Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1999-03-25
2001-02-27
Harrison, Robert H. (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S448000, C514S567000, C604S304000
Reexamination Certificate
active
06193996
ABSTRACT:
FIELD 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.
BACKGROUND OF THE INVENTION
Ortho-[(2,6-dichlorophenyl)amino]phenylacetic acid (hereinafter referred to as diclofenac) and its pharmaceutically acceptable salts are known compounds useful in the treatment of inflammation. Sodium [ortho[(2,6-dichlorophenyl)amino]phenyl]acetate, also variously known as 2-[2,6-dichlorophenyl)amino]benzeneacetic acid monosodium salt and diclofenac sodium, has been shown, for example, in pharmacological studies to possess potent anti-inflammatory and analgesic 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 of ocular inflammation has also been shown. See, for example, M. Agata et al.,
Nihon Ganka Gakkai
[Acta Soc. Ophthalmol. Japan], Vol. 87, pp. 19-28 (1983), and M. Agata 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 discloses a diclofenac sodium plaster. The plaster comprises a paste formulation that contains diclofenac sodium, a water-soluble polymer such as polyacrylic acid and a mixture of propylene glycol and 1-menthol as penetration enhancers.
EP 582727 discloses a transdermal therapeutic formulation that comprises 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. As suitable polymers there are mentioned acrylic adhesives such as copolymers of alkyl acrylates and acrylic acid. Among the list of alcohols there are mentioned polyols such as propylene glycol. EP 582727 further discloses that known penetration enhancers 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 discloses a medical adhesive comprising a plaster 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 and the layer forms a water-in-oil type emulsion. It is disclosed that diclofenac can be used as the medicinal ingredient.
WO 91/09592 discloses a transdermal system with a reservoir layer that comprises a complex of the drug and a cyclo compound. The release rate of the drug from the system is controlled by the dissociation of the complex. Diclofenac is disclosed as one of the drugs that can be used in such a system.
U.S. Pat. No. 5,505,956 discloses the delivery of a drug such as diclofenac from a transdermal device that has on a backing an adhesive layer that has a laminate structure of 2 to 5 layers and each layer has different water absorption capacity. The adhesive layer contains an adhesive resin such as a polyacrylate, a penetration enhancer, a water adsorptive material such as a polyol and a lenitive agent. Pyrrolidone derivatives and higher fatty acid esters are mentioned as penetration enhancers.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide 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 further an object of the present invention to improve the transdermal delivery of diclofenac.
These objects have been accomplished by providing 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) a 2-pyrrolidone derivative and
(iii) an alkane polyol; and
(c) a therapeutically effective amount of diclofenac or a pharmaceutically acceptable salt thereof.
It has in particular been observed that the delivery of 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 above pressure sensitive skin adhesive and the use of the pressure sensitive skin adhesive for the manufacture of a transdermal drug delivery device for the treatment of inflammation or relief of pain. In addition, the invention provides a method of 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 time sufficient to establish or maintain a therapeutically effective blood level of diclofenac or a pharmaceutically acceptable salt thereof in the subject.
DETAILED DESCRIPTION OF THE INVENTION
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 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-ethyloctyl, isooctyl, n-octyl and 2-ethylhexyl acrylates and methacrylates. Isooctyl acrylate is particularly preferred.
The hydrophilic monomers are typically monomers that have a tendency to bind or absorb water and are preferably monomers of which a homopolymer is capable of swelling in water or that can be dissolved in water. Examples of hydrophilic monomers include carboxylic acid containing 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 vinyl acetate; mono-(meth)acrylates of poly(oxyalkylene), mono (meth)acrylates of poly(alkyleneoxide) alkyl ether; amides such as acrylamides, methacrylamides, N-vinyl valerolactam, and N-vinyl caprolactam; tetra-alkylammonium containing monomers such as (meth)acryloxyethyl trimethylammonium chloride, (meth)acryloxyethyl triethylammonium chloride, and (meth)acrylamido-ethyl trimethyl ammonium 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 (meth)acrylamide and diethylamino-ethyl (meth)acrylamide. A mixture of two or more hydrophilic monomers may 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 and the hydrophilic monomer. Examples of such further monomers that can be copolymerised with the (meth)acrylate and hydrophilic monomer include short chain (1 to 4 carbon atom) alkyl acrylates and methacrylates 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 that is copolymerizable with the alkyl (meth)acrylate and hydrophilic monomer. The macromer preferably has a weight average molecular weight between 5000 and 500000 as measured by GPC relative to a pol
Becker Anja N.
Coors Carsten
Effing Jochem J.
3M Innovative Properties Company
Harrison Robert H.
Howard MarySusan
Ringsred Ted K.
Sprague Robert W.
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