FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
OPHTHALMIC COMPOSITION COMPRISING KETOROLAC TROMTHAMINE
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 ophthalmic composition comprising of ketorolac tromethamine and hydroxypropyl-p-cyclodextrin.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention provides ophthalmic composition comprising of ketorolac tromethamine and hydroxypropyl-p-cyclodextrin.
Ketorolac is a member of the pyrrolo-pyrrole group of nonsteroidal antiinflammatory drugs (NSAIDs) for ophthalmic use. Ketorolac tromethamine chemically is (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) of formula 1. Ketorolac ophthalmic solution is indicated for the temporary relief of ocular itching due to seasonal allergic conjunctivitis. It is also indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction.
I

US Patent No 5,110,493 disclose ophthalmologically acceptable non-steroidal anti-inflammatory drug formulation comprising an ophthalmologically acceptable non-steroidal anti-inflammatory carboxyl group-containing drug in an effective amount for ophthalmic treatment between 0.001% and 10.0% wt/vol; a quaternary ammonium preservative in an antimicrobially effective amount; and Octoxynol 40 in a stabilizing amount and an aqueous vehicle q.s. to 100%.
US Patent No 5,414,011 disclose ophthalmologically acceptable formulation containing ketorolac along with ophthalmologically acceptable antibiotic in an effective amount, a quaternary ammonium preservative, Octoxynol 40 and an aqueous preservative.
US Application No 20040248962 disclose an aqueous topical ophthalmic composition comprising less than 0.5% of ketorolac tromethamine.
The present invention relates to topical ophthalmic composition comprising ketorolac tromethamine and hydroxypropyl-β-Cyclodextrin. Ketorolac has problem of poor penetration into the corneal tissue. When used alone ketorolac does not get easily penetrated into the aqueous humour requiring higher doses to get the desired effect. The most common adverse effect associated with the use of larger dose of ketorolac is ocular irritation, primarily burning and stinging on instillation. Eliminating or reducing ocular irritation has the potential for improving compliance and effectiveness of formulation.
2

The present inventors have now found out that when 0.3% of ketorolac tromethamine is used with 1 to 1.5% of hydroxypropyl-β-Cyclodextrin, ketorolac gets more easily penetrated into the aqueous humour thereby reducing the dose of ketorolac which further results into reduced side effects.
Previously it was also observed that when Benzalkonium chloride was used as preservative in the ophthalmic composition containing non-steroidal antiinflammatory agent (NSAID), the complex was formed between NSAID and benzalkonium chloride. Due to formation of this complex, the formulation does not have the desired stability and shelf life.
The present inventors have now found out that when ketorolac tromethamine is used with hydroxypropyl-β-Cyclodextrin, the complex get formed between ketorolac tromethamine and hydroxypropyl-β-Cyclodextrin which further helps to minimize the complex formation between Benzalkonium chloride and ketorolac tromethamine thus rendering the formulation more stable to package, ship and store.
In one of the aspects of the present invention there is provided an aqueous topical ophthalmic composition comprising 0.3% w/w of ketorolac tromethamine and 1 to 1.5% w/w of hydroxypropyl-β-cyclodextrin along with a suitable carrier.
In yet another aspect of the present invention there is provided an aqueous topical ophthalmic composition comprising essentially of 0.3% w/w of ketorolac tromethamine.
The compositions according to the invention may also contain selected ophthalmologically acceptable adjuvants admixed with ketorolac tromethamine and hydroxypropyl-β-cyclodextrin, for example, preservative, chelating agent, tonicity adjusting agent and solubilizing agent.
3

The term preservative has the meaning commonly understood in the ophthalmic art. Preservatives are used to prevent bacterial contamination in multiple-use ophthalmic preparations and examples include benzalkonium chloride, phenylmercuric acetate, chlorobutanol, benzyl alcohol, parabens, and thimerosal. Preferably, the preservative is benzalkonium chloride.
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. In this invention edetate disodium is used as the chelating agent.
Tonicity adjusting agents are used in ophthalmic compositions to adjust the concentration of dissolved material to the desired isotonic range. Some examples include glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. In the present invention sodium chloride is used as the tonicity adjusting agent. For this invention, the preferred osmolality ranges from about 230-330 mOsm, measured according to standard methodology.
Suitable solubilizing agents include polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone and the like. In the present invention polyvinyl alcohol is used as solubilizing agent, which also helps to reduce irritation when the solution is instilled into the eye.
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.
4

Examples- Following formulations are representatives of the preferred compositions of the present invention. The preparation of example 1 is detailed below. Formulations of example 2, 3 and 4 can be prepared in similar fashion.
Table 1: Composition of ketorolac tromethamine ophthalmic solution

Sr. No. Ingredient Quantity (%)
Example1 Example 2 Example 3 Example 4
1 Ketorolac Tromethamine 0.3 % 0.3 % 0.3 % 0.3 %
2 Hydroxypropyl-β-Cyclodextrin 1.195% 1.195% 1.3% 1.5%
3 Polyvinyl alcohol 0.5 % 0.3 % 0.5 % 0.5 %
4 Benzalkonium chloride 0.01% 0.01% 0.01% 0.01%
5 Disodium edetate 0.1% 0.1% 0.1% 0.1%
6 Sodium Chloride 0.8% 0.8% 0.8% 0.8%
7 Water for Injection q.s. tomake 100ml q.s. to make100 ml q.s. to make 100 ml q.s. to make 100 ml
0.3% of ketorolac tromethamine was blended with 1.195 % of hydroxypropyl-p-Cyclodextrin and the blend was dissolved in water for injection. 0.5% polyvinyl alcohol was dissolved in water for injection in a separate vessel and this solution was added in above solution. 0.01% Benzalkonium chloride was dissolved in hot water for injection in a separate vessel and then added to above solution with stirring. 0.1% of disodium edetate was dissolved in small volume of water and then 0.8% of sodium chloride was added to this solution which further added to ketorolac containing solution. The pH of the solution was adjusted between the range 6 to 7.5 with the help of 1N sodium hydroxide. Osmolality of solution was adjusted between 230-330 mOsm. The resulting bulk solution was first sterilized by filtration through 0.2 μ filter and then filled aseptically into suitable containers.
5

WE CLAIM:
1. An aqueous topical ophthalmic composition comprising 0.3% of ketorolac tromethamine and 1 to 1.5% hydroxypropyl-p-Cyclodextrin along with a suitable carrier.
2. An aqueous topical ophthalmic composition comprising essentially of 0.3% of ketorolac tromethamine and ophthalmologically acceptable excipient.
3. Ophthalmic composition according to claims 1 or 2 further comprising chelating agent, tonicity-adjusting agent, solubilizing agent and a preservative.
4. Ophthalmic composition according to claim 3, wherein the chelating agents comprises of edetate disodium, edetate calcium disodium, edetate sodium, edetate trisodium or edetate dipotassium.
5. Ophthalmic composition according to claim 3, wherein the tonicity adjusting agents comprises of glycerin, mannitol, sorbitol, sodium chloride or other electrolytes.
6. Ophthalmic composition according to claim 3, wherein the preservative comprises of benzalkonium chloride, phenylmercuric acetate, chlorobutanol, benzyl alcohol, parabens or thimerosal.
7. Ophthalmic composition according to claim 1 or 2 comprising 0.3% ketorolac tromethamine, 1 to 1.5% hydroxypropyl-p-cyclodextrin, 0.3 to 0.5% polyvinyl alcohol, 0.01% benzalkonium chloride, 0.05 to 0.1% of disodium edetate, 0.6 to 0.9% of sodium chloride and an effective amount of sodium hydroxide to adjust the pH to from 6 to 7.5.
6

8. Ophthalmic composition according to claim 1 or 2 in which the solution has a pH between 6 to 7.5.
9. Ophthalmic composition according to claim 1 or 2, which has an osmolality of about 230-330 mOsm.

Dated this 28 th day of March, 2006