PATCH CONTAINING LIDOCAINE

Abstract

This patch is bioequivalent to existing formulations, even those with higher concentrations of lidocaine. It is highly safe and contains lidocaine or a lidocaine salt, lactic acid, and a 4- to 6-carbon hydroxy acid. The rate of skin penetration of lidocaine when the patch is applied is within an appropriate range, and the therapeutic effect of lidocaine is persistent over a long period. The lactic acid content is 0.6 to 1.2 mol per 1 mole of lidocaine or a lidocaine salt.

Description

The present invention relates to a patch preparation comprising lidocaine, more specifically to a patch preparation comprising lidocaine or a salt thereof, lactic acid and a hydroxy acid having 4 to 6 carbon atoms wherein the amount of lactic acid is 0.6 to 1.2 mol per mole of lidocaine or a salt thereof. Background of the Invention For lidocaine, a local anesthetic, several external preparations containing it have been studied, and some patch preparations containing lidocaine as the active ingredient have been marketed. For example, in the US, Lidoderm® (a poultice containing 5% lidocaine) and ZTlido® (a tape preparation containing 1.8% lidocaine) have been commercially available. Patch preparations containing lidocaine have a problem. Specifically, in these patch preparations, undissolved lidocaine disperses within the adhesive layer due to the precipitation of lidocaine crystals. Consequently, insufficient lidocaine is absorbed into the body, even when applied to the skin, and the desired effect is not achieved. Ref. 327098 sufficiently. For skin permeability, it has been reported that the skin permeability of lidocaine is enhanced by reacting lidocaine and lactic acid in equimolar amounts to form an equimolar lidocaine-lactic acid salt in the form of an ionic liquid (see patent document 1). However, patent document 1 focuses on improving the skin permeability of lidocaine and does not disclose or suggest that lidocaine can continuously penetrate the skin. Furthermore, lidocaine is known to affect the heart and can cause side effects such as shock, flushing, and a feeling of stimulation or lidocaine toxicity when used at high concentrations for an extended period. Therefore, when adding a high concentration of lidocaine to a preparation, it was necessary to demonstrate that the preparation is biologically equivalent to existing preparations, such as Lidoderm®, to ensure its efficacy and safety. For example, patent document 2 describes how a drug can continuously penetrate the skin for an extended period by controlling the amount of each ingredient in an adhesive layer and ensuring the layer's thickness falls within a predetermined range. However, in the preparation described in patent document 2, the amount of local anesthetic (lidocaine) added is adjusted to a low concentration and is not used at a high concentration. Furthermore, it has not been reported that a preparation comprising lidocaine can produce the same skin permeability and adhesiveness as preparations comprising lidocaine at low concentration and achieve more continuous absorption of lidocaine even when using lidocaine at high concentration by using lidocaine or a salt thereof and lactic acid in a specific molar ratio, as well as a hydroxy acid having 4 to 6 carbon atoms. Documents of the previous technique Patent documents Patent document 1: WO 2009 / 060629. Patent document 2: WO 2018 / 052039. Brief Description of the Invention Problem to be solved by the invention In a patch preparation, when 30-40% of a drug contained in the dressing (adhesive layer) is absorbed into the skin, the drug absorption rate decreases. As a result, the drug cannot be absorbed continuously. When a higher concentration of the drug is added to the dressing, the drug can be absorbed continuously for a longer period compared to when a lower concentration is used. On the other hand, it is found that a preparation comprising lidocaine prepared by a conventional method, for example, a preparation comprising lidocaine prepared by the method of patent document 2 (hot melt method), includes an organic acid such as tartaric acid and can control the amount of lidocaine absorbed. However, since an organic acid with a small molecular weight (e.g., tartaric acid) is highly soluble in water, the organic acid could not be added in the amount required to form a salt with lidocaine in a dressing comprising a lipophilic base when the lidocaine concentration is increased. As a result, the lidocaine is present in a free form with high crystallinity without forming a salt with an organic acid in the dressing, and the lidocaine in the free form causes the problem of lidocaine crystal precipitation during long-term storage.Therefore, it was necessary to adjust the lidocaine concentration to a low level in a preparation comprising lidocaine and a low molecular weight organic acid. This meant that such a preparation had some difficulty achieving sustained lidocaine absorption over a long period. Furthermore, prolonged use of a high concentration of lidocaine causes lidocaine toxicity, thus presenting a significant challenge in ensuring the efficacy and safety of the preparation even when the lidocaine concentration was increased. The present invention has been studied considering the above situation, and one object of the present invention is to provide a highly safe lidocaine patch preparation that can continuously produce the therapeutic effect of lidocaine for an extended period by adjusting the rate of skin penetration of lidocaine to a suitable range when applied to the skin, and also exhibits bioequivalence similar to existing lidocaine preparations even when using a high concentration of lidocaine. Furthermore, an object of the present invention is to prevent the precipitation of lidocaine crystals and to produce a patch that is difficult to remove during exercise without reducing adherence to the skin. Means to solve the problems The present inventors have achieved an improvement in the skin permeability of lidocaine in a patch preparation comprising lidocaine by forming an equimolar salt of lidocaine and lactic acid (an ionic liquid) and maintaining the lidocaine in a dissolved state even when a high concentration of lidocaine is contained in the tape-like dressing. Furthermore, the present inventors have considered the need to reduce the amount of lidocaine that permeates the skin per hour and to adjust the rate of skin permeation of lidocaine to an appropriate range when the preparation is used for an extended period. The present inventors have discovered that, although the amount of lidocaine that permeates the skin can be controlled by any method to reduce the amount of lidocaine to be applied, continuous skin permeation of lidocaine over an extended period may be lost when the amount of lidocaine to be applied is low.Based on these findings, the present inventors have also discovered that it is necessary to adequately control the amount of lidocaine that penetrates the skin while maintaining a high concentration of lidocaine. The present inventors attempted to control the amount of lidocaine penetrating the skin by adding a hydroxy acid having 4 to 6 carbon atoms (e.g., tartaric acid) to an equimolar salt of lidocaine and lactic acid, but this objective could not be achieved because the hydroxy acid did not dissolve. The present inventors have studied extensively to achieve this objective and have succeeded in preparing a mixture of lactic acid and tartaric acid in a specific quantity and then adding lidocaine in a specific molar ratio to prepare a uniform composition.Furthermore, the present inventors have discovered that a patch preparation comprising the resulting composition can adequately control the skin permeability rate of lidocaine, produce good permeability and adhesiveness on the skin, and ensure bioequivalence with Lidoderm®, which has been commercially available in the USA. Based on these new discoveries, the present invention has been completed. In other words, the present invention provides the following aspects. [1] A patch preparation comprising lidocaine or a salt thereof, lactic acid and a hydroxy acid having 4 to 6 carbon atoms, wherein the amount of lactic acid is 0.6 to 1.2 mol per mole of lidocaine or a salt thereof. [2] The patch preparation of point [1], wherein the hydroxy acid having 4 to 6 carbon atoms is either citric acid or tartaric acid. [3] The patch preparation of point [1] or [2], wherein the hydroxy acid having 4 to 6 carbon atoms is tartaric acid. [4] The patch preparation of any of points [1] to [3], wherein the amount of lactic acid is 1.0 to 1.2 mol per mole of lidocaine or a salt thereof. [5] The patch preparation of any of points [1] to [4], wherein the amount of lidocaine or a salt thereof is from 5 to 50%. [6] The patch preparation of any of points [1] to [5], wherein the amount of lidocaine or a salt thereof is 10 to 40%. [7] The patch preparation of any of points [1] to [6], wherein the amount of lidocaine or a salt thereof is 10 to 20%. [8] The patch preparation of any of points [1] to [7], wherein the amount of hydroxy acid having 4 to 6 carbon atoms is 0.2 to 5%. [9] The patch preparation of any of points [1] to [8], wherein the amount of hydroxy acid having 4 to 6 carbon atoms is from 0.3 to 0.8%.

[10] The patch preparation of any of points [1] to [9] comprising a backing, an adhesive layer and a peelable coating, wherein the adhesive layer comprises lidocaine or a salt thereof, lactic acid and a hydroxy acid having 4 to 6 carbon atoms.

[11] The patch preparation of point

[10] , wherein the adhesive layer further comprises an ester.

[12] The patch preparation of point

[11] , wherein the ester is diethyl sebacate, methyl laurate, diisopropyl adipate, isopropyl myristate, propylene carbonate or a mixture thereof.

[13] The patch preparation of any of points

[10] to

[12] , wherein the adhesive layer further comprises a surfactant.

[14] The patch preparation of point

[13] , wherein the surfactant is a non-ionic surfactant with an HLB value of 4 to 14.

[15] The patch preparation of any of points

[10] to

[14] , wherein the adhesive layer further comprises an elastomer.

[16] The patch preparation of point

[15] , wherein the elastomer is a styrene-isoprene-styrene (SIS) block copolymer.

[17] The patch preparation of any of points

[10] to

[16] , wherein the thickness of the patch preparation is 0.50 to 2.00 mm.

[18] The patch preparation of any of the points

[10] to

[17] , wherein the surface area of ​​the adhesive layer is 100 to 200 cm2.

[19] A method for manufacturing the patch preparation of any of points [1] to

[18] , comprising: (a) mixing lactic acid in an amount of 0.6 to 1.2 mol per mole of lidocaine or a salt thereof with a hydroxy acid having 4 to 6 carbon atoms; and (b) adding lidocaine or a salt thereof to the mixture of (a) above to prepare a uniform composition. Furthermore, the present invention provides the following features.

[20] A method for treating pain comprising administering a therapeutically effective amount of the patch preparation from any of points [1] to

[18] to a patient in need.

[21] The preparation of a patch from any of points [1] to

[18] for use in the treatment of pain.

[22] The use of the patch preparation of any of points [1] to

[18] in the manufacture of a drug to treat pain. Effects of the invention The present invention can adjust the rate of skin penetration of lidocaine when applied to the skin at a suitable interval and continuously produce the therapeutic effect of lidocaine for an extended period. Furthermore, the present invention can ensure bioequivalence with existing patch preparations comprising lidocaine, even when using a higher concentration of lidocaine, and can therefore maintain the therapeutic effect of lidocaine for a longer period compared to existing patch preparations comprising lidocaine and reduce the risk of side effects caused by prolonged use of the preparations. The patch preparation of the present invention maintains adhesion to the skin without precipitating lidocaine crystals in the adhesive layer and can therefore be used during exercise. Furthermore, the patch preparation ensures safety for long-term use and is therefore expected to reduce the number of applications. Brief Description of the Figures Figure 1 shows a graph representing the cumulative amounts of lidocaine skin permeation (pg / cm2) in the preparations of examples 1-3 and comparative example 1 in the in vitro skin permeation test. Figure 2 shows the proportions of the amounts of lidocaine that penetrate the skin (%) in the preparations of examples 1-3 when the amount of lidocaine that penetrates the skin in the preparation of comparative example 1 is defined as 100%. Figure 3 shows a graph representing the cumulative amounts of lidocaine skin permeation (pg / cm2) in the preparations of examples 4-8 and comparative example 2 in an in vitro skin permeation test. Figure 4 shows the proportions of the amounts of lidocaine that penetrate the skin (%) in the preparations of examples 4-8 when the amount of lidocaine that penetrates the skin in the preparation of comparative example 2 is defined as 100%. Figure 5 shows a graph representing the mean plasma concentration profile versus time after the Example 1 preparation (n = 32) and Lidoderm® (n = 28) are applied to the human back (mean i standard deviation). Figure 6 shows the changes in the average remaining adhesion area (%) over time for the preparation of Example 1 (n = 45) and Lidoderm® (n = 45). Figure 7 shows the changes in average adhesion score over time for Example 1 preparation (n = 45) and Lidoderm® (n = 45). Detailed Description of the Invention As used in this document, lidocaine may be in its free form or as a salt thereof. Lidocaine salts include, but are not limited to, salts with an inorganic acid and salts with an organic acid. Examples of salts with an inorganic acid include hydrochloride, hydrobromide, nitrate, and phosphate, and examples of salts with an organic acid include acetate, trifluoroacetate, propionate, oxalate, fumarate, and maleate. As used in this document, lidocaine or a salt thereof is preferably used as lidocaine (in the free form). The amount of lidocaine or a salt thereof may be from 1 to 50% by weight, from 5 to 50% by weight, from 5 to 45% by weight, from 10 to 50% by weight, from 10 to 40% by weight, from 10 to 35% by weight, from 10 to 30% by weight, from 10 to 25% by weight, from 10 to 20% by weight or from 10 to 15% by weight with respect to the total amount of the preparation, but is not limited to the same. Furthermore, the amount of it can be 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight or 50% by weight. As used in this document, lidocaine (in free form) can form an ion pair with lactic acid to prepare the lactic acid salt of lidocaine in the preparation, and can also be prepared as a salt with a hydroxy acid having 4 to 6 carbon atoms, e.g. citric acid or tartaric acid. As used in this document, lactic acid involves the formation of an ion pair with an equimolar amount of lidocaine to prepare the lactic acid salt of lidocaine (equimolar salt). As used in this document, the amount of lactic acid is 0.6 to 1.2 mol, and preferably 1.0 to 1.2 mol per mole of lidocaine or a salt thereof. As used in this document, lidocaine lactic acid salt is an ionic liquid (a molten salt at room temperature) produced by forming an ion pair of lidocaine and lactic acid in equimolar amounts, and is in a viscous liquid form at room temperature. The amount of lactic acid salt of lidocaine can be, for example, 1 to 50% by weight, and the amount of the same can be 5 to 50% by weight, 10 to 50% by weight, 10 to 40% by weight, 10 to 35% by weight, 10 to 30% by weight, 10 to 20% by weight or 10 to 15% by weight. In addition, the amount of lactic acid salt of lidocaine can be 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight or 50% by weight. The lactic acid salt of lidocaine can be prepared as an equimolar salt of lidocaine and lactic acid by mixing lidocaine and lactic acid in the presence or absence of a solvent and heating (e.g., to 80 °C). Alternatively, the lactic acid salt of lidocaine can be prepared by mixing lidocaine and lactic acid at room temperature. As used in this document, the lactic acid salt of lidocaine can be prepared as an equimolar salt by reacting one part lidocaine with one part lactic acid. Therefore, a preparation may contain lidocaine and unreacted lactic acid. As used in this document, a hydroxy acid having 4 to 6 carbon atoms means a carboxylic acid with linear or branched hydroxyl group(s) having 4 to 6 carbon atoms. Examples include, but are not limited to, tartaric acid and citric acid. The amount of the hydroxy acid having 4 to 6 carbon atoms can be from 0.1 to 10% by weight, from 0.2 to 5% by weight, from 0.25 to 4% by weight, from 0.25 to 3% by weight, from 0.3 to 2% by weight, from 0.3 to 1% by weight, from 0.3 to 0.8% by weight, from 0.35 to 0.8% by weight or from 0.4 to 0.8% by weight with respect to the total amount of the preparation, but is not limited to the same. Furthermore, the amount thereof may be 0.1% by weight, 0.15% by weight, 0.2% by weight, 0.25% by weight, 0.3% by weight, 0.35% by weight, 0.4% by weight, 0.45% by weight, 0.5% by weight, 0.55% by weight, 0.6% by weight, 0.65% by weight, 0.7% by weight, 0.75% by weight, 0.8% by weight, 0.85% by weight, 0.9% by weight, 0.95% by weight, 1% by weight, 1.1% by weight, 1.2% by weight, 1.3% by weight, 1.4% by weight, 1.5% by weight, 1.6% by weight, 1.7% by weight, 1.8% by weight, 1.9% by weight, 2% by weight, 2.5% by weight, 3% by weight, 3.5% by weight, 4% by weight, 4.5% by weight, 5% by weight, 5.5% by weight, 6% by weight, 6.5% by weight, 7% by weight, 7.5% by weight, 8% by weight, 8.5% by weight, 9% by weight, 9.5% by weight or 10% by weight. The patch preparation of the present invention may comprise a surfactant, an alcohol, an ester, a carbolic acid (excluding a hydroxy acid having 4 to 6 carbon atoms), and an amine, if necessary. These may be used alone or two or more of them in combination. Examples of surfactants include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. Surfactants can be used alone or in combination with other surfactants. Examples of nonionic surfactants include sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, glycerol monooleate, glycerol monostearate, decaglycerol monolaurate, hexaglycerin polyricinoleate, polyoxyethylene lauryl ether (9), polyoxyethylene lauryl ether (2), polyoxyethylene lauryl ether (4,2), polyoxyethylene nonylphenyl ether (5), polyoxyethylene nonylphenyl ether (7,5), polyoxyethylene nonylphenyl ether (10), polyoxyethylene octylphenyl ether (3), polyoxyethylene octylphenyl ether (10), polyoxyethylene (10) oleylamine, polyoxy(5) oleylamide, polyoxy(5) oleic acid amide, polyoxyethylene monolaurate (2), monoglyceride stearate, and polyoxyethylene castor oil (hydrogenated castor oil), but are not limited to them. The nonionic surfactant can be used alone or two or more of the nonionic surfactants can be used in combination. Examples of anionic surfactants include, but are not limited to, sodium lauryl sulfate, potassium lauryl sulfate, triethanolamine lauryl sulfate, sodium cetyl sulfate, sodium lauroylsarcosine, sodium di-2-ethylhexyl sulfosuccinate, sodium polyoxyethylene (10) lauryl ether phosphate, sodium polyoxyethylene (4) lauryl ether phosphate, sodium polyoxyethylene (5) cephalic ether phosphate, and sodium polyoxyethylene (6) oleyl ether phosphate. Anionic surfactants can be used alone, or two or more can be used in combination. Examples of cationic surfactants include, but are not limited to, stearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, benzalkonium chloride, and stearyl dimethylbenzyl ammonium chloride. Cationic surfactants can be used alone, or two or more cationic surfactants can be used in combination. Examples of amphoteric surfactants include, but are not limited to, lauryl dimethylaminoacetic acid betaine and 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolium betaine. Lauroyl diethanolamide can also be used as an amphoteric surfactant. Amphoteric surfactants can be used alone, or two or more amphoteric surfactants can be used in combination. The surfactant of the present invention is preferably a surfactant with an HLB value of 4 to 14, more preferably a surfactant with an HLB value of 4 to 14 comprising one or more non-ionic surfactants and, furthermore, preferably a surfactant with an HLB value of 6-12 comprising monoglyceride stearate and polyoxyethylene castor oil (hydrogenated castor oil). The amount of surfactant is, for example, from 0.01 to 2% by weight, and preferably from 0.01 to 1% by weight. Examples of alcohols include lower alcohols such as ethanol, propanol, isopropyl alcohol, and butanol; higher alcohols such as lauryl alcohol, myristic alcohol, oleyl alcohol, isostearyl alcohol, and cetyl alcohol; dihydric alcohols such as ethylene glycol, propylene glycol, butanediol (1,3-butanediol, 1,4-butanediol), pentanediol, and hexanediol; trihydric alcohols such as glycerin and hexanetriol; and aromatic alcohols such as glycol salicylate and benzyl alcohol. The alcohol of the present invention is preferably propylene glycol, 1,3-butanediol, and glycerin. The alcohol may be used alone, or two or more of the alcohols may be used in combination. The amount of alcohol is, for example, from 0.01 to 2% by weight, and preferably from 0.01 to 1% by weight. Examples of esters include isopropyl isostearate, methyl stearate, butyl myristate, ethyl linoleate, isopropyl linoleate, ethyl olivate, myristyl myristate, cetyl isooctanoate, octyldodecyl myristate, diisopropyl adipate, cetyl palmitate, retinyl palmitate, methyl laurate, methyl myristate, methyl caproate, methyl palmitate, isopropyl myristate, isopropyl palmitate, diethyl sebacate, diethyl adipate, glyceryl monooleate, glyceryl monocaproate, glyceryl dioleate, propylene glycol monostearate, decaglyceryl decaoleate, sorbitan monostearate, sorbitan monolaurate, sorbitan monooleate. sorbitan trioleate, ascorbyl palmitate, n-propyl gallate, diisopropyl adipate, propylene carbonate, and a pyrrolidone derivative such as N-methyl-2-pyrrolidone, but not limited to the same.The ester of the present invention is preferably isopropyl myristate, isopropyl palmitate, diethyl sebacate, propylene carbonate, and N-methyl-2-pyrrolidone, and further preferably propylene carbonate and N-methyl-2-pyrrolidone. The ester can be used alone or two or more of the esters can be used in combination. The amount of ester is, for example, from 0.01 to 2% by weight, and preferably from 0.01 to 1% by weight. Examples of carboxylic acids include, but are not limited to, fatty acids such as oleic acid, palmitic acid, succinic acid, lauric acid, myristic acid, stearic acid, isostearic acid, and decanoic acid; and keto acids such as levulinic acid. Carboxylic acids can be used alone, or two or more carboxylic acids can be used in combination. The amount of carboxylic acid is, for example, from 0.01 to 2% by weight, and preferably from 0.01 to 1% by weight. Examples of amines include, but are not limited to, monoethanolamine, diethanolamine, isopropanolamine, triethanolamine, triisopropanolamine, ethylenediamine, and trishydroxymethylaminomethane. An amine can be used alone, or two or more amines can be used in combination. The amount of amine is, for example, from 0.01 to 2% by weight, and preferably from 0.01 to 1% by weight. In the preparation of the patch of the present invention, when the total amount of alcohol, ester, carboxylic acid, and amine exceeds 30% by weight, the adhesive layer may soften. As a result, it is sometimes difficult to prepare the patch. The patch preparation of the present invention may have the form of a three-layer structure comprising a backing, an adhesive layer comprising lidocaine or a salt thereof, and a peelable liner. For example, the patch preparation may have the form of a structure in which the adhesive layer is laminated to one side of the backing and the peelable liner is laminated to the surface of the adhesive layer opposite the surface that adheres to the backing. The patch preparation of the present invention comprises lidocaine, lactic acid, and a hydroxy acid having 4 to 6 carbon atoms in the adhesive layer. In addition, an agent such as a surfactant, an alcohol, an ester, a carboxylic acid (excluding a hydroxy acid having 4 to 6 carbon atoms), and an amine are contained in the adhesive layer. The patch preparation of the present invention comprises a suitable elastomer (polymer) in the adhesive layer. The patch preparation of the present invention can be prepared as a matrix-type patch preparation by dispersing a solution comprising lidocaine or a salt thereof in an adhesive layer comprising an elastomer. When the patch preparation of the present invention is a matrix-type patch preparation, the amount of the lactic acid salt of lidocaine can be from 1 to 50% by weight, from 10 to 50% by weight, from 10 to 40% by weight, from 10 to 35% by weight, from 10 to 30% by weight, from 10 to 20% by weight, or from 10 to 15% by weight with respect to the total amount of the dry adhesive layer. The elastomer of the present invention includes, but is not limited to, a rubber polymer, an acrylic polymer, a silicon polymer, and a vinyl ether polymer. The elastomer can be used alone, or two or more of the elastomers can be used in combination. Examples of rubber polymers include, but are not limited to, synthetic rubber such as a styrene-isoprene-styrene block copolymer (hereafter also referred to as SIS), a styrene-butadiene-styrene block copolymer, an ethylene-butadiene-styrene block copolymer, styrene-butadiene rubber, polyisoprene, polyisobutylene, polybutene, butyl rubber, silicone rubber; and natural rubber. Examples of acrylic polymers include, but are not limited to, an acrylic acid-octyl acrylate ester copolymer, a 2-ethylhexyl-vinylpyrrolidone acrylate copolymer, a 2-ethylhexyl-N-vinyl-2-pyrrolidone-l,6-hexaneglycol acrylate-dimethacrylate copolymer, an acrylate-vinyl acetate copolymer, and a 2-ethylhexyl acrylate-2-hydroxyethyl-vinyl acetate acrylate copolymer. Examples of silicon polymers include, but are not limited to, silicon rubber, dimethylpolysiloxane, and diphenylpolysiloxane. In the preparation of the patch of the present invention, the adhesive layer may further comprise an additive such as a tackifying agent, a softener, a filler, and an antioxidant. Examples of tackifying agents include rosin, rosin ester resin, hydrogenated rosin ester, terpene resin, terpene phenolic resin, C5 petroleum resin, C5 / C9 petroleum resin, DCPD (dicyclopentadiene) petroleum resin, coumarone-indene resin, and alicyclic saturated hydrocarbon resin. Tackifying agents can be used alone, or two or more can be used in combination. The amount of the stickiness agent is, for example, from 0.01 to 50% by weight, preferably from 10 to 40% by weight and more preferably from 20 to 40% by weight. Examples of fabric softener include, but are not limited to, petroleum-based softeners such as process oil and polybutene, fatty oil-based softeners such as castor oil and coconut oil, purified lanolin, liquid paraffin, and gelled hydrocarbons. Fabric softener can be used alone or in combination with two or more softeners. The amount of fabric softener is, for example, from 0.01 to 50% by weight, preferably from 10 to 40% by weight, and more preferably from 20 to 40% by weight. Examples of filler include, but are not limited to, kaolin, titanium oxide, talc, calcium carbonate, magnesium carbonate, silicate, silicic acid, aluminum hydrate, barium sulfate, and calcium sulfate. The filler can adjust the adhesive layer to an appropriate hardness when it becomes too flexible. The amount of filler is, for example, from 0.01 to 5% by weight and preferably from 0.01 to 3% by weight. Examples of antioxidants include, but are not limited to, dibutylhydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, and sodium pyrosulfite. Antioxidants can be used alone or in combination with other antioxidants. The amount of antioxidant is, for example, from 0.01 to 2% by weight, and preferably from 0.01 to 1% by weight. A drug-impermeable, stretchable or non-stretchable backing material may be used as a support for the patch of the present invention. The support material is not particularly limited to such materials, provided it is commonly used in the pharmaceutical field. Examples include polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyester (such as polyethylene terephthalate), a synthetic resin film or sheet or laminated product thereof, a porous material, a foam, a film with deposited aluminum, paper, a woven fabric, and a non-woven fabric. ML / a / ZUZ 1 / U1 ¿Xóó In preparing the patch of the present invention, the peelable coating can be used to protect the adhesive layer until the preparation is applied to the skin. An aluminum laminate film can be used as the packaging material for the preparation of the present invention. Materials such as polyacrylonitrile, polyethylene terephthalate, and polyethylene can be used in the innermost layer of the aluminum laminate film. The patch preparation of the present invention can be prepared by any well-known method, such as the solvent coating method and the hot melt coating method. Examples of solvent-based coating methods include a method comprising preparing an adhesive layer composition comprising lidocaine lactic acid salt and the like, coating the composition directly onto a substrate, and then drying. Another method comprises coating the adhesive layer composition onto a release liner and drying it, removing the liner, and then pressing the adhesive layer onto a substrate. Examples of hot-melt coating methods include a method comprising heating and melting the adhesive layer composition, coating the composition directly onto a substrate, and then drying it. Furthermore, a method comprising heating the composition for the adhesive layer, coating the composition onto a peelable paper and drying, removing the paper and then pressing the adhesive layer onto a support by contact, can be used as a heat-fusion coating method. Furthermore, the composition for the adhesive layer in the patch preparation of the present invention can be prepared by mixing each ingredient into the adhesive layer and then stirring them. For example, a composition for the adhesive layer can be prepared by dissolving an elastomer and a tackifying agent in toluene, adding another additive such as a surfactant and a solvent such as an ester, and mixing with heating, dissolving the mixture, and then adding lidocaine, lactic acid, and a hydroxy acid having 4 to 6 carbon atoms and stirring them. Lidocaine can be added to the mixing solution produced by mixing lactic acid and a hydroxy acid having 4 to 6 carbon atoms. As used in this document, the thickness of the patch preparation is preferably from approximately 0.50 to approximately 2.00 mm, and more preferably from approximately 0.55 to approximately 1.00 mm. Its thickness may be, for example, approximately 0.50 mm, approximately 0.51 mm, approximately 0.52 mm, approximately 0.53 mm, approximately 0.54 mm, approximately 0.55 mm, approximately 0.56 mm, approximately 0.57 mm, approximately 0.58 mm, approximately 0.59 mm, approximately 0.60 mm, approximately 0.61 mm, approximately 0.62 mm, approximately 0.63 mm, approximately 0.64 mm, approximately 0.65 mm, approximately 0.66 mm, approximately 0.67 mm, approximately 0.68 mm, approximately 0.69 mm, approximately 0.70 mm, approximately 0.71 mm, approximately 0.72 mm, approximately 0.73 mm, approximately 0.74 mm, approximately 0.75 mm, approximately 0.76 mm, approximately 0.77 mm, approximately 0.78 mm, approximately 0.79 mm, approximately 0.80 mm, approximately 0.85 mm, approximately 0.90 mm, approximately 0.95 mm, approximately 1.00 mm, approximately 1.10 mm, approximately 1.20 mm, approximately 1.30 mm, approximately 1.40 mm, approximately 1.50 mm, approximately 1.60 mm, approximately 1.70 mm, approximately 1.80mm, about 1.90mm or about 2.00mm. When the thickness of the patch preparation is increased, particularly the thickness of the adhesive layer, without changing the amount of lidocaine, the lidocaine concentration is reduced. As a result, the amount of lidocaine absorbed can be controlled. On the other hand, some problems may arise; for example, a large amount of adhesive may adhere to the skin when the patch preparation is removed, and the solvent contained in the adhesive layer may increase skin irritation. As used in this document, the surface area of ​​the adhesive layer in the patch preparation is preferably 100 to 200 cm2, more preferably 120 to 180 cm2, and even more preferably 130 to 160 cm2. Furthermore, as used in this document, the amount of lidocaine lactic acid salt per unit area of ​​the adhesive layer is, for example, 1 to 5 mg / cm2, preferably 1 to 2 mg / cm2, and more preferably 1 to 1.5 mg / cm2. The patch preparation of the present invention maintains adhesion to the skin without precipitating lidocaine crystals in the adhesive layer. The patch preparation of the present invention is difficult to remove even during exercise and can therefore be used while exercising. The number of applications of the patch preparation of the present invention varies with the symptoms and the patient's age, but the number of applications is preferably once a day, once every two days, once every three days, or once a week, and most preferably once a day for an adult. The number of applications may be increased depending on the symptoms. The patch preparation of the present invention is used for the treatment or relief of various types of pain such as neuropathic pain deep in the skin (e.g., postherpetic neuralgia), cervico-omobrachial syndrome, and trigeminal nerve-derived migraine. As used in this document, the term treatment (cure) means any treatment of pain or associated symptoms, for example, treating or improving pain and relieving or inhibiting painful symptoms. Treatment also includes inhibiting the recurrence of pain. As used in this document, the term patient means a human being and an animal such as a dog, cat, or horse. Between these, the patient is preferably a human being. As used in this document, the term therapeutically effective amount means any amount effective in treating, improving, and / or relieving pain and its symptoms compared to untreated patients. The term also includes any amount effective in promoting normal physiological function over time. Examples The present invention is described more specifically below with reference to examples and test examples. However, the present invention is not intended to be limited to them in any way. Examples 1 to 3 Each ingredient was weighed in the quantities shown in Table 1 below, and the patch preparations of Examples 1 to 3 were prepared. Specifically, according to the solvent method, the styrene-isoprene-styrene (SIS) block copolymer and terpene resin were dissolved in toluene, and then glyceryl monostearate, polyoxylethylene 40 hydrogenated castor oil, propylene carbonate, and gelled hydrocarbon were added and mixed with heating. The mixture was then dissolved to prepare an adhesive layer. Separately, lactic acid (purity: 90%) and tartaric acid were mixed, and lidocaine was added to the mixing solution to prepare a uniform composition. This composition was then mixed with the adhesive layer to prepare a uniform composition for the adhesive layer.The resulting composition for the adhesive layer was coated onto the silicone-treated PET film and dried to remove the toluene, and then the resulting dressing was laminated onto a backing and cut to the size of 10 cm x 14 cm to prepare a patch preparation. Table 1 Example 1 Example 2 Example 3 Lidocaine 10% 10% 10% Lactic acid 5% 5% 5% Tartaric acid 0.4% 0.6% 0.8% Glyceryl monostearate 0.008% 0.008% 0.008% Hydrogenated castor oil 40% 0.017% 0.017% 0.017% Propylene carbonate 1% 1% 1% Gelled hydrocarbon 38.575% 38.375% 38.175% SIS 10% 10% 10% Terpene resin 35% 35% 35% Total 100% 100% 100% Comparative Example 1 Each ingredient was weighed in the amounts shown in Table 2 below, and the preparation of comparative example 1 was prepared according to a procedure similar to the preparations of examples 1 to 3, except that tartaric acid was not added. Table 2 Comparative Example 1 Lidocaine 10% Lactic Acid 5% Tartaric Acid - Glyceryl Monostearate 0.008% Hydrogenated Polyoxyethylene Castor Oil 40 0.017% Propylene Carbonate 1% Gelled Hydrocarbon 38.975% SIS 10% Terpene Resin 35% Total 100% Example test 1: Study of skin permeability to lidocaine by adding a hydroxy acid having 4 to 6 carbon atoms (1) According to the following procedure, the amounts of lidocaine that penetrate the skin were measured in the preparations of examples 1 to 3 and comparative example 1. A Franz cell was set up and filled with saline solution. The Franz cell was heated to approximately 32 °C. A disc with a φ15 mm hole was placed on a φ24 mm membrane filter on the back of a thawed miniature pig skin. The skin was pierced with a φ24 mm punch and placed in the Franz cell. Excess water was wiped away around the Franz cell and from the top surface of the skin. The skin was acclimated to the environment for approximately 20 minutes and then removed. Each preparation, perforated to φ12 mm, was applied to the center of the skin, and the skin was placed in the Franz cell. Excess water was wiped away around the Franz cell, the φ24 mm perforated filter paper was placed over the skin, and the Franz cell lid was closed and secured with a clamp. Sampling of each preparation was performed at 1 hour, 2.At 5, 6, 9, and 12 hours after the start of the test, the skin permeation amounts were measured using high-performance liquid chromatography (HPLC). The amounts were calculated as the mean value (n=3). The cumulative amounts of lidocaine by skin penetration after 1 hour, 2.5 hours, 6 hours, 9 hours, and 12 hours (pg / cm²) in the preparations are shown in Table 3 and Figure 1. Figure 2 shows the ratios of skin permeation amounts of lidocaine in the preparations of Examples 1 to 3 to the skin permeation amount of lidocaine in the preparation of Comparative Example 1 after 12 hours (%). Table 3 Example 1 Example 2 Example 3 Comparative Example 1 Cumulative amount of skin permeation after 1 h 1.81 1.39 2.62 2.65 Cumulative amount of skin permeation after 2.5 h 9.25 7.47 11.05 14.85 Cumulative amount of skin permeation after 6 h 31.79 23.55 28.56 46.56 Cumulative amount of skin permeation after 9 h 55.48 42.73 47.20 80.62 Cumulative amount of skin permeation after 12 h 76.55 59.81 63.22 108.26 It was shown that the amount of lidocaine that penetrates the skin could be reduced by the addition of tartaric acid (Table 3 and Figures 1-2). Example test 2: Study of skin permeability to lidocaine by adding a hydroxy acid having 6 carbon atoms (2) The skin permeability of each preparation comprising lidocaine comprising tartaric acid or citric acid as a hydroxy acid having 4 to 6 carbon atoms was studied. Each ingredient was weighed in the amounts shown in the table below. The preparations in Examples 4 to 8 were prepared according to a procedure similar to that of the preparations in Examples 1 to 3, and the preparation in Comparative Example 2 was prepared according to a procedure similar to that of the preparation in Comparative Example 1. The amounts of skin permeation of lidocaine in the preparations in Examples 4 to 8 and Comparative Example 2 were measured using a procedure similar to that of Test Example 1, except that a StratM® membrane (manufactured by Merck) was used instead of miniature pig skin, and sampling was performed at 1 hour, 3 hours, 6 hours, 9 hours, and 12 hours after the start of the test. The amounts were calculated as the mean value (n = 3). Table 4 Example 4 Example 5 Example 6 Example 7 Example 8 Comparative Example 2 Lidocaine 10% 10% 10% 10% 10% 10% Lactic acid 5% 5% 5% 5% 5% 5% Tartaric acid 0.2% 0.4% 0.5% - - - Citric acid - - - 0.2% 0.4% - Glycerin monostearate 0.008% 0.008% 0.008% 0.008% 0.008% 0.008% Polyoxyethylene hydrogenated castor oil 0.017% 0.017% 0.017% 0.017% 0.017% 0.017% Propylene carbonate 1% 1% 1% 1% 1% 1% Gelled hydrocarbon 38.775% 38.575% 38.475% 38.775% 38.975% 38.975% SIS 10% 10% 10% 10% 10% 10% Terpene resin 35% 35% 35% 35% 35% 35% Total 100% 100% 100% 100% 100% 100% The cumulative amounts of lidocaine penetrating the skin after 1 hour, 3 hours, 6 hours, 9 hours, and 12 hours (pg / cm2) in the preparations are shown in Table 5 and Figure 3. In addition, the ratios of the amounts of lidocaine penetrating the skin in the preparations of Examples 4 to 8 with respect to the amount of lidocaine penetrating the skin in the preparation of Comparative Example 2 after 12 h (%) are shown in Figure 4. Table 5 Example 4 Example 5 Example 6 Example 7 Example 8 Comparative Example 2 Cumulative amount of skin permeation after 1 h 1.57 1.258 1.121 1.713 1.478 1.716 Cumulative amount of skin permeation after 3 h 9.015 6.744 6.145 8.358 8.14 9.839 Cumulative amount of skin permeation after 6 h 24.235 17.915 16.992 22.193 21.236 25.467 Cumulative amount of skin permeation after 9 h 41.751 32.657 22.193 37.633 35.824 43.466 Cumulative amount of skin permeation after 12 h 61.029 47.6 43.394 54.721 52.128 62.082 It was shown that the amount of lidocaine that penetrates the skin could be controlled by adding not only tartaric acid but also citric acid (Table 4 and Figures 3-4). Example test 3: In vivo pharmacokinetic study of the preparation of the present invention and the existing preparation (Lidoderm®) According to the following procedure, the plasma concentrations of lidocaine were measured for the preparation in Example 1 and the patch preparation comprising lidocaine sold in the United States of America (Lidoderm®). In addition, each preparation was analyzed pharmacokinetically to assess bioequivalence with the existing preparation. Thirty-two healthy individuals (men and women, aged 19 to 65 years) were enrolled as subjects per group. Two sheets of Lidoderm or the preparation from Example 1 (size: 10 cm x 14 cm) were applied to the back of each subject and removed 12 hours after application. Blood was drawn at 1, 2, 3, 4, 6, 8, 10, 11, 12, 13, 14, 16, 18, 20, 24, 28, 36, and 44 hours after application of each preparation, and the plasma lidocaine concentration was measured using LC / MS / MS. Furthermore, non-compartmental pharmacokinetic analysis was performed based on the change in plasma lidocaine concentration using Phoenix WinNonlin Version 7.0 to calculate the AUC (area under the blood concentration-time curve) and Cmax (maximum blood concentration). Additionally, the geometric mean ratios of AUC and Cmax were calculated for the preparation in Example 1 and Lidoderm®. Four subjects who received Lidoderm® were excluded from the study because the applied preparation was withdrawn during the study. The change in plasma lidocaine concentration (mean ± standard deviation) is shown in Figure 5. The calculated AUC and Cmax are shown in Table 6. The 90% confidence intervals for the geometric mean relationships of the AUC and Cmax were within an acceptable range of 80%-125%. Table 6 Lidoderm® (n=28) Example 1 (n=32) Geometric mean ratio for Lidoderm® AUCo-t (ng*h / ml) 797.3 759.2 95.22 AUCo-inf(ng*h / ml) 823.7 780.6 94.77 Cmax (ng / ml) 50.05 48.62 97.14 It was confirmed that the preparation of Example 1 showed almost the same pharmacokinetic (PK) profile as Lidoderm® (Table 6 and Figure 5). That is, it was demonstrated that the preparation of the present invention is biologically equivalent to Lidoderm®. Furthermore, the lidocaine utilization rate 12 hours after application of the preparation to the skin was 29%. Therefore, approximately 70% of the lidocaine remains in the preparation, and thus the preparation can be used continuously. In other words, the preparation of the present invention can continuously produce the therapeutic effect of lidocaine for a much longer period compared to Lidoderm®. Example test 4: Adhesion test of the preparation of the present invention and the existing preparation (Lidoderm®) According to the following procedure, an adhesion test was performed on the preparation of Example 1 and the patch preparation comprising lidocaine sold in the United States of America (Lidoderm®) for humans to measure the remaining adhered area (%). In addition, according to the EDA guidance (Adhesion Assessment with Topical and Transdermal Delivery Systems for the ANDA Guide for Industry (Preliminary GUIDE) of October 2018), adhesion scores were calculated for each preparation (0: >90% adhered, 1: >75% to <90% adhered, 2: >50% to <75% adhered, 3: >0% to <50% adhered, 4: 0% adhered) to assess the durability of the adhesion of the preparations. Forty-five healthy individuals (men and women of all races) were enrolled as subjects per group. One sheet of the patch preparation (size: 10 cm x 14 cm) or one sheet of Lidoderm® was applied to the back of each subject. The adhered site on each subject was ensured to be anatomically equivalent. The average remaining adhesion area (%) and the average adhesion score were calculated at 3, 6, 9, and 12 hours after the start of the test to assess the durability of the preparations' adhesion. The changes in the average remaining adhesion area (%) over time for each preparation are shown in Figure 6. Additionally, the changes in the average adhesion score over time for each preparation are shown in Figure 7. In the preparation of the present invention, 44 subjects had adherence scores of 0 and 1 subject had an adherence score of 1, out of 45 subjects, at a time of 12 hours after application of the preparation. Therefore, it was demonstrated that the preparation of the present invention was difficult to remove for a long time and had the characteristic that it was difficult to remove even during exercise. Industrial applicability The present invention can adjust the rate of skin penetration of lidocaine when applied to the skin at a suitable interval and continuously produce the therapeutic effect of lidocaine for an extended period. Furthermore, the present invention can ensure bioequivalence with existing patch preparations comprising lidocaine, even when the lidocaine is contained at a higher concentration, and thus maintain the therapeutic effect of lidocaine for a longer period compared to existing patch preparations comprising lidocaine, and reduces the risk of side effects caused by prolonged use of the preparations. The patch preparation of the present invention maintains adhesion to the skin without precipitating lidocaine crystals in the adhesive layer and can therefore be used during exercise. Furthermore, the patch preparation ensures safety for long-term use and is therefore expected to reduce the number of applications. It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

1. A patch preparation comprising lidocaine or a salt thereof, lactic acid and a hydroxy acid having 4 to 6 carbon atoms, characterized in that the amount of lactic acid is 0.6 to 1.2 mol per mole of lidocaine or a salt thereof.

2. The patch preparation according to claim 1, characterized in that the hydroxy acid having 4 to 6 carbon atoms is citric acid or tartaric acid.

3. The patch preparation according to claim 1 or 2, characterized in that the hydroxy acid having 4 to 6 carbon atoms is tartaric acid.

4. The patch preparation according to any of claims 1 to 3, characterized in that the amount of lactic acid is 1.0 to 1.2 mol per mole of lidocaine or a salt thereof.

5. The patch preparation according to any of claims 1 to 4, characterized in that the amount of lidocaine or a salt thereof is from 5 to 50% by weight.

6. The patch preparation according to any of claims 1 to 5, characterized in that the amount of lidocaine or a salt thereof is from 10 to 40% by weight.

8. The patch preparation according to any of claims 1 to 7, characterized in that the amount of hydroxy acid having 4 to 6 carbon atoms is from 0.2 to 5% by weight.

9. The patch preparation according to any of claims 1 to 8, characterized in that the amount of hydroxy acid having 4 to 6 carbon atoms is 0.3 to 0.8% by weight.

10. The patch preparation according to any of claims 1 to 9, comprising a backing, an adhesive layer and a peelable coating, characterized in that the adhesive layer comprises lidocaine or a salt thereof, lactic acid and a hydroxy acid having 4 to 6 carbon atoms.

11. The patch preparation according to any of claims 1 to 10, characterized in that the adhesive layer further comprises an ester.

12. The patch preparation according to claim 11, characterized in that the ester is diethyl sebacate, methyl laurate, diisopropyl adipate, isopropyl myristate, propylene carbonate or a mixture thereof.

13. The patch preparation according to any of claims 1 to 12, characterized in that the adhesive layer further comprises a surfactant.

14. The patch preparation according to claim 13, characterized in that the surfactant is a non-ionic surfactant with an HLB value of 4 to 14.

15. The preparation of a patch according to any of claims 1 to 14, characterized in that the adhesive layer further comprises an elastomer.

16. The patch preparation according to claim 15, characterized in that the elastomer is a styrene-isoprene-styrene (SIS) block copolymer.

17. The patch preparation according to any of claims 10 to 16, characterized in that the thickness of the patch preparation is from 0.50 to 2.00 mm.

18. The preparation of a patch according to any of claims 10 to 16, characterized in that the surface area of ​​the adhesive layer is 100 to 200 cm2.

19. A method for manufacturing the patch preparation according to any of claims 1 to 18, characterized in that it comprises: (a) mixing lactic acid in an amount of 0.6 to 1.2 mol per mole of lidocaine or a salt thereof with a hydroxy acid having 4 to 6 carbon atoms; and (b) adding lidocaine or a salt thereof to the mixture of (a) above to prepare a uniform composition.