A composition containing cabazitaxel and lipids for oral administration.

Abstract

The present invention relates to compositions of cabazitaxel and the administration of compositions of cabazitaxel. Embodiments provide compositions in the form of tablets or capsules comprising cabazitaxel together with at least one lipid and / or guggulsterol and / or guggulsterol derivatives and / or sodium cholesteryl sulfate, and administration of such compositions to a subject.

Description

Technical Field

[0001] The present invention relates to compositions comprising cabazitaxel and a lipid. The present invention further relates to compositions comprising cabazitaxel, guggulsterol and / or a guggulsterol derivative and / or sodium cholesteryl sulfate. In some embodiments, the present invention relates to compositions comprising a lipid comprising cabazitaxel, phosphatidylcholine, and phosphatidylglycerol. In preferred embodiments, the present invention relates to compositions comprising cabazitaxel, phosphatidylcholine, and guggulsterol or a guggulsterol derivative or sodium cholesteryl sulfate. In certain embodiments, the present invention also relates to compositions comprising cabazitaxel and an additive in a tablet or capsule. The present invention further relates to administering the composition to a mammalian subject in the treatment or prevention of a disease. The compositions according to the present invention are suitable for implementation on an industrial production scale, and can be implemented, for example, as a continuous process.

Background Art

[0002] Taxanes have emerged as a major class of chemotherapeutic agents, as demonstrated by their widespread use as single agents for treating a wide variety of solid malignant tumors and in combination with other drugs. Cabazitaxel is a novel second-generation semi-synthetic derivative of natural taxoids. The mechanism of action of cabazitaxel is similar to that of paclitaxel and docetaxel. It binds to the N-terminal amino acid of the β-tubulin subunit, promotes microtubule polymerization, inhibits cell division by microtubules, and thereby arrests the tumor cell cycle and tumor growth. Cabazitaxel is superior to paclitaxel and docetaxel because it has low affinity for P-glycoprotein due to the presence of an extra methyl group. This enables it to be effective in docetaxel-resistant tumors.

[0003] Cabazitaxel, marketed as Jevtana®, is approved for use in patients with hormone-resistant metastatic prostate cancer who have previously been treated with docetaxel-containing regimens. The individual dose of cabazitaxel is 25 mg / m², administered every three weeks by a one-hour intravenous infusion, based on body surface area (BSA), in combination with oral prednisone 10 mg. 2 That is the case.

[0004] Jevtana® is supplied as a sterile, non-aqueous concentrate for infusion containing 60 mg / 1.5 ml of cabazitaxel in polysorbate 80, packed in a glass vial, along with an additional solvent for diluting the concentrate. The solvent is a sterile, non-pyrogenic 13% w / w aqueous solution of ethanol. The concentrate and solvent are intended for preparing a 10 mg / ml cabazitaxel premix solution before dilution with 0.9% saline or 5% dextrose solution in an infusion bag.

[0005] Taxanes, including cabazitaxel, are highly lipophilic and substantially insoluble in water. Due to this insolubility, various solubilizers, such as polysorbate 80, cremofol EL, and ethanol, have been effectively utilized to formulate taxanes for intravenous administration. However, hypersensitivity reactions and infusion-related toxicity are associated with the use of polysorbate 80, cremofol EL, and ethanol, and to reduce the risk of these side effects, patients are routinely premedicated with corticosteroids before treatment with taxane drugs.

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

[0007] To avoid the toxic effects of cabazitaxel and its excipients in currently available intravenous products, novel cabazitaxel compositions for oral administration are needed. [Overview of the project]

[0008] The present invention provides compositions containing cabazitaxel. In some embodiments, the composition contains phosphatidylcholine. In some embodiments, the composition further contains one or more guggulsterol, guggulsterol derivatives, and / or sodium cholesteryl sulfate. In some preferred embodiments, the composition further contains other additives. Certain embodiments include a composition containing cabazitaxel and administering the composition to a subject. In some embodiments, the subject is a mammal. In preferred embodiments, the subject is human.

[0009] In some embodiments, the present invention provides compositions comprising cabazitaxel and phosphatidylcholine for oral delivery to a subject. In preferred embodiments, the subject is a mammal, and in more preferred embodiments, the subject is a human. In some embodiments, the composition for oral delivery is in the form of tablets or capsules. In preferred embodiments, the tablets and / or capsules include an enteric coating.

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

[0011] In some embodiments, compositions comprising cabazitaxel and guggulsterol for oral delivery to a subject are provided herein. In preferred embodiments, the subject is a mammal, and in more preferred embodiments, the subject is a human. In some embodiments, the composition for oral delivery is in the form of a tablet or capsule. In preferred embodiments, the tablets and / or capsules include an enteric coating.

[0012] The present invention provides, in some embodiments, compositions comprising cabazitaxel and guggulsterol derivatives for oral delivery to a subject. In preferred embodiments, the subject is a mammal, and in more preferred embodiments, the subject is a human. In some embodiments, oral delivery is in the form of a tablet or capsule. In more preferred embodiments, the tablets and / or capsules include an enteric coating.

[0013] The present invention provides, in some embodiments, compositions comprising cabazitaxel and sodium cholesteryl sulfate for oral delivery to a subject. In preferred embodiments, the subject is a mammal, and in more preferred embodiments, the subject is a human. In some embodiments, oral delivery is in the form of a tablet or capsule. In more preferred embodiments, the tablets and / or capsules include an enteric coating.

[0014] The present invention provides, in some embodiments, compositions comprising cabazitaxel, phosphatidylcholine, and sodium cholesteryl sulfate for oral delivery to a subject. In preferred embodiments, the subject is a mammal, and in more preferred embodiments, the subject is a human. In some embodiments, oral delivery is in the form of a tablet or capsule. In more preferred embodiments, the tablets and / or capsules include an enteric coating.

[0015] The present invention provides, in some embodiments, compositions comprising cabazitaxel, phosphatidylcholine, and guggulsterol for oral delivery to a subject. In preferred embodiments, the subject is a mammal, and in more preferred embodiments, the subject is a human. In some embodiments, oral delivery is in the form of a tablet or capsule. In more preferred embodiments, the tablets and / or capsules include an enteric coating.

[0016] The present invention provides, in some embodiments, compositions comprising cabazitaxel, phosphatidylcholine, and guggulsterol derivatives for oral delivery to a subject. In preferred embodiments, the subject is a mammal, and in more preferred embodiments, the subject is a human. In some embodiments, oral delivery is in the form of a tablet or capsule. In more preferred embodiments, the tablets and / or capsules include an enteric coating.

[0017] In some embodiments, the cabazitaxel composition of the present invention is administered co-administered with other drugs. Drugs that can be administered co-administered with the cabazitaxel composition include anticancer agents such as doxorubicin, epirubicin, methotrexate, mitoxantrone, capecitabine, carboplatin, cisplatin, etoposide, 5-fluorouracil, cyclophosphamide, bendamustine, daunomycin, bleomycin, gemcitabine, irinotecan, SN-38, mitoxantrone, cytarabine, erlotinib, imatinib, ibrutinib, palbociclib, bortezomib, abiraterone, bicalutamide, flutamide, and temozolomide; Examples of medications that may be used include, but are not limited to, antihypertensive drugs such as dihydropyridine, antidepressants, and antiallergic drugs; corticosteroids such as prednisone, methylprednisolone, dexamethasone, budesonide, and hydrocortisone; antihistamines such as diphenhydramine, chlorpheniramine, dexchlorpheniramine, cetirizine, levocetoridine, loratadine, and desloratadine; and drugs for treating acid reflux such as cimetidine, ranitidine, famotidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.

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

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

[0020] The amount of guggulsterol or guggulsterol derivative or sodium cholesteryl sulfate contained in the cabazitaxel composition according to the present invention is not limited to any specific amount or percentage (weight percent) of the final composition or weight. In some embodiments, the proportion of guggulsterol or guggulsterol derivative or cholesteryl sulfate is about 0.1% to about 90% of the total weight, preferably about 0.1% to about 50% of the total weight, and more preferably about 0.1% to about 25% of the total weight.

[0021] definition

[0022] To facilitate understanding of the present invention, several terms and phrases are defined below.

[0023] As used herein, the terms “composition,” “preparation,” or “formulation” refer to a combination of an active agent (e.g., an active pharmaceutical compound) and an inactive or active carrier, additive, which makes the composition particularly suitable for in vitro, in vivo, or ex vivo diagnostic or therapeutic applications.

[0024] As used herein, the term "active" when used in reference to an agent, composition, or compound refers to an agent that produces a beneficial, desired, or expected result upon administration or application. Administration can be one or more administrations, applications, or doses, and is not intended to be limited to a particular formulation or route of administration. This term is not limited to any particular level of activity. For example, a formulation of an active agent does not need to have the same level of activity as a different formulation of the active agent, as long as the active agent in the formulation is sufficiently active that an effective amount of the active agent can be administered by administration of the formulation of the agent.

[0025] The terms "agent" and "compound" are used interchangeably herein to refer to any atom, molecular mixture, or more complex composition that possesses the attributed characteristics. For example, "active agent" or "active compound" refers to any atom, molecule, prepared mixture, and the like that produces a beneficial, desired, or expected result upon administration or application.

[0026] As used herein, the term "administration" or "administering" refers to the act of providing a drug, or active agent, or therapeutic treatment (e.g., the composition of the present invention) to a physiological system (e.g., a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs). Exemplary routes of administration to a subject, e.g., a mammal, can be via the mouth (oral), skin (transdermal), eye (ophthalmic), nose (nasal), and the like. Administration can be one or more administrations, applications, or dosages, and is not intended to be limited to a particular route of administration.

[0027] As used herein, the term "co-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 co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of ordinary skill in the art will understand that the formulations and / or routes of administration of the various agents or therapies used may vary. Appropriate dosages for co-administration can be readily determined by those skilled in the art.

[0028] As used herein, the term "additive" refers to an inactive ingredient (i.e., not pharmaceutically active) that is added to a preparation of an active ingredient. The disintegrants, anti-adherents, binders, plasticizers, fillers, coating agents, lubricants, preservatives, glidants, flavoring agents, colorants, adsorbents, sweeteners, antioxidants, penetration enhancers, wetting agents, emulsifiers, ointment bases, acidifying agents and / or alkalizing agents and / or buffering agents, gelling agents and protective agents described herein may generally be referred to as "additives".

[0029] As used herein, the term "disease" refers to any disorder-related condition, sign, and / or symptom of the normal state of a living animal or any of its organs or tissues that interferes with or alters the performance of normal functions and may be a response to environmental factors.

[0030] As used herein, the term "treatment" or grammatical equivalents encompasses amelioration and / or reversal of the symptoms of a disease (e.g., cancer), or reduction of the risk of developing the disease. When used in the screening method of the present invention, a compound that causes an improvement in any parameter associated with a disease can thereby be identified as a therapeutic compound. The term "therapy" refers to therapeutic treatment. For example, those who can benefit from treatment with the compositions of the present invention include those who already have a disease and / or disorder (e.g., cancer, or a symptom or condition consistent with cancer).

[0031] As used herein, the term "mammal" refers to a group of vertebrates that produce or secrete milk from mammary glands to nourish their offspring. Examples of mammals herein include humans, dogs, cats, horses, whales, and dolphins.

[0032] In the context describing the present invention (in particular in the context of the following claims), the terms “a,” “an,” and “the,” and similar reference subjects, should be interpreted as encompassing both singular and plural forms, unless otherwise indicated herein or unless the context clearly contradicts this interpretation. The terms “comprising,” “including,” “having,” and “containing,” should be interpreted as open-ended terms (i.e., “including, but limited”) unless otherwise specified. Any and all examples or illustrative language provided herein (e.g., “etc.”) are intended merely to better illustrate the present invention and do not limit the scope of the invention unless specifically claimed. No language in the specification should be interpreted as indicating that an unclaimed element is essential to the practice of the present invention. [Brief explanation of the drawing]

[0033] [Figure 1] Figure 1 is a graph showing the time course of cabazitaxel concentration in the blood of mice (Example 8).

[0034] [Figure 2] Figure 2 is a graph showing the time course of blood cabazitaxel concentrations in patients after oral or intravenous administration (Example 11). [Modes for carrying out the invention]

[0035] The present invention relates to compositions comprising cabazitaxel formulations. In some embodiments, the present invention includes administering the cabazitaxel composition to a subject, for example, to treat a disease. In some embodiments, the cabazitaxel-containing composition comprises lipids, such as phosphatidylcholine or phosphatidylglycerol. In certain embodiments, the cabazitaxel-containing composition comprises guggulsterol or a guggulsterol derivative or sodium cholesteryl sulfate. In other embodiments, the composition comprises phosphatidylcholine or phosphatidylglycerol and / or guggulsterol, a guggulsterol derivative or sodium cholesteryl sulfate. In preferred embodiments, the subject is a mammal, and in more preferred embodiments, the subject is a human.

[0036] Embodiments of the present invention are described in the summary of the invention and the modes for carrying out this invention. Although the present invention has been described in relation to specific embodiments, the claimed invention should not be unduly limited to such specific embodiments.

[0037] Examples of phosphatidylcholines suitable for use in the compositions of the present invention include soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (DSPC). Examples of phosphatidylglycerols include dimyristoyl phosphatidylglycerol (DMPG), distearoyl phosphatidylglycerol (DSPG), and dipalmitoyl phosphatidylglycerol (DMPG).

[0038] Examples of guggulsterol derivatives suitable for use in the compositions of the present invention include guggulsteryl laurate, guggulsteryl myristate, guggulsteryl palmitate, guggulsteryl stearate, guggulsteryl oleate, guggulsteryl linoleate, and guggulsteryl linolenate.

[0039] In some embodiments, the compositions of the present invention include 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.

[0040] The present invention provides a composition comprising cabazitaxel and a means of delivering such a composition to a subject, for example, a human subject. Any suitable amount of cabazitaxel sufficient to produce a desired effect, for example, a therapeutic effect, can be used. In a preferred embodiment, the suitable amount of cabazitaxel is an amount that can be appropriately incorporated into the tablets, capsules, etc. of the present invention.

[0041] In preferred embodiments, the amount of cabazitaxel in a tablet or capsule containing cabazitaxel and an excipient is 10 mg to 2000 mg, for example, 10 mg to 1000 mg or 10 mg to 700 mg. In preferred embodiments, the amount of cabazitaxel in a tablet or capsule containing cabazitaxel and an excipient is 10 mg to 500 mg.

[0042] In some embodiments, the amount of lipids in a tablet or capsule containing cabazitaxel, lipids, and additives is 10 mg to 5000 mg, for example, 10 mg to 3000 mg or 10 mg to 2000 mg and 10 mg to 1000 mg. In preferred embodiments, the amount of lipids in a tablet or capsule containing cabazitaxel and additives is 10 mg to 500 mg.

[0043] In some embodiments, the amount of guggulsterol or guggulsterol derivative or sodium cholesteryl sulfate in a tablet or capsule containing cabazitaxel, guggulsterol or a guggulsterol derivative or sodium cholesteryl sulfate and an additive is 1 mg to 500 mg, for example, 1 mg to 300 mg or 1 mg to 200 mg and 1 mg to 100 mg. In preferred embodiments, the amount of guggulsterol or a guggulsterol derivative or sodium cholesteryl sulfate in a tablet or capsule containing cabazitaxel and an additive is 1 mg to 500 mg.

[0044] In the present invention, guggulsterol or guggulsterol derivatives are in the form of Z-isomers, E-isomers, or mixtures of Z- and E-isomers. In a more preferred embodiment, guggulsterol or guggulsterol derivatives are in the form of Z-isomers.

[0045] In some embodiments, the cabazitaxel composition contains a disintegrant. The disintegrant swells and dissolves when wet, disintegrating the tablet in the gastrointestinal tract and releasing the active ingredient for absorption. Examples of disintegrants used in the present invention include, but are not limited to, cross-linked polymers such as cross-linked carboxymethylcellulose sodium (also known as croscarmellose or croscarmellose) and cross-linked polyvinylpyrrolidone (also known as crospovidone or crospovidone); starch, clay, cellulose, and sodium starch glycolate.

[0046] In some embodiments, the cabazitaxel composition contains a binder. The binder improves free flow by holding the components in the tablet together and formulating the granules to a desired hardness and size. Examples of binders used in the present invention include, but are not limited to, cellulose, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, polyvinylpyrrolidone, polypropylene-polyethylene copolymer, magnesium aluminometasilicate (Neuselin US2), sodium lauryl sulfate, glucose, sucrose, lactose, povidone, starch, gelatin, xylitol, sorbitol, and sugar alcohols such as maltitol.

[0047] In some embodiments, the cabazitaxel composition contains a lubricant. The lubricant prevents the components from agglomerating and adhering to a tablet punch or capsule filling machine. Examples of lubricants used in the present invention include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, surfactants, polyethylene glycol, and vegetable oils.

[0048] In some embodiments, the cabazitaxel composition contains an absorption enhancer. The enhancer increases absorption by promoting the diffusion or drug solubility of the active ingredient. Examples of absorption enhancers used in the present invention include, but are not limited to, vitamin E-PEG1000 succinate (TPGS), silicified microcrystalline cellulose (SMCC HD90), polyethylene glycol-polypropylene glycol-polyethylene glycol polymer (poloxamer), stearic acid, oleic acid, magnesium stearate, calcium stearate, surfactants, propylene glycol, polyethylene glycol, and vegetable oils.

[0049] In some embodiments, the cabazitaxel composition contains a flow enhancer. Flow enhancers are commonly used to improve the flow properties of powder mixtures by reducing friction between particles. Examples of flow enhancers used in the present invention include, but are not limited to, colloidal silicon dioxide, such as fumed silica, Aerosil®, corn starch, and magnesium carbonate.

[0050] In some embodiments, the cabazitaxel composition contains a diluent or filler. The diluent or filler typically constitutes the bulk of the solid unit dosage form when the drug itself is insufficient to produce a bulk. Examples of diluents or fillers used in the present invention include, but are not limited to, dextrose, lactose, starch, sorbitol, mannitol, microcrystalline cellulose, dicalcium phosphate, calcium carbonate, and magnesium stearate.

[0051] In some embodiments, the cabazitaxel composition contains a plasticizer. The plasticizer is added to provide elasticity and flexibility to the coating material in the case of tablets, and to determine the hardness and impart flexibility to the capsule shell in the case of soft gelatin capsules. Examples of plasticizers used in the present invention include, but are not limited to, diacetylated monoglycerides, castor oil, polyethylene glycol, polypropylene glycol, triethyl citrate, and triacetin.

[0052] In some embodiments, the cabazitaxel composition contains a coating material. The coating of the tablet or capsule protects the components from degradation due to moisture present in the air. Examples of coating materials used in the present invention include, but are not limited to, hydroxypropyl methylcellulose (HMPC), synthetic polymers, polysaccharides, povidone, ethylcellulose, gelatin, and shellac.

[0053] In some embodiments, the cabazitaxel composition further contains an enteric coating material. The enteric coating controls the rate of drug release and determines where the drug is released in the gastrointestinal tract. Examples of enteric coating materials used in the present invention include, but are not limited to, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), poly(methacrylate-co-methyl methacrylate), cellulose trimellitic acetate (CAT), polyvinyl acetate phthalate (PVAP), aleuritic acid ester (shellac), ethylcellulose, Opadry® enteric, methacrylate-methyl methacrylate copolymer or Eudragit®, and Acryl-EZE®.

[0054] In some embodiments, the cabazitaxel composition contains a colorant. The color is added to improve the appearance and identification of the product. Examples of colorants used in the present invention include, but are not limited to, FD and C, D and C dyes and lakes.

[0055] Pharmaceutical formulations used with the composition of the present invention include, but are not limited to, tablets, capsules, pills, and suspensions. In the form of oral administration, preferred forms of formulations include tablets, capsules, lozenges, and powders.

[0056] If necessary, compositions containing cabazitaxel or cabazitaxel, phosphatidylcholine and / or guggulsterol, or guggulsterol derivatives or sodium cholesteryl sulfate preparations may be encapsulated in enteric-coated tablets or capsules to protect them from stomach acid. The term "enteric-coated" refers to the small intestine, and the enteric coating prevents the release of the drug before it reaches the small intestine. Most enteric coatings work by presenting a surface that is stable at acidic pH but rapidly degrades at higher pH.

[0057] In some embodiments, cabazitaxel, guggulsterol, guggulsterol derivatives, or sodium cholesteryl sulfate are mixed with one or more additives such as croscarmellose sodium, polyvinylpyrrolidone, microcrystalline cellulose, and fumed silica (Aerosil), and the mixture is sieved to form granules. In some embodiments, the granules may further contain phosphatidylcholine. In some embodiments, these granules are mixed with a lubricant such as stearic acid and compressed into tablets. In preferred embodiments, the tablets are seal-coated with a polymer such as hydroxypropyl methylcellulose. In particularly preferred embodiments, the seal-coated tablets are further enterically coated with a polymer such as methacrylate copolymer (Acryl-EZE®) or hydroxypropyl methylcellulose polymer (Opadry® enteric).

[0058] In some embodiments, cabazitaxel, guggulsterol, guggulsterol derivatives, or sodium cholesteryl sulfate are mixed with one or more additives such as microcrystalline cellulose and an aerosol, and sieved to form granules. In some embodiments, the granules further contain phosphatidylcholine. In some embodiments, these granules are mixed with microcrystalline cellulose, croscarmellose sodium, lactose, and poloxamer 188 and compressed into tablets. In preferred embodiments, the tablets are seal-coated with a polymer such as hydroxypropyl methylcellulose (HPMC), ethylcellulose, or Opadry®. In particularly preferred embodiments, the seal-coated tablets are further enterically coated with a polymer such as methacrylate copolymer, Acryl-EZE®, methacrylate-methyl methacrylate copolymer, or Eudragit®.

[0059] In some embodiments, the compositions of the present invention include antioxidants. Examples of antioxidants include, but are not limited to, alpha-tocopherol (vitamin E), alpha-tocopherol polyethylene glycol succinate (TPGS), ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite (SMB), propyl gallate, cysteine, and citric acid.

[0060] In some embodiments, the composition of the present invention contains cabazitaxel in an amount of about 0.1% to about 90%, preferably about 0.5% to about 75%, and more preferably about 1% to about 50% of the total weight, by the total weight.

[0061] In some embodiments, the amount of cabazitaxel in a single tablet or capsule is 10 mg to 2000 mg, preferably 10 mg to 1000 mg, and more preferably 10 mg to 500 mg.

[0062] In some embodiments, the compositions of the present invention contain lipids in an amount of about 1% to about 90%, preferably about 2% to about 80%, and more preferably about 3% to about 50% of the total weight.

[0063] In some embodiments, the composition of the present invention contains guggulsterol in an amount of about 0.1% to about 90%, preferably about 0.1% to about 75%, and more preferably about 0.1% to about 50% of the total weight.

[0064] In some embodiments, the composition of the present invention contains a guggulsterol derivative in an amount of about 0.1% to about 90%, preferably about 0.1% to about 75%, and more preferably about 0.1% to about 50% of the total weight, by the total weight.

[0065] In some embodiments, the composition of the present invention contains sodium cholesteryl sulfate in an amount of about 0.1% to about 90%, preferably about 0.1% to about 75%, and more preferably about 0.1% to about 50% of the total weight.

[0066] The compositions of the present invention can be administered in any dosage form via any system that delivers the active ingredient, cabazitaxel, in vivo. In some embodiments, the compositions of the present invention are delivered in dosage forms selected from tablets, chewable tablets, capsules, and soft gelatin capsules. In some embodiments, the compositions are formulated into a desired dosage form to achieve an immediate-release, sustained-release, or delayed-release profile in vivo at the time of administration. [Examples]

[0067] Example 1

[0068] TPGS 1000 (5.0 g) and hydrogenated soybean phosphatidylcholine (HSPC) (15.0 g) were dissolved in alcohol (230 mL). Cabazitaxel (25.0 g) was then mixed in and heated to 30°C-35°C. Separately, Prosolve SMCC HD90 (30.0 g) and Neusilin US2 (10.0 g) were mixed and loaded into the top spray assembly bowl of a fluidized bed granulator. The mixture was granulated using the cabazitaxel-HSPC solution by the top spray method at an air supply temperature of 50°C-60°C and a product temperature of 27°C-35°C. After spraying was complete, the granules were dried and sieved through a #30 mesh sieve. The granules that passed through the 330 mesh were mixed with Neusilin US2 (6.0g), croscarmellose sodium (12.5g), sodium lauryl sulfate (2.5g), poloxamer 188 (12.5g), and hydrophilic fumed silica (Aerosil) (1.2g) in a blender for 5 minutes. The mixture was then smoothed with magnesium stearate for 5 minutes, and the smoothed mixture was compressed into tablets.

[0069] HPMC 3 CPS (12.0 g) was dispersed in isopropyl alcohol (140 mL), dichloromethane (90 mL) was added, and the mixture was stirred for 25 minutes. Using this mixture, a seal coating was performed in an automatic coater at an air supply temperature of 40°C to 45°C and a product temperature of 30°C to 35°C. The tablets were dried at a product temperature of 35°C to 40°C for 30 minutes.

[0070] Acrylic EZE White (23.0 g) was dispersed in purified water and stirred for 30 minutes. This mixture was then enterically coated in an automatic coater at an air supply temperature of 45°C to 55°C and a product temperature of 35°C to 40°C. The tablets were dried at a product temperature of 35°C to 40°C for 20 minutes.

[0071] Example 2

[0072] TPGS 1000 (5.0 g) and guggulsterol (15.0 g) were dissolved in alcohol (230 mL). Then, cabazitaxel (25.0 g) was mixed in and heated to 30°C to 35°C. Separately, Prosolve SMCC HD90 (30.0 g) and Neusilin US2 (10.0 g) were mixed and loaded into the top spray assembly bowl of a fluidized bed granulator. The mixtures were granulated using the cabazitaxel-guggulsterol solution by the top spray method at an air supply temperature of 50°C to 60°C and a product temperature of 27°C to 35°C. After spraying was complete, the granules were dried, sieved through a #30 mesh sieve, and mixed in a blender for 5 minutes with Neusilin US2 (6.0g), croscarmellose sodium (12.5g), sodium lauryl sulfate (2.5g), poloxamer 188 (12.5g), and hydrophilic fumed silica (Aerosil) (1.2g) that had passed through a 330 mesh sieve. The mixture was then smoothed with magnesium stearate for 5 minutes, and the smoothed mixture was compressed into tablets.

[0073] HPMC 3 CPS (12.0 g) was dispersed in isopropyl alcohol (140 mL), dichloromethane (90 mL) was added, and the mixture was stirred for 25 minutes. Using this mixture, a seal coating was performed in an automatic coater at an air supply temperature of 40°C to 45°C and a product temperature of 30°C to 35°C. The tablets were dried at a product temperature of 35°C to 40°C for 30 minutes.

[0074] Acrylic EZE White (23.0 g) was dispersed in purified water and stirred for 30 minutes. This mixture was then enterically coated in an automatic coater at an air supply temperature of 45°C to 55°C and a product temperature of 35°C to 40°C. The tablets were dried at a product temperature of 35°C to 40°C for 20 minutes.

[0075] Example 3

[0076] TPGS 1000 (5.0 g) and guggulsteryl laurate (15.0 g) were dissolved in alcohol (230 mL). Then, cabazitaxel (25.0 g) was mixed in and heated to 30°C to 35°C. Separately, Prosolve SMCC HD90 (30.0 g) and Neusilin US2 (10.0 g) were mixed and loaded into the top spray assembly bowl of a fluidized bed granulator. The mixture was granulated using the cabazitaxel-guggulsteryl laurate solution by the top spray method at an air supply temperature of 50°C to 60°C and a product temperature of 27°C to 35°C. After spraying was complete, the granules were dried, sieved through a #30 mesh sieve, and mixed in a blender for 5 minutes with Neusilin US2 (6.0g), croscarmellose sodium (12.5g), sodium lauryl sulfate (2.5g), poloxamer 188 (12.5g), and hydrophilic fumed silica (Aerosil) (1.2g) that had passed through a 330 mesh sieve. The mixture was then smoothed with magnesium stearate for 5 minutes, and the smoothed mixture was compressed into tablets.

[0077] HPMC 3 CPS (12.0 g) was dispersed in isopropyl alcohol (140 mL), dichloromethane (90 mL) was added, and the mixture was stirred for 25 minutes. Using this mixture, a seal coating was performed in an automatic coater at an air supply temperature of 40°C to 45°C and a product temperature of 30°C to 35°C. The tablets were dried at a product temperature of 35°C to 40°C for 30 minutes.

[0078] Acrylic EZE White (23.0 g) was dispersed in purified water and stirred for 30 minutes. This mixture was then enterically coated in an automatic coater at an air supply temperature of 45°C to 55°C and a product temperature of 35°C to 40°C. The tablets were dried at a product temperature of 35°C to 40°C for 20 minutes.

[0079] Example 4

[0080] TPGS 1000 (10.0 g) and sodium cholesteryl sulfate (5.0 g) were dissolved in alcohol (470 mL). Hydrogenated soybean phosphatidylcholine (HSPC) (25.0 g) was added until completely dissolved. Cabazitaxel (50.0 g) was then mixed in and heated to 30°C-35°C. Separately, Prosolve SMCC HD90 (60.0 g) and Neusilin US2 (20.0 g) were mixed and loaded into the top spray assembly bowl of a fluidized bed granulator. The mixture was granulated using the cabazitaxel-HSPC-sodium cholesteryl sulfate solution by the top spray method at an air supply temperature of 50°C-60°C and a product temperature of 27°C-35°C. After spraying was complete, the granules were dried and sieved through a #30 mesh sieve. The granules that passed through the 330 mesh sieve were mixed in a blender for 5 minutes with Neusilin US2 (13.0g), croscarmellose sodium (25.0g), sodium lauryl sulfate (5.0g), poloxamer 188 (25.0g), and hydrophilic fumed silica (Aerosil) (2.5g). The mixture was then smoothed with magnesium stearate for 5 minutes, and the smoothed mixture was compressed into tablets.

[0081] HPMC 3 CPS (25.0 g) was dispersed in isopropyl alcohol (280 mL), dichloromethane (190 mL) was added, and the mixture was stirred for 25 minutes. Using this mixture, a seal coating was performed in an automatic coater at an air supply temperature of 40°C to 45°C and a product temperature of 30°C to 35°C. The tablets were dried at a product temperature of 35°C to 40°C for 30 minutes.

[0082] Acrylic EZE White (45.0 g) was dispersed in purified water and stirred for 30 minutes. This mixture was then enterically coated in an automatic coater at an air supply temperature of 45°C to 55°C and a product temperature of 35°C to 40°C. The tablets were dried at a product temperature of 35°C to 40°C for 20 minutes.

[0083] Example 5

[0084] TPGS 1000 (10.0 g) and guggulsterol (5.0 g) were dissolved in alcohol (470 mL). Hydrogenated soybean phosphatidylcholine (HSPC) (25.0 g) was added until completely dissolved. Cabazitaxel (50.0 g) was then mixed in and heated to 30°C-35°C. Separately, Prosolve SMCC HD90 (60.0 g) and Neusilin US2 (20.0 g) were mixed and loaded into the top spray assembly bowl of a fluidized bed granulator. The mixture was granulated using the cabazitaxel-HSPC-guggulsterol solution by the top spray method at an air supply temperature of 50°C-60°C and a product temperature of 27°C-35°C. After spraying was complete, the granules were dried, sieved through a #30 mesh sieve, and mixed in a blender for 5 minutes with Neusilin US2 (13.0g), croscarmellose sodium (25.0g), sodium lauryl sulfate (5.0g), poloxamer 188 (25.0g), and hydrophilic fumed silica (Aerosil) (2.5g), which had passed through a 330 mesh sieve. The mixture was then smoothed with magnesium stearate for 5 minutes, and the smoothed mixture was compressed into tablets.

[0085] HPMC3CPS (25.0 g) was dispersed in isopropyl alcohol (280 mL), dichloromethane (190 mL) was added, and the mixture was stirred for 25 minutes. Using this mixture, a seal coating was performed in an automatic coater at an air supply temperature of 40°C to 45°C and a product temperature of 30°C to 35°C. The tablets were dried at a product temperature of 35°C to 40°C for 30 minutes.

[0086] Acrylic EZE White (45.0 g) was dispersed in purified water and stirred for 30 minutes. This mixture was then enterically coated in an automatic coater at an air supply temperature of 45°C to 55°C and a product temperature of 35°C to 40°C. The tablets were dried at a product temperature of 35°C to 40°C for 20 minutes.

[0087] Example 6

[0088] TPGS 1000 (10.0 g) and guggulsteryl laurate (5.0 g) were dissolved in alcohol (470 mL). Hydrogenated soybean phosphatidylcholine (HSPC) (25.0 g) was added until completely dissolved. Cabazitaxel (50.0 g) was then mixed in and heated to 30°C-35°C. Separately, Prosolve SMCC HD90 (60.0 g) and Neusilin US2 (20.0 g) were mixed and loaded into the top spray assembly bowl of a fluidized bed granulator. The mixture was granulated using the cabazitaxel-HSPC-guggulsteryl laurate solution by the top spray method at an air supply temperature of 50°C-60°C and a product temperature of 27°C-35°C. After spraying was complete, the granules were dried, sieved through a #30 mesh sieve, and mixed in a blender for 5 minutes with Neusilin US2 (13.5g), croscarmellose sodium (25.0g), sodium lauryl sulfate (5.0g), poloxamer 188 (25.0g), and hydrophilic fumed silica (Aerosil) (2.5g), which had passed through a 330 mesh sieve. The mixture was then smoothed with magnesium stearate for 5 minutes, and the smoothed mixture was compressed into tablets.

[0089] HPMC 3 CPS (12.50 g) was dispersed in isopropyl alcohol (280 mL), dichloromethane (190 mL) was added, and the mixture was stirred for 25 minutes. Using this mixture, a seal coating was performed in an automatic coater at an air supply temperature of 40°C to 45°C and a product temperature of 30°C to 35°C. The tablets were dried at a product temperature of 35°C to 40°C for 30 minutes.

[0090] Acrylic EZE White (22.50 g) was dispersed in purified water and stirred for 30 minutes. This mixture was then enterically coated in an automatic coater at an air supply temperature of 45°C to 55°C and a product temperature of 35°C to 40°C. Tablets containing 50 mg of cabazitaxel per tablet were dried at a product temperature of 35°C to 40°C for 20 minutes.

[0091] Example 7

[0092] TPGS 1000 (40.0 g) and guggulsteryl laurate (20.0 g) were dissolved in alcohol (1.9 L). Hydrogenated soybean phosphatidylcholine (HSPC) (100.0 g) was added until completely dissolved. Cabazitaxel (200.0 g) was then mixed in and heated to 30°C-35°C. Separately, Prosolve SMCC HD90 (240.0 g) and Neusilin US2 (80.0 g) were mixed and loaded into the top spray assembly bowl of a fluidized bed granulator. The mixture was granulated using the cabazitaxel-HSPC-guggulsteryl laurate solution by the top spray method at an air supply temperature of 50°C-60°C and a product temperature of 27°C-35°C. After spraying was complete, the granules were dried, sieved through a #30 mesh sieve, and mixed in a blender for 5 minutes with Neusilin US2 (54.0g), croscarmellose sodium (100.0g), sodium lauryl sulfate (20.0g), poloxamer 188 (100.0g), and hydrophilic fumed silica (Aerosil) (10.0g) that had passed through a 330 mesh sieve. The mixture was then smoothed with magnesium stearate for 5 minutes, and the smoothed mixture was compressed into tablets.

[0093] HPMC 3 CPS (100.0 g) was dispersed in isopropyl alcohol (1.14 L), dichloromethane (760 mL) was added, and the mixture was stirred for 25 minutes. Using this mixture, seal coating was performed in an automatic coater at an air supply temperature of 40°C to 45°C and a product temperature of 30°C to 35°C. The tablets were dried at a product temperature of 35°C to 40°C for 30 minutes.

[0094] Acrylic EZE White (180.0 g) was dispersed in purified water and stirred for 30 minutes. This mixture was then enterically coated in an automatic coater at an air supply temperature of 45°C to 55°C and a product temperature of 35°C to 40°C. Tablets containing 50 mg of cabazitaxel per tablet were dried at a product temperature of 35°C to 40°C for 20 minutes.

[0095] All publications and patents referenced in the above specification are incorporated herein by reference. Various modifications and alterations of the compositions described in the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the present invention has been described in relation to certain preferred embodiments, the present invention should not be unduly limited to such specific embodiments. In fact, various modifications of the described forms for carrying out the present invention, which will be apparent to those skilled in the art, are intended to be within the scope of the following claims.

[0096] Example 8 Pharmacokinetics of cabazitaxel tablets after oral administration in ICR(CD-1) mice

[0097] ICR(CD-1) mice aged 5-6 weeks were given a 19% protein rodent diet and free access to water. The mice were acclimatized in the facility for at least 7 days prior to use. There were 4 mice at each post-administration time point and 2 mice at the pre-administration time point. A total of 5 time points (0.0, 0.5, 1.0, 2.0, 4.0, and 6.0 hours) were obtained before and after administration.

[0098] Cabazitaxel tablets (50 mg) were weighed, crushed, and ground in a glass mortar and pestle until no lumps were visible in the powder. The powder was suspended in purified water at a 2 mg cabazitaxel / mL suspension. The suspension was sonicated for 2-3 minutes to ensure a homogeneous dosage formulation was achieved before administration. The dosage volume was calculated based on the body weight of each animal at 20 mL / kg.

[0099] A single oral dose of 40 mg cabazitaxel / kg body weight was administered orally to each animal using a 22-gauge stainless steel enteral feeding needle. After dose administration, blood samples were collected in pre-labeled micro-tainer tubes containing K2EDTA by retroorbital hemorrhage (under CO2 anesthesia). One blood sample was taken from each mouse. Immediately after collection, the blood sample was gently inverted several times to ensure complete mixing with the anticoagulant, and then stored in a refrigerator at 2–8°C. Plasma was separated after centrifugation (2000 × g for 10 minutes) and stored in cryovials in a freezer (-20°C or below) before analysis.

[0100] The concentration of cabazitaxel in plasma was quantified using C18 reversed-phase HPLC equipped with a UV detector (Figure 1).

[0101] Example 9 Subacute toxicity of orally administered cabazitaxel tablets in ICR(CD-1) mice

[0102] ICR(CD-1) mice (5-6 weeks old) were given a 19% protein rodent diet and free access to water. The mice were acclimatized in the facility for at least 7 days prior to use. A total of 48 animals (24 males and 24 females) were randomized into four groups (Table 1): A (control), B (low dose), C (medium dose), and D (high dose). The control group mice were given water. The treatment group mice were administered a daily dose of cabazitaxel for 5 days. All mice were euthanized on day 29 based on organ weight and gross findings.

[0103] [Table 1]

[0104] Before the start of the study, cabazitaxel tablets were weighed, crushed into powder, and stored at 2–8°C. Aliquots of the powder were weighed on each administration day and suspended in water at 3 mg cabazitaxel / mL as the administration formulation for mice in the high-dose group. For the medium-dose and low-dose groups, the suspensions were diluted to 2 mg / mL and 1 mg / mL, respectively. Cabazitaxel was administered orally using a 22-gauge stainless steel forced-oral needle. Mortality, clinical signs, body weight / organ weight, gross findings, hematology, and blood chemistry were evaluated.

[0105] Mortality: There were no deaths in the control or low-dose groups throughout the entire study period. A total of three male mice were found dead or in a critical condition on day 8. Two male mice in the high-dose group and one male mouse in the medium-dose group died. A total of three female mice were also found to have died in the high-dose group between days 8 and 11.

[0106] Clinical signs: Male mice in the medium-dose and high-dose groups showed clinical signs, including poor coat condition, dehydration, and hunched posture, starting from day 5. By day 10, all surviving mice showed no clinical signs. No clinical signs were observed in male mice in the low-dose and control groups. Female mice in the high-dose group showed clinical signs, including poor coat condition, dehydration, and hunched posture, starting from day 5. By day 10, all surviving mice showed no clinical signs. No clinical signs were observed in female mice in the low-dose, medium-dose, and control groups.

[0107] Body weight: In female mice, the maximum body weight loss (average 20% decrease from day 1) was observed in the high-dose group on day 8. A slight body weight loss (7.1% decrease from day 1) was also observed in the medium-dose mice on day 5. In male mice, the high-dose and medium-dose groups showed maximum body weight losses of 14.8% and 11.5%, respectively. The body weight of all remaining mice treated with cabazitaxel was comparable to that of the control group at the end of the study.

[0108] Organ weights: The weights of animal organs, including the liver, kidneys, heart, lungs, and spleen, were recorded at necropsy on day 29 and normalized to a mouse body weight of 20g. All organ weights were comparable to those of the control group.

[0109] Macroscopic findings: No lesions or abnormal changes were observed in any of the major organs.

[0110] Hematology and blood chemistry: No abnormal changes were observed in hematology or blood chemistry in any of the groups.

[0111] Example 10 Efficacy of orally administered cabazitaxel tablets for survival in mice with P388 leukemia

[0112] The in vivo P388 tumor-bearing CD2F1 mouse leukemia model is widely used for preclinical evaluation of the antileukemic activity of test compounds (Dykes, DJ et al., 2008). In this model, untreated control mice survive for only about 9–11 days. Depending on the effectiveness of the treatment, treated mice survive longer than control mice. Extended survival can be used as an endpoint in efficacy studies.

[0113] On day 1 of the experiment, 4-6 week old CD2F1 mice were given a 19% protein rodent diet and free access to water. The mice were acclimatized in the facility for at least 7 days prior to use.

[0114] Mouse leukemia cell line P388 (log phase cells) was transferred from the culture flask to a sterile test tube and centrifuged at 200 × g (approximately 1000 rpm) at 2–8°C for 5 minutes. The cells were washed twice with 10 mL of cold PBS and resuspended in 5 mL of cold PBS. After staining with trypan blue, the cell count was measured using a hemocytometer. 5 × 10 6 Cells were suspended in PBS at a concentration of / mL. On day 0, 1 × 10⁶ cells were found in 0.2 mL. 6 Cells / mice were administered intraperitoneally.

[0115] Cabazitaxel tablets (50 mg) were crushed and ground in a glass mortar and pestle until no lumps were visible in the powder. The powder was suspended in purified water at 2 mg cabazitaxel / mL. The suspension was sonicated for 2-3 minutes to ensure that a homogeneous suspension was achieved before dose administration at a 40 mg / kg / day dose level. Dilution with purified water was achieved to 1 mg cabazitaxel / mL for a 20 mg / kg / day dose level. The administration volume was calculated based on the body weight of each individual animal at 20 mL / kg.

[0116] Results: Treatment with oral cabazitaxel at a cumulative dose of 120 mg / kg resulted in a significant increase in survival of P388 tumor-bearing leukemia mice compared to the untreated control group (Table 2).

[0117] [Table 2]

[0118] Example 11

[0119] Maximum tolerated dose (MTD) and pharmacokinetics of oral cabazitaxel tablets in patients with advanced solid tumors that have failed conventional treatment.

[0120] An open-label, non-randomized, multicenter, dose-escalation, single-dose trial was conducted in patients with advanced solid tumors who had failed conventional treatment. Patients received a single oral dose of cabazitaxel lipid tablets (50, 100, 200, and 300 mg, equivalent to 1, 2, 4, and 6 tablets, respectively). Tablets were prepared according to Examples 6 and 7. Patients were initially enrolled in the lowest-dose group, followed by the higher-dose group. Blood, urine, and stool samples were collected at different time points for PK analysis.

[0121] Diagnostic and primary inclusion criteria: Patients with histopathologically / cytologically confirmed primary advanced solid tumors such as breast cancer, head and neck cancer, lung cancer, melanoma, gastric cancer, colon cancer, or prostate cancer for whom cabazitaxel monotherapy was a viable treatment option, or patients with advanced solid malignancies that were refractory to conventional treatment and had an ECOG performance status of 0-2 with adequate bone marrow, renal, and hepatic function, were enrolled in the study. 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).

[0122] For pharmacokinetic evaluation, a total of 20 blood samples (5 mL each) and 7 urine samples were collected from each patient in each dose group at the time specified in the protocol. Fecal samples were collected before administration, and all fecal samples were collected from each patient in each dose group up to 24 hours later. Pharmacokinetic parameters were calculated for cabazitaxel using a non-compartment model of Phoenix® WinNonlin® Version 8.3 (Certara L.P).

[0123] Plasma: Cmax, AUC0-t, AUC0-∞, Tmax, AUC_%Extrap_obs, Xz, Vd, Cl and tl / 2 Urine: Ae0-72h, Rmax, Tmax, R Feces:Ae0-24h

[0124] Figure 2 shows the plasma concentration of cabazitaxel over time. The pharmacokinetic parameters of cabazitaxel are summarized in the table below.

[0125] [Table 3]

[0126] [Table 4]

[0127] [Table 5]

[0128] The pharmacokinetic profile of cabazitaxel was well characterized in plasma at all dose levels. Nonlinear behavior was observed at higher dose levels after a single 200 mg dose. After a single dose, the median time to reach peak plasma concentration of cabazitaxel ranged from 3 to 7 hours, and the mean terminal phase half-life ranged from approximately 79 to 203 hours. A very small amount of the administered drug (i.e., <0.1%) was excreted in the urine over 72 hours after a single dose. The amount excreted in the feces ranged from approximately 4 to 22%.

[0129] Most importantly, a single dose of oral cabazitaxel lipid tablets yields mean AUCs of 889, 1187, or 1110 ng·h / mL at 100, 200, or 300 mg dose levels, respectively. On the other hand, a mean AUC of 991 ng·h / mL corresponds to 25 mg / m². 2 This can be achieved by intravenous administration of cabazitaxel at the recommended dose (Jevtana® Prescribing Information).

[0130] Safety variables included adverse events (AEs), clinical laboratory parameters, vital signs, and physical examination. All AEs reported during the study were included in the safety analysis. AEs were classified by organ-specific major classifications based on the terminology recommended from MedDRA version 24.0. The MTD for cabazitaxel lipid tablets was established as 300 mg.

[0131] References 1. Nightingale, G. and Ryu, J. Drug Forecast (2012), Vol. 37; 8:440-448. 2. Paller, CJ and Antonarakis, ES Drug Des. Devel. Ther. (2011), 5;117-124. 3. Palepu, N. US 2012 / 0065255 A1. 4. Cabazitaxel Injection for Intravenous Use- Prescribing Information 5. Meeter, AC, Figlin, R., Meeter, MM (2012), Clin. Cancer Res. 18(24): 6574–6579. 6. Abidi, AJ Pharmacology and Pharmacotherapeutics, (2013), 4:230-237. 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. 8. Schwartzberg , LS , Navari , RM Adv. Ther. (2018). 35:754-7 9. Dykes, DJ and Waud, WR Murine L1210 and P388 Leukemias, Tumor Models in Cancer Research (2008), Edited by: BA Teicher ▲c▼ Humana Press Inc., Totowa, NJ

Claims

1. A composition comprising cabazitaxel and at least one lipid and / or guggulsterol or a guggulsterol derivative or sodium cholesteryl sulfate in a seal-coated and / or enteric-coated tablet or capsule.

2. The composition according to claim 1, wherein the at least one lipid is selected from the group consisting of soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylglycerol (DSPG), dipalmitoyl phosphatidylglycerol (DMPG), cholesterol (Chol), cholesterol sulfate, and salts thereof.

3. The composition according to claim 1, wherein the guggulsterol derivative is selected from the group consisting of guggulsteryl laurate, guggulsteryl myristate, guggulsteryl palmitate, guggulsteryl stearate, guggulsteryl oleate, guggulsteryl linoleate, and guggulsteryl linolenate.

4. The composition according to claim 1, further comprising one or more additives selected from magnesium aluminometasilicate, tocopherol succinate polyethylene glycol, silicified microcrystalline cellulose, magnesium stearate, croscarmellose sodium, sodium lauryl sulfate, polyethylene glycol-polypropylene glycol-polyethylene glycol polymer, poloxamer 188, hydrophilic fumed silica, aerosol, and citric acid.

5. The composition according to claim 1, wherein the seal coating comprises one or more polymers selected from hydroxymethylpropylcellulose, methylhydroxyethylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, sodium carboxymethylcellulose, acrylate polymers, and polyethylene glycol.

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

7. The composition according to claim 1, wherein the amount 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, wherein the amount of lipid in one tablet or capsule is in the range of at least 10 mg to 1000 mg.

9. The composition according to claim 1, wherein the amount of guggulsterol or guggul derivative in one tablet or capsule is at least 2 mg to 500 mg.

10. The composition according to claim 1, wherein the amount of sodium cholesteryl sulfate in one tablet or capsule is at least 2 mg to 500 mg.

11. The composition according to 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 includes oral administration to a subject.

13. The composition according to claim 12, wherein the subject is a mammal.

14. The compositions according to claims 12 and 13, wherein the subject is a human.

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