Compositions containing cabazitaxel and lipids for oral administration

Abstract

The invention relates to a cabazitaxel composition and application of the cabazitaxel composition. Embodiments provide a composition comprising cabazitaxel and at least one lipid and / or cougsterol, and / or a cougsterol derivative, and / or sodium cholesterol sulfate, in the form of a tablet or capsule, and administering the composition to a subject.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Publication Number (43) Publication Date (21) Application Number 202480062072.0 (22) Application Date 2024.09.27 (30) Priority Data 63 / 585,913 2023.09.27 US (85) PCT International Application Entering National Phase Date 2026.03.26 (86) PCT International Application Application Data PCT / IB2024 / 059471 2024.09.27 (87) PCT International Application Publication Data WO2025 / 068971 EN 2025.04.03 (71) Applicant: Gina Pharmaceutical Company, Address: Illinois, USA (72) Inventors: Shaukat M. Ali, Paul Chen, Atik Ahmed, Saifuddin Sheikh Mogis U. Ahmed, Imran Ahmed (74) Patent Agency: Shanghai Shanggu Intellectual Property Agency Co., Ltd., 31342 Patent Attorney: Cai Jiqing (51) Int.Cl. A61K 9 / 20 (2006.01) A61K 9 / 48 (2006.01) A61K 9 / 28 (2006.01) A61K 31 / 337 (2006.01) A61K 47 / 14 (2006.01) A61K 47 / 28 (2006.01) (54) Invention Title Composition Containing Cabazitaxel and Lipids for Oral Administration (57) Abstract This invention relates to cabazitaxel compositions and the administration of cabazitaxel compositions. Embodiments A composition comprising cabazitaxel and at least one lipid and / or gulosterol, and / or gulosterol derivatives, and / or sodium cholesterol sulfate, in tablet or capsule dosage form, and administration of said composition to a subject. Claims 1 page Description 14 pages Drawings 1 page CN 121925252 A 2026.04.24 CN 1 21 92 52 52 A 1. A composition comprising cabazitaxel and at least one lipid and / or gulosterol or gulosterol derivatives or sodium cholesterol sulfate, in a sealed-coated and / or enteric-coated tablet or capsule. 2. The composition according to claim 1, wherein the at least one lipid is selected from soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylcholine (DPPC), distearate phosphatidylglycerol (DSPG), dipalmitoyl phosphatidylglycerol (DMPG), cholesterol (Choi), cholesterol sulfate and their salts.3. The composition according to claim 1, wherein the gulosterol derivative is selected from gulosterol laurate, gulosterol myristate, gulosterol palmitate, gulosterol stearate, gulosterol oleate, gulosterol linoleate, and gulosterol linoleate. 4. The composition according to claim 1, wherein the composition further comprises one or more excipients selected from magnesium aluminosilicate, tocopherol polyethylene glycol succinate, silicified microcrystalline cellulose, magnesium stearate, croscarmellose sodium, sodium lauryl sulfate, polyethylene glycol-polypropylene glycol-polyethylene glycol polymer, poloxamer 188, hydrophilic fumed silica, aerosols, and citric acid. 5. The composition according to claim 1, wherein the sealing coating comprises one or more polymers selected from hydroxymethylpropyl cellulose, methyl hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, sodium carboxymethyl cellulose, acrylate polymers, and polyethylene glycol. 6. The composition of claim 1, wherein the enteric coating comprises one or more polymers selected from hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, acrylate polymers, polyvinyl acetate phthalate, and methyl methacrylate copolymer. 7. The composition of claim 1, wherein the content of cabazitaxel in a single tablet or capsule is at least in the range of 20 mg to 1000 mg. 8. The composition of claim 1, wherein the content of lipids in a single tablet or capsule is at least in the range of 10 mg to 1000 mg. 9. The composition of claim 1, wherein the content of guggul sterol or guggul derivative in a single tablet or capsule is at least 2 mg to 500 mg. 10. The composition of claim 1, wherein the content of sodium cholesterol sulfate in a single tablet or capsule is at least 2 mg to 500 mg. 11. The composition of claim 1, wherein the composition is a tablet or capsule, and the administration includes oral administration. 12. The composition according to claim 1, wherein the composition comprises oral administration to a subject. 13. The composition according to claim 12, wherein the subject is a mammal. 14. The composition according to claims 12 and 13, wherein the subject is a human. Claims 1 / 1 page 2 CN 121925252 A Composition containing cabazitaxel and lipids for oral administration Field of Invention

[0001] The present invention relates to compositions containing cabazitaxel and lipids.This invention also relates to compositions comprising cabazitaxel, guggulsterol and / or guggulsterol derivatives and / or sodium cholesterol sulfate. In some embodiments, this invention relates to compositions comprising cabazitaxel, lipids (including phosphatidylcholine and phosphatidylglycerol). In preferred embodiments, this invention relates to compositions comprising cabazitaxel, phosphatidylcholine and guggulsterol or guggulsterol derivatives or sodium cholesterol sulfate. In some embodiments, this invention also relates to tablet or capsule compositions comprising cabazitaxel and excipients. This invention also relates to administering the compositions to mammalian subjects for the treatment or prevention of disease. The compositions of this invention are suitable for industrial-scale practice and can be implemented, for example, in a continuous process. Background of the Invention

[0002] Taxanes have become an important class of chemotherapeutic drugs, widely used for monotherapy and in combination with other drugs for the treatment of various solid malignancies. Cabazitaxel is a novel second-generation semi-synthetic natural taxane derivative. The mechanism of action of cabazitaxel is similar to that of paclitaxel and docetaxel. It binds to the N-terminal amino acid of the P-tubule protein subunit, promoting microtubule polymerization and inhibiting microtubule cell division, thereby arresting the tumor cell cycle and tumor proliferation. Cabazitaxel is superior to paclitaxel and docetaxel because it has an additional methyl group, resulting in a lower affinity for P-glycoprotein. This makes it effective in treating docetaxel-resistant tumors.

[0003] Cabazitaxel is marketed under the brand name Jevtana® and is approved for the treatment of patients with hormone-refractory metastatic prostate cancer who have previously received docetaxel-containing regimens. The individual dose of cabazitaxel is calculated based on body surface area (BSA) and administered as a one-hour intravenous infusion of 25 mg / m2 every three weeks, concurrently with 10 mg of prednisone orally.

[0004] Jevtana® is a sterile, non-water-soluble concentrate for infusion, containing 60 mg of cabazitaxel per 1.5 ml of polysorbate 80, packaged in glass vials, and also containing solvents for diluting the concentrate. The solvent is a 13% w / w sterile, pyrogen-free aqueous solution of ethanol. This concentrate and solvent are used to prepare a 10 mg / ml premixed cabazitaxel solution, which is then diluted in an infusion bag with 0.9% saline or 5% glucose solution.

[0005] Taxanes, including cabazitaxel, are highly lipophilic and practically insoluble in water. Due to their insolubility, various solubilizers such as polysorbate 80, Cremophore EL, and ethanol have been successfully used to formulate taxanes for intravenous administration. However, the use of polysorbate 80, Cremophore EL, and ethanol can cause hypersensitivity reactions and infusion-related toxicities. To reduce the risk of these side effects, patients are usually given corticosteroids before receiving taxane treatment.

[0006] Furthermore, all taxanes are inherently cytotoxic.The main dose-limiting toxicity of cabazitaxel is fatal febrile neutropenia, therefore complete blood cell counts should be monitored weekly and before each treatment cycle, and G-CSF supplementation should be administered if necessary. Other toxicities include nausea and vomiting.

[0007] To avoid the toxic effects of cabazitaxel and excipients in currently commercially available intravenous products, it is necessary to develop novel cabazitaxel compositions for oral administration. Summary of the Invention

[0008] The present invention provides compositions containing cabazitaxel. In some embodiments, the composition comprises a phosphatidylcholine base. In some embodiments, the composition further comprises one or more of gulosterol, gulosterol derivatives, and / or sodium cholesterol sulfate. In some preferred embodiments, the composition further comprises other excipients. Some embodiments include a composition containing cabazitaxel and administration of the composition to a subject. In some embodiments, the subject is a mammal. In a preferred embodiment, the subject is a human.

[0009] In some embodiments, the present invention provides a composition comprising cabazitaxel and phosphatidylcholine for oral delivery to a subject. In a preferred embodiment, the subject is a mammal, and in a more preferred embodiment, the subject is a human. In some embodiments, the composition for oral delivery is in tablet or capsule form. In a preferred embodiment, the tablet and / or capsule comprises an enteric coating.

[0010] In some embodiments, the composition of the present invention comprises cabazitaxel and phosphatidylglycerol for oral delivery to a subject. In a preferred embodiment, the subject is a mammal, and in a more preferred embodiment, the subject is a human. In some embodiments, the composition for oral delivery is in tablet or capsule form. In a preferred embodiment, the tablet and / or capsule comprises an enteric coating.

[0011] In some embodiments, this invention provides a composition comprising cabazitaxel and gulosterol for oral delivery to a subject. In a preferred embodiment, the subject is a mammal, and in a more preferred embodiment, the subject is a human. In some embodiments, the composition for oral delivery is in tablet or capsule form. In a preferred embodiment, the tablet and / or capsule comprises an enteric coating.

[0012] In some embodiments, the present invention provides a composition comprising cabazitaxel and a gulosterol derivative for oral delivery to a subject. In a preferred embodiment, the subject is a mammal, and in a more preferred embodiment, the subject is a human. In some embodiments, oral delivery is in the form of tablets or capsules. In a more preferred embodiment, the tablets and / or capsules comprise an enteric coating.

[0013] In some embodiments, the present invention provides a composition comprising cabazitaxel and sodium cholesterol sulfate for oral delivery to a subject.In a preferred embodiment, the subject is a mammal; in a more preferred embodiment, the subject is a human. In some embodiments, oral delivery is in the form of tablets or capsules. In a more preferred embodiment, the tablets and / or capsules contain an enteric coating.

[0014] In some embodiments, the present invention provides a composition comprising cabazitaxel, phosphatidylcholine, and sodium cholesterol sulfate for oral delivery to a subject. In a preferred embodiment, the subject is a mammal; in a more preferred embodiment, the subject is a human. In some embodiments, oral delivery is in the form of tablets or capsules. In a more preferred embodiment, the tablets and / or capsules contain an enteric coating.

[0015] In some embodiments, the present invention provides a composition comprising cabazitaxel, phosphatidylcholine, and gulosterol for oral delivery to a subject. In a preferred embodiment, the subject is a mammal; in a more preferred embodiment, the subject is a human. In some embodiments, oral delivery is in the form of tablets or capsules. In a more preferred embodiment, the tablets and / or capsules contain an enteric coating.

[0016] In some embodiments, the present invention provides a composition comprising cabazitaxel, phosphatidylcholine, and gulosterol derivatives for oral delivery to a subject. In a preferred embodiment, the subject is a mammal; in a more preferred embodiment, the subject is a human. In some embodiments, oral delivery is in the form of tablets or capsules. In a more preferred embodiment, the tablets and / or capsules contain an enteric coating.

[0017] In some embodiments, the cabazitaxel composition of the present invention is administered in combination with other drugs. Drugs that can be administered in combination with the cabazitaxel composition include, but are not limited to: anticancer drugs, such as doxorubicin, epirubicin, methotrexate, mitoxantrone, capecitabine, carboplatin, cisplatin, etoposide, 5-fluorouracil, cyclophosphamide, bendamustine, daunorubicin, bleomycin, gemcitabine, irinotecan, SN-38, mitoxantrone, cytarabine, erlotinib, imatinib, ibrutinib, Palbociclib, bortezomib, abiraterone, bicalutamide, flutamide, temozolomide, etc.; antihypertensive drugs, such as dihydropyridines, antidepressants, antihistamines, etc.; corticosteroids, such as prednisone, methylprednisolone, dexamethasone, budesonide, hydrocortisone, etc.; antihistamines, such as diphenhydramine, chlorpheniramine, dextrochlorpheniramine, cetirizine, levocetirizine, loratadine, desloratadine, etc.; drugs for treating acid reflux, such as cimetidine, ranitidine, famotidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, etc.

[0018] The amount of cabazitaxel contained in the cabazitaxel composition according to the present invention is not limited to any specific amount or percentage (by weight) of the final composition or weight.In some embodiments, the proportion of cabazitaxel is from about 1% to about 90% of the total weight, preferably from about 2% to about 75% of the total weight, and more preferably from about 5% to about 50% of the total weight.

[0019] The content of phosphatidylcholine or phosphatidylglycerol contained in the cabazitaxel composition according to the invention is not limited to any specific amount or percentage (by weight) of the final composition or weight. In some embodiments, the proportion of phosphatidylcholine is from about 1% to about 90% of the total weight, preferably from about 2% to about 80% of the total weight, and more preferably from about 3% to about 50% of the total weight.

[0020] The content of gulostrol, gulostrol derivatives, or sodium cholesterol sulfate contained in the cabazitaxel composition according to the invention is not limited to any specific amount or percentage (by weight) of the final composition or weight. In some embodiments, the proportion of gulostrol, gulostrol derivatives, or sodium cholesterol sulfate is from about 0.1% to about 90% of the total weight, preferably from about 0.1% to about 50% of the total weight, and more preferably from about 0.1% to about 25% of the total weight.

[0021] Definitions: For ease of understanding of the invention, the following terms and phrases are defined: The terms “composition,” “formulation,” or “dosage form” as used herein refer to a combination of an active pharmaceutical agent (e.g., an active pharmaceutical compound) with a carrier (inert or active) and excipients, such that the composition is particularly suitable for in vitro, in vivo, or ex vivo diagnostic or therapeutic use. The term “active pharmaceutical agent” as used herein, when referring to a pharmaceutical agent, composition, or compound, means a pharmaceutical agent that produces a beneficial, desired, or anticipated result upon administration or application. Administration may be a single or multiple administration, application, or ordination, and is not limited to a particular dosage form or route of administration. The term is not limited to any particular level of activity. For example, the level of activity of one active pharmaceutical agent dosage form need not be the same as that of another active pharmaceutical agent dosage form, as long as the active pharmaceutical agent in the dosage form has sufficient activity to provide an effective amount of the active pharmaceutical agent by application of the dosage form.

[0022] The terms “pharmaceutical agent” and “compound” are used interchangeably herein to refer to any mixture of atoms, molecules, or more complex compositions having specific properties. For example, "active agent" or "active compound" refers to any atom, molecule, formulation mixture, etc., that produces a beneficial, desired, or anticipated result upon administration or application.

[0023] As used herein, the terms "administration" or "application" mean the act of supplying a drug, active agent, or therapeutic treatment (such as the compositions of the present invention) to a physiological system (e.g., a subject or cells, tissues, and organs in vivo, in vitro, or ex vivo). Exemplary routes of administration to a subject (e.g., a mammal) may be oral, transdermal, ocular, nasal, etc. Administration may be performed once or multiple times, by application or ordination, and is not limited to a particular route of administration.

[0024] As used herein, the term “combined administration” refers to the administration of at least two agents (e.g., two separate compositions containing different active agents) or therapies to a subject. In some embodiments, the combined administration of two or more agents or therapies is performed simultaneously. In other embodiments, the first agent / therapy is administered before the second agent / therapy. Those skilled in the art will understand that the dosage forms and / or routes of administration of the various agents or therapies used may differ. Those skilled in the art can readily determine the appropriate dosage for combined administration.

[0025] As used herein, the term “excipient” refers to an inactive ingredient (i.e., a non-pharmacologically active ingredient) added to a formulation of the active ingredient. The disintegrants, anti-adhesion agents, adhesives, plasticizers, fillers, coating agents, lubricants, preservatives, flow aids, fragrances, colorants, adsorbents, sweeteners, antioxidants, penetration enhancers, humectants, emulsifiers, ointment bases, acidifiers and / or alkalizers and / or buffers, gelling agents, and protectants described herein can be collectively referred to as “excipients”.

[0026] The term “disease” as used herein refers to a state, sign, and / or symptom associated with any impairment of the normal state of a living animal or any of its organs or tissues, which interrupts or alters normal function and may be a response to environmental factors.

[0027] The term “treatment” or its grammatical equivalent as used herein encompasses the improvement and / or reversal of symptoms of a disease (e.g., cancer) or a reduction in the risk of disease occurrence. When used in the screening methods of the present invention, a compound may be identified as a therapeutic compound if it improves any parameter associated with a disease. The term “treatment” refers to therapeutic treatment. For example, people who may benefit from treatment with the compositions of the present invention include those who already have a disease and / or condition (e.g., cancer, or symptoms or pathology consistent with cancer).

[0028] As used herein, the term “mammal” refers to a group of vertebrates that produce or secrete milk through mammary glands to nurse their offspring. Examples of mammals herein include humans, dogs, felines, equines, cetaceans, and dolphins.

[0029] In the context of describing the invention (especially in the following claims), the terms “a,” “described,” and similar designations should be interpreted to cover both singular and plural unless otherwise stated herein or the context clearly contradicts it. The terms “comprising,” “including,” “having,” and “containing” should be interpreted as open-ended terms (i.e., meaning “including but not limited to”) unless otherwise indicated. The use of any and all examples or exemplary expressions (e.g., “such as”) provided herein is intended only to better illustrate the invention and does not limit the scope of the invention unless otherwise stated. No expression in the specification should be construed as indicating that any unclaimed element is essential to the implementation of the invention.

[0030] Figure 1 is a graph showing the blood concentration of cabazitaxel in mice over a period of time (Example 8).

[0031] Figure 2 is a graph showing the blood concentration of cabazitaxel in patients after oral or intravenous administration over a period of time (Example 11). Detailed Description

[0032] The present invention relates to a composition comprising a cabazitaxel formulation. In some embodiments, the invention includes administering the cabazitaxel composition to a subject, for example, for treating a disease. In some embodiments, the composition comprising cabazitaxel comprises lipids, such as phosphatidylcholine or phosphatidylglycerol. In some embodiments, the composition comprising cabazitaxel comprises gulostrol or gulostrol derivatives or sodium cholesterol sulfate. In other embodiments, the composition comprises phosphatidylcholine or phosphatidylglycerol and / or gulostrol, gulostrol derivatives or sodium cholesterol sulfate. In a preferred embodiment, the subject is a mammal; in a more preferred embodiment, the subject is a human.

[0033] Embodiments of the invention have been described in the Summary of the Invention and in this Detailed Description. Although the present invention has been described in conjunction with specific embodiments, the claimed invention should not be unduly limited to these specific embodiments.

[0034] Examples of phosphatidylcholine suitable for the compositions of the present invention include soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearyl phosphatidylcholine (DSPC). Examples of phosphatidylglycerols include dimyristoyl phosphatidylglycerol (DMPG), distearyl phosphatidylglycerol (DSPG), and dipalmitoyl phosphatidylglycerol (DMPG).

[0035] Examples of gugulasterol derivatives suitable for use in the compositions of the present invention include gugulasterol laurate, gugulasterol myristate, gugulasterol palmitate, gugulasterol stearate, gugulasterol oleate, gugulasterol linoleate, and gugulasterol linolenate.

[0036] In some embodiments, the compositions of the present invention comprise antioxidants and / or stabilizers. Examples of antioxidants suitable for use in the compositions of the present invention include: α-tocopherol (vitamin E), α-tocopherol polyethylene glycol succinate (TPGS), ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite (SMB), propyl gallate, cysteine, and citric acid.

[0037] The present invention provides compositions comprising cabazitaxel and delivers such compositions to subjects, such as human subjects. Any suitable amount of cabazitaxel sufficient to produce the desired effect (e.g., therapeutic effect) can be used. In a preferred embodiment, a suitable amount of cabazitaxel refers to an amount that can be suitably incorporated into the tablets or capsules of the present invention.

[0038] In a preferred embodiment, the tablet or capsule containing cabazitaxel and excipients contains cabazitaxel in a concentration between 10 mg and 2000 mg, for example, between 10 mg and 1000 mg or between 10 mg and 700 mg. In a preferred embodiment, the tablet or capsule containing cabazitaxel and excipients contains cabazitaxel in a concentration between 10 mg and 500 mg.

[0039] In some embodiments, the tablet or capsule containing cabazitaxel, lipids, and excipients contains lipids in a concentration between 10 mg and 5000 mg, for example, between 10 mg and 3000 mg, or between 10 mg and 2000 mg, and between 10 mg and 1000 mg. In a preferred embodiment, the tablet or capsule containing cabazitaxel and excipients contains lipids in a concentration between 10 mg and 500 mg.

[0040] In some embodiments, the tablets or capsules containing cabazitaxel, gulosterol, gulosterol derivatives, or sodium cholesterol sulfate and excipients contain gulosterol, gulosterol derivatives, or sodium cholesterol sulfate in an amount of 1 mg to 500 mg, for example, 1 mg to 300 mg, 1 mg to 200 mg, and 1 mg to 100 mg. In a preferred embodiment, the tablets or capsules containing cabazitaxel and excipients contain gulosterol, gulosterol derivatives, or sodium cholesterol sulfate in an amount of 1 mg to 500 mg.

[0041] The gulosterol or gulosterol derivative in this invention is a Z-isomer, an E-isomer, or a mixture of Z- and E-isomers. In a more preferred embodiment, the gulosterol or gulosterol derivative is a Z-isomer.

[0042] In some embodiments, the cabazitaxel composition contains a disintegrant. The disintegrant swells and dissolves upon contact with water, causing the tablet to break down in the digestive tract and release the active ingredient for absorption. Disintegrants used in this invention include, but are not limited to, cross-linked polymers, such as croscarmellose sodium (also known as croscarmellose or croscarmellose), croscarmellose polyvinylpyrrolidone (also known as croscarmellose or croscarmellose); starch, clay, cellulose, and sodium glycolate starch.

[0043] In some embodiments, the cabazitaxel composition contains a binder. The binder binds the ingredients in the tablet together and improves free flowability by formulating the particles to the desired hardness and size. Examples of binders that can be used in this invention include, but are not limited to, cellulose, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, polyvinylpyrrolidone, polypropylene-polyethylene copolymer, magnesium aluminum silicate (Neuselin US2), sodium lauryl sulfate, glucose, sucrose, lactose, povidone, starch, gelatin, and sugar alcohols (e.g., xylitol, sorbitol, maltitol).

[0044] In some embodiments, the cabazitaxel composition contains a lubricant. The lubricant prevents the ingredients from clumping and adhering to the tableting or capsule filling machine. Examples of lubricants that can be used in this invention include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, surfactants, polyethylene glycol, and vegetable oils.

[0045] In some embodiments, the cabazitaxel composition contains an absorption enhancer. The enhancer increases absorption by promoting the diffusion of the active ingredient or the solubility of the drug. Examples of absorption enhancers that can be used in this invention include, but are not limited to, vitamin E-PEG1000 succinate (TPGS), silicified microcrystalline cellulose (SMCC HD90), polyethylene glycol-polypropylene glycol-polyethylene glycol polymer (poloxam), stearic acid, oleic acid, magnesium stearate, calcium stearate, surfactants, propylene glycol, polyethylene glycol, and vegetable oils.

[0046] In some embodiments, the cabazitaxel composition contains a flow aid. Gliding agents are commonly used to improve the flow properties of powder mixtures by reducing friction between particles. Gliding agents available in this invention include, but are not limited to, colloidal silica (e.g., fumed silica, Aerosil®), corn starch, and magnesium carbonate.

[0047] In some embodiments, the cabazitaxel composition contains a diluent or filler. When the drug itself is insufficient to produce a volume of solid unit dosage form, a diluent or filler is typically used to make up the volume. Examples of diluents or fillers available in this invention include, but are not limited to, glucose, lactose, starch, sorbitol, mannitol, microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, and magnesium stearate.

[0048] In some embodiments, the cabazitaxel composition contains a plasticizer. Plasticizers are used to impart elasticity and flexibility to coating materials in tablets, and to determine the hardness and impart softness to capsule shells in soft capsules. Plasticizers available in this invention include, but are not limited to, diacetylated monoglycerides, castor oil, polyethylene glycol, polypropylene glycol, triethyl citrate, and triacetin.

[0049] In some embodiments, the cabazitaxel composition comprises a coating material. The coating of the tablet or capsule protects the ingredient from deterioration caused by moisture in the air. Examples of coating materials used in this invention include, but are not limited to, hydroxypropyl methylcellulose (HMPC), synthetic polymers, polysaccharides, povidone, ethylcellulose, gelatin, and shellac.

[0050] In some embodiments, the cabazitaxel composition also comprises an enteric coating material. The enteric coating controls the drug release rate and determines the site of drug release in the digestive tract.Examples of enteric coating materials that can be used in this invention include, but are not limited to, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polymethyl methacrylate-co-methyl methacrylate, cellulose trimellitate acetate (CAT), polyvinyl acetate phthalate (PVAP), shellac, ethyl cellulose, Opadri® enteric coating, methyl methacrylate-methyl methacrylate copolymer or Eudragit®, and Acryl-EZE®.

[0051] In some embodiments, the cabazitaxel composition contains a colorant. The colorant is added to improve the appearance and recognizability of the product. Examples of colorants that can be used in this invention include, but are not limited to, FD, C, D and C dyes and lakes.

[0052] Pharmaceutical formulations to which the compositions of this invention are suitable include, but are not limited to, tablets, capsules, pills and suspensions. For oral administration, preferred dosage forms include tablets, capsules, lozenges and powders.

[0053] If necessary, compositions containing cabazitaxel, or cabazitaxel, phosphatidylcholine and / or gulosterol, gulosterol derivatives, or sodium cholesterol sulfate preparations may be encapsulated in enteric-coated tablets or enteric-coated capsules to prevent them from being broken down by gastric acid in the stomach. The term "enteric" refers to the small intestine, and the enteric coating prevents the drug from being released before reaching the small intestine. Most enteric coatings work by forming a surface that is stable at acidic pH but rapidly decomposes at higher pH.

[0054] In some embodiments, cabazitaxel, gulosterol, gulosterol derivatives, or sodium cholesterol sulfate are mixed with one or more excipients (e.g., croscarmellose sodium, polyvinylpyrrolidone, microcrystalline cellulose, and fumed silica (Aerosil)) and sieved to form granules. In some embodiments, the granules may also contain phosphatidylcholine. In some embodiments, these granules are mixed with a lubricant (e.g., stearic acid) and compressed into tablets. In a preferred embodiment, the tablets are sealed-coated with a polymer such as hydroxypropyl methylcellulose. In a particularly preferred embodiment, the sealed-coated tablets are further enteric-coated with a polymer such as methacrylic acid copolymer (Acryl-EZE®) or hydroxypropyl methylcellulose polymer (Opadry®) enteric-coated.

[0055] In some embodiments, cabazitaxel, gulostrol, gulostrol derivatives, or sodium cholesterol sulfate are mixed with one or more excipients (e.g., microcrystalline cellulose) and an aerosol, and sieved to form granules. In some embodiments, the granules also contain phosphatidylcholine. In some embodiments, these granules are mixed with microcrystalline cellulose, crosslinked carboxymethyl cellulose sodium, lactose, and poloxamer 188, and compressed into tablets.In a preferred embodiment, the tablets are sealed-coated with a polymer (e.g., hydroxypropyl methylcellulose (HPMC), ethyl cellulose, or Opadry®). In a particularly preferred embodiment, the sealed-coated tablets are further enteric-coated with a polymer (e.g., methacrylic acid copolymer, Acryl-EZE®) or a functional polymer (e.g., methacrylic acid-methyl methacrylate copolymer, Eudragit®).

[0056] In some embodiments, the compositions of the present invention contain antioxidants. Examples of antioxidants include, but are not limited to, α-tocopherol (vitamin E), α-tocopherol polyethylene glycol succinate (TPGS), ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite (SMB), propyl gallate, cysteine, citric acid, etc.

[0057] In some embodiments, the compositions of the present invention contain about 0.1% to about 90% by weight, preferably about 0.5% to about 75% by weight, and more preferably about 1% to about 50% by weight of cabazitaxel.

[0058] In some embodiments, the amount of cabazitaxel in a single tablet or capsule is from 10 mg to 2000 mg, preferably from 10 mg to 1000 mg, more preferably from 10 mg to 500 mg.

[0059] In some embodiments, the composition of the present invention contains lipids comprising from about 1% to about 90% by weight, preferably from about 2% to about 80% by weight, more preferably from about 3% to about 50% by weight.

[0060] In some embodiments, the composition of the present invention contains gulosterol comprising from about 0.1% to about 90% by weight, preferably from about 0.1% to about 75% by weight, more preferably from about 0.1% to about 50% by weight.

[0061] In some embodiments, the composition of the present invention contains gulosterol derivatives comprising from about 0.1% to about 90% by weight, preferably from about 0.1% to about 75% by weight, more preferably from about 0.1% to about 50% by weight.

[0062] In some embodiments, the compositions of the present invention comprise about 0.1% to about 90% by weight, preferably about 0.1% to about 75% by weight, and more preferably about 0.1% to about 50% by weight. The compositions of the present invention can be administered in any dosage form and any system for delivering the active compound cabazitaxel in vivo. In some embodiments, the compositions of the present invention are delivered in a dosage form selected from tablets, chewable tablets, capsules, and soft gelatin capsules. In some embodiments, the compositions are formulated into the desired dosage form to achieve an immediate, sustained, or delayed release profile in vivo after administration.

[0063] Experimental Example Example 1 TPGS 1000 (5.0 g) and hydrogenated soybean phosphatidylcholine (HSPC) (15.0 g) were dissolved in ethanol (230 mL).Cabazitaxel (25.0 g) was then mixed and heated to 30–35 °C. Separately, Prosolve SMCC HD90 (30.0 g) and Neusilin US2 (10.0 g) were mixed and loaded into the top spray assembly hopper of the fluidized bed processor. The mixture was granulated using a cabazitaxel-HSPC solution at an inlet temperature of 50–60 °C and a bed temperature up to 27–35 °C via top spraying. After spraying, the granules were dried, passed through a 30-mesh sieve, and then mixed for 5 minutes with ultrafine Neusilin US2 (6.0 g) passed through a 330-mesh sieve, croscarmellose sodium (12.5 g), sodium dodecyl sulfate (2.5 g), poloxamer 188 (12.5 g), and hydrophilic fumed silica (Aerosil) (1.2 g). The mixture was lubricated with magnesium stearate for 5 minutes, and then compressed into tablets.

[0064] HPMC 3 CPS (12.0 g) was dispersed in isopropanol (140 mL), and dichloromethane (90 mL) was added. The mixture was stirred for 25 minutes. The mixture was then used for sealed coating in an automatic coating machine at an inlet temperature of 40-45 °C and a bed temperature of 30-35 °C. The tablets were dried at a bed temperature of 35-40 °C for 30 minutes.

[0065] Acryl EZE white (23.0 g) was dispersed in purified water and stirred for 30 minutes. The mixture was then used for enteric coating in an automatic coating machine at an inlet temperature of 45-55 °C and a bed temperature of 35-40 °C. The tablets were dried at a bed temperature of 35-40 °C for 20 minutes.

[0066] Example 2 Specification 7 / 14 pages 9 CN 121925252 A TPGS 1000 (5.0 g) and gulostrol (15.0 g) were dissolved in ethanol (230 mL). Cabazitaxel (25.0 g) was then mixed and heated to 30-35 °C. Separately, Prosolve SMCC HD90 (30.0 g) and Neusilin US2 (10.0 g) were mixed and loaded into the hopper of the top spray assembly of the fluidized bed processor. The mixture was granulated using a top spray process with the cabazitaxel-gulostrol solution at an inlet temperature of 50-60 °C and a bed temperature up to 27-35 °C. After spraying, the granules are dried, passed through a 30-mesh sieve, and then mixed in a mixer for 5 minutes with ultrafine Neusilin US2 (6.0 g), cross-linked sodium carboxymethyl cellulose (12.5 g), sodium dodecyl sulfate (2.5 g), poloxamer 188 (12.5 g), and hydrophilic fumed silica (Aerosil) (1.2 g) that have passed through a 330-mesh sieve.The mixture was lubricated with magnesium stearate for 5 minutes, and then the lubricated mixture was compressed into tablets.

[0067] HPMC 3 CPS (12.0 g) was dispersed in isopropanol (140 mL), and dichloromethane (90 mL) was added and stirred for 25 minutes. The mixture was then sealed and coated in an automatic coating machine at an inlet temperature of 40-45 °C and a bed temperature of 30-35 °C. The tablets were dried at a bed temperature of 35-40 °C for 30 minutes.

[0068] Acryl EZE white (23.0 g) was dispersed in purified water and stirred for 30 minutes. The mixture was then enteric coated in an automatic coating machine at an inlet temperature of 45-55 °C and a bed temperature of 35-40 °C. The tablets were dried at a bed temperature of 35-40 °C for 20 minutes.

[0069] Example 3 TPGS 1000 (5.0 g) and gugulasterol laurate (15.0 g) were dissolved in ethanol (230 mL). Cabazitaxel (25.0 g) was then mixed and heated to 30-35 °C. Separately, Prosolve SMCC HD90 (30.0 g) and Neusilin US2 (10.0 g) were mixed and loaded into the hopper of the top spray assembly of the fluidized bed processor. Granulation was performed using the cabazitaxel-gugulasterol laurate solution at an inlet temperature of 50-60 °C and a maximum bed temperature of 27-35 °C using a top spray process. After spraying, the granules were dried, passed through a 30-mesh sieve, and mixed with ultrafine granules of Neusilin US2 (6.0 g) passed through a 330-mesh sieve, croscarmellose sodium (12.5 g), sodium dodecyl sulfate (2.5 g), poloxamer 188 (12.5 g), and hydrophilic fumed silica (Aerosil) (1.2 g) in a mixer for 5 minutes. The mixture was lubricated with magnesium stearate for 5 minutes, and then the lubricated mixture was compressed into tablets.

[0070] HPMC 3 CPS (12.0 g) was dispersed in isopropanol (140 mL), and dichloromethane (90 mL) was added and stirred for 25 minutes. The mixture was sealed and coated in an automatic coating machine at an inlet temperature of 40-45 °C and a bed temperature of 30-35 °C. The tablets were dried at a bed temperature of 35-40 °C for 30 minutes.

[0071] Acryl EZE white (23.0 g) was dispersed in purified water and stirred for 30 minutes. Enteric coating was performed using this mixture in an automatic coating machine at an inlet temperature of 45-55 °C and a bed temperature of 35-40 °C. The tablets were dried at a bed temperature of 35-40 °C for 20 minutes.

[0072] Example 4: TPGS 1000 (10.0 g) and sodium cholesterol sulfate (5.0 g) were dissolved in ethanol (470 mL).Add hydrogenated soybean phosphatidylcholine (HSPC) (25.0 g) until completely dissolved. Then mix cabazitaxel (50.0 g) and heat to 30–35 °C. Separately, mix Prosolve SMCC HD90 (60.0 g) and Neusilin US2 (20.0 g) and load into the top spray assembly hopper of the fluidized bed processor. Granulate the mixture using cabazitaxel-HSPC-sod. Sodium cholesterol sulfate solution is processed using a top spray process at an inlet temperature of 50–60 °C and a bed temperature up to 27–35 °C. After spraying, the granules were dried, passed through a 30-mesh sieve, and mixed with ultrafine granules Neusilin US2 (13.0 g) passed through a 330-mesh sieve, croscarmellose sodium (25.0 g), sodium dodecyl sulfate (5.0 g), poloxamer 188 (25.0 g), and hydrophilic fumed silica (Aerosil) (2.5 g) in a mixer for 5 minutes. The mixture was lubricated with magnesium stearate for 5 minutes, and then the lubricated mixture was compressed into tablets.

[0073] HPMC 3 CPS (25.0 g) was dispersed in isopropanol (280 mL), and dichloromethane (190 mL) was added and stirred for 25 minutes. The mixture was then sealed and coated in an automatic coating machine at an inlet temperature of 40-45 °C and a bed temperature of 30-35 °C. The tablets were dried at a bed temperature of 35-40 °C for 30 minutes.

[0074] Acryl EZE white (45.0 g) was dispersed in purified water and stirred for 30 minutes. Enteric coating was performed with the mixture in an automatic coating machine at an inlet temperature of 45-55 °C and a bed temperature of 35-40 °C. The tablets were dried at a bed temperature of 35-40 °C for 20 minutes.

[0075] Example 5 TPGS 1000 (10.0 g) and gugur sterol (5.0 g) were dissolved in ethanol (470 mL). Hydrogenated soybean phosphatidylcholine (HSPC) (25.0 g) was added until completely dissolved. Cabazitaxel (50.0 g) was then mixed and heated to 30-35 °C. Additionally, Prosolve SMCC HD90 (60.0 g) and Neusilin US2 (20.0 g) were mixed and loaded into the hopper of the top spray assembly of the fluidized bed processor. The mixture was granulated using a cabazitaxel-HSPC-gugursterol solution at an inlet temperature of 50–60 °C and a bed temperature of up to 27–35 °C via top spraying.After spraying, the granules were dried, passed through a 30-mesh sieve, and mixed with ultrafine Neusilin US2 (13.0 g) passed through a 330-mesh sieve, croscarmellose sodium (25.0 g), sodium dodecyl sulfate (5.0 g), poloxamer 188 (25.0 g), and hydrophilic fumed silica (Aerosil) (2.5 g) in a mixer for 5 minutes. The mixture was lubricated with magnesium stearate for 5 minutes, and then compressed into tablets.

[0076] HPMC 3 CPS (25.0 g) was dispersed in isopropanol (280 mL), and dichloromethane (190 mL) was added and stirred for 25 minutes. The mixture was then sealed and coated in an automatic coating machine at an inlet temperature of 40-45 °C and a bed temperature of 30-35 °C. The tablets were dried at a bed temperature of 35-40 °C for 30 minutes.

[0077] Acryl EZE white (45.0 g) was dispersed in purified water and stirred for 30 minutes. Enteric coating was performed using this mixture in an automatic coating machine at a feed temperature of 45-55 °C and a bed temperature of 35-40 °C. The tablets were dried at a bed temperature of 35-40 °C for 20 minutes.

[0078] Example 6: TPGS 1000 (10.0 g) and gugur sterol laurate (5.0 g) were dissolved in ethanol (470 mL). Hydrogenated soybean phosphatidylcholine (HSPC) (25.0 g) was added until completely dissolved. Cabazitaxel (50.0 g) was then mixed and heated to 30-35 °C. Separately, Prosolve SMCC HD90 (60.0 g) and Neusilin US2 (20.0 g) were mixed and loaded into the top spray assembly hopper of the fluidized bed processor. Granulation was performed using a cabazitaxel-HSPC-gugur sterol laurate solution with a top spray process at an inlet temperature of 50-60 °C and a bed temperature of up to 27-35 °C. After spraying, the granules were dried, passed through a 30-mesh sieve, and mixed with ultrafine Neusilin US2 (13.5 g) passed through a 330-mesh sieve, croscarmellose sodium (25.0 g), sodium dodecyl sulfate (5.0 g), poloxamer 188 (25.0 g), and hydrophilic fumed silica (Aerosil) (2.5 g) in a mixer for 5 minutes. The mixture was lubricated with magnesium stearate for 5 minutes, and then the lubricated mixture was compressed into tablets.

[0079] HPMC 3 CPS (12.50 g) was dispersed in isopropanol (280 mL), and dichloromethane (190 mL) was added and stirred for 25 minutes. The mixture was used for sealed coating in an automatic coating machine at an inlet temperature of 40-45 °C and a bed temperature of 30-35 °C. The tablets were then dried at a bed temperature of 35-40 °C for 30 minutes.

[0080] Acryl EZE white (22.50 g) was dispersed in purified water and stirred for 30 minutes. Enteric coating was performed using this mixture in an automatic coating machine at an inlet temperature of 45-55 °C and a bed temperature of 35-40 °C. Each tablet containing 50 mg of cabazitaxel was dried at a bed temperature of 35-40 °C for 20 minutes.

[0081] Example 7: TPGS 1000 (40.0 g) and gugur sterol laurate (20.0 g) were dissolved in ethanol (1.9 L). Hydrogenated soybean phosphatidylcholine (HSPC) (100.0 g) was added until completely dissolved. Cabazitaxel (200.0 g) was then mixed and heated to 30-35 °C. Additionally, Prosolve SMCC HD90 (240.0 g) and Neusilin US2 (80.0 g) were mixed and loaded into the top spray assembly hopper of a fluidized bed processor. The mixture was granulated using a cabazitaxel-HSPC-gugur sterol laurate solution via top spraying at an inlet temperature of 50–60 °C and a bed temperature of up to 27–35 °C. After spraying, the granules were dried, passed through a 30-mesh sieve, and then mixed for 5 minutes with ultrafine granules of Neusilin US2 (54.0 g) passed through a 330-mesh sieve, croscarmellose sodium (100.0 g), sodium dodecyl sulfate (20.0 g), poloxamer 188 (100.0 g), and hydrophilic fumed silica (Aerosil) (10.0 g). The mixture was lubricated with magnesium stearate for 5 minutes, and then the lubricated mixture was compressed into tablets.

[0082] HPMC 3 CPS (100.0 g) was dispersed in isopropanol (1.14 L), and dichloromethane (760 mL) was added. The mixture was stirred for 25 minutes. The mixture was then used for sealed coating in an automatic coating machine at an inlet temperature of 40-45 °C and a bed temperature of 30-35 °C. The tablets were dried at a bed temperature of 35-40 °C for 30 minutes.

[0083] Acryl EZE white (180.0 g) was dispersed in purified water and stirred for 30 minutes. The mixture was then used for enteric coating in an automatic coating machine at an inlet temperature of 45-55 °C and a bed temperature of 35-40 °C. Each tablet containing 50 mg of cabazitaxel was dried at a bed temperature of 35-40 °C for 20 minutes.

[0084] All publications and patents mentioned in the above description are incorporated herein by reference. Various modifications and variations to the compositions described in this invention will be apparent to those skilled in the art without departing from the scope and spirit of this invention.Although the invention has been described in conjunction with specific preferred embodiments, the invention should not be unduly limited to these specific embodiments. In fact, various modifications to the embodiments of the invention will be apparent to those skilled in the art, and these modifications should be included within the scope of the following claims.

[0085] Example 8 Pharmacokinetics of Cabazitaxel Tablets after Oral Administration in ICR (CD-1) Mice ICR (CD-1) mice aged 5-6 weeks were fed a 19% protein rodent diet and provided with free access to water. The mice were housed in the facility for at least 7 days before administration. Four mice were taken at each time point after administration, and two mice were taken before administration. A total of 5 time points were taken before and after administration (0.0, 0.5, 1.0, 2.0, 4.0, and 6.0 hours).

[0086] Cabazitaxel tablets (50 mg) were weighed, crushed, and ground into powder without lumps using a glass mortar and pestle. The powder was suspended in purified water to a concentration of 2 mg cabazitaxel / mL suspension. The suspension was sonicated for 2-3 minutes to ensure a homogeneous formulation before administration. The dosage was calculated based on the weight of each animal and was 20 mL / kg.

[0087] A single oral administration of 40 mg cabazitaxel / kg body weight was administered to each animal using a 22-gauge stainless steel gavage needle. After administration, blood samples were collected retro-orbital (under carbon dioxide anesthesia) and collected into pre-labeled micro-blood collection tubes containing potassium ethylenediaminetetraacetate (K2EDTA). Blood was collected once per mouse. Immediately after collection, the blood samples were gently inverted several times to ensure complete mixing with the anticoagulant and then stored in a refrigerator at 2-8 °C. The plasma was separated by centrifugation (at 2000 times g acceleration for 10 minutes) and stored in frozen bottles (-20 °C or lower) for subsequent analysis.

[0088] The concentration of cabazitaxel in plasma was quantitatively analyzed by C18 reversed-phase HPLC with a UV detector (Figure 1).

[0089] Example 9 Subacute toxicity of oral cabazitaxel tablets in ICR (CD-I) mice ICR (CD-I) mice (5-6 weeks old) were fed 19% protein rodent feed and provided with free access to water. The mice were housed in the facility for at least 7 days before use. A total of 48 animals (24 males and 24 females) were randomly divided into 4 groups (Table 1): AA (control group), B (low-dose group), C (medium-dose group) and D (high-dose group). The control group mice were given water. The treatment group mice were given cabazitaxel daily for 5 consecutive days. All mice were sacrificed on day 29 for organ weighing and gross pathological examination.

[0090] Table 1. Dosage Groups

[0091] Cabazitaxel tablets were weighed and pulverized into powder before the start of the study and stored at 2–8°C.One portion of powder was weighed on each administration day and suspended in water at a concentration of 3 mg cabazitaxel / mL as the dosage formulation for the high-dose group mice. For the medium-dose and low-dose groups, the suspension was diluted to 2 mg / mL and 1 mg / mL, respectively. Cabazitaxel was administered orally via gavage using a 22 g stainless steel gavage needle. Mortality, clinical symptoms, body / organ weight, gross pathology, hematology, and blood chemistry were assessed.

[0092] Mortality: No deaths occurred in the control and low-dose groups throughout the study period. Three male mice died or were near death on day 8. Two male mice died in the high-dose group and one male mouse died in the medium-dose group. Three female mice also died in the high-dose group between day 8 and day 11.

[0093] Clinical symptoms: Male mice in the medium-dose and high-dose groups began to show clinical symptoms such as rough fur, dehydration, and arched back from day 5. By day 10, all surviving mice were free of clinical symptoms. No clinical symptoms were observed in male mice in the low-dose and control groups. Female mice in the high-dose group developed clinical symptoms such as rough fur, dehydration, and arched back starting from day 5. By day 10, no clinical symptoms were observed in any surviving mice. No clinical symptoms were observed in female mice in the low-dose, medium-dose, and control groups.

[0094] Body weight: For female mice, the high-dose group showed the largest decrease in body weight on day 8 (an average decrease of 20% from day 1). The medium-dose group also showed a smaller decrease in body weight on day 5 (a decrease of 7.1% from day 1). For male mice, the high-dose and medium-dose groups showed the largest decreases in body weight of 14.8% and 11.5%, respectively. At the end of the study, the remaining mice treated with cabazitaxel had body weights comparable to the control group.

[0095] Organ weight: The weights of animal organs (including liver, kidneys, heart, lungs, and spleen) were recorded at necropsy on day 29 and standardized to a mouse weight of 20 grams. All organ weights were comparable to the control group.

[0096] Gross pathology: No lesions or abnormal changes were found in any major organs.

[0097] Hematology and blood chemistry: No abnormal changes were found in hematology and blood chemistry in any group.

[0098] Example 10 Effect of oral cabazitaxel tablets on survival of mice carrying P388 leukemia The in vivo CD2F1 mouse leukemia model carrying P388 has been widely used for preclinical evaluation of the anti-leukemic activity of compounds (Dykes, DJ et al., 2008). In this model, untreated control mice survive for only about 9-11 days. Depending on the treatment effect, treated mice survive longer than control mice. Prolonged survival time can be used as an endpoint indicator for efficacy testing.

[0099] On the first day of the study, 4-6 week old CD2F1 mice were fed 19% protein rodent diet and provided with free access to water. Mice were housed in the experimental facility for at least 7 days before use.

[0100] The mouse leukemia cell line P388 (logarithmic growth phase cells) was transferred from the culture flask to a sterile test tube and centrifuged at 200 times the acceleration of gravity (approximately 1000 rpm) and 2-8 °C for 5 minutes. The cells were washed twice with 10 mL of cold PBS and then resuspended in 5 mL of cold PBS. After staining with trypan blue, the cells were counted using a hemocytometer. 5 × 10⁶ / mL of cells were suspended in PBS. On day 0, 1 × 10⁶ cells / mouse was injected intraperitoneally at a dose of 0.2 mL.

[0101] Cabazitaxel tablets (50 mg) were crushed and ground into a powder free of lumps using a glass mortar and pestle. The powder was suspended in purified water at a concentration of 2 mg cabazitaxel / mL. The suspension was sonicated for 2-3 minutes to ensure a homogeneous suspension before administration at a dose level of 40 mg / kg / d. Dilute with purified water to a concentration of 1 mg carbazide / mL, at a dose level of 20 mg / kg / day. Dosage volume was calculated based on individual animal weight, with a dose of 20 mL / kg.

[0102] Results: Compared with the untreated control group, treatment with a cumulative oral dose of 120 mg / kg significantly improved the survival rate of P388-carrying leukemia mice (Table 2).

[0103] Table 2. Summary of dose levels, dosing schedule, and median survival

[0104] Example 11 Maximum tolerated dose (MTD) and pharmacokinetics of oral carbazide tablets in patients with advanced solid tumors who have failed conventional therapy. An open-label, non-randomized, multicenter, dose-escalation, single-dose study was conducted on patients with advanced solid tumors who had failed conventional therapy. Patients received a single oral dose of carbazide lipoprotein tablets (50, 100, 200, and 300 mg, corresponding to 1, 2, 4, and 6 tablets, respectively). The tablets were prepared according to Examples 6 and 7. Patients were first enrolled in the lowest dose group, and then in the higher dose groups. Blood, urine, and stool samples were collected at different time points for pharmacokinetic analysis.

[0105] Diagnosis and primary inclusion criteria: This study included patients with primary advanced solid tumors (e.g., breast cancer, head and neck cancer, lung cancer, melanoma, gastric cancer, colon cancer, or prostate cancer) confirmed by histopathology / cytology and for whom cabazitaxel monotherapy was feasible, or patients with advanced solid malignancies that were unresponsive to conventional treatment and had an ECOG performance status score of 0-2 and normal bone marrow, liver, and kidney function. A total of 15 patients were enrolled (3 patients in each of the 50 mg, 100 mg, and 200 mg dose groups, and 6 patients in the 300 mg dose group).

[0106] To perform pharmacokinetic assessment, a total of 20 blood samples (0.5 mL each) and 0.7 urine samples were collected from each patient in each dose group at the time points specified in the protocol.Stool samples were collected prior to administration, and all stool samples were collected from each patient in each dose group up to 24 hours later. Pharmacokinetic parameters of cabazitaxel were calculated using a non-compartmental model with Phoenix® WinNonlin® version 8.3 (Certara LP).

[0107] Plasma: Cmax, AUCO-t, AUCO-∞, Tmax, AUC_%Extrap_obs, λz, Vd, Cl, and tl / 2 Urine: Ae0-72h, Rmax, Tmax, R Feces: Ae0-24h The plasma concentration-time curves of cabazitaxel are shown in Figure 2. The pharmacokinetic parameters of cabazitaxel are summarized in the following table.

[0108] Table 3. Descriptive statistics of cabazitaxel (plasma) pharmacokinetics, 12 / 14 pages, CN 121925252 A

[0109] Table 4. Descriptive statistics of cabazitaxel (urine) pharmacokinetics

[0110] Table 5. Descriptive statistics of cabazitaxel (feces) pharmacokinetics

[0111] The plasma pharmacokinetic characteristics of cabazitaxel were well characterized at all dose levels. Nonlinear behavior was observed at higher dose levels after a single 200 mg dose. The median time to reach peak plasma concentration of cabazitaxel after a single dose was 3 to 7 hours, and the mean terminal half-life was approximately 79 to 203 hours. Within 72 hours after a single dose, a very small amount (i.e., <0.1%) of the drug was excreted in the urine. The amount of drug excreted in the feces was approximately 4% to 22%.

[0112] Most importantly, the mean AUC of a single oral dose of cabazitaxel lipid tablets at dose levels of 100, 200, or 300 mg was 889, 1187, or 1110 ng·h / mL, respectively. Intravenous cabazitaxel, administered at the recommended dose of 25 mg / m² (see page 13 / 14 of the package insert, CN 121925252 A, Jevtana® Prescription Information), achieved a mean AUC of 991 ng·h / mL.

[0113] Safety variables included adverse events (AEs), clinical laboratory parameters, vital signs, and physical examinations. All AEs reported during the study were included in the safety analysis. AEs were classified by system organ according to the preferred terminology in MedDRA version 24.0. The maximum tolerated dose (MTD) of the cabazitaxel lipid tablets was determined to be 300 mg.

[0114] Reference 1. Nightingale, G. and Ryu, J. Drug Forecast (2012), Vol. 37; 8:440-448.

[0115] 2. Paller, C.J. and Antonarakis, E.S. Drug Design, Development and Therapy (Drug Des. Devel. Ther.) (2011), 5;117-124.

[0116] 3. Palepu, N. US 2012 / 0065255 A1.

[0117] 4. Jevtana® (cabatasoxetine) Intravenous Injection - Prescription Information.

[0118] 5. Mita, A.C., Figlin, R., Mita, M.M. (2012), Clin. Cancer Res. 18(24): 6574-6579.

[0119] 6. A bidi, A. J. Pharmacology and Pharmacotherapeutics, (2013), 4:230-237.

[0120] 7. Calcagno, F., Nguyen, T., Dobi, E., Villanueva, C., Curtit, E., Kim, S., Montcuquet, P., Kleinclauss, F., Pivot, X., Thiery-Vuillemin, A. Clinical Medicine Insights: Oncology (2013), 7:1-12.

[0121] 8. Schwartzberg, LS, Navari, RM Adv. Ther. (2018). 35:754-767.

[0122] 9. Dykes, DJ and Waud, WR, mouse L1210 and P388 leukemia, Tumor Models in Cancer Research (2008), edited by BA Teicher © Humana Press Inc., Totowa, NJ. Instruction manual 14 / 14 pages 16 CN 121925252 A Figure 1 Figure 2 Instruction manual illustrations 1 / 1 page 17 CN 121925252 A.

Claims

1. A composition, characterized in that, Containing cabazitaxel, and at least one lipid and / or gulosterol or gulosterol derivative or sodium cholesterol sulfate, in a sealed-coated and / or enteric-coated tablet or capsule.

2. The composition according to claim 1, characterized in that, The at least one lipid is selected from soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylcholine (DPPC), distearyl phosphatidylglycerol (DSPG), dipalmitoyl phosphatidylglycerol (DMPG), cholesterol (Choi), cholesterol sulfate and its salts.

3. The composition according to claim 1, characterized in that, The gugursterol derivatives are selected from gugursterol laurate, gugursterol myristate, gugursterol palmitate, gugursterol stearate, gugursterol oleate, gugursterol linoleate, and gugursterol linoleate.

4. The composition according to claim 1, characterized in that, The composition further contains one or more excipients selected from magnesium aluminosilicate, tocopherol polyethylene glycol succinate, silicified microcrystalline cellulose, magnesium stearate, croscarmellose sodium cellulose, sodium dodecyl sulfate, polyethylene glycol-polypropylene glycol-polyethylene glycol polymer, poloxamer 188, hydrophilic fumed silica, aerosols, and citric acid.

5. The composition according to claim 1, characterized in that, The sealing coating includes one or more polymers selected from hydroxymethylpropyl cellulose, methyl hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, sodium carboxymethyl cellulose, acrylate polymers, and polyethylene glycol.

6. The composition according to claim 1, characterized in that, The enteric coating comprises one or more polymers selected from hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, acrylate polymers, polyvinyl acetate phthalate, and methyl methacrylate copolymer.

7. The composition according to claim 1, characterized in that, The content of cabazitaxel in a single tablet or capsule is in the range of at least 20 mg to 1000 mg.

8. The composition according to claim 1, characterized in that, The lipid content in a single tablet or capsule is at least in the range of 10 mg to 1000 mg.

9. The composition according to claim 1, characterized in that, The content of the described guggul sterol or guggul derivative in a single tablet or capsule is at least 2 mg to 500 mg.

10. The composition according to claim 1, characterized in that, The content of sodium cholesterol sulfate in a single tablet or capsule is at least 2 mg to 500 mg.

11. The composition according to claim 1, characterized in that, The composition is a tablet or capsule, and the administration includes oral administration.

12. The composition according to claim 1, characterized in that, The composition includes oral administration to a subject.

13. The composition according to claim 12, characterized in that, The subjects were mammals.

14. The composition according to claims 12 and 13, characterized in that, The subjects were humans.

Images