MXPA00009361A - Device for the transdermal delivery of diclofenac - Google Patents

Abstract

The present invention provides a pressure sensitive skin adhesive comprising:(a) a copolymer of one or more alkyl(meth)acrylates containing 4 to 12 carbon atoms in the alkyl group and one or more hydrophilic monomers;(b) a mixture of penetration enhancers comprising:(i) an alkyl ester of an aliphatic monocarboxylic acid containing 1 to 5 carbon atoms in the alkyl group;(ii) an alkyl pyrrolidone and (iii) an alkane polyol;(c) a therapeutically effective amount of diclofenac or a pharmaceuticallyacceptable salt thereof. Further provided is a transdermal drug delivery device containing the pressure sensitive skin adhesive.

Description

DEVICE FOR THE TRANSDERMAL SUPPLY OF DICLOFENACO DESCRIPTION OF THE INVENTION The present invention relates to a transdermal drug delivery device for the delivery of diclofenac or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to a pressure sensitive skin adhesive containing diclofenac or a pharmaceutically acceptable salt thereof. Ortho [(2,6-diclphenyl) amino] phenylacetic acid (hereinafter referred to as diclofenac) and its pharmaceutically acceptable salts are known compounds useful in the treatment for inflammation. [Sodium ortho [(2,6-diclphenyl) amino] phenyl] acetate, also variously known as monosodium salt of 2- [2,6-dichlorophenyl) amino] benzeneacetic acid and diclofenac sodium, have shown, for example, in pharmacological studies possess powerful analgesic and anti-inflammatory properties. See, for example Riess et al., Scand. J. Rheumatol. Suppl., Vol. 22, pp. 17-29 (1978). The use of diclofenac sodium in the form of an aqueous solution in the treatment for ocular inflammation has also been shown. See, for example, M. gata et al-, Nihon Ganka Gakkai [Acta Soc. Ophthalmol. Japan], Vol. 87, pp. 19-28 (1983), and M. gata et al., Nihon Ganka Gakkai [Acta Soc. Ophthalmol. Japan, Vol. 88, No. 6, pp. 61-66 (1984).

The transdermal delivery of diclofenac or its pharmaceutically acceptable salts has been described in various publications. For example, EP 524582 describes a patch of diclofenac sodium. The patch comprises a paste formulation containing diclofenac sodium, a water soluble polymer such as polyacrylic acid and a mixture of propylene glycol and 1-menthol as penetration enhancers. EP 582727 describes a transdermal therapeutic formulation comprising a polymer having lipophilic monomer units and hydrophilic monomer units in a weight ratio of 98: 2 to 0: 100, a drug, an alcohol and a penetration enhancer. Suitable polymers are acrylic adhesives such as copolymers of alkyl acrylates and acrylic acid. Polyols such as propylene glycol are mentioned among the list of alcohols. EP 582727 further describes those known penetration enhancers that can be used such as isopropyl myristate. Diclofenac is among the list of drugs that can be used in the transdermal therapeutic formulation. EP 452837 describes a medical adhesive comprising a patch layer containing the following ingredients: (1) a medicinal ingredient; (2) a hydrophobic polymer having a glass transition temperature of -65 ° C to 35 ° C; (3) a percutaneous absorption promoting agent; (4) water and (5) a hydrophilic polymer which is soluble or capable of swelling in water. The hydrophobic polymer is present in larger amounts than the hydrophilic polymer in the layer and the layer forms a water-in-oil emulsion. It is disclosed that diclofenac can be used as the medicinal ingredient. WO 91/9592 describes a transdermal system with a container layer comprising a drug complex and a compound cycle. The rate of drug release from the system is controlled by the dissociation of the complex. Diclofenac is described as one of the drugs that can be used in such a system. US 5,505,956 describes the delivery of a drug such as diclofenac from a transdermal device having on its back an adhesive layer having a laminated structure of 2 to 5 layers and each layer having different water absorption capacity. The adhesive layer contains an adhesive resin such as a polyacrylate, a penetration enhancer, a water absorptive material, such as a polyol and a soothing agent. Pyrrolidone derivatives and high fatty acid esters are mentioned as penetration enhancers. It is an object of the present invention provides a pressure sensitive skin adhesive that can be used for the manufacture of a transdermal drug delivery device for the transdermal delivery of diclofenac or a pharmaceutically acceptable salt thereof. It is a further object of the present invention to improve the transdermal delivery of diclofenac. These objects have been achieved by providing a pressure sensitive skin adhesive comprising: (a) a copolymer of one or more alkyl (meth) acrylates containing from 4 to 12 carbon atoms in the alkyl group and one or more hydrophilic monomers; (b) a mixture of penetration improvers comprising: (i) an alkylester of an aliphatic monocarboxylic acid containing from 1 to 5 carbon atoms in the alkyl group, (ii) a 2-pyrrolidone derivative and (iii) a alkane polyol; and (c) a therapeutically effective amount of diclofenac or a pharmaceutically acceptable salt thereof. It has been observed in particular that the diclofenac or a pharmaceutically acceptable salt thereof is substantially improved by using the combination of penetration enhancers as set forth above. The present invention further provides a transdermal drug delivery device using the pressure sensitive skin adhesive and the use of the pressure sensitive skin adhesive for the manufacture of a transdermal drug delivery device for treatment for inflammation or pain relief. In addition, the invention provides a method for inducing analgesia in a subject comprising contacting the skin of the subject with a transdermal drug delivery device as described above and allowing the device to remain in contact with the skin for a sufficient time to establishing or maintaining a therapeutically effective blood level of diclofenac or a pharmaceutically acceptable salt thereof in the subject. The pressure sensitive skin adhesive of the present invention contains a copolymer of an alkyl acrylate and / or an alkyl methacrylate and at least one hydrophilic monomer. The alkyl group of the acrylate or methacrylate preferably contains from 4 to 12 carbon atoms. Examples of alkyl acrylates and alkyl methacrylates include n-butyl, n-pentyl, n-hexyl, cyclohexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, isobornyl, 2-ethylctyl, isooctyl, n-octyl and 2-ethylhexylacrylates and methacrylates. Isooctyl acrylate is particularly preferred.

Hydrophilic monomers are monomers that typically have a tendency to bind or absorb water and are preferably monomers of which a homopolymer is capable of swelling in water or which can be dissolved in water. Examples of hydrophilic monomers include carboxylic acid having monomers such as acrylic and methacrylic acid; hydroxy containing monomers such as 2-hydroxyethyl acrylate; vinyl containing monomers such as N-vinyl-2-pyrrolidone, vinylimidazoles, and vinylacetate; polyoxyalkylene mono- (meth) acrylates), poly (alkylene oxide) alkyl ester mono (meth) acrylates; amides such as acrylamides, methacrylamides, N-vinylvalerolactam, and N-vinylcaprolactam; tetraalkylammonium containing monomers such as (meth) acryloxyethyltrimethylammonium chloride, (meth) acryloxyethyltriethylammonium chloride, and (meth) acrylamidoethyltrimethylammonium chloride; and amino group containing monomers such as dimethylaminoethyl (meth) acrylate, diethylamino (meth) acrylate, morpholino-ethyl (meth) acrylate, piperidino-ethyl (meth) acrylate, piperidino-ethyl- (meth) acrylamide, dimethylamino-ethyl (met ) acrylamide and diethylamino-ethyl (meth) acrylamide. Mixtures of two or more hydrophilic monomers can also be used. Particularly preferred as a hydrophilic monomer is acrylic or methacrylic acid. The copolymer may further comprise units that are derived from monomers other than the alkyl (meth) acrylate monomer and the hydrophilic one. Examples of such additional monomers that can be copolymerized with the (meth) acrylate and hydrophilic monomer include short chain alkyl acrylates and methacrylates (1 to 4 carbon atoms) such as ethyl (meth) acrylate and methyl (meth) acrylate, acrylonitrile and styrene. According to a particular embodiment of the present invention, the copolymer comprises units derived from a macromer which is copolymerizable with the alkyl (meth) acrylate and hydrophilic monomer. The macromer preferably has an average molecular weight of between 5,000 and 500,000 as measured by GPC relative to a polystyrene standard, more preferably between 2,000 and 10,000 and more preferably between 5,000 and 30,000. Examples of suitable macromers include those described in W096 / 8229 and in Kra pe et al., U.S. Patent No. 4,693,776, the disclosure of which is incorporated herein by reference, and in particular includes polymethyl methacrylate macromer, polymethylacrylate macromer, polystyrene macromer, and polystyrene-acrylonitrile macromer . The polymethylmethacrylate macromers are commercially available under the trade designation "ELVACITE by ICI Acrylics (for example ELVACITE 1010, a polymethyl methacrylate macromonomer having an inherent viscosity of 0.070-0.080, a Tg of 105 ° C, a GPC of average molecular weight of 7,000-10,000, a GPC number of average molecular weight of 2,500-4,000, and a polydispersity of 2.5-3.0, and ELVACITE 1020, a polymethyl methacrylate macromonomer having an inherent viscosity of 0.085-0.10, a Tg of 105 ° C, a GPC of average molecular weight of 12,000-15,000, a GPC number of average molecular weight of 4,600-6,000, and a polydispersity of 2.5-3.0.) A copolymer comprising units derived from a macromer as described above is particularly useful in an adhesive for pressure-sensitive skin of a transdermal drug supply having a non-occlusive back portion The weight ratio of monomer units derived from The alkyl (meth) acrylates to the monomer units derived from the hydrophilic monomers in the copolymer are typically between 98: 2 and 80:20 and preferably between 96: 4 and 88:12. The copolymer of the pressure sensitive skin adhesive of this invention can be prepared by conventional free radical polymerization of the alkyl (meth) acrylates and hydrophilic monomers and / or optional additional macromers copolymerizable therewith. The polymerization may be a solution or emulsion polymerization and may be a thermally or photochemically initiated polymerization. Useful free radical initiators are known in the art and include azo compounds, such as azo-bisisobutyronitrile and 4,4'-azobis (4-cyanovaleric acid), hydroperoxides such eumeno, t-butyl and t-amylhydroperoxide, dialkylperoxides such as di-t-butyl and dicumylperoxide, peroxyesters such as t-butylperbenzoate and di-t-butylperoxy phthalate, diacyl peroxides such as benzoyl peroxide and lauroyl peroxide. Preferably the obtained copolymer is soluble in ethyl acetate and has an inherent viscosity in the range of 0.2 dl / g to about 2 dl / g, more preferably 0.4 dl / g to about 1.5 dl / g. Diclofenac or a pharmaceutically acceptable salt thereof such as the sodium salt is present in the skin adhesive - pressure sensitive in a "therapeutically effective amount". The latter term means that the concentration of the drug is such that in the composition it results in a therapeutic level of drug delivered during the term in which the dosage form is used.; for example, that a therapeutically effective blood level of the drug is achieved or maintained. Such delivery depends on a large number of variables including, for example, the period of time during which the individual dose unit is used, and the rate of flow of the drug from the system. The amount of drug needed can be determined experimentally. Generally, diclofenac or a pharmaceutically acceptable salt thereof is present in a device of the invention in a weight amount of from about 1 to about 12 percent, preferably from about 3 to 8 percent by weight based on the total weight of the product. adhesive for pressure sensitive skin. In a preferred embodiment the adhesive for pressure sensitive skin is free of solid undissolved drug. The pressure sensitive skin adhesive of this invention contains a mixture of at least 3 different types of penetration enhancers, ie at least one alkyl ester of an aliphatic monocarboxylic acid containing from 1 to 5 carbon atoms in the alkyl group, at least one derivative of 2-pyrrolidone and at least one alkane polyol. Preferably the alkyl ester of an aliphatic monocarboxylic acid is a lower alkyl ester (containing 1 to 6 carbon atoms) of an aliphatic monocarboxylic acid having 6 to 20 carbon atoms. Examples include isopropyl myristate, isopropyl palmitate, ethyl caprylate, methyl stearate, ethyl laurate, ethyl oleate, methyl oleate and propyl oleate. Isopropyl myristate is particularly preferred.

Preferred 2-pyrrolidone derivatives for use in the penetration enhancing mixture of the compositions are alkyl pyrrolidones, and particularly preferred are N-alkyl-2-pyrrolidone and derivatives thereof. Most preferred are N-alkyl-2-pyrrolidone wherein the alkyl group contains from 6 to 14 carbon atoms. Examples of suitable 2-pyrrolidone derivatives include the 2-pyrrolidone-5-carboxylic acid esters described in U.S. Patent 4,863,952 the disclosure of which is incorporated herein by reference; N-octyl-2-pyrrolidone; N-decyl-2-pyrrolidone and N-cetyl-2-pyrrolidone. The alkane polyols for use in the penetration enhancing mixture of the invention are preferably lower alkane polyols having 2 to 5 carbon atoms. Specific examples include lower alkanediols such as ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol and 1,5-pentanediol. Alkanetriols such as glycerin (1,2,3-propanetriol) can also be used. Propylene glycol is preferred. According to a preferred embodiment of the present invention, the mixture of penetration enhancers is comprised between 30 and 70% by weight of the alkyl ester of the aliphatic monocarboxylic acid, between 3 and 25% by weight of the 2-pyrrolidone derivative and between and 45% by weight of the alkanopolyol. A highly preferred blend of penetration improvers comprises between 45 and 65% by weight of isopropyl myristate, between 3 and 20% by weight of N-octylpyrrolidone and between 25 and 40% by weight of propylene glycol. The total amount of penetration enhancers in the pressure sensitive skin adhesive is typically between 10 and 40% by weight of the total weight of the pressure sensitive skin adhesive. The pressure sensitive skin adhesive of the present invention may additionally comprise a tackifier or plasticizer to improve the adhesive characteristics of the adhesive composition. Suitable tackifiers are those known in the art to include: (1) aliphatic hydrocarbons; (2) mixed aromatic and aliphatic hydrocarbons; (3) aromatic hydrocarbons; (4) substituted aromatic hydrocarbons; (5) hydrogenated esters; (6) polyterpenes; and (7) hydrogenated wood resins or rosins. The transdermal drug delivery device of the invention can be obtained by applying an adhesive layer containing the pressure sensitive skin adhesive described above to a backside. The transdermal drug delivery device according to the invention can be prepared for example by dissolving the copolymer, penetration enhancers and diclofenac or its pharmaceutically acceptable salt in an organic solvent (for example ethyl acetate) to produce a coating formulation. The coating formulation can be coated using conventional methods on a suitable release liner to provide a predetermined uniform thickness of the coating formulation. Suitable release liners include conventional release liners comprising a sheet of known material such as a polyester strip, a polyethylene strip, or a strip of polystyrene or a paper coated with polyethylene coated with a coating based on silicone or fluoropolymer suitable. A preferred release liner is the SCOTCHPAK ™ 1022 film (3M, St. Paul, MN). The release liner coated adhesive is then dried and rolled on a backing using known methods. The back can be occlusive, non-occlusive or a breathable film as desired. The back is flexible in such a way that it conforms to the skin. It can be any of the materials commonly used for pressure sensitive adhesive tapes, such as polyethylene, particularly low density polyethylene, linear low density polyethylene., high density polyethylene, nylon fibers, randomly oriented, polypropylene, ethylene-vinylacetate copolymer, polyurethane, rayon and the like. Backs with layers are also suitable, such as polyethylene-aluminum-polyethylene compounds. The back should be substantially non-reactive with the ingredients of the formulation. Particularly preferred backparts are SCOTHPAK ™ 1109 and COTRAN ™ 9726 which are available occlusive backs of 3M and CONTRAN ™ 9725 which are available non-occlusive backs of 3M. The transdermal drug delivery devices can be made in the form of an article such as a tape, a patch, a sheet, a garment or any other shape known to those skilled in the art. Generally, the device will be in the form of a patch of a suitable size to deliver a predetermined amount of diclofenac or its pharmaceutically acceptable salt through the skin. Generally the device will have a surface area of about 10 cm2 to about 100 cm2 and preferably between 30 and 85 cm2. A transdermal drug delivery device according to this invention containing diclofenac or its pharmaceutically acceptable salt can be used to treat any condition capable of treatment with this drug and in particular the treatment for inflammation and pain relief. The device can be placed on the skin and allowed to remain for a sufficient time to achieve or maintain the intended therapeutic effect. The time that constitutes a sufficient time may be selected by those skilled in the art in consideration of the flow rate of the device of the invention and the condition being treated. The examples set forth below are intended to illustrate the invention, and not to limit it in any way. In Vitro Skin Penetration Test Method The skin penetration data given in the following examples were obtained using the following test method. A static diffusion cell (Franz cell type) was used. Hairless mouse skin (3-4 week old female hairless mice) or human skin (obtained from surgery) was used. The skin is mounted with the epidermal side up between the upper and lower portion of the cell, which are held together by means of a ball joint clamp. The portion of the cell beneath the mounted skin is completely filled with "HEPES" receptor fluid (N- [2-hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid]) regulated in Hanks balanced salt solution, pH 7.2, supplemented with 4 ml of antibiotic (A 7292 obtained from Sigma) per liter in such a way that the receptor fluid is in contact with the skin. The receiving fluid is stirred using a magnetic stir bar. The sampling port is covered except when in use. When evaluating a transdermal delivery device, the release liner is removed from a 1.55 cm patch and the patch is applied to the skin and pressed to cause uniform contact with the skin and then the skin is placed through the hole in the skin. the lower portion of the diffusion cell. The diffusion cell is assembled and the lower portion is filled with receiving fluid. The cell is then placed in a chamber of constant temperature (32 ± 1.5 ° C) and humidity (45 + 10% relative humidity). The receptor fluid is agitated by means of a magnetic stirrer through the experiment to ensure a uniform sample and a reduced diffusion barrier on the dermal side of the skin. The entire volume of the receiving fluid is removed at specified time intervals (3, 6, 12, 24, 36 and 48 hours) and is immediately replaced with fresh receiving fluid. The extracted receptor fluid is analyzed for drug content using conventional high performance liquid chromatography. The cumulative amount of drug is calculated that penetrates the skin. The following abbreviations are used in the examples: IPM: isopropyl myristate PG: propylene glycol OCP: N-octylpyrrolidone Diclofenac-Na: diclofenac sodium salt IOA / AA-1: an isooctyl acrylate copolymer of acrylic acid containing 90% by weight weight of isooctyl acrylate of 10% by weight of acrylic acid. IOA / AA-2: similar to IOA / AA but containing 94% by weight of isooctyl acrylate and 6% by weight of acrylic acid. Example 1 (comparative): A 123.6 g of a solution containing 16% by weight of IOA / AA-1 in ethyl acetate, 1.8 g diclofenac-Na, 9 g of IPM, 16 g of ethanol and 30 g of n-hexane were added. The intimate mixture produced a homogeneous coating solution. The solution was coated on a release liner (Scotchpak ™ 1022) at a moisture thickness of 900 μm and dried in an oven for 20 minutes at 60 ° C. The dry coatings were then laminated on the back with Scotchpak ™ 1109. The resulting devices had a drug loading of 0.64 mg diclofenac-Na per 1 cm2. Samples of the device with a size of 1.55 cm2 were tested with respect to the characteristics of in vitro penetration through human skin (obtained from surgery). The results are shown in Table 1 below where each drug penetration value is the average of 4 independent determinations. Example 2 (comparative): At 95.2 of a solution containing 20.8% by weight of IOA / AA-1 in ethyl acetate, 1.8 g of diclofenac-Na, 6.3 g of IPM, 3.2 g of PG and 16 g of ethanol.

The intimate mixture produced a homogeneous coating solution. The solution was coated on a release liner (Scotchpak ™ 1022) at a moisture thickness of 900 μm and dried in an oven for 20 minutes at 60 ° C. The dry coatings were then laminated on the back with Scotchpak ™ 1109. The resulting devices had a drug loading of 0.56 mg diclofenac-Na per 1 cm2. The samples of the device with a size of 1.55 cm were tested with respect to the characteristics of in vitro penetration through human skin (obtained from surgery). The results are shown in Table 1 below where each drug penetration value is the average of 4 independent determinations. Example 3: To 90.2 g of a solution containing 22% by weight of IOA / AA-1 in ethyl acetate was added 1.8 g of diclofenac-Na, 4.6 g of IPM, 3.14 g of PG and 1.55 g of OCP and 16 g of ethanol. The intimate mixture produced a homogeneous coating solution. The solution was coated on a release liner (Scotchpak ™ 1022) at a moisture thickness of 900 μm and dried in an oven for 20 minutes at 60 ° C. The dry coatings were then laminated to the back with Scotchpak ™ 1109. The resulting devices had a drug loading of 0.58 mg of diclofenac-Na per 1 cm2. The samples of the device with a size of 1.55 cm2 were tested with respect to the characteristics of in vitro penetration through human skin (obtained from surgery). The results are shown in Table 1 below where each drug penetration value is the average of 4 independent determinations. Example 4: To 95.4 g of a solution containing 20.8% by weight of IOA / AA-1 in ethyl acetate, 1.8 g of diclofenac-Na, 5.72 g of IPM, 3.1 g of PG, 0.61 g of OCP and 16 g of ethanol. The intimate mixture produced a homogeneous coating solution. The solution was coated on a release liner (Scotchpak ™ 1022) at a moisture thickness of 900 μm and dried in an oven for 20 minutes at 60 ° C. The dry coatings were then laminated on the back with Scotchpak ™ 1109. The resulting devices had a drug loading of 0.58 mg of diclofenac-Na per 1 cm2. The samples of the device with a size of 1.55 cm2 were tested with respect to the characteristics of in vitro penetration through human skin (obtained from surgery). The results are shown in Table 1 below where each drug penetration value is the average of 4 independent determinations. Example 5: To 58.3 g of a solution containing 34% by weight of IOA / AA-2 in ethyl acetate was added 1.8 g of diclofenac-Na, 4.6 g of IPM, 3.15 g of PG, 1.6 g of OCP and 16 g of ethanol. The intimate mixture produced a homogeneous coating solution. The solution was coated on a release liner (Scotchpak ™ 1022) at a moisture thickness of 900 μm and dried in an oven for 20 minutes at 60 ° C. The dry coatings were then laminated on the back with Scotchpak ™ 1109. The resulting devices had a drug loading of 0.58 mg of diclofenac-Na per 1 cm. Samples of the device with a size of 1.55 cm2 were tested with respect to the characteristics of in vitro penetration through human skin (obtained from surgery). The results are shown in Table 1 below where each drug penetration value is the average of 4 independent determinations. TABLE 1: Example Adhesive Enhancers Coating Penetration load (% by weight) (mg / cm2) drug substance Example 6 (comparative) A 96.2 g of a solution containing 20.6% by weight of IOA / AA-1 in acetate of ethyl, 1.8 g of diclofenac-Na, 9 g of IPM, and 16 g of ethanol were added. The intimate mixture produced a homogeneous coating solution. The solution was coated on a release liner (Scotchpak ™ 1022) at a moisture thickness of 900 μm and dried in an oven during 20 minutes at 60 ° C. The dried coatings were then laminated on the back with Scotchpak ™ 1109. The resulting devices had a drug loading of 0.58 mg of diclofenac-Na per 1 cm. Samples of the device with a size of 1.55 cm 2 were tested with respect to the Features of in vitro penetration through human skin (obtained from surgery). The results are shown in Table 2 below where each drug penetration value is the average of 4 independent determinations. Example 7: A 123.3 g of a solution containing 16.3% by weight of IOA / AA-1 in ethyl acetate, 1.8 g of diclofenac-Na, 6 g of IPM, 3 g of OCP and 16 g of ethanol were added. The intimate mixture produced a homogeneous coating solution. The solution was coated on a release liner (Scotchpak ™ 1022) at a moisture thickness of 900 μm and dried in an oven for 20 minutes at 60 ° C. The dry coatings were then laminated on the back with Cotran ™ 9725. The resulting devices had a drug loading of 0.52 mg of diclofenac-Na per 1 cm2. The samples of the device with a size of 1.55 cm2 were tested with respect to the characteristics of in vitro penetration through human skin (obtained from surgery). The results are shown in Table 2 below where each drug penetration value is the average of 4 independent determinations. Example 8: To 122.7 g of a solution containing 16.3% by weight of IOA / AA-1 in ethyl acetate was added 1.8 g of diclofenac-Na, 4.5 g of IPM, 3.0 g of PG, 1.5 g of OCP and 16 g of ethanol. The intimate mixture produced a homogeneous coating solution. The solution was coated on a release liner (Scotchpak ™ 1022) at a moisture thickness of 900 μm and dried in an oven for 20 minutes at 60 ° C. The dried coatings were then laminated on the back with Cotran ™ 9725. The resulting devices had a drug loading of 0.57 mg diclofenac-Na per 1 cm2. The samples of the device with a size of 1.55 cm2 were tested with respect to the characteristics of in vitro penetration through human skin (obtained from surgery). The results are shown in Table 2 below where each drug penetration value is the average of 4 independent determinations. Example 9: To 123 g of a solution containing 16.3% by weight of IOA / AA-1 in ethyl acetate was added 1.8 g of diclofenac-Na, 5.4 g of IPM, 3.0 g of PG, 0.62 g of OCP and 16 g of ethanol. The intimate mixture produced a homogeneous coating solution. The solution was coated on a release liner (Scotchpak ™ 1022) at a moisture thickness of 900 μm and dried in an oven for 20 minutes at 60 ° C. The dried coatings were then laminated on the back with Cotran ™ 9725. The resulting devices had a drug loading of 0.59 mg of diclofenac-Na per 1 cm2. The samples of the device with a size of 1.55 cm were tested with respect to the characteristics of in vitro penetration through human skin (obtained from surgery). The results are shown in Table 2 below where each drug penetration value is the average of 4 independent determinations. TABLE 2: The present invention has been described in the specification and previous examples, which are provided for purposes of illustration and clarity of understanding only. No unnecessary limitations should be inferred from it. It will be apparent to those skilled in the art that many changes can be made in the described embodiments without departing from the scope of the invention. Thus, the scope of the invention should not be limited to the exact details of the compositions and structures described herein but is defined only by the claims that follow.

Claims (14)

1. CLAIMS 1. An adhesive for pressure sensitive skin characterized in that it comprises: (a) a copolymer of one or more alkyl (meth) acrylates containing 4 to 12 carbon atoms in the alkyl group and one or more hydrophilic monomers; (b) a mixture of penetration improvers comprising: (i) an alkylester of an aliphatic monocarboxylic acid containing from 1 to 5 carbon atoms in the alkyl group, (ii) a 2-pyrrolidone derivative and (iii) a alkane polyol; and (c) a therapeutically effective amount of diclofenac or a pharmaceutically acceptable salt thereof. The adhesive for pressure-sensitive skin according to claim 1, characterized in that the weight ratio of the monomer units derived from the alkyl (meth) acrylates to monomer units derived from the hydrophilic monomers in the copolymer is between 98: 2 and 80:20. 3. The adhesive for pressure sensitive skin according to claim 1, characterized in that the hydrophilic monomer is selected from the group consisting of carboxylic acid containing monomers, N-vinyl-2-pyrrolidone, vinylimidazoles, vinylacetates, (meth) acrylamides, N-vinyl valerolactam, N-vinyl caprolactam, hydroxy-containing monomers, poly (oxyalkylene) mono- (meth) acrylates, tetra-alkylammonium-containing monomers and monomers containing amino groups. 4. The pressure sensitive skin adhesive according to claim 1, characterized in that the hydrophilic monomer is selected from the group consisting of acrylic and methacrylic acid. 5. The adhesive for pressure sensitive skin according to claim 1, characterized in that the alkane polyol is selected from the group consisting of propylene glycol and ethylene glycol. 6. The adhesive for pressure-sensitive skin according to claim 1, characterized in that the 2-pyrrolidone derivative is an N-alkyl-2-pyrrolidone wherein the alkyl group contains 6 to 14 carbon atoms. The adhesive for pressure-sensitive skin according to claim 6, characterized in that the 2-pyrrolidone derivative is N-octyl 2-pyrrolidone. The adhesive for pressure-sensitive skin according to claim 1, characterized in that the alkylester of an aliphatic monocarboxylic acid is isopropyl myristate. 9. The pressure sensitive skin adhesive according to claim 1, characterized in that the total amount of the penetration improver mixture is between 10 and 40% by weight of the total weight of the adhesive for pressure sensitive skin. The adhesive for pressure-sensitive skin according to claim 9, characterized in that the mixture of penetration enhancers comprises between 30 and 70% by weight of the alkyl ester of an aliphatic monocarboxylic acid, between 3 and 25% by weight of the derivative of 2-pyrrolidone and between 20 and 45% by weight of the alkanopolyol. 11. The pressure sensitive skin adhesive according to claim 1, characterized in that the diclofenac or pharmaceutically acceptable salt thereof is diclofenac sodium. The pressure sensitive skin adhesive according to claim 1, characterized in that the diclofenac or the pharmaceutically acceptable salt thereof is present in an amount of about 3 to 8% by weight based on the total weight of the skin adhesive sensitive to pressures. 13. The transdermal drug delivery device characterized in that it comprises on a back part a layer of adhesive comprising the pressure sensitive skin adhesive according to claim 1. 14. The method for treating inflammation or pain relief in a subject characterized in that it comprises placing a pressure sensitive skin adhesive according to claim 1, in contact with the skin of the subject and allowing the adhesive for pressure sensitive skin to remain in contact with the skin for an effective time to establish or maintain a therapeutically effective blood level of diclofenac or a pharmaceutically acceptable salt thereof in the subject.