KR100956023B1 - Patches containing tulobuterol for transdermal administration - Google Patents

Abstract

The present invention relates to a patch for tolubuterol transdermal administration consisting of a drug protective layer, a tolobuterol-containing adhesive layer, and a release layer, wherein the tolobuterol-containing adhesive layer has a carboxyl group as a functional group or a functional group having no functional group or a hydroxy group. It is made by mixing an acrylate polymer having a hydroxy group as a functional group, and when the acrylate polymer having a carboxyl group has a mixing weight ratio of 1, the acrylate polymer having no functional group or a hydroxy group is mixed with 70 to 80 to have an acidic functional group. Provided is a patch for transdermal administration of tulobuterol for controlling the rate of drug release by the content of an acrylate-based polymer. Such a transdermal patch containing tulbuterol of the present invention has excellent skin permeability and long-term sustainability of the drug, and does not use additives and skin permeation accelerators, so that the skin irritation is remarkably low, so that it can be used as a tool without any side effects even during long-term use. Buterol can be safely delivered to the body, and the manufacturing method is 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.

Patch, Acrylate, Tolobuterol

Description

Patches containing tulobuterol for transdermal administration to control drug release rate by content of acrylate-based polymer having acidic functional group

The present invention relates to a patch for transdermal administration containing tulobuterol, and more particularly, to a patch for transdermal administration of tulobuterol, characterized in that the drug release rate is controlled by the content of an acrylate polymer having an acidic functional group. It is about.

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 short, so there is a problem that must be taken frequently. Therefore, the need to develop a new formulation to address these problems was emphasized. 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 preparations have long-term durability of the drug effect, but have a disadvantage of increasing the drug release rate at an early stage when the average particle size is less than 2 ㎛ or more than 20 ㎛. Therefore, no significant relationship between the persistence of drug effects can be found and it is difficult to secure uniformity of quality unless the size of the particles is precisely controlled.

Rubber pressure-sensitive adhesives such as polyisobutylene used in the patent have a very low permeability of air and moisture, and antioxidants or stabilizers should be added as needed to improve stability, and thus these substances may cause skin irritation. do. Thus, a silicone pressure-sensitive adhesive having good adhesion and less 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 describes a transdermal absorption type formulation containing tulobuterol dissolved in a plaster layer at a high concentration of 5% by weight or more, wherein an acrylate-based adhesive or a 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.

Therefore, the present inventors are studying a patch that can sufficiently exhibit the medicinal effect without skin irritation, and since tulobuterol has a secondary amine group showing basicity, when using an acrylate polymer having an acidic group such as a carboxyl group, Based on the fact that the groups and acidic groups interact with each other, making it difficult to escape from the polymer matrix, leading to a significant decrease in skin permeability, while very high skin permeability in acrylate polymers having no functional groups or basic functional groups. By controlling the release rate with the content of the acrylate-based polymer having acidic groups and the acrylate-based polymer having acidic groups, the drug can be continuously released for 24 hours with little skin irritation. It is confirmed that the present invention has been completed.

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.

In order to achieve the above technical problem, the present invention

A tolubuterol transdermal patch comprising a drug protective layer, a tolobuterol-containing adhesive layer, and a release layer,

The tolobuterol-containing adhesive layer is

It is made by mixing an acrylate polymer having a carboxyl group as a functional group and an acrylate polymer having no functional group or a hydroxy group as a functional group, and when the acrylate polymer having a carboxyl group is 1, the functional weight is absent or having a hydroxy group. Provided is a patch agent for transdermal administration of tolubuterol to control the drug release rate by the content of the acrylate-based polymer having an acidic functional group characterized in that the rate-based polymer is mixed to 70 to 80.

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Transdermal dosing agent containing tulobuterol of the present invention, while the production process is simple, excellent skin permeability and long-term persistence of the drug efficacy, significantly low skin irritation due to the absence of additives and skin permeation accelerators for long-term use In addition, tulobuterol can be safely delivered to the body without any side effects, and the manufacturing method is 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.

Hereinafter, the present invention will be described in detail.

The percutaneous administration patch containing tulobuterol according to the present invention comprises a drug protective layer, a tolobuterol-containing adhesive layer, and a release layer.

In the percutaneous administration patch containing tulobuterol according to the present invention, the drug protective layer, the content of tolobuterol contained in the adhesive layer, the release layer can be used as it is widely known in the art. In this regard, the drug protective layer is used to prevent the loss of tolubuterol from the formulation during attachment or storage on the skin, it is thin and flexible and does not cause an allergic reaction because it is not reactive with the skin. . A drug protective layer that absorbs water to prevent the patch from falling off due to 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 obtained by laminating the single layer film may be used, and any of drug-protective films used in conventional patching agents may be used.

In addition, 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, such as aluminum, cellulose, polyester, polyethylene, and polypropylene used in the conventional patch. A film or a thin film made of 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 addition, the content (dry weight) of tolubuterol contained in the drug-containing adhesive layer may be used within the range of conventionally used content, and a suitable example thereof may be 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, side effects such as respiratory failure due to exceeding the effective blood concentration This is because the frequency of occurrence may increase.

In the present invention, while research on a patch that can fully exhibit the effect without skin irritation, tolubuterol has a secondary amine group showing a basic, so when using an acrylate polymer having an acidic group such as carboxyl group, The group interacts with each other, making it difficult to escape from the polymer matrix, leading to a significant decrease in skin permeability. On the other hand, acidic groups are based on the fact that acrylate polymers that do not have functional groups or have basic functional groups show very high skin permeability. The eggplant has been confirmed that the drug can be continuously released for 24 hours with little skin irritation by controlling the release rate by mixing the acrylate-based polymer and such an acrylate polymer, the present invention is particularly The tolobuterol-containing drug adhesive layer is a mixture of an acrylate polymer having an acidic functional group and an acrylate polymer having no acidic functional group, that is, having no functional group or having a hydroxyl to basic functional group.

The acrylate-based polymer having an acidic functional group is a copolymer of roup) with an acidic functional group-containing monomer and can be used without particular limitation as long as it is known in the art. For example, alkyl having 4 to 17 carbon atoms as a main monomer. At least one monomer selected from acrylate or alkyl methacrylate, specifically 2-ethylhexyl acrylate (2-EHA), butyl acrylate (BA) , Ethyl acrylate (EA) and iso-octyl acrylate (iso-octyl acrylate, iso-OA) may be one or more monomers selected from the group consisting of acidic functional groups containing monomers are examples of acrylic acid ( arcylic acid) and maleic acid.

In addition, the acrylate-based polymer that does not have an acidic functional group means a polymer consisting only of an acrylate-based monomer or a copolymer with a hydroxy- to basic functional group-containing monomer, which is only known in the art. Examples of the acrylate polymer which can be used without limitation and do not have a functional group include a polymer composed of only the main monomers described above, and a hydroxy group that can be used to prepare an acrylate polymer having a hydroxy group functional group. Examples of the functional monomers include 2-hydroxyethyl acrylate and 2-hydroxypropyl acrylate.

In the case of Tolobutenol-containing transdermal patch, the initial blood concentration due to high skin permeability increases the therapeutic effect due to the decrease of drug concentration in the latter part, especially effective treatment for early morning seizures characteristic of asthma patients. It is important to be able to maintain the blood drug concentration appropriately for 24 hours because it may affect, for this purpose, in the present invention, when the acrylate-based polymer having an acidic functional group is 1 by weight ratio, the acrylate-based polymer is not 40. To 80, most preferably 70 to 80 to prepare a drug-containing adhesive layer.

In addition, it has been proved by various experiments that mixing of an acrylate copolymer having a carboxyl group with an acidic functional group and an acrylate copolymer having a hydroxy group as another functional group other than the acidic functional group is most suitable for achieving the above-mentioned effect.

The tolobuterol-containing transdermal patch according to the present invention does not include an additive and a skin permeation accelerator, thereby reducing the physical characteristics of the patch and the risk of skin irritation, thereby simplifying the structure and the production process. Have productivity.

Hereinafter, the tolobuterol-containing transdermal administration patch according to the present invention will be described in detail through Examples and Experimental Examples. The following Examples and Experimental Examples are provided only to more easily understand the present invention, but the contents of the present invention are not limited by the examples.

<Example 1>

Copolymer of acrylic acid (hereinafter referred to as "A") as a monomer having 2-ethylhexyl acrylate and an acidic functional group as a main monomer and 2-hydroxy as a monomer having 2-ethylhexyl acrylate and a hydroxy functional group as a main monomer A copolymer of ethyl acrylate (hereinafter referred to as "B") was mixed in a weight ratio as shown in Table 1 below, tolubuterol was added thereto, and 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) to a thickness of 30 μm, dried at 100 ° C. for a predetermined time, and then fluorocarbon The coated 70 μm-thick polyester peeling film (3M, Scotchpak 1022) was laminated to prepare a transdermal patch (tolubuterol content: 6.1 wt%).

A B Sample 1 0 One Sample 2 One 40 Sample 3 One 65 Sample 4 One 75

Experimental Example 1: Skin Permeability Measurement

In order to determine the skin permeability of the percutaneous administration patch containing tulobuterol prepared in Example 1, the following experiment was performed.

The extracted pig 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 12 ml, and the area of skin in contact with the receptor layer was 1.77 cm 2. After the percutaneous administration patch containing tulobuterol prepared in Example 1 and the commercially available hokunalin patch were adhered to the exposed portions of the skin, the samples were collected for up to 24 hours for each time period. Tolubuterol concentration was measured by high performance liquid chromatography, and the skin permeation rate (µg / cm 2 / hr) at steady-state was obtained.

As a control group, a commercially available tolubuterol transdermal absorber, Hokunalin Patch (0.5 mg / patch, manufactured by Abbott), was used.

The results are shown in Table 2.

Skin penetration rate (㎍ / ㎠ / hr) Control 7.96 ± 0.85 Sample 1 10.42 ± 1.75 Sample 2 5.15 ± 0.25 Sample 3 6.01 ± 0.48 Sample 4 7.73 ± 0.7.0

As shown in Table 2, while the sample 1 does not contain an acrylate-based polymer having an acidic functional group, the transmittance was decreased while increasing the content of the acrylate-based polymer having an acidic functional group. When A is 1, sample 4 having B of 75 is the most appropriate as the value is very similar to that of the control group.

Experimental Example 2: Measurement of Skin Irritability

In order to examine the skin irritation of the transdermal patch containing tulobuterol of the present invention, samples 1, 3, and 4 prepared in Example 1 were subjected to a primary irritation test on rabbit skin.

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 from each other. It was set as. The abrasion and skin were made by using a syringe needle tip to scratch the epidermis so that the epidermis was damaged but not the dermis.

The percutaneous administration patch containing the tulobuterol of Samples 2 to 4 was affixed to the skin of the rabbit's dorsal hair, and the formulation 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 following skin irritation criteria, 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 used as the primary skin stimulation index (PII value) as described later.

As a control, a commercially available tolubuterol transdermal absorbent, Hokunalin Patch (0.2 mg / patch, manufactured by Abbott), was used. The results are shown in Table 3.

<Skin irritation criteria>

Score 0: no erythema, no edema

Score 1: very mild erythema, very mild edema

Score 2: Obvious erythema, mild edema

Score 3: Severe erythema, moderate edema

Score 4: severe erythema, mild crusted severe edema

Primary Skin Stimulation Index (PII)

0 to 0.5: non-irritant

0.6 to 2.0: mildly irritating

2.1 to 5.0: moderate irritant

5.1 to 8.0: strong irritant

Primary skin irritation index (PII) division Control 2.21 Moderate irritant Sample 2 0.31 Non-irritant Sample 3 0.39 Non-irritant Sample 4 0.34 Non-irritant

As shown in Table 3, the primary skin irritation index of the transdermal patch (Tamples 2 to 4) containing the Tolubuterol of the present invention is 0.34 to 0.39, which is non-irritating to the skin and is higher than that of the control Hokunalin patch. It can be seen that the stimulation 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.

Claims (3)

A tolubuterol transdermal patch comprising a drug protective layer, a tolobuterol-containing adhesive layer, and a release layer, The tolobuterol-containing adhesive layer is It is made by mixing an acrylate polymer having a carboxyl group as a functional group and an acrylate polymer having a functional group or having a hydroxy group as a functional group. Tolubuterol transdermal patch for controlling the drug release rate by the content of the acrylate-based polymer having an acidic functional group, characterized in that the rate-based polymer is mixed to 70 to 80. delete delete