Search

US-12622921-B2 - Stable formulations comprising thiotepa

US12622921B2US 12622921 B2US12622921 B2US 12622921B2US-12622921-B2

Abstract

The present disclosure provides pharmaceutical compositions comprising thiotepa and one selected from PEG, such as PEG400 or PEG600, and DMSO, and optionally water or an aqueous saline solution and thiosulfate. The composition is free or substantially free of impurities. Also provided is a method for treating cancer in a subject, or myeloablation prior to bone marrow transplantation using the composition. A method for enhancing the stability of a thiotepa formulation is also contemplated.

Inventors

  • Sharon Cunningham
  • Orlaith RYAN
  • Johannes Jan Platteeuw

Assignees

  • SHORLA PHARMA LTD.

Dates

Publication Date
20260512
Application Date
20220829

Claims (20)

  1. 1 . A method for treating cancer or inducing myeloablation prior to bone marrow transplantation or controlling intracavitary effusions secondary to diffuse or localized, neoplastic diseases of various serosal cavities in a subject in need thereof comprising: administering to the subject a composition comprising thiotepa and a solvent, wherein the solvent is selected from the group consisting of dimethylsulfoxide (DMSO), polyethylene glycol 400 (PEG400), polyethylene glycol 600 (PEG600), dimethylacetamide (DMA), and N-methylpyrrolidone (NMP), and wherein the thiotepa is present in an amount between about 1 and about 100 mg/mL, wherein the composition is substantially free of an impurity, wherein the impurity is one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide, and wherein the cancer is selected from the group consisting of bladder cancer, malignant meningeal neoplasm, breast cancer, ovarian cancer, lymphoma, and leptomeningeal metastasis.
  2. 2 . The method of claim 1 , wherein the impurity is present in an amount selected from the group consisting of less than about 150 ppm, less than about 100 ppm, less than about 35 ppm, less than about 30 ppm, less than about 25 ppm, less than about 20 ppm, less than about 15 ppm, less than about 10 ppm, and less than about 5 ppm.
  3. 3 . The method of claim 1 , wherein the composition does not comprise water.
  4. 4 . The method of claim 3 , wherein the composition comprises one or more of: less than about 150 ppm formic acid; less than about 15 ppm acetic acid; less than about 15 ppm formaldehyde; less than about 15 ppm acetaldehyde; or less than about 35 ppm peroxide.
  5. 5 . The method of claim 4 , wherein the composition comprises: less than about 150 ppm formic acid; less than about 15 ppm acetic acid; less than about 15 ppm formaldehyde; less than about 15 ppm acetaldehyde; and less than about 35 ppm peroxide.
  6. 6 . The method of claim 5 , wherein the composition comprises thiotepa and PEG400.
  7. 7 . The method of claim 5 , wherein the composition comprises thiotepa and PEG600.
  8. 8 . The method of claim 5 , wherein the composition comprises thiotepa and DMSO.
  9. 9 . The method of claim 1 , wherein the composition further comprises water.
  10. 10 . The method of claim 9 , wherein the water is present in an amount selected from the group consisting of up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, and up to about 5%.
  11. 11 . The method of claim 10 , wherein the composition comprises one or more of: less than about 150 ppm formic acid; less than about 15 ppm acetic acid; less than about 15 ppm formaldehyde; less than about 15 ppm acetaldehyde; or less than about 35 ppm peroxide.
  12. 12 . The method of claim 11 , wherein the composition comprises: less than about 150 ppm formic acid; less than about 15 ppm acetic acid; less than about 15 ppm formaldehyde; less than about 15 ppm acetaldehyde; and less than about 35 ppm peroxide.
  13. 13 . The method of claim 12 , wherein the composition comprises thiotepa and PEG400.
  14. 14 . The method of claim 12 , wherein the composition comprises thiotepa and PEG600.
  15. 15 . The method of claim 12 , wherein the composition comprises thiotepa and DMSO.
  16. 16 . The method of claim 9 , wherein the water is an aqueous saline solution.
  17. 17 . The method of claim 1 , wherein the composition further comprises thiosulfate.
  18. 18 . The method of claim 17 , wherein the thiosulfate is present in an amount of about 0.01% to about 1.0%.
  19. 19 . The method of claim 1 , wherein the composition is administered via injection which is selected from the group consisting of subcutaneous injection, intramuscular injection, intravenous injection, infusion, intraperitoneal injection, intrapleural injection, intrapericardial injection, intracavitary injection, intrathecal injection, intra-arterial injection, intravesical injection, and intralesional injection.
  20. 20 . The method of claim 1 , comprising administering about 300 mg to about 700 mg thiotepa.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation in part of PCT Application PCT/IB2021/057527, filed on Aug. 16, 2021, which claims the benefit of U.S. Patent Application No. 63/066,378, filed on Aug. 17, 2020. This application also claims priority to U.S. Patent Application No. 63/310,638, filed on Feb. 16, 2022. The entire disclosure of both applications identified in this paragraph are incorporated herein by reference. FIELD The present disclosure relates to compositions comprising thiotepa and methods for using the same for treating a disease in a subject. BACKGROUND Thiotepa is a nitrogen mustard alkylating agent with antitumor properties. It is indicated for treating adenocarcinoma of the breast, superficial papillary carcinoma of the urinary bladder, and adult and pediatric hematological diseases (e.g., Hodgkin's disease or leukemia). Thiotepa is also indicated for controlling intracavitary effusions secondary to diffuse or localized neoplastic disease of serosal cavities. Thiotepa is also used as a conditioning treatment prior to allogeneic or autologous hematopoietic progenitor cell transplantation or for use in palliation of neoplastic diseases. Thiotepa is generally unstable in aqueous solutions, which leads to the generation of impurities and/or thiotepa degradation products following storage. The aqueous instability renders ready-to-use liquid dosage forms of thiotepa difficult to store. It is typically available as a freeze-dried product (15 mg to 100 mg) without excipients to be reconstituted to a concentration of 10 mg/mL in sterile water for injection. When provided intravenously, thiotepa can be provided as a 2-4 hour infusion at doses ranging from 3.24-14 mg/kg/day for a cumulative dose of 1050 mg/m2 (42 mg/kg) to treat solid tumors. US 2014/0005148 describes non-aqueous formulations of nitrogen mustards, including thiotepa. Nitrogen mustards are susceptible to nucleophilic attack by water and other aqueous solvents, such as ethanol, thereby degrading the nitrogen mustard into degradation products. EP 0 419 890 reports lyophilized and water-free thiotepa compositions comprising polyethylene glycol (PEG). This reference reports that thiotepa reconstituted in water should be used within five days because reconstituted thiotepa stored longer than five days show a substantial loss of potency. US 2020/0163979 describes pharmaceutically acceptable, injectable liquid formulations comprising thiotepa comprising at least one solvent or co-solvent, such as ethanol. The ethanol-comprising compositions are reported to have at least 90% purity of thiotepa following storage at 25° C./60% relative humidity after seven days. SUMMARY This section provides a general summary of disclosure and is not a comprehensive disclosure of its full scope or all of its features. The present disclosure relates to compositions comprising thiotepa, PEG or DMSO, and water or an aqueous saline solution. The disclosed compositions are stable and may be suitable for injection. In an embodiment, the thiotepa formulation can be administered for the treatment of a disease, particularly, cancer, or myeloablation prior to bone marrow transplantation. In an embodiment, the thiotepa composition comprises PEG such as PEG400 or PEG600. In another embodiment, the composition comprises DMSO. In an alternative embodiment, the composition is a waterless composition comprising thiotepa and a solvent, such as DMSO, PEG400, PEG600, DMA, and NMP, wherein the composition is free or substantially free of impurities. In an embodiment, the composition further comprises thiosulfate. In an embodiment, there is provided a method for treating cancer in a subject, the method comprising injection administration of a composition comprising thiotepa, PEG or DMSO, and, optionally, water or an aqueous saline solution. In a further embodiment, the PEG is PEG400 or PEG600. In a particular embodiment, the administered composition further comprises thiosulfate. In another embodiment, there is provided a method for myeloablation of a subject prior to bone marrow transplantation comprising administration of the thiotepa composition. In another embodiment, there is provided a method for enhancing the stability of a thiotepa preparation. BRIEF DESCRIPTION OF THE DRAWINGS The drawings described herein are for illustrative purposes only of selected embodiments and not all possible implementations and are not intended to limit the scope of the present disclosure. FIG. 1 shows chromatogram of a thiotepa composition of Example 1. DETAILED DESCRIPTION The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses. The term “thiotepa” refers to the chemical compound N,N′,N″-triethylenethiophosphoramide, and is also known by the trade names of Tepadina® or Thioplex®. Unless otherwise noted, thiotepa includes the compound itself and pharmaceutically acceptable salts thereof. The te