Liquid formulations of lurbinectedin

Abstract

A ready to use or ready to dilute stable liquid lurbinectedin pharmaceutical composition includes lurbinectedin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvent system comprising at least one organic solvent, wherein the liquid lurbinectedin pharmaceutical composition is stable without the need for lyophilization.

Description

TITLE OF THE INVENTIONLIQUID FORMULATIONS OF LURBINECTEDINFIELD OF THE INVENTION

[0001] The present invention relates to a liquid pharmaceutical formulation of lurbinectedin. Particularly, the present invention relates to a ready to use or ready to dilute liquid formulation of lurbinectedin, which does not require lyophilization for long term storage.BACKGROUND OF THE INVENTION

[0002] Lurbinectedin (Brand Name: ZEPZELCA®) was first approved by USFDA in 2020 for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. The chemical name of Lurbinectedin is(1' R,6R,6aR,7R, 13S, 14S, 16R)-8, 14-dihydroxy-6',9-dimethoxy-4, 10,23- trimethy 1-19-oxo-2',3',4',6,7,9' 12, 13, 14, 16-decahydro-6aH-spiro[7, 13-azano- 6,16-(epithiopropanooxymethano)[1 ,3]- dioxolo[7,8]isoquinolino[3,2- b][3]benzazocine-20,1' -pyrido[3,4-b]indol]-5-yl acetate. The chemical structure of Lurbinectedin is depicted below as compound of formula-l:Formula-l Lurbinectedin

[0003] The molecular formula of Lurbinectedin is C41H44N4O10S and the molecular weight of Lurbinectedin is 784.87 g / mol.

[0004] International PCT Publication No. WO2021098992A1 discloses the lyophilized formulation of lurbinectedin, which comprises of 4 mg lurbinectedin, 22.1 mg lactic acid, 5.1 mg sodium hydroxide and 800 mg sucrose. The composition is packaged in a 30 ml vial. For patient dosing, this composition must be reconstituted in 8 mL water, to yield a solution containing 0.5 mg / ml lurbinectedin. The lyophilized solid formulation of lurbinectedin can be stored for up to 36 months or more at 5° C ± 3° C, during which time the lurbinectedin retains its therapeutic effectiveness and exhibits minimal chemical degradation. This reference further discloses that after 24 months or 36 months of storage, the amount of Impurity D (lurbinectedin degradation product resulting from deacetylation of lurbinectedin) present in the composition is not more than 0.8% wt. / wt of lurbinectedin and the stored formulation does not contain more than 2.0% (area or wt / wt) total degradation products.

[0005] The main drawback associated with above mentioned reference are:• A requirement of lyophilization of an aqueous solution of the drug, where the drug is not very stable in the aqueous solution and lyophilization process is a costly and time-consuming technique; and• Lyophilized lurbinectedin may change the solid form upon storage and that can have different impurity profile, as well as solubility properties.

[0006] International PCT Publication No. WO 2024121864A1 discloses the ready to use injectable formulation of Lurbinectedin. The formulation includes a solvent selected from ethanol, dimethyl sulfoxide, and pharmaceutically acceptable excipient or adjuvant and optionally, a pharmaceutically acceptable stabilizing agent. The main solvents used in the injectable formulation are ethanol and dimethyl sulfoxide.

[0007] The main drawback associated with above mentioned reference are:• The injectable formulations of Lurbinectedin disclosed are reported to have stability for a short time (stability data only for 3 months in the application); and• The use of solvents like ethanol may cause pain and hemolysis in the patients. Furthermore, use of ethanol as solvent requires slower administration of injection.

[0008] The currently approved and marketed drug product ZEPZELCA® for injection contains 4 mg of lurbinectedin as a sterile, preservative-free, white to off-white lyophilized powder in a single-dose vial for reconstitution prior to intravenous infusion. It must be reconstituted with 8 ml of water for injection before administering to a patient. However, this reconstituted solution is only stable for a short time and must be used within 24 hours.

[0009] The stability of Lurbinectedin in water is measured in hours. Therefore, Lurbinectedin is not suitable for long-term storage in an aqueous solution form.

[0010] There exists a need for liquid lurbinectedin formulations that have good stability and impurity profile and ease of use as compared to the previously disclosed formulations. It is desired to provide a stable liquid lurbinectedin formulation that does not require lyophilization. In particular, it is desired to have liquid lurbinectedin formulations that exhibit long term stability under easily achievable storage conditions such as 2-8°C in a refrigerator. It is also desired that the liquid lurbinectedin formulation be easily manufactured by normal sterile manufacturing techniques using a readily available and stable form of lurbinectedin or its pharmaceutically acceptable salt(s). Hence there is a need to develop a liquid formulation of lurbinectedin, which is simple, cost effective and commercially viable at large scale.

[0011] The presently disclosed liquid formulation of lurbinectedin fulfills the above-mentioned objectives.SUMMARY OF THE INVENTION

[0012] Accordingly, the present invention provides a novel liquid formulation of lurbinectedin, including: a) lurbinectedin or its pharmaceutically acceptable salt; and b) at least one pharmaceutically acceptable solvent.

[0013] In some embodiment of the present invention, the liquid formulation of lurbinectedin is stable in the liquid form without the need for lyophilization.

[0014] Other features and advantages of the present invention will become apparent from the following more detailed description, which illustrates, by way of example, the principle of the invention.DETAILED DESCRIPTION OF THE INVENTION

[0015] The following detailed description is merely exemplary in nature and is not intended to limit the disclosed invention described herein. Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description.

[0016] The terms “comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited.

[0017] It is noted that, as used in the specification and the claims, the singular form “a,” “an,” and “the” comprises plural referents unless the context clearly indicates otherwise. For example, reference to a component in the singular is intended to comprise a plurality of components.

[0018] The terms "having" and "including" are to be construed as open ended. All ranges recited herein include the endpoints, including those that recite arange between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

[0019] The term “about” is to be construed as modifying a term or value such that it is not an absolute. This term will be defined by the circumstances. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value. In general, this term used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art. In general, such interval of accuracy is ±10%. Thus, “about ten” means 9 to 11 . All numbers in this description indicating amounts, ratios of materials, physical properties of materials, and / or use are to be understood as modified by the word “about,” except as otherwise explicitly indicated.

[0020] The term “essentially free” means here less than 5 wt. %, preferably less than 3 wt. % and in particular less than 1 wt. %, based on the total weight of the composition.

[0021] As used herein, "room temperature" or normal storage conditions, which mean storage in a dry, clean, well-ventilated area at room temperatures between 15° to 25°C (59°-77°F) as defined by USP.

[0022] The term “ready-to-use” refers to a ready-to-administer formulation that includes Lurbinectedin in dissolved or solubilized form and / or is intended to be used as such or upon further dilution in intravenous diluents e.g., water for injection or other suitable diluent, before use by the designated route. This term also refers to a Lurbinectedin formulation that is ready to administer to a patient without the need for reconstitution. The term “ready-to-dilute” refers to formulation that includes Lurbinectedin in solubilized form and / or is intendedto be used as such or upon further dilution in intravenous diluents e.g., water for injection or other suitable diluent, before use by the designated route.

[0023] In one embodiment of the present invention, a stable liquid formulation of lurbinectedin including lurbinectedin or its pharmaceutically acceptable salt; and a pharmaceutically acceptable solvent system comprising at least one pharmaceutically acceptable solvent.

[0024] Any lurbinectedin compound referred to herein is intended to represent hydrates, solvates, amorphous and crystalline or partially crystalline forms, and mixtures of thereof when such forms exist in the medium.

[0025] Lurbinectedin may be provided in suitable concentration sufficient to treat a desired condition. In some embodiment, lurbinectedin is provided in a concentration from about 0.5 mg / ml to about 25 mg / ml. In some embodiment, the liquid formulation has a concentration of lurbinectedin of less than about 5 mg / ml. In some embodiment, the liquid formulation has a concentration of lurbinectedin of less than about 10 mg / ml.

[0026] In some embodiment, the liquid formulation of lurbinectedin is stable for storage up to 6 months or more without the need for lyophilization.

[0027] The pharmaceutically acceptable suitable solvent may be selected from N,N, dimethylacetamide, glycerol, N-methyl-2-pyrrolidone, polyethylene glycol, propylene glycol, water and mixtures thereof.

[0028] In some embodiments, the pharmaceutically acceptable solvent system is comprised of N, N-dimethylacetamide and glycerol. The pharmaceutically acceptable solvent system may comprise about 5% v / v of glycerol to about 60% v / v of glycerol. Preferably, glycerol is about 10% v / v to about 50% v / v; more preferably, glycerol is about 15% v / v to about 40% v / v. In one embodiment, glycerol is about 15% v / v in the pharmaceutically acceptable solvent system; and another embodiment, glycerol is about 28% v / v in thepharmaceutically acceptable solvent system, with the remaining solvent being N, N- dimethylacetamide.

[0029] In some embodiments, the pharmaceutically acceptable solvent system is comprised of N, N-dimethylacetamide and water. The pharmaceutically acceptable solvent system may comprise about 1 % v / v of water to about 30% v / v of water. Preferably, water is about 2% v / v to about 25% v / v; more preferably, water is about 3% v / v to about 15% v / v. In one embodiment, water is about 3% v / v in the pharmaceutically acceptable solvent system; and another embodiment, water is about 10% v / v in the pharmaceutically acceptable solvent system, with the remaining solvent being N, N- dimethylacetamide.

[0030] In further embodiments, the pharmaceutically acceptable solvent system is comprised of polyethylene glycol and propylene glycol. The pharmaceutically acceptable solvent system may comprise from about 5% v / v to about 30% v / v of polyethylene glycol and from about 70% v / v to about 95% v / v of propylene glycol. Preferably, polyethylene glycol is about 80% v / v to about 95% v / v and propylene glycol is about 5% v / v to about 20% v / v. In one embodiment, polyethylene glycol is about 10% v / v in the pharmaceutically acceptable solvent system with the remaining solvent being propylene glycol.

[0031] In certain embodiments, the liquid formulation of lurbinectedin may comprise less than 5% v / v of ethanol. In some embodiment, the liquid formulation of lurbinectedin may be essentially free of ethanol.

[0032] The term “% v / v” (also written as “v / v %”) means the volume of a solute in the total volume of solution. As one skilled in the art would understand, when the solute is a liquid sometimes, it is convenient to express its concentration in volume / volume percent. The calculation of “% v / v” is:Concentration solute (v / v %)

[0033] The liquid formulation of lurbinectedin may further comprise pharmaceutically acceptable excipients, including but not limited to, one or more preservatives, antioxidants, stabilizing or bulking agents, and pH adjusting agents or buffers.

[0034] Pharmaceutically acceptable preservatives may include methyl paraben, propyl paraben, benzoic acid, sodium benzoate, sorbic acid, benzothonium chloride, benzalkonium chloride and any combination thereof.

[0035] Example of stabilizing / bulking agents include but are not limited to meglumine, cysteine, methionine, glucose, fructose, mannitol, glycine, sucrose, lactose, arginine, and combination thereof. In some embodiments, sucrose is used in the formulation.

[0036] The addition of an antioxidant may further contribute to the stabilization of the lurbinectedin-containing composition. Suitable antioxidants include, but not are limited to, monothioglycerol, thioglycerol, ascorbic acid, lipoic acid, propyl gallate, methionine, cysteine, metabisulfites, butylated hydroxyltoluene, sodium formaldehyde sulfoxylate, phenol-containing aromatic and aliphatic compounds, and dihydrolipoic acid. One or more antioxidants may be used in single lurbinectedin-containing formulation. In some embodiment, the antioxidant used in the pharmaceutical composition of the present invention is a stabilizing amount of monothioglycerol. The term “stabilizing amount” generally refers to those amounts which increase or enhance the stability of the lurbinectedin in the compositions described herein. The antioxidant may be in an amount of from about 0.2 % to about 2.0 %, preferably from about 0.25% to about 1 .0% by weight of the composition.

[0037] Examples of pharmaceutically acceptable pH adjusting agents / buffers include hydrochloric acid, boric acid, citric acid, acetic acid, orthophosphoric acid, succinic acid, sodium hydroxide, potassium hydroxide, potassium carbonate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine,sodium carbonate, sodium bicarbonate, triethanolamine, and combinations thereof. In some embodiments, lactic acid is used as a buffer agent.

[0038] The formulation has a pH value from about 3 to about 9. In some embodiments, the pH range is from about 3.5 to about 7. In other embodiments, the pH is about 4-6.

[0039] The inventive liquid formulations of lurbinectedin are storage-stable and ready-to-use or ready-to-dilute without requiring any additional reconstitution step at the time of administration.

[0040] Surprisingly, the inventors of the present invention have observed that there are many advantages of a solution formulation of lurbinectedin as opposed to a lyophilized formulation of lurbinectedin. The stability of Lurbinectedin in water is measured in hours, and an aqueous solution of lurbinectedin is therefore not suitable for long-term storage. The present inventors have found that a solution of lurbinectedin in a mixture of pharmaceutically acceptable solvents is stable for long term storage. The main advantage of such liquid formulation of lurbinectedin is that it does not require lyophilization to manufacture the product. Lyophilization on a commercial scale requires specialized equipment and precise temperature and vacuum controls during manufacture. As the drug is already in solution, it is easy to dilute it for administration to patients. Another benefit is that several polymorphic forms of lurbinectedin with varying physical properties such melting point, solubility and stability are known. There is no possibility of change in polymorphic form of lurbinectedin in solution formulation.

[0041] To evaluate the stability of the liquid Lurbinectedin pharmaceutical compositions, such compositions are stored at 2-8° C. In some embodiments, the liquid pharmaceutical composition of Lurbinectedin contains no more than 2.0% of total impurities after it has been stored at 2-8° C for two months. In additional embodiments, the liquid pharmaceutical composition ofLurbinectedin contains no more than 2.0%, and preferably no more than 1.8% of total impurities after it has been stored at 2-8° C for six months.

[0042] Liquid formulation of lurbinectedin is analyzed by HPLC by the method described below.

[0043] Mobile phase A: A buffer solution prepared by dissolving 2.72 g of potassium dihydrogen orthophosphate and 3 ml of triethyl amine in water (total volume 1000 ml) and the pH of the solution was adjusted to 2.5 with dilute orthophosphoric acid.

[0044] Mobile phase B: A mixture of 90% (v / v) acetonitrile and 10% (v / v) water.

[0045] Chromatographic conditions:Column - YMC Triart C18ExRS, 250mm x 4.6 mm, particle size 5 micron or equivalent;Flow rate - 0.8ml / min.Column temperature - 40 °C.Detector - UV detector. λ is 210nm;Run time is 90 min.Injection volume - 10 pL.

[0046] Gradient compositions:

[0047] The liquid lurbinectedin pharmaceutical formulations disclosed herein can be used to treat patients with metastatic small cell lung cancer (SCLC) and other solid tumors. Accordingly, the present invention also provides a method of treating a metastatic small cell lung cancer and other solid tumors in mammals, which includes the steps of diluting a pharmaceutical composition of the present invention, and administering an effective amount of said diluted pharmaceutical composition to a mammal in need thereof.

[0048] It should be noted that the invention in its broader aspects is not limited to the specific details, representative compositions, methods, and processes, and illustrative examples described in connection with the preferred embodiments and preferred methods. Modifications and equivalents will be apparent to practitioners skilled in this art and are encompassed within the spirit and scope of the appended claims.

[0049] Examples

[0050] Example 1 :

[0051] Lurbinectedin (12 mg) was added to 2.1 ml of N,N-dimethyl acetamide (DMA) in a vial cooled to 0 - 5°C and mixed to dissolve completely. In another vial, 600 mg of sucrose and 66.3 mg of lactic acid were mixed in 0.9 ml of water. The clear DMA solution of lurbinectedin was added to this vial cooled to 0-5°C. The contents were mixed to get a clear solution. This solution was divided into five equal parts in 5 vials. The vials were sealed and stored at 2- 8°C in stability chamber and analyzed by the HPLC method described above at various times. The stability data are reported in Table 1 .

[0052] Table 1 : Stability data of the liquid formulation of Example 1 :

[0053] Example 2:

[0054] Lurbinectedin (12 mg) was added to 2.7 ml of N,N-dimethyl acetamide (DMA) in a vial cooled to 0-5°C and mixed to dissolve completely. In another vial 30 mg of sucrose and 18 mg of lactic acid were mixed in 0.3 ml of water. The clear DMA solution of lurbinectedin was added to this vial cooled to 0- 5°C. The contents were mixed to get a clear solution. This solution was divided into five equal parts in 5 vials. The vials were sealed and stored at 2- 8°C in stability chamber and analyzed by HPLC method described above at various times. The stability data are reported in Table 2.

[0055] Table 2: Stability data of the liquid formulation of Example 2:

[0056] It should be noted that the invention in its broader aspects is not limited to the specific details, representative compositions, methods, and processes, and illustrative examples described in connection with the preferred embodiments and preferred methods. Modifications and equivalents will be apparent to practitioners skilled in this art and are encompassed within the spirit and scope of the appended claims.

Claims

AMENDED CLAIMS received by the International Bureau on 20 May 2025 (20.05.2025)What is claimed is:1 . A liquid lurbinectedin pharmaceutical composition, comprising: lurbinectedin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable solvent system comprising at least one organic solvent; wherein the liquid lurbinectedin pharmaceutical composition is stable for at least two months without the need for lyophilization; and wherein the composition contains no less than about 98% of the amount of the lurbinectedin upon analysis by HPLC at initial testing and after 6 months storage at 2-8°C.

2. The pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable solvent system comprises not more than three solvents.

3. The pharmaceutical composition according to claim 1 , wherein the at least one organic solvent is selected from N,N-dimethylacetamide, glycerol, N-methyl-2- pyrrolidone, polyethylene glycol, propylene glycol, water, and a mixture thereof.

4. The pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable solvent system consists essentially of N,N- dimethylacetamide and glycerol.

5. The pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable solvent system consists essentially of N,N- dimethylacetamide and water.

6. The pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable solvent system consists essentially of N,N- dimethylacetamide.

7. The pharmaceutical composition according to claim 1 , wherein the composition is essentially free from ethanol.

8. The pharmaceutical composition according to claim 1 , further comprising lactic acid.

9. The pharmaceutical composition according to claim 1 , wherein lurbinectedin or a pharmaceutically acceptable salt thereof is present in a concentration of between about 0.5 mg / mL to about 25 mg / mL.

10. The pharmaceutical composition according to claim 1 , wherein lurbinectedin or a pharmaceutically acceptable salt thereof is present in a concentration of less than about 10 mg / mL.

11. A ready to use or ready to dilute stable liquid lurbinectedin pharmaceutical composition, comprising: lurbinectedin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable solvent system comprising N,N- dimethylacetamide; wherein the liquid lurbinectedin pharmaceutical composition is stable for at least two months without the need for lyophilization.

12. The pharmaceutical composition according to claim 11 , wherein the pharmaceutically acceptable solvent system comprises N,N-dimethylacetamide and one or more additional solvents selected from glycerol, N-methyl-2-pyrrolidone, polyethylene glycol, propylene glycol, water, and a mixture thereof.

13. The pharmaceutical composition according to claim 11 , wherein the composition contains no less than about 98% of the amount of the lurbinectedin upon analysis by HPLC at initial testing and after 3 months storage at 2-8°C.

14. The pharmaceutical composition according to claim 11 , wherein the composition contains no less than about 98% of the amount of the lurbinectedin upon analysis by HPLC at initial testing and after 6 months storage at 2-8°C.

15. The pharmaceutical composition according to claim 11 , wherein the pharmaceutically acceptable solvent system consists essentially of N,N- dimethylacetamide and glycerol.

16. The pharmaceutical composition according to claim 11 , wherein the pharmaceutically acceptable solvent system consists essentially of N,N- dimethylacetamide and water.

17. The pharmaceutical composition according to claim 11 , wherein the pharmaceutically acceptable solvent system consists essentially of N,N- dimethylacetamide.

18. The pharmaceutical composition according to claim 11 , wherein the composition is essentially free from ethanol.

19. The pharmaceutical composition according to claim 11 , further comprising lactic acid.

20. A method of treating a metastatic small cell lung cancer in mammals, comprising the steps of: diluting the pharmaceutical composition of claim 1 , and administering an effective amount of said diluted pharmaceutical composition to mammal in need thereof.

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