Improved lyophilized formulation

Abstract

To provide stable formulations of tagraxofusp for intravenous injection.SOLUTION: The present invention provides a stable solution, comprising tagraxofusp, sucrose, polysorbate 80, and Tris HCl, and having a pH of 6.5 to 9.0, wherein the polysorbate 80 contains at most 3% peroxide.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a joint venture of U.S. Provisional Application No. 63 / 123,589, filed December 10, 2020. No. 6,313,635, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Improved freeze-drying of tagraxofusp with increased stability Formulations and methods for making same.

[0003] Sequence Listing This application contains a sequence listing that has been submitted electronically in ASCII format via EFS-Web. , the entire contents of which are incorporated herein by reference. The ASCII copy name is 2021-12-07_01214-0022-00PCT The file name is _Seq_List_ST25.txt and its size is 4,806 bytes. [Background technology]

[0004] Intravenous therapy (IV) or drug delivery is the delivery of fluids directly into a vein. The intravenous route of administration is: Injections using syringes with higher pressures as well as injections that are typically gravity fed. It can be used for both intravenous and intravenous infusions using pressure (also called drip infusion). These tracts deliver drugs rapidly throughout the body by introducing therapeutic agents directly into the circulation. Direct introduction of a drug formulation into the bloodstream makes the formulation 100% bioavailable, but The formulation must also be readily compatible with the subject's physiology and the acceptable range of action of the formulation must be within the range of This also means that the amount of harmful ingredients is limited. Injectable products are sterile and pyrogen-free. When in solution, the components can be free of particulate matter and isotonic. In addition, the components are sterilized using a terminal sterilization process. The material must be able to withstand sterile or aseptic manufacturing processes.

[0005] Described herein is a stable pharma- ceutically acceptable formulation for intravenous injection of tagraxofusp. As well as formulations and methods of making same, are provided. Summary of the Invention

[0006] As exemplified by the following list of non-limiting embodiments, the static administration of tagraxofusp Provided herein are stable, pharma- ceutically acceptable formulations for intravenous injection.

[0007] Embodiment 1 is a stable solution for lyophilization in a pharma- ceutically acceptable aqueous carrier. the law of nature, 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v of at least one disaccharide sugar )and, 0.05-1.5% w / v of at least one surfactant; At least one buffering agent at 5-25 mM, and having a pH of 6.5-9.0; The surfactant has 3% or less peroxide.

[0008] Embodiment 2 is the freeze-dried solution according to embodiment 1, wherein the freeze-dried solution is 2-10% It further comprises at least one bulking agent w / v.

[0009] Embodiment 3 is a freeze-dried solution according to any one of the preceding embodiments, Contains .4mg / mL tagraxofusp.

[0010] Embodiment 4 is a freeze-dried solution according to any one of the preceding embodiments, Contains tagraxofusp at .3mg / mL.

[0011] Embodiment 5 is a freeze-dried solution according to any one of the preceding embodiments, Contains .2 mg / mL tagraxofusp.

[0012] Embodiment 6 is a lyophilized solution according to any one of the preceding embodiments, comprising 1 mg / m Including tagraxofusp of L.

[0013] Embodiment 7 is a lyophilized solution according to any one of the preceding embodiments, further comprising a surfactant. is present in amounts of 0.07-1.5% w / v.

[0014] Embodiment 8 is a lyophilized solution according to any one of the preceding embodiments, further comprising a surfactant. is present in amounts of 0.1-1.3% w / v.

[0015] Embodiment 9 is a lyophilized solution according to any one of the preceding embodiments, further comprising a surfactant. is present in amounts of 0.15-1.2% w / v.

[0016] Embodiment 10 is a lyophilized solution according to any one of the preceding embodiments, comprising a surfactant. The agent is present in an amount of 0.25 to 1% w / v.

[0017] Embodiment 11 is a lyophilized solution according to any one of the preceding embodiments, comprising a surfactant. The agent is present in an amount of 0.24 to 0.26% w / v.

[0018] Embodiment 12 is a lyophilized solution according to any one of the preceding embodiments, comprising a surfactant. The agent is selected from a polysorbate or a poloxamer.

[0019] Embodiment 13 is a lyophilized solution according to any one of the preceding embodiments, comprising a surfactant. The agent is poloxamer 188, poloxamer 168, poloxamer 144, polysorbate 20, polysorbate 60, or polysorbate 80.

[0020] Embodiment 14 is a lyophilized solution according to any one of the preceding embodiments, comprising a surfactant. The agent is polysorbate 80.

[0021] Embodiment 15 is a lyophilized solution according to any one of the preceding embodiments, comprising a disaccharide sugar. is present in amounts of 2-8% w / v.

[0022] Embodiment 16 is a lyophilized solution according to any one of the preceding embodiments, comprising a disaccharide sugar. is present in amounts of 2-6% w / v.

[0023] Embodiment 17 is a lyophilized solution according to any one of the preceding embodiments, comprising a disaccharide sugar. is present in an amount of 2-4% w / v.

[0024] Embodiment 18 is a lyophilized solution according to any one of the preceding embodiments, comprising a disaccharide sugar. is present in an amount of 2-3% w / v.

[0025] Embodiment 19 is a lyophilized solution according to any one of the preceding embodiments, comprising a disaccharide sugar. is present in an amount of 2.45-2.55% w / v.

[0026] Embodiment 20 is a lyophilized solution according to any one of the preceding embodiments, comprising a disaccharide sugar. is selected from trehalose, lactose, and sucrose.

[0027] Embodiment 21 is a lyophilized solution according to any one of the preceding embodiments, comprising a disaccharide sugar. is sucrose.

[0028] Embodiment 22 is a lyophilized solution according to any one of the preceding embodiments, wherein the bulking agent is , present in an amount of 2-8% w / v.

[0029] Embodiment 23 is a lyophilized solution according to any one of the preceding embodiments, wherein the bulking agent is , present in an amount of 2-6% w / v.

[0030] Embodiment 24 is a lyophilized solution according to any one of the preceding embodiments, wherein the bulking agent is , present in an amount of 2-4% w / v.

[0031] Embodiment 25 is a lyophilized solution according to any one of the preceding embodiments, wherein the bulking agent is , present in an amount of 2-3% w / v.

[0032] Embodiment 26 is a lyophilized solution according to any one of the preceding embodiments, wherein the bulking agent is , present in an amount of 2.45-2.55% w / v.

[0033] Embodiment 27 is a lyophilized solution according to any one of the preceding embodiments, wherein the bulking agent is , glycine, maltose, glucose, mannitol, and sorbitol. .

[0034] Embodiment 28 is a lyophilized solution according to any one of the preceding embodiments, wherein the bulking agent is , mannitol.

[0035] Embodiment 29 is a lyophilized solution according to any one of the preceding embodiments, comprising at least The other buffer is at a concentration of 5 to 15 mM.

[0036] Embodiment 30 is a lyophilized solution according to any one of the preceding embodiments, comprising at least The other buffer is at a concentration of 7-12 mM.

[0037] Embodiment 31 is a lyophilized solution according to any one of the preceding embodiments, comprising at least The other buffer is at a concentration of 10 mM.

[0038] Embodiment 32 is a lyophilized solution according to any one of the preceding embodiments, wherein the buffering agent is , phosphate, arginine, histidine, and Tris HCl.

[0039] Embodiment 33 is a lyophilized solution according to any one of the preceding embodiments, wherein the buffering agent is , Tris HCl.

[0040] Embodiment 34 is a lyophilization solution according to any one of the preceding embodiments, wherein the pH is It is 6.5 to 8.

[0041] Embodiment 35 is a lyophilization solution according to any one of the preceding embodiments, wherein the pH is It's 7~8.

[0042] Embodiment 36 is a stable lyophilized pharmaceutically acceptable lyophilized pharmaceutically acceptable aqueous medium. It is a solution, 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v sucrose; 0.05-1.5% w / v polysorbate 80; 5 to 25 mM Tris HCl, It has a pH of 6.5 to 9. Polysorbate 80 has less than 3% peroxide.

[0043] Embodiment 37 is the freeze-dried solution according to embodiment 36, wherein the freeze-dried solution comprises 2 to 1 Further contains 0% w / v mannitol.

[0044] Embodiment 38 is a lyophilized solution according to embodiment 36, 1 mg / mL tagraxofusp; 2.45-2.55% w / v sucrose; 2.45-2.55% w / v mannitol; 0.24-0.26% w / v polysorbate 80; 9 to 11 mM Tris HCl; It has a pH of 6.5 to 9. Polysorbate 80 has less than 3% peroxide.

[0045] Embodiment 39 relates to a freeze-dried product prepared from the freeze-dried solution according to any one of the preceding embodiments. It is a lyophile.

[0046] Embodiment 40 is a lyophilisate according to embodiment 41, comprising an oxidized species of tagraxofusp. does not increase to more than 2% or more than 1% over a period of 12 to 36 months.

[0047] Embodiment 41 is a lyophilisate according to embodiment 41, comprising an oxidized species of tagraxofusp. does not increase to more than 2% or 1% over a period of 18 to 24 months.

[0048] Embodiment 42 is a lyophilisate according to embodiment 41, comprising an acidic species of Tagraxofusp. Relative abundance (%) of T. cerevisiae in liquid T. cerevisiae during storage for 18, 24, or 36 months The relative abundance (%) of the same acidic species of Tagraxofusp in the preparation will not increase by more than that of the same acidic species in the preparation.

[0049] Embodiment 43 is a lyophilizate according to embodiment 42, wherein the formulation, on a dry weight basis, Provides the required dose of 1-1.5mg.

[0050] Embodiment 44 is a lyophilisate according to embodiment 42 or 43, comprising a lyophilised product. The dried product is stable at storage temperatures between 2°C and 8°C for at least 24 months.

[0051] Embodiment 45 is a lyophilized product according to any one of embodiments 42 to 44, The dried product is stable for 24 months to 5 years at a storage temperature of 2°C to 8°C.

[0052] Embodiment 46 is a lyophilized product according to any one of embodiments 42 to 45, As determined by ultra-performance liquid chromatography (RP-UPLC), the oxidation impurities were: Less than 2% or less than 1%.

[0053] Embodiment 47 is a lyophilized product according to any one of embodiments 42 to 46, which is oxidized. The impurity was identified by mass spectrometry as a single peak at +16 Da from the tagraxofusp peak. It can be measured as a line.

[0054] Embodiment 48 is a lyophilizate according to any one of embodiments 42 to 47, comprising RP In the UPLC analysis, oxidation impurities were eluted before tagraxofusp, and RP-UP The peak of the oxidized impurity in the LC chromatogram was closest to the peak of tagraxofusp. It is a work.

[0055] Embodiment 49 is a stable lyophilisate, 1 mg of tagraxofusp, 25 mg of at least one disaccharide sugar; 25 mg of at least one surfactant; 2.4 mg of at least one buffering agent; The lyophilisate was purified by reversed-phase ultra-performance chromatography (RP-UPL) for at least 24 months. C) has 2% or less oxidation impurities.

[0056] Embodiment 50 is a stable lyophilizate according to embodiment 49, comprising at least 25 mg of The composition further comprises one bulking agent.

[0057] Embodiment 51 is a stable lyophilizate according to embodiment 49 or 50, comprising tagraxon. The relative abundance (%) of oxidized species of Fusp was greater than 2% or greater than 1% over a period of 18 to 24 months. will not increase.

[0058] Embodiment 52 is a method for preparing a tagraxofusp lyophilisate, comprising the steps of: a) providing a lyophilized solution according to any one of embodiments 1 to 41; b) freeze-drying the solution to form a lyophilisate.

[0059] Embodiment 53 is the method of embodiment 52, wherein the freeze-drying is carried out for 2 to 7 days. The test is carried out at temperatures between -40°C and 25°C.

[0060] Embodiment 54 is the method of embodiment 52 or 53, wherein lyophilization is performed after the loading step. at least one freezing step, at least one annealing step, and and at least one drying step.

[0061] Embodiment 55 is the method according to any one of embodiments 52 to 54, wherein the freeze-drying , a loading step, at least two freezing steps, and at least two annealing steps. and at least one drying step.

[0062] Embodiment 56 is the method of any one of embodiments 52 to 55, wherein freeze-drying is The loading step and at least two freezing steps are carried out over a period of not more than one day. At least two annealing steps, which are performed over 1–5 days, and at least one annealing step, which is performed over 1–5 days. and one drying step.

[0063] Embodiment 57 is the method according to any one of embodiments 52 to 56, wherein the freeze-drying , the following freeze-drying cycle: a) loading a sample containing a freeze-drying solution into a freeze-dryer; Pre-cool the loaded lyophilizer by lowering the temperature to 10 °C for 10 min at ambient pressure. To do, b) freezing the sample in a first freezing step, wherein the temperature of the freeze-dryer is freezing at ambient pressure in the vessel from 10°C to -40°C over a period of 180 minutes; c) freezing the sample in a second freezing step, wherein the temperature of the freeze-drier is and freezing the container at ambient pressure at -40°C for 60 minutes. d) annealing the sample in a first annealing step, comprising: The temperature is changed from -40°C to -15°C over a period of 60 minutes at ambient pressure in the freeze dryer. Annealing; and e) annealing the sample in a second annealing step, Annealing, in which the temperature is held at -15°C for 60 minutes at ambient pressure in a freeze dryer. and, f) annealing the sample in a third annealing step, The temperature is changed from -15°C to -40°C over a period of 60 minutes at ambient pressure in the freeze dryer. Annealing; and g) annealing the sample in a fourth annealing step, The temperature is held at -40°C for approximately 60 minutes at ambient pressure in the freeze dryer. And, h) drying the sample in a first primary drying step, the temperature of the freeze-drier being: The temperature was kept at 40°C and the freeze-dryer pressure was kept at 0.133 mBar for 10 minutes. Drying and i) drying the sample in a second primary drying step, the temperature of the freeze-drier being: The temperature was changed from 40°C to -25°C, and the freeze dryer pressure was 0.133 mbar for 60 minutes. ar kept dry, j) drying the sample in a third primary drying step, wherein the temperature of the freeze-drier is: The temperature is kept at 25°C and the freeze dryer pressure is kept at 0.133mBar for 2400 minutes. , drying; and k) drying the sample in a fourth primary drying step, wherein the temperature of the freeze-drier is: The temperature was changed from 25°C to 25°C, and the freeze dryer pressure was 0.133 mbar over a period of 840 minutes. ar kept dry, l) Drying the sample in a secondary drying step, the temperature of the freeze dryer being 25° C. The pressure in the freeze dryer is maintained at 0.133 mBar for 1390 minutes. This includes making the

[0064] Embodiment 58 is a pharma- ceutically acceptable preparation reconstituted in an aqueous medium for intravenous injection. It is an agent, 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v of at least one disaccharide sugar; 0.05-1.5% w / v of at least one surfactant; and 5 to 25 mM of at least one buffering agent.

[0065] Embodiment 59 is a stable lyophilisate according to embodiment 58, comprising tagraxofusp. The relative abundance (%) of oxidized species did not increase to more than 2% or 1% over a period of 18 to 24 months. stomach.

[0066] Embodiment 60 relates to a reconstituted formulation for intravenous injection according to embodiment 58 or 59. and the lyophilization solution further comprises 2-10% w / v of at least one bulking agent.

[0067] Embodiment 61 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 60. It is a formulation that contains 0.5 to 1.5 mg / mL tagraxofusp or 0.6 to 1. 4 mg / mL tagraxofusp, or 0.7 to 1.3 mg / mL tagraxofusp, 0.8 to 1.2 mg / mL tagraxofusp or 1 mg / mL tagraxofusp include.

[0068] Embodiment 62 relates to a reconstituted formulation for intravenous injection according to embodiment 58 or 61. and the surfactant is 0.07 to 1.5% w / v, or 0.1 to 1.3% w / v, or 0.15-1.2% w / v, or 0.25-1.0% w / v, or 0.24-0.26% Present in w / v amounts.

[0069] Embodiment 63 relates to a reconstituted formulation for intravenous injection according to embodiment 58 or 62. and the surfactant is selected from a polysorbate or a poloxamer.

[0070] Embodiment 64 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 63. The formulation is made of poloxamer 188, poloxamer 168, and poloxamer 188. Summer 144, Polysorbate 20, Polysorbate 60, or Polysorbate 80 do.

[0071] Embodiment 65 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 64. The formulation is prepared as described above, and the surfactant is polysorbate 80.

[0072] Embodiment 66 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 65. The preparation is made of a disaccharide sugar at a concentration of 2-8% w / v, 2-6% w / v, or 2-4% It is present in an amount of 2-3% w / v, or 2.45-2.55% w / v.

[0073] Embodiment 67 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 66. The formulation is prepared by the method of claim 1, wherein the disaccharide sugar is selected from trehalose, lactose, and sucrose. will be done.

[0074] Embodiment 68 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 67. The formulation is prepared as above, and the disaccharide sugar is sucrose.

[0075] Embodiment 69 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 68. The formulation is made of a filler having a concentration of 2-8% w / v, 2-6% w / v, or 2-4% w / v. / v, or 2-3% w / v, or 2.45-2.55% w / v.

[0076] Embodiment 70 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 69. The formulation is made of glycine, maltose, glucose, mannitol, and and sorbitol.

[0077] Embodiment 71 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 70. The formulation is prepared using a mannitol as a bulking agent.

[0078] Embodiment 72 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 71. The formulation is prepared by adding 5 to 15 mM, 7 to 12 mM, 9 to 11 mM, or 10 mM. At least one buffer of M is added.

[0079] Embodiment 73 is a reconstituted formulation for intravenous injection according to any one of embodiments 58 to 72. The formulation is made of phosphate, arginine, histidine, and Tris H. Cl.

[0080] Embodiment 74 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 73. The formulation is prepared using Tris HCl as the buffer.

[0081] Embodiment 75 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 74. The formulation has a pH of 6.5 to 9.

[0082] Embodiment 76 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 75. The formulation has a pH of 7-8.

[0083] Embodiment 77 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 76. It is a formulation that has been developed. 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v sucrose; 0.05-1.5% w / v polysorbate 80; 5 to 25 mM Tris HCl, It has a pH of 6.5 to 9.

[0084] Embodiment 78 is a reconstituted formulation according to embodiment 77, wherein the reconstituted formulation , and further containing 2-10% w / v mannitol.

[0085] Embodiment 79 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 78. It is a formulation that has been developed. 0.9 to 1.1 mg / mL tagraxofusp; 2.45-2.55% w / v sucrose; 2.45-2.55% w / v mannitol; 0.24-0.26% w / v polysorbate 80; 9-11 mM Tris HCl, It has a pH of 6.5 to 9.

[0086] Embodiment 80 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 79. The formulation is prepared as described above, and the aqueous medium is water for injection (WFI).

[0087] Embodiment 81 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 80. When diluted in the infusion bag, providing a fluid within a fluid bag, the fluid being essentially free of particulate matter.

[0088] Embodiment 82 is a reconstituted formulation for intravenous injection as described in embodiment 81, The infusion bag is a 50cc infusion bag.

[0089] Embodiment 83 is a reconstituted composition for intravenous injection according to any one of embodiments 58 to 82. It is a formulation that, when diluted in the infusion bag, provides fluid within the infusion bag and The body is essentially free of particulate matter and further the fluid in the infusion bag is saline or Contains % (w / v) dextrose.

[0090] Embodiment 84 relates to a method for treating myeloproliferative neoplasms (MPNs) with monocytosis. and administering to a subject in need of the reconstituted formulation an effective amount of any one of embodiments 58 to 83. The method includes administering a reconstituted formulation for intravenous injection as described in paragraph 1.

[0091] Embodiment 85 is a method for treating myeloproliferative neoplasms (MPNs), comprising administering to a patient a reconstituted An effective amount of the intravenous formulation according to any one of embodiments 58 to 83 is administered to a subject in need thereof. administering the reconstituted formulation for injection, wherein the MPN is polycythemia vera (PV), Essential thrombocythemia (ET), myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), Chronic neutrophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), symptomatic eosinophilia Symptomatic hypereosinophilic disorder er), or other bone marrow disorders (leading to excess production of red blood cells, white blood cells, and / or platelets or primary eosinophilic disorder is a personality disorder (PED).

[0092] Embodiment 86 is a method for treating acute myeloid leukemia (AML), comprising administering to a patient a reconstituted An effective amount of the intravenous formulation according to any one of embodiments 58 to 83 is administered to a subject in need thereof. The method includes administering the reconstituted formulation for intravenous injection.

[0093] Embodiment 87 is a method for treating chronic myelomonocytic leukemia (CMML), A subject in need thereof is administered an effective amount of the composition described in any one of embodiments 58 to 78. administering the reconstituted formulation for intravenous injection of

[0094] Embodiment 88 is a method for treating myelodysplastic syndrome (MDS), comprising administering to a patient a reconstituted An effective amount of the intravenous formulation according to any one of embodiments 58 to 83 is administered to a subject in need thereof. The method includes administering the reconstituted formulation for intravenous injection.

[0095] Embodiment 89 relates to a method for treating multiple myeloma in a subject in need of treatment. and administering to a subject in need of the reconstituted formulation an effective amount of any one of embodiments 58 to 83. The method includes administering a reconstituted formulation for intravenous injection as described in paragraph 1.

[0096] Embodiment 90 is a method for treating blastic plasmacytoid dendritic cell neoplasm (BPDCN). and administering to a subject in need of the reconstituted formulation an effective amount of any one of embodiments 58-83. Administering a reconstituted formulation for intravenous injection according to claim 1.

[0097] Embodiment 91 is a method of treating an autoimmune disease, which requires a reconstituted formulation. A subject is administered an effective amount of a reconstituted solution for intravenous injection according to any one of embodiments 58 to 83. The method includes administering the formulation.

[0098] Embodiment 92 is the method of embodiment 91, wherein the autoimmune disease is lupus (e.g., (e.g., systemic lupus erythematosus, cutaneous lupus, discoid lupus), Sjögren's syndrome, Inflammatory arthritis, systemic sclerosis (SSc), morphea, psoriasis, lichen planus, dermatomyositis, sclerosis Lichen genitalis, cutaneous graft-versus-host disease (GVHD), adrenergic drug resistance, alopecia areata, Ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune diseases of the adrenal gland, allergies autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inflammatory eye disease, autoimmune Autoimmune neonatal thrombocytopenia, autoimmune neutropenia, autoimmune oophoritis and orchitis, Autoimmune thrombocytopenia, autoimmune thyroiditis, Behçet's disease, bullous pemphigoid, myocardium heart failure, open heart syndrome, celiac sprue dermatitis, chronic active hepatitis, chronic fatigue immunodeficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome group, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dense deposits disease, essential mixed cryoglobulinemia, fibromyalgia / fibromyositis, glomerulonephritis (e.g., IgA nephropathy), gluten-sensitive enteropathy, Goodpasture's syndrome, Graves' disease, Guillain-Barr syndrome, Barrera, hyperthyroidism (Hashimoto's thyroiditis), idiopathic pulmonary fibrosis, idiopathic Addison's disease, idiopathic Intrathecal thrombocytopenic purpura (ITP), IgA neuropathy, juvenile arthritis, Meniere's disease , mixed connective tissue disease, multiple sclerosis, myasthenia gravis, myocarditis, type I or immune-mediated diabetes mellitus , neuritis, other endocrine gland deficiencies, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polyarteritis Chondritis, polyendocrinopathy, polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-MI , primary agammaglobulinemia, primary biliary cirrhosis, psoriatic arthritis, Raynaud's phenomenon, Relapsing polychondritis, Reiter's syndrome, rheumatic heart disease, rheumatoid arthritis, sarcoidosis stiff-man syndrome, Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, Urticaria, uveitis, uveitis ophthalmia, vasculitis (e.g. dermatitis herpetiformis type vasculitis), vitiligo and Wegener's granulomatosis.

[0099] Embodiment 93 is a method for treating or inhibiting a solid tumor, comprising administering the reconstituted formulation to a patient. A subject in need thereof is administered an effective amount of the composition for intravenous injection described in any one of embodiments 58 to 83. The present invention relates to a method for treating a chronic inflammatory bowel disease, comprising administering a reconstituted formulation to said patient.

[0100] Embodiment 94 is the method of embodiment 93, wherein the solid tumor is a sarcoma, a carcinoma, or lymphoma.

[0101] Embodiment 95 is the method according to any one of embodiments 84 to 94, further comprising: Fusp is administered at a dose of 4 μg / kg to 20 μg / kg.

[0102] Embodiment 96 is the method according to any one of embodiments 84 to 94, further comprising: Fusp is administered at a dose of 6 µg / kg to 16 µg / kg.

[0103] Embodiment 97 is the method according to any one of embodiments 84 to 94, further comprising: Fusp is administered at a dose of 7 μg / kg.

[0104] Embodiment 98 is the method according to any one of embodiments 84 to 94, further comprising: Fusp is administered at a dose of 9 μg / kg.

[0105] Embodiment 99 is the method according to any one of embodiments 84 to 94, further comprising: Fusp is administered at a dose of 12 μg / kg.

[0106] Embodiment 100 is the method according to any one of embodiments 84 to 94, Sofusp is administered at a dose of 12 μg / kg over 15 minutes.

[0107] Embodiment 101 is the method according to any one of embodiments 84 to 100, Xofusp is administered at a dose that is the maximum tolerated dose.

[0108] Embodiment 102 is the method according to any one of embodiments 84 to 101, Xofusp is administered once daily for five days.

[0109] Embodiment 103 is the method according to any one of embodiments 84 to 101, Xofusp is administered once daily for three days.

[0110] Embodiment 104 is the method according to any one of embodiments 84 to 103, further comprising: Multiple cycles of xofusp are administered.

[0111] Embodiment 105 is the method according to any one of embodiments 84 to 102, further comprising: Xofusp is administered on days 1-5 of a 21-day cycle.

[0112] Embodiment 106 is the method according to any one of embodiments 84 to 102, further comprising: Xofusp is administered on days 1-5 of a 28-day cycle.

[0113] Embodiment 107 is the method according to any one of embodiments 84 to 101 and 103. Tagraxofusp is administered on days 1 to 3 of a 21-day cycle.

[0114] Embodiment 108 is the method according to any one of embodiments 84 to 101, Xofusp is administered for 5 days on any one of the first 10 days of a 21-day cycle. will be done.

[0115] Embodiment 109 is a method for preparing a stable pharmaceutical composition according to any one of embodiments 1 to 41 in a vial. It is a physiologically acceptable lyophilized solution.

[0116] Embodiment 110 relates to a stable pharma- ceutically acceptable salt of embodiment 38 or 40 in a vial. It is a freeze-dried solution.

[0117] Embodiment 111 relates to a lyophilized liquid preparation according to any one of embodiments 42 to 51 in a vial. It is a dried food.

[0118] Embodiment 112 is a lyophilisate according to embodiment 49 or 50 in a vial.

[0119] Embodiment 113 is a lyophilisate according to embodiment 111 or 112 containing water. .

[0120] Embodiment 114 includes a reconstituted solution according to any one of embodiments 58 to 80. It is a vial containing

[0121] Embodiment 115 is a method for preparing a reconstructed image according to any one of embodiments 58, 60, 77, or 79. A vial containing the resulting solution.

[0122] Embodiment 116 is a solution or lyophilized product according to any one of embodiments 109 to 115. , or a vial, wherein the vial is a 2 mL or 3 mL vial.

[0123] Embodiment 117 relates to a stable solution for lyophilization in a pharma- ceutically acceptable aqueous carrier. and 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v of at least one disaccharide sugar; 0.05-1.5% w / v of at least one surfactant; At least one buffering agent at 5 to 25 mM; pH 6.5 to 9.0, The surfactant has 3% or less peroxide.

[0124] Embodiment 118 is a lyophilized solution according to embodiment 117, wherein the lyophilized solution comprises 2 Further comprising at least one bulking agent at ∼10% w / v.

[0125] Embodiment 119 is a lyophilized solution according to embodiment 117 or 118, comprising 0.6 to 1.0 μg of lyophilized solution. 1.4 mg / mL tagraxofusp or 0.7 to 1.3 mg / mL tagraxofus or 0.8 to 1.2 mg / mL tagraxofusp, or 1 mg / mL tagraxofusp Including fusp.

[0126] Embodiment 120 is a freeze-dried solution according to any one of embodiments 117 to 119. The surfactant is 0.07 to 1.5% w / v, or 0.1 to 1.3% w / v, or 0. 15-1.2% w / v, or 0.25-1% w / v, or 0.24-0.26% w / v exists in quantity.

[0127] Embodiment 121 is a freeze-dried solution according to any one of embodiments 117 to 120. and the surfactant is selected from polysorbate or poloxamer, or The active ingredient is poloxamer 188, poloxamer 168, poloxamer 144, polysorbate Polysorbate 20, Polysorbate 60, or Polysorbate 80, or the surfactant is , polysorbate 80.

[0128] Embodiment 122 is a freeze-dried solution according to any one of embodiments 117 to 121. and the disaccharide sugar is 2-8% w / v, or 2-6% w / v, or 2-4% w / v, or 2- It is present in an amount of 3% w / v, or 2.45 to 2.55% w / v.

[0129] Embodiment 123 is a freeze-dried solution according to any one of embodiments 117 to 122. and the disaccharide sugar is selected from trehalose, lactose, and sucrose, or The saccharide sugar is sucrose.

[0130] Embodiment 124 is a freeze-dried solution according to any one of embodiments 117 to 123. and the bulking agent is 2-8% w / v, or 2-6% w / v, or 2-4% w / v, or 2-3% w / v. % w / v, or 2.45 to 2.55% w / v.

[0131] Embodiment 125 is a freeze-dried solution according to any one of embodiments 117 to 124. The bulking agent is selected from glycine, maltose, glucose, mannitol, and sorbitol. Alternatively, the bulking agent is mannitol.

[0132] Embodiment 126 is a freeze-dried solution according to any one of embodiments 117 to 125. and at least one buffering agent is present at a concentration of 5 to 15 mM, or 7 to 12 mM, or 10 mM. It is.

[0133] Embodiment 127 is a freeze-dried solution according to any one of embodiments 117 to 126. and the buffer is selected from phosphate, arginine, histidine, and Tris HCl. Or the buffer is Tris HCl.

[0134] Embodiment 128 is a freeze-dried solution according to any one of embodiments 117 to 127. The pH is 6.5 to 8, or the pH is 7 to 8.

[0135] Embodiment 129 is a stable lyophilized pharmaceutically acceptable lyophilized pharmaceutically acceptable aqueous medium. It is a dry solution, 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v sucrose; 0.05-1.5% w / v polysorbate 80; 5 to 25 mM Tris HCl, It has a pH of 6.5 to 9. Polysorbate 80 has less than 3% peroxide.

[0136] Embodiment 130 is a lyophilized solution according to embodiment 129, wherein the lyophilized solution comprises 2 Further contains mannitol at -10% w / v.

[0137] Embodiment 131 is a lyophilized solution according to embodiment 130, 1 mg / mL tagraxofusp; 2.45-2.55% w / v sucrose; 2.45-2.55% w / v mannitol; 0.24-0.26% w / v polysorbate 80; 9 to 11 mM Tris HCl; It has a pH of 6.5 to 9. Polysorbate 80 has less than 3% peroxide.

[0138] Embodiment 132 is a method for producing a freeze-dried solution according to any one of embodiments 117 to 131. The freeze-dried product was prepared.

[0139] Embodiment 133 is a lyophilisate according to embodiment 132, (a) The relative abundance (%) of oxidized species of Tagraxofusp was measured over a 12-36 month period. % or not increased by more than 1%, or the relative abundance (%) of the oxidized species of tagraxofusp does not increase by more than 2% or 1% over a period of 18 to 24 months, (b) Relative abundance (%) of acidic species of Tagraxofusp over 18, 24, or 36 months. Relative abundance (% of the same acidic species of tagraxofusp in liquid tagraxofusp formulations during storage ) does not increase more than (c) the formulation provides a required dose of 1 to 1.5 mg on a dry weight basis; (d) The lyophilized product is stable for at least 24 months at a storage temperature of 2°C to 8°C. or freeze-dried product can be stored for 24 months to 5 years at a storage temperature of 2℃ to 8℃. and / or (e) Oxidation impurities were determined by reversed-phase ultra-performance chromatography (RP-UPLC). If so, it is 2% or less, or 1% or less, and / or the amount of oxidized impurities is Spectral analysis revealed a single peak at +16 Da from the tagraxofusp peak. measurable and / or oxidative impurities were detected in the RP-UPLC analysis The peak of the oxidized impurity on the RP-UPLC chromatogram was eluted before the peak of the oxidized impurity. , the peak closest to that of Tagraxofusp.

[0140] Embodiment 134 is a stable lyophilisate, 1 mg of tagraxofusp, 25 mg of at least one disaccharide sugar; 25 mg of at least one surfactant; 2.4 mg of at least one buffering agent; The lyophilisate was purified by reversed-phase ultra-performance chromatography (RP-UPL) for at least 24 months. C) has 2% or less oxidation impurities.

[0141] Embodiment 135 is a stable lyophilizate of embodiment 134, (a) further comprising 25 mg of at least one bulking agent; (b) The relative abundance (%) of oxidized species of Tagraxofusp increased over a period of 18–24 months. % or not increase by more than 1%.

[0142] Embodiment 136 is a method for preparing a tagraxofusp lyophilisate, comprising the steps of: a) providing a lyophilized solution according to any one of embodiments 117 to 131; b) freeze-drying the solution to form a lyophilisate.

[0143] Embodiment 137 is the method of embodiment 136, wherein the freeze-drying is carried out for 2 to 7 days. It is carried out at a temperature between 40°C and 25°C, and / or Lyophilization comprises a loading step, at least one freezing step, and at least one aniline step. and / or The freeze-drying step comprises a loading step, at least two freezing steps, and at least two aniline steps. and / or Freeze-drying involves a loading step, at least two freezing steps, and a period of no more than one day. At least two annealing steps are performed over a period of 1 to 5 days. and at least one drying step.

[0144] Embodiment 138 is the method of embodiment 136 or 137, wherein the lyophilization comprises: Freeze-drying cycle: a) loading a sample containing a freeze-drying solution into a freeze-dryer; Pre-cool the loaded lyophilizer by lowering the temperature to 10 °C for 10 min at ambient pressure. To do, b) freezing the sample in a first freezing step, wherein the temperature of the freeze-dryer is freezing at ambient pressure in the vessel from 10°C to -40°C over a period of 180 minutes; c) freezing the sample in a second freezing step, wherein the temperature of the freeze-drier is and freezing the container at ambient pressure at 40° C. for 60 minutes. d) annealing the sample in a first annealing step, comprising: The temperature is changed from 40°C to -15°C over a period of 60 minutes at ambient pressure in the freeze dryer. Kneeling and e) annealing the sample in a second annealing step, Annealing, in which the temperature is held at -15°C for 60 minutes at ambient pressure in a freeze dryer. and, f) annealing the sample in a third annealing step, The temperature is changed from 15°C to -40°C over a period of 60 minutes at ambient pressure in a freeze dryer. Kneeling and g) annealing the sample in a fourth annealing step, The temperature is held at 40° C. for about 60 minutes at ambient pressure in the freeze-dryer; h) drying the sample in a first primary drying step, the temperature of the freeze-drier being 4 The temperature is kept at 0°C and the freeze-dryer pressure is kept at 0.133 mBar for 10 minutes. And i) drying the sample in a second primary drying step, the temperature of the freeze-drier being 4 The temperature was changed from 0°C to -25°C, and the freeze dryer pressure was 0.133 mBa for 60 minutes. r, and drying; j) drying the sample in a third primary drying step, wherein the temperature of the freeze-drier is: The temperature is kept at 25°C and the freeze dryer pressure is kept at 0.133mBar for 2400 minutes. , drying; and k) drying the sample in a fourth primary drying step, wherein the temperature of the freeze-drier is 2 The temperature was changed from 5°C to 25°C, and the freeze dryer pressure was 0.133 mBa for 840 minutes. r, and drying; l) Drying the sample in a secondary drying step, the temperature of the freeze dryer being 25° C. The pressure in the freeze dryer is maintained at 0.133 mBar for 1390 minutes. This includes making the

[0145] Embodiment 139 is a pharma- ceutically acceptable medicament reconstituted in an aqueous medium for intravenous injection. A formulation, 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v of at least one disaccharide sugar; 0.05-1.5% w / v of at least one surfactant; and 5 to 25 mM of at least one buffering agent.

[0146] Embodiment 140 is a reconstituted formulation for intravenous injection as described in embodiment 139. the law of nature, (a) The relative abundance (%) of oxidized species of Tagraxofusp increased over a period of 18–24 months. % or not increase by more than 1% (b) the lyophilization solution further comprises at least one bulking agent at 2-10% w / v; (c) The formulation contains 0.5 to 1.5 mg / mL tagraxofusp or 0.6 to 1.4 mg / mL tagraxofusp, or 0.7 to 1.3 mg / mL tagraxofusp, 0.8 ~1.2 mg / mL tagraxofusp, or 1 mg / mL tagraxofusp, (d) The surfactant is 0.07 to 1.5% w / v, or 0.1 to 1.3% w / v, or 0 .15-1.2% w / v, or 0.25-1.0% w / v, or 0.24-0.26% w / v / v, (e) the surfactant is selected from polysorbates or poloxamers, or The active agent is poloxamer 188, poloxamer 168, poloxamer 144, polysorbate polysorbate 20, polysorbate 60, or polysorbate 80, or a surfactant is polysorbate 80, (f) the disaccharide sugar is 2 to 8% w / v, or 2 to 6% w / v, or 2 to 4% w / v, or 2 present in an amount of up to 3% w / v, or 2.45-2.55% w / v, (g) the disaccharide sugar is selected from trehalose, lactose, and sucrose; or the disaccharide sugar is sucrose; (h) The bulking agent is 2 to 8% w / v, or 2 to 6% w / v, or 2 to 4% w / v, or 2 to 3% w / v, or 2.45-2.55% w / v, (i) the bulking agent is glycine , maltose, glucose, mannitol, and sorbitol, or the bulking agent is mannitol; (j) at least 5 to 15 mM, or 7 to 12 mM, or 9 to 11 mM, or 10 mM One buffer is added, (k) the buffer is selected from phosphate, arginine, histidine, and Tris HCl; or the buffer is Tris HCl; and / or (l) The pH is 6.5 to 9, or the pH is 7 to 8.

[0147] Embodiment 141 relates to a reconstituted composition for intravenous injection according to embodiment 139 or 140. It is a formulation 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v sucrose; 0.05-1.5% w / v polysorbate 80; 5 to 25 mM Tris HCl; It has a pH of 6.5 to 9. The aqueous medium is water for injection (WFI).

[0148] Embodiment 142 is a reconstituted formulation according to embodiment 141, The agent further comprises 2-10% w / v mannitol.

[0149] Embodiment 143 is a method for intravenous injection according to any one of embodiments 139 to 142. is a reconstituted formulation of 0.9 to 1.1 mg / mL tagraxofusp; 2.45-2.55% w / v sucrose; 2.45-2.55% w / v mannitol; 0.24-0.26% w / v polysorbate 80; It contains 9-11 mM Tris HCl and has a pH of 6.5-9.

[0150] Embodiment 144 is a method for intravenous injection according to any one of embodiments 139 to 143. It is a reconstituted formulation that, when diluted in the infusion bag, provides fluid in the infusion bag. and the fluid is essentially free of particulate matter.

[0151] Embodiment 145 is a method for treating a disease, which requires a reconstituted formulation. A subject is administered an effective amount of a remdesivir for intravenous injection according to any one of embodiments 139 to 144. and administering the formulation to a patient suffering from a disease comprising: a) Myeloproliferative neoplasms (MPN) with monocytosis, b) Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytopenia, Myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CLE) Leukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), symptomatic eosinophilic disorders, or Other bone marrow disorders (which cause excess production of red blood cells, white blood cells, and / or platelets) myeloproliferative neoplasms (MPNs), which are primary eosinophilic disorders (PEDs); c) acute myeloid leukemia (AML), d) chronic myelomonocytic leukemia (CMML), e) myelodysplastic syndromes (MDS), f) multiple myeloma, g) blastic plasmacytoid dendritic cell neoplasm (BPDCN), h) autoimmune diseases; i) Autoimmune diseases, wherein the autoimmune disease is lupus (e.g., systemic lupus erythematosus lupus, cutaneous lupus, discoid lupus), Sjögren's syndrome, inflammatory arthritis, systemic sclerosis SSc, morphea, psoriasis, lichen planus, dermatomyositis, lichen sclerosus, and skin graft replacement Host disease (GVHD), Adrenergic drug resistance, Alopecia areata, Ankylosing spondylitis, Antiphospholipids syndrome, autoimmune Addison's disease, autoimmune disease of the adrenal glands, allergic encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inflammatory eye disease, autoimmune neonatal thrombocytopenia autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Autoimmune thyroiditis, Behcet's disease, bullous pemphigoid, cardiomyopathy, open-heart syndrome, parsley Axe Sprue dermatitis, chronic active hepatitis, chronic fatigue immune deficiency syndrome (CFIDS), chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cicatricial pemphigoid, CR EST syndrome, cold agglutinin disease, Crohn's disease, dense deposit disease, essential mixed cryog Globulinemia, fibromyalgia / fibromyositis, glomerulonephritis (e.g., IgA nephropathy), gluten intolerance Irritable bowel disease, Goodpasture's syndrome, Graves' disease, Guillain-Barre, hyperthyroidism (Hashimoto's thyroiditis), idiopathic pulmonary fibrosis, idiopathic Addison's disease, idiopathic thrombocytopenic purpura (I TP), IgA neuropathy, juvenile arthritis, Meniere's disease, mixed connective tissue disease, multiple myelopathy Sclerosis, myasthenia gravis, myocarditis, type I or immune-mediated diabetes, neuritis, other endocrine disorders Glandular failure, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyendocrinopathy , polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-MI, primary agammaglobulin psoriatic arthritis, Raynaud's phenomenon, relapsing polychondritis, leitmotif syndrome, rheumatic heart disease, rheumatoid arthritis, sarcoidosis, stiff-man syndrome , Takayasu's arteritis, temporal arteritis, giant cell arteritis, ulcerative colitis, urticaria, uveitis, bud Uveitis ophthalmia, vasculitis (e.g., dermatitis herpetiformis type vasculitis), vitiligo, and Wegener's granulomatosis An autoimmune disease selected from the group consisting of

[0152] Embodiment 146 is a method for treating or inhibiting a solid tumor, comprising administering to a subject a reconstituted formulation. An effective amount of the intravenous injection method according to any one of embodiments 139 to 144 is administered to a subject in need thereof. and optionally, the solid tumor is a sarcoma, The cancer is selected from carcinoma and lymphoma.

[0153] Embodiment 147 relates to a method for the preparation of a stabilizer according to any one of embodiments 117 to 131 in a vial. It is a stable pharma- ceutically acceptable lyophilized solution.

[0154] Embodiment 148 relates to a frozen product according to any one of embodiments 132 to 135 in a vial. It is a lyophilized product.

[0155] Embodiment 149 is a reconstituted solution according to any one of embodiments 139 to 144. A vial containing:

[0156] Embodiment 150 is a solution or lyophilisate according to any one of embodiments 147 to 149. , or a vial, wherein the vial is a 2 mL or 3 mL vial. [Brief description of the drawings]

[0157] [Figure 1A] 1 provides DSC data from the evaluation of stabilizing excipients detailed in Example 2.

[0158] [Figure 1B] 1 provides DSC data from the evaluation of stabilizing excipients detailed in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0159] I. Definition As used herein, the terms "administer" and "administered" refer to the administration of a desired portion. Delivery of the composition to a subject by a method or route that results in at least partial localization of the composition at the site. The composition may be delivered by any suitable route that results in effective treatment in the subject. The administration can be performed in a manner that results in delivery to a desired location in a subject, with a small amount of the composition being administered. At least a portion of the drug is delivered to the desired site for a certain period of time. Injection includes intravenous, intramuscular, intraarterial, intrathecal, intracardiac, and pulmonary. Intracellular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, These include, but are not limited to, intrathecal, intraspinal, intracerebrospinal, and intrasternal injection and infusion. In some embodiments, the route is intravenous.

[0160] As used herein, the term "agent" refers to a tagraxon disclosed herein. Any molecule, chemical, or other molecule for use in the prevention, treatment, management, and / or diagnosis of disease, including FSP. This refers to a compound, substance, and / or material.

[0161] As used herein, the term "buffer" or "buffering agent" refers to a compound added to an aqueous solution. When the solution is heated, when an acid or alkali is added, or when it is diluted with a solvent, the p This refers to one or more components that can protect against the fluctuation of H. In addition to phosphate buffer, glycine A buffer solution containing sodium chloride, carbonate, citrate, etc. can be used. Mn, potassium, or ammonium ions can serve as counterions.

[0162] As used herein, the term "bulking agent" refers to a bulking agent that forms the majority of the lyophilized product. This refers to one or more components that provide the cake with the proper structure. Used for low dose (high potency) drugs that do not have the bulk necessary to support their own structure. can be.

[0163] As used herein, the term "carrier" refers to a carrier that is used in conjunction with the compositions disclosed herein. In some embodiments, the term carrier refers to a diluent, adjuvant, or excipient that is administered with the carrier. The body is sterile. Water may be the carrier. Saline solutions and aqueous dextrose solutions and Aqueous glycerol solutions can also be used as liquid carriers.

[0164] As used herein, the term "charge variant profile" refers to a profile of a net charge This refers to the relative amounts of various species of proteins that have different charges. Proteins vary in charge, changing the overall charge of the molecule. The large number of chemical entities that are susceptible to a variety of post-translational enzymatic and chemical modifications that can In addition, chemical modifications such as oxidation or deamination may occur during the manufacturing process and storage. Charge state can affect the structure, stability, binding affinity, efficacy, and safety of biotherapeutics. Analysis of charge variants is usually a regulatory requirement for biotherapeutic proteins. This can be achieved using isoelectric focusing or ion exchange chromatography. Relative variation in the various charge variants due to process inconsistencies and / or stability-related events. Variations in amount can adversely affect the safety and efficacy of the biotherapeutic protein.

[0165] As used herein, the term "excipient" refers to a compound that is used to formulate a therapeutic agent into a pharmaceutical preparation. It refers to substances used to improve the quality of food and beverages, such as diluents, solubilizers, stabilizers, adjuvants, thickeners, and moisturizers. Any solid or liquid additives, such as lubricants, bulking agents, buffers, enhancers, antimicrobial agents, wetting agents, and surfactants. The additive may be a solid or semi-solid additive.

[0166] As used herein, the term "effective amount" or "sufficient amount" refers to a disease or disorder and its and preventing the onset, recurrence, or onset of one or more symptoms of the disease or disorder, and reducing the severity of the disease or disorder. or reduce the duration, alleviate one or more symptoms of a disease or disorder, or slow the progression of a disease or disorder. Prevent, cause regression of a disease or disorder, and / or enhance the therapeutic efficacy of another therapy. In embodiments, an "effective amount" refers to an amount of a therapeutic composition or therapy sufficient to cause a reduction or amelioration of a condition. Or, a "therapeutically effective amount" refers to that amount of a composition sufficient to effect a beneficial or desired outcome. A therapeutically effective amount will depend on the subject and disease state being treated, the weight and age of the subject, the severity of the disease state, and method of administration, which may be varied by one or more of those skilled in the art. In certain embodiments, a "sufficient amount" of a therapeutic composition is one that reduces the severity of a disease. The amount of the composition required to prevent, reduce, or alleviate at least one sign or symptom of Thus, the term "effective amount" refers to a dose that is administered to a typical subject (such as a patient suffering from cancer or autoimmune diseases, e.g., When administered to subjects with or at risk for an autoimmune disease, An effective amount also refers to the amount of a composition that is sufficient to delay the onset of symptoms of a disease. or altering the course of a disease symptom (e.g., but not limited to, slowing the progression of a disease symptom) In any given event, the amount of the compound will be sufficient to slow (delay) or reverse the symptoms of the disease. For examples, an appropriate "effective amount" can be determined by one of ordinary skill in the art using routine experimentation. It is understood that.

[0167] As used herein, the term "isotonic" refers to a solution having essentially the same osmotic pressure as human blood. Isotonic preparations generally have a viscosity of 250 to 350 mOsmol / KgH2O. Isotonicity can be measured, for example, using a vapor pressure or ice osmometer. .

[0168] As used herein, the terms "lyophilization" and "lyophilized" refer primarily to In this method, the material to be dried is frozen and then the ice or frozen solvent is evaporated by sublimation in a vacuum environment. Refers to the process by which something is removed.

[0169] As used herein, the term "lyophilized solution" refers to a solution that has undergone a lyophilization process. This refers to a preparation that

[0170] As used herein, the term "lyophile" refers to a liquid that is frozen. Any solid material obtained by lyophilization of a dry solution (i.e., freeze-drying of an aqueous solution) Point.

[0171] As used herein, the term "lyoprotectant" refers to a The term lyophilization, when combined with a protein of interest, before or during freeze-drying and during subsequent storage In particular, it refers to a molecule that prevents or reduces the chemical and / or physical instability of a protein. Lyophilization protection serves to stabilize the therapeutic agent and prevent its degradation both during and after lyophilization. It is defined as:

[0172] As used herein, in the context of administering a therapy to a subject, "administer" or "administer The terms "treatment," "management," and "management" refer to treatments that do not result in a cure of a disease or disorder, but do provide a therapeutic benefit to the subject. (e.g., a prophylactic or therapeutic composition) or beneficial effects obtained from a combination of therapies. In certain embodiments, the subject is receiving treatment with a disease inhibitor to prevent progression or worsening of the condition. To "manage" a disease, one or more therapies (e.g., one or more prophylactic or therapeutic compositions) may be administered. is administered.

[0173] As used herein, "peroxide" or "peroxide" refers to The term "oxygen oxides" refers to two oxygen atoms linked together by a single covalent bond. Organic peroxides refer to any of a class of chemical compounds that are or a compound having COOH. One example is tert-butyl hydroperoxy Peroxides can cause further degradation or destabilization of pharmaceutical formulations. Known to readily decompose into highly reactive free radical-containing moieties (CO· or HO·) It is being done.

[0174] As used herein, the term "pharmaceutical acceptable" means a compound that is acceptable according to sound medical judgment. Excessive toxicity, irritation, or allergic reactions, within the limits of reasonable benefit / risk ratio or other problems or complications. "Drugs" refers to compounds, materials, compositions, formulations, and / or dosage forms suitable for administering

[0175] As used herein, in the context of administration of a therapy to a subject, "prevent" or "prevent The terms "prevention" and "prevention" refer to a therapy (e.g., a prophylactic or therapeutic agent) or the prevention of a therapy. in a subject resulting from administration of a combination (e.g., a combination of prophylactic or therapeutic agents). Preventing or inhibiting the recurrence, onset, and / or development of a disease or disorder or a symptom thereof In certain embodiments, such terms refer to one of the following following administration of one or more therapies: , refers to two, three, or more outcomes: (1) delay in onset of disease symptoms; (2) shortening of the disease Altering the course of symptoms of the disease (e.g., but not limited to, slowing the progression of symptoms of the disease), 3) reversal of disease symptoms; (4) reduction in the rate of disease recurrence; and (5) extension of the time until disease recurrence. (6) an increase in the patient's disease-free, recurrence-free, progression-free, and / or overall survival; and (7) a decrease in the disease Improvement in associated symptoms and / or quality of life. In certain embodiments, such terms refer to In a further embodiment, such terms refer to a reduction in mortality and / or an increase in survival of a patient. In certain embodiments, such terms refer to an increase or improvement in the quality of life of a patient population. This refers to a reduction in the rate of hospitalization in a population and / or a reduction in the length of hospital stay in a patient population.

[0176] As used herein, the terms "reconstituted" or "reconstituted formulation" refer to refers to a formulation prepared by dissolving a lyophilisate in an aqueous carrier. In embodiments, the reconstituted formulation is administered intravenously (IV) in a patient in need thereof. Suitable for.

[0177] As used herein, the term "stable" refers to a therapeutic agent that is stable to treatment. A formulation or preparation that essentially retains its physical and chemical stability and integrity during processing and storage. The stability of a formulation can be measured at a selected temperature after a selected period of time. For example, increase in particles, formation of aggregates, or the presence of other impurities after lyophilization and storage. is an indicator of instability of a lyophilized drug product. In addition to the formation of aggregates, shelf life Stability means that the original clarity, color, and odor are maintained throughout the product's life. It is an indicator that can be used to monitor the solution.

[0178] As used herein, the terms "subject" and "patient" are used interchangeably. Although the term "subject" refers to a human subject, the methods described herein are encompassed by the term "subject." It is understood that the invention is effective with respect to all vertebrate species contemplated. "An indication" is a prescription for the treatment of an existing condition or disease, or for preventing the onset of a condition or disease. For human subjects for medical purposes, such as for prophylactic treatment, or for medical, veterinary or other Suitable animal subjects include primates, Mammals, including but not limited to humans, monkeys, apes, etc., bovine ) (e.g. cattle, bulls, etc.), ovine (e.g. sheep, Sheep, etc.), Caprine (e.g. goat, etc.) , porcine (e.g. pig, boar, etc.), equine e) (e.g. horse, donkey, zebra, etc.), feline (wild live and domestic cats (including cats), canines (including dogs), Lagomorphs (including rabbits, hares, etc.), and rodents (including mice, rats, etc.). In certain embodiments, the subject is a human (e.g., an infant, juvenile, or In addition, a "subject" refers to a person who is suffering from or has a condition or disease. This may include suspected patients.

[0179] As used herein, the term "surfactant" refers to a surfactant that is ... A table containing both alkyl chains and hydrophilic portions (e.g., carboxyl and carboxylic acid groups). Surfactants can be added to the formulations disclosed herein. Suitable surfactants for use in the formulations herein include polysorbates (e.g., polysorbates Rubate 20, 60, or 80), poloxamer (e.g., poloxamer 144, 168 , or 188), Sorbitan esters and derivatives, Triton sodium lauryl sulfate , sodium octyl glucoside, lauryl, myristyl, linoleyl, or stearyl Allyl-sulfobetamine, lauryl-, myristyl-, linoleyl-, or stearyl- Sarcosine, linoleyl, myristyl, or cetyl betaine, propyl lauroyl Cocamidopropyl, Linoleamidopropyl, Myrisamidopropyl, Palmidopropyl or isosteramidopropyl betaine (e.g., lauroamidopropyl), dopropyl-, palmidopropyl-, or isosteramidopropyl-dimethylamine, Sodium methyl cocoyl taurate or disodium methyl oleoyl taurate, and MONAQUAT (trademark) series (Mona Industries, Inc., Pa. tterson, NJ), polyethylene glycol, polypropyl glycol, and ethylene glycol. Copolymers of ethylene glycol and propylene glycol (e.g., Pluronics, PF68, etc., but are not limited to these.

[0180] As used herein, the terms "therapies" and "thera The term "prophylaxis" refers to the prevention of a disease, disorder, or condition, or one or more symptoms thereof. Refers to any method, composition, and / or agent that can be used in the treatment, treatment, and / or management of In certain embodiments, the terms "therapies" and "therapy" may be used interchangeably. The term "therapeutic therapy" includes steroid therapy, physical therapy, gene therapy, chemotherapy, Small molecule therapy, radioimmunotherapy, toxin therapy, prodrug-activated enzyme therapy, biological therapy, antibody therapy method, surgical therapy, hormonal therapy, immunotherapy, antiangiogenic therapy, targeted therapy, epigenetic therapy chemotherapy, demethylation therapy, histone deacetylase inhibitor therapy, differentiation therapy, radiation therapy, or a combination of the foregoing therapies, and / or a disease, disorder, or condition, or "Other therapies" refers to other therapies useful in the prevention, management, and / or treatment of one or more symptoms of

[0181] As used herein, in the context of administration of a therapeutic composition to a subject, "treat" or " The terms "treatment" and "treating" refer to the reduction or alleviation of a disease resulting from the administration of one or more therapies. Reversing, reducing, or inhibiting the progression and / or duration, preventing the onset of disease, or reduction, reduction in severity or amelioration of, and / or the severity of, the disease, disorder, or condition to which such term applies or refers to the improvement of one or more symptoms of a condition.

[0182] II. Improved Formulations ELZONRIS® is a treatment for the treatment of blastic plasmacytoid cell carcinoma in adult and pediatric patients 2 years of age and older. CD currently approved for use in the United States for the treatment of cystic dendritic cell neoplasms (BPDCN) ELZONRIS® is a cytotoxin directed against the 123 antibody. The commercial formulation of serotonin (sold in the United States under the generic name Tagroxofusp-ERZs) Tagraxofusp is a diphtheria toxin-IL-3 fusion protein that targets the IL-3 receptor. It is a fusion protein and can be found in DrugBank using the accession number DB14731. U.S. Patent Nos. 7,763,242, 8,470,307, and 9,181 ,317, 9,631,006, and 10,259,853. There are.

[0183] The embodiments disclosed herein include a composition comprising 0.5 to 1.5 mg / mL tagraxofusp. In another embodiment, the lyophilized solution is a stable, pharma- ceutically acceptable lyophilized solution. In another embodiment, the lyophilized The solution contains 0.7 to 1.3 mg / mL of tagraxofusp. The dry solution contains 0.8 to 1.2 mg / mL of tagraxofusp. The lyophilized solution contains 0.9 to 1.1 mg / mL of tagraxofusp. In the present embodiment, the lyophilized solution contains 1 mg / mL of tagraxofusp. The embodiment is a stable pharma- ceutically acceptable lyophilized solution containing 1 mg / vial of tagraxofusp. In another embodiment, the lyophilized solution is provided at 1.5 mg / vial of tagla. Including fucking fusp.

[0184] The embodiments disclosed herein include lyophilized, lyophilized, and / or lyophilized compositions according to the formulations and methods described herein. Contains lower levels of charge variants over its shelf life compared to unmodified formulations A stable, pharma- ceutically acceptable lyophilized solution is provided. In some embodiments, the charge barrier The ant profile can be determined or approximated based on the amount of acidic impurities measured. In some embodiments, the relative abundance (%) of the acidic species impurity is determined by the tagraxofusp drug. During storage of the drug product, the relative abundance of the acidic species impurity may increase. The reported values ​​(%) were 3 to 8 percentage points higher in the liquid product formulation of tagraxofusp. Although the relative abundance (%) of the same acidic species impurities may be increased, the relative abundance (%) of the same acidic species impurities may be increased by the lyophilization method described herein. Lyophile drug product formulation ) will increase by 0 to 2, 0 to 1, or 0 to 0.5 percentage points. In embodiments, the drug product comprises 12, 18, 24, or 36 In some embodiments, the pharmaceutical is stored for 24 months. In an embodiment, the relative abundance of the acidic species of Tagraxofusp in the lyophilisate described herein is Abundance (%) in liquid tagraxofusp formulations during 18, 24, or 36 months of storage The relative abundance (%) of the same acidic species of Tagraxofusp would not increase.

[0185] Without wishing to be bound by theory, it is believed that the surfactant used in the preparation of the lyophilization solution A judicious selection of agent type and purity is essential during manufacture, storage throughout the shelf life, and reconstitution. Prevent the formation of particulates and / or impurities during the synthesis process and during administration to patients. It is believed that it is possible.

[0186] In some embodiments, the lyophilized solution comprises tagraxofusp and at least one biphasic Sugars and at least one surfactant having 3% or less peroxide and at least one In some embodiments, the lyophilization solution comprises at least one buffer. The composition further comprises an agent.

[0187] In some embodiments, in the lyophilization solutions disclosed herein, the disaccharide sugar is In another embodiment, the disaccharide sugar is present in an amount of 2-10% w / v of the dry solution. In another embodiment, the disaccharide sugar is present in an amount of 2-6% w / v. In another embodiment, the disaccharide sugar is present in an amount of 2-4% w / v. The disaccharide sugar is present in an amount of 2-3% w / v. In some embodiments, the disaccharide sugar is present in an amount of trehalose. In another embodiment, the disaccharide sugar is selected from sucrose, lactose, and sucrose. It's loin.

[0188] In some embodiments, the lyophilization solutions disclosed herein comprise a surfactant. In some embodiments, the surfactant is present in an amount of 0.05-1.5% w / v of the lyophilized solution. In another embodiment, the surfactant is present in an amount of 0.07 to 1.5% w / v. In another embodiment, the surfactant is present in an amount of 0.1 to 1.3% w / v. In one embodiment, the surfactant is present in an amount of 0.15 to 1.2% w / v. In some embodiments, the surfactant is present in an amount of 0.25 to 1.0% w / v. The active agent is present in an amount of 0.24-0.26% w / v. The active agent is selected from polysorbates and poloxamers. The active ingredients are poloxamer 188, poloxamer 168, poloxamer 144, and polysorbate In another embodiment, the surface active agent is polysorbate 20, polysorbate 60, or polysorbate 80. The active agent is polysorbate 80.

[0189] The lyophilized solutions disclosed herein are commercially available ultra-purified (ultra-purified) They are prepared from refined or super-refined surfactants. The ultra-purification process is the process of removing impurities (primary and secondary) from excipients without changing their chemical composition. Processes that help remove oxidative products and reduce interactions and degradation of APIs It is.

[0190] In some embodiments, the surfactant is 3%, or 2.5%, or 2%, or 1.5%. %, or 1% or less of peroxide. The peroxide content shall be determined upon receipt from the manufacturer. When the container is first opened, the potential is measured according to the peroxide value in European Pharmacopoeia (EP) 2.5.5. It is assessed using potentiometric titration. To prevent the formation of peroxides, in some embodiments, the surfactant is Used within 6 months of use and / or manufacturer testing has not been completed, but If chemical surfactants are obtained, they should be used within six months of receipt. In some embodiments, the manufacturer reserves the right to sell the portion for use in preparing additional lyophilized formulations at a later date. Use containers for only one manufacturing step, rather than using them part-time and then storing them. It is possible.

[0191] In some embodiments, the lyophilization solutions disclosed herein comprise at least one buffer. In some embodiments, the buffering agent is phosphate, arginine, histidine, In another embodiment, the buffer is selected from Tris HCl. In some embodiments, 5 to 25 mM of at least one buffering agent is added. In another embodiment, 5 to 15 mM of at least one buffering agent is added. In some embodiments, 7 to 12 mM of at least one buffer is added. In another embodiment, at least 10 mM of a buffering agent is added. A buffer is added to each solution.

[0192] In some embodiments, the lyophilization solutions disclosed herein contain 2-10% w / v In another embodiment, the composition further comprises at least one bulking agent. In another embodiment, the bulking agent is present in an amount of 2-8% w / v. In another embodiment, the bulking agent is present in an amount of 2-6% w / v. In one embodiment, the bulking agent is present in an amount of 2-4% w / v. In another embodiment, the bulking agent is present in an amount of 2.45 to 2.55% w / v. In some embodiments, the bulking agent is at least one disaccharide sugar. In some embodiments, the bulking agent is glycine, maltose, glucose, mannitol, In some embodiments, the bulking agent is selected from mannitol, sorbitol, and sorbitol. It is.

[0193] The lyophilization solutions disclosed herein are prepared to have a pH of 6.5-9. In another embodiment, the pH is 7-8.

[0194] The embodiments disclosed herein are directed to stable pharma- ceutical compositions in a pharma-ceutical acceptable aqueous carrier. The present invention provides a lyophilized solution containing 0.5 to 1.5 mg / mL of tagraxofusp and 2 to 3 mg / mL of glycerol. 10% w / v of at least one disaccharide sugar and 0.05-1.5% w / v of at least one and 5 to 25 mM of at least one buffering agent, In other embodiments, the lyophilized solutions disclosed herein have a peroxide content of 3% or less. , further comprising 2-10% w / v of at least one bulking agent.

[0195] In some embodiments, the present disclosure provides a stable pharma- ceutical composition in a pharma-ceutical acceptable aqueous carrier. Provide an acceptable lyophilized solution, containing 0.5-1.5 mg / mL tagraxofusp and 2 ~10% w / v sucrose, 0.05-1.5% w / v polysorbate 80, and 5 ~25 mM tris HCl, has a pH of 6.5-9, and contains polysorbate 8 In another embodiment, the pharma- ceutically acceptable lyophilized The dry solution further contains 2-10% w / v mannitol.

[0196] In some embodiments, the present disclosure provides a stable pharma- ceutical composition in a pharma-ceutical acceptable aqueous carrier. Provide an acceptable lyophilized solution, containing 0.9-1.1 mg / mL tagraxofusp and 2 .45 to 2.55 w / v sucrose and 2.45 to 2.55 w / v mannitol, 0.24-0.26 w / v polysorbate 80 and 9-11 mM Tris HCl , having a pH of 6.5 to 9, and polysorbate 80 having 3% or less peroxide. do.

[0197] In some embodiments, the present disclosure provides a method for the preparation of pharmaceutical compositions prepared from the various pharmaceutical compositions described herein. In some embodiments, the lyophilizate formulation is provides the required dose of 1-1.5 mg.

[0198] In some embodiments, the lyophilized dry product has a shelf life of at least 2° C. to 8° C. In some embodiments, the lyophilized dry product is stable for at least 24 months. It is stable for 24 months to 5 years when stored at 2℃ to 8℃.

[0199] In some embodiments, the present disclosure provides a method for preparing a tagraxofusp lyophilisate. a) providing a lyophilization solution as disclosed throughout; and b) freezing the solution. and c) drying to form a lyophilisate.

[0200] In some embodiments, the lyophilization cycle includes a freezing step and an annealing step. The method includes a drying step, a primary drying step, and a secondary drying step.

[0201] In some embodiments, the lyophilization cycle is carried out at a temperature between -40°C and 25°C.

[0202] In some embodiments, the lyophilization cycle is carried out over a period of 3-4 days.

[0203] In some embodiments, lyophilization comprises a loading step and at least one freezing step. a heating step, at least one annealing step, and at least one drying step. include.

[0204] In some embodiments, lyophilization comprises a loading step and at least two freezing steps. a heating step, at least two annealing steps, and at least one drying step. include.

[0205] In some embodiments, lyophilization comprises a loading step and at least two freezing steps. and at least two annealing steps carried out over a period of one day or less. and at least one drying step, which is carried out for a period of 1 to 5 days.

[0206] In some embodiments, lyophilization comprises the following method: i. The product filled vial is fitted with an elastomeric stopper. The bottles are semi-stoppered with "sure" and kept at 10°C for pre-cooling. The samples are loaded onto the shelves of a freeze-drying chamber that has been ii. In the step designated as heat treatment or annealing, increase the shelf temperature to 3 hours. -40℃ from 10℃, kept at -40℃ for 1 hour, raised to -10℃ for 1 hour, then -10℃ C for 1 hour, return to -40°C for 1 hour, and then maintain at -40°C for another 1 hour. iii. After the above steps, cool the condenser to below -60℃ and press the vacuum pump. Rhyming, iv. The chamber pressure is then reduced to 0.133 mBar to allow for the primary drying step. Also known as ice sublimation, v. In the primary drying step, the shelf temperature is increased from -40°C to -25°C in 1 hour, and this temperature is maintained The shelf temperature was then increased to +25° C. for 14 hours. vi. The shelf temperature is then maintained for an additional 23.3 hours in the secondary drying step to complete the drying cycle. Complete the vii. The chamber is evacuated with nitrogen to 900 mBar atmosphere and the vial is then nitrogenized. Completely stopper the flask under vacuum and remove it from the chamber.

[0207] In some embodiments, the present disclosure provides a method for reconstituting a lyophilisate, the method comprising: adding the lyophilisate to a sterile vial; and adding a first aqueous medium to the vial. and removing the reconstituted lyophilisate from the second aqueous solution. and further diluting the compound with a suitable vehicle to a dosage suitable for administration to a patient.

[0208] In some embodiments of the method for reconstituting a lyophilisate, the first aqueous medium is water, saline, or the like. saline or 5% dextrose in water. Several methods for reconstituting the lyophilized product are In embodiments, the first aqueous medium is water. In embodiments, the second aqueous medium is water, saline, or 5% dextrose in water. In some embodiments of the method of reconstituting a lyophilisate, the second aqueous medium is water. .

[0209] In some embodiments of the method for reconstituting a lyophilisate, 1.0 to 1.5 mL of a first Adding an aqueous medium.

[0210] In some embodiments, the present disclosure provides a drug product reconstituted in an aqueous medium for intravenous injection. and providing a clinically acceptable formulation comprising 0.5 to 1.5 mg / mL tagraxofusp and 2 to 3 mg / mL cefotaxime. 10% w / v of at least one disaccharide sugar and 0.05-1.5% w / v of at least one The solution contains one surfactant and 5 to 25 mM of a buffering agent.

[0211] In some embodiments, the reconstituted formulation for intravenous injection comprises 2-10% w / v Some of the reconstituted formulations for intravenous injection further comprise at least one bulking agent. In one embodiment, the surfactant is selected from polysorbates and poloxamers. In embodiments, the surfactant is poloxamer 188, poloxamer 168, poloxamer 144, polysorbate 20, polysorbate 60, or polysorbate 80. In some embodiments, the surfactant is polysorbate 80.

[0212] In some embodiments of the reconstituted formulation for intravenous injection, the disaccharide sugar is trehalose. In some embodiments, the disaccharide is selected from the group consisting of sucrose, lactose, and sucrose. The sugar is sucrose.

[0213] In some embodiments of the reconstituted formulation for intravenous injection, the bulking agent is glycine , maltose, glucose, mannitol, and sorbitol. In an embodiment, the bulking agent is mannitol.

[0214] In some embodiments of the reconstituted formulation for intravenous injection, the buffer is a phosphate buffer. , arginine, histidine, and tris HCl. In the present invention, the buffer is tris HCl.

[0215] In some embodiments of the reconstituted formulation for intravenous injection, the pH is between 6.5 and 9. In some embodiments, the pH is 7 to 8. In some embodiments, the pH is H is 7.5.

[0216] In some embodiments of the reconstituted formulation for intravenous injection, the aqueous medium is Water (WFI).

[0217] In some embodiments of the reconstituted formulation for intravenous injection, the dilution is added to the infusion bag. Once infusion is complete, the reconstituted formulation in the infusion solution bag is essentially free of particulate matter.

[0218] In some embodiments of the reconstituted formulation for intravenous injection, the dilution is added to the infusion bag. Upon receipt, the reconstituted formulation in the infusion bag is essentially free of particulate matter and contains no particulate matter. The fluid in the bag further comprises saline or 5% (w / v) dextrose.

[0219] In some embodiments, the stable pharma- ceutically acceptable lyophilized solutions disclosed herein Provided herein is a vial containing the liquid. In another embodiment, the Provided herein is a vial containing a stable lyophilisate. The present invention relates to a vial containing a reconstituted solution comprising the reconstituted lyophilisate disclosed in the above document. In some embodiments, the vial is a 2 mL vial or a 3 mL vial. It's Ial.

[0220] III. Impurities Several trace impurities are present in tagraxofusp or tagraxofusp formulations. One impurity is associated with a single oxidation of the drug. Mass spectrometry was used to identify the identity of the oxidation impurity. The mass of the tactic is presented as a single peak at +16 Da from Tagraxofusp. The pure product is a single peak, but peptide mapping shows that it represents several species, each but has a single oxidation at one of several sites on tagraxofusp. In a forced degradation test of tagraxofusp using the treatment, the oxidized species of tagraxofusp were The amount of oxidation impurities increases. Tagraxofusp and other impurities were analyzed using high performance liquid chromatography (RP-UPLC). In RP-UPLC, the oxidation impurities were separated from the elution of tagraxofusp. The peak of the oxidation impurity on the RP-UPLC chromatogram is the tagraxonase. This is the most prominent impurity peak closest to the FUSP peak.

[0221] Without wishing to be bound by any particular theory, it is believed that the peroxy acid in commercial surfactants The oxide levels are based on the amount of oxidation impurities found in tagraxofusp or tagraxofusp formulations. is thought to contribute to the

[0222] In some embodiments, the present disclosure provides a method for the detection of chromatographically significant changes in a method for detecting chromatographically significant changes in a reversed-phase ultra-performance chromatography (RP-UPL). C) The oxidized species of tagraxofusp is 2% or less or 1% or less In another embodiment, the oxidized species of tagraxofusp is At least 24 were identified as markers of oxidative stress, as determined by high performance chromatography (RP-UPLC). In another embodiment, the oxidized species of tagraxofusp is a reversed-phase ultra-high performance At least 12, 18, as determined by chromatography (RP-UPLC). In another embodiment, the oxidized species of tagraxofusp is less than 2% for 24 or 36 months. 12, as determined by reversed-phase ultra-performance chromatography (RP-UPLC). 2% or less for 18, 24, or 36 months.

[0223] In some embodiments, the relative abundance (% abundance) of oxidized species of Tagraxofusp in the lyophilisate is ) for 12 to 36 months or for 18 to 24 months, more than 2% or more than 1% does not increase.

[0224] In some embodiments, the relative abundance (% abundance) of oxidized species of Tagraxofusp in the lyophilisate is ) is a liquid pharmaceutical formulation of tagraxofusp for 18, 24, or 36 months. The relative abundance (%) of the metabolized species will likely change less than the abundance (%) of the metabolized species.

[0225] In some embodiments, the present disclosure provides a stable lyophilizate, comprising 1.0 mg of tagla xofusp, 25 mg of at least one disaccharide sugar, and 2.5 mg of at least one and 2.4 mg of at least one buffering agent, and the lyophilized product is a reverse phase lyophilized product. At least 24 were identified as markers of oxidative stress, as determined by high performance chromatography (RP-UPLC). Monthly, 0.03 mg or less, 0.02 mg or less, or 0.01 mg or less of oxidation impurities In some embodiments, the lyophilizate comprises 25 mg of at least one bulking agent. Further includes.

[0226] IV. Treatment method In some embodiments, the present disclosure provides a method for treating blastic plasmacytoid dendritic cell neoplasm (BPDCN). The present invention provides a method for treating a subject in need thereof, comprising intravenously injecting an effective amount of the reconstituted formulation into the subject. The method includes administering the reconstituted formulation for injection.

[0227] In some embodiments, the present disclosure provides a method for treating or inhibiting myeloproliferative neoplasms (MPNs). and administering to a subject in need thereof an effective amount of the reconstituted formulation for intravenous injection. In some embodiments, the present disclosure provides a method for the treatment of a patient with a monocytogenetic disorder comprising administering the reconstituted formulation to a patient. The present invention provides a method for inhibiting or treating myeloproliferative neoplasms associated with or resulting from renal cell carcinoma. A subject in need of the reconstituted formulation is administered an effective amount of the reconstituted formulation for intravenous injection. In some embodiments, the MPN is polycythemia vera (PV), essential hemophilia C (ESC), or Thrombocytopenia (ET), Myelofibrosis (MF), Chronic Myelomonocytic Leukemia (CMML), Chronic Neutrophil Virus (CHV) Cytic leukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), symptomatic eosinophilia injury, or other bone marrow disorders (which cause excess production of red blood cells, white blood cells, and / or platelets) ), or primary eosinophilic disorder (PED).

[0228] In some embodiments, the present disclosure provides a method for treating or inhibiting acute myeloid leukemia (AML). and administering the reconstituted formulation to a subject in need thereof for intravenous injection in an effective amount. administering the reconstituted formulation.

[0229] In some embodiments, the present disclosure provides a method for treating or inhibiting chronic myelomonocytic leukemia (CMML). The present invention provides a method for inhibiting the release of a steroid hormone by administering an effective amount of the reconstituted formulation to a subject in need thereof, the method comprising the steps of: administering the reconstituted formulation for

[0230] In some embodiments, the present disclosure provides a method for treating or inhibiting myelodysplastic syndrome (MDS). and administering the reconstituted formulation to a subject in need thereof for intravenous injection in an effective amount. administering the reconstituted formulation.

[0231] In some embodiments, the present disclosure provides a method for treating or inhibiting multiple myeloma in a subject in need of the treatment or inhibition of multiple myeloma. and administering to a subject in need thereof an effective amount of the reconstituted formulation. Administering the reconstituted formulation for intravenous injection.

[0232] In some embodiments, the present disclosure provides a method of treating an autoimmune disease, comprising administering to a subject a reconstituted and administering to a subject in need thereof an effective amount of the reconstituted formulation for intravenous injection. In some embodiments, the autoimmune disease is lupus (e.g., systemic erythrocyte seizure disorder). erythematosus, cutaneous lupus, discoid lupus), Sjogren's syndrome, inflammatory arthritis, Systemic sclerosis (SSc), morphea, psoriasis, lichen planus, dermatomyositis, lichen sclerosus, and skin Graft-versus-host disease (GVHD), adrenergic drug resistance, alopecia areata, ankylosing spondylitis, Antiphospholipid syndrome, autoimmune Addison's disease, autoimmune diseases of the adrenal gland, allergic encephalomyelitis , autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inflammatory eye disease, autoimmune newborn Thrombocytopenia, autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia Thrombocytopenia, autoimmune thyroiditis, Behcet's disease, bullous pemphigoid, cardiomyopathy, cardiotomy Syndrome, Celiac Sprue Dermatitis, Chronic Active Hepatitis, Chronic Fatigue Immune Deficiency Syndrome (CFID) S), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial keratoid Smallpox, CREST syndrome, cold agglutinin disease, Crohn's disease, dense deposit disease, mixed essential type Cryoglobulinemia, fibromyalgia / fibromyositis, glomerulonephritis (e.g., IgA nephropathy), Gluten-sensitive enteropathy, Goodpasture's syndrome, Graves' disease, Guillain-Barre, thyroid Hyperthyroidism (Hashimoto's thyroiditis), idiopathic pulmonary fibrosis, idiopathic Addison's disease, idiopathic thrombocytopenia Purpura (ITP), IgA neuropathy, juvenile arthritis, Meniere's disease, mixed connective tissue Myasthenia gravis, myocarditis, type I or immune-mediated diabetes, neuritis, Other endocrine deficiencies, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular Endocrinopathy, polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-MI, primary non-cancer Maglobulinemia, primary biliary cirrhosis, psoriatic arthritis, Raynaud's phenomenon, recurrent multiple cartilage lesions inflammation, Reiter's syndrome, rheumatic heart disease, rheumatoid arthritis, sarcoidosis, stiff Mann syndrome, Takayasu's arteritis, temporal arteritis, giant cell arteritis, ulcerative colitis, urticaria, grapefruit Uveitis, uveitis ophthalmitis, vasculitis (e.g., dermatitis herpetiformis type vasculitis), vitiligo, and Wegener's disease - granulomatous disease.

[0233] In some embodiments, the present disclosure provides a method for treating or inhibiting a solid tumor. and administering to a subject in need thereof an effective amount of the reconstituted formulation for intravenous injection. In some embodiments, the solid tumor is a sarcoma, carcinoma, or lymphoma. It is a pancreatic tumor.

[0234] V. Dosage and Cycle / Timing The treatment regimens disclosed herein include those that require tagraxofusp or a pharmaceutical composition thereof. The method includes administering tagraxofusp or a pharmaceutical composition thereof to a subject. In another embodiment, the dose is 4 μg / kg to 20 μg / kg. The sparing is administered at a dose of 7 μg / kg to 16 μg / kg. Tagraxofusp is administered at a dose of 7 μg / kg. Laxofusp is administered at a dose of 9 μg / kg. Sofusp is administered at a dose of 12 μg / kg. In another embodiment, the tagra is administered at a dose of 12 μg / kg over a period of 15 minutes. Xofusp is administered at a dose that is the maximum tolerated dose.

[0235] The treatment regimens disclosed herein include a single dose of 4 μg / kg to 20 μg / kg or In multiple doses (e.g., 2, 3, 4, 5, 6, 7, 8, 10 or more doses) For example, administration of tagraxofusp or a pharmaceutical composition thereof to a subject. Splenol is 1μg / kg, 4μg / kg, 7μg / kg, 8μg / kg, 9μg / kg, 1 It is administered at doses of 2 μg / kg, 16 μg / kg, or 20 μg / kg.

[0236] In certain embodiments, the methods of treatment provided herein include administering the drug in a single or multiple doses. The method includes administering glaxofusp or a pharmaceutical composition thereof. In this case, tagraxofusp or the pharmaceutical composition is effective in treating and / or managing the disease being treated. In certain embodiments, the administration frequency is from once a day to In certain embodiments, the conjugate is administered once a day, ranging from once every 1 to 8 weeks. For example, in certain embodiments, tagraxofusp is administered at 4 μg / kg / day. It is administered once a day at a dose of 100-200 μg / kg / day. 1μg / kg / day, 4μg / kg / day, 7μg / kg, 8μg / kg / day, 9μg / kg , 12 μg / kg / day, 16 μg / kg / day, or 20 μg / kg / day. In certain embodiments, tagraxofusp is administered once daily at a dose of 7 μg / kg / day. In a particular embodiment, tagraxofusp is administered daily at a dose of 9 μg / kg / day. In a particular embodiment, tagraxofusp is administered at a dose of 12 μg / kg / day. In a particular embodiment, tagraxofusp is administered at a dose of 16 μg / kg / In certain embodiments, the conjugate is administered in a dose of 2 to 4 days once a day. The dose may be administered once or more than once per day, for example, twice a day, three times a day, four times a day, five or more times a day.

[0237] The daily dosages disclosed herein may be administered on consecutive and / or non-consecutive days. In certain embodiments, the daily dosage may be administered consecutively throughout the week. In another specific embodiment, the dose is administered on days when the patient is not a patient on the first day of the week, e.g., Monday, Wednesday, and Friday. The daily dose is calculated on consecutive days throughout the week, e.g., Monday through Sunday. or on a few consecutive days (eg, 5 days).

[0238] In certain embodiments, tagraxofusp is administered once daily for one or more consecutive days. For example, tagraxofusp can be administered for 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, tagraxofusp is administered once daily for three days. In another embodiment, tagraxofusp is administered once daily for five days. In certain embodiments, the conjugate is administered once a week, twice a week, three times a week, four times a week, In certain embodiments, the drug is administered 5 times a week, 6 times a week, or 7 times a week. The treatment should be administered at least twice weekly (e.g., 2, 3, 4, 5 or more times) or once a treatment cycle. It is administered during

[0239] In certain embodiments, tagraxofusp is administered in one cycle, e.g., The cycle should last at least 1 week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or more). In certain embodiments, each treatment cycle lasts for at least one week (e.g., one week For example, tagraxofusp is administered in multiple cycles (for 1, 2, 3, 4, or 5 weeks or more). For example, in one embodiment, administration of tagraxofusp is repeated for 2 weeks, 3 weeks, , over multiple treatment cycles of 4, 5, 6, 7, or 8 weeks or more. In certain embodiments, the administration of glaxofusp is repeated. Administration of Xofusp should consist of at least one dose per treatment cycle (e.g., one dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, or 7 or more doses) In certain embodiments, the administration of tagraxofusp is repeated. Glaxofusp should be administered 1 to 5 times per treatment cycle (e.g., 1, 2, 3, 4 Repeated administration of tagraxofusp in doses of 100 mg once, 100 mg once, 5 ... In an embodiment, tagraxofusp is administered once daily for 1 to 5 consecutive days. In an embodiment, tagraxofusp is administered during any of the first 10 days of a 21-day cycle. In another embodiment, tagraxofusp is administered 3 times a day during a 21-day cycle. In another embodiment, tagraxofusp is administered for 5 days in a 28 day cycle. It is given.

[0240] Tagraxofusp may be administered repeatedly for an unlimited number of cycles. For example, In certain embodiments, tagraxofusp is deemed warranted by the treating physician. In certain embodiments, tagraxofusp is administered for 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 3 2, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50 or more cycles may be administered.

[0241] In certain embodiments, the dose of tagraxofusp is, for example, 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 4 Intravenous infusion over 0, 45, 50, 55, 60, 120, 180, or 240 minutes In certain embodiments, tagraxofusp is administered intravenously over a period of 15 minutes. It is administered as an infusion.

[0242] VI. Combination Therapy The disclosure also provides a method for administering to a subject a therapeutically effective amount of tagraxofusp and one or more additional therapies. Also provided are methods for treating and / or managing diseases by administering In embodiments, the combination therapy includes a pharmaceutical composition according to the present disclosure having the same effect as the conjugate. and at least one other therapy having a mechanism of action. The method is different from the pharmaceutical composition identified according to the method of the present disclosure and the conjugate. and at least one other therapy (e.g., a prophylactic or therapeutic agent) having a mode of action.

[0243] The pharmaceutical compositions disclosed herein and the additional therapy may be administered separately, simultaneously, or sequentially. The drug combination may act additively or synergistically. Combination therapy can reduce side effects associated with the therapies (e.g., prophylactic or therapeutic agents). do.

[0244] The therapeutic agents of the combination therapy can be administered to a subject in the same pharmaceutical composition. The therapeutic agents of the method may be administered simultaneously to a subject in separate pharmaceutical compositions. may be administered to a subject by the same or different routes of administration.

[0245] Unless otherwise indicated, all numbers recited throughout are modified by the term about. and thereby includes values ​​not more than 10% above or below the modified value.

[0246] Throughout this application, compositions are referred to as having or including specific components. ), or comprising, or where the process is Having, including, or comprising certain process steps When a composition of the present teachings is described as being "an additive," the composition also contains the recited components. consist essentially of or The process of the present teachings also consists of the steps of the process enumerated. consist essentially of or It is contemplated that the .alpha.-amino acid sequence comprises

[0247] In this application, an element or component may be referred to as an enumerated list of elements or components. are said to be included in and / or selected from the list of elements or components enumerated in When a component is included in a list, the component or element may be any of the listed components or elements. There may be one or more of the elements or components listed. It is to be understood that the term may be selected from the group consisting of two or more of the following: The elements and / or features of the described compositions, devices, or methods may be incorporated herein by any means, either expressly or implicitly. However, the present teachings may be combined in various ways without departing from the spirit and scope of the present teachings. Please understand that this may be possible.

[0248] The phrase "at least one" is used without prejudice to the phrase unless otherwise understood from context and usage. Each of the enumerated objects subsequent thereto, and various combinations of two or more of the enumerated objects. It should be understood that this includes individually.

[0249] "include", "includes", "includes "having", "has", "having "contain", "contains" or "includes" The use of the term "containing" (including its grammatical equivalents) is Generally, unless otherwise stated or understood from the context, the terms are open-ended and non-limiting, e.g. For example, it should be understood not to exclude additional unrecited elements or steps. Any and all examples or exemplary terms provided herein (e.g., "such as," "including," "including" The use of "including," "for example," and "for example" is merely intended to better illustrate embodiments and is not intended to be limiting in any way with respect to the claims. Nothing in this specification limits the scope of the invention unless otherwise stated in the claims. Any language in the specification may be used to indicate that any unclaimed element is essential to the practice of the present teachings. The information contained herein should not be construed as indicating any

[0250] Use of the singular forms herein, e.g., "a," "an," or "the," specifically refers to Unless expressly stated, the plural is included (and vice versa).

[0251] To the extent that the present teachings are operable, any sequence of steps or steps for performing a particular action may be omitted. It should be understood that the order is not important. Further, two or more steps or actions may be performed simultaneously. can be executed at any time.

[0252] At various places in this specification, values ​​are disclosed in groups or ranges. Such range formats are not intended to be limiting unless otherwise specified. It should be understood that these terms are used for convenience and brevity and should be interpreted flexibly. The description includes each and every individual subcombination of the members of such groups and ranges. and any combination of the various endpoints within such groups or ranges. are specifically contemplated. For example, the integers in the range 0 to 40 can be expressed as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 1 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 , 33, 34, 35, 36, 37, 38, 39, and 40 are specifically disclosed. In the figure, the integers in the range from 1 to 20 are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, and 20 shall be disclosed separately. is specifically intended. EXAMPLES

[0253] In order that the invention described herein may be more fully understood, the following examples are set forth. These examples are included merely to illustrate certain aspects and embodiments of the disclosure and are not to be construed as limiting the scope of the invention in any way. It should be understood that the formulas should not be construed as limiting the invention. Reasonable variations as may occur to one skilled in the art may be made without departing from the scope of the disclosure. This can be done in the specification.

[0254] Tagraxofusp was genetically engineered to produce a target protein within the inclusion bodies. It is a fusion protein produced by fermentation in E. coli construct. Fusp proteins bind to human IL-3 and truncated diphtheria to target CD123-expressing cells It is a CD123-directed cytotoxin composed of a fusion protein with toxin (DT). The DT portion is a diphtheriae containing the catalytic and translocation domains. The amino acid sequence of Tagraxofusp is as follows: It is as below:MGADDVVDSSKSFVMENFSSYHGTKPGYVDS IQKGIQKPKSGTQGNYDDDWKGFYSTDNKYDAAGYSVDNE NPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSL TEPLMEQVGTEEFIKRFGDGASRVVLSLPFAEGSSSVEYI NNWEQAKALSVELEINFETRGKRGQDAMYEYMAQACAGNR VRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKM SESPNKTVSEEKAKQYLEEFHQTALEHPELSELKTVTGTN PVFAGANYAAWAVNVAQVIDSETADNLEKTTAALSILPGI GSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGEL VDIGFAAYNFVESIINLFQVVHNSYNRPAYSPGHKTRPHM APMTQTTSLKTSWVNCSNMIDEIITHLKQPPLPLLDFNNL NGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKN LLPCLPLATAAPTRHPIHIKDGDWNEFRRKLTFYLKTLEN AQAQQTTLSLAIF (sequence number 1).

[0255] Example 1: Baseline Aqueous Formulation The baseline aqueous formulation of injectable tagraxofusp was not a lyophilized formulation. The formulation did not exhibit the desired shelf life at the preferred storage temperatures as illustrated in this example. I did.

[0256] Tagraxofusp for injection (1 mg / mL (1 mL / vial)) is a colorless, transparent 2cc The liquid drug was provided in a glass vial. The composition of the drug solution was 75 mM N aCl (USP, EP), 5% (w / w) sorbitol (USP / NF, EP), and Tag at 1.0 mg / mL in 20 mM Tris buffer (USP, EP), pH 7.5 The drug product was laxofusp. The drug product is intended to be stable under refrigerated storage conditions (5 ± 3°C). However, when generating long-term stability data, it was determined that storage at -20°C was sufficient to achieve the desired shelf life. Reversed-phase ultra-performance chromatography (RP-UPLC), Size exclusion high performance chromatography (SEC-HPLC), sodium dodecyl sulfate poly( SDS-PAGE, AEX-UPLC, and cytotoxicity Stability testing, including evaluation by various analytical techniques such as potency by bioassay, is performed to determine the However, the desired acceptance criteria can be met within 12 to 18 months at 5±3°C. However, when stored at -20°C, the purity or potency is significantly reduced. The study demonstrated that all acceptance criteria were met up to 36 months into the study without any adverse events.

[0257] To obtain the desired shelf life at the preferred storage temperature, a lyophilized formulation of tagraxofusp is Examples 2-5 below show the formulations used to arrive at the final improved formulation for lyophilization. Some experimental processes and procedures that may be used are provided, examples of which are shown in Example 6.

[0258] Example 2: Evaluation of Surfactants for Use in Improved Formulations for Lyophilization of proteins that form microparticles, especially at the lower protein concentrations used for dose delivery. To counter this tendency, as a preventative measure, a suitable surfactant is added to the formulation.

[0259] Table 1 shows the results of adding lyophilized tagraxofusp to a 50cc saline infusion bag. , show the results of a study with varying amounts of surfactant stirred for 6 hours.

[0260] The freeze-drying step was carried out as follows: the product-filled vials were dried in an elastomeric solution. The flasks were semi-stoppered with stoppers and loaded onto shelves in a freeze-drying chamber maintained at 10°C for pre-cooling. The step designated as heat treatment or annealing involves increasing the shelf temperature from 10°C to 30°C for 3 hours. Then, lower the temperature to -40°C, keep it at -40°C for 1 hour, raise it to -10°C for 1 hour, and keep it at -10°C for 1 hour. The temperature was then lowered to -40°C for 1 hour and then maintained at -40°C for an additional hour. The condenser was then cooled to below -60°C and the vacuum pump was primed. The chamber pressure was reduced to 0.133 mBar to initiate ice sublimation (primary drying stage). During the primary drying stage, the shelf temperature is increased from -40°C to -25°C in 1 hour. and maintained at this temperature for 40 hours. The shelf temperature was then increased to +25° C. for 14 hours. After this, the shelf temperature was maintained for an additional 23.3 hours in the secondary drying stage to complete the drying cycle. Finally, the chamber was evacuated with nitrogen to an atmosphere of 900 mBar and then The vial was completely stoppered under nitrogen and removed from the chamber.

[0261] The results show that the products are due to aggregation (as seen by recovery studies using SEC-HPLC). A small amount of surfactant is sufficient to prevent loss of cellulose and the formation of visible particles. Both polysorbate 80 and poloxamer 188 reduced particle formation. However, polysorbate 80 was able to inhibit this reaction at a lower concentration than poloxamer 188. Based on these results, it was found that polysorbate 8 0 was selected as the surfactant and included in all subsequent development studies. [Table 1]

[0262] The test was carried out to determine the amount of peroxide in the surfactant and in the drug product upon release and during stability testing. The results show a correlation between the amount of impurities identified as oxidized species of tagraxofusp detected and the amount of oxidized species of tagraxofusp detected. Higher levels of peroxide in surfactants (e.g., peroxide values ​​>2 meqO2 / kg) , resulting in higher levels of this impurity (e.g., >1%) in the final drug product. The peroxide content of the preparation was determined by potentiometric titration according to the peroxide values ​​of the European Pharmacopoeia (EP) 2.5.5. The results were evaluated using the standard deviation.

[0263] Quantification of oxidized species of tagraxofusp by RP-UPLC Tagraxofuspida solution was analyzed using reversed-phase ultra-performance chromatography (RP-UPLC). The purity of the drug substance (DP) was determined using an Agilent Zorbax 30 A reversed-phase ultra-high performance liquid chromatography was performed using a 0SB-C3, 2.1 × 100 mm, 1.8 μm column. The analysis was carried out on a RP-UPLC system. The column was buffered with 0.1% TFA. The elution was performed using a discontinuous gradient of water and acetonitrile with A280. The peak areas of the main peak and the major impurities are reported as a percentage of the total peak area.

[0264] Equipment: Ultraviolet (UV) detector, degassing module, thermostatically controlled column compartment ment, and a refrigerated autosampler (e.g., a 250 μL mixer and a 50 μL injection loop) A 1.8 μm particle size detector was equipped with a Waters Acquity H class UPLC with a A liquid chromatography system capable of handling reversed-phase columns of any diameter.

[0265] Solution: Mobile phase A: Purified water containing 0.1% trifluoroacetic acid (TFA), Mobile phase B: 0 Acetonitrile (ACN) containing .1% TFA.

[0266] Reference standards and sample preparation: Reference materials were tested undiluted. The injection volume was calculated to reach the target volume. For the reference material, the target loading was 4.0 μg (1.5 ml). The target drug load was 4.0 μg (1 (4.0 ul of DP at 100 mg / mL was injected).

[0267] Equipment setup: analysis-specific conditions (injection loop size: 50 μL) [Table 2]

[0268] Sample Setup: Run sequence for sample analysis [Table 3] *Calculated based on a sample injection load of 4.0 μg (4 μL for 1.0 mg / mL DP). The sample amount determined by

[0269] Prior to sample analysis, a blank injection was performed followed by five injections of the reference standard for system suitability. After nine sample injections, the reference material (system suitability) was blocked after the final sample injection. A racket of injections was performed. Each sample was injected in triplicate.

[0270] Peak Integration: The identity of a peak in a sample is determined by the integration of the peak with the most recently injected reference material. Confirmed by comparison. Retention time of main peak of tagraxofusp reference material, impurity 1RR T, and impurity 2RRT were within the ranges specified under system suitability.

[0271] System suitability. The chromatograms of the reference materials are visually compared to the exemplary chromatograms. The bracketing reference material injections were the first five system suitability injections of the reference material. The purity of the main peak was within ±2.0% of the average purity (%) of the reference material. The main peak purity CV of the combined injection was less than 2%. The USP theoretical plate standard was ≥11,000. The P tailing was less than 2.2. The main peak of the reference material was from 13.9 to 16.0 min. The RRT of impurity 1 in the reference material ranged from 0.91 to 0.92. The RRT of impurity 2 in the reference material was 0.93-0.95.

[0272] Assay acceptance criteria: All samples were run before and after a bracketing standard. For each injection, the purity column volume (CV) (%) was 2% or more higher than the purity of the main peak. For three injections of the sample, the CV was The rate was less than 2% (n=3).

[0273] Example 3: Evaluation of stabilizers for use in improved formulations for lyophilization Thermal stability of tagraxofusp bulk drug substance (BDS) was determined by differential scanning calorimetry (DSC). Studies have evaluated the presence of various Generally Recognized As Safe (GRAS) stabilizers. Among the excipients evaluated, sucrose was found to provide the greatest increase in melting temperature (Tm). The results are shown in Table 2 and Figure 1. The high Tm values ​​indicate that the excipients By increasing the denaturation temperature, which is an indicator of better stabilization of the tagra molecule, As can be seen in Table 2, sucrose and mannose provide protection to the sufsuf molecule. Nititol was ranked the highest among the excipients evaluated. Sucrose was also A freeze-drying process that protects against denaturation during both the freezing and drying stages of the drying cycle. Additionally, mannitol also provides structure to the cake. Acts as a caking agent to aid in the removal of moisture during the sublimation and secondary drying processes. These studies were performed on non-lyophilized samples. [Table 4]

[0274] Example 4: Evaluation of buffers for improved formulations for lyophilization Four different buffers suitable for adjusting the desired pH to 7.5 were added to the lyophilized tagraxon. All formulations were evaluated in a short-term stability study of Fusp samples. buffer) was added to 10 mM buffer (phosphate, arginine, histidine, pH 7.5). These solutions were prepared by diafiltration into either 100% ethanol or Tris buffer. , sucrose (10% w / v) and polysorbate 80 (0.25% w / v) were added. The solution was filtered through a 0.22 μM low protein binding filter. The filtered solution was added to a clean 3 cc glass vial. The filled vial was , semi-stoppered with coated stoppers and placed in the chamber of a freeze-dryer (model: Epsilon The freeze-drying cycle used was as follows: The procedure was as follows: shelves were cooled to -40°C for 3 hours, followed by 1 hour at -15°C. The shelves were then cooled again to -45°C and the vacuum was started. The pressure was 0.133 Once below mBar, primary drying was carried out at a shelf temperature of -30°C for approximately 16 hours. The shelf temperature was raised to 25°C over 14 hours and maintained at 25°C for an additional 12 hours during secondary drying. At the end of the cycle, the chamber was vented with dry air and the vials were placed in the chamber. The stoppered vials were removed and crimped with aluminum crimps.

[0275] The quality of the cake was assessed by appearance and the reconstituted solution was analyzed by SEC-HPLC. The transparency and area (%) of the tagraxofusp monomer were tested. Immediately after freeze-drying The tests were performed at 0 °C and after 4 weeks of storage at 50 °C. The results are summarized in Table 3. The Tris buffer also functions as a buffer for the bulk drug substance, so the Tris buffer The use of is buffer can simplify the manufacturing process. was selected as the buffer for subsequent studies. [Table 5] PT = phosphate buffer containing polysorbate 80, AT = arginine buffer containing polysorbate 80 Nin buffer HT = histidine buffer with polysorbate 80, TT = T with polysorbate 80 Ris buffer

[0276] Example 5: Evaluation of bulking agents for improved formulations for lyophilization Laboratory-scale freezing using sucrose (10% w / v) as a bulking agent / stabilizer The first freeze-drying tests carried out in the dryer gave good cakes and freeze-dried tagla. The results showed acceptable stability of Xofusp. However, the larger freeze-dryer unit In scale-up trials at low temperatures, cake appearance was not consistently acceptable; It was observed that shrinkage and other issues caused the product to fail. To address this, additional Lyophilization experiments were performed in the laboratory, where another excipient commonly used in injectable products was Mannitol, which is a saccharide, was used as a bulking agent together with sucrose. The goal is to prevent freezing and cracking while providing a stiffer cake structure that ensures the cake does not shrink. Sucrose is added during the freeze-drying process to protect proteins from the stresses of lyophilization and / or dehydration. The objective of this study was to act as an amorphous cryo / lyoprotectant during cryoprotection.

[0277] Additional lyophilization experiments were performed after modifying the formulation to include mannitol as a bulking agent. To ensure control of fine particles in the new mannitol / sucrose matrix The amount of surfactant required was determined. Dried samples were analyzed for cake appearance, reconstitution time, pH, and Appearance after reconstitution, percentage of monomer by RP-HPLC, and Karl Fisher The results of these tests are summarized in Table 4. Polysorbate 80 surfactant at a level of 0.25% w / v was shown to last up to 11 months at room temperature. The acceptable stability of the lyophilized drug product for tagraxofusp remains adequate for the It was concluded that there was. [Table 6] * After storage at room temperature for approximately 11 months.

[0278] Example 6: Final composition of the solution for lyophilization: Based on the above results and confirmation from the formulation development run, tagraxon for lyophilization The formulation of Fusp solution (1 mg / mL) is recommended for the proposed clinical trials, as shown in Table 5. It was recommended that formulations be scaled consistently for all materials when presenting the 1.5 mg dose. This table lists the composition of the solution for lyophilization as well as the rationale for the addition of each component. do. [Table 7] *This amount does not include 4% overfill by weight **Removed during freeze-drying

[0279] Physicochemical and biological properties: The pH of the drug was set at 7.5, close to the physiological pH of 7.4. This pH was consistent with both the pH of the liquid drug formulations from DS at pH < 6.5. Provides security against the known physical instability / loss of activity (potency) of When the dried product was reconstituted with water for injection (WFI), it was formulated as a free 1 mg / mL dose of tagraxofusp. A clear liquid is delivered that is essentially particulate free. Low levels of surfactants are present. Currently, protein aggregation, a known attribute of DS, is prevented by using lower concentrations of DS than those used for injection. Prevent this by diluting the product.

[0280] The following is an example of a procedure for making one of the formulations disclosed herein.

[0281] Example 7: Preparation of injectable tagraxofusp The manufacturing process for tagraxofusp for injection (1 mg / vial) is as follows: Procedure: Formulate the solution for lyophilization, filter through a grade 0.22 μm sterile filter, and filter The process consists of filling glass vials with the sterile solution and freeze-drying the filled vials. and obtain the final pharmaceutical cake.

[0282] Formula: The formulation of the lyophilized product was established as outlined herein above. Verify the pH, density, and tagraxofusp concentration of the formulated drug solution before proceeding In order to achieve this, in-process specifications were established.

[0283] Sterilized through a 0.22 μm membrane filter: The bulk solution of tagraxofusp for injection, like all protein therapeutics, Terminal sterilization is not possible due to the heat sensitivity of the polymer molecules. Thus, standard sterile filtration is required. The procedure is carried out by passing the mixture through one 0.45 μm pre-filter, followed by a polycarbonate sterile filter. The housing contains two 0.22 μm hydrophilic polyvinylidene fluoride (PVDF) membranes. The bulk compounded solution was designed to be sterilized by membrane filtration through a sterilizer. As is typical in sterile filtration operations, the solution is passed through two sterilizing membranes in series to provide redundant sterilization capacity. Provide.

[0284] Aseptic filling of sterile solutions: The vial and stopper combination selected for Tagraxofusp for injection was The manufacturing line of the contract manufacturer was certified. Each vial contained 1.04 mL (1.0 6 grams) or 1.56 mL (1.59 grams) of membrane-filtered sterile solution of Tagraxofusp The liquid is filled into Type I depyrogenated glass vials and the vials are partially stoppered with sterile rubber stoppers. The filled vials are then transferred to shelves in the lyophilizer chamber for lyophilization. will be done.

[0285] Overfill: Clinical drug product: 1 mg / vial and 1.06 gm (1.04 mL) per vial Target fill of 1.5 mg / vial and 1.59 gm (1.56 mL) per vial Each vial is labeled with either a 4% overfill target fill or a 4% overfill target fill. It contains xofusp, and considering the displacement of the cake during reconstitution, during the dosage preparation, 1.0 After reconstitution with 1.5 mL / 1.5 mL WFI, the product concentration was precisely 1.0 mg / mL. This overfill allows for accurate dosing on a dose / kg basis. .

[0286] Freeze-drying cycle development: The main excipients in the injectable solution of tagraxofusp, sucrose and mannitol, are 25 mg / mL, and therefore significantly less active ingredient present at 1 mg / mL. Therefore, the thermal properties of a frozen solution depend on the freezing state of these two components. The determination of the temperature for freeze-drying by differential scanning calorimetry (DSC) is mainly determined by the properties of the The freezing behavior of the xofusp solution showed a slight endothermic event even at about 32°C. The drying parameters were set so that the product temperature remained below -32°C during the sublimation stage of drying. To ensure complete crystallization of mannitol and other metastable phases, the -1 This involves a heat treatment step during freezing at 5°C for approximately 1 hour. Once primary (sublimation) drying is complete, Secondary (desorption) drying was performed by increasing the shelf temperature to 25°C and maintaining it at 25°C for the remainder of the drying cycle. The steps are completed such that a dry product is obtained with low residual water levels.

[0287] Several experiments were performed using various combinations of shelf temperature, chamber pressure, and duration of each stage. After several experimental trials, a freeze-drying cycle was identified that consistently yielded a well-formed cake with low residual water. The final decision will be made.

[0288] Table 6 shows the final protocol used for lyophilization of injectable tagraxofusp. In addition to the cycle parameters listed above, standard process parameters for production-scale equipment are also listed. The final cycle includes any additional specified loading time and extended freezing time required for operation. Once the lyophilization process was complete, the dried vials were placed completely in the lyophilization chamber. The bottles are stoppered, unloaded, sealed with an aluminum crimp, and then rinsed. The vials are subjected to 100% visual inspection, quality testing, labeling, and packaging. [Table 8]

[0289] Density of tagraxofusp bulk solution for freeze-drying: The density of the tagraxofusp bulk solution for freeze-drying was measured at room temperature using the Anton-Paar It was determined using a density meter and found to be 1.02 g / mL.

[0290] Determination of the displacement volume of lyophilisates The replacement volume of the lyophilisate was replaced by 1.0 g or 1.5 g of lyophilised material. is the volume of the reconstituted solution in milliliters that was replaced. The replaced volume is exactly 1. to achieve a 1 mg / mL solution when reconstituted with 0 mL or 1.5 mL of WFI. This is necessary to determine the required overfill. 1000 mg of lyophilized material was placed in a 10 mL volumetric flask and then diluted with 10.0 mL The solids content was then determined by adding 100 ml of water. The volume of solution strained was measured to be greater than 10.0 mL. 1 gm of lyophilized material was dissolved. It was found that approximately 0.73 mL of water was displaced.

[0291] Using this relationship, the substitution value of the lyophilized cake was calculated as follows: Active Pharmaceutical Ingredient The total weight of (API) + excipients added per mL of drug product (DP) solution is 55. 94 mg. Therefore, 1.0 mL of fill is required for 1.0 mg / mL tagraxofusp. For the volume, the replacement value for dry material is 0.04 mL, giving a total volume of 1.04 mL or 0.9 6 mg / mL of active substance is obtained. This explains the discrepancy caused by the displacement volume. To do this, fill approximately 1.04 mL or 1.56 mL of solution, giving 1.0 mg / by, respectively. The resulting solution must be freeze-dried for 1.5 mg / vial filling and 1.5 mg / vial filling. The dry product contains sufficient Tagraxofus to deliver the target concentration in reconstituted solution. Contains pro-active substances. The present application provides the following aspects of the invention. (Aspect 1) A stable solution for lyophilization in a pharma- ceutically acceptable aqueous carrier, comprising: 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v of at least one disaccharide sugar; 0.05-1.5% w / v of at least one surfactant; At least one buffering agent at 5-25 mM, and having a pH of 6.5-9.0; A stable solution for lyophilization, wherein the surfactant has less than 3% peroxide. (Aspect 2) The method according to embodiment 1, wherein the lyophilization solution further comprises at least one bulking agent at 2-10% w / v. Lyophilized solution as above. (Aspect 3) 0.6 to 1.4 mg / mL tagraxofusp or 0.7 to 1.3 mg / mL tagraxofusp Laxofusp, or 0.8 to 1.2 mg / mL tagraxofusp, or 1 mg / mL The lyophilized solution of any one of the preceding aspects, comprising tagraxofusp. (Aspect 4) The surfactant is present in an amount of 0.07 to 1.5% w / v, or 0.1 to 1.3% w / v, or 0 .15-1.2% w / v, or 0.25-1% w / v, or 0.24-0.26% w / v The lyophilized solution of any one of the preceding aspects, wherein the solution is present in an amount of (Aspect 5) The surfactant is selected from polysorbates or poloxamers, or The surfactants are poloxamer 188, poloxamer 168, poloxamer 144, and polyiso polysorbate 20, polysorbate 60, or polysorbate 80, or 4. The lyophilized solution of any one of the preceding aspects, wherein the surfactant is polysorbate 80. . (Aspect 6) The disaccharide sugar is 2 to 8% w / v, or 2 to 6% w / v, or 2 to 4% w / v, or 2 any one of the preceding aspects, wherein the compound is present in an amount of from about 2.45 to about 3% w / v, or from about 2.45 to about 2.55% w / v. Item 7. The freeze-dried solution according to item 5. (Aspect 7) the disaccharide sugar is selected from trehalose, lactose, and sucrose; or 4. The lyophilization solution of any one of the preceding aspects, wherein the disaccharide sugar is sucrose. (Aspect 8) The bulking agent is 2 to 8% w / v, or 2 to 6% w / v, or 2 to 4% w / v, or 2 to Any one of the preceding aspects, wherein the compound is present in an amount of 3% w / v, or 2.45 to 2.55% w / v. The freeze-dried solution according to claim 1. (Aspect 9) The bulking agent is selected from the group consisting of glycine, maltose, glucose, mannitol, and sorbitol. or the bulking agent is mannitol. The lyophilized solution described. (Aspect 10) At least one buffering agent is present at a concentration of 5-15 mM, or 7-12 mM, or 10 mM. The lyophilization solution of any one of the preceding aspects. (Aspect 11) The buffer is selected from phosphate, arginine, histidine, and Tris HCl. or the buffer is Tris HCl. Lyophilization solution. (Aspect 12) Any of the preceding embodiments, wherein the pH is from 6.5 to 8, or the pH is from 7 to 8. 3. The freeze-dried solution according to claim 1 . (Aspect 13) A stable lyophilized solution in a pharma- ceutically acceptable aqueous medium, comprising: 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v sucrose; 0.05-1.5% w / v polysorbate 80; 5 to 25 mM Tris HCl; It has a pH of 6.5 to 9. A lyophilized solution, wherein the polysorbate 80 has 3% or less peroxide. (Aspect 14) 14. The method according to claim 13, wherein the lyophilization solution further comprises 2 to 10% w / v mannitol. Lyophilization solution. (Aspect 15) 1 mg / mL tagraxofusp; 2.45-2.55% w / v sucrose; 2.45-2.55% w / v mannitol; 0.24-0.26% w / v polysorbate 80; 9 to 11 mM Tris HCl; It has a pH of 6.5 to 9. 14. The lyophilized product of claim 13, wherein the polysorbate 80 has 3% or less peroxide. solution. (Aspect 16) 2. A lyophilisate prepared from the lyophilisation solution of any one of the preceding aspects. (Aspect 17) (a) Relative abundance (%) of oxidized species of Tagraxofusp over a period of 12–36 months. The relative abundance of the oxidized species of tagraxofusp (% ) does not increase by more than 2% or 1% over a period of 18 to 24 months; (b) Relative abundance (%) of acidic species of Tagraxofusp over 18, 24, or 36 months. The relative abundance of the same acidic species of tagraxofusp in liquid tagraxofusp formulations during storage ( %), (c) the formulation provides a required dose of 1 to 1.5 mg on a dry weight basis; (d) The lyophilized product is stable for at least 24 months at a storage temperature of 2°C to 8°C. or the freeze-dried product has a shelf life of 24 months at a storage temperature of 2°C to 8°C. ~5 years stable and / or (e) Oxidation impurities were determined by reversed-phase ultra-performance chromatography (RP-UPLC). and / or the oxidized impurities are 2% or less, or 1% or less, when , a single peak of +16 Da from the tagraxofusp peak in mass spectrometry and / or the oxidation impurities can be measured as It elutes before the glaxofusp peak and is the most abundant oxidized 17. The method according to claim 16, wherein the peak of the pure product is the closest peak to the peak of the tagraxofusp. Lyophilized product as above. (Aspect 18) A stable lyophilisate comprising: 1 mg of tagraxofusp, 25 mg of at least one disaccharide sugar; 25 mg of at least one surfactant; 2.4 mg of at least one buffering agent; The lyophilized material is subjected to reversed-phase ultra-performance chromatography (RP- A stable lyophilizate with less than 2% oxidative impurities as determined by UPLC. (Aspect 19) (a) further comprising 25 mg of at least one bulking agent; and / or (b) Relative abundance (%) of oxidized species of Tagraxofusp over a period of 18–24 months. 20. The stable lyophilisate according to embodiment 18, wherein the amount of lyophilisate per unit area does not increase by more than 2% or more than 1%. (Aspect 20) 1. A method for preparing a lyophilisate of tagraxofusp, comprising the steps of: a) providing a lyophilized solution according to any one of aspects 1 to 15; b) lyophilizing the solution to form a lyophilisate. (Aspect 21) The freeze-drying is carried out at a temperature between −40° C. and 25° C. for a period of 2 to 7 days, and / or The freeze-drying step comprises a loading step, at least one freezing step, and at least one and at least one drying step; and / or The freeze-drying step includes a loading step, at least two freezing steps, and at least two and at least one drying step; and / or The freeze-drying step includes a loading step, at least two freezing steps, and a time period of less than one day. At least two annealing steps are performed over a period of 1–5 days. and at least one drying step in which the drying step is performed. (Aspect 22) The freeze-drying process comprises the following freeze-drying cycle: a) loading a sample containing the lyophilization solution into a lyophilizer, said sample being Pre-cool the freeze-dryer at ambient pressure for 10 min by reducing the freeze-dryer temperature to 10 °C. To load and b) freezing the sample in a first freezing step, wherein the temperature of the freeze-dryer is The temperature changes from 10°C to -40°C over 180 minutes at ambient pressure in a freeze dryer. And, c) freezing the sample in a second freezing step, wherein the temperature of the freeze-dryer is , freezing the sample at -40°C for 60 minutes at ambient pressure in a freeze dryer; d) annealing the sample in a first annealing step, The temperature of the freeze dryer was changed from -40°C to -15°C over a period of 60 minutes at ambient pressure in the freeze dryer. Changing, annealing, e) annealing the sample in a second annealing step, The temperature of the freeze dryer is held at -15°C for 60 minutes at ambient pressure in the freeze dryer. And f) annealing the sample in a third annealing step, The temperature of the freeze dryer was changed from -15°C to -40°C over a period of 60 minutes at ambient pressure in the freeze dryer. Changing, annealing, g) annealing the sample in a fourth annealing step, The temperature of the freeze dryer is held at -40°C for approximately 60 minutes at ambient pressure in the freeze dryer. and h) drying the sample in a first primary drying step, comprising: The temperature was held at -40°C and the freeze dryer pressure was 0.133 mBar for 10 minutes. and drying the material. i) drying the sample in a second primary drying step, the freeze-dryer The temperature was changed from -40°C to -25°C and the pressure of the freeze dryer was increased for 60 minutes. Drying, held at 0.133mBar; j) drying the sample in a third primary drying step, comprising: The temperature was held at -25°C and the freeze dryer pressure was 2400 at 0.133 mBar. and drying the mixture for 10 minutes. k) drying the sample in a fourth primary drying step, The temperature was changed from -25°C to 25°C and the freeze dryer pressure was increased over a period of 840 minutes. Drying, held at 0.133mBar; l) drying the sample in a secondary drying step, wherein the temperature of the freeze-drier is The freeze-dryer pressure was maintained at 0.1333 mBar for 1390 minutes. 22. The method of claim 20 or 21, comprising: drying the mixture. (Aspect 23) A pharma- ceutically acceptable formulation reconstituted in an aqueous medium for intravenous injection, comprising: 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v of at least one disaccharide sugar; 0.05-1.5% w / v of at least one surfactant; and 5-25 mM of at least one buffering agent. (Aspect 24) (a) Relative abundance (%) of oxidized species of Tagraxofusp over a period of 18–24 months. not increase by more than 2% or more than 1%, (b) the lyophilization solution further comprises at least one bulking agent at 2-10% w / v; (c) The formulation contains 0.5 to 1.5 mg / mL of tagraxofusp, or 0.6 to 1. 4 mg / mL tagraxofusp, or 0.7 to 1.3 mg / mL tagraxofusp, 0.8 to 1.2 mg / mL tagraxofusp or 1 mg / mL tagraxofusp Including, (d) the surfactant is present at 0.07 to 1.5% w / v, or 0.1 to 1.3% w / v, or 0.15-1.2% w / v, or 0.25-1.0% w / v, or 0.24-0.2 present in an amount of 6% w / v, (e) the surfactant is selected from polysorbates or poloxamers; or The surfactant is poloxamer 188, poloxamer 168, poloxamer 144, Polysorbate 20, Polysorbate 60, or Polysorbate 80, or The surfactant is polysorbate 80, (f) the disaccharide sugar is 2 to 8% w / v, or 2 to 6% w / v, or 2 to 4% w / v; or in an amount of 2-3% w / v, or 2.45-2.55% w / v; (g) the disaccharide sugar is selected from trehalose, lactose, and sucrose; or the disaccharide sugar is sucrose; (h) The bulking agent is 2 to 8% w / v, or 2 to 6% w / v, or 2 to 4% w / v, or 2 2.45-2.55% w / v; and (i) the bulking agent is present in an amount of 1.0-3.0% w / v, or 2.45-2.55% w / v, selected from lysine, maltose, glucose, mannitol, and sorbitol; Or the bulking agent is mannitol, (j) at least 5 to 15 mM, or 7 to 12 mM, or 9 to 11 mM, or 10 mM Another buffer is added, (k) the buffer comprises phosphate, arginine, histidine, and Tris HCl; and / or the buffer is Tris HCl; and / or (l) The method according to claim 23, wherein the pH is 6.5 to 9, or the pH is 7 to 8. A reconstituted formulation for intravenous injection of. (Aspect 25) 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v sucrose; 0.05-1.5% w / v polysorbate 80; 5 to 25 mM Tris HCl; It has a pH of 6.5 to 9. 25. The method of claim 23, wherein the aqueous medium is water for injection (WFI). Reconstituted formulation for. (Aspect 26) 26. The method according to claim 25, wherein the reconstituted formulation further comprises 2-10% w / v mannitol. Reconstituted formulation as described above. (Aspect 27) 0.9 to 1.1 mg / mL tagraxofusp; 2.45-2.55% w / v sucrose; 2.45-2.55% w / v mannitol; 0.24-0.26% w / v polysorbate 80; 9 to 11 mM Tris HCl; 27. The method for intravenous injection according to any one of aspects 23 to 26, having a pH of 6.5 to 9. A reconstituted formulation of. (Aspect 28) When diluted in an infusion bag, the infusion bag is provided with a substantially particulate-free fluid. 28. The reconstituted composition for intravenous injection according to any one of aspects 23 to 27, formulation. (Aspect 29) A method for treating a disease comprising administering to a subject in need thereof an effective amount of a reconstituted formulation. Administering a reconstituted formulation for intravenous injection according to any one of aspects 23 to 28. wherein the disease is a) Myeloproliferative neoplasms (MPN) with monocytosis, b) Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential pulmonary hypertension (ESH), and Thrombocythemia (ET), myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), chronic myelofibrosis (CRC), Neutrophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), symptomatic eosinophilic disorders or other bone marrow disorders (which cause excess production of red blood cells, white blood cells, and / or platelets) myeloproliferative neoplasms (MPNs), which are primary eosinophilic disorders (PEDs), c) acute myeloid leukemia (AML), d) chronic myelomonocytic leukemia (CMML), e) myelodysplastic syndromes (MDS), f) multiple myeloma, g) blastic plasmacytoid dendritic cell neoplasm (BPDCN), h) autoimmune diseases; i) An autoimmune disease, wherein the autoimmune disease is lupus (e.g., systemic lupus erythema tos, cutaneous lupus, discoid lupus), Sjogren's syndrome, inflammatory arthritis, systemic Sexual sclerosis (SSc), morphea, psoriasis, lichen planus, dermatomyositis, lichen sclerosus, and skin transfers. Graft-versus-host disease (GVHD), adrenergic drug resistance, alopecia areata, ankylosing spondylitis, anti-rheumatoid arthritis phospholipid syndrome, autoimmune Addison's disease, autoimmune diseases of the adrenal gland, allergic encephalomyelitis, autoimmune diseases of the adrenal gland Autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inflammatory eye disease, autoimmune neonatal hematology Placopenia, autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia Myelopathy, autoimmune thyroiditis, Behcet's disease, bullous pemphigoid, cardiomyopathy, open heart syndrome , Celiac Sprue Dermatitis, Chronic Active Hepatitis, Chronic Fatigue Immune Deficiency Syndrome (CFIDS) , chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid , CREST syndrome, cold agglutinin disease, Crohn's disease, dense deposit disease, essential mixed Crohn's disease Myoglobulinemia, fibromyalgia / fibromyositis, glomerulonephritis (e.g., IgA nephropathy), glomerulonephritis Ten irritable bowel disease, Goodpasture's syndrome, Graves' disease, Guillain-Barre, thyroid function Hyperthyroidism (Hashimoto's thyroiditis), idiopathic pulmonary fibrosis, idiopathic Addison's disease, idiopathic thrombocytopenic purpura IgA neuropathy, juvenile arthritis, Meniere's disease, mixed connective tissue disease , multiple sclerosis, myasthenia gravis, myocarditis, type I or immune-mediated diabetes, neuritis, and other Endocrine deficiency, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular endocrine Secretory disorders, polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-MI, primary aggrand maggots Globulinemia, primary biliary cirrhosis, psoriatic arthritis, Raynaud's phenomenon, relapsing polychondritis, Reiter's syndrome, rheumatic heart disease, rheumatoid arthritis, sarcoidosis, stiff man syndrome, Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, urticaria, uveitis , uveitis ophthalmia, vasculitis (e.g., dermatitis herpetiformis type vasculitis), vitiligo, and Wegener's syndrome The method of claim 1, wherein the autoimmune disease is selected from the group consisting of blastoma and myeloma. (Aspect 30) Methods for treating or inhibiting solid tumors, comprising administering to a subject a reconstituted formulation. and an effective amount of a reconstituted preparation for intravenous injection according to any one of aspects 23 to 28. and optionally, the solid tumor is a sarcoma, a carcinoma, or a lymphoma. A method selected from the group consisting of (Aspect 31) A stable lyophilized pharmaceutical composition according to any one of aspects 1 to 15 in a vial. drying solution. (Aspect 32) 20. The lyophilisate according to any one of aspects 16 to 19, in a vial. (Aspect 33) A vial comprising a reconstituted solution according to any one of aspects 23 to 28. (Aspect 34) According to any one of aspects 31 to 33, the vial is a 2 mL or 3 mL vial. The solution, lyophilisate or vial as described.

Claims

1. A stable solution for lyophilization in a pharmaceutically acceptable aqueous carrier, comprising: 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v of at least one disaccharide sugar; 0.05-1.5% w / v of at least one surfactant; 5-25 mM of at least one buffering agent, and having a pH of 6.5-9.0; The stable solution wherein the surfactant has 3% or less peroxide.

2. 10. The lyophilization solution of claim 1, wherein the lyophilization solution further comprises 2-10% w / v of at least one bulking agent.

3. 2. The lyophilized solution of claim 1, comprising 0.6 to 1.4 mg / mL tagraxofusp, 0.7 to 1.3 mg / mL tagraxofusp, 0.8 to 1.2 mg / mL tagraxofusp, or 1 mg / mL tagraxofusp.

4. 2. The lyophilization solution of claim 1, wherein the surfactant is present in an amount of 0.07-1.5% w / v, 0.1-1.3% w / v, 0.15-1.2% w / v, 0.25-1% w / v, or 0.24-0.26% w / v.

5. The lyophilization solution of claim 1 , wherein the surfactant is selected from polysorbates or poloxamers.

6. 6. The lyophilization solution of claim 5, wherein the surfactant is poloxamer 188, poloxamer 168, poloxamer 144, polysorbate 20, polysorbate 60, or polysorbate 80.

7. The lyophilization solution of claim 6, wherein the surfactant is polysorbate 80.

8. 2. The lyophilization solution of claim 1, wherein the disaccharide sugar is present in an amount of 2-8% w / v, 2-6% w / v, 2-4% w / v, 2-3% w / v, or 2.45-2.55% w / v.

9. 2. The lyophilization solution of claim 1, wherein the disaccharide sugar is selected from trehalose, lactose, and sucrose.

10. 10. The lyophilization solution of claim 9, wherein the disaccharide sugar is sucrose.

11. 10. The lyophilization solution of claim 1, wherein the bulking agent is present in an amount of 2-8% w / v, 2-6% w / v, 2-4% w / v, 2-3% w / v, or 2.45-2.55% w / v.

12. 2. The lyophilization solution of claim 1, wherein the bulking agent is selected from glycine, maltose, glucose, mannitol, and sorbitol.

13. The lyophilization solution of claim 12, wherein the bulking agent is mannitol.

14. 10. The lyophilization solution of claim 1, wherein the at least one buffering agent is at a concentration of 5-15 mM, 7-12 mM, or 10 mM.

15. 2. The lyophilization solution of claim 1, wherein the buffering agent is selected from phosphate, arginine, histidine, and Tris HCl.

16. 16. The lyophilization solution of claim 15, wherein the buffer is Tris HCl.

17. 2. The lyophilization solution of claim 1, wherein the pH is 6.5 to 8.

18. The lyophilization solution of claim 17, wherein the pH is between 7 and 8.

19. A stable pharmaceutically acceptable lyophilized solution in a pharmaceutically acceptable aqueous medium, comprising: 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v sucrose; 0.05 to 1.5% w / v of polysorbate 80; 5-25 mM Tris HCl; 2-10% w / v mannitol; having a pH of 6.5 to 9; The lyophilized solution, wherein the polysorbate 80 has 3% or less peroxide.

20. 1 mg / mL tagraxofusp, and 2.45 to 2.55% w / v sucrose; 2.45 to 2.55% w / v mannitol; 0.24-0.26% w / v polysorbate 80; 9-11 mM Tris HCl; and having a pH of 6.5 to 9; 20. The lyophilization solution of claim 19, wherein the polysorbate 80 has 3% or less peroxide.

21. A lyophilisate prepared from the lyophilisation solution of claim 20.

22. (a) the relative percent abundance of oxidized species of Tagraxofusp does not increase by more than 2% or more than 1% over a period of 12 to 36 months; (b) the relative percent abundance of acidic species of tagraxofusp does not increase compared to the relative percent abundance of the same acidic species of tagraxofusp in a liquid tagraxofusp formulation during storage for 18, 24 or 36 months; (c) the formulation provides a required dose of 1 to 1.5 mg on a dry weight basis; (d) the lyophilized dry product is stable for at least 24 months at a storage temperature of 2°C to 8°C; and / or 22. The lyophilisate of claim 21, wherein (e) the oxidized impurity is 2% or less, or 1% or less, as determined by reversed-phase ultra-performance chromatography (RP-UPLC), and / or the oxidized impurity is measurable as a single peak at +16 Da from the tagraxofusp peak in mass spectrometry analysis, and / or the oxidized impurity elutes before the tagraxofusp peak in RP-UPLC analysis and the peak of the oxidized impurity on the RP-UPLC chromatogram is the peak closest to the tagraxofusp peak.

23. (a) the relative percent abundance of oxidized species of Tagraxofusp does not increase by more than 2% or more than 1% over a period of 18 to 24 months; (b) the relative percent abundance of acidic species of tagraxofusp does not increase compared to the relative percent abundance of the same acidic species of tagraxofusp in a liquid tagraxofusp formulation during storage for 18, 24 or 36 months; (c) the formulation provides a required dose of 1 to 1.5 mg on a dry weight basis; (d) the lyophilized dry product is stable for 24 months to 5 years at a storage temperature of 2°C to 8°C; (e) oxidation impurities are 2% or less, or 1% or less, as determined by reversed-phase ultra-performance chromatography (RP-UPLC); (f) the oxidation impurity is measurable in mass spectrometry as a single peak at +16 Da from the tagraxofusp peak; and / or (g) The lyophilized product according to claim 22, wherein the oxidized impurities are eluted before the peak of tagraxofusp in RP-UPLC analysis, and the peak of the oxidized impurities on the RP-UPLC chromatogram is the peak closest to the peak of tagraxofusp.

24. A stable lyophilisate comprising: 1 mg of tagraxofusp, 25 mg of at least one disaccharide sugar; 25 mg of at least one surfactant; 2.4 mg of at least one buffering agent; The stable lyophilisate, wherein the lyophilisate has 2% or less oxidation impurities as determined by reversed phase ultra-performance chromatography (RP-UPLC) for at least 24 months.

25. (a) further comprising 25 mg of at least one bulking agent; and / or 25. The stable lyophilisate of claim 24, wherein (b) the relative abundance (%) of oxidized species of Tagraxofusp does not increase to more than 2% or more than 1% over a period of 18 to 24 months.

26. A pharmaceutically acceptable formulation reconstituted in an aqueous medium for intravenous injection, comprising: 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v of at least one disaccharide sugar; 0.05-1.5% w / v of at least one surfactant; and 5 to 25 mM of at least one buffering agent.

27. (a) the relative percent abundance of oxidized species of Tagraxofusp does not increase by more than 2% or more than 1% over a period of 18 to 24 months; (b) the lyophilization solution further comprises 2-10% w / v of at least one bulking agent; (c) the formulation comprises 0.5 to 1.5 mg / mL tagraxofusp, 0.6 to 1.4 mg / mL tagraxofusp, 0.7 to 1.3 mg / mL tagraxofusp, 0.8 to 1.2 mg / mL tagraxofusp, or 1 mg / mL tagraxofusp; (d) the surfactant is present in an amount of 0.07-1.5% w / v, 0.1-1.3% w / v, 0.15-1.2% w / v, 0.25-1.0% w / v, or 0.24-0.26% w / v; (e) the surfactant is selected from polysorbates or poloxamers, or the surfactant is poloxamer 188, poloxamer 168, poloxamer 144, polysorbate 20, polysorbate 60, or polysorbate 80; (f) the disaccharide sugar is present in an amount of 2-8% w / v, 2-6% w / v, 2-4% w / v, 2-3% w / v, or 2.45-2.55% w / v; (g) the disaccharide sugar is selected from trehalose, lactose, and sucrose; (h) the bulking agent is present in an amount of 2-8% w / v, 2-6% w / v, 2-4% w / v, 2-3% w / v, or 2.45-2.55% w / v; (i) the bulking agent is selected from glycine, maltose, glucose, mannitol, and sorbitol; (j) at least one buffering agent is added in an amount of 5-15 mM, 7-12 mM, 9-11 mM, or 10 mM; (k) the buffering agent is selected from phosphate, arginine, histidine, and Tris HCl, or the buffering agent is Tris HCl; and / or (l) The reconstituted formulation for intravenous injection according to claim 26, wherein the pH is 6.5 to 9.

28. 28. The reconstituted formulation for intravenous injection of claim 27, wherein the surfactant is polysorbate 80, the disaccharide sugar is sucrose, the bulking agent is mannitol, the buffer is Tris HCl, and / or the pH is 7-8.

29. 0.5 to 1.5 mg / mL tagraxofusp; 2-10% w / v sucrose; 0.05 to 1.5% w / v of polysorbate 80; 5-25 mM Tris HCl; having a pH of 6.5 to 9; 29. The reconstituted formulation for intravenous injection of claim 27 or 28, wherein the aqueous medium is water for injection (WFI).

30. 30. The reconstituted formulation of claim 29, further comprising 2-10% w / v mannitol.

31. 0.9 to 1.1 mg / mL tagraxofusp; 2.45 to 2.55% w / v sucrose; 2.45 to 2.55% w / v mannitol; 0.24-0.26% w / v polysorbate 80; 9-11 mM Tris HCl; 29. The reconstituted formulation for intravenous injection according to claim 27 or 28, having a pH of 6.5 to 9.

32. 29. The reconstituted formulation for intravenous injection of claim 27 or 28, which, when diluted in an infusion solution bag, provides a substantially particulate matter-free fluid in said infusion solution bag.

33. 10. The stable, pharmaceutically acceptable lyophilized solution of claim 1 in a vial.

34. The lyophilisate according to claim 21 in a vial.

35. 29. A vial containing the reconstituted solution of claim 27 or 28.

36. 34. The solution, lyophilisate or vial of claim 33, wherein the vial is a 2 mL or 3 mL vial.

37. 10. A pharmaceutical composition for treating or inhibiting a solid tumor, comprising the lyophilized solution of claim 1, optionally wherein the solid tumor is selected from a sarcoma, a carcinoma, and a lymphoma.

38. A pharmaceutical composition for treating a disease, comprising the lyophilized solution of claim 1, wherein the disease is a) myeloproliferative neoplasms (MPNs) with monocytosis; b) Myeloproliferative neoplasms (MPNs), wherein the MPN is polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), symptomatic eosinophilic disorder, or other bone marrow diseases that cause excessive production of red blood cells, white blood cells, and / or platelets, or primary eosinophilic disorder (PED); c) acute myeloid leukemia (AML); d) chronic myelomonocytic leukemia (CMML), e) myelodysplastic syndrome (MDS), f) multiple myeloma, g) blastic plasmacytoid dendritic cell neoplasm (BPDCN); h) autoimmune diseases, and i) Autoimmune diseases, including lupus (e.g., systemic lupus erythematosus, cutaneous lupus, discoid lupus), Sjogren's syndrome, inflammatory arthritis, systemic sclerosis (SSc), morphea, psoriasis, lichen planus, dermatomyositis, lichen sclerosus, and cutaneous graft-versus-host disease (GVHD), adrenergic drug resistance, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune diseases of the adrenal gland, allergic encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inflammation eye disease, autoimmune neonatal thrombocytopenia, autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, autoimmune thyroiditis, Behçet's disease, bullous pemphigoid, cardiomyopathy, open-heart syndrome, celiac sprue dermatitis, chronic active hepatitis, chronic fatigue immune deficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dense deposit disease, essential mixed cryoglobulinemia, Fibromyalgia / fibromyositis, glomerulonephritis (e.g., IgA nephropathy), gluten-sensitive enteropathy, Goodpasture's syndrome, Graves' disease, Guillain-Barré, hyperthyroidism (Hashimoto's thyroiditis), idiopathic pulmonary fibrosis, idiopathic Addison's disease, idiopathic thrombocytopenic purpura (ITP), IgA neuropathy, juvenile arthritis, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, myocarditis, type I or immune-mediated diabetes mellitus, neuritis, other endocrine gland deficiencies, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, an autoimmune disease selected from polyendocrinopathy, polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-MI, primary agammaglobulinemia, primary biliary cirrhosis, psoriatic arthritis, Raynaud's phenomenon, relapsing polychondritis, Reiter's syndrome, rheumatic heart disease, rheumatoid arthritis, sarcoidosis, stiff-man syndrome, Takayasu's arteritis, temporal arteritis-giant cell arteritis, ulcerative colitis, urticaria, uveitis, uveitis ophthalmia, vasculitis (e.g., dermatitis herpetiformis-type vasculitis), vitiligo, and Wegener's granulomatosis; The pharmaceutical composition is selected from the group consisting of:

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