Stable liquid pharmaceutical composition containing melphalan

Abstract

The present invention relates to a stable liquid pharmaceutical composition comprising melphalan, at least one cyclodextrin, at least one non-aqueous solvent, water and / or at least one aqueous buffer, at least one antioxidant, optionally at least one chelating agent, and optionally at least one inorganic salt. The present invention also relates to the use of the composition of the present invention in the treatment of cancer, the preparation of the composition, and a dosage form containing the composition.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority based on U.S. Provisional Application No. 63 / 358,649, filed on July 6, 2022, the entire content of which is incorporated herein by reference.

[0002] The present invention relates to a stable liquid pharmaceutical composition of melphalan, methods for using and preparing the composition, and dosage forms containing the composition.

Background Art

[0003] Drugs for intravenous injection are required to have sufficient solubility in water or physiologically acceptable aqueous buffers. Injectable solutions should preferably exhibit sufficient stability during storage under room - temperature conditions.

[0004] Insufficient solubility in aqueous fluids may lead to the preparation of injectable formulations in non - aqueous organic solvents. Such products require dilution with physiologically compatible diluents. Even when a formulation is prepared using a non - aqueous solvent, it is not possible to ensure the stability of such a formulation.

[0005] Organic solvents are often used to formulate injectable drugs of drugs. Injectable formulations prepared using larger amounts of organic solvents are usually diluted with isotonic diluents such as sodium chloride or dextrose solutions before injection.

[0006] Non - aqueous products that are completely devoid of water may also have limited stability in their undiluted state and even after dilution with aqueous diluents.

[0007] To avoid stability issues, injectable drugs are typically lyophilized to obtain a rapidly soluble sterile cake that is reconstituted with a diluent to obtain an injectable solution.

[0008] A certain drug requires an organic solvent to dissolve the lyophilized cake even after lyophilization, and even after reconstitution, the resulting solution may not be stable for a long time. Rather, such solutions must be stored under refrigeration conditions if not used immediately.

[0009] In particular, melphalan, sold under the trade name Alkeran®, is a chemotherapy drug used to treat multiple myeloma, ovarian cancer, melanoma, and AL amyloidosis. It is also commercially available as Evomela®, and is approved for use as high-dose conditioning therapy before hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma (MM), and as palliative treatment for MM patients for whom oral therapy is not appropriate.

[0010] Melphalan is a DNA alkylating agent that acts by chemically altering the DNA nucleotide guanine by alkylation, causing cross-links between DNA strands. This chemical alteration inhibits DNA synthesis and RNA synthesis, which are functions necessary for cells to survive. These changes cause cytotoxicity in both dividing and non-dividing tumor cells. Melphalan has the following chemical structure:

Chemical formula

[0011] Melphalan is soluble in propylene glycol and dilute mineral acids, sparingly soluble in ethanol and methanol, and almost insoluble in water, chloroform, and ether.

[0012] Melphalan HCl for intravenous injection, marketed as Alkeran (registered trademark), is supplied as a lyophilized cake consisting of melphalan hydrochloride equivalent to 50 mg of melphalan and 20 mg of povidone, and contains a sterile diluent. The vial of sterile diluent contains 6 mL of propylene glycol, 0.52 mL of ethanol (96%), 0.2 g of sodium citrate, and an appropriate amount of water up to 10 mL in total. First, the lyophilized cake needs to be reconstituted with the sterile diluent, and then the dose is immediately diluted with physiological saline to a final concentration of melphalan of 0.45 mg / mL or less. The resulting diluted solution of melphalan must be injected within 1 hour after reconstitution. Since melphalan precipitates under refrigeration conditions, the diluted solution must not be stored in the refrigerator.

[0013] Evomela (registered trademark) contains melphalan hydrochloride and betadex sulfobutyl ether sodium. Evomela (registered trademark) is diluted with 0.9% sodium chloride injection solution to a final concentration of 0.45 mg / mL and is injected over 30 minutes. The Evomela (registered trademark) mixed solution is stable for only 4 hours at room temperature.

[0014] Reconstitution and mixing with the diluent consume both time and labor. Furthermore, reconstitution and mixing must be carried out within a designated sterile hood to avoid contamination.

[0015] A solution that only needs to be diluted without dissolving melphalan brings considerable advantages in the hospital environment and minimizes the risk of contamination. The process of using such a solution that only needs to be diluted without dissolving involves simply drawing the solution from the vial into the syringe and then pushing the solution in the syringe into an IV bag containing an isotonic diluent.

[0016] A solution that only needs to be diluted without dissolving and is stable over a sufficient period of time ensures a minimum preparation time for injection. Since such a solution that only needs to be diluted without dissolving can be diluted within less than 1 minute for injection, there is no need to dilute it in advance or store it in the refrigerator.

[0017] WO 2017 / 085696 A1 discloses a propylene glycol-free formulation of melphalan containing cyclodextrin and a solvent. However, melphalan is a lyophilized powder, the diluent is accompanied by cyclodextrin and other excipients, and a reconstitution step is required prior to dilution with an isotonic solution for injection. Further, after reconstitution and further dilution, the formulation began to decompose significantly within 6 hours.

[0018] U.S. Patent No. 10,537,520 discloses a liquid parenteral formulation comprising melphalan hydrochloride, a solvent selected from dimethylacetamide, polyethylene glycol, ethanol, propylene glycol, and glycerin, and an antioxidant selected from monothioglycerol, L-cysteine, and ascorbic acid. The non-aqueous formulation was stable at 2 - 8°C for 6 months, but the total impurities increased significantly after 6 months at 25°C / 60%RH. Further, solvents such as dimethylacetamide are known to leach chemicals from infusion bags and IV infusion sets, so using such solvents is not always a good strategy.

[0019] WO 2019 / 130228 A1 discloses a non-aqueous liquid pharmaceutical composition that is ready-to-use and only needs to be diluted, comprising (i) melphalan or a pharmaceutically acceptable salt thereof, and (ii) a polyoxyethylene sorbitan fatty acid ester. WO 2019 / 130228 A1 claims that the diluted composition is stable for up to about 24 hours. The surfactant made of polyoxyethylene sorbitan fatty acid ester causes severe allergic reactions that require pretreatment with antihistamines.

[0020] U.S. Patent No. 10,682,326 discloses a non-aqueous formulation that consists essentially of melphalan and a solvent selected from dimethylacetamide, polyethylene glycol, ethanol, propylene glycol, dimethyl sulfoxide, N-methylpyrrolidone, and glycerol, which does not require dissolution and only needs dilution, and the formulation does not contain antioxidants, organic acids, and added chloride ions. U.S. Patent No. 10,682,326 claims that the formulation is stable for a long time without significant physical instability, but only provides data for 6 months under refrigerated conditions for a formulation consisting of melphalan HCl, propylene glycol, polyethylene glycol, and dehydrated ethanol. Furthermore, such a formulation was stable for only up to 4 hours at room temperature after dilution with 0.9% sodium chloride.

[0021] U.S. Patent No. 10,864,183, U.S. Patent No. 10,940,128, and U.S. Patent No. 11,020,363 disclose lyophilized compositions of melphalan having a cyclodextrin sulfoalkyl ether derivative such as sulfobutyl ether cyclodextrin. Such compositions exhibit stability up to 48 hours after reconstitution when stored under refrigerated conditions. However, the reconstituted solution is not stable for longer than 10 hours when maintained at room temperature.

[0022] U.S. Patent No. 8,410,077 and U.S. Patent No. 9,200,088 disclose compositions containing sulfalkyl ether cyclodextrin in pure form.

[0023] U.S. Patent No. 9,493,582 and U.S. Patent No. 10,040,872 disclose compositions containing a low-chloride alkylated cyclodextrin composition containing sulfalkyl ether cyclodextrin, and a process for preparing the same.

[0024] The specification of European Patent No. 0317281 B1 describes an injectable formulation of melphalan comprising, as two separate components, a) freeze-dried melphalan HCl and a matrix former such as preferably polyvinylpyrrolidone, and b) a solvent diluent containing citrate, propylene glycol, water, and ethanol. The specification of European Patent No. 0317281 B1 does not mention anything about the stability of the reconstituted melphalan product.

[0025] There is still an urgent need for a liquid formulation of melphalan that does not contain harmful solvents such as dimethylacetamide and is stable at controlled impurity levels over a long period of time.

Summary of the Invention

[0026] The present invention relates to a stable liquid pharmaceutical composition comprising, consisting of, or essentially consisting of melphalan, at least one cyclodextrin, at least one non-aqueous solvent, water and / or at least one aqueous buffer, at least one antioxidant, optionally at least one chelating agent, and optionally at least one inorganic salt.

[0027] The present invention further relates to a stable liquid pharmaceutical composition of the present invention that is ready-to-use and only needs to be diluted.

[0028] The present invention further relates to a method for treating cancers including multiple myeloma, advanced ovarian adenocarcinoma, early and advanced breast cancer, pediatric neuroblastoma, and polycythemia vera.

[0029] The present invention also relates to a method for preparing the stable liquid pharmaceutical composition of the present invention.

[0030] The present invention further relates to a dosage form containing the stable liquid pharmaceutical composition of the present invention.

Modes for Carrying Out the Invention

[0031] The present invention relates to a stable liquid pharmaceutical composition comprising, consisting of, or consisting essentially of melphalan, at least one cyclodextrin, at least one non-aqueous solvent, water and / or at least one aqueous buffer, at least one antioxidant, optionally at least one chelating agent, and optionally at least one salt.

[0032] The "stable" composition of the present invention means a pharmaceutical composition having sufficient stability at room temperature conditions to have utility as a pharmaceutical. Preferably, the "stable" composition of the present invention has sufficient stability to allow storage for 6 months or more, 1 year or more (e.g., 2 years or more, 3 years or more, 4 years or more) at preferably about 2 to 25 °C, more preferably about 2 to 10 °C, and most preferably about 2 to 8 °C, and when determined by HPLC at a wavelength of 260 nm, the undecomposed melphalan is 90% or more (e.g., 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more), and the total impurities are 6% or less (e.g., 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.1% or less). The "stable" composition of the present invention can have a melphalan potency of 90% or more (e.g., 85% or more, 90% or more, 98% or more) when stored at room temperature or refrigerated conditions.

[0033] The amount of melphalan present in the composition of the present invention can vary depending on the amount required for therapeutic administration. For example, the composition of the present invention can contain about 1 to 100 mg / mL of melphalan, such as about 2 to 75 mg / mL, about 5 to 50 mg / mL, about 10 to 25 mg / mL, about 15 to 20 mg / mL. These dosage ranges are not intended to be limiting. A person skilled in the art can similarly administer the preferred composition of the present invention in single or divided doses depending on the desired therapeutic effect. For this reason, in certain clinical situations, it may be desirable to administer the composition of the present invention to provide an initial high level of drug and then a lower maintenance dose. The term "melphalan" includes melphalan or a pharmaceutically acceptable salt or ester thereof (e.g., melphalan HCl).

[0034] The composition of the present invention also contains at least one cyclodextrin. Particularly preferred cyclodextrins are hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, or mixtures thereof. Most preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. In some embodiments, the composition of the present invention does not contain charged cyclodextrins and / or sulfoalkyl ether cyclodextrins (e.g., sulfobutyl ether cyclodextrin) or derivatives thereof, such as those disclosed in U.S. Patent No. 10864183, U.S. Patent No. 10940128, U.S. Patent No. 11020363, U.S. Patent No. 8410077, U.S. Patent No. 9200088, U.S. Patent No. 9493582, and U.S. Patent No. 10040872.

[0035] At least one cyclodextrin can be present in the composition of the present invention in any amount effective to stabilize melphalan. The cyclodextrin is typically present in the composition in an amount up to about 20% by weight (e.g., 1-15, 2-13, 3-11, 4-9, 5-7% by weight). More preferably, the cyclodextrin is present in the composition in an amount in the range of about 1-5% by weight.

[0036] The composition of the present invention also contains at least one non-aqueous solvent. The term "non-aqueous solvent" means a solvent that contains minimal or no water. The term "minimal" in the context of non-aqueous solvents means a solvent that contains less than 1.0% v / v, preferably less than 0.1% v / v, more preferably less than 0.01% v / v, and even more preferably less than 0.001% v / v of water. Particularly preferred non-aqueous solvents are polyethylene glycols (PEGs) (e.g., PEG400, PEG500, PEG600) with an average molecular weight in the range of 400 - 600 g / mol. Also preferred are compositions containing PEG400, PEG300, or a mixture thereof as the non-aqueous solvent. Propylene glycol is another example of a non-aqueous solvent that may be present in the composition of the present invention. In other embodiments, the composition of the present invention does not contain propylene glycol.

[0037] The composition of the present invention can contain at least one non-aqueous solvent up to about 100% v / v, such as up to about 95% v / v, up to about 90% v / v, up to about 75% v / v, up to about 60% v / v, or up to about 45% v / v. Preferably, the composition of the present invention contains at least one non-aqueous solvent in an amount of about 5 - 100% v / v, such as about 10 - 70% v / v, about 20 - 60% v / v, or about 30 - 50% v / v. Preferably, the composition of the present invention contains at least one non-aqueous solvent in an amount of about 30 - 95% v / v (e.g., about 40% v / v).

[0038] The composition of the present invention also contains water and / or at least one aqueous buffer. Water and / or at least one aqueous buffer can be present in the composition of the present invention in an amount in the range of about 2 - 20% v / v, preferably about 2 - 15% v / v, and most preferably about 2 - 10% v / v (e.g., 3 - 9% v / v, 4 - 8% v / v, 5 - 7% v / v). Non-limiting examples of aqueous buffers that can be used in the composition of the present invention include, for example, sodium citrate / citric acid in water, sodium acetate and acetic acid in water, etc. Most preferably, the composition of the present invention contains water in an amount of about 5% v / v.

[0039] The composition of the present invention also contains at least one antioxidant. For example, the antioxidant can be selected from the group consisting of monothioglycerol (MTG), cysteine (e.g., L-cysteine HCl), tocopherol and its derivatives (e.g., α-tocopherol, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or simply TPGS)), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), inorganic sulfates (e.g., sodium sulfate and metabisulfite), aromatic compounds (e.g., gallic acid, gentisic acid, vanillic acid), and mixtures thereof. Preferably, combinations of antioxidants such as BHA-MTG and BHA-TPGS, more preferably BHA-MTG, may be used in the composition of the present invention. The antioxidant can be present in the composition of the present invention in an amount in the range of about 0.01 to 10% by weight, preferably about 0.02 to 5% by weight, more preferably about 0.03 to 1% by weight, and even more preferably about 0.04 to 0.5% by weight. In some embodiments, the composition of the present invention does not contain monothioglycerol.

[0040] The composition of the present invention may also contain at least one chelating agent, such as ethylenediaminetetraacetic acid (EDTA) or its salts (e.g., disodium EDTA). The chelating agent can be present in the composition of the present invention in an amount in the range of about 0.01 to 0.5 mg / mL (e.g., about 0.05 to 0.4 mg / mL, about 0.1 to 0.3 mg / mL, about 0.15 to 0.2 mg / mL). Preferably, the chelating agent is the disodium EDTA salt, and the disodium EDTA salt is present in an amount in the range of 0.01 to 0.2 mg / mL, most preferably about 0.1 mg / mL.

[0041] The composition of the present invention may also contain at least one inorganic salt in a stabilizing amount, such as sodium chloride, magnesium chloride, and other pharmaceutically acceptable salts. Preferably, the inorganic salt is a chloride salt such as sodium chloride and / or magnesium chloride, most preferably magnesium chloride. The inorganic salt may be present in the composition of the present invention in an amount in the range of about 0.01 to 5% by weight, preferably about 0.1 to 2.5% by weight, more preferably about 1 to 2% by weight.

[0042] The composition of the present invention may also contain at least one pharmaceutically acceptable excipient, such as a surfactant, an antibacterial agent, a preservative, an alkalizing agent, and a pH adjuster. Exemplary surfactants include, but are not limited to, poloxamer, Tween, Span, and other fatty acid esters. Exemplary antibacterial agents include, but are not limited to, benzoic acid, methyl, and propyl paraben. Exemplary preservatives include, but are not limited to, paraben, benzoate, alcohol, and quaternary ammonium salts. Exemplary alkalizing agents and pH adjusters include, but are not limited to, sodium hydroxide, potassium hydroxide, tromethamine, lysine, arginine, glycine, meglumine, and other suitable bases. Preferably, the alkalizing agent is sodium hydroxide and is present in the composition of the present invention in an amount in the range of about 0.01 to 5% by weight, preferably about 0.1 to 4% by weight, more preferably about 1 to 3% by weight, even more preferably about 1.5 to 2% by weight.

[0043] The composition of the present invention may also contain additional solubilizing agents, such as salt-forming agents, complexing agents, polymer micelle-forming agents, and other suitable excipients that assist in solubilizing the drug.

[0044] Pharmaceutically acceptable excipients and / or solubilizing agents may be present in the composition of the present invention in amounts typically known and used in the pharmaceutical formulation art.

[0045] The liquid dosage forms according to the present invention can be "ready-to-use" or "ready-to-dilute" formulations. As used herein, the term "ready-to-use" composition refers to a composition of the present invention that avoids reconstitution and may require dilution with a suitable diluent prior to administration to a patient. As used herein, the term "ready-to-dilute" composition refers to a composition of the present invention that requires a single dilution prior to administration to a patient.

[0046] Method of treatment

[0047] The present invention also relates to a method of treating cancer, comprising administering to a mammal (e.g., human, horse, cow, sheep, dog, cat, pig) in need of treatment for cancer an effective amount of a composition of the present invention. For example, the compositions of the present invention can be used in the treatment of multiple myeloma, advanced ovarian adenocarcinoma, early and advanced breast cancer, pediatric neuroblastoma, and polycythemia vera.

[0048] The compositions of the present invention can be administered parenterally to a mammal in need thereof, such as by subcutaneous, intramuscular, or intravenous routes. The composition may be administered directly without dilution, for example, by injection as a short-term infusion. Alternatively, the composition may be further diluted with a pharmaceutically acceptable diluent (e.g., solutions of dextrose, sodium chloride, sodium lactate, amino acids, glycerol, sorbitol, dextrose, mannitol, and mixtures thereof) prior to injection. After dilution with these solutions, the infusion volume may be 500 ml or less, 75 ml or less, 50 ml or less, and the infusion time may be 20 minutes or less, 15 minutes or less, or 10 minutes or less.

[0049] The composition of the present invention may be administered alone or in combination with other therapeutic agents having similar or different biological activities. For example, the composition of the present invention may be used in combination therapy, i.e., simultaneously in a single or separate dosage form, or in separate dosage forms within seconds, minutes, hours, or days of each other. Examples of therapeutic agents used in such combination therapy include chemotherapeutic agents, immunosuppressive agents, immunostimulatory agents, antipyretics, cytokines, opioids, cytotoxic agents, nuclease-degradable compounds, radioisotopes, receptors, prodrug-activating enzymes that may be naturally occurring or produced by recombinant methods, anti-inflammatory or antirheumatic agents, antibiotics, protease inhibitors, growth factors, bone-inducing factors, analgesics, anticonvulsants, antidepressants, natural opium alkaloids, antiepileptic agents, non-selective monoamine reuptake inhibitors, anilides, diphenylpropylamine derivatives, acetic acid derivatives and related substances, platelet aggregation inhibitors other than heparin, carboxamide derivatives, propionic acid derivatives, salicylic acid derivatives, local anesthetics, topical non-steroidal anti-inflammatory compounds, opium alkaloids and derivatives, topical anesthetics, drugs used for opioid use disorder, hydantoin derivatives, olipamide derivatives, phenylpiperidine derivatives, proton pump inhibitors (e.g., any of omeprazole and / or its stereoisomers), etc., but are not limited thereto.

[0050] Preparation of the composition of the present invention

[0051] The composition of the present invention can be prepared by various techniques known in the art. For example, the method may include combining melphalan with at least one cyclodextrin, at least one non-aqueous solvent, at least one chelating agent, one stabilizing salt, and at least one antioxidant. The components of the composition of the present invention may be combined in a single solution or prepared as separate solutions that are later combined.

[0052] Dosage forms containing the composition of the present invention

[0053] The composition of the present invention can be provided by unit presentation. The unit presentation can contain a single dose or multiple doses of the composition of the present invention respectively. For example, the unit containing the composition of the present invention may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses. The unit may be provided in any suitable type of sealed container known to those skilled in the art. For example, the unit may be packaged and provided in a vial, ampoule, syringe, sealed bottle, or sealed bag made of a pharmaceutically acceptable material such as glass or a pharmaceutically acceptable plastic.

[0054] The sealed unit containing the composition of the present invention can be stable during long-term storage before administration. For example, the sealed unit containing the composition of the present invention can be stable for a long time (e.g., 1 year or more, 2 years or more, 3 years or more, 4 years or more) under refrigerated conditions (about 2 - 8°C). When determined by HPLC, the decomposition of melphalan is minimal (e.g., retaining 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more of the undecomposed melphalan), and the impurities are below the tolerance limit (e.g., total impurities are 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.1% or less).

[0055] The unit containing the composition of the present invention can be parenterally administered to a mammal in need of melphalan treatment by routes such as subcutaneous, intramuscular, or intravenous routes.

[0056] Exemplary embodiments of the present invention

[0057] E1.a) Melphalan, and b) at least one cyclodextrin, and c) at least one non-aqueous solvent, and d) water and / or at least one aqueous buffer, and e) at least one antioxidant, and f) optionally at least one chelating agent, and g) optionally at least one inorganic salt A stable liquid pharmaceutical composition comprising, consisting essentially of, or consisting of them.

[0058] E2. The stable liquid pharmaceutical composition according to E1, wherein melphalan is present in an amount in the range of 1 to 100 mg / mL in the stable liquid pharmaceutical composition.

[0059] E3. The stable liquid pharmaceutical composition according to E1, wherein the cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, and mixtures thereof.

[0060] E4. The stable liquid pharmaceutical composition according to any one of E1 to E3, wherein the cyclodextrin is hydroxylpropyl-β-cyclodextrin.

[0061] E5. The stable liquid pharmaceutical composition according to E1 or E2, which does not contain charged cyclodextrin and / or sulfoalkyl ether cyclodextrin or derivatives thereof.

[0062] E6. The stable liquid pharmaceutical composition according to any one of E1 to E5, wherein at least one cyclodextrin is present in an amount in the range of about 1 to 20% w / v in the stable liquid pharmaceutical composition.

[0063] E7. The stable liquid pharmaceutical composition according to any one of E1 to E6, wherein the non-aqueous solvent is selected from the group consisting of PEG300, 400, PEG600, and mixtures thereof.

[0064] E8. The stable liquid pharmaceutical composition according to E7, wherein the non-aqueous solvent is PEG400.

[0065] E9. The stable liquid pharmaceutical composition according to E7, wherein the non-aqueous solvent is PEG300.

[0066] The stable liquid pharmaceutical composition according to any one of E1 to E9, wherein water and / or at least one aqueous buffer is present in the stable liquid pharmaceutical composition in an amount of up to about 40% v / v.

[0067] E11. The stable liquid pharmaceutical composition according to E10, wherein water and / or at least one aqueous buffer is present in the stable liquid pharmaceutical composition in an amount of about 2 to 20% v / v.

[0068] E12. The stable liquid pharmaceutical composition according to any one of E1 to E9, wherein water is present in the stable liquid pharmaceutical composition in an amount of about 5% v / v.

[0069] E13. The stable liquid pharmaceutical composition according to E12, which does not contain any aqueous buffer other than water.

[0070] E14. The stable liquid pharmaceutical composition according to any one of E1 to E13, wherein the antioxidant is selected from the group consisting of monothioglycerol, cysteine, tocopherol or its derivatives, butylated hydroxyanisole, butylated hydroxytoluene, inorganic sulfates, aromatic compounds, and mixtures thereof.

[0071] E15. The stable liquid pharmaceutical composition according to any one of E1 to E14, wherein the antioxidant is a combination of butylated hydroxyanisole - monothioglycerol or butylated hydroxyanisole - D-α-tocopherol polyethylene glycol 1000 succinate, preferably butylated hydroxyanisole - monothioglycerol.

[0072] E16. The stable liquid pharmaceutical composition according to any one of E1 to E15, wherein the antioxidant is present in the stable liquid pharmaceutical composition in an amount in the range of about 0.04 to 0.5% w / v.

[0073] E17. The stable liquid pharmaceutical composition according to any one of E1 to E16, wherein the chelating agent is EDTA or a salt thereof.

[0074] The stable liquid pharmaceutical composition according to E17, wherein EDTA is disodium EDTA.

[0075] E19. The stable liquid pharmaceutical composition according to any one of E1 to E18, wherein the chelating agent is present in an amount in the range of about 0.01 to 0.5 mg / mL, preferably 0.01 to 0.2 mg / mL, and most preferably about 0.1 mg / mL in the stable liquid pharmaceutical composition.

[0076] E20. The stable liquid pharmaceutical composition according to any one of E1 to E19, wherein the inorganic salt is a chloride salt.

[0077] E21. The stable liquid pharmaceutical composition according to E20, wherein the chloride salt is sodium chloride and / or magnesium chloride, preferably magnesium chloride.

[0078] E22. The stable liquid pharmaceutical composition according to any one of E1 to E21, wherein the inorganic salt is present in an amount in the range of about 0.01 to 5% by weight in the stable liquid pharmaceutical composition.

[0079] E23. The stable liquid pharmaceutical composition according to any one of E1 to E22, further comprising at least one pharmaceutically acceptable excipient.

[0080] E24. The stable liquid pharmaceutical composition according to E23, wherein the pharmaceutically acceptable excipient is selected from the group consisting of at least one surfactant, at least one antibacterial agent, at least one preservative, at least one alkalizing agent and pH adjuster, and mixtures thereof.

[0081] E25. The stable liquid pharmaceutical composition according to E24, wherein the alkalizing agent is sodium hydroxide.

[0082] E26. The stable liquid pharmaceutical composition according to E24 or E25, wherein the alkalizing agent is present in an amount in the range of about 0.01 to 2% v / v in the stable liquid pharmaceutical composition.

[0083] Melphalan is present in an amount in the range of 1 to 100 mg / mL in a stable liquid pharmaceutical composition, at least one cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, and mixtures thereof, at least one non-aqueous solvent is selected from the group consisting of PEG300, 400, PEG600, and mixtures thereof, water is present, at least one antioxidant is selected from the group consisting of monothioglycerol (MTG), cysteine, tocopherol or its derivatives, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), inorganic sulfates, aromatic compounds, and mixtures thereof, at least one chelating agent is EDTA or its salt, at least one inorganic salt is a chloride salt, the stable liquid pharmaceutical composition further comprises an alkalizing agent selected from sodium hydroxide, the stable liquid pharmaceutical composition according to E1.

[0084] E28. at least one cyclodextrin is hydroxypropyl-β-cyclodextrin, at least one non-aqueous solvent is PEG-300, at least one antioxidant is a combination of butylated hydroxyanisole-monothioglycerol (BHA-MTG) or butylated hydroxyanisole-D-α-tocopherol polyethylene glycol 1000 succinate (BHA-TPGS), at least one chelating agent is disodium EDTA, at least one inorganic salt is sodium chloride and / or magnesium chloride, the stable liquid pharmaceutical composition according to E27.

[0085] E29. at least one antioxidant is a combination of BHA-MTG, At least one inorganic salt is magnesium chloride, The stable liquid pharmaceutical composition according to E28.

[0086] E30. At least one cyclodextrin is hydroxypropyl-β-cyclodextrin, At least one non-aqueous solvent is PEG-400, At least one antioxidant is a combination of butylated hydroxyanisole-monothioglycerol (BHA-MTG) or butylated hydroxyanisole-D-α-tocopherol polyethylene glycol 1000 succinate (BHA-TPGS), At least one chelating agent is disodium EDTA, At least one inorganic salt is sodium chloride and / or magnesium chloride, The stable liquid pharmaceutical composition according to E27.

[0087] E31. At least one antioxidant is a combination of BHA-MTG, At least one inorganic salt is magnesium chloride, The stable liquid pharmaceutical composition according to E30.

[0088] E32. About 1 to 5% by weight of at least one cyclodextrin, About 30 to 95% v / v of at least one non-aqueous solvent, About 5% v / v of water, About 0.04 to 0.5% by weight of at least one antioxidant, About 0.1 mg / mL of at least one chelating agent, About 1 to 2% by weight of at least one inorganic salt, About 1.5 to 2% by weight of an alkalizing agent And the stable liquid pharmaceutical composition according to any one of E27 to E31.

[0089] A stable liquid pharmaceutical composition according to any one of E27 to E32, which does not contain charged cyclodextrin and / or sulfoalkyl ether cyclodextrin or a derivative thereof.

[0090] E34. A stable liquid pharmaceutical composition according to any one of E1 to E33, wherein the total impurities resulting from the decomposition of melphalan in the stable liquid pharmaceutical composition are 6% or less in the stable liquid pharmaceutical composition over one year or more at about 2 to 8 °C as determined by HPLC at a wavelength of 260 nm.

[0091] E35. The sealed unit dosage of the stable liquid pharmaceutical composition according to any one of E1 to E34.

[0092] E36. A method for treating cancer, comprising administering, consisting essentially of, or consisting of an effective amount of the stable liquid pharmaceutical composition according to any one of E1 to E35 to a mammal in need of treatment for cancer.

[0093] E37. The method according to E36, wherein the cancer is selected from the group consisting of multiple myeloma, advanced ovarian adenocarcinoma, early and advanced breast cancer, pediatric neuroblastoma, and polycythemia vera.

[0094] E38. The method according to E36 or E37, wherein the stable liquid pharmaceutical composition is not diluted before administration to a mammal.

[0095] E39. The method according to E36 or E37, wherein the stable liquid pharmaceutical composition is diluted with at least one pharmaceutically acceptable diluent before administration.

[0096] E40. The method according to any one of E36 to E39, wherein the stable liquid pharmaceutical composition is administered parenterally.

[0097] E41. The method according to E40, wherein the parenteral administration is by subcutaneous, intramuscular, or intravenous route.

[0098] Experiment

[0099] Materials and Characterization Evaluation:

[0100] Melphalan was obtained from Apothecon Pharmaceuticals Pvt.Ltd, India. PEG400 (USP / NF) was obtained from Merck. PEG300 and propylene glycol (PG) were obtained from Sigma Aldrich (for analysis or meeting USP specifications). Tocopherol, vitamin E TPGS, and monothioglycerol, cysteine hydrochloride, magnesium chloride were of analytical grade and purchased from Sigma-Aldrich. Hydroxypropyl-β-cyclodextrin (HPβCD) (Kleptose HPB, parenteral grade) was obtained from Roquette, Germany.

[0101] The stability of melphalan formulations was evaluated using the HPLC method, which employed the gradient elution mentioned in Table 1 below. Chromatography Conditions: Related Substances and Assay: Column: 150×4.6 mm, 5 μm (Avantor ACE) Flow rate: 1.5 mL / min Runtime: 35 min Injection volume: 20 μl Autosampler: 25 °C Needle wash: Methanol Column oven temperature: 25 °C Wavelength: 260 nm Mobile phase A: A mixture of 5 volumes of acetonitrile for chromatography and 95 volumes of water containing 0.01% v / v triethylamine, 0.05% m / m ammonium acetate, and 0.05% v / v glacial acetic acid. Mobile phase B: A mixture of 40 volumes of water containing 0.01% v / v triethylamine, 0.05% m / m ammonium acetate, and 0.05% v / v glacial acetic acid and 60 volumes of acetonitrile. Diluent: Methanol Gradient:

Table 1

[0102] Example 1: Melphalan preparation containing different non-aqueous solvents

[0103] First, formulations T-01 to T-03 were prepared by mixing all excipients and solvents and subjecting them to sonication to obtain a clear solution. Melphalan was added to the mixture of solvent and excipient and sonicated to obtain a clear solution. Table 2 shows the composition of formulations T-01 to T-03 and their stability. Furthermore, Table 2 shows the stability of these formulations at the initial stage, at 40 °C / 75% RH for 8 days, and for 4 months and 13 days, and at 25 °C / 60% RH for 2 months and 22 days, and for 6 months, as determined by HPLC.

Table 2

[0104] After 6 months at 25 °C / 60% RH, the titer decreases to less than 90% of the initial assay value in all formulations. However, those containing propylene glycol and PEG-300 were slightly better.

[0105] Example 2: Formulations containing PEG-300 or propylene glycol with and without water

[0106] For formulations F-10 and F-11 (Table 3), first MTG, TPGS, and hydroxypropyl-β-cyclodextrin (HPβCD) were dissolved in PEG-300, followed by the addition of melphalan. The mixture was sonicated to obtain a clear solution. For formulation F-12 (Table 3), first sodium chloride and HPβCD were dissolved in water, and then mixed with a PEG-300 solution containing MTG and TPGS. Finally, melphalan was added to the mixture and sonicated to obtain a clear solution. The stability of formulations F-10, F-11, and F-12 at 3 months (25 °C / 60% RH) was determined by HPLC (Table 4). Surprisingly, when water was included, the impurities decreased significantly by 30 - 40%, and the number of impurities exceeding 0.5% decreased from 3 in the formulation without water to 1 after the addition of water.

Table 3

Table 4

[0107] In formulation F-15 (Table 5), first, sodium chloride and HPβCD were dissolved in water, and MTG-TPGS was dissolved in propylene glycol (PG). The aqueous solution and the PG solution were mixed, and then melphalan HCl was added. The mixture was sonicated to obtain a clear solution. As demonstrated in Table 6, when water was included in the PG-based formulation, the stability was not improved as observed in formulation F-12 containing PEG-300. Thus, it is recognized that the combination of the solvent and water is favorable for stability and not simply by including water in the formulation.

Table 5

Table 6

[0108] Example 3A: Formulations Containing EDTA

[0109] Using the same process as used in Example 2 to prepare formulation F-12, formulation F-51 (Table 7) was prepared. The stability of formulation F-51 at initial (T0), 3 months and 6 months at 25°C / 60% RH, 6 months at 15°C (Table 8), and 1 month at 40°C / 75% RH (Table 9) was determined by HPLC.

Table 7

Table 8

Table 9

[0110] Unexpectedly, the stability was significantly improved when EDTA was included. Formulation F-51 containing EDTA had about 2.0% impurities after 3 months at 25°C / 60%RH, while formulation F-12 without EDTA had 3.85%. Formulation F-51 was found to be stable even after 6 months while maintaining an assay and impurity profile equivalent to 3 months. No further degradation was observed after 3 months. Formulation F-51 was not very stable at 40°C / 75%RH. Based on this and the improved stability at 25°C / 60%RH, this composition of the present invention can be sufficiently compatible with refrigerated conditions. However, this formulation became turbid after storage under refrigerated conditions and required about 60 minutes to become transparent.

[0111] Example 3B: Formulations Containing EDTA and Magnesium Chloride

[0112] For formulations 40013-137 and 40013-138 (Table 10), first magnesium chloride (MgCl2) and HPβCD were dissolved in water, and then mixed with a PEG-300 solution containing MTG and TPGS. Finally, melphalan was added to the mixture and sonicated to obtain a clear solution. The stability of formulations 40013-137 and 40013-138 at 40°C / 75%RH for 3 months was determined by HPLC (Table 11). [Table 10] [Table 11]

[0113] From the results of formulations 40013-137 and 40013-138 in Table 11, it was found that magnesium chloride has a better stabilizing effect than NaCl. Tables 10 and 11 also demonstrate that the water concentration is important, specifically that a larger amount of water (8% v / v) increased the degradation. Water at 5% or less increases the stability of melphalan.

[0114] Example 4: Formulations Containing Cysteine

[0115] Formulations 40013-078A and 40013-078B (Table 12) were prepared by dissolving L-cysteine, NaOH, NaCl, and cyclodextrin in water and dissolving TPGS in PEG-400. The aqueous phase and PEG400 were mixed. Finally, melphalan was added to the mixture and sonicated until a clear solution was obtained. For formulations 40013-83 and 40013-91 (Table 12), the aforementioned procedure (the same as 40013-137 to 138) was used except for the addition of TPGS. For formulations 40013-83 and 40013-91, TPGS was not added, and for formulation 40013-91, butylated hydroxyanisole (BHA) was dissolved in PEG-400 instead of TPGS. The stability of formulations 40013-078A and 40013-078B at the initial stage, at 70 °C for 5 hours, and at 40 °C / 75% RH for 1 month was determined by HPLC (Tables 13 and 14).

Table 12

Table 13

Table 14

[0116] When cysteine HCl was included in the composition of the present invention, a favorable effect on stability was achieved. Formulations 40013-078A and 40013-078B showed excellent stability after 1 month at 40 °C / 75% RH, with impurities being about 0.8 to 0.9%, while in formulation F-51 without cysteine, it exceeded 4%.

[0117] However, formulations 40013-078A and 40013-078B could not maintain physical stability after one month. The solutions showed precipitation after two months at 40 °C / 75% RH and further after 2.5 - 3.0 months at 25 °C / 60% RH. Similarly, formulations 40013-083 and 40013-091 also precipitated within one month at 40 °C / 75% RH, and the stability test was not conducted even at the one-month time point.

[0118] Formulation 40013-099 (Table 15) was prepared by dissolving L-cysteine, NaOH, NaCl, and cyclodextrin in water and dissolving TPGS in PEG-400. The aqueous phase and PEG400 were mixed. Finally, melphalan was added to the mixture and sonicated until a clear solution was obtained.

[0119] Surprisingly, formulation 40013-099 was similar to formulation 40013-078B and was found to be stable even after six months under three conditions, namely, six months at 40 °C / 75% RH, nine months at 30 °C / 65% RH, and nine months at 25 °C / 60% RH (Table 16). This may be due to the source of PEG400 used in the formulation and the pH of PEG400 (Table 17). However, the initial pH of the final formulation did not change between formulations 40013-078B and 40013-099, and the values were 2.26 and 2.29. In addition to the pH of PEG400, other factors such as polymer molecular weight and peroxide content may play a role, and the variability of these parameters between PEGs from different manufacturers contributes to the various physical stabilities of the formulations. The effect of pH was also confirmed when a larger amount of NaOH was added to formulations similar to 40013-078B and 40013-099 to bring the pH to 3.0, but the formulations showed precipitation. Cysteine precipitated when the pH increased from 2.2 to 3.0, which also occurred before the addition of melphalan. [Table 15] [Table 16]

Table 17

[0120] Example 5: Melphalan formulation containing BHA as an antioxidant but not containing cysteine

[0121] First, Formulations 40013-118 and 40013-144 were prepared by dissolving NaOH, MagCl2, ETDA, and HPβCD in water (Table 18), and BHA and MTG were dissolved in PEG-400. Both the aqueous solution and the PEG-400 solution were mixed, and finally melphalan HCl was added to the mixture and sonicated until a clear solution was obtained.

Table 18

Table 19

[0122] The stability of Formulations 40013-118 and 40013-144 was determined by HPLC using the conditions of 40°C / 75% RH for 3 months (Table 19). The formulations containing the antioxidant combination of BHA / MTG showed better stability in terms of impurities and assay. Also, as the BHA concentration increased, the stability improved.

[0123] Example 6: Effect of alkalinity on formulations containing BHA-MTG

[0124] First, Formulations 40013-153 and 40013-154 (Table 20) were prepared by dissolving NaOH, MagCl2, ETDA, and HPβCD in water, and BHA and MTG were dissolved in PEG-400. Both the aqueous solution and the PEG-400 solution were mixed, and finally melphalan HCl was added to the mixture and sonicated until a clear solution was obtained. The stability of Formulations 40013-153 and 40013-154 was determined by HPLC using the conditions of 40°C / 75% RH for 3 months (Table 21).

Table 20

Table 21

[0125] From the comparative data (Table 21) of Formulations 40013-153 and 40013-154 containing 0.4 and 0.5 mg / mL of NaOH respectively, it was found that Formulation 40013-153 containing a smaller amount of NaOH was better in terms of stability. Since the difference in the amount of NaOH was only 0.1 mg and the resulting difference in pH was 0.07 units, the total impurities were significantly reduced to 0.33%.

[0126] Formulation 40013-144 containing more BHA (1 mg / ml) in Example 5 showed more degradation than Formulation 40013-153 containing less BHA (0.4 mg / mL of BHA) (Table 19). This may be due to the larger amount of melphalan HCl in Formulation 40013-153. A larger amount of melphalan HCl lowers the pH, with Formulation 40013-153 having a pH of 2.54 while Formulation 40013-144 has a pH of 2.90. Therefore, the pH of the formulation has a great impact on stability.

[0127] Example 7: Formulation containing BHA with 5% water

[0128] First, Formulation 40013-160 was prepared by dissolving NaOH, MagCl2, ETDA, and HPβCD in water (Table 22), and BHA and TPGS were dissolved in PEG-400. Both the aqueous solution and the PEG-400 solution were mixed, and finally melphalan HCl was added to the mixture and sonicated until a clear solution was obtained. Formulation 40013-161 was prepared in the same manner as described above, except that MTG was used instead of TPGS (Table 22). The stabilities of Formulations 40013-160 and 40013-161 were determined by HPLC using conditions of 40°C / 75% RH for 2 months and 40°C / 75% RH for 3 months respectively (Table 23).

Table 22

Table 23

[0129] When the water in Formulations 40013 - 160 and 40013 - 161 was reduced to 5% v / v, the stability was improved (Table 23). The stability was significantly improved by both the increase in BHA and the decrease in water (Table 23). Formulation 40013 - 161 showed the lowest percentage of impurities (2.37%) after 3 months at 40 °C / 75% RH compared to all other formulations (Formulations 40013 - 144, 40013 - 153, and 40013 - 154) tested under these same conditions.

[0130] The combination of BHA - MTG functioned better than BHA - TPGS. The amount of impurities in Formulation 40013 - 160 was the same at 2 months compared to the 3 - month data at 40 °C / 75% RH (Table 23). From this comparison result, it is suggested that the combination of BHA - MTG functioned relatively better than BHA - TPGS because the 2 - month data of Formulation 40013 - 160 was equal to the 3 - month data of Formulation 40013 - 161.

[0131] Example 8: Formulations Containing BHA - MTG with Different Concentrations of EDTA

[0132] First, Formulations 40013 - 161 and 40013 - 162B were prepared (Table 24) by dissolving NaOH, MagCl2, ETDA, and HPβCD in water. BHA and MTG were dissolved in PEG - 400. Both the aqueous solution and the PEG - 400 solution were mixed, and finally melphalan HCl was added to the mixture and sonicated until a clear solution was obtained. The stability of Formulations 40013 - 161 and 40013 - 162B was determined by HPLC using conditions of 40 °C / 75% RH for 4 months (Table 25).

Table 24

Table 25

[0133] When the EDTA concentration was decreased from 0.1 to 0.05 mg / mL, the impurities moderately increased by about 0.3%. Therefore, since formulation 40013-162B containing 0.05 mg / mL of EDTA had slightly more impurities, 0.10 mg / mL of EDTA was considered to be optimal.

[0134] Conclusion

[0135] In summary, melphalan has limited stability in organic solvents even when using antioxidants. Surprisingly, adding water had a favorable effect on stability. Including EDTA further significantly improved stability and the impurities were reduced by half (e.g., formulation F-12 vs. F-51).

[0136] The chloride ion source had a favorable effect. Magnesium chloride was more effective in stabilizing the product than NaCl.

[0137] The combination of MTG-TPGS-MgCl2 stabilized melphalan and was suitable for storage in a refrigerator. However, turbidity appeared after refrigeration and it took 60 minutes after thawing to become clear.

[0138] Including cysteine improved chemical stability, but precipitation occurred after several months, so physical stability became an issue. A low pH of about 2 was required, but this is physiologically incompatible.

[0139] BHA-MTG or BHA-TPGS provided greater stability, and BHA-MTG showed a better stabilizing effect than BHA-TPGS. Also, about 5% v / v of water provided higher stability.

[0140] Finally, an EDTA concentration of 0.10 mg / mL showed a better stabilizing effect.

Claims

1. a) melphalan, and b) at least one cyclodextrin, and c) at least one non-aqueous solvent, and d) water and / or at least one aqueous buffer, and e) at least one antioxidant, and f) optionally at least one chelating agent, and g) optionally at least one inorganic salt comprising a stable liquid pharmaceutical composition.

2. The composition according to claim 1, wherein the melphalan is present in the composition in an amount in the range of 1 to 100 mg / mL.

3. The composition according to claim 1, wherein the cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, and mixtures thereof.

4. The composition according to claim 1, wherein the cyclodextrin is hydroxylpropyl-β-cyclodextrin.

5. The composition according to any one of claims 1 to 4, which does not contain charged cyclodextrin and / or sulfoalkyl ether cyclodextrin or derivatives thereof.

6. The composition according to claim 1, wherein the at least one cyclodextrin is present in the composition in an amount in the range of about 1 to 20% w / v.

7. The composition according to any one of claims 1 to 4, wherein the non-aqueous solvent is selected from the group consisting of PEG300, 400, PEG600, and mixtures thereof.

8. The composition according to claim 7, wherein the non-aqueous solvent is PEG400.

9. The composition according to claim 7, wherein the non-aqueous solvent is PEG300.

10. The composition according to any one of claims 1 to 4, wherein the water and / or at least one aqueous buffer is present in the composition in an amount of up to about 40% v / v.

11. The composition according to claim 10, wherein the water and / or at least one aqueous buffer is present in the composition in an amount in the range of about 2 to 20% v / v.

12. The composition according to any one of claims 1 to 4, wherein the water is present in the composition in an amount of about 5% v / v.

13. The composition according to any one of claims 1 to 4, wherein the antioxidant is selected from the group consisting of monothioglycerol (MTG), cysteine, tocopherol or its derivatives, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), inorganic sulfates, aromatic compounds, and mixtures thereof.

14. The composition according to claim 13, wherein the antioxidant is a combination of butylated hydroxyanisole - monothioglycerol (BHA - MTG) or butylated hydroxyanisole - D-α-tocopherol polyethylene glycol 1000 succinate (BHA - TPGS).

15. The composition according to claim 1, wherein the antioxidant is present in an amount in the range of about 0.04 to 0.5% w / v in the composition.

16. The composition according to any one of claims 1 to 4, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA) or a salt thereof.

17. The composition according to claim 16, wherein the EDTA is disodium EDTA.

18. The composition according to claim 1, wherein the chelating agent is present in an amount in the range of about 0.01 to 0.5 mg / mL in the composition.

19. The composition according to any one of claims 1 to 4, wherein the inorganic salt is a chloride salt.

20. The composition according to claim 19, wherein the chloride salt is sodium chloride and / or magnesium chloride.

21. The composition according to claim 20, wherein the chloride salt is magnesium chloride.

22. The composition according to claim 1, wherein the inorganic salt is present in an amount in the range of about 0.01 to 5% by weight in the composition.

23. The composition according to any one of claims 1 to 4, further comprising at least one pharmaceutically acceptable excipient.

24. The composition according to claim 23, wherein the pharmaceutically acceptable excipient is selected from the group consisting of at least one surfactant, at least one antibacterial agent, at least one preservative, at least one alkalizing agent and pH adjuster, and mixtures thereof.

25. The composition according to claim 24, wherein the alkalizing agent is sodium hydroxide.

26. The composition according to claim 24 or 25, wherein the alkalizing agent is present in an amount in the range of about 0.01 to 2% v / v in the composition.

27. The melphalan is present in the composition in an amount in the range of 1 to 100 mg / mL, the at least one cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, and mixtures thereof, the at least one non-aqueous solvent is selected from the group consisting of PEG300, 400, PEG600, and mixtures thereof, water is present, the at least one antioxidant is selected from the group consisting of monothioglycerol (MTG), cysteine, tocopherol or its derivatives, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), inorganic sulfates, aromatic compounds, and mixtures thereof, the at least one chelating agent is EDTA or a salt thereof, the at least one inorganic salt is a chloride salt, the composition further comprises an alkalizing agent selected from sodium hydroxide, The composition according to claim 1.

28. the at least one cyclodextrin is hydroxypropyl-β-cyclodextrin, the at least one non-aqueous solvent is PEG-300, the at least one antioxidant is a combination of butylated hydroxyanisole-monothioglycerol (BHA-MTG) or butylated hydroxyanisole-D-α-tocopherol polyethylene glycol 1000 succinate (BHA-TPGS), the at least one chelating agent is disodium EDTA, the at least one inorganic salt is sodium chloride and / or magnesium chloride, The composition according to claim 27.

29. the at least one antioxidant is a combination of BHA-MTG, the at least one inorganic salt is magnesium chloride, The composition according to claim 28.

30. the at least one cyclodextrin is hydroxypropyl-β-cyclodextrin, the at least one non-aqueous solvent is PEG-400, the at least one antioxidant is a combination of butylated hydroxyanisole-monothioglycerol (BHA-MTG) or butylated hydroxyanisole-D-α-tocopherol polyethylene glycol 1000 succinate (BHA-TPGS), The at least one chelating agent is disodium EDTA, The at least one inorganic salt is sodium chloride and / or magnesium chloride, The composition according to claim 27.

31. The at least one antioxidant is a combination of BHA-MTG, The at least one inorganic salt is magnesium chloride, The composition according to claim 30.

32. About 1 to 5% by weight of the at least one cyclodextrin; About 30 to 95% v / v of the at least one non-aqueous solvent; About 5% v / v of the water; About 0.04 to 0.5% by weight of the at least one antioxidant; About 0.1 mg / mL of the at least one chelating agent; About 1 to 2% by weight of the at least one inorganic salt; About 1.5 to 2% by weight of the alkalizing agent The composition according to any one of claims 27 to 31, comprising

33. The composition according to any one of claims 27 to 31, which does not contain charged cyclodextrin and / or sulfoalkyl ether cyclodextrin or derivatives thereof.

34. When determined by HPLC at a wavelength of 260 nm, the total impurities resulting from the decomposition of melphalan in the composition are 6% or less in the composition at about 2 to 8 °C over one year or more, for the composition according to any one of claims 1 to 4.

35. The sealed unit dosage of the composition according to any one of claims 1 to 4.

36. A method for treating cancer, comprising administering an effective amount of the composition according to any one of claims 1 to 4 to a mammal in need of treatment for cancer.

37. The method according to claim 36, wherein the cancer is selected from the group consisting of multiple myeloma, advanced ovarian adenocarcinoma, early and advanced breast cancer, pediatric neuroblastoma, and polycythemia vera.

38. The method according to claim 36, wherein the composition is not diluted before administration to the mammal.

39. The method according to claim 36, wherein the composition is diluted with at least one pharmaceutically acceptable diluent before administration.

40. The method according to claim 36, wherein the composition is administered parenterally.

41. The method according to claim 40, wherein the parenteral administration is by subcutaneous, intramuscular, or intravenous route.

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