DESC:FIELD OF INVENTION:
The present invention relates to a preservative-free pharmaceutical composition suitable for ophthalmic use comprising carbonic anhydrase inhibitor and a2 adrenergic receptor agonist and process to prepare the same. More particularly, the present invention relates to a preservative free ophthalmic composition comprising dorzolamide or its pharmaceutically acceptable salt thereof and brimonidine or its pharmaceutically acceptable salt thereof for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

BACKGROUND OF THE INVENTION:
Dorzolamide, a carbonic anhydrase inhibitor has the ability to reduce intraocular pressure, and thus is useful for the treatment of glaucoma or ocular hypertension. A formulation comprising dorzolamide is commercially available as “Trusopt” ophthalmic solution. Moreover, a formulation comprising dorzolamide and timolol is commercially available as “Cosopt” combined ophthalmic solution.

Furthermore, brimonidine is an a2 receptor agonist, also has the ability to reduce intraocular pressure, and thus is useful for treatment of glaucoma or ocular hypertension. A formulation comprising brimonidine is commercially available as “Alphagan P” ophthalmic solution which contains ‘Purite’ as a preservative.

Ophthalmic solutions should have a certain or higher level of preservative efficacy to prevent fungi and the like from propagation associated with repeated uses of the solutions. For example, the above “Trusopt” ophthalmic solution or “Cosopt” combined ophthalmic solution is formulated with benzalkonium chloride as a preservative. However, benzalkonium chloride has cytotoxicity and can induce corneal epithelium disorder if exposure is increased.

Preservative free ophthalmic composition of dorzolamide or its pharmaceutically acceptable salt thereof and/or brimonidine or its pharmaceutically acceptable salt thereof are well known in the arts and significantly reduce ocular symptoms including discomfort upon instillation, burning and stinging, foreign body sensation, and tearing.

US20190038598 discloses ophthalmic composition of dorzolamide or its pharmaceutically acceptable salt thereof and brimonidine or its pharmaceutically acceptable salt thereof having pH of 6.0 or more and which is free of preservative with excipients like sodium citrate hydrate, mannitol, and sodium hydroxide.

EP2886130 discloses ophthalmic composition of dorzolamide or its pharmaceutically acceptable salt thereof and brimonidine or its pharmaceutically acceptable salt thereof which is free of preservative with excipients like mannitol and hydroxy ethyl cellulose.

US20180169092 discloses method for treating or mitigating glaucoma using alpha 2 adrenergic agonist (brimonidine or its pharmaceutically acceptable salt thereof), carbonic anhydrase inhibitor (dorzolamide or its pharmaceutically acceptable salt thereof), ß - adrenergic antagonist and prostaglandin analog ingredients which are free of preservatives.

WO2024018090 discloses preservative-free ophthalmic composition comprising a carbonic anhydrase inhibitor for treatment of elevated intraocular pressure and discloses excipients like hydroxyethyl cellulose, mannitol, sodium citrate.

However, there is no such preservative free ophthalmic composition of dorzolamide hydrochloride and brimonidine tartrate that contains polysorbate 80.

Accordingly, there is a need to develop a preservative free ophthalmic formulation of dorzolamide hydrochloride and brimonidine tartrate with polysorbate 80 as a solubilizer and hydroxyethyl cellulose as a viscosity modifier.

OBJECT OF THE INVENTION:
An object of the present invention is to provide a preservative free ophthalmic composition comprising dorzolamide or its pharmaceutically acceptable salts thereof and brimonidine or its pharmaceutically acceptable salts thereof.

Another objective of the invention is to develop a preservative free ophthalmic composition comprising dorzolamide or its pharmaceutically acceptable salts thereof and brimonidine or its pharmaceutically acceptable salts thereof for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Further object of the invention is to provide a process of preparing a preservative free ophthalmic composition of dorzolamide hydrochloride and brimonidine tartrate.

SUMMARY OF THE INVENTION
The present invention relates to a preservative free ophthalmic composition comprising carbonic anhydrase inhibitor and a2 adrenergic receptor agonist and a process to preparing the same.

More particularly, the present invention relates to a preservative free ophthalmic composition comprising dorzolamide hydrochloride and brimonidine tartrate, and polysorbate 80 as a solubility enhancer to increase the solubility of dorzolamide and to prevent the crystallization in the finished formulation.

Further, the present invention relates to a preservative free ophthalmic composition comprising dorzolamide or its pharmaceutically acceptable salt thereof and brimonidine or its pharmaceutically acceptable salt thereof for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
The present invention further relates to a process of preparing a preservative free ophthalmic composition comprising dorzolamide hydrochloride and brimonidine tartrate.

DETAILED DESCRIPTION OF THE INVENTION
The present invention is to develop a preservative free ophthalmic ophthalmic composition comprising dorzolamide or its pharmaceutically acceptable salt thereof and brimonidine or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Dorzolamide hydrochloride is described chemically as (4S-trans)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b] thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. It has a molecular weight of 360.91. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol and has following structural formula:

Dorzolamide hydrochloride is a potent topical carbonic anhydrase inhibitor, which reduces the formation of bicarbonate and, consequently, the aqueous humor and thereby causes a reduction in elevated intraocular pressure.

Brimonidine tartrate is described chemically as 5-Bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate. Brimonidine appears as an off-white to pale-yellow powder and is water soluble and has following structural formula:

Brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow.

In one embodiment, the preservative free ophthalmic composition of the present invention comprises from about 0.1 to about 5% w/v of dorzolamide or its pharmaceutically acceptable salt thereof.

In another embodiment, the preservative free ophthalmic composition of the present invention comprises from about 0.01% to about 0.5% w/v of brimonidine or its pharmaceutically acceptable salt thereof.

In another embodiment, the preservative free ophthalmic composition of the present invention comprises from about 0.1% to about 5% w/v of dorzolamide hydrochloride and from about 0.01% to about 0.5% w/v of brimonidine tartrate.

In a further embodiment, the preservative free ophthalmic composition of the present invention comprises dorzolamide hydrochloride and brimonidine tartrate.

The preservative free ophthalmic compositions, according to the present invention may comprise one or more pharmaceutically acceptable excipients which include at least one excipient selected from, but are not limited to, buffering agent, tonicity agent, viscosity modifying agent, solubilizing agent, pH adjusting agent, and mixture thereof.

In an embodiment, the preservative free ophthalmic composition of the present invention further comprises from about 0.01% w/v to about 10% w/v of buffering agent, more preferably from about 0.1% w/v to about 3% w/v, and most preferably from about 0.2% w/v to about 2% w/v of the composition.

Buffering agents, that may be used, comprise, but are not limited to phosphate, acetate, glycine, citrate, imidazole, TRIS, MES, MOPS or mixtures thereof.

In another embodiment, the preservative free ophthalmic composition of the present invention further comprises from about 0.01% w/v to about 10% w/v tonicity adjusting agent, more preferably from about 0.1% w/v to about 5% w/v, and most preferably from about 1% w/v to about 3% w/v of the composition.

Tonicity-adjusting agents, that may be used, comprise, but are not limited to, mannitol, anhydrous glucose, glycerol, sorbitol, trehalose, boric acid, citric acid, sodium tartrate, sodium phosphate, potassium phosphate, sodium chloride, glycerin, propylene glycol or other inorganic or organic solutes, dextrose or mixtures thereof.

In an embodiment, the preservative free ophthalmic composition of the present invention comprises from about 0.1% w/v to about 5% w/v viscosity modifying agent, more preferably from about 0.1% w/v to about 1.5% w/v, most preferably from about 0.2% w/v to about 1% w/v of the composition.

Viscosity modifying agents include, but are not limited to, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or mixture thereof.

In another embodiment, the preservative free ophthalmic composition of the present invention comprises from about 0.1% w/v to about 5% w/v solubilizing agent, more preferably from about 0.1% w/v to about 1.0% w/v, most preferably from about 0.1% w/v to about 0.3% w/v of the composition.

Solubilizing agents, that may be used, comprise, but are not limited to poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls or mixture thereof.

In a preferred embodiment, the preservative free ophthalmic composition comprises polysorbate 80 as a solubilizing agent to increase solubility and to prevent the crystallization of dorzolamide hydrochloride or its pharmaceutically acceptable salt thereof.

In one embodiment, the preservative free ophthalmic composition of the present invention further comprises a pH adjusting agent.

pH adjusting agents, that may be used, comprise, but are not limited to hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate or mixture thereof.
In an embodiment, the preservative free ophthalmic composition of the present invention is an aqueous solution.

In particular, in preferred embodiment, the preservative free ophthalmic composition comprises dorzolamide hydrochloride and brimonidine tartrate and pharmaceutically acceptable excipients.

In preferred embodiment, the preservative free ophthalmic composition of dorzolamide hydrochloride and brimonidine tartrate comprises viscosity modifying agent, tonicity agent, buffering agent, solubilizing agent, pH adjusting agent and vehicle.

In another preferred embodiment, the preservative free ophthalmic composition of dorzolamide hydrochloride and brimonidine tartrate comprises hydroxy ethyl cellulose, mannitol, sodium citrate dihydrate, citric acid monohydrate, polysorbate 80, sodium hydroxide and water for injection.

According to another embodiment, the present invention also relates to a process of preparing a preservative free ophthalmic composition comprising mixing and sterilizing a polymer phase along with a drug buffer phase.

In an embodiment, the present invention also relates to preservative free ophthalmic composition for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Example 1:
Sr.
No. Ingredients Quantity
(%w/v)
1 Dorzolamide hydrochloride 2.226
2 Brimonidine Tartrate 0.100
3 Sodium Citrate dihydrate 0.294
4 Citric acid monohydrate 0.020
5 Mannitol 2.400
6 Polysorbate-80
(Tween 80) (Super refined) 0.250
7 Hydroxy ethyl cellulose
(Natrosol 250 HHX) 0.310
8 Hydroxy ethyl cellulose
(Natrosol 250 HX) 0.200
9 Sodium hydroxide q.s. to adjust pH

Manufacturing process:
1. Hydroxy ethyl cellulose and mannitol were dry mixed.
2. The dry mix obtained in step 1 was dissolved in water for injection and sterilized.
3. Sodium citrate dihydrate, citric acid, mannitol, polysorbate 80, dorzolamide hydrochloride, brimonidine tartrate were dissolved in water for injection.
4. The mixture obtained in step 2 was filtered and added to the mixture obtained in step 3.
5. The pH was adjusted with sodium citrate hydrate/citric acid monohydrate; and the volume of solution was adjusted with water for injection.

In an embodiment, a qualitative composition as well as a novel quantitative preservative free ophthalmic composition for the treatment of reduction of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma containing a combination of dorzolamide and brimonidine, with excipients such as hydroxyethyl cellulose and polysorbate 80, which allow for the co-existence of the two active principles with good stability.

Example 2: Stability studies with above example is tabulated below:
Test Specification Initial 40 ?C/20% RH
(6 months) 30 ?C/35% RH
(12 months)
Description Clear colourless solution Clear colourless solution Clear colourless solution
pH NLT 5.0 – NMT 6.5 5.51 5.59 5.58
Osmolality (mOsmol/kg) NLT 250– NMT 350 286 291 293
Assay
(Content of Dorzolamide hydrochloride equivalent to dorzolamide) NLT 90.0% – NMT 110.0% 101.4 103.4 103
Content of Brimonidine Tartrate NLT 90.0% – NMT 110.0% 102.7 103.6 100.6
Degradation products
Dorzolamide related compound B NMT 1.3% < 0.1 0.9 0.39
Brimonidine Impurity A NMT 1.0% ND ND ND
Any unspecified degradation product NMT 0.5% < 0.1 < 0.1 < 0.1
Total degradation product NMT 3.0% < 0.1 0.9 0.39

Conclusion: As per stability data, the initial and 6 months accelerated condition (40 ?C/20% RH) and 12 months (30 ?C/35% RH) long term stability results were satisfactory.
,CLAIMS:
1. A preservative free ophthalmic composition comprising dorzolamide or its pharmaceutically acceptable salts thereof, brimonidine or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

2. The preservative free ophthalmic composition according to claim 1 comprises dorzolamide hydrochloride, brimonidine tartrate and one or more pharmaceutically acceptable excipients.

3. The preservative free ophthalmic composition according to claim 1 comprises from about 0.1% w/v to about 5% w/v of dorzolamide hydrochloride, from about 0.01% w/v to about 0.5% w/v of brimonidine tartrate and one or more pharmaceutically acceptable excipients.

4. The preservative free ophthalmic composition according to claim 1 comprises 2.26% w/v dorzolamide hydrochloride, 0.1% w/v brimonidine tartrate and one or more pharmaceutically acceptable excipients.

5. The preservative free ophthalmic composition according to claim 1 comprises 2.26% w/v dorzolamide hydrochloride, 0.1% w/v brimonidine tartrate and one or more of buffering agent, tonicity agent, viscosity modifying agent, solubilizing agent, pH adjusting agent or mixtures thereof.

6. The preservative free ophthalmic composition according to claim 1 comprising

7. The preservative free ophthalmic composition according to claim 1 for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.