FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel 3)
1. TITLE OF THE INVENTION:
GEL FORMING OPHTHALMIC SOLUTION

2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: WOCKHARDT LIMITED, D-4, MIDC, CHIKALTHANA,
AURANGABAD (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides ophthalmic formulations or vehicle solutions, which are administrable as liquids and which gels upon instillation into the eye comprising ophthalmic pharmaceutically active agent, combination of gellan gum and polyvinyl pyrrolidone optionally with other ophthalmically acceptable carriers.
The following specification particularly describes the invention and the manner in which it is to be performed.

25 JUN 2008
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4. DESCRIPTION
The present invention provides ophthalmic formulations or vehicle solutions, which are administrate as liquids and which gels upon instillation into the eye comprising ophthalmic pharmaceutically active agent, combination of gellan gum and polyvinyl pyrrolidone optionally with other ophthalmically acceptable carriers.
Ophthalmic gel forming solutions are intended to form gel in situ after coming in contact with ocular fluids. This solution to gel transition occurs due to higher tonicity of the ocular fluids than the said ophthalmic formulations. These gel forming solutions are helpful not only to prolong the contact time of the formulation but also to slow down the rate of elimination of the drug.
U. S. Patent No. 4,861,760 discloses a liquid ophthalmological composition comprising gellan gum, which on administration to the eye changes from a liquid to a gel as a result of the ionic strength of the lacrimal fluid.
U. S. Patent No. 4,136,173 discloses the use of therapeutic compositions containing xanthan gum and locust bean gum, which are administered in liquid form and gel upon instillation,
U. S. Patent No. 6,583,124 discloses an artificial tear solution comprising a galactomannan polymer, a borate compound and water in amounts effective to form a gel or partial gel when the solution is topically administered to the eye, and does not contain a pharmaceutically active agent.
U. S. Patent No. 6,486,138 discloses a liquid anesthetic composition for topical application to the eye, comprising an effective amount of an ophthalmically acceptable anesthetic drug, galactomannan selected from the group consisting of guar or a derivative thereof, a borate compound and water, said liquid composition havinci a pH such that the composition thickens to form a pel or
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partial gel when one or more drops of the liquid composition are topically administered to the eye.
U. S. Patent No. 6,403,609 discloses a topical ophthalmic composition in the form of a liquid, said liquid composition comprising guar or a derivative thereof, a borate compound, and water, said liquid composition having a pH such that the liquid composition thickens to form a gel or partial gel when one or more drops of the liquid composition are topically administered to the eye.
Previously it was observed that the efficacy of cationic preservatives is affected with anionic polymers such as gellan gum and excess quantity of preservative therefore may be needed. This increase in preservative concentration may also increase eye irritation and toxicity of the composition upon storage. Further it was also observed that combination of one or more gel forming agents and preservative produces cloudy precipitation in the system; hence there is a need to stabilize the preservative and gel forming agent combination so as to provide effective preservation from microbial contamination without addition of excess quantity of preservative.
The present invention is now directed to ophthalmic solutions or to a formulation of stable ophthalmic solution suitable for preparation of ophthalmic compositions, which are administrable as liquids and which gel upon contact with the eye. The said ophthalmic solution or formulation comprises of ophthalmic pharmaceutically active agent, combination of gellan gum and polyvinyl pyrrolidone optionally with other ophthalmically acceptable carriers.
It was further observed that gel forming solutions facilitates increased contact time of the drug, slow down the rate of elimination of the drug and further helps to reduce the dose of the drug, which in turn increases patient compliance and reduces the irritability.

In one aspect of the invention there is provided an ophthalmic formulation which gel upon contact with the eye, the said solution comprising ophthalmic pharmaceutically active agent, combination of gellan gum and polyvinyl pyrrolidone optionally with other ophthalmically acceptable carriers.
The ophthalmically acceptable carriers comprise one or more of preservative, stabilizer, chelating agent, tonicity adjusting agent and the like.
The term preservative used in this invention has the meaning commonly understood in the art. The preservatives comprises one or more of benzalkonium chloride, benzyldodecinium bromide, chlorobutanol, sodium perborate, cetrimonium chloride, thiomersal, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbic acid and derivatives thereof, polyquaternium ammonium chloride, polyaminopropyl biguanide, phenyl mercuric nitrate, phenyl mercuric acetate, hydrogen peroxide and the like.
Gel forming agents used in this invention are of the types which undergoes liquid-gel phase transition gelling in situ under the effect of an increase in.the ionic strength of physiological liquid. The concentration of gel forming agent can vary from 0.01 to 3% by weight of the formulation. The gelling time was found to be between 5 seconds to maximum of 2 minutes.
The present inventors also noted that the composition does not form gel during manufacturing process or due to presence of very small amount of mono or divalent ions. The solution is less viscous as compared with the vehicle containing gellan gum only.
The present inventors further noted that when freeze thawing of ophthalmic formulation comprising active agent, preservative, gel forming agent and stabilizer is performed, precipitation or gelling or colour change was not observed. Freeze thawing is performed by exposing the ophthalmic formulation
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to repeated cycles of temperature from -20°C to room temperature. Further when the formulation is exposed to 600C for 7 days, there was no any colour change or gelling was observed. It was found that the ophthalmic formulation is stable during transit, which is acceptable to all the temperature conditions.
The pharmaceutically active agents can be selected from one or more of
antiglaucoma agents, vasoconstrictors, antibacterials, anti-inflammatory agents,
antihistaminics, antifungal agents, anticholinergics, mydriatics,
immunosuppressants, anesthetic agents and the like.
Polyvinyl pyrrolidone is available commercially under different trade names namely kollidon® and plasdone® and is 1-ethenyl-2-pyrrolidone homopolymer having molecular weight varying from 2500-3000000. The different grades comprise one or more from PVPK-12, PVPK-15, PVPK-25, PVPK-30, PVPK-60 or PVPK-90.
Addition of stabilizer significantly improves the stability of preservative in gel forming agent containing vehicle. It reduces the gelling effect between preservative and gel forming agent. This helps to maintain the stability of the preservative in the ophthalmic vehicle solution and there is no need to add excess concentration of preservative.
The term stabilizer used in this invention has the meaning commonly understood in the art. One or more stabilizers are used to both help facilitate the formation of the clear solution and improve its stability. The stabilizers comprises one or more of polyvinyl pyrrolidone, polyoxyl 35 castor oil, polysorbate 80 or the like and mixtures thereof.
Polyoxyl 35 castor oil, the fatty acid ester is a vegetable oil. A fatty acid ester has the meaning commonly understood in the art. Polyoxyl 35 castor oil acts as a
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stabilizer and helps to facilitate the formation of the clear solution and improve its stability.
Polysorbate 80 is used as the stabilizer. Polysorbate 80 is a mixture of oleate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, condensed with approximately 20 moles of ethylene oxide. Polysorbate 80 acts as a stabilizer and helps to facilitate the formation of the clear solution and improve its stability.
The mixture of polyoxyl 35 castor oil and polysorbate 80 has proved to be particularly good stabilizer that is tolerated extremely well by the eye.
The composition may be in the form of solution and have the advantages of liquid ophthalmic composition namely accurate and reproducible dosing. Ophthalmically acceptable carriers can be chelating agent, tonicijy-adjusting agent, buffering agent and the like.
The chelating agent is a compound that is capable of complexing a metal, as understood by those of ordinary skill in the chemical art. Chelating agents are used in ophthalmic compositions to enhance preservative effectiveness. Some useful chelating agents for the purposes of this invention are edetate salts like edetate disodium, edetate calcium disodium, edetate sodium, edetate trisodium,
and edetate dipotassium, sodium citrate, citric acid and the like.
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Tonicity adjusting agents are used in ophthalmic compositions to adjust the concentration of dissolved material to the desired isotonic range. Some examples include mannitol, sorbitol, glycerol, sodium chloride, sodium borate, and the like and the mixtures thereof.
The term buffering agent has the meaning commonly understood in the ophthalmic art and includes a substance, which stabilizes the pH of the solution.
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The buffering agent can be selected from one or more of boric acid, borax, tromethamine, citrate buffer, phosphate buffer, acetate buffer and the like.
Small amounts of pH adjusting agents are also used in the composition to achieve the desired pH range. The pH-adjusting agents comprise one or more from hydrochloric acid, sodium hydroxide and the like.
The present ophthalmic composition may be prepared by the methods well known to the ophthalmic art. Gellan gum was dispersed in the water for injection. Benzalkonium chloride and at least one stabilizer were dissolved in hot water for injection and both the solutions were mixed. The pH of the composition was adjusted with suitable pH adjusting agent and filtered aseptically.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples - Table 1 provides composition of the present invention.

Sr.No. Name of Ingredient Composition (%w/v)
1 Timolol maleate 0.25-0.5%
2 D-Mannitol 2-4%
3 Benzododecinium bromide 0.025-0.01%
4 Tromethamine 0.01-0.09%
5 Gellan Gum 0.1 to 0.6%
6 Polyvinyl pyrrolidone 0.1-1.8%
7 Water for Injection q.s.
Procedure - Gellan gum and polyvinyl pyrrolidone were dispersed in water for injection under stirring. D-mannitol, benzododecinium bromide, tromethamine and timolol maleate were added in separate container in water for injection. The
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two solutions were mixed thoroughly. pH of the solution was adjusted with suitable ph adjusting agent and aseptically filled into suitable container.
The gelling time of the formulation was found to be between 5 seconds to maximum of 2 minutes.
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WE CLAIM:
1. An ophthalmic formulation which gel upon contact with the eye, the said formulation comprising ophthalmic pharmaceutically active agent, combination of gellan gum and polyvinyl pyrrolidone optionally with other ophthalmically acceptable carriers.
2. The ophthalmic formulation as claimed in claim 1, wherein the ophthalmic pharmaceutically active agents comprises one or more of antiglaucoma agents, vasoconstrictors, antibacterials, anti-inflammatories, antihistaminics, antifungal agents, anticholinergics, mydriatics, immunosuppressants, anesthetic agents.

3. The ophthalmic formulation as claimed in claim 1, wherein the ophthalmically acceptable carriers comprises one or more of preservatives, chelating agent, tonicity adjusting agent, buffer component.
4. The ophthalmic formulation as claimed in claim 3, wherein the preservative comprises one or more of benzalkonium chloride, benzyldodecinium bromide chlorobutanol, sodium perborate, cetrimonium chloride, thiomersal, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbic acid and derivatives thereof, polyquaternium ammonium chloride, polyaminopropyl biguanide, phenyl mercuric nitrate, phenyl mercuric acetate, hydrogen peroxide.
5. The ophthalmic formulation as claimed in claim 3, wherein the chelating agents comprises one or more of edetate disodium, edetate calcium disodium, edetate sodium, edetate trisodium, edetate dipotassium.
6. The ophthalmic formulation as claimed in claim 3, wherein the tonicity adjusting agents comprises one or more of mannitol, sorbitol, glycerol.
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7. The ophthalmic formulation as claimed in claim 3, wherein the buffer
component comprises tromethamine.
8. The ophthalmic formulation as claimed in claim 1 has the gelling time between 5 seconds to 2 minutes.
9. The ophthalmic formulation as claimed in claim 1, wherein the polyvinyl pyrrolidone comprise one or more from PVPK-30, PVPK-60, PVPK-90.
Dated this day of June, 2008 For Wockhardt Limited
(Mandar (Kodgule) Authorized Signatory
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