WO2016005995A2

WO2016005995A2 - Glycol free stable liquid compositions of bendamustine

Info

Publication number: WO2016005995A2
Application number: PCT/IN2015/000279
Authority: WO
Inventors: Kocherlakota Chandrashekhar; Banda Nagaraju
Original assignee: Leiutis Pharmaceutials LLP
Current assignee: Leiutis Pharmaceutials LLP
Priority date: 2014-07-10
Filing date: 2015-07-09
Publication date: 2016-01-14
Anticipated expiration: 2017-01-10
Also published as: WO2016005995A3

Abstract

The present invention relates to ready to use stable liquid pharmaceutical formulations of Bendamustine or a pharmaceutically acceptable salt thereof; wherein the formulation is devoid of glycols. Further the present invention relates to pharmaceutical composition of Bendamustine hydrochloride comprising of saccharide, suitable solvent or mixture of solvents and suitable adjuvants thereof.

Description

[Complete specification

Field of Invention

The present invention relates to glycol free ready to use liquid pharmaceutical formulations of Bendamustine or its pharmaceutically acceptable salts, solvates and hydrates thereof. Further the present invention relates to pharmaceutical formulations of Bendamustine hydrochloride comprising one or more saccharides.

Background of the invention

Bendamustine was first synthesized in 1963 by Ozegowski and Krebs in East Germany. It was found useful in treating chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and lung cancer. Bendamustine hydrochloride has the following structure:

In the US, Bendamustine is available as powder for IV infusion and as Solution for IV infusion under the tradename Treanda^®.

Treanda^® powder for IV infusion is supplied as a sterile non-pyrogenic white to off- white lyophilized powder in a single-use vial in lOOmg and 25mg strengths. Each vial contains lOOmg of Bendamustine HC1 and 170mg of mannitol, USP. The pH of the reconstituted solution is 2.5-3.5.

Treanda^® injection is supplied in single-use vials containing either 45 mg/0.5 mL or 180 mg/2 mL of Bendamustine HC1. Each 0.5 mL vial contains 45 mg of Bendamustine hydrochloride, 162 mg of Propylene Glycol, USP and 293 n g of N,N-Dimethylacetamide, EP. Each 2 niL vial contains 180 mg of Bendamustine hydrochloride, 648 mg of Propylene Glycol, USP and 1172 mg of Ν,Ν-Dimethylacetamide, EP. An over fill of 0.2 mL is included in each vial. The injection is intended for intravenous infusion only after dilution with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP.lt is supplied as a sterile clear colorless to yellow solution in single-use vials at the concentration of 90 mg/mL of Bendamustine HC1.

The reconstitution of the Bendamustine lyophilized powder is time consuming and cumbersome. Moreover, lyophilization of solids on a commercial scale requires specialized equipment and incurs significant expense. Because of the patient-specific dosing, repeated administration, and a dosage regimen of six 28-day cycles, there is a strong need for ready- to-use formulations with enhanced stability. Unfortunately, while various attempts have been made to stabilize Bendamustine, all or almost all of them suffer from several disadvantages.

US 201 1/0184036A1 points out that stability of Bendamustine in aqueous solutions is very minimal and is limited to few hours; and is therefore, not suitable for long-term storage in liquid form.

Certain non-aqueous propylene glycol formulations have been disclosed in US 8,344,006, US 2013/041004, US 2014/080881, US 2012/0157505 to increase long-term stability.

Bendamustine solution formulated with non-aqueous polyethylene glycol (PEG) and/or propylene glycol (PG) are discussed in US Pat No. 8,609,707, U.S. patent applications 2013/253026, US 2014/024691, 2013/253025, 2013/210879 and 2014/094496.

In still further known attempts, Bendamustine is combined with first charged cyclopolysaccharide and a stabilizing agent (which is a second charged cyclopolysaccharide) with a charge opposite to that of the first cyclopolysaccharide as discussed in WO 2012/127277, WO 2010/097700, and US 2010/0216858.

Similarly, US 201 1/0015245 teaches use of various amphiphilic cationic compositions to stabilize Bendamustine, while WO 201 1/005714 teaches liposomal formulations encapsulating Bendamustine.

In another approach, stability of Bendamustine HC1 (0.25mg/ml in 0.9% sodium chloride) in water was studied. Here, Bendamustine was stable at 4°C for 4 days and at 23°C for 9 hours. While the temperature had adverse effects on stability, it was found that moderate concentrations of chloride ions increased the stability to at least some degree (Pharmazie 1994; 49, 10: 775-777). However, such compositions were yet again not stable over extended periods, and thus provide at best limited use as a ready-to-use aqueous composition, even under refrigerated conditions.

Alternatively, Bendamustine, is immobilized in a polymeric carrier to increase stability (J Pharm Biomed Anal. 2008 Dec 1;48(4): 1143-50). However, such specialized formulations are often complex to manufacture and/or significantly increase the cost of production.

US Patent No. 8,344,006 describes liquid formulations comprising Bendamustine or pharmaceutically acceptable salts thereof, and polar aprotic solvents like dimethylacetamide and propylene glycol. Propylene glycol has been identified by the American Academy of Pediatrics as a potentially dangerous additive. Even though propylene glycol is considered to be harmless, in high concentrations it causes lactic acidosis and hyperosmolarity, hemolysis, renal toxicity including tubular dysfunction and acute tubular necrosis. When propylene glycol is present in high doses in intravenous formulations, it increases the formulation osmolality. Hence its use in patients of diminished renal function, should be monitored by determining plasmatic osmolality daily. Further, solutions of Bendamustine in propylene glycol degrade to form impurities identified as propylene glycol esters of Bendamustine. Upon exposure to an alkylene glycol, for example, propylene glycol, esters of Bendamustine can form, e.g., PG-1 and PG- 2 depicted below.

The 90 mg/mL non-aqueous formulation of liquid Bendamustine HC1 described in US Patent No 8,344,006 exhibits bendamustine-propylene glycol ester degradation products following 12 months of storage at 5°C that are not formed after 24 months of storage of the lyophilized product. These esters are present at a level greater than 1% which may not be advisable for the patient.

The lyophilized product of Bendamustine possesses good chemical stability. However, reconstitution of the lyophilized product is clinically inconvenient, with implications of chemical instability. On the other hand, Bendamustine solutions formulated with nonaqueous polyethylene glycol (PEG) and/or propylene glycol may be stable but the use of propylene glycol presents acceptability limitations. Hence there is a need for ready to use (RTU) Bendamustine formulations having enhanced stability. The present invention addresses this need. Summary of the invention

The present invention relates to ready to use liquid formulations of Bendamustine including its pharmaceutically acceptable salts, solvates, hydrates thereof, and method of preparation of such compositions.

Another aspect of the present invention provides glycol free formulations of Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof.

Another aspect of the present invention is to provide ready to use pharmaceutical formulation comprising Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof; saccharides; suitable solvent or mixture of solvents; and other pharmaceutically acceptable adjuvants.

Yet another aspect of the present invention is to provide ready to use pharmaceutical formulation comprising of Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof, saccharide syrup; suitable solvent or mixture of solvents; anti-oxidant; buffer and other pharmaceutically acceptable adjuvants thereof.

Yet another aspect of the present invention is to provide ready to use pharmaceutical formulation comprising of Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof, saccharides such as sucrose syrup, suitable solvent such as N,N-Dimethyl acetamide, antioxidant/buffer such as cysteine, acetic acid and other pharmaceutically acceptable adjuvants thereof; wherein the formulation is free of glycol.

Another aspect of the present invention provides manufacturing process for preparing ready to use liquid formulations of Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof; wherein the formulation is free of glycol. Another aspect of the present invention provides manufacturing process for preparing ready to use liquid formulations of Bendamustine comprising of Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof, sucrose syrup, suitable solvent, cysteine and optionally other suitable pharmaceutically acceptable adjuvants thereof; wherein the formulation is free of glycol.

Detailed description of the invention

As used herein, "glycol" means class of organic chemicals characterized by having two hydroxyl (-OH) groups attached to separate carbon atoms; which may include dihydric alcohols such as Ethylene glycol, propylene glycol, butylene glycol and polyalkylene glycols such as polyethylene glycol, polypropylene glycol, polybutylene glycol and the like.

As used herein, "ready to use Bendamustine" formulations refers to formulations that contain Bendamustine in dissolved or solubilised form and are to be intended to be used as such or upon further dilution in intravenous diluents.

The pharmaceutical formulation of the present invention is a ready to use injectable formulation that is free of glycols. The inventors have surprisingly found that the presence of saccharide syrup in combination with suitable solvent yields a stable formulation overcoming the disadvantages associated with prior art.

In one preferred embodiment, the formulation may additionally comprise buffer, antioxidants and preservatives. In a further preferred embodiment, the formulations of the present invention comprise sucrose syrup, suitable solvent such as N,N-Dimethyl acetamide, antioxidant/buffer such as cysteine, acetic acid and optionally other pharmaceutically acceptable adjuvants. Suitable saccharides can be, but not limited to, sucrose, glucose, xylose, galactose, fructose, lactose, maltose, mannitol, sorbitol, xylitol, raffinose, dextrose, trehalose and the like. Of these the preferred saccharide is sucrose used as sucrose syrup. Sucrose is a disaccharide comprised of the monosaccharides glucose and fructose and has been used as a stabilizer in several Intravenous Immune Globulins (IVIG) products.

Formulations of the present invention comprise pharmaceutically useful concentrations of Bendamustine, or a pharmaceutically acceptable salt thereof. The concentrations may range from about 5 mg/mL to about 200 mg/mL. Preferably, the concentration of Bendamustine, or a pharmaceutically acceptable salt thereof, ranges from about 5 mg/mL to about 1 0 mg/mL.

Suitable solvents can be selected from, but are not limited to, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), Ethanol, N-methyl-2-pyrrolidone (NMP), l,3-dimethyl-2- imidazolidinone (DMI), acetone, tetrahydrofuran (THF), dimethylformamide (DMF), propylene carbonate (PC), glycerine, dimethyl isosorbide and mixtures thereof. Preferred solvents are dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) and ethanol. Most preferred solvent is dimethylacetamide (DMA). The percentage of solvent ranges from about 10% to 90% based upon total weight of the formulation.

The pharmaceutical compositions of the present invention also contain one or more antioxidants, preservatives, complexing agents and chelating agents such as, but are not limited to butylated hydroxyanisole (BHA), butylated hydroxyl toluene (BHT), citric acid, lactic acid, benzoic acid, tocopherol (Vitamin E), monothioglycerol, ascorbic acid, methyl paraben, benzyl alcohol, propyl gallate, surfactants, lipids, thioglycolic acid, niacinamide, nicotinic acid, creatine, cyclodextrins; ethylene diamine tetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis(B-aminoethyl ether)- tetraacetic acid (EGTA), N (hydroxy ethyl) ethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), triethanolamine, 8-hydroxyquinoline, citric acid, tartaric acid, phosphoric acid, gluconic acid, thiodipropionic acid, acetonic dicarboxylic acid, lecithin, di(hydroxyethyl)glycine, sorbitol and aminoacids such as cysteine, phenylalanine, tryptophan, glycine, proline, 4-hydroxyproline, threonine, arginine and ornithine, cystine, methionine, tyrosine, histidine and the like, or its pharmaceutically acceptable salts thereof. The composition of the present invention optionally contains additional stabilizers.

Most preferred anti-oxidants are Cysteine, monothioglycerol, ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxyl toluene (BHT) and citric acid. The percentage ranges from about 0.01% to 10% based upon total weight of the formulation.

The pharmaceutical compositions of the present invention optionally contain buffers such as citrate buffer, glutamate, bicarbonate, tartrate, benzoate, lactate, gluconate, glycine, TRIS buffer, acetate buffer, boric acid buffer, phosphate buffer, acetic acid, lactic acid, amino acids, meglumine, or any other suitable buffer and mixtures thereof. Most preferred buffer is acetic acid.

The pharmaceutical compositions of the present invention contain an aqueous vehicle such as water used for preparing saccharide syrup. The percentage of saccharide syrup ranges from 5% to 90% of total weight of the formulation. Most preferred saccharide syrup is sucrose syrup.

The invention further relates to a process of preparing ready to use formulations of Bendamustine comprising

(i) Dissolving Bendamustine in the solvent

(ii) adding the saccharide syrup and mixing to get a homogenous solution

(iii) adding anti-oxidants, preservatives, buffers and

(iv) stirring to get a clear solution.

(v) filling in to a suitable container or vials

(vi) sterilizing the filled container / vials. Bendamustine formulation prepared according to the invention was tested for stability under accelerated conditions. Another preparation with quantitative composition of Treanda^® (ready to use formulation) was prepared for a comparative stability study. The stability data of the invention formulation with the reference product is summarised in Table 1. The data confirms the inventors' finding that the use of sucrose syrup in combination with dimethyl acetamide and cysteine yields best result. No impurities were observed at relative retention time (RRT 1.05) for the invention product.

Table 1: Comparative stability data of invention formulation with Reference product

The product is tested for stability by storing at various conditions like 25°C± 60%RH; 40°C± 75%RH and at 2-8°C and the data is summarized below:

Table 2: Stability data for the product obtained from Example 1

(Sample is packed in 2 mL amber colored glass vial)

ND: Not detectable

The following examples further describe certain specific aspects and embodiments of the present 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:

Manufacturing Procedure:

1) Ν,Ν'-Dimethylacetamide is taken into a compounding vessel and cooled to 2- 8°C.

2) Bendamustine HCl is added to DMA and stirred till completely dissolved while maintaining the solution temperature at 2-8°C.

3) Sucrose syrup is added to the solution of step 2 and stirred to get homogenous solution.

4) Cysteine is added to the solution of step 3 and stirred to get clear solution.

5) The solution is filtered using 0.22μ sterile filters connected in series and filled into sterilized vials.

6) The vials are sealed with flip-off seals. Example 2

Manufacturing procedure:

6) The vials are sealed with flip-off seals.

Example 3

Manufacturing procedure

2) Bendamustine HCl is added to DMA and stirred till completely dissolved while maintaining the solution temperature at 2-8°C. 3) Sucrose syrup is added to the solution of step 2 and stirred to get homogenous solution.

6) The vials are sealed with flip-off seals.

Example 4

Manufacturing procedure

2) Bendamustine HC1 is added to DMA and stirred till completely dissolved while maintaining the solution temperature at 2-8°C.

5) Acetic acid is added to the solution of step 4.

6) The solution is filtered using 0.22μ sterile filters connected in series and filled into sterilized vials.

7) The vials are sealed with flip-off seals. Example 5

Manufacturing procedure

5) Acetic acid is added to the solution of step 4.

7) The vials are sealed with flip-off seals.

Example 6

Manufacturing procedure

1) Ν,Ν'-Dimethylacetamide is taken into a compounding vessel and cooled to 2- 8°C. ) Bendamustine HCl is added to DMA and stirred till completely dissolved while maintaining the solution temperature at 2-8°C.

) Sucrose syrup is added to the solution of step 2 and stirred to get homogenous solution.

) Acetic acid is added to the solution of step 3.

) The solution is filtered using 0.22μ sterile filters connected in series and filled into sterilized vials.

) The vials are sealed with flip-off seals.

Claims

We Claim:

1. A ready to use liquid pharmaceutical formulation comprising of Bendamustine or its pharmaceutically acceptable salts, solvates and hydrates thereof and a pharmaceutically acceptable adjuvant, wherein the formulation is devoid of glycols.

2. A ready to use liquid pharmaceutical formulation comprising

(i) Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof;

(ii) a saccharide or mixture of saccharides

(iii) solvent or mixture of solvents and optionally other pharmaceutically acceptable adjuvants.

3. The ready to use liquid pharmaceutical formulation of claim 2, which further comprises an antioxidant.

4. The ready to use liquid pharmaceutical formulation of claim 2 wherein the saccharide is selected from the group comprising sucrose, glucose, xylose, galactose, fructose, lactose, maltose, mannitol, sorbitol, xylitol, raffinose, dextrose, trehalose and the solvent is selected from the group comprising dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), Ethanol, N-methyl-2-pyrrolidone (NMP), l,3-dimethyl-2-imidazolidinone (DMI), acetone, tetrahydrofuran (THF), dimethylformamide (DMF), propylene carbonate (PC), glycerine, dimethyl isosorbide and mixtures thereof.

5. The ready to use liquid pharmaceutical formulation of claim 3, where the antioxidant is selected from the group comprising butylated hydroxyanisole (BHA), butylated hydroxyl toluene (BHT), citric acid, monothioglycerol, ascorbic acid and cysteine.

6. The pharmaceutical formulation of claim 2, wherein the saccharide is sucrose and the solvent is dimethylacetamide.

7. The pharmaceutical formulations of claims 1 or 2 comprising

Bendamustine hydrochloride

Sucrose

Dimethyl acetamide and

Cysteine