DESC:FIELD OF THE INVENTION

This invention relates to a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, with suitable pharmaceutically acceptable excipients. Further it relates to a process for the preparation of the said composition and uses thereof.

BACKGROUND OF THE INVENTION

Bendamustine chemically known as 4-[5-[Bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid is a nitrogen mustard, which is used in the treatment of chronic lymphocytic leukemia and lymphomas. It belongs to the family of drugs called alkylating agents.

Like other nitrogen mustards, bendamustine hydrolyzes in aqueous solution; hence it is available in the market as a lyophilized product, namely Ribomustin® and Treanda®. The lyophilized product contains bendamustine hydrochloride and mannitol, as a sterile lyophilized powder for intravenous use, which is reconstituted before administration. Further, bendamustine injections are also available as liquid formulations, namely Treanda® (90 mg/ml) and Bendeka® (25 mg/ml).

German Patent DE 159289 discloses an injectable solution of Bendamustine in anhydrous monovalent or polyvalent alcohol (polyol).

The U.S. Patent No. 8,436,190 discloses lyophilized bendamustine compositions, which needs to be reconstituted with sterile water for injection, or other suitable carrier, to provide liquid formulations of bendamustine.

The U.S. Patent No. 8,344,006 discloses a stable, non-aqueous liquid, pharmaceutical formulation comprising bendamustine or a pharmaceutically acceptable salt thereof, particularly solubilized in about 66% v/v of dimethylacetamide and about 34% v/v of propylene glycol.

The U.S. Patent No. 8,609,707 discloses a stable non-aqueous liquid bendamustine-containing composition, comprising: a) bendamustine or a pharmaceutically acceptable salt thereof, and b) a pharmaceutically acceptable fluid comprising: i) about 90% polyethylene glycol and about 10% propylene glycol; and ii) a stabilizing amount of an antioxidant. Further, this patent discloses i) one or more of PG, ethanol, PEG, benzyl alcohol and glycofurol; and ii) a stabilizing amount of a chloride salt. Furthermore, this patent discloses bendamustine-containing compositions with DMSO.

However, it has been very challenging to produce storage-stable bendamustine liquid formulations. Hence there exists a need for stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof.

OBJECTS OF THE INVENTION

The main objective of the present invention is to provide a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, with suitable pharmaceutically acceptable excipients.

Another object of the invention is to provide a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, with at least one polar solvent and at least one stabilizer.

Another object of the invention is to provide a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, dimethyl acetamide and at least one stabilizer.

Another object of the invention is to provide a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, polyethylene glycol and at least one stabilizer.

Another object of the invention is to provide a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, a mixture of dimethyl acetamide and polyethylene glycol, and at least one stabilizer.

Another object of the invention is to provide a process for the preparation of stable non-aqueous pharmaceutical composition of bendamustine or a pharmaceutically acceptable salt thereof, with suitable pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

In a first embodiment, the invention relates to a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, with at least one polar solvent and at least one stabilizer.

In another embodiment, the invention relates to a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, dimethyl acetamide and at least one stabilizer.

In another embodiment, the invention relates to a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, polyethylene glycol and at least one stabilizer.

In another embodiment, the invention relates to a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, a mixture of dimethyl acetamide and polyethylene glycol, and at least one stabilizer.

In another embodiment, the invention relates to a process for the preparation of stable non-aqueous pharmaceutical composition of bendamustine or a pharmaceutically acceptable salt thereof, with suitable pharmaceutically acceptable excipients.

DETAILED DESCRIPTION

The present invention relates to a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, with suitable pharmaceutically acceptable excipients.

The present invention further relates to a stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, with at least one polar solvent and at least one stabilizer.

The term "stable non-aqueous pharmaceutical composition" means, a pharmaceutical composition having sufficient stability to have utility as a pharmaceutical product. Preferably, a stable non-aqueous pharmaceutical composition has sufficient stability to allow storage at a convenient temperatures, about -20 0C and 40 0C, preferably about 2 0C to about 25 0C, more preferably about 2 0C to about 8 0C, for a reasonable period of time, e.g., the shelf-life of the product which can be as short as one month but is typically six months or longer, preferably at least 18 months or more preferably at least 2 years. Further, the stable non-aqueous pharmaceutical composition has minimal degradation of the active ingredient, e.g., it retains at least about 80% of active ingredient, preferably at least about 90%, and more preferably at least about 95%, after storage at typical commercial conditions.

For purpose of the present invention, the term "polar solvent" includes dimethyl acetamide (DMA), dimethyl sulfoxide, ethylene glycol, propylene glycol, and polyalkylene glycols, such as polyethylene glycol (PEG), polypropylene glycol, polybutylene glycol and mixtures thereof. Preferably the solvent is a mixture of DMA and PEG.

For purpose of the present invention, the term "stabilizer" means the ingredients that enhance the stability of the bendamustine or a pharmaceutically acceptable salt, and thereby it allows a long-term storage-stable bendamustine pharmaceutical composition for a shelf life of at least about 18 months when stored at temperatures about 2 0C to about 25 0C, more preferably about 2 0C to about 8 0C.

The “stabilizer” of the present invention includes, non-limiting examples, such as propyl gallate, methionine, Cysteine HCl, metabisulfites, Tocopherols, Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT) and mixtures thereof. Preferably the stabilizer is Cysteine HCl, alpha-Tocopherol or mixtures thereof.

For purpose of the present invention, the concentration of bendamustine, or a pharmaceutically acceptable salt thereof, ranges from about 5 mg/ml to about 120 mg/ml. Preferred concentrations include about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 40 mg/ml, about 50 mg/ml, about 60 mg/ml, and about 90 mg/ml of bendamustine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the amount of solvent mixture comprising DMA and PEG can also be varied within the ranges, i.e. the ratio of DMA:PEG can range from about 10:90 to about 70:30. Within this range, is the solvent mixture containing about 10% DMA and about 90% PEG, about 15% DMA and about 85% PEG, about 25% DMA and about 75% PEG, and preferably 33% DMA and 67% PEG. The molecular weight of the PEG will be within the range of pharmaceutically acceptable weights, although PEG 300 and PEG 400 are preferred in many aspects of the invention.

The stabilizer concentration can range from about 0.1 mg/ml to about 20 mg/ml, and preferably from about 0.5 mg/ml to about 2 mg/ml.

In another embodiment, the invention relates to a stable non-aqueous pharmaceutical composition comprising: i) from about 5 mg/ml to about 120 mg/ml of bendamustine or a pharmaceutically acceptable salt thereof, ii) a mixture of dimethyl acetamide and polyethylene glycol, and iii) at least one stabilizer.

In another embodiment, the invention relates to a stable non-aqueous pharmaceutical composition comprising: i) from about 5 mg/ml to about 120 mg/ml of bendamustine or a pharmaceutically acceptable salt thereof, ii) a mixture of about 33% dimethyl acetamide and 67% polyethylene glycol, and iii) at least one stabilizer in the concentration from about 0.1 mg/ml to about 20 mg/ml.

In addition to the above-mentioned ingredients, the stable non-aqueous pharmaceutical composition may also comprise further pharmaceutically acceptable excipients known in the art and include, for example, surfactants (e.g., Polysorbate), organic acids (e.g., citric acid), complexing agents (e.g., EDTA, cyclodextrins), and preservatives (e.g., benzyl alcohol).

In order to further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of present invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the scope of the invention.

Example 1: Stable non-aqueous pharmaceutical composition
Ingredients Concentration (mg/ml)
Bendamustine Hydrochloride 5 - 120 mg/ml
Polar Solvent q.s. to 1 ml
Stabilizer 0.1 - 20 mg/ml
Nitrogen Gas q.s to purging

The stable non-aqueous pharmaceutical compositions comprising bendamustine were prepared by dissolving the desired bendamustine HCl concentration in a solvent mixture of dimethyl acetamide and polyethylene glycol 400, and cysteine HCl as a stabilizer in the desired concentration.

The composition was maintained at 25.degree. C. for at least 3 months and analyzed periodically for drug content and total impurities.

Further, the stable non-aqueous pharmaceutical compositions for Examples 2 to 7, comprising bendamustine were prepared by the same procedure as described in Example 1.

Example 2 to 6: Stable non-aqueous pharmaceutical compositions
No. Ingredients Quantity (mg/ml)
1. Bendamustine HCl 25 mg/ml 25 mg/ml 90 mg/ml 90 mg/ml 90 mg/ml
2. DMA 15% 33% 33% - -
3. Cysteine HCl Monohydrate 1 mg/ml 0.9 mg/ml 1 mg/ml - 0.9 mg/ml
4. Alpha-Tocopherol - - - 0.5 mg/ml -
5. PEG 300 85% - 67% 100% -
6. PEG 400 - 67% - - 100%

Example 7: Stable non-aqueous pharmaceutical composition
No. Ingredient Quantity (mg/mL)
1. Bendamustine HCl Monohydrate 90.0
2. Dimethyl acetamide (HP Grade) 586.0
3. Cysteine Hydrochloride Monohydrate 0.9
4. Polyethylene Glycol 300 q.s. to 1.0 mL
5. Nitrogen Gas q.s. for sparging

Table-I: Stability Study of Bendamustine HCl Injection 90 mg/ml; 2 ml Pack at 25°C/60% RH & 2°C-8°C.

Sr. No. Test parameters Initial 1M
(25°C/
60%RH) 2M
(25°C/
60%RH) 3M
(25°C/
60%RH) 3M
(2°C – 8°C)
1. Description * * * * *
2. pH 3.39 3.32 3.42 3.28 3.18
3. Clarity of solution ** ** ** ** **
4. Assay for Bendamustine hydrochloride 102.5 % 103.0 % 102.2 % 103.0 % 102.8 %
* Pale yellow colored solution filled in amber glass vial
** Solution is clear as purified water.

Table-II: Stability study of Bendamustine HCl Injection 90 mg/ml; 0.5 ml Pack at 25°C/60% RH & 2°C-8°C.
Sr. No. Test parameters Initial 1M
(25°C/
60%RH) 2M
(25°C/
60%RH) 3M
(25°C/
60%RH) 3M
(2°C – 8°C)
1. Description * * * * *
2. pH 3.46 3.38 3.51 3.36 3.21
3. Clarity of solution ** ** ** ** **
4. Assay for Bendamustine hydrochloride 101.6 % 102.6 % 100.9 % 101.6 % 102.2 %
* Pale yellow colored solution filled in amber glass vial
** Solution is clear as purified water.

The non-aqueous pharmaceutical compositions comprising bendamustine remained stable at about 2.degree. C. to about 8.degree. C. for at least 3 months.

Further, the non-aqueous pharmaceutical compositions comprising bendamustine remained stable at about 25.degree. C. for at least 3 months.

All of the compositions and methods disclosed in this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the spirit and scope of the invention. ,CLAIMS:We claim:
1. A stable non-aqueous pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable salt thereof, with at least one polar solvent and at least one stabilizer.

2. The stable non-aqueous pharmaceutical composition according to claim 1, wherein the polar solvent is selected from the group consisting of dimethyl acetamide, dimethyl sulfoxide, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, polybutylene glycol and mixtures thereof.

3. The stable non-aqueous pharmaceutical composition according to claim 1, wherein the polar solvent is a mixture of dimethyl acetamide and polyethylene glycol in the ratio from about 10:90 to about 70:30.

4. The stable non-aqueous pharmaceutical composition according to claim 1, wherein the stabilizer is selected from the group consisting of propyl gallate, methionine, Cysteine HCl, metabisulfites, Tocopherols, Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT) and mixtures thereof.

5. The stable non-aqueous pharmaceutical composition according to claim 1, wherein the stabilizer is Cysteine HCl, alpha-Tocopherol or mixtures thereof.

6. The stable non-aqueous pharmaceutical composition according to claim 1, wherein the composition comprises from about 5 mg/ml to about 120 mg/ml bendamustine, or a pharmaceutically acceptable salt thereof.

7. A stable non-aqueous pharmaceutical composition comprising: i) from about 5 mg/ml to about 120 mg/ml of bendamustine or a pharmaceutically acceptable salt thereof, ii) a solvent mixture comprising dimethyl acetamide: polyethylene glycol in the ratio from about 10:90 to about 70:30, and iii) at least one stabilizer in the concentration from about 0.1 mg/ml to about 20 mg/ml.

8. A stable non-aqueous pharmaceutical composition comprising: i) 90 mg/ml of bendamustine or a pharmaceutically acceptable salt thereof, ii) a solvent mixture comprising dimethyl acetamide: polyethylene glycol in the ratio of about 33:67, and iii) Cysteine Hydrochloride in the concentration from about 0.5 mg/ml to about 2 mg/ml.

9. A stable non-aqueous pharmaceutical composition comprising: i) from about 5 mg/ml to about 120 mg/ml of bendamustine or a pharmaceutically acceptable salt thereof, ii) a solvent mixture comprising dimethyl acetamide: polyethylene glycol in the ratio from about 10:90 to about 70:30, and (iii) at least one stabilizer, wherein the composition retains at least about 95% of active ingredient, after storage at about 2.degree. C. to about 8.degree. C. for at least 3 months.

10. A stable non-aqueous pharmaceutical composition comprising: i) 90 mg/ml of bendamustine or a pharmaceutically acceptable salt thereof, ii) a solvent mixture comprising dimethyl acetamide: polyethylene glycol in the ratio from about 10:90 to about 70:30, and (iii) at least one stabilizer, wherein the composition retains at least about 95% of active ingredient, after storage at about 25.degree. C. for at least 3 months.