JP6695571B2 - Transdermal formulation - Google Patents

Description

  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 the opioid analgesics and mild in WHO cancer pain treatment. To weak opioids used for moderate to moderate pain. The analgesic effect of tramadol is considered to be due to inhibition of nociceptive transmission by binding to the μ opioid receptor and activation of the descending pain inhibitory system by inhibiting serotonin / noradrenaline reuptake. Tramadol is effective in reducing pain and chronic pain in various cancers, and is currently used as tramadol hydrochloride in the form of injections, oral preparations, suppositories, and the like. Tramadol hydrochloride has the chemical structure of formula (I):

There have been some reports to date on transdermal preparations of opioid analgesics.
In Patent Document 1, when menthol, O-ethylmenthol, or limonene was blended as an absorption enhancer into a tramadol-containing hydrogel, the transdermal absorbability of tramadol was enhanced as compared with the case where cholic acid was blended as an absorption enhancer. Is disclosed.
In Patent Document 2, isopropyl myristate and a compound selected from the group consisting of glyceryl monocaprylate, glyceryl monocaprate and glyceryl monolaurate are used as an absorption enhancer, and pentazocine which is an opioid receptor antagonist is used. It has been disclosed that the percutaneous absorption of is improved. Patent Document 2 also mentions tramadol hydrochloride as an opioid receptor antagonist, but does not disclose any example showing that the above-mentioned absorption enhancer improves transdermal absorption of tramadol.
Patent Document 3 discloses that high skin permeability of tramadol was obtained by formulating free form 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 in tramadol hydrochloride-containing organogel, the skin permeability of tramadol was extremely low.

JP, 2006-36687, A International publication WO2006 / 085521 International publication WO2011 / 059037

  The present inventors have been investigating in order to improve the skin permeability of tramadol in a transdermal preparation containing tramadol or a pharmaceutically acceptable salt thereof. It has been recognized that there is a problem that when an absorption promoter is added, bleeding (a phenomenon in which a liquid component oozes out from a drug-containing layer containing an adhesive) occurs, and cohesiveness may be reduced. Patent Documents 1 to 3 do not describe such a problem at all.

  Accordingly, the present invention provides a transdermal preparation containing tramadol or a pharmaceutically acceptable salt thereof, which does not cause bleeding and maintains cohesiveness while maintaining tramadol's skin permeability. With the goal.

As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that the use of fatty acid alkanolamide as an absorption enhancer enables high skin permeability of tramadol. Furthermore, the present inventors have found that when the content of the fatty acid alkanolamide is increased to a certain value or more in order to further improve the skin permeability, or when an absorption enhancer other than the fatty acid alkanolamide is further added, bleeding is It has been found that there is a new problem that it may occur and the cohesiveness may decrease. As a result of further studies, it was found that, even in such a case, by incorporating silicic acid in the drug-containing layer, bleeding does not occur and good cohesiveness can be maintained. Further, it was unexpectedly found that tramadol exhibits high storage stability in the drug-containing layer thus obtained.
The present inventors have conducted further research based on these findings and completed the present invention.
That is, the present invention is as follows.

[1] A transdermal preparation having a support and a drug-containing layer, the drug-containing layer containing tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid, and an adhesive. A transdermal formulation.
[2] The percutaneous absorption type preparation according to [1], wherein the adhesive contains a rubber resin as a main component.
[3] The percutaneous absorption-type pharmaceutical preparation according to [2], wherein the rubber resin contains a styrene-isoprene-styrene block copolymer and a tackifier.
[4] The transdermal preparation according to [3], wherein the tackifier is hydrogenated rosin glycerin ester.
[5] The percutaneous 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 preparation according to any one of [1] to [5], wherein the drug-containing layer further contains an absorption enhancer.
[7] The percutaneous absorption-type pharmaceutical preparation according to [6], wherein the absorption enhancer is at least one selected from fatty acid esters and organic acids.
[8] The percutaneously absorbable 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 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 transdermal preparation according to any one of [1] to [9], wherein the drug-containing layer contains a pharmaceutically acceptable acid addition salt of tramadol and a basic compound.
[11] The percutaneous absorption-type 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 the percutaneous absorption-type pharmaceutical preparation according to [1],
Preparing a mixture comprising tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid, and an adhesive,
The said manufacturing method including apply | coating or spreading the said mixture on a release liner, and forming a drug containing layer, and sticking a support body to the said drug containing layer.

  According to the present invention, in a transdermal preparation containing tramadol or a pharmaceutically acceptable salt thereof, the skin permeability of tramadol can be improved while maintaining good cohesiveness. Further, according to the present invention, the storage stability of tramadol in the drug-containing layer can be increased. Therefore, it is possible to provide a means for administering tramadol which is more convenient.

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

  In the present invention, the transdermal preparation is a parenteral preparation in which the active ingredient is absorbed through the skin and delivered to the bloodstream. The transdermal preparation of the present invention is a patch having a support and a drug-containing layer, and examples thereof include tapes, poultices, plasters and the like.

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

  From the viewpoint of ease of formulation design and 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.

  As used herein, 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 transdermal preparation of the present invention, the drug-containing layer contains tramadol or a pharmaceutically acceptable salt thereof. Tramadol has an analgesic effect 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 (nociceptive pain (e.g., low back pain, osteoarthritis, etc.), Neuropathic pain (for example, postherpetic neuralgia, diabetic neuropathic pain, etc., and psychogenic pain) and the like.

  The pharmaceutically acceptable salts of tramadol include acid addition salts such as inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates; and organic acid salts such as 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) and the like, but are not limited thereto.

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

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

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

  In the transdermal preparation of the present invention, the 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 and adding an absorption enhancer described below to the drug-containing layer. It can be carried out. The skin permeation rate of tramadol in the present invention means a value measured by an in vitro skin permeation test described in Examples below.

The skin permeation rate of tramadol is usually 40 μg / cm ² / hour or more, preferably 50 μg / cm ² / hour or more, and more preferably 60 μg / cm ² / hour. 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. When 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. When an acid addition salt is used as the pharmaceutically acceptable salt of the basic compound tramadol, it is preferable to include the basic compound in the drug-containing layer. Examples of the basic compound include inorganic bases and organic bases, for example, low molecular weight compounds containing a basic nitrogen (for example, ethanolamine, isopropanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine and the like). 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 (eg, sodium hydroxide, potassium hydroxide, etc.). Further, a commercially available basic acrylic resin such as Eudragit series (Eudragit E100, Eudragit EPO: manufactured by Evonik Industry) may be used. Of these, inorganic bases and aliphatic alkanolamines are preferable, and sodium hydroxide, potassium hydroxide and diisopropanolamine are more preferable.

  The basic compounds can be used alone or in admixture of two or more. The content of the basic compound is preferably 0.5 to 3 equivalents, and more preferably 0.7 to 2 equivalents based on the equivalent of the pharmaceutically acceptable salt of tramadol. The content of the basic compound is preferably 0.1 to 35% by mass, more preferably 0.5 to 30% by mass, and 1 to 25% by mass based on the drug-containing layer. Is more preferable. By containing such a basic compound, the basic compound acts on the 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 transdermal preparation of the present invention, the drug-containing layer contains fatty acid alkanolamide as an absorption promoter. Fatty acid alkanolamides are, for example, saturated with C _{12 to} C ₁₈ or fatty acid moieties having one or more double bonds (preferably 1 or 2 double bonds) and, for example, C ₂ to C substituted with one or more hydroxy. C ₆ alkyl (preferably monohydroxyalkyl C _2-4 alkyl) comprises a alkanolamide moiety or di alkanolamide moiety containing, for example, lauric acid diethanolamide, palmitic acid diethanolamide, stearic acid diethanolamide, diethanolamine oleic acid Ami And lauric acid monoisopropanolamide. Of these, lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide are preferable.

  The fatty acid alkanolamides can be used alone or in admixture of two or more. The content of the fatty acid alkanolamide in the transdermal preparation of the present invention is, in one aspect, 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, it is preferably 1 to 10% by mass, more preferably 1 to 5% by mass, and further preferably 1 to 3% by mass. When the content of the fatty acid alkanolamide is 1% by mass or more, the skin permeation rate of tramadol which can achieve a blood concentration effective for treating pain can be provided.

4. Other absorption enhancer In the percutaneous absorption type 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 which is recognized to have a skin permeation promoting action in transdermal administration, and examples thereof include acetic acid, caprylic acid, capric acid, lauric acid, myristic acid, and 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 benzenesulfonic acid, toluenesulfonic acid, saccharin or salts thereof; isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, hexadecyl isostearate, hexyl laurate, decyl oleate, oleyl oleate, diisopropyl adipate. , Diethyl sebacate, diisopropyl sebacate, medium-chain fatty acid triglyceride, glycerin tri (caprylic / capric acid), glyceryl monooleate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monopalmitate , Fatty acid esters such as propylene glycol monostearate, propylene glycol monooleate, propylene glycol monobehenate and propylene glycol dicaprate; esters such as triacetin, ethyl lactate, triethyl citrate; sorbitan monolaurate, sorbitan monooleate, etc. Fatty acid esters of polyoxyethylene sorbitan such as polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monostearate; polyethylene glycol monooleate; mono Polyoxyethylene fatty acid esters such as polyethylene glycol stearate, polyethylene glycol monopalmitate, polyethylene glycol monolaurate; decanol, lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, cetyl alcohol, hexyldecanol, octyldodecanol, benzyl alcohol Aliphatic or aromatic alcohols or ethers thereof; polyhydric alcohols having 3 to 8 carbon atoms (for example, propylene glycol, 1,3-butanediol, 1,4-butanediol, glycerin, dipropylene glycol, octanediol, etc.); phenol ethers such as polyoxyethylene nonyl phenyl ether, polyoxyethylene octyl phenyl ether; castor oil or hydrogenated castor oil; oleoyl sarcosine, lauryl dimethyl Ionic surfactants such as aminoacetic acid betaine 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 ether, polyoxyethylene behenyl ether, etc.); nonionic surfactants such as dimethyllaurylamine oxide; alkylmethyl sulfoxides such as dimethyl sulfoxide, decylmethyl sulfoxide; 2-pyrrolidone, N-methyl Pyrrolidones such as 2-pyrrolidone and N-ethyl-2-pyrrolidone; Azacycloalkanes such as 1-dodecylazacycloheptan-2-one and 1-geranylazacycloheptan-2-one; menthol, camphor, limonene Such as terpenes. The absorption promoters other than the fatty acid alkanolamides may be used alone or in combination of two or more. In a preferred embodiment, the absorption promoter 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 enhancer other than the fatty acid alkanolamide, and in the case where the drug-containing layer contains one, the content thereof is 1% by mass or more, for example, 2% by mass based on the total mass of the drug-containing layer. 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 promoter 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. The total content of the fatty acid alkanolamide and the absorption enhancer other than the fatty acid alkanolamide in the drug-containing layer may be 1% by mass or more and 25% by mass or less, for example, less than 20% by mass, unless bleeding occurs. , Less than 15% by mass and less than 10% by mass.

5. Silicic Acid In the transdermal preparation of the present invention, the drug-containing layer contains silicic acid. In the present invention, silicic acid means silicon dioxide (silicic anhydride) or a salt thereof, and examples thereof include silicic acid anhydride and silicates (for example, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate). , Sodium magnesium silicate, etc.), and silicic anhydride is preferable.

  The content of silicic acid is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and 1 to 10% by mass based on the total mass of the drug-containing layer. Is more preferable. When the content of silicic acid is 0.1% by mass or more, bleeding that occurs when a fatty acid alkanolamide and other absorption promoters are mixed in the drug-containing layer can be suppressed, and good cohesiveness can be maintained. .. Further, it is preferable that the drug-containing layer contains silicic acid such that the total amount of the fatty acid alkanolamide and the other absorption promoter 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 the drug-containing layer containing an adhesive, and the presence or absence of occurrence can be visually evaluated as described in Examples below. In the present invention, the cohesiveness is evaluated based on the cohesive force of the pressure-sensitive adhesive, which is examined by the test method described in Examples below.

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

  The pressure-sensitive adhesive preferably contains at least one selected from the group consisting of acrylic resins, rubber-based resins and silicone-based resins as a main component, and at least selected from the group consisting of rubber-based resins and acrylic resins. Those containing one kind as a main component are more preferable. Here, the "main component" means usually 70 mass% or more, further 80 mass% or more, further 90 mass% or more, and particularly 100 mass% with respect to the total mass of the pressure-sensitive adhesive.

  As the acrylic resin, for example, as a monomer unit, a (meth) acrylic acid ester represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like is used. A polymer or copolymer containing at least one kind may be mentioned. Specifically, for example, acrylic acid / acrylic acid octyl ester copolymer, acrylic acid 2-ethylhexyl / vinylpyrrolidone copolymer solution, acrylic acid 2-ethylexyl / 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 Dodecyl copolymer solution, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin alkanolamine solution and the like can be mentioned. In addition, DURO-TAK (registered trademark) acrylic adhesive series (DURO TAK 87-900A, 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 87-2353, DURO TAK 87-2852, DURO TAK 387-2051, DURO TAK 87-2051, DURO TAK 387-2052, DURO TAK 87-2052, DURO TAK 387-2054, DURO TAK 87-2054, DURO TAK 87-2194, DURO TAK 87- 2196: Henkel), GELVA series (GELVA GMS 3083, GELVA GMS 3253, GELVA GMS 788, GELVA GMS 9073: Henkel), MAS-683, MAS-811, MASCOS10, MAS11D1 (Cosmedy Pharmaceutical) You may use the commercially available acrylic resin of.

  Examples of the rubber resin include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), styrene isoprene rubber, polyisobutylene (PIB). ), Polybutene, butyl rubber, natural rubber, raw rubber, gum arabic, gum arabic powder, isoprene rubber and the like, but SIS is preferable. In addition, commercially available rubber resins such as Quintac (registered trademark) series (Quintac 3570C, etc .: manufactured by Zeon Corporation), Kraton D polymer series (manufactured by Kraton Polymer Japan), JSR SIS / TR series (manufactured by JSR Life Science) are used. You may.

  Examples of the silicone-based resin include polymers having an organopolysiloxane skeleton and derivatives thereof, and specific examples thereof include dimethylpolysiloxane, polymethylvinylsiloxane, polymethylphenylsiloxane, and diphenylsiloxane. Alternatively, a commercially available silicone resin such as BIO-PSA series (manufactured by Dow Corning) may be used.

  As the pressure-sensitive adhesive contained in the drug-containing layer of the transdermal preparation of the present invention, one type selected from the above acrylic resin, rubber type resin and silicone type resin may be used alone or in combination of two or more types. Can be used. More preferably, it is an acrylic or rubber resin.

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

7. Tackifier The drug-containing layer may further contain a tackifier for improving the adhesive strength. As the tackifier, for example, rosin, glycerin ester of rosin, 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, resin maleate, carnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, magnesium aluminum silicate, light anhydrous silicic acid, benzyl acetate, talc, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, Examples thereof include polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, and polyvinyl alcohol. 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.), and YS resin series (Yasuhara Chemical Co., Ltd.) You may use it suitably. Particularly when the rubber-based resin is used as the tackifier, it is preferable to use hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, terpene resin, and aliphatic saturated hydrocarbon resin as the tackifier. More preferred is rosin glycerin ester. The tackifiers may be used alone or in combination of two or more.

  The content of the tackifier is preferably 5 to 70% by mass, and 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 further preferable. When an acrylic resin is used as the pressure-sensitive adhesive, it is preferably 0 to 40% by mass, more preferably 0 to 30% by mass, and even 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, it is preferably 0 to 30% by mass, more preferably 0 to 20% by mass, further preferably 0 to 10% by mass, based on the drug-containing layer.

8. Plasticizer The drug-containing layer may further contain a plasticizer. Examples of the plasticizer include petroleum-based oils (for example, paraffin-based process oil, naphthene-based process oil, aromatic-based process oil, liquid paraffin, etc.), squalane, squalene, and plant-based oils (for example, olive oil, camellia oil, castor oil, tall oil). 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, glycol salicylate, crotamiton etc. Be done. Further, as the plasticizer, commercially available ones such as Moresco White series (manufactured by Moresco) and Hicol series (manufactured by Kaneda) may be appropriately used. In particular, when the rubber-based resin is used as the adhesive, liquid paraffin is preferably used as the plasticizer. The plasticizers may be used alone or in combination of two or more.

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

9. Other optional components The drug-containing layer further contains known additives such as a pH adjusting agent, a cross-linking agent, an antioxidant, a colorant, an ultraviolet absorber, a filler, or a preservative, if necessary. You may.

  The pH adjusting agent can be used for adjusting 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 which is usually used for pH adjustment in the field of pharmaceuticals, and examples thereof include hydrochloric acid, sulfuric acid, succinic acid, acetic acid, methanesulfonic acid and edetate. Acid, ammonia water, 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 and the like can be mentioned.

  Examples of the cross-linking agent include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic cross-linking agents, inorganic cross-linking agents such as metals or metal compounds. Is mentioned. Of these, isocyanate compounds or blocked isocyanate compounds are preferred.

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

  As the colorant, for example, indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitizer No. 201, Kumazasa extract, black iron oxide, quette, zinc oxide, titanium oxide, iron sesquioxide, amaranth, water Examples thereof include sodium oxide, talc, sodium copper chlorophyllin, green leaf extract of Hadakamugi, d-borneol, octyldodecyl myristate, methylene blue, manganese ammonium 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.

  Examples of the filler include calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, potassium hydrogen carbonate, silicates (for example, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate). Sodium, etc.), magnesium hydroxide, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.

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

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

The area of the drug-containing layer in the transdermal preparation of the present invention can be appropriately adjusted depending on the content of tramadol or a pharmaceutically acceptable salt thereof, the skin permeation rate of tramadol, and the like. Typically, it is in the range of ^{2 to} 140 cm ² , preferably 10 to 100 cm ² , and more preferably 20 to 70 cm ² . The shape is not particularly limited, and may be square, rectangular, circular, elliptical, or the like.

  The thickness of the drug-containing layer in the transdermal preparation of the present invention may be appropriately adjusted depending on the type of adhesive, the content of tramadol or a pharmaceutically acceptable salt thereof, the skin permeation rate of tramadol, and the like. It is possible and is not particularly limited. It is typically in the range of 20 to 300 μm, preferably 25 to 200 μm, more preferably 30 μm to 150 μm.

  Unexpectedly, tramadol exhibits higher storage stability in the drug-containing layer of the transdermal preparation of the present invention containing a fatty acid alkanolamide, as compared with a transdermal preparation without a fatty acid alkanolamide. In the present invention, the storage stability means the ratio of tramadol remaining in the drug-containing layer after the transdermal preparation is hermetically packaged in an aluminum bag and stored at 60 ° C. for 4 weeks (content at the start (%)). And means the test method described in Examples below. When the content (%) at the start is 98% or more, it is evaluated that the storage stability is high.

  Further, a transdermal drug preparation containing no fatty acid alkanolamide in the drug-containing layer may have relatively high skin irritation, but a transdermal drug preparation of the present invention containing a fatty acid alkanolamide in the drug-containing layer is It shows a certain level of tramadol skin permeability, but shows lower skin irritation than a transdermal patch, which does not contain a fatty acid alkanolamide in the drug-containing layer. In the present invention, the skin irritation is obtained by applying the transdermal preparation on the left and right side torso shaved and shaved of guinea pigs, removing the transdermal preparation after 24 hours, and applying the transdermal preparations 24, 48, and 72. It is evaluated by observing the skin reaction after time and calculating a skin irritation index (P.I.I.) based on Draize's standard (1959). P. I. I. The lower the value is, the lower the skin irritation is, and the lower the skin irritation is, the more preferable as a percutaneous absorption type preparation. The skin irritation is more specifically examined by the test method described in Examples below.

One embodiment of the drug-containing layer in the transdermal preparation of the present invention is one 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, silicic acid anhydride is preferable.
The pressure-sensitive adhesive preferably contains at least one selected from the group consisting of rubber-based resins and acrylic-based resins as a main component.
Based on the drug-containing layer, the content of tramadol or a pharmaceutically acceptable salt thereof is 1 to 40% by mass, the content of the basic compound is 0.1 to 35% by mass, and the content of the fatty acid alkanolamide is 1 to It is preferable that the content of the silica 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 aspect of the drug-containing layer in the transdermal preparation of the present invention, tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, an absorption promoter other than fatty acid alkanolamide, silicic acid, and an adhesive are contained. There are things 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 promoter 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, silicic acid anhydride is preferable.
The pressure-sensitive adhesive preferably contains at least one selected from the group consisting of rubber-based resins and acrylic-based resins as a main component.
Based on the drug-containing layer, the content of tramadol or a pharmaceutically acceptable salt thereof is 1 to 40% by mass, the content of the basic compound is 0.1 to 35% by mass, and the content of the fatty acid alkanolamide is 1 to 15% by mass, the content of the absorption promoter other than the fatty acid alkanolamide is 1 to 20% by mass, the content of silicic acid is 0.1 to 20% by mass, and the content of the adhesive is 10 to 96.8% by mass. Preferably.

<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, and examples thereof include polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.), Examples thereof include synthetic resin films or sheets of nylon, polyurethane, etc., or laminates thereof, porous bodies, foams, and films obtained by vapor deposition of aluminum. Further, in order to obtain a good anchoring property with the adhesive layer, paper, woven fabric, non-woven fabric, or a laminate of these and a film can be used as the support.

<Release liner>
The transdermal 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, which is 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, and is made of a polymer material such as polyethylene, polypropylene, polyester, polyethylene terephthalate. Examples of the film include a film, a film obtained by vapor deposition of aluminum, and a film obtained by applying silicone oil or the like on paper.

<Manufacture of transdermal formulation>
The transdermal preparation of the present invention can be produced according to a known method. A mixture containing tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid, and an adhesive, and optionally other components is prepared, and the mixture is applied or spread on a release liner to prepare a drug. It can be produced by forming a containing layer and attaching a support to the drug containing layer.

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

  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 liquid is not particularly limited, and is, for example, 30 to 90% by mass, preferably 40 to 80% by mass based on the entire coating liquid.

  Then, 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 preparation. You can Alternatively, the transdermal preparation can be obtained by applying or spreading the coating solution on a support, evaporating the solvent in the coating solution to form a drug-containing layer, and then bonding a release liner. .. From the viewpoint of ease of production, it is preferable to apply or spread the coating solution on a release liner, evaporate the solvent in the coating solution to form the drug-containing layer, and then bond the support. The coating or spreading of the coating liquid can be performed using a knife coater, a comma coater, a reverse coater, or a die coater. Although an example of the manufacturing flow is shown in FIG. 1, the manufacturing flow is not limited to this.

  Further, the transdermal preparation of the present invention comprises heating and melting the components in the drug-containing layer, coating or spreading the melt on a release liner to form the drug-containing layer, and then attaching a support. A transdermal preparation can also be produced by combining them. The percutaneous absorption-type preparation may be produced by applying or spreading the melt on a support to form a drug-containing layer and then sticking a release liner.

<Method of administration>
Treatment of pain with the transdermal preparation of the present invention can be performed by directly applying the transdermal preparation of the present invention to the skin of a 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 transdermal preparation of the present invention, the content of tramadol or a pharmaceutically acceptable salt thereof in the drug-containing layer is adjusted so as to achieve a blood concentration effective for treating pain. , The skin permeation rate of tramadol, the area of the drug-containing layer, the thickness of the drug-containing layer, etc. are appropriately adjusted, and then the transdermal preparation of the present invention is applied to the skin.

  The transdermal 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, the upper arm, the abdomen, the chest, the neck, the lower back, the buttocks or the legs. Can be attached.

  The transdermal administration of the transdermal preparation of the present invention to a subject may be combined with the 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 at staggered times, and the pharmaceutical composition may be administered intravenously, intraperitoneally, subcutaneously and intramuscularly, orally, topically or transmucosally. Can be administered by a variety of routes including. 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, non-steroidal anti-inflammatory analgesics such as diclofenac sodium, loxoprofen sodium, and local anesthetics such as lidocaine.

  Hereinafter, the present invention will be described more specifically based on Examples, but the present invention is not limited to the following Examples. In addition, in each of the examples,% is% by mass unless otherwise specified.

(Production of transdermal patch containing tramadol hydrochloride)
Example 1
-Preparation of rubber-based resin composition Styrene-isoprene-styrene block copolymer (Quintac 3570C, Nippon Zeon Co., Ltd.), hydrogenated rosin glycerin ester (Pine Crystal KE-311, Arakawa Chemical Industry Co., Ltd.), polyisobutylene ( Oppanol B12SFN, manufactured by BASF) was dissolved in a mixed liquid of toluene and hexane so that the solid content concentration was 30% to obtain a rubber-based resin composition.
Ingredient name Mix ratio Quintac 3570C (manufactured by Zeon Corporation) 45%
Pine Crystal KE-311 (Arakawa Chemical Industry Co., Ltd.) 45%
Opanol B12SFN (manufactured by BASF) 10%

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

  The coating solution was applied onto a release film (Film Vina 75E-0010 BD: manufactured by Fujimori Industry Co., Ltd.) so that the thickness after removal of the solvent was about 75 μm, and dried, and then the support (EH-1212: (Translated from Japan Vilene Co., Ltd.) were stuck together to produce a transdermal preparation.

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

Examples 8 and 9
As shown in Table 1, transdermal patches of Examples 2 to 7 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 silicic acid was not added and the compounding ratio of the rubber-based resin composition was increased accordingly. ..

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

Comparative Example 11
As shown in Table 2, a transdermal patch of Comparative Example 11 was produced in the same manner as in Example 8 except that the silicic acid was not compounded and the compounding ratio of the rubber resin composition was increased accordingly. ..

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

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

Test Example 1 In Vitro Skin Permeability Test Using the percutaneous absorption type patch obtained above, an in vitro skin permeability test was conducted according to the following procedure.
After applying the percutaneous patch of each Example and Comparative Example on the horny layer side of a 7-week-old male hairless mouse isolated skin (Hos: HR-1 system, Hoshino Experimental Animal Breeding Co., Ltd.), 32 A vertical diffusion cell (trade name: Palm Cell Vertical TP-6: manufactured by Beadlex Co.) in which warm water of 0.5 ° C. was circulated around the outer periphery was attached 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 with time, and the amount of tramadol in the receiver solution was measured by the HPLC method. The amount of permeated drug at each time was calculated from the measurement results, and the skin permeation rate of tramadol was calculated (n = 3 average value).

<HPLC measurement conditions>
Device: 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 0.5 mL / min
Detection wavelength: 215nm
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 absorption patches of Examples 1 to 9 and Comparative Examples 1 to 15, the skin permeation rate was 40 μg / cm ² / h, which showed good skin permeability.

Test Example 2 Evaluation of cohesiveness 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 patch, the surface of the drug-containing layer was strongly suppressed with a finger, and the amount of the adhesive remaining on the finger during peeling was visually observed and evaluated according to the following criteria.
A: It has a good cohesive force without leaving an adhesive.
B: The adhesive is 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 they had sufficient cohesiveness as a transdermal patch. However, the transdermal patches of Examples 1, 3, 8 and 9 were evaluated as A, while those of Comparative Examples 1, 2, 11, and 12 containing no silicic acid anhydride. The evaluation of the transdermal patch was B, suggesting that higher cohesiveness is obtained when silicic acid anhydride is incorporated in the drug-containing layer.

Test Example 3 Bleeding Evaluation With respect to the transdermal patch of each Example and Comparative Example, the surface of the removed release liner was visually observed to evaluate the bleeding.
○: No bleeding ×: With bleeding

  The obtained results are shown in Tables 1 to 3. No bleeding was observed in the transdermal patches of Examples 1-9. Bleeding was observed in the transdermal patches of Comparative Examples 1-12. Therefore, it was shown that the occurrence of bleeding caused by adding the fatty acid alkanolamide and the absorption enhancer other than the fatty acid alkanolamide to the drug-containing layer can be suppressed by adding the silicic acid. Since bleeding was observed in the transdermal patches of Comparative Examples 13 to 15, bleeding occurred when the fatty acid alkanolamide was blended in the drug-containing layer rather than when an absorption promoter other than the fatty acid alkanolamide was blended. It has been shown that the above can be suppressed.

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

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

<HPLC measurement conditions>
Device: 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 0.5 mL / min
Detection wavelength: 215nm
Mobile phase: 0.1% trifluoroacetic acid aqueous solution / acetonitrile mixture

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

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

Test Example 5 Primary Irritation Test of Guinea Pig Skin A 6-week-old Hartley male guinea pig was used. On the day before administration, the left and right body parts of the guinea pig were shaved and shaved into a size of about 4 × 8 cm. On the day after cutting hair, the patch (diameter 15 mm) of Example 1, Example 2, Example 6, and Comparative Examples 13 to 15 was applied to the left and right body parts, and an adhesive foam pad M (manufactured by 3M Healthcare). After fixing, polyethylene film tape (Keeppore A, manufactured by Nichiban Co., Ltd.) was wound around the body, and then fixed with Silky Tech (ALCARE No. 5). Twenty-four hours after administration, each patch was removed, and the patch was wiped with absorbent cotton moistened with acetone. The skin reaction was observed 24, 48, and 72 hours after administration, and the skin irritation index (P.I.I.) was calculated with reference to the Draize standard (1959) shown in Table 4. The skin irritation was evaluated. However, the observation 24 hours after administration was carried out about 1 hour after wiping. For each test substance, individual individual scores at 24, 48, and 72 hours after administration were calculated, and divided by the number of observations (3 times) to obtain P.I. I. I. (Individual P.I.I.) was calculated. Individual P.C. I. I. The values are totaled, and the average value is the P.I. of the transdermal patch. I. I. And

  In addition, evaluation of irritation was performed by P. I. When I was 0, it was designated as "non-irritant", when it was greater than 0 and less than 2, it was designated as "mild stimulant", when 2 or more and less than 5, it was designated as "moderate irritant", and when it was 5 or more, it was designated as "strong stimulant". No statistical processing was performed during the evaluation.

  The results are shown in Table 5. Although the skin irritation of all of the transdermal patches was mild, the transdermal patches of Examples 1, 2 and 6 had lower P.I. than the transdermal patches of Comparative Examples 13 to 15. I. I was shown. Therefore, the transdermal patch of the present invention shows substantially the same skin permeability of tramadol, but is significantly more skin irritating than the transdermal patch in which the drug-containing layer does not contain fatty acid alkanolamide. Has been shown to be reduced.

  According to the present invention, there is provided a transdermal preparation containing tramadol or a pharmaceutically acceptable salt thereof, which has high storage stability of tramadol and improves the skin permeability of tramadol while maintaining good cohesiveness. To be done. Therefore, it is possible to provide a means for administering tramadol which is more convenient.

Claims (12)

  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 percutaneous absorption-type pharmaceutical preparation according to claim 1, wherein the adhesive contains a rubber-based resin as a main component.   The percutaneous absorption type medical preparation according to claim 2 in which the rubber system resin contains a styrene-isoprene-styrene block copolymer and a tackifier.   The transdermal preparation according to claim 3, wherein the tackifier is hydrogenated rosin glycerin ester.   The transdermal 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 preparation according to any one of claims 1 to 5, wherein the drug-containing layer further contains an absorption enhancer.   The percutaneous absorption-type pharmaceutical preparation according to claim 6, wherein the absorption enhancer 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 an inorganic base and an aliphatic alkanolamine. A method for producing the percutaneous absorption-type pharmaceutical preparation according to claim 1,
Preparing a mixture comprising tramadol or a pharmaceutically acceptable salt thereof, a fatty acid alkanolamide, silicic acid, and an adhesive,
The said manufacturing method including apply | coating or spreading the said mixture on a release liner, and forming a drug containing layer, and sticking a support body to the said drug containing layer.

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