KR100298569B1 - Patches containing salbutamol and preparation method thereof - Google Patents

Abstract

The salbutamol patch according to the present invention is made by laminating a specially prepared acrylic adhesive, a salbutamol-containing drug layer and a skin adhesion layer having a drug solution control function on a polyester film, and a specially prepared ethyl acetate solvent type acrylic adhesive. And coating and drying the drug solution in which the drug is dissolved in the absorption accelerator on the polyester film to form a drug layer (thickness of 10 to 100 μm); An emulsifier is added to the acrylic adhesive and stirred to coat and dry (thickness 5 to 40 μm) on a silicone coated paper, and then transfer the coating onto the drug layer to form a skin adhesion layer.

These salbutamol patches have their own drug release control ability, which keeps the drug's efficacy uniformly, and has excellent adhesion to the skin so that it can be attached and detached several times if necessary. It is useful as a therapeutic agent for bronchial disorders such as asthma due to its excellent drug delivery rate.

Description

Patches containing salbutamol and preparation method thereof

The present invention relates to a patch containing salbutamol and a method for manufacturing the same, and more particularly, to a bronchial disorder therapeutic agent and a preparation for the percutaneous administration of salbutamol, a bronchodilator and a beta2 sympathetic stimulant It is about how to.

Asthma is an airway hyperresponsiveness caused by various stimuli and is an obstructive disease of the airways accompanied by spasm of bronchial smooth muscle, increased mucus secretion, and difficulty in breathing.

Among the known asthma treatment drugs so far is salbutamol, which has been formulated and used in the form of an inhalator.

However, in consideration of the fact that bronchial asthma patients are mainly children or elderly people, the cause of the disease is mainly allergies, and the need for continuous treatment over a long period of time, especially at night, in the form of inhaled salbutamol Therapeutic agents hardly exert their therapeutic effects. It also comes with the inconvenience of having it at all times.

Considering this situation, it is urgently needed to formulate salbutamol, an asthma treatment drug, in a patch form rather than an inhaler form.

In view of this, US Pat. No. 5,068,103 selected from natural rubber, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymers, polyacrylic acid ester copolymers, acrylic acid-acrylic acid ester-vinyl acetate copolymers and petroleum resins. 20 to 70% of a tacky material containing a macromolecular support; And from ethylene diamine tetraacetic acid, potassium polyphosphate, sodium polyphosphate, potassium metaphosphate, sodium metaphosphate, dimethylglyoxime, 8-hydroxyquinoline, nitrilotriacetic acid, dihydroxyethylglycine, glycomic acid, citric acid and tartaric acid Salbutamol formed by spraying 0.01 to 2% of a selected metal ion sequestering agent, an effective amount of salbutamol or a pharmaceutically acceptable salt thereof, and salbutamol containing adhesive agent laminated to the adhesive agent on a support layer. A salbutamol containing plaster consisting of a containing layer is disclosed.

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 the adhesion to the skin is excellent and attached as needed In addition, the present invention provides a novel salbutamol patch in a matrix form, which is adhered to the skin and can be sufficiently delivered through the skin.

A second object of the present invention is to develop an acrylic pressure sensitive adhesive in which a drug can be stably present in a matrix.

It is a third object of the present invention to provide a method for producing such salbutamol patches.

1 is a cross-sectional view of a salbutamol patch according to the present invention,

Figure 2 is a graph measuring the matrix drug release in phosphate buffer for salbutamol patch prepared according to the present invention,

3A and 3B are graphs of drug release through hairless mouse skin permeation for salbutamol patches prepared according to the present invention.

* Description of the symbols for the main parts of the drawings *

10-Polyester Film 20-Drug Layer

30-skin adhesion layer 40-release paper

Salbutamol-containing patch of the present invention for achieving this purpose is a polyester backing material layer; Salbutamol and hydrogen selected from 5-50% by weight of salbutamol, an absorption accelerator and N-methyl-2-pyrrolidone, acrylamide, methacrylamide, 2-hydroxyethyl methacrylate, acrylic acid and methacrylic acid A drug layer containing a compound having a carboxyl group capable of bonding, but comprising an acrylic pressure-sensitive adhesive containing 14-40% by weight of acrylic acid; And a skin adhesion layer obtained by dissolving an emulsifier or a skin penetration promoter in ethyl acetate, and then mixing and stirring an acrylic pressure-sensitive adhesive, and then coating the film on a silicone-coated release film.

The patch having the above structure can hydrogen bond with salbutamol selected from N-methyl-2-pyrrolidone, acrylamide, methacrylamide, 2-hydroxyethyl methacrylate, acrylic acid and methacrylic acid. Synthetic acrylic pressure-sensitive adhesive containing a compound having a carboxyl group, but containing 14 to 40% by weight of acrylic acid, and the drug layer by coating and drying the solution in which the drug is dissolved in the acrylic pressure-sensitive adhesive and absorption accelerator on a polyester film Manufacturing step; And dissolving a curing agent and an emulsifier or skin penetration accelerator in ethyl acetate, mixing and stirring an acrylic pressure-sensitive adhesive, coating and drying the silicone-coated paper, and transferring it onto the drug layer to form a skin adhesion layer. There is a characteristic.

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

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

The polyester film 10 serves as a support, and when water is in contact with water through a bath or the like due to the nature of the patch to be attached for a long time, moisture may pass through the skin to prevent the patch from being separated from the skin. It is preferable to use a polyester film which cannot be used.

The drug layer 20 is composed of an acrylic pressure-sensitive adhesive, an absorption accelerator and a drug, the drug is stable in the drug layer can form a hydrogen bond with salbutamol during drying to maximize the content of the drug without recrystallization occurs A compound having a functional group present is contained in the acrylic pressure-sensitive adhesive. These compounds, when dried, form hydrogen bonds with salbutamol to inhibit the diffusion of drugs in the drug layer to prevent recrystallization and enhance solubility. Once attached to the skin, hydrogen bonds are released by sweat emitted from the human body. It is destroyed so that the drug can freely diffuse and be absorbed into the skin.

Compounds having such a functional group are selected from N-vinylpyrrolidone, acrylamide, methacrylamide, 2-hydroxyethyl methacrylate, acrylic acid and methacrylic acid, the content of each of the acrylic pressure-sensitive adhesive component 1 to 99% by weight (based on the solid content), preferably 10 to 30% by weight.

On the other hand, the acrylic acid added in the acrylic pressure-sensitive adhesive component itself is not tacky and only acts as a binder of the drug, it is a component to enhance the degree of crosslinking to prevent the drug movement and recrystallization. The content of such acrylic acid is preferably 14 to 40% by weight of the entire pressure-sensitive adhesive component.

In addition, the absorption accelerator may be selected from fatty acid alcohol, sorbitan monooleate, n, n-diethyl-m-toluamide, myristic acid, N-methyl-2-pyrrolidone and cinemaol. have.

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. As a suitable solvent, it is preferable to use diethyltoluamide, dimethylformamide, dimethylsulfoxide, etc. which are excellent in solubility in drugs and have high boiling points and are not easily volatilized after coating. If only such a solvent is used alone, an excessive amount should be used in order to achieve sufficient transdermal absorption. As the amount of the solvent increases, the solvent may cause skin rash, so it is better to use it with an absorption accelerator having less skin irritation. At this time, the content of the absorption promoter is 10 to 90% by weight, preferably 10 to 50% by weight of the drug layer composition.

The therapeutic drug contained in the drug layer, that is, salbutamol is preferably contained in 1 to 90% by weight, preferably 10 to 50% by weight of the mixed solution with the above good solvent.

In the meantime, ethyl alcohol or N-methyl-2-pyrrolidone may be selectively added to the drug layer as a cosolvent, and the content of N-methyl-2-pyrrolidone to be added as a cosolvent may be increased. It is preferred for complete dissolution to 200 to 1000 parts by weight relative to butamol.

The drug solution is coated on a silicone coated paper or a polyester film, but the thickness of the acrylic adhesive is 10 to 100 μm after drying, preferably 15 to 60 μm.

Since the acrylic pressure-sensitive adhesive constituting the drug layer of the present invention has an excessive amount of acrylic acid and thus has little adhesive property in itself, the adhesive pressure should be imparted including the skin adhesion layer.

The skin adhesion layer 40, which plays such a role, dissolves an emulsifier or a skin penetration accelerator in ethyl acetate, and then mixes and stirs it with an acrylic adhesive, which is coated and dried on a silicone coated paper (thickness 5 to 30 µm), and then the drug layer. It is formed by the transfer coating on.

The skin adhesion layer 40 is simply coated with a thick adhesive in order to increase the adhesive force with the skin, the delay time (lag time) for releasing the drug is long. In other words, if the thickness is thicker than 40㎛ in order to increase the adhesive holding force, the drug release is not good, and if the thickness is less than 10㎛, the adhesive holding force on the skin is easily dropped even during the initial sticking, but easily falls during the activity. Therefore, the skin adhesion layer 40 is preferably formed in 5 ~ 40㎛, preferably 10 ~ 20㎛ thickness so as to release the drug at a constant rate while maintaining a strong adhesion to the skin.

When the skin adhesion layer 40 uses an emulsifier or skin penetration accelerator in an acrylic adhesive to be 10 to 50% by weight in the composition of the skin adhesion layer, the cohesion of the polymer matrix is reduced and a constant micropath is made in the polymer structure of the skin adhesion layer. Given a certain amount of time within a certain amount of the drug to be released can be obtained.

In this case, oleyl alcohol and sorbitan monooleate may be used as the emulsifier, and when used in the range of 5 to 20% by weight of the skin adhesion layer composition, physical properties may be deteriorated due to the bonding of carboxyl groups contained in the adhesive layer in a large amount. It is possible to achieve the effect that the drug is released in a certain time without losing adhesion.

As described above, the salbutamol patch according to the present invention contains a large amount of acrylic acid in the acrylic pressure-sensitive adhesive constituting the drug layer to enhance the degree of crosslinking to prevent drug movement and recrystallization, thereby restricting drug movement in the matrix to prevent recrystallization. After the skin adheres, the hydrogen bonds are destroyed by the sweat absorbed and release occurs smoothly.

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

Example 1

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

(1) A 100 mL three-necked flask was equipped with a cooler and a thermometer, 148 g of butyl acrylate, 30 g of acrylic acid, 30 g of methyl methacrylate, 2 g of 2-hydroxyethylhexyl methacrylate, and 250 g of ethyl acetate were added thereto, and the temperature was 85 ° C. Was maintained.

(2) 0.5 g of benzoyl peroxide was added when the temperature reached 85 ° C., and the reaction was maintained for 5 hours while maintaining the temperature.

(3) The reaction was terminated and the reactant was cooled to prepare a pressure-sensitive adhesive for drug layer.

B. Salbutamol-Containing Drug Layer Formation

11.11g of ethyl acetate solvent-type modified acrylic pressure-sensitive adhesive having a solid content of 45% prepared above was dissolved in 4 g of salbutamol in 8 g of N-methyl-2-pyrrolidone, and then sufficiently stirred and coated on a polyester fabric at 120 ° C. It was dried for 5 minutes. At this time, the thickness after drying was 25.5 μm.

C. Manufacture of skin adhesive layer acrylic adhesive

(1) The drug layer adhesive and the production method are the same, except that in the monomer used, 107 g of butyl acrylate, 75 g of 2-ethylhexyl acrylate, 6 g of acrylic acid, 5 g of methyl methacrylate, and 2-hydroxyethylhexyl methacrylate 2 g, acrylamide 5 g, and ethyl acetate 300 g were used.

(2) 12.5 g of the skin adhesion layer acrylic pressure-sensitive adhesive is uniformly mixed with 2.22 g of the drug layer pressure-sensitive adhesive, and 1 g of oleyl alcohol and 2.18 g of a curing agent (5% of epoch solids and solvent toluene) are mixed with 2.5 g of ethyl acetate. After stirring together, the film was coated on a silicone-coated release film, and dried at 120 ° C. for 2 minutes to have a thickness of 10 μm.

(3) The skin adhesion layer adhesive was transferred onto the drug layer (B) using a compression roll to form a skin adhesion layer.

Example 2

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

An acrylic adhesive was prepared in the same manner as in Example 1.

B. Salbutamol-Containing Drug Layer Formation

Prepared in the same manner as in the matrix prepared in Example 1, containing 2g salbutamol and the thickness was coated to 45㎛ after drying.

C. Manufacture of skin adhesive layer acrylic adhesive

(1) It was prepared in the same composition and method as in Preparation Example 1.

(2) The skin adhesion layer adhesive was transferred onto the drug layer (B) using a compression roll to form a skin adhesion layer.

Example 3

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

An acrylic adhesive was prepared in the same manner as in Example 1.

B. Salbutamol-Containing Drug Layer Formation

Prepared in the same manner as in Example 1, containing 2 g of salbutamol and 4 g of N-methyl-2-pyrrolidone, adding 0.5 g of sorbitan monooleate as an absorption accelerator, and 10 g of ethyl acetate as an auxiliary solvent. Was used, the thickness was coated to 34.5㎛ after drying.

C. Manufacture of skin adhesive layer acrylic adhesive

(1) It was prepared in the same composition and method as in Example 1 above.

(2) The skin adhesion layer adhesive was transfer-coated on the drug layer (B) using a compression roll to form a skin adhesion layer.

Example 4

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

An acrylic adhesive was prepared in the same manner as in Example 1.

B. Salbutamol-Containing Drug Layer Formation

It was prepared in the same manner as in the matrix of Example 3, but 0.5 g of cineol (eucalyptol) was added as an absorption accelerator and then coated to have a thickness of 34.5 μm after drying.

C, skin adhesion layer acrylic adhesive manufacturing

(1) It was prepared in the same composition and method as in Example 1.

(2) The skin adhesion layer adhesive was transfer-coated on the drug layer (B) using a compression roll to form a skin adhesion layer.

Example 5

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

An acrylic adhesive was prepared in the same manner as in Example 1.

B. Salbutamol-Containing Drug Layer Formation

The salbutamol containing drug layer was manufactured and formed in the same composition and method as the matrix prepared in Example 1.

C. Manufacture of skin adhesive layer acrylic adhesive

(1) It was prepared in the same composition and method as in Example 1, but the coating thickness was 20㎛ after drying.

(2) The skin adhesion layer adhesive was transferred onto the drug layer (B) using a compression roll to form a skin adhesion layer.

Example 6

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

An acrylic pressure-sensitive adhesive was prepared in the same manner as in Example 1.

B. Salbutamol-Containing Drug Layer Formation

Prepared in the same manner as in the matrix of Example 1, 22.22 g of an acrylic pressure-sensitive adhesive was used, 1 g of n, n-diethyl-toluamide was prescribed as an absorption accelerator, and 35 g of ethyl acetate was added as a co-solvent, followed by coating. The thickness was adjusted to 34.5 μm after drying.

C. Manufacture of skin adhesive layer acrylic adhesive

(1) It was prepared in the same composition and method as in Example 1.

(2) The skin adhesion layer adhesive was transfer-coated on the drug worm (B) using a compression roll to form a skin adhesion layer.

Example 7

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

An acrylic adhesive was prepared in the same manner as in Example 1.

B. Salbutamol-Containing Drug Layer Formation

Prepared in the same manner as in Example 6, 1g of glycerin was prescribed as an absorption accelerator, and the coating thickness was 34.5㎛ after drying.

C. Manufacture of skin adhesive layer acrylic adhesive

(1) It was prepared in the same composition and method as in Example 1.

(2) The skin adhesion layer adhesive was transferred onto the drug layer (B) using a compression roll to form a skin adhesion layer.

Example 8

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

An acrylic adhesive was prepared in the same manner as in Example 1.

B. Salbutamol-Containing Drug Layer Formation

It was prepared in the same manner as in Example 6, except that 1 g of myristic acid was prescribed as an absorption accelerator, and the coating thickness was 34.5 μm.

C. Manufacture of skin adhesive layer acrylic adhesive

(1) It was prepared in the same composition and method as in Example 1.

(2) The skin adhesion layer adhesive was transferred onto the drug layer (B) using a compression roll to form a skin adhesion layer.

Example 9

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

An acrylic adhesive was prepared in the same manner as in Example 1.

B. Salbutamol-Containing Drug Layer Formation

Prepared in the same manner as in Example 6, 3.4 g of salbutamol was used, 20 g of ethyl acetate as a co-solvent was used, and no absorption accelerator was used. The coating thickness was 35 μm after drying.

C. Manufacture of skin adhesive layer acrylic adhesive

(1) It was prepared in the same manner as in Example 1 except that 2 g of N-methyl-2-pyrrolidone and 0.6 g of salbutamol were dissolved and the coating thickness was 12 μm.

(2) The skin adhesion layer adhesive was transferred onto the drug layer (B) using a compression roll to form a skin adhesion layer.

Example 10

A. Preparation of ethyl acetate solvent type modified acrylic adhesive

An acrylic adhesive was prepared in the same manner as in Example 1.

B. Salbutamol-Containing Drug Layer Formation

The matrix was prepared in the same manner as in Example 1, except that 0.5 g of myristic acid as an absorption accelerator and 5 g of ethyl alcohol and 12 g of ethyl acetate were used as auxiliary solvents, and the coating thickness was 26.25 μm.

C. Manufacture of skin adhesive layer acrylic adhesive

(1) It was prepared in the same composition and method as in Example 1.

(2) The skin adhesion layer adhesive was transfer-coated on the drug layer (B) using a compression roll to form a skin adhesion layer.

Experimental Example 1

For each salbutamol patch prepared according to the above example, the amount of drug per unit area (loading amount), adhesiveness, the drug release trend experiment of the matrix, and the amount of drug release using the hairless mouse skin were measured. The results are shown in the following Tables 1 to 4, and the drug release over time is shown in FIGS. 2, 3a and 3b. At this time, the sample area was 10 cm ² in each experiment.

As shown in Tables 3 and 4, the salbutamol patch prepared according to the embodiment of the present invention exhibits different release amounts depending on the control of the skin adhesion layer, the drug concentration of the drug layer, and the type of absorption accelerator used. It can be seen that can be efficiently controlled.

In particular, the release amount of the matrix and the release amount of the drug solution using the hairless mouse skin are shown in FIGS. 2 and 3a and 3b to easily confirm the release effect determination according to the present invention.

As described in detail above, the salbutamol patch according to the present invention has the ability to control drug solution release on its own, and thus the drug is continuously maintained uniformly and has excellent adhesion to the skin. It adheres to the skin and has a merit that the drug can be sufficiently delivered through the skin, and has a functional group capable of forming hydrogen bonds with the drug in the drug layer to prevent recrystallization of the drug and sweat when attached to the skin. This breaks the hydrogen bonds, allowing the drug to be released continuously.

Claims (6)

A layer of polyester backing material; A drug layer comprising 5-50 wt% of salbutamol, an absorption accelerator, and an acrylic pressure-sensitive adhesive containing 2-hydroxyethyl methacrylate and acrylic acid, but containing 14-40 wt% of acrylic acid; And a salbutamol patch having a structure in which a skin adhesion layer obtained by dissolving an emulsifier or a skin penetration promoter in ethyl acetate and then mixing and stirring an acrylic pressure-sensitive adhesive and then coating it on a silicone-coated release film. The patch containing salbutamol according to claim 1, wherein the thickness of the acrylic adhesive constituting the drug layer is 10 to 100 µm. The method of claim 1, wherein the absorption accelerator is selected from oleyl alcohol, sorbitan monooleate, n, n-diethyl-m-toluamide, myristic acid, N-methyl-2-pyrrolidone and cineol. Salbutamol-containing patch, characterized in that. The patch containing salbutamol according to claim 3, wherein the N-methyl-2-pyrrolidone is contained in an amount of 200 to 1000 parts by weight based on 100 parts by weight of salbutamol. The salbutamol patch according to claim 1, wherein the skin adhesion layer has a thickness of 5 to 40 µm. Synthetic acrylic pressure-sensitive adhesive containing 2-hydroxyethyl methacrylate and acrylic acid, but containing 14 to 40% by weight of acrylic acid, and 5-50 weight of salbutamol on the acrylic pressure-sensitive adhesive and absorption accelerator on polyester film Coating and drying the dissolved solution so as to form a drug layer; And salbutamol comprising dissolving an emulsifier or a skin penetration accelerator 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 a containing patch.