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:
STABILIZED INJECTABLE FORMULATION OF CARBOPLATIN AND SALTS 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 a stabilized injectable pharmaceutical composition of carboplatin or salts thereof, which comprises of carboplatin or salts thereof dissolved in a suitable pharmaceutically acceptable vehicle along with purged oxygen wherein purged oxygen imparts better stability and significant reduction in the color development upon storage at accelerated stability conditions.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides a stabilized injectable pharmaceutical composition of carboplatin or salts thereof, which comprises of carboplatin or salts thereof dissolved in a suitable pharmaceutically acceptable vehicle along with purged oxygen wherein purged oxygen imparts better stability and significant reduction in the color development upon storage at accelerated stability conditions.
Carboplatin is a platinum coordination compound that is used as a cancer chemotherapeutic agent. The chemical name for carboplatin is platinum, diammine [1,1-cyclobutanedicarboxylato(2-)-0, 0']-,(SP-4-2) represented by Formula I. Carboplatin is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5-7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide.

Formula I
US Patent No. 4,140,707 (the '707 Patent) provides malonato platinum coordination compounds and a method of treating malignant tumors comprising the parenteral administration to an affected animal of a solution of the compound.
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Carboplatin is not stable in a simple aqueous solution. It has been postulated that carboplatin in aqueous media decomposes through various mechanisms, whereby the highly poisonous impurities can be formed. The carboplatin solutions have been known to develop color upon storage due to the decomposition of carboplatin into platinum and other impurities.
Several approaches have been explained in the prior art to stabilize carboplatin injectable formulations. US patent no. 5,104,896, 5,455,270, EP patent no. 743854(B1) and 642792(B1) disclose carboplatin compositions stabilized by maintaining pH. The carboplatin compositions comprising 1,1-cyclobutanedicarboxylic acid or an alkali metal salts are provided in US patent no. 6,589,988. EP patent no. 334551 (B1) provides a stable, aqueous, ready-made, injectable solution of carboplatin characterized in that it has not been made up by reconstituting a lyophilizate.
The present inventors while developing an injectable formulation of carboplatin or salt thereof have surprisingly found that purging of oxygen through injectable pharmaceutical composition comprising carboplatin imparts greater stability. The carboplatin composition with purged oxygen exhibits significant reduction in the color development upon storage at accelerated stability conditions. Also the inventors prepared and studied the stability of carboplatin compositions comprising purged nitrogen, carbon dioxide and compressed gas at accelerated stability conditions. They found that purging of oxygen, results in significant reduction of color development as compared to other purged gases.
In one of the aspects of present invention there is provided, a stable injectable pharmaceutical composition comprising carboplatin or salts thereof in admixture with pharmaceutically acceptable excipients wherein the said pharmaceutical composition is stabilized by purging oxygen.
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In yet another of the aspects of present invention there is provided, a method of stabilizing an injectable pharmaceutical composition comprising carboplatin or pharmaceutically acceptable salts wherein said method comprises the step purging oxygen.
The stabilized injectable composition of carboplatin and salts thereof can be prepared by dissolving accurately weighed quantity of carboplatin in a suitable pharmaceutically acceptable vehicle wherein oxygen is sparged continuously through the pharmaceutically acceptable vehicle. The solution can be stirred for sufficient time to dissolve the drug completely. The resultant solution may be filtered through sterile 0.22µ filters. Solution is then filled into suitable vial and oxygen gas is purged.
Purging of oxygen to prepare a stable injectable pharmaceutical composition comprising carboplatin imparts better stability by reducing the color development upon storage at accelerated stability conditions. The present inventors have found that color development measured as percentage transmission in injectable pharmaceutical composition comprising carboplatin and purged oxygen is reduced significantly in comparison to compositions comprising carboplatin and other purged gases. Table 1 shows percentage decrease in transmission value of pharmaceutical compositions comprising carboplatin and purged gases like nitrogen, oxygen, carbon dioxide, compressed gas or no gas, after two months of storage at 40°C and 75% relative humidity. Decrease in the transmission value is an indicative of extent of increase in color development. Transmission of carboplatin comprising compositions is measured at 440 nm and 650 nm against water as a blank in Perkin Elmer - Lambda 35 - Uv/Vis Spectrophotometer.
Table 1: Percent decrease in transmission value (at 650nm) of injectable compositions comprising carboplatin and purged with different gases.
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Time Percent decrease in transmission value at 650 nm
No-gas Compressed Gas Oxygen Nitrogen Carbon Dioxide
1 Month 2.55 2.44 0.52 31.73 32.79
2 Month 5.84 5.73 2.19 30.34 56.91
Pharmaceutically acceptable excipients can be selected from a group comprising of one or more of a pharmaceutically acceptable vehicle, preservatives, chelating agents, pH adjusting agents, tonicity adjustors and the like.
Suitable a pharmaceutically acceptable vehicle includes one or more of water, ethanol, propylene glycol and the like. Suitable preservatives include one or more of benzyl alcohol, methyl paraben, propyl paraben, benzyl paraben and the like. Suitable chelating agents include one or more of ethylenediaminetetraacetic acid, diethylene triamine pentaacetic acid, dimercaptosuccinic acid, deferoxamine and the like. Suitable pH adjusting agents include one or more of hydrochloric acid, sulphuric acid ascorbic acid, aspartic acid, benzoic acid, potassium dihydrogen phosphate, sodium hydrogen phosphate and the like. Suitable tonicity adjustors include one or more of sodium chloride, glucose, dextrose and the like.
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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Example 1
The injectable pharmaceutical composition of Carboplatin is provided in Table 2.
Table 2

S. No. Ingredients Each ml contains
1. Carboplatin 10 mg
2. Oxygen q.s.
3. Water for Injection q.s. to 1ml
Procedure:
Carboplatin is weighed accurately and added to water for injection and stir for
sufficient time to dissolve the drug completely with continuous sparging of 0.22
micron filtered oxygen. Resultant solution is filtered through 0.22 micron filters
and filled in vials followed by oxygen purging. Oxygen purged vials are sealed.
The entire manufacturing is carried out under subdued or sodium vapor lamp
light
Examples 2
The injectable pharmaceutical composition of Carboplatin is provided in Table 3.
Table 3

S. No. Ingredients Each ml contains
1. Carboplatin 10 mg
2. Carbon dioxide q.s.
3. Water for Injection q.s. to 1 ml

Procedure:

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Carboplatin is weighed accurately and added to water for injection and stir for sufficient time to dissolve the drug completely with continuous sparging of 0.22 micron filtered carbon dioxide. Resultant solution is filtered through 0.22 micro filters and filled in vials followed by carbon dioxide purging. Carbon dioxide purged vials are sealed. The entire manufacturing is carried out under subdued or sodium vapor lamp light
Example 3
Carboplatin injectable composition is prepared as explained in example 1 and 2. The injectable compositions are sparged and purged with different gases i.e. nitrogen, oxygen, carbon dioxide and compressed air. These compositions are stored for two months at 40°C and 75% relative humidity. The injectable compositions are analyzed at day 0, 1 month and 2 month, for percent transmission at 440 and 650 nm. Percentage transmission of carboplatin comprising compositions is measured at 440 nm and 650 nm against water as a blank in Perkin Elmer - Lambda 35 - Uv/Vis Spectrophotometer.
Table 4: Data showing effect of oxygen, carbon dioxide, compressed air and without any gas on the percentage transmission at 650 nm.

s.No. Carboplatininjection purgedwith followinggases Percentage transmission at 650 nm
Initial I Month 2 Month
1. Oxygen 99.9 99.94 99.16
2. Carbon Dioxide 97.38 72.49 52.46
3. Compressed air 99.84 99.55 98.94
4. Nitrogen 97 48.62 48.62
5. No Gas used 99.83 99.9 97.38
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Table 5: Data showing effect of oxygen, carbon dioxide, compressed air and without any gas on the percentage transmission at 440 nm.

s.No. Carboplatininjection purgedwith followinggases Percentage transmission at 440 nm
Initial I Month 2 Month
1. Oxygen 99.63 98.98 97.32
2. Carbon Dioxide 93.63 62.92 40.34
3. Compressed air 99.3 96.98 93.61
4. Nitrogen 91.18 59.38 32.9
5. No Gas used 99.22 96.68 93.42
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WE CLAIM:
1. A stable injectable pharmaceutical composition comprising carboplatin or salts thereof in admixture with pharmaceutically acceptable excipients wherein the said pharmaceutical composition is stabilized by purging oxygen.
2. A method of stabilizing an injectable pharmaceutical composition comprising carboplatin or pharmaceutically acceptable salts wherein said method comprises the step of purging oxygen.
3. A stable injectable pharmaceutical composition or a method of stabilizing an injectable pharmaceutical composition as per claims 1 and 2 wherein about 5 to 20 mg of carboplatin or salt thereof is present.
4. A stable injectable pharmaceutical composition or a method of stabilizing an injectable pharmaceutical composition as per claims 1 and 2 wherein stabilized injectable pharmaceutical composition exhibits 3% or less than 3% decrease in percentage transmission after two months of storage at 40°C and 75% relative humidity.
5. A stable injectable pharmaceutical composition or a method of stabilizing an injectable pharmaceutical composition as per claims 1 and 2 wherein pharmaceutically acceptable excipients are preservatives, chelating agents, pH adjusting agents and tonicity adjustors.
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6. A stable injectable pharmaceutical composition or a method of stabilizing an injectable pharmaceutical composition as per claims 1 and 2 wherein pharmaceutically acceptable vehicle is water.
Dated this 29TH day of September, 2006
For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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