WO2018104772A1

WO2018104772A1 - Percutaneous absorption-type preparation

Info

Publication number: WO2018104772A1
Application number: PCT/IB2017/001501
Authority: WO
Inventors: 傑石川; 貴史才
Original assignee: 王子ホールディングス株式会社
Priority date: 2016-12-05
Filing date: 2017-12-04
Publication date: 2018-06-14
Also published as: JP6695571B2; JP2018090539A

Abstract

The present invention provides a percutaneous absorption-type preparation containing tramadol or a pharmaceutically acceptable salt thereof, said percutaneous absorption-type preparation maintaining the skin permeability of tramadol without causing bleeding and also maintaining the aggregability. More specifically, the present invention pertains to a percutaneous absorption-type preparation comprising a support and a drug-containing layer, wherein the drug-containing layer contains tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid and an adhesive.

Description

Transdermal preparation

This application claims the priority based on Japanese Patent Application No. 2006-235562 for which it applied on December 5, 2016, and uses the content here.
The present invention relates to a transdermal preparation containing tramadol or a pharmaceutically acceptable salt thereof as an active ingredient.

Tramadol ((1RS, 2RS) -2-[(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol) is one of opioid analgesics and is mild in WHO cancer pain therapy. It is classified as a weak opioid used for moderate to moderate pain. The analgesic action of tramadol is thought to result from the suppression of nociceptive transmission by binding to the μ opioid receptor and the activation of the descending pain suppression system by inhibiting serotonin and noradrenaline reuptake. Tramadol is effective in alleviating pain and chronic pain in various cancers, and is currently used as tramadol hydrochloride in dosage forms such as injections, oral preparations, and suppositories. Tramadol hydrochloride has a chemical structure of the following formula (I):

There have been some reports on the transdermal preparations of opioid analgesics.
Patent Document 1 shows that when menthol, O-ethylmenthol, or limonene was added as an absorption enhancer to tramadol-containing hydrogel, the transdermal absorbability of tramadol was enhanced more than when cholic acid was added as an absorption enhancer. Is disclosed.
Patent Document 2 discloses that as an absorption promoter, pentazocine which is an opioid receptor antagonist is obtained by using a compound selected from the group consisting of isopropyl myristate and glyceryl monocaprylate, glyceryl monocaprate and glyceryl monolaurate. It is disclosed that percutaneous absorption is improved. However, Patent Document 2 also mentions tramadol hydrochloride as an opioid receptor antagonist, but does not disclose an example showing that the percutaneous absorption of tramadol is improved by the above-mentioned absorption enhancer.
Patent Document 3 discloses that high skin permeability of tramadol was obtained by formulating free tramadol as an organogel containing a fatty acid ester and a glycerin fatty acid ester. On the other hand, Patent Document 3 also discloses that tramadol hydrochloride-containing organogel had extremely low skin permeability for tramadol.

Japanese Unexamined Patent Publication No. 2006-36687 International Publication No. 2006/088551 International Publication No. 2011/059037

In the percutaneous absorption-type preparation containing tramadol or a pharmaceutically acceptable salt thereof, the present inventors have studied about improving the skin permeability of tramadol. It has been recognized that when an absorption accelerator is blended, there is a problem that bleeding occurs and the cohesiveness may decrease. Patent Documents 1 to 3 do not describe such a problem at all.

Accordingly, the present invention provides a transdermally absorbable preparation containing tramadol or a pharmaceutically acceptable salt thereof, in which bleeding is not caused and coagulation property is maintained while maintaining the skin permeability of tramadol, and It aims at providing the manufacturing method made from a transdermal absorption type.

As a result of intensive studies to achieve the above object, the present inventors have found that high skin permeability of tramadol can be obtained by using a fatty acid alkanolamide as an absorption accelerator. Further, the present inventors have found that bleeding is increased when the content of fatty acid alkanolamide is increased to a certain value or more in order to further improve skin permeability, or when an absorption accelerator other than fatty acid alkanolamide is further added. It has been found that there is a new problem that occurs and the cohesiveness may decrease. As a result of further studies, it was found that even in such a case, blending silicic acid in the drug-containing layer can prevent bleeding and maintain good cohesiveness. Furthermore, it was unexpectedly found that tramadol exhibits high storage stability in the drug-containing layer thus obtained.
The present inventors have further studied based on these findings and have completed the present invention.
That is, the present invention is as follows.

[1] A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer contains tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid, and an adhesive A transdermal absorption preparation.
[2] The transdermal absorption preparation according to [1], wherein the pressure-sensitive adhesive contains a rubber-based resin as a main component.
[3] The transdermal absorption preparation according to [2], wherein the rubber-based resin contains a styrene-isoprene-styrene block copolymer and a tackifier.
[4] The transdermal preparation according to [3], wherein the tackifier is a hydrogenated rosin glycerin ester.
[5] The transdermal absorption according to any one of [1] to [4], wherein the fatty acid alkanolamide is at least one selected from lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide. Mold formulation.
[6] The transdermal absorption preparation according to any of [1] to [5], wherein the drug-containing layer further contains an absorption enhancer.
[7] The percutaneous absorption preparation according to [6], wherein the absorption accelerator is at least one selected from fatty acid esters and organic acids.
[8] The transdermal absorption preparation according to [7], wherein the fatty acid ester is at least one selected from isopropyl myristate, isopropyl palmitate, and hexyl laurate.
[9] The transdermal absorption preparation according to [7], wherein the organic acid is at least one selected from acetic acid, caprylic acid, oleic acid, and isostearic acid.
[10] The percutaneous absorption preparation according to any of [1] to [9], wherein the drug-containing layer contains a pharmaceutically acceptable acid addition salt of tramadol and a basic compound.
[11] The transdermal preparation according to [10], wherein the basic compound is at least one selected from an inorganic base and an aliphatic alkanolamine.
[12] A method for producing a transdermally absorbable preparation according to [1], comprising preparing a mixture containing tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid, and an adhesive, A production method comprising applying or spreading the mixture on a release liner to form a drug-containing layer, and bonding a support to the drug-containing layer.

According to the present invention, in the percutaneous absorption type preparation containing tramadol or a pharmaceutically acceptable salt thereof, the skin permeability of tramadol can be improved while maintaining good aggregation. Moreover, according to the present invention, the storage stability of tramadol in the drug-containing layer can be enhanced. Therefore, the present invention can provide a means for administering tramadol with improved convenience.

It is a figure which shows an example of the manufacturing flow of the percutaneous absorption type formulation of this invention.

In the present invention, the “percutaneous absorption preparation” refers to a parenteral preparation in which an active ingredient is absorbed through the skin and delivered to the bloodstream. The transdermally absorbable preparation of the present invention is a patch having a support and a drug-containing layer, and examples thereof include a tape, a poultice, and a plaster.

The transdermally absorbable preparation of the present invention may be a matrix-type patch preparation containing an adhesive in the drug-containing layer, and a controlled-release membrane and skin for adjusting the transdermal absorption of the drug on the skin-applied side of the drug-containing layer It may be a reservoir-type patch preparation that further has an adhesive layer for sticking to the skin. With such a structure, tramadol can be efficiently transdermally absorbed.

From the viewpoint of formulation design and ease of production, a matrix-type patch preparation is preferable. Hereinafter, the matrix-type patch preparation will be described as an example, but the present invention is not limited thereto.

In this specification, the term “comprising” or “including” also includes the meaning of “consisting essentially of” or “consisting solely of”.

<Drug-containing layer>
1. Active ingredient In the transdermally absorbable preparation of the present invention, the drug-containing layer contains tramadol or a pharmaceutically acceptable salt thereof. Tramadol has analgesic action and is used to treat pain.

In the present specification, the pain is not particularly limited as long as it can be alleviated by tramadol. For example, pain in various cancers, chronic pain (eg, nociceptive pain (eg, low back pain, osteoarthritis, etc.), Neuropathic pain (eg, postherpetic neuralgia, diabetic neuropathic pain, and psychogenic pain).

Pharmaceutically acceptable salts of tramadol include acid addition salts such as inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; and organic acid salts such as, for example, Formate, acetate, trifluoroacetate, ascorbate, benzoate, cinnamate, citrate, fumarate, glutamate, tartrate, oxalate, glutarate, camphorate, adipine Acid salt, sorbate, lactate, maleate, linoleate, linolenate, malate, malonate, mandelate, methanesulfonate (mesylate), phthalate, salicylate, stearin Acid salt, isostearate, succinate, propionate, butyrate, pamoate, p-toluenesulfonate (tosylate), benzenesulfonate (besylate), etc. It is, but is not limited thereto.

Tramadol or a pharmaceutically acceptable salt thereof may be used in crystalline form. The crystal may be formed only from tramadol or a pharmaceutically acceptable salt thereof, or may form a co-crystal or a solvate (for example, a hydrate, preferably a monohydrate). Good. Any of tramadol or a pharmaceutically acceptable salt thereof may be used alone or in combination of two or more. In the present invention, it is preferable to use tramadol hydrochloride, which has already been established to be useful for intramuscular administration and oral administration, as a pain therapeutic agent.

The content of tramadol or a pharmaceutically acceptable salt thereof in the transdermal preparation of the present invention is an effective amount for the treatment of pain. Here, the “effective amount” is an amount capable of achieving a blood concentration of tramadol effective for treating pain when the transdermally absorbable preparation of the present invention is applied to the skin of a living body. Such content can be adjusted as appropriate based on information on the pharmacokinetics of oral administration, and may vary depending on the administration subject, disease, symptoms, and the like. For example, the amount is preferably 1 to 40% by mass, more preferably 5 to 35% by mass, and still more preferably 10 to 30% by mass with respect to the drug-containing layer (that is, based on the total mass of the drug-containing layer; the same shall apply hereinafter).

The blood concentration of tramadol effective for the treatment of pain can be similar to that of intramuscular or oral administration of tramadol.

In the transdermally absorbable preparation of the present invention, a blood concentration effective for treating pain can be achieved by adjusting the skin permeation rate of tramadol. The skin permeation rate can be adjusted by any means such as adjusting the content of tramadol or a pharmaceutically acceptable salt thereof in the drug-containing layer, or adding an absorption enhancer described later to the drug-containing layer. It can be carried out. In the present invention, the skin permeation rate of tramadol means a value measured by an in vitro skin permeability test described in Examples described later.

The skin permeation rate of tramadol is usually 40 μg / cm ² / hour or more, preferably 50 μg / cm ² / hour or more, more preferably 60 μg / cm ² / hour or more. If the skin permeation rate is 40 μg / cm ² / hour or more, a sufficient blood concentration can be obtained. The skin permeation rate of tramadol is usually less than 100 [mu] g / cm ² / time, preferably less than 90 [mu] g / cm ² / hour, more preferably less than 80 [mu] g / cm ² / hour. If the skin permeation rate is less than 100 μg / cm ² / hour, the blood concentration does not become too high, which is preferable from the viewpoint of safety.

2. Basic Compound When an acid addition salt is used as a pharmaceutically acceptable salt of tramadol, it is preferable to contain a basic compound in the drug-containing layer. Examples of basic compounds include inorganic bases and organic bases, such as low molecular weight compounds containing basic nitrogen (for example, ethanolamine, isopropanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, etc. Aliphatic alkanolamine); polymer compound containing basic nitrogen (for example, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, polyvinylpyridine, etc.); basic alkali metal salt (for example, sodium acetate, potassium acetate, boric acid) Sodium, sodium carbonate, sodium hydrogen carbonate, trisodium citrate, sodium silicate); alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide, etc.). Moreover, you may use commercially available basic acrylic resins, such as Eudragit series (Eudragit E100, Eudragit EPO: Evonik Industries company make). Of these, inorganic bases and aliphatic alkanolamines are preferable, and sodium hydroxide, potassium hydroxide, and diisopropanolamine are more preferable.

A basic compound can be used individually or in mixture of 2 or more types. The content of the basic compound is preferably 0.5 to 3 equivalents, more preferably 0.7 to 2 equivalents, relative to the equivalent amount of the pharmaceutically acceptable salt of tramadol. In addition, the content of the basic compound is preferably 0.1 to 35% by mass, more preferably 0.5 to 30% by mass, and more preferably 1 to 25% by mass with respect to the drug-containing layer. More preferably. By containing such a basic compound, the basic compound acts on a pharmaceutically acceptable salt of tramadol, and the skin permeability of tramadol is improved. In particular, by setting the content of the basic compound within the above range, the effect of improving the skin permeability becomes more remarkable as compared with the case where the content is outside the above range.

3. Fatty acid alkanolamide In the percutaneous absorption type preparation of the present invention, the drug-containing layer contains a fatty acid alkanolamide as an absorption accelerator. Fatty acid alkanolamides, for example C ₁₂ saturated at ~ C _18, or one or more double bonds (preferably, 1 or two double bonds) and fatty acid moieties having, C ₂ substituted with for example one or more hydroxy ~ C ₆ alkyl (preferably, monohydroxy C ₂ ~ C ₄ alkyl) comprises a alkanolamide moiety or di alkanolamide moiety containing, for example, lauric acid diethanolamide, palmitic acid diethanolamide, stearic acid diethanolamide, Examples include oleic acid diethanolamide and lauric acid monoisopropanolamide. Of these, lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide are preferable.

Fatty acid alkanolamides can be used alone or in admixture of two or more. In one embodiment, the content of the fatty acid alkanolamide in the transdermal preparation of the present invention is 15% by mass or less (for example, 14% by mass or less, 13% by mass or less, 12% by mass or less) with respect to the total mass of the drug-containing layer. 11 mass% or less, 10 mass% or less, 9 mass% or less, 8 mass% or less, 7 mass% or less, 6 mass% or less, 5 mass% or less, 4 mass% or less, or 3 mass% or less) For example, the content is preferably 1 to 10% by mass, more preferably 1 to 5% by mass, and still more preferably 1 to 3% by mass. If the content of the fatty acid alkanolamide is 1% by mass or more, it is possible to give a skin permeation rate of tramadol that can achieve a blood concentration effective for the treatment of pain.

4). Other absorption enhancer In the transdermal absorption preparation of the present invention, the drug-containing layer may further contain an absorption enhancer other than the fatty acid alkanolamide. The absorption enhancer other than the fatty acid alkanolamide may be any compound that has been recognized to promote skin permeation in transdermal administration, for example, acetic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid. , Stearic acid, isostearic acid, sorbic acid, oleic acid, linoleic acid, linolenic acid, oxalic acid, fumaric acid, succinic acid, glutaric acid, adipic acid, pimelic acid, sebacic acid, benzoic acid, nicotinic acid, methanesulfonic acid, Organic acids such as benzene sulfonic acid, toluene sulfonic acid, saccharin or salts thereof; isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, hexadecyl isostearate, hexyl laurate, decyl oleate, oleyl oleate, diisopropyl adipate Pills, diethyl sebacate, diisopropyl sebacate, medium chain fatty acid triglycerides, tri (caprylic / capric) glycerin, glyceryl monooleate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene monopalmitate Fatty acid esters such as glycol, propylene glycol monostearate, propylene glycol monooleate, propylene glycol monobehenate, propylene glycol dicaprate; esters such as triacetin, ethyl lactate, triethyl citrate; sorbitan monolaurate, sorbitan monooleate Sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate (polysorbate 80) Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monostearate; polyethylene glycol monooleate; polyethylene glycol monostearate, polyethylene glycol monopalmitate, polyethylene glycol monolaurate, etc. Oxyethylene fatty acid esters; aliphatic or aromatic alcohols such as decanol, lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, cetyl alcohol, hexyl decanol, octyldodecanol, benzyl alcohol, or ethers thereof; carbon number 3 To 8 polyhydric alcohols (eg, propylene glycol, 1,3-butanediol, , 4-butanediol, glycerin, dipropylene glycol, octanediol, etc.); phenol ethers such as polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl ether; castor oil or hydrogenated castor oil; oleoyl sarcosine, lauryldimethylamino Ionic surfactants such as betaine acetate and sodium lauryl sulfate; polyoxyethylene alkyl ethers having 10 to 22 carbon atoms (for example, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl) Ethers, polyoxyethylene behenyl ethers, etc.); nonionic surfactants such as dimethyl lauryl amine oxide; dimethyl sulfoxide, decylmethy Alkylmethyl sulfoxides such as sulfoxide; pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone; 1-dodecylazacycloheptan-2-one, 1-geranylazacyclo And azacycloalkanes such as heptan-2-one; and terpenes such as menthol, camphor and limonene. Absorption accelerators other than fatty acid alkanolamides can be used singly or in combination of two or more. In a preferred embodiment, the absorption accelerator other than the fatty acid alkanolamide is at least one selected from organic acids and fatty acid esters. The organic acid is preferably at least one selected from acetic acid, caprylic acid, oleic acid, and isostearic acid. The fatty acid ester is preferably at least one selected from isopropyl myristate, isopropyl palmitate, and hexyl laurate.

The drug-containing layer may not contain an absorption accelerator other than the fatty acid alkanolamide, and when it is included, the content thereof is, in one aspect, 1% by mass or more (for example, 2 mass% or more, 3 mass% or more, 4 mass% or more, or 5 mass% or more), 20 mass% or less (for example, 19 mass% or less, 18 mass% or less, 17 mass% or less, 16 mass% or less, 15 Mass% or less, 14 mass% or less, 13 mass% or less, 12 mass% or less, 11 mass% or less, or 10 mass% or less). The content of the absorption accelerator other than the fatty acid alkanolamide is, for example, preferably 0 to 20% by mass, more preferably 0 to 15% by mass, and further preferably 0 to 10% by mass. Further, the total content of fatty acid alkanolamides and absorption accelerators other than fatty acid alkanolamides in the drug-containing layer may be 1% by mass or more and 25% by mass, for example, 20% by mass, unless bleeding occurs. Less than 15% by mass and less than 10% by mass.

5). Silicic acid In the transdermally absorbable preparation of the present invention, the drug-containing layer contains silicic acid. In the present invention, “silicic acid” means silicon dioxide (anhydrous silicic acid) or a salt thereof. For example, anhydrous silicic acid, silicate (eg, aluminum silicate, magnesium silicate, calcium silicate, silicic acid) Magnesium aluminum, magnesium sodium silicate, etc.), preferably silicic anhydride.

The content of silicic acid is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and preferably 1 to 10% by mass with respect to the total mass of the drug-containing layer. More preferably. If the silicic acid content is 0.1% by mass or more, bleeding that occurs when a fatty acid alkanolamide and other absorption promoters are blended in the drug-containing layer can be suppressed, and good cohesiveness can be maintained. . Further, it is preferable to contain silicic acid in the drug-containing layer so that the total amount of fatty acid alkanolamide and other absorption accelerators is 2 to 5 parts by mass with respect to 1 part by mass of silicic acid. In the present invention, “bleeding” means a phenomenon in which a liquid component oozes out from a drug-containing layer containing an adhesive, and the presence or absence of occurrence is visually evaluated as described in Examples below. it can. In the present invention, the cohesiveness is evaluated based on the cohesive strength of the pressure-sensitive adhesive investigated by the test method described in the examples described later.

6). Adhesive In the transdermal preparation of the present invention, the drug-containing layer contains an adhesive. Examples of the pressure-sensitive adhesive contained in the drug-containing layer include those containing acrylic resins, rubber resins, silicone resins, and the like.

The pressure-sensitive adhesive preferably contains as a main component at least one selected from the group consisting of acrylic resins, rubber resins and silicone resins, and at least selected from the group consisting of rubber resins and acrylic resins. What contains 1 type as a main component is more preferable. Here, the “main component” means usually 70% by mass or more, further 80% by mass or more, further 90% by mass or more, and particularly 100% by mass with respect to the total mass of the pressure-sensitive adhesive.

As an acrylic resin, for example, (meth) acrylic acid ester represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like is used as a monomer unit. Examples thereof include a polymer or copolymer containing at least one kind. Specifically, for example, acrylic acid / octyl acrylate copolymer, 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution, 2-ethylexyl acrylate / N-vinyl-2-pyrrolidone / dimethacrylic acid-1 , 6-hexane glycol copolymer, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / methacrylic acid Examples thereof include a dodecyl copolymer solution, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and an acrylic resin alkanolamine solution. Also, DURO-TAK (registered trademark) acrylic adhesive series (DURO TAK87-900A, DURO TAK 87-9301, DURO TAK 87-4098, DURO TAK 387-2510, DURO TAK 87-2510, DURO TAK 387-2287, DURO TAK 87-2287, DURO TAK 87-4287, DURO TAK 387-2516, DURO TAK 87-2516, DURO TAK 87-2074, DURO TAK 387-235A, DURO TAK 387-2353, DURO TAK 87235D -2852, DURO TAK 387-2051, DURO TAK 87-2051, DURO TAK 3 7-2052, DURO TAK 87-2052, DUROTAK 387-2054, DURO TAK 87-2054, DURO TAK 87-2194, DURO TAK 87-2196: made by Henkel Corporation, GELVA series (GELVA GMS 3083, GELVA GMS32 GELVA GMS32GEL Commercially available acrylic resins such as GMS 788, GELVA GMS 9073 (manufactured by Henkel), MAS-683, MAS-811, MASCOS10, MAS11D1 (manufactured by Kosmedy Pharmaceutical) may be used.

Examples of rubber resins include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), styrene isoprene rubber, and polyisobutylene (PIB). ), Polybutene, butyl rubber, natural rubber, raw rubber, gum arabic, gum arabic powder, isoprene rubber and the like, preferably styrene-isoprene-styrene block copolymer (SIS). In addition, commercially available rubber resins such as Quintac (registered trademark) series (Quintac 3570C, etc .: manufactured by ZEON Corporation), Kraton D polymer series (produced by Kraton Polymer Japan), JSR SIS / TR series (manufactured by JSR Life Sciences), etc. May be used.

Examples of the silicone-based resin include polymers having an organopolysiloxane skeleton and derivatives thereof. Specific examples include dimethylpolysiloxane, polymethylvinylsiloxane, polymethylphenylsiloxane, and diphenylsiloxane. Commercially available silicone resins such as BIO-PSA series (Dow Corning) may also be used.

As the pressure-sensitive adhesive contained in the drug-containing layer of the transdermally absorbable preparation of the present invention, one of the acrylic resin, rubber resin, and silicone resin described above is used alone, or two or more kinds are combined. Can be used. More preferred are acrylic or rubber resins.

The amount of the adhesive contained in the drug-containing layer is adjusted in consideration of the formation of the drug-containing layer, sufficient skin permeability of tramadol, and the like. The content of the pressure-sensitive adhesive is usually 10 to 97.8% by mass, preferably 15 to 90% by mass with respect to the drug-containing layer. When the adhesive is a rubber-based resin, the content of the adhesive is preferably 10 to 97.8% by mass, more preferably 15 to 90% by mass, and further preferably 20 to 80% by mass with respect to the drug-containing layer. . When the adhesive is an acrylic resin, the content of the adhesive is preferably 10 to 97.8% by mass, more preferably 15 to 90% by mass, and further preferably 20 to 80% by mass with respect to the drug-containing layer. . When the pressure-sensitive adhesive is a silicone resin, it is preferably 10 to 97.8% by mass, more preferably 15 to 90% by mass, and still more preferably 20 to 80% by mass with respect to the drug-containing layer.

7). Tackifier The drug-containing layer may further contain a tackifier for improving the adhesive strength. Examples of the tackifier include rosin, rosin glycerin ester, hydrogenated rosin, rosin derivatives such as hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, alicyclic hydrocarbon resin, terpene resin, aliphatic saturated Hydrocarbon resin, aliphatic hydrocarbon resin, maleic resin, carnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, magnesium aluminum silicate, light anhydrous silicic acid, benzyl acetate, talc, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, Examples include polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, and polyvinyl alcohol. In addition, as the tackifier, commercially available products such as Alcon series (Arakawa Chemical Co., Ltd.), Pine Crystal series (Arakawa Chemical Co., Ltd.), Clearon series (Yasuhara Chemical Co., Ltd.), YS Resin Series (Yasuhara Chemical Co., Ltd.), etc. You may use suitably. In particular, when the rubber-based resin is used as an adhesive, it is preferable to use a hydrogenated rosin glycerin ester, an alicyclic saturated hydrocarbon resin, a terpene resin, or an aliphatic saturated hydrocarbon resin as a tackifier. Rosin glycerin ester is more preferred. A tackifier can be used individually by 1 type or in combination of 2 or more types.

The content of the tackifier is preferably 5 to 70% by mass, preferably 10 to 60% by mass with respect to the drug-containing layer when a rubber-based resin is used as the adhesive in consideration of sufficient adhesive strength as a patch. % Is more preferable, and 15 to 50% by mass is more preferable. When an acrylic resin is used as the pressure-sensitive adhesive, the content is preferably 0 to 40% by mass, more preferably 0 to 30% by mass, and still more preferably 0 to 20% by mass with respect to the drug-containing layer. When a silicone resin is used as the pressure-sensitive adhesive, the content is preferably 0 to 30% by mass, more preferably 0 to 20% by mass, and still more preferably 0 to 10% by mass with respect to the drug-containing layer.

8). Plasticizer The drug-containing layer may further contain a plasticizer. Plasticizers include petroleum oils (eg, paraffinic process oil, naphthenic process oil, aromatic process oil, liquid paraffin, etc.), squalane, squalene, vegetable oils (eg, olive oil, camellia oil, castor oil, tall Oil, peanut oil, etc.), silicone oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber, etc.), diethylene glycol, polyethylene glycol, salicylic acid glycol, crotamiton, etc. It is done. Moreover, as a plasticizer, you may use suitably what is marketed, such as the Moresco white series (made by Moresco), the high call series (made by Kaneda). In particular, when the rubber-based resin is used as an adhesive, liquid paraffin is preferably used as a plasticizer. A plasticizer can be used individually by 1 type or in combination of 2 or more types.

The content of the plasticizer is adjusted in consideration of sufficient permeability of tramadol and maintenance of sufficient cohesion as a transdermal preparation. When a rubber-based resin is used as the adhesive, it is preferably 0 to 70% by mass, more preferably 0 to 60% by mass, and still more preferably 0 to 40% by mass with respect to the drug-containing layer. When an acrylic resin is used as the pressure-sensitive adhesive, the content is preferably 0 to 50% by mass, more preferably 0 to 40% by mass, and still more preferably 0 to 30% by mass with respect to the drug-containing layer. When a silicone resin is used as the pressure-sensitive adhesive, the total amount is preferably 0 to 40% by mass, more preferably 0 to 30% by mass, and further preferably 0 to 20% by mass with respect to the drug-containing layer.

9. Other optional components The drug-containing layer further contains a known additive such as a pH adjuster, a crosslinking agent, an antioxidant, a colorant, an ultraviolet absorber, a filler, or an antiseptic, as necessary. Also good.

The pH adjusting agent can be used to adjust the pH of the drug-containing layer for the purpose of improving the solubility, stability, and skin permeability of tramadol and improving the safety to the skin. The pH adjusting agent may be any compound as long as it is an acid or base or a salt thereof that is usually used for pH adjustment in the pharmaceutical field. For example, hydrochloric acid, sulfuric acid, succinic acid, acetic acid, methanesulfonic acid, edetate Acid, aqueous ammonia, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, meglumine, trometamol, glycine, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, sodium citrate, acetic acid Sodium, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, etc. are mentioned.

Examples of crosslinking agents include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. Is mentioned. Among these, an isocyanate compound or a blocked isocyanate compound is preferable.

Examples of the antioxidant include tocopherol and ester derivatives thereof, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like.

Examples of the colorant include indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitive element 201, Kumazasa extract, black iron oxide, ketket, zinc oxide, titanium oxide, iron sesquioxide, amaranth, water Examples include sodium oxide, talc, copper chlorophyllin sodium, green leaf extract powder, d-borneol, octyldodecyl myristate, methylene blue, ammonium manganese phosphate, and rose oil.

Examples of the ultraviolet absorber include amino acid compounds, benzophenone compounds, cinnamic acid derivatives, cyanoacrylate derivatives, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, and the like. Can be mentioned.

Fillers include calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, potassium bicarbonate, silicate (eg, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate Sodium), magnesium hydroxide, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.

Examples of the preservative include ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.

The total content of other optional components is preferably 0 to 10% by mass, more preferably 0 to 5% by mass with respect to the drug-containing layer.

The area of the drug-containing layer in the transdermally absorbable preparation of the present invention can be appropriately adjusted according to the content of tramadol or a pharmaceutically acceptable salt thereof, the skin permeation rate of tramadol, and the like. Typically, the area of the drug-containing layer is in the range of 2 to 140 cm ² , preferably 10 to 100 cm ² , more preferably 20 to 70 cm ² . The shape of the drug-containing layer is not particularly limited, and may be a square, a rectangle, a circle, an ellipse, or the like.

The thickness of the drug-containing layer in the transdermal preparation of the present invention can be appropriately adjusted according to the type of pressure-sensitive adhesive, the content of tramadol or a pharmaceutically acceptable salt thereof, the skin permeation rate of tramadol, and the like. Yes, it is not particularly limited. Typically, the thickness of the drug-containing layer is in the range of 20 to 300 μm, preferably 25 to 200 μm, more preferably 30 μm to 150 μm.

Unexpectedly, in the drug-containing layer of the percutaneous absorption preparation of the present invention containing a fatty acid alkanolamide, tramadol shows a high storage stability compared to the percutaneous absorption preparation containing no fatty acid alkanolamide. In the present invention, “storage stability” refers to the ratio of tramadol remaining in the drug-containing layer (% to the starting content (%) after the transdermal preparation is hermetically packaged in an aluminum bag and stored at 60 ° C. for 4 weeks. )), Which is examined by the test method described in the examples below. When the content (%) at the start is 98% or more, it is evaluated that the storage stability is high.

Further, a transdermal preparation containing no fatty acid alkanolamide in the drug-containing layer may have relatively high skin irritation, but the transdermal preparation of the present invention containing the fatty acid alkanolamide in the drug-containing layer is the same. Although it exhibits a degree of tramadol skin permeability, it exhibits low skin irritation compared to a transdermal patch with no fatty acid alkanolamide in the drug-containing layer. In the present invention, for skin irritation, the transdermal preparation is applied to the left and right torso parts of guinea pigs that have been shaved and shaved, and the transdermal preparation is removed after 24 hours, and 24, 48, and 72 are removed from the application. It is evaluated by observing the skin reaction after time and calculating a skin irritation index (PI) based on the Draize standard (1959). P. I. I. The lower the value, the lower the skin irritation, and the lower the skin irritation for the percutaneous absorption preparation, the better. More specifically, the skin irritation is examined by a test method described in Examples described later.

One embodiment of the drug-containing layer in the transdermally absorbable preparation of the present invention includes those containing tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid, and an adhesive.
As tramadol or a pharmaceutically acceptable salt thereof, tramadol acid addition salt (particularly hydrochloride) is preferable. In this case, the drug-containing layer preferably contains a basic compound.
As the fatty acid alkanolamide, lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide are preferable.
As the silicic acid, anhydrous silicic acid is preferable.
As an adhesive, what contains at least 1 sort (s) chosen from the group which consists of rubber-type resin and acrylic resin as a main component is preferable.
The content of tramadol or a pharmaceutically acceptable salt thereof is 1 to 40% by mass, the content of basic compound is 0.1 to 35% by mass, and the content of fatty acid alkanolamide is 1 to It is preferable that the content is 9% by mass, the content of silicic acid is 0.1 to 20% by mass, and the content of the adhesive is 10 to 97.8% by mass.

As another embodiment of the drug-containing layer in the transdermally absorbable preparation of the present invention, it contains tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, an absorption accelerator other than the fatty acid alkanolamide, silicic acid, and an adhesive. To do.
As tramadol or a pharmaceutically acceptable salt thereof, tramadol acid addition salt (particularly hydrochloride) is preferable. In this case, the drug-containing layer preferably contains a basic compound.
As the fatty acid alkanolamide, lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide are preferable.
The absorption accelerator other than the fatty acid alkanolamide is preferably at least one selected from fatty acid esters and organic acids. The fatty acid ester is preferably isopropyl myristate, isopropyl palmitate, or hexyl laurate. The organic acid is preferably acetic acid, caprylic acid, oleic acid, and isostearic acid.
As the silicic acid, anhydrous silicic acid is preferable.
As an adhesive, what contains at least 1 sort (s) chosen from the group which consists of rubber-type resin and acrylic resin as a main component is preferable.
The content of tramadol or a pharmaceutically acceptable salt thereof is 1 to 40% by mass, the content of basic compound is 0.1 to 35% by mass, and the content of fatty acid alkanolamide is 1 to 15 mass%, content of absorption accelerator other than fatty acid alkanolamide is 1 to 20 mass%, content of silicic acid is 0.1 to 20 mass%, and content of adhesive is 10 to 96.8 mass% Preferably there is.

<Support>
As the support in the transdermal preparation of the present invention, a drug-impermeable, stretchable or non-stretchable support can be used. Such a support is not particularly limited as long as it is usually used in the field of pharmaceuticals. For example, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.), Examples thereof include synthetic resin films or sheets such as nylon and polyurethane, or laminates, porous bodies, foams, and films in which aluminum is vapor-deposited. In order to obtain good anchoring properties with the adhesive layer, paper, woven fabric, nonwoven fabric, or a laminate of these and a film can also be used as the support.

<Release liner>
The transdermally absorbable preparation of the present invention may further have a release liner. In this case, the release liner is laminated on the surface of the drug-containing layer laminated on the support opposite to the surface in contact with the support, and protects the drug-containing layer until the transdermal preparation is applied to the skin. can do. The release liner is not particularly limited as long as it is impermeable to at least tramadol or a pharmaceutically acceptable salt thereof in the drug-containing layer. For example, the release liner is made of a polymer material such as polyethylene, polypropylene, polyester, polyethylene terephthalate. Film, a film in which aluminum is vapor-deposited, and a film in which silicone oil or the like is coated on paper.

<Manufacture of transdermal preparation>
The transdermally absorbable preparation of the present invention can be produced according to a known method. Prepare a mixture containing tramadol or a pharmaceutically acceptable salt thereof, fatty acid alkanolamide, silicic acid, and adhesive, and other ingredients as required, and apply or spread this mixture on a release liner to create a drug It can manufacture by forming a content layer and bonding a support body to this drug content layer.

Specifically, the components in the drug-containing layer are added to an organic solvent so as to have the content, and mixed and stirred to prepare a coating solution.

As the organic solvent, ethyl acetate, hexane, pentane, heptane, toluene, cyclohexane, chloroform, methylene chloride, methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, cyclohexanone, acetone, a mixed solvent thereof or the like can be used. The content of the organic solvent in the coating solution is not particularly limited, and is, for example, 30 to 90% by mass, preferably 40 to 80% by mass with respect to the entire coating solution.

Next, this coating solution is applied or spread on a release liner, the solvent in the coating solution is evaporated to form a drug-containing layer, and then a support is attached to obtain a transdermal absorption preparation. Can do. Alternatively, a transdermal preparation can be obtained by applying or spreading a coating liquid on a support, evaporating the solvent in the coating liquid to form a drug-containing layer, and then attaching a release liner. . From the viewpoint of ease of production, a method in which a coating solution is applied or spread on a release liner, a solvent in the coating solution is evaporated to form a drug-containing layer, and then a support is bonded together is preferable. Coating or spreading of the coating solution can be performed using a knife coater, comma coater, reverse coater, or die coater. Although an example of a manufacturing flow is shown in FIG. 1, it is not limited to this.

In the percutaneous absorption type preparation of the present invention, the components in the drug-containing layer are heated and melted, and the melt is applied or spread on a release liner to form a drug-containing layer, and then the support is formed. A percutaneous absorption type preparation can also be produced by bonding. After the melt is applied or spread on a support to form a drug-containing layer, a transdermal preparation may be produced by laminating a release liner.

<Administration method>
The treatment of pain by the transdermal preparation of the present invention can be performed by directly applying the transdermal preparation of the present invention to the skin of the subject and transdermally administering tramadol. The subject in the present invention is a mammal such as a human, preferably a human.

When tramadol is transdermally administered by the transdermally absorbable preparation of the present invention, the content of tramadol or a pharmaceutically acceptable salt thereof in the drug-containing layer so as to achieve a blood concentration effective for the treatment of pain The percutaneously absorbable preparation of the present invention is applied to the skin after appropriately adjusting the skin permeation rate of tramadol, the area of the drug-containing layer, the thickness of the drug-containing layer and the like.

The percutaneous absorption type preparation of the present invention may be applied to the skin of any part of the body as long as it can be applied. For example, it can be applied to the upper arm, abdomen, chest, neck, waist back, buttocks or legs. Can be pasted.

Transdermal administration of the transdermal preparation of the present invention to a subject may be combined with administration of a pharmaceutical composition containing a pharmaceutical ingredient other than tramadol, if necessary. In this case, the administration form may be simultaneous administration or administration with a time difference, and the pharmaceutical composition may be intravenous, intraperitoneal, subcutaneous and intramuscular, oral, topical or transmucosal. It can be administered by various routes including: In addition, a pharmaceutical composition containing a pharmaceutical ingredient other than tramadol is administered to a subject by an administration route usually used for the pharmaceutical ingredient. Pharmaceutical components other than tramadol include, but are not limited to, analgesics such as acetaminophen, nonsteroidal anti-inflammatory analgesics such as diclofenac sodium and loxoprofen sodium, and local anesthetics such as lidocaine.

EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not limited to a following example. In each example, “%” is “% by mass” unless otherwise specified.

(Manufacture of tramadol hydrochloride-containing transdermal patches)
Example 1
-Preparation of rubber-based resin composition Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Nippon Zeon Co., Ltd.), hydrogenated rosin glycerin ester (Pine Crystal KE-311, manufactured by Arakawa Chemical Industries, Ltd.), polyisobutylene (Oppanol B12SFN) (Manufactured by BASF) was dissolved in a mixed solution of toluene and hexane so as to have a solid concentration of 30% to obtain a rubber-based resin composition.
Ingredient name Mixing ratio Quintac 3570C (made by Nippon Zeon) 45%
Pine Crystal KE-311 (Arakawa Chemical Industries) 45%
Opanol B12SFN (BASF) 10%

・ Manufacture of transdermal patches: Dissolve in tramadol hydrochloride as an active ingredient, rubber-based resin composition as an adhesive, and an appropriate amount of ethanol as a basic compound so that the solid content after coating and drying is as follows. Sodium hydroxide (manufactured by Kanto Chemical Co., Inc.), lauric acid diethanolamide as fatty acid alkanolamide, silicic anhydride as silicic acid, and isopropyl myristate as an absorption accelerator other than fatty acid alkanolamide after mixing and stirring in an appropriate amount of toluene A coating solution was obtained.
Ingredient name Mixing ratio Tramadol hydrochloride 15%
Rubber resin composition 65%
Sodium oxide 2%
Lauric acid diethanolamide 3%
Silicic anhydride 5%
Isopropyl myristate 10%

The coating solution was applied on a release film (film binder 75E-0010 BD: manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after evaporation of the solvent was about 75 μm and dried, and then the support (EH-1212: Nippon Viylene Co., Ltd.) was bonded to produce a transdermal absorption preparation.

Examples 2-7
As shown in Table 1, the same procedure as in Example 1 was performed except that the absorption accelerator other than the fatty acid alkanolamide was changed to isopropyl palmitate, hexyl laurate, acetic acid, caprylic acid, oleic acid, and isostearic acid, respectively. The transdermal patches of Examples 2 to 7 were produced.

Examples 8 and 9
As shown in Table 1, transdermal patches of Examples 8 and 9 were produced in the same manner as in Example 1 except that the fatty acid alkanolamide was changed to oleic acid diethanolamide and lauric acid monoisopropanolamide, respectively. .

Comparative Example 1
As shown in Table 2, a transdermal patch of Comparative Example 1 was produced in the same manner as in Example 1 except that no silicic acid was blended and the blending ratio of the rubber-based resin composition was increased accordingly. .

Comparative Examples 2-10
As shown in Table 2, absorption accelerators other than fatty acid alkanolamides are hexyl laurate, oleic acid, isostearic acid, propylene glycol monocaprylate, isostearyl alcohol, propylene glycol, 1,3-butylene glycol, triacetin, and Comparative percutaneously absorbable patches of Comparative Examples 2 to 10 were produced in the same manner as in Comparative Example 1 except that propylene carbonate was used.

Comparative Example 11
As shown in Table 2, the transdermal patch of Comparative Example 11 was produced in the same manner as in Example 8 except that no silicic acid was blended and the blending ratio of the rubber-based resin composition was increased accordingly. .

Comparative Example 12
As shown in Table 2, the transdermal patch of Comparative Example 12 was produced in the same manner as in Example 9 except that the silicic acid was not blended and the blending ratio of the rubber-based resin composition was increased accordingly. .

Comparative Examples 13-15
As shown in Table 3, lauric acid diethanolamides were respectively converted into POE (4.2) lauryl ether (BL-4.2: manufactured by Nikko Chemicals), sorbitan monolaurate (SPAN20: manufactured by Croda Japan), and glyceryl monocaprylate. Transdermal absorption patches of Comparative Examples 13 to 15 were produced in the same manner as in Example 1 except that (Capmul 708G: manufactured by ABITEC Corporation) was used.

Test Example 1 (In vitro skin permeability test)
Using the transdermal absorption patch obtained above, an in vitro skin permeability test was performed according to the following procedure.
After affixing the transdermal patches of each Example and Comparative Example to the horny layer side of 7-week-old male hairless mouse isolated skin (Hos: HR-1 system, manufactured by Hoshino Laboratory Animal Breeding Co., Ltd.), 32 It was attached to a vertical diffusion cell (trade name: Palm Cell Vertical TP-6: manufactured by Beadrex Co., Ltd.) in which warm water of 5 ° C. was circulated around the outer periphery so that the skin basement membrane was on the receiver side. The receiver cell was filled with phosphate buffered saline (PBS (-), manufactured by Wako Pure Chemical Industries, Ltd.), the receiver solution was sampled over time, and the amount of tramadol in the receiver solution was measured by HPLC. The amount of permeated drug at each time was calculated from the measurement results, and the skin permeation rate of tramadol was calculated (average value of n = 3).

<HPLC measurement conditions>
Apparatus: ACQUITY UPLC H-Class system (manufactured by Waters)
Column: ACQUITY UPLC BEH C18 1.7 μm, 2.1 × 50 mm (manufactured by Waters)
Column temperature: 40 ° C
Flow rate: About 0.5mL / min
Detection wavelength: 215 nm
Mobile phase: 0.1% trifluoroacetic acid aqueous solution / acetonitrile mixture

The obtained results are shown in Tables 1 to 3. In each of the transdermal patches of Examples 1 to 9 and Comparative Examples 1 to 15, the skin permeation rate was 40 μg / cm ² / h, and good skin permeability was exhibited.

Test example 2 (coagulation evaluation)
The cohesiveness of the transdermal patches of each Example and Comparative Example was evaluated by the following procedure. The release liner was removed from the transdermal absorption patch, the surface of the drug-containing layer was strongly suppressed with a finger, the amount of adhesive remaining on the finger when peeled off was visually observed, and evaluated according to the following criteria.
A: It has a good cohesive strength without leaving an adhesive.
B: Adhesive is only slightly left and has cohesive strength.
C: A large amount of adhesive remains and the cohesive force is weak.

The obtained results are shown in Tables 1 to 3. The evaluations of the transdermal patches of Examples 1 to 9 and Comparative Examples 1 to 15 were all A or B and had sufficient cohesiveness as the transdermal patches. However, the evaluation of the transdermal patches of Examples 1, 3, 8, and 9 was A, whereas Comparative Examples 1, 2, 11, and 12 in which no silicic acid anhydride was blended. The evaluation of the transdermal patch is B, suggesting that higher cohesiveness can be obtained when silicic anhydride is added to the drug-containing layer.

Test Example 3 (Bleeding evaluation)
About the transdermal absorption type patch of each Example and the comparative example, the surface of the removed release liner was observed visually and bleeding was evaluated.
○: No bleeding ×: With bleeding

The obtained results are shown in Tables 1 to 3. No bleeding was observed in the transdermal patches of Examples 1 to 9. Bleeding was observed in the transdermal patches of Comparative Examples 1-12. Therefore, it was shown that the occurrence of bleeding caused by adding a fatty acid alkanolamide and an absorption accelerator other than the fatty acid alkanolamide to the drug-containing layer can be suppressed by adding silicic acid. Further, since bleeding was observed in the transdermal absorption patches of Comparative Examples 13 to 15, the blending of the fatty acid alkanolamide in the drug-containing layer was more effective than the blending of an absorption accelerator other than the fatty acid alkanolamide. It was shown that generation can be suppressed.

Test Example 4 (Stability test)
The transdermal patches of Examples and Comparative Examples were hermetically packaged in aluminum bags and stored at 60 ° C. for 4 weeks, and then the tramadol content in the drug-containing layer of each patch was measured by the HPLC method. A sample preparation method and HPLC measurement conditions are shown below.

<Method for preparing sample solution>
After peeling off the release liner of each transdermal absorption type patch, it was placed in a screw tube, and 5 mL of an internal standard solution (ethyl 4-aminobenzoate / tetrahydrofuran solution) was added and extracted with shaking. 20 mL of methanol was added to this solution and shaken. After taking 1 mL of this solution and adding 4 mL of water, it was filtered through a 0.2 μm membrane filter to obtain a sample solution.

From the content of tramadol in the stored sample and the content of tramadol in the initial sample, the content at start (%) was calculated by the following formula.
Content at start (%) = tramadol content in the stored sample / tramadol content in the initial sample × 100

The obtained results are shown in Tables 1 to 3. All of the transdermal patches of Examples 1 to 9 had a high storage stability with a content (%) at the start after storage at 60 ° C. for 4 weeks of 98% or more. On the other hand, the percutaneous absorption type patches of Comparative Examples 1 to 4, 6, 11, and 12 had a content (%) at the start of 98% or more, but the percutaneous absorption types of Comparative Examples 5 and 7 to 10 In the patch, the content (%) at the start was less than 98%.
In contrast, the percutaneous absorption type patch of Example 1 had a starting content (%) of 98% or more, while the percutaneous absorption type patches of Comparative Examples 13 to 15 had a starting content (%). %) Was less than 98%. Therefore, it was shown that the storage stability of tramadol is higher when the fatty acid alkanolamide is added to the drug-containing layer than when an absorption accelerator other than the fatty acid alkanolamide is added.

Test Example 5 (guinea pig skin primary irritation test)
Six week old Hartley male guinea pigs were used. On the day before administration, the left and right torso parts of the guinea pig were shaved and shaved to a size of about 4 × 8 cm. On the next day of cutting, the patches (diameter 15 mm) of Examples 1, 2, 6 and Comparative Examples 13 to 15 were affixed to the left and right torso parts and fixed with an adhesive foam pad M (manufactured by 3M Healthcare). A polyethylene film tape (Keeppore A, manufactured by Nichiban Co., Ltd.) was wound around the body and fixed with Silky Tech (ALCARE No. 5). 24 hours after administration, each patch was removed, and the applied site was wiped with absorbent cotton moistened with acetone.
The skin reaction was observed 24, 48, and 72 hours after administration, and a skin irritation index (PI) was calculated with reference to the Draize criteria (1959) shown in Table 4. Skin irritation was evaluated. However, observation 24 hours after administration was performed about 1 hour after wiping. For each test substance, an individual score at 24, 48, and 72 hours after administration was calculated and divided by the number of observations (three times). I. I. (Individual PI) was calculated. Individual P.M. I. I. Values were summed, and the average value was calculated as P.P. I. I. It was.

The evaluation of irritation is based on P.I. I. When I was 0, it was designated as “non-irritant”, when it was greater than 0 and less than 2, “mildly irritating”, when 2 or more and less than 5, “moderately irritating”, and when 5 or more, “strongly irritating” Statistical processing was not performed during the evaluation.

The results are shown in Table 5. Although the skin irritation of any of the transdermal patches was mild, the transdermal patches of Examples 1, 2 and 6 had a lower P.P. than the transdermal patches of Comparative Examples 13-15. I. I was shown. Therefore, the transdermal absorption patch of the present invention exhibits substantially the same skin irritation compared to the transdermal absorption patch that shows the same level of tramadol skin permeability but does not contain a fatty acid alkanolamide in the drug-containing layer. Was shown to be reduced.

According to the present invention, there is provided a transdermal absorption preparation containing tramadol or a pharmaceutically acceptable salt thereof, which has high storage stability and improved the skin permeability of tramadol while maintaining good aggregation properties. Is done. Therefore, the present invention can provide a means for administering tramadol with improved convenience.

Claims

A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer contains tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid, and an adhesive. Skin absorption type preparation.
The transdermal preparation according to claim 1, wherein the adhesive contains a rubber-based resin as a main component.
The transdermal preparation according to claim 2, wherein the rubber-based resin contains a styrene-isoprene-styrene block copolymer and a tackifier.
The transdermal preparation according to claim 3, wherein the tackifier is a hydrogenated rosin glycerin ester.
The transdermal absorption preparation according to any one of claims 1 to 4, wherein the fatty acid alkanolamide is at least one selected from lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide.
The transdermal absorption preparation according to any one of claims 1 to 5, wherein the drug-containing layer further contains an absorption enhancer.
The percutaneous absorption preparation according to claim 6, wherein the absorption accelerator is at least one selected from fatty acid esters and organic acids.
The transdermal preparation according to claim 7, wherein the fatty acid ester is at least one selected from isopropyl myristate, isopropyl palmitate, and hexyl laurate.
The transdermal preparation according to claim 7, wherein the organic acid is at least one selected from acetic acid, caprylic acid, oleic acid, and isostearic acid.
The transdermal preparation according to any one of claims 1 to 9, wherein the drug-containing layer contains a pharmaceutically acceptable acid addition salt of tramadol and a basic compound.
The transdermal preparation according to claim 10, wherein the basic compound is at least one selected from inorganic bases and aliphatic alkanolamines.
A method for producing a transdermally absorbable preparation according to claim 1, comprising preparing a mixture comprising tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid, and an adhesive, A production method comprising applying or spreading on a release liner to form a drug-containing layer, and bonding a support to the drug-containing layer.