FIELD OF INVENTION

This invention relates to pharmaceutical composition/formulation for parenteral administration. More particularly, it relates to stable liquid formulations comprising bendamustine or its pharmaceutically acceptable salts N-methyl pyrrolidone (Pharmasolve®) and optionally one or more pharmaceutically acceptable excipients for parenteral administration and process for preparing the same.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Bendamustine, a chemotherapeutic agent for cancer therapy, is a bifunctional mechlorethamine derivative (nitrogen mustard group which contains a purine-like benzimidazole ring). The nitrogen mustard group is structurally similar to cyclophosphamide and chlorambucil and gives the drug its alkylating properties while the benzimidazole ring may be responsible for its antimetabolite properties. The precise cytotoxic mechanism of action remains unclear.

It is chemically known, (4-{5-[Bis(2-chloroethyl)amino]-l-methyl-2-benzimidazolyl} butyric acid, is an atypical structure with a benzimidazole ring, whose structure includes an active nitrogen mustard, having chemical structure as below:

Bendamustine is commercially available as Treanda® in the US market. It is available in single-use vials containing either 25 mg or 100 mg of bendamustine hydrochloride as white to off-white lyophilized powder. After reconstitution with water for injection it should be administered by intravenous infusion over 30 to 60 minutes. The U.S. Food & Drug Administration (US FDA) approved bendamustine for the treatment of patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin's lymphoma.
Prior art literatures relating to bendamustine pharmaceutical formulations are discussed below.

Denmark Patent No. DD159289 discloses method for producing stable injection of solutions using various solvents like 1,2-propylene glycol or ethanol with bendamustine which is ready-to use, that avoids lyophilization.

U.S. Publication No. 2011/0015245 discloses the composition comprising bendamustine and an amphiphilic cationic compound, which self assemble to form aggregates and enhance stability in aqueous solutions.

U.S. Publication No. 2006/0159713 relates to pharmaceutical formulations of lyophilized bendamustine suitable for pharmaceutical use. The publication also discloses that because of their high reactivity in aqueous solutions, nitrogen mustards are difficult to formulate as pharmaceuticals and in aqueous solution nitrogen mustards are subject to degradation by hydrolysis. Also, due to its degradation in aqueous solutions (like other nitrogen mustards), bendamustine is supplied as a lyophilized product.
WO2012/009299 relates to method of sterilizing bendamustine or a pharmaceutically acceptable salt form using dry heat sterilization, gamma irradiation and e beam radiation. Further, to determine the purity, bendamustine was added with N-methyl-2-pyrrolidone (NMP) and sterilized using the said methods and the results are studied using HPLC method.

WO2011/103150 describes lyophilized preparations comprising bendamustine and cyclodextrins and its process of preparations.

U.S. Publication No. 2011/0190363 discloses liquid pharmaceutical formulation comprising bendamustine, or a pharmaceutically acceptable salt or prodrug thereof, and a polar aprotic solvent. Also, the publication discloses solubility of bendamustine with various solvents including N-Methyl Pyrrolidone.

Further, the publication also discloses that based on the solubility study results of various solvents obtained, solvents like 66% dimethyl alcohol/34% propylene glycol and 100% propylene glycol are selected for further study like pharmacokinetic evaluation in monkey. The said publication, reported that N-methyl pyrrolidone can be used as one of the solvents in preparing bendamustine solution formulation, but there is no motivation and specific studies performed to show that N-methyl pyrrolidone could be used as a solvent which is stable on long term storage and further which could be diluted and administered to the patient.

It is known from the above mentioned prior arts that, bendamustine is unstable in aqueous solutions and several attempts have been made to produce stable non-aqueous bendamustine formulation without lyophilization. Such aqueous bendamustine solutions are not currently available because of its degradation in aqueous solutions which leads to poor solution stability. Currently marketed formulation Treanda® is also in lyophilized powder form.

As per the prescribing information of Treanda®, bendamustine lyophilized powder should be aseptically reconstituted with 20 mL of water for injection, USP. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. In further, aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% sodium chloride injection, USP (normal saline). The resulting final concentration of bendamustine HC1 in the infusion bag should be within 0.2 - 0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. Use sterile water for injection, USP, for reconstitution and then either 0.9% sodium chloride injection, USP, or 2.5% dextrose/0.45% sodium chloride injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. This lengthy and complex process of administering bendamustine in lyophilized powder makes the whole process inconvenient and non user-friendly.
Thus there is always a need for ready to use, ready to dilute bendamustine liquid formulations which are stable as aqueous solution and which is easier to dilute without involving the lengthy and complex process of lyophilization. This improvement/advancement in formulation development would help ease of preparation and reduce the administration process steps and the time involved.

The present inventors surprisingly found that, bendamustine is stable in solvent like N-methyl pyrrolidone (Pharmasolve®) for longer period of time and does not produce any significant degradation on long term storage. Further, formulation does not need to be lyophilized thereby resulting in being patient friendly on administration and cost effective from the manufacturing point of view.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to a stable liquid formulation comprising bendamustine or its pharmaceutically acceptable salts and optionally one or more pharmaceutically acceptable excipients for parenteral administration.

More particularly, the invention relates to a stable liquid formulation comprising bendamustine or its pharmaceutically acceptable salts and N-methyl pyrrolidone (Pharmasolve®) as solvent and optionally one or more pharmaceutically acceptable excipients for parenteral administration.

An objective of the invention relates to a stable liquid formulation comprising bendamustine or its pharmaceutically acceptable salts and N-methyl pyrrolidone (Pharmasolve®) as solvent and optionally one or more pharmaceutically acceptable excipients for parenteral administration.

An objective of the invention also relates to a process of preparing a stable liquid formulation comprising bendamustine or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

An objective of the invention relates to the process of preparing a stable liquid formulation comprising bendamustine or its pharmaceutically acceptable salts and N-methyl pyrrolidone (Pharmasolve®) and optionally one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to a stable liquid formulation comprising bendamustine or its pharmaceutically acceptable salts and optionally one or more pharmaceutically acceptable excipients. More particularly, the invention relates to a stable liquid formulation comprising bendamustine or its pharmaceutically acceptable salts and N-methyl pyrrolidone (Pharmasolve®) as solvent and optionally one or more pharmaceutically acceptable excipients for parenteral administration.

As mentioned in the background of the invention, it is very difficult to prepare a stable liquid formulation of bendamustine or its pharmaceutically acceptable salts because of its high reactivity in aqueous solutions and thereby being subjected to degradation by hydrolysis.

It was surprisingly found, that bendamustine or its pharmaceutically acceptable salts are stable in N-methyl pyrrolidone (Pharmasolve®) for longer period of time as concentrate/ solution and does not produce any significant degradation on long term storage.

The invention relates to a stable liquid pharmaceutical formulation for parenteral administration comprising: (i) bendamustine or its pharmaceutically

acceptable salts; (ii) N-methyl pyrrolidone (Pharmasolve®) and optionally one or more pharmaceutically acceptable excipients.

The wording herein below is implied with in the concept of invention as follows:

"Bendamustine" as used herein refers to bendamustine as base and/ or their pharmaceutically acceptable salts, solvates, enantiomers, diastereomers and polymorphs thereof. Preferably, bendamustine is used herein as hydrochloride salt which may be in crystalline or amorphous forms.

The term "stable liquid formulation" as used herein refers to formulation comprising bendamustine or their pharmaceutically acceptable salts, solvates, enantiomers, diastereomers and polymorphs thereof with one or more pharmaceutically acceptable excipients which may be filled into vial(s) or ampoule(s).
A "stable" formulation is one in which bendamustine or its pharmaceutically acceptable salts therein essentially retain its physical stability and/or chemical stability and/or biological activity during shelf-life. Stability can be measured at a selected temperature for a selected time period and the formulation according to the invention maintains at least about 96% of the initial amount of bendamustine or its salts after the storage period.

The term "long term storage" as used herein refers to formulation of bendamustine or their pharmaceutically acceptable salts having storage or shelf-life for at least three months at different temperature and storage conditions.

The term "total impurities" as used herein, refers to the sum of all the degradation products as formed in the formulation, upon storage/upon storage at accelerated conditions.

The temperature at which the parenteral formulation according to the invention are preferably kept either at room temperature or less (i.e., about 25° C or less).

According to the invention the stable liquid formulation comprising bendamustine may further contain one or more pharmaceutically acceptable excipients which include but or not limited to tonicity modifiers, buffering agent, antimicrobial preservative, antioxidants, additional vehicles or solvents etc.
The tonicity modifiers according to the invention may include, but are not limited to sodium chloride, potassium chloride, calcium chloride, mannitol, glucose, lactose, dextrose, sorbitol, glycerol and the like or combinations thereof.

The buffering agent according to the invention may include, but are not limited to acetate, succinate, phosphate, benzoate, ascorbate, lactate and citrate and the like or combinations thereof.
The antimicrobial preservative according to the invention may include, but are not limited to benzyl alcohol, benzoic acid, benzalkonium chloride, benzethonium chloride and the like or combinations thereof.

The antioxidants according to the invention may include, but are not limited to butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, a-tocopherol, sodium sulfite, sodium bisulfite, citric acid, ascorbic acid, thioglycerol, EDTA, thiourea, acetylcysteine and the like or combinations thereof.

The solvents according to the invention may include, but are not limited to water or sterile water for injection, N-methyl pyrrolidone (Pharmasolve®), ethanol, isopropanol, glycerol, macrogols, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, polybutylene glycol, glycerin, polysorbates, cyclodextrin and its derivatives. Preferably N-methyl pyrrolidone (Pharmasolve®) or ethanol is used. More preferably, N-methyl pyrrolidone (Pharmasolve®) is used.

N-methyl pyrrolidone is also known as NMP, l-methyl-2-pyrrolidone, N-methyl-2-pyrrolidinone, N-Methyl-2-pyrrolidone, N-methylpyrrolidinone and Pharmasolve®. NMP is a clear, colorless liquid with a mild amine odour. It is a basic and polar compound. NMP is hygroscopic. It is highly soluble in lower alcohols, lower ketones, ether, ethyl acetate, chloroform, and benzene and moderately soluble in aliphatic hydrocarbons, however it is miscible with water.

The pharmaceutically acceptable carriers that may be used for admixing with the sterile aqueous solution at the time of administration according to the invention may include, but are not limited to water for injection USP, 0.9% sodium chloride injection USP, Ringer's solution, dextrose solution, 2.5% dextrose and 0.45% sodium chloride injection USP, lactated Ringer's solution and the like.

The suitable containers used to dispense the formulation of the invention, may include, but are not limited to ampoules, vials or prefilled syringes which are made up of either glass or polymeric containers made of cyclic olefin polymer or copolymer, polyolefins or other non-glass components.

According to an embodiment of the invention, it relates to a stable liquid formulation comprising bendamustine or its pharmaceutically acceptable salts, N-methyl pyrrolidone (Pharmasolve®) and optionally one or more pharmaceutically acceptable excipients.

According to an embodiment of the invention, stable liquid pharmaceutical formulation for parenteral administration comprising: (i) bendamustine or its pharmaceutically acceptable salts; (ii) N-methyl pyrrolidone (Pharmasolve®) and optionally one or more pharmaceutically acceptable excipients.
According to an embodiment of the invention, the process for preparing the stable liquid formulation comprising bendamustine or its pharmaceutically acceptable salts involves the steps of:

i) collecting N-methyl pyrrolidone in beaker and purging nitrogen and maintaining the temperature below 8°C;

ii) adding bendamustine hydrochloride with N-methyl pyrrolidone obtained in step (i), under stirring to get the clear solution;

iii) adjusting the volume to 100 % batch size with N-methyl pyrrolidone (NMP) and with stirring;

iv) filtering the solution through 0.22um filter and fill in 5 ml amber colored glass vials.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Example 1:
Unit composition:

Brief Manufacturing Process:

i) Water for injection was collected in beaker and nitrogen was purged and temperature was maintained below 8°C; ii) To the above water for injection obtained in step (i), bendamustine hydrochloride was added under stirring to get the clear solution; iii) Volume was adjusted to 100 % batch size with water for injection and stirred; and iv) Solution obtained were filtered in aseptic conditions and further filled
in suitable containers under sterile conditions and stored at 2 - 25° C.

Example 2;
Unit composition:

Brief Manufacturing Process:

i) N-methyl pyrrolidone was collected in beaker and nitrogen was purged and temperature was maintained below 8°C; ii) To the above N-methyl pyrrolidone obtained in step (i), bendamustine
hydrochloride was added under stirring to get the clear solution; iii) Volume was adjusted to 100 % batch size with N-methyl pyrrolidone (NMP) and stirred; and iv) Solution obtained were filtered in aseptic conditions and further filled in suitable containers under sterile conditions and stored at 2 - 25° C.

Example 3;
Unit composition:

Brief Manufacturing Process:

i) Ethanol was collected in beaker and nitrogen was purged and temperature was maintained below 8°C; ii) To the above ethanol obtained in step (i), bendamustine hydrochloride was added under stirring to get the clear solution; iii) Volume was adjusted to 100 % batch size with ethanol and stirred; and iv) Solution obtained were filtered in aseptic conditions and further filled
in suitable containers under sterile conditions and stored at 2 - 25° C.

Example 4:
Unit Composition:

Brief Manufacturing Process:

i) N-methyl pyrrolidone was collected in beaker and nitrogen was purged
and temperature was maintained below 8°C; ii) To the above N-methyl pyrrolidone obtained in step (i), bendamustine hydrochloride was added under stirring to get the clear solution; iii) Volume was adjusted to 100 % batch size with N-methyl pyrrolidone (NMP) and stirred; and iv) Solution was filtered through 0.22um filter and filled in 5 ml amber colored glass vials.
Stability Data:

The formulations of examples 1-3 were subjected to accelerated stability conditions at 60°C for 1 week and analyzed for the assay.

Table-1
The assay value depicted in Table-1 indicates that the product stability improved when formulated in N-methyl Pyrrolidone (Pharmasolve®) when compared to formulation prepared using ethanol and water for injection.

The formulation prepared according to the Example 4 was subjected to various stability conditions for evaluating physical stability and chemical stability of the bendamustine hydrochloride and the results are depicted in Table-2.

Table-2
The results obtained showed that the formulation prepared Example 4 showed that there is no change in physical appearance of solution and showed impurities level within the acceptable limits under various stability conditions, thereby concludes that the aqueous bendamustine hydrochloride formulation prepared according to the invention are stable on long term storage.

The formulation of Example 4 is administered with additional diluents by diluting with sterile water for injection USP, 0.9% sodium chloride injection USP or 2.5% dextrose/0.45% sodium chloride injection USP. The final dilution concentration of the bendamustine aqueous formulation is 0.2 - 0.6mg/ml.

The solution obtained in the invention does not require any reconstitution step, rather it is directly injected into the infusion bags containing the above said diluents for IV infusion/ administration, thereby saving a lot of time in dilution and preparation of injection and avoiding medication errors.

We Claim:

1. A stable liquid pharmaceutical formulation for parenteral administration comprising:

a. bendamustine or its pharmaceutically acceptable salts thereof;
b. N-methyl pyrrolidone and
c. optionally one or more pharmaceutically acceptable excipients,

wherein said formulation is stable on long term storage.

2. The stable liquid pharmaceutical formulation for parenteral administration according to claim 1, wherein said formulation is stable at about 2-8°C for at least 3 months.

3. The stable liquid pharmaceutical formulation for parenteral administration according to claim 1, wherein said formulation is stable at about 25°C and 60% RH for at least 3 months.

4. The stable liquid pharmaceutical formulation for parenteral administration according to claim 1, wherein said formulation is stable at about 40°C and 75% RH for at least 3 months.

5. The stable liquid pharmaceutical formulation for parenteral administration according to claim 1, wherein said formulation contain at least 96% of bendamustine or its salts at the end of three months.

6. The stable liquid pharmaceutical formulation for parenteral administration according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group consisting of tonicity modifiers, buffering agents, antimicrobial preservatives, antioxidants, solvents or combinations thereof.

7. The stable liquid pharmaceutical formulation for parenteral administration according to claim 1, wherein the formulation is administered by diluting with sterile water for injection USP, 0.9% sodium chloride injection USP or 2.5% dextrose/0.45% sodium chloride injection USP and or combinations thereof.

8. A process for preparing a stable liquid pharmaceutical formulation for parenteral administration comprising bendamustine hydrochloride and N- methyl pyrrolidone and optionally one or more pharmaceutically acceptable excipients, wherein the process involves the steps of:

i) collecting N-methyl pyrrolidone in beaker and purging nitrogen and maintaining the temperature below
8°C;

ii) adding bendamustine hydrochloride with N-methyl pyrrolidone obtained in step (i), under stirring to get the clear solution;

iii) adjusting the volume to 100 % batch size with N-methyl pyrrolidone (NMP) and with stirring; and

iv) filtering the solution through 0.22um filter and fill in 5 ml amber colored glass vials.

9. A stable liquid pharmaceutical formulation for parenteral administration comprising bendamustine hydrochloride, having the following unit composition: