Description:FIELD OF THE INVENTION:
The present invention relates to an ophthalmic composition of Brimonidine, Timolol and Brinzolamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients. More particularly, the present invention relates to an ophthalmic composition of Brimonidine Tartrate, Timolol Maleate and Brinzolamide and one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION:
Alpha-2 agonist or beta blocker or carbonic anhydrase inhibitor are either in monotherapy or in double combinations are approved for the treatment of elevated of intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma.

Brimonidine is a highly selective alpha-2 agonist. It lowers intraocular pressure (IOP)-lowering by reducing aqueous humor production and increasing uveoscleral outflow.

Timolol is a nonselective β-adrenergic blocker that reduces intraocular pressure by decreasing aqueous secretion with little effect on episcleral venous pressures, facility of outflow or uveoscleral outflow.

Brinzolamide is a carbonic anhydrase inhibitor. It is indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Brinzolamide and Brimonidine Tartrate is approved in the USA under brand name Simbrinza® (brinzolamide/brimonidine tartrate ophthalmic suspension 1%/0.2%) for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. The recommended dose is one drop of Simbrinza® in the affected eye(s) three times daily.

In the fixed-dose combination (FDC) of Brinzolamide and Brimonidine, the addition of a third agent, which is a beta-blocker (often timolol), can further contribute to the reduction of intraocular pressure (IOP) in glaucoma.

Brimonidine and Timolol is approved in the USA under brand name Combigan® (brimonidine tartrate/timolol maleate ophthalmic solution 0.2%/0.5%,) for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. The recommended dose is one drop of Combigan® in the affected eye(s) two times daily.

US patent application US2009/0069345 (US’345) discloses ophthalmic composition of Timolol maleate, Dorzolamide hydrochloride and Brimonidine tartrate, which further contains a combination of a tonicity agent, a buffer agent and a solubilizing agent and a preservative agent. The US’345 discloses the said ophthalmic composition is for the treatment of ocular hypertension.

PCT Application WO2013/175285 (WO’285) discloses the ophthalmic composition of Brinzolamide in the suspension form. Further WO’285 discloses sterile ophthalmic suspension comprising brinzolamide, polymer, surfactant and one or more excipients and optionally a beta blocker such as atenolol, Timolol, Betaxolol, Arteolol and/or alpha adrenergic agonist such as Brimonidine, Epinephrine.

US Patent application US 2017/0304316 (US’316) discloses ophthalmic formulation comprising carbonic anhydrase inhibitor Brinzolamide alone, in an aqueous solution or a combination of two intraocular pressure (IOP) reducing and/or glaucoma treatment agents.

US Patent No. US 9,421, 265 (US’265) discloses ophthalmic composition of Brinzolamide and Brimonidine with, boric acid and two polyols.

US Patent no. US 7,030,149 (US’149) disclose ophthalmic composition of Brimonidine and Timolol maleate with buffer and preservative.

None of the cited prior arts mentioned above discloses the stable, ophthalmic composition of Brimonidine tartrate, Timolol maleate and Brinzolamide in the suspension form.

It is well known fact that, patients with advanced glaucoma or elevated intraocular pressure might not reach a treatment target with monotherapy or with dual combinations of alpha-2 agonist or beta blocker or carbonic anhydrase inhibitor. Either they require a frequent administration of single of double combination products or require an add on therapy with other antiglaucoma agent like prostaglandins.

There are tremendous efforts are required to develop an stable ophthalmic suspension composition of three active ingredients due to their solubility and compatibility with other active agents.

After extensive experimentation, the inventors of present invention have come up with an improved and stable ophthalmic composition with alpha-2 agonist, beta blocker and carbonic anhydrase inhibitor (Brimonidine, Timolol and brinzolamide) in a single dosage form with minimum use of excipients with mixing and homogenization process. The ophthalmic composition of the present invention has an advantage over the prior approved products with respect to
Enhanced Efficacy: The triple combination product with drugs of different mechanisms of action can be more effective than using a single drug. This is especially true for patients who may not respond well to monotherapy or who require additional pressure reduction.
Convenience: A triple combination drug simplifies treatment for patients by providing multiple mechanisms of action in a single eye drop. This can lead to better adherence to the treatment regimen, as patients only need to use one medication instead of multiple separate eye drops.
Reduced Side Effects: In some cases, using lower doses of each individual medication in a combination can reduce the potential for side effects compared to using higher doses of a single drug.

OBJECTIVES OF THE INVENTION:
An objective of the invention is to provide an ophthalmic composition of Brimonidine, Timolol and Brinzolamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION:
The present invention provides ophthalmic compositions of Brimonidine, Timolol and Brinzolamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate, Timolol maleate and Brinzolamide and one or more pharmaceutically acceptable excipients.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol maleate equivalent to Timolol 0.5% w/v and Brinzolamide 1 % w/v and one or more pharmaceutically acceptable excipients.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v and Brinzolamide 1 % w/v and one or more pharmaceutically acceptable excipients.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v and Brinzolamide 1 % w/v and one or more pharmaceutically acceptable excipients, wherein the ophthalmic composition in the form of suspension.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v and Brinzolamide 1% w/v and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from group consisting of suspending agent, buffering agents, preservatives, tonicity-adjusting agents, pH-adjusting agents, chelating agents, antioxidants and solvents.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v and Brinzolamide 1% w/v and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from group consisting of suspending agent, buffering agents, preservatives, tonicity-adjusting agents, pH-adjusting agents, chelating agents, antioxidants and solvents wherein ophthalmic composition in the form of suspension.

In one of the embodiment, the present invention provides an ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer, benzalkonium chloride, sodium chloride, tyloxapol, mannitol and disodium edetate.

In one of the embodiment, the present invention provides an ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer 0.1% w/v to 1% w/v, benzalkonium chloride 0.001% w/v to 0.01% w/v, sodium chloride 0.1% w/v to 1% w/v, tyloxapol 0.01% w/v to 0.1% w/v, mannitol 1% w/v to 10% w/v, and disodium edetate 0.001% w/v to 0.05% w/v.

In one of the embodiment, the present invention provides an ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer 0.1 % w/v to 1% w/v, benzalkonium chloride 0.001% w/v to 0.01% w/v, sodium chloride 0.1% w/v to 1% w/v, tyloxapol 0.01% w/v to 0.1% w/v, mannitol 1% w/v to 10% w/v and disodium edetate 0.001% w/v to 0.05% w/v, wherein the pH of the ophthalmic composition is in the range of 5.5 to 7.5, osmolality is in the range of 260-340 mOsm/Kg and viscosity is in the range of 50 to 140 cps.

In one of the embodiment, the present invention provides an ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer 0.5% w/v, benzalkonium chloride 0.02% w/v, sodium chloride 0.3% w/v, tyloxapol 0.025% w/v, mannitol 2% and disodium edetate 0.01% w/v.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine, Timolol and Brinzolamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients for the reduction of elevated intraocular pressure and the treatment of ocular hypertension and glaucoma specifically advanced glaucoma which is not treated with either monotherapy or dual combination therapy.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v and Brinzolamide 1% w/v and one or more pharmaceutically acceptable excipients for the reduction of elevated intraocular pressure and the treatment of ocular hypertension and glaucoma specifically advanced glaucoma which is not treated with either monotherapy or dual combination therapy.

In one of the embodiment, the present invention provides a stable ophthalmic suspension comprising Brimonidine tartrate 0.2% w/v, Timolol maleate equivalent to Timolol 0.5% w/v, Brinzolamide 1% w/v, wherein the content of total impurities is below 1.5% after storage at 300C/65% Relative humidity (RH) or 400C/75% RH for at least 6 months. Further there is no significant change in physicochemical properties and no significant change in assay from initial values up to 6 months’ storage at accelerated conditions 400C/75% RH.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides an ophthalmic composition of Brimonidine, Timolol and Brinzolamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate, Timolol maleate and Brinzolamide and one or more pharmaceutically acceptable excipients.

In the fixed-dose combination (FDC) of Brinzolamide and Brimonidine, the addition of a third agent, which is a beta-blocker (often Timolol), further contributes to the reduction of intraocular pressure (IOP) in glaucoma. The inclusion of a beta-blocker enhances the efficacy of the combination by providing an additional mechanism of action that complements the actions of Brinzolamide and Brimonidine.

The use of a fixed-dose combination product containing Brinzolamide, Brimonidine, and Timolol potentially reduces the dosing frequency compared to using individual eye drops of these medications. This reduction in dosing frequency is one of the key advantages of using fixed-dose combinations in glaucoma treatment.

The reduction in dosing frequency can be particularly beneficial for patients, as it simplifies their treatment regimen and improves adherence to the prescribed therapy. Rather than needing to administer multiple eye drops at different times throughout the day.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol maleate equivalent to Timolol 0.5% w/v and Brinzolamide 1 % w/v and one or more pharmaceutically acceptable excipients.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v and Brinzolamide 1 % w/v and one or more pharmaceutically acceptable excipients.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v and Brinzolamide 1 % w/v and one or more pharmaceutically acceptable excipients, wherein the ophthalmic composition in the form of suspension.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v and Brinzolamide 1% w/v and one or more pharmaceutically acceptable excipients, wherein and one or more pharmaceutically acceptable excipients selected from group consisting of suspending agent, buffering agents, preservatives, tonicity-adjusting agents, pH-adjusting agents, chelating agents, antioxidants and solvents.

Examples of suitable suspending agents include, but are not limited to carboxyvinyl polymer/carbomer (trade name: Carbopol), cellulose polymer (hydroxypropylmethylcellulose, hydroxypropylcellulose, methyl cellulose, ethyl cellulose, hydroxyethvlcellulose), tyloxapol, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan esters or combination thereof.

Examples of suitable preservatives include, but are not limited to benzalkonium chloride, benzethonium chloride, p-oxybenzoates such as methyl p-oxybenzoate or ethyl p-oxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or its salt, thimerosal, chlorobutanol, other quaternary amines and, chlorhexidine gluconate or combination thereof.

Examples of suitable tonicity adjusting agents include, but are not limited to polyethylene glycol, propylene glycol, mannitol, glycerine dextrose, trehalose, sucrose, electrolytes selected from sodium chloride, potassium chloride, magnesium chloride or calcium chloride or combination thereof.

Examples of suitable alkaline agents as pH adjusting agents, include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaHCO3) and other organic and inorganic bases or combination thereof.

Examples of suitable acidic agents as pH adjusting agents include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, lactic acid and other organic and inorganic acids or combination thereof.

Examples of suitable chelating agents include, but are not limited to, EDTA, disodium edetate, sodium citrate, condensed sodium phosphate or combination thereof.

Examples of suitable antioxidants include, but are not limited to, ascorbic acid, malic acid, citric acid, sodium citrate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium ascorbate, sodium metabisulfite or combination thereof.

Examples of suitable solvents include, but are not limited to, water, ethanol, propylene glycol or combination thereof.

In one of the embodiment, the present invention provides an ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer, benzalkonium chloride, sodium chloride, tyloxapol, mannitol, disodium edetate.

In one of the embodiment, the present invention provides an ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer 0.1% w/v to 1% w/v, benzalkonium chloride 0.001% w/v to 0.01% w/v, sodium chloride 0.1% w/v to 1% w/v, tyloxapol 0.01% w/v to 0.1% w/v, mannitol 1% w/v to 10% w/v and disodium edetate 0.001% w/v to 0.05% w/v.

In one of the embodiment, the present invention provides an ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer 0.1 % w/v to 1% w/v, benzalkonium chloride 0.001% w/v to 0.01% w/v, sodium chloride 0.1% w/v to 1% w/v, tyloxapol 0.01% w/v to 0.1% w/v, mannitol 1% w/v to 10% w/v and disodium edetate 0.001% w/v to 0.05% w/v, wherein the pH of the ophthalmic composition is in the range of 5.5 to 7.5, osmolality is in the range of 260-340 mOsm/Kg and viscosity is in the range of 50 to 140 cps.

In one of the embodiment, the present invention provides an ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer 0.5% w/v, benzalkonium chloride 0.02% w/v, sodium chloride 0.3% w/v, tyloxapol 0.025% w/v, mannitol 2% w/v and disodium edetate 0.01% w/v.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine, Timolol and Brinzolamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients for the reduction of elevated intraocular pressure and the treatment of ocular hypertension and/or glaucoma specifically advanced glaucoma which is not treated with either monotherapy or dual combination therapy.

In one of the embodiment, the present invention provides an ophthalmic composition of Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v and Brinzolamide 1% w/v and one or more pharmaceutically acceptable excipients for the reduction of elevated intraocular pressure and the treatment of ocular hypertension and glaucoma specifically advanced glaucoma which is not treated with either monotherapy or dual combination therapy.

In one of the embodiment, the present invention provides a stable ophthalmic suspension comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, wherein the content of total impurities is below 1.5% after storage at 300C/65% relative humidity (RH) or 400C/75% RH for at least 6 months. Further there is no significant change in physicochemical properties and no significant change in assay from initial values up to 6 months’ storage at accelerated conditions 400C/75% RH.

Following examples are provided for illustration and should not be considered for limiting the scope of invention.
Example 1. Ophthalmic suspension composition of Brimonidine tartrate Timolol maleate and Brinzolamide
Table 1.
S.NO Ingredients mg/ml % w/v
1 Brinzolamide 10 1
2 Brimonidine tartrate 2 0.2
3 Timolol maleate (Eq. to 0.5% of Timolol) 6.8 0.68
4 Benzalkonium chloride 0.2 0.02
5 Sodium chloride 3 0.3
6 Tyloxapol 0.25 0.025
7 Carbomer (Carbopol 974) 5 0.5
8 Disodium edetate 0.1 0.01
9 Mannitol 20 2
10 Sodium hydroxide q.s. to pH q.s. to pH
11 Hydrochloric acid q.s. to pH q.s. to pH
12 Water for Injections q.s. to 1 ml

Manufacturing procedure
1. Preparation of carbomer solution.
1.1 Sodium chloride was added and dissolved in the Water for injection.
1.2 Carbomer (carbopol 974) was added in the solution of step 1.1.
1.3 The solution as prepared in Step 1.2 was autoclaved at 121- 124° for to 30 minutes.
2. Preparation of tyloxapol Solution
2.1 Tyloxapol was added and dissolved in the water for injection.
2.2 The solution as prepared in Step 2.1 was autoclaved at 121- 124° for to 30 minutes.
3. Preparation of buffer solution
3.1 Disodium edetate was added and dissolved in the water for injection.
3.2 Mannitol was added and dissolved in the solution of step 3.1.
3.3 Brimonidine tartrate was dissolved in the solution of step 3.2
3.4 Timolol maleate was added and dissolved in the solution of step 3.3.
3.5 Benzalkonium chloride was added in the solution of step 3.4
3.6 pH of solution of step 3.5 was adjusted using NaOH or HCl to 6.4 -6.6.
4. Homogenization process
4.1 Brinzolamide was added in the tyloxapol solution of step 2.2 and the slurry obtained was homogenized in the homogenizer for 10 minutes at 5000 Rotation per minute (RPM).
5. Filtration process
5.1 . The solution obtained in the step 3.6 was filtered through 0.2 micron PVDF filter to the slurry obtained in the step 4.1.
6. Aseptic Transfer of carbomer solution to form a Suspension
6.1 Carbomer solution obtained in step 1.3 was aseptically transferred and mixed to the slurry obtained in the step 5.1 to form a suspension. The suspension obtained was further stirred for 30 minutes.
6.2 Sodium hydroxide solution was added to the suspension obtained in step 6.1 to maintain the pH 6.4 to 6.6.

Stability of ophthalmic composition as prepared in example 1
The stability of ophthalmic composition comprising Brimonidine, Timolol and Brinzolamide as prepared in example 1 stored at 40oC/75% relative humidity (RH), 30oC/65% RH was determined at periodic intervals over a 3 month and 6 months’ period by determining the impurity levels and Physicochemical properties.
Impurity levels and assay were determined by HPLC method with PDA or UV/PDA detector and the data is presented in table 2 as a percentage of specific impurity:
Table 2.
Name of the Impurity
Specification Percentage of Impurity
300C/65% (RH) Percentage of Impurity
400C/75% (RH)
Initial 3 Month 6 Month Initial 3 Month 6 Month
Assay of Brinzolamide NLT 90% and NMT 110% w/v 98.9% 99.2% 100.2% 98.9% 99.6% 100.6%
Assay of Brimonidine tartrate NLT 90% and NMT 110% w/v 100.4% 99.4% 101.3% 100.4% 98.7% 100.8%
Assay of Timolol NLT 90% and NMT 110% w/v 97.8% 98.3% 99.3% 97.8% 98.1% 99.7%
Assay of Benzalkonium chloride NLT 80% and NMT 120% w/v 96.1% 94.7% 96.4% 96.1% 96.4% 96.6%
Brinzolamide lmp-B NMT 0.5% ND ND ND ND ND ND
Brinzolamide Imp-G NMT 0.5% ND ND ND ND ND ND
Timolol Imp-D NMT 0.5% ND ND ND ND ND ND
Timolol Imp-C NMT 0.5% ND ND ND ND ND ND
Timolol Imp-B NMT 0.5% ND ND ND ND ND ND
Timolol Imp-F NMT 0.5% ND ND ND ND ND ND
Highest Unknown Impurity NMT 0.3% 0.005% 0.012% 0.044% 0.005% 0.044% 0.085%
Total Impurities NMT 1.4% 0.021% 0.061% 0.179% 0.021% 0.087% 0.198%
NMT: Not more than; NLT: not less than; ND: Not detected

Physicochemical properties of the ophthalmic composition comprising Brimonidine, Timolol and Brinzolamide as per example 1 at initial and at accelerated condition are presented in Table 3

Table 3.
Physico chemical properties
Specification Physicochemical properties
300C/65% (RH) Physicochemical properties
400C/75% (RH)
Initial 3 Month 6 Month Initial 3 Month 6 Month
Description Milky white to Pale yellow color suspension Off white color suspension Off white color suspension Off white color suspension Off white color suspension Off white color suspension Off white color suspension
pH Between
6.0 to 7.0 6.51 6.508 6.526 6.51 6.51 6.508
Osmolality Between
260-340 mOsm/Kg 292 284 312 292 310 303
Viscosity Between 50 to 140 cps 55.04 56.7 62.46 55.04 55.52 60.06

Conclusion
Based on the above stability data, it can be concluded that ophthalmic composition comprising Brimonidine, Timolol and Brinzolamide as per example 1 is stable as there is no significant increase in impurities, no significant change in physicochemical properties and no significant change in assay from initial values up to 6 months’ storage at accelerated conditions.

Example 2 Clinical Study of ophthalmic composition as prepared in example 1.
The Multicentric, Phase III, Prospective, Open-label study was performed on Ophthalmic suspension composition of Brimonidine tartrate Timolol maleate and Brinzolamide as prepared in example 1. The study was conducted at 10 centres across India. Subjects were instructed to instil One drop bid for 12 weeks. There were 5 visits with activities including recording of intra ocular pressure (IOP), physical examination, vital signs assessment, ophthalmology examinations, ECG, lab parameters. All subjects were enrolled according to pre-defined criteria. 200 subjects completed study. Efficacy endpoints: change in IOP from baseline at week 12 and at week 2, week 6. Safety endpoints included ophthalmic examination, recording of adverse events.
Results: Mean change in IOP from baseline to end of study (week 12) was 10.53±0.18 mmHg(p<0.001). The percentage decrease being 41.01%. IOP mean change from baseline to week 2 was 4.39±0.21 mmHg (p<0.001), week 6 was 7.57±0.20 mmHg (p<0.001). There was a gradual decrease of IOP. >86% of subjects achieved IOP ≤18 mmHg at end of study. There were no serious adverse events.
Conclusion: The current trial establishes that Ophthalmic suspension composition of Brimonidine tartrate Timolol maleate and Brinzolamide as prepared in example 1 is safe, effective and well tolerated in lowering IOP. Ophthalmic suspension composition of Brimonidine tartrate Timolol maleate and Brinzolamide is effective in Glaucoma management.
, Claims:1. An ophthalmic composition comprising Brimonidine, Timolol and Brinzolamide or their pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

2. The ophthalmic composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from a group consisting of suspending agents, buffering agents, preservatives, tonicity-adjusting agents, pH-adjusting agents, chelating agents, antioxidants and solvents.

3. The ophthalmic composition as claimed in claim 1 wherein the ophthalmic composition in the form of a suspension.

4. The ophthalmic composition as claimed in claim 1 wherein pH of the ophthalmic composition is in the range of 5.5 to 7.5, osmolality is in the range of 260-340 mOsm/Kg and viscosity is in the range of 50 to 140 cps.

5. An ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer, benzalkonium chloride, sodium chloride, tyloxapol, mannitol and disodium edetate.

6. An ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer 0.1 % w/v to 1% w/v, benzalkonium chloride 0.001% w/v to 0.01% w/v, sodium chloride 0.1% w/v to 1% w/v, tyloxapol 0.01% w/v to 0.1% w/v, mannitol 1% w/v to 10% w/v and disodium edetate 0.001% w/v to 0.05% w/v.

7. An ophthalmic composition comprising Brimonidine tartrate 0.2% w/v, Timolol 0.5% w/v, Brinzolamide 1% w/v, carbomer 0.5% w/v, benzalkonium chloride 0.02% w/v, sodium chloride 0.3% w/v, tyloxapol 0.025% w/v, mannitol 2%, disodium edetate 0.01% w/v.

8. The ophthalmic composition as claimed in claim 7 wherein ophthalmic composition in the form of a suspension.

9. The composition in the form of a medicament as claimed in claim 7 for the treatment of ocular hypertension and glaucoma to a subject in need thereof.

10. An ophthalmic composition comprising Brimonidine, Timolol and Brinzolamide or their pharmaceutically acceptable salts thereof for the treatment of ocular hypertension and advance glaucoma to a subject in need thereof.