MXPA98000359A - A formulation of adhesive tape for cutaneous administration which contains fentan - Google Patents

Abstract

An adhesive tape formulation for percutaneous administration containing fentanyl which comprises fentanyl or a salt thereof, a pressure sensitive adhesive and sodium acetate is described. The fentanyl salt is preferably fentanyl citrate. The adhesive tape formulation of the present invention has low skin irritation and is excellent at percutaneous permeation of fentanyl and has a high stability even after the passage of time.

Description

AN ADHESIVE TAPE FORMULATION FOR CUTANEOUS ADMINISTRATION CONTAINING FENTANILO DESCRIPTION OF THE INVENTION The present invention relates to a formulation of adhesive tape for percutaneous administration containing fentanyl (chemical name: 1-phenethyl-4-N-propionyl-anilino) -piperidine) or a salt thereof, which is quite excellent in transdermal permeable property and which has low irritant property for skins. The formulation of adhesive tape for percutaneous administration containing fentanyl of the present invention is greatly expected to be used as a long-acting anesthetic and analgesic. Fentanyl, in particular fentanyl citrate, is known as a pharmaceutical having a high analgesic effect. However, there is no useful method of administration of the pharmacist for pains that last relatively long such as carcinomatous pains, since their elimination half-life is short and thus their effects do not last although it is used to infuse constant proportion before and after of the operation. In the United States, a long-acting patch formulation containing fentanyl base is on the market (usual name: DURAGESIC). However, this has the disadvantage of being highly irritating to administered regions (The PII value showing a primary irritant index to rabbit skins of the patch formulation is 2.2, which is a very high value compared to that of the the present invention which is 0.3 to 0.8 (See Table 3.) In addition, although attempts have been made to formulate fentanyl citrate in an adhesive tape formulation for percutaneous administration, it can not be used clinically, since the solubility of citrate of fentanyl in non-aqueous base is low and in this way the transdermal permeable property of the formulation, in which the fentanyl is contained in a non-aqueous base is very low.Therefore, an object of the present invention is to eliminate the problems above along with the above techniques, and provide a formulation of adhesive tape for percutaneous administration containing fentanyl, which has irritating properties It goes down to the skin, which is extremely excellent in the transdermal permeable property of fentanyl, and which is stable during the storage period. The inventors of the present have seriously investigated in order to achieve the above object, and as a result, it has been found that an adhesive tape formulation for percutaneous administration which is extremely excellent in the transdermal permeable property and which has low property An irritant can be prepared by adding sodium acetate to a pressure-sensitive adhesive base containing fentanyl or salt thereof, and thus the present invention ends. In this way the present invention relates to a formulation of adhesive tape for percutaneous administration containing fentanyl which comprises fentanyl or a salt thereof, a pressure sensitive adhesive and sodium acetate. The present invention also relates to the formulation of adhesive tape for percutaneous administration containing fentanyl, which comprises 0.05 to 20% (w / w) of fentanyl or a salt thereof, 0.1 to 98% (w / w) of a pressure sensitive adhesive and 0.01 to 15% (w / w) of sodium acetate. The present invention also relates to a formulation of adhesive tape for percutaneous administration containing fentanyl, wherein the salt of fentanyl is fentanyl citrate. The present invention also relates to the formulation of adhesive tape for percutaneous administration containing fentanyl, wherein the weight ratio of the formulation of fentanyl citrate and sodium acetate is (3 a ): (1.5 to 2.5). The present invention also relates to the formulation of adhesive tape for percutaneous administration containing fentanyl, wherein the weight ratio of the formulation of fentanyl citrate and sodium acetate is 2: 1. The present invention also relates to the formulation of adhesive tape for percutaneous administration containing fentanyl, which also comprises an oil and / or a tackifier. The present invention also relates to the formulation of adhesive tape for percutaneous administration containing fentanyl, which further comprises a transdermal absorption enhancer. The present invention also relates to the formulation of adhesive tape for percutaneous administration containing fentanyl, wherein the pressure sensitive adhesive comprises two components of the block polymer of polyisobutylene and styrene-isoprene-styrene. The formulation of adhesive tape for percutaneous administration containing fentanyl of the present invention will be explained in detail, hereinafter. The active pharmacological component of the fentanyl-containing percutaneous administration adhesive tape formulation of the present invention is the same fentanyl or a salt thereof. The salt of fentanyl is not particularly limited, and an inorganic salt and an organic salt thereof can be used. As typical fentanyl salts, those of citrate, hydrochloride or fumarate and the like can be exemplified. Among them, fentanyl citrate is particularly preferred. Fentanyl or a salt thereof can be used only, and a mixture of at least two of them can be used. Fentanyl or a salt thereof is preferably contained in an amount in the range of 0.05 to 20% (weight / weight) based on the total amount of the adhesive layer of the adhesive tape formulation for percutaneous administration of the present invention. If the amount of fentanyl or a salt thereof is less than 0.05% (w / w), a sufficient permeation amount as well as an adhesive tape formulation for percutaneous administration can not be obtained, and if the amount exceeds 20% (weight / weight), this exerts a bad influence on the physical properties of the same formulation and in this way is not preferred. The pressure sensitive adhesive contained in the adhesive layer of the adhesive tape formulation for percutaneous administration containing fentanyl of the present invention, is not limited, but the polyisobutylene (PIB), the styrene-isoprene-styrene block copolymer (SIS) [for example, Califlex D-1111, Califlex Tr-1107 manufactured by Shell Chemical; JSR5000, JSR-5002, SR5100 manufactured by Japan Synthetic Rubber Co., Ltd., - Quintack 3421 manufactured by Nippon Zeon Co., Ltd.], elastic rubber of isoprene, styrene-butadiene-styrene copolymer (SBS) [for example , Califlex TR-1101 manufactured by Shell Chemical], acrylic polymer [e.g. a copolymer comprising at least two components selected from the group comprising 2-ethylhexyl acrylate, vinyl acetate, ethyl acrylate, methacrylate, methoxyethyl and acrylic acid, such as PE-300 (manufactured by Nippon Carbide Industries Co., Inc.,)] can be exemplified as preferred examples. These polymers can be used alone or a mixture of at least two of them can be used. Among them, two components comprising PIB and SIS are preferably used. In this case, the weight ratio of the PIB and SIS formulation is preferably 1: 1 to 1: 4. The pressure sensitive adhesive is preferably contained in an amount in the range of 0.1 to 98% (weight / weight), more preferably from 0.1 to 70% (w / w), the most preferred form from 0.1 to 50% (w / w), based on the total amount of the adhesive layer of the adhesive tape formulation for cutaneous administration of the present invention. If the amount of the pressure sensitive adhesive is less than 0.1% (w / w), the physical properties of the same formulation will be deficient and thus not preferable. If the amount exceeds 98 & (weight / weight), a satisfactory adhesive property can not be obtained for human skin and this is not preferred. The transdermal permeable property of fentanyl or a salt thereof is highly increased by formulating the sodium acetate in the adhesive layer of the adhesive tape formulation for percutaneous administration containing fentanyl of the present invention. Sodium acetate is preferably contained in an amount in the range of 0.01 to 15 & (weight / weight), more preferably from 0.01 to 10% (w / w), the most preferred form of 0.01 to 5% (w / w), based on the total amount of the adhesive layer. If the amount of the sodium acetate is less than 0.01% (w / w), the effect of markedly improving the transdermal permeable property can not be obtained. If the amount exceeds 15% (weight / weight), irritability increases in the skin, so it is not preferred. If the fentanyl salt is fentanyl citrate, the maximum effect on aspects of physical property and transdermal permeable property can be obtained when the weight ratio of formulation of fentanyl citrate and sodium acetate is (1 to 5): (0.5 to 2.5), preferably, (3 to 5): (1.5 to 2.5), more preferably 2: 1. The amount of sodium acetate is less than the proportion of the formulation, the transdermal permeable property of the drug is suddenly lowered, and the amount of the sodium acetate exceeds the proportion of the formulation, the adhesive tape formulation will be heterogeneous and the Physical properties such as adhesive property will be deficient and thus not preferred. further, a tackifier may be formulated in the adhesive layer of the formulation of the present invention to impart an adhesive property to the formulation since the adhesive property of the pressure sensitive adhesive is low. As preferred examples of the tackifiers, polyterpene resins, petroleum resins, rosins, rosin esters, oil soluble phenol resins and the like can be exemplified. As concrete examples of the tackifiers can be exemplified by usual names, Clearon P-105, Foral 105, Arcon P-100, KE-loo, Super Ester S-100, Tamanol 521, YS Resin 75, KR-610 and the like . The tackifiers are preferably contained in the range of 0.1 to 70% (weight / weight), more preferably 5 to 50% (weight / weight), and most preferred form 10 to 35% (weight / weight), based on the total amount of the adhesive layer of the formulation of the present invention. In addition, an oil can be formulated in the adhesive layer as a softening agent in order to improve processability and control the adhesive property of the adhesive tape formulation for percutaneous administration of the present invention. As the oil, for example, liquid paraffin, squalane, olive oil, Tsubaki oil, Persian oil and peanut oil, are preferred, and liquid paraffin is the most preferred. The oil is contained in the range of 1 to 70% (weight / weight), more preferably 10 to 60% (weight / weight), and most preferred form 20 to 50% (weight / weight), based on the total amount of the adhesive layer of the formulation of the present invention. In addition, a transdermal absorption enhancer can be formulated in the adhesive layer of the formulation of the present invention depending on the needs. As well as the transdermal absorption enhancer, any compounds that improve the absorption effect in skins that are recognized can be used. For example, fatty acids having carbon chains of 6 to 20, aliphatic alcohols, esters of fatty acids or ethers, aromatic organic acids, aromatic alcohols, esters or ethers of organic aromatic acids can be exemplified. In addition, the lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpene compounds, Azone or its derivatives, glycerin fatty acid esters, sorbitan fatty esters, polysorbates, polyethylene glycol fatty acid esters, castor hardened with polyoxyethylene, fatty acid esters of sucrose and the like can be exemplified. As concrete examples of the improver, caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linolic acid, linoleic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, cetyl alcohol, laurate methyl, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, salicylic acid, methyl salicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate, cresol, cetyl lactate, ethyl acetate, propyl acetate , geraniol, thymol, eugenol, terpineol, 1 -mentol, borneol, d-limonene, isoeugenol, isoborneol, nerol, dl-camphor, glycerol monolaurate, glycerol monooleate, sorbitan monolaurate, sucrose monlaurate, polysorbate 20, monolaurate polyethylene glycol, polyethylene glycol monostearate, HCO-60 (hardened castor oil), 1- [2- (decylthio) ethyl] azacyclopentan-2-one (hereinafter abbreviated as "pyrothiodecane") are preferred, and lauryl alcohol, myristyl alcohol, ethylene glycol salicylate, and pyrothiodecane are more preferred. These transdermal absorption enhancers are preferably contained in an amount in the range of 0.01 to 20% (w / w), more preferably in an amount in the range of 0.1 to 10% (w / w), and a more preferred amount in the range of 0.5 to 5% (weight / weight), based on the total amount of the adhesive layer of the formulation of the present invention. If the amount of transdermal absorption enhancer exceeds 20% (w / w), irritations to the skin such as erythema and edema are shown, and if the amount is less than 0.01% (w / w), the effect of formulating the Transdermal absorption enhancer can not be obtained, and thus is not preferred. In addition, a hydrophilic polymer may be contained in the formulation of the adhesive tape of the present invention depending on the needs in order to absorb the aqueous components such as sweat produced from the skin. As well as the hydrophilic polymer, for example, light silicic anhydride, cellulose derivatives [carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMCNa), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC)], derivatives of starch (Pullulan), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), vinyl acetate (VA), carboxyvinyl polymer (CVP), ethylvinyl acetate (EVA), Eudragit, gelatin, polyacrylic acid, sodium polyacrylate, polyisobutylene maleic anhydride copolymer, alginic acid, sodium alginate, carrageenan, gum arabic, tragacanth, karaya gum, and polyvinyl methacrylate are preferred, and light silicic anhydride, cellulose derivatives (CMCNa, HPMC, HPC) are more preferred. , MC) and Eudragit. The hydrophilic polymer is preferably contained in an amount in the range of 0.1 to 20% (weight / weight), more preferably from 0.5 to 10% (w / w), based on the total amount of the adhesive layer of the adhesive tape formulation for percutaneous administration of the present invention.

In addition, a crosslinking agent, a preservative, an antioxidant and other components can be formulated in the adhesive layer of the formulation of the present invention. As the crosslinking agent, a thermosetting resin such as an amino resin, a phenol resin, an epoxy resin, an alkyl resin, an unsaturated polyester, an isocyanate compound, a block isocyanate compound, an organic crosslinking, and an inorganic crosslinking agent such as a metal or a metal compound are preferred. As the preservative, ethyl p-oxybenzoate, propyl p-oxybenzoate, butyl p-oxybenzoate and the like are preferred. As the antioxidant, tocopherol and its ester derivatives, ascorbic acid, stearic acid ester, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA) and the like are preferred. The adhesive layer of the adhesive tape formulation of the present invention preferably comprises a non-aqueous base, and the effects of the present invention can be obtained effectively by making the non-aqueous base. The adhesive layer comprising the above components can be prepared by any conventional methods. For example, when the layer is prepared by a solvent method, the formulation of the present invention can be prepared by adding other components than the polymers to an organic solvent solution of the polymers, then by stirring, and applying the mixture on a film. of support and drying. When the polymers to be formulated can be applied by a hot melt method, the formulation of the present invention can be obtained by dissolving the polymer components, stirring, and applying on a support film. The adhesive tape formulation of the present invention can comprise any layers with the proviso that it has an adhesive layer having the above components, and other layers and components of the layers are not limited. For example, the adhesive tape formulation for percutaneous administration may comprise, in addition to the adhesive layer, a backing layer supporting the adhesive layer, a disposable alignment layer provided on the adhesive layer, and the like. The support layer may comprise, for example, fabric, non-spunbond, polyurethane, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, polybutylene terephthalate, paper, aluminum foil and the like, and a composite material thereof. . The adhesive tape formulation for percutaneous administration of the present invention is a very useful means of mitigating pain for patients who can not take an analgesic anesthetic orally easily, since fentanyl or a salt thereof is continuously absorbed via the skin by the skin. adhesive tape formulation of the present invention. In addition, the adhesive tape formulation of the present invention can be administered non-invasively and in this way can decrease patient problems compared to the method of continuous intradermal administration which is an invasive method. In addition, thus the dose can be easily controlled, for example, by cutting the formulation, depending on the conditions, ages, body weights, sex distinctions and other factors of the patients. EXAMPLES The present invention will be explained in more detail with the following Examples, hereinafter hereinafter. However, the present invention is not limited to the Examples, and the present invention extends to all modifications and variations as will be apparent to those skilled in the art without departing from the scope of the present invention. In the examples, all "%" are% (weight / weight) unless indicated. Example 1 Sodium acetate 2.5% Acrylic polymer (PE_300) 58.5% Toluene diisocyanate 1.0% Pyroothiodecane 3.0% Fentanyl citrate 5.0% Total amount 100 & Sodium acetate, pyrothiodecane and fentanyl citrate are added to ethanol, and stirred to dissolve at room temperature. Then, a solution of the acrylic polymer in ethyl acetate and the toluene diisocyanate are added to the mixture and stirred. The mixture is applied to a film of polyethylene terephthalate (PET) (30 m), and this is thermally crosslinked at 90 ° C for 15 minutes to have a 50 m adhesive layer. Using the adhesive layer, an adhesive tape formulation for percutaneous administration of the present invention is prepared by a conventional method. Example 2 Sodium acetate 1.5% Pirotiodecano 3.0% Liquid paraffin 38.0% Stickiness agent of polyterpene resin 29.5% Polyisobutylene 7.5% Styrene-isoprene-styrene block copolymer 16.5% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl citrate 3.0% Total amount 100.0% After the compounds except sodium acetate, pyrothiodecane and fentanyl citrate are dissolved and mixed at 180 ° C, the rest of the components are added and dispersed to have a homogenous mixture. The mixture is then applied to the PET film (30 m) to have a 100 m adhesive layer. Using the adhesive layer, an adhesive tape formulation for percutaneous administration of the present invention is prepared by a conventional method. Example 3 2.5% sodium acetate Pirotiodecano 3.0% Liquid paraffin 39.5% Stickiness agent of polyterpene resin 21.7% Polyisobutylene 6.8% Styrene-isoprene-styrene block copolymer 20.4% Antioxidant (BHT) 0.5% Aluminum silicate 0.6% Fentanyl citrate 5.0% Total amount 100.0% After the compounds except sodium acetate, pyrothiodecane and fentanyl citrate are dissolved and mixed at 180 ° C, the rest of the components are added and dispersed to have a homogenous mixture. Then the mixture is applied to the PET film (30 m) to have an adhesive layer of 100 m Using the adhesive layer, an adhesive tape formulation for percutaneous administration of the present invention is prepared by a conventional method.

Example 4 2.5% sodium acetate Liquid paraffin 12.5% Oil soluble phenol resin tackifier - 39.5% Polyisobutylene 7.5% Styrene-isoprene-styrene block copolymer 30.5% Antioxidant (BHT) 0.5% 2.0% lauryl alcohol Fentanyl citrate 5.0% Total amount 100.0% After the compounds except lauryl alcohol, sodium acetate and fentanyl citrate are dissolved and mixed at 180 ° C, the rest of the components are added and dispersed to have a homogeneous mixture. The mixture is then applied to the PET film (30 m) to have a 100 m adhesive layer. Then using the adhesive layer, an adhesive tape formulation for percutaneous administration of the present invention is prepared by a conventional method. Example 5 Sodium Acetate 1.5% Crotamiton 3.0% Liquid Paraffin 38.5% Polyurethane resin stickiness agent 29.5% Polyisobutylene 7.5% Styrene-isoprene-styrene block copolymer 16.5% Antioxidant (BHT) 0.5% Fentanyl citrate 3.0% Total amount 100.0% After stirring to dissolve the sodium acetate, crotamiton, fentanyl citrate and liquid paraffin at 80 ° C, mix the mixture with a solution of cyclohexane in which the copolymer has been previously dissolved of styrene-isoprene-styrene block, polyisobutylene, tackifier of polyterpene resin and antioxidant. The mixture is then applied to the PET film (30 m) to have a 100 m adhesive layer. Using the adhesive layer, an adhesive tape formulation for percutaneous administration of the present invention is prepared by a conventional method. Example 6: 2.5% sodium acetate Liquid paraffin 35.0% Polyterpene resin tackifier 25.5% Polyisobutylene 7.0% Styrene-isoprene-styrene block copolymer 24.0% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl citrate 5.0% Total amount 100.0% After the compounds except sodium acetate and fentanyl are dissolved and mixed at 180 ° C, the rest of the components are added and dispersed to have a homogenous mixture. The mixture is then applied to the PET film (30 m) to have a 100 m adhesive layer. Using the adhesive layer, a percutaneous administration adhesive tape formulation of the present invention is prepared by a conventional method. Example 7 Sodium acetate 0.5% Pirotiodecano 3.0% Liquid paraffin 29.0% Polyterpene resin tackifier agent 42.1% Polyisobutylene 7.0% Styrene-isoprene-styrene block copolymer 16.4% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl citrate 1.0% Total amount 100.0% Using the above components (Fentanyl citrate: sodium citrate = 2: 1), an adhesive tape formulation for percutaneous administration of the present invention is prepared by the method as described in Example 2. Example 8 Sodium acetate 1..5% Pirotiodecano 3. .0% Liquid paraffin 28..9% Polyterpene resin tackifier 41. .5% Polyisobutylene 6.9% Styrene-isoprene-styrene-nano block copolymer 16..2% Antioxidant (BHT) 0..5% Aluminum silicate 0..5% Fentanyl Citrate 1.. 0% Total Amount 100.0% Using the above components (Fentanyl citrate: sodium citrate = 2: 3), a percutaneous adhesive tape formulation of the present invention is prepared by the method as described in Example 2. Example 9 2.5% sodium acetate Pirotiodecano 3.0% Liquid paraffin 28.7% Polyterpene resin tackifier 41.0% Polyisobutylene 6.8% Styrene-isoprene-styrene block copolymer 16.0% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl citrate 1.0% Total amount 100.0% Using the above components (Fentanyl citrate: sodium citrate = 2: 5), an adhesive tape formulation for percutaneous administration of the present invention is prepared by the method as is described in Example 2. Example 10 Sodium acetate 0.5% Pirotiodecano 3.0% Liquid paraffin 28.7% Polyethylene resin tackifier 41.0% Polyisobutylene 6.8% Styrene-isoprene-styrene block copolymer 16.0% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl Citrate 3.0% Total Amount 100.0% Using the above components (Fentanyl citrate: sodium citrate = 6: 1), an adhesive tape formulation for percutaneous administration of the present invention is prepared by the method as described in Example 2. Example 11 Sodium acetate 1.5% Pirotiodecano 3.0% Liquid paraffin 28.5% 40.5% polyterpene resin tackifier Polyisobutylene 6.8% Styrene-isoprene-styrene block copolymer 15.7% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl Citrate 3.0% Total Amount 100.0% Using the above components (Fentanyl citrate: sodium citrate = 2: 1), an adhesive tape formulation for percutaneous administration of the present invention is prepared by the method as described in Example 2.

Example 12 Sodium Acetate 2.5% Pirotiodecano 3.0% Liquid paraffin 28.2% Polyterpene resin tackifier 40.0% Polyisobutylene 6.7% Styrene-isoprene-styrene block copolymer 15.6% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl citrate 3.0% Total amount 100.0% Using the above components (Fentanyl citrate: sodium citrate = 6: 5), an adhesive tape formulation for percutaneous administration of the present invention is prepared by the method as is described in Example 2.

Example 13 Sodium acetate 0.5% Pirotiodecano 3.0% Liquid paraffin 28.2% Polyterpene resin tackifier 40.0% Polyisobutylene 6.7% Styrene-isoprene-styrene block copolymer 15.6% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl Citrate 5.0% Total Amount 100.0% Using the above components (Fentanyl citrate: sodium citrate = 10: 1), an adhesive tape formulation for percutaneous administration of the present invention is prepared by the method as described in Example 2.

Example 14 Sodium acetate 1.5% Pirotiodecano 3.0% Liquid paraffin 28.2% Stickiness agent of polyterpene resin 39.5% Polyisobutylene 6.5% Styrene-isoprene-styrene block copolymer 15.3% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl Citrate 5.0% Total Amount 100.0% Using the above components (Fentanyl citrate: sodium citrate = 10: 5), an adhesive tape formulation for percutaneous administration of the present invention is prepared by the method as described in Example 2. Example 15 2.5% sodium acetate Pirotiodecano 3.0% Liquid paraffin 28.0% Polyethylene resin tackifier 38.9% Polyisobutylene 6.5% Styrene-isoprene-styrene block copolymer 15.1% Antioxidant (BHT) 0.5% Aluminum silicate 0.5% Fentanyl citrate 5.0% Total amount 100.0% Using the above components (Fentanyl citrate: sodium citrate = 2: 1), an adhesive tape formulation for percutaneous administration of the present invention is prepared by the method as is described in Example 2. Comparative Examples 1 to 5 Comparative Examples 1 to 5 are each corresponding to Examples 1 to 5, respectively. In each Comparative Example, an adhesive tape formulation for percutaneous administration is prepared by the method as described in the corresponding Example, with the proviso that the sodium acetate which is used in Examples 1 to 5, is not formulated. Test Example 1 (In vitro transdermal permeation test) As for each of the formulations for percutaneous administration obtained in Examples 1 to 5, 7 a and Comparative Examples 1 to 5, evaluations are made by an in vitro transdermal permeation test using hairless mouse skin. After taking the skin from the posterior region of the hairless mouse (6 to 9 weeks of age), the fat on the dermal side is carefully removed. The skin is installed in a continuous flow cell, in which water is circulated at 37 ° C around the outer periphery of the receiving layer, such that the side of the dermis is the receiving layer. Each of the adhesion tape formulations for percutaneous administration obtained in Examples 1 to 5, 7 to 15 and Comparative Examples 1 to 5 are applied to the stratum corneum side, and are sampled every hour for 24 hours in a 5 ml / hour ratio using physiological saline to the receiving layer. Then, the flow rates are determined exactly every hour, and the concentrations of the drug are determined by a high-resolution liquid chromatography method. The permeation ratios are calculated at one hour according to the following formula, and the permeation ratios at the steady state are determined. The results are shown in Table 1. Transdermal permeation ratio (g / cm2 / hr) = [Concentration of the drug (g / ml) X Flow ratio (ml)] / Applied surface area of the formulation (cm2) Table 1 Transdermal permeation ratio (g / cm2 / hr) __ Example 1 15.5 Example 2 25.3 Example 3 36.8 Example 4 35.2 Example 5 22.3 Example 7 Example 8 8.2 Example 9 7.6 Example 10 9.4 Example 11 22.2 Example 12 20.5 Example 13 12.2 Example 14 29.4 Example 15 35.8 Comparative example 1 1.2 Comparative example 2 1.0 Example comparative 3 1.2 Comparative example 4 1.5 Comparative example 5 1.1 As is clear from Table 2, the adhesive tape formulations for percutaneous administration obtained in Example 1 to 5 and 7 to 15 have higher proportions of transdermal permeation, compared with the adhesive tape formulations for percutaneous administration obtained in Comparative Examples 1 to 5. In particular, this tested as the adhesive tape formulations for percutaneous administration of Examples 1 to 5, 7, 11, 12, 14 and 15, in which the formulation ratios of fentanyl citrate and sodium acetate are (3 to 5): ( 1.5 to 2.5), have very high transdermal permeation ratios. Among them, it is proven that the adhesive tape formulations for percutaneous administration of Examples 1 to 5, 11 and 15 in which the formulation ratios of fentanyl citrate and sodium acetate are 2: 1, have proportions of transdermal permeation extremely high Test Example 2 (Primary irritant test for rabbit skin) Evaluations are made to each of the adhesive tape formulations for percutaneous administration obtained in Examples 1 to 5, by a primary irritant test in vivo using a skin of rabbit. Each of the adhesive tape formulations for percutaneous administration obtained in Examples 1 to 5 are applied to rabbit skin. Decisions are made according to the criteria of irritability to the skin shown in Table 2, such as erythema and edema at 24 and 48 hours after application. The total of the results is taken into account as the result in each period. In addition, the average value of the irritation results in each period are taken into account as the PII value. In addition, like the control groups, the Pharmacopoeia Japónica patch adhesive tape and a product commercially available in the United States of America are used. Table 2 Irritability criteria for skin Result Erythema Edema 0 None None 1 Extremely low Extremely low 2 Evident Evident 3 Medium grade up Medium grade to intense intense Scarlet, intense Intense Table 3 Skin irritability (PII value) Example 1 0.5 Example 2 0.7 Example 3 0.5 Example 4 0.7 Example 5 0.3 Formulation of Pharmoia 0.3 Japan DURAGEIC adhesive tape (Commercially available 2.2 * in USA) * Extracted from the FDA application documents. From the above results shown in Table 2, it is proved that the formulations for percutaneous administration of Examples 1 to 5 have very low irritant property and skins compared with the conventional product (DURAGESIC), have the irritating property in skins equal to the tape d Pharmaeia patch which has low irritant properties. INDUSTRIAL APPLICABILITY With the present invention, fentanyl or a salt thereof can be formulated in a percutaneous administration formulation which is of excellent low irritation in transdermal permeable property, which can be obtained by the prior art. In this way fentanyl or a salt thereof can be supplied in the body and the pharmacological effects of fentanyl or a salt thereof can be used continuously, using the fentanyl-containing percutaneous administration adhesive tape formulation of the present invention. Therefore, the fentanyl percutaneous administration adhesive tape formulation of the present invention will be a very useful means of mitigating pain for patients who can not easily take an analgesic anesthetic orally.

Claims (9)

1. CLAIMS 1. A formulation of adhesive tape for percutaneous administration containing fentanyl, which is characterized in that it comprises fentanyl or a salt thereof, a pressure sensitive adhesive and sodium acetate.
2. 2. The formulation of adhesive tape for percutaneous administration containing fentanyl according to claim 1, characterized in that it comprises 0.05 to 20% (w / w) of fentanyl or a salt thereof, 0.1 to 98 & (weight / weight) of the pressure sensitive adhesive and 0.01 to 15 & (weight / weight) of sodium acetate.
3. 3. The formulation of adhesive tape for percutaneous administration containing fentanyl according to claim 1 or 2, characterized in that the fentanyl salt is fentanyl citrate.
4. 4. The formulation of adhesive tape for percutaneous administration containing fentanyl according to claim 3, characterized in that the weight ratio of formulation of fentanyl citrate and sodium acetate is (1 to 5): (0.5 to 2.5).
5. 5. The formulation of adhesive tape for percutaneous administration containing fentanyl according to claim 3, characterized in that the weight ratio of formulation of fentanyl citrate and sodium acetate is (3 to 5): (1.5 to 2.5).
6. 6. The formulation of adhesive tape for percutaneous administration containing fentanyl according to claim 3, characterized in that the weight ratio of formulation of fentanyl citrate and sodium acetate is 2: 1.
7. 7. The formulation of adhesive tape for percutaneous administration that it contains fentanyl according to any of claims 1 to 6, characterized in that it also comprises an oil and / or tackifier.
8. 8. The adhesive tape formulation for percutaneous administration containing fentanyl according to any of claims 1 to 7, characterized in that it further comprises a transdermal absorption enhancer.
9. 9. The adhesive tape formulation for percutaneous administration containing fentanyl according to any of claims 1 to 8, characterized in that the pressure sensitive adhesive comprises two components of polyisobutylene and styrene-isoprene-styrene block copolymer.