FORM 2
THE PATENT ACT 1970
(39 of l970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
OPHTHALMIC COMPOSITION COMPRISING TIMOLOL OR SALT THEREOF
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 comprising of a timolol or salt thereof.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention provides ophthalmic composition comprising timolol or salt thereof.
Timolol is a non-selective beta-adrenergic receptor blocking agent which is chemically (-)-1-(fert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol. It is commercially available in the form of its maleate salt of Formula I which is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
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US Patent No 4,861,760 disclose a liquid aqueous ophthalmological composition comprising of gellan gum, which on administration to the eye changes from a liquid to a gel as a result of the ionic strength of the lacrimal fluid.
US Patent No 4,195,085 disclose ophthalmic composition in solution form for the topical treatment of glaucoma comprising an intra-ocular pressure lowering effective amount of timolol hydrogen maleate and a liquid ophthalmic carrier.
US Patent No 5,231,095 and US Patent No 5,496,820 disclose pharmaceutical composition comprising S-timolol hemihydrate together with an ophthalmic carrier.
The Timoptic® Ophthalmic solution available in market comprises of monobasic and dibasic sodium phosphate as tonicity adjusting agents. The quantity of these materials required to adjust the tonicity is very high and simultaneously the formulation does not withstand the freeze-thaw process and precipitates upon stability.
The present inventors have now found that in the preparation of ophthalmic composition of timolol maleate when sodium chloride is used for tonicity adjustment along with monobasic sodium phosphate and dibasic sodium phosphate, the amount of monobasic sodium phosphate and dibasic sodium phosphate is significantly reduced. This reduces the solid content of the solution
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and provides optimum osmolality to the solution. Also sodium chloride is the most important salt in the body for maintaining the osmotic tension of blood and tissue and as an excipient it may be regarded as an essentially non-toxic and non-irritant material.
The present inventors have also found that when freeze thawing of ophthalmic composition of timolol maleate comprising sodium chloride is performed, precipitation or crystals were not observed as compared to the composition without sodium chloride in which precipitation/crystals were observed within three days. Freeze thawing is performed by exposing the ophthalmic composition to repeated cycles of temperature from -20°C to room temperature. This was done to increase the stability of ophthalmic composition during transit and to make it acceptable to all the temperature conditions.
In one of the aspect of the present invention there is provided an ophthalmic composition comprising timolol or salt thereof together with an ophthalmic carrier in which the osmolality of the solution is between 270-330 mOsm and the total solid content of the solution is less than 3% w/v.
In yet another aspect of the present invention there is provided an ophthalmic composition comprising timolol or salt thereof and sodium chloride wherein the total solid content of the solution is less than 3% w/v.
In yet another aspect of the present invention there is provided an ophthalmic composition comprising timolol or salt thereof and sodium chloride wherein the osmolality of the solution is between 270-330 mOsm.
In yet another aspect of the present invention there is provided an ophthalmic composition comprising timolol or salt thereof and sodium chloride wherein the solution does not show precipitation after freeze-thaw analysis.
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Timolol can be present in the form of Timolol maleate. The compositions according to the invention may also contain selected ophthalmologically acceptable adjuvants admixed with the timolol or salt thereof active agent, for example a) to adjust or to stabilize pH, such as conventional bases or acids or buffers, such as phosphate buffers, borate buffer or the like, (b) to stabilize and to preserve the preparation, such as quaternary ammonium compounds, phenyl mercuric salts, thiomersal, methyl and propyl paraben, benzyl alcohol, phenylethanol and the like and (c) penetration enhancer such as polyvinyl alcohol or equivalent thereof.
Use of sodium chloride as tonicity adjusting agent helps in maintaining the osmolality of the solution of timolol or salt thereof within the acceptable limit so that the total solid content of the solution is maintained well below the acceptable limit for the freeze-thaw analysis.
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.
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Comparative Example: Timolol maleate ophthalmic solution 0.5%w/v

Formula Quantity (mg/ml)
Timolol maleate 6.8
Dibasic Sodium Phosphate dodecahydrate 16.72
Monobasic Sodium Phosphate dihydrate 13.62
Benzalkonium chloride 0.1
1N Sodium Hydroxide As needed
Water for Injection q. s.
pH 6.85
Different solutions were prepared by varying proportions of Dibasic Sodium Phosphate dodecahydrate and Monobasic Sodium Phosphate dihydrate for adjusting osmolality and these solutions were subjected to freeze thaw analysis. The crystals were observed in the solution after 2 days.
Example 1: Timolol maleate ophthalmic solution 0.25% (with sodium chloride) Table 1: Composition of Timolol maleate ophthalmic solution 0.25%

Formula Quantity (%)
Timolol maleate 0.25%
Dibasic Sodium Phosphate dodecahydrate 1.672%
Monobasic Sodium Phosphate dihydrate 0.312%
Sodium chloride 0.44%
Benzalkonium chloride 0.01%
1N Sodium Hydroxide As needed
Water for Injection q.s.
pH adjusted to 7
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Example 2: Timolol maleate ophthalmic solution 0.5% (with sodium chloride) Table 2: Comoosition of Timolol maleate ODhthalmic solution 0.5%

Formula Quantity (%)
Timolol maleate 0.5%
Dibasic Sodium Phosphate dodecahydrate 1672%
Monobasic Sodium Phosphate dihydrate 0.312%
Sodium chloride 0.39%
Benzalkonium chloride 0.01%
1N Sodium Hydroxide As needed
Water for Injection q. s.
pH adjusted to 7
Dibasic Sodium Phosphate dodecahydrate, Monobasic Sodium Phosphate dihydrate and Sodium chloride were dissolved sequentially in prefiltered hot Water for injection under continuous stirring. Benzalkonium chloride was dissolved in hot filtered Water for injection in a separate vessel and this solution was added to the above solution. This solution was cooled to room temperature. Timolol Maleate was dissolved in hot filtered Water for injection in a separate vessel and this drug solution was added to the above solution. pH of the resultant solution was adjusted with 1N NaOH solution(range 4 - 7.5). The resulting bulk solution was first sterilized by filtration through 0.2 n filter and then filled aseptically into suitable containers.
Example 3: Studies were carried out by varying the concentration of Monobasic Sodium Phosphate dihydrate and Dibasic Sodium Phosphate dodecahydrate with and without sodium chloride for osmolality adjustment. The total solid content was also observed. The results are provided in the following table.
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Table 3: Amount of buffers and sodium chloride required for tonicity adjustments along with total observed solid content

Sr. No. Batch Dibasic Sodium MonobasicSodium Sodium Chloride PH Osmolarity (mOsm) Total Solid
Initial Adjusted
Phosphate Phosphate PH PH Content
1 Timolol Maleate Ophthalmic Solution 0.25%w/v
i Timolol Maleate Ophthalmic Solution 0.25%w/v 1.672% 0.312% 0.44% 6.91 324 2.774%
ii Timolol MaleateOphthalmicSolution0.25%w/v 1.672% 0.312% 6.75 6.89 189 2.334%
iii Batch with Dibasic Sodium Phosphate adjusted for osmolality 4.36% 0.312% 7.36 320 5.022%
iv Batch withMonobasicSodiumPhosphateadjusted forosmolality 1.672% 1.485% 6.32 6.85 316 3.507%
V Batch with Dibasic Sodium Phosphate and Monobasic Sodium Phosphate adjusted for osmolality 3.018% 0.898% 6.75 6.88 323 4.226%

Sr. No. Batch Dibasic Sodium Phosphate MonobasicSodiumPhosphate Sodium Chloride PH Osmolarity (mOsm) Total Solid Content
Initial PH Adjusted PH
2 Timolol Maleate Ophthalmic Solution 0.5%w/v
i Timolol Maleate Ophthalmic Solution 0.5%w/v 1.672% 0.312% 0.394% 6.7 6.81 336 3.068%
ii Timolol Maleate Ophthalmic Solution 0.5%w/v 1.672% 0.312% 6.95 208 2.674%
iii Batch with Dibasic Sodium Phosphate adjusted for osmolality 4.08% 0.312% 7.2 330 5.082%
iv Batch withMonobasicSodiumPhosphateadjusted forosmolality 1.672% 1.362% 6.23 6.85 317 3.724%
V Batch with Dibasic Sodium Phosphate and Monobasic Sodium Phosphate adjusted for osmolality 2.8775% 0.837% 6.65 6.83 325 4.404%

WE CLAIM:
1. An ophthalmic composition comprising timolol or salt thereof together with an ophthalmic carrier in which the osmolality of the solution is between 270-330 mOsm and the total solid content of the solution is less than 3% w/v.
2. An ophthalmic composition comprising timolol or salt thereof and sodium chloride wherein the total solid content of the solution is less than 3% w/v.
3. An ophthalmic composition comprising timolol or salt thereof and sodium chloride wherein the osmolality of the solution is between 270-330 mOsm.
4. An ophthalmic composition comprising timolol or salt thereof and sodium chloride wherein the solution does not show precipitation after freeze-thaw analysis.
5. Ophthalmic composition according to claims 2 to 4 further comprising dibasic sodium phosphate and monobasic sodium phosphate.
6. Ophthalmic composition according to claims 2 to 4 wherein the sodium chloride is present in an amount from 0.1 to 1%.
7. Ophthalmic composition according to claims 1 to 4 wherein the timolol is in the form of timolol maleate.
8. Ophthalmic composition according to claims 1 to 4 further comprising effective amount of preservative and an agent to adjust the pH.
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9. Ophthalmic composition according to claim 8, wherein the preservatives comprises of quaternary ammonium compounds, phenyl mercuric salts, thiomersal, methyl and propyl paraben, benzyl alcohol, phenylethanol and the like.
Dated this 28th day of March, 2006
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