KR950013448B1 - Patch type pneparation - Google Patents

Abstract

The transdermal patch comprising an adhesive base material containing a support body, an adhesive resin, a medicine, a transdermal penetration stimulator, and a release film has a multi-layer structure of 2-5 layers of the adhesive base material, the adhesive resin for each layer being an acryl based resin having the lowest water retaining power at the bottom part in touch with the skin and having the larger water retaining power on coming upper in layer, and the medicine containing 0.1˜50wt.% of Keto propine.

Description

Patches for transdermal administration drugs

1 shows a cross-sectional view of a patch according to the present invention having a laminate multilayer structure.

* Explanation of symbols for main parts of the drawings

1 support 2 upper adhesive base

3: lower layer adhesive 4: release film

The present invention relates to a sustained release patch for continuously delivering a predetermined amount of a drug (physiologically active substance) through the skin or mucous membranes, in particular, the amount of drug required while dissolving the drug to the maximum in the adhesive layer in contact with the skin when applied to the skin. It is to promote the percutaneous penetration more effectively while appropriately percutaneous penetration.

Absorption of a drug (physiologically active substance) through the skin using a patch, which is a transdermal administration agent, has been performed to obtain a medicinal effect on the whole body or locally. Such transdermal administration has many advantages over conventional oral administration. For example, during oral administration of a drug, the drug absorbed in the intestine is first metabolized in the liver and degraded in large quantities before the drug takes effect at the desired location. However, in the transdermal administration, when the absorbed drug circulates in the body, the drug does not pass through the liver first, and thus, the drug efficacy is not greatly reduced by metabolism in the liver. In particular, nonsteroidal anti-inflammatory drugs are easy to cause gastrointestinal disorders upon oral administration, but by transdermal administration there is an advantage to reduce the occurrence of gastrointestinal disorders.

In light of these benefits, transdermal drug delivery has recently been delivered through the skin, overcoming the first-pass effect or gastrointestinal disorders seen during oral administration, and increasing its effectiveness and stability. System) has been increased to produce commercial products such as nitroglycerin and scopolamine.

However, the disadvantage of such a transdermal drug delivery system is that it is difficult to apply to more drugs. Because the skin that forms the body surface acts as a barrier to inhibit the influx of external pathogens or toxic substances and the permeability of the drug is limited. Thus, much effort has been made to expand the utility of transdermal delivery for more drugs and to remove barriers caused by living skin and membranes.

By controlling the absorbency of the drug, it is possible to alleviate the side effects caused by the drug being absorbed in large quantities in a short time. Maintaining a constant blood concentration for a long time is also possible by reducing the frequency of drug administration.

However, even if the drug is administered using a patch, the drug is difficult to penetrate the skin, so the bioavailability of the drug is often lowered. Therefore, it has been attempted to increase the absolute amount of drug in the patch to percutaneously absorb the required amount of drug. For example, Japanese Patent Application Laid-Open No. 60-185713 and USP 4,031,894 disclose transdermal absorption preparations in which a drug is contained above a saturated concentration in a base such as a patch, an ointment or a cream, and the drug is dispersed in a recrystallized particulate state. It has been. For example, as the patch is applied to the skin surface and the drug dissolved in the base is percutaneously absorbed, the drug present in the particulate form in the base is gradually dissolved to replenish the drug in the dissolved state. In reality, however, the drug in the form of a particle is difficult to re-dissolve into the base, and the rate at which the drug is absorbed through the skin is not so high.

As another method, a method of promoting percutaneous absorption of a drug by sealing sweat is also attempted. For example, attempts have been made to increase skin absorption by selecting a conflicting film of a patch as a film which is difficult to penetrate water in Japanese Unexamined Patent Publication No. 60-51478 and Japanese Unexamined Patent Publication No. 62-153215. However, this method has the disadvantage that the irritation caused by sweat and secretion, and the patch is peeled from the skin by sweat. In order to solve these disadvantages, it is proposed to use a support having excellent moisture permeability, such as nonwoven fabric or absorbent urethane, as in Japanese Patent Application Laid-Open No. 53-33984, Japanese Patent Application Laid-Open No. 56-20514, Japanese Patent Application Laid-Open No. 56-51412, and the like. But even these attempts do not ultimately deliver the required amount of drug.

Gelatin, polyvinyl alcohol, dextrin, gum arabic, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, and sodium alginate to improve skin irritation and adhesion. A method of using a water-soluble base using sodium polyacrylate or the like has also been disclosed. However, these formulations have very low skin adhesion and cannot be applied only with their patching agents, and should be used together with the adhesive cloth, and do not sufficiently deliver the drug to the skin.

U.S. Patent No. 4,814,168 discloses a skin composition suitable for use in a transdermal administration system of a drug, which composition may contain the maximum amount of drug in a patch and also exhibits adhesive properties such as shear, adhesion, and peelability. You can keep it as it is. The composition of the patent is a polypolymer consisting of a drug, vinyl acetate and ethylene monomers; It contains rubber and adhesives.

U.S. Patent No. 5,176,916 relates to a medicinal warning agent for transdermal administration of an active ingredient that is difficult to absorb percutaneously, wherein the hydrophilic active ingredient is contained in a hydrophobic polymer and water is contained as a solvent. According to this invention, as a solvent, water is contained in the warning base in an amount necessary for the W / O type. However, the patch of US Pat. No. 5,176,916 is suitable for transdermal administration of highly hydrophilic drugs because it contains water, but is not suitable for transdermal administration of useful drugs such as nonsteroidal anti-inflammatory drugs. not.

Under these circumstances, the present inventors have repeatedly studied to provide a transdermal patch that is suitable for transdermal administration of a useful drug, can safely release the drug, and can maintain its long-term efficacy. It has been found that the object can be achieved by using a patch containing a pressure-sensitive adhesive material having a different multilayer structure in which the water absorption capacity of each layer is different.

Accordingly, an object of the present invention is a support; Adhesives containing oil-soluble drugs, adhesive resins, transdermal penetration accelerators, superabsorbent substances, and skin irritant agents; And a patch made of a release film, wherein the pressure-sensitive adhesive agent has a multi-layered structure composed of 2 to 5 layers, and the adhesive resin of each layer has a different water function, and the lowest layer in contact with the skin has the lowest water content and a support. The uppermost layer in contact is to provide a transdermal patch for a oil-soluble drug, a nonsteroidal drug, which is characterized by having the highest functionality.

Another object of the present invention is a moisture-permeable support; Adhesive bases containing oil-soluble drugs, adhesive resins, transdermal penetration accelerators, absorbent substances, and skin irritant; And a release patch comprising a medicament patch, wherein the adhesive base has a multi-layered structure composed of 2 to 5 layers, and the adhesive resin of each layer has a different water function, and the lowest layer to which the skin is in contact has the highest water function. The highest layer in contact with is to provide a medicinal patch characterized by having the lowest functionality.

Hereinafter, described in detail with respect to the technical configuration of the present invention.

Transdermal absorption of the drug by the patch is performed due to the difference in concentration between the drug and the inside of the living body. In the case of actually penetrating the stratum corneum, the first step in the process of envisioning the absorber as a whole is described. Diffusion, the second, is divided into the distribution from the base to the surface of the stratum corneum, the diffusion in the third stratum corneum, the distribution from the fourth stratum corneum to the lower epidermal tissue, the fifth living epidermis, the diffusion in the dermal layer, and the transition from the sixth dermal layer to blood vessels.

As described above, the transdermal absorption process of the drug is considered to be divided into a diffusion process and a distribution process, but in reality, binding and metabolic reactions with the tissue proceed simultaneously with diffusion. Diffusion phenomena are described by Fick's first law, which describes the relationship between drug concentration gradient and the speed of movement, and by Fick's second law, which describes the time-dependent change in drug concentration at any location.

J / A = -D C / x ----- Fick's First Law

C / t = D ² C / x ² ----- Fick's Second Law

Where A is the area, C is the concentration of the drug, D is the diffusion coefficient, J is the permeation rate, t is the time, and x is the position.

The skin permeability of the drug is often determined by the rate of penetration at steady state. In addition, the drug permeation rate at steady state J = AC _V KCL (C _V : concentration of drug in substrate, K: drug distribution coefficient between skin / substrate, L: effective skin thickness) and permeation coefficient Kp = KD / L

As indicated above, it is advantageous to increase the concentration of the drug in the adhesive to permeate a large amount of the drug into the skin, but there are limitations in the methods currently used.

In the present invention, as one of the methods of increasing the solubility in the pressure-sensitive adhesive agent and reducing the adhesive properties and skin irritation, a pressure-sensitive adhesive similar to the solubility parameter of the drug was first selected and manufactured to maximize the concentration of the drug in the pressure-sensitive adhesive agent. The most suitable adhesive agent for this purpose is an acrylic adhesive agent. In the case of an acrylic adhesive, since it is easy to adjust the compounding ratio of the monomer to superpose | polymerize, there exists an advantage which can control the water solubility and the solubility with a drug in an adhesive. However, when the patch is applied to the skin, the water dissipation in the skin causes more moisture to exist than when first prepared in the adhesive, so that the solubility parameter in the adhesive changes and the saturation solubility of the drug is changed. Significant differences were observed with the actual solubility, and a considerable decrease was also found in the drug delivery amount and adhesive properties of the adhesive to the skin.

In order to eliminate this drawback, in the present invention, a multilayer lamination method is used, and each layer has a different water-soluble function, and a pressure-sensitive adhesive agent containing no water is used. 2 to 5 layers of adhesives are laminated to form a multi-layered patch, and the lowermost adhesive agent in contact with the skin has the lowest water content, and the uppermost adhesive agent in contact with the support has the highest water function. Has Alternatively, 2 to 5 layers of adhesives are laminated to form a multi-layered patch, and the lowermost adhesive agent in contact with the skin has the highest water content, and the uppermost adhesive material in contact with the support is the lowest. Have SAT

As shown in FIG. 2, the patch of the present invention comprises a support 1, an upper adhesive 2, a lower adhesive 3, and a release film 4.

As the support 1, the support used for the conventional patch can be used. For example, cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurepan, polyethylene, polyvinylidene chloride, Aluminum and the like. These are used, for example, as a single | mono layer sheet (film) or two or more laminated (laminate) bodies. As a material other than aluminum, a cotton cloth or a nonwoven fabric may be used. If the support 1 is made of an impervious material and it is desired to control the release of the drug, the lower layer pressure sensitive adhesive 3 has a lower functionality than that of the upper layer adhesive 2. Therefore, when the patch is applied to the skin, as water is released from the surface of the skin, the water is transferred to the lower pressure-sensitive adhesive material 3 containing the absorbent material, and the upper layer having a greater water-functionality than the lower pressure-sensitive adhesive material 3. It is gradually transferred to the adhesive agent (2). At equilibrium, the upper pressure sensitive adhesive 2 will contain more water than the lower pressure sensitive adhesive 3. At this time, the drug in the lower adhesive layer 3 is absorbed into the skin, and as more water is transferred to the lower adhesive group 3, and then to the upper adhesive group 2, the drug is absorbed more quickly into the skin. Thus, water and other water-soluble secretions are transferred from the skin to the upper layer, whereby the lower layer in contact with the skin always contains a certain amount of drug and water, reducing the side effects of the skin due to the accumulation of sweat or secretions.

On the contrary, in the case of initially penetrating a large amount of drug through the skin, and in order to obtain a burst effect, the support 1 may be a semi-permeable or moisture-permeable material such as a nonwoven fabric, cotton cloth or other breathable plastic film. It can be obtained by laminating the upper layer (2) having a significantly lower functionality than the lower layer (3) of the lower layer (3) to prevent the transfer of water emitted from the skin to the upper layer (2). In other words, if the adhesive agent having the desired functionality is selected and the drug is saturated, the drug concentration is initially high when introduced into the skin, so a large amount of the drug is delivered through the skin, but gradually absorbs moisture from the skin. The solubility of the drug is reduced to reduce the delivery of the drug, and when the absorption of moisture reaches a steady state, only a certain amount of the drug is properly delivered to the skin, thereby controlling the release of the drug.

The patch of the multi-layered structure according to the present invention can control the moisture content of each layer of the patch and control the release of the drug.

In the patch of the present invention, the number of laminated adhesives is 2 to 5, and has a laminate structure. The thickness of each layer is 5 to 150 µm, the optimum is 10 to 100 µm, the thickness of the entire adhesive is 30 to 200 µm, and the optimum is 50 to 500 µm.

As the support of the patch of the present invention, polyethylene, polypropylene, polyethylene terephthalate or nonwoven fabric, cotton cloth or the like is used.

The release film of the patch of the present invention uses a release film containing a silicone or a fluorine-based release agent.

Silicone adhesives, natural or synthetic rubbers, acrylic resins and the like are used as the adhesive resin in the present invention. Rosin-based resins, polyterpene resins, petroleum resins, terpene phenol resins, and the like may be used as the tackifier, and plasticizers, fillers, antioxidants, and the like may be added. In particular, as the acryl-based resin, a (co) polymer of an aliphatic alcohol having 4 to 18 carbon atoms and an (meth) acrylic acid alkyl ester or a (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms or different functional properties A tacky resin which is polymerized with a monomer can be used. Examples of the (meth) acrylic acid copolymer include butyl acrylate, isobutyl acrylate copy, and the like. Moreover, as said functional monomer, the monomer which has a hydroxyl group, the monomer which has a carboxyl group, the monomer which has an amide group, the monomer which has an amino group, etc. can be used. As a monomer which has a hydroxyl group, 2-hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, etc. are mentioned. As a monomer which has a carboxyl group, (alpha)-(beta) unsaturated carboxylic acids, such as acrylic acid and a methacrylic acid; Maleic acid monoalkyl esters such as butyl maleate; Phosphoric Acid in Mal; Fumaric acid; Crodon acid, etc., Maleic anhydride can also obtain the (co) polymer of the same type as maleic acid. As a monomer which has an amide group, Alkyl (meth) acrylamide, such as acrylamide, dimethyl acrylamide, and diethyl acrylamide; Alkyl ethyl methylol (meth) acrylamide such as butoxymethyl acrylamide ethoxymethyl acrylamide; Diacetone acrylamide; Vinylpyrrolidone; Dimethylaminoacrylate and the like.

Copolymer monomers other than those described above include vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene and the like, and copolymers with these exhibit good properties.

As the adhesive resin which can be used as the adhesive agent of the patch according to the present invention, the rubber is made of natural rubber, polyisoprene, polyisobutylene, styrene-butadiene-styrene copolymer, styrene-isoprene-styrene copolymer, styrene-ethylene / propylene- Styrene copolymer, styrene-ethylene / butylene-styrene copolymer, polyvinyl ether, polyurethane, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-butylene block copolymer and the like.

As the silicone resin, silicone rubber such as polyorganosiloxane is used.

When using acrylic resin as adhesive resin of an adhesive agent, it is good to contain (meth) acrylic-acid alkylester as 50 weight% or more as a (co) polymerization component.

In addition, in the case of acrylic resin as a method for reducing or increasing the water functionality, rubber and silicone-based resins are controlled by copolymerizing a monomer having high hydrophilicity, a monomer having a carboxyl group, a monomer having an amide group, and a monomer having an amino group. In the case of water, by adjusting the tackifier and additives to control the water functionality.

As another method, the absorbency can be adjusted using a super absorbent polymer, a polyhydric alcohol, and an absorbent inorganic substance. Examples of superabsorbent polymers include mucopolysaccharides such as hyaluronic acid, chondroitin sulfate, dermatin sulfate, and the like. A superabsorbent polymer having a large number of hydrophilic groups in a molecule such as chitin, chitin derivatives, starch and carboxymethyl cellulose and polyacryl Semi-synthetic and synthetic superabsorbent polymers of acid-based, polyoxyethylene-based, polyvinyl alcohol-based, polyacrylonitrile-based or copolymers, and absorbent inorganic materials include absorbent silica, zeolite, absorbent ceramics, and the like. As the propylene glycol, glycerol, sorbitol and the like can be used. At this time, the absorbent materials such as superabsorbent polymer, absorbent inorganic material and polyhydric alcohols may contain 0.140% by weight in the pressure-sensitive adhesive, the optimum is 120% by weight.

In the said adhesive agent, if necessary, various compounding agents, for example, rosin-type resin, polyterpene-based resin, coumaroindene-based resin, petroleum-based resin, terpene phenol crab resin, etc. , Plasticizers such as liquid polyisoprene and liquid polyacrylate, fillers and antioxidants are added.

Substances used as transdermal penetration enhancers to enhance skin absorption of drugs include dodecylsulfoxide, mono or dimethylacetamide, N-hydroxy ethyl lactide, higher fatty acid esters, salicylic acid, sorbitol, urea, glycerin, squalene, Skelan, acetylated lanolin, cetyllaurate, olive oil, castor oil, lauryl acid, oleic acid, lauryl alcohol, oleic alcohol, ethoxystearyl alcohol, derived paraffin, waserine, camphor, glycerin fatty acid ester, fatty acid mono (Or di) ethanolamide, ethylene glycol monoethylene ether, polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxypropylene alkyl ether, propylene glycol mono (di) alkyl ester, propylene glycol monolaurate, polyoxyethylene Uril ethers, pyrrolidone derivatives, and the like. The compounding quantity of such a penetration promoter is 0.1-40 weight%, and 1-20 weight% is the best.

In addition, tocopherol, tocopherol acetate, BH, BH, etc. may be used as antioxidants of drugs, penetration promoters and other additives, and ethyl parabens, methylparabens, butyl parabens, and the like may also be used as preservatives.

The base (adhesive) of such a tape agent or a patch agent can apply an adhesive force to skin surface for a long time at normal temperature, and can show adhesive force, and is not specifically limited. For example, an adhesive such as rubber or silicone resin may be used, and acrylic and rubber resins are usually used.

The drug which can be blended into the pressure-sensitive adhesive of the present invention is an oil-soluble drug, and any drug can be used as long as it can penetrate the skin in transdermal administration and change its solubility according to the change in moisture content in the base. Examples of nonsteroidal drugs include methyl salicylate, salicylic acid, ibuprofen, ketoprofen, flurbiprofen, indomethacin, diclofenoxdium, flfenamic acid, naproxen, mefenamic acid, phenopropene, phenclofenac, and pyrocampam And safe and useful amounts of pharmacologically effective compounds selected from their prodrugs. The compounding amount of such a drug is suitably 0.1 to 50% by weight.

In addition, skin irritation agents, inorganic fillers and organic fillers can be added to reduce adhesive properties and reduce skin irritation when drugs and penetration accelerators are used on tapes or patches. 0.01 to 10% by weight of milleoyl, allantoyl, glycerol, di-pandenol and the like are optimal.

Organic and inorganic materials for improving the adhesion characteristics include organic polymer particles such as cellulose, polyethylene, nylon 6, nylon 12, polypropylene, polyethylene terphthalate, and organic materials such as zinc oxide, calcium oxide, silica, kaolin, talc, and titanium oxide. It may contain -30% by weight, 0.5 to 10% by weight is optimal.

The concentration of the physiologically active ingredient contained in the pressure-sensitive adhesive is 1 to 40% by weight, preferably 5 to 32% by weight, more preferably 7 to 30% by weight of the sum of the weight of the physiologically active ingredient and the weight of the adhesive layer.

According to the present invention, the saturation concentration of the physiologically active ingredient in the pressure-sensitive adhesive layer depends on the composition of the pressure-sensitive adhesive, but the physiologically active ingredient has been found to be preferable when contained at a concentration near the saturation concentration in each pressure-sensitive adhesive layer composed of various compositions.

Example 1

(A) Preparation of adhesive resin (1)

97.4 parts of 2-ethylhexyl acrylate, 2.5 parts of methacrylic acid, 0.1 part of polyethylene glycol dimethacrylate, 1.0 part of benzoyl peroxide (BPO) and 100 parts of ethyl acetate were added to a reaction vessel having a reflux condenser and a stirrer, and under a nitrogen atmosphere. The polymerization was carried out with stirring at 60 ° C. In order to control the degree of polymerization, 100 parts of ethyl acetate was slowly added during the reaction and reacted for 9 hours. At this time, the polymerization addition rate was 99.9%. Appropriate amount of ethyl acetate was added to the obtained polymer solution, and solid content concentration was about 40 weight%.

(B) Preparation of adhesive resin (2)

70 parts of 2-ethylhexyl acrylate, 10 parts of acrylic acid, 1.0 part of benzoyl peroxide (BPO), and 20 parts of vinyl acetate were copolymerized with ethyl acetate under the same conditions as above. At this time, the polymerization rate was 99.9% or more, and the aluminum acetate was 200 rpm. It was added to be self-curing.

Appropriate amount of ethyl acetate was added to the obtained polymer and the solid content was made into about 40 weight%.

(C) Preparation of the lower layer adhesive agent 3 of FIG.

Ketoprofen is added to the tacky resin (1) at 20% by weight relative to the solid content, and dissolved in more than saturated solubility, and is applied to a release paper treated with silicone. At this time, the coating amount is adjusted so that the thickness at drying is 50 µm.

(D) Preparation of Upper Layer Adhesive 2 of FIG. 2

The drug is added to the adhesive resin (2) obtained above to 20% by weight to dissolve more than saturated solubility, so that the thickness at the time of drying on the silicone-treated release paper is 30㎛.

(E) Preparation of Patch

The upper pressure sensitive adhesive (2) is first transferred to a polyethylene film, and the lower pressure sensitive adhesive (3) is further laminated to prepare a patch consisting of two pressure sensitive adhesives. At this time, the drying conditions are left to stand at room temperature for 15 minutes, and then dried naturally at 90 ℃ for 10 minutes.

Example 2

(A) Preparation of Lower Layer Adhesive (3)

Ketoprofen was added to the tacky resin (1) obtained in Example 1 (A) at 20% by weight based on the solid content, and dissolved in more than saturated solubility, and evenly dispersed 5% by weight of hyaluronic acid and powder therein, and the thickness at drying. Was made into 40 micrometers, it apply | coated to silicone release paper, and it dried, and obtained the lower-layer adhesive agent (3).

(B) Preparation of Patch

The lower pressure-sensitive adhesive agent 30 is transferred to a polyester film, and the upper pressure-sensitive adhesive agent 2 obtained in Example 1 (D) is laminated thereon to prepare a patch consisting of two pressure-sensitive adhesive agents.

Example 3

(A) Preparation of Lower Layer Adhesive (3)

Ketoprofen was added to the tacky resin (1) obtained in Example 1 (A) in an amount of 20% by weight based on the solid content, and dissolved in more than saturated solubility, and polyoxyethylene (3) lauryl ether 10 was used as a transdermal penetration accelerator. After the weight% is added, 0.5 weight% of tocopherol acetate is added and dissolved as an antioxidant. And 3% by weight of colloidal silica in order to improve the deterioration of adhesion characteristics due to the percutaneous penetration promoter. The pressure-sensitive adhesive prepared in this way is applied to a release paper with a thickness of 60 占 퐉 upon drying and then dried.

(B) Preparation of Upper Layer Adhesive (2)

Ketoprofen was added to the tacky resin (2) obtained in Example 1 (B) in an amount of 20% by weight based on the solid content and dissolved in more than saturated solubility, and 10 wt% of polyoxyethylene (3) lauryl ether was used as a transdermal penetration accelerator. After adding%, 0.5% by weight of tocopherol acetate was added as an antioxidant to dissolve it, and then it was applied to the release paper so as to have a thickness of 40 占 퐉 upon drying.

(C) Preparation of Patch

The lower pressure sensitive adhesive 3 is transferred to a polyester film, and the upper pressure sensitive adhesive 2 is laminated thereon to prepare a patch composed of two pressure sensitive adhesives.

Example 4

Production of patch

Ketoprofen was added to the tacky resin (2) obtained in Example 1 (B) in an amount of 20% by weight based on the solid content, and dissolved above saturation solubility, and 10% by weight of propylene glycol monooleate was added thereto as a transdermal absorption accelerator. Thereafter, 0.5% by weight of tocopherol is added and dissolved as an antioxidant, and 2% by weight of bisabolol is added and dissolved as a skin irritant. And after disperse | distributing 3 weight% of cellulose powders (5-15 micrometers of particle diameters) uniformly with a water content regulator, it makes it thickness 70micrometer and apply | coats to a release paper. The lower layer adhesive 3 is obtained. This is transferred to a polyester film, and the upper layer adhesive agent 2 obtained in Example 3 (B) is laminated here, and the patch which consists of two layers of adhesive agents is manufactured.

[Test Example 1]

Transdermal penetration test

The abdominal hair of a male Ginaapic, weighing about 350 g, is shaved with an electric hair clipper, cut off a portion, stored frozen (less than -20C), and melted when necessary for testing.

The skin is placed in the middle of the Franz-type diffusion cell with the stratum corneum face up, and then 0.05M isotonic phosphate buffer solution (pH 7.4) is placed in the bottom space and the temperature of the diffuser is 37C. Keep it. The receptor solution (buffer solution) is agitated at a constant speed (600 rpm) while attaching the patch prepared in Example 1 to the skin. After a certain period of time, the solution in the receptor section is taken and replenished with the amount of fresh complete layer solution. The collected sample is measured by high pressure liquid chromatography (HPLC) to measure the concentration of ketoprofen.

Analytical conditions of high pressure liquid chromatography (HPLC).

Column: C ₁₈ μbondapak [01757, Massachusetts, Waters Chromatography, Milton]

Mobile phase: 55: 45 (V / V) = methanol: 0.02 M phosphate buffer (pH 4.0)

Flow rate: 1ml / min

Detector: UV 254nm Wavelength

Experimental results of the skin penetration of ketoprofen from the various patch according to the prescription of Table 1 as shown in Table 2 below.

TABLE 1 Types of patch used for skin palpation test

Note 1) The content of all the components means weight%.

2) The content of the remaining contents of Patch No. 1-10 corresponds to the acrylic resin (solid) of Example 1.

3) ¹ Propylene Glycol Monolaurate

4) ¹ polyoxyethylene (3) lauryl ether

TABLE 2 Comparison of skin penetration rate of ketoprofen from patch according to Table 1

Note 1) Numbers in parentheses mean standard horseshoe.

2) The number of experiments is more than 4 times.

3) * Ratio based on ketoprofen content of 10% and no penetration accelerator.

[result]

In order to increase the transdermal penetration of ketoprofen, the lower dose in the adhesive layer of ketoprofen was increased by the use of a percutaneous penetration accelerator than the preparation of the saturation concentration to enhance the transdermal penetration of ketoprofen. In view of the fact that when the transdermal penetration accelerator is included in the pressure-sensitive adhesive layer by a general technique, the adhesion property is greatly reduced and the effect of the transdermal penetration promotion is halved. Thus, the penetration accelerator of the present invention showed effective penetration promotion without a great change in the adhesion properties.

[Test Example 2. Skin Primary Stimulation Test]

The patch prepared in the same manner as in Example 1 was cut to a size of 2.5 cm 2, the peeling liner was removed, and then attached to the forearm arm of a healthy adult tester. After 24 hours of attachment, the patch is removed, and after 30 minutes, the degree of primary stimulation is observed according to the following judgment.

The observed degree of stimulus is calculated from the equation below.

The formulation of the patch used in the primary skin irritation test is shown in Table 3 and the test results are shown in Table 4.

TABLE 3 Types of patch used in the primary stimulation test

Note 1) ¹ Propylene Glycol Monolaurate

2) ¹ polyoxyethylene (3) lauryl ether

3) All content% is weight%

TABLE 4 Skin Primary Stimulation Test Results

Although bisabolol was not alleviated primary skin irritation in all cases, it showed that it could be useful as a stimulant remedy when used 1-2%, and the overall degree of irritation of the patch was safe within 10%.

Comparative Example 1

Only the adhesive agent 3 of Example 1 (C) was apply | coated to a release paper with the thickness set to 80 micrometers, and it laminates this with a polyethylene film, and manufactures a single layer patch.

Comparative Example 2

Ketoprofen was added to the tacky resin obtained in Example 1 (A) to 20% by weight with respect to solids and dissolved in saturated solubility or higher, and propylene glycol monooleate was added to 10% by weight as a transdermal absorption accelerator, followed by oxidation. 0.5% by weight of tocopherol is added as an inhibitor, and 2% by weight of bisabolol is added as a skin irritant. This is applied to the release paper to a thickness of 70㎛ and dried.

[Test Example 3]. Transdermal penetration test

Using the examples of the present invention and the comparative example, the results of experiments in the same manner as the transdermal penetration test are shown in Table 5 below.

TABLE 5 Comparison of Skin Penetration Rate of Ketoprofen

NOTE The numbers in parentheses mean the standard deviation.

[Test Example 4]. Skin primary irritation test

Using the patch of Examples 1-4 and Comparative Examples 1-2, the test result by the same method as the said skin primary irritation test is shown in Table 6.

TABLE 6 Comparison of skin primary irritation of ketoprofen

Claims (2)

In the transdermal drug-type patch made of a pressure-sensitive adhesive and a release film containing a support, an adhesive resin, a drug, a percutaneous penetration accelerator, and the like, the adhesive agent has a multilayer structure composed of 2 to 5 layers, and the adhesive resin of each layer. Is an acrylic resin having the lowest water function in the lowest layer in contact with the skin and having a higher water function toward the top; A patch for transdermal dosage form drug comprising 0.1 to 50% by weight of ketoprofen as a drug. According to claim 1, wherein the pressure-sensitive adhesive is selected from organic polymers and inorganic cellulose, polyethylene, nylon 6, nylon 12, polyethylene terephthalate, zincated, calcium oxide, silica, kaolin, talc or titanium dioxide to improve the adhesive properties Or 0.1-30% by weight of two or more kinds of percutaneous projection drug patch.