FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
STABLE TOPICAL COMPOSITIONS COMPRISING HYALURONATE LYASE WITH PHARMACEUTICALLY ACCEPTABLE ACTIVE AGENT
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a stable topical composition comprising at least one pharmaceutically acceptable active agent along with hyaluronate lyase, wherein hyaluronate lyase is stabilized in the said composition by immobilization. The invention relates to an agent for treating, prophylaxis and/or metaphylaxis of functional and structural disorders of the skin and/or mucosa on the basis of different medicaments and/or auxiliary substances through promotion of penetration from topical formulations in to skin.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. Description
The present invention provides a stable topical composition comprising at least one pharmaceutical^ acceptable active agent along with hyaluronate lyase, wherein hyaluronate lyase is stabilized in the said composition by immobilization. The invention relates to an agent for treating, prophylaxis and/or metaphylaxis of functional and structural disorders of the skin and/or mucosal on the basis of different medicaments and/or auxiliary substances through promotion of penetration from topical formulations in to skin.
Medicaments and/or active substances are used together with auxiliary substances in the form of liquid, semi-solid or even solid formulations of differing composition for the treatment, prophylaxis and metaphylaxis of functional and structural disorders of the skin and/or mucosa. In dependence on the physicochemical properties of the active substance or medicament, of the base used and of the auxiliary substances contained therein as well as of the nature of the area of the skin to be treated, the active substance molecules penetrate via different penetration mechanisms into the skin; in the given case they penetrate the latter until they are re-absorbed by the vascular system.
It has already been, known for a long time that through the presence of one or more special auxiliary substances the penetration of active substances can be made easier (penetration modulation). These substances are here in a position to alter, via different active mechanisms, the penetration or permeation of active substances and/or medicaments.
Hyaluronidase is a proteinaceous enzyme having the property of hydrolyzing hyaluronic acid. Hyaluronic acid is a mucopolysaccharide of high molecular weight forming an essential component of ground substance or cement substance of human body tissues. Because of hydrolytic action of hyaluronate lyase on hyaluronic acid, hyaluronate lyase has found successful clinical application in promoting the absorption by tissues of therapeutic agents. Its
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favorable action appears to be due to reduction in viscosity of tissue fluids by its hydrolytic action on hyaluronic acid.
Hyaluronate lyase, being high molecular weight proteinaceous enzyme has a tendency to break down into fractions with smaller molecular weights. This degradation of enzyme molecule results in loss of activity of the enzyme. Hyaluronate lyase containing compositions are unstable, which means that they cannot be stored for long time due to gradual loss of activity.
U.S. Patent No 5,912,009 provides the use of fatty acid glycol esters as penetration enhancers in transdermal delivery system.
U.S. Patent No. 4,933,184 discloses the use of menthol as percutaneous transfer enhancing agent for enhancing the transdermal delivery of active agents.
There are several other patents, which describe the use of plant oils (U.S. Patent No 5,229,130), isopropyl myristate (U.S. Patent No 5,618,555), eucalyptus oil (U.S. Patent No 4,440,777), fatty acid esters of lactic acid (U.S. Patent Nos 5,882,676 and 5,952,000) and lecithin (U.S. Patent No 4,783,450) as penetration enhancers.
Various substances are known in the art to have penetration enhancer effect such as dimethyl sulphoxide, dimethyl acetamide, dimethyl formamide, derivatives of polyethylene glycol and propylene glycol, polyoxyethylene ester, alkanolamides, alkanolamines, alkylamines, N-alkylpyrrolidones.
U.S. Patent No. 2,795,529 describes the stabilization of hyaluronate lyase using sodium salts of EDTA and calcium chloride.
U.S. Patent No 2,976,212 provides the stabilization of hyaluronate lyase using anhydrous paraffin ointment base.
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U.S. Patent No 2,806,815 discloses the use of certain stabilizing agents like arginine, valine, lysine, glycine etc for stabilization of hyaluronate lyase.
U.S. Patent No 7,115,408 discloses the use of annexin (calcium dependent phospholipid binding proteins) for stabilization of hyaluronate lyase.
U.S. Patent No 6,719,986 discloses composition of hyaluronate lyase derived from microorganism with urea, erythromycin, minocyclin, ciclopiroxolamine, glyceryl trinitrate, metronidazole, tretinoin etc. Here the composition is stabilized by addition of stabilizers.
European Patent No EP1365766 discloses use of composition containing steroids in association with hyaluronate lyase in absence or presence of NSAIDs for treatment of phimosis.
U.S. Application No 2003103955 discloses pharmaceutical composition of diclofenac containing hyaluronate lyase.
U.S. Application No 20060034824 discloses pharmaceutical composition of bromeline containing hyaluronate lyase.
There are several other patents/applications that disclose compositions of hyaluronate lyase with other actives like local anesthetics, antibiotics etc and stabilization with addition of stabilizers.
The present inventors while working on the hyaluronate lyase compositions have surprisingly found that by immobilizing hyaluronate lyase, a stable composition is obtained, which shows no decrease in enzyme activity even after long term storage. The present inventors have avoided the use of additional stabilizing agents in hyaluronate lyase containing compositions.
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One of the aspects of the present invention provides a stable topical composition comprising at least one pharmaceutically acceptable active agent along with hyaluronate lyase, wherein hyaluronate lyase is stabilized in the said composition by immobilization.
The term "immobilization" as used herein refers to covalent attachment of enzyme to a solid matrix so that it cannot move but still act on its substrate.
Hyaluronate lyase may be present in an amount from about 100 to 100000 IU.
Hyaluronate lyase may be obtained from bovine testes, ovine testes, microorganisms or biotechnological processes.
Immobilized hyaluronate lyase is stable at wide range of pH (4-7) and temperature (4-30°C). Immobilized hyaluronate lyase possesses the same activity as free hyaluronate lyase.
Immobilization of hyaluronate lyase can be carried out by various methods such as carrier binding which may include physical adsorption, inclusion complex method, ionic binding, covalent binding; cross-linking; entrapment which may include lattice type, microcapsule type, sol-gel entrapment or other suitable means well known in the art.
The term "pharmaceutically acceptable active agent" as used herein refers to drugs for treating, prophylaxis and metaphylaxis of functional and structural disorders of the skin and/or mucosa.
The pharmaceutically acceptable active agent can be selected from the group comprising one or more of antibiotics, anti-microbial agents, anti-fungal agents, anti-acne agents, anti-psoriasis agents, analgesics, non-steroidal antiinflammatory agents, steroids, anti-virals, anti-cancer agents, anti-ulcer agents and the like.
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Examples of the pharmaceutical^ acceptable active agents may include but not limited to nadifloxacin, aciclovir, adapalene, hydrocortisone, etretinate, alclometasone, alitretinoin, amcinonide, aminolevulinic acid, amlexanox, anidulafungin, azelaic acid, betamethasone, clotrimazole, mometasone, betaxolol, bexarotene, flutamide, octreotide, budesonide, bufexamac, buspirone, butenafine, calcipotriol, calcipotriene, cefamandol, ciclopirox, cyclosporin, cioteronel, clarithromycin, clofarabine, cloticasone, fluticasone, cyclomethasone, davasaicin, deflazacort, hydrocortisone, deprodone, diflorasone, difluprednate, docasanol, dromprednate, elfornithine, emedastine, emtricitabine, epervudine, epostane, epristeride, erythromycin, falecalcitriol, penciclovir, finasteride, flurithromycin, foscamet, fusidic acid, halometasone, imiquimod, dinoprostone, latanoprost, ketoconazole, lonapalene, maxacalcitol, miconazole, minoxidil, mupirocin, nadifloxacin, nalfurafine, nalmefene, ofloxacin, peldesine, pemirolast, pimecrolimus, prednicarbate, retapamulin, rifamixin, rupatadine, tacalcitol, tacrolimus, tazarotene, tacrolimus, terbinafine, trimetrexate, trospectomycin, ulobetasol, valdecoxib, rofecoxib, hydroquinone, misoprostol, piroxicam, nimesulide or salts thereof.
The topical composition of the present invention can be present in the form of paste, ointment, cream, lotion, patch, bandage, occlusive dressing, aerosol, emulsion, gel, stick or any other suitable means of topical application.
The topical composition of the present invention further comprises of pharmaceutical^ acceptable additives such as carrier oils, hydrophilic bases, fatty bases, gums, polymers, antioxidants, emulsifiers, surfactants, cosmetic additives and the like.
Suitable carrier oils may include one or more of liquid paraffin, jojoba oil peanut oil, olive oil, castor oil, sunflower oil, soyabean oil, coconut oil and the like.
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Suitable hydrophilic bases may include one or more of N-methyl-2-pyrrolidone, propylene glycol, polyethylene glycol, cetomacrogol and the like.
Suitable fatty bases may include one or more of cholesterol or its derivatives, beeswax, cetomacrogol, carnauba wax, lanolin, cetyl alcohol, stearyl alcohol, stearic acid, yellow wax, microcrystalline wax, petrolatum and the like.
Suitable anti-oxidants may include one or more of tocopherol, butylated hydroxy anisole, butylated hydroxytoluene, ascorbic acid, ascorbyl palmitate, N-acetyl-cysteine and the like.
Suitable gums may include one or more of xanthan gum, locust bean gum, guar gum, alginates, karaya gum and the like.
Suitable polymers may include one or more of hydroxy propyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose or other cellulose derivatives, carbopols and the like.
Suitable emulsifiers may include one or more of dimethicone, polyglyceryl-4 isostearate/cetyl dimethicone copolyol/hexyl laurate mixture, cetyl dimethicone copolyol, cyclomethicone/dimethicone copolyol mixture, incroquat behenyl trimonium methosulfate and the like.
Suitable surfactants may include one or more of polysorbates, poloxamers, sorbitan fatty acid esters, fatty alcohols, glyceryl esters, fatty acid esters of fatty alcohols and the like.
Suitable cosmetic additives may include but are not limited to one or more of coloring agents, fragrance, pigments, powders of silica, zinc oxide, and titanium dioxide.
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While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
Table 1: Nadifloxacin topical cream composition

S.No. Ingredients Qty (%w/w)
Immobilization of hyaluronate l\ rase
1 Hyaluronate lyase 100-100000 IU
2 Microcrystalline cellulose 0.1-10
3 Titanium trichloride solution q.s.
4 Sodium chloride 0.09
5 Phosphate buffer q.s.
Composition
1 Nadifloxacin 0.1-10
2 Immobilized hyaluronate lyase 100-100000IU
3 Liquid Parafin 0.5 to 60
4 Cetostearyl alcohol 1 to 20
5 Microcrystalline wax 1 to 20
6 Alpha tocopherol 0.01 to 5
7 Cetomacrogol 0.1 to 10
8 Dimethicone 0.01 to 5
9 Carbopol 0.1 to 8
10 Propyl paraben 0.01 to 0.1
11 Diethanolamine 0.01 to 10
12 Propyleneglycol 1.0 to 20
13 N- methyl -2 -pyrrolidone 0.1 to 5
14 Water qs 100
Procedure: Immobilization of hyaluronate lyase by covalent binding: Microcrystalline is treated with phosphate buffer by uniformly dispersing it in phosphate buffer and mixing at 25-30°C. Dispersion is filtered off and added to mixing tank containing titanium trichloride solution and stirring is continued for 24 hours. Microcrystalline cellulose gets activated by this process. The
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dispersion is filtered and excess of titanium chloride is removed by washing activated microcrystalline cellulose with phosphate buffer. Activated microcrystalline cellulose is taken in another mixing tank and dispersed in phosphate buffer solution; dispersion is cooled to 4-6°C. To this cooled dispersion, hyaluronate lyase is added and mixing is done. After this hyaluronate lyase gets immobilized and is collected by filtration. Preparation of composition: Aqueous phase: Cetomacrogol and carbopol are dissolved in purified water. Alpha tocopherol is added to it and mixed. To this phase, dispersion of nadifloxacin and immobilized hyaluronate lyase in N-methyl 2- pyrrolidone is added. Methyl paraben and propylparaben are dissolved in propyleneglycol by heating at 65 °C and added to above aqueous phase.
Oil phase: Liquid paraffin, cetostearyl alcohol, microcrystalline wax, diethanolamine, dimethicone are mixed mix and heated at 85 °C. The oil phase thus obtained is added into the aqueous phase prepared above with stirring and cooled to get cream of suitable consistency.
EXAMPLE 2
Table 2: Nadifloxacin topical cream composition

S.No. Ingredients Qty (%w/w)
Immobilization of hyaluronate lyase
1 Hyaluronate lyase 100-100000 IU
2 Trialose 0.02-80
3 Phosphate buffer q.s.
Composition
1 Nadifloxacin 0.1-10
2 Immobilized hyaluronate lyase 100-100000IU
3 Liquid Parafin 0.5 to 60
4 Cetostearyl alcohol 1 to 20
5 Microcrystalline wax 1 to 20
6 Alpha tocopherol 0.01 to 5
7 Cetomacrogol 0.1 to 10
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8
0.01 to 5
Dimethicone
9 Carbopol 0.1 to 8
10 Propyl paraben 0.01 to 0.1
11 Diethanolamine 0.01 to 10
12 Propyleneglycol 1.0 to 20
13 N- methyl -2 -pyrrolidone 0.1 to 5
14 Water qs 100

Procedure: Immobilization of hyaluronate lyase by physical adsorption: Trialose is mixed with phosphate buffer in mixing tank. Hyaluronate lyase is added to above dispersion of trialose in phosphate buffer and mixing is done. Immobilized hyaluronate lyase is collected by filtration. Preparation of composition: Aqueous phase: Cetomacrogol and carbopol are dissolved in purified water. Alpha tocopherol is added to it and mixed. To this phase, dispersion of nadifloxacin and immobilized hyaluronate lyase in N-methyl 2- pyrrolidone is added. Methyl paraben and propylparaben are dissolved in propyleneglycol by heating at 65 °C and added to above aqueous phase.
Oil phase: Liquid paraffin, cetostearyl alcohol, microcrystalline wax, diethanolamine, dimethicone are mixed mix and heated at 85 °C. The oil phase thus obtained is added into the aqueous phase prepared above with stirring and cooled to get cream of suitable consistency.
EXAMPLE 3
Table 3: Nadifloxacin topical cream composition

S.No. Ingredients Qty (%w/w)
Immobilization of hyaluronate lyase
1 Hyaluronate lyase 100-100000 IU
2 Sephalose 0.01-80
3 Phosphate buffer q.s.
Composition
1 Nadifloxacin 0.1-10
2 Immobilized hyaluronate lyase
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3 Liquid Parafin 0.5 to 60
4 Cetostearyl alcohol 1 to 20
5 Microcrystalline wax 1 to 20
6 Alpha tocopherol 0.01 to 5
7 Cetomacrogol 0.1 to 10
8 Dimethicone 0.01 to 5
9 Carbopol 0.1 to 8
10 Propyl paraben 0.01 to 0.1
11 Diethanolamine 0.01 to 10
12 Propyleneglycol 1.0 to 20
13 N- methyl -2 -pyrrolidone 0.1 to 5
14 Water qs 100
Procedure: Immobilization of hyaluronate lyase by physical adsorption: Sephalose is mixed with phosphate buffer in mixing tank. Hyaluronate lyase is added to above dispersion of sephalose in phosphate buffer and mixing is done. Immobilized hyaluronate lyase is collected by filtration. Preparation of composition: Aqueous phase: Cetomacrogol and carbopol are dissolved in purified water. Alpha tocopherol is added to it and mixed. To this phase, dispersion of nadifloxacin and immobilized hyaluronate lyase in N-methyl 2- pyrrolidone is added. Methyl paraben and propylparaben are dissolved in propyleneglycol by heating at 65 °C and added to above aqueous phase.
Oil phase: Liquid paraffin, cetostearyl alcohol, microcrystalline wax, diethanolamine, dimethicone are mixed mix and heated at 85 °C. The oil phase thus obtained is added into the aqueous phase prepared above with stirring and cooled to get cream of suitable consistency.
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EXAMPLE 4
Table 4: Nadifloxacin, mometasone and miconazole topical cream composition

S.No. Ingredients Qty (%w/w)
Immobilization of hyaluronate lyase
1 Hyaluronate lyase 100-100000 IU
2 Cyclodextrin 0.1-90
3 Phosphate buffer q.s.
Composition
1 Nadifloxacin 0.1-10
2 Mometasone furoate 0.01-1.0
3 Miconazole nitrate 0.1-10
4 Immobilized hyaluronate lyase 100-100000 IU
5 Liquid Parafin 0.5 to 60
6 Cetostearyl alcohol 1 to 20
7 Microcrystalline wax 1 to 20
8 Alpha tocopherol 0.01 to 5
9 Cetomacrogol 0.1 to 10
10 Dimethicone 0.01 to 5
11 Carbopol 0.1 to 8
12 Propyl paraben 0.01 to 0.1
13 Diethanolamine 0.01 to 10
14 Propyleneglycol 1.0 to 20
15 N- methyl -2 -pyrrolidone 0.1 to 5
16 Water qs 100
Procedure: Immobilization of hyaluronate lyase by inclusion complex method: Cyclodextrin is mixed with phosphate buffer in mixing tank. Hyaluronate lyase is added to above dispersion of cyclodextrins in phosphate buffer and mixing is done. Immobilized hyaluronate lyase is collected by filtration. Preparation of composition: Aqueous phase: Cetomacrogol and carbopol are dissolved in purified water. Alpha tocopherol is added to it and mixed. To this phase, dispersion of nadifloxacin, mometasone furoate, miconazole nitrate and Hyaluronate lyase in N-methyl 2- pyrrolidone is added. Methyl paraben and propylparaben are dissolved in propyleneglycol by heating at 65 °C and added to above aqueous phase.
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Oil phase: Liquid paraffin, cetostearyl alcohol, microcrystalline wax, dimethicone, diethanolamine are mixed mix and heated at 85 °C. The oil phase thus obtained is added into the aqueous phase prepared above with stirring and cooled to get cream of desired consistency.
EXAMPLE 5
Table 5: Nadifloxacin topical gel composition

S.No. Ingredients Qty (%w/w)
Immobilization of hyaluronate lyase
1 Hyaluronate lyase 100-100000 IU
2 Microcrystalline cellulose 0.1-10
3 Phosphate buffer q.s.
Composition
1 Nadifloxacin 0.1-10
2 Immobilized hyaluronate lyase 100-100000 IU
3 Carbopol 0.1 to 8
4 Methyl paraben 0.01-1.0
5 Propyl paraben 0.01 to 0.1
6 Diethanolamine 0.01 to 10
8 Sodium hydroxide 0.01-1.0
9 Propyleneglycol 1.0 to 20
10 N- methyl -2 -pyrrolidone 0.1 to 5
11 Water qs 100
Procedure: Immobilization of hyaluronate lyase by physical adsorption: Microcrystalline is treated with phosphate buffer by uniformly dispersing it in phosphate buffer and mixing it for some time. To this dispersion, hyaluronate lyase is added and mixing is done. After this hyaluronate lyase gets immobilized and is collected by filtration.
Composition: Carbopol, diethanolamine, sodium hydroxide are dissolved in water. To this, dispersion of nadifloxacin and Hyaluronate lyase in N-methyl 2- pyrrolidone is added and mixed. Methyl paraben and propylparaben are dissolved in propyleneglycol by heating at 65 °C and added to above mixture to get gel of suitable consistency
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EXAMPLE 6
Table 6: Nadifloxacin, mometasone topical cream composition

S.No. Ingredients Qty (%w/w)
Immobilization of hyaluronate lyase
1 Hyaluronate lyase 100-100000 IU
2 Sodium alginate 1-5
3 Calcium chloride 0.01-20
4 Potassium chloride 0.01-10
5 Glutaraldehyde 0.01-10
5 Phosphate buffer q.s.
Composition
1 Nadifloxacin 0.1-10
2 Mometasone furoate 0.01-1.0
3 Immobilized hyaluronate lyase 100-100000 IU
4 Liquid Parafin 0.5 to 60
5 Cetostearyl alcohol 1 to 20
6 Microcrystalline wax 1 to 20
7 Alpha tocopherol 0.01 to 5
8 Cetomacrogol 0.1 to 10
9 Dimethicone 0.01 to 5
10 Carbopol 0.1 to 8
11 Propyl paraben 0.01 to 0.1
12 Diethanolamine 0.01 to 10
13 Sodium hydroxide 0.01-1.0
14 Propyleneglycol 1.0 to 20
15 N- methyl -2 -pyrrol idone 0.1 to 5
16 Water qs100
Procedure: Immobilization of hyaluronate lyase by entrapment: Sodium alginate is dispersed in water to make gel. In the above gel, hyaluronate lyase is added and mixed uniformly. Separately, potassium chloride and calcium chloride are mixed in phosphate buffer. Hyaluronate lyase dispersed in sodium alginate beads is then added drop wise into above buffered calcium chloride solution. To above solution, glutaradehyde is also added to dropwise for cross-linking of alginate polymer. Beads containing entrapped hyaluronate lyase them thus formed are filtered out.
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Composition: Aqueous phase: Cetomacrogol and carbopol are dissolved in purified water. Alpha tocopherol is added to it and mixed. To this phase, dispersion of nadifloxacin, mometasone furoate, and hyaluronate lyase in N-methyl 2- pyrrolidone is added. Methyl paraben and propylparaben are dissolved in propyleneglycol by heating at 65 °C and added to above aqueous phase.
Oil phase: Liquid paraffin, cetostearyl alcohol, microcrystalline wax, dimethicone, diethanolamine are mixed and heated at 85 °C. The oil phase thus obtained is added into the aqueous phase prepared above with stirring and cooled to get cream of desired consistency.
EXAMPLE 7
Table 7: Nadifloxacin, adapalene topical gel composition

S.No. Ingredients Qty (%w/w)
Immobilization of hyaluronate lyase
1 Hyaluronate lyase 100-100000 IU
2 Sodium alginate 1-5
3 Calcium chloride 0.01-20
4 Potassium chloride 0.01-10
5 Phosphate buffer q.s.
Composition
1 Nadifloxacin 0.1-10
2 Adapalene 0.01-10
3 Immobilized hyaluronate lyase 100-100000 IU
4 Carbopol 0.1 to 8
5 Methyl paraben 0.01-1.0
6 Propyl paraben 0.01 to 0.1
7 Diethanolamine 0.01 to 10
8 Sodium hydroxide 0.01-1.0
9 Propyleneglycol 1.0 to 20
10 N- methyl -2 -pyrrolidone 0.1 to 5
11 Water qs100
Procedure: Immobilization of hyaluronate lyase by entrapment: Sodium alginate is dispersed in water to make gel. In the above gel, hyaluronate lyase
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is added and mixed uniformly. Separately, potassium chloride and calcium chloride are mixed in phosphate buffer. Hyaluronate lyase dispersed in sodium alginate beads is then added drop wise into above buffered calcium chloride solution. Beads containing entrapped hyaluronate lyase them thus formed are filtered out.
Composition: Carbopol, diethanolamine and sodium hydroxide are dissolved in water. To this, dispersion of nadifloxacin, adapalene and hyaluronate lyase in N-methyl 2- pyrrolidone is added and mixed. Methyl paraben and propylparaben are dissolved in propyleneglycol by heating at 65 °C and added to above mixture to get gel of suitable consistency.
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WE CLAIM:
1. A stable topical composition comprising at least one pharmaceutical^ acceptable active agent along with hyaluronate lyase, wherein hyaluronate lyase is stabilized in the said composition by immobilization.
2. The stable topical composition of claim 1, wherein immobilization is carried out by carrier binding method.
3. The stable topical composition of claim 1, wherein immobilization is carried out by cross-linking method.
4. The stable composition of claim 1, wherein immobilization is carried out by entrapment method.
5. The stable topical composition of claim 1, wherein hyaluronate lyase is present in the range between 100 to 100000 IU.
6. The stable topical composition of claim 1, wherein composition comprises one or more of paste, ointment, cream, lotion, patch, bandage, occlusive dressing, aerosol, emulsion, gel, or stick.
7. The stable topical composition of claim 1, wherein said at least one pharmaceutically acceptable active agent comprises one or more of nadifloxacin, aciclovir, adapalene, hydrocortisone, etretinate, alclometasone, alitretinoin, amcinonide, aminolevulinic acid, amlexanox, anidulafungin, azelaic acid, betamethasone, clotrimazole, mometasone, betaxolol, bexarotene, flutamide, octreotide, budesonide, bufexamac, buspirone, butenafine, calcipotriol, calcipotriene, cefamandol, ciclopirox, cyclosporin, cioteronel, clarithromycin, clofarabine, cloticasone, fluticasone, cyclomethasone, davasaicin, deflazacort, hydrocortisone, deprodone, diflorasone, difluprednate, docasanol, dromprednate, elfornithine, emedastine, emtricitabine, epervudine, epostane, epristeride,
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erythromycin, falecalcitriol, penciclovir, finasteride, flurithromycin, foscamet, fusidic acid, halometasone, imiquimod, dinoprostone, latanoprost, ketoconazole, lonapalene, maxacalcitol, miconazole, minoxidil, mupirocin, nadifloxacin, nalfurafine, nalmefene, ofloxacin, peldesine, pemirolast, pimecrolimus, prednicarbate, retapamulin, rifamixin, rupatadine, tacalcitol, tacrolimus, tazarotene, tacrolimus, terbinafine, trimetrexate, trospectomycin, ulobetasol, valdecoxib, rofecoxib, hydroquinone, misoprostol, piroxicam, nimesulide or salts thereof.
8. The stable topical composition of claim 1, wherein hyaluronate lyase is obtained from one or more of bovine testis, ovine testes, microorganisms or biotechnological processes.
9. The stable topical composition of claim 1 further comprises of pharmaceutically acceptable additives.
10. The stable topical composition of claim 9, wherein the pharmaceutically acceptable additives comprises one or more of carrier oils, solvents, hydrophilic bases, fatty bases, gums, anti-oxidants, polymers, emulsifiers, surfactants, cosmetic additives.

Dated this _TH day of June, 2007

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Abstract
The present invention provides a stable topical composition comprising at least one pharmaceutical^ acceptable active agent along with hyaluronate lyase, wherein hyaluronate lyase is stabilized in the said composition by immobilization. The invention relates to an agent for treating, prophylaxis and/or metaphylaxis of functional and structural disorders of the skin and/or mucosa on the basis of different medicaments and/or auxiliary substances through promotion of penetration from topical formulations in to skin.
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