KR100254319B1 - Estradiol patch and manufacturing method thereof - Google Patents

Abstract

PURPOSE: An estradiol patch having drug release regulating ability is provided, which maintains drug effect continuously and evenly, shows good adhesive ability to be stuck and removed repeatedly, keeps drug in matrix stably, and shows good drug-delivery rate. CONSTITUTION: A process for the preparation of estradiol patch comprises the steps of: pouring butylacrylate, 2-ethylhexyl acrylate, acrylic acid, acrylamide, glycidyl methacrylate, vinyl acetate, N-vinyl pyrrolidone and ethylacetate, and maintaining temperature at 80deg.C; adding benzoyl peroxide when temperature becoming 80deg.C, and maintaining reaction for 5hrs; cooling the reactant to get the acryl adhesives for drug layer; pouring the acryl adhesives, diethyltoluamide, estradiol, hardener(E10-X), and oleyl alcohol, and mixing till the mixture to be transparently by shaking; and removing bubbles and coating the prepared solution on polyester film, and drying to get the objective product.

Description

Estradiol patch and its manufacturing method

The present invention relates to an estradiol patch and a method of manufacturing the same, and more particularly, it is suitable for the treatment of menopausal disorders caused by the interruption of the supply of female hormones to postmenopausal women and to allow transdermal administration of estradiol, a female hormone Estradiol patch, a menopausal disorder.

Estradiol is a female hormone, and estradiol patch (trade name; Estraderm TTS, manufactured by Ciba-Geigy), which is distributed as a female hormone preparation for transdermal administration, contains a solution of estradiol dissolved in ethanol in a polyester film. Sealed with a drug release control membrane and coated with an adhesive on it, in this case, it is a relatively harmless absorption accelerator and uses ethanol which can dissolve estradiol well. There is an advantage that the emission control is easy. However, since a large amount of low-viscosity liquid ethanol is released, the physical properties of the adhesive layer on the skin are lowered, so that the adhesive is transferred to the skin, such a patch is not preferable in view of the nature of the formulation to be attached for a long time.

Meanwhile, the estradiol patch (trade name: β-Diol, manufactured by Ilyang Pharmaceutical Co., Ltd.) distributed in a matrix form, not a reservoir, is coated with an acrylic adhesive and a drug on an aluminum (Al) deposition film. Since there is no function of controlling the amount of release constantly, the amount of release of the drug is large after the adhesion to the skin, but the amount decreases with time. Eventually there is a problem that the drug dosage over time is not kept constant. In addition, since non-adhesive polymer materials such as powdered drugs such as estradiol and absorption accelerators are mixed with acrylic pressure sensitive adhesives, the adhesion to the skin is very weak, and since estradiol is incompatible with acrylic pressure sensitive adhesives, prolonged exposure to moisture When the drug is recrystallized in the matrix, in particular the release of the drug drops rapidly.

Therefore, in the art, the development of an estradiol patch with a good adhesive force and a constant amount of drug release per unit time is required to maintain the drug for a long time.

The present invention is to solve and improve the problems in the art, the first object is the ability to control the drug release in itself, the drug efficacy is continuously maintained uniformly and adhered to the skin many times as necessary, excellent adhesion. It is to provide a estradiol patch in the form of a matrix that can be detached and adhered to the skin so that the drug can be sufficiently delivered through the skin.

A second object of the present invention is the development of an acrylic pressure-sensitive adhesive to enable the drug to be stably present in the matrix.

It is a third object of the present invention to provide a method for producing the estradiol patch.

1 is a cross sectional view of an estradiol patch prepared according to the invention,

Figure 2 is a graph measuring the release amount of the drug for the estradiol patch prepared according to Preparation Example 4, Examples 1, 2 and Comparative Example 1 through Cadaver Skin,

FIG. 3 is a photograph (× 100) of a microscopic observation of crystal formation of a drug in a matrix for an estradiol patch prepared according to Example 1 of the present invention.

FIG. 4 is a photograph (× 100) of observing the crystal formation of a drug in a matrix through a microscope for an estradiol patch prepared according to Comparative Example 2.

<Explanation of symbols for main parts of drawing>

10: polyester film 20: drug layer

30: skin adhesion layer 40: release paper

An estradiol patch for achieving the object of the present invention is a polyester film, a drug layer in which estradiol is dissolved in an acrylic pressure-sensitive adhesive containing a functional group capable of hydrogen bonding with estradiol and an absorption accelerator, and a drug. The skin adhesion layer having a release control function is sequentially stacked. In particular, the estradiol patch of the present invention is characterized by having a composite laminate structure in which the drug layer and the adhesive layer are completely separated.

In addition, the patch synthesizes an acrylic pressure-sensitive adhesive containing 0.01 to 99% by weight of a compound having a functional group capable of hydrogen bonding with estradiol, coating a solution in which the drug is dissolved in the acrylic pressure-sensitive adhesive and absorption accelerator in a polyester film and Preparing a drug layer by drying, dissolving an emulsifier or organic salt penetration promoter in ethyl acetate, mixing and stirring an acrylic pressure-sensitive adhesive, coating it on a silicone coated paper and drying it, and then transferring the coating onto the drug layer to form a skin adhesion layer. It is prepared by a method comprising the step of forming a.

The present invention will be described in more detail as follows.

1 is a cross-sectional view of an estradiol patch according to the present invention. Referring to the drawings, the estradiol patch of the present invention, the drug layer 20, the skin adhesion layer 30 and the release paper 40 are sequentially stacked on the polyester film 10.

In the present invention, it is preferable that the polyester film 10 cannot pass moisture, which is a property of the female hormone patch that needs to be attached for a long time. This is to prevent the patch from detaching.

The drug layer 20 is composed of an acrylic pressure-sensitive adhesive, an absorption accelerator, and a drug. In the present invention, the drug is stabilized in the drug layer so as to hydrogen bond with estradiol during drying to maximize the content of the drug without recrystallization. A compound having a functional group that can be included in the acrylic pressure-sensitive adhesive. When the compound is dried, hydrogen bonds with estradiol to inhibit the diffusion of the drug in the drug layer to prevent recrystallization and improve solubility. Once attached to the skin, hydrogen bonds are destroyed by sweat emitted from the human body. Allow the drug to diffuse freely and be absorbed into the skin.

The compound having a functional group which plays such a role is at least one selected from N-vinylpyrrolidone, acrylamide, methacrylamide, 2-hydroxyethyl methacrylate, acrylic acid and methacrylic acid, and the content thereof is an acrylic pressure-sensitive adhesive It is 1-20 weight% of each composition. On the other hand, when the content of N-vinylpyrrolidone and acrylic acid is excessive, since the adhesiveness is poor, it is preferable to add N-vinylpyrrolidone in an acrylic pressure-sensitive adhesive component to 30% by weight or less and acrylic acid to 20% by weight or less.

In addition, the absorption accelerator may be selected from fatty acid alcohol, sorbitan monooleate, and bailsalt. The fatty acid alcohol may be selected from oleyl alcohol and derivatives thereof.

In addition to the absorption accelerator, it is preferable to contain a solvent that can dissolve the drug and can also be used as the absorption accelerator. Suitable solvents for this purpose are excellent in solubility in drugs and high boiling point, it is preferable to use diethyltoluamide, dimethylformamide, dimethyl sulfoxide, etc., which do not volatilize well after drying. If such a compound is used alone as a solvent, an excessive amount should be used in order to achieve sufficient transdermal absorption. As the amount of use increases, these solvents may cause skin rashes. It is good to use.

At this time, the content of the accelerator is preferably 10 to 30% by weight of the drug layer composition.

Estradiol added to the drug layer is preferably contained 1 to 90% by weight, preferably 10 to 30% by weight in a mixed solution with a good solvent.

As the polymer material constituting the drug layer, one or more selected from poly N-vinylpyrrolidone, polyamide, polyurethane, and ethylene-vinylacetate and an acrylic pressure-sensitive adhesive may be used alone or in combination.

The drug solution, that is, the matrix mixture of the drug-soluble polymer and the water-insoluble polymer is coated on a silicone coated paper or a polyester film, and after drying, the thickness is 10 to 100 μm, preferably 30 to 70 μm.

The skin adhesion layer 30 is 0.1 to 10% by weight in the skin adhesion layer composition of the emulsifier or organic salt component in the acrylic adhesive, preferably 0.1 to 0.5 in the case of an organic salt component, for example, Vailsalt. When used in weight percent, the moisture from the skin dissolves the salt and creates a constant micropath in the polymer structure of the skin adhesion layer without losing adhesion to the skin. You can get it.

At this time, emulsifiers include oleyl alcohol and sorbitan monooleate, and when used in the range of 5 to 10% by weight of the skin adhesion layer composition, the drug is fixed within a certain time without losing adhesion due to increased solubility in the drug. Can be released.

Such emulsifiers or skin penetration promoters of organic salt components are dissolved in ethyl acetate, mixed with an acrylic adhesive, stirred, and coated and dried on a silicone coated paper, wherein the drying thickness is preferably 5 to 40 μm.

In general, the skin adhesion layer 30 has a long delay time for the drug to be released if the adhesive is thickly coated in order to simply increase the adhesive force with the skin. In other words, if the thickness is greater than 40㎛ to increase the adhesive holding power is not good drug release, if the thickness is less than 5㎛ the adhesive holding strength on the skin is easy to drop even during the early sticking easily during the activity. Therefore, the skin adhesion layer 30 may be formed to a thickness of 5 ~ 40㎛, preferably 10 ~ 20㎛ so that the drug can be released at a constant rate while maintaining a strong adhesion to the skin.

Such estradiol patch according to the present invention contains a compound having a functional group capable of forming a hydrogen bond with the hydroxyl group of the drug contained in the adhesive layer to limit the movement of the drug in the matrix to prevent recrystallization and absorbed after skin adhesion Sweat breaks hydrogen bonds and releases smoothly.

Hereinafter, the present invention will be described in detail with reference to the following Examples, but the present invention is not limited by the Examples.

Production Example 1 Preparation of Acrylic Adhesive

In a 1000 ml three-necked flask equipped with a cooler and a thermometer, 96 g of butyl acrylate, 70 g of 2-ethylhexyl acrylate, 3 g of acrylic acid, 2 g of acrylamide, 5 g of glycidyl methacrylate, 22 g of vinyl acetate, and N-vinylpyrroli 32.23 g of pig and 300 g of ethyl acetate were added thereto and maintained at 80 ° C.

Then, when the temperature reached 80 ℃ 0.6g of benzoyl peroxide was added and the reaction was maintained for 5 hours while maintaining the temperature.

After completion of the reaction, the reaction product was cooled to obtain an acrylic pressure-sensitive adhesive for drug layer according to the present invention.

Production Example 2 Preparation of Acrylic Adhesive

An acrylic adhesive was prepared in the same manner as in Preparation Example 1, but the content of N-vinyl pyrrolidone was 43.6 g.

Preparation Example 3 Preparation of Drug Layer

31.5 g of the acrylic pressure sensitive adhesive prepared in Preparation Example 1, 4 g of diethyltoluamide, 1.3 g of ethistadiol, 1 g of a curing agent (E10-X), and 1 g of oleyl alcohol were added and stirred well until the solution became clear.

The solution is coated on a polyester film to have a thickness of 47 μm after drying.

Preparation Example 4 Preparation of Drug Layer

A drug layer was prepared in the same manner as in Preparation Example 3, except that an acrylic adhesive prepared according to Preparation Example 2 was used.

Example 1

0.72 g of oleyl alcohol and 0.18 g of sorbitan monooleate were added to 7.5 g of ethyl acetate and stirred well.

The above solution was mixed with 30 g of an acrylic adhesive (ST-97, manufactured by Suhtong Co., Ltd.), 0.6 g of a curing agent was added thereto, followed by stirring to remove bubbles.

The solution is coated on a release paper to have a thickness of 10 μm after coating.

This was coated on the drug layer prepared according to Preparation Example 3 above.

Example 2

80 g of natural rubber, 20 g of synthetic rubber, 30 g of terpene-based tackifier, 80 g of petroleum resin-based tackifier and 1 g of antioxidant were dissolved in toluene so as to have a solid content of 20% by weight.

0.72 g of oleyl alcohol and 0.18 g of sorbitan monooleate were added to 61.5 g of the solution, followed by stirring.

This was coated and dried on a release paper so that the thickness after drying was 10 μm.

This was a transfer coating on the drug layer prepared according to Preparation Example 3.

Example 3

A patch was prepared in the same manner as in Example 1, except that the transfer coating was performed on the drug layer prepared according to Preparation Example 4.

Example 4

A patch was prepared in the same manner as in Example 2, except that the transfer coating was performed on the drug layer prepared according to Preparation Example 4.

Comparative Example 1

Estraderm TTS 25 from Ciba-Geigy, which is distributed in the art, was used.

Comparative Example 2

Β-Diol of Ilyang Pharmaceutical, which is distributed in the art, was used.

Experimental Example 1

The amount of release from Cadaver Skin per unit area of the drug layer according to Preparation Example 4 and the patches according to Examples 1, 2 and Comparative Example 1 was measured and the results are shown in Table 1 and FIG. 1. .

As shown in Table 1 and the accompanying drawings, the drug layer containing the acrylic pressure-sensitive adhesive prepared according to the present invention, and the estradiol patch including the same, can be seen that the amount of drug release is uniform with time. It can be seen that the release of the drug can be efficiently controlled.

Experimental Example 2

The patch prepared according to Example 1 and Comparative Example 2 was tested for showing the recrystallization of the drug in the matrix, the results are shown in Figures 3 and 4 by observing through a microscope.

Experimental conditions were carried out under the conditions of RH 80%, 60 ℃, as a result of the patch according to Comparative Example 2 (Fig. 4) recrystallization occurred after about 24 hours, but the estradiol patch prepared according to the present invention (Fig. It can be seen that 3) delays or neglects the recrystallization.

As described in detail above, the estradiol patch according to the present invention has the ability to control drug solution release in itself, the drug is continuously maintained uniformly, has excellent adhesion to the skin and can be detached and detached as needed. When adhered to the skin, it has a merit that the drug can be sufficiently delivered through the skin. In addition, the drug layer contains a compound having a functional group capable of forming a hydrogen bond with the drug to prevent recrystallization of the drug, and when attached to the skin, the hydrogen bond is destroyed by sweat and the drug may be continuously released. .

Claims (8)

Functional group capable of hydrogen bonding with at least one estradiol selected from the group consisting of polyester film, N-vinylpyrrolidone, acrylamide, methacrylamide, 2-hydroxyethyl methacrylate, acrylic acid and methacrylic acid Estradiol having a structure in which an acrylic pressure-sensitive adhesive containing a compound having a compound and a drug layer in which estradiol is dissolved in an absorption accelerator, and a skin adhesion layer containing one or more skin penetration accelerators of an emulsifier or an organic salt component are sequentially laminated. Patch. The estradiol patch according to claim 1, wherein the acrylic pressure-sensitive adhesive contains N-vinylpyrrolidone to 30 wt% or less and acrylic acid to 20 wt% or less. The estradiol patch according to claim 1, wherein the drug layer contains at least one selected from poly N-vinylidone, ethylene-vinylacetate, polyurethane, and polyamide. The estradiol patch according to any one of claims 1 to 3, wherein the drug layer further comprises at least one compound selected from fatty acid alcohols, sorbitan monooleates, and wilsalt as absorption accelerators. The estradiol patch according to claim 4, wherein the fatty alcohol is at least one selected from oleyl alcohol and derivatives thereof. The estradiol patch according to claim 4, wherein the absorption accelerator is contained in 10 to 30% by weight of the drug layer composition. The estradiol patch according to claim 1, wherein the skin adhesion layer contains 0.1 to 10% by weight of one or more skin penetration accelerators of an emulsifier or an organic salt component. Synthetic an acrylic pressure-sensitive adhesive containing 1 to 20% by weight of a compound having a functional group capable of hydrogen bonding with estradiol, and the drug layer was coated and dried by coating a solution in which the drug is dissolved in the acrylic pressure-sensitive adhesive and absorption accelerator in a polyester film Preparing, dissolving an emulsifier or organic salt penetration promoter in ethyl acetate, mixing and stirring an acrylic pressure-sensitive adhesive, coating and drying the silicone-coated paper, and transferring the coating onto the drug layer to form a skin adhesion layer. Method for producing an estradiol patch.

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