WO2014068600A1

WO2014068600A1 - Stable transdermal pharmaceutical drug delivery system comprising diclofenac

Info

Publication number: WO2014068600A1
Application number: PCT/IN2013/000680
Authority: WO
Inventors: Abhay Sadashiv SAPRE; Nimesh Bharatagiri GOSWAMI; Snehal Dipakkumar SHETH
Original assignee: Zydus Technologies Limited
Priority date: 2012-11-02
Filing date: 2013-11-04
Publication date: 2014-05-08

Abstract

The present invention relates to stable transdermal pharmaceutical drug delivery system of diclofenac or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to a stable transdermal pharmaceutical drug delivery system of diclofenac or a pharmaceutically acceptable salt thereof which is free of any penetration enhancer. Further, the transdermal pharmaceutical drug delivery system may be free from any antioxidant. More particularly, the present invention relates to stable transdermal pharmaceutical drug delivery system of diclofenac or a pharmaceutically acceptable salt thereof, which provides an enhanced absorption of drug through skin, has a flexible backing, shows longer duration of action, and inhibits crystal formation of drug.substance during storage period.

Description

STABLE TRANSDERMAL PHARMACEUTICAL DRUG DELIVERY SYSTEM COMPRISING DICLOFENAC

FIELD OF THE INVENTION

The present invention relates to stable transdermal pharmaceutical drug delivery system of diclofenac or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to a stable transdermal pharmaceutical drug delivery system of diclofenac or a pharmaceutically acceptable salt thereof which is free of any penetration enhancer. Further, the transdermal pharmaceutical drug delivery system may be free from any antioxidant. More particularly, the present invention relates to stable transdermal pharmaceutical drug delivery system of diclofenac or a pharmaceutically acceptable salt thereof, which provides an enhanced absorption of drug through skin, has a flexible backing, shows longer duration of action, and inhibits crystal formation of drug substance during storage period.

BACKGROUND OF THE INVENTION

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely employed in musculoskeletal disease, both for their anti-inflammatory as well as their analgesic properties. Use of these agents may extend from the acute injury to the long-term chronic disorder, and includes conditions considered to be 'degenerative' as well as those of a clearly inflammatory etiology. .NSAIDs decrease inflammation (and thus, pain) by inhibiting the biosynthesis of prostaglandins, which are responsible for inflammatory vasodilation and generation of other inflammatory cells. Specifically, NSAIDs prevent the conversion of arachidonic acid in cellular membranes to prostaglandins by inhibiting the activity of the enzyme cyclooxygenase. Diclofenac is a well-established nonsteroidal antiinflammatory agent, widely used in musculoskeletal disorders, arthritis, toothache, dysmenorrhea, etc., for symptomatic relief of pain and inflammation. It is chemically known as 2- [(2,6dichlorophenyl) amino] benzeneacetic acid and has the following structure.

During oral administration, diclofenac undergoes substantial hepatic first-pass metabolism and thus only about 50% of the administered dose reaches systemic circulation. Moreover, an oral administration of diclofenac exhibits poor bioavailability (40-60%), short biological half-life (2-3 h), and therefore required a large amount of drug for the treatment. This originates the need of an alternative route of administration, which can bypass the hepatic first-pass metabolism as well as provides a substantial- amount of drug on the site of action.

Transdermal drug delivery system for delivering the drug through skin is widely known for a long period. Transdermal formulations offer various advantages such as maintenance of constant and prolonged drug plasma level with less fluctuation in plasma concentration, reduced frequency of dosing, minimization of inter and intra-patient variability, self-administration, patient compliance with reduced side effects, and the termination of medication by self-removing the transdermal patches.

Transdermal delivery of drugs with pressure-sensitive adhesive is available in two different forms: matrix and reservoir patches. The matrix patches include a pressure sensitive adhesive layer for affixing the patch to the skin and for carrying the drug and any excipient that are directly incorporated into this adhesive layer These adhesive matrix patches also typically include an inert, impervious backing layer and a release liner that is peeled off and discarded before applying the patch to the skin. These patches are distinguished from reservoir patches in that the drug is incorporated in a layer or compartment, which is separate from the pressure-sensitive adhesive layer and the release of drug is controlled through this pressure-sensitive membrane.

There are numerous transdermal pharmaceutical compositions of diclofenac are disclosed in the prior art, requiring the use of particular carriers or excipients. In discussing references, statements below about characteristics are based only on what is stated in the text of each reference. U.S. Patent No. 4,738,848 discloses an anti-inflammatory analgesic adhesive preparation containing diclofenac sodium and a pharmaceutically acceptable cerboxylic acid. The use of carboxylic acid in the preparation converts diclofenac sodium into free base and thus enhances the percutaneous absorption of drug.

U.S. Patent No. 4,999,379 discloses the transdermal therapeutic system containing diclofenac or a pharmaceutically acceptable salt thereof and N,Ndimethyllauroylamide or l-n-dodecylazacycloheptan-2-one as a · penetration enhancers and further excipients suitable for percutaneous absorption.

U.S. Patent No. 5,374,661 discloses the topical drug delivery containing therapeutically effective amount of diclofenac sodium, thickening agent, lower molecular weight alcohols, and glycols. The transdermal flux of diclofenac is enhanced by the addition of a lower molecular weight alcohol and a glycol.

U.S. Patent No. 5,505,956 discloses the transdermal delivery of diclofenac from a transdermal device with 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. The patent specification discloses pyrrolidone derivatives and higher fatty acid esters as penetration enhancers.

U.S. Patent No. 5,607,690 discloses an external anti-inflammatory and analgesic plaster preparation containing diclofenac epolamine, a pH adjuster, and optionally a pharmaceutically acceptable ingredient such as thickening agents, humectants, fillers, preservatives, cross linking agent. The pH of the said preparation is adjusted in the range of 7.3 to 9.0.

U.S. Patent No. 5,795,916 discloses an external composition containing a water- soluble salt of diclofenac in an aqueous solution of dialkylolamide. The preparation exhibits an excellent stability and permeation of diclofenac through the skin. The pH of the external preparation is between 7.0 to 9.0, preferably from 7.5 to 8.5.

U.S. Patent No. 5,985,317 discloses a pressure-sensitive adhesive matrix patches for transdermal delivery of the hydrophilic salts of pharmaceutical agents. The patent specification discloses a transdermal drug delivery system comprising a pressure-sensitive adhesive matrix patch of diclofenac sodium, a water-based adhesive selected from polyisobutylene and acrylic adhesives and an effective amount of penetration enhancers.

U.S. Patent No. 6,193,996 discloses a pressure sensitive skin adhesive system of diclofenac or a pharmaceutically acceptable salt thereof with a copolymer of alkylmethylacrylate and hydrophilic monomer, and a mixture of penetration enhancers. The absorption of diclofenac or a pharmaceutically acceptable salt thereof is substantially improved by mixture of penetration enhancers.

U.S. Patent No. 6,399,093 discloses the compositions for topical delivery of anti- inflammatory agents with an effective amount of penetration enhancers. The penetration enhancers may be selected from alcohols, polyols,- sulfoxides, esters, ketones, amides, oleates, surfactants, alkanoic acids, lactam compounds, alkalols, diatkylamtno acetates. U.S. Patent Nos. 6,582,724, 6,645,520 and 6,582,724 disclose a method for transdermally administering a nonsteroidal anti-inflammatory drug with hydroxy- releasing agent as penetration enhancers. The patent specification discloses use of hydroxy-releasing agent like inorganic hydroxides, inorganic oxides and alkali metal/alkaline metal salts of weak acids which enhances the permeation rate of nonsteroidal anti-inflammatory drug through the body surface of the patient.

U.S. Patent Nos. 6,723,337 and 7,691,404 disclose a transdermal drug delivery system for an anti-inflammatory analgesic agent comprises a matrix comprising diclofenac diethyl ammonium salt as active ingredient, a non-aqueous acrylic polymer as adhesive constituent, a non-ionic surfactant, a terpene as a penetration enhancer, and a dissolution assistant. This laminated matrix composition has a thickness of less than 300 μη and uses both dissolution assistants and penetration enhancers to increase the concentration of drug in the matrix system and to enhance the flux of drug the across skin.

U.S. Patent No. 7,795,309 discloses a topical formulation that is useful for topical or transdermal application comprising diclofenac or a pharmaceutically acceptable salt thereof and combination of two different penetration enhancers. The patent specification discloses the transdermal formulation containing a first unit having N- lauryl sarcosine as a penetration enhancer and a second unit having isopropyl myristate as a penetration enhancer.

U.S. Patent Application No. 20090221707 discloses a process for preparing a pharmaceutical composition with antiinflammatory and analgesic agents for administration via a patch for external use. The components includes a salt of diclofenac with a cyclic organic base chosen from hydroxyethylpyrrolidine or hydroxyethylpiperidine characterized in that diclofenac is added to a mixture of one or more of said components,; in the form of a solution in water and propylene glycol in a ratio of about 1: 1 parts by weight.

Khan et al; African J. of Pharmacy and pharmacology; vol. 6(6); 434-439 (2012); discloses the transdermal matrix patch containing diclofenac diethylamine, terpene oil as a penetration enhancer and carboxypolymethylene and ethylcellulose as polymeric substances. The patches are prepared by solvent evaporation technique. Terpene oils are used as penetration enhancers for a number of hydrophilic and lipophilic drugs and recognized by FDA for increasing the drug diffusivity in the stratum corneum.

Currently, marketed transdermal formulation of diclofenac diethylamine is available under the trade name of Nupatch® in India, which contains an acrylate adhesive matrix with oleyl alcohol as a permeation enhancer and butylated hydroxy toluene (BHT) as an antioxidant. The formulation is available in strengths of 100mg/50cm2 and 200mg/50cm2.

Another marketed transdermal formulation of diclofenac is available with epolamine salt under trade name of Elector^® in USA, which contains an adhesive material containing; 1.3% diclofenac epolamine, a penetration enhancer which is applied to a non-woven polyester felt backing and covered with a polypropylene film release liner. Another marketed product Solaraze^® gel in USA contains diclofenac sodium, benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and purified water. Thus it is apparent from the prior art that transdermal formulations of NSAIDs, specifically diclofenac or a pharmaceutically acceptable salt thereof use penetration enhancers to increase the flux of drug across the skin. The use of any penetration enhancer may lead to skin irritation during application, and may generate substantial amount of degradation substances during the storage period.

The important consideration for transdermal delivery is often desired for the drugs which are crystalline at room temperature may be completely dissolved in the composition and should not recrystallize over time. Techniques known in the art for preventing the recry stall ization of drug substances include the incorporation of solubilizing agents to increase the equilibrium solubility of the drug or addition of crystal growth inhibitors to slow the rate of crystal formation.

Hence, there still remains an unmet need for alternative transdermal formulations of diclofenac or a pharmaceutically acceptable salt thereof having characteristics which are fundamental to transdermal preparations and can accomplish the desired therapeutic effect with storage-stability.

The present invention is related to a stable transdermal pharmaceutical drug delivery system containing diclofenac or a pharmaceutically acceptable salt thereof, which is free of any penetration enhancer or an antioxidant: The present invention has circumvented the disadvantages associated with the transdermal formulations of diclofenac like reduced crystal formation of drug substance, and reduced degradation substances generation during storage period, adequate¹ flux of drug across the stratum corneum, treatment for adequate duration, consistent in-vitro and in-vivo release of drug from the transdermal system, flexible backing, and increase in the surface area of the system with respect to prior arts formulation. SUMMARY OF THE INVENTION

In one general aspect, there is provided a stable transdermal pharmaceutical drug delivery system comprising diclofenac or a pharmaceutically acceptable salt thereof, wherein the drug delivery system is free of any penetration enhancer.

In another general aspect, there is provided a transdermal pharmaceutical drug delivery system comprising a backing layer, diclofenac or a pharmaceutically acceptable salt thereof, an adhesive material, one or more pharmaceutically topically acceptable excipient, and a release liner, wherein the drug delivery system is substantially free of any antioxidant.

In another ; general - aspect, there is provided a stab le transdermal pharmaceutical rug delivery system comprising a backing layer, diclofenac or a pharmaceutically acceptable salt thereof, an adhesive material, a one or more pharmaceutically topically acceptable excipient, and a release liner, wherein the drug delivery system is free of any penetration enhancer or an antioxidant.

In another general aspect, there is provided a stable transdermal pharmaceutical drug delivery system comprising diclofenac or a pharmaceutically acceptable salt thereof, wherein the salt of diclofenac is selected from an alkali metal salt, an alkylamine salt, a hydroxyalkylamine salt, a quaternary ammonium salt, or a choline salt.

: In another general aspect, there is provided a stable transdermal pharmaceutical drug delivery system comprising diclofenac or a pharmaceutically acceptable salt thereof, wherein iclofenac or a pharmaceutically acceptable salt thereof is present in a micronized form having a particle size equal to or less than 150 μνη, wherein the drug delivery system is free of any penetration enhancer or an antioxidant.

In another general aspect, there is provided a stable transdermal pharmaceutical drug delivery system comprising diclofenac or a pharmaceutically acceptable salt thereof, wherein the drug delivery system is free of any penetration enhancer or an antioxidant, , and retains at least 80% of the potency of diclofenac in the composition after storage for three months at 40 0C and 75% relative humidity.

In another general aspect, there i s provided a stab le transdermal pharmaceutical drug del i very system compri s ing d ic lo fenac or a pharmaceutically acceptable salt thereof, wherein the drug delivery system is sufficient to inhibit the crystal formation of drug substance and degradation substance generation : during storage period.

In another general aspect, there is provided a process of preparing a stable transdermal pharmaceutical drug delivery system comprising diclofenac or a pharmaceutically acceptable salt thereof, wherein the drug delivery system is free of any penetration enhancer or an antioxidant, the process comprises preparing a drug mass comprising : diclofenac or a pharmaceutically acceptable salt thereof and one or more : topically acceptable excipients, casting the drug mass onto a release liner film, drying the release liner film and the drug mass to form adhesive layer on the release liner film, and applying a backing layer to the adhesive layer.

In another general ^' aspect, there is provided a stab le transdermal pharmaceutical drug del i very system compri s ing d ic lo fenac or a pharmaceutically acceptable salt thereof, wherein the drug delivery system is free of any penetration enhancer or an antioxidant, and exhibits no significant difference in rate and extent of absorption of diclofenac as compared to commercially marketed formulations of diclofenac under the trade name Nupatch^® and Flector^®.

In another general aspect, there is provided a stable transdermal pharmaceutical drug delivery system compris ing diclofenac or a pharmaceutically acceptable salt thereof, wherein the drug delivery system provides a drug release for a period of 24 hours after application.

In another general . aspect, there is provided a stable transdermal pharmaceutical drug delivery system compri sing diclofenac or a pharmaceutically acceptable salt thereof, wherein the thickness of the transdermal drug delivery system is from about 50 μπι to about 500 μην.

In another general aspect, there is provided a stable transdermal pharmaceutical drug delivery system comprising d iclo fenac or a pharmaceutically acceptable salt thereof, wherein the surface area of the transdermal drug delivery system ranges from about 10 cm² to about 100 cm².

In another general aspect, there is provided a stable transdermal pharmaceutical drug del ivery system compri s ing d iclo fenac or a pharmaceutically acceptable salt thereof, wherein the backing layer is a soft, flexible, and comfortable and is selected from woven or non-woven fabric materials.

Embodiments of the transdermal pharmaceutical drug delivery system may include one or more of.the. following features. For example, the drug delivery system may include one or more pharmaceutical excipients suitable for topical application selected from adhesive materials, humectants, preservatives, plasticizers, surfactants, stabilizers, tackifiers, fillers, and other topically acceptable excipients.

In another general aspect, there, is provided a method of treating joint pains, muscular pains, acute pain due to minor strains, sprains, and contusions in a patient by applying the transdermal drug delivery system comprising a backing layer, diclofenac or a pharmaceutically acceptable salt thereof, an adhesive material, and a release liner, wherein the drug delivery system is free of any penetration enhancer or an antioxidant. The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stable transdermal pharmaceutical drug delivery system comprising diclofenac or a pharmaceutically acceptable salt thereof, wherein the drug delivery system is free of any penetration enhancer or an antioxidant.

The inventors of the present invention have found surprisingly, in contrary to the teaching of the prior art that, it is possible to develop transdermal formulations of diclofenac or a pharmaceutically acceptable salt thereof without using penetration enhancer or an antioxidant. Such formulations exhibit excellent application characteristics and also allow for transdermal absorption and permeability of the drug for a longer period of time.

Moreover, the transdermal drug delivery system of the present invention was also found to exhibit no crystal formation of diclofenac and inhibition of residual substance during the storage-stability period, when subjected to storage for three months at 45°C and 75% relative humidity or stress stability.conditions.

In the absence of teaching/suggestion in the art about how to develop transdermal formulations of diclofenac or a pharmaceutically acceptable salt thereof and enhance the permeation of drug across skin without employing any penetration enhancer or an antioxidant, the inventors have devised a composition of diclofenac or a pharmaceutically acceptable salt thereof by proper selection of topically acceptable excipients, thickness and size of the drug delivery system, particle size of drug substance and flexible backing layer.

In one embodiment of the present invention, the invention provides a transdermal drug delivery system comprising a backing layer, diclofenac or a pharmaceutically acceptable salt thereof, an adhesive material, a one or more pharmaceutically topically acceptable excipient, and a release liner, wherein the drug delivery system is free of any penetration enhancer or an antioxidant.

The term "transdermal drug delivery system" refers to an administration of a drug to the skin surface of an individual, so that the drug passes through the skin tissue and into the individual's blood stream.

The term "a pharmaceutically acceptable salt thereof includes but not limited to an alkali metal salt, an alkylamine salt, a hydroxyalkylamine salt, a quarternary ammonium salt, or a choline salt. The salt may be selected from sodium, potassium, diethylamine, triethylamine, ethylenediamine, ethanolamine, dimethylethanolamine, tetramethylammonium, hydroxyethylpyrrolidone, hydroxyethylpiperidine, choline salt, or the like.

The term "% by weight" refers to a weight of the ingredient based on the total weight of the composition excluding a backing layer and a release liner.

The amount of diclofenac or a pharmaceutically acceptable salt thereof in the present invention may range from about 2% to about 40% . by weight, preferably from about 10% to 30% by weight, more preferably from about 20% to about 25% by weight. In the present invention, diclofenac or a pharmaceutically acceptable salt thereof is present in an amount from about 10 mg to about 250 mg, preferably from about 50 mg to about 230 mg. The exact amounts of diclofenac or a pharmaceutically acceptable salt thereof to be administered may depend on a number of factors, e.g. the drug release characteristics of the compositions, the drug penetration rate observed from in-vitro and in-vivo tests, the duration of action, the sizp of the skin contact area, and the part of the body to which the unit is fixed.

The particle size of drug is an important parameter for transdermal delivery of drug and it is required for the desired absorption of drug through the skin and for producing significant therapeutic effect. The particle ,size- of diclofenac or a pharmaceutically acceptable salt thereof in the composition is equal to or less than 150 μηι. The mean particle size _(d50) of diclofenac or a pharmaceutically acceptable salt thereof in the composition is equal to or less than about 50 μπτ, preferably less than 30 μιη, while at least about 90% of the particles _(d9o> of diclofenac or a pharmaceutically acceptable salt thereof is present with equal to or less than 150 μη , preferably from less than 100 μηι. The particle size was determined by using malvern mastersizer instrument, by using dry method.

In another embodiment, the transdermal pharmaceutical drug delivery system comprises one or more topically acceptable excipients including one or more adhesive materials, humectants, preservatives, plasticizers, surfactants, stabilizers, tackifiers, fillers, and other topically acceptable excipients, wherein the drug delivery system is free of any penetration enhancer or an antioxidant.

The term "penetration enhancer" refers to compounds that enhance the permeation of a drug across the skin. The penetration enhancer may also be referred as "permeation enhancer".

In the present invention, the transdermal pharmaceutical drug delivery system may be free of the following penetration enhancers: 1- dodecylazacycloheptan-2-one(azone) and N,N-diethyl-m-toluamide (DEET), polyhydric alcohols (for example propylene glycol, polybutylene, glycerol, dipropylene glycol), sodium carbonate, tri potassium phosphate, magnesium oxide, saturated and unsaturated fatty acids, esters, and alcohols thereof (for example oleic acid, ethyl oleate, propyl oleate, isopropyl myristate, glycerol monooleate, glycerol monolaurate, methyl laurate, lauryl alcohol, lauramide diethanolamide, and mixtures thereof, glyceryl monolaurate, ethyl palmitate), isopropyl myristate, lactic acid, lactic acid esters, monoglycerides, triacetin, methyl laurate, ethylvinylacetate, polyvinylpyrrolidone, transcutanol, dibutylsebacate, lauramide diethanolamine, propylene glycoisostearate, triglycerides (e.g. capric caprylic triglycerides), A IFAT (derived from glycerin, oleic acid and 2- pyrrolidone-5-carboxylic acid), hydroxy releasing agents like sodium hydroxide, potassium hydroxide, magnesium hydroxide, or a combination thereof.

The term "antioxidant" refers to a substance which lowers the level or prevents the formation^ of active radicals or active forms of oxygen. The transdermal drug delivery system may be free of or substantially free of the following antioxidants: tocopherol and its esters such as tocopherol acetate, a tocopherol, ascorbyl palmitate, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, propyl gallate, sodium sulfite, sodium bisulfite, sodium metabisulfite, thioglycolic acid or any salt form thereof, like monothioglycerol, L-cysteine or a combination thereof. As used herein, "substantially free of an antioxidant means that any antioxidant is present in an amount of less than 1000 ppm of the composition as a whole.

The term "adhesive material" refers to a viscoelastic material which adheres instantaneously to most substrates with the application of very slight pressure and remains tacky. The term "adhesive"¹ can be interchangeably used as "pressure-sensitive adhesive", if it has the properties of pressure-sensitive adhesive per se or function as a pressure-sensitive adhesive. The adhesives must be biocompatible and non-irritating. It is also important that the adhesive should be selected such that it is compatible with the other components of the therapeutic adhesive formulation of the present invention. Suitable adhesive materials are selected from, but not limited to one or more, acrylics, silicones, polyisoalkylenes, vinyl acetates, natural and synthetic rubbers, polyether block amide copolymers polyisobutylene (PIB), polybutadiene, styrene- butadiene (or isoprene)-styrene block copolymer rubber, acrylic rubber and natural rubber; vinyl-based high molecular weight materials such as polyvinyl alkyl ether, polyvinyl acetate, ethylenevinylacetate copolymers, a partially saponified product of polyvinyl acetate, polyvinyl alcohol and polyvinyl pyrrolidone, cellulose derivatives such as · methyl cell ulose, carboxylmethyl cel lu lose and hydroxypropyl cellu lose, polysaccharides such as pollutant, dextrin and agar, polyurethane elastomers, polyester elastomers or a combination thereof.

The acrylic adhesives include cross-linked and uncross-linked acrylic copolymers selected from polymethacrylate such as butyl acrylate, ethyl hexyl acrylate, vinyl acetate, (meth)acrylic acid such as butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, nonyl ^' (meth)acrylate, decyl (meth)acrylate, undecyl (meth)acrylate, dodecyl (meth)acrylate, and tridecyl (meth)acrylate, and copolymers of at least one of the above esters and other monomers copolymerizable therewith. Preferred acrylate polymer are available commercially under the trade name Gelva brand, e.g. Gelva-301 1 or Durotak^' brand available from National Starch and Chemical Company, Zutphen, Holland, e.g. Durotak 202A, 608, 4202, 4287, 2510, 617 A, 87- 2353, 87-2852, 87-2287, 87-2353, 387-2051 or 387-2052.

The polyisobutylene adhesives may contain blend of two different types of polyisobutylene having a different molecular weights. The high molecular weight polyisobutylene may range from about 450,000 to about 2,100,000 viscosity average mo lecu lar weight and a low molecular weight polyisobutylene may range from about 1,000 to about 450,000 viscosity average molecular weight The two polyisobutylenes with different molecular weight can be mixed with each other wherein the ratio of the polyisobutylene having the higher molecular weight to the polyisobutylene having the lower molecular weight is in the range from about 0.05: 1 to about 20: 1, preferably from about 0.5: 1 to about 2: 1, more preferably from about 1 : 1. Preferred polyisobutylenes are available commercially under the trade name of DuroTak^® 87-616A, DuroTak^® 87-608A from National Starch and the others are under the trade name of Vistanex^®.

The silicon adhesive refers to a polydimethylsiloxane based polymers. Suitable silicone adhesives are commercially available under the trademarks BIO-PSA X7-3027, BIO-PSA -X7-4503, BIO-PSA X7-4603, BIO-PSA X7-4301, BIO-PSA X7- 4303, BIO-PSA X7-4919, BIO-PSA X7-2685, and BIO-PSA X7- 3122 by Dow Corning Corporation, Medical Products, Midland, Mich.

The adhesive materials may be present in an amount from about 30 to 90% by weight, preferably from about 50 to about 80% by weight, more preferably from about 60% to about 70% by weight. The ratio of the amount of adhesive material to diclofenac or a pharmaceutically acceptable salt thereof in the composition may ranges from about 1:20 to about 20:1 in order to achieve the desire transdermal properties.

Suitable humectants are selected from, but not limited to glycerol, propylene glycol, polyethylene glycol, 1 ,3-butanediol and D-sorbitol solution or a combination thereof. The humectant may present in an amount from about 5% to about 70% by weight, preferably from about 10% to about 60% by weight, more preferably from about

30% to about 50% by weight.

Suitable stabilizers are selected from, but not limited to buffers and/or fatty acid esters, urea, organic acid esters, polyvinylpyrrolidone or a combination thereof. The buffers are selected from the group consisting of: basifying or basic buffers such as a phosphate buffer (for example dibasic or monobasic sodium phosphate), a citrate buffer (for example sodium citrate or potassium citrate), sodium carbonate, sodium bicarbonate, a mixture of sodium carbonate and sodium bicarbonate being preferable, or neutral buffers such as a tris buffer, preferably a phosphate buffer. The stabilizer may present in an amount from about 0.01 to about 2.5% by weight, preferably from about 0.5% to about 1.0% by weight. The term "plasticizer" refers to compounds that provide flexibility to the pharmaceutical composition. Suitable plasticizers are selected from, but not limited to mineral oil, polybutene oil, citric acid esters, triacetin, saturated triglycerides, triethyl citrate, acetyl tributyl citrate, low molecular weight hydrocarbons or a combination thereof, that act to plasticize adhesives and increase their permeability to the agent being delivered. The plasticizers may present in an amount from about 1% to about 25% by weight, preferably from about 5 to 15% about by weight.

The amount and type of plasticizers and/or softeners required may depend on a number of factors like drug content, and the amount of adhesive materials. The weight ratio of diclofenac or a pharmaceutically acceptable salt thereof to plasticizer in the composition preferably ranges from about 1 :0.25 to about 1:3.

Suitable surfactants are selected from, but , not limited to polysorbates, their ether ethoxylates, produced by reaction of sorbitan esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether, polyoxyethylene alkyl-aryl ether, polyoxyethylene monolaurate, polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylene sorbitol lanolin derivative, polyoxyethylene tridecylether, polyoxyethylene sorbitan esters of mixed fatty and resin acids, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, po lyoxyethylene monostearate, po lyoxyethy lene steary l ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether, polyoxyethylene fatty alcohol, polyoxyethylene alkyl amine, polyoxyethylene glycol monopalmitate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene cetyl ether, polyoxyethylene oxypropylene stearate, polyoxyethylene lauryl ether, polyoxyethylene lanolin derivative, sodium oleate, quaternary ammonium derivative, potassium oleate, N-cetyl N-ethyl morpholinium ethosulfate, sodium lauryl sulfate or a combination thereof. The surfactants may present in an amount from about 1% to about 20% by weight, preferably from about 5 to 5% about by weight. The term "tackifier" refers to an agent that improves the adhesive strength of the adhesive layer to the skin or mucosa. Suitable tackifiers are selected from, but not limited to aliphatic hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons, substituted aromatic hydrocarbons, highly hydrogenated rosin, terpene resin, petroleum resin, phenolic resin, xylene resin or a combination thereof. The tackifiers may present in ah amount from about 1% to about 20% by weight, preferably from about 5 to 15% about by weight.

Suitable fillers are selected from, but not limited to metal oxides (such as zinc oxide and titanium oxide), metal salts (such as calcium carbonate, magnesium carbonate and zinc stearate), silicic acid compounds (such as kaolin, talc, bentonite, colloidal silicone dioxide, hydrous silica, aluminum silicate, magnesium silicate and magnesium aluminometasilicate), metal hydroxides (such as aluminum hydroxide) or a combination thereof. The fillers may present in an amount from about 1% to about 10% by weight.

The solvents used in the present invention for dissolving the substantial amount of , drug substance are selected from aqueous or non-aqueous solvents. Non-aqueous solvents are selected from organic or inorganic solvents which include aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as acetone, heptane and hexane, alcohols such as methanol, ethanol, and isopropyl alcohol, aliphatic esters such as ethyl acetate or a combination thereof. The amount of solvents used in the present invention may depend on the drug content.

In another embodiment, the transdermal drug delivery system of the present invention retains at least 80% of the amount of diclofenac in the composition after storage for three months at 40 °C and 75% relative humidity. The transdermal drug delivery system of the present invention inhibits the crystal formation of drug substance during the storage period.

In another embodiment, the transdermal drug delivery system inhibits the formation of significant amount degradation substances during the storage period. It is very important for the drug composition to remain stable during the storage period and produces a consistent in-vitro and in-vivo release of drug from the transdermal system.

In the present invention, the amount of degradation substances formation during the storage period falls within the limits as specified by pharmacopeial standards and regulatory agencies guideline.

In another embodiment, the process of preparing the transdermal drug delivery system comprises the steps of preparing a drug mass comprising diclofenac or a pharmaceutically acceptable salt thereof and a one or more adhesive; casting the drug mass onto a release liner film; drying the release liner and the drug mass to form a layer on release liner; laminating a backing layer to the adhesive layer; slitting and trimming the laminated coated layer; and die-cutting the laminate into dosage units using fixed size rotary dies.

In another embodiment, the process for preparing the transdermal drug delivery system comprises the steps of dissolving or dispersing a drug with a one or more adhesive; applying the drug mass on the surface of release-controlling membrane made up from porous or non-porous materials and drying the drug mass; subsequently casting the drug mass onto the release liner; laminating the backing layer onto the upper surface of drug mass; slitting and trimming the laminated coated layer; and die-cutting the laminate into dosage units using fixed size rotary dies.

In another embodiment, the transdermal drug delivery system of the present invention comprising diclofenac or a pharmaceutically acceptable salt thereof, exhibits an area under the curve (AUCO-oo) from about 20 ng.hr/ml to about 200 ng.hr/ml, preferably from about 50 ng.hr/ml to about 100 ng.hr/ml., when the trials are carried out in human patients.

In another embodiment, the transdermal drug delivery system of the present invention comprising diclofenac or a pharmaceutically acceptable salt thereof, exhibits a peak plasma concentration (Cmax) from about 0.5 ng/ml to about 10 ng/ml, preferably from about 2 ng/ml to about 8 ng/ml, when the trials are carried out in human patients.

In still another embodiment, the transdermal drug delivery system of the present invention comprising diclofenac or a pharmaceutically acceptable salt thereof exhibits time to achieve maximum concentration time (T_max) from about 10 hours to about 20 hours http://ng.hr/ml., when the trials are carried out in human patients.

In still another embodiment, the transdermal drug delivery system of the present invention comprising diclofenac or a pharmaceutically acceptable: salt thereof exhibits when applied to a human patient a desirable combination of AUC0-∞, C_max, and T_max. In another embodiment, the transdermal drug delivery system minimizes skin irritation while maintaining adequate transdermal flux of diclofenac. The transdermal drug delivery system of the present invention provides a flux of diclofenac with a flux rate ranging from about 0.1 pg/cm².hr to about 10 μ /οηι².ηΓ, preferably from about 1 g/cm².hr to about 5 μg/cm².hr. In the present invention, the transdermal drug delivery system provides a drug release for a period of up to 24 hours after application.

The transdermal drug delivery system of the present invention is intended to be applied at intervals of about once a day. Diclofenac or a pharmaceutically acceptable salt thereof may, for example be administered in patch or film form at a dose of 200mg/80cm², 100mg/40cm², 50mg/20cm², and 25mg/10cm² for once every day. The patch or film may be applied to any painful area such as on the thigh, on a shoulder or upper arm.

The thickness of the transdermal drug delivery system of present invention is intended to be higher as compared to prior arts and commercially available diclofenac transdermal compositions. This leads to substantial amount of drug in dissolved form during application period. The thickness of the transdermal drug delivery system may range from about 50μηι to about 500μπι, preferably from about 200μηι to 400μηι.

In another embodiment of the present invention, the surface area of the transdermal drug delivery system is sufficient to maintain the effective contact with the skin during administration and also provides an intended drug delivery rate. The surface area of the transdermal drug delivery system may range from about 10cm² to about 100cm², preferably from about 20.cm² to about 80cm².

In another embodiment, the backing layer is selected from woven or nonwoven fabric materials. The backing layer serves as the upper layer of the device during use and functions as the primary structural element of the device. The backing layer of the present invention; is soft, flexible, and has the multi-directiona stretchable properties. When the external tensile force is applied, the backing layer is capable of stretching and, when the tensile force is removed, it has the capacity to return in the original position. The backing film provides mechanical support to the drug-adhesive matrix formulation. It also provides physical integrity to the system, maintenance of the physical dimensions and shape of the formulation which prevents direct contact of patch formulation with the environment. Suitable backing layer are selected from, but not limited to Scotchpak 9732, Scotchpak 9727, Scotchpak 1 109, Scotchpak 9730, Scotchpak 9733, Scotchpak 9735, Scotchpak 9736, Scotchpak 9738, CoTran 9700, CoTran 9708, CoTran 9718, CoTran 9719, CoTran 9720, and CoTran 9722. The backing layer is made of a sheet or film of a preferably flexible elastomeric material that is impermeable to the drug and any excipient that may be present. Suitable materials for backing layer are selected from natural or synthetic polymeric. A suitable natural polymeric material is selected from, but not limited to cellulose, silk, cotton and a suitable synthetic polymeric material is selected from, but not limited to polyvinyl chloride, polyurethane, polyester, polyamide, polypropylene and the like. The thickness of backing layer may range from about 150μπι to about 400μπι, preferably from about 200μηι to 300μηι.

The release liner may be a disposable element which serves to protect the pharmaceutical composition prior to its application. Typically the release liner is produced from a material impermeable to drug, and adhesive. This release liner may be easily stripped away from the adhesive. A preferred release liner is made of fluoro polymer coated polyester, or polyethylene terephthalate (PET) foil. The thickness of release liner may range from about 25μιη to 250μη , e. g. 50μ η th ickness PET fi lm, may be appl ied over the pharmaceutical composition. Suitable release liner are selected from, but not limited to Scotchpak^R and Loparex^R grades like Scotchpak 1022, Scotchpak 9741, Scotchpak 9742, Scotchpak 9744, Scotchpak 9748, Loparex 48015, Loparex 4801 1, and Loparex 48036.

The release liner may be silicone-coated. Said coating is preferably formed of any fluorosilicone compound which is conventionally used in the art, e.g. a polyfluoroalkylsiloxane. It is particularly preferred to employ such a fluorosilicone coating when the adhesive used to affix the pharmaceutical composition to the release liner is not itself a silicone adhesive.

The cover patch transdermal drug delivery system may conveniently be formed as a continuous sheet or webbing and may be cut, or torn along a frangible area dividing each device, into patches before use although such devices may be provided as discrete patches.

In another embodiment, the transdermal patches or films are typically packaged in unit dose pouches where a single patch is present inside a sealed and printed pouch. Pouching materials of the present invention are multi-laminate films where the outermost layer is printable and inner-most layer is heat sealable layer with a protective foil layer in between to provide barrier function. The selected pouching materials have characteristics of acceptable heat sealability, protected during stability and transportation.

The adhesive properties of a patch were characterized by considering: i) the force required to peel away a patch from a surface (peel force), ii) the ability to form a bond with the surface of another material on brief contact and under light pressure (tack); and iii) the resistance of the adhesive to flow (shear stress). Flux rate was carried out by using human cadaver skin in franz diffusion cell, which was used to determine ratio of diclofenac diethylamine to the polymer in final composition.

In further embodiment, the invention provides a method of treating joint pains, muscular pains, acute pain due to minor strains, sprains, and contusions in a patient, comprising administering to said patient a transdermal drug delivery system of diclofenac or a pharmaceutically acceptable salt thereof according to the present invention.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Examples:

Table 1:

Process:

Light mineral oil was mixed with a suitable organic solvent like heptane. The resulting mixture was stirred for about 10 minutes. Then, colloidal silicone dioxide was added to the above mixture with continuous stirring to make a semi solid premix mass. This premix mass was added to the mixture of high molecular weight and low molecular weight polyispbutylene (PIB) polymer with continuous stirring at about 500 rpm. At last, diclofenac diethylamine was added with continuous mixing to the PIB mixture until homogeneous dispersion was _; achieved. The homogenous dispersion was coated on silicone coated release liner with a wet thickness of about 500 micron and solvent was continuously removed in a drying oven at temperatures up to 100 °C for about 20 minutes to obtain drug containing adhesive matrix of 125 g/m² coating weight. The dried film matrix was laminated with a soft, flexible, comfortable non-woven fabric backing. The final patch was cut into a size of 80 cm² each.

The examples in which light mineral oil was not used, only heptane acted as a solvent. The particle size of diclofenac diethylamine used in the examples was such that d₅₀ was around 16 μπι.

The patches thus prepared were then evaluated for their adhesive properties by measuring and comparing the parameters like peel force, tack, shear stress and release force.

Table 2: Adhesiveness property evaluation

Examples: Transdermal compositions with varying concentration of diclofenac diethyl

Table 3: Compositions with different concentrations of drug and polymer

Ingredients

Quantity in mg/80 cm² pal tch

Ex. 7 (Ex. 8 [Ex. 9 . Ex. 10 Ex. 11 Diclofenac diethylamine 225 180 135 90 45

Light mineral oil 100 100 100 100 100

Colloidal silicone dioxide 40 40 40 40 40

Polyisobutylene 635 680 725 770 815

Total 1000 1000 1000 1000 1000

Backing Film

Release Liner

Table 4: Flux rate of diclofenac diethylamine through the human cadaver skin

Flux rate of diclofenac diethylamine from different compositions were measured by using human cadaver skin in franz diffusion cell. Comparative study of flux rate as shown in Table 4 is considered while selecting the amount of diclofenac diethylamine in the patch as per the invention.

While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be appafent to those skilled in the art and are intended to be included within the scope of the invention.

Claims

We claim:

1. A transdermal pharmaceutical drug delivery system comprising a backing layer, diclofenac or a pharmaceutically acceptable salt thereof, an adhesive material, one or more pharmaceutically topically acceptable excipients, and a release liner, wherein the drug delivery system is free of any penetration enhancer.

2. A transdermal pharmaceutical drug delivery system comprising a backing layer, diclofenac or a pharmaceutically acceptable salt thereof, an adhesive material, one or more pharmaceutically topically acceptable excipient, and a release liner, wherein the drug delivery system is substantially free of any antioxidant.

3. The transdermal pharmaceutical drug delivery system of claim 2, further characterized in that said transdermal pharmaceutical drug delivery system is free of any penetration enhancer.

4. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the drug delivery system is applied on to the skin in form of a patch, a film, or a plaster.

5. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the diclofenac or a pharmaceutically acceptable salt thereof is present in an amount from about 2% to about 40% by weight.

6. The transdermal pharmaceutical drug delivery system according to any of claims 1- 3, wherein the salt of diclofenac is selected from an alkali metal salt, an alkylamine salt, a hydroxyalkylamine salt, a quarternary ammonium salt, or a choline salt.

7. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the salt of diclofenac is selected from sodium, potassium, diethylamine, triethylamine, ethylenediamine, ethanolamine, dimethylethanolamine, tetramethylammonium, hydroxyethylpyrrolidone, hydroxyethylpiperidine, or choline salt.

8. The transdermal pharmaceutical drug delivery system according to any of claims 1- 3, wherein the adhesive material is selected from acrylics, silicones, polyisoalkylenes, vinyl acetates, natural and synthetic rubbers, ethylenevinylacetate copolymers, polyether block amide copolymers polyisobutylene . rubber, polybutadiene, styrene-butadiene (or isoprene)-styrene block copolymer rubber, acrylic rubber and natural rubber; vinyl-based high molecular weight materials such as polyvinyl alky I ether, polyvinyl acetate, a partially saponified product of polyvinyl acetate, polyvinyl alcohol and polyvinyl pyrrolidone; cellulose derivatives such as methyl cellulose, carboxylmethyl cellulose and hydroxypropyl cellulose; polysaccharides such as pullulan, dextrin and agar; polyurethane elastomers; and polyester elastomers or a combination thereof.

9. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the thickness of the transdermal drug delivery system is from about 50 μηι to about 500 μηι.

10. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the surface area of the transdermal drug delivery system ranges from about 10 cm² to about 100 cm².

1 1. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the backing layer is a soft, flexible, comfortable and is selected from a woven or a non-woven fabric materials.

12. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the drug delivery system provides drug release for a period of up to 24 hours after application.

13. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the diclofenac or a pharmaceutically acceptable salt thereof is present in a matrix or a reservoir form.

14. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the diclofenac or a pharmaceutically acceptable salt thereof is present in a micronized form having a particle size equal to or less than 150 μπι.

15. The transdermal pharmaceutical drug delivery system accjDrding to any of claims 1-3, wherein the drug delivery system is sufficient to inhibit the crystal formation of drug during storage-stable period of system.

16. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the drug delivery system is sufficient to inhibit the residual solvent generation during storage-stable period of system.

17. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the drug delivery system exhibits an area under the curve (AUCo-_t) from about 20 ng.hr/ml to about l00 ng.hr/ml.

18. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the drug delivery system exhibits a peak plasma concentration (C_max) from about 0.5 ng/ml to about 10 ng/ml.

19. The transdermal pharmaceutical drug delivery system according to any of claims 1-3, wherein the drug delivery system exhibits a peak plasma concentration time (T_max) from about 10 hours to about 20 hours.

20. A method of treatment of joint pains, muscular pains, acute pain due to minor strains, sprains, and contusions in a patient by applying transdermal pharmaceutical drug delivery system comprising a backing layer, diclofenac or a pharmaceutically acceptable salt thereof, an adhesive material, and a release liner, wherein the drug delivery system is free of any penetration enhancer.