JP6129632B2 - Patch - Google Patents

Description

  The present invention relates to a patch containing a basic drug and an acidic additive.

  As a patch, a configuration including a support and a pressure-sensitive adhesive layer formed on the surface of the support and blended with a drug is known. Here, taking into consideration the transdermal absorbability and the utilization rate of the drug, the drug is generally mixed in the pressure-sensitive adhesive layer in a dissolved state. Therefore, together with the drug, a component (dissolving agent) having a dissolving action on the drug is also blended in the pressure-sensitive adhesive layer. For example, when a basic drug is blended in the adhesive layer, an acidic additive is often used as a solubilizer. As the acidic additive, those using oleic acid, stearic acid or the like have been proposed (for example, Patent Documents 1 to 4).

Here, most of the drugs do not exhibit sufficient medicinal effects unless they are mixed in the pressure-sensitive adhesive layer at a high concentration except for a part. For this reason, as the amount of the drug is increased, the amount of the dissolving agent is usually increased. On the other hand, an increase in the blending amount of the solubilizer acts in the direction of lowering the physical properties of the pressure-sensitive adhesive layer. In particular, when an acidic additive is blended as a solubilizer, the physical properties of the pressure-sensitive adhesive layer are easily affected, and the feeling of use may be impaired due to the pressure-sensitive adhesive remaining on the skin. Furthermore, when an acidic additive is blended in a large amount, the pressure-sensitive adhesive gelates in the production stage, and there is a possibility that the patch cannot be produced. In addition, even when a cross-linking agent was blended in the pressure-sensitive adhesive layer and attempts were made to improve gel strength by cross-linking, the cross-linking reaction was slow due to the influence of acidic additives, and the physical properties of the pressure-sensitive adhesive layer were often not maintained. . Therefore, it is important to balance the blending amount of the dissolving agent and the physical properties of the preparation in the preparation design of the patch.
However, among the basic drugs blended in the pressure-sensitive adhesive layer, there is a drug without an excellent solubilizer such as imidafenacin. Therefore, when such a basic compound is blended in the pressure-sensitive adhesive layer, it is inevitably necessary to increase the addition amount of a solubilizer (acid additive). Depending on the pressure-sensitive adhesive described, it was impossible to suppress a decrease in physical properties of the pressure-sensitive adhesive layer.

  On the other hand, a patch capable of retaining a relatively large amount of liquid component in the pressure-sensitive adhesive layer without requiring a crosslinking agent has also been proposed (Patent Document 5). Patent Document 5 describes a patch that can be blended with a relatively large amount of a liquid component, using a non-crosslinked acrylic adhesive having a weight average molecular weight of 2 million or more as an adhesive. However, in the case of the method of Patent Document 5, in the normal production method, the viscosity of the pressure-sensitive adhesive component becomes too high in the stirring step of the constituent component of the pressure-sensitive adhesive layer containing the pressure-sensitive adhesive component, Could not be mixed well.

International Publication No. 00/61120 Pamphlet International Publication No. 01/007018 Pamphlet WO05 / 115355 pamphlet JP 2009-242303 A JP 2000-26285 A

  The present invention solves the above-described problems, and is excellent in maintaining a dissolved state of a basic drug in a pressure-sensitive adhesive layer and suppressing a decrease in physical properties of the pressure-sensitive adhesive layer even for a drug without an excellent dissolving agent. It aims at providing the technology which can realize an agent.

  As a result of intensive studies, the present inventor has found that a decrease in physical properties of the pressure-sensitive adhesive layer can be suppressed even when a basic drug is blended in the pressure-sensitive adhesive layer by setting the viscosity average molecular weight to 900,000 or more. The present inventor has also found that by using an acrylic pressure-sensitive adhesive having a carboxyl group as the pressure-sensitive adhesive, the solubility of the basic drug in the pressure-sensitive adhesive layer can be increased, and the present invention has been completed.

The gist of the present invention is as follows.
[1] a support;
Formed on the surface of the support, and having an adhesive layer containing an acrylic adhesive, a basic drug, and an acidic additive,
The patch wherein the acrylic pressure-sensitive adhesive has a carboxyl group and the viscosity average molecular weight is 900,000 or more and less than 2 million.
[2] The patch according to [1], wherein the basic drug is imidafenacin.
[3] The imidafenacin is blended in an amount of 9 to 30% by mass with respect to all components blended in the adhesive layer, and the acidic additive is blended in an amount of 10 to 40% by mass with respect to all components blended in the adhesive layer. The patch according to [2].
[4] The patch according to [2] or [3], wherein the blending amount of the acidic additive is 1/3 to 5 times (mass ratio) of the blending amount of imidafenacin.
[5] The patch according to any one of [2] to [4], wherein the acidic additive includes a hydroxycarboxylic acid having 3 to 6 carbon atoms, a higher fatty acid having 8 to 22 carbon atoms, or a mixture thereof. Agent.
[6] The patch according to [5], which contains lactic acid and at least one of oleic acid and capric acid as the acidic additive.

  According to the present invention, there is provided a technique capable of realizing a patch excellent in maintaining the dissolved state of a basic drug in a pressure-sensitive adhesive layer and suppressing the decrease in physical properties of the pressure-sensitive adhesive layer even for a drug without an excellent dissolving agent. can do.

It is a table | surface which shows the composition of the component contained in the adhesive layer of the patch of an Example, a comparative example, and a reference example. In addition, the evaluation results of solubility and skin patchability are also displayed. In addition, the meaning of the abbreviation contained in a table | surface is shown below. IMD: imidafenacin, OA: oleic acid, CA: capric acid, LA: lactic acid, IPM: isopropyl myristate

  Hereinafter, one embodiment of the present invention will be described in detail.

  The patch of the present embodiment has a support and a pressure-sensitive adhesive layer which is formed on the surface of the support and contains an acrylic pressure-sensitive adhesive, a basic drug and an acidic additive. Moreover, the patch of this embodiment contains the acrylic adhesive which has a carboxyl group as the acrylic adhesive contained in an adhesive layer and whose viscosity average molecular weight is 900,000 or more and less than 2 million.

  Here, in this specification, the patch refers to a preparation to be applied to the skin, and the drug is absorbed into the body through the skin. Patches include, for example, transdermal preparations in which a drug introduced into the body through the skin is absorbed into capillaries and delivered to the site of action according to blood flow.

Furthermore, in this specification, in addition to the basic drug which is an active ingredient, the ingredients blended in the pressure-sensitive adhesive layer are collectively referred to as additives.
Furthermore, in this specification, the ratio of each component contained in the pressure-sensitive adhesive layer to the total components of the pressure-sensitive adhesive layer refers to an acrylic pressure-sensitive adhesive, a basic drug, an acidic additive, and other components blended as necessary. This means that it is based on the total mass of the pressure-sensitive adhesive layer made of additives. However, the total mass of the reference pressure-sensitive adhesive layer does not include an organic solvent that may be used during production.

In the present embodiment, an acrylic pressure-sensitive adhesive having a carboxyl group and having a viscosity average molecular weight of 900,000 or more and less than 2 million is used as the pressure-sensitive adhesive constituting the pressure-sensitive adhesive layer. The acrylic pressure-sensitive adhesive according to this embodiment preferably has a viscosity average molecular weight of 1.4 million or more and less than 2 million.
When the viscosity average molecular weight is less than 900,000, there is no cohesive force, and the deterioration of the physical properties of the pressure-sensitive adhesive layer cannot be suppressed. Specifically, bleeding (bleeding) from the adhesive layer of volatile acidic additives such as lactic acid is likely to occur during product storage, and adhesive residue is likely to occur when the skin is applied. When the viscosity average molecular weight is 2 million or more, the viscosity of the base component becomes excessively high in the production process, particularly in the kneading process, which is not preferable because of the influence of decreasing the stirring efficiency. Furthermore, when the viscosity average molecular weight is 2 million or more, there is a concern about the effect on the drug efficacy such as a decrease in the transdermal absorbability of the drug.
Moreover, the patch of this embodiment can improve the solubility of the basic drug in an adhesive layer by having a carboxyl group.

The acrylic pressure-sensitive adhesive according to the present embodiment includes, for example, an acrylic ester homopolymer formed from one kind of acrylic ester, a copolymer formed from two or more kinds of acrylic ester, and an acrylic ester. It can be obtained from a copolymer with another functional monomer or a mixture thereof by containing a carboxy group in the molecule and having a viscosity average molecular weight of 900,000 to less than 2 million. it can.
The acrylic pressure-sensitive adhesive containing a carboxyl group is not particularly limited and can be appropriately selected by those skilled in the art. From the viewpoint of adhesive physical properties, an acrylic acid / acrylic acid octyl ester copolymer is preferable.
The viscosity average molecular weight can be adjusted by a usual method such as adjusting the reaction time or reaction temperature at the time of polymer formation.
Moreover, the value of the viscosity average molecular weight in this specification is a value which can be obtained in terms of polystyrene, for example. Specifically, the viscosity average molecular weight is a standard curve that defines the relationship between the limit viscosity and the viscosity average molecular weight for polystyrene from the intrinsic viscosity of an acrylic adhesive measured in ethyl acetate using an Ubbelohde viscometer. Can be obtained based on

  Although the ratio with respect to all the components mix | blended with the adhesive layer of an acrylic adhesive is not specifically limited, For example, it can be 50-90 mass% (preferably 50-80 mass%).

In the present embodiment, the adhesive layer contains a basic drug which is a compound having a basic group in its molecule and acts as an active ingredient of the patch. Examples of such basic drugs include butorphanol tartrate, which acts as an anti-inflammatory analgesic agent, buprenorphine hydrochloride, valdecoxib, celecoxib, acetaminophen, flurazepam hydrochloride which acts as a hypnotic sedative, rilmazafone hydrochloride, methamphenamine hydrochloride which acts as a stimulant / stimulant , Methylphenidate hydrochloride, chlorpromazine hydrochloride acting as a psychiatric agent, imipramine hydrochloride, fluvoxamine maleate, sertraline hydrochloride, oxybutynin hydrochloride acting as a urinary agent, imidafenacin, tizanidine hydrochloride acting as a skeletal muscle relaxant, epilysone hydrochloride , Pridinol mesylate, carpronium chloride acting as an agent for autonomic nerves, neostigmine bromide, pergonide mesylate acting as an anti-parkinsonian, bromocyl mesylate Putin, trihexyphenidyl hydrochloride, amantadine hydrochloride, ropinirole, clemastine fumarate acting as an antihistamine, diphenhydramine tannate, tulobuterol hydrochloride acting as a bronchodilator, procaterol hydrochloride, clenbuterol hydrochloride, isoprenaline hydrochloride acting as a cardiotonic agent, dopamine hydrochloride, Diltiazem hydrochloride acting as a coronary vasodilator, verapamil hydrochloride, nicamethate citrate acting as a peripheral vasodilator, trazoline hydrochloride, flunarizine hydrochloride acting as a circulatory organ agent, nicardipine hydrochloride, benidipine hydrochloride, efonidipine hydrochloride, arrhythmic agent Propranolol hydrochloride, alprenolol hydrochloride, ketotifen fumarate acting as an antiallergic agent, azelastine hydrochloride, narcotic analgesic Morphine hydrochloride to use, fentanyl, oxycodone hydrochloride acts as a serotonin receptor antagonist, granisetron, palonosetron hydrochloride, include pharmaceutically acceptable acid addition salts of ramosetron hydrochloride and the drug.
Although the ratio with respect to all the components mix | blended with the adhesive layer of these basic drugs is not specifically limited, For example, it can be 9-30 mass% (preferably 9-20 mass%).

In particular, the patch of the present embodiment has low solubility in various solubilizers and is effective for basic drugs that do not dissolve in large amounts in acidic additives. As such drugs, for example, imidafenacin (4 -(2-methyl-1-imidazolyl) -2,2-diphenylbutyramide) and pharmacologically acceptable acid addition salts thereof. Examples of acid addition salts of imidafenacin include inorganic acid salts such as hydrochloride, sulfate, or hydrobromide, or maleate, fumarate, acetate, oxalate, tartrate, or benzenesulfone. Organic acid salts such as acids can be mentioned.
In the following description, for ease of understanding, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyramide which is free and pharmaceutically acceptable acid addition salt thereof are used. Are collectively referred to as imidafenacin.

In the present embodiment, an acidic additive that is a compound having an acidic group in the molecule is blended in the pressure-sensitive adhesive layer together with the basic drug so that the basic drug is in a dissolved state.
Examples of the acidic additive blended in the present embodiment include carboxylic acids having 2 to 22 carbon atoms. Specifically, carboxylic acids having 2 to 7 carbon atoms such as acetic acid, propionic acid, butyric acid, pentanoic acid and heptanoic acid, hydroxycarboxylic acids having 3 to 6 carbon atoms such as glyceric acid, lactic acid, tartaric acid, and citric acid, and caprin Examples thereof include fatty acids having 8 to 22 carbon atoms such as acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, oleic acid, and undecylenic acid.

  The compounding amount of the acidic additive in the pressure-sensitive adhesive layer depends on the kind of drug to be blended or the drug content, but the basic drug is imidafenacin, and 9-30% by mass of the imidafenacin is blended in the pressure-sensitive adhesive layer. In the case, the ratio of the acidic additive to the total components blended in the pressure-sensitive adhesive layer can be, for example, 10 to 40% by mass (preferably 10 to 30% by mass).

  Further, when the basic drug is imidafenacin, the compounding ratio of the acidic additive and imidafenacin is preferably 1/3 to 5 times (mass ratio) the compounding amount of the acidic additive of the imidafenacin. Is 1 to 3 times (mass ratio). By making the compounding quantity of an acidic additive into 1/3 times or more quantity, the solubility of imidafenacin can further be improved. On the other hand, when the compounding amount of the acidic additive exceeds 5 times the amount, the effect of suppressing the decrease in physical properties of the pressure-sensitive adhesive layer may be smaller than in the range.

  Only one kind of acidic additive may be blended in the pressure-sensitive adhesive layer, or two or more acidic additives may be blended in the pressure-sensitive adhesive layer. When two or more kinds of acidic additives are combined, the solubility of these acidic additives with respect to the basic drug to be blended, or the phase of these acidic additives and other ingredients mixed in the pressure-sensitive adhesive layer In consideration of solubility or the like, a combination of a plurality of acidic additives is also preferably performed.

For example, when imidafenacin is selected as the basic drug, the acidic additive is preferably a hydroxycarboxylic acid having 3 to 5 carbon atoms, a fatty acid having 8 to 22 carbon atoms, or a mixture thereof, and the acidic additive having 3 to 3 carbon atoms. More preferably, 5 hydroxycarboxylic acids and C8-22 fatty acids are included.
Hydroxycarboxylic acids having 3 to 6 carbon atoms, particularly lactic acid, have the property that imidafenacin has very high solubility, but is not highly compatible with acrylic pressure-sensitive adhesives compared to other acidic additives. . On the other hand, higher fatty acids having 8 to 22 carbon atoms have relatively good compatibility with acrylic pressure-sensitive adhesives and can be blended in preparations in a relatively larger amount than lactic acid and the like, but lactic acid has a higher effect in terms of solubility of imidafenacin. Can't get.

Therefore, when the drug is imidafenacin, compatibility with an acrylic pressure-sensitive adhesive is obtained by combining a hydroxycarboxylic acid having 3 to 6 carbon atoms and a higher fatty acid having 8 to 22 carbon atoms in an appropriate mixing ratio. Thus, a more balanced patch of drug solubility in the base can be obtained.
In particular, the patch is prepared by adjusting the blending ratio of the hydroxycarboxylic acid (A) having 3 to 6 carbon atoms and the higher fatty acid (B) having 8 to 22 carbon atoms to (A) / (B) in the range of 1 to 3. An excellent effect can be obtained when it is blended.
A particularly preferred combination of a hydroxycarboxylic acid having 3 to 6 carbon atoms and a higher fatty acid having 8 to 22 carbon atoms is at least one of lactic acid, oleic acid and capric acid.

  Furthermore, in the patch of the present embodiment, an ester of a fatty acid having 6 to 20 carbon atoms may be contained in the adhesive layer. By containing an ester of a fatty acid having 6 to 20 carbon atoms in the pressure-sensitive adhesive layer, the physical properties of the pressure-sensitive adhesive layer can be further increased, and the transdermal absorbability of the basic drug to be blended can be further increased. Examples of the fatty acid ester having 6 to 20 carbon atoms include isopropyl myristate, isopropyl palmitate, and oleyl oleate.

  Although the ratio with respect to all the components mix | blended with the adhesive layer of the ester of fatty acid whose carbon number is 6-20 can be suitably selected according to the quantity etc. of the acidic additive mix | blended in an adhesive layer, it is 2-50, for example. It can be made into the mass%, Preferably it is 5-40 mass%.

  In the present embodiment, the pressure-sensitive adhesive layer may contain other components as additives. For example, a solubilizer, a softener, an absorption enhancer, a skin irritation relieving agent, an antioxidant, and the like can be mentioned.

  Soluble agents include higher fatty acid esters (such as isopropyl palmitate or oleyl oleate), higher alcohols (such as lauryl alcohol, isostearyl alcohol, octyldodecanol, or oleyl alcohol), fatty acids (isostearic acid, lauric acid, adipic acid) , Sebacic acid, or myristic acid), dibasic diesters (diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, etc.), triacetin, benzyl alcohol, cetyl lactate, octyl dodecyl lactate, liquid paraffin, crotamiton or these The mixture of 2 or more types can be mentioned.

  Softeners include paraffin oils such as liquid paraffin, animal oils such as squalane and squalene, vegetable oils such as almond oil, olive oil, camellia oil, castor oil, tall oil and peanut oil, silicone oil, polybutene, medium chain fatty acid triglyceride, mono Mention may be made of glyceryl stearate, isopropyl myristate, diisopropyl adipate, dipropylene glycol or mixtures of two or more thereof.

  Absorption accelerators include crotamiton, triacetin, fatty acids or aliphatic alcohols (lauric acid, myristic acid, oleyl alcohol, isopropanol, lauryl alcohol, dipropylene glycol, propylene glycol, etc.), fatty acid esters (glyceryl monolaurate, glyceryl) Monooleate, cetyl lactate, octyl dodecyl lactate, glycerol monolaurate, glycerol monooleate, propylene glycol monolaurate, propylene glycol monooleate, sorbitan monolaurate, or sorbitan monooleate), or two or more of these Mention may be made of mixtures.

  Examples of skin irritation mitigating agents include glycerin, allantoin, antihistamines (such as diphenhydramine), anti-inflammatory agents (such as glycyrrhetinic acid), steroids, and mixtures of two or more thereof.

Examples of the antioxidant include dibutylhydroxytoluene (BHT), DL-α-tocopherol, ascorbyl palmitate, or a mixture of two or more thereof.
Furthermore, other components may also be included as additives. Specifically, for example, petroleum resin (Quinton, Alcon, etc.); surfactant (polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene sorbite fatty acid ester (polysorbate 20, polysorbate 60, Polysorbate 80 or polyoxyethylene sorbitan monolaurate), polyoxyethylene fatty acid ester (polyoxyl 40 stearate), sorbitan fatty acid ester (sorbitan monooleate, sorbitan trioleate, sorbitan monolaurate, or sorbitan sesquioleate) Etc.), self-emulsifying type glyceryl monostearate, glyceryl monostearate, sorbitan monostearate, sucrose fatty acid ester, macrogol 400, lauromacro Sodium phosphate, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl ether, polyoxyethylene polyoxypropylene glycol (polyoxyethylene (120) polyoxy Propylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, or polyoxyethylene (20) polyoxypropylene (20) glycol), polyoxyethylene polyoxypropylene decyl tetradecyl ether, alkylallyl Polyether alcohol, polyoxyethylene cetyl ether, polyoxyethylene oleylamine, polyoxyethylene sorbit beeswax, lau Acid diethanolamide, stearyl alcohol, dibasic acid diesters (diethyl sebacate, etc.), squalane, cetanol, or cetomacrogol 1000, etc .; flavorings (mint oil, orange oil, chamomile oil, spearmint oil, clove oil, Turpentine oil, pine oil, cedar oil, bergamot oil, eucalyptus oil, lavender oil, rose oil, roman chamomile oil, peruvian balsam, d-camphor, dl-camphor, d-borneol, dl-borneol, dl-menthol, l -Menthol, geraniol, methyl salicylate, cinnamaldehyde, or piperonal), or a mixture of two or more thereof.

The patch of this embodiment can be produced by forming an acrylic pressure-sensitive adhesive layer on a support. The pressure-sensitive adhesive layer is preferably covered with a release liner for the purpose of protecting the pressure-sensitive adhesive layer until it is used. The method for producing the patch of the present embodiment is not particularly limited and can be appropriately selected by those skilled in the art.
For example, the patch of the present embodiment can be produced by a method generally called a hot melt method or a method called a solvent method.
When based on the hot melt method, for example, a mixture (base component) of a basic drug, an acidic additive, and an acrylic pressure-sensitive adhesive is melted by heat and applied to a release film or a support to form a pressure-sensitive adhesive layer. Form. Subsequently, a patch is obtained by bonding the formed pressure-sensitive adhesive layer to a support or a release film.
Further, when based on the solvent method, for example, a mixture of a basic drug, an acidic additive, and an acrylic adhesive is dissolved in an organic solvent such as methanol, ethanol, ethyl acetate, chloroform, or hexane, and a release film Or it extends and coats on a support. Next, the solvent is removed by drying to form an adhesive layer. Subsequently, a patch is obtained by bonding the formed pressure-sensitive adhesive layer to a support or a release film. In addition, the magnitude | size and thickness of an adhesive layer are not specifically limited, Those skilled in the art can set suitably.

  The material for the support of the patch of the present embodiment is not particularly limited, and can be appropriately set by those skilled in the art. For example, a stretchable or non-stretchable support can be used. For example, it can be selected from cloth, non-woven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate (PET), aluminum sheet, or a composite material thereof.

  Moreover, it does not specifically limit about the raw material of a peeling film, Those skilled in the art can select suitably. Specific examples include a silicon film coated polyethylene film, PET film, or polypropylene film.

  The administration method of the basic drug using the patch of the present embodiment is appropriately set according to the disease to be prevented or treated and the condition of the patient to be administered. Also, the affixing site is not particularly limited. In this embodiment, the amount of the basic drug contained in the pressure-sensitive adhesive layer is not particularly limited, and the disease to be prevented or treated, the size of the pressure-sensitive adhesive layer, the administration time, or the target imidafenacin It is set according to the blood concentration of the blood. For example, when the basic drug is imidafenacin, about 0.1 mg to about 30 mg can be blended in the preparation or in a single dose.

  As described above, in the patch of the present embodiment, the pressure-sensitive adhesive layer has a carboxyl group and has an acrylic pressure-sensitive adhesive having a viscosity average molecular weight of 900,000 to less than 2,000,000, whereby the pressure-sensitive adhesive itself is basic. In addition to having high drug solubility, a decrease in physical properties of the pressure-sensitive adhesive layer can be suppressed even when a higher proportion of acidic additives is blended than in the past. Therefore, according to this embodiment, a patch excellent in maintaining the dissolved state of the basic drug in the pressure-sensitive adhesive layer and suppressing the deterioration of the physical properties of the pressure-sensitive adhesive layer even for a drug without an excellent dissolving agent such as imidafenacin. Can be provided.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, the patch of the present invention is not limited to the form described in the examples. The pressure-sensitive adhesives used in Examples etc. are as shown in Table 1 below.

[Preparation of acrylic adhesives A to D]
95% of 2-octylhexyl acrylate and 5% of acrylic acid were polymerized in ethyl acetate (molar ratio) to prepare solutions of acrylic pressure-sensitive adhesives A to D (each with a solid content of 20% by mass). The temperature and reaction time in the polymerization reaction were adjusted, and the viscosity average molecular weight of the resulting pressure-sensitive adhesive was adjusted. About the obtained acrylic adhesive (polymer), the viscosity average molecular weight was measured based on the following method.

[Measurement of viscosity average molecular weight]
1) About several types of polystyrene with known viscosity average molecular weight, a solution was prepared using ethyl acetate with a solid content of 20% by mass. Each intrinsic viscosity in ethyl acetate was measured using an Ubbelohde viscometer, and a graph showing the relationship between the viscosity average molecular weight and the intrinsic viscosity was prepared.
2) For each of the acrylic adhesives A to D, the intrinsic viscosity in ethyl acetate was measured using an Ubbelohde viscometer.
3) The measured intrinsic viscosity of the acrylic pressure-sensitive adhesives A to D was applied to the graph, and the viscosity average molecular weight of the acrylic pressure-sensitive adhesives A to D was determined.

[Example 1]
9 g of imidafenacin (IMD), 3 g of lactic acid (LA), 7 g of oleic acid (OA), and 0.9 g of capric acid (CA) were dissolved in a mixed solvent of 40 g of methanol and 100 g of ethyl acetate. To this solution, 20.1 g of isopropyl myristate (IPM) was added and mixed well to obtain a main agent solution. Thereafter, the main agent solution was added to 300 g of acrylic pressure-sensitive adhesive B solution (60 g in weight of pressure-sensitive adhesive) and mixed well to prepare a pressure-sensitive adhesive solution. Apply the adhesive solution to a 75um PET film using a comma doctor so that the weight of the paste after drying is about 80g / m ² and dry for 10 minutes at a temperature of about 80 ° C. A layer was formed. The formed pressure-sensitive adhesive layer and a support (15-um thick PET film) were bonded together to obtain a patch of Example 1.

[Examples 2 and 8, Comparative Example 1]
The patches of Example 2, Example 8, and Comparative Example 1 were prepared in the same manner as in Example 1, except that acrylic adhesives having different viscosity molecular weights were used. The amounts of the components contained in the pressure-sensitive adhesive layer in Examples 2 and 8 and Comparative Example 1 are shown in FIG.

[Examples 3 to 7]
Except having changed the ratio of the component contained in an adhesive layer, the patch of Examples 3-7 was prepared by the method similar to Example 1. FIG. The amounts of components contained in the pressure-sensitive adhesive layer in Examples 3 to 7 are shown in FIG.

[Comparative Examples 2-3]
Except having changed the acrylic adhesive, the patch of Comparative Examples 2-3 was prepared by the method similar to Example 1. FIG. The amounts of components contained in the pressure-sensitive adhesive layer in Comparative Examples 2-3 are shown in FIG.

[Reference Examples 1-3]
Patches of Reference Examples 1 to 3 were prepared in the same manner as in Example 1 except that only imidafenacin and an adhesive were used. The amount of the component contained in the pressure-sensitive adhesive layer in Reference Examples 1 to 3 is shown in FIG.

[Study of solubility of drugs in adhesive base]
In Examples 1 to 8, Comparative Example 1 and Reference Examples 1 to 3, the drug solubility in the adhesive base was examined visually and by the CS method. Test methods and evaluation methods of test results are shown below. The test results are shown in FIG. In FIG. 1, the solubility was evaluated based on the following criteria.
Crystal growth observed visually or measured by CS method: ×
No crystal growth observed: ○

-Test method by CS method Only the adhesive layer part was manufactured with each composition of each Example, the comparative example 1, and the reference examples 1-3, and was affixed on the slide glass. Imidafenacin drug substance (100 mg) was directly sprayed on this adhesive layer, and the growth of crystals on the adhesive after standing for 5 days was observed with an electron microscope (model: KEYENCE VHX-600, magnification: 400 times).
-Evaluation When crystal growth is observed after standing for 5 days, imidafenacin is present in a supersaturated state in the pressure-sensitive adhesive layer, and it can be presumed that there is a concern about crystal precipitation in the future. On the other hand, if dissolution of the applied imidafenacin drug substance in the adhesive layer is observed or if almost no crystal growth is observed, it can be assumed that imidafenacin is present in a dissolved state in the adhesive.

[Dermal skin adhesion test]
The patches of Examples 1 to 8 and Comparative Examples 1 to 3 were applied to the volunteer's upper arm side under informed consent. After 24 hours, the patches were peeled off, and the adhesive remaining on the skin of the adhesive layer was determined. did. Judgment criteria are as follows.
○: Almost no adhesive remains on the skin surface during peeling.
(Triangle | delta): At the time of peeling, an adhesive remains on a skin surface slightly, or a liquid component adheres.
X: The adhesive remains on the skin surface at the time of peeling.
[Discussion]
As a result of examining the solubility of imidafenacin in an adhesive using the patches of Reference Examples 1 to 3, Reference Example 1 in which an adhesive layer was constructed using an acrylic adhesive having a carboxyl group was compared to imidafenacin. Excellent solubility was exhibited. On the other hand, in the patches of Reference Example 2 and Reference Example 3 in which the pressure-sensitive adhesive layer was formed using an acrylic pressure-sensitive adhesive having no carboxyl group, the solubility of imidafenacin in the pressure-sensitive adhesive was poor.
In addition, the adhesive patch of each example in which the adhesive layer was formed using an acrylic adhesive containing a carboxyl group and having a viscosity average molecular weight of 900,000 or more was the same as in Reference Example 1, the adhesive layer of the drug The solubility in was excellent. In addition, the patch of each example was excellent in the adhesiveness to the skin. On the other hand, the patches of Comparative Examples 1 to 3 in which the viscosity average molecular weight of the pressure-sensitive adhesive was less than 900,000 were inferior to the skin in comparison with the patches of Examples.
From the above, it can be judged that the patches of Examples have both high solubility of imidafenacin in the adhesive and excellent skin patchability.

  According to the present invention, it is possible to realize a patch excellent in maintaining a dissolved state of a basic drug in a pressure-sensitive adhesive layer and suppressing deterioration in physical properties of a pressure-sensitive adhesive layer even for a drug without an excellent dissolving agent. is there.

Claims (5)

A support;
Formed on the surface of the support, and having an adhesive layer containing an acrylic adhesive, imidafenacin, and a carboxylic acid having 2 to 22 carbon atoms ,
The patch wherein the acrylic pressure-sensitive adhesive has a carboxyl group and the viscosity average molecular weight is 900,000 or more and less than 2 million. The imidafenacin is blended in an amount of 9 to 30% by mass with respect to all the components blended in the pressure-sensitive adhesive layer, and the carboxylic acid having 2 to 22 carbon atoms is blended in the pressure-sensitive adhesive layer in a proportion of 10 to 10%. The patch according to claim 1 , wherein 40% by mass is blended. The patch according to claim 1 or 2 , wherein the compounding amount of the carboxylic acid having 2 to 22 carbon atoms is 1/3 to 5 times (mass ratio) of the compounding amount of imidafenacin. As the carboxylic acid wherein the carbon number of 2 to 22, hydroxy carboxylic acids having 3 to 6 carbon atoms, fatty acids having 8 to 22 carbon atoms, or any one of claims 1 to 3, mixtures thereof, The patch according to the description. The patch according to claim 4 , comprising lactic acid and at least one of oleic acid and capric acid as the carboxylic acid having 2 to 22 carbon atoms .

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