KR20100042319A - The composition of transepidermal drug delivery system containing tulobuterol - Google Patents

Abstract

PURPOSE: A percutaneous composition containing tulobuterol is provided to release bronchial smooth muscle and to treat dyspnea having asthma and respiratory disease. CONSTITUTION: A percutaneous composition has four layer comprising a support, drug layer, adhesive layer, and separation film. The drug layer contains tulobuterol and comprises acryl based adhesive of hydroxyl group and acryl based adhesive of carboxyl group in a ratio of 75-95:1. The adhesive layer comprises a rubber adhesive and tackifier. The acryl based adhesive of hydroxyl group and acryl based adhesive of carboxyl group comprise 2-ethylhexylacrylate, butylacrylate, ethylacrylate, isooctylacrylate, vinylacetate, methylacrylate, methylmethacrylate, ethylmethacrylate, acrylonitrile, or t-octylacrylamide.

Description

The composition of transepidermal drug delivery system containing tulobuterol}

The present invention relates to a transdermal absorbent formulation containing tulobuterol (alpha- (t-butylamino) methyl-3,5-diclobenzyl alcohol) for treating respiratory distress in asthma and respiratory diseases. In detail, the present invention is a transdermal absorption agent designed in four layers so that the drug is effectively absorbed through the skin and composed of a structure as shown in FIG. 1, which supports a drug layer and prevents contamination from the outside during application (1). ), Acrylic adhesive layer containing the main drug (2), rubber-based adhesive layer (3) in direct contact with the human skin, controlling the rate of drug release, protect the adhesive layer from foreign substances, and easily from the adhesive layer when using the product It is composed of a release paper or release film (4) to be separated. In particular, the present invention is to provide a transdermal absorbent formulation having a superior adhesive force than commercially available H (sales: HA), has a very low skin irritation, and transmits the drug through the skin at an equivalent level.

Tolubuterol has a secondary amine (I) with a molecular weight of 227

As an adrenaline drug, it selectively acts on the sympathetic β2 receptor to relax bronchial smooth muscle, so tulobuterol is useful for alleviating or treating breathing problems in asthma or respiratory disorders caused by airway narrowing. It has been used zero, and the development of a method of maintaining such bronchodilators in the body at an effective blood drug concentration for a long time has been of great interest in the pharmaceutical industry.

The present invention is a transdermal administration method that absorbs the drug through the skin, unlike the oral administration method, the drug can be continuously delivered to the body continuously for a long time, prevent the first metabolism in the liver, and also increase the patient's compliance Therefore, it has been known as a good way to reduce the frequency of drug administration and reduce side effects. However, the skin generally has very low permeability, and most drugs are not suitable for transdermal absorption in physicochemical or technically difficult to solve the human safety. Therefore, the drugs that can be developed for transdermal absorption are extremely limited. . Nevertheless, proposals for transdermal absorption preparations containing tulobuterol, a bronchodilator, have been made steadily.

In Japanese Patent No. 3930984, Tolubuterol contains a concentration higher than the solubility of the drug in the adhesive layer of the plaster, so that the drug is partially dispersed in the crystalline state in Japanese Patent Application Laid-Open No. 5-194202, Japanese Patent Publication No. 5-238953, Japanese Patent Application Laid-Open No. 7-285854, Japanese Patent Publication No. 7-25669 Explaining the prior art about the time-lapse stability and lowering the adhesion to the skin of the formulation, which is a problem of the adhesive layer of the plaster to absorb acrylic or transdermal By incorporating high concentrations of tulobuterol in rubber containing accelerators, it introduces excellent transdermal absorption, sustainability of drug and excellent adhesion to skin, even though it improves the quality of adhesion. Because of the potential for severe side effects such as erythema, itching or inflammation Without addition of a percutaneous absorption accelerator, and be capable of maintaining the continuity of the excellent transdermal absorption and efficacy.

In addition, the Republic of Korea Patent Registration 10-0535302 has a matrix layer comprising a tulobuterol, an acrylic adhesive, a permeation accelerator and a diffusion enhancer, and describes a transdermal absorption formulation having a thickness of 40 ㎛ to 225 ㎛, the Republic of Korea Patent 10-0439659 is a transdermal absorbent for an acrylic adhesive having a hydrophilic polymer grafted with an acrylic and a hydroxy group. The constructed matrix tulobuterol transdermal absorbent formulation is introduced.

As such, the main components of transdermal absorption preparations consist of drugs, adhesives, and transdermal absorption accelerators. Transdermal absorption accelerators are components that have a function of slightly damaging the skin so that the drug can be more easily permeated. Pharmaceutical research into the mechanism of safe absorption of dissolved main drug without damaging the skin through methods has been the core technology of transdermal absorption preparations.

The present inventors applied the structural characteristics of the main drug and the acrylic pressure-sensitive adhesive during the study of the transdermal absorption composition containing tulbuterol, and thus could prepare a physicochemically completely dissolved drug layer without adding the transdermal absorption accelerator. The percutaneous absorption agent in which the drug layer was laminated on the pressure-sensitive adhesive layer composed of a rubber-based pressure-sensitive adhesive penetrated the skin most efficiently with H, which is the control drug, and the adhesive layer did not contain the drug and the percutaneous absorption accelerator. Excellent adhesion, it was found that the skin irritation can be minimized to complete the present invention.

The present invention relates to a transdermal absorbent composition containing tulobuterol, a bronchial dilator, comprising a support layer, a drug layer in which the main drug is completely dissolved in an acrylic pressure sensitive adhesive, a pressure sensitive adhesive layer formed of a rubber pressure sensitive adhesive, and a release film. It is to provide a transdermal absorption agent that can effectively penetrate the drug through the skin through the structure, excellent adhesion, and minimize the skin irritation.

The present invention is a percutaneous absorption agent having a four-layer structure consisting of a support layer, a drug layer made of acryl-based adhesive containing tulobuterol, a rubber-based adhesive layer controlling a drug release rate, and a release film. It shows effective skin permeation effect in the range of, and it does not contain drugs and transdermal absorption accelerators in direct contact with the skin, so skin irritation is low even after long time use, and the adhesion is very good. Very useful for treating

In the present invention, in the transdermal absorbent formulation containing tulobuterol, which penetrates the drug most efficiently through the skin, has excellent adhesion, and minimizes skin irritation, the support, the drug layer, the adhesive layer, and the release film 4 It is a transdermal absorption agent formed in a layered structure.

The support used in the present invention may be used by selecting one of a polyester film deposited with aluminum or a non-woven polyester film so that the drug is administered in the skin direction without reverse diffusion, and the thickness of the support is The thickness of the support is preferably 25 μm to 50 μm at a level that does not cause discomfort when attached to the skin. In the present invention, a 35 μm-thick aluminum deposited polyester film was used.

The drug layer in the present invention is composed of a tulobuterol and an acrylic pressure-sensitive adhesive, the content of tulobuterol may be used 5 parts by weight to 15 parts by weight, and completely dissolved in the acrylic pressure-sensitive adhesive. The acrylic pressure sensitive adhesive is a pressure sensitive adhesive, in which an acrylic pressure sensitive adhesive having a functional group and a acrylic pressure sensitive adhesive having a carboxyl group is mixed and used at a constant ratio. Acrylic pressure sensitive adhesives are alkyl acrylates or alkyl methacrylates having 4 to 17 carbon atoms, such as 2-ethylhexyl acrylate, butyl acrylate, ethyl acrylate, isooctyl acrylate, vinyl acetate, methyl acrylate and methyl methacryl. Acryl type which consists of 1 type (s) or 2 or more types from the group which consists of a rate, ethyl methacrylate, an acrylonitrile, t-octyl acrylamide, and a functional group contains 1 type (s) or 2 or more types of monomers which have a hydroxyl group or a carboxyl group. It is an adhesive.

In the present invention, the acrylic pressure sensitive adhesive used in the drug layer may have a ratio of 75 to 95 to 1 ratio of the acrylic pressure sensitive adhesive having a hydroxyl group and the acrylic pressure sensitive adhesive having a carboxyl group. In particular, the tulobuterol contained in the drug layer in the present invention has a secondary amine group in its chemical structure and thus directly affects the dissolution and transdermal penetration rate of the drug because it is chemically bonded to the carboxyl group of the acrylic adhesive having a carboxyl group. Is given. Therefore, the composition ratio of the acrylic pressure-sensitive adhesive having a hydroxyl group and the acrylic pressure-sensitive adhesive having a carboxyl group in the present invention is a very important technique for controlling the dissolution rate and transdermal penetration rate. When the ratio of the acrylic pressure-sensitive adhesive having a hydroxyl group is less than 75, the composition ratio of the acrylic pressure-sensitive adhesive having a carboxyl group is relatively increased, so that the transdermal penetration efficiency is lowered. As a result, the drug release rate cannot be effectively controlled. In the present invention, the thickness of the drug layer is characterized in that 10㎛ to 35㎛.

In the present invention, the adhesive layer does not contain the drug as a part in direct contact with the skin, and is mainly composed of a rubber-based adhesive and a tackifier as a layer that controls the adhesive force and the dissolution rate of the drug. Rubber-based adhesives are polyisobutylene, polyisoprene, polybutene, polyisobutylene-polybutene copolymer, isoprene-isobutylene copolymer, styrene-diene-styrene copolymer (e.g., styrene-butadiene-styrene copolymer) , Styrene-isoprene-styrene copolymer), isoprene-butadiene copolymer, styrene-butadiene copolymer, etc. can be used one or two or more selected, tackifiers rosin glycerin ester, hydrogenated rosin glycerin ester, rosin Rosin derivatives such as pentaerythritol esters, alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins, terpene resins, maleic acid resins, carboxymethylcellulose or salts thereof, crospovidone, glycolic acid starch or salts thereof, alginic acid or salts thereof, locust 1 type (s) or 2 or more types can be mixed and used for vin gum, carrageenan, starch, etc. In the present invention, the adhesive layer is 32.5% to 95.0% by weight of polyisobutylene, 5.0% to 15.0% by weight of polybutene and 12.5% to 37.5% by weight of hydrogenated rosinglycerin ester, 0.1% to 10% by weight It is preferable to mix and use the sodium carboxymethylcellulose of%, the thickness of the adhesive layer in the present invention is characterized in that 5㎛ to 15㎛. If the thickness of the adhesive layer is less than 5㎛ the initial dissolution is high (burst effect), if it exceeds 15㎛ the dissolution rate is lowered overall and transdermal penetration efficiency is lowered.

The release film in the present invention is not particularly limited to protect the adhesive layer and provide convenience so that it can be easily separated from the adhesive layer when the product is used, but is not limited to polyester, polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, and the like. As the film or paper produced from the above, a laminated film of fine paper or glassine paper and polyolefin can be used. The release film is a silicone resin or a fluorine resin coated on the surface of the adhesive layer, it is preferable to use a polyethylene terephthalate film excellent in the long-term stability of the drug. As the release film in the present invention, a polyethylene terephthalate film having a thickness of 75 μm in which one surface was coated with a silicone resin was used.

Hereinafter, the present invention will be described in detail by Examples and Comparative Examples.

The examples and comparative examples in the present invention are taken from a number of repeated experiments carried out according to the experimental design method in order to help the understanding of the present invention the minimum example. Therefore, the content of the present invention is not limited to the following examples and comparative examples, and the addition order of each composition also describes one example in the production method, and therefore is not limited to the production method of the present invention.

Example 1.

The drug layer has a ratio of an acrylic pressure-sensitive adhesive having a hydroxy group which is a copolymer of 2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate and an acrylic pressure-sensitive adhesive having a carboxyl group which is a copolymer of vinyl acetate and butyl acrylate. Tolubuterol was completely dissolved in the mixed solution so that it was applied to a polyester support on which aluminum was deposited so as to have a thickness of 15 μm (tulobuterol content: 11.5 wt%). The pressure-sensitive adhesive layer was uniformly mixed with 65.0% by weight of polyisobutylene, 10.0% by weight of polybutene and 25.0% by weight of hydrogenated rosin glycerin ester, and applied to the release film at a thickness of 10 μm. The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 2.

The drug layer is a ratio of an acrylic pressure-sensitive adhesive having a hydroxy group which is a copolymer of 2-ethylhexyl acrylate, methyl acrylate and 2-hydroxyethyl acrylate, and an acrylic pressure-sensitive adhesive having a carboxyl group which is a copolymer of 2-ethylhexyl acrylate and vinyl acetate. Tolubuterol was completely dissolved in this mixed solution so as to be 75 to 1 and applied to a polyester support on which aluminum was deposited so as to have a thickness of 15 µm (tulbuterol content: 11.5 wt%). The pressure-sensitive adhesive layer was uniformly mixed with 72.5% by weight of polyisobutylene, 15.0% by weight of polybutene and 12.5% by weight of hydrogenated rosin glycerin ester, and applied to the release film at a thickness of 10 μm. The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 3.

The drug layer is an acrylic pressure-sensitive adhesive having a hydroxy group which is a copolymer of 2-ethylhexyl acrylate, methyl acrylate and 2-hydroxyethyl acrylate and a carboxyl group which is a copolymer of 2-ethylhexyl acrylate, methyl acrylate and acrylic acid. Tolubuterol was completely dissolved in the mixed solution so that the ratio of the pressure-sensitive adhesive was 95 to 1, and applied to the polyester support on which aluminum was deposited to have a thickness of 15 µm (tulbuterol content: 11.5 wt%). The pressure-sensitive adhesive layer was uniformly mixed with 60.0% by weight of polyisobutylene, 5.0% by weight of polybutene, and 37.5% by weight of hydrogenated rosinglycerin ester, and applied to the release film with a thickness of 10 μm. The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 4.

The drug layer is composed of an acrylic pressure sensitive adhesive having a hydroxy group which is a copolymer of 2-ethylhexyl acrylate, vinyl acrylate and 2-hydroxyethyl acrylate and a carboxyl group which is a copolymer of 2-ethylhexyl acrylate and vinyl acetate. Tolubuterol was completely dissolved in the mixed solution so that the ratio was 75 to 1 and applied to a polyester support on which aluminum was deposited so as to have a thickness of 15 μm (tulbuterol content: 11.5 wt%). The pressure-sensitive adhesive layer was prepared in the same manner as in Example 1, and the thickness of the pressure-sensitive adhesive layer was applied to the release film at 5 μm. The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 5.

The composition of the drug layer and the composition of the pressure-sensitive adhesive layer was prepared in the same manner as in Example 1, and the thickness of the drug layer was applied to the support at a thickness of 10 μm (tulobuterol content: 11.5 wt%) and the thickness of the adhesive layer at 15 μm. The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 6.

The composition of the drug layer, the composition and thickness of the pressure-sensitive adhesive layer was prepared in the same manner as in Example 1, and the thickness of the drug layer was applied to the support at 35 μm (tulbuterol content: 11.5 wt%). The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Comparative Example 1.

The drug layer has a ratio of an acrylic pressure-sensitive adhesive having a hydroxy group which is a copolymer of 2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate and an acrylic pressure-sensitive adhesive having a carboxyl group which is a copolymer of vinyl acetate and butyl acrylate. Tolubuterol was completely dissolved in the mixed solution so that it was applied to a polyester support on which aluminum was deposited to have a thickness of 30 µm (tulbuterol content: 11.5 wt%), and then laminated on a release film, followed by a constant temperature and humidity chamber (40 ± 2 ° C., 75 ± 5%) for 1 week.

Comparative Example 2.

The drug layer is such that the ratio of the acrylic pressure-sensitive adhesive which is a copolymer of 2-ethylhexyl acrylate, methyl acrylate and t-octyl acrylamide and the acrylic pressure-sensitive adhesive having a carboxyl group which is a copolymer of vinyl acetate and butyl acrylate is 74: 1. Tolubuterol was completely dissolved in the mixed solution, and applied to a polyester support on which aluminum was deposited so as to have a thickness of 15 μm (tulobuterol content: 11.5 wt%). The composition and thickness of the pressure-sensitive adhesive layer was prepared in the same manner as in Example 1. The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged under the same conditions as in Example 1.

Comparative Example 3.

The drug layer completely dissolves tolubuterol in a functional group-free acrylic adhesive which is a copolymer of 2-ethylhexyl acrylate, methyl acrylate, and t-octyl acrylamide so as to have a thickness of 15 μm (tolubuterol content: 11.5 wt%). Aluminum was applied to the deposited polyester support. The composition and thickness of the pressure-sensitive adhesive layer was prepared in the same manner as in Example 1. The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged under the same conditions as in Example 1.

Comparative Example 4.

The composition of the drug layer, the composition and thickness of the pressure-sensitive adhesive layer was prepared in the same manner as in Example 1, and the thickness of the drug layer was applied to the support at 9 μm (tulbuterol content: 11.5 wt%). The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Comparative Example 5.

The composition of the drug layer, the composition and thickness of the pressure-sensitive adhesive layer was prepared in the same manner as in Example 1, and the thickness of the drug layer was applied to the release film in 36㎛ (tulbuterol content: 11.5% by weight). The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Comparative Example 6.

The composition of the drug layer, the thickness and the composition of the pressure-sensitive adhesive layer was prepared in the same manner as in Example 1, the thickness of the pressure-sensitive adhesive layer was applied to the release film 16㎛. The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Comparative Example 7.

The composition of the drug layer, the thickness and the composition of the pressure-sensitive adhesive layer was prepared in the same manner as in Example 1, the thickness of the pressure-sensitive adhesive layer was applied to the release film at 4㎛. The drug layer applied to the support was laminated on the adhesive layer applied to the release film, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Experimental Example

In order to evaluate the quality level of the transdermal absorbents prepared in Examples 1 to 6 and Comparative Examples 1 to 7 and commercially available H (sales: HA), adhesion test, skin irritation degree, comparative dissolution Tests and transdermal penetration tests were performed. The adhesion test was measured by a tensile tester, and after dissolution and transdermal penetration, the content of tulobuterol was analyzed by HPLC. As an HPLC analysis condition, 80:20 mixture of 0.02M aqueous potassium dihydrogen phosphate solution and acetonitrile was used as the mobile phase, the injection amount was 20 µl, the flow rate was 1.2 ml / min, the detection wavelength was 211 nm, and the column was Agilent Zorbox XDB C18. Was used.

Experimental Example 1

Skin irritation test

Example 1 to Example 6, Comparative Examples 1 to 7 and H, which were cut into a circle having a diameter of 1.5 cm, were attached to each of the 20 subjects in the lower half of both arms, and the sample did not fall easily even in small movements. Fix it with an adhesive cloth. Eight hours after the sample was removed, the erythema state after 30 minutes after removing the sample was visually evaluated according to the evaluation scale of Table 1, the test results are shown in Table 2.

Table 1. Skin irritation index (5-point scale)

division -- - +- + ++ Scale 5.0 4.0 3.0 2.0 1.0

Table 2. Skin irritation of Examples 1 to 6, Comparative Examples 1 to 7 and H

Subject Example Comparative example H One 2 3 4 5 6 One 2 3 4 5 6 7 One -- -- -- -- -- -- +- -- +- -- - -- - +- 2 -- -- -- -- -- -- - -- + -- +- -- +- - 3 -- -- - -- -- -- + -- + -- + - + + 4 -- -- -- -- -- -- - - - - +- -- - - 5 -- -- -- - - - + - ++ - + - ++ ++ 6 -- -- -- -- -- -- - -- - -- +- -- - - 7 -- -- -- -- -- -- - -- + -- +- -- +- +- 8 -- -- -- -- -- -- - -- - -- +- -- - - 9 -- -- -- -- -- -- - -- - -- +- -- + - 10 -- -- - - -- -- + - ++ +- + - ++ + 11 -- -- -- -- -- -- + -- + -- + -- +- + 12 -- -- -- -- -- -- - -- - -- + -- +- - 13 -- -- -- -- -- -- + -- + -- - -- - + 14 -- -- -- -- -- -- - -- - -- - -- - - 15 -- -- -- -- -- -- - - - - - -- - -- 16 -- -- -- -- - - + -- ++ -- + -- + + 17 -- - - - - - ++ - ++ + ++ - + ++ 18 -- -- -- -- -- -- - -- - -- - -- - - 19 -- - -- -- - - +- - + -- + - + +- 20 -- -- - -- -- -- + - + - +- -- +- + Average 5.00 4.90 4.80 4.85 4.85 4.80 2.55 4.65 2.65 3.64 2.80 4.75 2.95 3.00

Experimental Example 2

Adhesion test

The adhesive force was applied to 20 test subjects after attaching Examples 1 to 6, Comparative Examples 1 to 7 and H to the chest or the back for 24 hours, and then evaluating the preference for adhesive force according to the evaluation scale of Table 3. And the average value is shown in Table 4.

Table 3. Adhesive Evaluation Scale (5 points)

division Very good great is average bad Very bad Scale 5.0 4.0 3.0 2.0 1.0

In addition, the adhesion to Examples 1 and H was measured using a tensile strength tester. In the test method, a sample was cut into 12 mm widths, and one end was attached to a phenolic resin test plate (25 mm width, 125 mm length, 5 mm thickness), which was left to stand in a thermostat at 37 ° C for 30 minutes, and a 850 g rubber roller was used. The sample was then passed through the sample twice at a rate of 300 mm / min and left in a 37 ° C. thermostat for 30 minutes. When the end of the sample attached to the test plate is bent at an angle of 180 °, taped, and the other end is fixed to the upper part of the tensile tester, and the test plate is fixed to the lower part, when pulling 20 mm at a speed of 300 mm / min. Measure the load of 10 times each. In Example 1, the adhesion of 192.8 gf and H was found to be 180.1 gf.

Table 4. Adhesion of Examples 1 to 6, Comparative Examples 1 to 7 and H

Experimental Example Example Comparative example H One 2 3 4 5 6 One 2 3 4 5 6 7 preference 5.0 5.0 5.0 5.0 5.0 5.0 3.0 5.0 5.0 5.0 5.0 5.0 3.0 3.5

Experimental Example 3

Comparative Dissolution Test

Each of Examples 1 to 6, Comparative Examples 1 to 7 and H was taken 6 sheets (10 cm 2/1 sheet) and attached to the center of the disk assembly of the eluator with double-sided adhesive tape. 500 ml of a phosphate buffer solution of pH 7.4 was placed in an elution vessel, and 0, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 5.0, 6.0, 8.0, 10.0, at a dissolution temperature of 32 ± 0.5 ° C and a paddle rotation speed of 50 rpm. Samples were taken at the elution time of 12.0 and 24.0 hours, and the similarity was determined according to the paddle over disk method of the USP transdermal preparation, and the test results are shown in FIG. 2.

Experimental Example 4

Transdermal Permeation Test

In Comparative Dissolution Test, Examples 1, 4, and 5 were selected from the experimental examples showing the same dissolution trend in the tolerance range (± 10%) with the reference drug H, Comparative Example 1, Comparative Example 2 And transdermal penetration test with reference drug H. Male 6-week-old male hairless rats are dissected to the cervical spine and the skin is removed to a size of 6 cm x 6 cm, and subcutaneous fat is removed. Example 1, Example 4, Example 5, Comparative Example 1, Comparative Example 2, and H having a size of 2.5 cm 2 cut in advance on the epidermal layer of the extracted skin were adhered to the Franz diffusion cell. The receptor layer of the Franz diffusion cell is carefully filled with PBS buffer of pH 7.4 so that no bubbles are generated, and the solution is stirred at 600 rpm while maintaining the temperature of the Franz diffusion device at 32 ± 0.5 ° C. As a sample, take 200 μl at 0, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, analyze the content of transdermal tolubuterol permeate by HPLC, and the same amount of buffer Fill in the floor. The effective skin area of the hairless rat attached to the Franz diffusion cell was 1.767 cm 2, and the volume of the receptor was 12.5 ml. The skin permeation test was performed under sink conditions. Transdermal penetration test results are shown in FIG. 3.

In the above quality evaluation results, the skin irritation was found to be almost no Examples 1 to 6, Comparative Example 2 and Comparative Example 6, Comparative Example 4 is a level that does not have a big problem in use, the reference drug H is usually Stimulation of, Comparative Example 1, Comparative Example 3, Comparative Example 4, Comparative Example 5 and Comparative Example 7 was found to be higher than the reference drug. The characteristics of the compositions of Examples 1 to 6, Comparative Example 2, Comparative Example 4, and Comparative Example 6, which have lower skin irritation than that of the reference drug H, are required because an adhesive layer containing no drug is applied at an appropriate thickness or more. It seems that skin irritation is low because drugs above the concentration do not directly reach the skin.

Cohesive quality is one of the physically important quality attributes in the path of drug absorption through the skin. In the results of the adhesion test, Examples 1 to 6 and Comparative Examples 2 to 6, except for Comparative Example 1 and Comparative Example 7, are in the initial state until all the quality evaluators artificially remove the product samples (after 24 hours). It was affixed as it was, and was evaluated as being superior to the reference drug H. The factor indicating the excellent adhesive strength is because the two-layer structure of the drug worm and the adhesive layer, which is the core technology of the present invention, shows excellent adhesive properties due to structural differences with the reference drug. In addition, in the adhesion test using the tensile strength, Example 1 was found to be superior to the reference drug.

Comparative dissolution test and transdermal penetration test are good test methods that can predict the equivalence with the reference drug for the efficacy effect of the present invention. In particular, the comparative dissolution test is a very important test to confirm the bioequivalence with the reference product and is approved by the Food and Drug Administration as biologically equivalent when the tolerance range of the control product and the dissolution rate is ± 10%. As a result of comparative dissolution test with Examples 1 to 6, Comparative Examples 1 to 7 and H of the present invention, Examples 1 to 6 were found to correspond to the reference drug H and the tolerance range ± 10%. appear. Comparative Example 1, which is composed of a drug layer without an adhesive layer, exhibited a burst effect in which the drug was almost eluted initially, and Comparative Example 2, in which the composition of the acrylic adhesive containing a carboxyl group in the drug layer had a higher dissolution rate than the reference drug, was used. Found to be low. In Comparative Examples 3 to 7, it can be seen that the dissolution tendency is different from that of the reference drug depending on the thickness of the drug layer and the thickness of the adhesive layer.

In the transdermal permeation test, Examples 1, 4, and 5 were selected from the experimental examples showing the same dissolution tendency within the tolerance range (± 10%) with the reference drug, Comparative Example 1, Comparative Example 2, The control group H was compared with the transdermal penetration tendency. The characteristic transdermal permeation test results showed that the release tendency of Examples 1, 4, 5, and 1, except for Comparative Example 2, in which the composition ratio of the carboxyl group among the functional groups of the acrylic adhesive constituting the drug layer was relatively high was large. It appeared similar to the treaty H. The release characteristics of Comparative Example 2 were found to be delayed by chemical bonding of the secondary amine of tulobuterol contained in the drug layer with the carboxyl group of the relatively high composition of acrylic adhesive.

1 is a cross-sectional view of the transdermal absorbent preparation prepared according to the present invention.

Figure 2 shows the comparative dissolution test results at pH 7.4 for Examples 1 to 6, Comparative Examples 1 to 7 and H of the present invention.

Figure 3 shows the transdermal permeability of Examples 1 to 6, Comparative Examples 1 to 6 and H products of the present invention.

* Explanation of reference numerals for the main parts

1: support 2: drug layer

3: adhesive layer 4: release film

Claims (3)

A four-layered transdermal absorption agent consisting of a retardation, a drug layer, an adhesive layer, and a release film, wherein the drug layer contains tulobuterol, and the ratio of the acrylic adhesive having a hydroxy group and the acrylic adhesive having a carboxyl group is 75 to 95 units. It is composed of a ratio of 1, the thickness thereof is 10 ㎛ to 35 ㎛, the pressure-sensitive adhesive layer is composed of a rubber-based adhesive and a tackifier, its thickness is 5 ㎛ to 15 ㎛ to sustain the skin penetration of the drug for a long time, skin irritation A percutaneous absorption preparation containing tulobuterol, which is low and has excellent adhesion. The acrylic pressure sensitive adhesive having a hydroxyl group and the acrylic pressure sensitive adhesive having a carboxyl group are alkyl acrylates or alkyl methacrylates having 4 to 17 carbon atoms, and 2-ethylhexyl acrylate, butyl acrylate and ethyl. It consists of 1 type (s) or 2 or more types chosen from the group which consists of an acrylate, isooctyl acrylate, a vinyl acetate, a methyl acrylate, a methyl methacrylate, ethyl methacrylate, an acrylonitrile, t-octyl acrylamide, and a functional group A transdermal absorbent formulation containing tulobuterol, characterized in that it comprises one or two or more monomers having a hydroxy group or a carboxyl group. The method of claim 1, wherein the adhesive layer is polyisobutylene, polyisoprene, polybutene, polyisobutylene-polybutene copolymer, isoprene-isobutylene copolymer, styrene-diene-styrene copolymer (e.g., styrene Butadiene-styrene copolymer, styrene-isoprene-styrene copolymer), isoprene-butadiene copolymer, styrene-butadiene copolymer, etc. can be used one or two or more selected from rosin glycerin, hydrogenated ester Rosin derivatives such as rosin glycerin ester and rosin pentaerythritol ester, alicyclic hydrocarbon resins, aliphatic hydrocarbon resins, terpene resins, maleic acid resins, etc. A transdermal absorbent formulation containing tulobuterol.

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