JP6675589B2 - Transdermal formulation - Google Patents

Description

  The present invention relates to a transdermal preparation containing a pharmaceutically acceptable salt of tramadol as an active ingredient.

  Tramadol ((1RS, 2RS) -2-[(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol) is one of the opioid analgesics and is mild in WHO-type cancer pain treatment. It is classified as a weak opioid used for moderate to moderate pain. The analgesic effect of tramadol is thought to be due to inhibition of transmission of noxious stimuli by binding to mu opioid receptors and activation of the descending pain suppression 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 dosage forms such as injections, oral preparations, and suppositories. Tramadol hydrochloride has the chemical structure of the following formula (I).

There have been several reports on transdermal preparations of opioid analgesics.
Patent Document 1 discloses that when menthol, O-ethyl menthol, or limonene is added as an absorption enhancer to tramadol-containing hydrogel, the transdermal absorbability of tramadol is enhanced as compared with the case where cholic acid is added as an absorption enhancer. Is disclosed.
Patent Document 2 discloses that pentazocine, an opioid receptor antagonist, is obtained by using isopropyl myristate and a compound selected from the group consisting of glyceryl monocaprylate, glyceryl monocaprate and glyceryl monolaurate as an absorption enhancer. 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 an example showing that the absorption enhancer enhances transdermal absorption of tramadol.
Patent Document 3 discloses that high skin permeability of tramadol was obtained by formulating a free form of 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 has extremely low skin permeability of tramadol.

JP 2006-36687 A International Publication WO2006 / 085521 International Publication WO2011 / 059037

  The present inventors, while repeatedly examining to improve the skin permeability of tramadol in a transdermal formulation containing a pharmaceutically acceptable salt of tramadol, a drug-containing layer containing an adhesive, The inventor has come to recognize that the blending of the absorption promoter causes bleeding (phenomena in which the liquid component oozes out of the drug-containing layer containing the pressure-sensitive adhesive) and the problem that the 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 a pharmaceutically acceptable salt of tramadol, in which bleeding does not occur and cohesiveness is maintained while maintaining the skin permeability of tramadol. Aim.

The present inventors have conducted intensive studies to achieve the above object, and found that the use of a fatty acid alkanolamide as an absorption enhancer enables high skin permeability of tramadol to be obtained, and that the fatty acid alkanolamide in the drug-containing layer can be obtained. It has been found that by controlling the content of, bleeding does not occur and good cohesiveness can be maintained. Furthermore, unexpectedly, it was found that by using a fatty acid alkanolamide as an absorption enhancer, tramadol in the drug-containing layer exhibited higher storage stability than when using other absorption enhancers.
The present inventors have further studied based on these findings, and completed the present invention.
That is, the present invention is as follows.

[1] A transdermal absorption preparation having a support and a drug-containing layer, wherein the drug-containing layer contains a pharmaceutically acceptable salt of tramadol, a basic compound, a fatty acid alkanolamide, and an adhesive. A transdermal preparation, wherein the content of the fatty acid alkanolamide is less than 10% by mass relative to the total mass of the drug-containing layer.
[2] The transdermal preparation according to [1], wherein the pressure-sensitive adhesive contains at least one of a rubber resin and an acrylic resin as a main component.
[3] The transdermal 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 preparation according to any one of [1] to [4], wherein the basic compound is at least one selected from an inorganic base and an aliphatic alkanolamine.
[6] The transdermal absorption according to any one of [1] to [5], wherein the fatty acid alkanolamide is at least one selected from lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide. Type formulation.
[7] A method for producing the transdermal absorption preparation according to [1],
Preparing a mixture comprising a pharmaceutically acceptable salt of tramadol, a basic compound, a fatty acid alkanolamide and an adhesive;
The above-mentioned production method, comprising applying or spreading the mixture on a release liner to form a drug-containing layer, and laminating a support to the drug-containing layer.

  ADVANTAGE OF THE INVENTION According to the present invention, in a transdermal absorption-type preparation containing a pharmaceutically acceptable salt of tramadol, 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 improved. Therefore, it is possible to provide a means for administering tramadol with improved convenience.

It is a figure showing an example of the manufacture flow of the transdermal absorption type preparation of the present invention.

  In the present invention, a transdermal preparation refers to 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 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 release-controlling film and a skin on the skin-applied side of the drug-containing layer for controlling transdermal absorption of the drug. It may be a reservoir-type patch preparation further having a pressure-sensitive adhesive layer for sticking to a patch. Such a structure allows tramadol to be efficiently transdermally absorbed.

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

  As used herein, the term "comprising" or "comprising" 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 a pharmaceutically acceptable salt of tramadol. Tramadol has an analgesic effect and is used for the treatment of 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 (eg, low back pain, osteoarthritis, etc.), Neuropathic pain (eg, postherpetic neuralgia, diabetic neuropathic pain, etc.), 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 Formate, acetate, trifluoroacetate, ascorbate, benzoate, cinnamate, citrate, fumarate, glutamate, tartrate, oxalate, glutarate, camphorate, adipate 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 not limited to these.

  A pharmaceutically acceptable salt of tramadol may be used in the form of a crystal, which may be formed solely from a pharmaceutically acceptable salt of tramadol, or a co-crystal or solvate (eg, Hydrate, preferably monohydrate). The pharmaceutically acceptable salts of tramadol may be used alone or in an appropriate combination of two or more. In the present invention, it is preferable to use tramadol hydrochloride, which has already been established for its usefulness in intramuscular administration and oral administration, as a therapeutic agent for pain.

  The content of the pharmaceutically acceptable salt of tramadol 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 absorption preparation of the present invention is applied to skin of a living body. Such 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, 1 to 40% by mass, preferably 5 to 35% by mass, more preferably 10 to 30% by mass, based on the drug-containing layer (that is, based on the total mass of the drug-containing layer; the same applies hereinafter).

  The blood concentration of tramadol that is effective in treating pain can be similar to that of intramuscular or oral administration of tramadol.

  In the transdermal preparation of the present invention, a blood concentration effective for treating pain can be achieved by adjusting the skin permeation rate of tramadol. Adjustment of the skin permeation rate is performed by any means such as adjusting the content of a pharmaceutically acceptable salt of tramadol in the drug-containing layer, adding an absorption enhancer described below to the drug-containing layer, and the like. be able to. 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, 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. If the skin permeation rate is less than 100 μg / cm ² / hour, the blood concentration is not too high, which is preferable from the viewpoint of safety.

2. Basic Compound In the transdermal preparation of the present invention, the drug-containing layer contains a basic compound. 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, etc.) Aliphatic alkanolamines); high molecular compounds containing basic nitrogen (eg, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, polyvinyl pyridine, etc.); basic alkali metal salts (eg, sodium acetate, potassium acetate, boric acid) Sodium, sodium carbonate, sodium hydrogen carbonate, trisodium citrate, sodium silicate); and alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.). Alternatively, a commercially available basic acrylic resin such as Eudragit series (Eudragit E100, Eudragit EPO: manufactured by Evonik Industries) may be used. Among them, inorganic bases and aliphatic alkanolamines are preferred, and sodium hydroxide, potassium hydroxide and diisopropanolamine are more preferred.

  The basic compounds can be used alone or in combination of two or more. The content of the basic compound is preferably 0.5 to 3 equivalents, more preferably 0.7 to 2 equivalents to the equivalent of the pharmaceutically acceptable salt of tramadol. Further, the content of the basic compound is preferably from 0.1 to 35% by mass, more preferably from 0.5 to 30% by mass, and preferably from 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 a pharmaceutically acceptable salt of tramadol, and the skin permeability of tramadol is improved. In particular, when the content of the basic compound is within the above range, the effect of improving 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 a fatty acid alkanolamide as an absorption enhancer. Fatty acid alkanolamides, for example C ₁₂ -C ₁₈ saturated, or one or more double bonds (preferably 1 or 2 double bonds) and fatty acid moiety having, for example, has been C ₂ ~ substituted by one or more hydroxy An alkanolamide or dialkanolamide moiety containing C ₆ alkyl (preferably monohydroxy C _2-4 alkyl), for example, lauric acid diethanolamide, palmitic acid diethanolamide, stearic acid diethanolamide, oleic acid diethanolamide. And lauric acid monoisopropanolamide. Of these, lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide are preferred.

  The fatty acid alkanolamides can be used alone or in combination of two or more. The content of the fatty acid alkanolamide in the transdermal preparation of the present invention is less than 10% by mass relative to the total mass of the drug-containing layer, for example, 9% by mass or less, 8% by mass or less, 7% by mass or less, It is at most 6% by mass, particularly preferably at most 5% by mass. When the content of the fatty acid alkanolamide is less than 10% by mass, occurrence of bleeding can be suppressed, and good cohesiveness can be maintained. In the present invention, bleeding refers to a phenomenon in which a liquid component oozes out of a drug-containing layer containing an adhesive, and the occurrence of the bleeding can be visually evaluated as described in Examples below. In the present invention, the cohesiveness is evaluated based on the cohesive strength of the pressure-sensitive adhesive, which is examined by a test method described in Examples described later.

  Further, the content of the fatty acid alkanolamide in the transdermal preparation of the present invention is preferably 1% by mass or more, more preferably 3% by mass or more, based on the total mass of the drug-containing layer. When the content of the fatty acid alkanolamide is 1% by mass or more, a skin permeation rate of tramadol that can achieve a blood concentration effective for treating pain can be provided.

  Furthermore, unexpectedly, the use of fatty acid alkanolamides as the absorption enhancer allows tramadol in the drug-containing layer to exhibit higher storage stability than when other absorption enhancers are used. In the present invention, the term "storage stability" refers to the ratio of tramadol remaining in the drug-containing layer after the percutaneous absorption-type preparation is sealed in an aluminum bag and stored at 60 ° C for 4 weeks (content at start (%)). Means, and can be examined by a test method described in Examples described later. When the content (%) at the start is 98% or more, the storage stability is evaluated to be high.

4. Other absorption enhancers 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 as long as bleeding does not occur. In one embodiment, when an absorption enhancer other than the fatty acid alkanolamide is contained, its content is 1% by mass or more, for example, 2% by mass or more, or 3% by mass or more, and 10% by mass with respect to the total mass of the drug-containing layer. %, For example, 9% by mass or less, 8% by mass or less, 7% by mass or less, 6% by mass or less, or 5% by mass or less. The drug-containing layer may not contain an absorption enhancer other than the fatty acid alkanolamide. 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 up to 25% by mass as long as bleeding does not occur, for example, less than 20% by mass. , Less than 15% by mass and less than 10% by mass.

  Absorption enhancers other than fatty acid alkanolamides may be any compound that has been shown to have a skin permeation promoting effect in transdermal administration, such as 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 benzenesulfonic acid, toluenesulfonic acid, and saccharin or salts thereof; isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, hexadecyl isostearate, hexyl laurate, decyl oleate, oleyl oleate, diisopropyl adipate Pill, diethyl sebacate, diisopropyl sebacate, medium-chain fatty acid triglyceride, tri (caprylic / capric acid) 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 and propylene glycol dicaprate; esters such as triacetin, ethyl lactate and triethyl citrate; sorbitan monolaurate and sorbitan monooleate Fatty acid esters such as sorbitan; polyoxyethylene sorbitan monooleate (polysorbate 80) Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monostearate; polyethylene glycol monooleate; polyethylene such as polyethylene glycol monostearate, polyethylene glycol monopalmitate and polyethylene laurate Oxyethylene fatty acid esters; aliphatic or aromatic alcohols such as decanol, lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, cetyl alcohol, hexyldecanol, octyldodecanol, and benzyl alcohol; or ethers thereof; To 8 polyhydric alcohols (for example, propylene glycol, 1,3-butanediol, 1,4-butanediol, glycerin, dipropylene glycol, octanediol, etc.); phenol ethers such as polyoxyethylene nonylphenyl ether and polyoxyethylene octylphenyl ether; castor oil or hydrogenated castor oil; oleoyl sarcosine, lauryl dimethyl Ionic surfactants such as betaine aminoacetate 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.); non-ionic surfactants such as dimethyl lauryl amine oxide; dimethyl sulfoxide, decylme Alkylmethyl sulfoxides such as rusulfoxide; pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone; 1-dodecylazacycloheptan-2-one, 1-geranyl Azacycloalkanes such as azacycloheptan-2-one; terpenes such as menthol, camphor and limonene; Absorption enhancers other than fatty acid alkanolamides can be used alone or in combination of two or more.

5. 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 an acrylic resin, a rubber resin, a silicone resin, and the like.

  The pressure-sensitive adhesive preferably contains, as a main component, at least one selected from the group consisting of an acrylic resin, a rubber-based resin, and a silicone-based resin, and at least one selected from the group consisting of a rubber-based resin and an acrylic resin. Those containing one type as a main component are more preferable. Here, the “main component” means usually 70% by mass or more, more preferably 80% by mass or more, still more 90% by mass or more, particularly 100% by mass, based on the total mass of the pressure-sensitive adhesive.

  Examples of the acrylic resin include, as monomer units, (meth) acrylates represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate, and the like. A polymer or a copolymer containing at least one kind is exemplified. Specifically, for example, acrylic acid / octyl acrylate copolymer, 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer solution, 2-ethyl exyl acrylate / N-vinyl-2-pyrrolidone / dimethacrylic acid-1 , 6-hexane glycol copolymer, acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / methacrylic acid Examples include a dodecyl copolymer solution, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and an alkanolamine solution of an acrylic resin. 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- GELVA series (GELVA GMS 3083, GELVA GMS 3253, GELVA GMS 788, GELVA GMS 9073: Henkel), MAS-683, MAS-811, MASCOS10, MAS11D1 (Cosmed Pharmaceutical) May be used.

  Examples of the rubber-based resin 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, powdered arabic, isoprene rubber, and the like, with SIS being preferred. Uses commercially available rubber-based resins such as Quintac (registered trademark) series (Quintac 3570C etc .: manufactured by Zeon Corporation), Clayton D polymer series (manufactured by Clayton Polymer Japan), JSR SIS / TR series (manufactured by JSR Life Science). May be.

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

  As the adhesive contained in the drug-containing layer of the transdermal absorption preparation of the present invention, one of the above-mentioned acrylic resins, rubber resins, and silicone resins is used alone or in combination of two or more. Can be used. More preferably, it is an acrylic or rubber resin.

  The amount of the pressure-sensitive 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 pressure-sensitive adhesive is usually 10 to 97.9% 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 97.9% 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. . When the pressure-sensitive adhesive is an acrylic resin, the content of the pressure-sensitive adhesive is preferably 10 to 97.9% 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. . When the pressure-sensitive adhesive is a silicone resin, it is preferably from 10 to 97.9% by mass, more preferably from 15 to 90% by mass, and still more preferably from 20 to 97.3% by mass, based on the drug-containing layer.

6. Tackifier The drug-containing layer may further contain a tackifier to improve 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, 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 thereof include polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, and polyvinyl alcohol. Commercially available tackifiers such as Alcon series (Arakawa Chemical), Pine Crystal series (Arakawa Chemical), Clearon series (Yashara Chemical), YS resin series (Yashara Chemical), etc. You may use it 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, an aliphatic saturated hydrocarbon resin as a tackifier, Rosin glycerin esters are more preferred. The tackifiers can be used alone or in combination of two or more.

  In the case where a rubber-based resin is used as the adhesive, the content of the tackifier is preferably 5 to 70% by mass, more preferably 10 to 60% by mass, when a rubber-based resin is used as the adhesive. % Is more preferable, and 15 to 50% by mass is further preferable. When an acrylic resin is used as the pressure-sensitive adhesive, the amount is preferably 0 to 40% by mass, more preferably 0 to 30% by mass, and still more preferably 0 to 20% by mass, based on 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, and still more preferably 0 to 10% by mass, based on the drug-containing layer.

7. The plasticizer drug-containing layer may further contain a plasticizer. Examples of the plasticizer include petroleum-based oils (eg, paraffin-based process oil, naphthenic-based process oil, aromatic-based process oil, liquid paraffin, etc.), squalane, squalene, and vegetable-based oils (eg, olive oil, camellia oil, castor oil, tall oil). Oil, peanut oil, etc.), silicone oil, dibasic acid esters (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber, etc.), diethylene glycol, polyethylene glycol, salicylate glycol, crotamiton, etc. Can be As the plasticizer, commercially available plasticizers such as the Moresco White Series (manufactured by Moresco) and the High Coal Series (manufactured by Kaneda) may be used as appropriate. In particular, when the rubber-based resin is used as an adhesive, it is preferable to use liquid paraffin as a plasticizer. One plasticizer can be used alone, or two or more plasticizers can be used in combination.

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

8. Silicic Acid In the transdermal preparation of the present invention, the drug-containing layer may further contain silicic acid. In the present invention, silicic acid means silicon dioxide (silicic anhydride) or a salt thereof, for example, silicic anhydride, silicate (eg, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate) , Magnesium sodium silicate, etc.), and preferred is silicic anhydride.

  The content of the 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 based on the total mass of the drug-containing layer. Is more preferable.

9. Other optional component drug-containing layer further contains known additives such as a pH adjuster, a cross-linking agent, an antioxidant, a coloring agent, an ultraviolet absorber, a filler, or a preservative, if necessary. May be.

  The pH adjuster 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 on the skin. The pH adjuster may be any compound as long as it is an acid or a base or a salt thereof, which is usually used for pH adjustment in the field of pharmaceuticals. 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 and the like can be mentioned.

  Examples of the crosslinking agent include amino resins, phenol resins, epoxy resins, alkyd resins, thermosetting resins such as unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. Is mentioned. Among them, 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, nordihydroguaiaretinic acid, dibutylhydroxytoluene (BHT), and butylhydroxyanisole.

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

  Examples of the ultraviolet absorber include an amino acid compound, a benzophenone compound, a cinnamic acid derivative, a cyanoacrylate derivative, a p-aminobenzoic acid derivative, an anthranilic acid derivative, a salicylic acid derivative, a coumarin derivative, an imidazoline derivative, a pyrimidine derivative, and a dioxane derivative. No.

  Examples of the filler include calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, potassium hydrogen carbonate, and silicates (eg, sodium silicate, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate) , Magnesium sodium silicate, 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 other optional components is preferably from 0 to 10% by mass, more preferably from 0 to 5% by mass, based on the drug-containing layer.

The area of the drug-containing layer in the transdermal absorption preparation of the present invention can be appropriately adjusted according to the tramadol content and / or the skin permeation rate. Typically, 2~140cm ^2, preferably 10 to 100 cm ^2, more preferably in the range of 20~70cm ^2. The shape 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 absorption preparation of the present invention can be appropriately adjusted according to the kind of the adhesive, the content of tramadol, and / or the skin permeation rate, and is not particularly limited. Typically, it is in the range of 20 to 300 μm, preferably 25 to 200 μm, and more preferably 30 to 150 μm.

One embodiment of the drug-containing layer in the transdermal absorption preparation of the present invention contains a pharmaceutically acceptable salt of tramadol, a basic compound, a fatty acid alkanolamide and an adhesive, and the content of the fatty acid alkanolamide is a drug. What is less than 10 mass% with respect to the total mass of a containing layer is mentioned.
As a pharmaceutically acceptable salt of tramadol, tramadol acid addition salt (particularly hydrochloride) is preferable.
As the basic compound, an inorganic base and an aliphatic alkanolamine are preferred, and sodium hydroxide, potassium hydroxide and diisopropanolamine are more preferred.
As fatty acid alkanolamides, lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide are preferred.
The pressure-sensitive adhesive preferably contains at least one selected from the group consisting of a rubber-based resin and an acrylic-based resin as a main component.
The content of a pharmaceutically acceptable salt of tramadol is 1 to 40% by mass, the content of a basic compound is 0.1 to 35% by mass, the fatty acid alkanolamide is 1% by mass or more, and It is preferable that the content of the agent is 10 to 97.9% by mass.

<Support>
As the support in the transdermal absorption 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 commonly used in the field of pharmaceuticals. For example, polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyester (such as polyethylene terephthalate), Examples thereof include a synthetic resin film or sheet of nylon, polyurethane, or the like, or a laminate, a porous body, a foam, or a film obtained by depositing aluminum on the film. Further, in order to obtain good anchoring property with the adhesive layer, paper, woven fabric, nonwoven fabric, or a laminate of these and a film can 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 absorption-type preparation is applied to the skin can do. The release liner is not particularly limited as long as it is impermeable to at least the pharmaceutically acceptable salt of tramadol in the drug-containing layer.For example, the release liner is made of a polymer material such as polyethylene, polypropylene, polyester, or polyethylene terephthalate. Examples thereof include a film, a film obtained by evaporating aluminum on a film, and a paper obtained by applying silicone oil or the like on paper.

<Manufacture of transdermal preparations>
The transdermal preparation of the present invention can be produced according to a known method. Prepare a mixture comprising a pharmaceutically acceptable salt of tramadol, a basic compound, a fatty acid alkanolamide, and an adhesive, and if necessary, other components, and apply or spread the mixture on a release liner to form a drug. It can be produced by forming a drug-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 content described above, and the mixture is 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 and 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, and preferably 40 to 80% by mass, based on the entire coating solution.

  Next, this 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 a support is attached to obtain a transdermal absorption-type preparation. Can be. Alternatively, a transdermal preparation can be obtained by applying or spreading a coating solution on a support, evaporating the solvent in the coating solution to form a drug-containing layer, and then attaching a release liner thereto. . From the viewpoint of ease of production, it is preferable to apply or spread the coating solution on the release liner, evaporate the solvent in the coating solution to form a drug-containing layer, and then bond the support. The application or spreading of the coating solution can be performed using a knife coater, comma coater, reverse coater, or die coater. An example of the manufacturing flow is shown in FIG. 1, but is not limited to this.

  In addition, the percutaneous absorption-type preparation of the present invention is obtained by heating and melting the components in the drug-containing layer, applying or spreading the melt on a release liner to form a drug-containing layer, and then attaching a support. By combining them, a transdermal preparation can also be produced. After applying or spreading the melt on a support to form a drug-containing layer, a transdermal preparation may be produced by laminating a release liner.

<Method of administration>
The treatment of pain with the percutaneous absorption preparation of the present invention can be performed by directly applying the percutaneous absorption 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 transdermally administering tramadol by the transdermal absorption preparation of the present invention, the content of a pharmaceutically acceptable salt of tramadol in the drug-containing layer and the content of the drug-containing layer are set so as to achieve an effective blood concentration for treating pain. After appropriately adjusting the permeation rate of tramadol to the skin, the area of the drug-containing layer, and / or the thickness of the drug-containing layer, the transdermal preparation of the present invention is applied to the skin.

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

  Transdermal administration of the transdermal absorption 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 at a time interval, and the pharmaceutical composition may be administered intravenously, intraperitoneally, subcutaneously and intramuscularly, orally, topically or transmucosally. Administration can be by various 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 ingredients other than tramadol include, but are not limited to, analgesics such as acetaminophen, non-steroidal anti-inflammatory analgesics such as diclofenac sodium and 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 each example, all percentages are 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, manufactured by Zeon Corporation), hydrogenated rosin glycerin ester (Pine Crystal KE-311, Arakawa Chemical Industries, Ltd.), liquid paraffin ( High Coal M-352, manufactured by Kaneda Co., Ltd.) was dissolved in a mixture of toluene and hexane so that the solid content concentration was 30%, to obtain a rubber-based resin composition.
Component name Mixing ratio Quintac 3570C (manufactured by Zeon Corporation) 45%
Pine Crystal KE-311 (Arakawa Chemical Industries) 45%
High Coal M-352 (Kaneda) 10%

・ Manufacture of percutaneous absorption type patch 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 application and drying is as shown below. Sodium hydroxide (manufactured by Kanto Chemical Co., Ltd.) and lauric acid diethanolamide as a fatty acid alkanolamide were mixed and stirred in an appropriate amount of toluene to obtain a coating solution.
Ingredient name Mixing ratio Tramadol hydrochloride 15%
Rubber-based resin composition 82%
Sodium hydroxide 2%
Lauric acid diethanolamide 1%

  The coating solution is applied on a release film (Film Binner 75E-0010 BD: manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after distilling off the solvent is about 75 μm and dried, and then the support (EH-1212: (Manufactured by Japan Vilene Co., Ltd.) to produce a transdermal patch.

Examples 2 and 3
As shown in Table 1, in the same manner as in Example 1, except that the compounding ratio of lauric acid diethanolamide was increased to 3% by weight and 5% by weight, respectively, and the compounding ratio of the rubber-based resin composition was reduced accordingly. The transdermal patches of Examples 2 and 3 were produced.

Examples 4 and 5
As shown in Table 1, the transdermal patches of Examples 4 and 5 were produced in the same manner as in Example 3 except that the fatty acid alkanolamide was changed to oleic acid diethanolamide and lauric acid monoisopropanolamide, respectively.

Example 6
As shown in Table 1, tramadol hydrochloride as an active ingredient, DURO TAK87-4098 (non-functional acrylic resin, manufactured by Henkel Co.), a basic compound as an active ingredient, so that the solid content after application and drying has the following compounding ratio. And lauric acid diethanolamide as fatty acid alkanolamide were mixed and stirred in an appropriate amount of ethyl acetate to obtain a coating solution. Otherwise, a transdermal patch was manufactured in the same manner as in Example 1.
Ingredient name Mixing ratio Tramadol hydrochloride 20%
DURO TAK87-4098 65%
Diisopropanolamine 10%
Lauric acid diethanolamide 5%

Comparative Example 1
As shown in Table 2, the active ingredient is tramadol hydrochloride, the rubber-based resin composition is used as an adhesive, and the hydroxide is dissolved in an appropriate amount of ethanol as a basic compound so that the solid content after coating and drying has the following compounding ratio. Sodium (manufactured by Kanto Chemical Co., Ltd.) was mixed and stirred in an appropriate amount of toluene to obtain a coating solution. Otherwise, a transdermal patch was manufactured in the same manner as in Example 1.
Ingredient name Mixing ratio Tramadol hydrochloride 15%
Rubber-based resin composition 83%
Sodium hydroxide 2%

Comparative Example 2
As shown in Table 2, the process of Comparative Example 2 was repeated in the same manner as in Example 1 except that the compounding ratio of lauric acid diethanolamide was increased to 10% by weight and the compounding ratio of the rubber-based resin composition was reduced accordingly. A skin-absorbable patch was produced.

Comparative Examples 3 to 8
As shown in Table 2, the absorption enhancers were changed to POE (4.2) lauryl ether, POE (10) hydrogenated castor oil, sorbitan monolaurate, glycerin monocaprylate, glyceryl monolaurate, and polyoxyethylene sorbitan monooleate, respectively. Except for the above, the transdermal patches of Comparative Examples 3 to 8 were produced in the same manner as in Example 3.

Comparative Example 9
As shown in Table 2, tramadol hydrochloride as an active ingredient, DURO TAK87-4098 (non-functional acrylic resin, manufactured by Henkel), a basic compound, and the like, so that the solid content after application and drying has the following compounding ratio, Was mixed and stirred in an appropriate amount of ethyl acetate to obtain a coating solution. Otherwise, a transdermal patch was manufactured in the same manner as in Example 1.
Ingredient name Mixing ratio Tramadol hydrochloride 20%
DURO TAK87-4098 70%
Diisopropanolamine 10%

Test Example 1 In Vitro (In Vitro) Skin Permeability Test Using the percutaneously absorbable patch obtained above, an in vitro skin permeability test was performed according to the following procedure.
After applying the transdermal patches of Examples and Comparative Examples to the stratum corneum side of the extirpated skin of a 7-week-old male hairless mouse (Hos: HR-1 type, manufactured by Hoshino Laboratory Animal Breeding Corporation), 32 A vertical diffusion cell (trade name: Palm Cell Vertical TP-6: manufactured by Beadrex 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. From the measurement results, the amount of permeated drug at each time was calculated, and the skin permeation rate of tramadol was calculated (average value of n = 3).

<HPLC measurement conditions>
Apparatus: ACQUITY UPLC H-Class system (Waters)
Column: ACQUITY UPLC BEH C18 1.7 μm, 2.1 × 50 mm (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 and 2. In the transdermal patches of Examples 1 to 6, the skin permeation rate was 40 µg / cm ² / h, indicating good skin permeability. In the transdermal patches of Comparative Examples 1 to 9, the skin penetration rate was less than 40 μg / cm ² / h, and the skin permeability was insufficient. Therefore, it was shown that good skin permeability of tramadol can be obtained by using a fatty acid alkanolamide as an absorption enhancer. Note that Comparative Example 2 was not subjected to this test because it did not have sufficient properties as a transdermal patch in terms of cohesiveness and bleeding.

Test Example 2 Evaluation of Cohesion The cohesion 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 adhesive remaining on the finger when peeled off was visually observed and evaluated according to the following criteria.
A: It has good cohesion without leaving an adhesive.
B: The adhesive is slightly left, and has cohesive strength.
C: A large amount of the pressure-sensitive adhesive remains and the cohesive strength is weak.

  The results obtained are shown in Tables 1 and 2. The evaluation of the transdermal patches of Examples 1 to 6 and Comparative Examples 1 and 3 to 9 was A or B, indicating that they had sufficient cohesiveness as the transdermal patches. The evaluation of the transdermal patch of Comparative Example 2 was C, and the transdermal patch did not have sufficient cohesiveness as the transdermal patch. Therefore, it was shown that when 10% by weight or more of lauric acid diethanolamide was blended as an absorption enhancer, sufficient cohesiveness as a transdermal patch could not be obtained.

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

  The results obtained are shown in Tables 1 and 2. No bleeding was observed in the transdermal patches of Examples 1 to 6 and Comparative Examples 1, 3, 4, and 9. Bleeding was observed in the transdermal patches of Comparative Examples 2 and 5 to 8. Therefore, bleeding occurs when 10% by weight or more of lauric acid diethanolamide is blended as an absorption promoter, and bleeding occurs even when the blending ratio is 5% by weight when an absorption promoter other than lauric acid diethanolamide is used. It has been shown that this can occur.

Test Example 4 Stability Test The transdermal patches of Examples and Comparative Examples were hermetically sealed 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 determined 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 put into a screw tube, and 5 mL of an internal standard solution (ethyl 4-aminobenzoate / tetrahydrofuran solution) was added to extract with shaking. 20 mL of methanol was added to this liquid and shaken. 1 mL of this solution was added, 4 mL of water was added, and the solution was filtered through a 0.2 μm membrane filter to obtain a sample solution.

<HPLC measurement conditions>
Apparatus: ACQUITY UPLC H-Class system (Waters)
Column: ACQUITY UPLC BEH C18 1.7 μm, 2.1 × 50 mm (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

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 start (%) = Tramadol content in stored sample / Tramadol content in initial sample × 100

  Table 3 shows the obtained results. In all of the transdermal patches of the examples, the content (%) at the start after storage at 60 ° C. for 4 weeks was 98% or more, whereas in the comparative examples, all were less than 98%. . Therefore, it was clarified that tramadol in the drug-containing layer exhibited higher storage stability by using a fatty acid alkanolamide as an absorption enhancer than when using other absorption enhancers.

  According to the present invention, there is provided a transdermal preparation containing a pharmaceutically acceptable salt of tramadol, which has high storage stability of tramadol, and has improved skin permeability of tramadol while maintaining good cohesiveness. You. Therefore, it is possible to provide a means for administering tramadol with improved convenience.

Claims (6)

A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer contains a pharmaceutically acceptable salt of tramadol, a basic compound, a fatty acid alkanolamide and a pressure-sensitive adhesive, and comprises a fatty acid alkanol. der less than 10% by weight relative to the total weight of the content of the drug-containing layer of the amide is, the fatty acid alkanolamides, lauric acid diethanolamide, at least one selected from oleic acid diethanolamide and lauric acid monoisopropanolamide, der Ru, percutaneous absorption type preparation.   The transdermal preparation according to claim 1, wherein the pressure-sensitive adhesive contains at least one of a rubber-based resin and an acrylic 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 preparation according to any one of claims 1 to 4, wherein the basic compound is at least one selected from an inorganic base and an aliphatic alkanolamine. A method for producing a transdermal preparation according to claim 1,
Preparing a mixture comprising a pharmaceutically acceptable salt of tramadol, a basic compound, a fatty acid alkanolamide and an adhesive;
The above-mentioned production method, comprising applying or spreading the mixture on a release liner to form a drug-containing layer, and laminating a support to the drug-containing layer.

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