DESC:FIELD OF THE INVENTION

The present invention related to a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof. The said stable ready to dilute pharmaceutical composition is further diluted to obtain a final diluted melphalan composition before administering to the patient in need thereof. Further, the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma.

BACKGROUND OF THE INVENTION

Melphalan is a bifunctional alkylating agent, which is a phenylalanine derivative of nitrogen mustard. It is also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin which is chemically known 4-[bis(2-chloroethyl)amino]-L-phenylalanine and molecular formula is C13H18Cl2N2O2.

Figure 1: Melphalan

Melphalan primarily degrades through sequential hydrolysis to the hydrolytic degradants monohydroxymelphalan and dihydroxymelphalan. Individual hydrolysis products, monohydroxymelphalan and dihydroxymelphalan, are observed as the main degradants in room temperature stored samples, along with small quantities of melphalan dimer. To overcome the hydrolytic degradation of Melphalan and preparing commercially available products, following approaches appear to have been made:

US4997651 patent discloses two-component pharmaceutical formulation of Melphalan comprising freeze-dried Melphalan hydrochloride and a solvent-diluent comprising a citrate, propylene glycol and ethanol.

US2013131174 patent application discloses a solid lyophilized composition of Melphalan hydrochloride having a pH between 4 and 6.

US2010311838, US2014213650 and US2014221488 patent application disclose parenteral compositions comprising Melphalan and a cyclodextrin derivative.

WO2017085696 patent application disclose a stable, parenteral formulation comprising Melphalan and cyclodextrin or its derivative thereof, wherein the formulation is free of propylene glycol.

US2014005148 patent application disclose a liquid formulations of nitrogen mustards.

US2018193255 patent application disclose ready to use liquid parenteral formulation comprising of Melphalan and pharmaceutically acceptable adjuvants thereof.

Commercially available parenteral preparations of Melphalan are manufactured by lyophilization. Melphalan is commercially available in tablet form (Alkeran®) and Injectable form (Alkeran®) and (Evomela®), for the treatment of multiple myeloma.

The commercial injectable formulation of Melphalan injectable Alkeran® is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each single use vial contains Melphalan hydrochloride equivalent to 50 mg Melphalan and 20 mg povidone. Alkeran® is reconstituted using the sterile diluent containing sodium citrate, propylene glycol, ethanol and water for injection to a volume of 10 mL.

The Alkeran® to be infused must be diluted to not more than 0.45 mg/ml in normal saline and infused over 15 minutes. However, the presence of high amounts of propylene glycol in the formulation often presents acceptability limitations. The diluted product needs to be administered within 60 minutes from time of reconstitution. The said reconstituted solution cause precipitation while store at 2-8 °C. Further slow addition of diluent or delay in shaking during reconstitution which resulting in formation of insoluble solid particles in solution.

The commercially available formulation of melphalan injectable Evomela® (50mg/vial) is a lyophilized composition and comprises of Melphalan and Betadex sulfobutyl ether sodium. The lyophilized composition must be reconstituted using 0.9% sodium chloride solution. The reconstituted solution is stable for 24 hours at refrigerated temperature without any precipitation due to the high solubility and stable for 1 hour at room temperature. On further dilution in sodium chloride, the solution is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution.

The inventors of the present invention have developed a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said pharmaceutical composition of Melphalan is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof. The said stable ready to dilute pharmaceutical composition has improved stability and can be stored for at least 72 hours at 2-8 °C without any precipitation. The said stable ready to dilute pharmaceutical composition is further diluted in 0.9% sodium chloride or 5% dextrose to obtain a final diluted melphalan composition and wherein the said final diluted melphalan composition is stable for at least 2 hours when stored at room temperature.

OBJECT OF THE INVENTION

The primary object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a process for preparation of liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients comprises the step of:
(a) mixing the solvents to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving one or more antioxidant to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
(e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, and wherein cyclodextrin derivative is present in a weight ratio of less than 50:1 relative to the melphalan or its pharmaceutically acceptable salt.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, wherein the said stable ready to dilute composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C).

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with sodium chloride solution or dextrose solution to obtain final diluted melphalan composition before administering to the patient in need thereof.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition before administering to the patient in need thereof.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to obtain a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain a final diluted melphalan composition.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to obtain a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution and 5% dextrose solution to obtain a final diluted melphalan composition, wherein the said final diluted melphalan composition is stable for at least 2 hours when stored at 25 °C.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D, more preferably the said composition does not have more than 2% of Impurity D when stored at 2-8 °C for at least 3 months.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D, more preferably the said composition does not have more than 2% (w/w) of Impurity D when stored at 25 °C for at least 3 months.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G, more preferably the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 2-8 °C for at least 3 months.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G, more preferably the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 25 °C for at least 3 months.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity, more preferably the said composition does not have more than 5% of total impurity when stored at 2-8 °C for at least 3 months.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity, more preferably the said composition does not have more than 5% of total impurity when stored at 25 °C for at least 3 months.

Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition is used for the treatment of multiple myeloma.

SUMMARY OF THE INVENTION

The present invention related to stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition and the said ready to dilute composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C) without any precipitation. The said stable ready to dilute pharmaceutical composition is further diluted with sodium chloride solution or dextrose solution to obtain a final diluted melphalan composition before administering to the patient in need thereof. Further, the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma.

DETAILED DESCRIPTION

Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.

The present invention related to stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Further, the present invention provides process for the preparation of the said composition and its use for the treatment of multiple myeloma.

The term “Melphalan” used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, preferably Melphalan Hydrochloride.

The term “liquid pharmaceutical composition” refers to a pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients. This liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, which is further diluted with sodium chloride or dextrose to obtain final diluted melphalan composition before administering to the patient in the need thereof.

The term “pharmaceutically acceptable” means salt, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical ingredients of a composition and are not deleterious to an individual treated with composition.

The term “diluent vehicle” refers to a vehicle composition which is used to first dilute the liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof. The diluent vehicle comprises of cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent.

The term “ready to dilute pharmaceutical composition” refers to a stable, liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, which is first diluted with a diluent vehicle comprising cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to obtain a stable ready to dilute pharmaceutical composition. The said stable ready to dilute pharmaceutical composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C).

The term “final diluted melphalan composition” refers to liquid pharmaceutical composition of melphalan diluted with diluent vehicle wherein diluent vehicle contains cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent to obtain stable ready to dilute melphalan composition, wherein the obtained stable ready to dilute melphalan composition is further diluted with sodium chloride solution or dextrose solution to obtain a final diluted melphalan composition, which is administered to the patient in need thereof.

The term “stable” as used throughout the specification, refers to a pharmaceutical composition in which the active pharmaceutical ingredients melphalan is present in an amount of at least 90% of the original label specified amount for each such ingredient during storage at 2-8 °C and 25°C.

The term “Impurity D” of melphalan as used throughout the specification, refers to below structure:

The term “Impurity G” of melphalan as used throughout the specification, refers to below structure:

The term “total impurities” of melphalan as used throughout the specification, refers to identified or unidentified degradation product or impurity structurally related with Melphalan which are arising from a manufacturing process or during storage of material.

In one of the embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients.

In one of another embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present invention is to provide a process for preparation of liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients comprises the step of:
(a) mixing the solvents to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving one or more antioxidant to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
(e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.

The one or more solvents can be selected from the group comprising of but not limited to dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, dimethylisosorbide, ethanol, propylene glycol, glycerine, polyethylene alcohol, propylene glycol esters, polyethylene glycols and the like. Preferred solvents are polyethylene glycols (PEG) and propylene glycol.

The anti-oxidant can be selected from the group comprising of but not limited to butylated hydroxyanisole, butylated hydroxyltoluene, tocopherol, ethylenediaminetetraacetic acid, monothioglycerol, ascorbic acid and their esters, L-cysteine, parabens, benzyl alcohol, propyl gallate, thioglycolic acid, tartaric acid, citric acid, or mixture thereof. Most preferred anti-oxidant is Monothioglycerol.

In one of the preferred embodiments, liquid pharmaceutical composition comprising melphalan HCl, monothioglycerol, sodium chloride, propylene glycol and polyethylene glycol.

In some of the embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof.

In some of the embodiments, the diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent.

In some of the embodiment, the diluent vehicle may be present in vial or Pre-Filled Syringe (PFS).

In one of the preferred embodiments, cyclodextrin derivative is present in less than 270 mg/ ml of total volume of diluent vehicle, more preferably less than 250 mg/ml of cyclodextrin, most preferably less than 200 mg/ ml of cyclodextrin of total volume of diluent vehicle. Accordingly, the diluent vehicle having a volume of 9 mL shall contain around 400 mg to 2450 mg, 500 mg to 2250 mg, 600 to 1800 mg of cyclodextrin derivatives of total weight of the diluent vehicle composition.

Cyclodextrins (CDs) derivatives are water soluble macrocyclic oligosaccharides with a-D-glucose units linked by a-(1?4) glycosidic bonds, widely used to solubilize various water insoluble drugs. It is driven by non-covalent interactions such as van der Waals forces, hydrogen bonding and hydrophobic interactions. Additionally, complex formation of CDs with drugs improve stability due to decrease in hydrolysis.

The cyclodextrin derivative can be selected from the group comprising of but not limited to a, ß and ?-cyclodextrin and cyclodextrins modified with alkyl-, hydroxy alkyl, dialkyl-, and sulfoalkyl-ether modified cyclodextrins such as methyl or hydroxypropyl ß-cyclodextrins (HPpCD), methyl-and-ethyl-P-cyclodextrin, sulfoalkylether-substituted beta-cyclodextrin, Betadex sulfobutyl ether sodium, sulfobutylether-P-cyclodextrin (SBECD) and the like. Most preferred cyclodextrin is Betadex sulfobutyl ether sodium.

In some of the embodiment, sodium chloride may be present in 0.9% of the total weight of the diluent vehicle.

In some of the embodiment, the diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent, wherein the said diluent vehicle is used to dilute the stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, to provide a stable ready to dilute pharmaceutical composition having pH of about 2-5.

In some of the embodiment, the diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and buffering agent, wherein the said diluent vehicle is used to dilute the liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, to provide a stable ready to dilute pharmaceutical composition having pH of about 4-5. The said buffering agents are, such as, but not limited to, citrate buffer, acetate buffers, phosphate buffer, amino acids, and the like. Preferred buffers are sodium citrate anhydrous and sodium acetate monohydrate.

In some of the embodiment, the diluent vehicle also contains water for injection as a preferred solvent.

In some of the embodiments, stable liquid pharmaceutical composition comprising 50 mg/ml of melphalan HCl, which is first diluted with 9 ml of diluent vehicle to provide the 5mg/ml of stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt.

In some of the embodiment, the stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts has a pH of about 2-5.

In one of the preferred embodiments, the stable ready to dilute pharmaceutical composition comprises cyclodextrin derivative, wherein the said cyclodextrin derivative is present in a ratio of less than 50:1 relative to the melphalan or its pharmaceutically acceptable salt.

In some of the embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, wherein the said stable ready to dilute composition is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C).

In one of the preferred embodiments, the stable ready to dilute pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt and cyclodextrin derivatives is stable for at least 72 hours when stored at 2-8 °C and for at least 1 hour when stored at room temperature (25 °C), wherein the cyclodextrin derivative is present in a ratio of less than 50:1 relative to the melphalan or its pharmaceutically acceptable salts.

In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with sodium chloride solution or dextrose solution to obtain final diluted melphalan composition, which is administered to the patient in need thereof.

In one of the preferred embodiments, the stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition, which is administered to the patient in need thereof.

In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain a final diluted melphalan composition for the stability study.

In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to obtain a stable ready to dilute pharmaceutical composition, and the said stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution and 5% dextrose solution to obtain a final diluted melphalan composition, wherein the said final diluted composition is stable for at least 2 hours when stored at 25 °C.

In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D when stored at 2-8 °C for at least 3 months.

In one of the preferred embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 2% (w/w) of Impurity D when stored at 2-8 °C for at least 3 months.

In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 7.5% (w/w) of Impurity D when stored at 25 °C for at least 3 months.

In one of the preferred embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 2% (w/w) of Impurity D when stored at 25 °C for at least 3 months.

In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G when stored at 2-8 °C for at least 3 months.

In one of the preferred embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 2-8 °C for at least 3 months.

In yet another embodiment, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 1% (w/w) of Impurity G when stored at 25 °C for at least 3 months.

In one of the preferred embodiments, the present invention is to provide a stable liquid pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 0.6% (w/w) of Impurity G when stored at 25 °C for at least 3 months.

In yet another embodiment, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity, when stored at 2-8 °C for at least 3 months.

In one of the preferred embodiments, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 5% of total impurity when stored at 2-8 °C for at least 3 months.

In yet another embodiment, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 10% (w/w) of total impurity after being stored at 25 °C for at least 3 months.

In one of the preferred embodiments, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising Melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition does not have more than 5% of total impurity after being stored at 25 °C for at least 3 months.

In yet another embodiment, the present invention is to provide a stable, ready to dilute pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the said composition is used for the treatment of multiple myeloma.

EXAMPLES:

The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The scope of the invention is in no manner limited by the disclosed example.

Example 1: Liquid melphalan composition
Sr. No Ingredients Quantity/mL
1 Melphalan 50 mg
2 Sodium chloride 1.0-2.0 mg
3 Anti-oxidant 2.0-5.0 mg
4 one or more solvent q.s. to 1 ml

Manufacturing Process:
(a) mixing the solvents to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving one or more antioxidant to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
(e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.

Example 2: Liquid melphalan composition
Sr. No Ingredients Quantity/mL
1 Melphalan 50 mg
2 Sodium chloride 2.0 mg
3 Monothioglycerol 5.0 mg
4 Propylene glycol 0.1 mL
5 Polyethylene glycol 400 q.s. to 1.0 mL

Manufacturing Process:
(a) mixing propylene glycol and polyethylene glycol 400 to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving monothioglycerol to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
(e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.

Example 3: Liquid melphalan composition
Sr. No Ingredients Quantity/mL
1 Melphalan 50 mg
2 Sodium chloride 2.0 mg
3 Citric acid (anhydrous) 0.5 mg
4 Butylated hydroxytoluene 0.06 mg
5 Propylene glycol 0.1 mL
6 Polyethylene glycol 400 q.s. to 1.0 mL

Manufacturing Process:
(a) mixing propylene glycol and polyethylene glycol 400 to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving butylated hydroxytoluene and citric acid to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
(e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.

Example 4: Liquid melphalan composition
Sr. No Ingredients Quantity/mL
1 Melphalan 50 mg
2 Sodium chloride 2.0 mg
3 Alpha tocopherol 0.7 mg
4 Propylene glycol 0.1 mL
5 Polyethylene glycol 400 q.s. to 1.0 mL

Manufacturing Process:
(a) mixing propylene glycol and polyethylene glycol 400 to obtain the clear solution;
(b) dissolving sodium chloride to the clear solution obtained in step a);
(c) dissolving alpha tocopherol to the solution obtained in step b);
(d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
(e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.

Example 5: Composition of diluent vehicle
Sr. No Ingredients Quantity/mL
1 Cyclodextrin 50 - 250 mg
2 Sodium chloride 9.0 mg
3 Buffers 0-5.0 mg
4 Solvent q.s. to 1.0 mL

Stability Study:

Table 1: Stability data of Liquid melphalan composition of Example 2 at 25 °C/65% RH and 2-8 °C storage condition

Time-point Description Assay (%) Impurity
D Impurity
G Any unspecified Impurity Total Impurity
Initial Clear colorless solution 100.0 0.110 0.175 0.086 0.832
25°C/1M Clear colorless solution 98.6 0.109 0.207 0.228 1.484
25°C/3M Clear colorless solution 100.0 0.135 0.265 0.165 2.119
2-8°C/1M Clear colorless solution 99.0 0.109 0.146 0.103 0.910
2-8°C/3M Clear colorless solution 101.2 0.129 0.192 0.091 0.800
Limit Clear colorless solution 95 - 105 NMT 7.5 NMT 1.0 NMT 0.3 NMT 10.0

Table 2: Stability data of diluted melphalan solution with diluent solution of 50 mg/mL SBE-CD in 0.9% Sodium chloride under different time interval at storage conditions of 2-8 °C and 25 °C

Time-point Description pH Impurity
D Impurity
G Any unspecified Impurity Total Impurity
At 2-8 °C
Initial Clear colorless solution 2.60 0.160 0.184 0.047 0.692
24 Hrs Clear colorless solution 2.56 1.093 0.270 0.051 1.753
48 Hrs Clear colorless solution 2.53 0.992 0.264 0.043 1.622
72 Hrs Clear colorless solution 2.70 0.957 0.261 0.044 1.601
At 25 °C
1 Hr Clear colorless solution 2.68 0.644 0.229 0.064 1.252
Limit Clear colorless solution 2-5 NMT 7.5 NMT 1.0 NMT 0.3 NMT 10.0

Table 3: Stability data of diluted melphalan solution with diluent solution of 200 mg/mL SBE-CD in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C.

Time-point Description pH Impurity
D Impurity
G Any unspecified Impurity Total Impurity
At 2-8 °C
Initial Clear colorless solution 2.58 0.144 0.182 0.046 0.676
24 Hr Clear colorless solution 2.62 0.336 0.193 0.056 0.898
48 Hr Clear colorless solution 2.71 0.338 0.194 0.051 0.887
72 Hr Clear colorless solution 2.64 0.333 0.193 0.051 0.885
At 25 °C
1 Hr Clear colorless solution 2.70 0.233 0.190 0.062 0.801
Limit Clear colorless solution 2-5 NMT 7.5 NMT 1.0 NMT 0.3 NMT 10.0

Table 4: Stability data of diluted melphalan solution with diluent solution of 250 mg/mL SBE-CD in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C

Time-point Description pH Impurity
D Impurity
G Any unspecified Impurity Total Impurity
At 2-8 °C
Initial Clear colorless solution 2.61 0.145 0.181 0.048 0.673
24 Hr Clear colorless solution 2.81 0.237 0.184 0.057 0.816
48 Hr Clear colorless solution 2.63 0.252 0.187 0.051 0.790
72 Hr Clear colorless solution 2.67 0.287 0.188 0.052 0.832
At 25 °C
1 Hr Clear colorless solution 2.60 0.246 0.182 0.056 0.737
Limit Clear colorless solution 2-5 NMT 7.5 NMT 1.0 NMT 0.3 NMT 10.0

Table 5: Stability data of diluted melphalan solution with diluent solution of 250 mg/mL SBE-CD and 4.5 mg/mL Sodium Citrate in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C

Time-point Description pH Impurity
D Impurity
G Any unspecified Impurity Total Impurity
At 2-8 °C
Initial Clear colorless solution 4.76 0.143 0.186 0.048 0.686
24 Hr Clear colorless solution 4.74 0.454 0.250 0.049 1.099
48 Hr Clear colorless solution 4.99 0.335 0.202 0.041 0.825
72 Hr Clear colorless solution 4.77 0.379 0.239 0.044 0.998
At 25 °C
1 Hr Clear colorless solution 4.90 0.247 0.206 0.056 0.846
Limit Clear colorless solution 4-5 NMT 7.5 NMT 1.0 NMT 0.3 NMT 10.0

Table 6: Stability data of diluted melphalan solution with diluent solution of 250 mg/mL SBE-CD and 4.5 mg/mL Sodium Acetate in 0.9% Sodium chloride under different time interval at storage condition of 2-8 °C and 25 °C

Time-point Description pH Impurity
D Impurity
G Any unspecified Impurity Total Impurity
At 2-8 °C
Initial Clear colorless solution 4.80 0.142 0.185 0.046 0.677
24 Hr Clear colorless solution 4.81 0.476 0.254 0.082 1.156
48 Hr Clear colorless solution 4.79 0.383 0.237 0.066 1.006
72 Hr Clear colorless solution 4.84 0.400 0.247 0.072 1.051
At 25 °C
1 Hr Clear colorless solution 4.81 0.321 0.225 0.055 0.954
Limit Clear colorless solution 4-5 NMT 7.5 NMT 1.0 NMT 0.3 NMT 10.0

The above data shows impurity D and total impurity not more than 2% and 4% respectively in the ready to dilute melphalan formulation, indicative of stability of melphalan HCl in the drug product. Further there is no precipitation observed even after 72 hours when stored at 2-8 °C Storage.

Table 7: Stability data of final diluted melphalan composition

The liquid pharmaceutical composition of melphalan diluted with diluent vehicle where in diluent vehicle contains 250 mg/mL SBE-CD in 0.9% Sodium chloride to obtained ready to dilute melphalan composition and stored at 25 °C for 1 hour. The resulted ready to dilute melphalan composition is further diluted with 0.9% Sodium Chloride to obtain 0.45 mg/mL concentration of final diluted melphalan composition. The results of stability data for final diluted melphalan composition is summarized in below table.

Time-point Description pH Impurity
D Impurity
G Any unspecified Impurity Total Impurity
Initial Clear colorless solution 3.08 0.278 0.174 0.074 0.867
1 Hr Clear colorless solution 3.10 0.962 0.185 0.072 1.547
2 Hr Clear colorless solution 3.10 1.630 0.196 0.074 2.223
4 Hr Clear colorless solution 3.15 2.822 0.214 0.072 3.435
Limit Clear colorless solution 2-5 NMT 7.5 NMT 1.0 NMT 0.3 NMT 10.0

Table 8: Stability data of final diluted melphalan composition

The liquid pharmaceutical composition of melphalan diluted with diluent vehicle where in diluent vehicle contains 250 mg/mL SBE-CD and 4.5 mg/mL Sodium Acetate in 0.9% Sodium chloride to obtained ready to dilute melphalan composition and stored at 25 °C for 1 hour. The resulted ready to dilute melphalan composition is further diluted with 0.9% Sodium Chloride and 5% dextrose injection to obtain 0.45 mg/mL concentration of final diluted melphalan composition. The results of stability data for final diluted melphalan composition is summarized in below table.

Time-point Description pH Impurity
D Impurity
G Any unspecified Impurity Total Impurity
Diluted in 0.9% Sodium Chloride Injection and stored at 25 °C:
Initial Clear colorless solution 4.58 0.396 0.207 0.068 1.056
1 Hr Clear colorless solution 4.54 1.373 0.232 0.070 2.057
2 Hr Clear colorless solution 4.55 2.126 0.252 0.081 2.828
4 Hr Clear colorless solution 4.52 3.971 0.325 0.093 4.802
Diluted in 5% Dextrose Injection and stored at 25 °C:
Initial Clear colorless solution 4.62 0.542 0.232 0.069 1.317
1 Hr Clear colorless solution 4.58 3.151 0.358 0.092 4.024
2 Hr Clear colorless solution 4.60 5.376 0.469 0.133 6.532
Limit Clear colorless solution 4-5 NMT 7.5 NMT 1.0 NMT 0.3 NMT 10.0

The above data shows impurity D, impurity G and total impurity are not more than specified limit in the formulation, which is indicative of stability of melphalan HCl in the drug product at 25 °C.

The stability data as mentioned above indicate that the liquid pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof are stable. Further, the ready to dilute melphalan composition is stable for at least 72 hours at 2-8 °C and for at least 1 hours at 25 °C. Also, the final diluted melphalan composition obtained after dilution with 0.9% sodium chloride or 5% dextrose is stable for at least 2 hours at 25 °C. ,CLAIMS:We Claims:

1. A stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof, wherein the said stable ready to dilute pharmaceutical composition is stable for at least 72 hours when stored at 2-8°C.

2. The stable liquid pharmaceutical composition according to claim 1, wherein the said stable ready to dilute pharmaceutical composition is stable for at least 1 hour when stored at 25°C.

3. The stable liquid pharmaceutical composition according to claim 1, comprising melphalan or its pharmaceutically acceptable salt thereof, one or more solvents, one or more antioxidants, sodium chloride and optionally one or more pharmaceutically acceptable excipients.

4. The stable liquid pharmaceutical composition according to claims 1, wherein the said stable liquid pharmaceutical composition is first diluted with a diluent vehicle to provide a stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salt thereof, wherein the said diluent vehicle comprises cyclodextrin derivative, sodium chloride, one or more solvents and optionally buffering agent.

5. The stable liquid pharmaceutical composition according to claims 1, wherein the stable ready to dilute pharmaceutical composition of melphalan or its pharmaceutically acceptable salts thereof comprises cyclodextrin derivative, wherein the said cyclodextrin derivative is present in a ratio of less than 50:1 relative to the melphalan or its pharmaceutically acceptable salt.

6. The stable liquid pharmaceutical composition according to claims 1, wherein the stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition, which is administered to the patient in need thereof.

7. The stable liquid pharmaceutical composition according to claims 1, wherein the stable ready to dilute pharmaceutical composition is further diluted with 0.9% sodium chloride solution or 5% dextrose solution to obtain final diluted melphalan composition, wherein the said final diluted composition is stable for at least 2 hours when stored at 25°C.

8. The stable liquid pharmaceutical composition according to claims 1, wherein the said stable liquid pharmaceutical composition contains not more than 7.5% (w/w) of Impurity D, not more than 1% (w/w) of Impurity G, and not more than 10% of total impurity, when stored at 2-8 °C and 25 °C for at least 3 months.

9. The stable liquid pharmaceutical composition according to claims 1, wherein the said composition is used for the treatment of multiple myeloma.

10. A process for the preparation of stable liquid pharmaceutical composition comprising melphalan or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients comprising the steps of:
a) mixing the solvents to obtain the clear solution;
b) dissolving sodium chloride to the clear solution obtained in step a);
c) dissolving one or more antioxidant to the solution obtained in step b);
d) dissolving melphalan or its pharmaceutically acceptable salt in solution obtained in step c) and making up the volume.
e) filtering the solution obtained in step d) and filling the filtered solution in suitable vials.