CZ20003587A3 - Device for transfer of diclofenac through skin - Google Patents

Abstract

The pressure skin patch comprises: (a) one or more copolymers; more alkyl acrylates (alkyl methacrylates) containing 4-12 carbon atoms in the alkyl group and one or more hydrophilic monomers; (b) a mixture of penetration enhancers, which consist of: (i) an aliphatic monocarboxylic alkyl ester acids having from 1 to 5 carbon atoms in the alkyl group; (ii) an alkylpyrrolidone and (iii) an alkanoyl polyol; (C) a therapeutically effective amount of diclofenac or a diclofenac thereof pharmaceutical salts suitable salts. Drug delivery device over the skin contains said pressure skin patch.

Description

Technical field

The present invention relates to a skin drug delivery device used for the transfer of diclofenac or a salt thereof suitable for pharmaceutical purposes. Particular attention is paid to a pressurized skin patch containing just diclofenac or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Ortho - [(2,6-dichlorophenyl) amino] phenylacetic acid (hereafter referred to as diclofenac) and its pharmaceutically acceptable salts are known compounds used to treat inflammatory diseases. [Ortho [2,6-dichlorophenylamino] phenyl] sodium acetate, known also as the sodium salt of 2- [2,6-dichlorophenylamino] benzeneacetic acid and sodium diclofenac, is described, for example, in pharmacological studies for its strongly anti-inflammatory and pain-soothing properties. One such study is, for example, Riess et al: Scand. J. Rheumatol. Suppl., Vol. 22 (1978), pp. 17-29. The use of an aqueous solution of diclofenac sodium for the treatment of ocular inflammation is discussed, for example, by M. Agata et al: Nihon Ganka Gakkai [Acta Soc. Ophthalmol. Japan], Vol. 87 (1983) pp. 19-28 and M. Aghata et al: Nihon Ganka Gakkai [Acta Soc. Ophthalmol. Japan], Vol. 88. No. 6 (1984), pp. 61-66.

(2638-00.doc) •

Transmission of diclofenac or its pharmaceutically usable salts through the skin has been the subject of many publications. For example, EP 524582 describes patches with diclofenac sodium. The patch includes a paste containing diclofenac sodium, a water-soluble polymer such as polyacrylic acid, and a mixture of propylene glycol and 1-menthol to enhance penetration.

EP 582727 discloses a composition of a substance useful for treatment through the skin. This substance contains a polymer whose lipophilic monomer! units and hydrophilic monomers are in a weight ratio of from 98: 2 to 0: 100, as well as drug, alcohol and penetration enhancers. Suitable polymers are acrylic binders such as copolymers of alkyl acrylates and acrylic acids. A number of alcohols include polyols such as propylene glycol. This patent (EP 582727) further states that known agents, such as isopropyl myristate, can be used as penetration enhancers. Diclofenac is one of the drugs that can be used for treatment through the skin.

EP 452837 discloses a medical binder formed

a layer of patch containing the following folders: (1) an active ingredient; (2) a hydrophobic polymer having -65 to 35 ° C; cure temperature from (3) an absorption enhancer leather; (4) water and (5) a hydrophilic polymer that dissolves in water or swells.

The hydrophobic polymer is present in greater quantity than the hydrophilic polymer and the layer forms an oil-water emulsion. The active ingredient is diclofenac.

(2638-00.doc)

• • • •

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WO 91/9592 discloses a skin transfer system with a storage layer comprising a drug substance complex and a cyclo compound. The rate of drug release is determined by the rate of complex decomposition. One of the active substances used in this system is diclofenac.

US Patent 5,505,956 discloses the transfer of drug substances such as diclofenac from a skin transfer device. This device has a binder layer on the reverse side consisting of 2 to 5 sub-layers, each having a different water absorption capacity. The binder layer comprises a resin binder such as a polyacrylate, a penetration enhancer, a hygroscopic such as a polyol, and a soothing agent. Penetration enhancers include pyrrolidone derivatives and higher fatty acid esters.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a pressurized skin patch useful in the manufacture of a drug delivery device through the skin, in particular for the transfer of diclofenac or a pharmaceutically acceptable salt thereof. Furthermore, the present invention is directed to improving diclofenac through the skin.

The solution is to prepare a pressure skin patch that consists of:

(a) copolymers of one or more alkyl acrylate (alkyl methacrylate) containing 4 to 12 carbon atoms in the alkyl group and one or more hydrophilic monomers;

(b) a mixture of penetration enhancers, containing:

(i) an alkyl ester of an aliphatic monocarboxylic acid having 1 to 5 carbon atoms (2638-OO.doc) in the alkyl group, (ii) a 2-pyrrolidone derivative and (iii) an alkanpolyol; and (c) a therapeutically effective amount of diclofenac or a salt thereof suitable for pharmaceutical purposes.

It has also been shown that the transfer of diclofenac or its pharmaceutically acceptable salts is substantially improved when using the penetration enhancers in the combination mentioned in the preceding paragraph.

The present invention further provides a skin drug delivery device utilizing said pressure skin patch, as well as the use of a skin skin pressure patch for the manufacture of a skin drug delivery device for the treatment of inflammatory diseases or pain relief. In addition, the invention provides a method of eliciting an analgesic effect on a subject. The method is based on contacting the subject's skin with the device described above and contacting until a therapeutically effective level of diclofenac or a pharmaceutically acceptable salt thereof in the subject's blood is established or maintained.

The pressurized skin patch described in the present invention comprises a copolymer of alkyl acrylate or alkyl methacrylate, optionally both, and at least one hydrophilic monomer. The alkyl group of acrylate or methacrylate typically contains 4 to 12 carbon atoms.

Alkyl acrylates or alkyl methacrylates are, for example, n-butyl, n-pentyl, n-hexyl, cyclohexyl, isoheptyl, rinonyl, ndecyl, isohexyl, isobornyl, 2-ethylacyl, isooctyl, n-octyl and 2-ethylhexyl acrylates and methactylates. Isooctylacrylate is particularly preferred.

(2638-00) • 9

Hydrophilic monomers are typical monomers that tend to bind or absorb water. Particularly suitable are those monomers whose homogeneous polymers are water-soluble or swell in contact with water. Hydrophilic monomers are, for example, carboxylic acids containing monomers such as acrylic and methacrylic acid; a hydroxy-containing hydroxy group such as 2-hydroxyethyl acrylate; vinyl containing monomers such as A-vinyl-2-pyrrolidone, vinylimidazoles and vinyl acetate; polyoxylalkylene monoacrylates (monoacrylates), alkyl ether monoacrylates (monoacrylates) of polyalkylene oxide; amides such as acrylamides, matacrylamides, A-vinyl valerolactam and A-vinyl caprolactam; a tetraalkylammonium group containing monomers such as methacryloxylethyl trimethylammonium chloride and acrylamido (methacrylamido) ethyl trimethyl ammonium chloride; an amino group containing monomers such as dimethylaminoethyl acrylate (methacrylate), diethylaminoacrylate (methacrylate), morpholinoethyl acrylate (ethyl methacrylate), piperidinoethylacrylate (ethyl methacrylate), piperidinoethylacrylamide (methacrylamide), dimethylaminoethyl acrylamide (methacrylaminoethyl acrylamide), dimethylaminoethyl acrylamide (methacrylamide). It is also possible to use a mixture of two or more hydrophilic monomers. Particularly preferred hydrophilic monomers are acrylic or methacrylic acid.

The copolymer may contain other units derived from monomers other than the aforementioned alkyl acrylates (alkyl methacrylates) and hydrophilic monomers. Examples of such monomers that can polymerise together with acrylates (methacrylates) and hydrophilic monomers are short chain (1 to 4 carbon atoms) monomers of alkyl acrylates and methacrylates such as ethyl acrylate (ethyl methacrylate) and methyl acrylate (methyl methacrylate), (2638-00. doc) · · · · · · - - - - - - - - - - - - - - - - - - - - - - -) - Acrylonitrile and styrene.

A particular group of the present invention is a copolymer comprising macromer-derived units that can polymerize together with an alkyl acrylate (methacrylate) and a hydrophilic monomer. A suitable average molecular weight of the macromer is between 5,000 and 500,000, preferably between 2,000 and 10,000, and optimally between 5,000 and 30,000 (measured by the GPC method on polystyrene standard). Examples of suitable macromers are disclosed in WO96 / 8229 and Krampe et al. Patent No. 4,693,776. DETAILED DESCRIPTION OF THE INVENTION The text of the present invention is referred to in detail, but particularly includes a macromer of polymethyl methacrylate, polymethyl acrylate, polystyrene and polystyrene acrylonitrile.

Polymethyl methacrylate macromers are commercially available under the trade name "ELVACITE using ICI acrylates (for example ELVACITE 1010 - a polymethyl methacrylate macromonomer having a viscosity of 0.070-0.080 and a cure temperature T _g = 105 ° C, GPC average molecular weight of 7,000-10,000 and GPC number value ranges from 2.500 to 4.000, the polydispersity is from 2.5 to 3.0; another example is Elvacite 1020 - macromer polymethyl methacrylate having a corresponding viscosity of 0, 085-0, 1 T _g = 105 ° C, GPC value the average molecular weight is 12,000-15,000 and the GPC number is in the range of 4,600 to 6,000, the polydispersity is 2.5-3.0). The copolymer containing units derived from the macromer described above are particularly suitable for those skin drug delivery devices that contain pressurized skin patches on an open backing.

Weight ratio of monomer units derived from alkyl acrylates (alkyl methacrylates) to monomer units (2638-00.doc)

- Ί »99

999 9 · 4 · 4 derived from hydrophilic monomers in copolymers typically range between 98: 2 and 80:20, preferably between 96: 4 and 88:12.

The pressurized skin patch copolymer of the present invention is prepared by conventional polymerization of the free radicals of alkyl acrylates (alkyl methacrylates) and hydrophilic monomers, to which additional monomers or macromers, or both, may optionally be added. These "optional radicals must be capable of copolymerization with the major radicals. The polymerization takes place in solution or emulsion and can be thermally or photochemically initiated. Useful free radical initiators are conventional substances, including azo compounds such as azo-bis (isobutyronitrile) and 4,4'-azo-bis (-4-cyanovaleric acid), hydroperoxides such as cumene, t-butyl and t-amyl hydroperoxide, dialkyl peroxides such as di-t-butyl and dicumyl peroxide, peroxyesters such as t-butyl perbenzoate and di-t-butyl peroxy phthalate, diacyl peroxides such as benzoyl peroxide and lauroyl peroxide. It is preferred that the copolymer obtained is soluble in ethyl acetate and has a base viscosity in the range of from 0.2 dl / g to 2 dl / g, more preferably from 0.4 to 1.5 dl / g.

Diclofenac or a pharmaceutically acceptable salt thereof, such as the sodium salt, is present in a therapeutically effective amount in a pressurized skin patch. That is, the concentration of the drug is such that the required amount of the drug is transferred during the time of dose treatment; that is, to achieve a therapeutically effective blood level of the drug, or to maintain the desired level. Transmission itself depends on a number of variable factors, such as the time for which a single dose is intended and the rate of drug flow from the system. The amount of drug required is determined experimentally. Generally, the device described in the present invention contains about 1 to 12 weight percent of a drug satisfactory (2638-00.doc).

Tf is about 3 to 8 weight percent (based on the total weight of the pressurized skin patch). Preferably, the pressurized skin patch does not contain a solid insoluble drug component.

The pressurized skin patch of the present invention comprises a mixture of at least three different types of penetration enhancers; this is at least one alkyl ester of an aliphatic carboxylic acid having 1 to 5 carbon atoms in the alkyl group, at least one 2-pyrrolidone derivative and at least one alkanpolyol.

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. Such compounds include, for example, isopropyl methistate, isopropyl palmitate, ethyl caprylate, methyl stearate, ethyl laurate, ethyl oleate, methyl oleate, and propyl oleate. Isopropylmiristate is preferred.

Suitable 2-pyrrolidone derivatives which are used to enhance penetration are alkylpyrrolidones, especially N-alkyl2-pyrrolidone and derivatives thereof. Most preferred are -alkyl-2-pyrrolidones whose alkyl group contains 6 to 14 carbon atoms. Examples of such derivatives are the 2-pyrrolidone-5-carboxylic acid esters disclosed in U.S. Patent 4,863,952, to which the text of the present invention refers - N-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone and N-cetyl-2-pyrrolidone.

The alkane polyols used in the mixture of penetration enhancers are primarily lower alkanpolyols having 2 to 5 carbon atoms. Specific examples of these compounds are lower (2638-00.doc)

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) may also be used. Of these, propylene glycol is preferred.

Thus, a suitable mixture of the compounds of the present invention of an alkyl ester by weight of acid, between 3 and 25 and between 20 and 40 penetration enhancers, comprises between 30 and 70% aliphatic monocarboxylic acid derivative of 2-pyrrolidone by weight alkanpolyol. A highly preferred mixture of penetration enhancers comprises between 45 and 65% by weight of isopropylmiristate, 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 is usually 10 to 40 weight of the pressurized skin patch.

of the total

The pressurized skin patch of the present invention may further comprise a plasticizer or tackifiers to increase the adhesion of the adhesive compounds.

Suitable tackifiers rather known in the art include: (1) aliphatic hydrocarbons; (2) a mixture of aliphatic and aromatic hydrocarbons; (3) aromatic hydrocarbons; (4) substituted aromatic hydrocarbons; (5) hydrogenated esters; (6) polyterpenes; and (7) hydrogenated resins or rosin.

The skin drug delivery device of the present invention is obtained by applying an adhesive layer comprising the above-described pressure skin patch to a substrate. Such a device can be prepared in accordance with the present invention, for example, by dissolving copolymers, substances (2638-00.doc).

-10 · zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš zvyš a coating was formed. Conventional methods may be used to coat it, for example a plastic foil, which ensures that the prepared coating has a predetermined uniform thickness. Conventional materials are perfectly suited for this purpose, for example, films comprising a cross-linked form of polyester, polyethylene or polystyrene, or polyethylene coated paper covered with a suitable fluoropolymer or silicone sheath are known. The preferred material of this type is SCOTCHPAK * 1022 film (3M, St. Paul, MN).

The adhesive layer in the plastic sheath is then dried and applied to the substrate by conventional methods. The backing may be closed, open or in the form of a breathable film, as desired. It is flexible, so it adapts well to the skin. Materials commonly used for pressure-sensitive adhesive plasters, such as polyethylene, especially low density polyethylene, linear low density polyethylene, high density polyethylene, disordered nylon fibers, polypropylene, ethylene vinyl acetate copolymer, polyurethane, cellulose-based fibers and others are used to prepare the backing. Layered substrates, such as polyethylene-aluminum-polyethylene combinations, are also suitable for this purpose.

The substrate should be practically inert to the coating components. Particularly suitable pads are SCOTCHPAK ™ 1109 and COTRAN ™ 9726, both open and available from 3M, as well as COTRAN ™ 9725, which are sealed pads and is also available from 3M.

The drug delivery device can be manufactured in the form of a tape, patch, sheet, bandage, or any other device (2638-OO.doc). * • «« «· · · · ·

in a form known in the art. In general, the device will actually be a patch of just such size that a predetermined amount of diclofenac or a pharmaceutically acceptable salt thereof is passed through the skin. The device will typically have a surface area of 10 cm ² to 100 cm ^2, or between 30 and 8, 5 cm ^second

The skin drug delivery device of the present invention containing diclofenac or a pharmaceutically acceptable salt thereof can be used to treat any drug problems, particularly inflammation, and the device is placed on the skin and allowed to act for the time necessary to achieve or maintain the desired therapeutic effect. The time sufficient to achieve a therapeutic effect can be determined by considering the flow rate in the device, taking into account the difficulties to be treated.

treatable by this painful condition.

The following examples are intended to illustrate and illustrate the present invention, but are not intended to limit the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Tube test method for transmission through skin

The skin transfer data reported in the described examples were obtained by the following test method. A static diffusion cell (Franz-cell type) was used. Bare mouse skin (3-4 weeks old female of female mice) or human skin (obtained surgically) are suitable for the experiment. The skin is deposited with the epidermal side up between the upper and lower cell space, which it holds together by means of a spherical clamp.

(2638-00.doc)

4 «

4 4

4 4 4

44

4 * 4

4 4 · «

4 ·· * ·

4 4 ·· ·

4 4 4 4 • 44 444

-12The space below the skin is completely filled with the liquid receptor "HEPES (N- [2-Hydroxyethyl] piperazine - N '- [2-ethanesulfonic acid]), buffered with Hanks' saline solution at pH = 7.2 and supplemented with 4 ml / 1 antibiotics. (A 7292 obtained from Sigma) such that the liquid receptor is in contact with the skin. The receptor is stirred with a magnetic rod stirrer. The sampling area is covered except when in use.

When using the transfer device through the skin of the pad 1.55 cm ² removes the plastic packaging pad is applied to the skin and pressed to completely adhere to the skin. The skin is then placed over an opening in the lower space of the diffusion cell. The diffusion cell is assembled together and the lower space is filled with the liquid receptor.

The cell is then placed in a chamber of constant temperature (32 ± 1.5 ° C) and humidity (relative humidity 45 ± 10%). The liquid receptor is agitated with a magnetic stirrer throughout the experiment to ensure sample homogeneity and to reduce the diffusion barrier on the dermal (outer) side of the skin. The entire volume of liquid receptors is sealed in the cell for a predetermined period of time (3, 6, 12, 24, 36 and 48 hours) and then replaced with fresh receptor immediately. At the receptors used, the drug content is analyzed by a conventional method of high-sensitivity liquid chromatography. From the analytical data obtained, the increase in drug penetrated through the skin is calculated as a function of time.

The following abbreviations are used to describe the experiments: IPM: isopropyl myristate (2638-00.doc)

A A A · A

AAA AAA

AAAA

AAAA

AA • AA

-13PG: propylene glycol

OCP: N-octylpyrrolidone

Diclofenac-Na: sodium salt of diclofenac

IOA / AA-1: copolymer of isooctylacrylate and acrylic acid containing 90% by weight of isooctylacrylate and 10% by weight of acrylic acid

IOA / AA-2: copolymer similar to IOA / AA-1 but containing 94% by weight of isioctylacrylate and 6% by weight of acrylic acid

Example 1 (comparative):

To 123.6 g of a solution containing 16% by weight

IOA / AA-1 in ethyl acetate was added 1.8 g Diclofenac -Na, 9 g IPM, 16 g ethanol and 30 g n-hexane. Thorough mixing allows homogeneous application of the solution.

The solution was applied to a plastic sheet (Scotchpak ™ 1022) in a 900 µm (wet) layer and dried in an oven at 60 ° C for 20 minutes. The dry surface is then overlaid with Scotchpak ™ 1109, which serves as a backing. The resulting devices contain 0.64 mg Diclofenac-Na per cm ² .

1.55 cm ² specimens of the device are tested for penetration through human skin (obtained surgically). The results are shown in Table 1, where each penetration value is the average of four independent measurements.

Example 2 (comparative):

To 95.2 g of a solution containing 20.8% IOA / AA-1 in ethyl acetate was added 1.8 g of diclofenac-Na, 6.3 g of IPM, 3.2 g of PG and 16 g of ethanol. Thorough mixing allows homogeneous application of the solution. The solution is applied to a plastic sheet (Scotchpak ™ 1022) in a 900 µm (wet) layer and (2638-00.doc). · · · · · · · · · · · · · ·

Dry in an oven at 60 ° C for 20 minutes. The dry surface is then overlaid with Scotchpak ™ 1109, which serves as a backing. The resulting devices contain 0.56 mg Diclofenac-Na per cm ² .

1.55 cm ² specimens of the device are tested for penetration through human skin (obtained surgically). The results are shown in Table 1, where each penetration value is the average of four independent measurements.

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, 1.55 g of OCP and 16 g of ethanol. Thorough mixing allows homogeneous application of the solution.

The solution is applied to a plastic sheet (Scotchpak ™ 1022) in a 900 μιη (wet) layer and dried in an oven at 60 ° C for 20 minutes. The dry surface is then overlaid with Scotchpak ™ 1109, which serves as a backing. The resulting devices contain 0.58 mg diclofenac-Na per cm ² .

1.55 cm ² specimens of the device are tested for penetration through human skin (obtained surgically). The results are shown in Table 1, where each penetration value is the average of four independent measurements.

Example 4:

To 95.4 g of a solution containing 20.8% by weight

IOA / AA-1 in ethyl acetate was added 1.8 g diclofenac-Na, 5.72 g IPM, 3.1 g PG, 0.61 g OCP and 16 g ethanol. Thorough mixing allows homogeneous application of the solution.

The solution is applied to a plastic sheet (Scotchpak ™ 1022) in a 900 μπι (wet) layer and dried in an oven at (2638-00. Doc).

-15 ° C for 20 minutes. The dry surface is then overlaid with Scotchpak ™ 1109, which serves as a backing. The resulting devices contain 0.58 mg diclofenac-Na per cm ² .

1.55 cm ² specimens of the device are tested for penetration through human skin (obtained surgically). The results are shown in Table 1, where each penetration value is the average of four independent measurements.

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. Thorough mixing allows homogeneous application of the solution.

The solution was applied to a plastic sheet (Scotchpak ™ 1022) in a 900 µm (wet) layer and dried in an oven at 60 ° C for 20 minutes. The dry surface is then overlaid with Scotchpak ™ 1109, which serves as a backing. The resulting devices contain 0.58 mg diclofenac-Na per cm ² .

1.55 cm ² specimens of the device are tested for penetration through human skin (obtained surgically). The results are shown in Table 1, where each penetration value is the average of four independent measurements.

Example 6 (comparative):

To 96.2 g of a solution containing 20.6% by weight of IOA / AA-1 in ethyl acetate was added 1.8 g of diclofenac-Na, 9 g of IPM and 16 g of ethanol. Thorough mixing allows homogeneous application of the solution.

The solution was applied to a plastic sheet (Scotchpak ™ 1022) in a 900 µm (wet) layer and dried in an oven at 60 ° C for 20 minutes. The dry surface then overlaps (2638-00.doc)

Cotran ™ 9725, which serves as a pad. The resulting devices contain 0.58 mg diclofenac-Na per cm ² .

1.55 cm ² specimens of the device are tested for penetration through human skin (obtained surgically). The results are shown in Table 2, where each penetration value is the average of four independent measurements.

TABLE 1:

Example Patch Penetration enhancers (% wt.) Surface (mg / cm ² ) Drug dosage (mg / cm ² ) Drug Penetration (pg / cm ² .24 hrs) 1 IOA / AA-1 30% IPM 11 0.64 63.5 2 IOA / AA-1 20% IPM 10% PG 9.6 0.56 39.4 3 IOA / AA-1 15% IPM 10% PG 5% OCP 10 0.58 83.7 4 IOA / AA-1 18% IPM 10% PG 2% OCP 10 0.58 79.4 5 IOA / AA-2 15% IPM 10% PG 5% OCP 10 0.58 175

Example 7:

To 123.3 g of a solution containing 16.3% by weight

IOA / AA-1 in ethyl acetate was added 1.8 g diclofenac-Na, 6 g IPM, 3 g OCP and 16 g ethanol. Thorough mixing allows homogeneous application of the solution.

The solution was applied to a plastic sheet (Scotchpak ™ 1022) in a 900 nm (wet) layer and dried in an oven at 60 ° C for 20 minutes. The dry surface is then overlaid with Cotran ™ 9725, which serves as a backing. The resulting devices contain 0.52 mg diclofenac-Na per cm ² .

1.55 cm ² specimens of equipment are tested (2633-00.doc) • 9 9 99 for penetration through human skin (obtained surgically). The results are shown in Table 2, where each penetration value is the average of four independent measurements.

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 g of PG, 1.5 g of OCP and 16 g of ethanol. Thorough mixing allows homogeneous application of the solution.

The solution was applied to a plastic sheet (Scotchpak ™ 1022) in a 900 µm (wet) layer and dried in an oven at 60 ° C for 20 minutes. The dry surface is then overlaid with Cotran ™ 9725, which serves as a backing. The resulting devices contain 0.57 mg diclofenac-Na per cm ² .

1.55 cm ² specimens of the device are tested for penetration through human skin (obtained surgically). The results are shown in Table 2, where each penetration value is the average of four independent measurements.

Example 9:

To 123 g of a solution containing 16.3% by weight

IOA / AA-1 in ethyl acetate was added 1.8 g diclofenac-Na, 5.4 g IPM, 3 g PG, 0.62 g OCP and 16 g ethanol. Thorough mixing allows homogeneous application of the solution.

The solution was applied to a plastic film (Scotchpak ™ 1022) in a 900 µm (wet) layer and dried in an oven at 60 ° C for 20 minutes. The dry surface is then overlaid with Cotran 9725, which serves as a substrate. The resulting devices contain 0.59 mg diclofenac-Na per cm ² .

1.55 cm ² specimens of the device are tested for penetration through human skin (obtained surgically).

(2638-00.doc) •

The results are shown in Table 2, where each penetration value is the average of four independent measurements.

TABLE 2:

Example Patch Substances increasing penetration (% wt.) Surface (mg / cm ² ) Drug dosage (mg / cm ² ) Drug Penetration (pg / cm ² .24 hrs) 6 IOA / AA-1 30% IPM 10 0.58 6.0 7 IOA / AA-1 20% IPM 10% OCP 8.9 0.52 11.2 8 IOA / AA-1 15% IPM 10% PG 5% OCP 9.8 0.57 34.7 9 IOA / AA-1 18% IPM 10% PG 2% OCP 10 0.59 14

The foregoing specifications and examples describing the present invention merely illustrate and elucidate the problem. However, they are by no means limiting. Many changes can be made to the processes described without departing from the scope of the invention. Thus, the possibilities of the present invention are not limited to the precise details of the disclosed compositions and structures, but are clearly defined in the claims.

Claims (4)

PATENT CLAIMS 1. A pressure-sensitive skin patch comprising: (a) a copolymer of one or more alkyl acrylate (alkyl methacrylates) of 4 to 12 carbon atoms in the alkyl group and one or more hydrophilic monomers; (b) a mixture of penetration enhancers containing: (i) an alkyl ester of an aliphatic monocarboxylic acid having 1 to 5 carbon atoms in the alkyl group; (ii) a 2-pyrrolidone derivative and (iii) an alkanpolyol; and (c) a therapeutically effective amount of diclofenac or a pharmaceutically acceptable salt thereof. 2. The pressure skin patch of claim 1 wherein the weight ratio of monomer units derived from alkyl acrylates (alkyl methacrylates) to monomer units derived from hydrophilic monomers in the copolymers is between 98: 2 and 80:20. The pressure-sensitive skin patch of claim 1, wherein the hydrophilic monomer is selected from the group consisting of a carboxylic acid containing monomers, N-vinyl-2-pyrrolidone, vinylimidazoles, vinyl acetate, acrylamides (methacrylamides), N-vinyl valerolactam, Nvinyl caprolactam, hydroxy-containing monomers, monoacrylates (methacrylates) poles (oxyalkylene), tetraalkylammonium-containing monomers and amino-containing monomers. -204. The pressurized skin patch according to claim 1, wherein the hydrophilic monomer is selected from the group consisting of acrylic and methacrylic acid. 5. A skin patch according to claim 1 wherein the alkanpolyol is selected from the group consisting of propylene glycol and ethylene glycol. 6. The pressurized skin patch of claim 1, wherein the 2-pyrrolidone derivative is N-alkyl-2-pyrrolidone, wherein the alkyl group contains 6 to 14 carbon atoms. 7. The pressurized skin patch of claim 6, wherein the 2-pyrrolidone derivative is N-octyl-2-pyrrolidone. 8. A skin patch according to claim 1, wherein the alkyl ester of the aliphatic monocarboxylic acid is isopropyl myristate. 9. A pressurized skin patch according to claim 1, wherein the total amount of the penetration enhancer mixture comprises 10 and 40% of the total weight of the pressurized skin binder. 10. A pressure-sensitive skin patch according to claim 9, wherein the penetration enhancer mixture comprises between 30 and 70% by weight of an alkyl ester of an aliphatic monocarboxylic acid, between 3 and 25% by weight of a 2-pyrrolidone derivative and between 20 and 45% by weight of alkanpolyol. 16 (2639-OO.doc) 11. 11. 12. 12. 13. 13. 14. 4 4 44 4 4 4 4 4 4 4 4 4 A pressurized skin patch according to claim 1, wherein diclofenac or a pharmaceutically acceptable salt thereof is diclofenac sodium. A pressurized skin patch according to claim 1, characterized in that diclofenac or a pharmaceutically acceptable salt thereof constitutes 3 to 8 weight percent based on the total weight of said pressurized skin patch. A drug delivery device comprising a backing and an adhesive layer, characterized in that the adhesive layer comprises a pressurized skin patch according to claim 1. A method of treating a subject's inflammation or pain relief, comprising contacting the pressurized skin patch of claim 1 with the subject's skin and maintaining such contact for a time necessary to establish or maintain a therapeutically effective level of diclofenac or a pharmaceutically acceptable salt thereof in the blood. subject.