KR20060025080A - Percutaneous Patches Containing Tulobuterol - Google Patents

Abstract

The present invention relates to a percutaneous administration patch containing tulobuterol, and specifically, 1) a drug protective layer, 2) an acrylate copolymer and a drug-containing adhesive layer containing tulobuterol, and 3) an acrylate system. And a drug-free adhesive layer comprising a copolymer, and 4) a release layer.

The percutaneous administration patch containing tulobuterol of the present invention has excellent skin permeability and long-term sustainability of the drug, and the skin irritation is remarkably low so that it can be safely delivered to the body without any side effects even when used for a long time. Also very simple and economically very useful. Therefore, the transdermal patch containing tulbuterol of the present invention can be used for treating asthma in children or the elderly as it is possible to release the drug for 24 hours and is particularly useful for seizure of dawn.

Description

Patches comprising tulobuterol for transdermal administration             

1 is a view showing a cross-sectional view of a transdermal patch containing a tulobuterol prepared according to a preferred embodiment of the present invention.

The present invention relates to a transdermal patch containing tulobuterol.

Tulobuterol; Alpha- (t-butylamino) methyl-3,5-dichlorobenzyl alcohol] is a beta-adrenergic drug that selectively acts on the beta2-receptor of the sympathetic nerve to relax bronchial smooth muscle. Let's do it. Therefore, tulobuterol is widely used to reduce and treat dyspnea in patients with asthma and respiratory diseases suffering from airway stenosis. Tolubuterol is generally used in the form of oral preparations using tablets, anhydrous syrups, or inhalants using aerosols.However, this method is difficult due to the difficulty in administering to children and the rapid increase in drug concentration in the blood. Expression of side effects such as triggered palpitations and tremors, and the half-life of the drug in the blood is shortened and has to be taken frequently. Therefore, there is a need to develop a new formulation to solve this problem. Among them, transdermal preparations that deliver drugs through the skin, unlike oral administration, can avoid metabolism in the liver and can reduce the side effects because the active ingredients can be delivered to the body continuously at a constant rate. At the same time, there is an advantage to reduce the number of administration can be applied in a way to compensate for the above disadvantages, research on this is being actively conducted.

As a related art for transdermal administration containing tulobuterol, Korean Patent Nos. 10-5142 and US Pat. No. 5,254,348 use styrene-1,3-diene-styrene block copolymer to contain tulobuterol. It describes about the manufacturing method of the matrix patch which is mentioned. In this method, there is an advantage in that it is possible to considerably prevent the environment and surrounding pollution caused by the solvent by not using a solvent. However, since the manufacturing process is performed by the hot melt coating method, a considerable amount of heat must be applied, and thus the manufacturing process is somewhat complicated. The active ingredient may decompose.

Korean Patent No. 10-381120 describes a transdermal absorption type tulobuterol preparation obtained by laminating a pressure-sensitive adhesive layer containing a microcrystalline tulobuterol having an average particle size of 2 to 20 µm and containing a synthetic rubber on a support. It is. However, these formulations have long-term persistence of drug effects but have a disadvantage of increasing drug release rate at an early stage when the average particle size is less than 2 μm or more than 20 μm. Therefore, there is a problem that can not find a significant relationship between the persistence of the drug effect and it is difficult to ensure the uniformity of quality if the size of the particles is not precisely controlled.

Rubber pressure-sensitive adhesives such as polyisobutylene used in the patent have very low permeability of air and moisture, and antioxidants or stabilizers should be added as necessary to improve stability, and these substances cause skin irritation. . Thus, a silicone pressure-sensitive adhesive having good adhesive strength and little skin irritation is used. However, there is a problem that the silicone pressure-sensitive adhesive is expensive. Therefore, there is no need for additives such as antioxidants or stabilizers, and many studies have been conducted using acrylate-based pressure-sensitive adhesives, which are less likely to cause skin irritation because air or moisture pass relatively freely.

Korean Patent Laid-Open Publication No. 10-1999-62986 discloses a transdermal absorption type formulation containing tulobuterol dissolved in a plaster layer at a high concentration of 5% by weight or more, wherein the acrylate-based adhesive or rubber-based adhesive is used as the adhesive. Use This method does not change over time the drug release and adhesive properties caused by precipitation of drug crystals over time. However, there is concern about the side effects due to the increase of transdermal absorption rate in the early stages, and excellent effects can be expected when the tolubuterol is present in the acrylate polymer having various functional groups in the dissolved state. Because of having an amine group, when using an acrylate-based polymer having an acidic group such as a carboxyl group, the amine group and the carboxyl group interact with each other, making it difficult to escape from the polymer matrix, thereby significantly reducing skin permeability.

Korean Patent No. 10-439659 discloses a transdermal absorption containing a tulobuterol comprising a matrix composed of one or two or more of an acrylate polymer having a hydrophilic polymer and a hydroxy group having a hydroxy group as a matrix substrate. It is described about the patch for solvent. In addition, Korean Patent Publication No. 10-2003-65829 discloses a percutaneous absorption type formulation including a tulobuterol, an acrylate-based adhesive, a permeation accelerator, and a diffusion enhancer. However, these patents may cause skin irritation due to the use of skin permeation accelerators.

Korean Patent Laid-Open Publication No. 10-2003-89908 discloses a matrix patch including a cationic polymer, a dissolution aid, and a matrix base to increase the skin permeability of an asthma treatment agent, an active ingredient. These patchs have excellent skin permeability, shorten the onset of drug efficacy, prolong the effective time of action, and excellent adhesion, and reduce the skin irritation. However, beta-adrenergic drugs such as tulobuterol have their own skin. There is a problem that can cause irritation and is not suitable for prolonged administration.

Thus, the present inventors while studying a patch that can fully exhibit the drug efficacy without skin irritation, patch agent comprising a drug-containing pressure-sensitive adhesive layer and a drug-free pressure-sensitive adhesive layer prepared by using an acrylate-based pressure-sensitive adhesive to tolubuterol In the skin permeability is excellent, there is almost no skin irritation, and the drug was released continuously for 24 hours and completed the present invention.

The present invention seeks to provide a transdermal patch containing tulobuterol which has excellent skin permeability, almost no skin irritation, and continuously releases the drug for 24 hours.

The present invention provides a transdermal patch containing tulobuterol.

Hereinafter, the present invention will be described in detail.

Transdermal dosing patch containing the tolubuterol of the present invention 1) drug protective layer, 2) drug-containing adhesive layer comprising an acrylate-based copolymer and tolubuterol, 3) a drug comprising an acrylate-based copolymer And a 4) release layer.

In the transdermal patch containing tulbuterol of the present invention, the drug protective layer is thin and flexible to prevent the loss of tulbuterol from the formulation during adhesion or storage to the skin and is not allergic to the skin. Use something that doesn't cause it. A drug protective layer that absorbs water to prevent the patch from falling off by monolayer films such as polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, and aluminum treated polyester, or moisture emitted from the human body. Nonwoven fabrics, cotton cloth, woven fabrics, and the like, and a multilayer laminate film in which the single layer film is laminated may be used.

In the transdermal dosing patch containing the tolubuterol of the present invention, the acrylate copolymer used as the pressure sensitive adhesive (PSA) in the drug-containing adhesive layer and the drug-free adhesive layer is composed of primary monomers and Copolymers of comonomers (modifying monomers) or copolymers of main monomers, comonomers and monomers with functional groups.

The main monomer constituting the acrylate copolymer includes one or more monomers selected from alkyl acrylate or alkyl methacrylate having 4 to 17 carbon atoms, and specifically 2-ethylhexyl Group consisting of 2-ethylhexyl acrylate (2-EHA), butyl acrylate (BA), ethyl acrylate (EA) and iso-octyl acrylate (iso-OA) At least one monomer selected from. Main monomers generally have a T _g of about -50 to -70 ° C. It has a value, and is extremely sticky and soft in nature, giving tack and flexibility to the adhesive.

The comonomer constituting the acrylate-based copolymer is vinyl acetate (VAc), methyl acrylate (MA), methyl methacrylate (MMA), ethyl methacrylate (ethyl methacrylate, EMA), acrylonitrile (AN) and t-octyl acrylamide (t-OA). The comonomer has a high T _g value and is characterized by imparting strength, thereby copolymerizing with the main monomer to adjust the balance between cohesion and cohesion of the pressure-sensitive adhesive.

The functional group-containing monomer constituting the acrylate-based copolymer may include at least one monomer selected from monomers containing a hydroxy group, an epoxy group, an amine group, or an organo-silane group, and specifically, 2-hydrate Hydroxyl-containing monomers, such as 2-hydroxyethyl acrylate (2-HEA) and 2-hydroxypropyl acrylate (2-HPA), glycidyl acrylate (GA) And epoxy group-containing monomers such as glycidyl methacrylate (GMA), amine group-containing monomers such as acrylamide (AM), and 3-methacryloxylpropyl trimethoxylsilane And at least one monomer selected from the group consisting of the same organosilane group-containing monomers. Functional group containing monomers are used to form crosslinking of acrylate copolymers.

In the transdermal patch containing the tulobuterol of the present invention, the acrylate copolymer used as the pressure-sensitive adhesive of the drug-containing adhesive layer and the drug-free adhesive layer is a copolymer of the main monomer and the comonomer, or the main monomer, the comonomer And a copolymer of a functional group-containing monomer, wherein for each monomer, at least one monomer selected from the group consisting of 2-ethylhexyl acrylate, comonomer is vinyl acetate, methyl acrylate, t-octyl acrylamide, And the functional group-containing monomer preferably includes at least one monomer selected from the group consisting of 2-hydroxyethyl acrylate and glycidyl methacrylate.

In the transdermal patch containing the tulobuterol of the present invention, the release layer serves to support the product when the patch is cut to a suitable size and is removed when the product is applied to the skin. Thin films of aluminum, cellulose, polyester, polyethylene, polypropylene, or paper can be used, and these films can be laminated as necessary. In addition, it is preferable to use what remove | eliminates the debris of a matrix easily and does not remain in a peeling layer when removing a peeling layer from a patch, and what kind of material or form normally used for a transdermal formulation may be used.

In the transdermal patch containing the tulobuterol of the present invention, the content (dry weight) of the tulobuterol contained in the drug-containing adhesive layer is preferably 3.0 to 12.0 wt% based on the weight of the drug-containing adhesive layer. If the content of tolubuterol is less than 3.0% by weight, it is difficult to reach a sufficient effective blood concentration, whereas if the content of tolubuterol exceeds about 12.0% by weight, the side effects such as respiratory failure are exceeded due to the effective blood concentration. Frequency of occurrence may increase.

The preparation method of the percutaneous administration patch containing the tulobuterol of this invention is as follows.

Tolubuterol was added to the acrylate copolymer, stirred and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution is applied on the drug protection film using a rep coater dryer and dried at 60 ° C. for about 1 hour to prepare a homogeneous and transparent surface-containing drug-containing pressure-sensitive adhesive layer.

On the other hand, with an acrylate copolymer solution and applied to the film for peeling in the same manner as above and dried for about 1 hour at 60 ℃, to prepare a drug-free adhesive layer.

The drug-containing adhesive layer and the drug-free adhesive layer prepared above are laminated to face each other to prepare a transdermal patch.

In the transdermal patch containing the tulobuterol of the present invention, the thickness of the drug-containing adhesive layer is 15 ~ 30㎛, the thickness of the drug-free adhesive layer is preferably 15 ~ 60㎛, the thickness of the adhesive layer It can be adjusted appropriately. In addition, the patch for transdermal administration containing tulobuterol of the present invention is preferably attached to the affected part once a day, and the area attached to the affected part once is 2.5-20 cm 2.

The percutaneous administration patch containing tulobuterol of the present invention has excellent skin permeability and long-term sustainability of the drug, and the skin irritation is remarkably low so that tulobuterol can be safely delivered to the body without any side effects even during long-term use. Therefore, the transdermal patch containing tulbuterol of the present invention can be used for the treatment of asthma in children or the elderly as it is possible to release the drug for 24 hours, particularly useful for early morning seizures between 8 pm and the next morning Do.

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the Examples.

Example  One  Of the present invention For transdermal administration Patchwork  Produce

Commercial adhesives DuroTac 87-4098 and DuroTac 87-2516 (National Starch & Chemical Ltd.) were prepared as an adhesive. DuroTac 87-4098 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as the main monomer and vinyl acetate (VAc) as the comonomer. DuroTac 87-2516 is a monomer containing 2-ethylhexyl acrylate (2-EHA) as a main monomer, vinyl acetate (VAc) as a comonomer, and 2-hydroxyethyl acrylate (2-HEA) as a functional group-containing monomer. It is a copolymer consisting of.

Tolubuterol was added to DuroTack 87-4098, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied on a 50 μm thick drug protection film (3M, Scotchpak 9732) using a rep coater dryer (Suthe Mathis, Switzerland), and dried at 60 ° C. for about 1 hour. The thickness was 30 μm and the surface was homogeneous. A transparent drug-containing adhesive layer (A) was prepared.

On the other hand, with a solution of DuroTack 87-2516 and coated with a fluorocarbon coating in the same manner to 70㎛ thick polyester peeling film (3M, Scotchpak 1022) and dried at 60 ℃ for about 1 hour, the thickness A drug-free adhesive layer (B) having a thickness of 15 μm was prepared.

The drug-containing adhesive layer (A) prepared above and the drug-free adhesive layer (B) were laminated so as to face each other to prepare a transdermal administration patch (tolubuterol content: 6.1 wt%).

Example  2

Commercial adhesives DuroTac 87-4098 and DuroTac 87-2510 (National Starch & Chemical Ltd.) were prepared as an adhesive. DuroTac 87-4098 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as the main monomer and vinyl acetate (VAc) as the comonomer. DuroTack 87-2510 contains 2-ethylhexyl acrylate (2-EHA) as the main monomer, methyl acrylate (MA) as the comonomer, and contains 2-hydroxyethyl acrylate (2-HEA) as a functional group. It is a copolymer which consists of monomers.

Tolubuterol was added to DuroTack 87-4098, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied on a 50 μm thick drug protection film (3M, Scotchpak 9732) using a rep coater dryer (Suthe Mathis, Switzerland), and dried at 60 ° C. for about 1 hour. The thickness was 30 μm and the surface was homogeneous. A transparent drug-containing adhesive layer (A) was prepared.

On the other hand, it was applied to a 70-micrometer-thick polyester peeling film (3M, Scotchpak 1022) coated with a fluorocarbon in the same manner as above with DuroTack 87-2510 solution and dried at 60 ° C for about 1 hour, A drug-free adhesive layer (B) having a thickness of 30 μm was prepared.

The drug-containing adhesive layer (A) prepared above and the drug-free adhesive layer (B) were laminated so as to face each other to prepare a transdermal administration patch (tolubuterol content: 6.1 wt%).

Example  3

Commercially available gel bars 3083 (Solutia Inc.) and Durotack 87-2510 (National Starch & Chemical Ltd.), which are acrylate polymer solutions, were prepared as an adhesive. Gelbar 3083 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as the main monomer and methyl acrylate (MA) as the comonomer. DuroTack 87-2510 contains 2-ethylhexyl acrylate (2-EHA) as the main monomer, methyl acrylate (MA) as the comonomer, and contains 2-hydroxyethyl acrylate (2-HEA) as a functional group. It is a copolymer which consists of monomers.

Tolubuterol was added to gel bar 3083, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied on a 50 μm thick drug protection film (3M, Scotchpak 9732) using a rep coater dryer (Suthe Mathis, Switzerland), and dried at 60 ° C. for about 1 hour. The thickness was 15 μm and the surface was homogeneous. A transparent drug-containing adhesive layer (A) was prepared.

On the other hand, it was applied to a 70-micrometer-thick polyester peeling film (3M, Scotchpak 1022) coated with a fluorocarbon in the same manner as above with DuroTack 87-2510 solution and dried at 60 ° C for about 1 hour, A drug-free adhesive layer (B) having a thickness of 15 μm was prepared.

The drug-containing adhesive layer (A) prepared above and the drug-free adhesive layer (B) were laminated so as to face each other to prepare a percutaneous administration patch (tolubuterol content: 3.2% by weight).

Example  4

Commercially available DuroTac 87-9301 (National Starch & Chemical Ltd.) and Gel Bar 7880 (Solutia Inc.), which are acrylate polymer solutions, were prepared as an adhesive. DuroTac 87-9301 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as a main monomer and methyl acrylate (MA) and t-octyl acrylamide (t-OA) as a comonomer. Gelba 7880 has 2-ethylhexyl acrylate (2-EHA) as the main monomer, vinyl acrylate (VAc) as the comonomer, 2-hydroxyethyl acrylate (2-HEA) and glycidyl methacryl It is a copolymer which consists of a rate (GMA) as a functional group containing monomer.

Tolubuterol was added to Durotek 87-9301, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied on a 50 μm thick drug protection film (3M, Scotchpak 9732) using a rep coater dryer (Suthe Mathis, Switzerland), and dried at 60 ° C. for about 1 hour. A transparent drug-containing adhesive layer (A) was prepared.

Meanwhile, the gel bar 7880 solution was applied to a 70 μm-thick polyester stripping film (3M, Scotchpak 1022) coated with fluorocarbons in the same manner as above, and dried at 60 ° C. for about 1 hour, and the thickness was 30 μm. A drug-free adhesive layer (B) was prepared.

The drug-containing adhesive layer (A) prepared above and the drug-free adhesive layer (B) were laminated so as to face each other to prepare a percutaneous administration patch (tolubuterol content: 12.0 wt%).

Example  5

Commercial adhesives DuroTac 87-4098 and DuroTac 87-2516 (National Starch & Chemical Ltd.) were prepared as an adhesive. DuroTac 87-4098 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as the main monomer and vinyl acetate (VAc) as the comonomer. DuroTac 87-2516 is a monomer containing 2-ethylhexyl acrylate (2-EHA) as a main monomer, vinyl acetate (VAc) as a comonomer, and 2-hydroxyethyl acrylate (2-HEA) as a functional group-containing monomer. It is a copolymer consisting of.

Tolubuterol was added to DuroTack 87-4098, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied on a 50 μm thick drug protective film (3M, Scotchpak 9732) using a rep coater dryer (Suthe Mathis, Switzerland), and dried at 60 ° C. for about 1 hour. The thickness was 15 μm and the surface was homogeneous A transparent drug-containing adhesive layer (A) was prepared.

On the other hand, it was applied to a 70-micrometer-thick polyester peeling film (3M, Scotchpak 1022) coated with fluorocarbon in the same manner as above with DuroTack 87-2516 solution and dried at 60 ° C for about 1 hour, A drug-free adhesive layer (B) having a thickness of 60 μm was prepared.

The drug-containing adhesive layer (A) prepared above and the drug-free adhesive layer (B) were laminated so as to face each other to prepare a percutaneous administration patch (tolubuterol content: 12.0 wt%).

Example  6

Commercial adhesives Duro-Tac 87-9301 and Duro-Tac 87-2287 (National Starch & Chemical Ltd.) were prepared as an adhesive. DuroTac 87-9301 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as a main monomer and methyl acrylate (MA) and t-octyl acrylamide (t-OA) as a comonomer.

Tolubuterol was added to Durotek 87-9301, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied on a 50 μm thick drug protection film (3M, Scotchpak 9732) using a rep coater dryer (Suthe Mathis, Switzerland), and dried at 60 ° C. for about 1 hour. The thickness was 30 μm, and the surface was homogeneous. A transparent drug-containing adhesive layer (A) was prepared.

On the other hand, it was applied to a 70 탆 thick polyester peeling film (3M, Scotchpak 1022) coated with fluorocarbon in the same manner as above with DuroTack 87-2287 solution and dried at 60 ° C for about 1 hour, A drug-free adhesive layer (B) having a thickness of 15 μm was prepared.

The drug-containing adhesive layer (A) prepared above and the drug-free adhesive layer (B) were laminated so as to face each other to prepare a transdermal administration patch (tolubuterol content: 6.1 wt%).

Comparative example  One

A commercially available product DuroTack 87-4098 (National Starch & Chemical Ltd.) was prepared as an adhesive. DuroTac 87-4098 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as the main monomer and vinyl acetate (VAc) as the comonomer.

Tolubuterol was added to DuroTack 87-4098, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied to a 70 μm-thick polyester peeling film (3M, Scotchpak 1022) using a rep coater dryer (Mathis, Switzerland) and dried at 60 ° C. for about 1 hour, while having a thickness of 30 μm and homogeneous. A drug-containing adhesive layer (A) having a transparent surface was prepared. The drug-containing adhesive layer (A) prepared above was laminated on a 50 μm-thick drug protective film (3M, Scotchpak 9732) to prepare a transdermal patch (tolubuterol content: 6.1 wt%).

Comparative example  2

A commercially available product DuroTack 87-2287 (National Starch & Chemical Ltd.) was prepared as an adhesive.

Tolubuterol was added to Durotek 87-2287, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied to a 70 μm-thick polyester peeling film (3M, Scotchpak 1022) using a rep coater dryer (Mathis, Switzerland) and dried at 60 ° C. for about 1 hour, while having a thickness of 30 μm and homogeneous. A drug-containing adhesive layer (A) having a transparent surface was prepared. The drug-containing adhesive layer (A) prepared above was laminated on a 50 μm-thick drug protective film (3M, Scotchpak 9732) to prepare a transdermal patch (tolubuterol content: 6.1 wt%).

Comparative example  3

A commercially available DuroTac 87-2852 (National Starch & Chemical Ltd.), an acrylate polymer solution, was prepared as an adhesive. DuroTac 87-2852 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as the main monomer, methyl acrylate (MA) as the comonomer, and acrylic acid (AA) as the functional group-containing monomer.

Tolubuterol was added to Durotek 87-2852, stirred, and dissolved to prepare a homogeneous drug-containing adhesive solution. The prepared pressure-sensitive adhesive solution was applied to a 70 μm-thick polyester peeling film (3M, Scotchpak 1022) using a rep coater dryer (Mathis, Switzerland) and dried at 60 ° C. for about 1 hour, while having a thickness of 30 μm and homogeneous. A drug-containing adhesive layer (A) having a transparent surface was prepared. The drug-containing adhesive layer (A) prepared above was laminated on a 50 μm-thick drug protective film (3M, Scotchpak 9732) to prepare a transdermal patch (tolubuterol content: 6.1 wt%).

Comparative example  4

Commercially available DuroTac 87-4098 (National Starch & Chemical Ltd.) and Gel Bar 3083 (Solutia Inc.), which are acrylate polymer solutions, were prepared as an adhesive. DuroTac 87-4098 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as the main monomer and vinyl acetate (VAc) as the comonomer. Gelbar 3083 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as the main monomer and methyl acrylate (MA) as the comonomer.

Tolubuterol was added to DuroTack 87-4098, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied on a 50 μm thick drug protection film (3M, Scotchpak 9732) using a rep coater dryer (Suthe Mathis, Switzerland), and dried at 60 ° C. for about 1 hour. The thickness was 30 μm and the surface was homogeneous. A transparent drug-containing adhesive layer (A) was prepared.

On the other hand, with a gel bar 3083 solution and applied to a 70㎛ thick polyester peeling film (3M, Scotchpak 1022) coated with a fluorocarbon in the same manner as above and dried at 60 ℃ for about 1 hour, the thickness is 30㎛ A drug-free adhesive layer (B) was prepared.

The drug-containing adhesive layer (A) prepared above and the drug-free adhesive layer (B) were laminated so as to face each other to prepare a transdermal administration patch (tolubuterol content: 6.1 wt%).

Comparative example  5

Commercially available DuroTac 87-9301 (National Starch & Chemical Ltd.) and Gel Bar 2883 (Solutia Inc.), which are acrylate polymer solutions, were prepared as an adhesive. DuroTac 87-9301 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as a main monomer and methyl acrylate (MA) and t-octyl acrylamide (t-OA) as a comonomer. Gelbar 2883 is a monomer containing 2-ethylhexyl acrylate (2-EHA) as the main monomer, methyl acrylate (MA) as the comonomer, and acrylic acid (AA) and glycidyl methacrylate (GMA). It is a copolymer consisting of.

Tolubuterol was added to Durotek 87-9301, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied on a 50 μm thick drug protection film (3M, Scotchpak 9732) using a rep coater dryer (Suthe Mathis, Switzerland), and dried at 60 ° C. for about 1 hour. The thickness was 30 μm and the surface was homogeneous. A clear drug containing adhesive layer (A) was prepared.

On the other hand, with a gel bar 2883 solution and applied to a 70㎛ thick polyester peeling film (3M, Scotchpak 1022) coated with a fluorocarbon in the same manner as above and dried at 60 ℃ for about 1 hour, the thickness is 15㎛ A drug-free adhesive layer (B) was prepared.

The drug-containing adhesive layer (A) prepared above and the drug-free adhesive layer (B) were laminated so as to face each other to prepare a percutaneous administration patch (tolubuterol content: 12.0 wt%).

Comparative example  6

Commercial adhesives DuroTac 87-2510 and DuroTac 87-4098 (National Starch & Chemical Ltd.) as acrylate polymer solutions were prepared as an adhesive. DuroTack 87-2510 contains 2-ethylhexyl acrylate (2-EHA) as the main monomer, methyl acrylate (MA) as the comonomer, and contains 2-hydroxyethyl acrylate (2-HEA) as a functional group. It is a copolymer which consists of monomers. DuroTac 87-4098 is a copolymer comprising 2-ethylhexyl acrylate (2-EHA) as the main monomer and vinyl acetate (VAc) as the comonomer.

Tolubuterol was added to Durotek 87-2510, stirred, and dissolved to prepare a homogeneous drug-containing pressure-sensitive adhesive solution. The prepared pressure-sensitive adhesive solution was applied on a 50 μm thick drug protection film (3M, Scotchpak 9732) using a rep coater dryer (Suthe Mathis, Switzerland), and dried at 60 ° C. for about 1 hour. The thickness was 30 μm and the surface was homogeneous. A clear drug containing adhesive layer (A) was prepared.

On the other hand, with a solution of Duro-Tack 87-4098 and coated with a fluorocarbon coated polyester film 70μm thick (3M, Scotchpak 1022) and dried at 60 ℃ for about 1 hour, A drug-free adhesive layer (B) having a thickness of 15 μm was prepared.

The drug-containing adhesive layer (A) prepared above and the drug-free adhesive layer (B) were laminated so as to face each other to prepare a transdermal administration patch (tolubuterol content: 6.1 wt%).

Experimental Example  One  : Skin permeability measurement

In order to determine the skin permeability of the transdermal patch containing tulobuterol of the present invention, the following experiment was performed.

One. Rat  Skin extraction

Male Sprague-Dawley rats weighing 230-250 g are anesthetized with ether, and the abdomen's hair is removed with an electric hair remover (TGC Inc., model 900, Japan) and the area of 5 cm x 5 cm Subcutaneous fat was removed and skin was removed so as not to damage the skin. Extracted skin was stored at -20 ℃ until used in the experiment, and the storage period did not exceed 3 days.

2. Skin Permeability Measurement

The extracted rat skin was thawed at room temperature, hydrated in saline for about 30 minutes, and then mounted on a Franz diffusion cell. After mounting the cell in a diffusion cell drive console (Fine Scientific Instrument, model FCD8-900A), using a constant temperature circulating pump (Fine Scientific Instrument, model FT-101) while maintaining the temperature of the receptor layer at 37 ± 0.5 ℃ Rotation was constant at 600 rpm using a star-head magnetic bar. 0.01 M phosphate buffer solution (pH 7.4) was used as the receptor layer, the volume of the receptor layer was about 11.5 ml, and the area of the skin in contact with the receptor layer was 1.77 cm 2. 1, 2, 3, after the percutaneous administration patch containing tulobuterol prepared in Examples 1 to 6, Comparative Examples 1-6 and a commercially available hokunaline patch were adhered to the exposed portions of the skin. At 4, 5, 6, 7, 8, and 10 hours, 0.2 ml of receptor layer was taken from the sampling port using a micro syringe and supplemented with fresh 0.01 M phosphate buffer (pH 7.4) by the same amount. Tolubuterol concentration in the sample was measured by high performance liquid chromatography, and the skin permeation rate (µg / cm 2 / hr) at steady-state was obtained.

As a control, a commercially available tocobuterol transdermal absorber, Hokunalin Patch (0.2 mg / patch, manufactured by Abbott), was used.

The results are shown in Table 1.

Skin penetration rate (㎍ / ㎠ / hr) Latency (hr) Example 1 11.08 ± 0.81 3.66 ± 0.17 Example 2 10.02 ± 0.81 3.44 ± 0.13 Example 3 9.98 ± 1.22 3.71 ± 0.15 Example 4 11.21 ± 0.61 3.21 ± 0.34 Example 5 10.14 ± 0.66 3.83 ± 0.21 Example 6 11.68 ± 0.24 3.22 ± 0.27 Comparative Example 1 14.0 ± 1.59 2.77 ± 0.26 Comparative Example 2 14.7 ± 0.59 2.50 ± 0.20 Comparative Example 3 0.42 ± 0.02 3.70 ± 0.21 Comparative Example 4 8.07 ± 1.09 3.18 ± 0.10 Comparative Example 5 0.29 ± 0.07 3.58 ± 0.39 Comparative Example 6 9.82 ± 1.00 2.57 ± 0.25 Control group (Hokunurin patch) 11.49 ± 1.23 3.62 ± 0.25

As shown in Table 1, the skin permeability of the transdermal patch (Thus 1-6) containing the tulobuterol of the present invention appeared similar to the skin permeability of commercially available Hokunalin patch, The time spent in the body was similar. On the other hand, in Comparative Examples 3 and 5 using an acrylate pressure sensitive adhesive containing a monomer having a carboxyl group as a functional group, the amine group of tolubuterol interacts with the carboxyl group of the acrylate pressure sensitive adhesive to escape from the polymer matrix. It is difficult to see that the skin permeability is greatly reduced.

Therefore, it can be seen that the patch for transdermal administration containing tulobuterol of the present invention has excellent skin permeability and long-term sustainability of the drug.

Experimental Example  2  : Skin irritation measurement

In order to investigate the skin irritation of the transdermal patch containing tulobuterol of the present invention, rabbit skin was subjected to a first irritation test.

The dorsal hairs of six mature white rabbits, weighing 2.5-3.5 kg, were removed to an approximately 10 cm length by an electric epilator (TGC Inc., model 900, Japan). The skin of the depilated rabbit is divided into right and left, and the left side is divided into the administration compartment and the right side is divided into the healthy skin or the abrasion skin to be distributed diagonally to each other. 2 healthy skins of 2.5cm × 2.5cm and 2 abrasion skins It was set as. The abrasion skin was made using the tip of the syringe needle, so that the epidermis was injured but the dermis was injured so that it would not bleed.

The percutaneous administration patch containing tulobuterol prepared in Examples 1 to 3 was affixed to the skin of the rabbit's dorsal hair, and the preparation was removed after 24 hours. The erythema and edema immediately after removal (24 hours after application) and 48 hours after removal (72 hours after application) were determined according to the skin irritation criteria of Table 2, and the sum of the amount scores obtained was the stimulus of each time. The average value of the stimulus scores at each time was taken as the primary skin stimulation index (PII value) shown in Table 3.

As a control, a commercially available tocobuterol transdermal absorber, Hokunalin Patch (0.2 mg / patch, manufactured by Abbott), was used.

The results are shown in Table 4.

Skin irritation criteria Score Erythema and crust formation Edema formation 0 No erythema No edema One Very light erythema Very mild edema 2 Obvious erythema Mild edema 3 Slightly severe erythema Common edema 4 Severe erythema, mild skin formation Severe edema

Primary skin irritation index (PII) Primary skin irritation index (PII) division 0 to 0.5 Non-irritant 0.6 to 2.0 Mild irritant 2.1 to 5.0 Moderate irritant 5.1 to 8.0 Strong irritant

Primary skin irritation index (PII) division Example 1 0.35 Non-irritant Example 2 0.48 Non-irritant Example 3 0.27 Non-irritant Control group (Hokunurin patch) 2.21 Moderate irritant

As shown in Table 4, the primary skin irritation index of the transdermal patch (Thus 1 to 3) containing the Tolubuterol of the present invention is 0.27 to 0.48, which is non-irritating to the skin, and is higher than that of the control hokunelin patch. It can be seen that the skin irritation is significantly improved.

Therefore, the transdermal patch containing tulobuterol of the present invention has a remarkably low skin irritation and can safely deliver tulobuterol into the body without any side effects even when used for a long time.

Percutaneous administration patch containing tulobuterol of the present invention has excellent skin permeability and long-term sustainability, and skin irritation is remarkably low so that tulobuterol can be safely delivered to the body without any side effects even in long-term use. Also very simple and economically very useful. Therefore, the transdermal patch containing tulbuterol of the present invention can be used for treating asthma in children or the elderly as it is possible to release the drug for 24 hours and is particularly useful for seizure of dawn.

Claims (9)

A tool layer consisting of 1) a drug protective layer, 2) a drug-containing adhesive layer comprising an acrylate copolymer and tulobuterol, 3) a drug-free adhesive layer comprising an acrylate copolymer, and 4) a release layer A transdermal patch containing terrol. The method of claim 1, wherein the acrylate-based copolymer is a copolymer of primary monomers and comonomers (modifying monomers) or monomers, comonomers and monomers containing functional groups (monomers with functional group) A patch for transdermal administration containing tulobuterol, characterized in that the copolymer. The method of claim 2, wherein the main monomer is 2-ethylhexyl acrylate (2-EHA), butyl acrylate (BA), ethyl acrylate (EA) and isooctyl acrylic A patch for transdermal administration containing tulobuterol, characterized in that it comprises at least one monomer selected from the group consisting of a rate (iso-octyl acrylate, iso-OA). The method of claim 2, wherein the comonomer is vinyl acetate (VAc), methyl acrylate (MA), methyl methacrylate (MMA), ethyl methacrylate (ethyl methacrylate, EMA) For transdermal administration containing tulobuterol, comprising at least one monomer selected from the group consisting of acrylonitrile (AN) and t-octyl acrylamide (t-OA) Patches. The method of claim 2, wherein the functional group-containing monomer is a hydroxyl group such as 2-hydroxyethyl acrylate (2-hydroxyethyl acrylate, 2-HEA) and 2-hydroxypropyl acrylate (2-HPA) Containing monomers, epoxy group-containing monomers such as glycidyl acrylate (GA) and glycidyl methacrylate (GMA), amine group-containing monomers such as acrylamide (AM), and 3- A transdermal patch containing tulobuterol, characterized in that it comprises at least one monomer selected from the group consisting of organic silane group-containing monomers such as methacryloxylpropyl trimethoxylsilane. The method according to claim 2, wherein the main monomer is 2-ethylhexyl acrylate, the comonomer is at least one monomer selected from the group consisting of vinyl acetate, methyl acrylate, t-octyl acrylamide, and the functional group-containing monomer is 2- A transdermal patch containing tulobuterol, characterized in that it comprises at least one monomer selected from the group consisting of hydroxyethyl acrylate and glycidyl methacrylate. 2. The transdermal patch containing tulobuterol according to claim 1, wherein the content (dry weight) of tulobuterol in the drug-containing adhesive layer is 3.0 to 12.0 wt% based on the weight of the drug-containing adhesive layer. The patch for transdermal administration containing tulobuterol according to claim 1, wherein the drug-containing adhesive layer has a thickness of 15 to 30 µm. The patch for transdermal administration containing tulobuterol according to claim 1, wherein the drug-free adhesive layer has a thickness of 15 to 60 µm.

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