Transdermal patch containing butorphanol

Abstract

The present application provides an adhesive agent having a support layer and an adhesive layer, wherein the adhesive layer contains at least one drug selected from butorphanol and pharmaceutically acceptable salts thereof and a silicone-based adhesive base, and the mass per unit area of the adhesive layer is 30 to 90 g / m 2 .

Description

Technical Field

[0001] This invention relates to an adhesive patch containing butorphanol, and more specifically to an adhesive patch containing butorphanol and / or its pharmaceutically permissible salts. Background Technology

[0002] Butorphanol is the generic name for 17-(Cyclobutylmethyl)morphinan-3,14-diol, which has a morphinan skeleton. Butorphanol is classified as an opioid analgesic and is generally used as an injectable form containing its tartaric acid adduct salt, butorphanol tartrate. For example, N-cyclobutylmethyl-3,14-dihydroxymorphinan is disclosed in U.S. Patent No. 3,775,414 (Patent Document 1).

[0003] Furthermore, for example, Drug Development and Industrial Pharmacy (M. Svozil et al., 2007, 33(5), pp. 559-67) (Non-Patent Document 1) describes a drug in which butorphanol is used as a transdermal absorption formulation. Furthermore, International Publication No. 2016 / 060122 (Patent Document 2) describes an adhesive having a support layer and an adhesive layer, wherein the adhesive layer contains at least one selected from butorphanol and pharmaceutically permissible salts thereof, a higher aliphatic alcohol, and a non-crosslinked polyvinylpyrrolidone that does not contain vinyl acetate as a constituent monomer.

[0004] Furthermore, while transdermal absorption formulations generally offer advantages such as reduced dosing frequency and ease of administration, and can achieve sustained release that is difficult to achieve with injectable formulations, a more rapid onset of efficacy is required depending on the therapeutic purpose of the administered drug. For example, Japanese Patent Application Publication No. 2006-45099 (Patent Document 3) describes a transdermal absorption formulation aimed at increasing the initial release rate, which involves applying 100–360 g / m² of the drug onto a support. 2 A transdermal absorption patch (poop) is formed by coating an aqueous ointment containing a pharmaceutical active ingredient. However, no butorphanol-containing patch has been disclosed that exhibits sufficiently rapid efficacy. Furthermore, poops containing an aqueous base, as described in Patent Document 3, have the following problem: when such a poop is applied to the skin, there is concern that the skin permeability or utilization of the drug may be unstable due to the evaporation or runoff of the aqueous component.

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: US Patent No. 3,775,414

[0008] Patent Document 2: International Publication No. 2016 / 060122

[0009] Patent Document 3: Japanese Patent Application Publication No. 2006-45099

[0010] Non-patent literature

[0011] Non-patent literature 1: M. Swozil et al., Drug Development and Industrial Pharmacy, 2007, 33, pp. 559-567 Summary of the Invention

[0012] [The problem the invention aims to solve]

[0013] The present invention was made in view of the above-mentioned problems, and aims to provide a butorphanol-containing patch that enables the drug to exert its effects sufficiently quickly, that is, with sufficiently short lag time and time to reach maximum skin penetration (Tmax), excellent skin permeability, and sufficiently high drug utilization.

[0014] [Technical means used to solve the problem]

[0015] The inventors have made repeated efforts to achieve the above-mentioned objectives, and have found that in an adhesive comprising a support layer and an adhesive layer, by making the adhesive layer contain at least one drug selected from butorphanol and its pharmaceutically permissible salts (hereinafter, as applicable, referred to as "butorphanol and / or its pharmaceutically permissible salts") and an organosilicon adhesive base, and by setting the mass per unit area of ​​the adhesive layer to, in particular, 30 to 90 g / m², the following method is employed. 2 Within this range, the lag time and the time to reach maximum skin penetration (Tmax) are sufficiently short, thus enabling butorphanol to exert its effects very rapidly.

[0016] The delay time is usually calculated using the following formula: Delay time = (Skin thickness) 2The formula / (6 × drug diffusion coefficient in skin) represents the delay time. Therefore, it is assumed that as long as the compounding components considered to affect the drug diffusion coefficient and their proportions are the same, the delay time will not change regardless of the mass per unit area of ​​the adhesive layer of the patch. However, the inventors have found that, surprisingly, the delay time is shorter in patches with the above-described configuration where the mass per unit area of ​​the adhesive layer is within a specific range.

[0017] Furthermore, the inventors discovered that, according to the above-described adhesive patch, even with a decrease in drug content (absolute amount) due to a smaller mass per unit area of ​​the adhesive layer, excellent skin permeability (skin penetration rate and amount of drug) can still be achieved. Furthermore, it was found that, compared to using a rubber-based adhesive that is also a non-aqueous adhesive, similar to the above-described silicone-based adhesive, the skin penetration rate, amount of drug permeation, and utilization rate are further improved in the above-described adhesive patch, thus completing the present invention.

[0018] That is, the adhesive of the present invention is characterized in that it comprises a support layer and an adhesive layer, and

[0019] The aforementioned adhesive layer contains at least one drug selected from butorphanol and its pharmaceutically permissible salts, and an organosilicon adhesive base, and

[0020] The mass of the adhesive layer per unit area is 30–90 g / m². 2 .

[0021] In the adhesive of the present invention, the adhesive layer preferably further contains at least one absorption enhancer selected from aliphatic alcohols and fatty acid esters, more preferably at least one selected from isostearyl alcohol, oleyl alcohol, octyldodecyl alcohol, and propylene glycol monolaurate. Furthermore, the content of the absorption enhancer in the adhesive layer is preferably a mass ratio (converted mass of butorphanol and / or its pharmaceutically permissible salt to the absorption enhancer of butorphanol tartaric acid addition salt: mass of absorption enhancer) of 2:1 to 1:4, and preferably 1.5 to 25% by mass relative to the total mass of the adhesive layer.

[0022] Furthermore, in the adhesive of the present invention, the content of butorphanol and / or its pharmaceutically permissible salts in the adhesive layer is preferably 3 to 9% by mass relative to the total mass of the adhesive layer, calculated as butorphanol tartaric acid addition salt.

[0023] Furthermore, in the adhesive of the present invention, the content of the organosilicon adhesive base in the adhesive layer is preferably 50 to 97% by mass relative to the total mass of the adhesive layer.

[0024] Furthermore, the adhesive of the present invention preferably also contains an adsorbent. The content of the adsorbent in the adhesive layer is preferably a mass ratio of butorphanol and / or its pharmaceutically permissible salt to the adsorbent (converted mass of butorphanol tartaric acid addition salt of butorphanol and / or its pharmaceutically permissible salt: mass of adsorbent) of 3:1 to 1:4, and preferably 1 to 20% of the total mass of the adhesive layer.

[0025] [The effects of the invention]

[0026] According to the present invention, it is possible to provide a butorphanol-containing patch with sufficiently short delay time and time to reach maximum skin penetration rate (Tmax), excellent skin permeability of the drug, and sufficiently high utilization rate. Detailed Implementation

[0027] The present invention will now be described in detail based on its preferred embodiments.

[0028] The adhesive of the present invention comprises a support layer and an adhesive layer, wherein the adhesive layer contains at least one drug selected from butorphanol and pharmaceutically permissible salts thereof, and an organosilicon adhesive base, and the mass of the adhesive layer per unit area is 30 to 90 g / m². 2 .

[0029] The adhesive of the present invention comprises a support layer and an adhesive layer. As for the support layer, there are no particular limitations as long as it is capable of supporting the adhesive layer, and any known support layer for the adhesive can be appropriately used. Examples of materials for the support layer of the present invention include: polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymers, vinyl acetate-vinyl chloride copolymers, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate, and polyethylene naphthalate; cellulose derivatives; synthetic resins such as polyurethane; and metals such as aluminum. From the viewpoint of drug non-absorption and drug non-permeability, polyesters and polyethylene terephthalate are preferred. Examples of forms of the support layer include: films; sheets, sheet-like porous bodies, sheet-like foams, etc.; fabrics such as woven fabrics, knitted fabrics, and non-woven fabrics; foils; and laminates thereof. Furthermore, there are no particular limitations on the thickness of the aforementioned support layer, but from the viewpoint of ease of operation and manufacturing when applying the adhesive, it is preferably in the range of 5 to 1000 μm.

[0030] The adhesive of the present invention may further include a release liner on the side of the adhesive layer opposite to the support layer. Examples of such release liners include films or sheets and laminates thereof made of the following materials: polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymers, vinyl acetate-vinyl chloride copolymers, polyvinyl chloride, etc.; polyamides such as nylon; polyesters such as polyethylene terephthalate; cellulose derivatives; synthetic resins such as polyurethane; aluminum; paper, etc. Preferably, these release liners are those for which a release treatment, such as coating with a fluorinated compound, has been applied to the side in contact with the adhesive layer in a manner that allows for easy peeling from the adhesive layer.

[0031] The adhesive layer of the present invention contains at least one drug selected from butorphanol and its pharmaceutically permissible salts. In the present invention, butorphanol refers to a substance with the molecular formula C... 21 H 29 NO2 represents 17-(Cyclobutylmethyl)morphinan-3,14-diol.

[0032] In this invention, the form of butorphanol contained in the adhesive layer can be a free body, a pharmaceutically permissible salt, or a free body formed by desalting a pharmaceutically permissible salt of butorphanol during manufacturing and / or in the manufactured formulation. It can be one of these or a mixture of two or more. From the viewpoint of further improving drug stability, an acid addition salt is preferred as a pharmaceutically permissible salt of butorphanol. Examples of acids that can be used as such acid addition salts include: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phosphorous acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, tartaric acid, lauric acid, stearic acid, palmitic acid, oleic acid, myristic acid, lauryl sulfate, linolenic acid, and fumaric acid. Among these, the tartaric acid addition salt (butorphanol tartrate) represented by the following structural formula (1) is preferred as a pharmaceutically permissible salt of butorphanol.

[0033]

[0034] In this invention, the content of butorphanol and / or its pharmaceutically permissible salts contained in the adhesive layer (the content of butorphanol or the content of pharmaceutically permissible salts of butorphanol, or the total content of both, hereinafter the same) is preferably 3 to 9% by mass relative to the total mass of the adhesive layer, more preferably 3 to 6% by mass, and even more preferably 3 to 5% by mass, calculated as butorphanol tartaric acid addition salt. If the content of butorphanol and / or its pharmaceutically permissible salts is less than the lower limit, there is a tendency for the skin penetration rate or amount of butorphanol to decrease. On the other hand, if the upper limit is exceeded, there is a tendency for the performance of butorphanol as an adhesive to be impaired, such as crystallization of butorphanol, decrease in the adhesive strength of the adhesive layer, or loss of uniformity of content.

[0035] That is, if the content of butorphanol and / or its pharmaceutically permissible salts as a drug is in the range of 3 to 9% by mass (more preferably 3 to 6% by mass, and even more preferably 3 to 5% by mass), there is a tendency to make the delay time and the time to reach the maximum skin penetration rate (Tmax) sufficiently short, to further increase the skin penetration rate and the amount of skin penetration of the drug, and to make an appropriate amount of drug crystals dissolve in the adhesive base.

[0036] The adhesive layer of the present invention must contain an organosilicon-based adhesive base. By containing the organosilicon-based adhesive base in the adhesive layer, the delay time and the time to reach the maximum skin penetration rate (Tmax) can be sufficiently short, thereby enabling sufficiently high drug utilization. Furthermore, even if the drug concentration and absolute amount in the adhesive layer are reduced, the skin penetration rate and amount of drug can still be sufficiently high. In addition, by containing an organosilicon-based adhesive base, the adhesion of the adhesive layer to the skin can be further improved.

[0037] In this invention, the so-called organosilicon adhesive refers to a polymer (polysiloxane) containing siloxane units represented by the following structural formula (2) and having siloxane bonds (-Si-O-) as the main chain.

[0038]

[0039] In the siloxane unit represented by equation (2), n represents a number greater than 2. Furthermore, R 1 and R 2 Each group independently represents a group bonded to a Si atom. As R 1 and R 2The components are not particularly limited, but are preferably each independently composed of a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, aryl group, or alkoxy group. Furthermore, the polymer can be linear, branched, or cyclic, or a polymer composed of these components. The ends of the polymer are also not particularly limited, but are preferably each independently composed of a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, aryl group, alkoxy group, trimethylsilyl group, or trimethylsiloxy group.

[0040] As an organosilicon adhesive base of the present invention, it can be listed in ASTM standard (ASTM D 1418) as MQ (polydimethylsiloxane, R in formula (2)). 1 and R 2 Silicone rubbers such as methyl, VMQ (polymethylvinylsiloxane), PMQ (polymethylphenylsiloxane), and PVMQ (polyphenylvinylmethylsiloxane), or a mixture of at least one of these with organosilicon resins other than silicone rubber such as polybis(trimethylsilyl)siloxane, may be used alone or in combination of two or more. Furthermore, when mixing organosilicon resins other than silicone rubber, the mixture is preferably 0.5 to 20% by mass relative to the total mass of the organosilicon adhesive.

[0041] In addition, commercially available silicone adhesives can also be used as these silicone adhesive bases. For example, silicone adhesives provided by Dow Corning in the following models can also be used: BIO-PSA7-410X, BIO-PSA7-420X, BIO-PSA7-430X, BIO-PSA7-440X, BIO-PSA7-450X, BIO-PSA7-460X (each X is 1 or 2 independently), BIO-PSA AC7-4201, BIO-PSA AC7-4301, BIO-PSA AC7-4302, MD7-4502, MD7-4602, 7-9700, MG7-9800, MG7-9850, and BIO-PSA 7-4560 as a hot melt silicone adhesive. One of them can be used alone or in combination of two or more.

[0042] Furthermore, as the organosilicon adhesive of the present invention, in order to improve cohesiveness, the organosilicon adhesive may be, for example, the following: an adhesive formed by crosslinking the methyl groups by dehydrogenating the hydrogen atoms of the methyl groups through the coordination of a peroxide when methyl groups are present; an adhesive formed by crosslinking the vinyl groups by bonding a crosslinking agent including a siloxane compound containing a SiH group when vinyl groups are present; an adhesive formed by crosslinking the silanol groups through dehydration condensation when hydroxyl groups are present (i.e., when silanol groups are present), etc.

[0043] In this invention, the content of the organosilicone adhesive base contained in the adhesive layer is preferably 50 to 97% by mass relative to the total mass of the adhesive layer, more preferably 60 to 90% by mass, and even more preferably 65 to 85% by mass. If the content of the organosilicone adhesive base is less than the lower limit, there is a tendency for the utilization rate of butorphanol to decrease or the adhesive strength of the adhesive layer to decrease. On the other hand, if it exceeds the upper limit, the content of butorphanol and / or its pharmaceutically permissible salts, absorption enhancers, etc., in the adhesive layer becomes relatively less, and therefore, there is a tendency for the skin penetration of butorphanol to decrease.

[0044] As the adhesive layer of the present invention, it is preferable to further contain an absorption enhancer (transdermal absorption enhancer). Examples of such absorption enhancers include at least one selected from aliphatic alcohols, fatty acid esters, fatty acid amides, and aliphatic alcohol ethers. From the viewpoint that the maximum skin penetration rate (Jmax) of butorphanol and / or its pharmaceutically permissible salts tends to be particularly high, at least one selected from aliphatic alcohols and fatty acid esters is preferred.

[0045] (Aliphatic alcohols)

[0046] As the aliphatic alcohol of the present invention, a monoaliphatic alcohol with 6 to 20 carbon atoms is preferred. When the number of carbon atoms in the aliphatic alcohol is less than the lower limit mentioned above, there is a tendency for increased skin irritation; on the other hand, when it exceeds the upper limit mentioned above, there is concern about the formation of waxy lumps in the formulation. Examples of aliphatic alcohols with 6 to 20 carbon atoms include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, linolenic acid alcohol, octyldodecanool, and mixtures thereof. From the viewpoint that butorphanol and / or its pharmaceutically permissible salts tend to have better skin permeability, at least one selected from isostearyl alcohol, oleyl alcohol, and octyldodecanool is particularly preferred.

[0047] (fatty acid esters)

[0048] The fatty acid ester of the present invention is preferably selected from at least one of the following: alkyl esters of fatty acids having 6 to 20 carbon atoms (alkyl fatty acid esters), esters of fatty acids having 6 to 20 carbon atoms with glycerol or polyglycerol (glycerol fatty acid esters), esters of fatty acids having 6 to 20 carbon atoms with polyoxyalkylene (polyoxyalkylene fatty acid esters), and esters of fatty acids having 6 to 20 carbon atoms with carbohydrates (carbohydrate fatty acid esters).

[0049] In this invention, the aforementioned fatty acid alkyl ester is an ester compound of a fatty acid having 6 to 20 carbon atoms and an alkyl alcohol (preferably a lower alkyl alcohol). Examples of such fatty acid alkyl esters include: isopropyl myristate, oleate, isopropyl palmitate, triethyl citrate, ethyl linoleate, hexyl laurate, cetyl myristate, octyl dodecyl myristate, decyl oleate, octyl dodecyl oleate, octyl dodecyl neodecanoate, cetyl ethylhexanoate, cetyl palmitate, stearate, and mixtures thereof. From the viewpoint that butorphanol and / or its pharmaceutically permissible salts tend to have better skin permeability, at least one selected from isopropyl myristate and isopropyl palmitate is preferred.

[0050] In this invention, examples of the aforementioned glycerol fatty acid esters include: glycerol monolaurate, polyglycerol monolaurate, glycerol monostearate, polyglycerol monostearate, glycerol monooleate, polyglycerol monooleate, trimyristic acid glyceride, tri(caprylic / capric acid) glyceride, triisostearate, and tricaprylic acid glyceride. The degree of polymerization of the aforementioned polyglycerol is preferably 50 or less. Preferably, the aforementioned glycerol fatty acid ester is selected from at least one of glycerol monolaurate, polyglycerol monolaurate, glycerol monostearate, polyglycerol monostearate, glycerol monooleate, and polyglycerol monooleate.

[0051] Furthermore, the aforementioned glycerol fatty acid ester can also be a glycerol fatty acid ester formed by further adding a polyoxyethylene (POE) group to the OH group of glycerol. The degree of polymerization of the ethylene oxide in the aforementioned polyoxyethylene group is preferably 50 or less.

[0052] In this invention, the above-mentioned polyoxyalkylene fatty acid ester is a compound in which the carboxyl group of a fatty acid having 6 to 20 carbon atoms is bonded with polyoxyalkylene compounds such as ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, and copolymers of ethylene oxide and propylene oxide. Examples of such polyoxyalkylene fatty acid esters include: ethylene glycol monolaurate, polyoxyethylene monolaurate (hereinafter, polyoxyethylene is referred to as "POE" and oxyethylene as "OE" as appropriate), propylene glycol monolaurate (PGML), polyoxypropylene monolaurate (hereinafter, polyoxypropylene is referred to as "POP" and oxypropylene as "OP" as appropriate), ethylene glycol monopalmitate, POE monopalmitate, propylene glycol monopalmitate, POP monopalmitate, ethylene glycol monostearate, POE monostearate, propylene glycol monostearate, POP monostearate, ethylene glycol monooleate, POE monooleate, propylene glycol monooleate, POP monooleate, propylene glycol dioleate, and polyethylene glycol distearate. In copolymers of POE, POP, OE, and OP, the degree of polymerization of each copolymer is preferably 50 or less. Of these, propylene glycol monolaurate is particularly preferred as the polyoxyalkylene fatty acid ester, given the view that the maximum skin penetration rate (Jmax) of butorphanol and / or its pharmaceutically permissible salts tends to be particularly large.

[0053] In this invention, the fatty acid esters of the aforementioned sugars are compounds in which a sugar is bonded to the carboxyl group of a fatty acid having 6 to 20 carbon atoms via an ester bond. Examples of such sugars include tetramonosaccharides (erythrose, threose), pentamonosaccharides (xylose, arabinose), hexamonosaccharides (glucose, galactose), sugar alcohols (xylitol, sorbitol), and disaccharides (sucrose, lactose, maltose). Examples of fatty acid esters of such sugars include: sorbitol monolaurate (Span 20), sorbitol monopalmitate (Span 40), sorbitol monostearate (Span 60), sorbitol tristearate (Span 65), sorbitol monooleate (Span 80), sorbitol trioleate, and sorbitol sesquioleate (Span 83).

[0054] Furthermore, the fatty acid esters of the aforementioned sugars may also have polyoxyethylene (POE) groups added to the OH groups of the sugar residues. The degree of polymerization of the ethylene oxide in the aforementioned polyoxyethylene group is preferably 50 or less. Examples of such compounds include polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 65 (Tween 65), and polysorbate 80 (Tween 80).

[0055] (Fatty acid amide)

[0056] As the fatty acid amides of the present invention, examples include amides of fatty acids having 6 to 20 carbon atoms, such as: lauric acid diethanolamide, oleic acid diethanolamide, stearic acid diethanolamide, ethylene bis-stearamide, stearic acid monoamide, oleic acid monoamide, ethylene dioleoamide, erucic acid monoamide, and mixtures thereof.

[0057] (Aliphatic alcohol ethers)

[0058] In this invention, the aforementioned aliphatic alcohol ethers are compounds in which ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, copolymers of ethylene oxide and propylene oxide, glycerol, polyglycerol, and other polyoxyalkylene compounds are ether-bonded to the OH group of an aliphatic alcohol having 6 to 20 carbon atoms. Examples of such aliphatic alcohol ethers include: POE oil ether, POE lauryl ether, POE cetyl ether, POE stearyl ether, POE octyl dodecyl ether, POE palmitate ether, and mixtures thereof.

[0059] Other examples of absorption promoters that may be included in the adhesive layer of the present invention include POE-cured castor oil, lecithin, phospholipids, soybean oil derivatives, and triacetylglycerol.

[0060] Furthermore, the adhesive layer of the present invention is preferably a surface-active compound that functions as an absorbency enhancer, as described above. Such a surface-active compound is preferably selected from at least one of the following: propylene glycol monolaurate, sorbitol monooleate, glyceryl monolaurate, glyceryl monooleate, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. Furthermore, the surface-active compound is preferably nonionic.

[0061] In this invention, the content of the absorption enhancer contained in the adhesive layer is preferably a mass ratio (converted mass of tartaric acid addition salt of butorphanol and / or its pharmaceutically permissible salt: mass of absorption enhancer) of 2:1 to 1:4, more preferably 2:1 to 1:3. If the content of the absorption enhancer is within the above range, there is a tendency that even if the concentration and absolute amount of butorphanol and / or its pharmaceutically permissible salt are relatively low, the delay time and the time to reach maximum skin penetration (Tmax) can be shorter, and the skin permeability and amount of the drug can be further increased, thereby further improving the utilization rate. On the other hand, when the content of the absorption promoter is less than the lower limit, there is a tendency for the time to reach the maximum skin penetration rate of butorphanol (Tmax) and the delay time to become longer. When the content exceeds the upper limit, there is a tendency for crystals derived from butorphanol to precipitate over time or for the adhesive layer to undergo a qualitative change, resulting in a decrease in adhesiveness.

[0062] Furthermore, in this invention, the content of the absorption promoter relative to the total mass of the adhesive layer is preferably 1.5 to 25% by mass, more preferably 2 to 25% by mass, and even more preferably 3 to 20% by mass. When the content of the absorption promoter is less than the lower limit, there is a tendency for the time to reach the maximum skin penetration rate (Tmax) of butorphanol and / or the delay time to become longer. On the other hand, when the content exceeds the upper limit, there is a tendency for crystals derived from butorphanol to precipitate over time or for the adhesive strength of the adhesive layer to decrease.

[0063] As the adhesive layer of the present invention, it may also contain additives such as adsorbents, desalting agents, thickeners, plasticizers, stabilizers, solvents for pharmaceuticals, fillers, and preservatives, without hindering the effects of the present invention.

[0064] (Adsorbent)

[0065] As the aforementioned adsorbent, examples include hygroscopic inorganic and / or organic substances, more specifically: minerals such as talc, kaolin, and bentonite; silicon compounds such as pyrolytic silica (Aerogel, a registered trademark), and hydrated silica; metal compounds such as zinc oxide and dried aluminum hydroxide gel; weak acids such as lactic acid and acetic acid; sugars such as dextrin; and polymers such as polyvinylpyrrolidone, aminoalkyl methacrylate copolymers, crosslinked polyvinylpyrrolidone, carboxyvinyl polymers, and butyl methacrylate-methyl methacrylate copolymers. One of these can be used alone, or two or more can be combined. From the viewpoint that the adhesive layer of the present invention can suppress the crystallization and precipitation originating from butorphanol, it is preferable that it also contains polyvinylpyrrolidone (PVP).

[0066] When the adhesive layer also contains the adsorbent (preferably polyvinylpyrrolidone), its content is preferably 0.05 to 2 mg / cm², calculated per unit area of ​​the adhesive layer. 2 Furthermore, the content relative to the total mass of the adhesive layer is preferably 1 to 20% by mass. Moreover, the mass ratio of butorphanol and / or its pharmaceutically permissible salt to the adsorbent (preferably polyvinylpyrrolidone) (mass of butorphanol and / or its pharmaceutically permissible salt in tartaric acid addition form: mass of the adsorbent) is preferably 3:1 to 1:4. When the content of polyvinylpyrrolidone is less than the lower limit, there is a tendency for crystals derived from butorphanol to easily precipitate; on the other hand, when the content exceeds the upper limit, there is a tendency for decreased skin permeability of butorphanol and / or its pharmaceutically permissible salt or decreased adhesiveness of the adhesive layer.

[0067] (Desalinizing agent)

[0068] The aforementioned desalting agent is primarily formulated to convert all or part of the basic drug into a free body. There are no particular limitations on the type of desalting agent; for example, when a formulation containing free butorphanol is obtained by combining an acid addition salt of butorphanol with the aforementioned drug, a basic substance is preferred, and more preferably a desalting agent containing metal ions or a desalting agent containing basic nitrogen atoms. Examples of such desalting agents containing metal ions include sodium acetate (including anhydrous sodium acetate), sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, and potassium bicarbonate; one of these can be used alone or in combination of two or more. Among these, sodium acetate and sodium hydroxide are particularly preferred as desalting agents. Furthermore, the adhesive layer of the present invention may also contain a compound derived from the aforementioned basic drug and the aforementioned desalting agent (for example, sodium tartrate in the case of combining butorphanol tartrate with sodium acetate). When the adhesive layer also contains such a desalting agent and compounds derived from alkaline drugs and desalting agents, the content of such a substance, from the viewpoint of inhibiting drug decomposition, is preferably 0.5 to 5 equivalents of acid-base equivalents relative to the tartaric acid addition salt of butorphanol, and more preferably 0.5 to 4 equivalents of acid-base equivalents relative to the desalting agent.

[0069] (Thickening agent)

[0070] The aforementioned tackifier is formulated primarily to improve the adhesion of the aforementioned adhesive base. Examples of such tackifiers include rosin-based resins, terpene-based resins, petroleum-based resins, phenolic resins, and xylene-based resins; one of these can be used alone, or two or more can be combined. When the adhesive layer also contains such a tackifier, its content, from the viewpoint of improving the adhesion of the adhesive layer and / or reducing local irritation during peeling, is preferably 0.5 to 20% by mass, more preferably 3 to 15% by mass, relative to the total mass of the adhesive layer.

[0071] (Plasticizer)

[0072] The aforementioned plasticizers are mainly formulated to adjust the adhesive properties of the adhesive layer, the flow characteristics during the manufacture of the adhesive layer, and the transdermal absorption characteristics of the drug. Examples of such plasticizers include: silicone oil; petroleum-based oils such as paraffin-based, naphthenic-based, and aromatic-based processing oils; squalane and squalene; vegetable oils such as olive oil, camellia oil, castor oil, tall oil, and peanut oil; diesters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; diethylene glycol, polyethylene glycol, propylene glycol, and dipropylene glycol; one of these can be used alone or in combination. Among these, silicone oil, liquid paraffin, and liquid polybutene are preferred as plasticizers.

[0073] (Soluble)

[0074] The aforementioned solvents are primarily formulated to promote the dissolution of the aforementioned drugs. Examples of such solvents include organic acids such as acetic acid, aliphatic alcohols, and surfactants; one of these can be used alone, or two or more can be combined. Among these, organic acids and aliphatic alcohols are preferred as solvents.

[0075] (filler)

[0076] The fillers mentioned above are mainly used to adjust the adhesion of the adhesive layer. Examples of such fillers include: aluminum hydroxide, calcium carbonate, magnesium carbonate; silicates such as aluminum silicate and magnesium silicate; silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, and titanium oxide. One of them can be used alone or in combination of two or more.

[0077] As the adhesive layer of this invention, the mass per unit area (area of ​​the adhesion surface) must be 30-90 g / m². 2 If the mass per unit area is less than the lower limit, the skin penetration rate and amount of the drug will decrease significantly, and the adhesive strength of the adhesive layer will also decrease. Furthermore, there is a tendency for the thickness of the adhesive layer to be difficult to control during manufacturing, or for the support layer to directly contact the skin during application, resulting in physical irritation. On the other hand, if the mass per unit area exceeds the upper limit, the delay time and the time to reach the maximum skin penetration rate (Tmax) will become longer, and the drug utilization rate will decrease. From the viewpoint that the mass per unit area of ​​the adhesive layer can further shorten the delay time and the time to reach the maximum skin penetration rate (Tmax), maintain the skin penetration rate and amount of the drug within a good range, and improve utilization rate, a mass of 40–90 g / m² is more preferable. 2 The preferred value is 40-80 g / m³. 2 .

[0078] Furthermore, the area of ​​the adhesive layer of the present invention can be appropriately adjusted according to the purpose of treatment or the target of application, and is typically 0.5 to 150 cm². 2 The range.

[0079] The adhesive according to the present invention enables a sufficiently short delay time and a time to reach maximum skin penetration (Tmax). As the aforementioned delay time, the mass per unit area of ​​the adhesive surface containing butorphanol and / or its pharmaceutically permissible salts in the adhesive layer, converted to butorphanol tartaric acid addition salt, is 0.36 mg / cm³. 2 In the following cases (e.g., the adhesive layer contains 4% by mass of butorphanol and / or its pharmaceutically permissible salts, converted to butorphanol tartaric acid addition salts), the mass of the adhesive layer per unit area is 90 g / m². 2 In the following cases, it is preferable to use 5 hours or less. Furthermore, as the time to reach the maximum skin penetration rate (Tmax) mentioned above, the mass per unit area of ​​the adhesive layer containing butorphanol and / or its pharmaceutically permissible salts, converted to butorphanol tartaric acid addition salt, is 0.36 mg / cm³. 2 In the following cases, it is preferable to be less than 14 hours, and more preferably less than 10 hours.

[0080] In this invention, specifically, the delay time and the time to reach the maximum skin penetration rate (Tmax) are determined by the following method. Furthermore, the delay time can also be determined as described above based on skin thickness and the drug diffusion coefficient in the skin, and in this invention, it is determined by the following method. First, an adhesive patch is applied to the epidermal side of the body of a de-fat-removed hairless mouse, with the dermal side in contact with the receiving solution (preferably PBS, 32°C). While the receiving solution is being delivered at a flow rate of approximately 2.5 ml / hr, the receiving solution is collected at specific time intervals. The concentration of butorphanol in the collected receiving solution (calcified by tartaric acid addition salt) is determined by high-performance liquid chromatography or similar methods. The cumulative skin penetration of butorphanol per unit area of ​​the patch surface at each time point (calcified by tartaric acid addition salt, unit: μg / cm³) is calculated. 2 And the amount of butorphanol absorbed per unit area of ​​the adherent surface per hour, i.e., the skin penetration rate (converted from tartaric acid addition salt, unit: μg / cm³). 2 / hr). Then, in the cumulative skin penetration-time curve obtained by setting the x-axis to the elapsed time since application (time [hr]) and the y-axis to the cumulative skin penetration, an approximate straight line is drawn at the point where the increase or decrease of y reaches a constant state (the point where the skin penetration rate reaches a constant state). The x-intercept of this line intersecting the x-axis can be calculated as the delay time (the delay time used to allow the skin penetration rate to reach a constant state, unit: hr). Furthermore, based on the velocity-time curve obtained by setting the x-axis to the elapsed time since application (time [hr]) and the y-axis to the skin penetration rate, the value of x when y reaches its maximum value can be calculated as the time to reach the maximum skin penetration rate (Tmax, unit: hr).

[0081] The butorphanol-containing adhesive of the present invention is not particularly limited and can be manufactured by appropriately employing known adhesive manufacturing methods. For example, firstly, butorphanol and / or its pharmaceutically permissible salts, the aforementioned organosilicon adhesive base, and, if necessary, the aforementioned absorption enhancer, solvent, and the aforementioned additives are mixed according to conventional methods to obtain a uniform adhesive layer composition. Examples of solvents include anhydrous ethanol and toluene. Then, the adhesive layer composition is applied to the surface of the aforementioned support layer (usually one side) in a manner that is the aforementioned mass per unit area, and the solvent is dried and removed by heating if necessary, thereby forming an adhesive layer. This layer is then cut into the desired shape as needed, thereby obtaining the adhesive of the present invention.

[0082] Furthermore, the method for manufacturing the butorphanol-containing adhesive of the present invention may further include the step of bonding the release liner to the side of the adhesive layer opposite to the support layer. Alternatively, the adhesive layer composition may first be applied to one side of the release liner to form an adhesive layer in a manner that is the aforementioned mass per unit area, and then the support layer may be bonded to the side of the adhesive layer opposite to the release liner. The adhesive may then be cut into a specific shape as needed, thereby obtaining the adhesive of the present invention. Furthermore, the obtained adhesive may be sealed in a storage packaging container (e.g., an aluminum laminated bag) as a packaging body as needed.

[0083] [Example]

[0084] The present invention will now be described in more detail based on embodiments and comparative examples, but the present invention is not limited to the following embodiments. Furthermore, in each embodiment and comparative example, the skin penetration test was performed by the method shown below.

[0085] <Skin Penetration Test (In Vitro Skin Penetration Test in Hairless Mice)>

[0086] First, the skin of the hairless mouse's body was peeled off and the fat removed. Cut sections of 2 or 2.5 cm were then attached to the side of the epidermis. 2 The adhesive patch, with the release liner removed, was placed in a flow-through Franz permeation test unit with the dermal side in contact with the receiving solution, and the unit was filled with the receiving solution (PBS). Then, while warm circulating water was circulated around the periphery to keep the receiving solution at 32°C, the receiving solution was delivered at a flow rate of approximately 2.5 ml / hr, and samples were collected every 4 hours for up to 24 hours. The concentration of butorphanol in the collected receiving solution (converted to tartaric acid adduct salt) was determined by high-performance liquid chromatography (HPLC), and the cumulative skin permeation of butorphanol per unit area of ​​the patch at each time point (converted to tartaric acid adduct salt, unit: μg / cm³) was calculated. 2 ) and the amount of butorphanol per unit area of ​​the application surface per hour (converted from tartaric acid addition salt, unit: μg / cm³) 2 / hr).

[0087] Subsequently, based on the cumulative skin penetration-time curve obtained by setting the x-axis to the elapsed time (hr) since application and the y-axis to the cumulative skin penetration, the delay time (hr) is calculated using the above method. Furthermore, based on the velocity-time curve obtained by setting the x-axis to the elapsed time (hr) since application and the y-axis to the skin penetration rate, the maximum value of y is set as the maximum skin penetration rate (Jmax), and the x-value at which y reaches its maximum value is set as the time to reach the maximum skin penetration rate (Tmax). Finally, the cumulative skin penetration from the start of application to 24 hours is set as the 24-hr cumulative skin penetration (A, unit: μg / cm³). 2 The 24hr drug utilization rate (%) is set as the value obtained by the following formula: A / B×100, which is the content of butorphanol per unit area (B) in the adhesive layer of the patch before application, calculated as tartaric acid addition salt.

[0088] (Example 1)

[0089] First, weigh out 4.0 parts by weight of butorphanol tartrate, 1.4 parts by weight of sodium acetate as a desalting agent, 5.0 parts by weight of oleyl alcohol, 9.0 parts by weight of polyvinylpyrrolidone (PVP), 10.0 parts by weight of tackifier (terpene resin), 1.4 parts by weight of plasticizer (silicone oil), and 69.2 parts by weight of organosilicon adhesive base 1 (organosilicon adhesive, model: BIO-PSA7-4201, manufactured by Dow Corning), and add appropriate amounts of solvent (anhydrous ethanol and toluene) to mix them to obtain an adhesive layer composition.

[0090] The composition of the adhesive layer composition (excluding the solvent) is shown in Table 1 below. The obtained adhesive layer composition was then applied to a release liner (a polyethylene terephthalate film that had undergone a release treatment), and the solvent was removed by drying, resulting in an adhesive layer with a mass of 40 g / m² per unit area. 2 The adhesive is formed in the following manner. On the side of the adhesive layer opposite to the release liner, a support layer (polyethylene terephthalate film) is laminated to obtain an adhesive formed by sequentially laminating a support layer / adhesive layer / release liner.

[0091] [Table 1]

[0092] Quality Butorphanol tartrate 4.0 Sodium acetate 1.4 Oil alcohol 5.0 Polyvinylpyrrolidone 9.0 Tackifier 10.0 plasticizer 1.4 Organosilicon adhesive 1 69.2 total 100.0

[0093] (Examples 2-4, Comparative Examples 1-3)

[0094] The mass per unit area of ​​the adhesive layer is as shown in Table 2 below, except that each adhesive is obtained in the same manner as in Example 1.

[0095] (Comparative Example 4)

[0096] First, 9.0 parts by weight of butorphanol tartrate, 3.1 parts by weight of sodium acetate as a desalting agent, 7.0 parts by weight of oleyl alcohol, 9.0 parts by weight of polyvinylpyrrolidone (PVP), and 71.9 parts by weight of rubber-based adhesive base agent 1 were weighed out and mixed with an appropriate amount of solvent (anhydrous ethanol and toluene) to obtain an adhesive layer composition. As rubber-based adhesive base agent 1, a mixture of 50 parts by weight of styrene-isoprene-styrene block copolymer (SIS), 50 parts by weight of polyisobutylene (PIB), 115.4 parts by weight of tackifier (terpene resin), and 61.5 parts by weight of liquid paraffin was used.

[0097] Subsequently, the obtained adhesive layer composition was applied to a release liner (a polyethylene terephthalate film that had undergone a release treatment), and the solvent was dried to remove it, resulting in an adhesive layer with a mass of 81 g / m² per unit area. 2 The adhesive is formed by stacking a support layer (polyethylene terephthalate film) on the side of the adhesive layer opposite to the release liner, thereby obtaining an adhesive formed by sequentially stacking a support layer / adhesive layer / release liner.

[0098] Skin penetration tests were performed on the adhesives obtained in Examples 1-4 and Comparative Examples 1-4. The results obtained in Examples 1-4 and Comparative Examples 1-3, along with the mass per unit area of ​​each adhesive layer, are shown in Table 2. Furthermore, the 24-hour drug utilization rate in Comparative Example 4 was 58%.

[0099] [Table 2]

[0100]

[0101] (Examples 5-7)

[0102] The composition of the adhesive layer composition is set as shown in Table 3 below, and the mass of the adhesive layer per unit area is set to 90 g / m². 2 Otherwise, each adhesive was obtained in the same manner as in Example 1. That is, instead of polyvinylpyrrolidone, isostearyl alcohol (Example 5), octyldodecyl alcohol (Example 6), and propylene glycol monolaurate (Example 7) were used instead of oleyl alcohol. In addition, silicone adhesive 2 (silicone adhesive, model: BIO-PSA7-4302, manufactured by Dow Corning) was used instead of silicone adhesive base 1. The tackifier was set to 11.1 parts by weight, the plasticizer to 1.6 parts by weight, and the silicone adhesive base 2 to 76.9 parts by weight. Otherwise, each adhesive was obtained in the same manner as in Example 1.

[0103] Skin penetration tests were performed on the adhesives obtained in Examples 5-7. The results obtained, along with the composition (excluding solvent) of each adhesive layer composition and the mass per unit area of ​​the adhesive layer, are shown in Table 3.

[0104] [Table 3]

[0105]

[0106] (Example 8)

[0107] The composition and mass per unit area of ​​the adhesive layer were set as shown in Table 4 below, except that the adhesive was obtained in the same manner as in Example 1. That is, no tackifier or plasticizer was used, and 80.6 parts by mass of silicone adhesive 3 (silicone adhesive, model: BIO-PSA AC7-4201, manufactured by Dow Corning) was used instead of silicone adhesive base agent 1, with the mass per unit area of ​​the adhesive layer set to 44 g / m². 2 Otherwise, the adhesive was obtained in the same manner as in Example 1.

[0108] (Example 9)

[0109] Using 2.7 parts by mass of butorphanol (free) instead of butorphanol tartrate and sodium acetate, the mass of the adhesive layer per unit area was set at 48 g / m². 2 Otherwise, the adhesive was obtained in the same manner as in Example 8.

[0110] Skin penetration tests were performed on the adhesives obtained in Examples 8-9. The results obtained, along with the composition (excluding solvent) of each adhesive layer composition and the mass per unit area of ​​the adhesive layer, are shown in Table 4.

[0111] [Table 4]

[0112]

[0113] (Example 10, Comparative Example 5)

[0114] The composition and mass per unit area of ​​the adhesive layer composition were set as shown in Table 5 below, except that each adhesive was obtained in the same manner as in Example 1. That is, without using tackifiers and plasticizers, the amount of butorphanol tartrate was set to 9.0 parts by mass, the amount of sodium acetate was set to 3.1 parts by mass, 73.9 parts by mass of silicone adhesive 3 was used instead of silicone adhesive base agent 1, and the mass per unit area of ​​the adhesive layer was set to 97 g / m². 2 and 47g / m 2 In addition, each adhesive was obtained in the same manner as in Example 1.

[0115] (Comparative Example 6)

[0116] An acrylic adhesive base (2-ethylhexyl acrylate·2-ethylhexyl methacrylate·dodecyl methacrylate copolymer) was used instead of silicone adhesive 3, and the mass of the adhesive layer per unit area was set at 45 g / m². 2 Otherwise, the adhesive was obtained in the same manner as in Example 10.

[0117] Skin penetration tests were performed on the adhesives obtained in Example 10 and Comparative Examples 5-6. The results obtained, together with the composition (excluding solvent) of each adhesive layer composition and the mass per unit area of ​​the adhesive layer, are shown in Table 5.

[0118] [Table 5]

[0119] Comparative Example 5 Example 10 Comparative Example 6 Butorphanol tartrate 9.0 9.0 9.0 Sodium acetate 3.1 3.1 3.1 Oil alcohol 5.0 5.0 5.0 Polyvinylpyrrolidone 9.0 9.0 9.0 Organosilicon adhesive 3 73.9 73.9 - acrylic adhesives - - 73.9 Total [parts by weight] 100.0 100.0 100.0 <![CDATA[Adhesive layer mass [g / m 2 > 97 47 45 Delay time [hr] 6.4 4.9 5.7 Time to reach maximum skin penetration rate (Tmax) [hr] 18 14 18

[0120] Based on the results shown in Tables 2-5, it can be confirmed that the mass per unit area of ​​the adhesive layer is 90 g / m². 2 In the patch of the present invention described below, the delay time and the time to reach the maximum skin penetration rate (Tmax) become particularly short, and the drug utilization rate becomes particularly high. Furthermore, it has been found that the lower the mass per unit area of ​​the adhesive layer, the shorter the delay time and the time to reach the maximum skin penetration rate (Tmax), and the higher the drug utilization rate tends to be. Furthermore, if the mass per unit area of ​​the adhesive layer is consistently 81 g / m²...2 Comparing the drug utilization rates of Example 4 and Comparative Example 4, it was confirmed that the drug utilization rate of 58% over 24 hours in Comparative Example 4 was not sufficient, but the drug utilization rate was higher in the patch of the present invention in Example 4, even though the content of the absorption enhancer (oleyl alcohol) was less than that in Comparative Example 4.

[0121] Furthermore, it was confirmed that even though the mass per unit area of ​​the adhesive layer was lower, and the accompanying butorphanol content (total amount) was also lower, the mass per unit area of ​​the adhesive layer was still 30–90 g / m². 2 Within the scope of the adhesive of the present invention, the maximum skin penetration rate (Jmax) is also sufficiently high, and the cumulative skin penetration amount over 24 hours is also sufficiently high. On the other hand, it has been confirmed that if the mass of the adhesive layer per unit area is less than 30 g / m², the maximum skin penetration rate (Jmax) is sufficiently high. 2 Then the maximum skin penetration rate (Jmax) and the cumulative skin penetration over 24 hours decrease sharply.

[0122] [Industry availability]

[0123] As explained above, according to the present invention, it is possible to provide a butorphanol-containing patch with sufficiently short delay time and time to reach maximum skin penetration rate (Tmax), sufficiently high amount of drug permeation through the skin, and sufficiently high utilization rate.

Claims

1. An adhesive comprising a support layer and an adhesive layer, The adhesive layer described above contains at least one drug selected from butorphanol and its pharmaceutically permissible salts, and an organosilicon-based adhesive base. The content of butorphanol and / or its pharmaceutically permissible salts in the aforementioned adhesive layer, calculated as butorphanol tartaric acid addition salts, is 3-5% by mass relative to the total mass of the aforementioned adhesive layer. The content of the aforementioned silicone-based adhesive in the adhesive layer is 65-85% by mass relative to the total mass of the adhesive layer, and The mass of the adhesive layer per unit area is 40–80 g / m². 2 .

2. The adhesive as claimed in claim 1, wherein the adhesive layer further comprises at least one absorption enhancer selected from aliphatic alcohols and fatty acid esters.

3. The adhesive as described in claim 2, wherein the absorption enhancer is selected from at least one of isostearyl alcohol, oleyl alcohol, octyldodecyl alcohol, and propylene glycol monolaurate.

4. The adhesive as described in claim 2 or 3, wherein the content of the absorption promoter in the adhesive layer is based on the mass ratio of butorphanol and / or its pharmaceutically permissible salt to the absorption promoter, i.e., the mass of butorphanol tartaric acid addition salt of butorphanol and / or its pharmaceutically permissible salt to the mass of the absorption promoter is 2:1 to 1:

4.

5. The adhesive as described in claim 2 or 3, wherein the content of the absorption promoter in the adhesive layer is 1.5 to 25% by mass relative to the total mass of the adhesive layer.

6. The adhesive as described in any one of claims 1 to 3, wherein the adhesive layer further comprises an adsorbent.

7. The adhesive as claimed in claim 6, wherein the content of the adsorbent in the adhesive layer is based on the mass ratio of butorphanol and / or its pharmaceutically permissible salts to the adsorbent, i.e., the mass of butorphanol tartaric acid addition salt of butorphanol and / or its pharmaceutically permissible salts: the mass of the adsorbent is 3:1 to 1:

4.

8. The adhesive as claimed in claim 6, wherein the content of the adsorbent in the adhesive layer is 1 to 20% by mass relative to the total mass of the adhesive layer.

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