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:
OPHTHALMIC COMPOSITION COMPRISING BRIMONIDINE OR SALT THEREOF
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 brimonidine or salt thereof along with ophthalmically acceptable carriers.
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 ophthalmic composition comprising of brimonidine or salt thereof along with ophthalmically acceptable carriers.
Brimonidine tartrate is a relatively selective alpha-2 adrenergic agonist for ophthalmic use. The chemical name of brimonidine tartrate is 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate of formula 1. It is off-white to pale yellow powder. It has a molecular weight of 442.24 as the tartrate salt, and is both soluble in water (0.6 mg/mL) and in the product vehicle (1.4 mg/mL) at pH 7.7. Brimonidine is indicated for the lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension

I \ COOH
HN NH
Y
H-C'-OH
I IIO-C— H
I
COOH
Br
to
'N FORMULA 1
US Patent 5,424,078 provides preserved ophthalmic formulation comprising an ophthalmically acceptable aqueous medium and, included therein, stabilized chlorine dioxide, at least one ophthalmically acceptable buffer component at a pH in the range of about 6.8 to about 8, and at least one ophthalmically acceptable tonicity component.
US Patent 6,562,873 provides composition comprising a alpha-2-adrenergic agonists and mixtures thereof, a solubility enhancing component, other than a cyclodextrin, an oxy-chloro component in an effective amount to at least aid in preserving the composition; and a liquid carrier component
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US Patent 6,627,210 provides aqueous composition comprising a therapeutically active alpha-2-adrenergic agonist component selected from the group consisting of 5-bromo-6-(2-imidozolin-2-ylamino) quinoxaline, a salt thereof, and an ester thereof; and a polyanionic solubility enhancing component.
US Patent 6,641,834 provides therapeutically effective aqueous ophthalmic composition comprising: up to about 0.15% (w/v) of 5-bromo-6-(2-imidozolin-2-ylamino)quinoxaline tartrate, the composition having a pH of about 7.0 or greater, and the 5-bromo-6-(2-imidozolin-2-ylamino) quinoxaline tartrate being soluble in the composition at about 21 °C.
US Patent 6,673,337 provides ophthalmic composition comprising an alpha-2-adrenergic agonist component; and a solubility enhancing component other than a cyclodextrin.
US Patent Application 2005-0250778 provides topically administrable ophthalmic composition comprising 0.05-0.2% (w/v) brimonidine tartrate; polyquaternium-1; boric acid; polyvinylpyrrolidone, a tonicity adjusting agent, wherein the tonicity adjusting agent is selected from the group consisting of metal chloride salts; mannitol; and mixtures of metal chloride salts and mannitol; and water, wherein the composition is a solution and has a pH from 6.5-7.5.
US Patent Application 2005-0026924 provides aqueous ophthalmic composition comprising about 0.1% (w/v) of an alpha 2 adrenergic agonist selected from the group comprising 5-bromo-6-(2-imidozolin-2-ylamino) quinoxaline, a salt of 5-bromo-6-(2-imidozolin-2-ylamino) quinoxaline, and an ester of 5-bromo-6-(2-imidozolin-2-ylamino) quinoxaline, wherein the composition has a pH of about 7.7.
US Patent Application 20020198210 provides composition comprising an alpha-2-adrenergic agonist, and a fatty acid component, the fatty acid component forms
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a complex with the alpha-2-adrenergic agonist; the complex remaining substantially intact in an aqueous environment.
The present invention now provides an ophthalmic composition comprising brimonidine or salt thereof, cyclodextrin or derivatives thereof along with ophthalmically acceptable carriers. The brimonidine or salt thereof is used in admixture with cyclodextrin or derivative thereof. The brimonidine can also present in the form of complex with cyclodextrin or derivative thereof.
The present invention also provides a stabilized ophthalmic composition comprising 0.15% brimonidine or salt thereof in admixture with ophthalmically acceptable carriers wherein composition comprises benzalkonium chloride as preservative.
In one of the aspects of the present invention there is provided an ophthalmic composition comprising therapeutically effective amount of brimonidine or salt thereof wherein brimonidine or salt thereof is present in admixture with cyclodextrin or derivative thereof along with ophthalmically acceptable carriers.
In another aspect of the present invention there is provided an ophthalmic composition comprising therapeutically effective amount of brimonidine or salt thereof along with ophthalmically acceptable carriers wherein brimonidine is present in the form of complex with cyclodextrins or derivatives thereof.
In yet another aspect of the present invention there is provided a stabilized ophthalmic composition comprising 0.15% brimonidine or salt thereof in admixture with ophthalmically acceptable carriers wherein composition comprises benzalkonium chloride in an effective amount to act as a preservative.
Alpha-2-adrenergic agonist components are the compounds, which are effective to act on or bind to alpha-2-adrenergic receptors and provide a therapeutic effect.
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Brimonidine-cyclodextrin complex helps to improve aqueous solubility of the Brimonidine. This increased solubility of brimonidine helps to promote uniform and accurate administration.
The interior of the cyclodextrin molecule is hydrophobic while the exterior is sufficiently hydrophilic to allow the cyclodextrin to be dissolved in water. This difference between the interior and exterior faces allows the cyclodextrin to act as a host molecule and to form inclusion complexes with brimonidine. The cyclodextrin-brimonidine inclusion complex can then be dissolved in water thereby providing for the introduction of brimonidine into an aqueous environment.
Cyclodextrins are cyclic (a-1,4)-linked oligosaccharides of a-D-gluco-pyranose containing a relatively hydrophobic central cavity and hydrophilic outer surface. In the pharmaceutical industry, cyclodextrins have mainly been used as complexing agents to increase the aqueous solubility of poorly water-soluble drugs, and to increase their stability. Light, thermal and oxidative stability of actives may be improved through the formation of cyclodextrin complexes. Suitable cyclodextrin derivatives may be selected from hydroxypropyl-β-cyclodextrin, β-cyclodextrin, α-cyclodextrin, hydroxypropyl- α-cyclodextrin and the like.
Hydroxypropyl-β-cyclodextrin, a chemically modified p-cyclodextrin is highly water soluble, stable and its safety and tolerance has been well documented. Its ability to improve aqueous solubility has been attributed to the formation of inclusion complex between cyclodextrins and 'guest' drug molecule. The prepared HP-β-CD complex is stable and increases aqueous solubility.
Benzalkonium chloride is a detergent type, quaternary ammonium antimicrobial preservative used in topical multiuse ophthalmic preparations. Benzalkonium chloride is highly efficacious against numerous microbes and works by
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denaturing proteins and causing lysis of cytoplasmic membranes. The surfactant abilities of benzalkonium chloride enable it to solubilize the intercellular cement of the corneal epithelium thereby increasing penetration of benzalkonium chloride. The benzalkonium chloride can accumulate in ocular tissue, remaining for relatively lengthy periods. As a result, benzalkonium chloride can induce different types of cell death in a dose-dependent manner.
Benzalkonium chloride is used in combination with disodium edetate and octoxynol 12.5 or octoxynol 40, which further helps to reduce the quantities of benzalkonium chloride i. e. below 0.005% and between 0.001% to 0.004%.
Therapeutically effective amount of brimonidine or salt thereof was added to the formulation in the form of complex. The complex of brimonidine and HP-β-CD was prepared by various processes including solvent evaporation, kneading, spray drying, colloidal milling, high speed mixing, trituration or simple mixing. The brimonidine is in an amount relative to the cyclodextrin such that a molar ratio between the brimonidine and the cyclodextrin is from about 1:1 to 1:10.
The brimonidine ophthalmic solution may be prepared by the processes known in the art. Polyvinyl alcohol is dissolved in suitable solvent. Brimonidine and all other ingredients are added to this solution. pH of solution is adjusted by using suitable pH adjusting agent. Solution is filtered through 0.22pm filter and filled in suitable container and capped.
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.
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EXAMPLES
The composition of the batches is provided in example 1, example 2 and example 3 and example 4.
Example 1 -
Table 1 - Brimonidine tartrate ophthalmic solution

Sr.No Ingredients % Composition
1 Brimonidine Tartrate 0.15%
2 Polyvinyl Alcohol 0.3 to 1.0%
3 Sodium Citrate 0.5% to 2.0%
4 Citric acid 0.5 t0 1.5%
5 Sodium Chloride 0.001 % to 0.9%
6 Disodium Edetate 0.01%-0.05%
7 Benzalkonium Chloride 0.002% to 0.004
8 Water For injection q.s. 100%
Procedure:
Polyvinyl alcohol is dissolved in suitable solvent. Brimonidine and all other ingredients are added to this solution. pH of solution is adjusted by using suitable pH adjusting agent. Solution is filtered through 0.22um filter and filled in suitable container and capped.
Example 2 -
Table 2 - Brimonidine tartrate ophthalmic solution

Sr.No Ingredients % Composition
1 Brimonidine Tartrate 0.15%
2 Polyvinyl Alcohol 0.3 to 1.0%
3 Sodium Citrate 0.5% to 2.0%
4 Citric acid 0.5 t0 1.5%
5 Sodium Chloride 0.001 % to 0.9%
6 Octoxynol 12.5 or Octoxynol 40 0.001 %-0.05%
7 Benzalkonium Chloride 0.002% to 0.004
8 Water For injection q.s. 100%
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Procedure:
Polyvinyl alcohol is dissolved in suitable solvent. Brimonidine and all other ingredients are added to this solution. pH of solution is adjusted by using suitable pH adjusting agent. Solution is filtered through 0.22um filter and filled in suitable container and capped.
Example 3 -
Table 3 - Brimonidine tartrate ophthalmic solution with HPβCD and Polyvinyl alcohol

Sr.No Ingredients % Composition
1 Brimonidine Tartrate 0.15%
2 Hydroxypropyl betacyclodextrin 0.5 to 1.5%
3 Polyvinyl Alcohol 0.3 to 1.0%
4 Sodium Citrate 0.5% to 2.0%
5 Citric acid 0.5 t0 1.5%
6 Sodium Chloride 0.001 % to 0.9%
7 Octoxynol 12.5 or Octoxynol 40 0.001 %-0.05%
8 Benzalkonium Chloride 0.002% to 0.004
9 Water For injection q.s. 100%
Procedure:
Brimonidine tartrate and hydroxypropyl betacyclodextrin are mixed together.
Polyvinyl alcohol is dissolved in suitable solvent. All other ingredients are added
to this solution. pH of solution is adjusted by using suitable pH adjusting agent.
Solution is filtered through 0.22p.m filter and filled in suitable container and
capped.
Example 4 -
Table 4 - Brimonidine tartrate ophthalmic solution Brimonidine tartrate ophthalmic solution with HPβCD and without polyvinyl alcohol
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Sr.No Ingredients % Composition
1 Brimonidine Tartrate 0.15%
2 Hydroxypropyl betacyclodextrin 0.5 to 1.5%
3 Sodium Citrate 0.5% to 2.0%
4 Citric acid 0.5 t0 1.5%
5 Sodium Chloride 0.001 % to 0.9%
6 Octoxynol 12.5 or Octoxynol 40 0.001 %-0. 05%
7 Benzalkonium Chloride 0.002% to 0.004
8 Water For injection q.s. 100%
Procedure:
Brimonidine tartrate and hydroxypropyl betacyclodextrin are mixed together. All other ingredients are added to this solution. pH of solution is adjusted by using suitable pH adjusting agent. Solution is filtered through 0.22p.m filter and filled in suitable container and capped.
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WE CLAIM:
1. An ophthalmic composition comprising therapeutically effective amount of brimonidine or salt thereof wherein brimonidine or salt thereof is present in admixture with cyclodextrin or derivative thereof along with ophthalmically acceptable carriers.
2. An ophthalmic composition comprising therapeutically effective amount of brimonidine or salt thereof along with ophthalmically acceptable carriers, wherein brimonidine is present in the form of complex with cyclodextrins or derivatives thereof.
3. A stabilized ophthalmic composition comprising 0.15% brimonidine or salt thereof in admixture with ophthalmically acceptable carriers wherein composition comprises benzalkonium chloride in an effective amount to act as a preservative.
4. An ophthalmic composition according to claims 1 and 2, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin.

5. An ophthalmic composition according to claims 1, 2 and 3, wherein ophthalmically acceptable carriers comprises water.
6. An ophthalmic composition according to claim 3, wherein the benzalkonium chloride has the concentration between 0.002% to 0.004.
7. Ophthalmic composition according to claim 1, 2 and 3 further comprises chelating agent, tonicity adjusting agent, buffer component and a preservative.
8. Ophthalmic composition according to claim 7, wherein the chelating agents
comprises of edetate disodium, edetate calcium disodium, edetate sodium,
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edetate trisodium, edetate dipotassium and the like.
9. Ophthalmic composition according to claim 7, wherein the tonicity adjusting agents comprises of mannitol, sorbitol, sodium chloride, other electrolytes and the like.
10. Ophthalmic composition according to claim 7, wherein the buffer component comprises of boric acid, potassium chloride and the like.
Dated this 29th day of September, 2006 For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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