Stable formulations containing thiotepa
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2023-02-15
- Publication Date
- 2026-04-01
Smart Images
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Abstract
Description
[Technical field]
[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 310,638, filed February 16, 2022. The entire disclosures of the applications identified in this paragraph are incorporated herein by reference.
[0002] Technical Field The present disclosure relates to compositions comprising thiotepa and methods of using same to treat disease in a subject. [Background technology]
[0003] Thiotepa is a nitrogen mustard alkylating agent with antineoplastic properties. It is indicated for the treatment of adenocarcinoma of the breast, superficial papillary carcinoma of the bladder, and adult and pediatric hematological disorders (e.g., Hodgkin's disease or leukemia). Thiotepa is also indicated for the control of intraluminal effusions secondary to diffuse or localized neoplastic disease of the serous cavities. Thiotepa is also used as a conditioning regimen for allogeneic or autologous hematopoietic progenitor cell transplantation or for the palliation of neoplastic disease.
[0004] Thiotepa is generally unstable in aqueous solutions, which results in impurities and / or thiotepa degradants after storage. Because of its instability in water, storage of ready-to-use liquid dosage forms of thiotepa is difficult.
[0005] Typically, thiotepa is available as an excipient-free lyophilized product (15 mg to 100 mg) that is reconstituted with sterile water for injection to a concentration of 10 mg / mL. When thiotepa is administered intravenously, a cumulative dose of 10 to 50 mg / m is required for the treatment of solid tumors. 2 (42 mg / kg) can be given as a 2- to 4-hour infusion in the range of 3.24 to 14 mg / kg / day.
[0006] US Patent Application Publication No. 2014 / 0005148 describes non-aqueous formulations of nitrogen mustard, including thiotepa. Nitrogen mustards are susceptible to nucleophilic attack by water and other aqueous solvents, such as ethanol, which decomposes the nitrogen mustard into degradation products.
[0007] A lyophilized water-free thiotepa composition containing polyethylene glycol (PEG) is reported in European Patent No. 0419890. The document reports that thiotepa reconstituted in water should be used within 5 days, since reconstituted thiotepa stored for longer than 5 days loses substantial efficacy.
[0008] US Patent Publication No. 2020 / 0163979 describes pharma- ceutically acceptable injectable liquid formulations containing thiotepa that contain at least one solvent or co-solvent, such as ethanol. Compositions containing ethanol are reported to have a purity of at least 90% thiotepa after storage at 25° C. / 60% relative humidity for 7 days. Summary of the Invention
[0009] This section provides a general summary of the disclosure and is not an exhaustive disclosure of its entire scope or all of its features.
[0010] The present disclosure relates to a composition comprising thiotepa, PEG or DMSO, and water. In one embodiment, the compositions are free or substantially free of impurities. The disclosed compositions are stable and can be suitable for injection. In one embodiment, the thiotepa formulations can be administered for the treatment of diseases, particularly cancer or myeloablation prior to bone marrow transplantation.
[0011] In one embodiment, the thiotepa composition comprises a PEG, such as PEG 400 or PEG 600. In another embodiment, the composition comprises DMSO.
[0012] In an alternative embodiment, the composition is an anhydrous composition comprising thiotepa and a solvent such as DMSO, PEG400, PEG600, DMA, NMP, etc., and the composition is free or substantially free of impurities.
[0013] In one embodiment, the composition further comprises a thiosulfate salt.
[0014] In one embodiment, a method for treating cancer in a subject is provided, the method comprising administering by injection a composition comprising thiotepa, PEG or DMSO, and water. In a further embodiment, the PEG is PEG400 or PEG600. In certain embodiments, the administered composition further comprises a thiosulfate salt.
[0015] In another embodiment, a method is provided for bone marrow ablation of a subject prior to bone marrow transplantation comprising administration of a thiotepa composition.
[0016] In another embodiment, a method for increasing the stability of a thiotepa formulation is provided. [Brief description of the drawings]
[0017] The drawings described herein are only for purposes of illustrating selected embodiments, rather than all possible embodiments, and are not intended to limit the scope of the present disclosure.
[0018] [Figure 1] FIG. 1 shows a chromatogram of the thiotepa composition of Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0019] The following description is merely exemplary in nature and is in no way intended to limit the present disclosure, its application, or uses.
[0020] The term "thiotepa" refers to the compound N,N',N"-triethylenethiophosphoramide, also known under the trade names Tepadina® and Thioplex®. [ka] Unless otherwise specified, thiotepa includes the compound itself and its pharma- ceutically acceptable salts.
[0021] The term "non-aqueous" refers to a composition (e.g., a solution, liquid, or suspension) that does not include, or is essentially free of water.
[0022] The term "subject" refers to an animal that can receive a thiotepa composition. In some embodiments, the subject is a human. In certain embodiments, the subject has or is believed to have cancer. In another embodiment, the subject requires myeloablation or lymphodepletion prior to bone marrow transplantation or other therapy requiring transplant conditioning. In another embodiment, the subject requires gene therapy.
[0023] The term "cancer" includes, but is not limited to, bladder cancer, malignant meningeal neoplasms, breast cancer, ovarian cancer, hematological malignancies, lymphoma, metastatic brain tumors, and leptomeningeal metastases.
[0024] The term "injection" refers to a method of administration in which the composition is administered into the body through a needle. In one embodiment, the injection is selected from the group consisting of subcutaneous injection, intramuscular injection, intravenous injection, drip infusion, intraperitoneal injection, intrapleural injection, intrapericardial injection, intrathecal injection, intraarterial injection, intravesical injection, and intralesional injection. The injection can be a single injection, including an acute injection or continuous injection. The injection can be delivered over several days.
[0025] The term "substantially free" refers to the amount of a component that is not intended to be present in the composition, but may nevertheless be present due to manufacturing procedures and / or post-manufacturing degradation products. As used herein, the compositions described below may be substantially free of impurities, including, but not limited to, formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxides. In some embodiments, the compositions may be substantially free of impurities when processed and / or purified beyond what is conventional in the art. For example, PEG 400 may undergo further processing and / or purification and may be referred to as "ultra-purified", such as Super Refined™ PEG 400 offered by Croda Health Care and EMPROVE™ PEG offered by Sigma.
[0026] In some embodiments, a composition is substantially free of impurities when the impurity is present in the composition in an amount of less than about 100 ppm. In other embodiments, a composition that is substantially free of impurities contains impurities in an amount of less than about 95 ppm, less than about 90 ppm, less than about 85 ppm, less than about 80 ppm, less than about 75 ppm, less than about 70 ppm, less than about 65 ppm, less than about 60 ppm, less than about 55 ppm, less than about 50 ppm, less than about 45 ppm, less than about 40 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, less than about 5 ppm, or less than about 1 ppm. Alternatively, the amount of impurities in the composition can be expressed as a range of, for example, about 1 to about 100 ppm, about 1 to about 95 ppm, about 1 to about 80 ppm, about 1 to about 75 ppm, about 1 to about 70 ppm, about 1 to about 65 ppm, about 1 to about 60 ppm, about 1 to about 55 ppm, about 1 to about 50 ppm, about 1 to about 45 ppm, about 1 to about 40 ppm, about 1 to about 35 ppm, about 1 to about 30 ppm, about 1 to about 25 ppm, about 1 to about 20 ppm, about 1 to about 15 ppm, about 1 to about 10 ppm, about 1 to about 5 ppm, or about 1 to about 3 ppm.
[0027] When the concentration of a component is listed as a percentage of a composition, the composition is substantially free of impurities. In this method, a composition that is substantially free of impurities may contain impurities in amounts less than 0.0001%, less than 0.000095%, less than 0.00009%, less than 0.000085%, less than 0.00008%, less than 0.000075%, less than 0.00007%, less than 0.000065%, less than 0.00006%, less than 0.000055%, less than 0.00005%, less than 0.000045%, less than 0.00004%, less than 0.000035%, less than 0.00003%, less than 0.000025%, less than 0.00002%, less than 0.000015%, less than 0.00001%, less than 0.000005%, or less than 0.000001%. Alternatively, the amount of an impurity in a composition may be in a percentage range, e.g., 0.0000 01%~0.0001%, 0.000001%~0.000095%, 0.000001%~0.00009%, 0.000001%~0.000085%, 0.000001%~0.00008%, 0.000001%~0.000075%, 0.000001%~0.00007%, 0.000001%~0.000065%, 0.000001%~0.00006%, 0.000001%~0.000055%, 0.000001%~0. It can be expressed as 00005%, 0.000001% to 0.000045%, 0.000001% to 0.00004%, 0.000001% to 0.000035%, 0.000001% to 0.00003%, 0.000001% to 0.000025%, 0.000001% to about 0.00002%, 0.000001% to about 0.000015%, 0.000001% to about 0.00001%, or 0.000001% to about 0.000005%.
[0028] The term "impurity" or "impurities" refers to substances other than those specifically identified components present in the compositions of the present disclosure. In some embodiments, the impurities are one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxides.
[0029] The term "peroxide value" refers to the concentration of hydroperoxides, which are molecules that have a peroxide (-OOH) moiety (e.g., H2O2). Typically, peroxide value is measured as milliequivalents of active O2 per kg of fat (mEq O2 / kg fat).
[0030] composition The present disclosure provides compositions comprising thiotepa or a derivative thereof, such as a metabolite, and one or more excipients. Such compositions include pharmaceutical compositions comprising thiotepa, PEG or DMSO, and water. Thiotepa is the active ingredient of the formulation, the amount of which can be adjusted as needed. In general, any known / approved amount of thiotepa can be used with the formulation. In one embodiment, thiotepa is present in an amount of about 1 to about 100 mg / mL. In a further embodiment, thiotepa is present in an amount of about 5 to about 50 mg. In a particular embodiment, thiotepa is present at a concentration of about 10 mg / mL.
[0031] In embodiments, water is present in an amount up to about 40% by weight. In another embodiment, water is present in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 20%, about 25%, or about 30% by weight. In certain embodiments, water is present in an amount of about 10% by weight. In some embodiments, water is distilled, purified, or ultra-purified. In another embodiment, water comprises saline or phosphate buffer to prepare an isotonic solution.
[0032] The compositions described herein are free or substantially free of impurities, including, but not limited to, formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxides. The compositions can contain impurities in amounts 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, less than about 5 ppm, or less than about 1 ppm. Alternatively, the impurities can be present in ranges such as about 1 to about 35 ppm, about 1 to about 30 ppm, about 1 to about 25 ppm, about 1 to about 20 ppm, about 1 to about 15 ppm, about 1 to about 10 ppm, about 1 to about 5 ppm, or about 1 to about 3 ppm.
[0033] The compositions described herein can have a peroxide value of less than about 2.0, less than about 1.5, less than about 1.0, less than about 0.5, or less than about 0.1. In certain embodiments, when the excipient is PEG400, the peroxide value is less than about 1.0, preferably less than about 0.5.
[0034] Multiple impurities, such as formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxy acid When two or more of the impurities are present, the composition may be substantially free of one or more of each impurity. For example, the composition may be substantially free of formic acid but not substantially free of peroxide. Furthermore, when two or more impurities are present, the overall composition may be considered to be substantially free of each impurity present at different levels. For example, the composition may include less than about 15 ppm formic acid, less than 15 ppm acetic acid, less than 15 ppm formaldehyde, less than 15 ppm acetaldehyde, less than 35 ppm peroxide, or a combination thereof. In another example, the composition may include less than about 15 ppm formic acid, less than 15 ppm acetic acid, less than 15 ppm formaldehyde, less than 15 ppm acetaldehyde, and less than 35 ppm peroxide impurities.
[0035] In one embodiment, the composition comprises PEG in an amount of about 80% to about 100%. In another embodiment, the PEG can be PEG 200 to PEG 400. In certain embodiments, the PEG is selected from PEG 400 and PEG 600. In certain embodiments, the composition comprises Super Refined™ PEG 400 or EMPROVE™ PEG.
[0036] In an alternate embodiment, the composition comprises dimethyl sulfoxide (DMSO) in an amount from about 90% to about 100%.
[0037] In another embodiment, the thiotepa composition further comprises one or more antioxidants. In some embodiments, the antioxidants include ascorbic acid, tocopherol, methionine (such as L-methionine), metabisulfite, propyl gallate, butylated hydroxyanasol, butylated hydroxytoluene, meglumine, and thiosulfate. More preferred antioxidants are propyl gallate, thiosulfate, preferably sodium thiosulfate, and tocopherol, preferably α-tocopherol, more preferably α-tocopherol-PEG-succinate. α-tocopherol-PEG-succinate is a commercially available conjugate of α-tocopherol and PEG1000, which has high solubility for short PEGs. Most preferred antioxidants are thiosulfate, preferably sodium thiosulfate, and tocopherol, preferably α-tocopherol, more preferably α-tocopherol-PEG-succinate. In a preferred embodiment, a composition according to the present invention is provided which further comprises an antioxidant such as thiosulfate, propyl gallate, or tocopherol. In a more preferred embodiment, a composition according to the present invention is provided which further comprises an antioxidant selected from thiosulfate and / or tocopherol. In a most preferred embodiment, a composition according to the present invention is provided which further comprises an antioxidant selected from thiosulfate and tocopherol, preferably α-tocopherol-PEG-succinate.
[0038] In certain embodiments, the antioxidant, such as thiosulfate, is present in an amount of about 0.01% to about 1.0% by weight. In yet further embodiments, the thiosulfate is present in an amount of about 0.1% by weight.
[0039] The thiotepa compositions can further comprise additional excipients, non-limiting examples of which include buffers, antioxidants, and / or osmotic agents.
[0040] In certain embodiments, the composition comprises about 1 to about 100 mg / mL thiotepa, PEG or DMSO, and up to about 20% water by weight. When PEG is used, it can be either PEG 400 or PEG 600. The composition can further comprise a thiosulfate salt. Specific embodiments of thiotepa compositions are illustrated in Table 1.
[0041] [Table 1]
[0042] In another embodiment, the thiotepa composition is in the form of a solution, suspension, or liquid. In a further embodiment, the thiotepa composition is an aqueous solution. In some embodiments, the composition is in the form of a parenteral formulation suitable for injection.
[0043] In alternative embodiments, thiotepa is formulated into an anhydrous composition. In one embodiment, the anhydrous thiotepa composition comprises thiotepa and a solvent selected from the group consisting of DMSO, PEG400, PEG600, dimethylacetamide (DMA), and n-methyl-2-pyrrolidone (NMP). In another embodiment, the anhydrous thiotepa composition further comprises an antioxidant (such as a tocopherol) and / or an organic base (such as a Tris base). In certain embodiments, the thiotepa composition comprises about 1 to about 100 mg / mL thiotepa and DMSO, PEG400, PEG600, DMA, or NMP. Specific embodiments of anhydrous thiotepa compositions are shown in Table 2.
[0044] [Table 2]
[0045] Specific compositions that are substantially free of impurities are shown in Table 3 below.
[0046] [Table 3]
[0047] The compositions of the present disclosure address, among other things, the stability issue of thiotepa in aqueous solutions. Thiotepa is known to have stability issues in aqueous solutions, such as the generation of impurities and the degradation of the active ingredient during storage. Because of its instability in water, storage of ready-to-use liquid dosage forms of thiotepa is difficult. The stable thiotepa compositions of the present disclosure are suitable for ready-to-use liquid dosage formulations. In one embodiment, the thiotepa composition is stable for 1 month, 2 months, 3 months, or longer in the dark at room temperature (e.g., 21-25° C.) or refrigerated (e.g., 4-5° C.). In another embodiment, thiotepa is stable for up to 6 months at room temperature (relative humidity 50%) or refrigerated. In certain embodiments, the thiotepa composition is stored for a period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or 3 years.
[0048] Treatment methods The present disclosure provides various methods of using thiotepa compositions for the treatment of disease(s), such as cancer. In one embodiment, the thiotepa composition is administered to a subject to treat cancer, the subject being in need of such treatment. Various cancers can be treated with the compositions, and in some embodiments, the cancer is selected from the group consisting of bladder cancer, malignant meningeal neoplasms, breast cancer, and ovarian cancer. In some other specific embodiments, the methods are used to treat adenocarcinoma of the breast, to control intracavitary effusions secondary to diffuse or localized neoplastic disease of various serous cavities, and / or to treat superficial papillary carcinoma of the bladder. In one embodiment, the compositions are used in combination with one or more chemotherapeutic agents for adult and pediatric subjects suffering from hematological diseases, such as Hodgkin's disease and leukemia.
[0049] The thiotepa composition is administered to provide a therapeutically effective dosage to achieve the goal or goals of treatment. In some embodiments, the therapeutically effective amount is sufficient to treat cancer. In certain embodiments, the therapeutically effective amount is about 300 mg to about 700 mg. If a patient requires more than 850 mg of thiotepa, the drug can be administered two or more times per day. In another embodiment, the therapeutically effective amount of thiotepa is approximately about 4 to about 20 mg / kg body weight. In an alternative embodiment, the therapeutically effective amount is approximately 1 20~300mg / m 2 Thiotepa can be administered over multiple days, for example, over 1 to 5 days, particularly 1 to 2 days per day.
[0050] Thiotepa composition therapy can be combined with various cancer treatments known in the art. In one embodiment, the thiotepa composition is administered to a subject in conjunction with radiation therapy. In yet another embodiment, the thiotepa composition is administered before, after, or simultaneously with an additional chemotherapeutic agent. For the treatment of breast or ovarian cancer, a therapeutically effective dose can range from about 20 mg to about 40 mg, administered every 1 to 4 weeks.
[0051] In some embodiments, a therapeutically effective amount of thiotepa is administered to induce bone marrow myeloablation before bone marrow transplantation. In certain embodiments, the therapeutically effective amount of thiotepa is between 300 mg / mL and 700 mg / mL. In other embodiments, the therapeutically effective amount of thiotepa for bone marrow myeloablation before bone marrow transplantation is given over 1-5 days, or over 1-2 days. The total amount of thiotepa delivered during bone marrow myeloablation before bone marrow transplantation treatment can be about 850 mg or more.
[0052] How to improve stability In one embodiment, a method for enhancing the stability of a thiotepa formulation is provided. In one embodiment, the method includes the following steps: combining thiotepa, water, and an excipient (wherein the excipient is PEG or DMSO); and homogenizing the combination. In some embodiments, the thiotepa concentration in the formulation after homogenization is about 1 to about 100 mg / mL. In some embodiments, the water comprises about 1% to about 20% of the composition by weight. In certain embodiments, the thiotepa is present at about 10 mg / mL and the water is present at about 10% or 20% by weight. In certain embodiments, the PEG is PEG400 or PEG600. In certain embodiments, the thiotepa formulation with enhanced stability consists of 10 mg / mL thiotepa, PEG400, and 10% water by weight. In certain embodiments, the thiotepa formulation with enhanced stability consists of 10 mg / mL thiotepa, PEG600, and 20% water by weight. In certain embodiments, the enhanced stability formulation of thiotepa consists of 10 mg / mL thiotepa, DMSO, and 10% water by weight, hi yet another embodiment, the formulation further comprises thiosulfate.
[0053] Further embodiments include:
[0054] 1. A composition comprising thiotepa, water, and an excipient, wherein the excipient is polyethylene glycol (PEG) or dimethylsulfoxide (DMSO), thiotepa is present in an amount of about 1 to about 100 mg / mL, water is present approximately up to about 40%, and the composition is substantially free of impurities, the impurities being one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide.
[0055] 2. The composition of paragraph 1, wherein thiotepa is present in an amount of about 1 to about 10 mg / mL.
[0056] 3. The composition of item 1 or 2, wherein the excipient is PEG400 or PEG600.
[0057] 4. The composition of paragraph 1 or 2, wherein the excipient is DMSO.
[0058] 5. The composition of any one of paragraphs 1 to 4, wherein water is present in an amount selected from the group consisting of at most about 30%, at most about 25%, at most about 20%, at most about 15%, at most about 10%, and at most about 5%.
[0059] 6. The composition of paragraph 5, wherein water is present in an amount up to about 10%.
[0060] 7. The composition of any one of paragraphs 1 to 6, wherein the impurities are present in an amount selected from the group consisting of 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.
[0061] 8. The composition of items 1 to 7, wherein the impurity is present in an amount selected from the group consisting of about 1 to about 35 ppm, 1 to about 30 ppm, 1 to about 25 ppm, 1 to about 20 ppm, 1 to about 15 ppm, 1 to about 10 ppm, and 1 to about 5 ppm.
[0062] 9. The composition of any one of paragraphs 1 to 8, wherein the impurities are one or more of: less than about 15 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.
[0063] 10. The composition of any one of paragraphs 1 to 8, wherein the impurities are one or more of: less than about 15 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.
[0064] 11. The composition of any one of paragraphs 1 to 10, further comprising a thiosulfate salt.
[0065] 12. The composition of claim 11, wherein the thiosulfate is present in an amount of about 0.01% to about 1.0%.
[0066] 13. The composition of paragraph 11 or 12, wherein the thiosulfate is present in an amount of about 0.1%.
[0067] 14. The composition of paragraph 1, comprising thiotepa, PEG 400, water, and less than about 10 ppm formic acid; less than about 15 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.
[0068] 15. The composition of paragraph 14, comprising about 10 mg / mL thiotepa and about 10% water by weight.
[0069] 16. The composition of paragraph 1, comprising thiotepa, PEG 600, water, and less than about 15 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.
[0070] 17. The composition of claim 16, comprising about 10 mg / mL thiotepa and about 20% water by weight.
[0071] 18. The composition of paragraph 1, comprising thiotepa, DMSO, water, and less than about 15 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.
[0072] 19. The composition of claim 11, comprising about 10 mg / mL thiotepa and about 10% water by weight.
[0073] 20. The composition of any one of paragraphs 1 to 19, further comprising tocopherol.
[0074] 21. The composition of paragraph 1, wherein the excipient is PEG400 and has a peroxide value of less than about 1.0 mEq O2 / kg fat.
[0075] 22. The composition of paragraph 21, having a peroxide value of less than about 0.5 mEq O2 / kg fat.
[0076] 23. An anhydrous composition comprising thiotepa and a solvent, the solvent being dimethyl sulfoxide (DMSO), polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG600), dimethylacetamide (DMA), and N-methylpyrrolidone (NMP), wherein thiotepa is present in an amount of about 1 to about 100 mg / mL, and the composition is substantially free of impurities, the impurities being one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxides.
[0077] 24. The composition of paragraph 23, wherein the impurities are present in an amount selected from the group consisting of 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.
[0078] 25. The composition of item 23 or 24, wherein the impurity is present in an amount selected from the group consisting of about 1 to about 35 ppm, 1 to about 30 ppm, 1 to about 25 ppm, 1 to about 20 ppm, 1 to about 15 ppm, 1 to about 10 ppm, and 1 to about 5 ppm.
[0079] 26. The composition of any one of paragraphs 23 to 25, wherein the impurities are one or more of: less than about 15 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.
[0080] 27. The composition of any one of paragraphs 23 to 26, wherein the impurities are one or more of: less than about 15 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.
[0081] 28. The anhydrous composition of any one of items 23 to 27, further comprising an antioxidant or an organic base.
[0082] 29. The anhydrous composition of any one of paragraphs 23 to 28, wherein the antioxidant is tocopherol.
[0083] 30. The anhydrous composition of any one of paragraphs 23 to 29, wherein the organic base is a Tris base.
[0084] 31. A method for treating cancer in a subject in need thereof, comprising administering to the subject a composition according to any one of items 1 to 30.
[0085] 32. The method of paragraph 31, wherein the cancer is selected from the group consisting of bladder cancer, malignant meningeal neoplasm, breast cancer, and ovarian cancer.
[0086] 33. The method of paragraph 31 or 32, wherein the composition is administered via injection.
[0087] 34. The method of paragraph 33, wherein the injection is selected from the group consisting of subcutaneous injection, intramuscular injection, intravenous injection, infusion, intraperitoneal injection, intrapleural injection, intrapericardial injection, intrathecal injection, intraarterial injection, intravesical injection, and intralesional injection.
[0088] 35. Any one of the methods of paragraphs 31 to 34, comprising administering between about 300 mg and about 700 mg of thiotepa.
[0089] 36. The method of any one of paragraphs 31 to 35, wherein thiotepa is stabilized.
[0090] 37. A method for bone marrow ablation prior to bone marrow transplantation in a subject in need thereof, comprising administering to the subject any one of the compositions of paragraphs 1 to 30.
[0091] 38. A method for enhancing the stability of a thiotepa formulation comprising the steps of: and DMSO; and homogenizing the combination, wherein a concentration of thiotepa after the homogenizing step is from about 1 to about 100 mg / mL, water comprises from about 1 to about 40% of the composition by weight, and the composition is substantially free of impurities, the impurities being one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide.
[0092] 39. The method of claim 38, wherein the concentration of thiotepa is about 10 mg / mL.
[0093] 40. The method of paragraph 38 or 39, wherein water constitutes about 10% or about 20% of the composition by weight.
[0094] 41. The method of any one of items 38 to 40, wherein the PEG is PEG400 or PEG600.
[0095] 42. The method of any one of paragraphs 38 to 41, wherein the thiotepa formulation consists of 10 mg / mL thiotepa, PEG 400, and 10% water by weight.
[0096] 43. The method of any one of paragraphs 38 to 42, wherein the thiotepa formulation consists of 10 mg / mL thiotepa, PEG 600, and 20% water by weight.
[0097] 44. The method of any one of paragraphs 38 to 43, wherein the thiotepa formulation consists of 10 mg / mL thiotepa, DMSO, and 10% water by weight.
[0098] 45. The method of any one of paragraphs 38 to 44, further comprising adding a thiosulfate to the composition.
[0099] 46. The method of claim 45, wherein the thiosulfate comprises about 0.01% to about 10% by weight.
[0100] 47. The method of paragraph 46, wherein the thiosulfate constitutes about 0.1% by weight. EXAMPLES
[0101] Example 1: Stability of Thiotepa Compositions Containing Water
[0102] 100 mg of thiotepa was weighed into an amber container and 10 mL of PEG400, PEG600, or DMSO (as appropriate) was added to the container. Purified water was added to the container at 10% (Examples 1, 2, 5, and 6) or 20% (Examples 3-4) by weight. 0.1% thiosulfate (by weight) was added to Examples 2, 4, and 6. The preparations were homogenized with a magnetic stirrer and stirred overnight. The preparations were aliquoted into separate vials and stored at 5°C or 25°C / 60% relative humidity (RH).
[0103] The preparations were analyzed by HPLC after 2 weeks, 1.5 months (6 weeks), 3.5 months, and 5 months. The relative standard deviation (RSD) was calculated for each sample. Total impurities and chloroethyl impurities were also quantified by HPLC. HPLC was performed on a Waters Xbridge shield Rp18, 75×4.6 mm, dp=2.5 μm, flow rate 1.5 mL / min, injection volume 8 μL, and run time 12 min.
[0104] Tables 4 and 5 show the stability of thiotepa formulations at 5° C. and 25° C. / 60% RH, respectively.
[0105] [Table 4]
[0106] [Table 5]
[0107] As can be seen in the table above, PEG and DMSO formulations containing 10% or 20% water were stable when stored at 5° C. The PEG400- and PEG600-containing formulations are stable for up to 5 months at both 5° C. and 25° C. / 60% RH. FIG. 1 shows a chromatogram of the thiotepa composition of Example 1.
[0108] Example 2: Stability of Anhydrous Thiotepa Compositions
[0109] 100 mg of thiotepa was weighed into an amber container and 10 mL of PEG400, PEG600, DMSO, DMA, or NMP (as appropriate) was added to the container. Some preparations included tocopherol and Tris base. Preparations were homogenized on a magnetic stirrer and stirred overnight. Preparations were aliquoted into separate vials and stored at 5° C. or 25° C. / 60% RH.
[0110] The preparations were analyzed by HPLC after 2 weeks, 1 month, and 2 months. The relative standard deviation (RSD) was calculated for each sample. Total impurities and chloroethyl impurities were also quantified by HPLC. HPLC was performed on a Waters Xbridge shield Rp18, 4.6×150 mm, dp=3.5 μm, flow rate 1.0 mL / min, and injection volume 20 μL.
[0111] Tables 6 and 7 show the stability of thiotepa formulations at 5° C. and 25° C. / 60% RH, respectively.
[0112] [Table 6]
[0113] [Table 7]
[0114] The foregoing description of the embodiments is provided for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure. Individual elements or features of a particular embodiment are generally not limited to that particular embodiment and, where applicable, even if not specifically shown or described, can be interchangeable and used in selected embodiments. It can also be varied in many ways. Such variations should not be considered departures from the disclosure, and all such variations are intended to be included within the scope of the present disclosure.
Claims
1. An anhydrous composition comprising thiotepa and a solvent, The solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), polyethylene glycol 400 (PEG400), polyethylene glycol 600 (PEG600), dimethylacetamide (DMA), and N-methylpyrrolidone (NMP). The thiotepa is present in an amount of approximately 1 to approximately 100 mg / mL. It contains virtually no impurities. The impurity is one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxides. The aforementioned anhydrous composition.
2. The anhydrous composition according to claim 1, wherein the impurity is present in an amount selected from the group consisting of less than about 100 ppm, less than about 75 ppm, less than about 50 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. The anhydrous composition according to claim 1, wherein the impurity is present in an amount selected from the group consisting of about 1 to about 100 ppm, 1 to about 75 ppm, 1 to about 50 ppm, about 1 to about 35 ppm, 1 to about 30 ppm, 1 to about 25 ppm, 1 to about 20 ppm, 1 to about 15 ppm, 1 to about 10 ppm, and 1 to about 5 ppm.
4. The aforementioned impurities Formic acid at less than approximately 15 ppm; Acetic acid at less than approximately 15 ppm; Formaldehyde at approximately less than 15 ppm; Acetaldehyde less than approximately 15 ppm; or Peroxide content less than approximately 35 ppm The anhydrous composition according to claim 1, which is one or more of the following.
5. The composition is Formic acid at less than approximately 15 ppm; Acetic acid at less than approximately 15 ppm; Formaldehyde at approximately less than 15 ppm; Acetaldehyde less than approximately 15 ppm; and Peroxide content less than approximately 35 ppm The anhydrous composition according to claim 1, comprising:
6. The anhydrous composition according to claim 1, further comprising an antioxidant or an organic base.
7. The anhydrous composition according to claim 6, wherein the antioxidant is tocopherol.
8. The anhydrous composition according to claim 6, wherein the organic base is a Tris base.
9. An anhydrous composition according to any one of claims 1 to 8, for treating cancer, inducing bone marrow removal before bone marrow transplantation, or for controlling intracavitary exudate secondary to diffuse or localized neoplastic disease of the serosal space.
10. The anhydrous composition according to claim 9, wherein the cancer is selected from the group consisting of bladder cancer, malignant meningeal neoplasm, breast cancer, ovarian cancer, hematological malignancies, lymphoma, metastatic brain tumor, and leptomeningeal meningeal metastasis.
11. The anhydrous composition according to claim 10, wherein the cancer includes adenocarcinoma of the breast and superficial papillary carcinoma of the bladder.
12. The anhydrous composition according to claim 9, for administration by injection.
13. The anhydrous composition according to claim 12, wherein the injection is selected from the group consisting of subcutaneous injection, intramuscular injection, intravenous injection, intradrip infusion, intraperitoneal injection, intrapleural injection, intrapericardial injection, intrathecal injection, intraarterial injection, intravesical injection, and intralesional injection.
14. The anhydrous composition according to claim 9 for administering approximately 300 mg to approximately 700 mg of thiotepa.
15. The anhydrous composition according to claim 9, wherein the thiotepa is stabilized.
16. A method for improving the stability of thiotepa preparations, Mixing thiotepa, water, and components selected from PEG and DMSO; and Homogenizing the aforementioned mixture, Includes The concentration of thiotepa after the homogenization step is approximately 1 to approximately 100 mg / mL. The water constitutes approximately 1 to approximately 40% by weight of the composition. The composition is substantially free of impurities, The impurity is one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxides. The aforementioned method.
17. The method according to claim 16, wherein the concentration of the thiotepa is about 10 mg / mL.
18. The method according to claim 16, wherein the water constitutes about 10% or about 20% by weight of the composition.
19. The method according to claim 16, wherein the PEG is PEG400 or PEG600.
20. The method according to claim 16, wherein the thiotepa preparation comprises 10 mg / mL of thiotepa, PEG400, and 10% by weight of water.
21. The method according to claim 16, wherein the thiotepa preparation comprises 10 mg / mL of thiotepa, PEG400, and 20% by weight of water.
22. The method according to claim 16, wherein the thiotepa preparation comprises 10 mg / mL of thiotepa, DMSO, and 10% by weight of water.
23. The method according to claim 16, further comprising adding a thiosulfate to the composition.
24. The method according to claim 23, wherein the thiosulfate constitutes about 0.01% to about 10% by weight.
25. The method according to claim 24, wherein the thiosulfate constitutes about 0.1% by weight.