TW201605498A - Clonidine-containing adhesive patch - Google Patents

Abstract

An adhesive patch for local pain relief, which is provided with a supporting body and an adhesive layer that is laminated on the supporting body. The adhesive layer contains clonidine or a pharmaceutically acceptable salt thereof, a skin permeation suppressant for clonidine or a pharmaceutically acceptable salt thereof, and an adhesive. The skin permeation suppressant for clonidine or a pharmaceutically acceptable salt thereof is composed of at least one substance selected from the group consisting of citric acid, oleic acid, stearic acid, isostearic acid, malic acid, lactic acid, a copolymer of methacrylic acid and a methacrylic acid ester, and a polyethylene glycol. The content of clonidine or a pharmaceutically acceptable salt thereof is 0.9% by mass or less based on the total mass of the adhesive layer.

Description

Containing Clonidine patch

The present invention relates to a patch containing clonidine.

Clonidine is also known as "2-(2,6-dichlorophenylimino)imidazolidinium" and is widely known as an adrenergic alpha 2 receptor agonist. Clonidine inhibits the transmission of sympathetic signals generated by stimulation of the central α2 receptor and acts with the α2 receptor present in the presynaptic membrane of the peripheral adrenergic neuronal terminals, inhibiting the decrease by the stimulation of the sympathetic nerves. The adrenaline is free and therefore has a blood pressure lowering effect.

Coronine has been developed as a therapeutic drug for oral hypertension. If the blood concentration of Clonidine is increased, there is a problem that side effects such as gastrointestinal disorders are prone to occur. When oral administration of Clonidine is administered in a dose of 0.225 to 0.45 mg per day for 3 times a day, the blood concentration of Clonidine which is effective for treating hypertension is 0.2 to 2.0 ng/mL (Non-Patent Document 1) ).

Therefore, in order to reduce side effects such as gastrointestinal disorders, the application of clonidine in percutaneous absorption preparations has been examined (Patent Documents 1 to 3).

In addition, in addition to the blood pressure lowering effect, Clonidine has been found to exhibit local analgesic action at a lower dose, and the development of a percutaneous absorption type preparation has been attracting attention (Patent Documents 4 to 7). In particular, Patent Document 7 discloses that the α2 agonist in the square for pain treatment has a skin permeation rate of at least 1 μg/cm ² /hr.

In recent years, Catapres-TTS (registered trademark; Boehringer Ingelheim) has been marketed abroad, and its blood concentration is 0.2 ng/mL or more, showing a blood pressure lowering effect. Patent Document 4 discloses that in Catapres-TTS (registered trademark)-2 (attachment area 3.5 cm ² ) and Catapres-TTS (registered trademark)-3 (attachment area 7.0 cm ² ), Coronine dominates sympathetic nerves. Pain or neuropathic pain shows local analgesic effects.

[Previous Technical Literature] [Patent Document]

[Patent Document 1] Japanese Patent Laid-Open No. Hei 6-116145

[Patent Document 2] Japanese Laid-Open Patent Publication No. 60-193920

[Patent Document 3] Japanese Patent Publication No. 62-14526

[Patent Document 4] US Patent No. 5447947

[Patent Document 5] Japanese Patent Laid-Open Publication No. 2013-10770

[Patent Document 6] Japanese Patent Publication No. 2009-514970

[Patent Document 7] Japanese Patent Publication No. 2009-524586

[Non-patent literature]

[Non-Patent Document 1] Catapres tablet interview form

In addition, in the case of Coronine, because it inhibits the vasomotor center, it shows central side effects such as lethargy, depression, thirst, and decreased libido. When the drug is suddenly stopped, it is known to show rapid withdrawal of blood pressure and other withdrawal syndromes (withdrawal syndrome). ). However, in the above prior art documents, the insight into the systemic effects of the absence of clonidine is not disclosed at all.

Further, such as the above, Clonidine exhibits a local analgesic effect with a lower administration amount lower than the blood pressure lowering effect. Therefore, it is expected to have a local analgesic effect. When a patch for antihypertensives containing clonidine hydrochloride is used, the desired local analgesic effect can be exerted, and the blood pressure lowering effect can be exerted, but there is a display. The possibility of hypotensive symptoms such as dizziness has become a problem from the viewpoint of user safety and compliance.

Further, in general, the patch for local analgesia needs to have a large area which can sufficiently cover the affected part. Here, if the attachment area of the patch is simply increased, the content of the drug contained in the preparation also increases. However, in the case of a patch containing clonidine for the purpose of local analgesia, if the blood concentration of clonidine is increased, the possibility of a blood pressure lowering effect is also increased, and therefore, the content of coronine in the preparation needs to be lowered. .

The present inventors have found that in the patch containing clonidine, there is a problem that the stability of the clonidine in the preparation is lowered as the content of the clonidine is lowered. That is, in the conventional patch, the concentration of the coronine in the preparation which does not show systemic side effects is 0.5% by mass or less, but in this case At the concentration of Clonidine, the stability of the Clonidine in the formulation is low and lacks practicality.

The present invention has been made to solve the above problems, and to provide a patch containing clonidine which exhibits a local analgesic action and is excellent in drug stability.

As a result of intensive studies by the present inventors, it has been found that a specific component can exert a function as a skin permeation inhibitor for clonidine, and the present invention has been completed. That is, the present invention provides a local analgesic patch comprising a support and a local analgesic patch laminated on the support, the adhesive layer comprising: coronine or a pharmaceutically acceptable salt; a skin permeation inhibitor against clonidine or a pharmaceutically acceptable salt thereof; and an adhesive, the skin permeation inhibitor selected from the group consisting of citric acid, oleic acid, stearic acid, and isostearic acid At least one of a group of malic acid, lactic acid, a copolymer of methacrylic acid and methacrylic acid ester, and polyethylene glycol, the content of the above-mentioned clonidine or a pharmaceutically acceptable salt thereof, and the above-mentioned adhesive The total amount of the layer is based on 0.9% by mass.

The content of the clonidine or the pharmaceutically acceptable salt thereof is 0.9% by mass or less based on the total amount of the adhesive layer, and further contains a selected from the group consisting of citric acid, oleic acid, stearic acid, and isostearic acid. A patch of at least one of a copolymer of malic acid, lactic acid, methacrylic acid and methacrylic acid ester and polyethylene glycol can sufficiently inhibit the skin of clonidine or a pharmaceutically acceptable salt thereof Permeation rate, only showing local analgesic effect, The duration stability of Lenin or its pharmaceutically acceptable salt is also excellent.

In the patch of the present invention, the maximum skin penetration rate of the Clonidine or its pharmaceutically acceptable salt is preferably 0.5 μg/cm ² /hr or less. If the maximum skin penetration rate of clonidine or its pharmaceutically acceptable salt is 0.5 μg/cm ² /hr or less, the blood concentration of clonidine does not rise sharply, and local analgesic effect can be continuously exhibited.

The patch of the present invention is preferably enclosed in a packaging material together with a desiccant or enclosed in a functional packaging material having a drying function.

Further, the present invention is also understood to provide a method for alleviating or treating pain by applying the above patch to the skin of the subject complaining of the pain symptom (for example, the affected part skin). Here, "treatment" refers to a degree that is suppressed to the above-mentioned subject without causing pain symptoms; "moderate" means that the above-mentioned subject feels pain symptoms, but the pain symptom is suppressed compared to the case where the patch is not applied. .

Furthermore, the present invention is also understood to provide a composition comprising a skin permeation inhibitor, an adhesive, and a solvent for clonidine or a pharmaceutically acceptable salt thereof, for clonidine or a pharmaceutically acceptable salt thereof. A method of manufacturing a local analgesic patch that is stretched onto a support or release liner.

According to the patch containing clonidine of the present invention, the skin permeation rate of clonidine or its pharmaceutically acceptable salt can be sufficiently inhibited, and only local analgesic action, coronine or its pharmaceutically acceptable salt in the patch is exhibited. The stability over time is also excellent.

The patch of the present embodiment includes a support and an adhesive layer laminated on the support. Further, the adhesive layer contains clonidine or a pharmaceutically acceptable salt thereof, and a skin permeation inhibitor against clonidine or a pharmaceutically acceptable salt thereof.

As the support, a stretchable or non-stretchable substance which can be usually used for a patch is used. Specifically, polyesters such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, and the like; polyolefins such as polyethylene, polypropylene, and polybutadiene may be suitably used. a film or sheet formed of a synthetic resin such as ethylene vinyl acetate polymer, polyvinyl chloride, nylon, polyurethane, cellulose derivative, polyacrylonitrile or synthetic resin such as cotton or the like, or a laminate thereof A porous film, a foam, a fabric such as a woven fabric or a non-woven fabric, a porous film, a foam, a paper, or the like.

The adhesive layer of the present embodiment contains clonidine or a pharmaceutically acceptable salt thereof; a skin permeation inhibitor against clonidine or a pharmaceutically acceptable salt thereof; and an adhesive.

Clonidine is also known as "2-(2,6-dichlorophenylimino)imidazolidinium", and is a compound having a structure represented by the following chemical formula (1). Clonidine is widely known as an adrenergic alpha 2 receptor agonist.

As the clonidine or a pharmaceutically acceptable salt thereof, a clonidine hydrochloride is preferred. In this specification, the term "Cloning" is also used to include the pharmaceutically acceptable salts of Clonidine, unless otherwise stated.

In the patch of the present embodiment, the content of the ketone or the pharmaceutically acceptable salt thereof is 0.9% by mass or less based on the total amount of the adhesive layer, and the lower limit value is based on the local analgesic effect. Preferably, it is 0.1% by mass or more. Further, when the content of clonidine or a pharmaceutically acceptable salt thereof exceeds 0.9% by mass, precipitation tends to occur in the adhesive solution during the production of the patch, and a homogeneous adhesive layer is not easily obtained. When the content of clonidine or its pharmaceutically acceptable salt in the adhesive layer is low, the content of clonidine or its pharmaceutically acceptable salt is based on the difference from the conventional patch in view of the decrease in the stability of the drug. More specifically, it is preferably 0.5% by mass or less based on the total amount of the adhesive layer.

In the patch of the present embodiment, the skin penetration rate of clonidine is preferably 0.5 μg/cm ² /hr or less. When it is 0.5 μg/cm ² /hr or less, the blood concentration of Clonidine is not easily increased when the patch is attached, and side effects such as a blood pressure lowering action are less likely to occur. Moreover, when it is 0.002 μg/cm ² /hr or more, a local analgesic action can be exerted, and a sufficient local concentration can be ensured.

In the present specification, the term "local concentration" means the concentration of a drug in the tissue of the skin that penetrates the site (affected part) to which the patch is applied.

A skin permeation inhibitor against clonidine or a pharmaceutically acceptable salt thereof means a compound which inhibits the transfer of clonidine or a pharmaceutically acceptable salt thereof into the blood, and specifically, citric acid ,oil Acid, stearic acid, isostearic acid, malic acid, lactic acid, copolymer of methacrylic acid and methacrylic acid ester and polyethylene glycol.

Examples of the copolymer of methacrylic acid and methacrylic acid ester include poly(methacrylic acid-co-methyl methacrylate), poly(methacrylic acid-co-ethyl methacrylate), and the like. The polymerization of methacrylic acid and methacrylic acid ester is preferably 1:1~1:2. Specifically, EUDRAGIT (registered trademark) L100, EUDRAGIT (registered trademark) L30D-55, EUDRAGIT (registered trademark) S100, and the like can be given.

The polyethylene glycol is not particularly limited as long as it is pharmaceutically acceptable, and preferably has a number average molecular weight of from 100 to 20,000, more preferably from 200 to 600. Preferred polyethylene glycols include, for example, polyethylene glycol 400.

The skin penetration inhibitor for clonidine or a pharmaceutically acceptable salt thereof may be used singly or in combination of two or more. Further, the above skin permeation inhibitor may be an anhydride or a hydrate. As the hydrate type skin permeation inhibitor, for example, citric acid monohydrate can be mentioned. Further, when the optical isomer is present in the above skin permeation inhibitor, only one of the optical isomers may be used, or a mixture of optical isomers may be used as the racemate. As the skin penetration inhibitor which is a mixture of optical isomers, for example, DL-malic acid can be mentioned.

The above skin penetration inhibitor does not include a salt form. Therefore, a salt such as sodium citrate or zinc stearate is not contained in the skin permeation inhibitor against clonidine or a pharmaceutically acceptable salt thereof in the present embodiment.

In the patch of the embodiment, the drug or the drug thereof The content of the skin permeation inhibitor of the salt which is permissible is preferably from 0.1 to 10% by mass, more preferably from 3 to 9% by mass based on the total amount of the adhesive layer. When it is 0.1% by mass or more, the blood concentration of Clonidine is not easily increased when the patch is attached, and side effects such as a blood pressure lowering effect are less likely to occur. In addition, when it is 10% by mass or less, a sufficient local concentration can be secured because a local analgesic action can be exerted.

The adhesive layer of the present embodiment contains at least one type of adhesive selected from the group consisting of a styrene block copolymer-based adhesive, a polyisobutylene-based adhesive, and a polyoxyn-based adhesive. The styrene block copolymer-based adhesive has a weak adhesive force, and is preferred in that it is less likely to cause pain when attached to a pain-sensitive affected part or peeled off.

The styrene block copolymer-based adhesive refers to a person who imparts adhesion to a styrene block copolymer by adding a tackifier resin or the like. Examples of the styrene block copolymer-based adhesive include styrene-isoprene-styrene (SIS)-based adhesive, styrene-butadiene-styrene (SBS)-based adhesive, and styrene. - an ethylene-butylene-styrene (SEBS)-based adhesive or a styrene-ethylene-propylene-styrene (SEPS)-based adhesive.

The polyisobutylene-based adhesive refers to a person who imparts a plasticizer or the like to polyisobutylene (PIB) to impart adhesiveness.

Polyisobutylene (PIB) may also be mixed with a plurality of polyisobutylenes having different average molecular weights.

Examples of the plasticizer include a saturated hydrocarbon plasticizer; a petroleum-based oil such as a paraffin-based processing oil, a naphthenic processing oil, and an aromatic processing oil; olive oil, camellia oil, castor oil, and tall oil; Plants such as peanut oil a lubricating oil; a di-protonate such as dibutyl phthalate or dioctyl phthalate; a liquid rubber such as polybutene and liquid isoprene rubber; squalane; squalene; Polyethylene glycol; propylene glycol; dipropylene glycol and the like. These may be used alone or in combination of two or more. As the plasticizer, it is particularly preferably a liquid paraffin or a polybutene.

The content of the plasticizer in the adhesive layer can be appropriately adjusted by the person having ordinary knowledge in the art as a sufficient adhesion of the adhesive, but preferably based on the total amount of the adhesive layer, preferably 40 to 80 mass. %, more preferably 50 to 70% by mass, and particularly preferably 55 to 65% by mass.

The polyoxygenated adhesive refers to an adhesive composed of a condensed reactant of dimethyl polysiloxane and a phthalate resin having a three-dimensional structure, and examples thereof include Bio-PSA 7-4102 (manufactured by Dow Corning Co., Ltd.). ; product name) and so on.

These various adhesives may be used alone or in combination of two or more. Further, the content of the adhesive can be appropriately set for those who have a general knowledge in the art to consider the formation and adhesiveness of the adhesive layer and the tissue penetration of the active ingredient. For example, the content of the adhesive may be 40 to 98% by mass based on the total amount of the adhesive layer, and may be 50 to 95% by mass. Especially 60 to 95% by mass is preferred.

In the adhesive layer of the present embodiment, in order to adjust the adhesive force and local irritation at the time of peeling, a tackifier resin may be further contained.

As the tackifying resin, it is suitable to use an alicyclic saturated hydrocarbon resin; rosin derivatives such as rosin, rosin glyceride, hydrogenated rosin, hydrogenated rosin glyceride or rosin pentaerythritol ester; terpene resin, petroleum resin or cisplatin Acetyic acid resin and the like. Specifically, for example, Ester Gum (manufactured by Arakawa Chemical Co., Ltd.; trade name), Harister (manufactured by Harima Chemicals Co., Ltd.; trade name), Pentalin (registered trademark; manufactured by Eastman Chemical Co., Ltd.; trade name), and Foral (Eastman Chemical Co., Ltd.) can be used. Ruthenium resin such as rosin resin, YS Resin (product name of YASUHARA CHEMICAL Co., Ltd.; PICCOLITE (Ruth and Dilworth Co., Ltd. product name)) Resin, Alcon (registered trademark; manufactured by Arakawa Chemical Co., Ltd.; trade name), REGALREZ (manufactured by Eastman Chemical Co., Ltd.; trade name), PICCOLASTIC (manufactured by Eastman Chemical Co., Ltd.; trade name), Escorez (manufactured by Exxon Co., Ltd.; trade name), A petroleum resin, a phenol resin, a xylene resin, or the like, such as Wing-tack (manufactured by Goodyear Co., Ltd.; trade name), Quinton (registered trademark; manufactured by Zeon Corporation, Japan).

These tackifier resins may be used alone or in combination of two or more. Moreover, the content of the tackifying resin can be appropriately set by a person having ordinary knowledge in the art to consider the sufficient adhesive force of the patch and the local irritation at the time of peeling, but it is preferably 2 to 60 based on the total amount of the adhesive layer. The mass% is more preferably 3 to 50% by mass, particularly preferably 5 to 40% by mass.

The adhesive layer may also contain, as an additive, a filler, an ultraviolet absorber, an antioxidant, a solvent, a fragrance, and the like.

Examples of the filler include citrate such as aluminum citrate or magnesium citrate, aluminum hydroxide, aluminum carbonate, magnesium carbonate, citric acid, barium sulfate, calcium sulfate, calcium zincate, zinc stearate, zinc oxide, and oxidation. Titanium, etc.

Examples of the ultraviolet absorber include a p-aminobenzoic acid derivative, an ortho-aminobenzoic acid derivative, a salicylic acid derivative, a coumarin derivative, an amino acid derivative, an imidazoline derivative, and a pyrimidine derivative. Dioxane derivatives and the like.

As the antioxidant, tocopherol and its ester derivatives, ascorbic acid and its ester derivatives, dibutylhydroxytoluene, butylhydroxyanisole, pyrophosphoric acid and salts thereof can be suitably used.

The filler, the ultraviolet absorber and the antioxidant are represented by a total of 0.01 to 10% by mass, more preferably 0.01 to 5% by mass, and particularly preferably 0.1 to 3 by mass based on the total amount of the adhesive layer. The amount of % is blended.

As the solvent, for example, ethanol, acetone, ethyl acetate, toluene, tetrahydrofuran, acetonitrile or the like can be suitably used.

Further, in the patch of the present embodiment, in order to protect the adhesive layer from the external environmental influence during storage, the surface of the adhesive layer can be coated with the release liner. In the case where the patch is provided with a release liner, when the patch is used, the release liner is peeled off and removed.

As the release liner, a paper, a film, a foil, a laminate or the like which is generally used as a release liner for a patch can be used, and a plastic film which is substantially drug-impermeable is preferable. In particular, polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate, polyethylene naphthalate, polyolefins such as polyethylene and polypropylene, and the like can be suitably used. Metal such as aluminum, cellulose, and the like.

The surface of the release liner facing the adhesive layer can also be applied. Release treatment with polyfluorene and Teflon (registered trademark). It can be easily peeled off by performing a release treatment. In particular, the release treatment using polyoxymethylene is more preferable, and the peeling property can be stably maintained over time.

The patch of the present embodiment is preferably stored in a package (also referred to as a packaging material) made of aluminum. In the aluminum packaging material, it is more preferable to contain a preservative such as a desiccant or a deoxidizer together with the patch of the present embodiment. For example, PharmaKeep (registered trademark; manufactured by MITSUBISHI GAS CHEMICAL Co., Ltd.) can be used as the preservative agent, for example, calcined diatomaceous earth, uncalcined diatomaceous earth, crystalline cerium oxide, sorbic acid, or the like. AGELESS (registered trademark; manufactured by MITSUBISHI GAS CHEMICAL Co., Ltd.). Further, the above-mentioned packaging material may be a functional packaging material. As the functional packaging material, for example, a packaging material having a drying function, a deoxidizing function, or the like can be given. Specific examples include DRY KEEP (registered trademark; Sasaki Chemical Co., Ltd.), NS-AAP (Nissin Seal Industry Co., Ltd.), Moistcatch (registered trademark; Co-Print Co., Ltd.), and Oxycatch (registered trademark; Co-Printing Co., Ltd.). The stability of the drug to be hydrolyzed by the clonidine or its pharmaceutically acceptable salt contained in the patch can be further improved by encapsulating it with the desiccant or encapsulating it into a functional packaging material having a drying function. Further, by sealing together with the deoxidizing agent into the packaging material, the drug stability of the Clonidine or its pharmaceutically acceptable salt contained in the patch to oxygen can be further improved.

In this specification, the term "maintaining sufficient drug stability" means the inhibition of the fraction of Clonidine hydrochloride contained in the patch. For example, in the case of storage at 60 ° C for one week, the content of the clonidine in the patch remains at least 94% with respect to the content of the coronine at the time of preparation of the patch.

The patch of the present embodiment can be produced, for example, by the following method. First, an adhesive is mixed with a solvent and other components as required in a solvent to prepare a uniform base. Next, the adhesive agent solution is prepared by mixing the obtained base with clonidine or a pharmaceutically acceptable salt thereof, and a skin permeation inhibitor against clonidine or a pharmaceutically acceptable salt thereof. Thereafter, after the obtained adhesive solution was spread on the release-treated film (release liner), the solvent was dried and removed to form an adhesive layer. Finally, the support is crimped onto the adhesive layer to obtain a patch. Thus, the resulting patch is laminated in the order of release liner, adhesive layer, and support. Further, in order to suppress precipitation of crystals of clonidine or a pharmaceutically acceptable salt thereof, the obtained patch may be heated. Further, in the step of forming the adhesive layer, in place of the above adhesive solution, the adhesive, clonidine or a pharmaceutically acceptable salt thereof, and skin permeation against clonidine or a pharmaceutically acceptable salt thereof may be used. The inhibitor is heated and mixed, and is produced by a hot melt method.

[Examples] (Method of manufacturing patch)

Styrene-isoprene-styrene block copolymer (SIS), polyisobutylene (PIB), tackifying resin, flowing paraffin, additive A and toluene were mixed by a mixer according to the ratios shown in Table 1. , modulated into uniform Base 1~4. The numerical values in Table 1 refer to the mass (g). Next, according to the ratios shown in Table 2, any of the above-mentioned bases 1 to 4 was mixed with clonidine and an additive B as required, to obtain an adhesive solution. Extending the obtained adhesive solution on the release-treated film (release liner), drying the solvent to form an adhesive layer, laminating the support thereon, and laminating the support and the adhesive And get a patch. Thus, the obtained patch is laminated in the order of releasing the liner, the adhesive layer, and the support.

(drug stability test)

The drug stability of the patches of the examples, comparative examples and reference examples was evaluated in the following manner.

The prepared patch was punched out into a rectangular shape of 25 mm × 25 mm, and each of them was individually sealed in an aluminum packaging material, and then the packaging material was stored under the conditions (temperature, time) described in Tables 3 to 5. After the time described in Table 3, the patch was taken out from the package, tetrahydrofuran and toluene were added to the obtained patch, and vibration and ultrasonic treatment were performed to extract the drug (Clonidine) contained in the patch. High performance liquid chromatography after concentration of the obtained extract The absorbance was measured by an instrument (HPLC). From the obtained absorbance, the drug content of each patch was calculated based on the calibration curve. Further, the drug content in the patch before storage was calculated in the same manner as the initial drug content. The drug residual ratio in the patch in the drug stability test was calculated according to the following formula (1), and it was a value indicating the stability of the drug.

Drug residual rate = (drug content per patch after test) / (drug content per patch before test) × 100 (%)... (1)

(skin permeability test)

The skin permeability of the patches of the examples, the comparative examples and the reference examples was evaluated in the following manner.

The back skin of the hairless mice was peeled off, and the dermis side of the peeled skin was set to the receptor layer side, and was attached to a flow cell having a warm water circulation of 37 ° C in the outer peripheral portion. Next, a patch (adhering area: 3.14 cm ² ) was attached to the stratum corneum side of the skin, and a physiological saline solution to which a phosphate buffer (pH 7.4) was added as a receptor layer was used at a rate of 1.25 mL/hr per 4 After the sample solution was sampled for 24 hours in an hour, the flow rate was measured, and the concentration of clonidine in the receptor solution was measured by HPLC. The drug permeation rate per hour was calculated from the obtained measured value, and it was the skin permeation rate per unit area of the drug in a constant state.

Test Example 1: Relationship between Clonidine content and drug stability and skin permeability

According to the description of Table 2, the base 1 and the clonidine were mixed to prepare a patch of Reference Examples 1 to 4 in which the content of the Clonidine was different. The evaluation results of the drug stability and skin permeability of the patches of Reference Examples 1 to 4 are shown in Table 3. As shown in Table 3 As shown, it is apparent that as the content of clonidine in the patch decreases, the skin penetration rate and drug stability decrease.

Test Example 2: Changes in drug stability and skin permeability due to the addition of Additive B

The patches of Examples 1 to 13 and Comparative Examples 1 to 7 were prepared to evaluate drug stability and skin permeability. The evaluation results are shown in Tables 4 and 5. By adding Additive B (citric acid, oleic acid, stearic acid, isostearic acid, malic acid, lactic acid, EUDRAGIT (registered trademark) L100/polyethylene glycol and citric acid/polyethylene glycol), 94 is displayed. The residual rate of Cloning above %, the stability of the drug in the patch and the skin permeability were improved. In particular, in the patches of Examples 5 and 6, the effect of suppressing skin permeability was extremely remarkable. On the other hand, when the patch of Comparative Examples 1 to 7 was stored at 60 ° C for one week, the residual ratio of clonidine was 73 to 93%.

Claims (4)

A patch for local analgesia, comprising a support and a local analgesic patch for laminating an adhesive layer on the support, the adhesive layer comprising: clonidine or a pharmaceutically acceptable salt thereof; a skin permeation inhibitor against clonidine or a pharmaceutically acceptable salt thereof; and an adhesive, the skin permeation inhibitor is selected from the group consisting of citric acid, oleic acid, stearic acid, isostearic acid, malic acid, lactic acid, and At least one of a copolymer of a base acrylic acid and a methacrylate and a polyethylene glycol, the content of the clonidine or a pharmaceutically acceptable salt thereof is based on the total amount of the adhesive layer. 0.9% by mass or less. The patch of claim 1, wherein the content of the skin permeation inhibitor is 0.1 to 10% by mass based on the total amount of the adhesive layer. The patch of claim 1 or 2, wherein the maximum skin penetration rate of the clonidine or its pharmaceutically acceptable salt is 0.5 μg/cm ² /hr or less. The patch according to any one of claims 1 to 3, which is enclosed in a packaging material together with a desiccant or enclosed in a functional packaging material having a drying function.