FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification [See Sections 10 and rule 13]
TITLE: TAXANE DERIVATIVE COMPOSITION
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Nationality: Indian
(c) 2nd Floor, Chinubhai Centre Off Nehru Bridge. Ashram Road Ahmedabad-380009, Gujrat
The following specification describes the invention:

Field of the invention:
The present invention relates to a novel composition comprising taxane derivative. The invention particularly relates to injectable pharmaceutical composition of taxane derivative like Docetaxel without using ethanol.
Background and Prior Art:
Docetaxel has very low water solubility. So surfactant and ethanol were essentially used to prepare injectable formulation containing docetaxel. Ethanol has been regarded as the best biocompatible solvent for taxane derivative like docetaxel. Ethanol is either used as a solvent for docetaxel or as a dilution additive with water for injection to dilute the drug concentrates before administering it to the patient.
Docetaxel injection is marketed as Taxotere by Sanofi Aventis. Taxotere injection 20mg '0.5ml contains 20mg docetaxel in 0.5 ml polysorbate 80 and diluent for taxotere (13% w/w ethanol in water for injection).
US 5438072 by Rhone-Poulenc claims injectable compositions comprising taxane derivatives in a surface active agent selected from polysorbates, ethylene oxide esters-ethers and fatty acids glycerides, and a water solution of an effective amount of a dilution additive selected from organic compounds having a hydroxyl group an amine functional group and a molecular weight of less than 200 or sodium chloride. So the drug-surfactant concentration is diluted by dilution additive water solution before administering it to the patient.
I S 5750561 claims injectable solution consisting essentially of docetaxel dissolved in a mixture of ethanol and a polysorbate, which contains up to about 1 mg/ml of docetaxel wherein said injectable solution is capable of being injected without anaphylactic or alcohol intoxication manifestations being associated therewith. The ethanol and polysorbate mixture contains less than 5% each of ethanol and polysorbate.
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US 5698582 claims compositions comprising a taxane derivative dissolved in a surfactant
selected from polysorbate or polyethoxylated castor oil, and essentially free or free of
ethanol. The process of preparation of the injectable formulation according to this patent
is either by any of the following process:
The first process comprises dissolving taxane derivative in ethanol, and gradually adding
the surfactant. The ethanol is then completely or almost completely eliminated.
I he second process invokes dissolving docetaxel in solution comprising surfactant in
small amount of ethanol (preferably 1 to 2%).
The patent discloses that presence of small amount of ethanol has several advantages like lower viscosity of surfactant-ethanol solution and improved wetting and filtration of active powder docetaxel.
US 5714512 claims a composition which comprises dissolving docetaxel in a surfactant selected from polysorbate, polyoxyethylated vegetable oil, and polyethoxylated castor oil, said composition being essentially free or free of ethanol. The process of preparing the composition comprises dissolving active ingredient in ethanol, adding surfactant and finally removing the ethanol.
Further patents like IIS20061 88566 claims nanoparticulate docetaxel composition with atleast one surface stabilizer wherein the average particle size of docetaxel is less than 2000 nm.
JP2005225818 claims composition containing paclitaxel or docetaxel with ethanol and pol\ ethylene glycol wherein the ratio of ethanol to polyethylene glycol is 1:4 to 4:1. CN1850056 claims freeze-dried powder injection and process of its preparation. This injection comprises docetaxel, co-solvent (like polyethylene glycol and / or poloxamer, polysorbate 80 or combination of poloxamer and polysorbate 80) and skeleton-supporting agent mannitol.
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WO 9528923 claims pharmaceutical composition comprising active principle which can be docetaxel, at least one unsaturated phospholipid and at least one negative phospholipid, wherein both mentioned phospholipids are different.
Ethanol is used either as a solvent for docetaxel or as a dilution additive with water for injection to dilute the drug concentration before administering to a patient. Use of ethanol in injectable composition of docetaxel has drawback like it can cause anaphylactic shock or alcohol intoxication. So even if ethanol is used as a solvent for docetaxel, it has been eliminated from the final composition to minimize its amount to less than 5%, more preferably within 1-2%. Reducing ethanol from formulation helps to reduce the intoxication drawback of the formulation.
So there is a scope to formulate a stable docetaxel injection which completely avoids use of ethanol. 1 he present invention is intended to a stable docetaxel injection which completely avoids use of ethanol. It is neither used as a solvent for docetaxel nor as a dilution additive. So the chance of anaphylactic shock or alcoholic intoxication is completely avoided upon administration of this injection to a patient.
Object of the Invention:
The prime object of the invention is to formulate a docetaxel injection which completely avoids use of ethanol in the formulation, so the chance of alcoholic intoxication or anaphylactic shock is completely avoided.
Further object of the invention is to formulate a stable docetaxel injection which completely avoids use of ethanol in the formulation.
One more object of the invention is to provide the process of preparation of docetaxel injectable formulation which completely avoids use of ethanol in the formulation.
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Summary of the Invention:
The present invention provides a stable injectable composition of taxane derivative preferably docetaxel which completely avoids use of ethanol in the formulation. The invention further provides process of preparation of the stable docetaxel injection.
Detailed Description of the Invention:
The pharmaceutical formulation of the present invention is taxane derivative injection which is completely free ol' ethanol till its administration to a patient. This ethanol free taxane derivative injection completely avoids the chance of anaphylactic shock or
alcoholic intoxication to the patient.
The preferable taxane derivative of the injection of present invention is docetaxel. The drug concentrate comprising docetaxel is diluted with a diluent constituting of a mixture of solvent one of which is water for injection. This perfusion has concentration of 5 to 15 mg/ml which is diluted with 0.9% NaCl or 5% dextrose solution before administration to the patient.
The ethanol free solvent can be a part of drug product formulation which doesn't need to
be reconstituted prior to further dilution.
The injection comprises active pharmaceutical ingredient which is taxane derivative and surfactant. It may also contain a co-solvent and stabilizer. The preferred taxane derivative used in the formulation of the present invention is docetaxel. Docetaxel is used in amount of 10 to 60 mg / ml more preferably 25 to 45 mg / ml.
The preferred surfactant used in the injectable formulation of present invention is polysorbate (e.g. Tween). polyoxyethylated vegetable oil (e.g. Emulphor) and polyethoxylated castor oil (e.g. Cremophor). It is used in sufficient quantity to maintain the volume upto 1 ml.
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In the formulation of the present invention, additional excepient like stabilizer and co-solvent can also be used.
The stabilizer used in the formulation of the present invention is for pH adjustment. The preferred stabilizers are inorganic or organic acids. More preferably citric acid is used as stabilizer in the formulation of present invention. The quantity of stabilizer used in the formulation is amount sufficient to maintain the pH of the formulation between 2 to 5 more preferably between 3 to 4.
The co-solvent used in the formulation of present invention further helps to solubilize the active ingredient. This co-solvent can be propylene glycol, polyethylene glycol (of more than 200 m.wt preferably PEG 400), glucose and sorbitol either as a solvent or as a part of reconstitulion solvent. The amount of solubilizer used in the formulation of present invention is 10 to 60 % of the formulation, more preferably between 20 to 40 % of the formulation calculated as wt/vol.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is. the use of these words may imply the inclusion of an element or elements not specifically recited.
Example:
The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of the appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The above said invention can be illustrated by but not limited to following example(s).
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Table-1

Sr. No. Ingredients Quantity
1. Docetaxel 10-60mg/ml
2. PEG 400 10-60%
3. Citric acid q.s
4. Polysorbate 80 q.s
Process of preparation:
I his injectable formulation can be prepared by any of the following two processes:
Process-I: It comprises the following steps:
i) Take polysorbate 80 and to this add citric acid for pH adjustment.
ii) To this solution of step-i. add PEG 400.
iii) To the solution prepared of step-ii, add docetaxel.
iv) Filter the solution of step-iv through 0.2 micron filter.
v) After the filtration, fill the solution into vial.
Process-11: It comprises the following steps:
i) Take polysorbate 80 and to this add PEG 400.
ii) To this solution of step-i, add citric acid for pH adjustment.
iii) 10 the solution prepared of step-ii. add docetaxel.
iv) Filter the solution of step-iv through 0.2 micron filter.
v) After the filtration, fill the solution into vial.
The drug concentrate prepared as per the above process is taken from the vial and is diluted with water for injection for further use.
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Table-II

Sr. No. Ingredients % Range

1. Docetaxel 10-60 mg/ml
2. Citric acid q.s
3. Polysorbate 80 q.s
This injectable formulation can be prepared by following process:
i) Take polysorbate 80 and to this add citric acid for pH adjustment.
ii) To the solution of step-i. add docetaxel.
in) filler the solution of step-ii through 0.2 micron filter.
iv) After the filtration, fill the solution into vial.
The drug concentrate prepared as per the above process is taken from the vial and is diluted by water for injection or mixture of water for injection and polyethylene glycol of more than 200 m.wt. preferably PEG 400 for further use.
Dated this 29th day of September 2007

The Controller of patent The Patent Office At Mumbai
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