JP2013116861A - Aqueous adhesive patch having local anesthetic action - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an aqueous adhesive patch which does not ooze out (oil flotation) a medicine on a surface of the patch, gives a good feeling of use, and has adhesiveness on a plaster itself comprising a eutectic mixture of a basic local anesthetic.SOLUTION: The aqueous adhesive patch is characterized by comprising (A) a eutectic mixture oily at room temperature and comprising lidocaine and one or more other basic local anesthetics, (B) an acrylic acid-based polymer having a free carboxylic acid, (C) a cross-linking agent, (D) an emulsifier, and (E) water, wherein the ratio (free carboxylic acid/lidocaine) of the molar quantity of the free carboxylic acid contained in the (B) to the molar quantity of the lidocaine in (A) the eutectic mixture oily at room temperature is 0.4-3.0.

Description

  The present invention relates to an aqueous patch containing a basic local anesthetic.

  Basic local anesthetics are mainly used for surface anesthesia, and various external preparations for application to the skin or mucous membrane have been studied, and ointments, solutions and patches have been proposed. As one of these preparations, there is an external preparation using a eutectic mixture having a eutectic point below room temperature composed of a combination of two or more basic local anesthetics (Patent Documents 1 and 2). When administered as an eutectic mixture, it is known to show superior local anesthetic action compared to when administered as a single agent (Non-patent Documents 1 and 2), lidocaine and procaine, lidocaine and prilocaine, and A combination of lidocaine and tetracaine basic local anesthetics has been used. For example, creams and patches made into oil-in-water emulsions using the property that lidocaine-prilocaine eutectic mixture becomes oily at room temperature are known.

  However, the cream does not have a dramatic effect by simple application, and in order to obtain a sufficient local anesthetic action, first, the cream is spread so as to be thickly swelled on the skin area, and then the sealing closure method ( ODT) is indispensable, and its operation is very complicated not only for patients but also for medical staff. There is also a report (Patent Document 3) that solves the above problems by changing the dosage form from a cream to a tape so that it can be used more easily, but it is said that the tape has a problem in immediate effect. It has been broken. Furthermore, the tape agent has a strong adhesive force and is difficult to peel off. However, the high adhesive force causes physical irritation such as exfoliation during peeling and causes adverse events such as redness. Reference 3).

  On the other hand, the patch is a preparation characterized by having a non-adhesive plaster containing a drug in the center and an adhesive surface around the plaster. The plaster part of this preparation has insufficient adhesiveness, and in particular, there is a case where sufficient medicinal effects cannot be obtained in a part with unevenness. In addition, since the adhesive surface around the plaster is a tape base using a hydrophobic base, the adhesive layer is strongly adhesive and may cause the stratum corneum to be peeled off.

  By the way, the aqueous patch which contains water | moisture content in a formulation and has adhesiveness to plaster itself is known (patent documents 4-8). Each of these aqueous patches contains lidocaine alone as an active ingredient, and an aqueous patch having adhesiveness to the plaster itself using a eutectic mixture of basic local anesthetics as an active ingredient is not yet known. The existing topical anesthetic-containing external preparations have various problems such as low skin permeability and difficulty in obtaining sufficient medicinal effects, such as venous needle puncture, dura mater or lumbar spine or joint puncture However, it has not yet achieved a satisfactory effect on local anesthesia before minor skin surgery, pain reduction at intravenous injection in children, and the like. From the medical field, there is a need for a new topical anesthetic patch that can be used by elderly people and children with weak skin, replacing the existing topical preparation with sufficient local anesthetic action and safety. ing.

11-510075 JP 2003-512401 A JP2010-222231 JP 04-305523 JP 10-316590 A International Publication No. 01/047559 Pamphlet JP-A-2005-179319 JP2011-088890

S-CaineTM Patch, FDA Application No. (NDA) 021623, StudySC-41-03 Acta Dermatovener, 59, 556-559 (1979) Pharma Medica, 25 (2), 113-117 (2007)

  In order to obtain a topical anesthetic preparation with sufficient local anesthetic action and safety, it is an aqueous patch having adhesiveness to the paste itself, and the active ingredient to be added is basic local anesthesia. Two points were considered to be important factors: eutectic mixture of drugs. However, unlike the case of using a solid active ingredient at room temperature, in the preparation of an aqueous patch with an eutectic mixture of a basic local anesthetic that becomes oil at room temperature, in many common formulations, an oily Oil floating from the paste of the eutectic mixture to the surface of the preparation (seepage of the eutectic mixture from the paste to the surface of the preparation) occurred, making formulation difficult, and further contrivance was necessary. From such a background, the present invention provides an aqueous patch having adhesiveness to a plaster having a good feeling of use, which has solved the problems of existing topical anesthetic preparations and has overcome the above-mentioned preparation problems. The purpose is to provide.

  As a result of diligent research, the present inventors have a sufficient local anesthetic action, suppress oil floating of the eutectic mixture on the surface of the preparation, and in order to obtain an aqueous patch having adhesiveness to the plaster itself, The inventors found that it is important to set the ratio of the molar amount of free carboxylic acid and the molar amount of lidocaine in the acrylic acid polymer in the aqueous plaster to be used within a specific range, and completed the present invention. It was.

The main configuration of the present invention is as follows.
[1] (A) Room temperature oily eutectic mixture consisting of lidocaine and other basic local anesthetics, (B) Acrylic acid polymer having free carboxylic acid, (C) Crosslinker, (D) Emulsifier, And (E) the ratio of the molar amount of the free carboxylic acid contained in (B) above and (A) the molar amount of lidocaine in the eutectic mixture oily at room temperature (free carboxylic acid / lidocaine) However, 0.4 to 3.0 is an aqueous adhesive plaster.
[2] 3-20% by mass of lidocaine and other basic local anesthetics constituting the eutectic mixture of (A) with respect to the entire plaster, and 0.1-20% by mass of (B) acrylic acid polymer. %, The said (C) crosslinking agent 0.01-10 mass%, the said (D) emulsifier 0.1-20 mass%, and the said (E) water-containing 10-90 mass% water-based patch as described in [1] Plaster for medicines.

[3] The aqueous plaster according to [1] or [2], further comprising (F) a hydrophilic polymer.
[4] The aqueous plaster according to [3], containing 0.1 to 30% by mass of the hydrophilic polymer (F) with respect to the entire plaster.
[5] The aqueous patch according to any one of [1] to [4], wherein the other basic local anesthetic (A) is one selected from the group consisting of procaine, prilocaine and tetracaine. Plaster for medicines.

[6] In any one of [1] to [5], the mixing ratio of the mass of lidocaine and other basic local anesthetics constituting the eutectic mixture of (A) is 2: 3 to 3: 2. The paste for aqueous patches as described.
[7] The (B) acrylic acid polymer is a partially neutralized polyacrylic acid, polyacrylic acid, sodium polyacrylate, methacrylic acid / n-butyl acrylate copolymer, acrylic acid / octyl acrylate ester The aqueous plaster according to any one of [1] to [6], which is one or more selected from copolymers.

[8] An aqueous patch obtained by spreading a support and the aqueous patch paste according to any one of [1] to [7] on the support.
[9] The aqueous patch according to [8], wherein the eutectic mixture oozes from the plaster layer to the surface thereof in an amount of 0.001 to 0.9 mg / 15 cm ² and the plaster layer has adhesiveness.

 [10] At least (A) a room temperature oily eutectic mixture consisting of lidocaine and other basic local anesthetics, (B) an acrylic acid-based polymer having a free carboxylic acid, (C) a crosslinking agent, (D) An emulsifier and (E) a method for producing a plaster for an aqueous patch by mixing water, wherein the molar amount of the free carboxylic acid derived from (B) contained in the plaster and the above (A) A method for producing a plaster for an aqueous patch, wherein the molar ratio (free carboxylic acid / lidocaine) of lidocaine in the eutectic mixture is adjusted to 0.4 to 3.0.

[11] Lidocaine and other basic local anesthetics constituting the eutectic mixture of (A) are each 3 to 20% by mass with respect to the whole base, and (B) acrylic acid polymer is 0.1 to 20%. The mass (%) is adjusted to 0.01 to 10 mass%, the (D) emulsifier is adjusted to 0.1 to 20 mass%, and the water (E) is adjusted to 10 to 90 mass%. [10] The manufacturing method of the paste for aqueous patchs as described in any one of.
[12] The method for producing a plaster for an aqueous patch according to [10] or [11], wherein (F) a hydrophilic polymer is further mixed.

[13] The method for producing an aqueous plaster according to [12], wherein the hydrophilic polymer (F) is adjusted to 0.1 to 30% by mass with respect to the entire plaster.
[14] The aqueous patch according to any one of [10] to [13], wherein the other basic local anesthetic (A) is one selected from the group consisting of procaine, prilocaine and tetracaine. A method for producing an adhesive paste.

[15] Any one of [10] to [14], wherein the mixing ratio of the mass of lidocaine constituting the eutectic mixture of (A) to other basic local anesthetics is adjusted to 2: 3 to 3: 2. The manufacturing method of the paste for aqueous patchs as described in any one of.
[16] The (B) acrylic acid polymer is a partially neutralized polyacrylic acid, polyacrylic acid, sodium polyacrylate, methacrylic acid / n-butyl acrylate copolymer, acrylic acid / octyl acrylate ester The method for producing a plaster for an aqueous patch according to any one of [10] to [15], which is one or more selected from copolymers.

[17] A method for producing an aqueous patch, wherein the aqueous patch paste produced by the method for producing an aqueous patch paste according to any one of [10] to [16] is spread on a support.
[18] The method according to [17] for producing an aqueous patch in which the eutectic mixture exudes from the plaster layer to the surface thereof is 0.001 to 0.9 mg / 15 cm ² and the plaster layer has adhesiveness. A method for producing an aqueous patch.

  According to the present invention, there are provided an aqueous patch having a sufficient local anesthetic action and safety, the paste layer having adhesiveness, and a good feeling in use, and an aqueous patch for the same. Can do.

Hereinafter, the aqueous patch having local anesthetic action of the present invention will be described.
As the aqueous patch of the present invention, patches and cataplasms published in the Japanese Pharmacopoeia are applicable. The aqueous patch of the present invention is produced by spreading the aqueous patch paste of the present invention on a suitable support to form a paste layer. Therefore, for the content of the following components, the content ratio (mass%) relative to the entire aqueous plaster is often described, and this is abbreviated as the content ratio (mass%) relative to the entire plaster. The content ratio (mass%) with respect to the whole plaster layer and the content ratio (mass%) with respect to the whole preparation are meant.

  The eutectic mixture refers to a mixture that melts at a temperature lower than a normal melting point of each component by lowering the freezing point by mixing two or more components. The room temperature oily eutectic mixture comprising (A) lidocaine and other basic local anesthetics used in the present invention becomes oily (liquid) at room temperature (about 1 to 30 ° C.). Examples of combinations of basic local anesthetics include a combination of lidocaine and procaine, a combination of lidocaine and prilocaine, a combination of lidocaine and tetracaine, and the like. Among these, a combination of lidocaine and prilocaine and a combination of lidocaine and tetracaine are preferable, and a combination of lidocaine and tetracaine is more preferable. However, two or more kinds of other basic local anesthetics combined with lidocaine may be used. All of these eutectic mixtures melt at a temperature below the melting point of the pure material due to freezing point depression and are oily components at room temperature.

The blending mass ratio of lidocaine to procaine is preferably 51:49 to 58:42 (Pharmacology, 50 (4), 354-359 (1990)). The blending mass ratio of lidocaine to prilocaine is preferably 40:60 to 60:40, more preferably 1: 1 (J. Pharm. Sci., 73 (4),
481-484 (1984)). The blending mass ratio of lidocaine and tetracaine is preferably 45:55 to 55:45, more preferably 1: 1 (Pharmacology, 50 (4), 354-359
(1990)). Thus, the compounding ratio of lidocaine to other basic local anesthetics is preferably 2: 3 to 3: 2, more preferably about 1: 1.

The content of lidocaine and other basic local anesthetics is preferably 3 to 20% by mass, more preferably 3 to 15% by mass, based on the entire aqueous plaster. If the content of each basic local anesthetic is less than 3% by mass of the whole preparation, it may be difficult to ensure sufficient preparation characteristics.
In order to have good tackiness, the amount of oil floatation (exudation of eutectic mixture from the paste into the surface) of lidocaine and other basic local anesthetics is 0.001 to 0.9 mg / 15 cm ² (sheet) is preferable, 0.001 to 0.4 mg / 15 cm ² (sheet) is more preferable, and 0.001 to 0.2 mg / 15 cm ² (sheet) is more preferable. When the oil floating amount of the eutectic mixture exceeds 0.9 mg / 15 cm ² , exudation of the eutectic mixture to the adhesive surface will not result in good adhesion.

  Furthermore, in order to make an aqueous patch containing an eutectic mixture of a basic local anesthetic as an active ingredient free from problems such as oil floatation, the free release contained in the acrylic polymer in the aqueous patch is used. The ratio of the molar amount of the carboxylic acid to the molar amount of lidocaine contained in the aqueous plaster is important (free carboxylic acid / lidocaine, hereinafter referred to as the molar ratio). In general, when an acidic adhesive base having a basic drug and a carboxylic acid is allowed to coexist, there is a concern that acid-base interaction occurs and drug release properties are reduced. However, in the present invention, the eutectic mixture of basic local anesthetics is present in the adhesive base through free carboxylic acid (acidic group) and acid-base interaction in the polymer adhesive base, and the oil floats. It has been found that there is a specific molar ratio range that is excellent in balance between (adhesiveness) and drug release (skin permeability). That is, the molar ratio needs to be 0.4 to 3.0. The molar ratio is preferably 0.5 to 2.8, more preferably 0.7 to 2.7, and still more preferably 0.8 to 2.0. When the molar ratio is less than 0.4, oil floating occurs and good tackiness cannot be obtained. On the other hand, if the molar ratio is larger than 3.0, the skin permeation rate is lowered and sufficient medicinal effects cannot be obtained.

  The molar ratio can be appropriately adjusted by adding a basic component such as sodium hydroxide or an acidic component such as hydrochloric acid to the aqueous plaster. For example, the molar ratio can be adjusted by adding sodium hydroxide to the polyacrylic acid partial neutralized product and / or polyacrylic acid. Alternatively, the molar ratio can be adjusted by adding hydrochloric acid to the partially neutralized polyacrylic acid and / or sodium polyacrylate. Moreover, the molar ratio is adjusted by preparing from the respective salts of lidocaine and other basic local anesthetics, or by converting to the respective salts of lidocaine and other basic local anesthetics. Is possible. In addition, the molar ratio can be adjusted by adding a basic or acidic emulsifier and / or a basic or acidic crosslinking agent.

  (B) As acrylic polymer having free carboxylic acid, polyacrylic acid partially neutralized product, polyacrylic acid, sodium polyacrylate, methacrylic acid / n-butyl acrylate copolymer, acrylic acid / acrylic Examples thereof include acid octyl ester copolymers. In the present invention, one or more of these may be used in combination. The content of the acrylic acid polymer is preferably 0.1 to 20% by mass, more preferably 0.1 to 10% by mass, based on the entire aqueous plaster. When the content is more than 20% by mass, the plaster when spread on the support becomes hard, and there is a concern that the medicinal effect, adhesiveness, manufacturability and the like deteriorate.

The partially neutralized polyacrylic acid is a product obtained by partially neutralizing and polymerizing acrylic acid. These partially neutralized products of polyacrylic acid can be obtained commercially. For example, Viscomate (registered trademark; Showa Denko KK), Acparna (registered trademark; Sumitomo Seika Co., Ltd.) and Aronbis (registered trademark; Toa) Synthetic Co., Ltd.).
The partially neutralized polyacrylic acid can also be produced by adding a base such as sodium hydroxide to polyacrylic acid. In this case, polyacrylic acid and a base are mixed during the preparation of the preparation, and some of the free carboxylic acid of polyacrylic acid is neutralized in the aqueous plaster. It is a partially neutralized product.

A partially neutralized polyacrylic acid product can be produced by adding an acid such as hydrochloric acid to a salt such as sodium polyacrylate. In this case, polyacrylic acid partial neutralization is also possible in the case where a salt such as sodium polyacrylate and an acid are mixed during production of the preparation, and the polyacrylic acid partial neutralized product is in the aqueous plaster. It is a thing.
In addition, a completely neutralized product such as sodium polyacrylate and free polyacrylic acid are mixed so that the carboxylic acid neutralized and the free carboxylic acid as a whole are mixed with polyacrylic. Acid neutralized product.

(C) As a crosslinking agent, dry aluminum hydroxide gel, dihydroxyaluminum acetate, aluminum sulfate, aluminum chloride, magnesium metasilicate aluminate, magnesium aluminate silicate, aluminum stearate, aluminum lactate, kaolin, synthetic aluminum silicate, Examples thereof include calcium hydroxide, magnesium hydroxide, alumina magnesium hydroxide, and potassium aluminum sulfate hydrate. In the present invention, these can be used alone or in combination. These crosslinking agents are all general-purpose components and can be obtained commercially. Of these, basic crosslinking agents such as dry aluminum hydroxide gel and dihydroxyaluminum acetate are preferred.
The content of the crosslinking agent is preferably from 0.01 to 101% by mass, more preferably from 0.01 to 8% by mass, based on the entire aqueous plaster. When the amount is more than 10% by mass, plaster curing occurs due to excessive progress of crosslinking, and there is a concern that drug efficacy, adhesiveness, formulation characteristics, manufacturability and the like are deteriorated.

  (D) As an emulsifier, an ionic surfactant or a nonionic surfactant is mentioned, As an ionic surfactant, an anionic surfactant, a cationic surfactant, and a zwitterionic surfactant are mentioned. The content of the emulsifier is preferably 0.1 to 20% by mass, more preferably 0.1 to 10% by mass, based on the entire aqueous plaster. When it is more than 20% by mass, the emulsification balance is deteriorated, and there is a concern about the possibility of phase transition.

  Examples of emulsifiers include anionic surfactants such as sodium N-cocoyl-N-methylaminoethyl sulfonate, sodium dodecylbenzene sulfonate, sodium lauryl sulfate, sodium lauroyl sarcosine, sodium polyoxyethylene lauryl ether, phosphoric acid Polyoxyethylene oleyl ether, sodium N-acyl-L-glutamate, alkylbenzene sulfonate, higher fatty acid salt, dioctyl sodium sulfosuccinate, potassium stearate, sodium cetyl sulfate, neutral anhydrous sodium sulfate, polyoxyethylene oleyl ether Sodium phosphate, polyoxyethylene stearyl ether phosphate, sodium polyoxyethylene cetyl ether phosphate, sodium N-lauroyl-L-glutamate Sodium alkyl naphthalene sulfonate, and the like.

Examples of the cationic surfactant include benzalkonium chloride, cetylpyridinium chloride, polyoxyethylene polycyclic phenyl ether sulfate ammonium salt, and the like.
Furthermore, examples of the zwitterionic surfactant include lecithin, alkyldiaminoethylglycine hydrochloride, lauryldimethylamine oxide and the like.
On the other hand, nonionic surfactants include glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene lanolin, lanolin alcohol, beeswax derivative, poly Oxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyethylene glycol fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene polyoxypropylene glycol, polyoxyethylene monoester, sucrose Examples include fatty acid esters.

  In the present invention, one or more emulsifiers selected from the above ionic surfactants and nonionic surfactants can be used in combination. Among these emulsifiers, in the present invention, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene lanolin, lanolin alcohol, beeswax derivative, polyethylene glycol glycol fatty acid ester, polyoxyethylene glycerol fatty acid ester, poly Oxyethylene polyoxypropylene glycol or polyoxyethylene hydrogenated castor oil is used.

  In the present invention, for the purpose of enhancing the shape retention and / or adhesiveness of the aqueous patch, (F) a hydrophilic polymer can be added as necessary. Such hydrophilic polymers include gelatin, pullulan, agar, dextran, sodium alginate, soluble starch, carboxy starch, dextrin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyethylene oxide, poly Acrylamide, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl ether, maleic acid copolymer, methoxyethylene maleic anhydride copolymer, isobutylene maleic anhydride copolymer, polyethyleneimine, polyvinyl alcohol partially saponified product, hydroxypropyl methylcellulose, xanthan gum, N-vinylacetamide etc. can be mix | blended. The content of the hydrophilic polymer is preferably from 0.1 to 30% by mass, more preferably from 0.1 to 20% by mass, based on the entire aqueous plaster.

  In the present invention, a dispersant may be added as necessary. The dispersant plays a role of uniformly mixing the oil and water in the plaster layer, and can use oily components such as polyhydric alcohols, fatty acids and esters thereof, animal and vegetable oils, and terpene compounds. . Examples thereof include polyhydric alcohols such as glycerin, ethylene glycol, diethylene glycol, polyethylene glycol, 1,3-butylene glycol, propylene glycol, dipropylene glycol, sorbitol, xylitol, and maltitol. Capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, linoleic acid, stearic acid, lauryl lactate, isopropyl myristate, isopropyl palmitate, oleyl oleate, diisopropyl adipate, diisopropyl sebacate, glyceryl monocaprylate Medically acceptable fatty acids such as ethylene glycol monoisooctanoate and esters thereof can also be used. In addition, almond oil, olive oil, camellia oil, persic oil, peppermint oil, soybean oil, sesame oil, sink oil, cottonseed oil, corn oil, safflower oil, coconut oil, eucalyptus oil, castor oil, hardened castor oil, soybean lecithin, squalene , Dl or l-menthol, l-mentholone, limonene, pinene, piperiton, terpinene, terpinolene, terpinol, carbeol, dl-camphor, N-methyl-2-pyrrolidone, liquid paraffin and other animal and vegetable oils, mineral oil and terpene compounds, etc. The oily component can be used. These polyhydric alcohols, fatty acids and esters thereof, and oil components may be used alone or in combination of two or more. The content of the dispersing agent is preferably 1 to 30% by mass, and more preferably 3 to 20% by mass, based on the entire aqueous plaster.

  The plaster for an aqueous patch of the present invention is an additive other than the additives described above, and an additive generally used in the manufacture of a preparation for external use can be further added. Examples of such additives include stabilizers, solubilizers, buffers, bases, antioxidants, fragrances, cooling agents, flavoring agents, coloring agents, adhesives, pH adjusting agents, excipients, Examples include fillers, preservatives, solubilizers, and solubilizers. The pH of the preparation of the present invention is preferably 6.0 to 9.0, more preferably 6.5 to 8.0 from the viewpoint of skin irritation.

  The aqueous plaster body of the present invention is produced, for example, as follows. After preparing lidocaine and other basic local anesthetics to prepare a eutectic mixture, a drug-containing suspension A in which an emulsifier, a crosslinking agent, and an acrylic acid polymer are further mixed is prepared. Here, if necessary, a dispersant such as glycerin may be added at the same time. On the other hand, a mixed liquid B in which a water-soluble polymer such as gelatin is dissolved and dispersed in water is prepared, and the drug-containing suspension A is added to the mixed liquid B and sufficiently kneaded. In the case where a hydrophilic polymer such as gelatin is not used, water may be used in place of the mixed solution B. Thus, in the process of adding and mixing the components, the ratio of the molar amount of free carboxylic acid contained in the acrylic polymer and the molar amount of lidocaine in the eutectic mixture (free carboxylic acid / lidocaine) is 0.4 to By adjusting to 3.0, the plaster for aqueous patch of the present invention can be produced. Moreover, about other content components, those content etc. will be adjusted based on the description so far.

The plaster layer is formed by spreading the prepared paste for aqueous patch of the present invention on an appropriate support in this manner, and can be used as the aqueous patch of the present invention.
The support is not particularly limited as long as it can support the plaster layer, and a stretchable or non-stretchable support can be used. Specific examples include woven fabrics, nonwoven fabrics, vinyl chloride films, polyethylene films, polypropylene films, polyester films, polyurethane films, or composite materials thereof. In addition, the thickness of the said support body is not specifically limited, It can determine suitably.
The release sheet is not particularly limited as long as it covers the plaster layer, and examples thereof include a vinyl chloride film, a polyethylene film, a polypropylene film, a polyester film, and a polyurethane film. Further, for the purpose of facilitating peeling of the release sheet, a silicon-treated sheet or an embossed sheet can be used.

  The aqueous patch of the present invention contains a eutectic mixture having a local anesthetic action as an active ingredient, and relieves pain due to anesthesia, dura mater / lumbar puncture, and joint puncture when performing arteriovenous indwelling needle treatment before surgery, etc. It is effective for skin surface anesthesia for dermatological treatment such as laser treatment and pain reduction for intravenous injection in children. When the aqueous patch of the present invention is applied to the skin, the application time (action onset time) is usually within 120 minutes, preferably within 60 minutes, more preferably within 30 minutes.

EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.
[Example 1] A preparation in which the ratio of the molar amount of free carboxylic acid and the molar amount of lidocaine in the partially neutralized polyacrylic acid in the plaster layer is 0.76. Lidocaine 11.4 g and tetracaine 11.4 g are mixed together. After preparing the molten mixture, 9.1 g of glycerin is added, 60 2.7 g of polyoxyethylene hydrogenated castor oil, 0.3 g of dry aluminum hydroxide gel, 0.3 g of dihydroxyaluminum acetate, and partially neutralized polyacrylic acid (Viscomate (registered trademark)) NP-800) Prepare a drug-containing suspension mixed with 4.5 g. Meanwhile, 3.6 g of gelatin is dissolved in 56.7 g of water to prepare a solution. A drug-containing suspension is added to this mixed solution, and kneaded sufficiently to produce a target aqueous plaster. The obtained plaster for aqueous patch is spread on a support, cut into a desired size, and allowed to stand at 25 ° C. for 2 weeks to form a mole of carboxylate in sodium acrylate in the preparation. A co-reagent with a ratio of the amount to the molar amount of lidocaine was 0.76.

[Examples 2 to 7]
Examples 2 to 7 were processed in the same manner as in Example 1 to obtain co-reagents for preparations having the molar ratios shown in Tables 2 and 4.

[Comparative Example 1] A preparation in which the ratio of the molar amount of carboxylate in sodium polyacrylate in the plaster layer to the molar amount of lidocaine is 0.90. Lidocaine 12.8g and tetracaine 12.8g are mixed to prepare a eutectic mixture. After that, 9.1 g of glycerin is added, 60 2.7 g of polyoxyethylene hydrogenated castor oil, 0.3 g of dried aluminum hydroxide gel, 0.3 g of dihydroxyaluminum acetate, and 4.5 g of sodium polyacrylate (Viscomate (registered trademark) F-480SS) A mixed drug-containing suspension is prepared. Meanwhile, a mixed solution in which 3.6 g of gelatin is dissolved and dispersed in 53.8 g of water is prepared. Thereafter, the same treatment as in Example 1 was performed to obtain a co-reagent for a preparation in which the ratio of the molar amount of carboxylate to the molar amount of lidocaine in sodium acrylate in the preparation was 0.90.

[Comparative Examples 2 to 7]
Comparative Examples 2 to 3 were treated in the same manner as Comparative Example 1 to obtain preparation co-agents with molar ratios shown in Table 2. In addition, Comparative Examples 4 to 7 were processed in the same manner as in Example 1 to obtain co-reagents for preparations having molar ratios shown in Table 4.

<Oil float test method>
Release the release sheet gently from the prepared preparation, add the release sheet to a mixture of 10 mL of acetonitrile, 20 mL of purified water and 5 mL of internal standard solution (isopentylacetonitrile benzoate solution (75 → 1000)) and shake for 15 minutes. It was. The filtrate which was filtered through a 0.45 μm filter after shaking was used as a sample solution. 20 μL of the sample solution was subjected to HPLC under the measurement conditions shown in Table 1 below.

<Method of measuring adhesive strength (ball tack test)>
A ball tack test was performed by the method described on pages 116 to 117 of the “Pharmaceutical Manufacturing and Sales Guidelines 2010”. Install this product in the center of a plate with a 30 ° slope so that the adhesive surface of this preparation is on top. Roll a steel ball (No. 4 ball) with a diameter of 7.9 mm and a weight of 2.0 g from the top of the slope, and the ball will stick to the center. The adhesive strength was evaluated as good when stopped on the surface.
○: Steel ball stops ×: Steel ball does not stop

<Adhesive strength sensory evaluation test method>
The liner was gently peeled from the prepared preparation, and the plaster surface was brought into close contact with the forearm. The adhesion to the skin at this time was evaluated according to the following criteria.
◎: Strong and strong adhesive strength ○: Adhesive strength and acceptable ×: No adhesive strength and unacceptable

<In vitro skin permeation test method>
The skin was removed from the hairless mouse (HR-1 / Hos) so as to be 3 cm × 3 cm, and fixed to a vertical skin permeation test cell (Frantz cell) that was kept at 37 ° C. in advance. The preparation was affixed to the stratum corneum of the permeation cell, and 7.5 mL of purified water was added as a receptor solution to the dermis layer side. During the 6-hour skin permeation test, 1.0 mL of the receptor solution was collected in a timely manner. To this sample solution, an internal standard solution (isopentylacetonitrile benzoate solution (25 → 1000)) was added, and the filtrate filtered through a 0.45 μm filter was used as a sample solution, which was subjected to HPLC for measurement of drug concentration. The HPLC measurement conditions are the same as in Table 1. At the time of collecting the receptor solution, 1.0 mL of purified water not containing a drug kept at 37 ° C. was added to keep the volume of the receptor solution constant.

<Guinea pig pin prick test method>
The back of the guinea pig was removed, and after applying the base (placebo) or test preparation to one side across the spine for 30 minutes, the target position across the spine was stimulated alternately at 20 locations. Neuropen and Neurotip were used for stimulation, and the reflex (neck contraction response) caused by applying a predetermined stimulus was evaluated. A score of 2 was shown when the response was equivalent to that of the control, a score of 1 was shown when the response was lighter than that of the control, and a score of 0 was shown when no response was found. The total score value of 20 places was calculated, and the total value of the base and the total value of each preparation were tested. The drug efficacy at this time was evaluated according to the following criteria.
○: Significantly effective against placebo total value ×: Not significantly effective against placebo total value

<Test 1>
In order to confirm the effects of the partially neutralized polyacrylic acid and sodium polyacrylate on oil floating, adhesiveness and skin permeability, the aqueous patches of Examples 1 and 2 and Comparative Examples 1 to 3 were The oil floating test, the adhesive force measurement test (ball tack test), the adhesive force sensory test, and the in vitro skin permeation test were performed by the methods described above. Table 2 shows the formulations and molar ratios of Examples 1 and 2 and Comparative Examples 1 to 3, and Table 3 shows the results of each test.

  From the results of Examples 1 and 2 and Comparative Examples 1 to 3, it was found that the presence or absence of carboxylic acid in the adhesive base greatly affects the physical properties of the preparation. In Examples 1 and 2 using the partially neutralized polyacrylic acid as an adhesive base, the suppression of oil floating was good. On the other hand, in Comparative Examples 1 to 3 using sodium polyacrylate, oil floating cannot be suppressed even if the ratio of the molar amount of carboxylate and the molar amount of lidocaine in sodium polyacrylate is changed variously. It was. That is, the free carboxylic acid of the acrylic acid polymer is important as the adhesive base.

<Test 2>
To confirm the effect of the ratio of the molar amount of free carboxylic acid and the molar amount of lidocaine contained in the partially neutralized polyacrylic acid in the plaster layer on oil floating, stickiness, skin permeability, and medicinal properties In addition, for the aqueous patches of Examples 1 to 7 and Comparative Examples 4 to 7, using the previous method, oil floating test, adhesive strength measurement test (ball tack test), adhesive force sensory test, in vitro skin permeation Tests and guinea pig pin prick tests were performed. Table 4 shows the formulations and molar ratios of Examples 1 to 7 and Comparative Examples 4 to 7, and Table 5 shows the results of each test.

NT: not tested

From the results for Examples 1 to 7 and Comparative Examples 4 to 7, when the ratio of the molar amount of free carboxylic acid and the molar amount of lidocaine in the partially neutralized polyacrylic acid was 0.4 or more, oil floating was significantly reduced. And it was confirmed that it has sufficient adhesiveness. On the other hand, when the ratio of the molar amount of free carboxylic acid to the molar amount of lidocaine in the partially neutralized polyacrylic acid is 3.0 or less, a significant difference from the placebo preparation is confirmed in terms of efficacy, and the efficacy may be significantly expressed. confirmed. Here, the amount of oil floating in Example 3 is the ratio between the molar amount of acrylic acid and the molar amount of lidocaine between Example 1 and Example 2, and it was estimated that oil floating was suppressed, so the measurement was Not done.
From the above results, in order to prepare a desired aqueous patch having a good feeling of use, the ratio of the molar amount of free carboxylic acid and the molar amount of lidocaine in the partially neutralized polyacrylic acid was 0.4 to 3.0. It is important to:

Claims (18)

  (A) a room temperature oily eutectic mixture consisting of lidocaine and other basic local anesthetics, (B) an acrylic polymer with a free carboxylic acid, (C) a crosslinker, (D) an emulsifier, and (E The ratio of the molar amount of free carboxylic acid contained in (B) and (A) lidocaine in the eutectic mixture oily at room temperature (free carboxylic acid / lidocaine) is 0.4. A paste for aqueous patch, which is ˜3.0.   Lidocaine and other basic local anesthetics constituting the eutectic mixture of (A) are each 3 to 20% by mass, and (B) acrylic acid polymer is 0.1 to 20% by mass, The aqueous plaster according to claim 1, comprising (C) a crosslinking agent in an amount of 0.01 to 10% by mass, (D) an emulsifier in an amount of 0.1 to 20% by mass, and (E) 10 to 90% by mass of water. body. The aqueous plaster for an aqueous patch according to claim 1 or 2, further comprising (F) a hydrophilic polymer. The aqueous plaster according to claim 3, comprising 0.1 to 30% by mass of the hydrophilic polymer (F) with respect to the entire plaster.   The aqueous plaster according to any one of claims 1 to 4, wherein the other basic local anesthetic (A) is one selected from the group consisting of procaine, prilocaine and tetracaine.   The aqueous patch according to any one of claims 1 to 5, wherein a blending ratio of masses of lidocaine and other basic local anesthetics constituting the eutectic mixture of (A) is 2: 3 to 3: 2. Plaster.   The (B) acrylic acid polymer is a partially neutralized polyacrylic acid, polyacrylic acid, sodium polyacrylate, methacrylic acid / n-butyl acrylate copolymer, acrylic acid / octyl acrylate ester copolymer The aqueous patch preparation according to any one of claims 1 to 6, which is one or more selected from the group consisting of:   A support and an aqueous patch obtained by spreading the aqueous plaster according to any one of claims 1 to 7 on the support. The aqueous patch according to claim 8, wherein the exudation of the eutectic mixture from the plaster layer to the surface thereof is 0.001 to 0.9 mg / 15 cm ² , and the plaster layer has adhesiveness.   At least (A) a room temperature oily eutectic mixture consisting of lidocaine and other basic local anesthetics, (B) an acrylic polymer with free carboxylic acid, (C) a crosslinker, (D) an emulsifier, and (E) A method for producing a paste for an aqueous patch by mixing water, wherein the molar amount of the free carboxylic acid derived from (B) contained in the paste and the eutectic mixture of (A) A method for producing an aqueous plaster for an aqueous patch, comprising adjusting the ratio of the molar amount of lidocaine (free carboxylic acid / lidocaine) to 0.4 to 3.0.   Lidocaine and other basic local anesthetics constituting the eutectic mixture of (A) are each 3 to 20% by mass, and (B) acrylic acid polymer is 0.1 to 20% by mass with respect to the entire plaster. The (C) cross-linking agent is adjusted to 0.01 to 10% by mass, the (D) emulsifier is adjusted to 0.1 to 20% by mass, and the (E) water is adjusted to 10 to 90% by mass. A method for producing a paste for an aqueous patch.   Furthermore, (F) The manufacturing method of the paste for aqueous patchs of Claim 10 or 11 which mixes a hydrophilic polymer.   The method for producing a plaster for an aqueous patch according to claim 12, wherein the hydrophilic polymer (F) is adjusted to 0.1 to 30% by mass with respect to the entire plaster.   The other basic local anesthetic of (A) is one selected from the group consisting of procaine, prilocaine and tetracaine, according to any one of claims 10 to 13. Production method.   The aqueous patch according to any one of claims 10 to 14, wherein the mass mixing ratio of lidocaine and other basic local anesthetics constituting the eutectic mixture of (A) is adjusted to 2: 3 to 3: 2. A method for producing an adhesive paste.   The (B) acrylic acid polymer is a partially neutralized polyacrylic acid, polyacrylic acid, sodium polyacrylate, methacrylic acid / n-butyl acrylate copolymer, acrylic acid / octyl acrylate ester copolymer The method for producing an aqueous plaster for an aqueous patch according to any one of claims 10 to 15, which is one or more selected from the group consisting of:   The manufacturing method of the aqueous patch which spreads the aqueous paste preparation manufactured by the manufacturing method of the aqueous patch preparation in any one of Claims 10-16 on a support body. The aqueous patch according to claim 17, for producing an aqueous patch in which the exudation of the eutectic mixture from the plaster layer to the surface thereof is 0.001 to 0.9 mg / 15 cm ² and the plaster layer has adhesiveness. Manufacturing method.