FIELD OF INVENTION

The present invention relates to transdermal patch composition comprising active ingredient having anti-inflammatory, analgesic and antipyretic activities.

The present invention specifically relates to transdermal patch composition comprising Diclofenac as an active ingredient, high concentration of hot melt pressure sensitive adhesive, low concentration of tackifier and other pharmaceutically acceptable excipients.

The present invention more specifically relates to transdermal patch comprising Diclofenac diethylamine as active ingredient, high concentration of hot melt pressure sensitive adhesive, low concentration of tackifier and other pharmaceutically acceptable excipients for relieving short term pain due to minor strains, sprains and bruises associated with musculo skeletal disorders, Arthritis, Myalgia, Tennis elbow, etc.

The present invention also relates to process for the preparation of Diclofenac diethylamine transdermal patch by using hot-melt coating technique (HMC) comprising the steps of melting, mixing, coating, laminating and cutting.

BACKGROUND OF INVENTION

Diclofenac is a phenylacetic acid derivative and belongs to the acetic acid class of NSAIDs. Diclofenac acts as by inhibiting cellular cyclooxygenases (Cox-1 and Cox-2) which results in a decrease in production of pro-inflammatory prostaglandin, prostacyclin and thromboxane products, important mediators of inflammation and pain. Diclofenac has analgesic as well as antipyretic and antiinflammatory activities. Diclofenac diethylamine, chemically diethylammonium} o- [(2,6- dichlorophenyl)-amino] -phenyl} acetate. Diclofenac diethylamine has a chemical formula of C18H22CI2N2O2 and a molecular mass of 369.3 g/mol. It has a structural formula of:

Diclofenac diethylamine is administered topically (patch, cream, ointment, spray, gel). When applied topically in ointment or cream form, formulation is easily removed by clothing, making it difficult to control the effective therapeutic dosage. Hence, to overcome such side effects and the problems associated with conventional dosage forms, there is a requirement for the development of safe and easy to use formulation, which can provide sustained drug release.

NuPatch Patch is marketed by Zydus Cadila. Each 37.5 cm patch contains 100 mg of Diclofenac diethylamine, Light mineral oil, Colloidal silicon dioxide, Polyisobutylene as pharmaceutically acceptable excipients.

US Patent No. 6,723,337 B1 discloses transdermal drug delivery system for anti-inflammatory analgesic agent comprising Diclofenac diethylammonium salt, wherein the transdermal penetration and adhesion of the patch to the body are enhanced by means of a matrix layer which comprises a Diclofenac diethylammonium salt as active ingredient, non-aqueous acrylic polymer as adhesive constituent, non ionic surfactant as absorption enhancer, terpene, dissolution assistant, volatile and non-volatile constituents of the composition are separately applied therein for significantly reducing the manufacturing time thereof.

US Patent No. 8,114,434 B2 discloses analgesic anti-inflammatory patch of a hydrophobic type for topical application comprising Pressure Sensitive Adhesive (PSA) which is a styrene-isoprene- styrene block copolymer (SIS), Diclofenac sodium, pyrrolidone or a derivative thereof, a polyhydric alcohol fatty acid ester and an organic acid.

US Patent No. 8,158,145 B2 discloses transdermal patch comprising a backing and an adhesive layer laminated on the backing, wherein the adhesive layer comprises a rosin-based resin and petroleum resin as a tackifier. US Publication No. 2004/0037872 A1 discloses active substance-containing adhesive patch comprising a) an impermeable backing layer, (b) a matrix layer comprising 1-15% of Diclofenac or a topically acceptable salt thereof, 15-42% of matrix-forming polymer selected from styrene-isoprene- styrene copolymer and ethylene- vinyl acetate copolymer, 42-70% of tackifier selected from aliphatic hydrocarbon resins and thermoplastic terpenic resins, 2-20% of one or more solvents selected from the group consisting of oleic acid and derivatives thereof, fatty acid alkyl esters and N-alkyl-pyrrolidones, (c) a protective layer which can be pulled off; with the proviso that said patch does not contain isostearic acid. WO Publication No. 2013/133387 A1 discloses an adhesive patch in which an adhesion layer containing Diclofenac or a salt thereof is formed on a supporting body, wherein: the adhesion layer contains a thermoplastic elastomer (styrene-isoprene- styrene block copolymer), a liquid paraffin, Diclofenac or a salt thereof and a dissolving agent; the adhesion layer may contain 10% or less of a tackifier.

The inventors of the present invention provide composition of Diclofenac transdermal patch comprising high concentration of hot melt pressure sensitive adhesive, low concentration of tackifier and pharmaceutically acceptable excipients. The inventors of present invention also provide efficient process for the preparation of Diclofenac diethylamine transdermal patch by using hot-melt coating technique (HMC) comprising the steps of melting, mixing, coating, laminating and cutting.

OBJECTIVE OF INVENTION The main objective of the present invention is to provide transdermal patch composition comprising active ingredient having anti-inflammatory, analgesic and antipyretic activities.

Another objective of the present invention is to provide transdermal patch composition comprising Diclofenac or its salts as an active ingredient, high concentration of hot melt pressure sensitive adhesive, low concentration of tackifier and other pharmaceutically acceptable excipients.

Another objective of the present invention is to provide composition transdermal patch composition comprising Diclofenac diethylamine as an active ingredient, high concentration of hot melt pressure sensitive adhesive, low concentration of tackifier and permeation enhancers, dissolving agents, vehicle as other pharmaceutically acceptable excipients. Still another objective of the present invention is to provide process for the preparation of Diclofenac diethylamine transdermal patch by using hot-melt coating technique (HMC) comprising the steps of melting, mixing, coating, laminating and cutting. Still another objective of the present invention is to provide process for the preparation of Diclofenac or its salts transdermal patch comprising steps of melting hot melt adhesives under stirring, adding tackifier and vehicle to molten adhesive, adding active ingredient in dissolving agents separately and transferring to molten adhesive blend, adding permeation enhancers to molten drug-adhesive blend under stirring, coating, laminating and cutting into desired size. Yet another objective of the present invention is to provide relief from short term pain due to minor strains, sprains and bruises associated with musculo skeletal disorders, Arthritis, Myalgia, Tennis elbow, etc. by transdermal application of Diclofenac diethylamine patch.

SUMMARY OF INVENTION

Accordingly, the present invention provides composition of transdermal patch useful in facilitating relief from short term pain due to minor strains, sprains and bruises associated with musculoskeletal disorders, arthritis, myalgia, tennis elbow, etc.

One embodiment of the present invention provides transdermal patch composition comprising active ingredient having anti-inflammatory, analgesic and antipyretic activities.

Another embodiment of the present invention provides transdermal patch composition comprising Diclofenac or its pharmaceutically acceptable salts, high concentration of hot melt pressure sensitive adhesive, low concentration of tackifier and other pharmaceutically acceptable excipients.

Another embodiment of the present invention provides composition transdermal patch composition comprising Diclofenac diethylamine, high concentration of hot melt pressure sensitive adhesive, low concentration of tackifier, permeation enhancers, dissolving agents, and vehicle.

Another embodiment of the present invention provides transdermal patch composition comprising:

0.1% to 20% (w/w) of active ingredient,

30% to 80 % (w/w) of hot melt pressure sensitive adhesive,

0.5% to 5% (w/w) of permeation enhancers,

1% to 20% (w/w) of tackifier, and 1% to 30 % (w/w) of other excipients.

Another embodiment of the present invention provides transdermal patch composition comprising:

0.1% to 20% (w/w) of Diclofenac diethylamine,

30% to 80 % (w/w) of polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,

0.5% to 5% (w/w) of oleic acid,

0.5% to 5% (w/w) of L-menthol,

1% to 20% (w/w) of saturated alicyclic hydrocarbon resins, and 1% to 30 % (w/w) of other excipients.

Another embodiment of the present invention provides transdermal patch composition comprising:

0.1% to 20% (w/w) of active ingredient,

30% to 80 % (w/w) of hot melt pressure sensitive adhesive,

0.5% to 5% (w/w) of permeation enhancers,

1% to 20% (w/w) of tackifier,

1% to 30% (w/w) of dissolving agents, and 1% to 30 % (w/w) of other excipients.

Another embodiment of the present invention provides transdermal patch composition comprising:

0.1% to 20% (w/w) of Diclofenac diethylamine,

30% to 80 % (w/w) of polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,

0.5% to 5% (w/w) of oleic acid,

0.5% to 5% (w/w) of L-menthol,

1% to 20% (w/w) of saturated alicyclic hydrocarbon resins,

1% to 15% (w/w) of propylene glycol, and 1% to 10% (w/w) of polyethylene glycol.

Another embodiment of the present invention provides transdermal patch composition comprising:

0.1% to 20% (w/w) of Diclofenac diethylamine,

30% to 80 % (w/w) of polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,

0.5% to 5% (w/w) of oleic acid,

0.5% to 5% (w/w) of L-menthol,

1% to 20% (w/w) of saturated alicyclic hydrocarbon resins,

1% to 15% (w/w) of propylene glycol,

1% to 10% (w/w) of polyethylene glycol, and 1% to 20% (w/w) of white mineral oil.

Another embodiment of the present invention provides transdermal patch composition comprising:

0.1% to 20% (w/w) of Diclofenac diethylamine,

30% to 70 % (w/w) of polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,

1% to 20% (w/w) of ethyl vinyl acetate,

0.5% to 5% (w/w) of oleic acid,

0.5% to 5% (w/w) of L-menthol,

1% to 20% (w/w) of saturated alicyclic hydrocarbon resins,

1% to 15% (w/w) of propylene glycol,

1% to 10% (w/w) of polyethylene glycol, and 1% to 20% (w/w) of white mineral oil.

Another embodiment of the present invention provides transdermal patch composition comprising:

0.1% to 20% (w/w) of Diclofenac diethylamine, 30% to 80 % (w/w) of polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,

0.5% to 5% (w/w) of diethylene glycol monoethyl ether,

0.5% to 5% (w/w) of L-menthol, 1% to 20% (w/w) of saturated alicyclic hydrocarbon resins,

1% to 15% (w/w) of propylene glycol,

1% to 10% (w/w) of polyvinyl pyrrolidone, and 1% to 20% (w/w) of white mineral oil. Another embodiment of the present invention provides process for the preparation of Diclofenac diethylamine transdermal patch by using hot-melt coating technique (HMC) comprising the steps of melting, mixing, coating, laminating and cutting. Still another embodiment, the present invention provides a process for preparing transdermal patch, the process comprising steps of: a) melting hot melt pressure sensitive adhesive under stirring at 120°C - 140°C, b) adding tackifier and vehicle to molten adhesive base under stirring at 120°C - 140°C, c) adding active ingredient in dissolving agents at 70°C to 80°C, transferring to molten adhesive blend under stirring to obtain homogenous material at 80°C to 90°C, d) adding permeation enhancers to molten drug- adhesive blend under stirring to obtain homogenous material at 80°C to 90°C, e) coating at 85°C to 100°C on to the polyethylene terephthalate release liner, f) laminating the obtained adhesive matrix, and g) cutting into desired size to get transdermal patch, pouching and labelling.

In yet another embodiment, the present invention provides process for preparing transdermal patch, the process comprising steps of: a) melting hot melt pressure sensitive adhesive and tackifier under stirring at 120°C - 140°C and cooling it to 100°C, b) solubilising dissolving agents in a glass beaker under stirring to form a clear solution, c) obtained solution is added to melted adhesive mixture at 100°C, d) adding permeation enhancer to the obtained adhesive mixture to form homogeneous adhesive blend, e) adding vehicle and stirring to form homogeneous blend, f) cooling the temperature of adhesive blend to 85°C and adding active ingredient to the obtained blend to form drug- adhesive blend, g) adding another permeation enhancer to molten drug-adhesive blend under stirring to obtain homogenous final blend, h) coating at 85°C to 100°C on to the polyethylene terephthalate release liner, i) laminating the obtained adhesive matrix, and j) cutting into desired size to get transdermal patch, pouching and labelling.

In yet another embodiment, the present invention provides a process for preparing Diclofenac diethylamine transdermal patch, the process comprising steps of: a) melting polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and saturated alicyclic hydrocarbon resins under stirring at 120°C - 140°C, b) adding mineral oil to molten adhesive base under stirring at 120°C - 140°C, c) adding diclofenac diethylamine in combination of propylene glycol and polyethylene glycol at 70°C to 80°C, transferring to molten adhesive blend under stirring to obtain homogenous material at 80°C to 90°C, d) adding Oleic acid and L-menthol to molten drug-adhesive blend under stirring to obtain homogenous material at 80°C to 90°C, e) coating at 85°C to 100°C on to the polyethylene terephthalate release liner, f) laminating the obtained adhesive matrix, and g) cutting into desired size to get transdermal patch, pouching and labelling. In yet another embodiment, the present invention provides process for preparing transdermal patch, the process comprising steps of: a) melting polycyclopentadiene, poly-alpha-pinene, styrene isoprene styrene block copolymer and saturated alicyclic hydrocarbon resins under stirring at 120°C - 140°C and cooling it to 100°C, b) solubilising propylene glycol and polyvinyl pyrrolidone K30 in a glass beaker under stirring to form a clear solution, c) obtained solution is added to melted adhesive mixture at 100°C, d) adding diethylene glycol monoethyl ether to the obtained adhesive mixture to form homogeneous adhesive blend, e) adding white mineral oil and stirring to form homogeneous blend, f) cooling the temperature of adhesive blend to 85°C and adding diclofenac diethylamine to the obtained blend to form drug-adhesive blend, g) adding L-menthol to molten drug-adhesive blend under stirring to obtain homogenous final blend, h) coating at 85°C to 100°C on to the polyethylene terephthalate release liner, i) laminating the obtained adhesive matrix, and j) cutting into desired size to get transdermal patch, pouching and labelling.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows comparative Invitro drug release study (Flux pg/sq. cm/hr) through Human cadaver skin of Example 4 composition Vs Nupatch ^® .

Figure 2 shows comparative Invitro drug release study (Flux pg/sq.cm/hr) through Human cadaver skin of Example 11 Vs Nupatch ^® .

DETAILED DESCRIPTION OF THE INVENTION

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise. The present invention provides transdermal patch composition comprising active ingredient having anti-inflammatory, analgesic and antipyretic activities.

The present invention provides transdermal patch composition comprising Diclofenac as active ingredient, high concentration of hot melt pressure sensitive adhesive, low concentration of tackifier and pharmaceutically acceptable excipients.

The term “active ingredient” of the present invention is used to relieve a person from short term pain due to minor strains, sprains and bruises associated with musculo skeletal disorders, Arthritis, Myalgia, Tennis elbow, etc. Preferably used active ingredient shows anti-inflammatory, analgesic and antipyretic activities. Most preferably used active ingredient is Diclofenac diethylamine.

Diclofenac is an acetic acid nonsteroidal antiinflammatory drug (NSAID) with analgesic and antipyretic properties. The antiinflammatory effects of Diclofenac are believed to be due to inhibition of both leukocyte migration and the enzyme cylooxygenase (COX-1 and COX-2), leading to the peripheral inhibition of prostaglandin synthesis. The concentration of Diclofenac diethylamine used in the transdermal patch in the range of 0.1% to 20% (w/w), preferably 10% (w/w) of the total weight of the composition.

The term “hot melt adhesives” of the present invention includes alone or combination of one or more hot melt adhesive selected from the group of hot melt pressure sensitive adhesives, ethylene-vinyl acetate copolymer series, styrene- isoprene- styrene block copolymer, styrene isoprene rubber, silicon rubber, acrylate polymer, natural rubber and polyurethane based rubber, polyolefin based adhesive, polyamide based adhesive, polyurethane-based hot melt adhesives, polyester-based hot melt adhesives, polycyclopentadiene and poly-alpha-pinene and styrene isoprene styrene block copolymer (Pressen 1471). Preferably used hot melt adhesive includes combination of polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and ethylene-vinyl acetate copolymer or polycyclopentadiene, poly- alpha-pinene and styrene isoprene styrene block copolymer alone.

The concentration of hot melt adhesives used in the transdermal patch is in the range of 30% to 80% (w/w). Preferably used concentration of hot melt adhesives is in the range of 35% to 75% (w/w) of the total weight of the composition. Permeation enhancers used in the composition of the present invention include, but are not limited to azones, isopropylmyristate, fatty acids, menthol, essential oils, terpenes, terpenoids, N-methyl-2-pyrrolidone, l-dodecyl-azacycloheptan-2-one, oleic acid, diethylene glycol monoethyl ether, oleyl alcohol, linoleic acid, isopropyl linoleate, butanediol, lauryl alcohol, lauryl acetate, lauryl lactate, ethyl acetate, dimethyl isosorbide, isostearic acid. Preferably, the permeation enhancer used is the combination of oleic acid and L-menthol or combination of diethylene glycol monoethyl ether and L-menthol.

The concentration of permeation enhancers used in the transdermal patch is 0.5% to 5% (w/w). Preferably used concentration of permeation enhancers is in the range of 1% to 4% (w/w) of the total weight of the composition.

Tackifier used in the composition of the present invention include, but are not limited to petroleum resins (e.g., aliphatic hydrocarbon resins, alicyclic hydrocarbon resins, and aromatic hydrocarbon resins), phenolic resins, xylene resins and coumarone indene resins rosin derivatives (e.g., rosin, glycerin esters of rosin, hydrogenated rosins, glycerin esters of hydrogenated rosin, pentaerythritol esters of rosin, etc.), saturated alicyclic hydrocarbon resins (e.g., ARKON P-100), aliphatic hydrocarbon resins (e.g., Quintone B170) terpene resins (e.g., Clearon P-125), maleic acid resins and the like. Preferably used tackifier is saturated alicyclic hydrocarbon resins (Arkon-P 100).

The concentration of tackifier used in the transdermal patch is 1% to 20% (w/w). Preferably used concentration of tackifier is 5% to 16% (w/w) of the total weight of the composition.

The term “dissolving agent” includes effective proportion of propylene glycol, polyvinyl pyrrolidone K30, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ^® ), polyethylene glycol 400 and polyethylene glycol has an average molecular weight in a range selected from the group consisting of 10,000-30,000 in combination. Preferably used dissolving agents include combination of Propylene glycol and Polyethylene glycol 20000 or Propylene glycol and polyvinyl pyrrolidone K30 or Propylene glycol, Polyethylene glycol 20000 and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ^® ). The concentration of dissolving agents used in the transdermal patch is 1% to

30% (w/w). Preferably used concentration of dissolving agents is in the range of 5% to 25% (w/w) of the total weight of the composition.

The present invention provides transdermal patch composition comprising of high concentration of hot melt pressure sensitive adhesive. Higher concentration of hot melt pressure sensitive adhesive is considered for better solubility of drug in adhesive matrix and providing desired controlled and sustained release of drug at the site of application. The use of higher concentration of tackifier in transdermal patch formulation can cause skin sensitization and skin irritation. The transdermal patch of the present invention comprises of low or optimum concentration of tackifier alone or in combination in order to avoid skin sensitization and skin irritation. Optimum concentration of tackifier is also necessary to achieve optimum adhesion (tack) property of the patch, when applied to the skin, it is adhered to the skin for complete 24 hours without lifting off from the skin and produce relief of pain for complete 24 hrs. The transdermal patch of the present invention uses combination of dissolving agents in an optimum concentration to keep drug in dissolved form into the adhesive matrix to avoid drug crystallization and achieve desired drug release from transdermal patch to the site of application. Preferably used dissolving agents include combination of Propylene glycol and Polyethylene glycol 20000 or Propylene glycol and polyvinyl pyrrolidone K30 or Propylene glycol, Polyethylene glycol 20000 and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ^® ). Most preferably, a combination of propylene glycol & Polyvinyl pyrrolidone -K30 is been used in the present invention.

"Vehicle" as used herein refer to carrier materials suitable for transdermal drug administration, and include any such materials known in the art, i.e., any liquid gel, solvent, liquid diluent, adhesive, or the like, which is nontoxic and which does not interact with other components of the composition in a deleterious manner. Vehicle, which also may function as solvents in some instances, are used to provide the compositions of the invention in their preferred form. Examples include, but not limited to, water, ethanol, propanol, isopropanol, mineral oil, silicone, polyethylene glycol, polypropylene glycol, liquid sugars, waxes, petroleum jelly and a variety of other oils, aloe and polymeric materials along with polyacrylate, silicone, natural and synthetic rubbers or other adhesives. Preferably used vehicle is mineral oil.

The concentration of vehicle used in the transdermal patch is 1% to 10% (w/w). Preferably used concentration of vehicle is 5% to 10% (w/w) of the total weight of the composition.

The transdermal patch of the present invention has been prepared by hot melt coating technique. The advantage of this technique is simple and easy to manufacture, more economical and solvent free technique. Using HMC technique tuning drug release, adhesiveness (tack) and physical properties of patch is relatively good compared to solvent-based coating technique.

The transdermal patch of the present invention is prepared using hot melt coating technique using PET (polyethylene terephthalate) liner or Paper Liner one side silicon coated and laminated using 100% Polyester woven fabric one way stretchable or 100% Polyester non-woven fabric. More preferably, 100% Polyester woven fabric one way stretchable is used.

The physical nature of the patch like adhesion & flexibility is achieved with the combination of polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer (Pressen 1471) and saturated alicyclic hydrocarbon resins (Arkon P- 100). Tackifier plays an important role in the adhesion property of the patch.

Permeation enhancer is used to enhance the permeation of the active ingredient through the skin and to provide faster onset of action.

Various properties associated with each component of the transdermal patch compositions may affect the properties of the final product. Properties associated with the selection of raw materials, molecular weight, concentration and viscosity may influence the adhesive matrix formation, adhesion and therapeutic effect.

The invention disclosed herein is process for the preparation of transdermal patch useful in the treatment of short term pain due to minor strains, sprains and bruises associated with musculo skeletal disorders, Arthritis, Myalgia, Tennis elbow, etc.

The transdermal patch is prepared by melting and mixing of above starting materials. Further coating on a PET release liner or Paper liner and laminated on woven or non- woven fabric.

The present invention is illustrated in detail but not limiting to, the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Example 1

Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms) Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process:

The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer was melted at 120°C to 140°C in a stainless steel vessel and then temperature was reduced to 80°C to 90°C. In another vessel, propylene glycol and polyethylene glycol 20000 were heated at 70°C to 80°C to melt polyethylene glycol 20000. Diclofenac diethylamine was added to the solution under continuous stirring to get clear drug solution. The drug solution was transferred to adhesive blend under continuous stirring at 80°C to 90°C. Oleic acid and L-menthol were transferred to the drug-adhesive blend and stirring was continued until uniform homogeneous blend was formed. The drug-adhesive blend was coated on Polyethylene terephthalate (75 micron) release liner maintaining coating temperature of 90°C to 100°C and laminated with Polyester 100% woven fabric one way stretchable (115 gms) backing membrane. The laminate was further cut into required patch size.

Example 2

Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms). Release liner: Polyethylene terephthalate (75 micron)

Example 3

Total matrix weight: 220 to 280 gms Backing type: Polyester 100% woven fabric one way stretchable (115 gms). Release liner: Polyethylene terephthalate (75 micron)

Example 4

Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms) Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process for Example 2, Example 3 and Example 4:

The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and saturated alicyclic hydrocarbon resins were melted at 120°C to 140°C in a stainless steel vessel, white mineral oil was added to it under continuous stirring and temperature was reduced to 80°C to 90°C. In another vessel, propylene glycol and polyethylene glycol 20000 were heated at 70°C to 80°C to melt polyethylene glycol 20000. Diclofenac diethylamine was added to the solution under continuous stirring to get clear drug solution. The drug solution was transferred to adhesive blend under continuous stirring at 80°C to 90°C. Oleic acid and L-menthol were transferred to the drug-adhesive blend and stirring was continued until uniform homogeneous blend was formed. The drug-adhesive blend was coated on Polyethylene terephthalate (75 micron) release liner maintaining coating temperature of 90°C to 100°C and laminated with Polyester 100% woven fabric one way stretchable (115 gms) backing membrane. The laminate was further cut into required patch size.

Example 5

Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms). Release liner: Polyethylene terephthalate (75 micron)

Example 6

Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms). Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process for Example 5 and Example 6: The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and saturated alicyclic hydrocarbon resins were melted at 120°C to 140°C in a stainless steel vessel, then temperature was reduced to 80°C to 90°C. In another vessel, propylene glycol and polyethylene glycol 20000 were heated at 70°C to 80°C to melt polyethylene glycol 20000. Diclofenac diethylamine was added to the solution under continuous stirring to get clear drug solution. The drug solution was transferred to adhesive blend under continuous stirring at 80°C to 90°C. Oleic acid and L-menthol were transferred to the drug-adhesive blend and stirring was continued until uniform homogeneous blend was formed. The drug-adhesive blend was coated on Polyethylene terephthalate (75 micron) release liner maintaining coating temperature of 90°C to 100°C and laminated with Polyester 100% woven fabric one way stretchable (115 gms) backing membrane. The laminate was further cut into required patch size.

Example 7

Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms). Release liner: Polyethylene terephthalate (75 micron)

Example 8

Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms). Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process of Example 7 and Example 8:

The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and saturated alicyclic hydrocarbon resins were melted at 120°C to 140°C in a stainless steel vessel, then temperature was reduced to 80°C to 90°C. In another vessel, polyethylene glycol 400, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and polyethylene glycol 20000 were heated at 70°C to 80°C to melt polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and polyethylene glycol 20000. Diclofenac diethylamine was added to the solution under continuous stirring to get clear drug solution. The drug solution was transferred to adhesive blend under continuous stirring at 80°C to 90°C. Oleic acid and L-menthol were transferred to the drug-adhesive blend and stirring was continued until uniform homogeneous blend was formed. The drug-adhesive blend was coated on Polyethylene terephthalate (75 micron) release liner maintaining coating temperature of 90°C to 100°C and laminated with Polyester 100% woven fabric one way stretchable (115 gms) backing membrane. The laminate was further cut into required patch size.

Example 9

Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms). Release liner: Polyethylene terephthalate (75 micron)

Example 10 Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms). Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process for Example 9 and Example 10:

The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer, ethylene vinyl acetate and saturated alicyclic hydrocarbon resins were melted at 120°C to 140°C in a stainless steel vessel, white mineral oil was added to it under continuous stirring and temperature was reduced to 80°C to 90°C. In another vessel, propylene glycol and polyethylene glycol 20000 were heated at 70°C to 80°C to melt polyethylene glycol 20000. Diclofenac diethylamine was added to the solution under continuous stirring to get clear drug solution. The drug solution was transferred to adhesive blend under continuous stirring at 80°C to 90°C. Oleic acid and L-menthol were transferred to the drug-adhesive blend and stirring was continued until uniform homogeneous blend was formed. The drug-adhesive blend was coated on Polyethylene terephthalate (75 micron) release liner maintaining coating temperature of 90°C to 100°C and laminated with Polyester 100% woven fabric one way stretchable (115 gms) backing membrane. The laminate was further cut into required patch size.

Example 11

Total matrix weight: 220 to 280 gms

Backing type: Polyester 100% woven fabric one way stretchable (115 gms). Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process for Example 11:

The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and saturated alicyclic hydrocarbon resins were melted at 140°C in a stainless steel vessel, mixed uniformly and allowed to cool at 100°C. In a glass beaker propylene glycol was taken and polyvinyl pyrrolidone K30 was added to it under stirring to dissolve completely and to form a clear solution. Propylene glycol and Polyvinyl Pyrrolidone K30 solution was then transferred to above melted adhesive mixture maintained at temperature 100°C. Stirring was continued until uniform adhesive blend was formed. Diethylene glycol monoethyl ether was added to it and stirring was continued to get homogeneous adhesive blend. Then, white mineral oil was transferred to the adhesive blend and stirring was continued to yield a homogeneous blend. The temperature of the adhesive blend was reduced to 85 °C and diclofenac diethylamine was added to it. Stirring was continued to get a uniform homogeneous drag-adhesive blend. Further, menthol was added to drug-adhesive blend and stirring was continued until uniform homogeneous final blend was formed. The drug-adhesive blend was coated on Polyethylene terephthalate (75 micron) release liner maintaining coating temperature of 85°C to 90°C and laminated with Polyester 100% woven fabric one way stretchable (115 gms) backing membrane. The laminate was further cut into required patch size.

In Vitro Drug Release study of Diclofenac Transdermal patch of present invention Vs, NuPatch ^® (Reference Product) Diclofenac Transdermal Patch prepared using composition and process of the present invention was compared with reference product NuPatch ^® Diclofenac Transdermal Patch (Manufactured by Zydus Healthcare Ltd)

In vitro release test performed through human cadaver skin by using Franz diffusion cell. The 1.539 cm patch was attached on the human cadaver skin and then placed between the donor and receptor compartments of the cells, with the skin side in direct contact with the receptor medium. Approx. 7 ml of the Phosphate buffer (pH 7.4) was placed in the receptor compartment. Its temperature was maintained at 32+0.5 °C using a water bath. This whole assembly was kept on a magnetic stirrer and solution in cell. The 1.539 cm patch was attached on the human cadaver skin and then placed between the donor and receptor compartments of the cells, with the skin side in direct contact with the receptor medium. Approx. 7 ml of the Phosphate buffer (pH 7.4) was placed in the receptor compartment. Its temperature was maintained at 32+0.5 °C using a water bath. This whole assembly was kept on a magnetic stirrer and solution in the receiver compartment was continuously stirred during the whole experiment using magnetic bead. The samples were withdrawn at different time intervals and an equal amount of phosphate buffer (pH 7.4) was replaced each time. Absorbance of the samples was read spectrophotometrically. The amount of diclofenac diethylamine permeated per square centimetre at each time interval was calculated and plotted against time with the receptor medium shown in Figure 1 & Figure 2. Based on the results of in vitro-skin permeation study, the in Diclofenac Transdermal System of present invention is bioequivalent with NuPatch ^® Diclofenac Transdermal Patch. The matrix adhesive patch prepared as per the Example no. 4 of the present invention is evaluated for the stability at different conditions and the data is given in below tables 1-3;

Table 1

Table 2

Table 3

As per the above data, the compositions of the present invention have shown good stability under different conditions.