FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate for the treatment of glaucoma and ocular hypertension.

BACKGROUND OF THE INVENTION

Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.

A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acid and have important functions in the body. Prostaglandins have notoriously low water solubility, and are generally unstable.
Travoprost is a synthetic prostaglandin F 2a analogue which reduces IOP. Travoprost increase aqueous humor outflow, either by enhancing the pressure-sensitive (presumed trabecular) outflow pathway or by increasing the pressure-insensitive (uveoscleral) outflow.

Brimonidine tartrate is a highly selective alpha-2 adrenergic antagonist ocular antihypertensive drug. Some studies suggest that brimonidine may be used as a joint treatment to topical beta-blocker therapy, producing an additive effect of intraocular pressure reduction from 5 and 3.7 mm of Hg.

Timolol is a non-selective Pi and 02 beta-adrenergic blocking agent, which reduces high and regular intraocular pressure. The start of the drug's action with one drop of it can be detected within a single hour of topical ocular instillation, with a peak effect observed within 2 to 4 hours. A significant reduction of intraocular pressure can be maintained for periods of up to 24 hours with a single dose.

To date, there is no known ophthalmic formulation, which specifically suggests the combination of Travoprost, Timolol Maleate and Brimonidine Tartrate for the treatment of ocular hypertension, and thus the present invention has inventive merits of its own as will become evident through the following description.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a method for treating and controlling glaucoma and ocular hypertension, which comprises administering combination of a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate and a pharmacologically effective amount of Brimonidine Tartrate.

One more objective of the present invention is to provide a pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate and a pharmacologically effective amount of Brimonidine Tartrate for the treatment of glaucoma and ocular hypertension.

One more objective of the present invention is to provide qualitative composition as well as a novel quantitative composition for the treatment of ocular hypertension comprising of a combination of Travoprost, Timolol Maleate and Brimonidine Tartrate, with Polyoxyethylene hydrogenated castor oil 40, which allow for the co-existence of the three active principles with good stability and synergic effect in order to treat glaucoma and ocular hypertension.

One more objective of the present invention is to determine whether any chemical reactions that produce modifications in the active molecules take place in the combinations of Travoprost, Timolol Maleate and Brimonidine Tartrate, with Polyoxyethylene hydrogenated castor oil 40.

One more objective of the present invention is to provide a method for producing
pharmaceutical composition of Timolol Maleate, Travoprost and Brimonidine Tartrate, which is physico-chemically compatible and stable and there is no antagonistic effect among Travoprost, Timolol Maleate, and Brimonidine Tartrate, which produce modifications in the active molecules.

Another objective of the present invention is to determine the qualitative composition of the excipients in pharmaceutical composition of Travoprost, Timolol Maleate, and Brimonidine Tartrate, which is physico-chemically compatible, stable and there is no antagonistic effect among Timolol Maleate, Travoprost and Brimonidine Tartrate, which produce modifications in the active molecules.

DETAILED DESCRIPTION OF THE INVENTION

The term "Travoprost" as used in the invention is meant to cover Travoprost in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof.

The term "Brimonidine" as used in the invention is meant to cover Brimonidine in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof.

The term "Timolol" as used in the invention is meant to cover Timolol in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof.

The term "Pharmaceutical composition" herein refers to the combination of one or more drug substances and one or more excipients such as "Drug product," "pharmaceutical dosage form," "dosage form," "final dosage form" and the like, refer to a pharmaceutical composition that is administered to a subject in need of treatment and generally may be in the form of solution, emulsion, suspension, eye drop, gel, eye patch and the like.

Polyoxyethylene hydrogenated castor oil 40 according to present invention is a reaction product of castor oil and ethylene oxide, for example the commercial- products Cremophor EL® or Cremophor RH 40®. The amount added is typically sufficient to solubilize or stabilize the active ingredient. For example, the concentration of the Polyoxyethylene hydrogenated castor oil 40 is from 0.1 to 5000 times the concentration of the active ingredient.

Unless otherwise indicated, all ingredient concentrations are presented in units of % weight/volume (% w/v).

In addition, the compositions of the present invention may contain one or more other ingredients as excipients.

For example, the compositions may include one or more pharmaceutically acceptable buffering agents, preservatives, tonicity-adjusting agents, antioxidants, pH-adjusting agents.

Examples of buffering agents include but are not limited to phosphate, borate, citrate, acetate, carbonate, borate-polyol complexes, boric acid and the like.

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

Examples of tonicity-adjusting agents include but are not limited to mannitol, xylitol, sodium chloride and the like.

Examples of 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 and the like and mixtures thereof.

Examples of the alkaline agents that may be used as pH adjusting agents, include, but are not limited to sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium bicarbonate (NaHCOa,) tromethamine, monoethanolamine and other organic and inorganic bases.
Examples of the acidic agents that may be used as pH adjusting agents include, but are not limited to hydrochloric acid, citric acid, tartaric acid, lactic acid and other organic and mineral acids and the like and mixtures thereof.

Examples of chelating agents include but are not limited to EDTA, sodium edetate, sodium citrate, condensed sodium phosphate and the like.

The various embodiments of the present invention can be assembled in several different ways.

In one embodiment the present invention provides a method for treating and controlling glaucoma and ocular hypertension, which comprises administering combination of a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate and a pharmacologically effective amount of Brimonidine Tartrate.

In yet another embodiment the present invention provides a pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate and a pharmacologically effective amount of Brimonidine Tartrate and one or more excipient(s) for the treatment of glaucoma and ocular hypertension.

In yet another embodiment the present invention provides, a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 for the treatment of glaucoma and ocular hypertension.

In yet another embodiment the present invention, provides a process for preparing a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 for the treatment of glaucoma and ocular hypertension.

In yet another embodiment the present invention, provide a qualitative and quantitative stable composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 for the treatment of glaucoma and ocular hypertension.

In yet another preferred embodiment the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 as solubilizing agent and one or more excipients for the treatment of glaucoma and ocular hypertension.

In yet another preferred embodiment, the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 as stability enhancing agent and one and more excipients.

In yet another embodiment the present invention, provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, with Polyoxyethylene hydrogenated castor oil 40 for the treatment of glaucoma and ocular hypertension, wherein Travoprost is present from about 0.001 mg/ml to about 0.2 mg/ml of the composition.
In yet another embodiment the present invention, provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, with Polyoxyethylene hydrogenated castor oil 40 for the treatment of glaucoma and ocular hypertension, wherein Timolol as Timolol Maleate is present from about 0.5 mg/ml to about 10.0 mg/ml of the composition.

In yet another embodiment the present invention, provides a stable pharmaceutical composition for comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, with Polyoxyethylene hydrogenated castor oil 40 for the treatment of glaucoma and ocular hypertension, wherein Brimonidine Tartrate is present from about 0.5 mg/ml to about 4.0 mg/ml of the composition.

In yet another embodiment the present invention, provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, with Polyoxyethylene hydrogenated castor oil 40 for the treatment of glaucoma and ocular hypertension, wherein the Polyoxyethylene hydrogenated castor oil 40 is present from about 0.01% w/v to about 5% w/v of the composition, preferably 0.5% w/v of the composition.

In another preferred embodiment the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 wherein the osmolality of solution is in the range of about 200 to about 350 mOsmol/Kg., preferably from about 270 to about 320 mOsmol/Kg.
In another preferred embodiment the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 wherein the viscosity of composition is in the range of from about 1 cps to about 5 cps, preferably from about 1 cps to about 3 cps.

In another preferred embodiment the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40, wherein the pH of solution is in the range of from about 4 to about 7, preferably from about 5.5 to about 6.7.

In another preferred embodiment the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40, wherein the drop size (μl) of solution is in the range of from about 5ul to about 40 ul preferably from about 15 ul to about 35 fj.1.

In another preferred embodiment the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40, which is safe and effective for topical administration.

In another preferred embodiment the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 wherein compositions are packed in containers selected from HDPE, LDPE and polypropylene materials, preferably LDPE containers.

In another preferred embodiment the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 wherein compositions are packed in containers selected from HDPE, LDPE and polypropylene materials, preferably LDPE containers wherein containers are BFS or Three piece containers, sterilized or non-sterilized.

In another preferred embodiment the present invention provides a stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 can be stored without refrigeration.

In yet another embodiment the present invention provides, synergistic ophthalmic formulation consist of therapeutically effective amount of Travoprost, Timolol Maleate, and Brimonidine Tartrate with buffering agent, chelating agent, tonicity agent and preservative agent, solubilizing agent and which is characterized by having excellent stability properties. In particular, the present invention relates to storage stable, pharmaceutical compositions containing Travoprost, Timolol and Brimonidine.

In yet another embodiment the present invention provides a stable ophthalmic composition comprising:

a) Travoprost 0.004% w/v of the composition;

b) Timolol maleate 0.5% w/v of the composition;

c) Brimonidine Tartrate 0.2% w/v of the composition;

d) Polyoxyethylene hydrogenated castor oil 40 from about 0.01% w/v to about 5% w/v of the composition;

e) and one or more pharmaceutically acceptable excipients

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

Example 1 Table No. 1

6.8 mg of Timolol maleate is equivalent to 5.0 mg of timolol

Manufacturing Process:

1 Take Water for injection (WFI) and purge with nitrogen.

2 Take 40% of WFI Add and dissolve Disodium edetate, Benzalkonium chloride, Tromethamine, Boric acid, Mannitol, Timolol maleate and Brimonidine tartrate one by one, check the clarity.

3 Take 40% of WFI in a beaker add and dissolve Cremophor RH-40.

4 Weigh the Travoprost in to a glass beaker, add Cremophor RH-40solution and stir till the clear solution is obtained.

5 Add and mix the solution of step 2 in to solution of step 4, check the clarity of the solution

6 Check the pH; if necessary adjust to 6.0 with 10% NaOH/HC1

7 Make up the volume to 100%.

The batch prepared using formula as shown in Table No. 1 and filled in different containers and studied for stability at different stability conditions.

The results obtained are presented in Table No. 2 and Table No. 3

Table No. 2
Pack: 5 mL (LDPE Three piece)

Table No. 3

Pack: 5 mL LDPE BFS Containers

We claim:

1. A stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost or its pharmaceutically acceptable salt, a pharmacologically effective amount of Timolol or its pharmaceutically acceptable salt, and a pharmacologically effective amount of Brimonidine or its pharmaceutically acceptable salt and one or more excipient(s) for the treatment of glaucoma and ocular hypertension.

2. A stable pharmaceutical composition according to claim 1 wherein Travoprost is present from about 0.001 mg/ml to about 0.2 mg/ml of the composition.

3. A stable pharmaceutical composition according to claim 1 wherein Timolol as Timolol Maleate is present from about 0.5 mg/ml to about 10.0 mg/ml of the composition.

4. A stable pharmaceutical composition according to claim 1 wherein Brimonidine as Brimonidine Tartrate is present from about 0.5 mg/ml to about 4.0 mg/ml of the composition.

5. A stable pharmaceutical composition comprising a pharmacologically effective amount of Travoprost, a pharmacologically effective amount of Timolol Maleate, and a pharmacologically effective amount of Brimonidine Tartrate, and Polyoxyethylene hydrogenated castor oil 40 for the treatment of glaucoma and ocular hypertension.

6. A stable pharmaceutical composition according to claim 5 wherein Travoprost is present from about 0.001 mg/ml to about 0.2 mg/ml of the composition.

7. A stable pharmaceutical composition according to claim 5 wherein Timolol Maleate is present from about 0.5 mg/ml to about 10.0 mg/ml of the composition.

8. A stable pharmaceutical composition according to claim 5 wherein Brimonidine Tartrate is present from about 0.5 mg/ml to about 4.0 mg/ml of the composition.

9. A stable pharmaceutical composition according to claim 5 wherein the Polyoxyethylene hydrogenated castor oil 40 is present from about 0.01% w/v to
about 5% w/v of the composition.

10. A stable pharmaceutical composition according to claim 5 wherein the Polyoxyethylene hydrogenated castor oil 40 is present 0.5% w/v of the composition.

11. A stable pharmaceutical composition according to claim 5 wherein the osmolality of pharmaceutical composition is in the range of about 200 to about 350 mOsmol/Kg.

12. A stable pharmaceutical composition according to claim 5 wherein the osmolality of pharmaceutical composition is in the range from about 270 to about 320 mOsmol/Kg.

13. A stable pharmaceutical composition according to claim 5 wherein viscosity of pharmaceutical composition is in the range of from about 1 cps to about 5 cps.

14. A stable pharmaceutical composition according to claim 5 wherein viscosity of pharmaceutical composition is in the range from about 1 cps to about 3 cps.

15. A stable pharmaceutical composition according to claim 5 wherein the pH of pharmaceutical composition is in the range of from about 4 to about 7.

16. A stable pharmaceutical composition according to claim 5 wherein the pH of pharmaceutical composition is in the range of from about 5.5 to about 6.7.

17. A stable pharmaceutical composition according to claim 5 wherein the drop size (μl) of pharmaceutical composition is in the range of from about 5ul to about 40 1*1-

18. A stable pharmaceutical composition according to claim 5 wherein the drop size (μl) of pharmaceutical composition is in the range of from about 15 μl to about 35 μl.

19. A stable pharmaceutical composition according to claim 5 wherein the pharmaceutical composition is suitable for topical application.

20. A stable ophthalmic composition comprising:

a. Travoprost 0.004% w/v of the composition;

b. Timolol maleate 0.5% w/v of the composition;

c. Brimonidine Tartrate 0.2% w/v of the composition;

d. Polyoxyethylene hydrogenated castor oil 40 from about 0.01% w/v to about
5% w/v of the composition;

e. and one or more pharmaceutically acceptable excipients.