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KR-20260062992-A - IMPROVED LYOPHILIZED FORMULATION

KR20260062992AKR 20260062992 AKR20260062992 AKR 20260062992AKR-20260062992-A

Abstract

An improved formulation of lyophilized taglaxofusf used to manufacture a stable formulation of intravenous injection taglaxofusf is provided herein.

Inventors

  • 코놀리, 조안
  • 에릭슨, 프레데릭
  • 카마트, 마드하브
  • 와서맨, 제니퍼
  • 자브레키, 제임스

Assignees

  • 스템라인 테라퓨틱스, 인코포레이티드

Dates

Publication Date
20260507
Application Date
20211209
Priority Date
20201210

Claims (20)

  1. As a stable freeze-dried solution in a pharmaceutically acceptable aqueous carrier, 0.5 to 1.5 mg/mL of taglaxofusp, At least one disaccharide sugar in an amount of 2 to 10% w/v, At least one surfactant of 0.05 to 1.5% w/v, and At least one 5 to 25 mM buffer Includes, It has a pH of 6.5 to 9.0, and The surfactant contains 3% or less of peroxide, and A solution optionally further comprising at least one extender of 2 to 10% w/v.
  2. In paragraph 1, 0.6 to 1.4 mg/mL of taglaxofusp, 0.7 to 1.3 mg/mL of taglaxofusp, 0.8 to 1.2 mg/mL of taglaxofusp, or 1 mg/mL Taglaxofusf A solution containing
  3. In paragraph 1, The surfactant is present in an amount of 0.07 to 1.5% w/v, 0.1 to 1.3% w/v, 0.15 to 1.2% w/v, 0.25 to 1% w/v, or 0.24 to 0.26% w/v, and The surfactant is selected from polysorbate or poloxamer, and Optionally, the surfactant is poloxamer 188, poloxamer 168, poloxamer 144, polysorbate 20, polysorbate 60, or polysorbate 80, and Optionally, the surfactant is a solution of polysorbate 80.
  4. In paragraph 1, Disaccharide sugars are present in amounts of 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 to 2.55% w/v, and The disaccharide sugar is selected from trehalose, lactose, and sucrose, and A solution in which the disaccharide sugar is optionally sucrose.
  5. In paragraph 1, The extender is present in an amount of 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 to 2.55% w/v, and The extender is selected from glycine, maltose, glucose, mannitol, and sorbitol, and A solution in which the optional extender is mannitol.
  6. In paragraph 1, At least one buffer is at a concentration of 5 to 15 mM, or 7 to 12 mM, or 10 mM, and The buffer is selected from phosphate, arginine, histidine, and Tris HCl, and Optionally, a solution in which the buffer is Tris HCl.
  7. In claim 1, a solution having a pH of 6.5 to 8 or 7 to 8.
  8. As a stable pharmaceutically acceptable lyophilized solution in a pharmaceutically acceptable aqueous medium, 0.5 to 1.5 mg/mL of taglaxofusp, 2 to 10% w/v sucrose, Polysorbate 80 at 0.05 to 1.5% w/v, 5 to 25 mM Tris HCl, and 2 to 10% w/v mannitol Includes, It has a pH of 6.5 to 9, and Polysorbate 80 is a freeze-dried solution having 3% or less peroxide.
  9. In paragraph 8, 1 mg/mL of taglaxofusf, 2.45 to 2.55% w/v sucrose, 2.45 to 2.55% w/v mannitol, Polysorbate 80 at 0.24 to 0.26% w/v, and 9 to 11 mM Tris HCl Includes, It has a pH of 6.5 to 9, and Polysorbate 80 is a freeze-dried solution having 3% or less peroxide.
  10. As a freeze-dried product prepared from the solution of claim 9, Optionally, (a) The percentage of relative abundance of oxidized species of Taglaxofus will increase to 2% or less, or 1% or less, over a period of 12 to 36 months, and Optionally, the percentage of relative abundance of oxidized species of Taglaxofus will increase to 2% or less, or 1% or less, over a period of 18 to 24 months, and/or, (b) The percentage of relative abundance of the oxidized species of Taglaxofusp will increase less than the percentage of relative abundance of the same acidic species of Taglaxofusp in the liquid Taglaxofusp formulation during storage for 18, 24, or 36 months, and/or, (c) Providing a required dose of 1 to 1.5 mg based on dry weight, and/or, (d) stable at a storage temperature of 2°C to 8°C for at least 24 months, and Optionally stable at storage temperatures of 2°C to 8°C for 24 months to 5 years, and/or, (e) Oxidation impurities are 2% or less, or 1% or less when determined by reverse-phase ultra-high performance chromatography (RP-UPLC), and/or, Oxidation impurities can be measured in mass spectrum analysis as a single peak of +16 Da from the Taglaxofusp peak and/or, In RP-UPLC analysis, oxidative impurities are eluted before the Taglaxofusf peak, and the oxidative impurity peak on the RP-UPLC chromatogram is the lyophilized peak closest to the Taglaxofusf peak.
  11. As a stable freeze-dried material, 1 mg of taglaxofusf, 25 mg of at least one disaccharide, 25 mg of at least one surfactant, and 2.4 mg of at least one buffer Includes, Having less than 2% oxidation impurities when determined by reverse-phase ultra-high performance chromatography (RP-UPLC) for at least 24 months, Optionally (a) additionally comprising at least one extender of 25 mg, or/or (b) A freeze-dried product in which the percentage of relative abundance of the oxidized species of taglaxofusph will increase to 2% or less, or 1% or less, over 18 to 24 months.
  12. As a pharmaceutically acceptable intravenous injection formulation that is reconstituted in an aqueous medium, 0.5 to 1.5 mg/mL of taglaxofusp, At least one disaccharide sugar in an amount of 2 to 10% w/v, At least one surfactant of 0.05 to 1.5% w/v, and At least one 5 to 25 mM buffer A solution containing, Optionally (a) The percentage of relative abundance of oxidized species of Taglaxofus will increase to 2% or less, or 1% or less, over a period of 18 to 24 months, and/or, (b) The solution further comprises at least one extender in an amount of 2 to 10% w/v, or/or (c) The solution is 0.5 to 1.5 mg/mL of taglaxofusp, 0.6 to 1.4 mg/mL of taglaxofusp, 0.7 to 1.3 mg/mL of taglaxofusp, 0.8 to 1.2 mg/mL of taglaxofusp, or 1 mg/mL Taglaxofusf Includes/or, (d) The surfactant is present in an amount of 0.07 to 1.5% w/v, 0.1 to 1.3% w/v, 0.15 to 1.2% w/v, 0.25 to 1.0% w/v, or 0.24 to 0.26% w/v, and/or, (e) The surfactant is selected from polysorbate or poloxamer, and Optionally, the surfactant is poloxamer 188, poloxamer 168, poloxamer 144, polysorbate 20, polysorbate 60, or polysorbate 80, and Optionally, the surfactant is polysorbate 80 and/or, (f) Disaccharide sugars are present in amounts of 2 to 8% w/v, 2 to 6% w/v, 2 to 4% w/v, 2 to 3% w/v, or 2.45 to 2.55% w/v, and/or, (g) Disaccharide sugars are selected from trehalose, lactose, and sucrose, and Optionally, the disaccharide sugar is sucrose and/or, (h) The extender is present in an amount of 2 to 8% w/v, 2 to 6% w/v, 2 to 4% w/v, 2 to 3% w/v, or 2.45 to 2.55% w/v, and/or, (i) The extender is selected from glycine, maltose, glucose, mannitol, and sorbitol, and Optionally, the extender is mannitol and/or, (j) At least one buffer is added in an amount of 5 to 15 mM, 7 to 12 mM, 9 to 11 mM, or 10 mM, and/or, (k) The buffer is selected from phosphate, arginine, histidine, and Tris HCl, and Optionally, the buffer is Tris HCl and/or, (l) The pH is 6.5 to 9, and Optionally, a formulation with a pH of 7 to 8.
  13. In Paragraph 12, 0.5 to 1.5 mg/mL of taglaxofusp, 2 to 10% w/v sucrose, Polysorbate 80 at 0.05 to 1.5% w/v, and 5 to 25 mM Tris HCl Includes, It has a pH of 6.5 to 9, and The aqueous medium is water for injection (WFI), and An intravenous formulation optionally further comprising 2 to 10% w/v mannitol.
  14. In Paragraph 12, Taglaxofusph of 0.9 to 1.1 mg/mL, 2.45 to 2.55% w/v sucrose, 2.45 to 2.55% w/v mannitol, Polysorbate 80 at 0.24 to 0.26% w/v, and 9 to 11 mM Tris HCl Includes, An intravenous injection formulation having a pH of 6.5 to 9.
  15. In paragraph 12, an intravenous injection formulation that provides a fluid in an infusion fluid bag that is substantially free of particulate matter when diluted into an infusion fluid bag.
  16. In paragraph 1, It is contained in a vial, Optionally, the vial is a solution that is a 2 mL or 3 mL vial.
  17. In Paragraph 10, It is contained in a vial, Optionally, the vial is a lyophilized product that is a 2 mL or 3 mL vial.
  18. In Paragraph 12, It is contained in a vial, Optionally, the vial is a formulation that is a 2 mL or 3 mL vial.
  19. A pharmaceutical composition for treating or inhibiting solid tumors comprising an effective amount of the formulation of any one of claims 12 to 15, A pharmaceutical composition in which the solid tumor is selectively selected from sarcoma, carcinoma, and lymphoma.
  20. A pharmaceutical composition for treating a disease comprising an effective amount of a formulation of any one of claims 12 to 15, Diseases a) Myeloproliferative neoplasm with mononucleosis (MPN), b) Myeloproliferative neoplasms (MPN) that are polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), symptomatic hypereosinophilic disorder, or other bone marrow disorders or primary eosinophilic disorders (PED) that cause excessive production of red blood cells, white blood cells, and/or platelets, c) Acute myeloid leukemia (AML), d) Chronic myelomonocytic leukemia (CMML), e) Myelodysplastic syndrome (MDS), f) Multiple myeloma, g) Brachytherapy Plasma-like Dendritic Neoplasm (BPDCN), h) Autoimmune disease, i) Lupus (e.g., Systemic Lupus Erythematosus, Cutaneous Lupus, Discoid Lupus), Sjögren's Syndrome, Inflammatory Arthritis, Systemic Sclerosis (SSc), Focal Scleroderma, 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 Disease of the Adrenal Gland, Allergic Encephalomyelitis, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Autoimmune Inflammatory Eye Disease, Autoimmune Neonatal Thrombocytopenia, Autoimmune Neutropenia, Autoimmune Ovarian Inflammation and Orchitis, Autoimmune Thrombocytopenia, Autoimmune Thyroiditis, Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy, Incision Syndrome, Celiac Sprue Dermatitis, Chronic Active Hepatitis, Chronic Fatigue Immunodeficiency Syndrome (CFIDS), Chronic Inflammatory Demyelinating Polyneuropathy, Churg-Strauss Syndrome, Pemphigoid Scarring, CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease, Dentistry, Essential Mixed Cryoglobulinemia, Fibromyalgia-Fibromyositis, Glomerulonephritis (e.g., IgA nephropathy), Gluten-Sensitive Enteropathy, Goodpasture Syndrome, Graves' Disease, Guillain-Barré, Hyperthyroidism (i.e., 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 1 or Immune-Mediated Diabetes Mellitus, Neuritis, Other Endocrine Insufficiency, Pemphigoid Vulgaris, Pernicious Anemia, Nodular A pharmaceutical composition for an autoimmune disease selected from polyarteritis, polychondritis, polyendocrine disorders, polylinear syndrome, rheumatic polymyalgia, polymyositis, post-MI, primary agammaglobulinemia, primary biliary cirrhosis, psoriatic arthritis, Raynaud's syndrome, recurrent polychondritis, Reiter's syndrome, rheumatic heart disease, rheumatic arthritis, sarcoidosis, Stiff-Mann syndrome, Takayasu's arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, urticaria, uveitis, ocular uveitis, vasculitis, e.g. herpetic dermatitis vasculitis, vitiligo, and Wegener's granulomatosis.

Description

Improved Lyophilized Formulation Cross-reference regarding related applications This application claims priority to U.S. Provisional Application No. 63/123,589 filed on December 10, 2020, the entire disclosure of which is incorporated herein by reference. Technology field An improved lyophilized formulation of Taglaxofusf with increased stability and a method for preparing the same. Sequence list The present application includes a list of sequences that are electronically submitted in ASCII format via EFS-Web and whose entire contents are incorporated herein by reference. The name of the said ASCII copy created on December 7, 2021 is 2021-12-07_01214-0022-00PCT_Seq_List_ST25.txt and its size is 4,806 bytes. Intravenous therapy (IV) or drug delivery involves delivering fluids directly into a vein. Intravenous administration routes can be used for both injections, which utilize syringes at higher pressures, and infusions (also known as drips), which typically use only pressure supplied by gravity. Intravenous routes rapidly deliver drugs throughout the body by introducing therapeutic agents directly into the circulatory system. While direct introduction of a drug formulation into the bloodstream makes 100% of the formulation bioavailable, this also implies that the formulation must be immediately compatible with the subject's physiology, which limits the acceptable components within the formulation. Injectable products must be sterile, pyrogen-free, particulate-free in solution form, and may be isotonic. Additionally, the components must be able to withstand final sterilization or sterile manufacturing processes. A stable pharmaceutically acceptable formulation for intravenous injection of taglaxofusf, a formulation for the same, and a method for manufacturing the same are provided herein. summation As illustrated in the following list of non-limiting embodiments, a stable pharmaceutically acceptable formulation for intravenous injection of taglaxofusf is provided herein. Embodiment 1 is a stable freeze-dried solution in a pharmaceutically acceptable aqueous carrier, wherein 0.5 to 1.5 mg/mL of taglaxofusf; At least one disaccharide sugar in an amount of 2 to 10% w/v; At least one surfactant of 0.05 to 1.5% w/v; Comprising at least one 5 to 25 mM buffer; and pH 6.5-9.0, The above surfactant has 3% or less of peroxide. Embodiment 2 is a freeze-dried solution of Embodiment 1, wherein the freeze-dried solution further comprises at least one extender of 2 to 10% w/v. Embodiment 3 is a freeze-dried solution of any one of the aforementioned embodiments, comprising 0.6 to 1.4 mg/mL of taglaxofusp. Embodiment 4 is a freeze-dried solution of any one of the aforementioned embodiments, comprising 0.7 to 1.3 mg/mL of taglaxofusp. Embodiment 5 is a freeze-dried solution of any one of the aforementioned embodiments, comprising 0.8 to 1.2 mg/mL of taglaxofusp. Embodiment 6 is a freeze-dried solution of any one of the aforementioned embodiments, comprising 1 mg/mL of taglaxofusp. Embodiment 7 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the surfactant is present in an amount of 0.07 to 1.5% w/v. Embodiment 8 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the surfactant is present in an amount of 0.1 to 1.3% w/v. Embodiment 9 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the surfactant is present in an amount of 0.15 to 1.2% w/v. Embodiment 10 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the surfactant is present in an amount of 0.25 to 1% w/v. Embodiment 11 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the surfactant is present in an amount of 0.24 to 0.26% w/v. Embodiment 12 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the surfactant is selected from polysorbate or poloxamer. Embodiment 13 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the surfactant is poloxamer 188, poloxamer 168, poloxamer 144, polysorbate 20, polysorbate 60, or polysorbate 80. Embodiment 14 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the surfactant is polysorbate 80. Embodiment 15 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the disaccharide sugar is present in an amount of 2 to 8% w/v. Embodiment 16 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the disaccharide sugar is present in an amount of 2 to 6% w/v. Embodiment 17 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the disaccharide sugar is present in an amount of 2 to 4% w/v. Embodiment 18 is a freeze-dried solution of any one of the aforementioned embodiments, wherein the disaccharide sugar is present in an amount of 2 to 3% w/v. Embodiment 19 is a freeze-dried solution of any one of the aforementioned embodiments, whe