JPH06205839A - Poultice for percutaneously loading-type medicine - Google Patents

Abstract

PURPOSE: To reduce irritation to the skin by preparing an adhesive piled up on a supportive body with a specific percutaneous permeation promoting agent, adhesive resin and medicine or precursor medicine with its solubility variable in proportion to the water content in the adhesive layer. CONSTITUTION: The adhesive for percutaneously administering medicine is to use multilayer film, nonwoven cloth, woven cloth and the like as a supportive body 1, on which is laid a pressure sensitive adhesive 2 that is further covered with a release film 5. In this case, the pressure sensitive adhesive 2 is formed with more than one kind of a percutaneous permeation promoting agent 0.1-40 wt.% selected from a group consisting of aliphatic ester, polyoxyethylene derivative, glycerin aliphatic ether, propylene glycol fatty acid ester and the like, more than one kind of adhesive resin selected from a group consisting of silicone polymer, natural or synthetic rubber and acrylic resin and 0.1-50% medicine or precursor medicine with its solubility variable in proportion to the water content in the adhesive layer.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release patch which continuously delivers a certain amount of drug (physiologically active substance) through the skin or mucous membrane. In particular, the present invention relates to a drug which, when applied to the skin, maximizes dissolution of the drug in the adhesive layer in contact with the skin, transdermally transfers a necessary amount of the drug, and promotes transdermal penetration of the drug. Adhesive patch.

[0002]

2. Description of the Related Art In order to obtain a medicinal effect systemically or locally, a patch (transdermal preparation) is used to absorb a drug (physiologically active substance) through the skin. Such a transdermal administration method has many advantages over conventional oral administration methods. For example, in the method of oral administration of a drug, the drug absorbed from the intestine is first metabolized in the liver and decomposed in large amounts before it exerts its effect at the desired position. However,
In the transdermal administration method, the absorbed drug does not first pass through the liver during circulation in the body, and therefore metabolism in the liver does not significantly reduce its drug efficacy. Particularly, in the case of a non-steroidal anti-inflammatory drug, gastrointestinal disorders are likely to occur during oral administration, but transdermal administration thereof has an advantage that the occurrence of gastrointestinal disorders can be reduced.

In view of such an advantage, recently, the drug is transmitted through the skin to overcome the first-pass effect and the gastrointestinal disorder appearing at the time of oral administration. Research on transdermal drug delivery systems that increase stability has increased and commercial products such as nitroglycerin and scopolamine have been produced. Such a delivery system offers the inherent advantage of having a sustained, constant form of drug release, eliminating the problem of rapid metabolism that occurs upon oral administration. Furthermore, while having the same therapeutic effect as when a large amount is orally administered, the patient's compliance with the patient's intentions (compliance) is improved, and the convenience of the patient for treating diseases is greatly increased. Will be done.

However, a drawback of such a transdermal drug delivery system is that it is difficult to apply it to various drugs. This is because the skin, which is the surface of the body, acts as a barrier that suppresses the inflow of external pathogens or toxic substances into the body, and the permeability of drugs must be limited. Thus, many efforts have been attempted to extend the utility of transdermal delivery to more drugs and to remove the skin and membrane barriers of living organisms.

[0005] Much work trying to utilize systems having as little area as possible on the skin has focused on promoting the diffusion of drugs in and / or through the barrier layers described above. In particular, efforts have been devoted to increasing the transdermal penetration of the skin barrier itself. According to the studies reported so far, some results have been achieved as a result of the above-mentioned efforts, but when used frequently or in a large amount, damage and irritation to tissues at the site of use are caused, which is more undesirable. In some cases systemic side effects may be induced. It is a known fact that non-steroidal anti-inflammatory analgesics are superior in anti-inflammatory properties and analgesics.

However, in general, all non-steroidal anti-inflammatory analgesics produce various side effects including gastrointestinal disorders. Therefore, many attempts have been made to administer non-steroidal anti-inflammatory analgesics by various administration routes, and many patches containing a percutaneous penetration enhancer for enhancing drug absorption have been established. Came. Penetration enhancers are generally salicylic acid, urea, dimethylsulfoxide, propylene glycol, glycerin, azone (az
on) and many other compounds are used. However,
In many cases, it is not possible to raise the transdermal absorbability of a drug to the levels required above.

Substances reported as acting as an accelerator for transdermal drug delivery include dimethyl sulfoxide (US Pat. No. 3,551,554), ethanol (US Pat. No. 4,615,699, 4,698,0
62 and 4,262,539), cyclourea (US Pat. No. 4,667,131) and substituted azacycloalkane-2-ones (US Pat. No. 3,989,81).
No. 6, No. 4,316,893 and No. 4,405,61
No. 6).

US Pat. Nos. 4,557,934 and 4,537,776 disclose ethanol, certain glycols, pyrrolidone, 1- (2-hydroxyethyl) -aza-cyclopentan-2-one and 1. Topical compositions of non-steroidal anti-inflammatory and analgesic compounds, anti-viral and other drugs containing ~ 35% 1-dodecylazacycloheptan-2-one (azone) are described.

A method has also been developed in which oleic acid, which is one of the fatty acids, is used as a useful penetration enhancer [Ref: Cooper, ER, J. Pharm. Sci. Vol. 73, No.
8, 1153-1156 (1984)]. Cooper discloses a method of utilizing oleic acid in various concentrations in the presence of a solvent called propylene glycol to promote percutaneous penetration of salicylic acid, which is an active ingredient. Disclosed is a method for use in combination with a polyhydric alcohol. Cooper points out that his method helps to promote transdermal penetration of non-polar molecules, with different effects depending on the chain length of the fatty acids. Furthermore, Cooper points out that the surfactant enhances the transdermal penetration of polar molecules and is quite effective. However, such surfactants are generally reported not to enhance the transdermal penetration of non-polar molecules. Therefore, Cooper's method teaches that the addition of small amounts of fatty acids, polyhydric alcohols, or alcohols in the formulation enhances the transdermal penetration of non-polar molecules.

On the other hand, Patel et al. So
c. Cosmetic Chem. No. 36, No. 303
On page 311 (1985), the concentration of propylene glycol, which is one of the polyhydric alcohols widely used as a solvent in conventional transdermal delivery systems, is 1
It is described that when it exceeds 0%, it causes skin hypersensitivity and sensitization. That is, a substance that can be used as a percutaneous penetration enhancer must have little or no side effects on the skin, and must be a substance compatible with a transdermal administration system.

In addition, US Pat. No. 4,490,206, which relates to the use of patches, discloses the use of different forms of transdermal delivery systems consisting of physiologically active ingredients uniformly dispersed within the adhesive layer. There is. According to such a system, the physiologically active ingredient is dispersed in the pressure-sensitive adhesive layer that adheres to the skin. The drug then diffuses through the skin from the adhesive layer and is delivered to the desired site on the patient. Many other forms of transdermal delivery systems are also known, all of which are all different and have their own advantages and disadvantages depending on the system to which the physiologically active ingredient is administered transdermally. is doing.

US Pat. No. 4,738,670 discloses a medical plaster in which an anti-inflammatory analgesic is mixed in a polyisobutylene adhesive layer and a carrier such as triglyceride is mixed. However, the method of this U.S. patent deals primarily with plaster supports and does not address whether the carrier used has a role as a transdermal penetration enhancer.

By adjusting the absorbability of the drug, it is possible to reduce side effects caused by absorbing a large amount of the drug in a short time. Further, it is possible to maintain a constant blood concentration over a long period of time by reducing the frequency of drug administration. However, even if a drug is administered using a patch, the drug is often difficult to penetrate the skin, and the bioavailability of the drug often decreases.
In order to solve this problem, attempts have been made to increase the absolute amount of the drug in the patch to a level that ensures the transdermal absorption of the required amount of the drug. For example, JP-A-60-18
No. 5,713, U.S. Pat. No. 4,031,894, etc., a drug is dissolved in a base such as a patch, ointment or cream at a level exceeding its saturation concentration, and the drug is re-dissolved. A percutaneous absorption preparation dispersed in a crystalline fine particle state is disclosed. When this type of patch is applied to the skin surface, the drug dissolved in the base is absorbed transdermally,
Then, the drug present in the form of fine particles in the base is gradually dissolved, and the dissolved drug is replenished. Because of this, it is believed possible to administer larger amounts of drug through the skin as compared to conventional formulations containing the corresponding drug at levels below the saturation solubility of the drug. However, actually, the drug existing in the form of fine particles is difficult to be redissolved in the base, and the ratio of the drug passing through the skin and being absorbed is not so high.

As another method, a method of promoting percutaneous absorption of a drug by sealing sweat has been attempted. For example, Japanese Examined Patent Publication No. 60-51,478 and Japanese Patent Laid-Open No. 62-62.
No. 153,215 and the like disclose a method of promoting percutaneous absorption of an active ingredient by selecting a substantially water-impermeable film as the upper layer film of the patch. However, such a method has drawbacks such as irritation caused by sweat and secretions, and the patch is peeled from the skin due to sweat. Further, in order to solve such a defect, Japanese Patent Publication No. 53-33,984 and Japanese Patent Laid-Open No. 56-2
No. 0,514 and Japanese Patent Laid-Open No. 56-51,412 propose that a nonwoven fabric uses a support having excellent moisture permeability such as absorbent urethane. However, such an attempt cannot ultimately deliver the required amount of drug through the skin.

In order to reduce skin irritation and improve stickiness, such as gelatin, polyvinyl alcohol, dextrin, gum arabic, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, sodium alginate, sodium polyacrylate, etc. A method utilizing a water-soluble base has also been proposed. For example, JP-A-58-167,510 and JP-A-64-16,718 disclose a non-woven fabric coated with a water-soluble base containing a drug and a penetration enhancer to prepare a preparation. . However, such a preparation has a very low skin adhesiveness, and the patch cannot be applied to the skin by itself, so that it must be used together with an adhesive cloth, and the drug is not effectively administered through the skin. Not enough.

[0016]

The main object of the present invention is to:
It is intended to provide a transdermal administration system which is useful for transdermal administration and exerts an appropriate function. The main objects of the present invention are achieved by achieving the following detailed objects of the present invention.
The first object of the present invention is to use (a) an anti-inflammatory analgesic and others by using a pressure-sensitive adhesive suitable for a transdermal system and containing a useful transdermal penetration enhancer and skin irritation suppressor. In the form of a tape which can effectively administer the drug of (b), it has very little skin irritation,
(C) Due to its excellent ability to release and transfer physiologically active ingredients to the skin, it rapidly shows a medicinal effect against diseases such as arthritis, and (d) it has an excellent medicinal effect at the minimum adhesion area to the skin. Therefore, the object of the present invention is to provide a transdermal patch for drug, which can reduce discomfort caused by adhesion to the skin.

Second, in order to effectively absorb the drug through the skin, one of the methods for increasing the solubility of the drug in the adhesive base and reducing the adhesive property and skin irritation is similar to the solubility parameter of the drug. Another object of the present invention is to provide an adhesive patch in which the concentration of the drug from the base is maximized by selecting various acrylic adhesives and rubber adhesives. Third, to provide a sustained-release patch which controls the water content in the adhesive base by using a multi-layer lamination method to deliver the drug to a desired concentration through the skin or mucous membrane by a more effective method. Especially.

[0018]

The technical constitution of the present invention will be described in detail below. The percutaneous absorption of a drug by a patch is performed due to the difference in the drug concentration between the base and the living body. Is transmitted through and absorbed.
(1) Diffusion in the base, (2) Degradation from the base to the corneal surface, (3) Diffusion in the stratum corneum, (4) Degradation from the stratum corneum to the lower epidermal tissue, (5) Living Diffusion in the existing epidermis and dermis layer, and (6) translocation to blood vessels in the dermis.

As described above, the transdermal absorption process of a drug is considered separately as a diffusion process and a decomposition process, but in reality, the binding with the tissue and the metabolic reaction proceed simultaneously with the diffusion. This diffusion phenomenon is explained by Fick's first law, which expresses the relationship between the drug concentration gradient and the migration speed, and Fick's second law, which is described with respect to the time change of the drug concentration at a certain position, It is also calculated. J / A = -D C / X ...... first law ^{C / t = D 2 C /} X 2 ...... Fick's second law of Fick (where, A: area, C: concentration of the drug, D: diffusion coefficient,
J: administration rate, t: time, X: position. )

The skin permeability of a drug is often determined by its permeation rate under normal conditions. The permeation rate of the drug in a normal state is J = ACvKDL (where Cv is the concentration of the drug in the base, K is the drug partition coefficient between the skin and the base, and L is the effective skin thickness). The coefficient (Kp) is represented by the formula Kp = KD / L (however, K, D, and L are the same as above). As indicated above, increasing the concentration of drug in the base is advantageous for permeating large amounts of drug into the skin, but currently used methods have limitations.

In the present invention, as one of the methods for increasing the solubility in the adhesive base and simultaneously reducing the adhesive properties and skin irritation, first, an adhesive having a solubility parameter similar to that of the drug is selected and produced, and Maximize the concentration of drug in the drug. The most suitable adhesive for such purpose is an acrylic adhesive. In the case of an acrylic pressure-sensitive adhesive, since it is easy to control the compounding ratio of the monomers to be polymerized, there is an advantage that the water content in the pressure-sensitive adhesive base and the solubility with a drug can be controlled. However, when such a patch is applied to the skin, due to the wicking of water in the skin, there is more water present than initially adjusted in the adhesive base, and the solubility parameter in the adhesive base is Changes and the saturated solubility of the drug changes, showing a considerable difference from the actual solubility, and at the same time, the drug delivery to the skin of the adhesive and the adhesive property are also considerably reduced.

In order to solve such a problem, a multi-layer lamination method is adopted in the present invention. Figure 1
In FIG. 2, as the support (1), a multilayer film or laminated film of polyethylene, polypropylene, polyethylene terephthalate or the like, a non-woven fabric or a cotton cloth is used, and the non-woven cloth or the cotton cloth is a plastic which does not have moisture permeability as required. It is used by laminating with a film. As the pressure-sensitive adhesive, a pressure-sensitive adhesive layer of the pressure-sensitive adhesive base (2) in FIG. 1 or the pressure-sensitive adhesive base (3, 4) in FIG. 2 can be formed, and the pressure-sensitive adhesive base (3) and the pressure-sensitive adhesive base in FIG. A laminating adhesive capable of forming the multilayer of (4) is used. The pressure-sensitive adhesive base (3) of FIG. 2 is obtained by laminating a pressure-sensitive adhesive composition having a higher water content than the lower layer, and if necessary, a drug is mixed in a saturated amount or more and an additive such as skin permeation acceleration is also mixed. And the adhesive base (4) of FIG. 2 has a lower water content than the upper layer,
An adhesive having a high solubility for the drug is used, and the drug is blended in a saturated amount or more like the adhesive base (3) as the upper layer, and is blended with the skin penetrant and other additives. In addition,
Similar to the lamination of the adhesive base (3) and the adhesive base (4), a plurality of adhesive bases (2) are appropriately laminated in multiple layers so that a certain amount of drug is continuously and appropriately passed through the skin or mucous membranes. It can be absorbed by the skin. At this time,
The adhesive base (2) can be formed in multiple layers so as to perform the same function as the adhesive bases (3, 4) of FIG.

The release film (5) shown in FIGS. 1 and 2 is formed of a release film containing release paper and silicone or a fluoro-based release agent. To explain this in detail, first, when trying to administer a larger amount of drug to the skin, in order to prevent deterioration of the solubility and adhesive properties of the drug due to divergence from the skin, the bottom layer that adheres to the skin Into the above, an adhesive base having a low water content is introduced, and an adhesive having a high water content is introduced to the upper part. Therefore, when the patch is applied to the skin, the moisture is transmitted to the upper layer through the adhesive layer as the moisture diverges from the skin surface, and the adhesive layer contacting the lower skin has a constant level. Since only a small amount of water is present, the saturated concentration of the whole drug and the physical properties of the adhesive layer will be maintained as they are, and skin side effects due to accumulation of sweat or secretions will be reduced. be able to. by this,
The administration of the drug through the skin is effectively achieved. If the support is a non-woven fabric, cotton fabric or other breathable plastic film, its efficiency can be maximized by laminating it or using it as it is to adjust the moisture permeability. In particular, such formulations may give better results than formulations for controlling large amounts of drug.

In contrast to this, by administering a large amount of drug through the skin immediately after application, a burst effect (bu
When it is desired to obtain the rst effect), an adhesive base material having a desired limit of water content is selected as the adhesive layer, and the drug is saturated therein. When such a preparation is applied to the skin, a large amount of the drug is administered through the skin immediately after the application because the concentration of the drug is high. However, as the adhesive layer absorbs water from the skin, the solubility of the drug will gradually decrease, which will reduce the delivery of the drug from the skin. Then, when the water absorption reaches a normal state, only a certain amount of the drug is properly transmitted through the skin, and the drug release is controlled. At this time, the number of laminated adhesive bases is usually 1 to 10, preferably 1 to 5. Furthermore,
The thickness of each layer is usually 5 to 150 μm, preferably 10 to 1
It is 00 μm. The thickness of the entire adhesive base is usually 30 to 200 μm, preferably 50 to 500 μm.

As the adhesive base, an adhesive resin such as silicone polymer, natural or synthetic rubber, acrylic resin is used, and as the tackifier, rosin resin, polyterpene resin, petroleum resin, A terpene phenol resin or the like is used, and a plasticizer, a filler, an antioxidant or the like is optionally added. Especially as an acrylic resin,
Polymer of (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms and / or 4 to 18 carbon atoms
Adhesive resin, which is a copolymer of (meth) acrylic acid alkyl ester having an alkyl group and a different functional monomer such as vinyl acetate, is used. Examples of the (meth) acrylic acid copolymer include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate,
Stearyl acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate,
There are isooctyl methacrylate, decyl methacrylate, etc., and as the functional monomer, a monomer having a hydroxyl group, a monomer having a carboxyl group,
Examples thereof include a monomer having an amide group and a monomer having an amino group. Here, as the monomer having a hydroxyl group, there are hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate, and as the monomer having a carboxyl group, acrylic acid, methacrylic acid and the like. Α-β unsaturated carboxylic acid, maleic acid monoalkyl ester such as butyl maleate, maleic acid, fumaric acid, crotonic acid, etc., and maleic anhydride also has the same form of (co) polymer as maleic acid. Form. Further, as the monomer having an amide group, acrylamide, dimethyl acrylamide, alkyl acrylamide such as diethyl acrylamide, alkylethyl methylol (meth) acrylamide such as butoxymethyl acrylamide, ethoxymethyl acrylamide, and the like,
Examples include diacetone acrylamide, vinylpyrrolidone, and dimethylamino acrylate.

Copolymer monomers other than those mentioned above include, for example, vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene and the like, and copolymers with these also show good properties. The pressure-sensitive adhesive preferably contains (meth) acrylic acid alkyl ester as a (co) polymerization component in an amount of 50% by weight or more.

As a method for decreasing or increasing the water content, in the case of acrylic resin, a monomer having a large hydrophilicity, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and the like are used. The water content can be adjusted by polymerization, and in the case of rubber and silicone resin, the water content can be adjusted by adding a tackifier and an additive. Further, as a different method, a water-absorbing ability can be adjusted by utilizing a highly water-absorbent resin, a polyhydric alcohol and a water-absorbing inorganic substance. Examples of superabsorbent polymers include mucopolysaccharides such as hyaluronic acid controitin sulfate, sumatin sulfate, etc., which are present in many molecules such as chitin, chitin derivatives, starch and carboxycellulose. Semi-synthetic and synthetic super absorbent polymers of a super absorbent polymer having a hydrophilic group and polyacrylic acid type, polyoxyethylene type, polyvinyl alcohol type, polyacrylonitrile type homopolymers or copolymers may be mentioned. As the water-absorbing inorganic substance, there are water-absorbing silica, zeolite, water-absorbing ceramics and the like, and as the polyhydric alcohol, propylene glycol, glycerin, sorbitol and the like can be used. At this time, a water-absorbing substance such as a super-water-absorbing polymer, a water-absorbing inorganic substance and a polyhydric alcohol is contained in the adhesive base in an amount of 0.1 to 40% by weight, preferably 1 to 20% by weight. Can be made.

As the rubber adhesive, 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 can be used, and silicone rubber such as polyorganosiloxane is used as the silicone resin adhesive.

Among the above-mentioned pressure-sensitive adhesives, if necessary, various compounding agents such as rosin-based resins, polyterpene-based resins, coumarone-indene-based resins, petroleum-based resins, terpene-phenol-based resins, etc. , Liquid polybutene resin,
Adhesive auxiliary agents such as petroleum-based resins and terpene-phenolic resins, plasticizers such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, and liquid polyacrylate, fillers, and antioxidants are added.

The present invention provides a pharmaceutical preparation in the form of a transdermal administration system in which a physiologically active ingredient is dispersed or dissolved in a pressure-sensitive adhesive layer. The pressure-sensitive adhesive layer is characterized by containing a certain transdermal penetration enhancer, and is characterized by the fact that the transdermal penetration enhancer does not reduce the original adhesive strength of the pressure-sensitive adhesive layer. It is attached. Other additives may also be included in order to obtain improved adhesive properties.

As a substance used as a percutaneous penetration enhancer for enhancing the skin absorbability of a drug, dodecyl sulfoxide, mono- or dimethyl acetate, N-hydroxyethyl lactide, higher fatty acid ester, salicylic acid,
Sorbitol, urea, glycerin, squalene, squalane, acetylated lanolin, cetyl laurate, olive oil, castor oil, lauric acid, oleic acid, lauryl alcohol, oleyl alcohol, ethoxystearyl alcohol, liquid paraffin, petrolatum, camphor, glycerin fatty acid ester, Fatty acid mono (or di) ethanolamide, ethylene glycol monoethylene ether,
Examples thereof include polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxypropylene alkyl ether, propylene glycol mono (di) alkyl ester, propylene glycol monolaurate, polyoxyethylene lauryl ether, and pyrrolidone derivative.

That is, the present inventors have revealed that the percutaneous penetration rate of a drug can be significantly increased by using a transdermal penetration enhancer such as a polyoxyethylene derivative or a pyrrolidone derivative. In addition, increasing the transdermal penetration efficiency by using a penetration enhancer
It has been shown to be particularly effective for non-steroidal anti-inflammatory analgesics such as ketoprofen. One aspect of the present invention is a fatty acid ester (eg, as a transdermal penetration enhancer at a ratio of 1 to 39% by weight based on the total amount of the carrier, for example,
Methyl laurate, isopropyl myristate), polyoxyethylene derivative, glycerin fatty acid ester, propylene glycol fatty acid derivative, pyrrolidone derivative, and the like, and a carrier containing one or more compounds selected from the group and physiologically active ingredients. A dermal administration pharmaceutical composition is provided.

In order to become a compound useful as a percutaneous penetration enhancer, various requirements must be met,
Among them, the important requirements are as follows. First, it must be a dermatologically acceptable compound that does not cause any irritation or sensitization when used on the skin. Second,
Such compounds must be well mixed with the carrier and active ingredient in the transdermal delivery system. If immiscible, phase separation occurs or a reaction occurs that destroys or prevents the physiological activity of the active ingredient. Thirdly, the compound must either have no pharmacological activity or be predictable as such, and also have a considerable effect on promoting percutaneous penetration of the drug, which is a physiologically active ingredient. Must be, and preferably US FDA (Food a
nd Drug Administration).

The present inventors have investigated a large number of compounds in order to find one or more useful compounds as transdermal penetration enhancers which are suitable for the above purposes. Typical of such compounds is propylene glycol monolaurate. Another compound investigated by the inventors is polyoxyethylene lauryl ether. The present inventors have further bisabolol as a skin primary irritation relief agent,
Α in chamomile oil, allantoin, dipanthenol
-We have found that bisabolol is the most useful substance.

The stable and effective amount of the physiologically active ingredient used in the medicated patch composition of the present invention provides a therapeutically useful blood concentration and / or local concentration of the active compound by the transdermal administration system. Means the amount to do. The content of these penetration enhancers is 0.1 to 40% by weight, preferably 1 to
It is 20% by weight. Furthermore, tocopherol, tocopherol acetate, BHA, BHT, etc. can be used as drug penetration enhancers and antioxidants of other additives,
As the preservative, ethylparaben, methylparaben, butylparaben or the like can be used.

The base material (adhesive) of such a tape or patch is not particularly limited as long as the adhesive can be adhered to the skin surface for a long time at room temperature to maintain the adhesive strength. For example, an adhesive such as rubber or silicone resin is used, and usually acrylic or rubber resin is used.

At this time, any drug can be incorporated into the base as long as it permeates the skin upon percutaneous administration and the solubility changes with the change of water content in the base. It is not particularly limited. As non-steroidal drugs, methyl salicylate, salicylic acid, ibuprofen, ketoprofen, phlorobiprofen, indomethacin, diclofenac sodium, flofenamic acid,
A pharmacologically effective compound selected from nafloxene, mefenamic acid, fenoprofen, fenclofenac, piroxicam, and their precursors is used within its safe and effective amount range.

Other drugs include antipyretic and anti-inflammatory analgesics,
Steroidal anti-inflammatory drug, vasodilator, antihypertensive and antiarrhythmic drug, antihypertensive drug, antitussive expectorant, antitumor drug, hormone drug, antiasthma and antinasal allergic drug, antihistamine drug, anticoagulant drug, cerebral circulation or metabolism Examples thereof include improving agents, antidepressants, anxiolytics, hypoglycemic agents, antirheumatic agents and antiarthritic agents.

As the tape or patch support, a support generally used for patching is used. Such support materials include cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl-vinyl chloride, polyurethane, polyethylene, poly There are vinylidene chloride, aluminum, etc. Such a material is used, for example, as a single-layer sheet (film) or a laminate of two or more layers (laminate). As a material other than aluminum, cotton cloth or non-woven cloth is preferably used.

Further, in order to reduce the deterioration of the adhesive property and the skin irritation that often occur when a drug or a penetration enhancer is applied to the tape or patch, a skin irritation alleviating agent or an inorganic / organic filler may be added. At this time, bisabolol, chamomile oil, allantoin, glycerol, dipanthenol, etc. are used as skin irritation alleviation agents in 0.01
It may be present in the range of -10 wt%, preferably 0.1-5 wt%. As organic and inorganic substances for improving the adhesive property, organic polymer fine particles such as cellulose, polyethylene, nylon 6, nylon 12, polypropylene, polyethylene terephthalate, zinc white, calcium oxide, silica, kaolin, talc, titanium, etc. The inorganic substance may be contained in the range of 0.1 to 30% by weight, preferably 0.5 to 10% by weight.

The concentration of the physiologically active ingredient contained in the adhesive is such that the sum of the weight of the physiologically active ingredient and the adhesive is 1 to 40.
% By weight, preferably 5 to 35% by weight, more preferably 7
~ 30% by weight.

According to the present invention, as is clear from the above description, the saturated concentration of the physiologically active ingredient in the adhesive layer depends on the composition of the adhesive, but the physiologically active ingredient is different from various compositions. It is desirable that the adhesive layer be contained at a level of almost saturated concentration.

[0043]

EXAMPLES The present invention will be specifically described below based on Examples, Test Examples and Comparative Examples. However, these examples are merely illustrative and do not limit the scope of the invention.

Example 1 The following components were uniformly mixed in the proportions (% by weight) shown below to prepare a pharmaceutical composition for transdermal administration of anti-inflammatory / analgesic for use in the form of a patch. Ketoprofen 10 Propylene glycol monolaurate 10 Tocopherol acetate 1 Zinc white 5 Acrylic resin A ¹⁾ 74 Overall 100 (Note 1) Acrylic resin A: Fluid of copolymer resin of butyl acrylate, octyl acrylate and vinyl acetate (solid content: 48 0.0%) A PET release liner treated with silicon was coated with the mixture thus obtained, allowed to stand at room temperature for 20 minutes or longer, and then dried at 90 ° C. for 10 minutes or more to have a dry thickness of 80 μm. The material produced in (1) was interleaved with a stretchable nonwoven fabric to produce a final patch in the form of a tape.

Example 2 The following components were uniformly mixed in the following proportions (% by weight),
A pharmaceutical composition for percutaneous anti-inflammatory / analgesic administration for use in the form of a patch was produced. Indomethacin 10 Glycerol monooleate 10 Tocopherol acetate 1 Zinc white 5 Acrylic resin B ²⁾ 75 Overall 100 (Note 2) Acrylic resin B: vinyl acetate-resin multipolymer fluid (solid content: 31.0%) The obtained mixture was coated on a silicone-treated release paper, dried, and then the product substance was slipped on a stretchable nonwoven fabric to prepare a final patch in the form of a tape.

Example 3 The following components were uniformly mixed in the following proportions (% by weight),
A pharmaceutical composition for transdermal administration of anti-inflammatory / analgesic drug for use in the form of a patch was produced. Diclofenac sodium 10 Polyoxyethylene lauryl ether (EO = 3) ³⁾ 10 Tocopherol acetate 1 Bisabolol 2 Zinc white 5 Acrylic resin A 72 100 (Note 3) O. = 3: means that the number of moles of ethylene oxide in the polyoxyethylene lauryl ether is 3. The mixture thus obtained was treated with siliconized P
After being coated on an ET release liner and dried, the resulting properties were interleaved with a stretchable nonwoven fabric to produce a final patch in the form of a tape.

Example 4 [Adhesive 1] 2-ethylhexyl acrylate 97.4
Parts, methacrylic acid 2.5 parts, polyethylene glycol dimethacrylate 0.1 parts, benzoyl peroxide (BP
O) 1.0 part and ethyl acetate 100 parts were charged into a reaction vessel having a reflux condenser and a stirrer, and the mixture was heated to 60 ° C. under a nitrogen atmosphere.
The polymerization reaction was carried out while gradually stirring. To control the degree of polymerization, 100 parts of ethyl acetate was gradually added during the reaction and the reaction was carried out for 9 hours. The polymerization rate at this time is 99.9.
%Met. An appropriate amount of ethyl acetate was added to the obtained polymer solution to adjust the concentration of solid content to about 40% by weight.

[Adhesive 2] 70 parts of 2-ethylhexyl acrylate, 10 parts of acrylic acid, benzoyl peroxide (B
1.0 part of PO) and 20 parts of vinyl acetate were copolymerized by adding ethyl acetate under the same conditions as the pressure-sensitive adhesive 1. The polymerization rate at this time was 99.9% or more.
Further, aluminum acetate (200 rpm) was added to obtain a self-curing type. An appropriate amount of ethyl acetate was added to the obtained polymer solution to adjust the concentration of solid content to about 40% by weight.

[Production of Adhesive Base (3)] Ketoprofen was added to the above-mentioned "Adhesive 1" in an amount of 20% by weight based on the solid content, and dissolved therein at a concentration exceeding the saturation solubility. The treated release paper was coated to a dry thickness of 50 μm.

[Manufacture of Adhesive Base (4)] To the above-mentioned "adhesive (2)" was added a drug in an amount of 20% by weight and dissolved therein at a concentration exceeding the saturated solubility. The resulting mixture had a thickness of 30 μm when dried on silicone-treated release paper.
Was coated so that "Adhesive base (4)" is first transferred to polyethylene film, and then "Adhesive base (3)"
Was laminated to produce a patch comprising a two-layer adhesive base (3, 4). At this time, the drying was carried out under the conditions of leaving at room temperature for 15 minutes to be naturally dried, and then at 90 ° C. for 10 minutes.

Example 5 [Production of adhesive base (4)] Ketoprofen was added to "Adhesive 1" obtained in Example 4 so as to be 20% by weight based on the solid content, and the saturated solubility thereof was exceeded. Dissolves in concentration,
Hyaluronic acid powder was uniformly dispersed in this at a ratio of 5% by weight, and then coated on a silicone release paper and dried so that the thickness when dried was 40 μm. The thus obtained "adhesive base (4)" was transferred onto a polyester film, and the "adhesive base (3)" of Example 4 was laminated thereon to form a two-layer adhesive base. A patch was manufactured.

Example 6 [Production of Adhesive Base (3)] Ketoprofen was added to "Adhesive 1" obtained in Example 4 in an amount of 20% by weight based on the solid content, and saturated solubility was added thereto. After dissolving at a concentration exceeding 10% by weight of polyoxyethylene lauryl ether (EO = 3) as a transdermal penetration enhancer, 0.5% by weight of tocopherol acetate as an antioxidant was added.
Was added and dissolved. Next, colloidal silica was blended at a ratio of 3% by weight in order to improve the deterioration of the adhesive property due to the transdermal penetration enhancer. The pressure-sensitive adhesive base thus produced was applied to release paper so that the thickness when dried was 60 μm, and then dried.

[Manufacture of Adhesive Base (4)] Ketoprofen was added to "Adhesive 2" obtained in Example 4 so that the content of ketoprofen was 20% by weight based on the solid content, and the concentration thereof was higher than the saturated solubility. After dissolving, 10% by weight of polyoxyethylene lauryl ether (EO = 3) was added as a transdermal penetration enhancer, and then 0.5% by weight of tocopherol acetate was added as an antioxidant. The obtained solution was applied to release paper so that the thickness when dried was 40 μm. Next, the above-mentioned "adhesive base (3)" is transferred to a polyester film, and the "adhesive base (4)" obtained here is further laminated thereon to form a patch comprising a two-layer adhesive base. Was manufactured.

Example 7 To the "adhesive 2" obtained in Example 4, ketoprofen was added so as to be 20% by weight based on the solid content, and dissolved therein at a concentration exceeding the saturated solubility, and then percutaneously absorbed into this. After adding 10% by weight of propylene glycol monooleate as an accelerator, 0.5% by weight of tocopherol as an antioxidant
In addition, it was dissolved. Then, 3% by weight of cellulose powder (particle size: 5 to 1.5 μm) as a water content adjusting agent was uniformly dispersed, and this was coated on a release paper so as to have a thickness of 70 μm and dried.

Example 8 The following components were uniformly mixed in the proportions (% by weight) shown below to prepare a pharmaceutical composition for transdermal administration of anti-inflammatory / analgesic for use in the form of a patch. Ketoprofen 10 Propylene glycol monolaurate 5 Tocopherol acetate 2 Zinc white 10 Rubber-based resin C1 ⁴⁾ 73 Overall 100 (Note 4) The composition of the rubber-based resin C1 is as follows. Styrene-butadiene-styrene block copolymer 100 Terpene resin 75 Polybutene 20 Liquid paraffin 20 BHA 2 The release paper was coated with the mixture thus obtained and dried, and then the produced substance was combined with a stretchable nonwoven fabric. It was made to paper and the tape-shaped final patch was manufactured.

Example 9 The following components were uniformly mixed in the proportions (% by weight) shown below to prepare a pharmaceutical composition for transdermal administration of anti-inflammatory / analgesic for use in the form of a patch. Piroxicam 10 Glycerin monooleate 5 Tocopherol acetate 2 Zinc white 10 Rubber resin C1 73 Whole 100 After coating the mixture thus obtained on release paper and drying, the resulting substance was mixed with a stretchable nonwoven fabric. The final patch in the form of a tape was produced by making it paper.

Example 10 The following components were uniformly mixed in the proportions (% by weight) shown below to prepare a drug for transdermal administration for anti-inflammatory / analgesia for use in the form of a patch. Ketoprofen 15 Polyoxyethylene sorbitan monolaurate 5 L-menthol 3 DL-camphor 2 tocopherol acetate 2 zinc white 10 Rubber-based resin C2 ⁵⁾ 73 Overall 100 (Note 5) The composition of rubber-based resin C2 is as follows. Styrene-isoprene-styrene block copolymer 100 hydrogenated rosin 80 polybutene 20 lanolin 20 BHA 2 The release paper was coated with the mixture thus obtained, and after drying, the produced substance was combined with a stretchable nonwoven fabric. The final patch in the form of a tape was produced by making it paper.

The patches obtained in Examples 1, 2 and 3 were subjected to a percutaneous penetration test and a primary skin irritation test as follows. The results are also shown.

Percutaneous Penetration Test After cutting the hair of the abdomen of a male Guinea pig with a body weight of about 350 g with an electric hair clipper, a certain part of the hair was cut out, stored in a freezer (-20 ° C. or below), and thawed when necessary. Used. A cut-out skin is provided in the middle of a Franz type diffusion cell with the stratum corneum side facing upward, and then 0.05M phosphate buffer solution (p
H7.4) was added and the temperature of the diffusion cell was kept at 37 ° C.
Receptor solution (buffer solution) at a constant speed (600 rp
The patch obtained in Example 1 was applied to the skin while stirring in m). After a certain period of time, the solution in the receptor part was collected, and this collected amount of fresh buffer solution was replenished. The concentration of ketoprofen was measured using high pressure liquid chromatography (HPLC) for the collected sample amount. [Analysis conditions of high pressure liquid chromatography (HPLC)] Column: C ₁₈ μbondapak [Massachusetts 0
1757, Milton, Waters Chromatography product] Mobile phase: 55:45 v / v Methanol: 0.02 M phosphate buffer (pH 4.0) Flow rate: 1 ml / min Detector: UV light 254 nm wavelength

Starting with the patch prepared in Example 1,
With respect to each patch having various formulations shown in Table 1, a skin penetration test of ketoprofen was conducted in the same manner as above.
The results are shown in Table 2.

[0061]

[Table 1]

[0062]

[Table 2]

[Results] In the case of using a transdermal penetration enhancer, the content of ketoprofen in the adhesive layer was increased in order to increase the transdermal penetration of ketoprofen, and the transdermal penetration enhancer was used instead of the saturated concentration. Better the transdermal penetration of ketoprofen. When a transdermal penetration enhancer is contained in the adhesive layer by a general technique, the adhesive properties are significantly reduced and the transdermal penetration enhancer effect is halved. It showed excellent penetration promotion without significant changes.

Primary Skin Irritation Test 2.5c of the patch prepared by the same method as in Example 1 was used.
After cutting to a size of m ² and peeling off the release liner, it was attached to the forearm arm of a healthy adult tester. 24 after attachment
The patch was peeled off after a lapse of time, and after 30 minutes, the degree of primary irritation was observed according to the following criteria. Judgment number Stimulation level 0 No stimulation 1 Slight stimulation 2 Redundant 3) Extreme stimulation (redness, edema) 4 Extremely severe stimulation (redness, edema) The degree of observed stimulation Based on this, the reactivity was calculated by the following formula. Reactivity (%) = [sum of (number of responders × number of judgments) / (number of testers × 4)] × 100 The prescription of the patch used in the primary skin irritation test is shown in Table 3, and the test results are The results are shown in Table 4.

[0065]

[Table 3]

[0066]

[Table 4]

As is clear from the above data, the effect of reducing primary skin irritation was not observed in all cases where bisabolol was added, but bisabolol was
Used as an effective skin irritation reliever at concentrations of ~ 2%. In addition, the degree of general patch irritation was within 10%, and these patches were found to be safe against skin irritation.

Comparative Example 1 Only the adhesive base (3) prepared in Example 4 had a thickness of 8
The release paper was applied so as to have a thickness of 0 μm, and this was laminated with a polyethylene film to produce a single-layer patch.

Comparative Example 2 Ketoprofen was added to "Adhesive 1" prepared in Example 4 so as to be 20% by weight based on the solid content, and dissolved therein at a concentration exceeding the saturated solubility to promote percutaneous absorption. After adding 10% by weight of propylene glycol monooleate as an agent, 0.5% by weight of tocopherol as an antioxidant was added and dissolved, and 2% by weight of bisabolol as a skin stimulant was added and dissolved. This was applied to release paper so as to have a thickness of 70 μm and dried.

Transdermal penetration test according to Examples 4, 5, 6 and 7 and Comparative Examples 1 and 2 Tests were conducted in the same manner as the above-mentioned transdermal penetration test. The results are shown in Table 5.

[0071]

[Table 5]

Primary Irritation Test According to Examples 4, 5 and 6 and Comparative Examples 1 and 2 Tests were carried out in the same manner as the above skin primary irritation test.
The results are shown in Table 6.

[0073]

[Table 6]

[0074]

EFFECTS OF THE INVENTION The transdermal patch of the present invention has very little irritation to the skin, and is excellent in the release and transfer of physiologically active ingredients to the skin, so that it is effective against diseases such as arthritis. The medicinal effect is rapidly exhibited, and the medicinal effect is excellent in the minimum area of adhesion to the skin, so that discomfort caused by adhesion to the skin can be reduced.
Moreover, according to this transdermal drug patch, the solubility of the drug in the adhesive base can be increased, and the drug can be effectively absorbed through the skin. Furthermore, it can be adhered using a multilayer lamination method. By controlling the water content in the base, it is possible to obtain a sustained-release patch in which the drug is brought to a desired concentration and administered through the skin or mucous membranes.

[Brief description of drawings]

FIG. 1 is a cross-sectional explanatory view of a patch for single-layer controlled release transdermal administration.

FIG. 2 is a cross-sectional explanatory view of the multilayer transdermal patch of the present invention.

FIG. 3 shows that the transdermal administration system of the present invention is applied to the skin of guinea pig,
It is a graph which showed the change of the percutaneous penetration of a medicine with respect to time.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor An Jiang Gen 602-1-22 Dongdae-dong, Daejeon-gu, Seoul, Republic of Korea

Claims (16)

[Claims] 1. A transdermal drug patch, comprising a pressure-sensitive adhesive as a pressure-sensitive adhesive layer coated on one surface of a support, and an adhesive layer in the form of a single-layer or multi-layer laminate. , A release film formed on this adhesive layer,
And the above-mentioned adhesive is at least one percutaneous penetration enhancer selected from the group consisting of fatty acid ester, polyoxyethylene derivative, glycerin fatty acid ether, propylene glycol fatty acid ester and pyrrolidone derivative.
% By weight, one or more adhesive resins selected from the group consisting of silicone polymers, natural or synthetic rubbers, and acrylic resins, and the solubility of itself changes as the water content in the adhesive layer changes. Drugs or prodrugs 0.1 to
50%, and further contains one or more additives selected from the group consisting of tackifiers, plasticizers, fillers, skin irritation and antioxidants. Transdermal drug patch. 2. A polymer of an alkyl ester of (meth) acrylic acid having an alkyl group having 4 to 18 carbon atoms, or an alkyl ester of (meth) acrylic acid having an alkyl group of 4 to 18 carbon atoms and vinyl acetate. The transdermal drug patch according to claim 1, which is a copolymer with another functional monomer such as 3. The transdermal drug patch according to claim 2, wherein the (meth) acrylic acid alkyl ester polymer is contained in an amount of 50% by weight or more. 4. A synthetic rubber-based resin comprising styrene-butadiene-styrene, styrene-isoprene-styrene, styrene-ethylene / propylene-styrene, styrene-ethylene / butylene-styrene block copolymer as a main base material The transdermal drug for use according to claim 1, which contains at least one additive selected from the group consisting of an auxiliary agent, a tackifier, an inorganic filler, a softening agent, and an antioxidant. Patch. 5. The transdermal administration according to claim 1, wherein the water content of the pressure-sensitive adhesive is controlled by adjusting the compounding ratio of the monomer having a hydrophilic group in the monomer in the copolymerization reaction. Type drug patch. 6. The pressure-sensitive adhesive contains 0.01 to 40% by weight of one or more compounds selected from the group consisting of superabsorbent polymers, water-absorbing inorganic substances or polyhydric alcohols. The transdermal patch for drug according to any one of claims 1 to 5. 7. The transdermal patch for drug according to claim 1, wherein the tackifier is a rosin resin, a polyterpene resin, a petroleum resin or an olefin resin. 8. The skin stimulant comprises at least one compound selected from the group consisting of bisabolol, chamomile oil, allantoin, glycerin and pantheol, and is present in an amount of 0.01 to 10% by weight. The transdermal patch for drug according to claim 1. 9. The drug is an antipyretic analgesic, a steroidal anti-inflammatory drug, a vasodilator, a therapeutic agent for hypertension and arrhythmia, an antihypertensive agent, an antitussive expectorant, an antitumor agent, a local anesthetic, a hormone agent,
From the group consisting of anti-asthma and anti-nasal allergic agents, anti-histamines, anti-coagulants, antispasmodics, cerebral circulation or metabolism improvers, anti-depressants, anxiolytics, hypoglycemic agents, anti-ulcer agents, and their precursors The transdermal patch for drug according to claim 1, which is selected. 10. The transdermal patch according to claim 1, wherein the nonsteroidal anti-inflammatory drug is contained as a drug in an amount of 1 to 40% by weight. 11. A non-steroidal anti-inflammatory agent is ketoprofen, diclopenac sodium, indomethacin,
The transdermal patch of claim 10, wherein the patch is fluorobiprofen or piroxicam. 12. The transdermal patch of claim 1, wherein the fatty acid ester is methyl laurate or isopropyl myristate. 13. The polyoxyethylene derivative according to claim 1, which is a polyoxyethylene ether or a polyoxyethylene ester containing 2 to 20 mol of a polyoxyethylene group linked to an oleyl or lauryl group. Transdermal drug patch. 14. The transdermal patch according to claim 1, wherein the glycerin fatty acid ether has a fatty acid of lauric acid or oleic acid. 15. The transdermal patch of claim 1, wherein the fatty acid of the propylene glycol fatty acid ester is lauric acid or oleic acid. 16. A pressure-sensitive adhesive as an organic polymer and an inorganic substance for improving the pressure-sensitive adhesive property, cellulose, polyethylene, nylon 6, nylon 12, polyethylene terephthalate, zinc white, calcium oxide, silica, kaolin, talc and titanium. The transdermal patch for medical administration according to claim 1, which comprises at least one selected from the group consisting of dioxides in a proportion of 0.1 to 30% by weight.