JP2552716B2 - Transdermal patch - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention contains estradiol and / or its ester as a drug and supplies the drug by transdermal absorption to stabilize the blood concentration of the drug over time. The present invention relates to a transdermal patch that can achieve the following.

(Prior Art) Estradiol and its ester are known as one of female hormones, and they are effective as drugs for menopausal disorders and abnormal menstruation in women. When this drug is administered orally, the liver metabolism rate is high, so that the burden on the liver is large, and the drug's bioavailability is significantly reduced by metabolism. Therefore, this drug is usually administered by injection. However, when the drug is administered by injection, the blood concentration of the drug temporarily rises, but the blood concentration is not maintained for a long time, and the drug must be frequently administered. Therefore, the use of sustained-release preparations is desired, and for example, transdermal preparations are considered to be suitable. However, it is generally difficult to administer a sufficient amount of drug through the skin, because the skin has a biological defense function of spuning foreign substances into the body. Therefore, it has been attempted to increase the area of the drug-containing patch or to add a transdermal absorption enhancer, but the drug release property is still not sufficient.

In order to effectively transdermally administer estradiol or its ester, for example, JP-A-57-154122 discloses a multilayer patch. This patch comprises a support, and a drug-enhancing agent-containing layer, a diffusion film layer, and a pressure-sensitive adhesive layer, which are sequentially laminated on the support. 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 hydroxypropyl cellulose or the like. Both the drug and ethanol permeate the diffusion membrane layer and the pressure-sensitive adhesive layer and are absorbed through the skin.
The absorption rate of ethanol through the skin is about 100-800 mcg /
hr / cm ² , therefore, the drug dissolved in ethanol also promotes absorption through the skin. Drug release can be controlled by the amount of ethanol used. However, since such a patch has a multi-layer structure,
The manufacturing process is complicated, and when applied to the skin, it gives a feeling of strangeness due to its thickness. Since volatile ethanol is used, it has the drawback that ethanol is volatilized during storage or after application, changing the drug release capacity. Since ethanol is irritating to the skin, it is highly likely to cause skin damage such as redness. Furthermore, since a diffusion film layer (which functions as a control film) is present, the release of ethanol and drugs cannot be said to be sufficient, and in order to obtain satisfactory drug efficacy, a patch with a relatively large area should be used. I need.

Japanese Patent Laid-Open No. 61-155321 discloses that an estradiol-containing adhesive is formed on a support, and a rubber, an adhesive resin material,
And a polymer capable of swelling in water, such as galactomannan. This patch does not become bulky like the above-mentioned patch having a multi-layered structure, and can supply a drug relatively stably in a predetermined period. However, the overall drug release is still not sufficient.

(Problems to be Solved by the Invention) The present invention is to solve the above-mentioned conventional problems, and an object of the present invention is to contain estradiol and / or its ester, and to enhance the skin permeability of the drug,
It is intended to provide a transdermal absorption patch capable of supplying a sufficient amount of a drug even in a small area. Another object of the present invention is to
An object of the present invention is to provide a percutaneous absorption patch which has the above-mentioned excellent properties, does not damage the skin, and has a simple structure, which is easy to manufacture.

(Means for Solving the Problems) The inventors have found an adhesive base which can dissolve estradiol and / or its ester at a high concentration and has low skin irritation, and by using this, estradiol and / or We succeeded in obtaining a transdermal patch with high ester release.

The transdermal patch of the present invention is a transdermal patch in which an adhesive layer containing a drug in a compatible state and in a stable supersaturated state is provided on a drug-impermeable flexible support. hand,
The adhesive base of the adhesive layer contains 2-ethylhexyl acrylate as a main component in a proportion of 45 to 80 mol%, and N-
The main component is a copolymer containing vinyl-2-pyrrolidone in a proportion of 20 to 55 mol%, and the drug is estradiol and / or its ester, and the drug concentration in the adhesive layer is 6 ~ 25% by weight, which achieves the above objectives.

Here, containing the drug in a stable supersaturated state means that when the drug crystal is placed on the surface of the adhesive base, the crystal does not disappear or dissolve with time, and the crystal does not grow.

The medicinal component 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, cypionic acid ester, propionic acid ester and the like. This drug is the total weight of the adhesive layer (adhesive base,
6 to 25% by weight, preferably 8 to 20% by weight, based on the total weight of the drug and, if necessary, the percutaneous absorption enhancer.
More preferably, it is contained in a proportion of 10 to 14% by weight. If it is too small, the drug effect is insufficient, and if it is too large, the drug crystallizes in the adhesive base and is not sufficiently released.

The adhesive base used in the patch of the present invention contains a copolymer containing 2-ethylhexyl acrylate (EHA) and N-vinyl-2-pyrrolidone (VP) as copolymerization components as main components. The content of EHA is 45 to 80 mol%, preferably 55 to 70 mol%, and the content of VP is 20 to 55 mol%, preferably 30 to 45 mol%. Too much EHA and too little VP will reduce the solubility of estradiol and / or its ester. On the contrary, if the amount of VP is excessive and the amount of EHA is too small, the adhesive properties deteriorate and the sticking property deteriorates. If desired, such a copolymer may further contain a (meth) acrylate monomer as a copolymerization component. The carbon number of the (meth) acrylate monomer is preferably 6 to 16, and examples thereof include propyl (meth) acrylate, butyl (meth) acrylate, hexyl (meth) acrylate, 2-ethylbutyl (meth) acrylate and heptyl. There are (meth) acrylates, octyl (meth) acrylates, nonyl (meth) acrylates, decyl (meth) acrylates and lauryl (meth) acrylates. The content of (meth) acrylate monomer is 35 mol% or less, preferably 15
It is not more than mol%. If it is excessive, estradiol and its ester cannot be compatible with each other at a high concentration. Further, in order to improve the cohesiveness of the copolymer, the polyfunctional monomer is used in an amount of 0.005 to 0.5% by weight of all the monomers forming the copolymer.
It is preferable to contain it in a ratio of. Polyfunctional monomers include di (meth) acrylate, tri (meth) acrylate, and tetra (meth) acrylate, including hexamethylene glycol dimethacrylate, trimethylolpropane triacrylate, and the like.

A transdermal absorption enhancer is contained in the adhesive base as needed. As the percutaneous absorption enhancer, both a fatty acid ester compound and a compound having an amide bond are used in combination. As the fatty acid ester, a fatty acid ester obtained from a fatty acid having 10 to 18 carbon atoms and an alcohol having 1 to 20 carbon atoms is used. As the fatty acid ester, isopropyl myristate and / or isopropyl palmitate are preferable, and isopropyl myristate is particularly preferable.

Examples of compounds having an amide bond include N-acyl sarcosine and fatty acid ethanolamide. N-
The acyl group of acyl sarcosine preferably has 6 to 18 carbon atoms. For example, N-lauroyl sarcosine is preferably used. As fatty acid ethanolamides, both mono- and diethanolamides can be used. These alkylene oxide adducts can also be utilized. The fatty acid constituting the fatty acid ethanolamide preferably has 12 to 16 carbon atoms. For example, lauroyl monoethanolamide, palmitic acid monoethanolamide, myristic acid diethanolamide, lauric acid
Myristic acid diethanolamide, coconut oil fatty acid monoethanolamide, polyoxyethylene-added lauroyl monoethanolamide, polyoxyethylene-added coconut oil fatty acid monoethanolamide, lauroyl diethanolamide, coconut oil fatty acid diethanolamide, polyoxyethylene-added lauroyl diethanolamide and Examples include polyoxyethylene-added coconut oil fatty acid diethanolamide. The number of added moles of the above polyoxyethylene adduct is suitably 1-40. Here, the number of addition moles being 1 means that the number of addition molecules of alkylene oxide is 1 per molecule in the case of monoethanolamide and 2 in the case of diethanolamide. .

The fatty acid ester is contained in an amount of 1 to 80 parts by weight, and the compound having an amide bond is included in an amount of 0.05 to 30 parts by weight, based on 100 parts by weight of the adhesive base. Both of them are contained in a total amount of 1.05 to 100 parts by weight with respect to 100 parts by weight of the adhesive base. In a preferred embodiment, the adhesive base 10
N-lauroyl sarcosine is 1 to 30 parts by weight, more preferably 3 to 6 parts by weight, and isopropyl myristate is 1 to 30 parts by weight, more preferably 2 to 12 parts by weight, based on 0 parts by weight. Contained in.

As a support for the patch, a drug-impermeable support usually used for patches is used. Materials for such a support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride. , Aluminum, etc. These are used, for example, as a single-layer sheet (film) or a laminate of two or more sheets (laminate).

A pressure-sensitive adhesive layer is formed on the surface of the above-mentioned support, which comprises a mixture of estradiol and / or its ester and, if necessary, a transdermal absorption enhancer and other additives in a pressure-sensitive adhesive base, to give a patch. To be To form the pressure-sensitive adhesive layer, various coating methods such as solvent coating method and hot melt coating method can be used. Among them, the solvent coating method is preferable. To form the adhesive layer by the solvent coating method, for example,
The adhesive base is diluted with an appropriate solvent, and the above-mentioned drug, and if necessary, an absorption promoter and other additives are added thereto and mixed uniformly, and the resulting solution is applied to the surface of the support and dried. . Instead of applying the solution directly to the surface of the support, the solution may be applied to a release paper coated with a silicone resin or the like, and then dried and then brought into close contact with the support. The thickness of the pressure-sensitive adhesive layer is not particularly limited, but is usually 30 to 200 μm.

(Operation) The adhesive base used in the transdermal patch of the present invention can dissolve estradiol and / or its ester at a high concentration. Therefore, the amount of drug released per unit area and unit time and the migration of the drug through the skin into the skin are extremely large. Furthermore, when the patch is applied to the skin, the contained drug has an excellent effect of being released in a predetermined amount over a long period of time. Thus, compared to the conventional estradiol-containing patch, a patch having the same area gives a patch with a large effective dose. In other words, a patch with a small area has the same effect as a conventional patch.

When the absorption enhancer is contained in the adhesive layer, the migration of the drug into the skin becomes higher. This is because the absorption enhancer changes the physical properties of the adhesive or the skin in the adhesive or in the skin, and as a result, the distribution coefficient of the drug between the adhesive layer and the skin changes, or the diffusion rate of the drug. Is thought to change. Thus, by containing the absorption enhancer, a patch capable of maintaining a high blood concentration in a small area for a long time can be obtained. On the other hand, when a conventional adhesive base with low drug solubility is used, the drug crystals are deposited on the adhesive layer in a size that can be visually observed, or in a size that can be observed by an optical microscope. To do. Even when the drug is supersaturated when the patch is prepared,
Preservation of this causes precipitation of drug crystals. When the drug is crystallized, the diffusion of the compatible drug is also hindered, so that the release rate of the drug and the total release amount of the drug are reduced. Furthermore, the release of the drug is not a predetermined rate, and the rate decreases with the application time.

Furthermore, the adhesive base of the patch of the present invention has high hydrophilicity and does not contain an acidic monomer such as (meth) acrylic acid, and therefore has extremely low skin irritation. Furthermore, as described above, a patch having a small area can provide sufficient medicinal effect, and thus even an individual sensitive to skin irritation can avoid erythema. Since the area is small, the sticking operation is easy and there is little discomfort when sticking. Since the adhesive layer has a single simple structure, it is easy to manufacture and can be prepared in a thin shape. Since this patch does not contain a volatile component unlike the patch containing ethanol disclosed in the section of the prior art, the composition does not change during storage and the prescribed quality is maintained.

(Example) Hereinafter, the present invention will be described with reference to Examples.

Example 1 (A) Preparation of patch: 2-ethylhexyl acrylate (EHA) 302.0 g (65 mol%), vinylpyrrolidone (VP) 9
8.0 g (35 mol%) and hexamethylene glycol dimethacrylate 40.0 mg (0.02 wt% based on total monomer)
Was charged into a separable flask, and 70.6 g of ethyl acetate was added to adjust the monomer concentration to 85% by weight. This solution was heated at 60 ° C under nitrogen atmosphere, lauroyl peroxide (polymerization initiator) and ethyl acetate were added little by little, and the polymerization reaction was carried out for 32 hours. An ethyl acetate solution was obtained. A solution of 17-β-estradiol in tetrahydroflorane was added to the obtained polymer to give a solid content (weight sum of polymer and estradiol) of 22% by weight.
And the concentration of elastradiol in the solid content was 10.5% by weight, and this was uniformly mixed with a dissolver. Similarly, solutions were prepared so that the concentration of the estradiol was 12% by weight and 15% by weight. Each of these solutions was applied to a 38 μm-thick polyethylene terephthalate (PET) -siliconized release paper so that the thickness after drying was 40 μm, and then dried. A 38 μm-thick PET film support was attached to this to obtain a patch.

Example 2 EHA 215.2 g (45 mol%), VP 129.7 g (45 mol%), decyl methacrylate 55.1 g (10 mol%), and trimethylol propane triacrylate 40.0 mg (0.01 wt% of all monomers) were used. The same as Example 1, except that the polymer was obtained in the same manner as in Example 1.

Example 3 17β was added to the polymer-containing solution obtained in Example 1.
-Estradiol, N-lauroyl sarcosine and isopropyl myristate were added so that the solid content (corresponding to the total of the above components and the polymer) in the solution was 25% by weight. However, 17β-estradiol was added at 10.5% by weight, N-lauroylsarcosine at 1.0% by weight, and isopropyl myristate at 10.0% by weight based on the total solid content. The mixed solution was uniformly mixed with a dissolver, and a patch was obtained in the same manner as in Example 1. Separately, patches were prepared such that N-lauroyl sarcosine was 3% by weight and 5% by weight, respectively.

Comparative Example 1 The amount of EHA was 188.7 g (35 mol%), and the amount of VP was 211.3 g.
The polymer was prepared in the same manner as in Example 1 with g (65 mol%), and the patch was prepared according to Example 1. However, the concentration of 17β-estradiol in the solid content was 16,1
By setting the content to 8, 20 and 22% by weight, 4 kinds of patches were obtained.

Comparative Example 2 EHA amount of 377.5 g (85 mol%) and VP amount of 40.1 g
(15 mol%), the polymer was prepared in the same manner as in Example 1, and the patch was prepared according to Example 1. However, the concentration of 17β-estradiol in the solid content was 4, 6, 8
And 10.5% by weight to obtain 4 kinds of patches.

Comparative Example 3 EHA 294.8 g (80 mol%), 2-ethylhexyl methacrylate (EHMA) 39.7 g (10 mol%), dodecyl methacrylate 50.4 g (10 mol%) and dimethacrylate 1,6-hexane glycol 80 mg ( Polymerization was carried out in the same manner as in Example 1 using 0.02 mol%). Using the obtained polymer, four types of patches having estradiol concentrations in the solid content of 0.1, 0.3, 4.0, and 10.5 wt% were obtained.

Experimental Example 1 Using the patches obtained in Examples 1 to 3 and Comparative Examples 1 to 3 described above, the saturated solubility of 17β-estradiol was measured and the adhesive properties were evaluated. To measure the saturated solubility, part of the release paper of the patch was once peeled, 17β-estradiol fine powder was placed on the adhesive surface, and then the release paper was attached again, and this was placed in a bag made of an aluminum laminate film. The sample was sealed in a container and stored at room temperature for 1 month, and judged by the presence or absence of growth of the crystal (observed with an optical microscope; × 200). The adhesive property is the ball tack value at room temperature immediately after the production of each patch (adhesive tape / adhesive sheet test method JIS-Z0237
It was evaluated by measuring Table 1 shows the results. In the first column of crystal growth, ○ indicates that no crystal growth was observed; △ indicates that the crystal grew, and × indicates that the crystal clearly grew. . In the column of adhesive properties, ○ means
Good adhesive property is shown; and x means poor adhesive property.

From Table 1, it is clear that the patch of the present invention can retain a relatively high concentration of estradiol in a dissolved state for a long period of time; and has excellent adhesive physical properties. On the other hand, it can be seen that the patch of Comparative Example 1 using the adhesive base having a composition with a high VP content is inferior in adhesive physical properties. On the contrary, the adhesive patch of Comparative Example 2 using an adhesive base having a high EHA amount (low VP amount) and the adhesive patch of Comparative Example 3 using an adhesive base consisting only of an acrylate-based monomer are soluble in estradiol. Inferior to.

Experimental Example 2 Among the patches prepared in Examples 1 to 3 and Comparative Examples 2 to 3, a patch having a 17β-estradiol content of 10.5% by weight was used. The amount of 17β-estradiol in these patches is 4 mg / 10 cm ² , respectively. Separately, as a commercially available estradiol patch, Estraderm 0.05 (manufactured by CIBA; having the same structure as the patch disclosed in JP-A-57-154122) was used as the patch of Comparative Example 4.

The patches obtained in the above Examples and Comparative Examples of the present invention,
As for the above-mentioned Estraderm, the aluminum sealed packaging was opened and each was stored in air for 30 days. 17β after storage
− Optical microscope (× 20
I checked it in 0). As a result, Examples 1 to 3 and Comparative Example 4
No precipitation of crystals was observed in the patch of No. 3, and precipitation of crystals was observed in the patches of Comparative Examples 2 to 3.

A drug permeability test through the skin was performed using these patches. A diffusion cell 10 shown in FIG. 1 was prepared. The diffusion cell 10 has a cylindrical bottomed receptacle tank 1 and a cylindrical bottomed donor tank 2 having an opening 21 at the bottom. The donor tank 2 is stacked above the receptor tank 1 airtightly and concentrically via a pair of O-rings 31 and 32. The receptor tank 1 has a sampling port 11 protruding laterally on its side. The skin 4 used for the test is sandwiched between the O-rings 31 and 32, and the opening 21 of the donor tank 2 is entirely covered with the skin 4.

Hairless mice (male, 6 weeks old) were killed by cervical dislocation,
Peel off the skin and remove the subcutaneous fat composition, about 5 cm x 5 cm
A skin piece of The above patch (10 cm ² ) was attached to this, and it was set between both O-rings 31 and 32 of the diffusion cell 10. The receptor tank 1 is filled with the following receptor liquid,
The stirrer 12 stirred the receptor solution.

Receptor solution preparation method: NaH ₂ PO ₄ 5 × 10 ^-4 M, NaH _{2 in} distilled water
PO ₄ 2 × 10 ^-4 M, NaCl 1.5 × 10 ^-1 M and gentamicin 10 pp
The pH is adjusted to 7.2 by adding an aqueous solution of NaOH to a buffer solution containing m, and polyethylene glycol 400 is added to this at a ratio of 20% by weight to prepare a receptor solution.

The entire diffusion cell 10 was placed in a constant temperature bath maintained at 37 ° C. 1,3,6,18 and 24 hours after the start of the test, 1 ml of the receptor fluid was collected from the sampling port 11, respectively,
1 ml of fresh receptor fluid was added. The drug concentration of the collected receptor solution was measured and the drug permeability was calculated. The number of experimental samples was 3, and the average value was calculated. The results are shown in FIGS. 2 (a) and 2 (b). FIG. 2 (b) is a large scale of the vertical axis of FIG. 2 (a). In Fig. 2 (a) and (b),
Shows Example 1, + shows Example 2, ◇ shows Example 3, Δ shows Comparative Example 2, X shows Comparative Example 3, and ▽ shows the amount of drug permeation when the patch of Comparative Example 4 is used.

From FIGS. 2 (a) and 2 (b), it is understood that the patch of the present invention is superior in the permeability of 17β-estradiol through the skin as compared with the patch of each comparative example. In particular, the patch of Example 3 containing the absorption enhancer shows excellent drug release over a long period of time. Furthermore, it is clear that the patch of the present invention can maintain excellent performance without being kept under special conditions such as sealing the patch.

Experimental Example 3 The same patch (10 cm ² ) as that used in Experimental Example 2 was applied to the upper arm of each of three test subjects (healthy person, male), and after 72 hours, this was peeled and collected. The patch was extracted with methanol and the concentration of 17β-estradiol was measured by HPLC. After peeling, the patch of Comparative Example 4 was cut into small pieces and extracted with methanol. The drug remaining in the patch after peeling was calculated from the drug concentration, and the difference with the drug initially 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.

It can be seen from Table 2 that the patch of the present invention has an extremely large amount of drug transfer to the skin when the patch has the same area and the same dose as each patch of the comparative example.

(Effect of the Invention) According to the present invention, as described above, a drug which contains estradiol and / or its ester has a high skin permeability and a sufficient amount of the drug can be supplied even in a small area. A skin absorption patch is provided. Further, the drug has an excellent effect that it is released in a predetermined amount over a long period of time. A patch containing a predetermined absorption enhancer is further excellent in drug release. The adhesive base used in the patch has no skin irritation and avoids skin injuries such as redness. The patch of the present invention can be widely used as a sustained release preparation of estradiol.

[Brief description of drawings]

FIG. 1 is a perspective view showing a diffusion cell for testing the skin permeability of a drug contained in the patch, and FIGS. 2 (a) and 2 (b) are estradiol contained in the present invention and other patches. 3 is a graph showing the skin permeability of

Claims (4)

(57) [Claims] 1. A percutaneous absorption preparation in which a pressure-sensitive adhesive layer containing a drug in a compatible state and in a stable supersaturated state is provided on a drug-impermeable flexible support, the pressure-sensitive adhesive layer. The adhesive base of 2-ethylhexyl acrylate as a main component in a proportion of 45 to 80 mol% and N-
The main component is a copolymer containing vinyl-2-pyrrolidone in a proportion of 20 to 55 mol%, and the drug is estradiol and / or its ester, and the drug concentration in the adhesive layer is 6 ~ 25% by weight
Is a transdermal preparation. 2. The copolymer comprises 2-ethylhexyl acrylate in a proportion of 55 to 70 mol% and N-vinyl-acrylate.
The percutaneous absorption preparation according to claim 1, which contains 2-pyrrolidone in a proportion of 30 to 45 mol%. 3. The percutaneous absorption preparation according to claim 1, wherein the adhesive layer contains a percutaneous absorption promoter. 4. The percutaneous absorption preparation according to claim 1, wherein the percutaneous absorption enhancer contains a fatty acid ester and a compound having an amide bond.