FIELD OF THE INVENTION
The present invention relates to parenteral compositions of carmustine and process for the preparation thereof.
BACKGROUND OF THE INVENTION
Carmustine is a p-chloro-nitrosourea compound useful in chemotherapy of certain neoplastic diseases. It has the chemical name, 1,3-bis (2-chloroethyl)-l-nitrosourea, with a molecular weight of 214.06 and its empirical formula is 05^02^02, with the following structure:
It is very soluble in alcohol, such as tertiary butanol, dichloromethane, and ether, and slightly soluble in water with a solubility of 4 mg/mL. Carmustine readily gets hydrolyzed in water at pH >6. Carmustine has a Log P value of 1.53. Its anti neoplastic activity is mainly due to its effect on DNA, RNA, mitochondrial glutathion reductase and Cytochrome P450 enzyme.
Carmustine is commercially available as a sterile lyophilized powder for injection under the tradename BiCNU®, indicated for the treatment of brain tumors, multiple myeloma, hodgkin's disease, and non-hodgkin lymphoma (NHL).
BiCNU® (carmustine for injection) is available in single dose vials as lyophilized powder containing 100 mg of carmustine, co-packaged with ethanol as sterile diluent. The . lyophilized carmustine appears as pale yellow dry flakes or dry congealed mass. Prior to injection, the lyophilized carmustine is reconstituted with ethanol and the solution is further diluted with water. The reconstitution results in a clear, colorless to yellowish solution which is further diluted with 5% Dextrose Injection, USP or Sodium Chloride Injection, USP.
Carmustine has poor stability in aqueous medium and is slightly soluble in water and thus forms cloudy solution or suspension resulting in reduced drug efficiency in vivo.

The powder formulation of carmustine possesses good chemical stability. However, reconstitution of the powder is an inconvenient and time taking process.
Thus, there is a need to develop an improved, robust non-powder formulations of carmustine with simple process without using lyophilization technique. Accordingly, inventors of the present invention are developing stable liquid formulations of carmustine that makes the process before administration simpler and easier.
SUMMARY OF THE INVENTION
1 The present invention relates to liquid parenteral compositions of carmustine.
One embodiment of the present invention relates to a "ready-to-use" non-aqueous liquid formulation comprising carmustine for parenteral administration. '
Another embodiment of the present invention relates to a "ready-to-dilute" non-aqueous liquid formulation comprising carmustine for parenteral administration.
Another embodiment of the present invention relates to ready to use parenteral composition comprising carmustine or its pharmaceutically acceptable salt, one or more solvents selected from propylene glycol, polyethylene glycol, dimethylacetamide, N-methyl pyrrolidone, diethylene glycol monoethyl ether or mixtures thereof, optionally other pharmaceutical ly acceptable excipients.
Another embodiment of the present invention relates to parenteral compositions comprising carmustine, N, N-dimethylacetamide and polyethylene glycol.
Another embodiment of the present invention relates to parenteral compositions ' comprising carmustine, N, N-dimethylacetamide and propylene glycol.
Further embodiment of the present invention. relates to parenteral compositions comprising carmustine and diethylene glycol monoethyl ether (transcutol).
Yet another embodiment of the present invention relates to parenteral compositions comprising carmustine and N-methyl pyrrolidone.

Another embodiment relates to use of carmustine compositions of the present invention for the treatment of certain neoplastic diseases, specifically, brain tumors, multiple, myeloma, hodgkin's disease, or non-hodgkin's lymphoma.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to liquid parenteral compositions of carmustine. More particularly, the present invention relates to ready to use parenteral compositions of carmustine in the form of solution.
The term "active ingredient" or "active agent" or "drug" used interchangeably, is defined to mean active drug (e.g. carmustine), that induce a desired pharmacological or physiological effect.
The term "pharmaceutically acceptable" as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
The term "excipients" 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, subcutaneous, intracutaneous, intra-articular, intrathecal routes of administration.
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 an ingredient used for dissolving an ingredient. Suitable • solvents that can be used according to the present invention includes but not limited to solvents selected from propylene glycol, dimehtyl acetamide (N, N-dimethylacetamide/ DMA), N-methyl pyrrolidone, polyethylene glycol of various molecular weights, polyethylene glycol 400 (PEG-

400), polyethylene glycol 800 (PEG-800), diethylene glycol monoethyl ether (transcutol), dimethyl sulfoxide (DMSO), ethanol, methanol, tertiary-butyl alcohol, isopropyl alcohol, methylene chloride, ethyl acetate, acetone and combinations thereof. Preferred solvents include propylene glycol, polyethylene glycol, N-methyl pyrrolidone, dimehtyl acetamide and diethylene glycol monoethyl ether.
Diethylene glycol monoethyl ether is a highly purified solvent for poorly water soluble active pharmaceutical ingredients, marketed by Gattefosse under the brand name "Transcutol®".
One embodiment of the present invention relates to ready to use parenteral composition comprising carmustine or its pharmaceutically acceptable salt, propylene glycol,'N, N-dimehtyl acetamide, N-methyl pyrrolidone, polyethylene glycol, diethylene glycol monoethyl ether and optionally one or more surfactants.
The composition according to the present invention comprises about 10 mg to about 100 mg of carmustine for each ml of solvent.
Another embodiment of the present invention relates to process for the preparation of pharmaceutical compositions of carmustine comprising the steps of:
(a) addition of weighed quantity of carmustine to non aqueous solvent in a vessel with continuous stirring until it gets dissolved completely, (b) filtering the solution of step (a), and filling into vials, (c) finally stoppering and sealing the vials of step (b).
Another embodiment of the present invention relates to process for the preparation of pharmaceutical compositions of carmustine comprising the steps of:
(a) addition of weighed quantity of carmustine to N,N dimethyl acetamide and propylene glycol in a vessel with continuous stirring until it gets dissolved completely,
(b) filtering the solution of step (a) and filling into vials,
(c) finally stoppering and sealing the vials of step (b).

Another embodiment of the present invention relates to process for the preparation of pharmaceutical compositions of carmustine comprising the steps of:
(a) addition of weighed quantity of carmustine to N,N dimethyl acetamide and polyethylene glycol in a vessel with continuous stirring until it gets dissolved completely,
(b) filtering the solution of step (a), and filling into vials,
(c) finally stoppering and sealing the vials of step (b).
Another embodiment of the present invention relates to process for the preparation of pharmaceutical compositions of carmustine comprising the steps of:
(a) addition of weighed quantity of carmustine to diethylene glycol monoethyl ether, optionally other solvents in a vessel with continuous stirring until it gets dissolved completely,
(b) filtering the solution of step (a), and filling into vials,
(c) finally stoppering and sealing the vials of step (b).
Another embodiment of the present invention relates to process for the preparation of pharmaceutical compositions of carmustine comprising the steps of:
(a) addition of weighed quantity of carmustine to N-methyl pyrrolidone in a vessel with
continuous stirring until it gets dissolved completely,
(b) filtering the solution of step (a), and filling into vials,
(c) finally stoppering and sealing the vials of step (b).
The present invention optionally further comprise one or more other pharmaceutically acceptable excipients selected from a bulking agent, a solubilizer, a surface active agents, a buffer, a pH adjustment aid, a chelating agent, an antioxidant, an antibacterial preservative or combinations thereof.
Bulking agents according to the present invention includes but not limited to mannitol, lactose, sucrose, sodium chloride, trehalose, dextrose, starch, hydroxyethyl starch, cellulose, cyclodextrins, glycine or mixtures thereof.
Solubilizers according to the present invention can be surface active agents, co-solvents and complexing agents or combinations thereof.

Surface active agents according to the present invention are hydrophilic in nature and includes but are not limited to sorbitan fatty acid esters, polysorbates, poloxamers, oleoyl and linoleoyl polyoxylglycerides (such as Labrafil), caprylocaproylpolyoxylglycerides, (such as Labrasol), medium-chain triglycerides (such as Labrafac lipophile), propylene glycol dicaprylocaprate (such as Labrafac® PG) or mixtures thereof.
Buffers 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 combinations thereof.
pH adjustment aids 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 combinations thereof. ,
Chelating agents according to the present invention includes but are not limited to ethylenetetraamineacetic acid, ethylenediaminetetraacetic acid (EDTA), and salts, derivatives and combinations thereof.
Compositions of the present invention can be directly administered or can be diluted using 0.9% sodium chloride injection, USP, or 2.5% or 5% dextrose/0.45% sodium chloride injection, USP before parenteral administration.
Liquid dosage forms according to the present invention may be "ready-to-use" or "ready to dilute" formulations.
The term "ready to use" composition as used herein refers to the composition which avoids reconstitution and may require dilution with a suitable diluent before administration to the patient.
The term "Ready to dilute" compositions according to the present invention requires a single dilution before administering to a patient.
The composition of the present invention is useful for the treatment of certain neoplastic diseases, brain tumors, multiple myeloma, Hodgkin's disease, or non-Hodgkin lymphoma.

EXAMPLES
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.
Example
Brief manufacturing process:
1. Transfer measured quantity of N, N-dimethylacetamide and propylene glycol in a clean and dried SS316 vessel at controlled room temperature,
2. add weighed quantity of carmustine and dissolve in step (1) with continuous stirring until a clear solution is obtained,
3. filtering the final solution of step (2) through sterile filter,
4. filling the filtered solution of step (3) into the 5mL/20mm neck Type-I clear glass vial with the fill volume of NLT 1 mL, stoppered and sealed the vials, and
5. finally, storing the vials of step (4) at 2°C-8°C.

Brief manufacturing process:
1. Transfer measured quantity of polyethylene glycol and N, N-dimelhylacetamide in a clean and dried SS316 vessel at controlled room temperature,
2. add weighed quantity of carmustine and dissolve in step (1) with continuous stirring until a clear solution is obtained,
3. filtering the final solution of step (2) through sterile filter,
4. filling the filtered solution of step (3) into the 5mL/20mm neck Type-I clear glass vial with the fill volume of NLT 1 mL, stoppered and sealed the vials, and
5. finally, storing the vials of step (4) at 2°C-8°C.

Brief manufacturing process:
1. Transfer measured quantity of diethylene glycol monoethyl ether in a clean and dried SS316 vessel at controlled room temperature,
2. add weighed quantity of carmustine and dissolve in step (1) with continuous stirring until a ' clear solution is obtained,
3. filtering the final solution of step (2) through sterile filter,
4. filling the filtered solution of step (3) into the 5mL/20mm neck Type-I clear glass vial with the fill volume of NLT 4 mL, stoppered and sealed the vials, and
5. finally, storing the vials of step (4) at 2°C-8°C.

Brief manufacturing process:
1. Transfer measured quantity of N-methyl pyrrolidine in a clean and dried SS316 vessel at controlled room temperature,
2. add weighed quantity of carmustine and dissolve in step (1) with continuous stirring until a clear solution is obtained,
3. filter the final solution of step (2) through sterile filter,
4. fill the filtered solution of step (3) into the 5mL/20mm neck Type-I clear glass vial with the fillvolume of NLT 4 mL, stoppered and sealed the vials, and
5. finally, store the vials of step (4) at 2°C-8°C.