FORM 2 THE PATENT ACT (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION(See section 10 and rule13)

1. TITLE OF THE INVENTION:
STABILIZED INJECTABLE PHARMACEUTICAL COMPOSITION OFDOCETAXEL

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 docetaxel, which comprises of docetaxel, surfactant and
ethanol, wherein the pH of the injectable is adjusted between 3 and 6 using a
suitable acid.
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 a stabilized injectable pharmaceutical composition of docetaxel, which comprises of docetaxel, surfactant and ethanol, wherein the pH of the injectable is maintained between 3 and 6 using a suitable acid.
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-te/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 water solution having ethanol as dilution additive.
US Patent No 5,714,512 and US Patent No. 5,698,582 disclose an injectable composition having a stock solution of docetaxel and water diluent which is essentially free or free of ethanol.
United States Patent No. 5,750,561 discloses an injectable composition of docetaxel wherein the injectable solution being capable of being injected without anaphylactic or alcohol intoxication manifestations being associated therewith.
US Patent No. 5,616,330; 6,660,286 and 6,660,286, PCT application no. 2005065676 and 2005065677 disclose intravenous composition of docetaxel wherein docetaxel is formulated as a stable oil-in-water emulsion.
United States 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 long-term shelf life of pharmaceutical formulations comprising docetaxel is problematic. Injectable formulations comprising docetaxel dissolved in a suitable surfactant and essentially free of ethanol are known in the prior art US patents no. '561 and '512. Although reduction of ethanol has a therapeutic advantage, the stability of these formulations is suspected. Reduced long-term shelf life leads to increased manufacturing costs due to extensive consumption of raw materials and yields a product of inferior quality, both translating into higher costs to the patient. Therefore, a stabilization strategy is needed to prevent the degradation of docetaxel in injectable pharmaceutical compositions.
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In light of prior art and problems exemplified above, the present inventors while working on the injectable pharmaceutical composition of docetaxel have surprisingly found that injectable compositions comprising docetaxel dissolved in a suitable surfactant and ethanol can be stabilized by adjusting the pH of solution between 3 and 6 by the addition of a suitable acid.
In one of the aspects of present invention there is provided, an injectable pharmaceutical composition of docetaxel for human administration comprises of docetaxel dissolved in Polysorbate 80, ethanol and an acid wherein the pH of the solution is between 3 and 6.
In yet another aspect of the present invention there is provided, a method of stabilizing docetaxel in an injectable composition such that at least about 80% of the potency of docetaxel is maintained after storage for at least three month at 40°C and 75% relative humidity, wherein said method comprises of the step of adjusting pH of a mixture of polysorbate 80 and ethanol between 3 and 6 by using an acid, followed by dissolving docetaxel in the said mixture.
In yet another aspect of the present invention there is provided, a method of stabilizing docetaxel in an injectable composition such that at least about 80% of the potency of docetaxel is maintained after storage for at least three month at 40°C and 75% relative humidity, wherein said method comprises the steps of
a. adjusting pH of the mixture of polysorbate 80 and ethanol between 3 and
6 by using an acid,
b. dissolving docetaxel in the soltion of step (a).
An injectable pharmaceutical composition of docetaxel can be prepared by mixing accurately measured amount of polysorbate 80 and ethanol. This mixture can be acidified between pH 3 to 6 with a suitable acid. Docetaxel or salts thereof, is weighed accurately and dissolved in acidified polysorbate 80 and ethanol mixture to form a clear solution. This solution may be sterilized by
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passing through a sterile 0.22u filter. Sterilized solution may optionally be sparged with an inert gas.
Docetaxel or salts thereof containing injectable pharmaceutical composition can also be prepared by first adjusting the pH of an accurately measured amount of polysorbate 80 between 3 to 6 with an acid, followed by adding ethanol in acidified polysorbate. Docetaxel can be dissolved in the resultant solution to form a clear solution. This solution may be sterilized by passing through a sterile 0.22u filter and an inter gas may optionally be sparged into the final solution.
The injectable composition comprises docetaxel or salts thereof wherein docetaxel or salts thereof can be docetaxel trihydrate.
Polysorbate 80 is an oily liquid. It is a class of emulsifiers used in some pharmaceuticals and food preparation. Polysorbates come in polysorbate 20, 60 and 80. Polysorbate 80 has been widely used as emulsifier and solubilizer in pharmaceutical formulations.
Ethanol is the best pharmaceutical solvent, which makes it possible to solubilize molecules like docetaxel or its salts thereof. The present invention has used this property of ethanol to aid in dissolving docetaxel wherein ethanol is used absolute ethanol (95% v/v) in a concentration of 5 to 43% v/v.
The stability of injectable pharmaceutical composition comprising docetaxel or salts thereof is problematic. Therefore, by adjusting the pH of the solution between 3 and 6 with an acid, the long-term stability of the docetaxel containing compositions is improved. An acid can be an organic or mineral acid. Mineral acid may be one or more selected from a group of hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid and the like. Organic acid may be one or more selected from a group of ascorbic acid, aspartic acid, benzoic acid, benzene sulphonic acid, tartaric acid, diatriazoic acid, glutamic acid, lactic acid, maleic
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acid, succinic acid, fumaric acid, citric acid anhydrous, citric acid monohydrate, edetic acid 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
1. Docetaxel trihydrate 40 mg
2. Polysorbate 80 651.69 mg
3. Absolute Ethanol 0.39 ml
4. Lactic acid q.s. to adjust pH
Procedure:
Polysorbate 80 and ethanol are measured accurately and mixed homogenously by gentle stirring. The pH of this solution is adjusted to pH 3.0 - 6.0 with lactic acid. Docetaxel trihydrate is weighed accurately and dissolved in the acidified solution to form a clear solution. This solution is filtered through sterile 0.22u filter followed by sparging of an inert gas.
Examples 2
The pharmaceutical composition of docetaxel is provided in Table 2.
Table 2
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S. No. Ingredients Each ml contains
1. Docetaxel trihydrate 40 mg
2. Polysorbate 80 651.69 mg
3. Absolute Ethanol 0.39 ml
4. Hydrochloric acid (cone.) q.s. to adjust pH
Procedure:
Polysorbate 80 is measured accurately and its pH is adjusted between 3.0 and 6.0 with hydrochloric acid. Ethanol is mixed with acidified polysorbate 80. Docetaxel trihydrate is weighed accurately and dissolved in the above solution to form a clear solution. This solution is filtered through sterile 0.22u filter followed by sparging of an inert gas.

WE CLAIM:
1. A stabilized injectable pharmaceutical composition of docetaxel for human administration comprises docetaxel dissolved in Polysorbate 80, ethanol and an acid wherein the pH of the final solution is between 3 and 6.
2. A method of stabilizing docetaxel in an injectable composition such that at least about 80% of the potency of docetaxel is maintained after storage for at least three month at 40°C and 75% relative humidity, wherein said method comprises the step of adjusting pH of a mixture of polysorbate 80 and ethanol between 3 to 6 by using an acid, followed by dissolving docetaxel in the said mixture.
3. A method of stabilizing docetaxel in an injectable composition such that at least about 80% of the potency of docetaxel is maintained after storage for at least three month at 40°C and 75% relative humidity, wherein said method comprises the steps of
a. adjusting pH of the mixture of polysorbate 80 and ethanol
between 3 and 6 by using an acid,
b. dissolving docetaxel in the solution of step (a).
4. A stabilized injectable pharmaceutical composition as per claim 1 is such that at least about 80% of the potency of docetaxel is maintained after storage for at least three month at 40°C and 75% relative humidity.
5. As per claims 1 to 3, about 20 to 80 mg of docetaxel or salt thereof is present.
6. As per claims 1 to 3, about 0.5 to 1% v/v of polysorbate 80 is present.
7. As per claims 1 to 3, about 5 to 43% v/v of ethanol is present.
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8. As per claims 1 to 3, docetaxel or salt thereof is docetaxel trihydrate.
9. As per claims 1 to 3, said pharmaceutical formulation has a pH of 3.6.
10. As per claims 1 to 3, the said acid is a mineral acid or organic acid.