JP2018090538A - Percutaneous absorption type preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a percutaneous absorption type preparation containing pharmaceutically acceptable salt of tramadol in which bleeding does not occur while skin permeability of tramadol is maintained, and cohesiveness is maintained.SOLUTION: There is provided a percutaneous absorption type preparation having a substrate and a medicine-containing layer, in which the medicine-containing layer contains pharmaceutically acceptable salt of tramadol, basic compound, fatty acid alkanolamide and adhesive agent, the content of fatty acid alkanolamide is less than 10 mass% with respect to the total mass of the medicine-containing layer.SELECTED DRAWING: None

Description

  The present invention relates to a transdermally absorbable 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 cancer pain treatment It is classified as a weak opioid used for moderate to moderate pain. The analgesic action of tramadol is thought to be due to inhibition of nociceptive transmission by binding to the μ opioid receptor and activation of the descending pain suppression system by inhibiting serotonin and noradrenaline reuptake. Tramadol is effective in alleviating pain and chronic pain in various cancers, and is currently used as tramadol hydrochloride in dosage forms such as injections, oral preparations, and suppositories. Tramadol hydrochloride has a chemical structure of the following formula (I):

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

JP 2006-36687 A International Publication WO2006 / 088551 International Publication No. WO2011 / 059037

  In the percutaneous absorption-type preparation containing tramadol pharmaceutically acceptable salt, the present inventors have repeatedly studied to improve the skin permeability of tramadol, and for the drug-containing layer containing an adhesive, When an absorption accelerator is blended, bleeding (a phenomenon in which a liquid component oozes out from a drug-containing layer containing an adhesive) occurs, and it has been recognized that there is a problem that cohesion may be reduced. Patent Documents 1 to 3 do not describe such a problem at all.

  Accordingly, the present invention provides a transdermally absorbable preparation containing a pharmaceutically acceptable salt of tramadol that maintains the skin permeability of tramadol, does not cause bleeding, and maintains aggregability. Objective.

As a result of intensive studies to achieve the above object, the present inventors have obtained that high skin permeability of tramadol can be obtained by using a fatty acid alkanolamide as an absorption accelerator, and that a fatty acid alkanolamide in a drug-containing layer. It has been found that by adjusting the content of, no bleeding occurs and good cohesiveness can be maintained. Furthermore, unexpectedly, it has been found that by using a fatty acid alkanolamide as an absorption accelerator, tramadol in the drug-containing layer exhibits higher storage stability than when other absorption accelerators are used.
The present inventors have further studied based on these findings and have completed the present invention.
That is, the present invention is as follows.

[1] A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer contains a pharmaceutically acceptable salt of tramadol, a basic compound, a fatty acid alkanolamide, and an adhesive. The transdermal preparation, wherein the fatty acid alkanolamide content 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 absorption preparation according to [2], wherein the rubber-based resin contains a styrene-isoprene-styrene block copolymer and a tackifier.
[4] The transdermal preparation according to [3], wherein the tackifier is a hydrogenated rosin glycerin ester.
[5] The transdermally absorbable preparation according to any one of [1] to [4], wherein the basic compound is at least one selected from inorganic bases and aliphatic alkanolamines.
[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. Mold formulation.
[7] A method for producing a 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 said manufacturing method including apply | coating or spreading the said mixture on a release liner, forming a drug containing layer, and bonding a support body to the said drug containing layer.

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

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

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

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

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

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

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

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

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

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

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

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

  In the transdermally absorbable preparation of the present invention, a blood concentration effective for treating pain can be achieved by adjusting the skin permeation rate of tramadol. The skin permeation rate is adjusted by any means such as adjusting the content of a pharmaceutically acceptable salt of tramadol in the drug-containing layer, or adding an absorption enhancer described later to the drug-containing layer. 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, 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 does not become 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 basic compounds include inorganic bases and organic bases, such as low molecular weight compounds containing basic nitrogen (for example, ethanolamine, isopropanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, etc. Aliphatic alkanolamine); polymer compound containing basic nitrogen (for example, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, polyvinylpyridine, etc.); basic alkali metal salt (for example, sodium acetate, potassium acetate, boric acid) Sodium, sodium carbonate, sodium hydrogen carbonate, trisodium citrate, sodium silicate); alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide, etc.). Moreover, you may use commercially available basic acrylic resins, such as Eudragit series (Eudragit E100, Eudragit EPO: Evonik Industries company make). Of these, inorganic bases and aliphatic alkanolamines are preferable, and sodium hydroxide, potassium hydroxide, and diisopropanolamine are more preferable.

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

3. Fatty Acid Alkanolamide In the transdermal absorption preparation of the present invention, the drug-containing layer contains a fatty acid alkanolamide as an absorption accelerator. Fatty acid alkanolamides are, for example, C ₁₂ -C ₁₈ saturated, or fatty acid moieties having one or more double bonds (preferably 1 or 2 double bonds), for example C ₂ -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.

  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 less than 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, It is preferably 6% by mass or less, and particularly preferably 5% by mass or less. If the content of the fatty acid alkanolamide is less than 10% by mass, the occurrence of bleeding can be suppressed and good cohesiveness can be maintained. In the present invention, bleeding means a phenomenon in which a liquid component oozes out from a drug-containing layer containing a pressure-sensitive adhesive, and the presence or absence of occurrence can be evaluated visually as described in Examples below. In the present invention, the cohesiveness is evaluated based on the cohesive strength of the pressure-sensitive adhesive investigated by the test method described in the examples described later.

  The content of the fatty acid alkanolamide in the transdermal preparation of the present invention is preferably 1% by mass or more, and more preferably 3% by mass or more, based on the total mass of the drug-containing layer. If the content of the fatty acid alkanolamide is 1% by mass or more, it is possible to give a skin permeation rate of tramadol that can achieve a blood concentration effective for the treatment of pain.

  Furthermore, unexpectedly, by using a fatty acid alkanolamide as an absorption enhancer, tramadol in the drug-containing layer exhibits higher storage stability than when other absorption enhancers are used. In the present invention, storage stability refers to the ratio of tramadol remaining in the drug-containing layer (vs. starting content (%)) after the transdermal preparation is hermetically packaged in an aluminum bag and stored at 60 ° C. for 4 weeks. And is examined by the test methods described in the examples below. When the content (%) at the start is 98% or more, it is evaluated that the storage stability is 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 promoter other than fatty acid alkanolamide is contained, the content thereof is 1% by mass or more, for example, 2% by mass or more, or 3% by mass or more, or 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 accelerator other than the fatty acid alkanolamide. Further, the total content of fatty acid alkanolamides and absorption accelerators other than fatty acid alkanolamides in the drug-containing layer may be 1% by mass or more and 25% by mass unless bleeding occurs, for example, less than 20% by mass. , Less than 15% by mass and less than 10% by mass.

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

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 acrylic resins, rubber resins, silicone resins, and the like.

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

  As an acrylic resin, for example, (meth) acrylic acid ester represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like is used as a monomer unit. Examples thereof include a polymer or copolymer containing at least one kind. Specifically, for example, acrylic acid / octyl acrylate copolymer, 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution, 2-ethylexyl acrylate / N-vinyl-2-pyrrolidone / dimethacrylic acid-1 , 6-hexane glycol copolymer, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / methacrylic acid Examples thereof include a dodecyl copolymer solution, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and an acrylic resin alkanolamine solution. 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: manufactured by Henkel), GELVA series (GELVA GMS 3083, GELVA GMS 3253, GELVA GMS 788, GELVA GMS 9073: manufactured by Henkel), MAS-683, MAS-811, MASCOS10, MAS11D1 (manufactured by Cosmed Pharmaceutical) Commercially available acrylic resins may be used.

  Examples of rubber resins include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), styrene isoprene rubber, and polyisobutylene (PIB). ), Polybutene, butyl rubber, natural rubber, raw rubber, gum arabic, gum arabic powder, isoprene rubber and the like, preferably SIS. Also, commercially available rubber resins such as the Quintac (registered trademark) series (Quintac 3570C, etc .: manufactured by Nippon Zeon Co., Ltd.), the Clayton D polymer series (Clayton Polymer Japan Co., Ltd.), and the JSR SIS / TR series (JSR Life Science Co., Ltd.) are used. May be.

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

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

  The amount of the adhesive contained in the drug-containing layer is adjusted in consideration of the formation of the drug-containing layer, sufficient skin permeability of tramadol, and the like. The content of the pressure-sensitive adhesive is usually 10 to 97.9% by mass, preferably 15 to 90% by mass with respect to the drug-containing layer. When the adhesive is a rubber-based resin, the content of the adhesive is preferably 10 to 97.9% 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 10-97.9% by mass, more preferably 15-90% by mass, and still more preferably 20-97.3% by mass with respect to the drug-containing layer.

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

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

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

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

8). Silicic acid In the transdermally absorbable preparation of the present invention, the drug-containing layer may further contain silicic acid. In the present invention, silicic acid means silicon dioxide (anhydrous silicic acid) or a salt thereof, for example, anhydrous silicic acid, silicate (for example, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate). , Magnesium silicate, etc.), preferably silicic anhydride.

  The content of silicic acid is preferably 0.1 to 20% by mass, more preferably 0.5 to 15% by mass, and 1 to 10% by mass with respect to the total mass of the drug-containing layer. More preferably.

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

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

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

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

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

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

  Fillers include calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, potassium hydrogen carbonate, silicate (for example, 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, and butyl paraoxybenzoate.

  0-10 mass% is preferable with respect to a drug content layer, and, as for the total content of other arbitrary components, 0-5 mass% is more preferable.

The area of the drug-containing layer in the transdermally absorbable preparation of the present invention can be appropriately adjusted according to the content of tramadol and / or the skin permeation rate. Typically, it is in the range of ^{2 to} 140 cm ² , preferably 10 to 100 cm ² , more preferably 20 to 70 cm ² . The shape 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 transdermally absorbable preparation of the present invention can be appropriately adjusted according to the type of 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, more preferably 30 μm to 150 μm.

As one aspect of the drug-containing layer in the transdermal preparation of the present invention, it 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 content layer is mentioned.
As a pharmaceutically acceptable salt of tramadol, tramadol acid addition salt (especially hydrochloride) is preferable.
As a basic compound, an inorganic base and an aliphatic alkanolamine are preferable, and sodium hydroxide, potassium hydroxide, and diisopropanolamine are more preferable.
As the fatty acid alkanolamide, lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide are preferable.
As an adhesive, what contains at least 1 sort (s) chosen from the group which consists of rubber-type resin and acrylic resin as a main component is preferable.
The content of the pharmaceutically acceptable salt of tramadol is 1 to 40% by mass, the content of the basic compound is 0.1 to 35% by mass, and the fatty acid alkanolamide is 1% by mass or more with respect to the drug-containing layer. It is preferable that content of an agent is 10-97.9 mass%.

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

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

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

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

  As the organic solvent, ethyl acetate, hexane, pentane, heptane, toluene, cyclohexane, chloroform, methylene chloride, methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, cyclohexanone, acetone, a mixed solvent thereof or the like can be used. Content of the organic solvent in a coating liquid is not specifically limited, For example, it is 30-90 mass% with respect to the whole coating liquid, Preferably it is 40-80 mass%.

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

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

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

  When tramadol is transdermally administered with the transdermally absorbable preparation of the present invention, the content of a pharmaceutically acceptable salt of tramadol in the drug-containing layer and a drug-containing layer so as to achieve a blood concentration effective for the treatment of pain and After the skin permeation rate of tramadol and / or the area of the drug-containing layer and / or the thickness of the drug-containing layer are appropriately adjusted, the transdermal preparation of the present invention is applied to the skin.

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

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

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not limited to a following example. Moreover, in each Example,% is mass% unless there is particular notice.

(Manufacture of tramadol hydrochloride-containing transdermal patches)
Example 1
-Preparation of rubber-based resin composition Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Nippon Zeon), hydrogenated rosin glycerin ester (Pine Crystal KE-311, manufactured by Arakawa Chemical Industries), liquid paraffin ( High Coal M-352 (manufactured by Kaneda Co., Ltd.) was dissolved in a mixed solution of toluene and hexane so that the solid content concentration was 30% to obtain a rubber-based resin composition.
Ingredient name Mixing ratio Quintac 3570C (made by Nippon Zeon) 45%
Pine Crystal KE-311 (Arakawa Chemical Industries) 45%
High call M-352 (manufactured by Kaneda) 10%

・ Manufacture of transdermal patches: Dissolve in tramadol hydrochloride as an active ingredient, rubber-based resin composition as an adhesive, and an appropriate amount of ethanol as a basic compound so that the solid content after coating and drying is as follows. Sodium hydroxide (manufactured by Kanto Chemical Co., Inc.) and lauric acid diethanolamide as a fatty acid alkanolamide were mixed and stirred in an appropriate amount of toluene, and then a coating solution was obtained.
Ingredient name Mixing ratio Tramadol hydrochloride 15%
Rubber resin composition 82%
Sodium hydroxide 2%
Lauric acid diethanolamide 1%

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

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

Examples 4 and 5
As shown in Table 1, 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), basic compound so that the solid content after coating and drying has the following blending ratio As diisopropanolamine (manufactured by Tokyo Chemical Industry Co., Ltd.) and lauric acid diethanolamide as a fatty acid alkanolamide were mixed and stirred in an appropriate amount of ethyl acetate, and then a coating solution was obtained. Otherwise, a transdermal patch was produced in the same manner as in Example 1.
Ingredient name Composition ratio Tramadol hydrochloride 20%
DURO TAK87-4098 65%
Diisopropanolamine 10%
Lauric acid diethanolamide 5%

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

Comparative Example 2
As shown in Table 2, the process of Comparative Example 2 was performed in the same manner as in Example 1 except that the blending ratio of lauric acid diethanolamide was increased to 10% by weight and the blending ratio of the rubber-based resin composition was decreased by that amount. A skin-absorbing patch was produced.

Comparative Examples 3-8
As shown in Table 2, the absorption accelerator was changed to POE (4.2) lauryl ether, POE (10) hydrogenated castor oil, sorbitan monolaurate, glyceryl monocaprylate, glyceryl monolaurate, and polyoxyethylene sorbitan monooleate, respectively. Except for the above, the transdermal patch of Comparative Examples 3 to 8 was produced in the same manner as 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), basic compound so that the solid content after coating and drying has the following blending ratio As a mixture, diisopropanolamine (manufactured by Tokyo Chemical Industry Co., Ltd.) was mixed and stirred in an appropriate amount of ethyl acetate, and then a coating solution was obtained. Otherwise, a transdermal patch was produced in the same manner as in Example 1.
Ingredient name Composition ratio Tramadol hydrochloride 20%
DURO TAK87-4098 70%
Diisopropanolamine 10%

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

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

The obtained results are shown in Tables 1 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 absorption patches of Comparative Examples 1 to 9, the skin permeation 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 fatty acid alkanolamide as an absorption accelerator. Note that Comparative Example 2 was not tested because it did not have sufficient properties as a transdermal absorption patch in terms of cohesiveness and bleeding.

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

  The obtained results are shown in Tables 1 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 and had sufficient cohesiveness as a transdermal patch. The evaluation of the transdermal patch of Comparative Example 2 was C, and it did not have sufficient cohesiveness as a transdermal patch. Therefore, it was shown that when 10% by weight or more of lauric acid diethanolamide is blended as an absorption accelerator, sufficient cohesiveness cannot be obtained as a transdermal patch.

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

  The obtained results 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 absorption patches of Comparative Examples 2 and 5-8. Therefore, bleeding occurs when 10 wt% or more of lauric acid diethanolamide is blended as an absorption accelerator, and when an absorption accelerator other than lauric acid diethanolamide is used, bleeding occurs even at a blending ratio of 5 wt%. It has been shown that it can occur.

Test Example 4 Stability test The transdermal patches of each Example and Comparative Example were 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 determined by HPLC. Measured by the method. A sample preparation method and HPLC measurement conditions are shown below.

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

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

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

  The obtained results are shown in Table 3. In all of the transdermal patches of Examples, the content at start (%) after storage at 60 ° C. for 4 weeks was 98% or more, whereas in Comparative Examples, all were less than 98%. . Therefore, it has been clarified that the use of fatty acid alkanolamide as an absorption enhancer allows the tramadol in the drug-containing layer to exhibit higher storage stability than when other absorption enhancers are used.

  INDUSTRIAL APPLICABILITY According to the present invention, there is provided a transdermal preparation containing a pharmaceutically acceptable salt of tramadol having high storage stability of tramadol and improving the skin permeability of tramadol while maintaining good aggregation. The Therefore, it is possible to provide a means for administering tramadol with improved convenience.

Claims (7)

  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 an adhesive, and a fatty acid alkanol A transdermally absorbable preparation, wherein the amide content is less than 10% by mass relative to the total mass of the drug-containing layer.   The transdermally absorbable 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 inorganic bases and aliphatic alkanolamines.   The transdermal preparation according to any one of claims 1 to 5, wherein the fatty acid alkanolamide is at least one selected from lauric acid diethanolamide, oleic acid diethanolamide, and lauric acid monoisopropanolamide. A method for producing a transdermally absorbable 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 said manufacturing method including apply | coating or spreading the said mixture on a release liner, forming a drug containing layer, and bonding a support body to the said drug containing layer.

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