DESC:FORM 2

THE PATENTS ACT, 1970
(SECTION 39 OF 1970)
&
The Patent Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

KETOPROFEN ADHESIVE PATCH COMPOSITION AND IT’S PROCESS

We, HETERO HEALTHCARE LIMITED,
a company incorporated under the companies act, 1956 having address at
Sy. No. 80-84, Melange Towers, 4th Floor, C-wing, Patrikanagar, Madhapur, Hyderabad-500081, Telangana State, India

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a composition of anti-inflammatory matrix adhesive patch.
The present invention specifically relates to a composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, hot melt adhesives, tackifying agents, plasticizers, antioxidants and other pharmaceutically acceptable excipients.
The present invention also relates to a composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, hot melt adhesives, tackifying agents, plasticizers, antioxidants and other pharmaceutically acceptable excipients for treating mild to moderate pain, relieving symptoms of arthritis (osteoarthritis and rheumatoid arthritis), such as inflammation, swelling, stiffness, joint pain as well as sports injuries such as sprains and tendonitis.
The present invention also relates to process for the preparation of Ketoprofen matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.
BACKGROUND OF INVENTION
Non-steroidal anti-inflammatory drugs (NSAIDs) have been extensively used for decades in the treatment of inflammatory diseases such as arthritis and associated conditions. These compounds have been shown to exhibit anti-inflammatory, analgesic, antipyretic activities among others. While their mechanisms of action have not yet been fully established, it is known that their main mechanism of action is the inhibition of prostaglandin synthesis through the inhibition of cylooxygenase (COX).
A number of undesirable side effects have been attributed to NSAIDs such as gastrointestinal ulcerations and bleeding, as well as renal, skin and hypertension effects. Additionally, NSAIDs can prolong bleeding time by effecting platelet function. These problems are amplified by the fact that only a small percentage of orally administered NSAIDs actually reach the site of inflammation, thus necessitating relatively large doses of NSAIDs when ingested orally.
Due to these limitations on the oral use of NSAIDs, topical forms of NSAIDs have been developed to more precisely deliver the drugs to the site of inflammatory focus. These forms have proven particularly useful when inflammatory disorders are restricted to a superficial joint or to particular structures. A number of pharmacological studies have shown that topical forms of a variety of NSAIDs are useful in the treatment of inflammatory diseases and/or disorders such as myalgias, sprains, and tendonitis.
Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID). The chemical name for Ketoprofen is 2-(3-benzoylphenyl)-propionic acid. Ketoprofen has a chemical formula of C16H14O3 and a molecular mass of 254.29 g/mol. It has a structural formula of:

EP Publication No. 0 827 741 A2 discloses transdermal delivery system containing Ketoprofen dispersed in nonpolar polymers designed to continuously maximize thermodynamic activity and further to increase the skin permeability of said active ingredient using fatty acid, fatty acid ester, fatty acid alcohol, propylene glycol, propylene glycol fatty acid ester, oleic acid, olein alcohol, ethylene glycol monoethylether or its mixture as a solubilizing agent or permeation enhancer, if deemed necessary.
US Patent No. 5,478,567 A discloses antiphlogistic analgesic plaster which comprises as essential ingredients comprising: (a) Ketoprofen as nonsteroidal antiphlogistic analgesic drug, (b) a solubilizer comprising a combination of a rosin ester derivative with l-menthol, (c) a styrene/isoprene/styrene block copolymer employed as a base polymer, (d) a softener, and (e) a backing comprising a polyester cloth.

US Patent No. 5,869,087 A discloses patch for external use in application to the body, which comprises a plaster having a substantially anhydrous formulation and attached on a backing, the plaster comprising 1) Ketoprofen as antiphlogistic drug, 2) l-menthol and 3) a metal salt of a fatty acid. This patent also discloses that preparation further comprises an adhesive composed of an elastic material, a tackifier and a softener. Elastic material is at least one member selected from the group consisting of styrene-isoprene-styrene block copolymers, polyisobutylene and polyisoprene, tackifier is at least one member selected from the group consisting of polyterpene resins, petroleum resins, rosins, hydrogenated rosins, hydrogenated rosin esters and oil soluble phenol resins, softener is at least one member selected from the group consisting of almond oil, olive oil, camellia oil, persic oil, peanut oil, olefin acids and liquid paraffin.
US Patent No. 6,190,690 B1 discloses sustained/immediate acting Ketoprofen patch. A moisture permeable backing, a moisture non-permeable primer, a moisture high-permeable drug layer containing Ketoprofen and a skin adhesion layer controlling release of a drug solution are piled up. An ethyl acetate soluble acrylic/rubber adhesive is coated onto a silicon coated paper, dried and transfer coated onto the backing to form the primer. The drug layer is formed by coating a drug solution onto a silicon coated paper, drying and transfer coating onto the primer. The skin adhesion layer is formed by coating a mixture of a solution prepared by dissolving an emulsifier in ethyl acetate and acrylic adhesive, drying and transfer coating onto the drug layer. The Ketoprofen patch has a drug release controlling function and good adhesion strength.
US Patent No. 8,173,156 B2 discloses anti-inflammatory-containing plaster may include, e.g., a styrene-isoprene-styrene block copolymer, a high molecular weight polyisobutylene, a low molecular weight polyisobutylene, a tackifier, a plasticizer, a dispersant, and an anti-inflammatory having a carboxyl group or a salt thereof.

US Patent No. 9,132,100 B2 discloses patch containing a non-steroidal anti-inflammatory drug including an adhesive layer composed of a transdermal preparation on a support, the transdermal preparation including a) 10 to 40% by weight of a non aqueous base material based on the total weight of the transdermal preparation, b) 1 to 10% by weight of a non-steroidal anti-inflammatory drug based on the total weight of the transdermal preparation, and c) a polyethylene glycol component composed of 0.3 to 5% by weight of a low molecular weight polyethylene glycol based on the total weight of the transdermal preparation, and 1 to 10% by weight of a high molecular weight polyethylene glycol based on the total weight of the transdermal preparation. This patent discloses non aqueous base material capable of being included in the transdermal preparation include a natural rubber, polyisoprene, a styrene-isoprene-styrene block copolymer (SIS), a styrene-butadiene-styrene block copolymer (SBS), a styrene-butadiene rubber, polyisobutylene, and a mixture of two or more of them.
US Patent No. 9,271,944 B2 discloses water-based patch that contains Ketoprofen as an active ingredient, provides high transdermal absorbability of the Ketoprofen, and has high safety and high storage stability. The water-based patch contains the Ketoprofen, an amine, and polyethylene glycol.
US Publication No. 2006/0263420 A1 discloses adhesive comprising a base with tackiness, an oil and Ketoprofen, wherein the adhesive contains no L-menthol, the base is composed at least of a tacky composition comprising an elastomer and a tackifier and/or a tacky polymer containing an unsaturated monomer with a total of 5 or more carbon atoms as the monomer unit, the oil is an oil that is compatible with the tacky composition and the tacky polymer, and the oil content is 150-175 parts by weight with respect to 100 parts by weight as the total of the tacky composition and the tacky polymer. This patent discloses elastomers for the tacky composition include styrene-based block copolymers, and particularly preferred is styrene-isoprene-styrene block copolymer having a styrene content of 10-30 wt % and a diblock content of no greater than 40 wt %.
The inventors of the present invention provide composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer as hot melt adhesives, hydrogenated hydrocarbon resin and/or rosin ester derivative as tackifying agent, mineral oil as plasticizer, tocopherol Acetate as antioxidant and other pharmaceutically acceptable excipients. The inventors of present invention also provide process for the preparation of Ketoprofen matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide composition of anti-inflammatory matrix adhesive patch.
Another objective of the present invention is to provide composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, hot melt adhesives, tackifying agents, plasticizers, antioxidants and other pharmaceutically acceptable excipients.
Another objective of the present invention is to provide composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, hot melt adhesives, tackifying agents, plasticizers, antioxidants and other pharmaceutically acceptable excipients for treating mild to moderate pain, relieving symptoms of arthritis (osteoarthritis and rheumatoid arthritis), such as inflammation, swelling, stiffness, joint pain as well as sports injuries such as sprains and tendonitis.
Another objective of the present invention is to provide composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer as hot melt adhesives, tackifying agents, plasticizers, antioxidants and other pharmaceutically acceptable excipients.
Still another objective of the present invention is to provide composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer as hot melt adhesives, tackifying agent, plasticizers, antioxidants and solubilizers, penetration enhancers, counter-irritants as pharmaceutically acceptable excipients.
Still another objective of the present invention is to provide process for the preparation of Ketoprofen matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.
Still another objective of the present invention is to provide process for the preparation of Ketoprofen matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting adhesive materials and tackifying agent, cooling melted solution, dissolving active ingredient in antioxidant, plasticizer, optionally counter irritant, solubilizer, penetration enhancer and adding into cooled adhesive mixture, coating, drying, laminating and cutting into desired size.
Still another objective of the present invention is to provide a process for the preparation of Ketoprofen matrix adhesive patch by hot-melt coating technique (HMC) which is a solvent-free technique, faster and more economic coating process. In addition, HMC technique has several advantages including drug release, adhesiveness (tack) and physical properties of patch can be tuned relatively easy compared to solvent based coating technique.
In yet another objective of the present invention is to provide relief from mild to moderate pain, symptoms of arthritis (osteoarthritis and rheumatoid arthritis), such as inflammation, swelling, stiffness, joint pain as well as sports injuries such as sprains and tendonitis by the application of Ketoprofen matrix adhesive patch.
SUMMARY OF INVENTION
Accordingly, the present invention provides a composition of Ketoprofen matrix adhesive patch useful in facilitating and relieving moderate pain, symptoms of arthritis (osteoarthritis and rheumatoid arthritis), such as inflammation, swelling, stiffness, joint pain as well as sports injuries such as sprains and tendonitis.
One embodiment of the present invention relates to a composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, hot melt adhesives and pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer as hot melt adhesives, tackifying agents, plasticizers, antioxidants and other pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer as hot melt adhesives, tackifying agents, plasticizers, antioxidants and solubilizers, penetration enhancers, counter-irritants as pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer as hot melt adhesives, hydrogenated hydrocarbon resin and/or rosin ester derivative as tackifying agent, mineral oil as plasticizer, Tocopherol Acetate as antioxidant, polyethylene glycol 400 as solubilizer, isopropyl myristate as penetration enhancer and l-menthol as counter-irritant.
In another embodiment, the present invention provides a process for the preparation of Ketoprofen matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.
In another embodiment, the present invention provides an anti-inflammatory matrix adhesive patch composition comprising:
(a) 1% to 5% (w/w) of active ingredient,
(b) 40% to 90% (w/w) of adhesive materials,
(c) 1% to 30% (w/w) of tackifying agents,
(d) 0.5% to 10% (w/w) of plasticizers,
(e) 0.1% to 1% (w/w) of antioxidants, and
(f) 0.1% to 30% (w/w) of other pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides an anti-inflammatory matrix adhesive patch composition comprising:
(a) 1% to 5% (w/w) of active ingredient,
(b) 40% to 90% (w/w) of adhesive materials,
(c) 1% to 30% (w/w) of tackifying agents,
(d) 0.5% to 10% (w/w) of plasticizers,
(e) 0.1% to 1% (w/w) of antioxidants, and optionally
(f) 0.1% to 30% (w/w) of solubilizers, penetration enhancers and counter irritant.
In another embodiment, the present invention provides a matrix adhesive patch composition comprising:
(a) 1% to 5% (w/w) of Ketoprofen,
(b) 40% to 90% (w/w) of adhesive materials,
(c) 1% to 30% (w/w) of tackifying agents,
(d) 0.5% to 10% (w/w) of plasticizers,
(e) 0.1% to 1% (w/w) of antioxidants, and
(f) 0.1% to 30% (w/w) of other pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a matrix adhesive patch composition comprising:
(a) 1% to 5% (w/w) of Ketoprofen,
(b) 40% to 90% (w/w) of combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,
(c) 1% to 30% (w/w) of hydrogenated hydrocarbon resin and/or rosin ester derivative,
(d) 0.5% to 10% (w/w) of mineral oil,
(e) 0.1% to 1% (w/w) of tocopherol acetate, and optionally
(f) 0.1% to 30% (w/w) of other pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a matrix adhesive patch composition comprising:
(a) 1% to 5% (w/w) of Ketoprofen,
(b) 40% to 90% (w/w) of combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,
(c) 1% to 30% (w/w) of hydrogenated hydrocarbon resin and/or rosin ester derivative,
(d) 0.5% to 10% (w/w) of mineral oil,
(e) 0.1% to 1% (w/w) of tocopherol acetate, and
(f) 0.1% to 10% (w/w) of l-menthol.
In yet another embodiment, the present invention provides a matrix adhesive patch composition comprising:
(a) 1% to 5% (w/w) of Ketoprofen,
(b) 40% to 90% (w/w) of combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,
(c) 1% to 30% (w/w) of hydrogenated hydrocarbon resin and/or rosin ester derivative,
(d) 0.5% to 10% (w/w) of mineral oil,
(e) 0.1% to 1% (w/w) of tocopherol acetate,
(f) 1% to 5% (w/w) of polyethylene glycol 400,
(g) 1% to 3% (w/w) of isopropyl myristate, and optionally
(h) 0.1% to 10% (w/w) of l-menthol.
In still another embodiment, the present invention provides a process for the preparation of Ketoprofen matrix adhesive patch by hot-melt coating technique (HMC) which is a solvent-free technique, faster and more economic coating process. In addition, HMC technique has several advantages including drug release, adhesiveness (tack) and physical properties of patch can be tuned relatively easy compared to solvent based coating technique.
In yet another embodiment, the present invention provides a process for preparing matrix adhesive patch, the process comprising steps of:
(a) melting adhesive materials and tackifying agents at 150ºC-170 ºC under continuous stirring,
(b) cooling obtained melted solution of step (a) to 100ºC to 120ºC,
(c) adding active ingredient, antioxidants, plasticizers, one or more other excipients selected from counter irritant, solubilizer, penetration enhancer to the obtained cooled adhesive mixture of step (b) at 90ºC to 100ºC under continuous stirring until homogenous mixture of plaster solution is formed,
(d) coating obtained plaster solution on opaque silicon coated with polyethylene terephthalate release liner and laminating with one way stretchable, beige colour woven fabric 100% polyester, and
(e) cutting into rectangle size to get matrix adhesive patch, pouching and labelling.
In yet another embodiment of the present invention provides a process for matrix adhesive patch, the process comprising steps of:
(a) melting styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and/or rosin ester derivative at 150ºC-170ºC under continuous stirring,
(b) cooling obtained melted solution of step (a) to 100ºC to 120ºC,
(c) adding Ketoprofen, tocopherol acetate, mineral oil, one or more selected from l- menthol, polyethylene glycol 400, isopropyl myristate to the obtained cooled adhesive mixture of step (b) at 90ºC to 100ºC under continuous stirring until homogenous mixture of plaster solution is formed,
(d) coating obtained Ketoprofen plaster solution on opaque silicon coated with polyethylene terephthalate release liner and laminating with one way stretchable, beige colour woven fabric 100% polyester, and
(e) cutting into rectangle size to get Ketoprofen matrix adhesive patch, pouching and labelling.
In yet another embodiment of the present invention provides a process for preparing matrix adhesive patch, the process comprising steps of:
(a) melting styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and/or rosin ester derivative at 150ºC-170 ºC under continuous stirring,
(b) cooling obtained melted solution of step (a) to 100ºC to 120ºC,
(c) adding Ketoprofen, Tocopherol Acetate, mineral oil, l-menthol to the obtained cooled adhesive mixture of step (b) at 90ºC to 100ºC under continuous stirring until homogenous mixture of plaster solution is formed,
(d) coating obtained Ketoprofen plaster solution on opaque silicon coated with polyethylene terephthalate release liner and laminating with one way stretchable, beige colour woven fabric 100% polyester, and
(e) cutting into rectangle size to get Ketoprofen matrix adhesive patch, pouching and labelling.
In yet another embodiment of the present invention provides a process for preparing matrix adhesive patch, the process comprising steps of:
(a) melting styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and/or rosin ester derivative at 150ºC-170 ºC under continuous stirring,
(b) cooling obtained melted solution of step (a) to 100ºC to 120ºC,
(c) adding Ketoprofen, Tocopherol Acetate, mineral oil, polyethylene glycol 400, isopropyl myristate and/or l- menthol to the obtained cooled adhesive mixture of step (b) at 90ºC to 100ºC under continuous stirring until homogenous mixture of plaster solution is formed,
(d) coating obtained Ketoprofen plaster solution on opaque silicon coated with polyethylene terephthalate release liner and laminating with one way stretchable, beige colour woven fabric 100% polyester, and
(e) cutting into rectangle size to get Ketoprofen matrix adhesive patch, pouching and labelling.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows comparison of in vitro skin permeation of in house anti-inflammatory matrix adhesive patch according to Example 1 with Ketoplast™.
Figure 2 shows comparison of in vitro skin permeation of in house anti-inflammatory matrix adhesive patch according to Example 2 with Ketoplast™.
Figure 3 shows comparison of in vitro skin permeation of in house anti-inflammatory matrix adhesive patch according to Example 3 with Ketoplast™.
Figure 4 shows comparison of in vitro skin permeation of in house anti-inflammatory matrix adhesive patch according to Example 6 with Ketoplast™.
Figure 5 shows comparison of in vitro skin permeation of in house anti-inflammatory matrix adhesive patch according to Example 7 with Ketoplast™.
Figure 6 shows comparison of in vitro skin permeation of in house anti-inflammatory matrix adhesive patch according to Example 8 with Ketoplast™.
Figure 7 shows comparison of in vitro skin permeation of in house anti-inflammatory matrix adhesive patch according to Example 10 with Ketoplast™.
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 anti-inflammatory matrix adhesive patch comprising anti-inflammatory as active ingredient and pharmaceutically acceptable excipients.
The present invention provides composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, hot melt adhesives and pharmaceutically acceptable excipients.
The present invention provides composition of anti-inflammatory matrix adhesive patch comprising Ketoprofen as active ingredient, hot melt adhesives and tackifying agents, plasticizers, antioxidants, optionally solubilizers, penetration enhancers and counter-irritants as other pharmaceutically acceptable excipients.
The term “active ingredients” of the present invention is used to relieve moderate pain, symptoms of arthritis (osteoarthritis and rheumatoid arthritis), such as inflammation, swelling, stiffness, joint pain as well as sports injuries such as sprains and tendonitis. Preferably used active ingredient is anti-inflammatory agent.
Anti-inflammatory agent used in the composition of the present invention includes, but not limited to Sulindac, Diclofenac, Tenoxicam, Ketorolac, Naproxen, Ketoprofen, Celecoxib, Rofecoxib, Meloxicam, Etoricoxib, Valdecoxib, Ibuprofen, Dexibuprofen, Flurbiprofen, Fenoprofen, Fenbufen, Benoxaprofen, Dexketoprofen, Tolfenamic Acid, Nimesulide and Oxaprozin. Most preferably used anti-inflammatory agent is Ketoprofen.
The concentration of active ingredient used in the matrix adhesive patch is 1% to 5% (w/w). Preferably used concentration of active ingredient is 3% (w/w) of the total weight of the composition.
The term “patch” refers to a medicated patch, e.g., a patch, comprising a composition comprising at least one active ingredient that is placed on the skin to deliver a continuous dosage of the active ingredient through the skin and into the surrounding tissue. “Patch” may also be referred to herein as a “topical delivery system”, a “topical patch delivery system”, an “adhesive patch”, a “transdermal patch”, a “transdermal delivery system”, an “analgesic patch”, a “dressing”, a “topical carrier system”.
The present invention relates to Ketoprofen matrix adhesive patch. The patch is required to have a matrix weight for 10 cm x 7 cm size of patch, the matrix weight may be 0.6 g to 3.0 g because the Ketoprofen content of the matrix may be 1% to 5% w/w, the amount of Ketoprofen per patch can be kept as 30 mg.
The anti-inflammatory matrix adhesive patch of the present invention requires amount of Ketoprofen which is sufficiently dissolved, and thereby the Ketoprofen can be released stably and reliably over a long period of time.
Adhesive materials used in the composition of the present invention includes combination of one or more adhesive materials and includes at least two adhesives selected from the group of styrene isoprene styrene block copolymer, ethylene vinyl acetate, hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer (Pressen 1471), synthetic rubber-based hot melt adhesives, polyolefin based hot melt adhesive, polyamide based hot melt adhesive, polyester-based hot melt adhesives, polyurethane-based hot melt adhesives, styrene isoprene thermoplastic elastomer. Preferably used adhesive materials are styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer (Pressen 1471).
The term “hot melt adhesive Pressen 1471” used in the present invention comprises polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer.
The concentration of adhesive materials used in the Ketoprofen matrix adhesive patch is from 40% to 90% (w/w) and most preferably is from 60%-80% (w/w) of the total weight of the composition.
Tackifying agents used in the composition of the present invention include, but 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. The rosin ester derivative as used herein refers to those obtained by esterifying various rosins followed by the hydrogenation or purification of the same so esterified. Depending on the type of the ester, methyl esters, glycerol esters, pentaerythritol esters, and the like may be cited. Preferably used tackyfying agent is hydrogenated hydrocarbon resin and optionally hydrogenated rosin ester derivative.
The concentration of tackyfying agents used in the Ketoprofen matrix adhesive patch is from 1% to 30% (w/w). Preferably used concentration of tackyfying agents are from 2% to 25% (w/w) of the total weight of the composition.
Plasticizer used in the composition of the present invention includes but not limited to mineral oil, linseed oil, octyl palmitate, squalene, squalane, silicone oil, isobutyl myristate, isostearyl alcohol, oleyl alcohol, liquid paraffins, hydrogenated oils, hydrogenated castor oil, higher alcohols such as octyldodecanol, castor oil, petroleum-based oil (for example, paraffinic process oil, naphthenic process oil, or aromatic process oil), vegetable based oils (for example, olive oil, camellia oil, tall oil or arachis oil), dibasic acid esters (for example, dibutyl phthalate, dioctyl phthalate, or the like), liquid rubbers (for example, polybutene, liquid isoprene rubber), liquid fatty acid esters (isopropyl myristate, hexyl laurate, diethyl sebacate, or diisopropyl sebacate), diethylene glycol, polyethylene glycol; glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, crotamiton. Preferably used plasticizer is mineral oil.
The concentration of plasticizers used in the Ketoprofen matrix adhesive patch is from 0.5% to 10% (w/w). Preferably used concentration of plasticizer is from 1% to 8% (w/w) of the total weight of the composition.
Antioxidant is added to Ketoprofen matrix adhesive patch to prevent the degradation of preparation.
Antioxidant used in the composition of the present invention includes but not limited to butylated hydroxy toulene, tocopherol and ester derivatives thereof, butylated hydroxy anisole, ascorbic acid, ascorbyl stearate, ascorbyl palmitate, nordihydroguaiaretic acid, etc. Preferably used antioxidant is Tocopherol Acetate.
The concentration of antioxidant used in the Ketoprofen matrix adhesive patch is from 0.1% to 1% (w/w). Preferably used concentration of antioxidant is 0.1% to 0.5% (w/w) of the total weight of the composition.

Solubilizer as used in the composition of the present invention includes that can efficiently dissolve Ketoprofen over a long period of time, revealing that solubilising agent composed allows continuous and reliable dissolution of Ketoprofen.
The term “solubilizer” as used herein includes but not limited to propylene glycol, di-propylene glycol, 1,3-butylene glycol, polyethylene glycol 400, glycerine, transcutol, N-methyl pyrrolidone etc. Preferably used solubilizer is polyethylene glycol 400.
The most effective proportion of solubilising agent i.e. polyethylene glycol 400 is 2% to 3% w/w relative to 3% w/w of Ketoprofen. The reason for using this proportion i.e. 2% to 3% w/w of solubilizer is, when the amount of solubilising agent used is less than 2% w/w, Ketoprofen cannot be stably dissolved into it and therefore there may be a chance of less drug release from patch and there may be a chance of crystallization. It was observed that when the solubilising agent use of 2% to 3 % w/w relative to 3% w/w of Ketoprofen, there was complete dissolution of Ketoprofen in it and also observed an optimum and uniform release of Ketoprofen from patch compare with reference-listed drug product (Ketoplast). It was also observed that there was an inherent solubility of Ketoprofen due to adhesive material used in hot melt technique.
The concentration of solubilizer used in the Ketoprofen matrix adhesive patch is from 1% to 5% (w/w). Preferably used concentration of solubilizer is 1% to 3% (w/w) of the total weight of the composition.
Penetration enhancer is added to increase the penetration of Ketoprofen from the plaster into the systemic circulation through the skin, which leads to increase the release & bioavailability of Ketoprofen.
Penetration enhancer used in the composition of the present invention includes but not limited to isopropyl myristate, diethylene glycol monoethyl ether, dodecyl sulfoxide mono- or dimethyl acetamide, N-hydroxy ethyl lactide, higher fatty acid esters, salicylic acid, sorbitol, urea, glycerin, squalene, squalane, acetylated lanolin, cetyl laurate, olive oil, castor oil, lauric acid, oleic acid, lauryl alcohol, oleyl alcohol, ethoxy stearyl alcohol, liquid paraffin, vaseline, camphor, glycerin fatty acid ester, fatty acid mono- (or di-) ethanol amide, ethylene glycol mono ethyl ether, polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxypropylene alkyl ether, propylene glycol mono(di)alkyl ester, propylene glycol monolaurate, polyoxyethylene lauryl ether, pyrrolidone derivatives. Preferably used penetration enhancer is isopropyl myristate.
The concentration of penetration enhancer used in the Ketoprofen matrix adhesive patch is from 1% to 3% (w/w). Preferably used concentration of penetration enhancer is 1% to 2% (w/w) of the total weight of the composition.
Counter irritant as used in the composition of present invention is to impart a cooling effect and by initially stimulating nociceptors and then desensitizing them. Topically applied menthol as counter-irritant may also activate central analgesic pathways.
Counter irritant used in the composition of the present invention includes but not limited to l-menthol, dl-menthol, dl-camphor, d-camphor, methyl salicylate, glycol salicylate, mentha oil, eucalyptus oil, capsaicin, capsicum extract, and noncyclic vanillylamide. Preferably used counter irritant is l-menthol.
The concentration of counter irritant used in the Ketoprofen matrix adhesive patch is from 0.1% to 10% (w/w). Preferably used concentration of counter irritant is from 0.3% to 9% (w/w) of the total weight of the composition.
The present invention provides process for the preparation of for the preparation of Ketoprofen matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.
The anti-inflammatory matrix adhesive patch of the present invention is endowed with 40% elongated in the longitudinal or lateral direction as to enable the anti-inflammatory matrix adhesive patch to be applied even to a flexional part. This stretchability makes it possible not only to conveniently use the anti-inflammatory matrix adhesive patch of the present invention but also to reduce the friction and oppression at the time of application of the patch owing to the fact that the patch fall.
The anti-inflammatory matrix adhesive patch of present invention is particularly characterized by finding that when compounded with l-menthol in a specified ratio, a hydrogenated hydrocarbon resin which has been known as a tackiness-providing resin to those skilled in the art, will serve as a solubilizer for the NSAID. It has been further found that the hydrogenated hydrocarbon resin so compounded will greatly improve the release of the NSAID. In order to satisfactorily dissolve the NSAID and release the same, it is preferable that the selected NSAID, hydrogenated hydrocarbon resin and/or rosin ester derivative and 1-menthol be mixed together in ratio by weight of 1:7:2 to 3. Within the range of said ratios, the NSAID will exhibit satisfactory solubility and releasability.
The process of present invention involves mixing of NSAID, hydrogenated hydrocarbon resin, hydrogenated rosin ester derivative and 1-menthol in ratio by weight of 1:3 to 6:1:0.1 to 1.
The process of present invention involves mixing of NSAID, hydrogenated hydrocarbon resin, hydrogenated rosin ester derivative and polyethylene glycol 400 be mixed together in ratio by weight of 1:3:1:1.
The process of present invention involves mixing of NSAID, hydrogenated hydrocarbon resin, hydrogenated rosin ester derivative, polyethylene glycol 400 and l-menthol together in ratio by weight of 1:3:1:1:0.1.
The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative.

Example 1
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 55.90
3. Styrene isoprene styrene block copolymer 10
4. Hydrogenated hydrocarbon resin 21
5. l-Menthol 9
6. Tocopherol Acetate 0.1
7. Mineral oil 1
Total 100%
Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)
Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and styrene isoprene styrene block copolymer and hydrogenated hydrocarbon resin were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Ketoprofen, l-menthol, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).

Example 2
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 64.90
3. Styrene isoprene styrene block copolymer 10
4. Hydrogenated hydrocarbon resin 9
5. Rosin ester derivative 3
6. Polyethylene glycol 400 3
7. Isopropyl Myristate 2
8. Tocopherol Acetate 0.1
9. Mineral oil 5
Total 100%
'Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)s
Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and rosin ester derivative were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Ketoprofen, polyethylene glycol 400, isopropyl myristate, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).

Example 3
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 64.50
3. Styrene isoprene styrene block copolymer 10
4. Hydrogenated hydrocarbon resin 9
5. Rosin ester derivative 3
6. l- Menthol 0.3
7. Polyethylene glycol 400 3
8. Isopropyl Myristate 2
9. Tocopherol Acetate 0.1
10. Mineral oil 5
Total 100%
Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)
Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and rosin ester derivative were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Ketoprofen, l-menthol, polyethylene glycol 400, isopropyl myristate, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).

Example 4
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 64.90
3. Ethylene vinyl acetate 10
4. Hydrogenated hydrocarbon resin 9
5. Rosin ester derivative 3
6. Polyethylene glycol 400 3
7. Isopropyl Myristate 2
8. Tocopherol Acetate 0.1
9. Mineral oil 5
Total 100%
Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)
Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and ethylene vinyl acetate, hydrogenated hydrocarbon resin and rosin ester derivative were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Ketoprofen, polyethylene glycol 400, isopropyl myristate, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. . The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).

Example 5
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 64.50
3. Ethylene vinyl acetate 10
4. Hydrogenated hydrocarbon resin 9
5. Rosin ester derivative 3
6. l- Menthol 0.3
7. Polyethylene glycol 400 3
8. Isopropyl Myristate 2
9. Tocopherol Acetate 0.1
10. Mineral oil 5
Total 100%
Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)
Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and ethylene vinyl acetate, hydrogenated hydrocarbon resin and rosin ester derivative were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Ketoprofen, l-menthol, polyethylene glycol 400, isopropyl myristate, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).
Example 6
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 54.90
3. Styrene isoprene styrene block copolymer 10
4. Hydrogenated hydrocarbon resin 18
5. Rosin ester derivative 3
6. l- Menthol 3
7. Tocopherol Acetate 0.1
8. Mineral oil 8
Total 100%
Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)
Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and rosin ester derivative were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Ketoprofen, l-menthol, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).

Example 7
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 69.90
3. Styrene isoprene styrene block copolymer 10
4. Hydrogenated hydrocarbon resin 9
5. Rosin ester derivative 3
6. l- Menthol 0.3
7. Tocopherol Acetate 0.1
8. Mineral oil 5
Total 100%
Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)
Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and rosin ester derivative were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Ketoprofen, l-menthol, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).

Example 8
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 66.90
3. Styrene isoprene styrene block copolymer 10
4. Hydrogenated hydrocarbon resin 9
5. Rosin ester derivative 3
6. l- Menthol 3
7. Tocopherol Acetate 0.1
8. Mineral oil 5
Total 100%
Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)
Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and rosin ester derivative were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Ketoprofen, l-menthol, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).

Example 9
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 69.90
3. Styrene isoprene styrene block copolymer 10
4. Hydrogenated hydrocarbon resin 9
5. Rosin ester derivative 3
6. Tocopherol Acetate 0.1
7. Mineral oil 5
Total 100%
Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)
Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and rosin ester derivative were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Then the Ketoprofen, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).
Example 10
S.No Ingredients Quantity (% w/w)
1. Ketoprofen 3
2. polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer 54.90
3. Styrene isoprene styrene block copolymer 10
4. Hydrogenated hydrocarbon resin 10
5. Rosin ester derivative 11
6. l-Menthol 6
7. Tocopherol Acetate 0.1
8. Mineral oil 5
Total 100%
Backing type: 100% Polyester, woven fabric, one way stretchable, Beige colour (115 gms), Release liner: Opaque silicon coated polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and rosin ester derivative were placed in a dissolution mixer, melted and stirred continuously under heating at 150ºC-170ºC. The melted solution was cooled to 100ºC to 120ºC. Ketoprofen, l-menthol, Tocopherol Acetate and mineral oil were added to the obtained adhesive mixture and stirred continuously at 90ºC to 100ºC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on opaque silicon coated polyethylene terephthalate release liner, and was then laminated with one way stretchable, beige colour woven fabric 100% polyester. The resultant was then cut into a rectangle size (10 cm x 7 cm: 70 cm2).

Physical properties of adhesive matrix patch
The physical property of adhesive matrix i.e. tack adhesion of patch of the present invention was found to be more than reference products, the value was between 5.0 newton to 8.0 newton tested by probe tack method using universal testing machine with application of test product to human skin for 12 hrs, after removal of patch from skin, no residue was remained on the skin. The results are as follows.
Table No. 1: Tack adhesion test
S.No Anti-inflammatory patch of present invention (Newtons) Ketoplast™ (Newtons)
1 7.906 2.603
2 6.399 2.947
3 8.288 2.762
4 6.416 2.817
5 5.026 2.904
Average 6.807 2.807

The method of manufacturing the in-house patch of the present invention is by hot melt coating technique.

In vitro drug release test of In house Ketoprofen patch Vs Ketoplast™
In house patch containing 3% w/w Ketoprofen was compared with reference product Ketoplast™ (Manufactured by Teikoku Seiyaku Co. Ltd and Marketed by Zuventus Healthcare Ltd.)
In vitro release test performed through human cadaver skin by using franz diffusion cell. The 1.539 cm2 patch was attached on the human cadaver skin and then placed between the donor and receptor compartments of the cells, with the human cadaver skin side in direct contact with the receptor medium. Approx. 7 ml of the Mcllvaine buffer (pH 6.8) 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 Mcllvaine buffer (pH 6.8) was replaced each time. Absorbances of the samples were read spectrophotometrically. The amount of Ketoprofen permeated per square centimetre at each time interval was calculated and plotted against time with the receptor medium shown in figures. Based on the results of in vitro-skin permeation study, the in house anti-inflammatory matrix adhesive patch is bioequivalent with Ketoplast™.
The matrix adhesive patches prepared as per the Example no. 10 of the present invention is evaluated for the stability at different conditions and the data is given below table;

Table No. 2: Stability Study Compilation of Example 10 (Stability Condition: 40°C/75% RH)
Stability Condition: 40°C/75% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description A Transparent to pale yellow colour matrix type transdermal patch that is rectangular shape consisting of tan colour stretchable woven fabric & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 30 mg of Ketoprofen
Limit: 27 mg to 33 mg
i.e 90% to 110% of label claim 105.6 97.8 93.8 91.1
Uniformity of Dosage Units (by Content Uniformity) L1 = 15 2.8 2.8 4.3 5.8
Dissolution NLT 20 of Ketoprofen is released in 1 hr

NLT 40 of Ketoprofen is released in 4 hr

NLT 55 of Ketoprofen is released in 8 hr

NLT 60 of Ketoprofen is released in 12 hr

NLT 70 of Ketoprofen is released in 24 hr
1 Hr: 31.20%

4 Hrs: 57.60%

8 Hrs: 72.00%

12Hrs:78.80%

24Hrs:91.70%
1 Hr: 29.80%

4 Hrs: 57.10%

8 Hrs: 71.50%

12Hrs:78.80%

24Hrs:90.20%
1 Hr: 30.60%

4 Hrs: 55.40%

8 Hrs: 67.20%

12 Hrs:72.60%

24 Hrs:79.10%
1 Hr: 28.80%

4 Hrs: 53.00%

8 Hrs: 63.80%

12 Hrs:68.40%

24 Hrs:74.20%
Related Substances Any individual impurity: NMT 1.0

Total impurities: NMT 3.0 Max individual Impurities: 0.093%

Total Imp: 0.264% Max individual Impurities: 0.591%

Total Imp: 0.934% Max individual Impurities: 0.506%

Total Imp: 0.976% Max individual Impurities: 0.897%

Total Imp: 1.732%
Tocopherol Acetate Content Each patch contains 1 mg of Tocopherol Acetate
Limit: 0.85 mg to 1.15 mg
i.e 85% to 115% of label claim 101.8% 100.9% 99.2% 99.9%
Tack Test NLT 3.0 N 4.371 5.3084 5.4613 5.1027

Table No. 3: Stability Study Compilation of Example 10 (Stability Condition: 30°C/75% RH)
Stability Condition: 30°C/75% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description A Transparent to pale yellow colour matrix type transdermal patch that is rectangular shape consisting of tan colour stretchable woven fabric & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 30 mg of Ketoprofen
Limit: 27 mg to 33 mg
i.e 90% to 110% of label claim 105.6 99.6 100.2 97.8
Uniformity of Dosage Units (by Content Uniformity) L1 = 15 2.8 1.7 2.5 2.3
Dissolution NLT 20 of Ketoprofen is released in 1 hr

NLT 40 of Ketoprofen is released in 4 hr

NLT 55 of Ketoprofen is released in 8 hr

NLT 60 of Ketoprofen is released in 12 hr

NLT 70 of Ketoprofen is released in 24 hr
1 Hr: 31.20%

4 Hrs: 57.60%

8 Hrs: 72.00%

12 Hrs: 78.80%

24 Hrs: 91.70%
1 Hr: 32.40%

4 Hrs: 60.10%

8 Hrs: 74.00%

12 Hrs: 77.20%

24 Hrs: 87.10%
1 Hr: 31.80%

4 Hrs: 56.60%

8 Hrs: 67.90%

12 Hrs:73.10%

24 Hrs:78.30%
1 Hr: 29.50%

4 Hrs: 56.10%

8 Hrs: 69.30%

12 Hrs: 75.90%

24 Hrs: 83.80%
Related Substances Any individual impurity: NMT 1.0

Total impurities: NMT 3.0 Max individual Impurities: 0.093%

Total Imp: 0.264% Max individual Impurities: 0.485%

Total Imp: 0.833% Max individual Impurities: 0.501%

Total Imp: 0.892% Max individual Impurities: 0.832%

Total Imp: 1.385%
Tocopherol Acetate Content Each patch contains 1 mg of Tocopherol Acetate
Limit: 0.85 mg to 1.15 mg
i.e 85% to 115% of label claim 101.8% 100.3% 101.6% 101.2%
Tack Test NLT 3.0 N 4.371 5.8663 5.8601 5.2403

Table No. 4: Stability Study Compilation of Example 10 (Stability Condition: 25°C/60% RH)
Stability Condition: 25°C/60% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description A Transparent to pale yellow colour matrix type transdermal patch that is rectangular shape consisting of tan colour stretchable woven fabric & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 30 mg of Ketoprofen
Limit: 27 mg to 33 mg
i.e 90% to 110% of label claim 105.6 101.3 100.4 101.7
Uniformity of Dosage Units (by Content Uniformity) L1 = 15 2.8 2.4 4.9 1.3
Dissolution NLT 20 of Ketoprofen is released in 1 hr

NLT 40 of Ketoprofen is released in 4 hr

NLT 55 of Ketoprofen is released in 8 hr

NLT 60 of Ketoprofen is released in 12 hr

NLT 70 of Ketoprofen is released in 24 hr
1 Hr: 31.20%

4 Hrs: 57.60%

8 Hrs: 72.00%

12 Hrs: 78.80%

24 Hrs: 91.70%
1 Hr: 31.30%

4 Hrs: 59.60%

8 Hrs: 73.30%

12 Hrs:80.00%

24 Hrs:92.40%
1 Hr: 32.00%

4 Hrs: 60.50%

8 Hrs: 73.00%

12 Hrs:78.40%

24 Hrs:85.20%
1 Hr: 32.70%

4 Hrs: 53.10%

8 Hrs: 63.20%

12 Hrs: 70.20%

24 Hrs: 75.10%
Related Substances Any individual impurity: NMT 1.0

Total impurities: NMT 3.0 Max individual Impurities: 0.093%

Total Imp: 0.264% Max individual Impurities: 0.418%

Total Imp: 0.746% Max individual Impurities: 0.416%

Total Imp: 0.816% Max individual Impurities: 0.952%

Total Imp: 1.333%
Tocopherol Acetate Content Each patch contains 1 mg of Tocopherol Acetate
Limit: 0.85 mg to 1.15 mg
i.e 85% to 115% of label claim 101.8% 100.2% 101.6% 102.0%
Tack Test NLT 3.0 N 4.371 4.2706 5.6947 5.1506

,CLAIMS:WE CLAIM:
1. A matrix adhesive patch composition comprising:
(a) 1% to 5% (w/w) of Ketoprofen,
(b) 40% to 90% (w/w) of adhesive materials,
(c) 1% to 30% (w/w) of tackifying agents,
(d) 0.5% to 10% (w/w) of plasticizers,
(e) 0.1% to 1% (w/w) of antioxidants, and
(f) 0.1% to 30% (w/w) of other pharmaceutically acceptable excipients.
2. The matrix adhesive patch composition as claimed in claim 1, wherein said pharmaceutically acceptable excipients are selected form one or more of solubilizer, penetration enhancer and counter irritant.
3. The matrix adhesive patch composition as claimed in claim 1, wherein said adhesive materials selected from styrene isoprene styrene block copolymer, ethylene vinyl acetate, hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer, synthetic rubber-based hot melt adhesives, polyolefin based hot melt adhesive, polyamide based hot melt adhesive, polyester-based hot melt adhesives, polyurethane-based hot melt adhesives and styrene isoprene thermoplastic elastomer or combinations thereof.
4. The matrix adhesive patch composition as claimed in claim 1, wherein said tackifying agents are selected from petroleum resins, phenolic resins, xylene resins and coumarone indene resins rosin derivatives, saturated alicyclic hydrocarbon resins, aliphatic hydrocarbon resins, terpene resins and maleic acid resins or combinations thereof.
5. The matrix adhesive patch composition as claimed in claim 1, wherein said plasticizer is selected from mineral oil, linseed oil, octyl palmitate, squalene, squalane, silicone oil, isobutyl myristate, isostearyl alcohol, oleyl alcohol, liquid paraffins, hydrogenated oils, hydrogenated castor oil, higher alcohols such as octyldodecanol, castor oil, petroleum-based oil, vegetable based oils, dibasic acid esters, liquid rubbers, liquid fatty acid esters, diethylene glycol, polyethylene glycol; glycol salicylate, propylene glycol, dipropylene glycol, triacetin and triethyl citrate or combinations thereof.
6. The matrix adhesive patch composition as claimed in claim 1, wherein said antioxidant is selected from butylated hydroxy toulene, tocopherol and ester derivatives thereof, butylated hydroxy anisole, ascorbic acid, ascorbyl stearate, ascorbyl palmitate and nordihydroguaiaretic acid or combinations thereof.
7. The matrix adhesive patch composition as claimed in claim 2, wherein said solubilizer is selected from propylene glycol, di-propylene glycol, 1,3-butylene glycol, polyethylene glycol 400, glycerine, transcutol and N-methyl pyrrolidone or combinations thereof.
8. The matrix adhesive patch composition as claimed in claim 2, wherein said penetration enhancer is selected from isopropyl myristate, diethylene glycol monoethyl ether, dodecyl sulfoxide mono- or dimethyl acetamide, N-hydroxy ethyl lactide, higher fatty acid esters, salicylic acid, sorbitol, urea, glycerin, squalene, squalane, acetylated lanolin, cetyl laurate, olive oil, castor oil, lauric acid, oleic acid, lauryl alcohol, oleyl alcohol, ethoxy stearyl alcohol, liquid paraffin, vaseline, camphor, glycerin fatty acid ester, fatty acid mono- (or di-) ethanol amide, ethylene glycol mono ethyl ether, polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxypropylene alkyl ether, propylene glycol mono(di)alkyl ester, propylene glycol monolaurate, polyoxyethylene lauryl ether and pyrrolidone derivatives or combinations thereof.
9. The matrix adhesive patch composition as claimed in claim 2, wherein said counter irritant is selected from l-menthol, dl-menthol, dl-camphor, d-camphor, methyl salicylate, glycol salicylate, mentha oil, eucalyptus oil, capsaicin, capsicum extract and noncyclic vanillylamide or combinations thereof.
10. The matrix adhesive patch composition as claimed in claims 1 to 9, wherein said composition comprising:
(a) 1% to 5% (w/w) of Ketoprofen,
(b) 40% to 90% (w/w) of combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,
(c) 1% to 30% (w/w) of hydrogenated hydrocarbon resin and/or rosin ester derivative,
(d) 0.5% to 10% (w/w) of mineral oil,
(e) 0.1% to 1% (w/w) of tocopherol acetate, and optionally
(f) 0.1% to 30% (w/w) of other pharmaceutically acceptable excipients.
11. The matrix adhesive patch composition as claimed in claims 1 to 9, wherein said composition comprising:
(a) 1% to 5% (w/w) of Ketoprofen,
(b) 40% to 90% (w/w) of combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,
(c) 1% to 30% (w/w) of hydrogenated hydrocarbon resin and/or rosin ester derivative,
(d) 0.5% to 10% (w/w) of mineral oil,
(e) 0.1% to 1% (w/w) of tocopherol acetate, and
(f) 0.1% to 10% (w/w) of l-menthol.
12. The matrix adhesive patch composition as claimed in claims 1 to 9, wherein said composition comprising:
(a) 1% to 5% (w/w) of Ketoprofen,
(b) 40% to 90% (w/w) of combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer,
(c) 1% to 30% (w/w) of hydrogenated hydrocarbon resin and/or rosin ester derivative,
(d) 0.5% to 10% (w/w) of mineral oil,
(e) 0.1% to 1% (w/w) of tocopherol acetate,
(f) 1% to 5% (w/w) of polyethylene glycol 400,
(g) 1% to 3% (w/w) of isopropyl myristate, and optionally
(h) 0.1% to 10% (w/w) of l-menthol.
13. The process for preparing matrix adhesive patch as claimed in claim 1, wherein said process comprising steps of:
(a) melting adhesive materials and tackifying agents at 150ºC-170 ºC under continuous stirring,
(b) cooling obtained melted solution of step (a) to 100ºC to 120ºC,
(c) adding active ingredient, antioxidants, plasticizers, optionally one or more other excipients selected from counter irritant, solubilizer, penetration enhancer to the obtained cooled adhesive mixture of step (b) at 90ºC to 100ºC under continuous stirring until homogenous mixture of plaster solution is formed,
(d) coating obtained plaster solution on opaque silicon coated with polyethylene terephthalate release liner and laminating with one way stretchable, beige colour woven fabric 100% polyester, and
(e) cutting into rectangle size to get matrix adhesive patch, pouching and labelling.
14. The process for preparing matrix adhesive patch as claimed in claim 11, wherein said process comprising steps of:
(a) melting styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and/or rosin ester derivative at 150ºC-170 ºC under continuous stirring,
(b) cooling obtained melted solution of step (a) to 100ºC to 120ºC,
(c) adding Ketoprofen, Tocopherol Acetate, mineral oil, l-menthol to the obtained cooled adhesive mixture of step (b) at 90ºC to 100ºC under continuous stirring until homogenous mixture of plaster solution is formed,
(d) coating obtained Ketoprofen plaster solution on opaque silicon coated with polyethylene terephthalate release liner and laminating with one way stretchable, beige colour woven fabric 100% polyester, and
(e) cutting into rectangle size to get Ketoprofen matrix adhesive patch, pouching and labelling.
15. The process for preparing matrix adhesive patch as claimed in claim 12, wherein said process comprising steps of:
(a) melting styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and/or rosin ester derivative at 150ºC-170 ºC under continuous stirring,
(b) cooling obtained melted solution of step (a) to 100ºC to 120ºC,
(c) adding Ketoprofen, Tocopherol Acetate, mineral oil, polyethylene glycol 400, isopropyl myristate and/or l- menthol to the obtained cooled adhesive mixture of step (b) at 90ºC to 100ºC under continuous stirring until homogenous mixture of plaster solution is formed,
(d) coating obtained Ketoprofen plaster solution on opaque silicon coated with polyethylene terephthalate release liner and laminating with one way stretchable, beige colour woven fabric 100% polyester, and
(e) cutting into rectangle size to get Ketoprofen matrix adhesive patch, pouching and labelling.

Dated this Third (03rd) day of September, 2021

__________________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883