WO2023156911A1 - Formulations stables comprenant du thiotépa - Google Patents

Formulations stables comprenant du thiotépa Download PDF

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WO2023156911A1
WO2023156911A1 PCT/IB2023/051366 IB2023051366W WO2023156911A1 WO 2023156911 A1 WO2023156911 A1 WO 2023156911A1 IB 2023051366 W IB2023051366 W IB 2023051366W WO 2023156911 A1 WO2023156911 A1 WO 2023156911A1
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composition
thiotepa
water
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PCT/IB2023/051366
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Sharon CUNNINGHAM
Orlaith RYAN
Johannes Jan Platteeuw
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Shorla Pharma Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • compositions comprising thiotepa and methods for using the same for treating a disease in a subject.
  • 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.
  • 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/m 2 (42mg/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).
  • PEG polyethylene glycol
  • 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 Q C/60% relative humidity after seven days.
  • compositions comprising thiotepa, PEG or DMSO, and water.
  • the compositions are free or substantially free of impurities.
  • the disclosed compositions are stable and may be suitable for injection.
  • the thiotepa formulation can be administered for the treatment of a disease, particularly, cancer, or myeloablation prior to bone marrow transplantation.
  • the thiotepa composition comprises PEG such as PEG400 or PEG600. In another embodiment, the composition comprises DMSO.
  • 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.
  • a solvent such as DMSO, PEG400, PEG600, DMA, and NMP
  • the composition further comprises thiosulfate.
  • a method for treating cancer in a subject comprising injection administration of a composition comprising thiotepa, PEG or DMSO, and water.
  • a composition comprising thiotepa, PEG or DMSO, and water.
  • the PEG is PEG400 or PEG600.
  • the administered composition further comprises thiosulfate.
  • a method for myeloablation of a subject prior to bone marrow transplantation comprising administration of the thiotepa composition.
  • FIG. 1 shows chromatogram of a thiotepa composition of Example 1 .
  • thiotepa refers to the chemical compound N,N’,N”- triethylenethiophosphoramide, and is also known by the trade names of Tepadina® or Thioplex®.
  • thiotepa includes the compound itself and pharmaceutically acceptable salts thereof.
  • non-aqueous refers to compositions (e.g. solutions, liquids, or suspensions) which are free of or essentially free of water.
  • the term “subject” refers to an animal that can receive administration of the thiotepa composition.
  • the subject is human.
  • the subject has, or is thought to have cancer.
  • the subject is in need of myeloablation or lymphodepletion prior to bone marrow transplantation or other therapy requiring a conditioning regimen.
  • the subject is in need of gene therapy.
  • cancer includes, but is not exclusive of, bladder cancer, malignant meningeal neoplasm, breast cancer, ovarian cancer, hematological malignancies, lymphoma, brain metastases, and leptomeningeal metastasis.
  • injection refers to a method of administration where the composition is administered to the body via needle.
  • the injection is selected from the group consisting of subcutaneous injection, intramuscular injection, intravenous injection, infusion, intraperitoneal injection, intrapleural injection, intrapericardial injection, intrathecal injection, intra-arterial injection, intravesical injection, and intralesional injection.
  • the injection can be a single injection, including an acute injection or a continuous injection.
  • the injection can be delivered over a number of days.
  • substantially free refers to the amount of a component that is not intended to be present in a composition but still may be present due to manufacturing procedures and/or post-manufacturing degradation products.
  • compositions described below may be substantially free of impurities, including but not limited to formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide.
  • a composition may be substantially free of impurities when it is processed and/or refined beyond what is conventional in the art.
  • PEG400 may undergo additional processing and/or refining and may be called “super refined, such as Super RefinedTM PEG400 offered by Croda Health Care and EM PROVETM PEG offered by Sigma.
  • a composition is substantially free of an impurity, when the impurity is present in the composition in an amount of less than about 100 ppm.
  • a composition substantially free of an impurity comprises the impurity 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.
  • the amount of an impurity in the composition may be expressed as a range, for example between about 1 and about 100 ppm, between about 1 and about 95 ppm, between about 1 and about 80 ppm, between about 1 and about 75 ppm, between about 1 and about 70 ppm, between about 1 and about 65 ppm, between about 1 and about 60 ppm, between about 1 and about 55 ppm, between about 1 and about 50 ppm, between about 1 and about 45 ppm, between about 1 and about 40 ppm, between about 1 and about 35 ppm, between about 1 and about 30 ppm, between about 1 and about 25 ppm, between about 1 and about 20 ppm, between about 1 and about 15 ppm, between about 1 and about 10 ppm, between about 1 and about 5 ppm, or between about 1 and about 3 ppm.
  • a composition is substantially free of an impurity, when concentration of the component is described as a percentage of the composition.
  • a composition substantially free of an impurity may comprise the impurity in an amount of less than about 0.0001 %, less than about 0.000095%, less than about 0.00009% less than about 0.000085%, less than about 0.00008%, less than about 0.000075%, less than about 0.00007%, less than about 0.000065%, less than about 0.00006%, less than about 0.000055%, less than about 0.00005%, less than about 0.000045%, less than about 0.00004%, less than about 0.000035%, less than about 0.00003%, less than about 0.000025%, less than about 0.00002%, less than about 0.000015%, less than about 0.00001 %, less than about 0.000005%, or less than about 0.000001 %.
  • the amount of an impurity, in the composition may be expressed as a range of percentages, for example between about 0.000001 % and about 0.0001 %, between about 0.000001 % and about 0.000095%, between about 0.000001 % and about 0.00009%, between about 0.000001 % and about 0.000085%, between about 0.000001 % and about 0.00008%, between about 0.000001 % and about 0.000075%, between about 0.000001 % and about 0.00007%, between about 0.000001 % and about 0.000065%, between about 0.000001 % and about 0.00006%, between about 0.000001% and about 0.000055%, between about 0.000001 % and about 0.00005%, between about 0.000001 % and about 0.000045%, between about 0.000001 % and about 0.00004%, between about 0.000001 % and about 0.000035%, between about 0.000001 % and about 0.00003%, between about 0.000001 % and about 0.000025%, between 0.000001
  • impurity refers to a substance that is other than the components specifically identified and included in a composition of the present disclosure.
  • the impurity is one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide.
  • peroxide value refers to the concentration of hydroperoxides, which are molecules having a peroxide (-O-O-H) moiety (e.g., H2O2). Peroxide value is typically measured as milliequivalents of active O2 per kg of fat matter (mEq 02/kg fat).
  • compositions comprising thiotepa or its derivative, such as a metabolite, and one or more excipients.
  • compositions include pharmaceutical compositions comprising thiotepa, PEG or DMSO, and water.
  • Thiotepa is the active ingredient of the formulation and its amount can be adjusted as needed. Generally, all known/approved amounts of thiotepa can be used with the formulation.
  • the thiotepa is present in an amount of about 1 to about 100 mg/mL.
  • the thiotepa is present in an amount of about 5 to about 50 mg.
  • the thiotepa is present at a concentration of about 10 mg/mL.
  • the water is present at in an amount up to about 40% by weight. In another embodiment, the 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 1 1 %, about 12%, about 13%, about 14%, about 15%, about 20%, about 25%, or about 30% by weight. In a particular embodiment, the water is present in an amount of about 10% by weight. In some embodiments, the water is distilled, purified, or ultrapurified. In another embodiment, the water may include saline or a phosphate buffer to prepare an isotonic solution.
  • 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 may comprise impurities in an amount 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, less than about 5 ppm, or less than about 1 ppm.
  • the impurities may be present in a range, such as between about 1 and about 35 ppm, about 1 and about 30 ppm, between about 1 and about 25 ppm, between about 1 and about 20 ppm, between about 1 and about 15 ppm, between about 1 and about 10 ppm, between about 1 and about 5 ppm, or between about 1 and about 3 ppm.
  • compositions described herein may 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 .
  • the peroxide value is less than about 1 .0, preferably less than about 0.5.
  • the composition may be substantially free of one or more of each impurity.
  • the composition may be substantially free of formic acid but not substantially free of peroxides.
  • the overall composition may be considered substantially free of each impurity is present at different levels.
  • the composition may comprise 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 peroxides, or a combination thereof.
  • the comprise may comprise 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 peroxides of each of the impurities.
  • the composition comprises PEG in an amount of between about 80% to about 100%.
  • the PEG may be a PEG between PEG200 and PEG400.
  • the PEG is selected from PEG400 and PEG 600.
  • the composition comprises Super RefinedTM PEG400 or EMPROVETM PEG.
  • the composition comprises dimethyl sulfoxide (DMSO) in an amount between about 90% to about 100%.
  • DMSO dimethyl sulfoxide
  • the thiotepa composition further comprises one or more antioxidants.
  • the antioxidant includes ascorbic acid, tocopherols, methionine (such as L-methionine), metabisulphite, propyl gallate, butylated hydroxyanasole, butylated hydroxytoluene, meglumine, thiosulphate salts. More preferred antioxidants are propyl gallate, thiosulphate salts, preferably sodium thiosulphate, and tocopherols, preferably a -tocopherols, more preferably a-tocopherol- PEG-succinate.
  • A-tocopherol-PEG-succinate is a commercially available conjugate of a- tocopherol with PEG1000, and has high solubility in short PEGs.
  • Most preferred antioxidants are thiosulphate salts, preferably sodium thiosulphate, and tocopherols, preferably a-tocopherols, more preferably a-tocopherol-PEG-succinate.
  • the composition according to the invention further comprising an antioxidant such as a thiosulphate salt, propyl gallate, or a tocopherol.
  • an antioxidant selected from thiosulphate salt and/or a tocopherol is provided.
  • the composition according to the invention further comprising an antioxidant selected from sodium thiosulphate and/or an a-tocopherol, preferably a-tocopherol-PEG-succinate.
  • the antioxidant such as thiosulfate
  • the antioxidant is present in an amount between about 0.01 % and about 1.0%, by weight.
  • the thiosulfate is present in an amount of about 0.1 %, by weight.
  • the thiotepa composition can further comprise additional excipients and non-limiting examples of such excipients include buffers, antioxidants, and/or osmotic agents.
  • the composition comprises about 1 to about 100 mg/mL thiotepa, PEG or DMSO, and up to about 20% water, by weight. If PEG is used, the PEG can be either PEG400 or PEG600.
  • the composition may further comprise thiosulfate. Specific embodiments of the thiotepa composition are exemplified in Table 1 . [0041] Table 1 : Thiotepa-containing formulations
  • 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 compositions are in the form of a parenteral formulation suitable for injection.
  • the thiotepa is formulated in waterless compositions.
  • the waterless thiotepa composition comprises thiotepa and a solvent selected from the group consisting of DMSO, PEG400, PEG600, dimethayacetamide (DMA), and n-methyl-2-pyrrolidone (NMP).
  • the waterless thiotepa composition further comprises an antioxidant (such as tocopherol) and/or an organic base (such as Tris base).
  • the thioptepa composition comprises about 1 to about 100 mg/mL thiotepa, and DMSO, PEG400, PEG600, DMA, or NMP. Specific embodiments of the waterless thiotepa compositions are in Table 2.
  • compositions substantially free of impurities are shown in Table 3 below.
  • the composition of the present disclosure is to address, among other things, stability issues of thiotepa in an aqueous solution.
  • Thiotepa is known to have stability issues in aqueous solutions, such as generation of impurities and degradation of the active ingredient during storage.
  • the aqueous instability renders ready-to-use liquid dosage forms of thiotepa difficult to store.
  • the stable thiotepa composition of the present disclosure is suitable for a ready-to-use liquid dosage drug product.
  • the thiotepa composition is stable at room temperature (e.g., 21 -25°C) or under refrigeration (e.g., 4-5°C) for one month, two months, three months, or longer in the dark.
  • the thiotepa is stable for up to six months at room temperature (50% relative humidity) or under refrigeration.
  • the thiotepa composition is stored for a period of time, such as for 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, 1 1 months, 1 year, 2 years, or 3 years.
  • the present disclosure provides various methods of using the thiotepa composition for the treatment of disease(s) such as cancer.
  • the thiotepa composition is administered to a subject to treat cancer, wherein the subject is in need of such treatment.
  • Various cancers can be treated by the composition and in some embodiments, the cancer is selected from the group consisting of bladder cancer, malignant meningeal neoplasm, breast cancer, and ovarian cancer.
  • the method is used for treating adenocarcinoma of the breast, controlling intracavitary effusions secondary to diffuse or localized, neoplastic diseases of various serosal cavities, and/or treating superficial papillary carcinoma of the urinary bladder.
  • the composition is 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.
  • the thiotepa composition is administered to provide a therapeutically effective dose to achieve the goal or goals of the therapy.
  • the therapeutically effective amount is sufficient to treat cancer.
  • the therapeutically effective amount is between about 300 mg and about 700 mg. If a patient requires more than 850 mg thiotepa, the drug may be administered over two or more doses in a day.
  • the therapeutically effective amount of thiotepa is about between about 4 and about 20 mg/kg body weight.
  • the therapeutically effective amount is between about 120 and about 300 mg/m 2 .
  • the thiotepa can be administered in a single day over the course of multiple days, such as over the course of between 1 and 5 days, in particular between 1 and 2 days.
  • the thiotepa composition therapy can be combined with various cancer treatments known in the art.
  • the thiotepa composition is administered to the subject in conjunction with radiotherapy.
  • the thiotepa composition is administered before, after, or concurrently with an additional chemotherapeutic agent.
  • the therapeutically effective dose may be between about 20 mg and about 40 mg administered every 1 to 4 weeks.
  • a therapeutically effective amount of thiotepa is administered to induce myeloablation prior to bone marrow transplantation.
  • the therapeutically effective amount of thiotepa is between 300 mg/mL and 700 mg/mL.
  • the therapeutically effective amount of thiotepa for myeloablation prior to bone marrow transplantation is provided over 1 to 5 days, or over 1 to 2 days.
  • the total amount of thiotepa delivered over the course of treatment for myeloablation prior to bone marrow transplantation may be about 850 mg or more.
  • a method for enhancing the stability of a thiotepa formulation comprises the steps of: combining thiotepa, water, and an excipient, wherein the excipient is PEG or DMSO; and homogenizing the combination.
  • the thiotepa concentration of the thiotepa in formulation following homogenization is between about 1 and about 100 mg/mL.
  • the water comprises between about 1 % and about 20%, by weight of the composition.
  • the thiotepa is present at about 10 mg/mL and the water is present at about 10% or 20%, by weight.
  • the PEG is PEG400 or PEG600.
  • the thiotepa formulation with enhanced stability consists of 10 mg/mL thiotepa, PEG 400, and 10% water, by weight.
  • the thiotepa formulation with enhanced stability consists of 10 mg/mL thiotepa, PEG 600, and 20% water, by weight.
  • the thiotepa formulation with enhanced stability consists of 10 mg/mL thiotepa, DMSO, and 10% water, by weight.
  • the formulation further comprises thiosulfate.
  • a composition comprising thiotepa, water, and an excipient, wherein the excipient is polyethylene glycol (PEG) or dimethylsulfoxide (DMSO), wherein the thiotepa is present in an amount between about 1 and about 100 mg/mL, wherein the water is present in about up to about 40%, wherein the composition is substantially free of an impurity, and wherein the impurity is one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide.
  • PEG polyethylene glycol
  • DMSO dimethylsulfoxide
  • composition of any one of paragraphs 1 -8, wherein the impurity is 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.
  • composition of any one of paragraphs 1 -8, wherein the impurity is 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.
  • composition of paragraph 1 which consists of thiotepa, PEG400, 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.
  • composition of paragraph 14 which comprises about 10 mg/mL thiotepa and about 10% water, by weight.
  • paragraph 16 The composition of paragraph 1 , which consists of thiotepa, PEG600, 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.
  • composition of paragraph 16 which comprises about 10 mg/mL thiotepa and about 20% water, by weight.
  • composition of paragraph 1 which consists of 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.
  • composition of paragraph 11 which comprises about 10 mg/mL thiotepa and about 10% water, by weight.
  • a waterless 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), dimetylacetamide (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, and wherein the impurity is one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide.
  • DMSO dimethylsulfoxide
  • PEG400 polyethylene glycol 400
  • PEG600 polyethylene glycol 600
  • DMA dimetylacetamide
  • NMP N-methylpyrrolidone
  • a method for treating cancer in a subject in need thereof comprising administering to the subject the composition of any one of paragraphs 1 -30.
  • cancer selected from the group consisting of bladder cancer, malignant meningeal neoplasm, breast cancer, and ovarian cancer.
  • injection is selected from the group consisting of subcutaneous injection, intramuscular injection, intravenous injection, infusion, intraperitoneal injection, intrapleural injection, intrapericardial injection, intrathecal injection, intra-arterial injection, intravesical injection, and intralesional injection.
  • a method for enhancing the stability of a thiotepa formulation comprising: combining thiotepa, water, and a component selected from PEG and DMSO; and homogenizing the combination, wherein the concentration of thiotepa after the step of homogenizing is between about 1 and about 100 mg/mL, wherein the water comprises between about 1 and about 40%, by weight, of the composition, wherein the composition is substantially free of an impurity, and wherein the impurity is one or more selected from the group consisting of formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide.
  • Example 1 Stability of aqueous thiotepa compositions
  • Table 4 Thiotepa stability at 5 Q C (RSD is relative standard deviation)
  • Table 5 Thiotepa stability at 25 Q C/60% RH
  • PEG and DMSO formulations with 10% or 20% water were stable when stored at 5 Q C.
  • PEG400- and PEG600-containing formulations are stable up to 5 months, at both 5 Q C and 25 Q C/60% RH.
  • FIG. 1 shows a chromatogram of a thiotepa composition of Example 1 .
  • Example 2 Stability of waterless thiotepa compositions
  • Tables 6 and 7 show the stability of thiotepa formulations at 5 Q C and 25 Q C/60% RH, respectively.

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant du thiotépa, de l'eau, un élément choisi parmi le PEG, tel que PEG400 ou PEG600, et le DMSO, et éventuellement du thiosulfate ou de telles compositions qui sont exemptes ou sensiblement exemptes d'impuretés. L'invention concerne également une méthode de traitement du cancer chez un sujet, ou une myéloablation avant une greffe de moelle osseuse à l'aide de la composition. L'invention concerne en outre un procédé d'amélioration de la stabilité d'une formulation de thiotépa.
PCT/IB2023/051366 2022-02-16 2023-02-15 Formulations stables comprenant du thiotépa WO2023156911A1 (fr)

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Citations (3)

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EP0419890A2 (fr) 1989-09-29 1991-04-03 American Cyanamid Company Formulations pharmaceutiques stables pour des composés antinéoplastiques avec plus d'un groupement éthylèneimine et procédé
US20140005148A1 (en) 2012-06-29 2014-01-02 Coldstream Laboratories Inc. Stable liquid formulations of nitrogen mustards
US20200163979A1 (en) 2018-11-28 2020-05-28 RK Pharma Solutions LLC Storage-Stable Ready-To-Use Injectable Formulations Of Thiotepa

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419890A2 (fr) 1989-09-29 1991-04-03 American Cyanamid Company Formulations pharmaceutiques stables pour des composés antinéoplastiques avec plus d'un groupement éthylèneimine et procédé
US20140005148A1 (en) 2012-06-29 2014-01-02 Coldstream Laboratories Inc. Stable liquid formulations of nitrogen mustards
US20200163979A1 (en) 2018-11-28 2020-05-28 RK Pharma Solutions LLC Storage-Stable Ready-To-Use Injectable Formulations Of Thiotepa

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