JPH0791194B2 - Estradiol-containing patch - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to an estradiol-containing patch useful for the prevention and amelioration of disorders often observed in postmenopausal women such as menopausal disorders, osteoporosis, and Alzheimer's dementia. .

<Prior art> Menopause, osteoporosis, which is often observed in postmenopausal women,
As the cause of Alzheimer's dementia, etc., the decrease in estrogen associated with menopause is emphasized.
Estriol and its derivatives are mainly oral agents,
It is clinically applied as an injection.

However, since estrogen is often used, side effects such as an increase in endometrial cancer occur. Therefore, when using it, the bioavailability (BA) will be increased as much as possible with the minimum dose required, and the drug in blood It is desired that the concentration be maintained stably.

Among various kinds of estrogen that are clinically applied, estradiol is one of the so-called natural type estrogen that is originally synthesized and used in the living body, and is a drug with high pharmacological activity and safety. Though considered the most suitable estrogen for use, 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 of estradiol, BA can be markedly improved and stable drug blood concentration can be maintained.

It is known that estradiol is percutaneously absorbed as a derivative such as an ester thereof, and is disclosed in Japanese Patent Publication No. 46-5427 and Japanese Patent Publication No. 57-154122. In particular, the patch shown in JP-A-57-154122 is excellent in that it improves BA and stabilizes the drug concentration in blood. 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. . Especially in the case of patches
Although the most serious problems are discomfort at the time of application and the occurrence of skin rashes, the conventional techniques have not sufficiently considered this point.

<Problems to be Solved by the Invention> 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 the drug is in blood. The transdermal patch, which has a stable concentration, has a problem that it causes discomfort and causes skin irritation.

The object of the present invention is to provide an estradiol-containing patch which has a high BA and a stable drug blood concentration, and which significantly improves the discomfort and skin irritation, which are the drawbacks of conventional estradiol transdermal patches, and which has high patient compliance. To provide the agent.

<Means for Solving the Problems> The present inventors diligently studied means for improving the discomfort and skin irritation, which are the drawbacks of the transdermal patch, and providing a means for providing a stable blood concentration in the patch. , (1) The flexibility of the adhesive patch is increased as much as possible, and the discomfort can be remarkably eliminated by reducing the size of the adhesive patch. (2) The residue in the adhesive is selected by selecting the type of conventional base material and adhesive. In addition to reducing the amount of monomers and residual solvent, skin irritation can be further reduced by controlling the moisture vaporization of the patch and the gas permeability of gases such as oxygen and carbon dioxide. (3) Exists in a dissolved state By keeping the concentration of estradiol as high as possible and using a pressure-sensitive adhesive that has a distribution ratio that does not impede transfer to the skin, or a base material that can replace the pressure-sensitive adhesive, The inventors arrived at the present invention by finding that the degree can be stabilized, that is, the transdermal absorption amount of estradiol can be stabilized.

That is, the present invention relates to polyvinylpyrrolidone with about 3 to about
An estradiol-containing patch comprising a polyvinylpyrrolidone layer containing 17% by weight of estradiol, and the surface area of the polyvinylpyrrolidone layer in direct contact with human skin is 2 to 50 cm ² .

The estradiol referred to in the present invention refers to natural estrogen and synthetic estrogen, and includes, for example, estradiol benzoate, estradiol dipropionate, estradiol valerate, ethinyl estradiol (hereinafter abbreviated as E ₂ ).

The patch of the present invention comprises a polyvinylpyrrolidone layer containing 3 to 17% by weight of E ₂ with respect to polyvinylpyrrolidone. The polyvinylpyrrolidone of the present invention is N-vinyl-
A polymer of 2-pyrrolidone, with a molecular weight of 5,000
Those of 1 to 1,000,000 are usually preferred. Further, the core vinylpyrrolidone may be copolymerized with other monomer components or polymer components to the extent that the properties such as solubility in an organic solvent are not significantly impaired.

In order to increase the flexibility of the polyvinylpyrrolidone layer and control its absorbability, 30% by weight or less of polyethylene glycol, glycerin, ethylene glycol, propylene glycol, ethyl lactate, organic additives such as surfactants are added to polyvinylpyrrolidone. It may contain a substance or an inorganic substance such as sodium acetate or magnesium chloride.

By using polyvinylpyrrolidone, it becomes possible to maintain E ₂ in a high concentration and in a dissolved state. As a method of uniformly containing E ₂ in the polyvinylpyrrolidone layer, for example, E ₂ and polyvinylpyrrolidone in methanol,
There is a method of dissolving in an organic solvent such as ethanol or chloroform and coating or spraying the E ₂ -containing polyvinylpyrrolidone solution by a known coating technique.

When the water content of the polyvinylpyrrolidone layer is lower than the equilibrium water content, the polyvinylpyrrolidone layer may have insufficient tackiness by itself.

Therefore, not only to reduce skin irritation, but to absorb a sufficient effective dose of E ₂ to humans from such a polyvinylpyrrolidone layer having insufficient tackiness, a polyvinylpyrrolidone layer containing E ₂ is almost always used. It is desirable to provide an auxiliary adhesive layer to contact the patient's skin. However, even when the auxiliary adhesive layer is provided, if the area of the E ₂ -containing polyvinylpyrrolidone layer required to absorb a sufficient amount of E ₂ is increased, the entire surface of the E ₂ -containing polyvinylpyrrolidone layer is It is difficult to keep it adhered to human skin almost all the time, and there is always only partial contact.
In such a state, the contact area changes due to the passage of time, the movement of the patient, and the state of the body, and the blood concentration cannot be stably maintained at a high level.

In order to eliminate such inconvenience, it is preferable that the area of the required polyvinylpyrrolidone layer containing E ₂ is as small as possible. For that purpose, the E ₂ concentration in the polyvinylpyrrolidone layer with respect to polyvinylpyrrolidone is preferably 3% by weight or more. At higher concentrations, the percutaneous absorption rate of E ₂ tends to gradually increase, but at about 10% by weight, it reaches an almost maximum, and when it exceeds about 17% by weight, the percutaneous absorption rate is extremely ineffective. It drops to a sufficient level. According to the present inventors, in the E ₂ containing state of concentration higher than 17 wt%, most of E ₂ in polyvinylpyrrolidone layer obtained was found to have precipitated as a crystal.

Therefore, in the present invention, the concentration of E ₂ in the polyvinylpyrrolidone layer is about 3 to 17% by weight, preferably about 7 to 10% by weight, based on polyvinylpyrrolidone.

In the present invention, such a polyvinylpyrrolidone layer containing E ₂ is formed on a plastic film or paper, and as an appropriate shape, it is also considered that it is percutaneously absorbed by sticking it, but the effective amount of E Stable ₂ and E ₂
In order for a patient in need of administration to use it with ease and without worry, it is preferable to further devise the following. E ₂
When the polyvinylpyrrolidone layer containing the compound is dried to some extent, the adhesive strength of the polyvinylpyrrolidone itself becomes very weak. Therefore, it is desirable to provide an auxiliary adhesive layer for easy use by the patient. Pressure-sensitive adhesive layer of such aid is almost like the entire surface is stably in contact with human skin of polyvinylpyrrolidone layer containing E _2, and to increase the percutaneous absorbability giving sealing effect, containing E ₂ It is preferable to provide the polyvinylpyrrolidone layer by pressure bonding or the like so as to cover the entire one surface. In order to enhance the sealing effect, polyethylene, polypropylene,
A gas semipermeable or impermeable single or composite membrane made of vinyl chloride, ethylene-vinyl acetate copolymer, nylon, polyester or the like is preferably attached. The thickness of the film is preferably as thin as 0.5 to 30 μ. Since the polyvinylpyrrolidone layer containing E ₂ is fixed to human skin by using such an auxiliary adhesive layer, the area of the adhesive layer is preferably ² to 100 cm ² larger than the area of the polyvinylpyrrolidone layer. In the production of such a patch, the pressure-sensitive adhesive layer is first pressure-bonded to the gas semipermeable or impermeable film, and then the polyvinylpyrrolidone layer containing E ₂ is formed on the pressure-sensitive adhesive layer to improve the efficiency. The patch of the present invention can be obtained well.

That is, an organic solvent solution having E ₂ and polyvinylpyrrolidone dissolved on a pressure-sensitive adhesive layer having a gas semi-permeable or impermeable film attached thereto is dropped into a strip having a width of 1 mm to 30 mm, or a diameter of 1
mm to 50 mm in a circle, and then remove the organic solvent by drying to remove E of 10 μ to 300 μ in thickness on the adhesive layer.
A polyvinylpyrrolidone layer containing ₂ can be made. An arbitrary number of polyvinylpyrrolidone layers having a band shape, a circular shape or any other shape can be prepared in a patch of ² to 50 cm ² .

In particular, in order for the polyvinylpyrrolidone layer to stably contact human skin, it is preferable that there are two or more such polyvinylpyrrolidone layers having a band shape, a circle shape, a square shape, and a gap of 3 mm or more between each layer.

In the present invention, in the case of forming a polyvinylpyrrolidone layer having such a band shape, a circle shape, a quadrangle shape, etc., on a pressure-sensitive adhesive layer having a gas semipermeable or impermeable membrane attached thereto, in a desired shape in advance, Moreover, a fabric having a basis weight of 5 to 400 g / m ² is placed, and an organic solvent solution in which E ₂ and polyvinylpyrrolidone are dissolved is dropped on the fabric to form a more stable E ₂ -containing polyvinylpyrrolidone layer. be able to.

Further, in the present invention, the fabric having a basis weight of 5 to 400 g / m ² has E ₂
And, after dropping the organic solvent solution in which polyvinylpyrrolidone is dissolved, the organic solvent is removed, and the polyvinylpyrrolidone layer containing E ₂ formed so that the fabric is almost buried is cut into a desired shape, and this is gas. A method of pressing on a pressure-sensitive adhesive layer having a semi-permeable or impermeable non-adhesive film attached thereto can also be preferably used.

When the basis weight of the fabric is 5 g / m ² or less, the handleability of the fabric is poor and the liquid retaining ability of the fabric is not sufficient, which is not preferable. When the basis weight exceeds 400 g / m ² , the amount of the polyvinylpyrrolidone layer containing E ₂ can be increased, but the resulting patch becomes too hard, and even if measures such as adding water are taken, it is flexible. Even if given, it is not preferable because it causes high skin irritation during use.

In the present invention, it is particularly preferable that the fabric is a woven or knitted product made of hollow fibers having holes penetrating in the outer peripheral direction.

When a solution of an organic solvent in which E ₂ and polyvinylpyrrolidone are dissolved is dropped, dipped or contacted, such a cloth absorbs the solvent quickly, and the E ₂ -containing polyvinylpyrrolidone is contained between the hollow portion and the single fiber. Since the solution can be sufficiently retained, it is possible to make a polyvinylpyrrolidone layer containing the desired E ₂ with a small amount of fabric. Moreover, the hollow fiber having a hole penetrating in the outer peripheral direction is excellent in shape stability because the yarn itself is flexible and has a woven or knit structure, and is a polyvinyl containing E ₂ as compared with the case where such a cloth is not used. The pyrrolidone layer is remarkably stable and easy to handle.

The hollow fiber having a hole penetrating in the outer peripheral direction used in the present invention is a hollow fiber having fine holes scattered throughout the surface of the hollow fiber, arranged in the fiber axial direction, and at least a part of which communicates with the hollow portion. Is 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 both the outer shape and the hollow portion are substantially circular, one of the outer shape and the hollow portion is substantially circular and the other is irregular, and the outer shape and the hollow portion may be similar or dissimilar. . The size of the outer shape is not particularly limited, but the flexibility of the fiber is affected by the thickness of the single yarn, so the thickness of the single yarn is preferably 0.2 to 20 denier. Particularly preferred is 1 to 5 denier.

The hollow ratio of the hollow fiber of the present invention may be arbitrary, but it is particularly preferably 5% or more, and the ratio of the hole penetrating in the outer peripheral direction to the fiber cross-sectional area is 0.001 of the fiber cross-sectional area excluding the hollow part. ˜70% is preferable, 0.01 to 50% is more preferable, and 1 to 50% is particularly preferable.

In the present invention, such a hollow fiber has good handleability, a good feel on the skin, and an excellent sustained-release effect of a drug, particularly when used in a textured form such as a woven fabric, a knitted fabric, and a nonwoven fabric. Therefore, it is preferable. Of these, the knitted fabric is particularly stretchable, and has little discomfort when applied to a human as a holding body, which is particularly preferable. A knitted fabric has a basis weight of 5 to 400 g /
Those with m ² and especially from 10 to 400 g / m ² are preferred.

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; nylon 6,
Any polyamide such as nylon 66; polyurethane, cellulose acetate, polyacrylonitrile, polyvinyl chloride, polyvinyl acetate, etc. can be selected. Among these, polyester is preferable, and polyethylene terephthalate is particularly preferable because it has good thermal stability, is chemically stable, has little interaction with drugs, and is safe as a preparation.

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, 56-43420 and the like.

The polyvinylpyrrolidone layer containing E ₂ of the present invention absorbs E ₂ in the body by contacting the skin of the patient,
The shape of the polyvinylpyrrolidone layer such as a band, a circle, and a quadrangle is important in order to make the contact more reliable. When this shape is a quadrangle, the aspect ratio is 0.7 or less, preferably 0.5 or less. It is desirable to make it slender. If it is circular and its diameter exceeds 3 cm, it is better to have an elliptical shape with a length / width ratio of 0.1 or less.

The polyvinylpyrrolidone layer containing E ₂ of the present invention has an area of 2 to 50 cm that directly contacts or adheres to human skin.
^{Is 2} .

When the contact area is 2 cm ² or less, the amount of E ₂ absorbed by the patient is insufficient, and it is difficult to obtain the desired therapeutic effect. On the other hand, when it is 50 cm ² or more, the skin area to be stimulated is too large and the burden on the patient is heavy. Also, if it is 50 cm ² or more, it becomes difficult to stably contact or adhere to the human skin on the entire surface, and it is not possible to increase the absorption amount despite the increased area, so consider the burden on the patient due to increasing the area. There is a limit.

In the present invention, as the pressure-sensitive adhesive forming the auxiliary pressure-sensitive adhesive layer, any known pressure-sensitive adhesive such as rubber-based, silicone-based, acrylic-based can be used, and among the known pressure-sensitive adhesives, biological safety High (1) at least 80% of (meth) acrylic acid alkyl ester of alkyl group having 4 or more carbon atoms
An acrylic pressure-sensitive adhesive obtained by copolymerizing 98 mol% and (2) 2 to 20 mol% of acrylic acid and / or methacrylic acid as a main component is preferable. In the present invention, E ₂ is contained in the adhesive layer.
It is also a desirable mode to increase the amount of absorption and the like.

The pressure-sensitive adhesive layer has a thickness of 10 to 100 μm, and when two pressure-sensitive adhesive layers are used to give air permeability to the pressure-sensitive adhesive layer, and a fabric is laminated between them, skin rash can be further improved. In addition, the handleability of the patch can be improved.

In particular, when such a fabric is a hollow fiber having a hole penetrating in the outer peripheral direction as described above and is a woven or knitted fabric having a basis weight of 5 to 400 g / m ² , there is a seeming contradiction of ensuring sufficient air permeability as well as sufficient airtightness. Can meet your requirements.

In the present invention, when E ₂ is released from such patch and absorbed by human skin, the water content in the patch plays an important role. On the other hand, when storing the patch, the less water in the patch, the more stable E ₂ can be stored. The moisture content of the E ₂ -containing patch of the present invention during storage is preferably 18% by weight or less based on the polyvinylpyrrolidone of the patch, and 18% by weight or more when applied to a human.

To a moisture content in the plaster and 18% by weight, the as E ₂
And polyvinylpyrrolidone can be achieved by a method of forming an E ₂ -containing polyvinylpyrrolidone layer using an organic solvent. When water is used as the solvent, sufficient drying is required so that the water content will be a predetermined value.

As described above, by covering the polyvinylpyrrolidone layer containing E ₂ with the pressure-sensitive adhesive layer having the gas semi-permeable or impermeable membrane, the sweat generated by the physiological action of human is appropriately absorbed and evaporated more than necessary. Since it can be eliminated, it is also possible to achieve an increase in water content when applied to a human.

Hereinafter, the present invention will be described in more detail with reference to examples. Parts in the examples and reference examples indicate parts by weight.

Reference Example 1 Preparation of hollow fiber sample 297 parts dimethyl terephthalate, ethylene glycol 265
Parts, sodium 3,5-di (carbomethoxy) benzenesulfonate 53 parts (11.7 mol% relative to dimethyl terephthalate), manganese acetate tetrahydrate 0.084 parts and sodium acetate trihydrate 1.22 parts with rectification column glass Put in a flask, perform transesterification reaction according to a conventional method, after the theoretical amount of methanol was distilled out, the reaction product was placed in a flask for polycondensation with a rectification tower, 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, and the reaction was carried out at a temperature of 275 ° C. under normal pressure for 20 minutes under reduced pressure of 30 mmHg for 15 minutes, then under high vacuum for 100 minutes at a final internal pressure of 0.38 mmHg.
The obtained copolymer had an intrinsic viscosity of 0.405 and a softening point of 20.
It was 0 ° C. After completion of the reaction, the copolymerized polymer was made into chips by a conventional method.

15 parts of this copolymerized polymer chip and 85 parts of polyethylene terephthalate chip having an intrinsic viscosity of 0.640 were mixed in a Nauta mixer (manufactured by Hosokawa Iron Works) for 5 minutes, and then in a nitrogen stream at 110 ° C. for 2 hours, and further. After drying at 150 ° C. for 7 hours, the mixture was melt-kneaded at 290 ° C. using a twin-screw type extruder to form chips. The intrinsic viscosity of this chip was 0.520 and the softening point was 262 ℃.

The chips are dried by a conventional method, and the spinneret has a width of 0.05 mm,
Using a circular slit with a diameter of 0.6 mm and two circular arc openings that are closed, spin it according to the usual method, and use a hollow fiber (hollow ratio 25%) with an outer diameter to inner diameter ratio of 2: 1. Had made. This raw yarn was 300 denier / 24 filament, and this raw yarn was drawn at a draw ratio of 4.2 times according to a conventional method to obtain a 71 denier / 24 filament multifilament. This multifilament was put into a knitted fabric (abbreviated as raw cloth), scoured and dried by a conventional method, and then treated with a 1% caustic soda aqueous solution at a boiling temperature for 2 hours to reduce the alkali weight reduction ratio of 15
%, A water absorption rate of 3 seconds, a water absorption rate of 82%, and a fabric having a basis weight of 135 g / m ² were obtained.

The water absorption rate and the water absorption rate were measured by the following methods.

(A) Water absorption rate test method (in conformity with JIS-L1018) The above-mentioned cloth was used as an anionic detergent Zab (manufactured by Kao Soap Co., Ltd.).
Repeat the washing with a 3% aqueous solution for 30 minutes at 40 ° C with a household electric washing machine, then dry and stretch the sample horizontally, and drop one drop (0.04cc) of water from the height of 1cm above the sample. , Measure the time until water is completely absorbed by the sample and no reflected light is observed.

(B) Water Absorption Rate Measurement Method A sample obtained by drying a 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.

Water absorption rate = (sample weight after dehydration-dry sample weight) / dry sample weight (%) The hollow fibers obtained by the above method are scattered over the entire surface of the hollow fibers and arranged in the fiber direction, and at least 1 The part was a hollow fiber having fine pores communicating with the hollow part.

Reference Example 2 Preparation of acrylic adhesive solution and adhesive layer 2-ethylhexyl acrylate 97.4 parts, methacrylic acid 2.5 parts, polyethylene glycol (degree of polymerization 14) dimethacrylate 0.1 part, benzoyl peroxide 1.0 part and ethyl acetate 100 parts under reflux A reaction vessel equipped with a condenser and an agitator was charged, and the polymerization was continued for 9 hours while slowly stirring 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% to obtain an adhesive solution.

The ethyl acetate solution containing the adhesive was coated on a silicone-coated release paper so that the thickness after drying would be 40μ, and 90
It dried at 10 degreeC for 10 minutes, and obtained the adhesive layer.

Example 1 0.6 parts of estradiol (E ₂ ) and 5.4 parts of polyvinylpyrrolidone having a molecular weight of 1,200,000 (K-90 manufactured by GAF) were dissolved in 50 parts of methanol (solution A).

Solution A was dropped on 10 parts of the hollow fiber sample shown in Reference Example 1 and air-dried to remove methanol. This operation, that is, dropping and air drying was repeated 3 times to drop the whole amount of the solution A onto the hollow fiber sample, and then the air was dried to completely remove the methanol E ₂
A polyvinylpyrrolidone layer containing was obtained. This product was punched out into a circle with a size of 5 cm ² . The moisture content of polyvinylpyrrolidone in the patch was 3.2%.

On the other hand, a 3.5 μm-thick polyethylene terephthalate film was pressure-bonded to the entire surface of one side of the acrylic pressure-sensitive adhesive layer obtained in Reference Example 2 to prepare an auxiliary pressure-sensitive adhesive layer composition in which the other side was entirely free to measure its size. It was 4 cm x 4 cm. The circular E ₂ -containing polyvinylpyrrolidone layer having a size of 5 cm ² obtained above was pressure-bonded onto the pressure-sensitive adhesive layer of the composition to obtain a patch for test evaluation (Example 1).

FIG. 1 shows the present embodiment which comprises a polyethylene terephthalate film (1) as a gas semipermeable membrane, an acrylic adhesive layer (2) as an adhesive layer, and a polyvinylpyrrolidone layer (3) containing E _2. FIG. 3 is a cross-sectional view of a case where a release paper (4) for storage is further used as the patch.

The patch was applied to the back of a 7-week-old male hairless rat that had been hair-removed with an electric clipper (n = 5), and blood was collected at 2 hours, 4 hours, and 8 hours after application to separate the serum from the serum. E ₂ was measured by radioimmunoassay. The results are shown in Table 1.

As shown in Table 1, the E ₂ -containing patch of the present invention achieved a good E ₂ blood concentration and was also good in sustainability.

Examples 2 to 3 All patches were obtained in the same manner as in Example 1 except that E ₂ was changed to 0.3 parts and 1.0 parts, respectively, and the results of the animal test as in Example 1 are shown in Table 1. .

Comparative Examples 1 to ₂ All the patches were obtained in the same manner as in Example 1 except that E ₂ was changed to 0.1 part and 1.4 parts, respectively, and the results of animal tests conducted in the same manner are shown in Table 1.

Example 4 Prior to testing in the same manner as in Example 1 with the patch obtained in Example 1, the patch was prepared at 25 ° C. and 80% relative humidity.
Table 1 shows the results of the test after humidity control for 16 hours.

The water content of polyvinylpyrrolidone in the patch at this time was 19%.

[Brief description of drawings]

FIG. 1 is a cross-sectional view of the estradiol (E ₂ ) -containing patch of the present invention obtained in Example 1. Numbers in the figure (1-
4) shows the following contents, respectively. 1 ... Membrane (polyethylene terephthalate film) 2 ... Adhesive layer 3 ... Polyvinylpyrrolidone layer containing E ₂ 4 Release paper (Peel off when using formulation, discard and stick to adhesive layer during storage deep)

Claims (6)

[Claims] 1. About 3 to 17 with respect to polyvinylpyrrolidone
An estradiol-containing patch comprising a polyvinylpyrrolidone layer containing 1% by weight of estradiol, wherein the surface area of the polyvinylpyrrolidone layer that directly contacts human skin is 2 to 50 cm ² . 2. A semipermeable or impermeable film of gas is formed on the surface of the polyvinylpyrrolidone layer opposite to the surface that directly contacts human skin and on the surface opposite to the surface laminated with the polyvinylpyrrolidone layer. The estradiol-containing patch according to claim 1, wherein the pressure-sensitive adhesive layers that have been laminated are laminated. 3. The polyvinylpyrrolidone layer has a basis weight of 2 to 2.
The estradiol-containing patch according to claim 1 or ^{2, wherein} a fabric of 400 g / m ² is formed so as to be almost buried in the layer. 4. A woven or knitted fabric made of hollow fibers having holes penetrating in the outer peripheral direction.
The described estradiol-containing patch. 5. The polyvinylpyrrolidone layer has a length / width ratio.
The estradiol-containing patch according to claim 1, which is formed so as to have a ratio of 0.7 or less. 6. The estradiol according to claim 1, wherein the moisture content of the patch during storage is 18% or less with respect to polyvinylpyrrolidone, and the moisture content when applied to a patient is 18% or more. Containing patch.