JPH0317018A - Transcutaneous absorption preparation - Google Patents

Abstract

PURPOSE:To provide a transcutaneous absorption preparation containing a drug composed of estradiol or its ester, etc., and an absorbefacient composed of dibasic carboxylic acid, its salt, etc., in a base, exhibiting high transcutaneous permeability of drug and enabling the supply of a sufficient amount of drug through a small area of skin. CONSTITUTION:The objective transcutaneous absorption preparation contains 8-12wt.% of a drug composed of estradiol and/or its ester (e.g. benzoic acid ester or propionic acid ester) and 0.1-30wt.% (preferably 3-7wt.%) of an absorbefacient composed of a 2-10C dibasic carboxylic acid (e.g. oxalic acid or phthalic acid) and/or its salt in the base. It may further contain an ester derived from a 10-18C higher fatty acid and a 1-20C alcohol as other absorbefacient. The above preparation is preferably used in the form of a tape produced by forming a tacky adhesive layer (preferably acrylic tacky adhesive) containing the drug and the absorbefacient on one surface of a substrate. It exhibits sustained release without causing the dermatic disorder such as flare.

Description

[Detailed Description of the Invention] (Industrial Application Field) The present invention... The present invention relates to a transdermal absorption preparation that contains estradiol and/or its ester as a drug and is capable of achieving a stable blood concentration of the drug over time by supplying the drug through transdermal absorption.

(Prior art) Estradiol and its ester are known as one of the female hormones. It is effective as a drug for menopausal symptoms and menstrual abnormalities in women. Oral administration of this drug places a heavy burden on the liver due to its high hepatic metabolic rate. Moreover, the utilization rate of the drug in the body decreases significantly due to metabolism. Therefore, this drug is usually administered by injection. but. When administered by injection, the blood concentration of the drug temporarily increases, but this blood concentration is not maintained for a long period of time, making it necessary to administer the drug frequently. Therefore, the use of sustained-release preparations is desired, and for example, transdermal absorption-type preparations are considered appropriate. However, the skin has a biological defense function that prevents foreign substances from entering the body. in general,
It is difficult to administer sufficient amounts of drugs through the skin. For this reason, efforts have been made to increase the area of drug-containing patches or to include transdermal absorption enhancers, but drug release properties are still not sufficient.

For effective transdermal administration of estradiol and its esters, for example, Japanese Patent Application Laid-open No. 154122/1983 discloses a multilayer patch. This patch has a drug enhancer-containing layer on a support. Expanded defeat! It consists of an x-layer and a tactile adhesive layer laminated in sequence. The drug enhancer-containing layer is composed of a drug-containing gel containing estradiol in a gel-like substance obtained by gelatinizing ethanol with hydroxybuvir cellulose or the like. What are drugs and ethanol?
Both pass through the diffusion membrane layer and the tactile adhesive layer and are absorbed through the skin. The rate of absorption of ethanol through the skin is about 100-800 mcg/hr/cm, and therefore drugs dissolved in ethanol also have enhanced absorption through the skin. Drug release properties can be controlled by controlling the amount of ethanol used. but. Because such patches have a multilayer structure, the manufacturing process is complicated.
Moreover, when it is applied to the skin, it gives a feeling of discomfort due to its thickness. Due to the use of ethanol, which easily volatizes, it is currently being stored. Or, the ethanol evaporates after application. The disadvantage is that the ability to release the drug changes. Ethanol is irritating to the skin, so there is a high possibility that it will cause skin damage such as redness. More diffusion film 1! (which functions as a control membrane), the release of ethanol and drug is still not sufficient, and a patch with a relatively large area is required to obtain satisfactory drug efficacy.

In JP-A-61-155321. Disclosed is a patch having an estradiol-containing adhesive layer formed on a support, the adhesive base comprising mainly rubber, adhesive resin materials, and polymers capable of swelling in water, such as galactomannan. shall be. This patch does not become bulky like the multilayered patch described above. Moreover, it is possible to supply the drug relatively stably for a given period of time.
However, the overall release performance of the drug is still not sufficient.

JP-A-60-152413 discloses a transdermal absorption preparation containing menthol as a transdermal absorption enhancer. This publication describes 17β as a drug in a lipophilic base.
When using a preparation containing monoestradiol-3-sodium. It is stated that high drug permeability was achieved in a skin test using nude mice. but. This preparation is. Since menthol is used, the menthol evaporates as in the case of ethanol, and the drug release ability changes. moreover. Menthol only promotes percutaneous absorption when the drug is water-soluble. Therefore, as mentioned above, estradiol must be in the form of a salt for its effects to be obtained.

JP-A No. 61-17513 discloses a predetermined ratio (1:
A mixture of brobylene glycol and glycerin of 1 to 1:5 W/W) and, if necessary, the drug at 0.5
A transdermal formulation is disclosed that dissolves at a rate of 1 llg/rnl and contains a pharmacologically acceptable solvent.

This formulation allows relatively effective administration of the drug under conditions that are mild to the skin.

but. Since a solvent is used, this evaporates and changes the release properties of the drug. moreover. The overall release properties of the drug are still insufficient, and a patch with a relatively large area is required to obtain a satisfactory drug effect.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional problems.The purpose of the present invention is to: contain estradionole and/or its ester, and improve the skin permeability of the drug. high,
The object of the present invention is to provide a transdermal absorption preparation capable of supplying a sufficient amount of a drug even in a small amount or small area. Another object of the present invention is. The object of the present invention is to provide a transdermal absorption preparation that has the above-mentioned excellent properties, does not cause damage to the skin, and has a simple structure that is easy to manufacture.

(Means for Solving the Problems) The transdermal absorption preparation of the present invention is as follows. A transdermal absorption preparation containing a drug and an absorption enhancer for the drug in a base, the drug being estradiol and/or an ester thereof,
and. The absorption enhancer is a divalent carboxylic acid having 2 to 10 carbon atoms and/or a salt thereof, thereby achieving the above object.

The medicinal effect of the transdermal patch of the present invention is estradiol and/or its ester, and examples of the ester include benzoic acid ester. Valeric acid ester, sibionic acid ester. Examples include brobionic acid ester.

The drug is present in the formulation in an amount of 5-30% by weight, preferably 8-30% by weight.
Contained at a rate of 12%. This proportion is the same for ointments,
For cream preparations, etc., the content is shown in relation to the entire preparation.
for example. For patches such as tape preparations and poultices, the content is shown relative to the drug-containing layer (adhesive layer). The same applies to the content of the transdermal absorption enhancer described below. If too little drug is used, the drug's efficacy will be insufficient. If it is in excess, the drug will crystallize in the base and will not be released adequately.

As the percutaneous absorption enhancer contained in the percutaneous absorption preparation of the present invention, a divalent carboxylic acid having 2 to 10 carbon atoms and/or a salt thereof is used. Examples of such divalent carboxylic acids include oxalic acid, malonic acid, fumaric acid, and maleic acid. Tartaric acid, malic acid, succinic acid, glutaric acid, adipic acid.
Examples include phthalic acid, isophthalic acid, and terephthalic acid. Salts of these chemical compounds include sodium salts and potassium salts. Examples include magnesium acid, calcium salts, and aluminum salts. In particular, fumaric acid and/or its salts are preferred. The above divalent carboxylic acid and/or its salt is contained in the preparation in an amount of 0.1 to 30% by weight, preferably 1 to 20% by weight,
More preferably, << is contained in a proportion of 3 to 7% by weight. ，
If the amount is too low, the effect of promoting transdermal absorption of the drug cannot be obtained. If it is in excess, the compatibility with the base material will decrease. In the case of a tape formulation in which the adhesive layer contains a drug, the adhesive physical properties are reduced.

The formulation may further contain higher fatty acid esters as other transdermal absorption enhancers. The higher fatty acid esters include higher fatty acids having 10 to 18 carbon atoms. A fatty acid ester obtained from an alcohol having 1 to 20 carbon atoms is used. Examples of fatty acids having 10 to 18 carbon atoms that can form higher fatty acid esters include myristic acid, palmitic acid, lauric acid, stearic acid, and palmitoleic acid. These include oleic acid, vaccenic acid, linoleic acid, and linolenic acid. Examples of alcohols having 1 to 20 carbon atoms include methanol, ethanol, propanol, isoprobanol, butanol, hexanol, pentanol, hebutanol, octanol, decanol, and cetanol. As the higher fatty acid ester, isobrobyl myristate, isoprobyl valmitate, etc., and isoprobyl myristate is particularly preferred. The higher fatty acid ester has the function of enhancing the transdermal absorption promoting effect of the divalent carboxylic acid. When the formulation is a tape formulation, the adhesive properties of the adhesive base and the adhesion of the formulation are improved. Higher fatty acid esters. It is contained in the preparation at a ratio of 30% by weight or less, preferably 1 to 25% by weight, and more preferably 3 to 10% by weight. If the higher fatty acid ester is in excess, estradiol will precipitate in the base. As a result, for example, tape formulations have reduced adhesion.

The transdermal absorption enhancer is 1 part by weight per 100 parts by weight of the above adhesive base.
The total amount is 1 to 100 parts by weight. Preferably. 5-20
Contained in parts by weight.

The transdermal absorption preparation of the present invention contains the above-mentioned estradiol and/or its ester and the above-mentioned absorption enhancer. Tape formulation. Patch agent. Poultices, ointments, cream preparations, and liniment preparations are available.

Among the above preparations, tape preparations and batch preparations have an adhesive layer containing a drug and an absorption enhancer formed on one side of a support. The base (adhesive) for tape preparations and batch preparations is not particularly limited as long as it has enough adhesive strength to fix the preparation to the skin surface for a long time at room temperature. For example, acrylic adhesives, rubber adhesives, silicone resin adhesives, etc. can be used, and are usually used. Acrylic adhesive is used.

Especially with acrylic adhesives, due to their adhesive properties.
A (co)polymer of a (meth)acrylic acid alkyl ester obtained from an aliphatic alcohol having 4 to 18 carbon atoms and (meth)acrylic acid, and/or the above (meth)acrylic acid alkyl ester and other functional monomers. A copolymer of is preferably used.

The above (meth)acrylic esters include butyl (meth)acrylate, isobutyl (meth)acrylate,
Hexyl (meth)acrylate, Octyl (meth)acrylate. 2-ethylhexyl (meth)acrylate,
Isooctyl (meth)acrylate, Decyl (meth)acrylate, Isodecyl (meth)acrylate. (meth)acrylic acid lauryl. Examples include stearyl (meth)acrylate.

The above functional monomers include monomers having a hydroxyl group. A monomer with a carboxyl group. Examples include monomers having an amide group and monomers having an amino group. Examples of monomers having a hydroxyl group include hydroxyalkyl (meth)acrylates such as 2-hydroxyethyl (meth)acrylate and hydroxybutyl (meth)acrylate. Acrylic acid is an example of a monomer having a carboxyl group. Examples include α-β unsaturated carboxylic acids such as methacrylic acid; maleic acid monoalkyl esters such as butyl maleate; maleic acid; fumaric acid; and crotonic acid. Maleic anhydride also provides the same (co)polymerization properties as maleic acid. Examples of monomers having an amide group include acrylamide, dimethylacrylamide, alkyl(meth)acrylamide such as diethylacrylamide; alcohol ether methylol(meth)acrylamide such as ptoxymethylacrylamide and ethoxymethylacrylamide, diacetone acrylamide; vinylpyrrolidone, etc. There is. As a heptanomer with an amino group. Examples include dimethylaminoacrylate.

Among acrylic adhesives, 45 to 80 mol% of 2-ethylhexyl acrylate (El{^) and N-vinyl-
Copolymers containing 20 to 55 mol% of 2-pyrrolidone (VP), especially 55 to 70 mol% of El{^ and VP 30 to 45
Copolymers containing mol % are preferred. H like this}
The copolymer containing IA and vp has a copolymerization ratio of 1
In addition, 35 mol% of acrylic esters other than EHA
It can be contained preferably in a proportion of 15 mol% or less.

Acrylic acid esters other than E}IA used here include proyl (meth)acrylate, butyl (meth)acrylate, hexyl (meth)acrylate, 2-
Ethylbutyl (meth)acrylate, heptyl (meth)
Acrylate octyl (meth)acrylate, nonyl [
[meth]acrylatedecyl (meth)acrylate, lauryl (meth)acrylate, etc.

In order to increase the cohesiveness of the acrylic copolymer, the polyfunctional monomer has an o.
It is preferably contained in a proportion of oos to 0.5%. Polyfunctional monomers include di(meth)acrylate, tri(meth)acrylate, and tetra(meth)acrylate.
Acrylates are mentioned. For that. Examples include hexamethylene glycol dimethacrylate and trimethylolpropane trimethacrylate.

As a support for tape preparations, batch preparations, and poultice preparations to be described later, supports commonly used for adhesive patches are used. The material for such a support is: cellulose acetate,
Ethyl cellulose, polyethylene terephthalate} (P
ET), plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride. Polyurethane. polyethylene. Examples include polyvinylidene chloride and aluminum. These are used, for example, as a single-layer sheet (film) or a laminate of two or more sheets (inconsistent). Materials other than aluminum may be used as woven or non-woven fabrics.

A drug-containing (adhesive) layer containing a drug and an absorption enhancer is formed on the surface of the support to obtain a tape preparation or a batch preparation. Various coating methods can be used to form the adhesive layer, such as a solvent coating method, a hot melt coating method, and an electron beam curing emulsion coating method. Among these, solvent coating methods are preferred. How to shape the adhesive layer using solvent coating method. For example, dilute the adhesive with an appropriate solvent and add the drug to it. Absorption enhancer. Furthermore, add compounding agents as necessary and mix uniformly. The obtained solution is applied to the surface of the support and dried. Instead of applying the solution directly to the surface of the support, it may be applied onto a release paper coated with silicone resin or the like, and after drying, the solution may be brought into close contact with the support. Such release paper is used to ensure the surface of the adhesive layer of the patch until use. The thickness of the adhesive layer also varies depending on the dosage form and purpose of use. Usually 53
It is 0 to 200 μm. If the diameter is less than 30 μm, the required amount of drug cannot be contained and the adhesiveness is insufficient.

If the thickness exceeds 200 μm, the drug contained in the adhesive layer near the support will not spread sufficiently, resulting in decreased drug release properties.

Vaps also have a drug-containing layer containing a drug and an absorption enhancer on one side of the support. It is usually fixed to the skin surface with a bandage because it has poor adhesiveness compared to tape or batch preparations. The main base of vasoplasty agents is:
for example. Natural polymers such as sodium alginate, gelatin, cornstarch, gum tragacanth; methylcellulose 2-hydroxyethylcellulose. Cellulose polymers such as carboxymethyl cellulose; starch polymers such as dextrin and carboxymethyl starch; polyvinyl alcohol and sodium polyacrylate. Methoxyethylene-maleic anhydride copolymer. Synthetic polymers such as polyvinyl ether and polyvinylpyrrolidone are used.

A desired poultice can be obtained by uniformly mixing the base material containing the above-mentioned polymer, the drug, and the absorption enhancer, and forming a drug-containing layer on the surface of the support.

The drug-containing layer further includes purified water; polyhydric alcohol (
for example. Humectants such as glycerin, brobylene glycol; kaolin, bentonite, zinc oxide. Inorganic fillers such as titanium dioxide; viscosity modifiers; crosslinking agents; anti-aging agents, etc. may be contained.

Millo is the main base for ointments and creams. Fats and oils. Lanolin. White petrolatum, paraffin. Plastibase, higher fatty acids, higher alcohols. Emulsifier, macrogol. Carboxyvinyl polymers and the like are used. An ointment or cream preparation is obtained by mixing a drug and an absorption enhancer with a base mainly containing these compounds. When mixing, add a ton of crotch if necessary. Liquid paraffin. Isoprovil myristate. Lipid-soluble solubilizers such as diethyl sebacate; Purified water: Water-soluble solubilizers such as ethanol and polyhydric alcohols (e.g. glycerin); Stabilizers,
A pHlm adjuster and the like are added.

(Function) The absorption enhancer contained in the formulation of the present invention changes the physical properties of the base or skin in the base or in the skin, and as a result, the distribution coefficient of the drug between the base layer and the skin changes. Alternatively, it is thought that the diffusion rate of the drug in the base, stratum corneum, epidermis, and dermis changes. Therefore. By containing the absorption enhancer. In a small area. A preparation is obtained that can maintain a high blood concentration of estradiol (ester) for a long period of time. for example. In tape formulations, sufficient medicinal efficacy can be obtained even in a small area. The absorption enhancer used in the present invention has no irritation to the skin and is highly safe.

Therefore, erythema can be avoided even in people who are sensitive to skin irritation. The preparation of the present invention, for example, in the case of a tape preparation, has a small area, so it is easy to apply and there is little discomfort when applied. Since the adhesive layer has a single and simple structure, it is easy to manufacture and can be made into a thin shape. This kind of tape formulation. Unlike the ethanol-containing patch disclosed in the prior art section, since it does not contain volatile components, the composition does not change during storage and a predetermined quality is maintained.

(Example) The present invention will be described below with reference to Examples.

2-ethylhexyl acrylate (EHA) 302.0
g (65 mol%), vinyl birolide 7 (VP) 98
．． 0 g (35 mol%) and hexamethylene glycol dimethacrylate}40.0■ (0.02% by weight based on the total monomers) were placed in a separable flask, and 70.6 g of ethyl acetate was added to adjust the monomer concentration. 85% by weight
And so. This solution. The mixture was heated at 60°C under a nitrogen atmosphere, and lauroyl peroxide (polymerization initiator) and ethyl acetate were added little by little. The polymerization reaction was carried out for 32 hours. A tetrahydrofuran solution of 17-β-estradiol and fumaric acid was added to the obtained polymer so that the solid content (sum of weight of polymer, estradiol, and fumaric acid) concentration was 22% by weight. In addition, estradiol and fumaric acid were added so that their solid content concentrations were 10.5% by weight and 2% by weight, respectively, and the mixture was uniformly mixed using a dissolver. Similarly, solutions were prepared in which the fumaric acid concentrations were 5% by weight and 7% by weight, respectively. Each of these solutions was coated onto a 40 μm thick polyethylene terephthalate (PET) release paper treated with silicon so that the thickness after drying would be 40 μm, and then dried. A corona-treated polyethylene support with a thickness of 50 μm was attached to this to obtain a patch. Table 1 shows a set of patches prepared in this example, Examples 2 to 3, and Comparative Examples 1 to 3, which will be described later.

Husband 2 ERA 2L5.2 g (45 mol%), vp
129.7 g (45-E-le%), 55.1 g (10 mole %) of decyl methacrylate. and 40.0 mg (0.01% by weight of total monomers) of trimethylolpropane triacrylate. The procedure was the same as in Example 1 except that the polymer was obtained in the same manner as in Example 1.

For the polymer-containing solution obtained in Akira Sanetoyo Main Example 1, l7β
Mono-estradiol, fumaric acid and isoprobil bilistate. The solid content in the solution (corresponding to the sum of the above-mentioned portion and the polymer) was added so that the amount was 25% by weight. However, 17β-estradiol is 1 out of the total solid content.
The contents were 0.5% by weight, 5.0% by weight of fumaric acid, and 2.0% by weight of ξisobrobylstate. Mix the mixture uniformly with a dissolver. A patch was obtained in the same manner as in Example 1. Separately,
Patches were prepared in which the content of isobrovir myristate was 5% by weight and 7% by weight instead of the above 2.0% by weight.

The procedure was the same as in Example 3, except that fumaric acid was not used and the concentration of ξisobrovir listate in the solid content was 5% by weight.

The procedure was the same as in Example 3, except that chloric acid was used instead of fumaric acid, which was the main flame stopper.

The procedure is the same as in Example 3, except that myristyl lactate was used instead of fumaric acid, which is the blocking agent.

(Left below) Actually. 12LL A test was conducted using the second patch from among the patches of Examples 1 to 3 and Comparative Examples 1 to 3.

For Examples 1 and 2, the solid concentration of fumaric acid was 5
For Example 3, the patch had a solid concentration of 5% by weight for each of fumaric acid and isobrovir myristate; For Comparative Example 2. The solid content concentration of danlystic acid and isobrovir chlorinate is 5, respectively.
Patch with solid content of 5% by weight: For Comparative Example 3, a patch in which the solid content of myristyl lactate and isoprobil myristate was 5% by weight was used. The amount of l7β-estradiol in these patches is 4flg each.
/10cJ. Another commercially available estradiol patch is Estraderm O. 05 (CIB
A patch manufactured by Company A (having the same structure as the patch disclosed in JP-A-57-154122) was used as the patch of Comparative Example 4.

For the patches obtained in the Examples and Comparative Examples of the present invention and the Estraderm described above, open the sealed aluminum packaging. Each was stored in air for 30 days. After saving. No precipitation of 17β-estradiol crystals was observed in any of the patches.

Use these patches. A drug permeation test through the skin was conducted. A diffusion cell 10 shown in FIG. 1 was prepared. This diffusion cell IO. It has a cylindrical receptor tank 1 with a bottom and a cylindrical donor tank 2 with a bottom and an opening 21 at the bottom. Donor tank 2 is located above receiver tank 1. They are stacked airtightly and concentrically via a pair of O-rings 3l and 32. The receptor tank 1 has a sampling hole 11 projecting laterally on its side. ○Ring 3
Between 1 and 32. The skin 4 used for the test is sandwiched, and the opening 21 of the donor tank 2 is completely covered by the skin 4.

Hairless mice (male, 6 weeks old) were killed by cervical dislocation.
Peel off the skin. The subcutaneous fat tissue was removed. Approximately 5 c+
A piece of skin measuring m x 5 cm was obtained. Add this to the patch 4 above.
1 (10 cd) and both O rings 31. of the diffusion cell 10. It was set for 32 hours. The receptor 11 was filled with the following receptor liquid, and the receptor liquid was stirred by the stirrer I2.

Receiver solution preparation method: Nall2PO45 in distilled water
XIO-'M, NaHzPOn 2 XIO-'M
, NaOH aqueous solution was added to a buffer solution containing NaC1 1.5 do.

The entire diffusion cell 10 was placed in a constant temperature bath maintained at 37°C. 1st, 3rd, 6th, 18th and 24th hours after the start of the test, the 1st reservoir fluid was collected from the sampling chamber 11 and replenished with 1 ml of new reservoir fluid. The drug concentration of the collected receptor fluid was measured, and the drug permeability was calculated. The number of experimental samples was 3. The average value was calculated. The results are shown in FIGS. 2 and 3.

From Figures 2 and 3. It can be seen that the patch of the present invention has superior permeability of 17β-estradiol through the skin compared to the patches of each comparative example.

In particular, the patch of Example 3 further containing a higher fatty acid ester as an absorption enhancer exhibits excellent drug release over a long period of time. Furthermore, it is clear that the patch of the present invention can maintain its excellent performance even without storing it under special conditions such as sealing the patch.

Tip 1 A patch (10c++1) similar to that used in Experimental Example 1 was applied to the screening area of 2 each of 3 subjects (healthy, male). After 72 hours, it was peeled off and collected.

This patch was extracted with methanol and analyzed by 8PLC.
The concentration of 7β-estradiol was measured. The patch of Comparative Example 4 was peeled off, cut into small pieces, and extracted with methanol. Calculate the drug remaining in the patch after removal from the drug concentration. The difference from the drug originally contained in the patch was defined as the amount transferred to the skin.

Table 2 shows the amount of skin transfer when each patch was used.

(The following is a blank space) Table 2 Table 2 shows that the patch of the present invention has an extremely large amount of drug transferred to the skin compared to each patch of the comparative example when the patch area is the same and the dose is the same.

Disaster relief 1 Two of the patches similar to those used in Experimental example 1 Examples 1-
3, and the patches of Comparative Examples 1, 3 and 4 (10CIa
) was prepared. The patch was applied to the hairless area of a rabbit (New Zealand White breed, 3-3.5 kg, male) that had a normal hairless area one week after shaving its back with clippers. Immediately before applying the patch, after applying it 1, 3, 5
．． Blood was collected from the right ear vein 7 and 24 hours later. The obtained blood was centrifuged and separated into a serum portion and a blood smear portion. Estradiol concentration in the serum portion was measured by radioimmunoassay (1?IA) method.

The above test was conducted with three rabbits per group for each formulation. FIG. 4 shows the relationship between the time after application and the concentration of estradiol in the blood. It is clear from FIG. 4 that when the patch of the present invention is used, estradiol in the blood is maintained at a high concentration for a long period of time. In particular, the effect of the patch of Example 3 which further contains a higher fatty acid ester as an absorption enhancer is significant.

(Effects of the Invention) According to the present invention, the drug contains estradiol and/or its ester, has high skin permeability, and can supply a sufficient amount of the drug even in a small area. Dermal absorption formulations are provided.

moreover. The drug is also recognized to have an excellent effect in that it is released in a predetermined amount over a long period of time. The adhesive base used in tape formulations does not irritate the skin, and skin damage such as redness is avoided. The formulation of the present invention can be widely used as a sustained release formulation of estradiol.

4. Fig. 1 is a perspective view showing a diffusion cell for testing the skin permeability of drugs contained in patches, and Figs. Figure 4 is a graph showing the relationship between the application time and the blood concentration of estradiol when the patch of the present invention and other patches are applied to the skin of rabbits.

that's all

Claims (1)

[Scope of Claims] 1. A transdermal absorption preparation containing a drug and an absorption enhancer for the drug in a base, wherein the drug is estradiol and/or an ester thereof; A transdermal absorption preparation, wherein the agent is a divalent carboxylic acid having 2 to 10 carbon atoms and/or a salt thereof. 2. The transdermal absorption preparation according to claim 1, wherein the divalent carboxylic acid is contained in a proportion of 0.1 to 30% by weight. 3. Furthermore, as another transdermal absorption enhancer, a carbon number of 10 to 1
2. The transdermal absorption preparation according to claim 1, which contains a higher fatty acid ester obtained from a higher fatty acid having 8 carbon atoms and an alcohol having 1 to 20 carbon atoms. 4. The transdermal absorption preparation according to claim 3, wherein the total amount of the transdermal absorption enhancer is 1 to 100 parts by weight based on 100 parts by weight of the base. 5. Claim 1, which is a tape preparation in which an adhesive layer containing the drug and the absorption enhancer is provided on one side of a support.
The transdermal absorption preparation described in . 6. The transdermal absorption preparation according to claim 5, wherein the adhesive base of the adhesive layer is an acrylic adhesive. 7. The acrylic adhesive has an alkyl group having 4 to 18 carbon atoms (meth)
It is a (co)polymer of an acrylic acid alkyl ester and/or a copolymer of a (meth)acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms and another functional monomer, and the adhesive contains ( The transdermal absorption preparation according to claim 6, wherein the meth)acrylic acid alkyl ester (co)polymer is contained in a proportion of 50% by weight or more.