A PHARMACEUTICAL COMPOSITION OF TRABECTEDIN AND ITS PROCESS FOR PREPARATION
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising Trabectedin, also known as ecteinascidin-743 or ET-743, and bulking agent and the process for preparation thereof.
BACKGROUND OF THE INVENTION
Trabectedin (I), chemically known as (l'R,6R,6aR,7R,13S,14S,16R)-5(acetyloxy)-3',4',6,6a,7,13,14,16-octahydro-6',8, i 4-trihydroxy-7\9-dimethoxy-4,10, 23-trimethy lspiro[6,16-(epith iopropanoxymethano)-7,13-imino-12H-1,3-dioxolo [7,8]LSoquino[3,2b][3]benzazocine-20,r(2'H)-isoquinolin]-19-one, has been approved by USFDA under the brand name YONDELIS which is a sterile lyophilized white to off-white powder/cake in a single-dose vial containing trabectedin, potassium dihydrogen phosphate, sucrose, and phosphoric acid and potassium hydroxide and stored at 2°C to 8°C. It is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.
(I) The patent publication WO 2000/69441 describes the lyophilized pharmaceutical formulation containing trabectedin (ET-743), mannitol, monopotassium phosphate and phosphoric acid to adjust the pH between 4 and 6, with the 4.8 is the preferred pH.

The patent US 8895557 B2 describes the composition containing trabectedin and disaccharide. The disaccharide is selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, sorbose, turanose, melibiose, gentiobiose, and mixtures thereof.
There is a need to develop a stable pharmaceutical composition of trabectedin and its process for preparation.
SUMMARY OF THE INVENTION
One embodiment of the present invention provides a pharmaceutical composition comprising trabectedin or its pharmaceutically acceptable salt and bulking agent which is selected from monosaccharide or sugar alcohol or combination thereof.
Another embodiment of the present invention provides a process for preparation of pharmaceutical composition comprising trabectedin or its pharmaceutically acceptable salt and bulking agent which is selected from monosaccharide or sugar alcohol or combination thereof.
Another embodiment of the present invention provides a pharmaceutical composition comprising trabectedin or its pharmaceutically acceptable salt and bulking agent which is selected from combination of sugar alcohol and disaccharide.
Another embodiment of the present invention provides a process for preparation of pharmaceutical composition comprising trabectedin or its pharmaceutically acceptable salt and bulking agent which is selected from combination of sugar alcohol and disaccharide.
Another embodiment of the present invention provides a pharmaceutical composition comprising trabectedin or its pharmaceutically acceptable salt and bulking agent which is selected from amino acids.
Another embodiment of the present invention provides a process for preparation of pharmaceutical composition comprising trabectedin or its pharmaceutically acceptable salt and bulking agent which is selected from amino acids.

DETAILED DESCRIPTION OF THE INVENTION
First embodiment of the present invention provides a pharmaceutical composition comprising trabectedin or its pharmaceutically acceptable salt and bulking agent which is selected from monosaccharide or sugar alcohol or combination thereof.
The pharmaceutically acceptable salt is selected from acid addition salt and the base addition salt. The acid is selected from formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, malonic acid, malic acid, fumaric acid, hydrochloric acid, phosphoric acid, sulfuric acid and the like. The base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, amine and the like.
The monosaccharide is selected from dextrose, fructose and galactose; preferably dextrose and fructose. The sugar alcohol is selected from mannitol, sorbitol xylitol, maltitol and lactitol and the like; preferably mannitol. The combination of monosaccharide with sugar alcohol is selected from the combination of dextrose with mannitol, combination of fructose with mannitol and the like.
The present pharmaceutical formulation further comprises pH adjusting agent which is selected from acid and base. The acid is selected from hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid and the like; preferably phosphoric acid. The base is selected from sodium hydroxide, potassium hydroxide and the like; preferably potassium hydroxide. The pH agent is used to adjust the pH of the pharmaceutical formulation of the present invention to acidic pH. Preferable pH range is between 3.00 and 6.00; more preferably between 3.5 and 5.0.
The present pharmaceutical formulation further comprises a buffering agent. The buffer is selected from the group of acetate, phosphate, citrate, TRIS, maleate, bicarbonate, succinate or a combination thereof; preferably acetate and phosphate buffer; more preferably sodium dihydrogen phosphate or potassium dihydrogen phosphate.
The present pharmaceutical formulation optionally further comprising surfactant. The surfactant is selected from polyoxyethylene (20), sorbitan ester,

poly(ethylene glycol)-40 castor oil and poloxamer 188 and the like. The formulation optionally further comprises tonicity modifier, antioxidant, preservatives, diluents and other pharmaceutical ly acceptable excipients.
The pharmaceutical formulation of the present invention is in the form of lyophilized powder/cake or ready to dilute solution or ready to use solution for parenteral administration.
Another embodiment of the present invention provides a pharmaceutical composition comprising trabectedin or its pharmaceutical ly acceptable salt and bulking agent which is selected from combination of sugar alcohol and disaccharide.
The sugar alcohol is selected from mannitol, sorbitol xylitol, maltitol and lactitol and the like; preferably mannitol. The disaccharide is selected from maltose, lactose, sucrose, trehalose and the like.
The present pharmaceutical formulation further comprising pH adjusting agent selected from acid and base. The acid is selected from hydrochloric acid, .sulfuric acid, acetic acid, phosphoric acid and the like; preferably phosphoric acid. The base is selected from sodium hydroxide, potassium hydroxide and the like; preferably potassium hydroxide. The pH agent is used to adjust the pH of the pharmaceutical formulation of the present invention to acidic pH. Preferable pH range is between 3.00 and 6.00; more preferably between 3.5 and 5.0.
The present pharmaceutical formulation further comprises a buffering agent. The buffer is selected from the group of acetate, phosphate, citrate, TRIS, maleate, bicarbonate, succinate or a combination thereof; preferably acetate and phosphate buffer; more preferably sodium dihydrogen phosphate or potassium dihydrogen phosphate.
The present pharmaceutical formulation optionally further comprising
surfactant. The surfactant is selected from polyoxyethylene (20), sorbitan ester,
poly(ethylene glycol)-40 castor oil and poloxamer 188 and the like. The formulation
optionally further comprises tonicity modifier, antioxidant, preservatives, diluents
and other pharmaceutical ly acceptable excipients.
XI3ZEEI32EIZCEE&KKT Tvrrrr-T-rarv-r- -r tr*-->-~> —

The pharmaceutical formulation of the present invention is in the form of lyophilized powder/cake or ready to dilute solution or ready to use solution for parenteral administration.
Another embodiment of the present invention provides a pharmaceutical composition comprising trabectedin or its pharmaceutical^ acceptable salt and bulking agent which is selected from amino acids.
The amino acid is selected from glycine, L-arginine, histidine, alanine, isoleucine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, valine, ornithine, proline, selenocysteine, serine, tyrosine or pharmaceutically acceptable salt thereof. Preferably L-arginine or its pharmaceutical^ acceptable salt.
The present pharmaceutical formulation further comprising pH adjusting agent selected from acid and base. The acid is selected from hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid and the like; preferably phosphoric acid. The base is selected from sodium hydroxide, potassium hydroxide and the like; preferably potassium hydroxide. The pH agent is used to adjust the pH of the pharmaceutical formulation of the present invention to acidic pH. Preferable pH range is between 3.00 and 6.00; more preferably between 3.5 and 5.0.
The present pharmaceutical formulation further comprises a buffering agent. The buffer is selected from the group of acetate, phosphate, citrate, TRIS, maleate, bicarbonate, succinate or a combination thereof; preferably acetate and phosphate buffer; more preferably sodium dihydrogen phosphate or potassium dihydrogen phosphate.
The present pharmaceutical formulation optionally further comprising surfactant. The surfactant is selected from polyoxyethylene (20), sorbitan ester, poly(ethylene glycol)-40 castor oil and poloxamer 188 and the like. The formulation optionally further comprises tonicity modifier, antioxidant, preservatives, diluents and other pharmaceutical ly acceptable excipients.

The pharmaceutical formulation of the present invention is in the form of lyophilized powder/cake or ready to dilute solution or ready to use solution for parenteral administration.
Another embodiment of the present invention provides a process for preparation of pharmaceutical composition comprising trabectedin or its pharmaceutically acceptable salt, comprising;
a) Dissolving the bulking agent in the solution comprising trabectedin or its pharmaceutically acceptable salt and buffer
b) Adding suitable solvent to sufficient quantity,
c) Optionally adjusting the pH between 3 and 6 and
d) Lyophilizing the solution to obtain the solid.
Trabectedin or its pharmaceutically acceptable salt is dissolved in acidic medium; preferably in aqueous acidic medium. The acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid and the like. The bulking agent and buffer are added to the solution of trabectedin or its pharmaceutically acceptable salt in aqueous acidic medium. To the resulting solution, a suitable solvent for example water for injection and the like is added to sufficient quantity.
The pH of the resulting solution is adjusted between 3 and 6. Preferable pH range is between 3.5 and 5.0. The pH adjusting agent is selected from acid and base. The acid is selected from hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid and the like; preferably phosphoric acid. The base is selected from sodium hydroxide, potassium hydroxide and the like; preferably potassium hydroxide.

Claim:
1. A pharmaceutical composition of trabectedin comprising;
a) Trabectedin or its pharmaceutically acceptable salt and
b) bulking agent which is selected from monosaccharide or sugar alcohol or combination thereof.
2. A pharmaceutical composition of trabectedin comprising;
a) Trabectedin or its pharmaceutically acceptable salt and
b) bulking agent which is selected from combination of sugar alcohol and disaccharide.
3. A pharmaceutical composition of trabectedin comprising;
a) trabectedin or its pharmaceutically acceptable salt and
b) bulking agent which is selected from amino acids.

4. The pharmaceutical composition as claimed in claim I, wherein the monosaccharide is selected from dextrose, fructose and galactose.
5. The pharmaceutical composition as claimed in claims 1 and 2, wherein the sugar alcohol is selected from mannitol, sorbitol xylitol, maltitol and lactitol.
6. The pharmaceutical composition as claimed in claim 1, wherein the combination of monosaccharide with sugar alcohol is selected from the combination of dextrose with mannitol, combination of fructose with mannitol.
7. The pharmaceutical composition as claimed in claim 2, wherein the disaccharide is selected from maltose, lactose, sucrose and trehalose.
8. The pharmaceutical composition as claimed in claim 3, wherein the amino acid is selected from glycine, L-arginine, histidine, alanine, isoleucine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, valine, ornithine, proline, selenocysteine, serine, tyrosine or pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition as claimed in claims 1, 2 and 3, wherein the composition further comprising pH adjusting agent, buffering agent and suitable solvent.
10. A process for the preparation of pharmaceutical composition as claimed in claim 1, 2 and 3, wherein the process comprising

a) dissolving the bulking agent in the solution comprising trabectedin or its pharmaceutically acceptable salt and buffer
b) adding suitable solvent to sufficient quantity,
c) optionally adjusting the pH between 3 and 6 and
d) lyophilizing the solution to obtain the solid.