KR20030000344A - Transdermal delivery system for tulobuterol - Google Patents

Abstract

PURPOSE: A patch agent prepared by using tulobuterol as an effective ingredient, one or two or more absorption promoters, a solubilizing agent and a matrix substrate is provided which is effective in continuous release of tulobuterol for a long period of time and efficient in production of a patch. CONSTITUTION: The patch agent contains: (a)1 to 30% by weight of tulobuterol; (b)1 to 20% by weight of one or two or more absorption promoters selected from the group consisting of polyglyceryl olate(Plurol Oleique), PEG-8 glyceryl caprylate/caprylate (Labrasol), PEG-8 glyceryl linolate(Labrafil 2609), sorbitan fatty acid ester(Span) and polyoxyethylene-sorbitan-fatty acid ester(Tween); (c)1 to 20% by weight of one or more alkalinizing agents selected from alkanolamine, alkylamine, sodium bicarbonate, caustic soda and a basic compound having ammonium ion, amine group and pyridine group; and (d)70 to 99% by weight of one or more of hydroxyl-containing acrylate-based or grafted acrylate-based polymers as a matrix substrate.

Description

Transdermal delivery system for tulobuterol containing tulobuterol

The present invention relates to a percutaneous absorption patch containing the main component of tulobuterol useful as a therapeutic agent for bronchial asthma and a method for producing the same. More specifically, the present invention is designed to maintain a constant blood concentration in the body by continually releasing the drug by adhering to the skin, using a tulobuterol and a specific absorption accelerator and solvent, alkalizing agent and matrix substrate as the main component It relates to a percutaneous absorption patch of Tulobuterol to be produced and a method for producing the same.

Tulobuterol is a drug that acts directly on the beta2-receptor of the sympathetic nerve and has been used to treat bronchial smooth muscle to treat dyspnea in patients with asthma and respiratory diseases. In these bronchodilators, the development of methods to maintain the effective drug concentration in the blood for as long as possible and for as long as possible has long been of great interest in the pharmaceutical field. Most conventional bronchodilator drugs have been administered to patients with bronchial asthma in the form of oral administration using tablets, anhydrous syrup, etc., but in the case of oral administration, the half-life of the drug in the blood is shortened and the concentration of the drug is sharp. Problems have been raised that they should be taken frequently along with side effects such as palpitations and tremors. In order to solve this problem, a lot of efforts have recently been made to prepare these drugs as patches. Transdermal absorbents absorb the active ingredients through the skin, which, unlike oral administration, can prevent metabolism in the liver and deliver the active ingredients to the body continuously at a constant rate, thereby reducing side effects and at the same time. There is an advantage to reduce the can be applied in a way to supplement the disadvantages of the active ingredient. However, only a few of these drugs can be developed as patches, because the skin has extremely low permeability, and most of them are chemically or structurally unsuitable for patches, too high a daily dose or stability. Because there is a problem. Nevertheless, many studies have been reported on the formulation of various bronchodilating drugs as patches, for example, the study of applying salbutamol to osmotic transdermal absorption devices (SK Jain et al., Drug Development and Industrial). Pharmacy, 16 (9), 1565-1577 (1990)) and terbutalin-containing patching agents (Key Pharm. Inc. and DE-OS 37,32,642) using polymer matrices. .

Percutaneous tolubuterol formulations are disclosed in U.S. Patent No. 5,254,348 (LTS Lohmann Therapy Systeme GmbH & CO.KG) to prepare a tolubuterol-containing matrix patch using a styrene-1.3diene-styreneblock copolymer. The method is described. However, in the case of the disclosed method, since a large amount of heat must be applied when manufacturing the hot melt coating method, the manufacturing process is rather complicated and there is a concern that the active ingredient is decomposed at a high temperature. European Patent No. A 0 374,980 (Nitto Denko Corporation, Hokuriku Seiyaku CO., LTD) uses polyisobutylene as a matrix substrate to ensure sufficient skin permeability and stability, but acrylic polymers have low blood concentration and inadequate stability. There was no research on acrylic polymers showing various properties. In addition, Korean Patent Publication No. 99-0064272 (Hokuriku Seiyaku Kabushigakishi) refers to a transdermal absorbent preparation containing tulobuterol microcrystals, and the significance between the crystal grain size of tulobuterol and the persistence of drug effects No relationship can be found and quality uniformity is difficult to achieve unless the particle size is accurately controlled. European Patent No. 0922453 said that excellent effects can be expected when present in acrylic polymers having various functional groups in the state of dissolving more than 5% of the active ingredient, but since tulobuterol has a secondary amine group showing basicity, acidic groups such as carboxyl groups When the acrylic polymer is used, the effect is greatly reduced.

The present inventors consider Tulosbuterol (α-[(t-butylamino) methyl] -3,5-chlorobenzyl alcohol), which is used as a bronchodilator, in consideration of the general details of such transdermal absorption preparations. Intensive studies have been conducted to prepare transdermal absorbent preparations. Tolubuterol is a drug used as a therapeutic agent for bronchial asthma because it binds to the beta2-receptor of the sympathetic nervous system and causes bronchial dilatation. However, when taken orally, the absorption of the drug occurs rapidly and the side effects and lasting effects of the drug cannot be expected.

Accordingly, an object of the present invention is to provide a method capable of conveniently delivering tulobuterol through the skin at a constant and constant skin penetration rate. In addition, an object of the present invention is to provide a composition that can maintain the clinically effective blood concentration by continuously delivering tolubuterol to the systemic circulation.

The present invention provides a tulobuterol-containing percutaneous absorption patch containing a specific acrylic polymer and an absorption accelerator.

More specifically, in the present invention, tulobuterol as an active ingredient is dispersed evenly in the acrylate-based polymer and the acrylate-based polymer is sufficient to serve as a carrier for drug delivery. However, considering the chemical structural formula of tulobuterol, when the drug is dispersed in the acrylic polymer having a carboxyl group, the amine group of the tulobuterol interacts with the carboxyl group, making it difficult to escape from the polymer matrix. There is a problem that the adhesion of the is reduced. In addition, if the affinity between the active ingredient and the polymer matrix is too great, the thermodynamic activity decreases, thereby delaying the release of the active ingredient.

In the present invention, in consideration of the chemical structural characteristics of the active ingredient as described above in the patch, as the matrix substrate, a polymer having a relatively hydrophilic property such as polyethylene oxide, polyvinylpyrrolidone, etc. is grafted with an acrylic polymer polymer and a hydroxyl group. It was found that the use of one or two or more selected acrylic functional polymers without functional groups showed very good skin permeability and adhesion. In particular, in the present invention, the grafted acrylic polymer polymer not only increases the release rate of tulobuterol but also has a good influence on stabilization of the drug. However, when the absorption accelerator is used on the grafted acrylic polymer, the adhesive strength is significantly reduced, and thus the patch does not adhere to the skin within the application period. Therefore, when the acrylic polymer having hydroxyl group or functional group is mixed in an appropriate ratio, the adhesive force of the matrix is used. It serves to complement.

The amount of polymer based on the matrix in the patch of the invention is generally used in a ratio of 70 to 99% by weight, preferably 90 to 97% by weight, based on the total weight of the drug-containing matrix. When the polymer is used in an amount of less than 70% by weight, it does not provide sufficient adhesive strength to the desired degree, and when used in an amount exceeding 99% by weight, the clinical effect is low and it is difficult to control the content of the active ingredient in the patch. It is not preferable because there are problems such as difficulty and also change in the drug release pattern from the matrix.

Tolubuterol, the main component in the patch of the present invention, comprises 1 to 30% by weight, preferably 2 to 20% by weight, based on the total weight of the drug-containing matrix.

Absorption accelerator in the patch of the present invention polyglyceryl oleate (Plurol Oleque), PEG-8 glyceryl capriate / caprate (Labrasol), PEG-8 glyceryl linoleate (Labrafil 2609), sorbitan fatty acid ester (Span ), Polyoxyethylene-sorbitan-fatty acid ester (Tween). As evidenced by the skin permeation test using Franz diffusion cells below, among these absorption accelerators, polyglyceryl oleate is particularly preferred.

Absorption accelerators in the patch of the invention are used in a ratio of 1 to 20% by weight, preferably 2 to 10% by weight, based on the total weight of the drug-containing matrix. If the absorption accelerator is used in an amount of less than 1% by weight, it does not provide the sufficient amount of tulobuterol to promote absorption of the desired degree. On the contrary, the problem of lowering the adhesive force of the patch may appear, which is not preferable.

In the patch of the present invention, as the alkalizing agent, basic pharmaceutically usable materials such as alkanolamine and alkylamine may be used. In the patch, the alkalizing agent inhibits ionization of the secondary amine group on the chemical structure of the active ingredient tulobuterol, prevents the decrease of the skin permeability of the drug, and also acts as a thickener and complements adhesion.

The alkalizing agent in the patch of the invention is used in a ratio of 1 to 20% by weight, preferably 2 to 10% by weight, based on the total weight of the drug-containing matrix. If the alkaline agent is used in an amount of less than 1% by weight, it is not sufficient to prevent ionization of the drug. If the alkaline agent is used in an amount of more than 20% by weight, redness or pruritus due to skin irritation due to the high pH of the alkaline agent is used. It is undesirable because it causes side effects.

The percutaneous absorption patch according to the present invention first dissolves tulobuterol as a main component in a solvent, and thereafter, an absorption accelerator is added to uniformly disperse it in the polymer matrix matrix, and then the mixture is evenly inverted on a release layer to give a thin film. After preparing to dry at a temperature of about 75 to 90 ℃ to evaporate the solvent to generate an adhesive force, and then cooled and covered with a support and then cut into pieces of appropriate size can be prepared. At this time, the thickness is about 10 to 500㎛ after drying.

In the method of the present invention, a support is used that is thin and flexible and does not cause allergic reaction because it is not reactive with the skin. In addition, hydration is maintained by preventing the skin from hydration and air must be circulated instead to help skin breathing. Any support that is commercially available for this purpose can be used. The release paper supports the product when the patch is cut to a suitable size and is removed when the product is applied to the skin. When the release paper is removed from the patch, the debris of the drug-containing matrix can be easily removed without remaining on the release paper. Should be For this purpose, for example, it is possible to use a polyester film having a silicon coating on one side. In addition, any commercially available release paper capable of achieving the above object can be used.

The tulobuterol transdermal absorption patch prepared according to the present invention as described above is very effective in continuously releasing tulobuterol for a long time and is effective in patch production.

The present invention is explained in more detail by the following examples and experimental examples, but the present invention is not limited in any way by these.

Examples 1-7

Tolubuterol, a major component in ethyl acetate, was dissolved and hydrophilic polymer grafted to this solution (Durotak 87-5298, National Starch and Chemical) or acrylate solution with hydroxyl group (Durotak 87-2516, National Starch and Chemical) are added together. According to the presence or absence of the absorption accelerator and the additive of the prescription below, the absorption accelerator and the additive is added to the solution and stirred for 10 minutes with a shaker to obtain a uniform solution. The obtained solution was then inverted to a suitable thickness using a casting knife on a release coating silicone coated film, and left at room temperature for 10 minutes, and then dried at 80 ° C. for 15 minutes in order to prepare a 70 μm tolubuterol-containing matrix. . The matrix was cooled to room temperature and a patch was prepared by covering it with a Cotran ^TM # 9722 polyolefin film as a support.

Example Tulobuterol glue Absorption accelerator additive One 30mg Durotak 87-5298 3.1g 2 30mg Durotak 87-5298 3.1g Plurol oleique 50μl 3 30mg Durotak 87-5298 3.1g 50 μl Labrasol 4 30mg Durotak 87-5298 3.1g 50 μl Labrafil 2609 5 30mg Durotak 87-5298 3.1g Span 80 50μl 6 30mg Durotak 87-5298 2.2gDurotak 87-2516 0.75g 20 μl Plurol oleique 7 30mg Durotak 87-5298 2.2gDurotak 87-2516 0.75g 20 μl Plurol oleique Ethanolamine 30 μl

[Comparative Example 1]

Main ingredient: Tolubuterol 30mg

Solvent: 1 ml of chloroform

After dissolving the main component of tulobuterol in a solvent of chloroform and dissolving it, 3.39 g (National Starch and Chemical) of polyisobutylene solution was added thereto, followed by stirring for at least 10 minutes to obtain a homogeneous solution. The obtained solution was prepared into a film and a patch was prepared in the same manner as in Example 1.

[Comparative Example 2]

Main ingredient: Tolubuterol 30mg

Solvent: 1 ml of dichloromethane

Tolubuterol, the main component, was dissolved in dichloromethane as a solvent, and then 1.75 g (Dow Corning) of Bio-PSA 7-4302 was added to the solution with a silicone adhesive, followed by stirring for at least 10 minutes to obtain a homogeneous solution. The solution was dried on fluorocarbon diacrylate-coated (3M) release paper and prepared into a film according to the same method as in Example 1, and a patch was prepared.

[Comparative Example 3]

Main ingredient: Tolubuterol 30mg

Solvent: 1 ml of methyl ethyl ketone

Plasticizer: shellflex # 6371 100 μl

Toluene is dissolved in methyl ethyl ketone, a solvent, and the main component, tulobuterol, is dissolved in this solution for 10 minutes by adding plasticizer shellflex # 6371 and styrene-butadiene-styrene block copolymer DuroTak 87-6174 (National Starch and Chemical). Stirring gave a homogeneous solution. The obtained solution was prepared into a film and a patch was prepared in the same manner as in Example 1.

[Comparative Example 4]

Main ingredient: Tolubuterol 30mg

Solvent: Ethyl Acetate 1ml

After dissolving the drug in ethyl acetate as a solvent and adding the acrylate polymer DuroTak 87-2677 2.59 g (National Starch and Chemical) to the solution for 10 minutes, the resulting solution was prepared into a film according to the same method as in Example 1. And a patch was prepared.

[Comparative Example 5]

Main ingredient: Tolubuterol 30mg

Solvent: Ethyl Acetate 1ml

Absorption accelerator: 200 μl PEG-20 Almond Glyceride (Crovol A40)

After dissolving the drug in ethyl acetate as a solvent and adding 2.59 g (National Starch and Chemical) of the acrylate polymer DuroTak 87-2677 to the solution, adding the absorption accelerator and shaking for 10 minutes, the obtained solution was subjected to the same method as in Example 1. According to the film and prepared patch.

Experimental Example 1

The skin absorption capacity of the patch prepared according to the present invention and the patch of the prior art was measured by the following method. Patches prepared according to the formulations described in Examples 1 to 7 were used as test patches, and patches prepared according to Comparative Examples 1 to 5 were used as control patches. The skin absorption test was performed using a well-known vertical Franz Diffusion cell (volume: 5.5 ml, surface area 2 cm ² ) as a general evaluation method for transdermal absorption preparations, and flow using a multichannel peristalitic pump and a fraction collector. A true diffusion device was constructed. Phosphate buffered saline (PBS) adjusted to pH 7.4 was used as the receptor medium for the cells, and the skin of 6-7 week old male hairless mice was carefully removed to prevent injury, and then fat and blood vessels inside the skin were removed. Skin fragments from which unnecessary tissue debris was removed were attached to the upper portion of the Franz diffusion cell, and then, a test patch and a control patch were attached thereto, and the lid was closed and clamped securely. The temperature of the cell was kept constant at 37 ° C. at all times, and the specimen was collected by the fraction collector at regular time intervals for 32 hours. The amount of active ingredient released from the patch by the HPLC and passed through the skin and then reached the cell's aqueous medium was quantified, and the rate of permeation and the amount of permeation of the drug were calculated from the values obtained here.

<HPLC operating condition>

Column: Alltima 4.6X150㎜, C8, 5㎛

Mobile phase: 38% methanol + water (0.1% phosphoric acid)

Flow rate: 1ml / min

Detection: UV 210 nm

Test Product Average skin penetration rate (㎍ / cm ² / hr) Example 1 4.66 Example 2 6.38 Example 3 5.16 Example 4 5.97 Example 5 6.11 Example 6 4.92 Example 7 6.03 Comparative Example 1 3.43 Comparative Example 2 3.21 Comparative Example 3 1.94 Comparative Example 4 0.33 Comparative Example 5 1.57

Experimental Example 2

In order to test skin adhesion, Example 1, Examples 6 to 7, and Comparative Example 5 were cut into 10 cm ² , respectively, and attached to the upper arm of the arm, and the adhesion after 24 hours and the adhesion at the shower were tested.

Test Product Skin adhesion After 24 hours Shower Example 1 Excellent adhesion Maintain adhesion Example 6 Excellent adhesion Maintain adhesion Example 7 Excellent adhesion Maintain adhesion Comparative Example 5 Lack of adhesion Loss of adhesion

Examples 1, 6 and 7 showed excellent adhesion within the application period in the skin adhesion test, and also maintained the adhesion even in the shower so that the patch was not peeled from the skin or the patch edge was floating. However, in Comparative Example 5, the adhesive strength was weak, so that the patch did not adhere during the application period of 24 hours. In particular, the adhesive strength decreased rapidly in the shower, and the patch exposed to moisture easily peeled off the skin.

The present invention is a tulobuterol as an active ingredient; Polyglyceryl Oleque, PEG-8 Glyceryl Capriate / Caprate (Labrasol), PEG-8 Glyceryl Linoleate (Labrafil 2609), Sorbitan Fatty Acid Ester (Span), Polyoxyethylene-Sorbitan One or two or more absorption promoters selected from the group consisting of fatty acid esters (Tween); Alkanolamines as alkalizing agents; The present invention relates to a tulobuterol-containing percutaneous absorption patch containing a matrix composed of one or two or more of an acrylate polymer having a hydrophilic polymer and a hydroxyl group grafted with a hydrophilic polymer as a matrix substrate. It is very effective for sustained long-term release of the drug tulobuterol, and is effective in producing patches.

Claims (8)

a) tulobuterol as an active ingredient; b) Polyglyceryl Oleque, PEG-8 Glyceryl Capriate / Caprate (Labrasol), PEG-8 Glyceryl Linoleate (Labrafil 2609), Sorbitan Fatty Acid Ester (Span), Polyoxyethylene- At least one absorption promoter selected from the group consisting of sorbitan-fatty acid esters (Tween); c) at least one alkalizing agent selected from the group consisting of alkanolamines, alkylamines, sodium bicarbonate, caustic soda and ammonium ions, amine groups, pyridine groups as alkalizing agents; And d) a drug-containing matrix composed of at least one matrix substrate of an acrylate-based or grafted acrylate-based polymer having a hydroxyl group. The percutaneous absorption patch according to claim 1, wherein the active ingredient tulobuterol is contained in an amount of 1 to 30% by weight based on the total weight of the drug-containing matrix. The percutaneous absorption patch according to claim 1, wherein the absorption accelerator contains polyglyceryl oleate at a rate of 1 to 20% based on the total weight of the drug-containing matrix. The patch for transdermal absorption according to claim 1, characterized by containing 1 to 20% of ethanol amine as the alkalizing agent. The percutaneous absorption patch according to claim 1, wherein the matrix base is contained in a proportion of 70-99% by weight based on the total weight of the drug-containing matrix. The method according to any one of claims 1 to 5, based on the total weight of the drug-containing matrix, 2-20% by weight of tulobuterol as an active ingredient, and polyglyceryl oleique as an absorption accelerator. -10% by weight, containing 2-10% ethanol amine as alkalizing agent and at least 90% to 97% by weight of acrylate polymer polymer or acrylate polymer polymer having hydroxyl group grafted as matrix substrate Percutaneous absorption patch 7. The percutaneous absorption patch according to claim 6, wherein the drug-containing matrix has a thickness of 10 to 500 mu m. Tolubuterol, which is a main component in a solvent, is dissolved, and an absorption accelerator is added thereto to uniformly disperse in the polymer matrix matrix, and then the mixture is evenly inverted to a thickness of about 10 to 500 µm on a release layer to prepare a thin film. And then drying at a temperature of about 75 to 90 ° C. to evaporate the solvent, and after cooling to cover the support, to prepare a tolubuterol-containing transdermal patch according to any one of claims 1 to 7.