JP2569396B2 - Transdermal drug patch - Google Patents

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 for continuously transmitting a fixed amount of a drug (a physiologically active substance) through the skin or mucous membrane. In particular, the present invention relates to a drug that, when applied to the skin, dissolves the drug in the adhesive layer that is in contact with the skin to a maximum extent, transmits a required amount of the drug transdermally, and promotes the transdermal penetration of the drug. Patch for medical use.

[0002]

2. Description of the Related Art In order to obtain a medicinal effect from a whole body or a local area, a drug (a physiologically active substance) is absorbed through the skin using a patch which is a preparation for transdermal administration. Such transdermal administration methods have 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 before it exhibits its medicinal effect at the desired location, and a large amount of the drug is degraded. However,
In transdermal administration, the absorbed drug does not first pass through the liver during systemic circulation, so metabolism in the liver does not significantly reduce its efficacy. In particular, in the case of a nonsteroidal anti-inflammatory drug, gastrointestinal disorders are likely to occur during oral administration, but transdermal administration of these drugs has the advantage of reducing the occurrence of gastrointestinal disorders.

[0003] In view of these advantages, recently, drugs have been transmitted through the skin to overcome the first-pass effect and gastrointestinal disorders that appear during oral administration. Studies on transdermal drug delivery systems that increase stability have increased, and commercial products such as nitroglycerin and scopolamine have been produced. Such a delivery system offers the inherent advantages of being sustained, having a certain form of drug release characteristics, and eliminating the problem of rapid metabolism that occurs upon oral administration. Furthermore, while having the same therapeutic effect as when a large amount is administered orally, the patient's compliance with the patient's instruction is improved, and the convenience of the patient for treating the disease is greatly increased. Will be done.

[0004] However, a disadvantage of such transdermal drug delivery systems is that they are difficult to apply to various drugs. This is because the skin, which forms the surface of the body, acts as a barrier to prevent 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 usefulness of transdermal delivery for more drugs and to remove skin and membrane barriers in living organisms.

[0005] Much research aimed at utilizing systems with as little area as possible to the skin has focused on promoting the diffusion of drugs into and / or through the aforementioned barrier layers. In particular, efforts have been devoted to increasing transdermal penetration into the skin barrier itself. Although studies reported to date have shown some success as a result of the above efforts, frequent or high-volume use may result in damage and irritation to the tissue at the site of use, which is less desirable. In some cases, systemic side effects may be induced. It is a known fact that non-steroidal anti-inflammatory analgesics are excellent in anti-inflammatory properties and analgesics.

However, in general, all non-steroidal anti-inflammatory analgesics cause various side effects including gastrointestinal disorders. Accordingly, many attempts have been made to administer non-steroidal anti-inflammatory drugs by various administration routes, and a number of patches containing a transdermal penetration enhancer for enhancing the absorbability of the drug have been established. Have been. Penetration enhancers generally include salicylic acid, urea, dimethyl sulfoxide, propylene glycol, glycerin, azone (az
on) and many others. However,
In many cases, the transdermal absorption of a drug cannot be raised to the level required above.

Substances reported to act as transdermal drug delivery enhancers include dimethyl sulfoxide (US Pat. No. 3,551,554) and ethanol (US Pat. Nos. 4,615,699, 4,698,0
Nos. 62 and 4,262,539), cycloureas (U.S. Pat. No. 4,667,131) and substituted azacycloalkane-2-ones (U.S. 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, antivirals and other drugs containing .about.35% 1-dodecylazacycloheptan-2-one (azone) are described.

Also, a method has been developed in which oleic acid, one of the fatty acids, is used as a useful penetration enhancer [see: Cooper, ER, J. Pharm. Sci. Vol. 73, No.
8, 1153-1156 (1984)]. Cooper discloses a method of utilizing oleic acid at various concentrations in the presence of a solvent called propylene glycol to promote the transdermal penetration of the active ingredient salicylic acid, and also discloses oleic acid and other varieties. It discloses a method of using it together with a polyhydric alcohol. Cooper points out that his method has helped to promote the transdermal penetration of nonpolar molecules, with different effects depending on the fatty acid chain length. Cooper further points out that the surfactant enhances the percutaneous penetration of polar molecules and has a considerable effect. However, it has been reported that such surfactants generally do not 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 to the formulation enhances the transdermal penetration of non-polar molecules.

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

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

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

It is possible to reduce the side effects caused by absorbing a large amount of a drug in a short time by adjusting the absorption of the drug. Further, by reducing the number of times of administration of the drug, it is possible to maintain a constant blood concentration over a long period of time. However, even when a drug is administered using a patch, the drug does not easily penetrate the skin, and the bioavailability of the drug often decreases.
To solve this problem, attempts have been made to increase the absolute amount of drug in the patch to a level that ensures transdermal absorption of the required amount of drug. For example, JP-A-60-18
In U.S. Pat. No. 5,713, U.S. Pat. No. 4,031,894, a drug is dissolved in a base such as a patch, ointment, cream or the like at a level exceeding its saturation concentration, and the drug is reconstituted. A transdermal absorption preparation dispersed in the form of crystalline fine particles 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 material gradually dissolves, and the dissolved drug is replenished. For this reason, it is believed that larger amounts of the drug can be administered through the skin than conventional formulations containing the corresponding drug at levels below the drug's saturation solubility. However, in practice, drugs that exist in the form of fine particles are hardly redissolved in the base, and the rate of drug absorption through the skin is not very high.

As still another method, a method of promoting percutaneous absorption of a drug by sealing perspiration has been attempted. For example, Japanese Patent Publication No. Sho 60-51,478,
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 an upper layer film of a patch. However, such a method has drawbacks such as irritation caused by sweat and secretions, and the patch is peeled from the skin by sweat. In order to solve such disadvantages, Japanese Patent Publication No. 53-33,984 and Japanese Patent Application Laid-Open No.
No. 0,514 and JP-A-56-51,412 propose that the nonwoven fabric uses a support having excellent moisture permeability such as absorbent urethane. However, even such attempts ultimately fail to deliver the required amount of drug through the skin.

[0015] In order to reduce skin irritation and improve the feeling of adhesion, gelatin, polyvinyl alcohol, dextrin, gum arabic, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, sodium alginate, sodium polyacrylate, etc. A method using a water-soluble base has also been proposed. For example, JP-A-58-167510 and JP-A-64-16718 disclose a nonwoven fabric prepared by applying a water-soluble base containing a drug and a penetration enhancer to a nonwoven fabric. . However, such a preparation has a very low skin adhesion, so that the patch alone cannot be applied to the skin, it must be used together with a cohesive cloth, and it has an effect of administering the drug through the skin. Not enough.

[0016]

SUMMARY OF THE INVENTION The main object of the present invention is to:
It is an object of the present invention to provide a transdermal administration system which is useful for transdermal administration and exhibits an appropriate function. The main objects of the present invention are achieved by achieving the following detailed objects of the present invention.
First, the object of the present invention is to use a pressure-sensitive adhesive suitable for a transdermal system and to incorporate a useful percutaneous penetration enhancer and a skin irritation inhibitor to (a) an anti-inflammatory analgesic and other (B) very little irritation to the skin,
(C) Due to its excellent ability to release and transfer physiologically active ingredients to the skin, it shows a rapid response to diseases such as arthritis, and (d) exhibits a superior efficacy in the area of minimal adhesion to the skin. Accordingly, it is an object of the present invention to provide a transdermal administration type patch for a drug which can reduce discomfort due to 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 properties and skin irritation is similar to the solubility parameter of the drug. It is an object of the present invention to provide a patch which maximizes the concentration of a drug from a base by selecting a suitable acrylic adhesive and a rubber adhesive. Third, there is provided a sustained-release patch which controls the water content in the adhesive base by using a multi-layer lamination method to provide a drug at a desired concentration by a more effective method and delivers the drug through the skin or mucous membrane. It is in.

[0018]

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

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

[0020] The skin permeability of a drug is often determined by the rate of penetration under normal conditions. The permeation rate J 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 equation Kp = KD / L (where K, D, and L are the same as described above). As indicated above, increasing the concentration of the drug in the base is advantageous for allowing large amounts of the drug to penetrate the skin, but the methods currently used have limitations.

In the present invention, as one of the methods for increasing the solubility in the adhesive base and at the same time reducing the adhesive properties and skin irritation, an adhesive having a similar solubility parameter to the drug is first selected and manufactured. Maximize the concentration of drug in the drug. An acrylic pressure-sensitive adhesive is the most suitable pressure-sensitive adhesive for such a purpose. In the case of an acrylic pressure-sensitive adhesive, it is easy to adjust the compounding ratio of the monomer to be polymerized, so that 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, the release of water in the skin results in more water being present than was initially adjusted in the adhesive base, and the solubility parameter in the adhesive base was Changes, the saturation solubility of the drug changes, showing a considerable difference from the actual solubility, and at the same time, the amount of the drug delivered to the skin by the adhesive and the adhesive properties show a considerable decrease.

In order to solve such a problem, the present invention employs a multilayer lamination method. FIG.
In FIG. 2 and FIG. 2, as the support (1), a multilayer film or a laminate film of polyethylene, polypropylene, polyethylene terephthalate, or the like, or a nonwoven fabric or a cotton cloth is used, and if necessary, the nonwoven fabric or the cotton cloth is a plastic having no moisture permeability. 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 bases (3, 4) in FIG. 2 can be constituted, and the pressure-sensitive adhesive base (3) and the pressure-sensitive adhesive base in FIG. The laminate adhesive capable of forming the multilayer of (4) is used. The pressure-sensitive adhesive base (3) in FIG. 2 is obtained by laminating a pressure-sensitive adhesive composition having a higher water content than the lower layer, blending a drug in a saturated amount or more as necessary, and blending additives for promoting skin penetration and the like. And the adhesive base (4) of FIG. 2 has a lower moisture content than the upper layer,
An adhesive having a high solubility for the drug is used, and the drug is compounded in an amount equal to or higher than the saturated amount and is mixed with the skin penetrant and other additives, similarly to the adhesive base (3) as the upper layer. In addition,
As in the case of laminating 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 the drug can be continuously and appropriately passed through the skin or mucous membrane. It can be absorbed into the skin,
The adhesive base (2) can be formed in multiple layers so as to perform the same function as the adhesive base (3, 4) of FIG.

The release film (5) shown in FIGS. 1 and 2 is formed of a release paper containing a release paper and a silicone or fluoro-based release agent. More specifically, first, when a larger amount of the drug is to be administered to the skin, the lowermost layer that is adhered to the skin should be prevented in order to prevent the solubility and adhesive properties of the drug from being reduced due to the release from the skin. , A pressure-sensitive adhesive having a low water content is introduced, and a pressure-sensitive adhesive having a high water content is introduced toward the upper portion. Therefore, when the patch is applied to the skin, as the water emanates from the surface of the skin, this water is transmitted to the upper layer through the adhesive layer, and is fixed to the lower adhesive layer in contact with the skin. Since only a small amount of water is present, the saturated concentration of the whole drug and the physical properties of the adhesive layer are maintained as they are, and skin side effects due to accumulation of sweat or secretions are reduced. be able to. by this,
The administration of the drug through the skin is effectively achieved. If the support is a nonwoven fabric, cotton cloth or other breathable plastic film, its efficiency can be maximized by laminating it or using it as it is and adjusting the moisture permeability. In particular, such formulations can provide better results than formulations for regulating large amounts of drug.

Alternatively, a burst effect (budding effect) can be achieved by administering a large amount of drug through the skin immediately after application.
If it is desired to obtain a rst effect, an adhesive base having a desired limit of water content for the adhesive layer is selected and the drug is saturated there. When such a preparation is applied to the skin, a large amount of the drug is administered through the skin immediately after the application due to the high concentration of the drug. However, as the adhesive layer absorbs the skin's moisture, the drug's solubility gradually decreases, thereby reducing drug transmission from the skin. Thereafter, when the water absorption reaches a normal state, only a certain amount of the drug is properly transmitted through the skin, and the release of the drug is controlled. At this time, the number of laminations of the adhesive base 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 μm.
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 a silicone polymer, a natural or synthetic rubber, or an acrylic resin is used. As the adhesive imparting agent, a rosin resin, a polyterpene resin, a petroleum resin, A terpene phenol resin or the like is used, and a plasticizer, a filler, an antioxidant and the like are optionally added. Especially as acrylic resin,
Polymer of alkyl (meth) acrylate having an alkyl group having 4 to 18 carbon atoms and / or 4 to 18 carbon atoms
Adhesive resin which is a copolymer of a (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, and the like.
Stearyl acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate,
There are isooctyl methacrylate, decyl methacrylate and the like, and as the functional monomer, a monomer having a hydroxyl group, a monomer having a carboxyl group,
Examples include a monomer having an amide group and a monomer having an amino group. Here, examples of the monomer having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate, and examples of the monomer having a carboxyl group include acrylic acid and methacrylic acid. Α-β unsaturated carboxylic acids, monoalkyl esters of maleic acid such as butyl maleate, maleic acid, fumaric acid, crotonic acid and the like. Maleic anhydride is also a (co) polymer having the same form as maleic acid. Form. Examples of the monomer having an amide group include acrylamide, dimethylacrylamide, alkyl (meth) acrylamide such as diethylacrylamide, butoxymethylacrylamide, and alkylethylmethylol (meth) acrylamide such as ethoxymethylacrylamide.
Examples include diacetone acrylamide, vinylpyrrolidone, and dimethylaminoacrylate.

Other copolymer monomers include, for example, vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene, and copolymers with these also exhibit good properties. The pressure-sensitive adhesive preferably contains at least 50% by weight of (meth) acrylic acid alkyl ester as a (co) polymerization component.

As a method for decreasing or increasing the water content, in the case of an acrylic resin, a monomer having high hydrophilicity, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and the like are used in combination. The water content can be adjusted by polymerization, and in the case of rubber and silicone resins, the water content can be adjusted by blending a tackifier and an additive. Further, as another method, the water absorbing ability can be adjusted by using a highly water-absorbing resin, a polyhydric alcohol, and a water-absorbing inorganic substance. Examples of superabsorbent polymers include mucopolysaccharides such as hyaluronic acid controitin sulfate and samatin sulfate, and many such molecules as chitin, chitin derivatives, starch, and carboxycellulose. Semi-synthetic and synthetic superabsorbent resins of a superabsorbent polymer having a hydrophilic group and a polyacrylic acid-based, polyoxyethylene-based, polyvinyl alcohol-based, or polyacrylonitrile-based homo- or copolymer. Examples of the water-absorbing inorganic substance include water-absorbing silica, zeolite, and water-absorbing ceramic, and examples of the polyhydric alcohol include propylene glycol, glycerin, and sorbitol. At this time, a water-absorbing substance such as a superabsorbent 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 done.

Examples of the rubber-based pressure-sensitive adhesive include 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 as the silicone resin-based pressure-sensitive adhesive, silicone rubber such as polyorganosiloxane is used.

Among the above-mentioned pressure-sensitive adhesives, various additives such as rosin-based resins, polyterpene-based resins, coumarone-indene-based resins, petroleum-based resins, terpene-phenol-based resins, etc. , Liquid polybutene resin,
Adhesive aids such as petroleum resins and terpene phenol 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. In order to obtain more improved adhesive properties, further additives can be incorporated.

Substances used as a percutaneous penetration enhancer to enhance the skin absorption of the drug include dodecyl sulfoxide, mono- or dimethyl acetate, N-hydroxyethyl lactide, higher fatty acid esters, salicylic acid,
Sorbitol, urea, glycerin, squalene, squalane, acetylated lanolin, cetyl laurate , olive oil, castor oil, lauric acid , oleic acid, lauryl alcohol, oleyl alcohol, ethoxysteryl alcohol, liquid paraffin, vaseline, camphor, glycerin fatty acid ester, Fatty acid mono (or di) ethanolamide, ethylene glycol monoethylene ether,
Examples include polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxypropylene alkyl ether, propylene glycol mono (di) alkyl ester, propylene glycol monolaurate, polyoxyethylene lauryl ether, and pyrrolidone derivatives.

That is, the present inventors have clarified that the use of a transdermal penetration enhancer such as a polyoxyethylene derivative or a pyrrolidone derivative can significantly increase the transdermal penetration rate of a drug. Also, by using a penetration enhancer to increase the transdermal penetration efficiency,
It has been shown to be particularly effective for non-steroidal anti-inflammatory analgesics such as ketoprofen. One aspect of the present invention relates to a fatty acid ester (for example, as a transdermal penetration enhancer) in a proportion of 1 to 39% by weight based on the total amount of the carrier.
Methyl laurate, isopropyl myristate), a polyoxyethylene derivative, a glycerin fatty acid ester, a propylene glycol fatty acid derivative, a pyrrolidone derivative and the like. A skin-administered pharmaceutical composition is provided.

In order to be a compound useful as a transdermal penetration enhancer, various requirements must be satisfied.
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 carriers and active ingredients in the transdermal administration system. If not, phase separation occurs or a reaction occurs that destroys or prevents the physiological activity of the active ingredient. Third, the compound must have no or no predictable pharmacological activity per se, and have a significant effect on promoting the transdermal penetration of the drug, a physiologically active ingredient. And preferably US FDA (Food a
nd Drug Administration).

The present inventors have searched a number of compounds to find one or more useful compounds as transdermal penetration enhancers meeting the above objectives. Representative of such compounds is propylene glycol monolaurate. Another compound investigated by the inventors is polyoxyethylene lauryl ether. The present inventors furthermore, as a primary skin irritation relieving agent, bisabolol (bisabolol),
Α in chamomile oil, allantoin, dipanthenol
-Bisabolol was found to be the most useful substance.

The stable and effective amount of the physiologically active ingredient used in the medicated patch composition according to the present invention provides a therapeutically useful blood concentration and / or local concentration of the active compound by a transdermal administration method. Means the amount to do. The compounding amount of these penetration enhancers is 0.1 to 40% by weight, preferably 1 to 40% by weight.
20% by weight. Further, tocopherol, tocopherol acetate, BHA, BHT and the like can be used as an antioxidant for a drug penetration enhancer and other additives,
And, as the preservative, ethyl paraben, methyl paraben, butyl paraben and the like can be used.

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

At this time, any drug can be incorporated into the base as long as it can penetrate the skin during transdermal administration and its solubility changes with a change in the water content in the base. There is no special limitation. Non-steroidal drugs include methyl salicylate, salicylic acid, ibuprofen, ketoprofen, fluorobiprofen, indomethacin, diclofenac sodium, furofenamic acid,
A pharmacologically effective compound selected from nafloxene, mefenamic acid, fenoprofen, fenclofenac, piroxicam, and their precursor drugs is used within a safe and effective amount.

Other drugs include antipyretic and antiphlogistic analgesics,
Steroidal anti-inflammatory drugs, vasodilators, antihypertensive and arrhythmic drugs, antihypertensive drugs, antitussive expectorants, antitumor drugs, hormonal drugs, antiasthmatic and antinasal alleggi drugs, antihistamines, anticoagulants, cerebral circulation or metabolism Examples include ameliorating agents, antidepressants, anxiolytics, hypoglycemic agents, antirheumatic and antiarthritic agents, and the like.

As a support for a tape or a patch, a support generally used for a patch is used. Examples of such a support material include cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl-vinyl chloride, polyurethane, polyethylene, and polyethylene. Examples include vinylidene chloride and aluminum. 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, it is preferable to use a cotton cloth or a nonwoven fabric.

Further, in order to reduce the adhesive property and the skin irritation which often occur when a drug or a penetration enhancer is applied to the tape or patch, a skin irritation alleviating agent or an inorganic or organic filler may be added. At this time, bisabolol, chamomile oil, allantoin, glycerol, dipanthenol, etc. are used as the skin irritation alleviating agent.
It may be present in the range from 10 to 10% by weight, preferably from 0.1 to 5% by weight. Organic and inorganic substances for improving the adhesive properties include organic polymer fine particles such as cellulose, polyethylene, nylon 6, nylon 12, polypropylene, and polyethylene terephthalate, zinc white, calcium oxide, silica, kaolin, talc, titanium, and the like. Can 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% by weight.
３０30% 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 more concentrated than various compositions. It is desirable that the compound be contained at a substantially saturated concentration level in each of the adhesive layers.

[0043]

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 at the following ratios (% by weight) to prepare a preparation for transdermal administration of anti-inflammatory and analgesic for use in the form of a patch. Ketoprofen 10 Propylene glycol monolaurate 10 Tocopherol acetate 1 Zinc flower 5 Acrylic resin A ¹⁾ 74 All 100 (Note 1) Acrylic resin A: Fluid of a copolymer resin of butyl acrylate, octyl acrylate and vinyl acetate (solid content: 48) 0.0%) The thus obtained mixture was coated on a silicone-treated PET release liner, left at room temperature for 20 minutes or more, dried at 90 ° C. for 10 minutes or more, and dried to a thickness of 80 μm. The resulting substance was interleaved with a stretchable nonwoven fabric to produce a tape-shaped final patch.

Example 2 The following components were uniformly mixed in the following ratio (% by weight)
A pharmaceutical composition for anti-inflammatory / analgesic transdermal administration for use in the form of a patch was prepared. Indomethacin 10 glycerol monooleate 10 tocopherol acetate 1 zinc white 5 acrylic resin B ²⁾ 75 whole 100 (Note 2) acrylic resin B: fluid of vinyl acetate-resin multipolymer (solid content: 31.0%) The resulting mixture was coated on a release paper treated with silicon, dried, and then the resulting material was inserted into a stretchable nonwoven fabric to produce a final patch in the form of a tape.

Example 3 The following components were uniformly mixed in the following ratio (% by weight)
A pharmaceutical composition for anti-inflammatory and analgesic transdermal administration for use in the form of a patch was prepared. Diclofenac sodium 10 Polyoxyethylene lauryl ether (EO = 3) ³⁾ 10 Tocopherol acetate 1 Bisabolol 2 Zinc white 5 Acrylic resin A 72 All 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 is treated with silicon-treated P
After coating with an ET release liner and drying, 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] 97.4 2-ethylhexyl acrylate
Parts, methacrylic acid 2.5 parts, polyethylene glycol dimethacrylate 0.1 part, benzoyl peroxide (BP
O) 1.0 part of ethyl acetate and 100 parts of ethyl acetate were charged into a reaction vessel having a reflux condenser and a stirrer, and were heated at 60 ° C.
To carry out a polymerization reaction while gradually stirring. In order to adjust the degree of polymerization, 100 parts of ethyl acetate was gradually added during the reaction, and the reaction was carried out for 9 hours. At this time, the conversion was 99.9.
%Met. An appropriate amount of ethyl acetate was added to the obtained polymer solution, and the concentration of the solid content was adjusted to about 40% by weight.

[Adhesive 2] 70 parts of 2-ethylhexyl acrylate, 10 parts of acrylic acid, benzoyl peroxide (B
PO) and 1.0 part of vinyl acetate were copolymerized under the same conditions as for the pressure-sensitive adhesive 1 by adding ethyl acetate. At this time, the polymerization rate was 99.9% or more.
In addition, 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 the solid content to about 40% by weight.

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

[Preparation of Adhesive Base (4)] A drug in an amount of 20% by weight was added to the above-mentioned "Adhesive (2)" and dissolved therein at a concentration exceeding the saturation solubility. The obtained mixture is dried on a silicone-treated release paper to a thickness of 30 μm when dried.
It coated so that it might become. "Adhesive base (4)" is first transferred to a polyethylene film, and then "adhesive base (3)"
Was laminated to produce a patch comprising two layers of the adhesive base (3, 4). At this time, the drying was performed under the conditions of allowing to stand at room temperature for 15 minutes to air dry, and then drying at 90 ° C. for 10 minutes.

Example 5 [Production of pressure-sensitive adhesive base (4)] Ketoprofen was added to "pressure-sensitive adhesive 1" obtained in Example 4 so as to have a solid content of 20% by weight, and exceeded the saturation solubility. Dissolved in concentration,
Hyaluronic acid powder was uniformly dispersed at a ratio of 5% by weight, and then applied to silicone release paper so that the thickness when dried was 40 μm, and dried. The “adhesive base (4)” thus obtained was transferred onto a polyester film, and the “adhesive base (3)” of Example 4 was laminated on the polyester film to form a two-layer adhesive base. A patch was produced.

Example 6 [Production of Adhesive Base (3)] Ketoprofen was added to “Adhesive 1” obtained in Example 4 so as to have a solid content of 20% by weight, and the saturated solubility was determined. At a concentration exceeding 10% by weight of polyoxyethylene lauryl ether (EO = 3) as a transdermal penetration enhancer, and 0.5% by weight of tocopherol acetate as an antioxidant.
And dissolved. Next, colloidal silica was blended at a ratio of 3% by weight in order to improve the decrease in adhesive properties caused by the transdermal penetration enhancer. The adhesive base thus produced was applied to release paper so that the thickness when dried was 60 μm, and then dried.

[Production of Adhesive Base (4)] Ketoprofen was added to “Adhesive 2” obtained in Example 4 so as to have a solid content of 20% by weight, and a concentration exceeding the saturation solubility was added thereto. After dissolution, 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 Ketoprofen was added to "Adhesive 2" obtained in Example 4 so as to have a solid content of 20% by weight, and dissolved therein at a concentration exceeding the saturation solubility. 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 a cellulose powder (particle size: 5 to 1.5 μm) as a water-content controlling agent was uniformly dispersed, and then applied to a release paper to a thickness of 70 μm and dried.

Example 8 The following components were uniformly mixed in the following proportions (% by weight) to prepare a pharmaceutical composition for transdermal administration of anti-inflammatory and analgesic drugs for use in the form of a patch. Ketoprofen 10 Propylene glycol monolaurate 5 Tocopherol acetate 2 Zinc white 10 Rubber-based resin C14 ⁾ 73 All 100 (Note 4) The composition of rubber-based resin C1 is as follows. Styrene-butadiene-styrene block copolymer 100 terpene resin 75 polybutene 20 liquid paraffin 20 BHA 2 The mixture thus obtained is coated on a release paper and dried, and the resulting substance is combined with an elastic nonwoven fabric. The paper was made to produce a tape-shaped final patch.

Example 9 The following components were uniformly mixed at the following ratios (% by weight) to prepare a pharmaceutical composition for anti-inflammatory and analgesic transdermal administration for use in the form of a patch. Piroxicam 10 glycerin monooleate 5 tocopherol acetate 2 zinc white 10 rubber-based resin C1 73 whole 100 The mixture thus obtained is coated on a release paper, dried, and the resulting substance is combined with an elastic nonwoven fabric. The paper was made to produce a final patch in the form of a tape.

Example 10 The following components were uniformly mixed in the following proportions (% by weight) to prepare a drug for transdermal administration of anti-inflammatory and analgesic 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 whole 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 mixture thus obtained is coated on a release paper, dried, and the resulting substance is combined with an elastic nonwoven fabric. The paper was made to produce a final patch in the form of a tape.

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 abdominal hair of a male guinea pig weighing about 350 g with an electric clipper (hair clipper), a certain portion was cut off, stored in a freezer (-20 ° C. or lower), and thawed when necessary. Used. After placing a cut skin with the stratum corneum facing upward in the middle of a Franz diffusion cell, a 0.05 M phosphate buffer solution (p
H7.4) was added, and the temperature of the diffusion cell was maintained at 37 ° C.
The receptor solution (buffer solution) is supplied at a constant speed (600 rpm).
The patch obtained in Example 1 was adhered to the skin while stirring in m). After a certain period of time, the solution of the receptor portion was collected, and a new buffer solution was replenished in an amount corresponding to the collected amount. The concentration of ketoprofen was measured for the collected sample using high pressure liquid chromatography (HPLC). [Analytical conditions for high pressure liquid chromatography (HPLC)] Column: C ₁₈ μbondapak [Massachusetts 0
1575, Milton, Waters Chromatography, Inc.] Mobile phase: 55:45 v / v Methanol: 0.02 M phosphate buffer (pH 4.0) Flow rate: 1 ml / min Detector: UV light at 254 nm wavelength

Starting with the patch prepared in Example 1,
About each patch with various formulations shown in Table 1, the skin penetration test of ketoprofen was performed in the same manner as described above.
Table 2 shows the results.

[0061]

[Table 1]

[0062]

[Table 2]

[Results] In order to increase the percutaneous penetration of ketoprofen, the content of ketoprofen in the adhesive layer was increased so that the production using the percutaneous penetration enhancer was higher than that when the production was higher than the saturation concentration. Better enhanced transdermal penetration of ketoprofen. When a percutaneous penetration enhancer is contained in the adhesive layer by a general technique, the adhesive property is significantly reduced, and the percutaneous penetration enhancer effect is reduced by half, whereas the penetration enhancer of the present invention has an adhesive property. Excellent penetration enhancement without significant changes.

Skin primary irritation test A patch prepared in the same manner as in Example 1
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 adhesion
After a lapse of time, the patch was peeled off, and after 30 minutes, the degree of the primary stimulus was observed according to the following criteria. Judgment number Stimulation level 0 No stimulation 1 Slight stimulation 2 Severe stimulation (redness) 3 Severe stimulation (redness, edema) 4 Extremely severe stimulation (redness, edema) The reactivity was determined based on the following formula. Reactivity (%) = [sum of (number of responders × judgment number) / (number of testers × 4)] × 100 The formulation of the patch used in the primary skin irritation test is as shown in Table 3, and the test results are as follows. As shown in Table 4.

[0065]

[Table 3]

[0066]

[Table 4]

As is apparent from the above data, no effect of reducing primary skin irritation was observed in any case where bisabolol was added.
At concentrations of ~ 2% it is used as an effective skin irritation relieving agent. In addition, the overall degree of patch irritation was within 10%, indicating that these patches were safe against skin irritation.

Comparative Example 1 Only the pressure-sensitive adhesive base (3) prepared in Example 4 had a thickness of 8
It was applied to release paper 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 have a solid content of 20% by weight, and was dissolved therein at a concentration exceeding the saturation solubility to promote percutaneous absorption. After adding 10% by weight of propylene glycol monooleate as an agent, 0.5% by weight of tocopherol was added and dissolved as an antioxidant, and 2% by weight of bisabolol was added and dissolved as a skin irritation alleviating agent. This was applied to release paper so as to have a thickness of 70 μm and dried.

Percutaneous Penetration Test According to Examples 4, 5, 6, 7 and Comparative Examples 1 and 2 The test was conducted in the same manner as the above-mentioned percutaneous penetration test. Table 5 shows the results.

[0071]

[Table 5]

Primary irritation test according to Examples 4, 5, and 6 and Comparative Examples 1 and 2 The test was carried out in the same manner as the primary skin irritation test described above.
Table 6 shows the results.

[0073]

[Table 6]

[0074]

EFFECT OF THE INVENTION The patch for transdermal administration of the drug of the present invention has very little irritation to the skin, and is excellent in releasing and transferring physiologically active ingredients to the skin. Since the medicinal effect is rapidly exhibited and the medicinal effect has an excellent medicinal effect in a minimum area of adhesion to the skin, discomfort caused by adhesion to the skin can be reduced.
In addition, according to this transdermal patch, the solubility of the drug in the adhesive base can be increased, the drug can be effectively absorbed through the skin, and the adhesive can be formed using a multilayer lamination method. By controlling the water content in the base, it is possible to obtain a sustained-release patch for administering the drug at a desired concentration through the skin or mucous membrane.

[Brief description of the drawings]

FIG. 1 is an explanatory cross-sectional view of a monolayer controlled release transdermal patch.

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

FIG. 3 shows that the system for transdermal administration of the present invention was applied to the skin of a guinea pig.
FIG. 7 is a graph showing changes in the transdermal penetration amount of a drug with respect to time.

 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Han Soo Han, 570-36, Bacho-dong, Changan-si, Gyeonggi-do, Republic of Korea (56) References JP-A-55-35633 (JP, A) JP-A-57-75918 (JP, A) JP-A-58-79918 (JP, A) JP-A-60-252412 (JP, A) JP-A-63-225314 (JP, A) 64-40420 (JP, A) JP-A-1-250317 (JP, A) JP-A-4-13617 (JP, A)

Claims (16)

(57) [Claims] 1. A support and a viscous material on one surface of the support.
A pressure-sensitive adhesive layer formed by applying a
Transdermal consisting of a release film laminated on the adhesion layer
In a patch for administration type drug, the adhesive is one or more transdermal penetration enhancers selected from the group consisting of fatty acid esters, polyoxyethylene derivatives, glycerin fatty acid ethers, propylene glycol fatty acid esters and pyrrolidone derivatives. ~ 40% by weight and a silicone polymer,
One or more adhesive resins selected from the group consisting of natural or synthetic rubbers and acrylic resins, and a drug or precursor drug 0.1 whose solubility changes as the water content in the adhesive layer changes. co to have been configured with a 50%
In addition, the pressure-sensitive adhesive layer has a low water-absorbing capacity of the lowermost layer that adheres to the skin.
As a multi-layered laminate with higher water content in the upper layer
A patch for transdermal drug administration characterized by being formed . 2. A polymer of an alkyl (meth) acrylate having an alkyl group having 4 to 18 carbon atoms or an alkyl (meth) acrylate having an alkyl group having 4 to 18 carbon atoms, and vinyl acetate. 2. The patch for transdermal administration type drug according to claim 1, wherein the patch is a copolymer with another functional monomer. 3. The transdermal patch for drug 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 a styrene-butadiene-styrene, styrene-isoprene-styrene, styrene-ethylene / propylene-styrene, styrene-ethylene / butylene-styrene block copolymer as a main substrate, and an adhesive. The transdermal administration type drug according to claim 1, wherein the composition contains one or more additives selected from the group consisting of an auxiliary agent, a tackifier, an inorganic filler, a softener, 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 blending ratio of a monomer having a hydrophilic group in the monomer in the copolymerization reaction. Patch for type drug. 6. The pressure-sensitive adhesive comprises 0.01 to 40% by weight of at least one compound selected from the group consisting of superabsorbent polymers, water-absorbing inorganic substances and polyhydric alcohols. The transdermal patch for drug according to any one of claims 1 to 5. 7. The transdermal patch according to claim 1, wherein the tackifier is a rosin resin, a polyterpene resin, a petroleum resin or an olefin resin. 8. The skin irritation-relieving agent comprises one or more compounds selected from the group consisting of bisabolol, chamomile oil, allantoin, glycerin and pantheol, and is present in a proportion of 0.01 to 10% by weight. The patch for transdermal administration type drug according to claim 1, characterized in that: 9. The drug may be an antipyretic analgesic, a steroidal anti-inflammatory, a vasodilator, a hypertension and arrhythmia treatment, a hypotensive, an antitussive expectorant, an antitumor agent, a local anesthetic, a hormone,
From the group consisting of anti-asthmatic and anti-nasal allergies, antihistamines, anticoagulants, antispasmodics, cerebral circulation or metabolism improvers, antidepressants, anxiolytics, hypoglycemic agents, antiulcer agents, and their precursors 2. The patch for transdermal administration type drug according to claim 1, which is selected. 10. The patch for transdermal administration of a drug according to claim 1, wherein the nonsteroidal anti-inflammatory drug is contained in a proportion of 1 to 40% by weight as a drug. 11. A nonsteroidal anti-inflammatory analgesic, wherein ketoprofen, diclopenac sodium, indomethacin,
The transdermal patch for drug according to claim 10, wherein the patch is fluorobiprofen or piroxicam. 12. The patch for transdermal administration type drug according to claim 1, wherein the fatty acid ester is methyl laurate or isopropyl myristate. 13. The polyoxyethylene derivative or polyoxyethylene ester according to claim 1, wherein the polyoxyethylene derivative 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 patch for drug. 14. The patch for transdermal administration according to claim 1, wherein the fatty acid of the glycerin fatty acid ether is 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. The pressure-sensitive adhesive is an organic polymer or an inorganic substance for improving the adhesive property, such as cellulose, polyethylene, nylon 6, nylon 12, polyethylene terephthalate, zinc white, calcium oxide, silica, kaolin, talc and titanium. The transdermal patch for transdermal administration according to claim 1, wherein the patch contains 0.1 to 30% by weight of at least one selected from the group consisting of dioxides.