JPH07247217A - Percutaneously absorbable pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To obtain a percutaneously absorbable pharmaceutical preparation, containing at least either of 17-beta-estradiol and its ester derivatives as a medicine, having low skin irritancy and capable of supplying a sufficient dose of a medicine in a small area. CONSTITUTION:This percutaneously absorbable pharmaceutical preparation comprises a base, a medicine and a percutaneous absorbefacient. The base is polyvinylpyrrolidone or polyethylene glycol and the medicine is at least either of 17-beta-estradiol and its ester derivatives. The percutaneous absorbefacient is one or more compounds selected from the group consisting of (a) a salt of an N-acylsarcosine, (b) a salt of an 8-18C higher fatty acid and (c) a higher fatty acid ester of a 10-18C higher fatty acid with a 1-20C aliphatic alcohol.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 17-β-as a drug.
The present invention relates to a percutaneous absorption preparation containing at least one selected from estradiol and its ester form.

[0002]

BACKGROUND OF THE INVENTION Estradiol and its ester form are known as ovarian hormones, and their administration is known to be a drug effective for menopausal disorders, reduction of osteoporosis and disorders such as menstrual disorders in women. . When this drug is orally administered, the liver is heavily metabolized, which imposes a heavy burden on the liver, and the bioavailability of the drug is significantly reduced. Therefore, this drug is usually administered by injection.

However, although the blood concentration of the drug is temporarily increased when the drug is administered by injection, the blood concentration is not maintained for a long time and frequent administration is required. Is desired. Examples of sustained-release preparations include transdermal preparations.

However, since the skin has a biological defense function of preventing the entry of foreign substances into the body, it is generally difficult to administer a sufficient amount of drug through the skin. Therefore, increasing the area of the drug-containing patch or using a percutaneous absorption enhancer together has been studied, but a sufficient one has not been obtained yet.

In order to effectively transdermally administer estradiol or its ester, a patch having a multi-layer structure in which a drug-enhancing agent-containing layer, a diffusion film layer and a pressure-sensitive adhesive layer are sequentially laminated on a support is disclosed. (JP-A-57-15412)
No. 2). In this patch, the drug-enhancing agent-containing layer is composed of a drug-containing gel containing estradiol in a gel-like substance obtained by gelling ethanol with hydroxypropylcellulose or the like. What are drugs and ethanol?
Both penetrate the diffusion membrane layer and the pressure-sensitive adhesive layer and are absorbed through the skin. The rate of absorption of ethanol through the skin is about 100-800 mg / hr / cm ² , which also promotes absorption of drugs dissolved in ethanol. Therefore, it becomes possible to control the release of the drug depending on the amount of ethanol used.

However, since the above-mentioned patch has a multi-layered structure, the thickness of the patch becomes thicker, which complicates the manufacturing process, gives a feeling of strangeness when applied to the skin, and uses volatile ethanol. There was a problem that ethanol was volatilized after application and the drug releasing ability was reduced. In addition, since ethanol is irritating to the skin, it is highly likely to cause skin disorders such as redness,
Furthermore, since a diffusion layer film (which functions as a control film) is interposed, the release properties of ethanol and drugs are not yet sufficient, and a relatively large patch area is required to obtain a satisfactory drug effect. There was a problem.

Further, a patch having an estradiol-containing pressure-sensitive adhesive layer formed on a support has been disclosed (Japanese Patent Laid-Open No. Sho 6-62).
No. 1-155321). This patch is an adhesive base,
The main component is a polymer that swells in water, such as rubber, an adhesive resin material, and galactomannan. This patch is not bulky like a patch having a multi-layered structure and can supply a relatively stable drug in a predetermined period, but the release of the drug as a whole was not sufficient. .

Further, a predetermined ratio (weight ratio 1: 1 to 1: 1).
A mixture of propylene glycol and glycerin of 5);
And, a transdermal preparation containing a pharmacologically acceptable solvent in which a drug is dissolved at a rate of 0.5 mg / ml as required is disclosed (JP-A-61-17513). With this formulation, it is possible to administer the drug relatively effectively to the skin under mild conditions.However, since a solvent is used, the release of the drug changes due to this volatilization, However, there is a problem in that a relatively large area of the preparation is required to obtain a satisfactory drug effect.

[0009]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned drawbacks, and an object thereof is to use at least one of 17-β-estradiol and its ester compound as a drug. The object of the present invention is to provide a percutaneous absorption preparation which contains, as an agent, has low skin irritation, and can supply a sufficient amount of drug in a small area.

[0010]

[Means for Solving the Problems]

The percutaneous absorption preparation of the present invention comprises a base, a drug and a percutaneous absorption enhancer.

As the above-mentioned base, polyethylene glycol (for example, "Macrogol ointment" in the Japanese Pharmacopoeia) or polyvinylpyrrolidone is used.

The above-mentioned bases, if necessary, include water-soluble solubilizers such as purified water, ethanol and polyhydric alcohols (eg glycerin) when mixed; fat-soluble solubilizers such as crotamiton, liquid paraffin and diethyl sebacate. A pH adjuster or the like may be added.

The above drug is at least one of 17-β-estradiol and its ester form.
Seeds are used, and the amount thereof is preferably 5 to 30% by weight, more preferably 8 to 15% by weight in the pressure-sensitive adhesive layer.

As the percutaneous absorption enhancer, one or more compounds selected from the group consisting of N-acyl sarcosine salt (a), higher fatty acid salt (b) and higher fatty acid ester (c) are used. .

Examples of the salt of N-acyl sarcosine (a) include salts of N-lauroyl sarcosine, coconut oil fatty acid sarcosine, N-stearoyl sarcosine, oleoyl sarcosine, palmitoyl sarcosine, and the like. For example, sodium salt, potassium salt,
Examples thereof include magnesium salt, calcium salt, aluminum salt and the like.

Examples of the higher fatty acid salt (b) include fatty acids having 8 to 18 carbon atoms such as capric acid, myristic acid, palmitic acid, lauric acid, stearic acid, palmitoleic acid, oleic acid, vaccenic acid and linoleic acid. , Linolenic acid and the like, and examples of the salt include sodium salt, potassium salt, magnesium salt, calcium salt, aluminum salt and the like.

The higher fatty acid ester (c) is an ester of a higher fatty acid having 10 to 18 carbon atoms and an aliphatic alcohol having 1 to 20 carbon atoms. Examples of the higher fatty acid having 10 to 18 carbon atoms include capric acid, lauric acid,
Examples include myristic acid, palmitic acid, stearic acid and the like. Examples of the aliphatic alcohol having 1 to 20 carbon atoms include methanol, ethanol, propanol, isopropanol, butanol, hexanol, pentanol, heptanol, octanol, decanol, cetanol and the like.

When the amount of the above-mentioned percutaneous absorption enhancer used is small, a sufficient percutaneous absorption enhancer effect cannot be obtained, and when the amount is large, the compatibility with the pressure-sensitive adhesive decreases and the adhesive strength decreases, so the pressure-sensitive adhesive layer The content is preferably 0.1 to 30% by weight, more preferably 3 to 15% by weight.

The percutaneous absorption preparation of the present invention is used as an ointment or cream preparation and can be obtained by mixing predetermined amounts of a base, a drug, a percutaneous absorption enhancer and the like.

Next, the present invention 2 will be described. Invention 2
The percutaneously absorbable preparation has a pressure-sensitive adhesive layer provided on a support, and the pressure-sensitive adhesive layer comprises a base, a drug and a percutaneous absorption enhancer.

The support is preferably a flexible and drug-impermeable material such as cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate. A single layer sheet made of a material such as a copolymer, an ethylene-methyl acrylate copolymer, plasticized polyvinyl chloride, polyethylene, polyurethane, polyvinylidene chloride, and aluminum is used, and two or more kinds of laminates are used. Further, materials other than aluminum may be used as a woven fabric or a non-woven fabric.

Polyvinylpyrrolidone is used as the above-mentioned base. If necessary, a flocculating aid such as a polymer such as methyl methacrylate, methacrylic acid, ethyl acrylate or a copolymer thereof, and a fluidity imparting agent such as glycerin may be added to this base.

The same components as those used in the present invention are used as the drug and the transdermal absorption enhancer.

The constitution of the transdermal patch of the present invention 2 is as described above, and the pressure-sensitive adhesive layer is formed on the support by a conventionally known method for producing a pressure-sensitive adhesive tape such as a solvent coating method. In the case of solvent coating, for example, a predetermined amount of a base, a drug and a percutaneous absorption enhancer are dissolved or dispersed in a solvent such as ethyl acetate, and then this is coated on a support and dried to give an adhesive. A method of forming a layer, a method of applying on a release paper and drying to form a pressure-sensitive adhesive layer, and transferring to a support are used. This release paper may be used to protect the adhesive layer of the patch until use.

When the thickness of the above-mentioned pressure-sensitive adhesive layer becomes thin, the required amount of drug cannot be contained and the adhesive force becomes insufficient, and when it becomes thick, the drug does not sufficiently diffuse into the pressure-sensitive adhesive layer and is effectively utilized. Therefore, the thickness is preferably 30 to 200 μm.

The percutaneous absorption preparation of the present invention 2 is preferably used as a tape preparation, a patch preparation and the like.

[0028]

EXAMPLES Next, examples of the present invention will be described. Example 1 5.6 g of polyethylene glycol (Japanese Pharmacopoeia “Macrogol ointment”), 1.2 g of 17-β-estradiol and 1.2 g of sodium N-lauroylsarcosine were placed in a mortar and uniformly mixed to transdermally. An absorption preparation was obtained.

(Example 2) Polyvinylpyrrolidone 180
Parts by weight, methyl methacrylate-methacrylic acid (2:
1) To 5.6 g (solid content conversion) of an ethanol solution (solid content concentration 47% by weight) of 10 parts by weight copolymer, 10 parts by weight ethyl acrylate-methyl methacrylate (1: 1) copolymer and 75 parts by weight glycerin. On the other hand, 5.0 g of methanol, 7.0 g of ethanol, 1.2 g of 17-β-estradiol and 1.2 g of sodium N-lauroylsarcosine were placed in a container and uniformly mixed using a mix rotor. On the polyethylene terephthalate film on which this mixed solution was released, the thickness after drying was 60 μm.
The adhesive layer was applied so as to have a thickness of m and dried in an oven at 60 ° C. for 30 minutes to form an adhesive layer, and then a polyethylene terephthalate film was laminated on the adhesive layer to obtain a transdermal absorption preparation.

Example 3 A transdermal preparation was obtained in the same manner as in Example 2 except that 1.2 g of sodium caprate was used instead of N-lauroylsarcosine sodium.

Example 4 Polyethylene glycol (Japanese Pharmacopoeia “Macrogol ointment”) 5.6 g, 17-β-
1.2 g of estradiol and 1.2 g of isopropyl myristate were placed in a mortar and uniformly dispersed and mixed to obtain a percutaneous absorption preparation.

Example 5 A transdermal preparation was obtained in the same manner as in Example 4 except that 1.2 g of isopropyl caprate was used instead of isopropyl myristate.

Example 6 A transdermal preparation was obtained in the same manner as in Example 4 except that 1.2 g of methyl linoleate was used instead of isopropyl myristate.

(Example 7) Polyethylene glycol (Japanese Pharmacopoeia "Macrogol ointment") 6.5 g, 17-β-
1.29 g of estradiol, 1.29 g of isopropyl myristate and 0.43 g of sodium N-lauroylsarcosine were placed in a mortar and uniformly mixed to obtain a transdermal preparation.

(Example 8) A transdermal preparation was obtained in the same manner as in Example 7 except that 0.43 g of sodium coconut oil fatty acid sarcosine was used in place of N-lauroyl sarcosine sodium.

Example 9 Instead of N-lauroylsarcosine sodium, oleylsarcosine sodium 0.
A transdermal preparation was obtained in the same manner as in Example 7 except that 43 g was used.

Example 10 In place of sodium N-lauroylsarcosine, isopropyl myristate 1.2 was used.
A transdermal preparation was obtained in the same manner as in Example 2 except that g was used.

Example 11 1.2 g of isopropyl caprate in place of N-lauroyl sarcosine sodium
A percutaneous absorption preparation was obtained in the same manner as in Example 2 except that was used.

Example 12 A transdermal preparation was obtained in the same manner as in Example 2 except that 1.2 g of methyl linoleate was used in place of N-lauroylsarcosine sodium.

Example 13 Polyvinylpyrrolidone 18
0 parts by weight, methyl methacrylate-methacrylic acid (2:
1) To 5.6 g (solid content conversion) of an ethanol solution (solid content concentration 47% by weight) of 10 parts by weight copolymer, 10 parts by weight ethyl acrylate-methyl methacrylate (1: 1) copolymer and 75 parts by weight glycerin. On the other hand, methanol 5.0 g, ethanol 7.0 g, 17-β-estradiol 1.29 g, isopropyl myristate 1.29
g and N-lauroyl sarcosine sodium 0.43 g
After being placed in a container and uniformly mixed using a mix rotor, a transdermal preparation was obtained in the same manner as in Example 1.

(Example 14) A transdermal preparation was obtained in the same manner as in Example 13 except that 0.43 g of sodium coconut oil fatty acid sarcosine was used in place of N-lauroyl sarcosine sodium.

(Example 15) A transdermal preparation was obtained in the same manner as in Example 13 except that 0.43 g of sodium oleylsarcosine was used in place of sodium N-lauroylsarcosine.

Example 16 0.43 g of sodium caprate in place of sodium N-lauroylsarcosine
A percutaneous absorption preparation was obtained in the same manner as in Example 13 except that the above was used.

(Example 17) 0.43 g of sodium oleate in place of N-lauroyl sarcosine sodium
A percutaneous absorption preparation was obtained in the same manner as in Example 13 except that the above was used.

(Example 18) 0.43 g of sodium linoleate in place of sodium N-lauroylsarcosine
A percutaneous absorption preparation was obtained in the same manner as in Example 13 except that the above was used.

Comparative Example 1 Polyethylene glycol (Japanese Pharmacopoeia "Macrogol ointment") 6.8 g and 17-β
-1.2 g of estradiol was placed in a mortar and uniformly dispersed and mixed to obtain a transdermal preparation.

Comparative Example 2 A percutaneous absorption preparation was obtained in the same manner as in Example 1 except that N-lauroylsarcosine sodium was used in place of N-lauroylsarcosine sodium.

(Comparative Example 3) A transdermal preparation was obtained in the same manner as in Example 2 except that the concentration of estradiol was set to 15% by weight based on the total solid content and sodium N-lauroylsarcosine was not used at all. .

Comparative Example 4 A percutaneous absorption preparation was obtained in the same manner as in Example 2 except that N-lauroylsarcosine was used in place of N-lauroylsarcosine sodium.

COMPARATIVE EXAMPLE 5 55 parts by weight of a silicone-based adhesive (“Shirasucon 355” manufactured by Dow Corning) and 45 parts by weight of a terpene resin in a tetrahydrofuran solution (solid content concentration 15% by weight) 84 g (solid content conversion), tetrahydrofuran 10 g, 17-β-estradiol 18 g and N-lauroylsarcosine sodium 18 g were placed in a container and mixed uniformly, and then a transdermal preparation was obtained in the same manner as in Example 1.

Performance Evaluation of Transdermal Preparations The transdermal preparations obtained in the above Examples and Comparative Examples are
The following performance evaluation was performed, and the results are shown in FIGS.
Shown in 2. (1) Skin Permeability Test (I) Using the Franz diffusion cell 1 shown in FIG. 1, a skin permeability test was performed to measure the skin permeation amount (μg). In FIG. 1, a diffusion cell 1 is a cylindrical bottomed receptor tank 2
And a cylindrical bottomed donor tank 3 disposed on the receptor tank 2. An opening 4 is provided at the center of the bottom wall of the donor tank 3, and an upper flange 5 and a lower flange 6 are provided at the lower end of the donor tank 3 and the upper end of the receptor tank 2, respectively. Further, a sampling port 7 protruding laterally is attached to the side wall of the receptor tank 2. The flange 5 and the flange 6 are overlapped with each other so as to face each other, and the receptor tank 2 and the donor tank 3 are stacked so as to be airtight and concentric.
A magnetic stirring bar 9 is placed inside the receptor tank 2.

Hairless mice (6 weeks old, ♂) were sacrificed by cervical dislocation, and immediately the back skin was peeled off, and subcutaneous fat and muscle layer were removed to obtain a skin piece 8 of about 5 cm × 5 cm.
The obtained skin piece 8 was sandwiched between the flange 5 and the flange 6 of the diffusion cell 1, and the opening 4 of the donor layer 3 was completely closed by the skin piece 8. 3 was attached to the central part of the skin piece 8 in the opening 4.

The receptor layer 2 was filled with the receptor solution and placed in a constant temperature bath maintained at a temperature of 37 ° C., and the magnetic stirrer 9 was rotated and stirred. Test start 3, 18
And 24 hours later, 1 ml of the receptor solution was collected from the sampling port 7 and 17-β- in the collected receptor solution was collected.
The amount of estradiol was measured by high performance chromatography, and the amount of skin permeation per test piece 3.14 cm ² was measured as shown in FIG.
3, 5-7. When collecting the receptor liquid, the receptor liquid was replenished after the collection. The test is n
= 3, and the average value was calculated.

The receptor liquid was NaH ₂ PO ₄ 5 × 10 ^-4.
mol, Na ₂ HPO ₄ 2 × 10 ^-4 mol, NaCl 1.5 × 10 ^-1 mol and gentamicin 10 ppm were dissolved in distilled water and the pH was adjusted to 7.2 by adding 1N aqueous solution of NaOH. It was prepared by blending 400 in a proportion of 20% by weight.

The following test pieces were used. (B) The preparations of Examples 1, 4 to 9 and Comparative Examples 1, 2, and 6 were applied to a polyethylene terephthalate film cut out in a circular shape (area 3.14 cm ² ) to give test pieces. (B) Examples 2, 3, 10-15 and Comparative Examples 3-5, 7
A test piece was obtained by cutting out the preparation ( ¹ ) into a circle (area: 3.14 cm ² ).

(2) Skin Permeability Test (II) A preparation having an application area of 10 cm ² was used as a test piece, and the test piece was applied to the abdomen of a Japanese white male rabbit (body weight: about 3 kg) from which hair had been removed on the previous day. Blood was collected from the ear veins 3, 9, 18 and 24 hours after application, and plasma obtained by a conventional method was analyzed by high performance chromatography to measure the drug concentration in the plasma.
The test was conducted with the sample number n = 3, and the average value is shown in FIG.
And 8 are shown.

(3) Skin Irritation Test A preparation cut into an application area of 3.14 cm ² was occluded and applied on the back of a New Zealand White male rabbit whose hair was shaved during acclimation. At the time of application, it was protected with gauze, fixed with a bandage and fitted with a neck ring. The skin was peeled off after being applied for 24 hours, and the skin irritation 30 minutes after peeling and 24 hours after the peeling, the naked eye determination and the color difference measurement were performed according to the Draize criterion. The test was carried out with the sample number n = 6, and the average value thereof is shown in Table 1.

[0058]

[Table 1]

[0059]

The composition of the percutaneous absorption preparation of the present invention is as described above, and as the percutaneous absorption promoter, one selected from the group consisting of higher fatty acid ester, acyl sarcosine salt and higher fatty acid salt. Since the above compounds are used, a sufficient amount of drug can be percutaneously absorbed in a small area without irritating the skin.

[Brief description of drawings]

FIG. 1 is a perspective view of a diffusion cell used in a skin permeability test (I).

FIG. 2 is a graph showing the results of a skin permeability test (I).

FIG. 3 is a graph showing the results of a skin permeability test (I).

FIG. 4 is a graph showing the results of skin permeability test (II).

FIG. 5 is a graph showing the results of skin permeability test (I).

FIG. 6 is a graph showing the results of skin permeability test (I).

FIG. 7 is a graph showing the results of skin permeability test (I).

FIG. 8 is a graph showing the results of skin permeability test (II).

[Explanation of symbols]

 1 Diffusion Cell 2 Receptor Tank 3 Donor Tank 4 Opening 5,6 Flange 7 Sampling Port 8 Skin Piece 10 Test Piece

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location A61K 9/06 F 9/70 353 363 364 47/12 E 47/14 E 47/16 E 47 / 32 B Z 47/34 B

Claims (2)

[Claims] 1. A percutaneous absorption preparation comprising a base, a drug and a transdermal absorption enhancer, wherein the base is polyvinylpyrrolidone or polyethylene glycol, and the drug is 17-
At least one kind of β-estradiol and its ester form, wherein the percutaneous absorption enhancer is
(A) N-acyl sarcosine salt, (b) carbon number 8 to 1
A salt of a higher fatty acid of 8 and (c) one or more compounds selected from the group consisting of a higher fatty acid ester of a higher fatty acid having 10 to 18 carbon atoms and an aliphatic alcohol having 1 to 20 carbon atoms, Percutaneous absorption preparation. 2. A percutaneous absorption preparation in which an adhesive layer comprising a base, a drug and a transdermal absorption enhancer is provided on a support, wherein the base is polyvinylpyrrolidone and the drug is 17 At least one of -β-estradiol and its ester form, wherein the percutaneous absorption enhancer is (a) a salt of N-acyl sarcosine and (b) has 8 carbon atoms.
To 18 salts of higher fatty acids and (c) one or more compounds selected from the group consisting of higher fatty acid esters of higher fatty acids having 10 to 18 carbon atoms and aliphatic alcohols having 1 to 20 carbon atoms. Percutaneous absorption preparation.