FIELD OF THE INVENTION
The present invention relates to stable parenteral compositions of artesunate and the process for preparing the same.
BACKGROUND OF THE INVENTION
Artesunate is a derivative of artemisinin, chemically known as (3R,5aS,6R,8aS,9R, I OS, 12R, 12aR)-3>6,9-trimethyitfecahydro-3,l 2-epoxypyrano[4,3-j]-l ,2-benzodioxepin-10-yl hydrogen butanedioate; or Butanedioic acid, mono ((SR^aS^R^aS^R, 1 OS, 12R, 12aR)-decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl) ester. The molecular formula for artesunate is Ci^gOsand is structurally depicted as follows:
Artesunate is an anti-malarial product marketed as 30mg, 60mg and 120mg powder for solution for injection under the brand name of Artesun® by Guilin Pharmaceuticals.
US 7,956,086 & US 7,678,828 assigned to USA-Secretary of Army disclose method of producing storage stable artesunic acid powder for injection formulation.
WO 2011/009956 AI assigned to Dafra Pharma disclose powder composition comprising artesunate,-hydroxycarbohydrate and a phosphate salt.
The available prior arts disclose powder for solution for injection, formulations of artesunate and marketed formulation of Artesunate is available as a kit consisting of a vial with artesunate powder for injection which needs to be reconstituted with sodium bicarbonate solution

provided in an ampoule packed in the same box. The reconstituted solution needs a dilution step in addition before intravenous or intramuscular administration.
Also, as per the available literature, artesunate has poor stability in aqueous medium and is slightly soluble in water and thus forms cloudy solutions or suspensions resulting in reduced drug efficiency in vivo.
The powder formulation of artesunate possesses good chemical stability. However, reconstitution of the powder is an inconvenient and time taking process and not stable if it is made soluble in aqueous solvents. Thus, there is a need for developing alternate artesunate non-powder formulations having enhanced stability and ease of manufacturing to use.
Accordingly, inventors of the present invention have developed stable liquid formulations of artesunate using various non-aqueous solvents that makes the process before administration simpler and at ease.
SUMMARY OF THE INVENTION
The present invention relates to stable pharmaceutical parenteral compositions of artesunate. Particularly to stable parenteral compositions of artesunate in the form of solution.
One embodiment of the present invention is in the form of a "liquid concentrate" comprising artesunate solubilized in a non-aqueous solvent system for.parenteral administration.'
Another embodiment of the present invention relates to a "ready-to-dilute" non-aqueous . liquid formulation comprising artesunate for parenteral administration.
Another embodiment of the present invention relates to a "ready-to-use" non-aqueous liquid formulation comprising artesunate for parenteral administration.
Further embodiment of the present invention relates to method for the treatment of malaria in a patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to parenteral compositions of artesunate. Particularly, the present invention relates to parenteral compositions of artesunate in the form of solution.
The term "active ingredient" or "active agent" or "drug" used interchangeably, is defined to mean active drug (e.g. artesunate), that produce a desired pharmacological or physiological effect.
The term "pharmaceutical^ acceptable" as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
The term "excipients" as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term "parenteral" as used herein means administration through intravenous, intramuscular, intracutaneous, subcutaneous, intra-articular or intrathecal routes.
The term "composition" as used according to the present invention can be used interconvertibly with the term "formulation".
As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, reference to "a method" includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure so forth.
The term "solvent" refers to a substance used for dissolving artesunate. Preferably, non-aqueous solvents are used in the present invention. Suitable non-aqueous solvents include but are not limited to polyethylene glycol 400 (PEG-400), polyethylene glycol 800 (PEG-800), propylene glycol, dimethyl acetamide, methylene chloride, ethyl acetate, acetone, glycerol, N-methyl pyrrolidone, mono thioglycerol, alcohols selected form ethanol, methanol, tertiary-butyl alcohol, dehydrated alcohol, isopropyl alcohol, and the like and combinations thereof.

The pharmaceutical parenteral formulations according to the present invention comprise artesunate in an amount of 30mg, 60mg and 120mg.
Liquid dosage forms according to the present invention relates to a liquid concentrate, ready to dilute or ready-to-use formulation.
Formulations according to the present invention are in the form of a solution or suspension. Preferably, in the form of solution.
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One embodiment of the present invention is in the form of a liquid concentrate comprising artesunate solubilized in a non-aqueous solvent system for parenteral administration.
. "Liquid concentrate" according to the present invention is a formulation which requires the steps of primary dilution and secondary dilution before administering to a patient.
Another embodiment of the present invention relates to a ready-to-dilute non-aqueous liquid formulation for parenteral administration.
"Ready to dilute" compositions according to the present invention requires a single dilution before administering to a patient.
One another embodiment of the present invention relates to a "Ready-to-use" liquid formulation comprising artesunate for parenteral administration that can be directly administered to a patient without the requirement of reconstitution and/or dilution step(s) before administration.
Formulations of the present invention provide an advantage of avoiding sterilization of dry powder, as these are prepared under special processing conditions and at the same time one can overcome the problem of variability observed during powder filling of API into vials.
Yet another embodiment of the present invention relates to process for the preparation of pharmaceutical formulations of artesunate comprising the steps of:
1) adding artesunate to a non-aqueous solvent under continuous stirring and checking the pH,
2) filtering the solution of step. 1 through a suitable filter,
3) filling the filtered solution of step 2 into suitable size vials,
4) finally, stoppering and sealing the filled vials of step 3.

Formulations of the present invention can be directly administered or can be diluted using 0.9% Sodium chloride or 5% Dextrose before parenteral administration or may be preceded by the step of.diluting with sodium bicarbonate solution.
The present invention further comprise one or more other pharmaceutically acceptable excipients selected from a buffer, a pH adjusting aid, a solubilizer, a chelating agent, an antioxidant, an antibacterial preservative and the like and combinations thereof.
Buffers used in the present invention includes an acid or a base and its conjugate base or acid, respectively. Suitable buffers include mixtures of weak acids and alkali metal salts (e.g., sodium, potassium) of the weak acids, such as acetate, citrate, tartarate, phosphate, benzoate and bicarbonate buffers and the like and combinations thereof.
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pH adjusting aids used according to the present invention includes but are not limited to tartaric acid, citric acid, malic acid, sodium chloride, potassium chloride, sodium hydroxide, potassium hydroxide, sodium carbonate, meglumine and the like and combinations thereof.
Solubilizers used according to the present invention include but are not limited to sorbitan fatty acid esters, polysorbates, poloxamers, oleoyl and linoleoyl polyoxylglycerides (such as Labrafil), caprylocaproyl polyoxylglycerides (such as Labrasol), Medium-chain triglycerides (such as Labrafac lipophile), propylene glycol dicaprylocaprate (such as Labrafac® PG) and the like and mixtures thereof.
Chelating agents used according to the present invention includes but are not limited to ethylenetetraamineacetic acid, ethylenediaminetetraacetic acid (EDTA), and salts, derivatives and the like and combinations thereof.
Antioxidants used according to the present invention include but are not limited to ascorbic acid, sodium sulfite, sodium bisulfite and sodium metabisulfite and the like and combinations thereof.
Antibacterial preservatives used according to the present invention includes but are not limited to phenylmercuric nitrate^ thiomersal, benzalkonium chloride, benzethonium chloride, phenol, cresol and chlorobutanol and the like and combinations thereof.-

One aspect of the present invention relates to a pharmaceutical composition comprising a liquid concentrate, wherein the liquid concentrate is first diluted using sodium bicarbonate solution and the obtained solution is further diluted using 0.9% sodium chloride solution or 5% dextrose solution prior to intravenous or intramuscular administration and used immediately.
Another aspect of the present invention relates to a ready-to-dilute non-aqueous liquid formulation, wherein the formulation is directly diluted using 0.9% sodium chloride solution or 5% dextrose solution prior to intravenous or intramuscular administration and used immediately.
Further embodiment of the present invention relates to a method for the treatment of malaria in a patient in need thereof.
The following examples further describe and demonstrate particular embodiments within the scope of the present invention. The examples are given solely for illustration and are not to be construed as limitations as many variations are possible without departing from spirit and scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Brief manufacturing process:
1) Artesunate was added to non-aqueous solvent under continuous stirring for 15 to 20 min, the obtained solution was checked for an appropriate pH of 5 - 8, and was made upto the volume,
2) solution of step 1 was filtered the through 0.2 u filter,
3) filtered solution of step 2 was filled into suitable size vials and
4) finally, filled vials of step 3 were stoppered and sealed.
Example 5 -12: Parenteral compositions of Artesunate in double solvent system.

Brief manufacturing process:
1) Required volumes of two non-aqueous solvents were mixed under continuous stirring,
2) artesunate was added to the solvent mixture of step 1 under continuous stirring for 15 to 20 min and the obtained solution was checked for an appropriate pH of 5 - 8, and made upto the volume,
3) solution of step 2 was filtered through 0.2 u filter,
4) filtered solution of step 3 was filled into suitable size vials and
5) finally, filled vials of step 4 were stoppered and sealed.
Formulations of the present invention as exemplified above can be in the form of liquid concentrate, ready-to-dilute or ready-to-use formulations that are administered directly or may be subjected to single dilution step using 0.9% Sodium chloride or 5% Dextrose or may be preceded by the step of diluting with sodium bicarbonate solution before administration to a patient in need thereof.