comparative Example 1-7 A patch was obtained in the same manner as in Examples 1-4 except that the hollow fiber sample (2) was used in place of the hollow fiber sample (1), and the patch test on rats was performed. The results are shown in Table 1-4.

However, when the hollow fiber sample (2) was used, the acetone solution containing 30% by weight was continuously brought into contact with the free knitted surface of the hollow fiber sample (2) so that the acetone solution was uniformly distributed on the knitted surface. However, the continuous method could not be adopted because the hollow fiber sample (2) did not absorb the acetone solution. Then, the acetone solution was uniformly sprayed onto the free surface of the hollow fiber sample (2). At this time, the variation in the ISDN amount on the hollow fiber sample (2) was obviously 2-3 times larger than that when the hollow fiber sample (1) was used. In addition, if the acetone on the hollow fiber sample (2) impregnated with ISDN was not treated carefully until about 30 to 50% or more of the total amount of acetone was evaporated, it caused the content variation.

Also, after the acetone is completely evaporated, ISDN crystals are fragile and adhere to the fiber surface on the hollow fiber sample (2), which is probably why the pressure bonding with the adhesive layer (2) is very weak. Since it was only given, it was judged that it was not suitable for continuous industrial production.

Examples 1-6, 1-7 and Comparative Examples 1-8 to 1-10 Hollow fiber samples (1) Knitted fabrics and woven fabrics having different basis weights using the 71 denier / 24 filament multifilaments shown in the section of preparation After scouring and drying according to the usual method,
A knitted fabric and a woven fabric having an alkali weight loss rate of about 15% were obtained by treating the solution with a 1% aqueous solution of casein soda and boiling temperature for 2 hours.
Using this woven or knitted fabric, a rat sticking test was conducted in the same manner as in Examples 1-4. The results are shown in Table 1-5.

Example 1-8 Instead of the hollow fiber sample (1) in Example 1-4, a hollow fiber obtained by the method for producing the hollow fiber sample (1) so as to have a hollowness rate of 8% and an alkali weight loss rate of 22%. A patch patch containing ISDN was obtained in the same manner except that the sample was used.

The ISDN in plasma was measured in the same manner as in Example 1-4 using the obtained patch fabric, and the blood concentration remained almost the same, and no skin rash or the like was observed at the patch site. .

Example 2-1 2.5 parts of estradiol was added to 500 parts of a pressure-sensitive adhesive solution having a solid content of 20%, and then coated on a silicone-coated release film so that the thickness of the adhesive layer after drying would be 20 μm. And dried at 70 ° C. for 2 minutes and 110 ° C. for 3 minutes.
The remaining amount of ethyl acetate in the obtained pressure-sensitive adhesive layer is 39 ppm,
The content of estradiol was 0.53 g / m ² . The pressure-sensitive adhesive layer containing the estradiol was divided into three to obtain three pressure-sensitive adhesive layers having the same composition (they are referred to as pressure-sensitive adhesive layer d1, pressure-sensitive adhesive layer d2, and pressure-sensitive adhesive layer b).

Next, a 3.5 μm thick film of polyethylene terephthalate (a in FIG. 1) was pressure-bonded to one surface of the pressure-sensitive adhesive layer b. Next, the hollow fiber sample (1) (c in FIG. 1) was pressure-bonded to the free surface of the pressure-sensitive adhesive layer b. A pressure-sensitive adhesive layer d1 was pressure-bonded to the free surface of the hollow fiber sample (1), and a pressure-sensitive adhesive layer d2 was pressure-bonded to the free surface of the pressure-sensitive adhesive layer d1 to obtain 1.6 g of estradiol / A patch original fabric containing m ² and having a residual solvent of 34 ppm was obtained.

The thickness of the backing film side adhesive layer (b in FIG. 1) of this patch was 20 μm, and the thickness of the human skin side adhesive layer was 40 μm (d in FIG. 1).

The patch original fabric was cut into 2 cm × 2 cm, and the patch was applied to the back of a hair-removed rat having a body weight of about 180 g, and blood was collected at a predetermined time, and estradiol in plasma was measured by a radioimmunoassay method. The results are shown in Table 2-1.

Comparative Example 2-1 After adding 2.5 parts of Estordiol to 500 parts of an adhesive solution having a solid content of 20%, the thickness of the adhesive layer after drying on the silicone-coated release film becomes 60 μm. And coated at 70 ° C. for 1 minute and 90 ° C. for 3 minutes.

The remaining amount of ethyl acetate in the obtained adhesive is 172 ppm,
The content was 1.6 g / m ² . When the drying temperature was 90 ° C. for 1 minute and 130 ° C. for 3 minutes in order to reduce the residual amount of ethyl acetate, the content of estradiol was 1.6 g / m ² . The residual ethyl acetate at this time was 83 ppm.

A 3.5 μm-thick polyethylene terephthalate film was pressure-bonded to one surface of the pressure-sensitive adhesive, cut into a size of 2 cm × 2 cm, and a rat sticking test was conducted in the same manner as in Example 2-1.

The results are shown in Table 2-1. The formulation looked like a flaky film and was very difficult to handle.

Further, obvious erythema was observed on the skin of the rats after the test.

Comparative Example 2-2 A patch was obtained in the same manner as in Example 2-1 except that the hollow fiber sample (2) was used in place of the hollow fiber sample (1), and the patch test on rats was performed. The results are shown in Table 2-1.

In the touch test, this preparation was obviously harder than the patch of Example 2-1 and erythema was observed on the skin of the rat after the test.

Examples 2-2 to 2-3 and Comparative Examples 2-3 to 2-5 Knitted fabrics and woven fabrics having different basis weights using the multifilament of 71 denier / 24 filaments shown in the section of preparation of hollow fiber sample (1) After scouring and drying according to the usual method,
It was treated with a 1% caustic soda aqueous solution and at a boiling temperature for 2 hours to obtain a knitted fabric and a woven fabric having an alkali weight loss rate of about 15%. Using this woven or knitted fabric, a rat sticking test was conducted in the same manner as in Example 2-1. The results are shown in Table 2-2.

From Table 2-2, it is clear that the patch of the present invention exhibits excellent sustained release properties. On the other hand, Comparative Example 2-3
Does not provide a sufficient blood concentration, and Comparative Examples 2-4,2-
No. 5 showed erythema on the skin of the rat after the test.

Example 3-1 Estradiol (E ₂ ) 0.5 was added to 100 parts of the adhesive solution (1).
All parts of the solution dissolved in 15 parts of methanol were added, 25 parts of ethyl acetate was further added, and the mixture was stirred to obtain a uniform dope. A pressure-sensitive adhesive containing 2.5% by weight of E ₂ coated on a silicone-coated release paper with the dope so that the thickness after drying is 20 μm and 40 μm, and dried at 90 ° C. for 1 minute and 120 ° C. for 2 minutes. Layers were obtained.

The residual solvent in the obtained pressure-sensitive adhesive layer of 20 and 40 μm was 41 ppm and 123 ppm, respectively, and the water content was 0.7.
% By weight.

A polyethylene terephthalate film having a thickness of 3.5 μm (a in FIG. 1) was pressure-bonded to the entire surface of one side of the obtained 20 μm pressure-sensitive adhesive layer (b in FIG. 1), and the opposite side of the adhesive layer which was free The knitted fabric (c in FIG. 1) of the hollow fiber sample (3) was pressure-bonded to the entire surface, and the adhesive layer (d in FIG. 1) having a thickness of 40 μm was pressure-bonded to the free surface of the knitted fabric. The original patch was obtained. The patch original fabric was cut into a size of 5 cm ² , dehumidified by the following method, and packaged. That is, it is heated in a vacuum dryer under a pressure of about 5 mmHg or less for 24 hours, and after taking out from the vacuum dryer, the aluminum foil is 12 mm thick while avoiding moisture absorption, and it is placed in a polyethylene bag laminated with heat. Sealed.

The E ₂ content in the patch thus obtained was
The content was 2.5% by weight, the water content with respect to the adhesive layer was 0.17% by weight, and the residual solvent was 20 ppm or less. The patch has a temperature of 40 ° C., which is a usual short-term stability evaluation condition for pharmaceuticals,
A humidity of 75% RH was used, and the moisture content was 0.17% even after 3 months had passed under the conditions.

The patch after 3 months at 40 ° C and 75% RH was applied to the back of a 7-week-old, male hairless rat that had been hair-removed with electric clippers (n = 5), and 2 hours, 4 hours, and 8 hours after application. Blood was collected at 24 hours, serum was separated, and E ₂ in the serum was measured by a radioimmunoassay method.

The blood concentration results are shown as the maximum blood concentration C _max and the blood concentration VS.
The area under the curve of time is summarized in AUC and shown in Table 3-1.

Examples 3-2 to 3-5 and Comparative Examples 3-1 to 3-5 The amount of estradiol (E ₂ ) used was changed.
Example 3 except that the E ₂ concentration and the water content were changed by changing the dehumidification conditions after cutting the patch original fabric.
Obtain the patch by the same operation as -1, temperature 40 ℃, humidity 75%
The results of a hairless rat patch test after aging for 3 months at RH are shown in Table 3-1.

It is clear from Table 3-1 that the patch of the present invention has excellent stability over time and exhibits excellent effects even with AUC and C _max .

Comparative Example 3-6 The patch obtained in Example 3-1 having an E ₂ content of 2.5% by weight and a moisture content of 0.17% with respect to the pressure-sensitive adhesive layer was not packaged in an aluminum bag.
The water content was 1.9% after 2 weeks under conditions of 40 ° C. and 75% RH, and E ₂ was aggregated in the pressure-sensitive adhesive layer, and the results of the patch test of hairless rats are also shown in Table 3-1. Yes, it was very bad.

Example 3-6 The patch obtained in Example 3-1 having an E ₂ content of 2.5% by weight and a water content of 0.17% relative to the pressure-sensitive adhesive layer was packed in an aluminum bag.
At this time, instead of the aluminum foil having a thickness of 12 mm used in Example 3-1, a bag of 7 mm of aluminum foil was heat-sealed with a seal width of 6 mm to obtain 20 bags each containing one patch. Get
The change in water content was examined with the average of 5 sheets each time at 40 ° C. and 75% RH.

It was 0.23% by weight after 1 month, 0.31% by weight after 2 months, 0.38% by weight after 3 months, and 0.44% by weight after 4 months, showing a large variation.

Example 3-7 A patch having an E ₂ content of 2.5% by weight and a moisture content of 0.17% based on the pressure-sensitive adhesive layer obtained in Example 3-1 was placed in the aluminum bag used in Example 3-6 and dried together with the patch. 1 g of silica gel was enclosed and heat-sealed in the same manner as in Example 3-6 to obtain 20 patches of the patch. When the change in the water content of the adhesive layer of this patch was traced in the same manner as in Example 3-6, the water content was 0.17% or less by 4 months and the variation was extremely small.

Example 4-1 A solution prepared by dissolving 0.5 part of estradiol (E ₂ ) in 15 parts of methanol (solution A), and a solution prepared by dissolving 0.2 part of PVP (K-90 manufactured by GAF, K-90) having a molecular weight of 1,200,000 in chloroform (solution B).
And 55 parts of ethyl acetate to 100 parts of acrylic adhesive solution (1)
Parts and add strong stirring to make a uniform dope, then coat it on silicone-coated release paper to a dry thickness of 40 μm and dry at 90 ° C for 20 minutes to obtain E ₂ (2.5 wt. %) And PVP (1% by weight) to obtain an acrylic pressure-sensitive adhesive layer.

Two layers (b and d in Fig. 1) of the pressure-sensitive adhesive layer having the thickness of 40 µm and containing E ₂ and PVP were prepared, and the intermediate yarn sample (3) was placed between the _two pressure-sensitive adhesive layers. After sandwiching (c in Fig. 1) and applying pressure, a polyethylene terephthalate film (a in Fig. 1) with a thickness of 3.5 μm is pressure-bonded to the entire surface of one side of the adhesive layer that is free 5 cm ²
Table 4-1 also shows the results of the evaluation of the patch ((E ₂ (2.5% by weight), PVP (1% by weight)) obtained by cutting into
It was shown to. This formulation maintained the flexibility sufficiently and was excellent in handling property.

Example 5-1 A solution prepared by dissolving 1.5 parts of buprenorphine in a mixed solution of 15 parts of methanol and 270 parts of ethyl acetate was added to 100 parts of the adhesive solution (1), and 0.2 parts of HCO-60 was further dissolved in 15 parts of ethyl acetate. The liquid was added, and the mixture was vigorously mixed and stirred to obtain a uniform solution (dope).

The thickness of the pressure-sensitive adhesive layer containing buprenorphine after drying on the release sheet obtained by coating the obtained dope with silicon
It was coated so as to have a thickness of 30 μm, and dried at 50 ° C. for 10 minutes, 70 ° C. for 2 minutes, and further at 50 ° C. for 120 minutes. The residual amount of ethyl acetate in the obtained pressure-sensitive adhesive layer was 46 ppm, and the content of buprenorphine was 2.9 g / m ² .

The pressure-sensitive adhesive layer containing buprenorphine was divided into two to obtain two pressure-sensitive adhesive layers having the same composition (this is referred to as b and d).

Next, a 3.5 μm-thick polyethylene terephthalate film as a backing film was pressure-bonded to one surface of the pressure-sensitive adhesive layer b. The hollow fiber sample (1) was pressure-bonded to the free surface of the pressure-sensitive adhesive layer b, and the pressure-sensitive adhesive layer d was pressure-bonded to the free surface of the hollow fiber sample (1) (c layer). Further, a silicone-coated film was attached as a release sheet to the free surface of the pressure-sensitive adhesive layer d to obtain a patch original fabric containing buprenorphine 2.9 g / m ² as shown in FIG.

After cutting the patch original fabric into a circle with a size of 9 cm ² ,
Attached to the back of a hairless rat with a weight of about 180 g,
Blood was collected at a predetermined time, and the buprenorphine concentration in plasma was measured. The content of buprenorphine in this patch is
The content was 2.6 mg and the content was 7.5% by weight. The results are shown in Table 5-1.

Example 5-2 In Example 5-1, 1.6 parts of buprenorphine hydrochloride was used instead of 1.5 parts of buprenorphine, and HCO-6
Example 5 except that a mixture of 0.2 parts of HCO-60 and 0.2 parts of diisopropanolamine was used instead of 0.2 parts.
By the same procedure as in 1 and the whole, buprenorphine hydrochloride was contained in an amount of 2.8 g / m ^{2 in} terms of buprenorphine, and an adhesive patch having an ethyl acetate residual amount of 43 ppm in the adhesive layer was obtained.

The obtained patch original fabric was cut into a circle having a size of 9 cm ² and then a hairless rat patch test was conducted in the same manner as in Example 5-1. The results are shown in Table 5-1.

The content and content of buprenorphine in this patch are
It was 2.5 mg and 7.5% by weight.

Example 5-3 Hydrochloric acid was prepared by the same procedure as in Example 5-2 except that 0.2 part of polyvinylpyrrolidone K-90 was used in place of the mixture of 0.2 part of HCO-60 and 0.2 part of diisopropanolamine in Example 5-2. Buprenorphine converted to buprenorphine
A patch stock containing 2.8 g / m ^{2 and} containing 37 ppm of ethyl acetate in the adhesive layer was obtained.

The obtained patch original fabric was cut into a circular shape having a size of 9 cm ² (buprenorphine content 2.5 mg, content rate 7.5% by weight), and hairless rat patch test was conducted in the same manner as in Example 5-2. The results are shown in Table 5-1.

Example 5-4 Using 1.6 parts of buprenorphine hydrochloride in place of 1.5 parts of buprenorphine in Example 5-1 and HCO-6
In the same manner as in Example 5-1, except that 0.2 part of diisopropanolamine was used instead of 0.2 part, buprenorphine hydrochloride was contained in an amount of 1.4 g / m ^{2 in} terms of buprenorphine, and the residual amount of ethyl acetate in the adhesive layer was After obtaining an adhesive layer containing buprenorphine hydrochloride having a thickness of 45 μm and a thickness of 30 μm, the size is 3 ×
It was cut into 3 cm ² (buprenorphine content 1.3 mg, content 7.5% by weight).

An ethylene-vinyl acetate copolymer polymer (vinyl acetate ratio 10%) film (C) having a thickness of 50 μm and a size of 4 × 4 cm ² is formed so as to cover the entire one surface of the pressure-sensitive adhesive layer having a size of 9 cm ^2. A mixture of ethanol and hydroxypropyl cellulose (90:10) was placed on the free surface of the ethylene-vinyl acetate copolymer polymer film in a size of 3 × 3 cm ² in the center, and the mixture was placed on top of it. Was coated on one side with a 3.5 μm polyethylene terephthalate film laminated with an ethylene-vinyl acetate copolymer polymer film (D) having a size of 4 × 4 cm ^{2 and} a thickness of 50 μm. The ethylene-vinyl acetate copolymer polymer film (C) and the ethylene-vinyl acetate copolymer polymer film (D) are in the shape of a bag that wraps ethanol and hydroxypropyl cellulose, and ethanol and hydroxypropyl cellulose do not escape. Thus, the edges of the four sides were heat-sealed with a width of about 5 mm.

The results obtained by applying the thus-obtained buprenorphine hydrochloride having an ethanol reservoir to the back of hairless rats in the same manner as in Example 5-1, are shown in Table 1. It was confirmed by the GC method that ethanol was gradually released from the ethanol reservoir of this example through the ethylene-vinyl acetate copolymer polymer film.

Example 5-5 A patch having a size of 4.5 cm ² , a buprenorphine content of 1.3 mg and a content of 7.5% by weight was obtained in the same manner as in Example 5-1, except that HCO-60 was not used.

The obtained preparation was applied to the back of a hairless rat having a body weight of about 180 g, which was applied for 8 hours, then removed, and the amount of buprenorphine in the preparation after application was extracted with methanol.
The amount of buprenorphine absorbed 8 hours after application was estimated by the HPLC method. The results are shown in Table 2.

Examples 5-6 to 5-15 In the same manner as in Example 5-1, except that buprenorphine hydrochloride was used instead of buprenorphine, and the accelerator shown in Table 5-2 was used instead of HCO-60. size
A patch having a buprenorphine content of about 1.3 mg and a content of 7.5% by weight was obtained at 4.5 cm ² .

The patch thus obtained was subjected to a patch test in the same manner as in Example 5-5, and the results of estimating the absorption amount of buprenorphine from the difference in buprenorphine concentration in the preparation before and after patching are shown in Table 5-2.

It can be seen that buprenorphine and buprenorphine hydrochloride have better absorption. Also, the hydrochloride had a considerably low percutaneous absorption without the absorption enhancer. However, when any of the preparations was applied, hairless rats exhibited symptoms that seemed to be due to the medicinal effects of buprenorphine, such as extremely poor response to external heat stimuli.

[Brief description of drawings]

FIG. 1 is a preferred embodiment of the present invention, and Example 1-1.
It is a cross-sectional view of the sustained-release patch obtained in 2-1.3-1.4-1 and 5-1. In FIG. 1, a is a film layer, b is an adhesive layer, c is a hollow fiber knitted layer, d is an adhesive layer, and e is a release sheet. 2 and 3 are preferred examples of the structure of the hollow fiber knitted fabric of the present invention. FIG. 2 is composed of 5 and 7 loops in the length and width, respectively, and the knitted fabric in FIG. 3 is 4 in the length and width. , 6 loops.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Toshiyuki Kato 1-100, Takamatsucho, Tachikawa, Tokyo Teizan Pharmaceutical Co., Ltd. Tachikawa factory (72) Inventor, Osamu Magoshi 1-100, Takamatsucho, Tachikawa, Tokyo Teizan Pharmaceutical Co., Ltd. In Tachikawa Factory (56) Reference JP-A-2-237926 (JP, A)

Claims (20)

[Claims] 1. A water-impermeable or semi-water-permeable film (a layer), one pressure-sensitive adhesive layer (b layer) laminated on one side of the film, and an outer peripheral direction on the b layer. Another pressure-sensitive adhesive layer (d layer) laminated via a knitted fabric (c layer) having a basis weight of 10 to 100 g / m ² and comprising hollow fibers having through holes and substantially containing no drug therein. ) And a patch containing an evaporative or non-evaporable drug in at least one of the layers b and d. 2. The patch according to claim 1, wherein the hollow fibers are polyethylene terephthalate hollow fibers. 3. The patch according to claim 1, wherein the film has a thickness of 0.5 to 4.9 μm. 4. A knitted fabric has a sum of the number of loops in the vertical and horizontal directions.
The patch according to claim 1, which is a knitted fabric having a structure of 15 to 37 cells / cm. 5. The drug is at least one evaporative drug selected from nitrates, guaiazulene, camphor, menthol and salicylates.
The patch described above. 6. The patch according to claim 1, wherein the drug is at least one non-evaporable drug selected from hormones, analgesics and heart disease drugs. 7. The patch according to claim 1, wherein the drug is a nitrate ester and the content thereof is 0.1 to 20% by weight based on the patch. 8. The patch according to claim 1, wherein each pressure-sensitive adhesive layer is a pressure-sensitive adhesive layer having a thickness of 5 to 100 μm and made of an acrylic resin. 9. The patch according to claim 8, wherein the drug is estradiol or a derivative thereof, and the content thereof is 0.5 to 5% by weight based on the patch. 10. The water content in each adhesive layer is 0.5% by weight.
10. The patch according to claim 9, wherein the hollow fiber is a polyethylene terephthalate hollow fiber and the film has a thickness of 0.5 to 4.9 [mu] m. 11. An adhesive layer (b layer and / or d layer) containing estradiol or a derivative thereof contains polyvinylpyrrolidone having a molecular weight of 0.5 to 15% by weight based on the adhesive and having a molecular weight of about 100,000 or more, and is hollow. The patch according to claim 9, wherein the fiber is a hollow fiber of polyethylene terephthalate, and the film is a film having a thickness of 0.5 to 4.9 μm. 12. The patch according to claim 8, wherein the drug is buprenorphine and the content thereof is 1 to 20% by weight based on the pressure-sensitive adhesive. 13. The adhesive patch according to claim 12, wherein the buprenorphine is buprenorphine hydrochloride, the hollow fiber is a polyethylene terephthalate hollow fiber, and the film is a film having a thickness of 0.5 to 4.9 μm. 14. A water-impermeable or water-semipermeable film (layer a) having one adhesive layer (layer b) on one side and a hole penetrating in the outer peripheral direction and containing substantially no drug. A knitted fabric (c layer) having a basis weight of 10 to 100 g / m ² and another pressure-sensitive adhesive layer (d layer) made of fibers are laminated in the order of a, b, c, d layers, and b The method for producing a patch according to claim 1, wherein an adhesive layer containing an evaporative or non-evaporable drug is used as at least one of the layer and the d layer. 15. A laminated body comprising a layer a and a layer b laminated on one surface of the layer a, and a layer c is laminated on the layer b.
15. The method for producing a patch according to claim 14, further comprising laminating the d layer on the c layer. 16. The method for producing a patch according to claim 14 or 15, wherein the drug is at least one non-evaporable drug selected from hormones, analgesics and heart disease drugs. (1) A water-impermeable or water-semipermeable film (layer a) and an evaporative drug laminated on one side of the layer a are substantially free or / or contain a small amount. A pressure-sensitive adhesive layer (layer b) and a hollow fiber having a hole penetrating in the outer peripheral direction on the layer b and containing substantially no drug therein, and having a basis weight of 10 to 100 g / m ² . A certain knit (layer c)
The surface of the c layer of the laminated body in which is laminated is impregnated with a drug solution obtained by dissolving the evaporative drug in a volatile solvent, and (2) a state in which the surface of the c layer is not in contact with air. Then, the laminate is heated to transfer the evaporative drug in the knitted portion to the b layer, and (3) after that, the evaporative drug may be contained on the c layer. A method for producing a patch, which comprises laminating the pressure-sensitive adhesive layer (d layer). 18. The method for producing a patch according to claim 17, wherein the drug is at least one evaporative drug selected from nitrates, guaiazulene, camphor, menthol and salicylate. (1) A water-impermeable or semi-water-permeable film (a layer) and an evaporative drug laminated on one side of the a layer are substantially free or / or contain a small amount. A pressure-sensitive adhesive layer (b layer) and a hollow fiber having a hole penetrating in the outer peripheral direction on the b layer and having substantially no drug therein, having a basis weight of 10 to 100 g / m ² . A certain knit (layer c)
The surface of the c layer of the laminated body in which is laminated is impregnated with a drug solution obtained by dissolving the evaporative drug in a volatile solvent, and (2) then the evaporative drug is placed on the c layer. Another pressure-sensitive adhesive layer (d layer) that may contain a drug is laminated to obtain a laminate, and (3) after that, the laminate is heated to remove the vaporizable drug in the knitted portion from the adhesive. A method for producing a patch, which comprises migrating to layer b and / or layer d. 20. The method for producing a patch according to claim 19, wherein the drug is at least one evaporative drug selected from nitrates, guaiazulene, camphor, menthol, and salicylate.