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:
ASEPTICALLY FILLED OPHTHALMIC DOSAGE FORM
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: WOCKHARDT LIMITED, D-4, MIDC, CHIKALTHANA,
AURANGABAD (M.S.) INDIA.

3. PREAMBLE TO THE DESCRIPTION
The present invention provides an aseptically filled ophthalmic dosage form comprising dorzolamide or salt thereof optionally with ophthalmically acceptable carriers.
The following specification particularly describes the invention and the manner in which it is to be performed.

25 JUN 2008

4. DESCRIPTION
The present invention provides an aseptically filled ophthalmic dosage form comprising dorzolamide or salt thereof optionally with ophthalmically acceptable carriers.
Dorzolamide hydrochloride is described chemically as (4S-fr-ans)-4-(ethylamino)-. 5,6-dihydro-6-methyl-4/-/-thieno[2,3-jb]thiopyran-2-sulfonamide7,7-dioxide mono hydrochloride. Dorzolamide hydrochloride is optically active. Dorzolamide is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
U. S. Patent No. 4,797,413 is a product patent, which generically and specifically covers dorzolamide.
U.S. Patent No. 5,620,970 discloses topical ophthalmic composition for treating and controlling glaucoma and ocular hypertension comprising 0.1-10.0 wt. % of a carbonic anhydrase inhibitor and 0.01-10.0 wt. % of a polyethoxylated derivative of castor oil.
U.S. Patent No. 6,156,785 discloses method for increasing the optic nerve and retinal oxygen tension which comprises applying to the eye an effective amount of a carbonic anhydrase inhibitor.
Steam sterilization or autoclaving of ophthalmic dosage forms is common practice in pharmaceutical industry to make the product sterile. It involves heating the ophthalmic solution or suspension, to be sterilized, placed in suitable container, at 121°C for about 15-20 minutes. However, in many cases it is not
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advisable due to heat sensitivity of the drug or excipients, incompatibility of excipients with drug at higher temperature and cost involved.
Further, ophthalmic solutions containing thickening agents such as one or more cellulose polymers may be manufactured by using aseptic techniques. In this technique the polymer solution is prepared separately and then is sterilized by autoclaving. Active ingredient and other ingredients may be dissolved in water for injection and filter sterilized. The polymer solution and active ingredient solution is filled aseptically. This process is very complex and there is always high risk of microbial contamination. Further the solution prepared by aseptic mixing have particulate matters count on higher side.
While working on the development of dorzolamide ophthalmic solution dosage form, present inventors have embarked upon a simple technique, which eliminates the steam sterilization or autoclaving or aseptic mixing. It was surprisingly found that aseptic filing of the solution for ophthalmic administration comprising dorzolamide or salt thereof, one or more thickening agent can impart the same sterility to the ophthalmic dosage form as that obtained with autoclaving and/or aseptic mixing. At the same time since aseptic filing of the dorzolamide solution takes place at lower temperature there is no heat incompatibility issue and very less particulate matters count was observed during accelerated stability storage conditions.
In one aspect of the present invention there is provided an aseptically filled ophthalmic solution dosage form comprising dorzolamide or salt thereof optionally with ophthalmically acceptable carriers.
In another aspect there is provided a process for preparation of ophthalmic dosage form comprising dorzolamide or salt thereof wherein the said process comprises of aseptic filing in to the desired container, a solution containing dorzolamide or salt thereof optionally with ophthalmically acceptable carriers.
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Dorzolamide may be present in the form of dorzolamide hydrochloride. Ophthalmic compositions of this invention comprise a therapeutically effective amount of dorzolamide or salt thereof
The ophthalmic composition may be prepared by using ophthalmically acceptable carrier components. Ophthalmically acceptable carriers may be selected from one or more of preservative, chelating agent, thickening agent, tonicity adjusting agent, buffering agent and the like.
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.
The term thickening agent is the agent which is capable of building the viscosity of the solutions and comprise one or more of hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, xanthan gum, gellan gum, polyvinyl pyrrolidone, corbopols and the like.
Tonicity adjusting agents are used in ophthalmic compositions to adjust the concentration of dissolved material to the desired isotonic range. Some examples
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include mannitol, sorbitol, sodium chloride, sodium borate, and the like and the mixtures thereof.
Several sterilizing grade membrane filters are available for aseptic filtration of water based pharmaceutical ophthalmic dosage forms such as cellulose acetate, nylon, polyether sulfone (PES), polyvinyl difluoride (PVDF) and the like. The ophthalmic dosage form developed as a part of present invention has been tested for the sterility and is found to be sterile after multiple testing.
The present composition may be prepared by the processes known in the art. Hydroxyethyl cellulose, Mannitol and Sodium citrate dihydrate were dissolved in water for injection under stirring. Benzalkonium chloride was dissolved in separate hot water for injection and this preservative solution was dissolved in above solution. Dorzolamide hydrochloride was dissolved in above solution under stirring. The pH of the solution was adjusted to 5.0 - 6.0 with 1N NaOH solution. The solution was checked for desired osmolality (230-330mOsm). This solution was filtered through 0.2 ja filter and aseptically filled into desired container.
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 formulation is representative of the preferred composition
of the present invention. The preparation of example 1 is detailed below.
The analytical data/stability data of initial and three-month stability (both up-right
and inverted) at 25°C±2°C NMT 40±5%RH is provided in Table 2.
The analytical data/stability data of initial, one-month, two-month, three-month
stability at 40°C±2°C NMT 25%RH is provided in Table 3.
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Example 1 -
Table 1 - Composition of Dorzolamide ophthalmic solution

Sr. No Ingredients % w/v
1 Dorzolamide Hydrochloride 0.05 to 5%
2 Hydroxyethyl cellulose 0.05 -0.5 %
3 Mannitol 0.1-4.6%
4 Sodium citrate dihydrate 0.05-1.4%
5 Benzalkonium hydrochloride 0.001-0.02%
6. NaOH and HCI (for pH adjustment) PH 5.0 to 6.0
Procedure - Hydroxyethyl cellulose, Mannitol and Sodium citrate dihydrate were dissolved in hot water for injection (60-65°C) under stirring at a mixing speed of 800-890RPM. Benzalkonium chloride was dissolved in separate hot water for injection and this preservative solution was dissolved in above solution. The solution was cooled to room temperature. Dorzolamide hydrochloride was dissolved in above solution under stirring. The pH of the solution was adjusted to 5.0 - 6.0 with 1N NaOH solution. The solution was checked for desired osmolality (230-330mOsm). This solution was filtered through 0.2 n filter and aseptically filled into desired container.
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Stability Data -Table 2 -
1) Storage Condition - 25°C±2°C NMT 40±5%RH

Test Specifications Initial 3 month
Clear Colourless solution Clear Colourless solution Clear Colourless solution Clear Colourless solution
Particulate Matter:
1)Particles > 10um 2)Particles > 25pm NMT 50 particles/ml NMT 5 particles/ml 19 particles/ml 2 particles/ml NA NA
PH Between 5.0 and 6.0 5.7 5.4
Sterility Test . Should comply as per USP Complies NA
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Table 3 -
2) Storage Condition - 40°C±2°C NMT 25%RH

Test Specifications Initial 1 month 2 month 3 month

Upright Inverted
Clear
Colourless
solution Clear
Colourless
solution Clear
Colourless
solution Clear
Colourless
solution Clear
Colourless
solution Clear
Colourless
solution Clear
Colourless
solution
Particulate Matter:
1)Particles
> 10um
2)Particles
> 25um NMT 50 particles/ml
NMT 5 particles/ml 4partioles/ml 2partioles/ml NA NA NA NA 21 particles/ml 1 particle/ml 24particles/ml 1 particle/ml
PH Between 5.0 and 6.0 57 5.5 5.5 5.6 5.5
Sterility Test Should comply as per USP Complies NA NA Complies Complies
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WE CLAIM:
1. An aseptically filled ophthalmic solution dosage form comprising dorzolamide or salt thereof.
2. A process for preparation of ophthalmic solution dosage form comprising dorzolamide or salt thereof wherein the said process comprises of aseptic filing in to the desired container, a solution containing dorzolamide or salt thereof and pharmaceutical^ acceptable excipients.
3. The ophthalmic solution dosage form as claimed in claim 1 or 2, wherein the dorzolamide is present as dorzolamide hydrochloride.
4. The ophthalmic composition as claimed in claim 1 or 2, wherein the ophthalmically acceptable carrier comprise one or more of chelating agent, tonicity adjusting agent, thickening agent, buffer component and a preservative.
5. The ophthalmic composition as claimed in claim 4, wherein the chelating agents comprises one or more of edetate disodium, edetate calcium disodium, edetate sodium, edetate trisodium, edetate dipotassium.
6. The ophthalmic composition as claimed in claim 4, wherein the tonicity adjusting agents comprises one or more of mannitol, sorbitol, sodium chloride, other electrolytes.
7. The ophthalmic composition as claimed in claim 4, wherein the buffer component comprises one or more of boric acid, potassium chloride.
8. The ophthalmic composition as claimed in claim 4, wherein the preservative comprises one or more of benzalkonium chloride,
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phenylmercuric acetate, benzyl alcohol, chlorobutanol, parabens, thimerosal.
9. The ophthalmic composition as claimed in claim 4, wherein the thickening agent comprises one or more of hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, xanthan gum, gellan gum, polyvinyl pyrrolidone, corbopols.
10.The ophthalmic composition as claimed in claim 1 or 2, wherein sterilizing grade 0.2-micron membrane is used for imparting sterility.

Dated this 2TH day of June, 2008. For Wockhardt Limited

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(Mandar Kodgule) Authorized Signatory