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:
INJECTABLE PHARMACEUTICAL COMPOSITION OF DOCETAXEL 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 an injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and 5 to 50% of ethanol and the diluent solution "essentially consists" of water and is "free or essentially free" of ethanol.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides an injectable pharmaceutical composition of docetaxel and salts thereof, comprising a stock solution and a diluent solution, wherein stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and 5 to 50% of ethanol and the diluent solution "essentially consists" of water and is "free or essentially free" of ethanol.
Docetaxel is an antineoplastic agent that acts by disrupting the micro-tubular network in cells that is essential for mitotic and interphase cellular functions. Chemically it is (2R,3S)-N-carboxy-3-phenylisoserine,N-fe/t-butyl ester, 13-ester with 5b-20-epoxy-1,2a,4,7b, 10b, 13a-hexahydroxytax-11 -en-9-one 4-acetate 2-benzoate, trihydrate (Formula I). It is commercially marketed under the trade name of TAXOTERE®. Docetaxel is indicated for the treatment of locally advanced or metastatic breast cancer. Docetaxel is also indicated for the treatment of locally advanced or metastatic small cell lung cancer. Docetaxel is indicated for the treatment of prostrate cancer.

US Patent No. 4,814,470 (the "470 Patent) and European Patent EP 253,738 disclose a compound Docetaxel and its stereoisomeric forms thereof.
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US Patent No. 5,438,072 and European Patent EP 671, 912 discloses an injectable compositions of docetaxel which comprises a stock solution having docetaxel & polysorbate, and a diluent solution having ethanol as dilution additive in water.
US Patent No 5,714,512, US Patent No. 5,698,582 and US patent no. 5,403,858 disclose an injectable composition having a stock solution of docetaxel and a surface active agent, wherein the composition is essentially free or free of ethanol.
United States Patent No. 5,750,561 discloses an injectable composition of docetaxel wherein the injectable composition has a stock solution comprising docetaxel and a surface-active agent.
US Patent No. 5,977,163 discloses a pharmaceutical composition comprising a water-soluble conjugate of an anti-tumor with a polyglutamic acid polymer to form.
US Patent No. 5,616,330; 6,660,286 and 6,660,286, 5,670,536, US application no. 2006067952, PCT application no. WO2005065676 and WO2005065677 disclose intravenous composition of docetaxel wherein docetaxel is formulated as a stable oil-in-water emulsion.
US Patent No. 6,153,644 and United States Patent No. 6,071,952 discloses an injectable composition and a method for preparing stabilizing parenteral pharmaceutical composition of docetaxel by adding an antioxidant.
It well known from the prior art that an injectable pharmaceutical composition comprising docetaxel is prepared by mixing stock solution with a diluent wherein the stock solution comprises docetaxel or salts thereof, a solubilizing agent and ethanol. The stock solution preferably contains less than 5% ethanol and more
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preferably less than 2% ethanol. The presence of a small quantity of ethanol provides several advantages, the medium has a low viscosity, and the wetting of the powder is enhanced as well as the final filtration of the solution. The diluent solution is an aqueous solution containing an additive that promotes the dissolution of stock solution in the diluent solution and also impart better stability. The present inventors while working on the development of a stabilized docetaxel injectable pharmaceutical compositions have surprisingly found that the injectable composition of docetaxel can be prepared by adding 5 to 50% of ethanol in the stock solution along with other pharmaceutically acceptable excipients. The stock solution can be diluted with a diluent solution, which is "essentially consists" of water and is "free or essentially free" of ethanol.
In one of the aspects of present invention there is provided, an injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein the stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and 5 to 50% of ethanol.
In yet another aspect of present invention there is provided, an injectable pharmaceutical composition of docetaxel and salts thereof, comprising a stock solution and a diluent solution, wherein the diluent "essentially consists" of water.
In yet another aspect of present invention there is provided, an injectable pharmaceutical composition of docetaxel and salts thereof, comprising a stock solution and a diluent solution, wherein the diluent is "free or essentially free" of ethanol.
In yet another aspect of present invention there is provided, an injectable pharmaceutical composition of docetaxel and salts thereof, comprising a stock solution and a diluent solution, wherein
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a) stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and 5 to 50% of ethanol.
b) diluent solution is "free or essentially free" of ethanol.
In yet another aspect of present invention there is provided, an injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein
a) stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and 5 to 50% of ethanol.
b) diluent solution "free or essentially consists" of water.
In yet another aspect of present invention there is provided, an injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein
a) stock solution comprises docetaxel or salts thereof along with pharmaceutical^ acceptable excipients and 5 to 50% of ethanol.
b) diluent solution essentially consists" of water and is "free or essentially free" of ethanol.
In yet another aspect of present invention there is provided, a process for preparing an injectable pharmaceutical composition of docetaxel or salts thereof, wherein the said process comprises the step of mixing a stock solution and a diluent solution, wherein stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and 5 to 50% of ethanol and diluent solution essentially consists" of water and is "free or essentially free" of ethanol.
An injectable pharmaceutical composition of docetaxel and salts thereof, wherein the stock solution can be prepared by dissolving docetaxel in ethanol followed by gradually adding a surface active agent. The pH of the stock solution can be adjusted between 3 and 6 with a suitable mineral or organic acid. Stock solution
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can thus be prepared having 20 to 100 mg/ml of docetaxel and about 50 to 90% v/v of surface-active agent.
An injectable pharmaceutical composition of docetaxel and salts thereof, wherein diluent solution "essentially consists" of water. The term "essentially consist" herein refers to an aqueous solution, which does not comprise an additive that promotes the dissolution of stock solution comprising docetaxel.
An injectable pharmaceutical composition of docetaxel and salts thereof wherein diluent solution is "free or essentially free" of ethanol. The term "free or essentially free" herein refers to either complete elimination of ethanol or to that extent where it does not promote the dissolution of stock solution in diluent.
An injectable pharmaceutical composition of the present invention can be prepared by mixing stock solution and diluent solution to achieve a concentration of 10 mg/ml of docetaxel in the said composition. The composition is stable for at least 8 hours at room temperature wherein the solution remains clear and does not precipitate.
The injectable composition comprises docetaxel or salts thereof wherein docetaxel or salts thereof can be docetaxel trihydrate.
The stock solution of the injectable composition may comprise a mineral acid or an organic acid as a pH-adjusting agent.
Pharmaceutically acceptable excipients can be selected from a group comprising of one or more of solubilizing agent, preservatives, non-aqueous vehicle, chelating agents, antioxidants and reducing agent, buffers and pH adjusting agents, tonicity adjustors and the like.
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A surface-active agent can be one or more selected from a group consisting of polyethylene glycol, polysorbates, sodium lauryl sulfate and the like.
Suitable preservatives include one or more of benzyl alcohol, methyl paraben, propyl paraben, benzyl paraben and the like.
Suitable non-aqueous vehicles include one or more of polysorbates, cremophore, polyethylene glycols, oils like castor oil or sesame oil, ethanol, benzyl alcohol, propylene glycol and the like.
Suitable chelating agents include one or more of ethylenediaminetetraacetic acid, diethylene triamine pentaacetic acid, dimercaptosuccinic acid, deferoxamine and the like.
Suitable antioxidants and reducing agents include one or more of ascorbic acid, gentisic acid tocopherol-derived compounds, butylated hydroxyanisole, butylated hydroxytoluene, citric acid and the like.
Suitable buffers and 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.
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 1
The pharmaceutical composition of docetaxel is provided in Table 1.
Table 1

S. No. Ingredients Each ml contains
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Stock Solution
1. Docetaxel trihydrate 40 mg
2. Polysorbate 80 652 mg
3. Absolute Ethanol 0.4 ml
4. Lactic acid q.s. to adjust pH
Diluent solution
5. Water for injection q.s.
Procedure:
Stock solution: Docetaxel is weighed accurately and dissolved in a mixture of ethanol and polysorbate 80. The pH of this solution is adjusted to pH 3.0 - 6.0 with lactic acid. This solution is filtered through sterile 0.22u filter. Stock solution as prepared above is diluted with diluent solution to achieve a concentration of 10 mg/ml of docetaxel.
Examples 2
The pharmaceutical composition of docetaxel is provided in Table 2.
Table 2

S. No. Ingredients Each ml contains
1. Docetaxel trihydrate 20 mg
2. Polysorbate 80 652 mg
3. Absolute Ethanol 0.4 ml
4. Lactic acid q.s. to adjust pH
Diluent solution
6. Water for injection q.s.
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Stock solution: Docetaxel is weighed accurately and dissolved in a mixture of ethanol and polysorbate 80. The pH of this solution is adjusted to pH 3.0 - 6.0 with lactic acid. This solution is filtered through sterile 0.22u filter. Stock solution as prepared above is diluted with diluent solution to achieve a concentration of 10 mg/ml of docetaxel.
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WE CLAIM:
1. An injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein the stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and 5 to 50% of ethanol.
2. An injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein the diluent "essentially consists" of water.
3. An injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein the diluent is "free or essentially free" of ethanol.
4. An injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein
a. stock solution comprises docetaxel or salts thereof along with
pharmaceutically acceptable excipients and 5 to 50% of ethanol.
b. diluent solution is "free or essentially free" of ethanol.
5. In yet another aspect of present invention there is provided, an injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein
a. stock solution comprises docetaxel or salts thereof along with
pharmaceutically acceptable excipients and 5 to 50% of ethanol.
b. diluent solution "essentially consists" of water.
6. In yet another aspect of present invention there is provided, an injectable pharmaceutical composition of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein
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a. stock solution comprises docetaxel or salts thereof along with
pharmaceutical^ acceptable excipients and 5 to 50% of ethanol.
b. diluent solution essentially consists" of water and is "free or
essentially free" of ethanol.
7. A process for preparing an injectable pharmaceutical composition of docetaxel or salts thereof, wherein the said process comprises the step of mixing a stock solution with diluent solution, wherein stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and 5 to 50% of ethanol and diluent solution essentially consists" of water and is "free or essentially free" of ethanol.
8. As per claims 1 to 7, about 20 to 100 mg/ml of docetaxel or salt thereof is present in stock solution.
9. As per claims 1 to 7, pharmaceutically acceptable excipients present in stock solution are solubilizing agent and pH adjusting agents.
10. As per claims 1 to 7, about 10 mg/ml of docetaxel or salt thereof is present in injectable pharmaceutical composition.