A self-emulsifying oral formulation of cabazitaxel and a preparation method thereof

Abstract

The present application relates to a kind of cabazitaxel self-emulsifying oral preparation and its preparation method.The preparation raw materials of the cabazitaxel self-emulsifying oral preparation include: cabazitaxel active substance, oil, surfactant and co-surfactant;The cabazitaxel active substance is cabazitaxel or its pharmaceutically acceptable salt, ester, solvate.The cabazitaxel self-emulsifying oral preparation developed in the present application can spontaneously form nanoemulsion with small particle size (below 450 nm) after contacting with aqueous medium, can quickly release drug, and can bypass liver first-pass effect through lymphatic transport, so as to realize higher oral bioavailability;The present application provides a comprehensive technical solution that can simultaneously solve the three big problems of dissolution, permeation and metabolism, opens up a new and feasible path for oral administration of cabazitaxel active substance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a self-emulsifying oral formulation of cabazitaxel and its preparation method. Background Technology

[0002] Cabazitaxel is a new-generation taxane-based microtubule inhibitor that exerts a potent anti-tumor effect by binding to microtubules, promoting microtubule assembly and inhibiting their depolymerization, thereby blocking tumor cell mitosis. It has attracted significant attention due to its continued activity against docetaxel-resistant prostate cancer cells and has become a key second-line drug for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, like many taxanes, cabazitaxel is highly hydrophobic and has extremely low water solubility, making it impossible to directly formulate a water-soluble injection solution.

[0003] As clinical research progresses, cabazitaxel's antitumor spectrum is continuously expanding, demonstrating potential therapeutic value in various solid tumors such as breast cancer, non-small cell lung cancer, and pancreatic cancer, with broad prospects for future market application. According to market analysis reports, the global prostate cancer drug market continues to grow, and as an important treatment option, cabazitaxel's market demand is stable with room for growth. Developing safer and more convenient new formulations of cabazitaxel will not only solidify its position in the treatment of mCRPC but also provide crucial support for expanding its indications, possessing significant clinical value and commercial potential.

[0004] Currently, the only clinically available dosage form is an injectable concentrate, which necessitates the use of a high proportion of ethanol and the nonionic surfactant Tween 80 (polysorbate 80) as a solubilizer. While this classic solubilization method solves the fundamental problem of injectable administration, it also introduces serious safety risks.

[0005] Commercially available carbamate injections used in clinical practice (such as Jevtana®) require a complex dilution process before administration, and due to their high content of Tween 80 and ethanol, they have revealed significant problems in clinical application:

[0006] (1) Severe allergic reactions: The injection contains a high amount of Tween 80, which can cause anaphylactic shock, including rashes, difficulty breathing, decreased blood pressure, and even life-threatening symptoms. Therefore, patients must undergo pretreatment with glucocorticoids and antihistamines before infusion, which increases the complexity of medication and medical costs;

[0007] (2) Unique toxic side effects: The injection contains a high amount of Tween 80 and ethanol, which can cause hemolysis, neurotoxicity and rare non-cardiac pulmonary edema, limiting the safety window of the drug and forcing some patients to discontinue treatment due to intolerance.

[0008] (3) Poor patient compliance: The treatment regimen requires patients to frequently visit the hospital for intravenous infusions lasting several hours, which involves the constriction of the infusion tubing and the potential risk of phlebitis, seriously affecting the quality of life of patients, especially for patients with advanced cancer who require long-term treatment. In addition, the ethanol in the formula also poses a risk to patients with liver dysfunction.

[0009] Developing an oral formulation of cabazitaxel, based on its existing injectable formulation, is an ideal way to solve the aforementioned problems. Oral administration can greatly improve patient compliance and quality of life, making outpatient and even home-based cancer treatment possible. Simultaneously, oral administration allows for absorption through the portal venous system, potentially bypassing the first-pass effect of the liver via the intestinal lymphatic transport pathway, which may improve drug exposure. However, achieving oral administration of cabazitaxel faces three major physiological and pharmacological hurdles:

[0010] (1) Extremely low oral bioavailability: Cabazitaxel belongs to the Biopharmaceutical Classification System (BCS) Class IV drugs, which means low water solubility and low intestinal permeability;

[0011] (2) Strong first-pass effect: Cabazitaxel is a substrate of the intestinal P-glycoprotein efflux pump and will be actively pumped back into the intestinal lumen; at the same time, it is also an important substrate of liver cytochrome P450 3A4 enzyme and is metabolized in large quantities during absorption.

[0012] (3) Gastrointestinal instability: In the harsh environment of gastric acid, the drug may degrade and become ineffective.

[0013] Therefore, developing a self-emulsifying oral formulation of cabazitaxel by adjusting the formula to solve the three major challenges of dissolution, penetration, and metabolism in oral cabazitaxel administration, and opening up a new route for oral cabazitaxel administration, has become one of the technical problems that urgently need to be solved. Summary of the Invention

[0014] To address the shortcomings of existing technologies, the present invention aims to provide a self-emulsifying oral formulation of cabazitaxel and its preparation method.

[0015] To achieve this objective, the present invention employs the following technical solution:

[0016] In a first aspect, the present invention provides a self-emulsifying oral formulation of cabazitaxel, characterized in that the raw materials for preparing the self-emulsifying oral formulation of cabazitaxel include: active ingredient of cabazitaxel, oil, surfactant and co-surfactant;

[0017] The active ingredient of cabazitaxel is cabazitaxel or its pharmaceutically acceptable salt, ester, or solvate.

[0018] The present invention relates to a self-emulsifying oral formulation of cabazitaxel that self-emulsifies in an aqueous medium to form droplets with a particle size of less than 450 nm, thereby forming microemulsions or nanoemulsions. This invention changes the route of administration of cabazitaxel from injection to oral administration, solving the key technical challenges of cabazitaxel's extremely low water solubility and poor oral absorption, thus improving bioavailability and enhancing patient convenience and compliance.

[0019] Preferably, the solvate of the cabazitaxel is a cabazitaxel-acetone compound.

[0020] Preferably, the oil comprises any one or a combination of at least two of medium-chain triglycerides, ethyl oleate, isopropyl palmitate, caprylic / capric triglycerides, monooleate, tricaprylic triglycerides, or monolinoleate.

[0021] Preferably, the oil is any one or a combination of two of glyceryl monolinoleate and ethyl oleate, and more preferably glyceryl monolinoleate.

[0022] In this invention, using monolinoleic glycerol or ethyl oleate (preferably monolinoleic glycerol) as the oil to prepare a self-emulsifying oral formulation of cabazitaxel can further increase the solubility of the drug and the stability of the self-emulsifying system.

[0023] Preferably, the surfactant comprises any one or a combination of at least two of the following: polysorbates, polyoxyethylene castor oil derivatives, polyoxyethylene hydrogenated castor oil, polyethylene glycol glycerides, caprylic / capric glycerides, or vitamin E polyethylene glycol succinate.

[0024] Preferably, the surfactant comprises a combination of polysorbate 80 and polyethylene glycol glycerol caprylate.

[0025] Preferably, the surfactant comprises a combination of polysorbate 80, polyethylene glycol glycerol caprylate and PEG-E succinate.

[0026] This invention creatively discovers that polysorbate 80 and polyethylene glycol glycerol caprylate and caprylic acid glycerol can form a highly efficient self-emulsifying system, which has a significant synergistic effect in improving the stability of the formulation.

[0027] Furthermore, the surfactant further includes vitamin E polyethylene glycol succinate. Here, the specific ternary system of polysorbate 80, PEG-glycerol caprylate / capric acid, and vitamin E polyethylene glycol succinate can form a more efficient and stable self-emulsifying system. The three components have a significant synergistic effect in improving formulation stability; this system can dissolve cabazitaxel active ingredient in molecular form, and upon contact with gastrointestinal fluid, instantly form nanoemulsions with extremely small particle sizes, greatly increasing the drug absorption surface area.

[0028] In addition, the aforementioned surfactants have the effect of inhibiting the efflux of P-glycoprotein, which may improve the oral bioavailability of cabazitaxel from a mechanistic perspective.

[0029] Therefore, the surfactant containing specific components in this invention improves the stability of the formulation while enhancing the bioavailability of the drug, providing a comprehensive technical solution to better address the three major problems of dissolution, penetration, and metabolism.

[0030] Preferably, the mass ratio of polysorbate 80, PEG-3-glycerol caprylate, and PEG-3-vitamin E succinate is (10-45):(10-40):(0-10).

[0031] Among them, the specific point values ​​in 10-45 can be 10, 15, 20, 25, 30, 35, 40, 45, etc., the specific point values ​​in 10-40 can be 10, 15, 20, 25, 30, 35, 40, etc., and the specific point values ​​in 0-10 can be 0, 0.1, 0.3, 0.5, 0.7, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0032] Preferably, the co-surfactant comprises any one or a combination of at least two of polyethylene glycol, ethanol, glycerol, or diethylene glycol monoethyl ether, and is preferably polyethylene glycol.

[0033] This invention uses polyethylene glycol as a co-surfactant, which allows for better control of the dispersibility and particle size range of the self-emulsifying system.

[0034] Preferably, the molecular weight of the polyethylene glycol is 200-600 Da, for example, it can be 200 Da, 300 Da, 400 Da, 500 Da, 600 Da, etc.

[0035] Preferably, the self-emulsifying oral formulation of cabazitaxel self-emulsifies in an aqueous medium to form droplets with a particle size of less than 450 nm.

[0036] Among them, the specific point values ​​below 450 nm can be 450 nm, 400 nm, 350 nm, 300 nm, 250 nm, 200 nm, 150 nm, 100 nm, 50 nm, 30 nm, etc.

[0037] Preferably, the raw materials for preparing the self-emulsifying oral formulation of cabazitaxel, by weight percentage, include: 0.01%-25% cabazitaxel active ingredient, 5%-20% oil, 30%-80% surfactant, and 5%-65% co-surfactant.

[0038] Among them, the specific point values ​​in the range of 0.01%-25% can be 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, etc.; the specific point values ​​in the range of 5%-20% can be 5%, 8%, 11%, 14%, 17%, 20%, etc.; the specific point values ​​in the range of 30%-80% can be 30%, 40%, 50%, 60%, 70%, 80%, etc.; and the specific point values ​​in the range of 5%-65% can be 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, etc.

[0039] This invention improves the oral bioavailability of cabazitaxel by controlling the raw materials used in the preparation of the self-emulsifying oral formulation within the aforementioned ranges. Furthermore, the solubility of cabazitaxel in an oily concentrate enhances drug stability. Simultaneously, the self-emulsifying oral cabazitaxel formulation of this invention exhibits high bioavailability and high drug loading capacity, reducing the dosage volume and consequently decreasing the overall intake of excipients, including surfactants. This reduces gastrointestinal adverse reactions and avoids hemolysis and other serious infusion side effects caused by the ethanol and Tween 80 contained in commercially available injectable solutions.

[0040] Preferably, the raw materials for preparing the self-emulsifying oral formulation of cabazitaxel also include pharmaceutically acceptable excipients.

[0041] Preferably, the pharmaceutically acceptable excipients include any one or a combination of at least two of the following: diluents, dispersants, binders, fillers, thickeners, lubricants, pH adjusters, flavor maskers, colorants, antioxidants, or antibacterial agents.

[0042] Preferably, the dosage form of the self-emulsifying oral cabazitaxel preparation is an oral capsule preparation, an oral liquid preparation, or an oral solid preparation.

[0043] In a second aspect, the present invention provides a method for preparing a self-emulsified oral formulation of cabazitaxel as described in the first aspect, the method comprising the following steps:

[0044] Oils, surfactants, and co-surfactants are mixed to obtain a mixed solvent; the active ingredient of cabazitaxel is mixed with the mixed solvent under stirring to obtain a self-emulsifying oral formulation of cabazitaxel.

[0045] Preferably, after mixing the cabazitaxel active ingredient with the mixed solvent, the mixture further includes filling the resulting concentrated mixture into soft capsules, hard capsules, or oral liquid packaging.

[0046] Preferably, after mixing the cabazitaxel active ingredient with the mixed solvent, the mixture further includes mixing the resulting concentrated mixture with a pharmaceutically acceptable solid excipient to form an oral solid dosage form.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] (1) Improved medication adherence: The self-emulsified oral formulation of cabazitaxel developed in this invention avoids the problems of high pain index, high risk of allergies and long hospital stay caused by intravenous injection through oral administration, making it possible to treat tumors in outpatient and home settings, which will greatly improve the quality of life of patients.

[0049] (2) Improved absorption performance: The self-emulsifying oral formulation of cabazitaxel developed in this invention can spontaneously form nanoemulsions with small particle size (less than 450 nm) after contact with an aqueous medium, which can rapidly release the drug and bypass the first-pass effect of the liver through lymphatic transport, thereby achieving high oral bioavailability.

[0050] (3) Simple preparation process: The self-emulsifying oral preparation of cabazitaxel involved in this invention does not require complicated equipment in the preparation process, only physical mixing is required, the conditions are mild, it is easy to realize industrial production, and the product quality is controllable. Attached Figure Description

[0051] Figure 1 This is a comparison of blood drug concentrations at different time points after rats were given the self-emulsified oral pre-concentrated cabazitaxel solution via gavage and intravenous injection, as obtained in Examples 1 and 10 of Test Example 3. Detailed Implementation

[0052] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0053] The sources of each component / raw material in the following specific implementation method are shown in Table 1.

[0054] Table 1

[0055]

[0056] It should be noted that the sources of each component / raw material in Table 1 are merely exemplary disclosures that are fully disclosed. This invention does not impose any special limitations on their sources. Those skilled in the art will understand that any conventionally available source that conforms to the basic characteristics of the components / raw materials described in this invention can be applied to this technical solution and achieve the corresponding technical effects. Such alternative sources all fall within the protection scope of this invention.

[0057] The SD rats used in the following specific embodiments were purchased from Guangdong Vital River Laboratory Animal Technology Co., Ltd., and weighed 200-250 g.

[0058] Example 1

[0059] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0060] (1) Its formula, by weight percentage, includes 5% cabazitaxel active ingredient, 10% oil, 50% surfactant, and the remainder is co-surfactant;

[0061] Among them, the active ingredient of cabazitaxel is cabazitaxel acetone compound;

[0062] The oil is a monolinoleic acid glyceride;

[0063] The surfactant is polysorbate 80, caprylic / capric glyceride polyethylene glycol glycerol and vitamin E polyethylene glycol succinate in a mass ratio of 12:33:5.

[0064] The co-surfactant is polyethylene glycol 400.

[0065] (2) Its preparation method is as follows:

[0066] Weigh the oil, surfactant, and co-surfactant into a beaker, heat in a water bath at 40℃±5℃, and mix evenly with magnetic stirring to obtain a mixed solvent; slowly add the cabazitaxel active ingredient raw material into the mixed solvent and continue stirring until completely dissolved to obtain a pale yellow oily liquid.

[0067] Example 2

[0068] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0069] (1) Its formula, by mass percentage, includes 0.01% cabazitaxel active ingredient, 20% oil, 50% surfactant, and the remainder is co-surfactant;

[0070] Among them, the active ingredient of cabazitaxel is cabazitaxel acetone compound;

[0071] The oil is a monolinoleic acid glyceride;

[0072] The surfactant is polysorbate 80, caprylic / capric glyceride polyethylene glycol glycerol and vitamin E polyethylene glycol succinate in a mass ratio of 12:33:5.

[0073] The co-surfactant is polyethylene glycol 400.

[0074] (2) The preparation method is the same as in Example 1.

[0075] Example 3

[0076] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0077] (1) Its formula, by weight percentage, includes 0.5% cabazitaxel active ingredient, 10% oil, 50% surfactant, and the remainder is co-surfactant;

[0078] Among them, the active ingredient of cabazitaxel is cabazitaxel acetone compound;

[0079] The oil is a monolinoleic acid glyceride;

[0080] The surfactant is polysorbate 80, caprylic / capric glyceride polyethylene glycol glycerol and vitamin E polyethylene glycol succinate in a mass ratio of 12:33:5.

[0081] The co-surfactant is polyethylene glycol 400.

[0082] (2) The preparation method is the same as in Example 1.

[0083] Example 4

[0084] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0085] (1) Its formula, by mass percentage, includes 15% cabazitaxel active ingredient, 10% oil, 61% surfactant, and the remainder is co-surfactant;

[0086] Among them, the active ingredient of cabazitaxel is cabazitaxel acetone compound;

[0087] The oil is a monolinoleic acid glyceride;

[0088] The surfactant is polysorbate 80, caprylic / capric glyceride polyethylene glycol glycerol and vitamin E polyethylene glycol succinate in a mass ratio of 27:33:1.

[0089] The co-surfactant is polyethylene glycol 400.

[0090] (2) The preparation method is the same as in Example 1.

[0091] Example 5

[0092] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0093] (1) Its formula, by mass percentage, includes 18% cabazitaxel active ingredient, 9% oil, 68% surfactant, and the remainder is co-surfactant;

[0094] Among them, the active ingredient of cabazitaxel is cabazitaxel acetone compound;

[0095] The oil is a monolinoleic acid glyceride;

[0096] The surfactant is polysorbate 80, caprylic / capric glyceride polyethylene glycol glycerol ester and vitamin E polyethylene glycol succinate in a mass ratio of 30:33:5.

[0097] The co-surfactant is polyethylene glycol 400.

[0098] (2) The preparation method is the same as in Example 1.

[0099] Example 6

[0100] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0101] (1) Its formula, by weight percentage, includes 25% cabazitaxel active ingredient, 5% oil, 65% surfactant, and the remainder is co-surfactant;

[0102] Among them, the active ingredient of cabazitaxel is cabazitaxel acetone compound;

[0103] The oil is a monolinoleic acid glyceride;

[0104] The surfactant is polysorbate 80, caprylic / capric glyceride polyethylene glycol glycerol and vitamin E polyethylene glycol succinate in a mass ratio of 45:10:10.

[0105] The co-surfactant is polyethylene glycol 400.

[0106] (2) The preparation method is the same as in Example 1.

[0107] Example 7

[0108] This embodiment provides a self-emulsifying oral pre-concentrate of cabazitaxel, which differs from Example 1 only in that the total mass of the surfactant remains unchanged, and the surfactant is adjusted to be polysorbate 80 and vitamin E polyethylene glycol succinate in a mass ratio of 12:5. The rest of the formulation and preparation method are the same as in Example 1.

[0109] Example 8

[0110] This embodiment provides a self-emulsifying oral pre-concentrate of cabazitaxel, which differs from Example 1 only in that the total mass of the surfactant remains unchanged, and the surfactant is adjusted to be 33:5 of PEG-glycerol caprylate and PEG-succinate vitamin E. The rest of the formulation and preparation method are the same as in Example 1.

[0111] Example 9

[0112] This embodiment provides a self-emulsifying oral pre-concentrate of cabazitaxel, which differs from Example 1 only in that the total mass of the surfactant remains unchanged, and the surfactant is adjusted to be polysorbate 80 and caprylic / capric acid glyceride polyethylene glycol ester in a mass ratio of 12:33. The rest of the formulation and preparation method are the same as in Example 1.

[0113] Example 10

[0114] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0115] (1) Its formula, by weight percentage, includes 0.5% cabazitaxel active ingredient, 10% oil, 50% surfactant, and the remainder is co-surfactant;

[0116] Among them, the active ingredient of cabazitaxel is cabazitaxel acetone compound;

[0117] The oil is a monolinoleic acid glyceride;

[0118] The surfactant is polysorbate 80 and polyethylene glycol glycerol caprylate in a mass ratio of 17:33;

[0119] The co-surfactant is polyethylene glycol 400.

[0120] (2) Its preparation method is as follows:

[0121] Weigh the oil, surfactant, and co-surfactant into a beaker, heat in a water bath at 40℃±5℃, and mix evenly with magnetic stirring to obtain a mixed solvent; slowly add the cabazitaxel active ingredient raw material into the mixed solvent and continue stirring until completely dissolved to obtain a pale yellow oily liquid.

[0122] Example 11

[0123] This embodiment provides a self-emulsifying oral pre-concentrate of cabazitaxel, which differs from Example 1 only in that the total mass of the oil remains unchanged, and monolinoleic glycerides are replaced with medium-chain triglycerides. The rest of the formulation and preparation method are the same as in Example 1.

[0124] Example 12

[0125] This embodiment provides a self-emulsifying oral pre-concentrate of cabazitaxel, which differs from Example 1 only in that the total mass of the oil remains unchanged, and glyceryl monolinoleate is replaced with ethyl oleate. The rest of the formulation and preparation method are the same as in Example 1.

[0126] Example 13

[0127] This embodiment provides a self-emulsifying oral pre-concentrate of cabazitaxel, which differs from Example 1 only in that the total mass of the co-surfactant remains unchanged, and polyethylene glycol 400 is replaced with ethanol. The rest of the formulation and preparation method are the same as in Example 1.

[0128] Example 14

[0129] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0130] (1) Its formula, by weight percentage, includes 1% of cabazitaxel active ingredient, 10% of oil, 50% of surfactant, and the remainder is co-surfactant;

[0131] The active ingredient in cabazitaxel is cabazitaxel.

[0132] The oil is a monolinoleic acid glyceride;

[0133] The surfactant is polysorbate 80, caprylic / capric glyceride polyethylene glycol glycerol and vitamin E polyethylene glycol succinate in a mass ratio of 12:33:5.

[0134] The co-surfactant is polyethylene glycol 400.

[0135] (2) Its preparation method is as follows:

[0136] Weigh the oil, surfactant, and co-surfactant into a beaker, heat in a water bath at 40℃±5℃, and mix evenly with magnetic stirring to obtain a mixed solvent; slowly add the cabazitaxel active ingredient raw material into the mixed solvent and continue stirring until completely dissolved to obtain a pale yellow oily liquid.

[0137] Example 15

[0138] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0139] (1) Its formula, by weight percentage, includes 1% of cabazitaxel active ingredient, 10% of oil, 50% of surfactant, and the remainder is co-surfactant;

[0140] The active ingredient in cabazitaxel is cabazitaxel.

[0141] The oil is a monolinoleic acid glyceride;

[0142] The surfactant is polysorbate 80, caprylic / capric glyceride polyethylene glycol glycerol and vitamin E polyethylene glycol succinate in a mass ratio of 14:33:3;

[0143] The co-surfactant is polyethylene glycol 400.

[0144] (2) Its preparation method is as follows:

[0145] Weigh the oil, surfactant, and co-surfactant into a beaker, heat in a water bath at 40℃±5℃, and mix evenly with magnetic stirring to obtain a mixed solvent; slowly add the cabazitaxel active ingredient raw material into the mixed solvent and continue stirring until completely dissolved to obtain a pale yellow oily liquid.

[0146] Example 16

[0147] This embodiment provides a self-emulsifying oral pre-concentrated cabazitaxel solution.

[0148] (1) Its formula, by weight percentage, includes 5% cabazitaxel active ingredient, 10% oil, 50% surfactant, and the remainder is co-surfactant;

[0149] Among them, the active ingredient of cabazitaxel is cabazitaxel acetone compound;

[0150] The oil is ethyl oleate;

[0151] The surfactant is polysorbate 80 and polyethylene glycol glycerol caprylate in a mass ratio of 17:33;

[0152] The co-surfactant is polyethylene glycol 400.

[0153] (2) Its preparation method is as follows:

[0154] Weigh the oil, surfactant, and co-surfactant into a beaker, heat in a water bath at 40℃±5℃, and mix evenly with magnetic stirring to obtain a mixed solvent; slowly add the cabazitaxel active ingredient raw material into the mixed solvent and continue stirring until completely dissolved to obtain a pale yellow oily liquid.

[0155] Test Example 1

[0156] Freeze-thaw stability, water dispersion stability, and thermal stability tests.

[0157] (1) Sample to be tested: Cabazitaxel self-emulsified oral pre-concentrate obtained in the above examples.

[0158] (2) Test method:

[0159] (2.1) Freeze-thaw stability:

[0160] Each sample was placed at -20 to -10℃ for 2 days, and then at 40℃ for 2 days to observe its physical stability.

[0161] (2.2) Water dispersion stability:

[0162] Take 0.05 mL of the concentrated solution of each sample to be tested, add it to 10 mL of pure water, stir at 500 rpm, and spontaneously emulsify and disperse evenly to obtain an aqueous dispersion. Observe the stability of the aqueous dispersion at room temperature.

[0163] (2.3) Thermal stability (cloud point) test:

[0164] Take 0.05 mL of the concentrated solution of each sample to be tested, add it to 10 mL of pure water, and stir at 500 rpm to spontaneously emulsify and disperse evenly to obtain an aqueous dispersion. Heat the aqueous dispersion in a water bath and record the temperature at which the dispersion becomes darker / turbid.

[0165] (3) Test results:

[0166] The test results for each sample are shown in Table 2.

[0167] Table 2

[0168]

[0169] Note: N / A indicates that the test was not performed.

[0170] As can be seen from the data in Table 2, the self-emulsified oral formulation of cabazitaxel involved in this invention has excellent freeze-thaw stability, water dispersion stability and high cloud point.

[0171] As can be seen from the data in Examples 1-6, the drug formulations prepared using different concentrations of carbamate acetone as active ingredients all exhibited relatively excellent stability, with a precipitation time of more than 2 hours and high thermal stability.

[0172] A comparison of the data from Examples 1 and 7-10 shows that polysorbate 80, PEG-3-glycerol caprylate, and PEG-3-vitamin E succinate have a significant synergistic effect in improving the long-term stability of the formulation, especially in improving the water dispersion stability and thermal stability of the formulation.

[0173] A comparison of the data from Example 1 and Examples 11-12 shows that the pharmaceutical formulation prepared by monolinoleic glyceride has better stability than other oils such as medium-chain triglycerides or ethyl oleate.

[0174] A comparison of the data from Example 1 and Example 13 shows that polyethylene glycol, compared with other co-surfactants such as ethanol, can better balance the water dispersion stability and thermal stability of the formulation.

[0175] As can be seen from the data in Examples 14-15, the self-emulsified oral formulations of cabazitaxel prepared using different concentrations of cabazitaxel as the active ingredient have excellent freeze-thaw stability.

[0176] As can be seen from the data in Example 16, when the surfactant is kept to be a combination of polysorbate 80 and polyethylene glycol glycerol caprylate, replacing glycerol monolinoleate with ethyl oleate results in a pharmaceutical formulation with better freeze-thaw stability, but the thermal stability will decrease to some extent.

[0177] Test Example 2

[0178] Particle size and polydispersity index were determined.

[0179] (1) Samples to be tested: Cabazitaxel self-emulsified oral pre-concentrate obtained in Examples 1, 3, 10 and 16.

[0180] (2) Test method:

[0181] Take 0.05 mL of the concentrated solution of each sample to be tested, add it to 5 mL of pure water, and stir at 500 rpm to obtain an aqueous dispersion. Use a Malvern particle size analyzer to determine the particle size and polydispersity index of each aqueous dispersion.

[0182] (3) Test results:

[0183] The test results for each sample are shown in Table 3.

[0184] Table 3

[0185]

[0186] As can be seen from the data in Table 3, the self-emulsifying oral formulation of cabazitaxel involved in this invention can self-emulsify in an aqueous medium to form small and uniform droplets, and the particle size of the aqueous dispersion will also change accordingly with the change of oil type and surfactant components.

[0187] Test Example 3

[0188] In vivo pharmacokinetic studies.

[0189] (1) Sample to be tested: Cabazitaxel self-emulsified oral pre-concentrate obtained in Example 1 and Example 10.

[0190] (2) Test method:

[0191] (2.1) Administration method:

[0192] Nine healthy male SPF-grade SD rats, weighing 200-250 g, were randomly divided into three groups of three. They were administered the self-emulsified oral pre-concentrated cabazitaxel solution obtained in Examples 1 and 10 via gavage (PO) and intravenous (IV) cabazitaxel injection (prepared as 21.4 mg / mL cabazitaxel acetone / Tween 80 stock solution (containing 20 mg / mL cabazitaxel), diluted with 5% ethanol saline solution to a 0.5 mg / mL cabazitaxel injection solution).

[0193] Dosage volume: The self-emulsified oral preconcentrate of cabazitaxel obtained in Example 1 was administered by gavage at a dose of 1.4 mL / kg, the self-emulsified oral preconcentrate of cabazitaxel obtained in Example 10 was administered by gavage at a dose of 10 mL / kg, and the intravenous cabazitaxel injection was administered at a dose of 5 mL / kg.

[0194] Dosage: The self-emulsified oral preconcentrate of cabazitaxel obtained in Example 1 was administered by gavage at a dose of 70 mg / kg. The self-emulsified oral preconcentrate of cabazitaxel obtained in Example 10 was administered by gavage at a dose of 50 mg / kg, and the intravenous cabazitaxel injection was administered at a dose of 2.5 mg / kg.

[0195] Patients were fasted for 12 hours before the gavage administration test, but were allowed free access to water; they were given food 2 hours after administration.

[0196] (2.2) Sampling and testing:

[0197] (2.2.1) Gavage administration: 0 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, and 8.0 h after administration;

[0198] (2.2.2) Intravenous administration: 0 min, 5 min, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h after administration.

[0199] At the time points specified above, 0.1 mL of blood was collected from the posterior venous plexus of the rat eyeball, placed in an EDTA anticoagulant tube, centrifuged at 6000 rpm for 10 min, and the plasma was separated and frozen at -20℃ for analysis.

[0200] (3) Test results:

[0201] (3.1) The pharmacokinetic parameters of each sample are shown in Table 4.

[0202] Table 4

[0203]

[0204] (3.2) Results of blood drug concentration tests at different time points after rats were administered carbazide by gavage and intravenous injection are as follows: Figure 1 As shown.

[0205] The results showed that the absolute bioavailability of the self-emulsified oral formulation of cabazitaxel involved in this invention reached 5%-45%, which is higher than the oral bioavailability of ordinary cabazitaxel suspension (usually <5%), demonstrating the excellent effect of this formulation in significantly improving oral absorption.

[0206] The applicant declares that the technical solution of this invention is illustrated by the above embodiments, but this invention is not limited to the above embodiments, that is, it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials for the products of this invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

[0207] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0208] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A self-emulsifying oral formulation of cabazitaxel, characterized in that, The raw materials for preparing the self-emulsifying oral formulation of cabazitaxel include: cabazitaxel active ingredient, oil, surfactant, and co-surfactant; The active ingredient of cabazitaxel is cabazitaxel or a pharmaceutically acceptable salt or solvate thereof; The oil is any one or a combination of two of glyceryl monolinoleate and ethyl oleate. The surfactant comprises a combination of polysorbate 80, polyethylene glycol glycerol caprylate and caprylic / capric acid succinate and vitamin E polyethylene glycol succinate. The mass ratio of polysorbate 80, caprylic / capric acid glyceride polyethylene glycol glycerol ester and vitamin E polyethylene glycol succinate is (10-45):(10-40):(0-10); The co-surfactant is polyethylene glycol; The raw materials for preparing the self-emulsifying oral formulation of cabazitaxel, by weight percentage, include: 0.01%-25% cabazitaxel active ingredient, 5%-20% oil, 30%-80% surfactant, and 5%-65% co-surfactant.

2. The self-emulsifying oral formulation of cabazitaxel according to claim 1, characterized in that, The solvate of the cabazitaxel is a cabazitaxel-acetone compound.

3. The self-emulsifying oral formulation of cabazitaxel according to claim 1, characterized in that, The molecular weight of the polyethylene glycol is 200-600 Da.

4. The self-emulsifying oral formulation of cabazitaxel according to claim 1, characterized in that, The raw materials for preparing the self-emulsifying oral formulation of cabazitaxel also include pharmaceutically acceptable excipients.

5. The self-emulsifying oral formulation of cabazitaxel according to claim 4, characterized in that, The pharmaceutically acceptable excipients include any one or a combination of at least two of the following: diluents, dispersants, binders, fillers, thickeners, lubricants, pH adjusters, flavor maskers, colorants, antioxidants, or antibacterial agents.

6. The self-emulsifying oral formulation of cabazitaxel according to claim 1, characterized in that, The dosage form of the self-emulsifying oral cabazitaxel preparation is an oral capsule preparation, an oral liquid preparation, or an oral solid preparation.

7. A method for preparing a self-emulsifying oral formulation of cabazitaxel as described in any one of claims 1-6, characterized in that, The preparation method includes the following steps: Oils, surfactants, and co-surfactants are mixed to obtain a mixed solvent; the active ingredient of cabazitaxel is mixed with the mixed solvent under stirring to obtain a self-emulsifying oral formulation of cabazitaxel.

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