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 COMPOSITIONS COMPRISING DORZOLAMIDE AND
TIMOLOL
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 comprisingdorzolamide or salt or enantiomers or diastereomers or mixtures thereof andtimolol or an ophthalmically acceptable salt thereof along with ophthalmicallyacceptable carriers.
The following specification particularly describes the invention and the mannerin which it is to be performed.
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4. DESCRIPTION
The present invention provides ophthalmic composition comprising dorzolamide or salt or enantiomers or diastereomers or mixtures thereof and timolol or an ophthalmically acceptable salt thereof along with ophthalmically acceptable carriers.
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 of formula 1. 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.

Timolol maleate is described chemically as (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt) of formula 2. Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. It has a molecular weight of 432.50. It is a white, odorless, crystalline powder, which is soluble in water, methanol, and alcohol. Timolol maleate is stable at room temperature. The combination is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers
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US Patent No 4,797,413 is a product patent, which generically and specifically covers dorzolamide.
US Patent No 6, 248, 735 provides a topical formulation for treatment of ocular hypertension or glaucoma comprising an ophthalmologically acceptable carrier, dorzolamide, the individual diastereomers, enantiomers or mixtures thereof, or an ophthalmologically acceptable salt thereof, and timolol or an ophthalmologically acceptable salt thereof.
US Patent No 6, 316, 443 provides an ophthalmic formulation for treatment of ocular hypertension comprising an ophthalmologically acceptable carrier, 0.5 to 5% (w/w) of a carbonic anhydrase inhibitor dorzolamide, the individual diastereomers, enantiomers or mixtures thereof, or an ophthalmologically acceptable salt thereof and 0.01 to 1.0% of a beta-adrenergic antagonist selected from betaxolol, bufenolol, carteolol, levobunolol, metipranolol, and timolol, or an ophthalmologically acceptable salt thereof.
The present invention now provides a stable ophthalmic combination composition comprising dorzolamide, the individual diastereomers, enantiomers or mixtures thereof, or an ophthalmologically acceptable salt thereof, and timolol or an ophthalmologically acceptable salt thereof in admixture with hydroxypropyl methylcellulose (HPMC) along with ophthalmically acceptable excipients. The use of HPMC in the ophthalmic composition helps to increase solubility and stability of the composition. Further the use of HPMC in the formulation provides
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emollient effect to the eye and thus can also be used in the treatment of dry eye syndrome.
In one of the aspects of the present invention there is provided an ophthalmic combination composition comprising dorzolamide, the individual diastereomers, enantiomers or mixtures thereof, or an ophthalmologically acceptable salt thereof, and timolol or an ophthalmologically acceptable salt thereof in admixture with hydroxypropyl methylcellulose (HPMC) along with ophthalmically acceptable excipients.
Dorzolamide 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. Timolol, the β-adrenergic antagonist, reduces intraocular pressure and possesses many other advantages like local unaesthetic property. When dorzolamide is combined together with timolol, the composition provides an effect that reduces the intraocular pressure below that obtained by either medicament individually.
Dorzolamide when used for the treatment of abnormal eye conditions such as glaucoma increases the thickness of the human cornea, due to which the cornea loses the capacity to use its compensatory mechanisms and thus disturbs the fluid transportation mechanism. Thus leading to dry eye conditions. This further leads to discomfort to the contact lens wearing patients as the surface of contact lens must have sufficient degree of hydrophilicity to be wet by tears. Tear wettability is in turn necessary to provide the lens wearer with comfort and good vision. Use of HPMC provides a cushion between the lens and the eye, which is equated with increased wettability as it provides comfort and tolerance to the patient.
Due to higher degree of solid content present in the dorzolamide-timolol combination composition, the viscosity of the composition increases to a greater
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degree. This high viscosity can lead to grittiness and local irritation after instillation of the product into the eye. Use of HPMC in the composition decreases evaporation of the solvent from the composition upon instillation and forms surface protection film which further helps to reduce irritation in the eye. The present composition has the viscosity of 2 to 30 cps
The ophthalmic composition further contains ophthalmically acceptable carriers. Ophthalmically acceptable carriers can be preservative, chelating agent, tonicity adjusting agent, buffering agent.
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 mannitol, sorbitol, sodium chloride, sodium borate, and the like and the mixtures thereof.
The present composition may be prepared by the processes known in the art. Hydroxypropyl methylcellulose is dissolved in water for injection. All the carrier
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substances are dissolved in the water. Dorzolamide and timolol is further dissolved in this solution. pH was adjusted in the range of 4.5 to 7.0 with sodium hydroxide. The solution was filtered and filled in suitable containers.
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.
Examples- Following formulations are representatives of the preferred compositions of the present invention. The preparation of example 1,2 and 3 is detailed below.
Example 1
Table 1 - Dorzolamide-Timolol Ophthalmic composition.

Sr.No Ingredients Quantity (%)
1 Dorzolamide Hydrochloride 2.226
2 Timolol Maleate 0.68
3 Sodium Citrate 0.1 to 1.0
4 Mannitol 1 to 10
5 Benzalkonium Chloride 0.075
6 Sodium Hydroxide As needed
7 Hydroxypropyl methylcellulose 0.1 to 0.5
8 Water for Injection q.s.
Procedure:
Hydroxypropyl methylcellulose is dissolved in suitable solvent. Sodium citrate, mannitol, benzalkonium chloride is dissolved in the water. Dorzolamide and timolol is further dissolved in this solution. Desired pH was adjusted with suitable pH adjusting agents. The solution was filtered and filled in suitable containers.
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Example 2
Table 2 - Dorzolamide-Timolol Ophthalmic composition.

Sr.No Ingredients Quantity (%)
1 Dorzolamide Hydrochloride 2.226
2 Timolol Maleate 0.68
3 Hydroxypropyl methyl cellulose 0.1 to 2.0
4 Sodium Chloride 0.1 to 0.9
5 Benzalkonium Chloride 0.075
6 Sodium Hydroxide As needed
7 Potassium chloride 0.01 to 0.5
8. Water for Injection q.s.
Procedure:
Hydroxypropyl methylcellulose is dissolved in suitable solvent. Sodium chloride,
potassium chloride, benzalkonium chloride is dissolved in the water. Dorzolamide
and timolol is further dissolved in this solution. Desired pH was adjusted with
suitable pH adjusting agents. The solution was filtered and filled in suitable
containers.
Example 3
Table 3 - Dorzolamide-Timolol Ophthalmic composition.

Sr.No Ingredients Quantity (%)
1 Dorzolamide Hydrochloride 2.226
2 Timolol Maleate 0.68
3 Hydroxypropyl methyl cellulose 0.1 to 1.0
4 Edetate disodium 0.01 to 0.5
5 Benzalkonium Chloride 0.075
6 Sodium Hydroxide As needed
7 Sodium chloride 0.1 to 0.9
8 Sodium biphosphate 0.01 to 1.0
9 Sodium phosphate 0.01 to 0.1
10 Water for Injection q.s.
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Procedure:
Hydroxypropyl methylcellulose is dissolved in suitable solvent. Sodium chloride, edetate sodium, benzalkonium chloride, sodium biphosphate, sodium phosphate is dissolved in the water. Dorzolamide and timolol is further dissolved in this solution. Desired pH was adjusted with suitable pH adjusting agents. The solution was filtered and filled in suitable containers.
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WE CLAIM:
1. An ophthalmic combination composition comprising dorzolamide, the individual diastereomers, enantiomers or mixtures thereof, or an ophthalmologically acceptable salt thereof, and timolol or an ophthalmologically acceptable salt thereof in admixture with hydroxypropyl methylcellulose (HPMC) along with ophthalmically acceptable carriers.
2. An ophthalmic combination composition according to claim1, wherein the dorzolamide is present as dorzolamide hydrochloride.
3. An ophthalmic combination composition according to claim1, wherein the timolol is present as timolol maleate.
4. An ophthalmic combination composition according to claim1, wherein the HPMC is present in the concentrations from 0.1 to 0.5%.
5. An ophthalmic composition according to claim 1, wherein the carrier component comprises water.
6. An ophthalmic composition according to claim 1 further comprises chelating agent, tonicity adjusting agent, buffer component and a preservative.
7. An ophthalmic composition according to claim 6, wherein the chelating agents comprises of edetate disodium, edetate calcium disodium, edetate sodium, edetate trisodium, edetate dipotassium and the like.
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8. An ophthalmic composition according to claim 6, wherein the tonicity adjusting agents comprises of mannitol, sorbitol, sodium chloride, other electrolytes and the like.
9. An ophthalmic composition according to claim 6, wherein the buffer component comprises of boric acid, potassium chloride and the like.
10. An ophthalmic composition according to claim 6, wherein the preservative
comprises of benzalkonium chloride, phenylmercuric acetate, benzyl
alcohol, chlorobutanol, , parabens, thimerosal and the like.

Dated this 29TH day of September, 2006 For Wockhardt Limited

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(Mandar Kodgule) Authorized Signatory