FIELD OF THE INVENTION

The present invention relates to parenteral pharmaceutical compositions of bendamustine and process for preparation thereof.

BACKGROUND OF THE INVENTION

Bendamustine is a nitrogen mustard with bifunctional alkylating activity. Chemically Bendamustine, is (4-{5-[Bis(2-chloroethyl)amino]-l-methyl-2-benzimidazolyl}butyric acid, is an atypical structure with a benzimidazole ring.

Bendamustine was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 in that location under the name Cytostasan®. Bendamustine received its first marketing approval in Germany where it was marketed under the trade name Ribomustin® by Astellas Pharma GmBH's licensee, Mundipharma International Corporation ltd. It has been widely used in Germany to treat chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer.

Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic aikyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways.
Bendamustine is active against both quiescent and dividing cells.

Bendamustine HC1 injection approved by USFDA and sold under the trade name TREANDA by Cephalon as both lyophilized powder for IV infusion available in strengths of 100 mg/vial, 25 mg/vial and also as liquid injections for IV infusion in the strengths of 180mg/2mL (90mg/mL) and 45 mg/0.5mL (90mg/mL), for treating Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma.

United States patent No 8,436,190, United States patent No 8,609,863 and United States patent No 8,791,270 disclose lyophilized powder compositions bendamustine hydrochloride and mannitol.

United States patent No 8,895,756 discloses vial containing a reconstituted solution of lyophilized bendamustine.

United States patent No 8,344,006 discloses stable, non-aqueous liquid formulations comprising bendamustine, solubilized in dimethylacetamide and propylene glycol, diluents without lyophilization.

Later Bendamustine HC1 liquid injection was approved by the USFDA under the brand name Bendeka for Egal pharmaceuticals with a composition comprising of polyethylene glycol, propylene glycol and Monothioglycerol as antioxidant.

United States patent No 8,609,707 discloses long term storage stable non-aqueous liquid bendamustine-containing composition with fluid comprising polyethylene glycol, about 10% propylene glycol and an antioxidant.

Method of treating a bendamustine-responsive condition in a subject requiring restricted fluid and/or sodium intake has been disclosed in United States patent No 9,000,021.

United States patent No. 8.389,558 disclose bendamustine and an amphiphilic anionic compound.

PCT application No 20150104720 discloses ready to use parenteral composition comprising bendamustine, diethylene glycol monoethyl ether and N-methyl-2-pyrrolidone.

United .States patent application No 20130210878 disclose ready to use bendamustine formulation for injection with a mixture of a non-aqueous solvent system and an aqueous chloride-containing water phase.

PCT application No 20160005995 disclose ready to use liquid pharmaceutical formulation comprising of Bendamustine wherein the formulation is devoid of glycols.

There are a number of other patent applications which have been made for compositions of bendamustine or pharmaceutically acceptable salt thereof. However, none of these attempted formulations has resulted in a successful commercial product to compete with BENDEKA to date. The approved TREANDA of RTU formulation contains 0.2 mL overfill which makes about 28% excess fill volume in the case of 0.2 mL fill and about 10% excess in 2 mL fill. Further, handling 0.2 mL fill volume is cumbersome as further dilution is there which needs to be done in accordance with pack insert recommended volume [0.2 to 0.7 mg/mL]. The present BENDEKA formulation has Propylene Glycol which may cause for the formation of propylene glycol adducts over a period of time. Thus there is still a need to provide improved composition of bendamustine or pharmaceutically acceptable salt thereof with greater stability that gives maximum potency till end of shelf life. Accordingly, there is still a need for the development of a new pharmaceutical preparation that can offer improved storage stability with lesser degradation components and less toxicity.

Surprisingly, the inventors of a present invention prepared a bendamustine salt liquid composition by an alternate solvent system, which makes possible to store the composition of bendamustine salt at room temperature. It is further surprising that bendamustine with alternate antioxidants like butylated hydroxyl toluene and butylated hydroxyl anisole produced stable liquid composition with maximum potency.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide stable parenteral pharmaceutical compositions of bendamustine.

Another objective of the present composition is to provide a process for the preparation of stable parenteral pharmaceutical compositions of bendamustine in which bendamustine has significantly increased stability over prolonged periods of time.

Another objective of the present composition is to prepare ready to use parenteral pharmaceutical composition comprising bendamustine or its pharmaceutical^ acceptable salt, glycerol, ethanol and antioxidants butylated hydroxyl toluene and / or butylated hydroxyl anisole with maximum potency even after storing the product for one month.

Another objective of the present invention is to prepare clear, colorless pharmaceutical liquid non-aqueous liquid pharmaceutical compositions of bendamustine which remains clear, colorless during the shelf life of the product.

Another objective of the present invention is to provide room temperature storable product of bendamustine parenteral formulation.

Also included in the present invention is the use of bendamustine compositions for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma.

SUMMARY OF THE INVENTION

The present invention relates to stable parenteral pharmaceutical compositions of bendamustine using alternate solvents.

The present invention further relates to a process of preparing the stable pharmaceutical liquid compositions of bendamustine hydrochloride comprising the steps of:

a) Mixing butylated hydroxyl toluene and / or butylated hydroxyl anisole in ethanol with continuous stirring,

b) Adding glycerol to step (a) with continuous stirring,

c) Adding bendamustine hydrochloride to step (b) with continuous stirring.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to parenteral compositions of bendamustine. More particularly, the present invention includes ready to use parenteral compositions of bendamustine in the form of liquid.

DEFINITONS:

The term "active ingredient" or "active agent" or "drug" used interchangeably, is defined to mean active drug (e.g. bendamustine), that induces a desired pharmacological or physiological effect.

The term "bendamustine" as used herein includes bendamustine in the form of a free base, a pharmaceutical^ acceptable salt thereof, amorphous bendamustine, crystalline bendamustine or any isomer, derivative, hydrate, solvate, or prodrug or combinations thereof. Preferably, bendamustine is in the form of the hydrochloride salt. More preferably, the bendamustine salt is bendamustine hydrochloride monohydrate.

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" 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, subcutaneous, intracutaneous, intra-articular, or intrathecal routes of administration, preferably, intravenous.

The term "composition" is intended to encompass a combination including active ingredients and pharmaceutically acceptable excipients, as well as any product which results, directly or
indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions involving one or more of the ingredients.

The term "stable" or "stability" as used herein includes both physical and chemical stability. The term "physical stability" refers to maintenance of the form of active agents, such as crystalline or amorphous, and the term "chemical stability" relates to a limited formation of impurities.

"Carrier" or "vehicle" as used herein refers to pharmacologically inert materials that provide a more or less fluid matrix, suitable for topical drug administration. Carriers and vehicles useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of a pharmaceutical formulation or drug delivery system in a deleterious manner.

The term "antioxidant" or "antioxidants" includes individual antioxidant or a combination or mixtures of antioxidant.

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 process" includes one or more processes, 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 "ready to use composition" as used herein refers to a composition which avoids reconstitution and may require dilution with a suitable diluent before administration to the patient.

The term "solvent" refers to an ingredient used for dissolving an active ingredient. Exemplary polar solvents include N-methyl-2-pyrrolidone, l,3-dimethyl-2-imidazolidinone, dimethylacetamide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide,
propylene carbonate, alkyl alcohols, ethylene glycol, propylene glycol, butylene glycol, glycerin, polysorbates, polyalkylene glycols such as polyethylene glycol, and primary amides and combinations thereof Preferably, the solvent is N-methyl-2-pyrrolidone, polyethylene glycol, or a combination thereofOne embodiment of the present invention relate to innovative stable parenteral
pharmaceutical compositions of bendamustine with glycerol, ethanol and antioxidants selected from butylated hydroxyl toluene (BHT) and/or butylated hydroxyl anisole (BHA) and one or more pharmaceutical^ acceptable carrier / vehicle.
The composition according to the present invention is in the form of a liquid, solution, suspension, emulsion or lyophilized powder. Preferably, the composition is in the form of a solution.

Another embodiment of the present invention relates to a ready to use parenteral composition comprising about 25 mg/mL to about 100 mg/mL of bendamustine, bulking agent and antioxidants.

Another embodiment of the present invention relates to a ready to use parenteral composition comprising, consisting essentially of, or consisting of, per each mL of composition (a) 25 mg of bendamustine hydrochloride and (b) glycerol and (c) antioxidants.

In another embodiment, a storage stable liquid pharmaceutical composition is contemplated that includes bendamustine in a therapeutically effective amount. As used herein, the term "storage stable clear colorless liquid pharmaceutical composition" refers to a liquid pharmaceutical composition in which bendamustine is dissolved in a solvent or solvent system, and in which at least 90% of the pharmaceutical^ active ingredient remain in an undegraded state after storage of the composition over one month after autoclaving at 121°C for 15 minutes.

In comparison with the prior available compositions and its concern with stability the present invention has overcome those concerns and the advantage of the present invention is use of
bulking agent glycerol and antioxidants BHA and /or BHT, which stabilizes the active ingredient bendamustine and provides potency of about 95%.

The present invention relates to a pharmaceutical liquid composition comprising bendamustine hydrochloride and one or more pharmaceutically acceptable excipients.

The present invention further relates to a pharmaceutical stable clear non-aqueous liquid composition comprising bendamustine hydrochloride and one or more pharmaceutically acceptable carrier/vehicle.

Another embodiment relates to a liquid composition comprising pharmaceutically acceptable excipients include bulking agents, solubilizers, buffers, pH adjustment aids, chelating agents, antioxidants, antibacterial preservatives and combinations thereof.
Bulking agents include but are not limited to mannitol, lactose, sucrose, sodium chloride, trehalose, dextrose, starch, hydroxyethylstarch, cellulose, cyclodextrins, glycine, glycerol and mixtures thereof.

Solubilizers include surface active agents, co-solvents, complexing agents and combinations thereof.

Surface active agents 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 mixtures thereof.

pH adjustment aids include 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 include but are not limited to ethylenetetraamineacetic acid, ethylenediaminetetraacetic acid (EDTA), and salts, derivatives and combinations thereof. Antibacterial preservatives include but are not limited to phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, cresol and chlorobutanol and combinations thereof.

Other embodiment of the present invention relates to process for the preparation of parenteral compositions of bendamustine hydrochloride comprising, consisting essentially of, or consisting of the steps of:

a) weighed quantity of ethanol was taken,

b) adding a weighed quantity of butylated hydroxyl toluene and butylated hydroxy anisole to ethanol with continuous stirring,

c) adding glycerol to the step (a) with continuous stirring,

d) adding bendamustine hydrochloride to the step (b) with continuous stirring,

In yet another embodiment, the composition of the present invention is useful for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma.

EXAMPLES

The following examples serve to provide further appreciation of the invention but not meant in any to restrict the effective 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 known to the industry.
Brief manufacturing Process:

1. Take weighed quantity ethanol into a compounding vessel,

2. Add weighed quantity of butylated hydroxyl toluene (q.s) and butylated hydroxy anisole (q.s) to ethanol containing vessel under stirring,

3. Weigh 0.4 mL of glycerol and add it to step 2 under stirring,

4. Weigh 25mg of bendamustine hydrochloride and add it to step 3 under stirring,

5. Finally make up the volume with ethanol and stir for about 5 minutes.

Example 2:

Parenteral compositions of Bendamustine:

Brief manufacturing Process:

1. Take weighed quantity propylene glycol into a compounding vessel,

2. Add weighed quantity of butylated hydroxyl toluene (q.s) and butylated hydroxy anisole (q.s) to propylene glycol containing vessel under stirring,

3. Weigh 25mg of bendamustine hydrochloride and add it to step 2 under stirring

4. Weigh 0.4 mL of glycerol and add it to step 3 under stirring,

5. Finally make up the volume with propylene glycol and stir for about 5 minutes.
Example 3:

Parenteral compositions of Bendamustine:

Brief manufacturing Process:

1. Take weighed quantity of N, N, DMA into a compounding vessel,

2. Add weighed quantity of butylated hydroxyl toluene (q.s) and butylated hydroxy anisole (q.s) to N, N. DMA containing vessel under stirring,

3. Weigh 25mg of bendamustine hydrochloride and add it to step 2 under stirring,

4. Weigh 0.4 mL of glycerol and add it to step 3 under stirring,

5. Finally make up the volume with glycerol and stir for about 5 minutes.

We Claim,

1. A ready to use parenteral composition comprising:

(a) bendamustine or its pharmaceutical^ acceptable salt thereof

(b) glycerol,

(c) butylated hydroxyl toluene and butylated hydroxyl anisole,

(d) ethanol,

(e) one or more pharmaceutical^ acceptable carrier / vehicle.

2. The composition of claim 1, wherein the bendamustine is in the form of bendamustine hydrochloride.

3. The composition of claim 1, in the form of a liquid and / or solution.

4. The composition of claim 1 is for parenteral administration.

5. The composition of to claim 1, comprising about 25 mg to about 100 mg of bendamustine hydrochloride per each mL of composition.

6. The composition of claim 1, comprising one or more other pharmaceutically acceptable carrier / vehicle selected from a bulking agent, a solubilizer. a buffer, a pH adjustment aid, a chelating agent, an antioxidant, an antibacterial preservative and combinations thereof

7. A process for the preparation of a composition of claim 1, comprising;

a) weighed quantity of ethanol was taken in to a compounding vessel,

b) add butylated hydroxyl toluene and butylated hydroxy anisole to ethanol under stirring,

c) add glycerol to the step (a) under stirring,

d) add bendamustine hydrochloride to the step (b) under stirring,

e) finally make up the volume with ethanol and stir for about 5 minutes.