A liquid-solid compressed enteric-coated tablet of cabazitaxel and a preparation method thereof

Abstract

This invention provides a cabazitaxel liquid-solid compressed enteric-coated tablet and its preparation method, belonging to the field of pharmaceutical formulation technology. This invention utilizes a carrier to absorb and solidify the cabazitaxel self-emulsifying formulation. It also utilizes a coating to improve the flowability of the cabazitaxel self-emulsifying liquid-solid powder. By limiting the mass ratio of the carrier and coating materials and the liquid loading coefficient of the cabazitaxel self-emulsifying liquid-solid powder, the powder exhibits excellent flowability and thus good compressibility, resulting in cabazitaxel liquid-solid compressed enteric-coated tablets with high hardness and low brittleness. Furthermore, by limiting the composition of the cabazitaxel self-emulsifying formulation to cabazitaxel, Tween 80, glyceryl monooleate, and glyceryl tricaprylate, and by limiting the mass ratio of each component, this invention improves the solubility of cabazitaxel, overcoming the problem of poor cabazitaxel solubility.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a cabazitaxel liquid-solid compressed enteric tablet and its preparation method. Background Technology

[0002] Cabazitaxel (CTX, trade name Jevtana) is a taxane drug, readily soluble in methanol and ethanol, but practically insoluble or insoluble in water. Clinically, cabazitaxel is used in combination with prednisone for the treatment of mCRPC. Its clinical pharmacological targets include CYP2C8, SLCO1B1, ABCB1, TUBA4A, TUBB1, SLCO1B3, CYP3A4, CYP3A5, and ABCG2. The pharmacological mechanism of cabazitaxel is similar to other taxane compounds, acting as a microtubule inhibitor and inhibiting mitosis and interphase cell function in cancer cells.

[0003] Although cabazitaxel exhibits high antitumor activity, a broad antitumor spectrum, and strong therapeutic effects against drug-resistant tumors, it belongs to the BCS class IV drug according to the biopharmaceutical classification system (BCS), indicating poor water solubility (4.13 μg / mL). -1 Furthermore, Jevtana is an intravenous injection solution. To improve the water solubility of cabazitaxel, a high concentration of Tween 80 is used as a solubilizer in the formulation. However, intravenous injection of Tween 80 can cause serious adverse reactions, the most serious of which are allergic reactions and fluid retention. Because it is difficult to mix Tween 80 evenly with water, Jevtana needs to be pre-diluted with a 13% (v / v) aqueous ethanol solution before use. Intravenous chemotherapy drugs contain ethanol, which may lead to patient poisoning; at the same time, some drugs (such as analgesics and hypnotics) may interact with the ethanol in the formulation, further exacerbating the toxic effect. In addition to pre-diluting with an aqueous ethanol solution, Jevtana also needs to be diluted with a 0.9% sodium chloride solution or a 5% glucose solution before injection. These two dilution processes undoubtedly increase the complexity of clinical preparation and administration. Finally, paclitaxel drugs have severe vascular irritant properties. Intravenous injection can irritate the veins of cancer patients, causing phlebitis. Furthermore, extravasation during intravenous infusion can cause inflammation, damage, and necrosis of the surrounding tissues. Local necrosis and damage caused by chemotherapy drugs can sometimes be permanent. Therefore, commercially available Jevtana injections currently suffer from these drawbacks.

[0004] Oral administration differs from non-physiological routes of administration like injection. As the most traditional method of drug delivery, it offers several advantages: First, oral administration is highly safe, causing no organic damage to the skin or mucous membranes and reducing disease-related complications. Second, it simplifies the treatment process. Finally, oral formulations do not require a sterile environment for production, resulting in low industrial production costs. Oral chemotherapy drugs can maintain tolerable drug concentrations, making them suitable for postoperative and post-chemotherapy maintenance, thus enriching patients' clinical treatment options. However, cabazitaxel has poor water solubility and is prone to precipitation in clinical settings, leading to very low bioavailability of orally administered cabazitaxel. Therefore, the poor water solubility of oral cabazitaxel formulations limits their application. Summary of the Invention

[0005] The purpose of this invention is to provide a water-soluble carbamate liquid-solid compressed enteric tablet and its preparation method.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a cabazitaxel liquid-solid compressed enteric-coated tablet, comprising a cabazitaxel self-emulsifying liquid-solid powder, excipients, and an enteric coating material. The cabazitaxel self-emulsifying liquid-solid powder comprises a cabazitaxel self-emulsifying formulation, a carrier, and a coating; the liquid loading coefficient of the cabazitaxel self-emulsifying liquid-solid powder is 0.8–1.0; and the mass ratio of the carrier to the coating is 10–20:1.

[0008] The self-emulsifying cabazitaxel formulation is composed of cabazitaxel, Tween 80, monooleate glyceryl ester and tricaprylate glyceryl ester, wherein the mass ratio of cabazitaxel, Tween 80, monooleate glyceryl ester and tricaprylate glyceryl ester is (0.5-10):(20-55):(10-30):(30-90).

[0009] Preferably, the mass ratio of the cabazitaxel, Tween 80, monooleate glyceride and tricaprylate is (5-10):(30-50):(20-30):(50-90).

[0010] Preferably, the additives include one or more of fillers, disintegrants, and lubricants.

[0011] Preferably, the filler includes MCCPH102, MCCKG802, or pregelatinized starch.

[0012] Preferably, the mass ratio of the cabazitaxel self-emulsifying liquid solid powder to the additives is (300-400):(250-350).

[0013] Preferably, the coating weight gain of the cabazitaxel liquid-solid compressed enteric tablets is 7-9%.

[0014] Preferably, the carrier includes SyloidXDP3050 or XDP3150.

[0015] Preferably, the coating comprises Syloid244FP.

[0016] This invention provides a method for preparing the cabazitaxel liquid-solid compressed enteric-coated tablets described above, comprising the following steps:

[0017] (1) Cabazitaxel, Tween 80, glyceryl monooleate and glyceryl trioctanoate were mixed to obtain a self-emulsifying formulation of cabazitaxel.

[0018] (2) The cabazitaxel self-emulsifying formulation obtained in step (1) is mixed sequentially with the carrier and coating material to obtain cabazitaxel self-emulsifying liquid-solid powder;

[0019] (3) The self-emulsifying liquid-solid powder of cabazitaxel obtained in step (2) is mixed with an adjuvant and compressed into a tablet core. Then, the tablet core is coated with an enteric coating material to obtain a cabazitaxel liquid-solid compressed enteric tablet.

[0020] Preferably, the mixing in step (2) includes: mixing the cabazitaxel self-emulsifying agent with the carrier so that the cabazitaxel self-emulsifying agent is completely absorbed by the carrier to obtain a mixture, and mixing the mixture with the coating material to obtain a cabazitaxel self-emulsifying liquid-solid powder.

[0021] This invention provides a cabazitaxel liquid-solid compressed enteric-coated tablet, comprising a cabazitaxel self-emulsifying liquid-solid powder, excipients, and an enteric coating material. The cabazitaxel self-emulsifying liquid-solid powder comprises a cabazitaxel self-emulsifying formulation, a carrier, and a coating. The liquid loading coefficient of the cabazitaxel self-emulsifying liquid-solid powder is 0.8–1.0. The mass ratio of the carrier to the coating is 10–20:1. The cabazitaxel self-emulsifying formulation is composed of cabazitaxel, Tween 80, monooleate, and tricaprylate, and the mass ratio of cabazitaxel, Tween 80, monooleate, and tricaprylate is (0.5–10):(20–55):(10–30):(30–90). This invention utilizes a carrier to absorb and solidify the self-emulsifying cabazitaxel formulation. It also utilizes a coating to improve the flowability of the self-emulsifying cabazitaxel liquid-solid powder. By controlling the mass ratio of the carrier and coating materials, as well as the liquid loading coefficient of the self-emulsifying cabazitaxel powder, this invention achieves excellent flowability and thus good compressibility. This results in cabazitaxel liquid-solid compressed enteric-coated tablets with high hardness and low brittleness, preventing tablet breakage, improving tablet quality stability, and ensuring the drug is emulsified and released only upon reaching the intestines. The self-emulsifying cabazitaxel formulation in this invention is composed of cabazitaxel, Tween 80, glyceryl monooleate, and glyceryl tricaprylate. By controlling the mass ratio of each component to (0.5–10):(20–55):(10–30):(30–90), the microemulsion particle size of the self-emulsifying cabazitaxel formulation can be reduced, thereby significantly improving the solubility of cabazitaxel and overcoming the problem of poor cabazitaxel solubility. The results of the examples show that the self-emulsifying liquid-solid powder microemulsion of cabazitaxel in the cabazitaxel liquid-solid compressed enteric tablets provided by the present invention has a particle size of 162.23±4.86 nm. The small particle size of the microemulsion is more conducive to improving the solubility of cabazitaxel. The polydispersity index (PDI) is 0.175±0.037 and the zeta potential is -18.45±1.63 mV, which shows excellent solubility. It enables the cabazitaxel liquid-solid compressed enteric tablets to be emulsified and released into the intestines before absorption, thus solving the problem of poor water solubility of cabazitaxel liquid-solid compressed enteric tablets. Attached Figure Description

[0022] Figure 1 This is a particle size distribution diagram of the microemulsion obtained from the self-emulsifying carbamate preparation prepared in step (1) of Example 1 of the present invention.

[0023] Figure 2 The Zeta potential diagram is shown for the microemulsion prepared from the self-emulsifying carbamate formulation prepared in step (1) of Example 1 of this invention.

[0024] Figure 3 The image shows a TEM image of the self-emulsifying carbamate preparation prepared in step (1) of Example 1 of this invention.

[0025] Figure 4 The particle size distribution diagram of the microemulsion obtained after redispersing the self-emulsified liquid-solid powder of cabazitaxel prepared in step (1) of Example 1 of the present invention is shown.

[0026] Figure 5 The Zeta potential diagram is shown for the microemulsion obtained after redispersing the self-emulsified liquid-solid powder of cabazitaxel prepared in step (1) of Example 1 of this invention.

[0027] Figure 6 SEM images of the cabazitaxel active pharmaceutical ingredient, the physical mixture of the active pharmaceutical ingredient and the carrier material, the carrier material, the blank self-emulsifying liquid-solid powder, and the cabazitaxel self-emulsifying liquid-solid powder used in this invention.

[0028] Figure 7 The DSC curves of the cabazitaxel active pharmaceutical ingredient, the physical mixture of the active pharmaceutical ingredient and the carrier material, the carrier material, the blank self-emulsifying liquid-solid powder, and the cabazitaxel self-emulsifying liquid-solid powder of the present invention are shown.

[0029] Figure 8 The XRD patterns are of the cabazitaxel active pharmaceutical ingredient, the physical mixture of the active pharmaceutical ingredient and the carrier material, the carrier material, the blank self-emulsifying liquid-solid powder, and the cabazitaxel self-emulsifying liquid-solid powder of the present invention.

[0030] Figure 9 The images show the FTIR spectra of the cabazitaxel active pharmaceutical ingredient, the physical mixture of the active pharmaceutical ingredient and the carrier material, the carrier material, the blank self-emulsifying liquid-solid powder, and the cabazitaxel self-emulsifying liquid-solid powder of the present invention.

[0031] Figure 10 The dissolution curves of the cabazitaxel liquid-solid compressed enteric tablets prepared in Examples 1-2 and Comparative Examples 1-2 of this invention in hydrochloric acid (pH 1.0);

[0032] Figure 11 Dissolution curves of the cabazitaxel liquid-solid compressed enteric tablets prepared in Examples 1 and 2 of this invention in phosphate buffer (pH 6.8). Detailed Implementation

[0033] The present invention provides a cabazitaxel liquid-solid compressed enteric-coated tablet, comprising cabazitaxel self-emulsifying liquid-solid powder, excipients and enteric coating material.

[0034] In this invention, the cabazitaxel self-emulsifying liquid-solid powder includes a cabazitaxel self-emulsifying agent, a carrier, and a coating.

[0035] In this invention, the self-emulsifying cabazitaxel formulation comprises cabazitaxel, Tween 80, glyceryl monooleate, and glyceryl tricaprylate. The mass ratio of cabazitaxel, Tween 80, glyceryl monooleate, and glyceryl tricaprylate is (0.5–10):(20–55):(10–30):(30–90), preferably (5–10):(30–50):(20–30):(50–90). In this invention, the self-emulsifying cabazitaxel formulation uses cabazitaxel, Tween 80, glyceryl monooleate, and glyceryl tricaprylate as co-solvents to improve the solubility of cabazitaxel. When the mass ratio of each component is within the above range, cabazitaxel can exhibit excellent solubility, solving the problem of poor water solubility of cabazitaxel.

[0036] In this invention, the carrier preferably comprises SyloidXDP3050 or XDP3150, more preferably SyloidXDP3050. In this invention, when the carrier is of the above type, it can fully absorb the self-emulsifying cabazitaxel formulation. In this invention, the SyloidXDP3050 or XDP3150 is silica, and the preferred source of the SyloidXDP3050 or XDP3150 is Grace Pharmaceuticals, Inc., USA.

[0037] In this invention, the coating material preferably includes Syloid 244FP. When the coating material is of the type described above, the flowability of the cabazitaxel self-emulsifying liquid-solid powder can be significantly improved. In this invention, the Syloid 244FP is preferably sourced from Grace Pharmaceuticals, Inc., USA.

[0038] In this invention, the liquid loading coefficient of the cabazitaxel self-emulsifying liquid-solid powder is 0.8 to 1.0, preferably 0.8, 0.9, or 1.0. In this invention, the formula for calculating the loading coefficient is preferably as shown in equation (1): Lf = W / Q (Equation (1))

[0039] In the formula (1), Lf is the loading coefficient, W is the mass of the self-emulsifying carbamate, and Q is the mass of the carrier.

[0040] In this invention, the mass ratio of the carrier to the coating is simply referred to as R. R is preferably 10 to 20:1, more preferably 15 to 20:1, that is, R is preferably 10 to 20, and more preferably 20. In this invention, the formula for calculating R is preferably as shown in equation (2): R = Q / q (Equation (2))

[0041] In equation (2), Q is the mass of the carrier and q is the mass of the coating material.

[0042] In this invention, when Lf and R are within the above-mentioned ranges, the angle of repose of the self-emulsified liquid-solid powder of cabazitaxel is less than 40°, the Karl index is less than 25%, and the Hausner ratio is close to 1.25. Therefore, the powder has good flowability. When the liquid-solid powder is directly compressed into tablets, the resulting tablets have a hardness of 63.00 N, good compressibility, and can prevent tablet breakage that could lead to cabazitaxel leakage.

[0043] In this invention, the excipients preferably include one or more of fillers, disintegrants, and lubricants. The fillers preferably include MCCPH102, MCC KG802, or pregelatinized starch, more preferably MCCPH102. The fillers improve tablet hardness. The disintegrant is preferably CCMC-Na, which eliminates binding forces caused by adhesives or high compression, thereby causing the tablet to disintegrate in water. The lubricant is preferably magnesium stearate, which improves the flowability of the cabazitaxel self-emulsifying liquid-solid powder. This invention does not specifically limit the source of the fillers, disintegrants, and lubricants; commercially available products well known to those skilled in the art can be used.

[0044] In this invention, the preferred mass ratio of the self-emulsifying liquid-solid powder of cabazitaxel to the excipients is (300-400):(250-350), more preferably (330-380):(270-320). In this invention, the preferred mass ratio of the filler, disintegrant, and lubricant is (200-300):(10-50):(1-10), more preferably (250-300):(15-25):(1-5). When the mass ratios of the self-emulsifying liquid-solid powder of cabazitaxel to the excipients, and the mass ratios of the filler, disintegrant, and lubricant are within the above ranges, the cabazitaxel liquid-solid compressed enteric-coated tablets can have good strength.

[0045] This invention does not specifically limit the type of enteric coating material; any commercially available enteric coating material well-known to those skilled in the art can be used. In this invention, the enteric coating material protects the cabazitaxel self-emulsifying liquid-solid powder, ensuring its release and absorption only upon reaching the intestines. In this invention, the enteric coating material is preferably a pH-type acrylic resin, more preferably Eudragit L30D-55. In this invention, the Eudragit L30D-55 is preferably sourced from Evonik Specialty Chemicals Ltd.

[0046] In this invention, the coating weight gain of the cabazitaxel liquid-solid compressed enteric-coated tablets is preferably 7-9%, more preferably 7% or 9%. When the coating weight gain of the cabazitaxel liquid-solid compressed enteric-coated tablets is within the above range, the tablets are relatively stable and less prone to breakage.

[0047] The present invention provides a cabazitaxel liquid-solid compressed enteric-coated tablet that utilizes a carrier to absorb and solidify the self-emulsifying cabazitaxel formulation. By limiting the mass ratio of the carrier and coating and the liquid loading coefficient of the self-emulsifying cabazitaxel powder, the present invention enables the self-emulsifying cabazitaxel powder to possess excellent flowability and thus good compressibility. This results in greater hardness after preparation into a cabazitaxel liquid-solid compressed enteric-coated tablet, preventing tablet breakage, improving tablet quality stability, and ensuring that the drug is emulsified and released only upon reaching the intestines. Furthermore, by limiting the composition of the self-emulsifying cabazitaxel formulation, the present invention yields microemulsion particles with smaller sizes, significantly improving the solubility of cabazitaxel and overcoming the problem of poor cabazitaxel solubility.

[0048] The present invention also provides a method for preparing the cabazitaxel liquid-solid compressed enteric-coated tablets described in the above technical solution, comprising the following steps:

[0049] (1) Cabazitaxel, Tween 80, glyceryl monooleate and glyceryl trioctanoate were mixed to obtain a self-emulsifying formulation of cabazitaxel.

[0050] (2) The cabazitaxel self-emulsifying formulation obtained in step (1) is mixed sequentially with the carrier and coating material to obtain cabazitaxel self-emulsifying liquid-solid powder;

[0051] (3) The self-emulsifying liquid-solid powder of cabazitaxel obtained in step (2) is mixed with an adjuvant and compressed into a tablet core. Then, the tablet core is coated with an enteric coating material to obtain a cabazitaxel liquid-solid compressed enteric tablet.

[0052] This invention mixes cabazitaxel, Tween 80, glyceryl monooleate and glyceryl tricaprylate to obtain a self-emulsifying cabazitaxel formulation.

[0053] This invention does not specifically limit the method of mixing cabazitaxel, Tween 80, glyceryl monooleate, and glyceryl tricaprylate, as long as the above components are mixed evenly. In this invention, the preferred method of mixing cabazitaxel, Tween 80, glyceryl monooleate, and glyceryl tricaprylate includes: dissolving Tween 80, glyceryl monooleate, and glyceryl tricaprylate in ethanol to obtain an ethanol solution; mixing cabazitaxel with the ethanol solution to obtain a mixed solution; and removing the ethanol from the mixed solution to obtain a self-emulsifying cabazitaxel formulation.

[0054] In this invention, ethanol acts as a solvent, removing it after the carbamate, Tween 80, glyceryl monooleate, and glyceryl tricaprylate have dissolved to form a mixed solution, thus promoting uniform mixing of the components. This invention does not have a specific limitation on the amount of ethanol used; it can be adjusted according to experimental needs to ensure sufficient dissolution of the components. This invention also does not have a specific limitation on the method for removing ethanol; any solvent removal method well-known to those skilled in the art can be used. In this invention, rotary evaporation is preferred as the method for removing ethanol.

[0055] After obtaining the self-emulsifying formulation of cabazitaxel, the present invention mixes the self-emulsifying formulation of cabazitaxel with a carrier and a coating material in sequence to obtain a self-emulsifying liquid-solid powder of cabazitaxel.

[0056] In this invention, the sequential mixing of the cabazitaxel self-emulsifying agent with the carrier and the coating material preferably includes: mixing the cabazitaxel self-emulsifying agent with the carrier so that the cabazitaxel self-emulsifying agent is completely absorbed by the carrier to obtain a mixture; and mixing the mixture with the coating material to obtain a cabazitaxel self-emulsifying liquid-solid powder.

[0057] In this invention, the method of mixing the cabazitaxel self-emulsifying agent with the carrier preferably includes: adding the cabazitaxel self-emulsifying agent dropwise onto the carrier and grinding it until the cabazitaxel self-emulsifying agent is completely absorbed by the carrier.

[0058] In this invention, the preferred method for mixing the mixture with the coating material is grinding. In this invention, when the cabazitaxel self-emulsifying agent is mixed sequentially with the carrier and the coating material using the above method, the cabazitaxel self-emulsifying agent is completely absorbed by the carrier and then coated, improving the flowability of the cabazitaxel self-emulsifying liquid-solid powder.

[0059] After obtaining the self-emulsifying liquid-solid powder of cabazitaxel, the present invention mixes the self-emulsifying liquid-solid powder of cabazitaxel with an adjuvant, compresses it to obtain a tablet core, and then coats the tablet core with an enteric coating material to obtain a cabazitaxel liquid-solid compressed enteric tablet.

[0060] The present invention does not have any particular limitation on the method of mixing the self-emulsifying liquid-solid powder of cabazitaxel with the additives. Any solid mixing method known to those skilled in the art can be used to mix the above components evenly.

[0061] This invention does not specifically limit the tableting method; any tableting method well-known to those skilled in the art can be used. Preferably, the tableting method includes: mixing cabazitaxel self-emulsifying liquid-solid powder with excipients according to the formula to obtain a powder, which is used as a bottom layer powder, an intermediate layer powder, and a top layer powder; pre-compressing the bottom layer powder on a tablet press to obtain a bottom layer; placing the intermediate layer powder on the bottom layer and pre-compressing it to form an intermediate layer on the bottom layer; placing the top layer powder on the intermediate layer and pressing the entire mixture to obtain a tablet core. In this invention, the composition of the top layer powder and the bottom layer powder is the same, and the amount of filler in the intermediate layer powder is lower than that in the top or bottom layer. In this invention, the preferred mass ratio of filler, cabazitaxel self-emulsifying liquid-solid powder, disintegrant, and lubricant in the upper and lower layer powders is (30-80):(10-40):(1-5):(0.1-1.0), more preferably (50-70):(20-30):(3-4):(0.5-1.0); the preferred mass ratio of filler, cabazitaxel self-emulsifying liquid-solid powder, disintegrant, and lubricant in the middle layer powder is (10-40):(25-80):(1-5):(0.1-1.0), more preferably (20-40):(25-70):(3-4):(0.5-1.0). In this invention, when the mass ratio of filler to carbazide self-emulsifying liquid-solid powder in the upper and lower layers of powder, and the mass ratio of filler, carbazide self-emulsifying liquid-solid powder, disintegrant, and lubricant in the middle layer of powder are within the above-mentioned ranges, the filler content in the upper and lower layers of the tablet core is relatively high, which enables the tablet core to have higher hardness and prevents the tablet core from breaking; the carbazide self-emulsifying liquid-solid powder content in the middle layer of powder is relatively high, which enables the tablet core to have a higher drug loading.

[0062] After obtaining the tablet core, the present invention uses an enteric coating material to coat the tablet core to obtain cabazitaxel liquid-solid compressed enteric tablets.

[0063] This invention does not specifically limit the coating method and process parameters; any enteric coating method and process parameters well-known to those skilled in the art can be used. In this invention, the preferred coating process parameters include: Eudragit L30D-55 as the coating material, a feed amount of 20–100 g, a spray gun height of 10–12 cm, an inlet air temperature of 50–60 °C, and a liquid supply rate of 2–4 r / min. -1 The fan speed is 1500~2000 r·min -1 The main engine speed is 7-10 r / min -1The pressure of the ejector pin is 0.15–0.30 MPa, the atomization pressure is 0.15–0.30 MPa, and the pressure of the fan surface is 0.1–0.3 MPa; more preferably, the feed rate is 30–50 g, the spray gun height is 10 cm, the air inlet temperature is 50 °C, and the liquid supply rate is 2.1–3 r / min. -1 The fan speed is 1500 r·min -1 The main engine speed is 7-10 r / min -1 The ejector pin pressure is 0.3 MPa, the atomization pressure is 0.17–0.2 MPa, and the fan-shaped pressure is 0.22–0.3 MPa. In this invention, when the coating process parameters are within the above range, a continuous, firm, and smooth coating layer can be formed, which is beneficial for improving the stability of carbataxel liquid-solid compressed enteric tablets.

[0064] The method provided by this invention is simple to operate and can obtain stable quality cabazitaxel liquid-solid compressed enteric tablets. Furthermore, the self-emulsified liquid-solid powder of cabazitaxel in the enteric tablets has excellent solubility, which can solve the problem of poor solubility of cabazitaxel.

[0065] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0066] Example 1

[0067] The preparation method of cabazitaxel liquid-solid compressed enteric tablets includes the following steps:

[0068] (1) Accurately weigh 300 mg of Tween 80, 150 mg of monooleate, and 550 mg of tricaprylate into a round-bottom flask, add 4 mL of anhydrous ethanol, and vortex thoroughly. Then add 55 mg of cabazitaxel raw material, dissolve by sonication, and remove the anhydrous ethanol by rotary evaporation at 50°C for 1 h to prepare a self-emulsifying cabazitaxel formulation. The mass ratio of cabazitaxel, Tween 80, monooleate, and tricaprylate is 5.5:30:15:55.

[0069] (2) Weigh the carrier material SyloidXDP3050 into a mortar, and accurately weigh an equal amount of cabazitaxel self-emulsifying agent and add it dropwise to the powder (Lf = 1.0). Grind until the cabazitaxel self-emulsifying agent is completely absorbed. Accurately weigh the coating material Syloid244FP and add it to the mortar (R = 20). Continue grinding until homogeneous to obtain the cabazitaxel self-emulsifying liquid-solid powder.

[0070] (3) Mix the self-emulsifying liquid-solid powder of cabazitaxel obtained in step (2) with the additives, accurately weigh the self-emulsifying liquid-solid powder of cabazitaxel obtained in step (2), mix it evenly with MCC PH102, CCMC-Na and magnesium stearate, and add the powder in three batches for tableting. Specifically: bottom layer powder, middle layer powder, and top layer powder were prepared separately. The composition of the bottom layer powder, middle layer powder, and top layer powder is shown in Table 1. The mass ratio of cabazitaxel self-emulsifying liquid-solid powder to additives is 350:290. The mass ratio of filler (MCCPH102), cabazitaxel self-emulsifying liquid-solid powder, disintegrant (CCMC-Na), and lubricant (MgSt) in the top layer powder and bottom layer powder is 60:30:3:0.6. The mass ratio of filler (MCCPH102), cabazitaxel self-emulsifying liquid-solid powder, disintegrant (CCMC-Na), and lubricant (MgSt) in the middle layer powder is 14.5:29:1.5:0.28. The bottom layer powder is pre-compressed on a tablet press to obtain the bottom layer; the middle layer powder is placed on the bottom layer and pre-compressed to form the middle layer on the bottom layer; the top layer powder is placed on the middle layer and pre-compressed to form the top layer on the middle layer; then the tablets obtained after the three pre-compressions are pressed as a whole to obtain the tablet core.

[0071] Table 1: Composition of powder in each layer

[0072] Upper / lower layers Intermediate layer Cabazitaxel self-emulsifying liquid-solid powder 30mg 290mg MCCPH102 60mg 145mg CCMC-Na 3mg 15mg MgSt 0.6mg 2.8mg

[0073] The obtained tablet cores were coated with Eudragit L30D-55 as the coating material, resulting in a 7% weight gain. This yielded cabazitaxel liquid-solid compressed enteric-coated tablets. The enteric coating process was as follows: feed rate 30g, spray gun height 10cm, inlet air temperature 50℃, and liquid delivery rate 2.1r·min. -1 The fan speed is 1500 r·min -1 The main engine speed is 7-10 r / min -1 The pressure of the ejector pin is 0.3 MPa, the pressure of atomization is 0.17 MPa, and the pressure of the fan surface is 0.22 MPa.

[0074] Example 2

[0075] The difference from Example 1 is that the coating weight gain in step (3) is 9%.

[0076] Test Example 1

[0077] (1) Detection of the self-emulsifying cabazitaxel preparation (CTX-SEDDS) prepared in step (1) of Example 1:

[0078] (a) Particle size and zeta potential of the self-emulsifying formulation of cabazitaxel:

[0079] The self-emulsifying formulation of cabazitaxel prepared in step (1) of Example 1 was added to purified water at 37±0.5℃ and gently stirred to prepare a homogeneous and clear microemulsion. The microemulsion prepared by diluting the self-emulsifying formulation of cabazitaxel was measured using a Malvern laser particle size analyzer, and the particle size distribution was obtained as shown in the figure. Figure 1 As shown, the Zeta potential diagram is as follows: Figure 2 As shown. From Figure 1 and Figure 2 It can be seen that the self-emulsifying carbamate preparation prepared in Example 1 forms microemulsions with a particle size of 140.87±0.85nm, a PDI of 0.166±0.02, and a Zeta potential of -18.60±0.26mV (n=3) in water, which can improve the solubility of carbamate in water.

[0080] (b) Micromorphology of self-emulsifying cabazitaxel formulation

[0081] The self-emulsifying carbazone preparation prepared in step (1) of Example 1 was diluted to an appropriate ratio. One drop of the sample was placed on a copper grid and allowed to stand for about 10 minutes to air dry. Then, one drop of a 3% phosphotungstic acid solution was added to the copper grid for negative staining for about 3 minutes. Excess stain was absorbed with filter paper, and the sample was allowed to air dry. The microstructure of the emulsion was observed using a JEM1200EX transmission electron microscope. The resulting TEM image of the self-emulsifying carbazone preparation is shown below. Figure 3 As shown. From Figure 3 As can be seen, the self-emulsifying cabazitaxel preparation in Example 1 produces spherical droplets with a uniform morphological distribution and a particle size of about 140 nm. The smaller particle size is more conducive to improving the solubility of cabazitaxel.

[0082] (c) Take an appropriate amount of the self-emulsified cabazitaxel preparation prepared in step (1) of Example 1, dilute it with methanol, filter it through a 0.45 μm filter membrane, and determine the drug content by HPLC. After injection analysis, the cabazitaxel drug content (i.e., drug loading) determined by the external standard method was 49.82 ± 0.34 mg·g. -1 .

[0083] (2) Detection of the self-emulsified liquid-solid powder of cabazitaxel prepared in step (2) of Example 1:

[0084] (a) Flowability and compressibility of cabazitaxel self-emulsified liquid-solid powder

[0085] The cabazitaxel self-emulsifying liquid-solid powder prepared in step (2) of Example 1 has a liquid loading coefficient Lf = 1.0 and R = 20, an angle of repose of less than 40°, a Karl index of less than 25%, and a Hausner ratio close to 1.25, indicating good powder flowability. Direct compression of this liquid-solid powder yielded tablets with a hardness of 63.00 N, demonstrating good powder compressibility.

[0086] (b) Redispersibility of Cabazitaxel self-emulsifying liquid-solid powder

[0087] Cabazitaxel self-emulsified solid powder was added to purified water at 37±0.5℃ and gently stirred until fully emulsified. A sample was then filtered through a 0.45μm filter membrane. The filtrate was collected and its appearance was observed. Simultaneously, its particle size, PDI, and Zeta potential were measured using a Malvern laser particle size analyzer. The resulting particle size distribution is shown in the figure below. Figure 4 As shown, the Zeta potential diagram is as follows: Figure 5 As shown. The results indicate that the cabazitaxel self-emulsifying liquid-solid powder can be redispersed in the medium. After filtering out the insoluble components, the solution is a clear, slightly bluish, homogeneous liquid. The particle size of the microemulsion in the medium was measured to be 162.23±4.86 nm using a Malvern particle size analyzer, the polydispersity index (PDI) was 0.175±0.037, and the zeta potential was -18.45±1.63 mV. This indicates that the cabazitaxel self-emulsifying formulation prepared in step (1) of Example 1, after being prepared into a cabazitaxel self-emulsifying liquid-solid powder, still retains its good water solubility.

[0088] (3) SEM analysis

[0089] The test subjects were: cabazitaxel active pharmaceutical ingredient (CTX), physical mixture of cabazitaxel active pharmaceutical ingredient and carrier material, carrier material (SyloidXDP3050), blank self-emulsifying liquid-solid powder (BlankS-SEDDS), and cabazitaxel self-emulsifying liquid-solid powder (CTXS-SEDDS).

[0090] The cabazitaxel active pharmaceutical ingredient is the cabazitaxel used in Example 1;

[0091] Physical mixture of cabazitaxel active pharmaceutical ingredient and carrier material: obtained by directly grinding the cabazitaxel active pharmaceutical ingredient used in Example 1 and the carrier material used in Example 1;

[0092] The carrier material is SyloidXDP3050, which was used in Example 1;

[0093] Blank self-emulsifying liquid-solid powder: prepared by the same method as steps (1) and (2) of Example 1, except that no cabazitaxel raw material was added when preparing the self-emulsifying preparation in step (1);

[0094] The self-emulsified liquid-solid powder of cabazitaxel was prepared in step (2) of Example 1.

[0095] Detection method: Cabazitaxel active pharmaceutical ingredient (API), a physical mixture of cabazitaxel API and carrier material, the carrier material, a blank self-emulsifying liquid-solid powder, and a cabazitaxel self-emulsifying liquid-solid powder sample were placed on conductive tape on a lead plate and observed using a scanning electron microscope (SEM). The SEM images are shown below. Figure 6 As shown. In Figure 6 In Figure 6, A is the SEM image of the cabazitaxel active pharmaceutical ingredient (API), B is the SEM image of the carrier material, C is the SEM image of the physical mixture of the API and the carrier material, D is the SEM image of the blank self-emulsifying liquid-solid powder, and E is the SEM image of the cabazitaxel self-emulsifying liquid-solid powder. As can be seen from Figure 6, the cabazitaxel API consists of plate-like crystals of varying sizes. The carrier material exhibits a porous solid structure with a relatively uniform morphology. Drug crystals dispersed around the carrier particles can be observed in the physical mixture, while no cabazitaxel drug crystals were found in the blank self-emulsifying liquid-solid powder or the cabazitaxel self-emulsifying liquid-solid powder. The two have similar appearances, and the surface of the carrier material appears roughened from grinding, with some grinding debris scattered around it. It can be inferred that the cabazitaxel self-emulsifying formulation is loaded into the internal pores of the carrier material, and the drug exists in an amorphous or molecular state.

[0096] (4) DSC analysis

[0097] The tested substances were: cabazitaxel active pharmaceutical ingredient (CTX), physical mixtures of cabazitaxel active pharmaceutical ingredient and carrier material, carrier material (SyloidXDP3050), blank self-emulsifying liquid-solid powder (BlankS-SEDDS), and cabazitaxel self-emulsifying liquid-solid powder (CTXS-SEDDS). (All samples were the same as those used in the SEM analysis of this test example.)

[0098] Cabazitaxel active pharmaceutical ingredient (API), a physical mixture of cabazitaxel API and carrier material, the carrier material, a blank self-emulsifying liquid-solid powder, and a cabazitaxel self-emulsifying liquid-solid powder were used as samples. After sieving, approximately 10 mg of the uniform powder from each sample was placed in a crucible. A blank crucible was used as a reference for scanning. Experimental parameters: nitrogen was used as the protective gas, and the heating rate was 10.00 °C / min. -1 The scanning temperature was 30–200℃. The obtained DSC results are as follows: Figure 7 As shown.

[0099] from Figure 7It can be seen that the cabazitaxel active pharmaceutical ingredient exhibits a distinct endothermic peak around 150℃, indicating that cabazitaxel begins to melt at this temperature. This characteristic peak is not observed in the liquid-solid powder obtained by adsorbing the blank self-emulsifying formulation with SyloidXDP3050. However, the differential scanning calorimetry (DSC) of the physical mixture shows an endothermic peak near 150℃, indicating that cabazitaxel still exists in a crystalline state within the mixture. The liquid-solid powder obtained by adsorbing the cabazitaxel self-emulsifying formulation using SyloidXDP3050 as a carrier material does not exhibit a drug-induced endothermic peak, and its image is similar to that of the blank self-emulsifying formulation. Therefore, it can be determined that cabazitaxel exists in an amorphous or molecular state in the liquid-solid powder of the cabazitaxel self-emulsifying formulation.

[0100] (5) PXRD analysis

[0101] Test subjects: Cabazitaxel active pharmaceutical ingredient (CTX), physical mixture of cabazitaxel active pharmaceutical ingredient and carrier material, carrier material (SyloidXDP3050), blank self-emulsifying liquid-solid powder (BlankS-SEDDS), and cabazitaxel self-emulsifying liquid-solid powder (CTXS-SEDDS).

[0102] Using Cu-Ka as the target source, with a tube voltage of 40 kV and a tube current of 100 mA, XRD analysis was performed on cabazitaxel active pharmaceutical ingredient (API), physical mixtures of cabazitaxel API and carrier materials, carrier materials, blank self-emulsifying liquid-solid powder, and cabazitaxel self-emulsifying liquid-solid powder. The 2θ scan range was 3–50°, and the scan rate was 8°·min. -1 With a step size of 0.02°, the XRD pattern is obtained as follows. Figure 8 As shown. From Figure 8 It can be seen that the active pharmaceutical ingredient (API) cabazitaxel and the physical mixture of cabazitaxel and the carrier both showed several high-intensity characteristic diffraction peaks at different diffraction angles, reflecting that the API cabazitaxel exists in a crystalline state; while Syloid XDP3050 did not show any sharp diffraction peaks; compared with the two sets of powder XRD patterns of the drug and the physical mixture, the X-ray diffraction pattern of the self-emulsified liquid-solid powder of cabazitaxel is similar to that of the blank SEDDS, and all the diffraction peaks of the drug crystals have disappeared. This confirms that the drug cabazitaxel exists in a molecular or amorphous state in the liquid-solid powder, indicating that the self-emulsified cabazitaxel formulation is absorbed by the carrier material and embedded in its internal pores.

[0103] (6) FTIR analysis

[0104] Test subjects: Cabazitaxel active pharmaceutical ingredient (CTX), physical mixture of cabazitaxel active pharmaceutical ingredient and carrier material, carrier material (SyloidXDP3050), blank self-emulsifying liquid-solid powder (BlankS-SEDDS), and cabazitaxel self-emulsifying liquid-solid powder (CTXS-SEDDS).

[0105] Samples were prepared from the following: cabazitaxel active pharmaceutical ingredient (API), a physical mixture of cabazitaxel API and carrier material, the carrier material, a blank self-emulsifying liquid-solid powder, and a cabazitaxel self-emulsifying liquid-solid powder. Measurement conditions were set as follows: Scan range: 400–4000 cm⁻¹ -1 Resolution: 2cm -1 The FTIR spectrum obtained by KBr pelleting is shown below. Figure 9 As shown, the possible chemical interactions between the drug and the carrier are studied by observing the shifts or changes in the width of characteristic peaks in the infrared spectrum. From... Figure 9 It can be seen that no significant decrease in the intensity of the characteristic peak of cabazitaxel was observed in the infrared spectrum of the physical mixture of cabazitaxel and the carrier material. Furthermore, the characteristic peak of cabazitaxel in the infrared spectrum of the self-emulsified liquid-solid powder did not shift; only the absorption intensity changed. This indicates that the preparation of the self-emulsified liquid-solid powder of cabazitaxel does not affect the structure of cabazitaxel.

[0106] Comparative Example 1

[0107] The difference from Example 1 is that the coating weight gain in step (3) is 3%.

[0108] Comparative Example 2

[0109] The difference from Example 1 is that the coating weight gain in step (3) is 5%.

[0110] Test Example 2

[0111] The dissolution rate of the cabazitaxel liquid-solid compressed enteric tablets prepared in Examples 1-2 and Comparative Examples 1-2 was tested.

[0112] (1) Dissolution of cabazitaxel liquid-solid compressed enteric tablets in hydrochloric acid (pH 1.0)

[0113] Measure 0.1 mol·L -1 900 mL of hydrochloric acid solution was poured into four dissolution vessels. Once the temperature of the dissolution medium was constant at 37 ± 0.5 °C, six tablets each from Examples 1-2 and Comparative Examples 1-2 were added to the four dissolution vessels, taking care to avoid surface bubble formation. The rotation speed was set to 75 r·min. -1Samples were taken at 5, 15, 30, 45, 60, 90, and 120 min, with a sample volume of 5 mL each time. The isothermal and equal-volume dissolution medium was replenished promptly. The samples were filtered through a 0.45 μm microporous membrane, the initial filtrate was discarded, and subsequent filtrates were diluted with methanol to an appropriate concentration. 10 μL of each subsequent filtrate was accurately pipetted and analyzed by HPLC. The peak areas were recorded, and the cumulative dissolution rate at each time point was calculated using the external standard method. The results are as follows: Figure 10 As shown. From Figure 10 It can be seen that tablets with a coating weight gain of 3% and 5% experienced enteric coating damage and drug leakage within 2 hours, with more than 10% of the drug released within 2 hours; tablets with a coating weight gain of 7% and 9% were more stable.

[0114] (2) Dissolution of cabazitaxel liquid-solid compressed enteric tablets in phosphate buffer (pH 6.8)

[0115] Tablets with 7% and 9% weight gain from coating were selected for further testing. The acid solutions in each dissolution vessel were discarded, and 900 mL of phosphate buffer (pH 6.8) at 37 ± 0.5 °C was immediately added. It was determined that adding 0.06% sodium dodecyl sulfate (SDS) could achieve the desired dissolution conditions; therefore, 0.06% SDS was selected as the medium. The rotation speed was set to 75 r / min. -1 Samples were taken at 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, and 6 h, with a sample volume of 5 mL each time. The isothermal and equal-volume dissolution medium was replenished promptly. The samples were filtered through a 0.45 μm microporous membrane, the initial filtrate was discarded, and subsequent filtrates were diluted with methanol to an appropriate concentration. 10 μL of each subsequent filtrate was accurately pipetted and analyzed by HPLC. The peak areas were recorded, and the cumulative dissolution rate at each time point was calculated using the external standard method. The dissolution curves are shown below. Figure 11 As shown. From Figure 11 It can be seen that both formulations can be completely released within 2 hours; compared with the tablet with a coating weight gain of 9%, the tablet with a coating weight gain of 7% has a faster release rate, and the cumulative dissolution rate reaches 95% in 1 hour.

[0116] Comparative Example 3

[0117] (1) Blank SEDDS were prepared according to the method of step (1) in Example 1, except that cabazitaxel raw material was not added.

[0118] (2) Weigh 1g each of the traditional materials microcrystalline cellulose, starch, lactose, and the novel materials Syloid244FP, SyloidXDP3050, and SyloidXDP3150 into a mortar. Weigh blank SEDDS and add it dropwise into the mortar (Lf is 0.2 for all materials). Grind until the SEDDS is completely absorbed to obtain a liquid-solid powder. Measure the flowability of the liquid-solid powder after different materials adsorb SEDDS in the same proportion. The results are shown in Table 2.

[0119] Table 2: Flowability of liquid-solid powders after adsorption of SEDDS on different carriers

[0120]

[0121] Table 2 shows that when Lf = 0.2, the liquid-solid powders prepared by adsorption of SyloidXDP3050 and XDP3150 have better flowability, while the liquid-solid powders prepared by adsorption of MCC, starch, lactose, and Syloid244FP have poor flowability. The results indicate that SyloidXDP3050 and XDP3150 have better adsorption capacity than the other materials.

[0122] Comparative Example 4

[0123] Using SyloidXDP3050 as the carrier material and Syloid244FP as the coating material, according to the formula designed in Table 3, the prescribed amount of SyloidXDP3050 was weighed into a mortar, and blank SEDDS was accurately weighed and added drop by drop into the mortar (Lf = 1.2). The mixture was ground until the SEDDS was completely absorbed. Syloid244FP was accurately weighed into the mortar with an R value of 10, and the mixture was ground until homogeneous to obtain a liquid-solid powder, designated as LS1.

[0124] Comparative Example 5

[0125] Liquid-solid powder was prepared according to the formulation designed in Table 3, and was numbered LS2. The difference between LS2 and Comparative Example 4 is that Lf is 1.2 and R is 15. The test results are shown in Table 4.

[0126] Comparative Example 6

[0127] Liquid-solid powder was prepared according to the formulation designed in Table 3, and was numbered LS3. The difference between LS3 and Comparative Example 4 is that Lf is 1.2 and R is 20. The test results are shown in Table 4.

[0128] Comparative Example 7

[0129] Liquid-solid powder was prepared according to the formulation designed in Table 3, numbered LS4. The difference from Comparative Example 4 is that Lf is 1.2 and R is 25. The test results are shown in Table 4.

[0130] Comparative Example 8

[0131] Liquid-solid powder was prepared according to the formulation designed in Table 3, numbered LS5. The difference from Comparative Example 4 is that Lf is 1 and R is 10. The test results are shown in Table 4.

[0132] Comparative Example 9

[0133] Liquid-solid powder was prepared according to the formulation designed in Table 3, numbered LS6. The difference from Comparative Example 4 is that Lf is 1 and R is 15. The test results are shown in Table 4.

[0134] Comparative Example 10

[0135] Liquid-solid powder was prepared according to the formulation designed in Table 3, numbered LS7. The difference from Comparative Example 4 is that Lf is 1 and R is 20. The test results are shown in Table 4.

[0136] Comparative Example 11

[0137] Liquid-solid powder was prepared according to the formulation designed in Table 3, numbered LS8. The difference from Comparative Example 4 is that Lf is 1 and R is 25. The test results are shown in Table 4.

[0138] Comparative Example 12

[0139] Liquid-solid powder was prepared according to the formulation designed in Table 3, numbered LS9. The difference from Comparative Example 4 is that Lf is 0.8 and R is 10. The test results are shown in Table 4.

[0140] Comparative Example 13

[0141] Liquid-solid powder was prepared according to the formulation designed in Table 3, numbered LS10. The difference from Comparative Example 4 is that Lf is 0.8 and R is 15. The test results are shown in Table 4.

[0142] Comparative Example 14

[0143] Liquid-solid powder was prepared according to the formulation designed in Table 3, numbered LS11. The difference from Comparative Example 4 is that Lf is 0.8 and R is 20. The test results are shown in Table 4.

[0144] Comparative Example 15

[0145] Liquid-solid powder was prepared according to the formulation designed in Table 3, numbered LS12. The difference from Comparative Example 4 is that Lf is 0.8 and R is 25. The test results are shown in Table 4.

[0146] Table 3 Comparative Examples 4-15 Prescriptions

[0147]

[0148]

[0149] Test Example 3

[0150] The flowability of the liquid-solid powders prepared in Comparative Examples 4–15 was evaluated by measuring and calculating the angle of repose, Hausner ratio, and Karl elliptic index. The compressibility of the liquid-solid powders was assessed by compressing them into tablets at the same pressure for 3 seconds using a tableting machine and measuring the tablet hardness. The test results are shown in Table 4.

[0151] Table 4. Performance test results of the liquid-solid powders prepared in Comparative Examples 4–15

[0152]

[0153] As shown in Table 4, although the liquid-solid powder has the highest SEDDS loading at Lf = 1.2, the powder viscosity is high and the flowability is poor, making it difficult to use for tablet preparation. As the liquid SEDDS adsorption decreases, the flowability and compressibility of the liquid-solid powder gradually improve. The liquid-solid powders prepared at Lf = 1.0 and Lf = 0.8 have the best flowability and compressibility. Compared with Lf = 1.0, the amount of SEDDS loaded at Lf = 1.0 is higher. Considering both the SEDDS loading and powder properties, the liquid loading coefficients Lf = 1.0 and R = 20 are more conducive to preparing cabazitaxel liquid-solid compressed enteric tablets with good overall performance.

[0154] Comparative Example 16

[0155] The difference from Example 1 is that in step (3), the tablet core is prepared according to the prescription in Table 5, but the tablet core is not coated. The remaining steps are the same as in Example 1, and the obtained tablet core is numbered F1.

[0156] Comparative Example 17

[0157] The difference from Comparative Example 16 is that in step (3), the tablet core was prepared according to the prescription in Table 5, and the obtained tablet core was numbered F2.

[0158] Comparative Example 18

[0159] The difference from Comparative Example 16 is that in step (3), the tablet core was prepared according to the prescription in Table 5, and the obtained tablet core was numbered F3.

[0160] Comparative Example 19

[0161] The difference from Comparative Example 16 is that in step (3), the tablet core was prepared according to the prescription in Table 5, and the obtained tablet core was numbered F4.

[0162] Comparative Example 20

[0163] The difference from Comparative Example 16 is that in step (3), the tablet core was prepared according to the prescription in Table 5, and the obtained tablet core was numbered F5.

[0164] Comparative Example 21

[0165] The difference from Comparative Example 16 is that in step (3), the tablet core was prepared according to the prescription in Table 5, and the obtained tablet core was numbered F6.

[0166] Comparative Example 22

[0167] The difference from Comparative Example 16 is that in step (3), the tablet core was prepared according to the prescription in Table 5, and the obtained tablet core was numbered F7.

[0168] Comparative Example 23

[0169] The difference from Comparative Example 16 is that in step (3), the tablet core was prepared according to the prescription in Table 5, and the obtained tablet core was numbered F8.

[0170] Table 5. Formulations for different types and amounts of fillers in Comparative Examples 16–23

[0171]

[0172]

[0173] Test Example 4

[0174] Tablet cores prepared according to the formulations of Comparative Examples 16–23 were tested, and the performance results of the tablet cores with different types and amounts of fillers are shown in Table 6.

[0175] Table 6. Performance test results of the tablet cores prepared according to the formulations of Comparative Examples 16–23

[0176]

[0177] As shown in Table 6, Formula 3, using MCCKG802 as a filler, has poorer powder flowability than Formula 2, which uses MCCPH102; Formula 4, using pregelatinized starch, has too little tablet hardness and too much fine powder; and some tablets in Formulas 5-7 cracked. Therefore, using MCCKG802 and MCCPH102 as fillers can improve powder flowability and give the tablet core better hardness.

[0178] Comparative Example 24

[0179] The difference from Example 1 is that in step (3), the mass of the cabazitaxel self-emulsifying liquid-solid powder in the middle layer is 280 mg, and the mass of MCCPH102 is 140 mg. Furthermore, the mass of the cabazitaxel self-emulsifying liquid-solid powder in the upper / lower layers is 30 mg, and the mass of MCCPH102 is 60 mg, designated as Formula F9. The tablet core was prepared according to step (3) of Example 1, but without coating. The remaining steps were the same as in Example 1.

[0180] Comparative Example 25

[0181] The difference from Comparative Example 24 is that the mass of the self-emulsified solid powder of cabazitaxel in the upper / lower layer is 40 mg, the mass of MCCPH102 is 80 mg, and the formula is designated as F10. The rest of the steps are the same as those in Comparative Example 24.

[0182] Comparative Example 26

[0183] The difference from Comparative Example 24 is that the mass of the self-emulsified solid powder of cabazitaxel in the upper / lower layers is 50 mg, the mass of MCCPH102 is 100 mg, and the formula is designated as F11. The remaining steps are the same as those in Comparative Example 24.

[0184] Test Example 5

[0185] The wafer cores obtained from comparative examples 24 to 26 were tested, and the results are shown in Table 7.

[0186] Table 7 shows the performance test results of the wafer cores obtained in Comparative Examples 24-26.

[0187]

[0188] As shown in Table 7, the F9 tablet has a hardness of over 80N and a friability of 0.74%, which meets the requirements. Since the upper and lower layers have a larger proportion of MCC, under the premise of a fixed tablet weight, the thinner the upper and lower layers and the thicker the middle layer, the higher the liquid-solid powder content. Therefore, while meeting the requirements for hardness and friability, F9 carries more liquid-solid powder than F10 and F11, which are loaded with CTX-SEDDS. Thus, the mass ratio of liquid-solid powder to MCCPH102 in the upper and lower layers is 1:2, and the F9 tablet better ensures the hardness of the tablet core.

[0189] Comparative Example 27

[0190] The difference from Comparative Example 24 is that the mass of the cabazitaxel self-emulsifying liquid-solid powder in the intermediate layer of step (3) is 200 mg, and the mass of MCCPH102 is 100 mg. The remaining steps are the same as those in Comparative Example 24. The resulting core is numbered F12.

[0191] Comparative Example 28

[0192] The difference from Comparative Example 27 is that the mass of the cabazitaxel self-emulsifying liquid-solid powder in the intermediate layer of step (3) is 225 mg, and the mass of MCCPH102 is 75 mg. The remaining steps are the same as those in Comparative Example 27. The resulting core is numbered F13.

[0193] Comparative Example 29

[0194] The difference from Comparative Example 28 is that the mass of the cabazitaxel self-emulsifying liquid-solid powder in the intermediate layer of step (3) is 240 mg, and the mass of MCCPH102 is 60 mg. The remaining steps are the same as those in Comparative Example 28. The resulting core is numbered F14.

[0195] Comparative Example 30

[0196] The difference from Comparative Example 29 is that the mass of the cabazitaxel self-emulsifying liquid-solid powder in the intermediate layer of step (3) is 250 mg, and the mass of MCCPH102 is 50 mg. The remaining steps are the same as those in Comparative Example 29. The resulting core is numbered F15.

[0197] Test Example 6

[0198] The wafer cores prepared in Comparative Examples 27–30 were tested, and the test results are shown in Table 8.

[0199] Table 8: Test results of the wafer cores prepared in Comparative Examples 27-30

[0200]

[0201] As can be seen from Table 8, when the ratio of MCC to liquid-solid powder is greater than 1:2, a flaking phenomenon will occur. This may be due to insufficient adhesion between particles. Therefore, the ratio of MCC to liquid-solid powder in the intermediate layer is determined to be 1:2.

[0202] As can be seen from the test results of the above embodiments and comparative examples, the cabazitaxel self-emulsifying liquid-solid powder in the cabazitaxel liquid-solid compressed enteric-coated tablets provided by the present invention has excellent solubility, which can solve the problem of poor solubility of cabazitaxel self-emulsifying liquid-solid powder. Furthermore, after the cabazitaxel self-emulsifying liquid-solid powder is prepared into cabazitaxel liquid-solid compressed enteric-coated tablets, it exhibits excellent stability, ensuring that the cabazitaxel liquid-solid compressed enteric-coated tablets are not destroyed before reaching the intestines.

[0203] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A cabazitaxel liquid-solid compressed enteric-coated tablet, comprising cabazitaxel self-emulsifying liquid-solid powder, excipients, and enteric coating material, characterized in that, The cabazitaxel self-emulsifying liquid-solid powder includes a cabazitaxel self-emulsifying agent, a carrier, and a coating; The liquid loading coefficient of the cabazitaxel self-emulsifying liquid-solid powder is 0.8~1.0; the mass ratio of the carrier to the coating is 10~20:1; The self-emulsifying cabazitaxel formulation is composed of cabazitaxel, Tween 80, monooleate glyceryl ester and tricaprylate glyceryl ester, wherein the mass ratio of cabazitaxel, Tween 80, monooleate glyceryl ester and tricaprylate glyceryl ester is (0.5~10):(20~55):(10~30):(30~90); The additives include one or more of fillers, disintegrants, and lubricants; The carrier includes SyloidXDP3050 or XDP3150; The coating includes Syloid244FP; The formula for calculating the liquid load factor is shown in equation (1): Lf=W / Q (Equation (1)) In the formula (1), Lf is the liquid loading coefficient, W is the mass of the self-emulsifying carbamate, and Q is the mass of the carrier.

2. The cabazitaxel liquid-solid compressed enteric-coated tablet according to claim 1, characterized in that, The mass ratio of the cabazitaxel, Tween 80, monooleic glyceride and trioctyl glyceride is (5~10):(30~50):(20~30):(50~90).

3. The cabazitaxel liquid-solid compressed enteric-coated tablet according to claim 1, characterized in that, The filler includes MCCPH102, MCCKG802, or pregelatinized starch.

4. The cabazitaxel liquid-solid compressed enteric-coated tablet according to claim 1 or 2, characterized in that, The mass ratio of the self-emulsifying liquid solid powder and the additives in the cabazitaxel is (300~400):(250~350).

5. The cabazitaxel liquid-solid compressed enteric-coated tablet according to claim 1 or 2, characterized in that, The weight gain of the coating of the cabazitaxel liquid-solid compressed enteric tablets is 7-9%.

6. A method for preparing the cabazitaxel liquid-solid compressed enteric-coated tablets according to any one of claims 1 to 5, comprising the following steps: (1) Cabazitaxel, Tween 80, glyceryl monooleate and glyceryl trioctanoate were mixed to obtain a self-emulsifying formulation of cabazitaxel. (2) The cabazitaxel self-emulsifying formulation obtained in step (1) is mixed sequentially with the carrier and coating material to obtain cabazitaxel self-emulsifying liquid-solid powder; (3) The self-emulsifying liquid-solid powder of cabazitaxel obtained in step (2) is mixed with an adjuvant and compressed into a tablet core. Then, the tablet core is coated with an enteric coating material to obtain a cabazitaxel liquid-solid compressed enteric tablet.

7. The preparation method according to claim 6, characterized in that, The mixing in step (2) includes: mixing the cabazitaxel self-emulsifying agent with a carrier so that the cabazitaxel self-emulsifying agent is completely absorbed by the carrier to obtain a mixture; and mixing the mixture with a coating material to obtain a cabazitaxel self-emulsifying liquid-solid powder.

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