Co-crystal of cabazitaxel and plant essential oil active ingredients as well as preparation method and application of co-crystal

Abstract

The invention discloses a co-crystal of cabazitaxel and plant essential oil active ingredients as well as a preparation method and application of the co-crystal. The co-crystal provided by the invention is a co-crystal formed by self-assembling raw materials including cabazitaxel and plant essential oil active ingredients. Mixing cabazitaxel and plant essential oil to form a material to be crystallized; and performing crystallization treatment to obtain the eutectic crystal of cabazitaxel and plant essential oil active ingredients. According to the cabazitaxel-plant essential oil active component eutectic, the problems that a solvent is easily removed from a cabazitaxel solvate in the heating or long-term storage process to cause component change or crystal form conversion and cabazitaxel in a solvent-free form easily absorbs moisture in the long-term storage process are solved, and the stability of cabazitaxel is improved. Meanwhile, the inhibition effect of the co-crystal on tumor cells is remarkably improved, and the anti-tumor activity of cabazitaxel can be further improved. In conclusion, the eutectic crystal of cabazitaxel and plant essential oil active ingredients has good stability, does not have solvent toxicity, is relatively high in safety, and can better meet the patent medicine requirements in the aspects of production, quality control, clinical application and the like.

Description

Technical Field

[0001] This invention relates to the technical field of medicinal chemistry, and more specifically, to the cocrystal of cabazitaxel and active ingredients of plant essential oils, their preparation methods, and applications. Background Technology

[0002] Cabazitaxel, a taxane-based antitumor drug, possesses significant anticancer and antileukemic activity and was approved by the FDA on June 17, 2010. Its chemical name is 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotaxane-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, with the molecular formula C2. 45 H 57 NO 14 The structural formula is as follows:

[0003]

[0004] Due to its excellent therapeutic effects, cabazitaxel's solid form has been extensively studied, resulting in the discovery of numerous solvates, amorphous forms, hydrates, and other amorphous compounds. Patent WO2005028462, issued by Aventis Pharmaceuticals, reported an acetone solvate of cabazitaxel (containing 6.5% acetone by mass). WO2009115655, also issued by Aventis Pharmaceuticals, further disclosed five amorphous forms, three polycrystalline ethanolates, an ethanol / water binary solvate, and two hydrates (monohydrate and dihydrate) of cabazitaxel. Patents WO2014067207A1, CN103058960B, CN103450119A, WO2013088335A1, CN102746258A, CN103910697A, CN103910696A, WO2013111157A1, CN103044364B, etc., disclose various amorphous, solvated, and non-crystalline forms of cabazitaxel.

[0005] The above research results indicate that cabazitaxel readily forms solvates and exhibits polymorphism; different crystallization processes may yield cabazitaxel with different crystal forms or containing different solvents. Acetone solvate is currently the only FDA-approved pharmaceutical form, but it is unstable and easily loses acetone during prolonged storage or under high temperatures. The anhydrous form of cabazitaxel is less stable, transforming into corresponding hydrates after a period of time under different humidity levels. At ambient temperature and with relative humidity of 10% and 60%, it forms monohydrate and dihydrate, respectively. Solvates are prone to solvent loss during heating or long-term storage, resulting in changes in composition or crystal form, which negatively impacts the pharmaceutical efficacy of cabazitaxel. Furthermore, clinical drug use has clear limits on solvent residues; the solvent content in the solvates undoubtedly exceeds the limits of relevant national standards, posing a potential safety hazard to the drug.

[0006] Given the broad prospects of cabazitaxel in the pharmaceutical field, developing new solid forms of cabazitaxel that are simple to prepare, have high safety and good stability will have very important application value. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a co-crystal of cabazitaxel and active ingredients from plant essential oils, along with its preparation method and applications. This invention provides a novel co-crystal of cabazitaxel and active ingredients from plant essential oils. Because the preparation of this co-crystal requires no solvent, there is no solvent residue. Furthermore, plant essential oils, as plant-derived substances, have advantages such as being human- and environmentally friendly and possessing diverse biological activities, and are widely used in the pharmaceutical and food fields. This invention solves the toxicity problem of cabazitaxel solvates in existing technologies. In addition, the co-crystal of cabazitaxel and active ingredients from this invention exhibits good stability and will not transform into any other solid form of cabazitaxel under various humidity conditions, solving the problem of moisture absorption in existing anhydrous cabazitaxel forms. Finally, the co-crystal of cabazitaxel and active ingredients from this invention has a significant inhibitory effect on tumor cells, demonstrating significantly enhanced anti-tumor activity.

[0008] The first aspect of this invention is to provide a cocrystal of cabazitaxel and active plant essential oil components, wherein the cocrystal is formed by the self-assembly of raw materials including cabazitaxel and active plant essential oil components. Cabazitaxel, as a taxane-based antitumor drug, contains taxane, acetyl, benzoyloxy, hydroxyl, dimethoxy, amide, and ester groups in its molecular structure. These groups can form hydrogen bonds or other non-covalent interactions with functional groups such as hydroxyl, aldehyde, carbonyl, and ester groups in plant essential oil molecules. These interactions promote the self-assembly of the two components into a cocrystal under appropriate crystallization conditions. The cocrystal of cabazitaxel and active plant essential oil components of this invention does not require the addition of an external solvent during preparation; it can be obtained simply by crystallizing a mixture of cabazitaxel and active plant essential oil components. This avoids the problem of solvent residue from the source and also avoids the problems of existing cabazitaxel solvates easily losing solvent and undergoing compositional changes or crystal form transformations during heating or long-term storage, as well as the problem of cabazitaxel easily absorbing moisture during long-term storage in solvent-free form, thus improving the stability of cabazitaxel.

[0009] In this invention, the active ingredient of plant essential oil refers to a chemical component extracted from a plant through a specific method, which has specific biological activity or pharmacological effect. It can be a specific component of plant essential oil, or a mixture of one or more components.

[0010] In a preferred embodiment, the active ingredient of the plant essential oil is selected from at least one of alcohols, phenols, aldehydes, ketones, esters, or olefins; and / or,

[0011] In the eutectic, the molar ratio of the cabazitaxel to the active ingredient of the plant essential oil is 3:1 to 1:3; for example, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3.

[0012] Preferably,

[0013] The alcohols are selected from at least one of menthol, patchouli alcohol, eucalyptol, linalool, citronellol, geraniol, nerol, syringol, terpineol, camphenol, eucalyptol, vanillin, or perillyl alcohol; and / or,

[0014] The phenolic compounds are selected from at least one of eugenol, methyleugenol, carvacrol, paeonol, or thymol; and / or,

[0015] Aldehydes are selected from at least one of citral, citronellol, cinnamaldehyde, trans-cinnamaldehyde, perillaldehyde, cuminaldehyde, anisaldehyde, vanillin, cinnamaldehyde, or cyclocitral; and / or,

[0016] The ketone compound is selected from at least one of menthone, carvone, sennae, camphene, malbenzene, flavanone, thujone, patchoulione, or naringenone; and / or,

[0017] The ester compound is selected from at least one of methyl salicylate, cinnamyl acetate, geraniol acetate, linaloyl acetate, citronellol acetate, or nepeta lactone; and / or,

[0018] The olefin compounds are selected from at least one of limonene, elemene, pinene, camphene, sabinene, carene, caryophyllene, terpinene, ocimene, myrcene, elemene, perillane, cymene, dipentene, bisabolene, farnesene, gingerene, or phellandrene.

[0019] In a preferred embodiment, the active ingredient of the plant essential oil is selected from menthol, wherein the cabazitaxel-menthol eutectic comprises a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2° showing characteristic peaks at 7.417, 8.936, 10.250, 12.585, 14.552, 15.413, 16.990, 17.791, 18.469, 20.518, and 21.995.

[0020] Preferably, the cabazitaxel-menthol eutectic also has one or more additional peaks at 21.192, 23.632, 25.172, 26.914, 29.006, and 29.478 in the powder X-ray diffraction pattern expressed as 2θ±0.2° diffraction angle;

[0021] More preferably, the cabazitaxel-menthol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 11.502, 13.628, 19.185, 23.001, 27.678, 29.864, 30.832, 31.239, 32.141, 32.509, 32.986, 33.311, 35.812, 37.310, and 39.255.

[0022] More preferably, the powder X-ray diffraction pattern of the cabazitaxel-menthol eutectic is as follows: Figure 1 As shown;

[0023] And / or,

[0024] The active ingredient of the plant essential oil is selected from eucalyptol, wherein the cabazitaxel-eucalyptol cocrystal includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 6.187, 7.497, 8.095, 9.716, 11.889, 14.408, 15.456, 16.479, 17.609, and 18.591.

[0025] Preferably, the cabazitaxel-eucalyptol eutectic also has one or more additional peaks in the powder X-ray diffraction pattern expressed as 2θ±0.2° at 10.574, 11.376, 12.300, 12.912, 14.964, 15.739, 16.216, 17.215, 18.020, 20.028, and 21.767.

[0026] More preferably, the cabazitaxel-eucalyptol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 9.284, 13.117, 13.628, 19.305, 22.587, 22.979, 23.448, 23.881, 24.271, 29.009, and 32.920.

[0027] More preferably, the cabazitaxel-eucalyptol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 19.618, 21.174, 25.374, 26.424, 26.914, 27.285, 27.816, 28.273, 29.436, 30.110, 31.322, 32.012, 33.577, 33.943, 34.236, 35.422, and 37.268.

[0028] Further preferably, the powder X-ray diffraction pattern of the cabazitaxel-eucalyptol eutectic is as follows: Figure 3 As shown;

[0029] And / or,

[0030] The active ingredient of the plant essential oil is selected from linalool, wherein the cabazitaxel-linalool cocrystal includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 5.268, 6.170, 7.131, 7.501, 9.059, 10.188, 13.876, 15.023, 16.172, 18.366, 19.101, 19.470, and 22.197.

[0031] Preferably, the cabazitaxel-linalool eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 11.148, 11.806, 12.462, 12.728, 13.115, 16.909, 17.448, 17.713, 20.091, 21.539, and 23.965.

[0032] More preferably, the cabazitaxel-linalool eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 14.223, 15.415, 20.664, 23.265, 24.521, 25.012, 25.253, 25.979, 30.520, 31.995, 32.959, and 35.503.

[0033] More preferably, the cabazitaxel-linalool eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 10.509, 28.469, 29.289, 32.386, 33.800, 34.191, 34.623, 36.217, and 38.227.

[0034] More preferably, the powder X-ray diffraction pattern of the cabazitaxel-linalool eutectic is as follows: Figure 4 As shown.

[0035] As a preferred implementation method,

[0036] The active ingredient of the plant essential oil is selected from eugenol, wherein the cabazitaxel-eugenol cocrystal includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 7.174, 8.958, 10.617, 10.986, 11.850, 12.585, 15.045, 16.722, 19.085, and 20.824.

[0037] Preferably, the cabazitaxel-eugenol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 9.614, 11.665, 15.598, 16.134, 17.691, 20.397, 21.543, 21.933, 22.566, 25.521, and 26.340.

[0038] More preferably, the cabazitaxel-eugenol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 13.124, 14.120, 14.346, 17.954, 18.552, 19.658, 23.471, 23.841, 25.274, 26.811, 27.221, and 36.300.

[0039] More preferably, the cabazitaxel-eugenol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 11.414, 13.633, 24.579, 27.512, 27.867, 28.393, 28.883, 29.252, 29.646, 30.049, 30.379, 30.851, 31.818, 32.059, 32.269, 32.613, 33.270, 34.047, 34.742, 35.355, 37.350, 37.839, 38.149, and 39.440.

[0040] More preferably, the powder X-ray diffraction pattern of the cabazitaxel-eugenol eutectic is as follows: Figure 5 As shown;

[0041] And / or,

[0042] The active ingredient of the plant essential oil is selected from carvacrol, wherein the cabazitaxel-carvacrol eutectic includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 7.176, 7.357, 8.816, 10.105, 12.647, 14.351, 15.272, 17.591, 17.893, 18.593, 21.625, and 22.260.

[0043] The cabazitaxel-carvacrol eutectic also has one or more additional peaks in the powder X-ray diffraction pattern expressed as 2θ±0.2° at 13.449, 20.583, 20.785, 20.999, 22.852, 23.351, and 26.770.

[0044] Preferably, the cabazitaxel-carvacrol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 15.619, 16.845, 18.831, 23.842, 25.063, 25.276, 27.059, 28.512, 29.205, and 29.544.

[0045] More preferably, the powder X-ray diffraction pattern of the cabazitaxel-carvacrol eutectic is as follows: Figure 6 As shown;

[0046] And / or,

[0047] The active ingredient of the plant essential oil is selected from citral, wherein the cabazitaxel-citral eutectic exhibits characteristic peaks at 7.687, 8.382, 9.427, 10.737, 11.235, 12.175, 13.732, 14.756, 15.430, 16.847, 17.789, 19.229, and 22.018 in the powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°.

[0048] Preferably, the cabazitaxel-citral eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 11.540, 13.094, 14.288, 15.970, 17.410, 18.224, 18.841, 19.739, 20.642, 21.502, 22.897, 23.737, 24.416, 25.580, 26.260, and 27.384.

[0049] More preferably, the cabazitaxel-citral eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 20.102, 22.490, 23.286, 24.187, 25.257, 28.124, 28.657, 29.112, 29.807, 30.256, 31.031, 31.547, 32.205, 33.062, 33.596, 33.944, 34.804, 36.940, and 37.739.

[0050] More preferably, the powder X-ray diffraction pattern of the cabazitaxel-citral eutectic is as follows: Figure 7 As shown.

[0051] In a preferred embodiment, the active ingredient of the plant essential oil is selected from menthone, wherein the cabazitaxel-menthone cocrystal includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2° showing characteristic peaks at 7.560, 8.728, 10.104, 12.543, 13.120, 14.267, 15.600, 16.887, 17.504, 18.160, 19.290, 21.380, and 22.671.

[0052] Preferably, the cabazitaxel-menthone eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 8.974, 13.323, 14.759, 15.130, 15.887, 18.613, 20.211, 20.851, 22.075, 23.121, 23.638, 24.845, and 30.501.

[0053] More preferably, the cabazitaxel-menthone eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 12.116, 24.271, 25.113, 26.198, 26.792, 27.406, 27.691, 28.167, 28.740, 29.192, 29.663, 29.965, 30.931, 33.480, 34.008, 34.381, 35.031, 35.345, 36.553, and 38.558.

[0054] More preferably, the powder X-ray diffraction pattern of the cabazitaxel-menthone eutectic is as follows: Figure 8 As shown; and / or,

[0055] The active ingredient of the plant essential oil is selected from methyl salicylate, wherein the cabazitaxel-methyl salicylate eutectic exhibits characteristic peaks at 7.537, 9.387, 12.072, 15.187, 15.417, 17.749, and 18.924 in the powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°.

[0056] Preferably, the cabazitaxel-methyl salicylate eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 7.705, 8.418, 10.616, 11.048, 11.324, 13.590, 16.666, 21.414, 21.768, 22.188, 22.794, 23.405, 25.851, and 31.155.

[0057] More preferably, the cabazitaxel-methyl salicylate eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 12.888, 14.017, 16.443, 17.287, 20.027, 20.329, 23.845, 24.396, 27.307, 28.288, 29.396, 29.948, 32.477, 33.516, and 35.155.

[0058] More preferably, the cabazitaxel-methyl salicylate eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 14.361, 14.610, 16.043, 19.458, 26.542, 27.120, 29.036, 31.467, 31.828, 33.211, and 34.500.

[0059] Further preferably, the powder X-ray diffraction pattern of the cabazitaxel-methyl salicylate eutectic is as follows: Figure 9 As shown;

[0060] And / or,

[0061] The active ingredient of the plant essential oil is selected from limonene, wherein the cabazitaxel-limonene eutectic includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2° showing characteristic peaks at 6.169, 7.480, 8.894, 10.203, 13.057, 13.877, 14.964, 16.110, and 19.082.

[0062] Preferably, the cabazitaxel-limonene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 5.227, 6.520, 7.032, 11.009, 11.750, 12.420, 18.348, 19.309, 20.086, 22.119, 30.378, and 31.893.

[0063] More preferably, the cabazitaxel-limonene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 9.484, 12.728, 16.848, 17.762, 18.730, 19.679, 20.489, 21.448, 21.851, 22.607, 23.943, 24.593, 32.959, and 35.445.

[0064] More preferably, the cabazitaxel-limonene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 10.529, 15.456, 23.268, 25.027, 27.444, 27.997, 28.429, 29.293, 30.074, 32.381, 33.741, 34.144, 34.681, 35.711, 36.799, and 37.186.

[0065] More preferably, the powder X-ray diffraction pattern of the cabazitaxel-limonene eutectic is as follows: Figure 10 As shown;

[0066] And / or,

[0067] The active ingredient of the plant essential oil is selected from pinene, wherein the cabazitaxel-pinene eutectic exhibits characteristic peaks at 6.268, 7.089, 7.522, 8.936, 10.269, 11.845, 12.320, 12.727, 13.837, 14.963, 15.536, 19.289, and 22.097 in the powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°.

[0068] Preferably, the cabazitaxel-pinene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 5.247, 11.049, 11.316, 13.054, 16.071, 16.829, 17.591, 18.450, 21.313, and 30.458.

[0069] More preferably, the cabazitaxel-pinene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 14.201, 20.191, 20.687, 23.328, 24.084, 24.640, 25.239, 25.589, 25.851, 26.935, 32.244, 34.072, 37.084, and 38.707.

[0070] More preferably, the powder X-ray diffraction pattern of the cabazitaxel-pinene eutectic is as follows: Figure 11 As shown.

[0071] A second objective of this invention is to provide a method for preparing a co-crystal of cabazitaxel and active ingredients of plant essential oils as described in one objective of this invention, wherein cabazitaxel and active ingredients of plant essential oils are mixed to form a material to be crystallized; then crystallization is performed to obtain a co-crystal of cabazitaxel and active ingredients of plant essential oils.

[0072] As a preferred implementation method,

[0073] The molar ratio of cabazitaxel to the active ingredient of plant essential oil is 50:1-1:50; preferably, the molar ratio of cabazitaxel to the active ingredient of plant essential oil is 10:1-1:10; more preferably, the molar ratio of cabazitaxel to the active ingredient of plant essential oil is 3:1-1:3.

[0074] As a preferred implementation method,

[0075] The crystallization process of the cabazitaxel and the active ingredients of the plant essential oil is selected from the following methods:

[0076] Method a: Crystallize the material to be crystallized by volatilization or vacuum evaporation concentration; preferably, the volume of the concentrated material is 10%-60% of the volume of the material to be crystallized, more preferably 20%-40%; or,

[0077] Method b: Cool the material to be crystallized and then crystallize it; preferably, cool it below the crystallization point; preferably, the cooling temperature range is from 40-80℃ to below the crystallization point; or,

[0078] Method c: Grind the material to be crystallized, and allow it to stand to evaporate. Preferably, the grinding frequency is 15-30Hz, more preferably 20-30Hz; the grinding time is preferably 10-120min, and more preferably 30-60min; or...

[0079] Method d: The material to be crystallized is stirred. Preferably, the stirring temperature is 20-50℃ and the stirring time is 24-72h.

[0080] A third objective of this invention is to provide the application of a cocrystal of cabazitaxel and active plant essential oil components, as described in one objective of this invention, in the preparation of anticancer drugs.

[0081] A fourth objective of the present invention is to provide a pharmaceutical composition comprising a cocrystal of cabazitaxel and active plant essential oil components as described in one objective of the present invention, and a medically acceptable carrier.

[0082] Compared with the prior art, the present invention has the following advantages:

[0083] (1) No solvent residue, higher safety: The eutectic of cabazitaxel and plant essential oil active ingredients of the present invention does not require the addition of external solvents during preparation. It can be obtained by crystallization of the mixture of cabazitaxel and plant essential oil active ingredients, thus avoiding the problem of solvent residue from the source. Moreover, the preparation method is simple and more suitable for industrial applications.

[0084] (2) Better product stability: The co-crystal of cabazitaxel and plant essential oil active ingredients in this invention avoids the problem that cabazitaxel solvates are prone to solvent loss and compositional changes or crystal transformations during heating or long-term storage, and that cabazitaxel is prone to moisture absorption during long-term storage in solvent-free form, thus improving the stability of cabazitaxel.

[0085] (3) Stronger anti-tumor activity: The plant essential oil components in the co-crystal of the present invention have the effect of promoting drug penetration and absorption, and can work together with cabazitaxel to further enhance the anti-tumor activity of cabazitaxel; and the plant essential oil part of the present invention has anti-cancer, antibacterial, antiviral, analgesic, anti-inflammatory and other medicinal activities, and can be used as a pharmaceutical active ingredient in combination with cabazitaxel.

[0086] In summary, the cocrystal of cabazitaxel and plant essential oil active ingredients of the present invention has good stability, no solvent toxicity, and high safety, and can better meet the pharmaceutical needs in terms of production, quality control and clinical application. Attached Figure Description

[0087] Figure 1 PXRD pattern of the eutectic of cabazitaxel and menthol;

[0088] Figure 2 The unit cell packing diagram of the eutectic of cabazitaxel and menthol;

[0089] Figure 3 PXRD pattern of the cocrystal of cabazitaxel and eucalyptol;

[0090] Figure 4 PXRD pattern of the cocrystal of cabazitaxel and linalool;

[0091] Figure 5 PXRD pattern of the cocrystal of cabazitaxel and eugenol;

[0092] Figure 6 PXRD pattern of the cocrystal of cabazitaxel and carvacrol;

[0093] Figure 7 PXRD pattern of the cocrystal of cabazitaxel and citral;

[0094] Figure 8 PXRD pattern of the cocrystal of cabazitaxel and menthone;

[0095] Figure 9 PXRD pattern of the cocrystal of cabazitaxel and methyl salicylate;

[0096] Figure 10 PXRD pattern of the eutectic of cabazitaxel and limonene;

[0097] Figure 11 PXRD pattern of the eutectic of cabazitaxel and pinene;

[0098] Figure 12 The PXRD pattern of the acetone solvate of cabazitaxel in Comparative Example 1 is shown.

[0099] Figure 13 PXRD patterns of the cabazitaxel and menthol cocrystal stored at room temperature for 6 months;

[0100] Figure 14 PXRD pattern of the cocrystal of cabazitaxel and eugenol stored at room temperature for 6 months;

[0101] Figure 15PXRD patterns of the cabazitaxel and citral cocrystal stored at room temperature for 6 months;

[0102] Figure 16 PXRD patterns of the cabazitaxel and menthone cocrystal stored at room temperature for 6 months;

[0103] Figure 17 PXRD patterns of the cabazitaxel and limonene cocrystal stored at room temperature for 6 months;

[0104] Figure 18 PXRD patterns of cabazitaxel acetone solvate after exposure to different humidity levels at 25°C for 7 days;

[0105] Figure 19 PXRD patterns of cabazitaxel and menthol cocrystals exposed to different humidity levels at 25°C for 7 days;

[0106] Figure 20 PXRD patterns of the cocrystal of cabazitaxel and eugenol exposed to different humidity at 25°C for 7 days;

[0107] Figure 21 PXRD patterns of cabazitaxel and citral cocrystal exposed to different humidity levels at 25°C for 7 days;

[0108] Figure 22 PXRD patterns of cabazitaxel and menthone cocrystal exposed to different humidity levels at 25°C for 7 days;

[0109] Figure 23 PXRD patterns of cabazitaxel and pinene eutectic exposed at 25°C and different humidity levels for 7 days;

[0110] Figure 24 To assess the antitumor activity of different solid forms of cabazitaxel. Detailed Implementation

[0111] The present invention will now be described in detail with reference to the accompanying drawings and embodiments. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the content of the present invention are still within the scope of protection of the present invention.

[0112] Unless otherwise specified, the raw materials used in this invention are all publicly available in the prior art, such as those that can be directly purchased or prepared according to publicly available methods. The cabazitaxel raw material used in the embodiments of this invention was purchased from Anage Chemicals and can be in any solid form.

[0113] Test method:

[0114] PXRD (Powder X-ray Diffraction) method: Instrument model: Bruker-D8 ADVANCE, target: Cu-Kα (40kV, 40mA), performed at room temperature using an EIGER2 R detector. The scanning range was from 5° to 40° in the 2θ interval, with a step size of 0.02° and a scanning speed of 10° / min.

[0115] Measurement discrepancies associated with these powder X-ray diffraction (PXRD) analysis results are caused by a variety of factors, including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration discrepancies, (d) operator errors (including errors occurring when determining peak positions), and (e) the properties of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in shifts in the same direction for all peaks. When using a flat support, small differences in sample height can lead to large shifts in PXRD peak positions. Systematic studies have shown that a 1 mm sample height difference can result in peak shifts as high as 1° 2θ. These shifts can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the shifts (applying a systematic calibration factor to all peak position values) or by recalibrating the instrument. As mentioned above, measurement errors from different instruments can be corrected by applying a systematic calibration factor to ensure consistent peak positions.

[0116] Example 1

[0117] Preparation of the cabazitaxel and menthol eutectic: 100.0 mg of cabazitaxel was placed in a 10 mL glass bottle and dissolved in 5 mL of menthol at 40 °C to obtain a clear solution. The solution was filtered into a perforated vial and allowed to stand at room temperature to evaporate. After crystallization, one crystal was selected for single-crystal structure determination. The remaining crystals were filtered and dried under vacuum at 40 °C. The resulting solid was the cabazitaxel and menthol eutectic.

[0118] The PXRD pattern of the cabazitaxel and menthol cocrystal prepared by the above method is shown below. Figure 1 As shown in Table 1, the basic diffraction angle data are as follows.

[0119] Table 1. PXRD data of the cabazitaxel and menthol cocrystal.

[0120]

[0121] The single-crystal structure of the cabazitaxel and menthol cocrystal prepared by the above method was determined at 113 K, exhibiting a monoclinic crystal system with space group P21. The crystallographic parameters are recorded in Table 2. Structural analysis shows that the molar ratio of cabazitaxel to menthol in the cocrystal is 1:1. Cabazitaxel forms cavities through intermolecular interactions, with menthol molecules located within these cavities. Figure 2 ).

[0122] Table 2. Crystallographic parameters of the eutectic of cabazitaxel and menthol

[0123]

[0124]

[0125] Example 2

[0126] Preparation of the cocrystal of cabazitaxel and eucalyptol: 100.0 mg of cabazitaxel and 30 μL of eucalyptol were milled in a ball mill (Retsch MM400) at 25 Hz for 30 min. The remaining essential oil was allowed to dry in air to obtain the cocrystal of cabazitaxel and eucalyptol. Its PXRD pattern is shown below. Figure 3 As shown in Table 3, the basic diffraction angle data are as follows.

[0127] Table 3. PXRD data of the cocrystal of cabazitaxel and eucalyptol

[0128]

[0129]

[0130] Example 3

[0131] Preparation of the cabazitaxel and linalool cocrystal: 30.0 mg of cabazitaxel and 20 μL of linalool were milled in a ball mill (Retsch MM400) at 30 Hz for 10 min. The remaining essential oil was allowed to dry in air to obtain the cabazitaxel and linalool cocrystal. Its PXRD pattern is shown below. Figure 4 As shown in Table 4, the basic diffraction angle data are as follows.

[0132] Table 4. PXRD data of the cocrystal of cabazitaxel and linalool

[0133]

[0134]

[0135] Example 4

[0136] Preparation of the cabazitaxel and eugenol cocrystal: 500.0 mg of cabazitaxel was placed in a 10 mL glass bottle and dissolved in 3 mL of eugenol at 50 °C. The solution was filtered to remove insoluble impurities, and then the temperature was slowly lowered to 20 °C at a rate of 10 °C / h. Crystals precipitated were filtered and dried under vacuum at 40 °C. The resulting solid was the cabazitaxel and eugenol cocrystal. Its PXRD pattern is shown below. Figure 5 As shown in Table 5, the basic diffraction angle data are as follows.

[0137] Table 5. PXRD data of the cocrystal of cabazitaxel and eugenol

[0138]

[0139]

[0140] Example 5

[0141] Preparation of the cabazitaxel and carvacrol cocrystal: 100.0 mg of cabazitaxel and 20 μL of carvacrol were ground in a ball mill (Retsch MM400) at 20 Hz for 20 min, and then allowed to dry in air to obtain the cabazitaxel and carvacrol cocrystal. Its PXRD pattern is shown below. Figure 6 As shown in Table 6, the basic diffraction angle data are as follows.

[0142] Table 6. PXRD data of the cocrystal of cabazitaxel and carvacrol

[0143]

[0144]

[0145] Example 6

[0146] Preparation of the cabazitaxel and citral cocrystal: 100.0 mg of cabazitaxel and 50 μL of citral were milled in a ball mill (Retsch MM400) at 30 Hz for 30 min, and then dried in air to obtain the cabazitaxel and citral cocrystal. Its PXRD pattern is shown below. Figure 7 As shown in Table 7, the basic diffraction angle data are as follows.

[0147] Table 7 PXRD data of the cabazitaxel and citral cocrystal

[0148]

[0149]

[0150] Example 7

[0151] Preparation of the cabazitaxel and menthone cocrystal: 200.0 mg of cabazitaxel and 40 μL of menthone were milled in a ball mill (Retsch MM400) at 30 Hz for 30 min, and then dried in air to obtain the cabazitaxel and menthone cocrystal. Its PXRD pattern is shown below. Figure 8 As shown in Table 8, the basic diffraction angle data are as follows.

[0152] Table 8 PXRD data of the cocrystal of cabazitaxel and menthone

[0153]

[0154]

[0155] Example 8

[0156] Preparation of the cabazitaxel and methyl salicylate cocrystal: 30.0 mg of cabazitaxel and 20 μL of methyl salicylate were ground in a ball mill (Retsch MM400) for 30 min, and then allowed to dry in air to obtain the cabazitaxel and methyl salicylate cocrystal. Its PXRD pattern is shown below. Figure 9 As shown in Table 9, the basic diffraction angle data are as follows.

[0157] Table 9. PXRD data of the cocrystal of cabazitaxel and methyl salicylate

[0158]

[0159]

[0160] Example 9

[0161] Preparation of the cabazitaxel and limonene cocrystal: 100.0 mg of cabazitaxel was suspended in 2 mL of limonene and stirred at 300 rpm at 25 °C. After suspension crystallization for 48 h, the mixture was filtered and allowed to dry in air. The resulting solid was the cabazitaxel and limonene cocrystal, and its PXRD pattern is shown below. Figure 10 As shown in Table 10, the basic diffraction angle data are as follows.

[0162] Table 10 PXRD data of the cabazitaxel and limonene cocrystal

[0163]

[0164]

[0165] Example 10

[0166] Preparation of the cabazitaxel and pinene eutectic: 100.0 mg of cabazitaxel and 30 μL of pinene were ground in a ball mill (Retsch MM400) for 30 min, and then dried in air to obtain the cabazitaxel and pinene eutectic. Its PXRD pattern is shown below. Figure 11 As shown in Table 11, the basic diffraction angle data are as follows.

[0167] Table 11 PXRD data of the cabazitaxel and pinene eutectic

[0168]

[0169] Comparative Example 1

[0170] Preparation of Cabazitaxel-acetone solvate: Following the preparation method in patent WO2005028462A1, 120.0 mg of cabazitaxel and 20 μL of acetone were milled in a ball mill (Retsch MM400) at 30 Hz for 30 min. The residual solvent was allowed to dry in air to obtain a previously known 1:1 molar ratio of cabazitaxel-acetone solvate. Its PXRD pattern is shown below. Figure 12 As shown in Table 12, the basic diffraction angle data are as follows.

[0171] Table 12 PXRD data for acetone solvates of cabazitaxel

[0172]

[0173] Example 11

[0174] Stability Study of Cabazitaxel-Plant Essential Oil Active Ingredient Cocrystals: Cabazitaxel-menthol cocrystals, cabazitaxel-eugenol cocrystals, cabazitaxel-citral cocrystals, cabazitaxel-menthone cocrystals, and cabazitaxel-limonene cocrystals were used as representative systems for stability studies of cabazitaxel cocrystals with alcohols, phenols, aldehydes, ketones, and olefins, respectively. Appropriate amounts of the cabazitaxel-menthol cocrystals prepared in Example 1, the cabazitaxel-eugenol cocrystals prepared in Example 4, the cabazitaxel-citral cocrystals prepared in Example 6, the cabazitaxel-menthone cocrystals prepared in Example 7, and the cabazitaxel-limonene cocrystals prepared in Example 9 were sealed and stored at 25°C for 6 months. The samples were then subjected to PXRD testing to assess their stability. The PXRD spectra are shown below. Figure 13 , Figure 14 , Figure 15 , Figure 16 and Figure 17 As shown. The results indicate that the carbamate eutectic of the present invention has good stability and can be stored at room temperature for at least 6 months without undergoing a phase transition.

[0175] The eutectic of cabazitaxel-plant essential oil active ingredients prepared in other embodiments of the present invention also has good stability and can be stored at room temperature for at least 6 months without phase change.

[0176] Example 12

[0177] Humidity stability test

[0178] The cabazitaxel-acetone solvate prepared in Comparative Example 1, the cabazitaxel-menthol cocrystal prepared in Example 1, the cabazitaxel-eugenol cocrystal prepared in Example 4, the cabazitaxel-citral cocrystal prepared in Example 6, the cabazitaxel-menthone cocrystal prepared in Example 7, and the cabazitaxel-pinene cocrystal prepared in Example 10 were simultaneously exposed to 25°C and 43% and 85% relative humidity for 7 days. PXRD analysis was performed before and after exposure to the specific relative humidity. The results are as follows: Figure 18 , Figure 19 , Figure 20 , Figure 21 , Figure 22 and Figure 23 As shown, the acetone solvate of Comparative Example 1 underwent a phase transition after 7 days of storage at 25°C and 43% and 85% relative humidity, exhibiting poor stability. In contrast, the cabazitaxel-plant essential oil cocrystal of the present invention demonstrates excellent stability and does not transform into any other solid form of cabazitaxel under various humidity conditions. This is because plant essential oils are highly hydrophobic, a property that hinders water molecules from entering the cocrystal lattice. Therefore, the cabazitaxel-plant essential oil cocrystal of the present invention exhibits good stability under various humidity conditions.

[0179] Example 13

[0180] In vitro anticancer activity test

[0181] The in vitro antitumor effects of the novel cocrystal form of cabazitaxel-plant essential oil active ingredients were evaluated using the MTT assay. The direct killing effects on tumor cells were investigated using cytotoxicity experiments on the cabazitaxel-menthol cocrystal prepared in Example 1, Example 4, Example 6, Example 7, and Example 10, respectively. Cabazitaxel-menthone cocrystal prepared in Example 1 was used as a positive control. Logarithmic growth phase human prostate cancer cells PC-3 were collected and subjected to 5 × 10⁻⁶ cells / cells. 3 Cells were seeded at a density of 0.5 μg / well in sterile 96-well plates and cultured for 24 h. The original culture medium was discarded and replaced with fresh culture medium containing different forms of cabazitaxel at concentrations of 0.01, 0.1, 1, 10, and 100 μg / mL, with 6 parallel wells for each concentration group. A blank control group was also included. After 24 h of incubation, 20 μL of 5 mg / mL MTT solution was added to each well, and incubation continued for 3 h. The culture medium was carefully discarded, and 100 μL of DMSO was added to each well. The cells were shaken to dissolve completely, and the absorbance was measured at 490 nm to calculate cell viability.

[0182] like Figure 24As shown, compared with the acetone solvate of cabazitaxel in Comparative Example 1, the cabazitaxel-plant essential oil cocrystal prepared in this embodiment of the invention significantly enhances the inhibitory effect on tumor cells, and the plant essential oil has the effect of promoting drug penetration and absorption. Therefore, the essential oil components in the cabazitaxel-plant essential oil cocrystal prepared in this embodiment of the invention work together with cabazitaxel to further enhance the antitumor activity of cabazitaxel.

[0183] The cabazitaxel-plant essential oil cocrystal prepared in other embodiments of the present invention also has a significant inhibitory effect on tumor cells, which can further enhance the anti-tumor activity of cabazitaxel.

[0184] The present invention has been described in detail above with reference to specific embodiments and exemplary examples; however, these descriptions should not be construed as limiting the present invention. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and embodiments of the present invention without departing from the spirit and scope of the invention, and all such modifications and improvements fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims.

[0185] All publications, patent applications, patents, and other references mentioned in this specification are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used in this specification have the meanings commonly understood by those skilled in the art. In case of conflict, the definitions in this specification shall prevail.

[0186] When this specification uses the prefixes “known to those skilled in the art,” “prior art,” or similar terms to derive materials, substances, methods, steps, apparatus, or components, the objects derived from such prefixes cover those commonly used in the art at the time of this application, but also include those that are not currently commonly used but will become generally recognized in the art as suitable for similar purposes.

[0187] In the context of this specification, except where expressly stated otherwise, any matters or issues not mentioned shall apply directly to those known in the art without any modification.

Claims

1. A cocrystal of cabazitaxel and plant essential oil active ingredients, characterized in that: The eutectic is formed by the self-assembly of raw materials including cabazitaxel and active ingredients from plant essential oils.

2. The cocrystal of cabazitaxel and plant essential oil active ingredients according to claim 1, characterized in that: The active ingredients of the plant essential oil are selected from at least one of alcohols, phenols, aldehydes, ketones, esters, or olefins; and / or, In the eutectic, the molar ratio of the cabazitaxel to the active ingredient of the plant essential oil is 3:1 to 1:3; Preferably, The alcohols are selected from at least one of menthol, patchouli alcohol, eucalyptol, linalool, citronellol, geraniol, nerol, syringol, terpineol, camphenol, eucalyptol, vanillin, or perillyl alcohol; and / or, The phenolic compounds are selected from at least one of eugenol, methyleugenol, carvacrol, paeonol, or thymol; and / or, Aldehydes are selected from at least one of citral, citronellol, cinnamaldehyde, trans-cinnamaldehyde, perillaldehyde, cuminaldehyde, anisaldehyde, vanillin, cinnamaldehyde, or cyclocitral; and / or, The ketone compound is selected from at least one of menthone, carvone, sennae, camphene, malbenzene, flavanone, thujone, patchoulione, or naringenone; and / or, The ester compound is selected from at least one of methyl salicylate, cinnamyl acetate, geraniol acetate, linaloyl acetate, citronellol acetate, or nepeta lactone; and / or, The olefin compounds are selected from at least one of limonene, elemene, pinene, camphene, sabinene, carene, caryophyllene, terpinene, ocimene, myrcene, elemene, perillane, cymene, dipentene, bisabolene, farnesene, gingerene, or phellandrene.

3. The cocrystal of cabazitaxel and plant essential oil active ingredients according to claim 1, characterized in that: The active ingredient of the plant essential oil is selected from menthol, wherein the cabazitaxel-menthol eutectic includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 7.417, 8.936, 10.250, 12.585, 14.552, 15.413, 16.990, 17.791, 18.469, 20.518, and 21.

995. Preferably, the cabazitaxel-menthol eutectic also has one or more additional peaks at 21.192, 23.632, 25.172, 26.914, 29.006, and 29.478 in the powder X-ray diffraction pattern expressed as 2θ±0.2° diffraction angle; More preferably, the cabazitaxel-menthol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 11.502, 13.628, 19.185, 23.001, 27.678, 29.864, 30.832, 31.239, 32.141, 32.509, 32.986, 33.311, 35.812, 37.310, and 39.

255. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-menthol eutectic is shown in Figure 1; And / or, The active ingredient of the plant essential oil is selected from eucalyptol, wherein the cabazitaxel-eucalyptol cocrystal includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 6.187, 7.497, 8.095, 9.716, 11.889, 14.408, 15.456, 16.479, 17.609, and 18.

591. Preferably, the cabazitaxel-eucalyptol eutectic also has one or more additional peaks in the powder X-ray diffraction pattern expressed as 2θ±0.2° at 10.574, 11.376, 12.300, 12.912, 14.964, 15.739, 16.216, 17.215, 18.020, 20.028, and 21.

767. More preferably, the cabazitaxel-eucalyptol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 9.284, 13.117, 13.628, 19.305, 22.587, 22.979, 23.448, 23.881, 24.271, 29.009, and 32.

920. More preferably, the cabazitaxel-eucalyptol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 19.618, 21.174, 25.374, 26.424, 26.914, 27.285, 27.816, 28.273, 29.436, 30.110, 31.322, 32.012, 33.577, 33.943, 34.236, 35.422, and 37.

268. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-eucalyptol eutectic is shown in Figure 3; And / or, The active ingredient of the plant essential oil is selected from linalool, wherein the cabazitaxel-linalool cocrystal includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 5.268, 6.170, 7.131, 7.501, 9.059, 10.188, 13.876, 15.023, 16.172, 18.366, 19.101, 19.470, and 22.

197. Preferably, the cabazitaxel-linalool eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 11.148, 11.806, 12.462, 12.728, 13.115, 16.909, 17.448, 17.713, 20.091, 21.539, and 23.

965. More preferably, the cabazitaxel-linalool eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 14.223, 15.415, 20.664, 23.265, 24.521, 25.012, 25.253, 25.979, 30.520, 31.995, 32.959, and 35.

503. More preferably, the cabazitaxel-linalool eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 10.509, 28.469, 29.289, 32.386, 33.800, 34.191, 34.623, 36.217, and 38.

227. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-linalool eutectic is shown in Figure 4.

4. The cocrystal of cabazitaxel and plant essential oil active ingredients according to claim 1, characterized in that: The active ingredient of the plant essential oil is selected from eugenol, wherein the cabazitaxel-eugenol cocrystal includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 7.174, 8.958, 10.617, 10.986, 11.850, 12.585, 15.045, 16.722, 19.085, and 20.

824. Preferably, the cabazitaxel-eugenol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 9.614, 11.665, 15.598, 16.134, 17.691, 20.397, 21.543, 21.933, 22.566, 25.521, and 26.

340. More preferably, the cabazitaxel-eugenol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 13.124, 14.120, 14.346, 17.954, 18.552, 19.658, 23.471, 23.841, 25.274, 26.811, 27.221, and 36.

300. More preferably, the cabazitaxel-eugenol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 11.414, 13.633, 24.579, 27.512, 27.867, 28.393, 28.883, 29.252, 29.646, 30.049, 30.379, 30.851, 31.818, 32.059, 32.269, 32.613, 33.270, 34.047, 34.742, 35.355, 37.350, 37.839, 38.149, and 39.

440. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-eugenol eutectic is shown in Figure 5; And / or, The active ingredient of the plant essential oil is selected from carvacrol, wherein the cabazitaxel-carvacrol eutectic includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 7.176, 7.357, 8.816, 10.105, 12.647, 14.351, 15.272, 17.591, 17.893, 18.593, 21.625, and 22.

260. The cabazitaxel-carvacrol eutectic also has one or more additional peaks in the powder X-ray diffraction pattern expressed as 2θ±0.2° at 13.449, 20.583, 20.785, 20.999, 22.852, 23.351, and 26.

770. Preferably, the cabazitaxel-carvacrol eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 15.619, 16.845, 18.831, 23.842, 25.063, 25.276, 27.059, 28.512, 29.205, and 29.

544. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-carvacrol eutectic is shown in Figure 6; And / or, The active ingredient of the plant essential oil is selected from citral, wherein the cabazitaxel-citral eutectic exhibits characteristic peaks at 7.687, 8.382, 9.427, 10.737, 11.235, 12.175, 13.732, 14.756, 15.430, 16.847, 17.789, 19.229, and 22.018 in the powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°. Preferably, the cabazitaxel-citral eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 11.540, 13.094, 14.288, 15.970, 17.410, 18.224, 18.841, 19.739, 20.642, 21.502, 22.897, 23.737, 24.416, 25.580, 26.260, and 27.

384. More preferably, the cabazitaxel-citral eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 20.102, 22.490, 23.286, 24.187, 25.257, 28.124, 28.657, 29.112, 29.807, 30.256, 31.031, 31.547, 32.205, 33.062, 33.596, 33.944, 34.804, 36.940, and 37.

739. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-citral eutectic is shown in Figure 7.

5. The cocrystal of cabazitaxel and plant essential oil active ingredients according to claim 1, characterized in that: The active ingredient of the plant essential oil is selected from menthone, wherein the cabazitaxel-menthone cocrystal includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°, showing characteristic peaks at 7.560, 8.728, 10.104, 12.543, 13.120, 14.267, 15.600, 16.887, 17.504, 18.160, 19.290, 21.380, and 22.

671. Preferably, the cabazitaxel-menthone eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 8.974, 13.323, 14.759, 15.130, 15.887, 18.613, 20.211, 20.851, 22.075, 23.121, 23.638, 24.845, and 30.

501. More preferably, the cabazitaxel-menthone eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 12.116, 24.271, 25.113, 26.198, 26.792, 27.406, 27.691, 28.167, 28.740, 29.192, 29.663, 29.965, 30.931, 33.480, 34.008, 34.381, 35.031, 35.345, 36.553, and 38.

558. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-menthone eutectic is shown in Figure 8; and / or, The active ingredient of the plant essential oil is selected from methyl salicylate, wherein the cabazitaxel-methyl salicylate eutectic exhibits characteristic peaks at 7.537, 9.387, 12.072, 15.187, 15.417, 17.749, and 18.924 in the powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°. Preferably, the cabazitaxel-methyl salicylate eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 7.705, 8.418, 10.616, 11.048, 11.324, 13.590, 16.666, 21.414, 21.768, 22.188, 22.794, 23.405, 25.851, and 31.

155. More preferably, the cabazitaxel-methyl salicylate eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 12.888, 14.017, 16.443, 17.287, 20.027, 20.329, 23.845, 24.396, 27.307, 28.288, 29.396, 29.948, 32.477, 33.516, and 35.

155. More preferably, the cabazitaxel-methyl salicylate eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 14.361, 14.610, 16.043, 19.458, 26.542, 27.120, 29.036, 31.467, 31.828, 33.211, and 34.

500. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-methyl salicylate eutectic is shown in Figure 9; And / or, The active ingredient of the plant essential oil is selected from limonene, wherein the cabazitaxel-limonene eutectic includes a powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2° showing characteristic peaks at 6.169, 7.480, 8.894, 10.203, 13.057, 13.877, 14.964, 16.110, and 19.

082. Preferably, the cabazitaxel-limonene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 5.227, 6.520, 7.032, 11.009, 11.750, 12.420, 18.348, 19.309, 20.086, 22.119, 30.378, and 31.

893. More preferably, the cabazitaxel-limonene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 9.484, 12.728, 16.848, 17.762, 18.730, 19.679, 20.489, 21.448, 21.851, 22.607, 23.943, 24.593, 32.959, and 35.

445. More preferably, the cabazitaxel-limonene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 10.529, 15.456, 23.268, 25.027, 27.444, 27.997, 28.429, 29.293, 30.074, 32.381, 33.741, 34.144, 34.681, 35.711, 36.799, and 37.

186. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-limonene eutectic is shown in Figure 10; And / or, The active ingredient of the plant essential oil is selected from pinene, wherein the cabazitaxel-pinene eutectic exhibits characteristic peaks at 6.268, 7.089, 7.522, 8.936, 10.269, 11.845, 12.320, 12.727, 13.837, 14.963, 15.536, 19.289, and 22.097 in the powder X-ray diffraction pattern expressed as a diffraction angle of 2θ±0.2°. Preferably, the cabazitaxel-pinene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 5.247, 11.049, 11.316, 13.054, 16.071, 16.829, 17.591, 18.450, 21.313, and 30.

458. More preferably, the cabazitaxel-pinene eutectic also has one or more additional peaks in its powder X-ray diffraction pattern, expressed as a diffraction angle of 2θ ± 0.2°, at 14.201, 20.191, 20.687, 23.328, 24.084, 24.640, 25.239, 25.589, 25.851, 26.935, 32.244, 34.072, 37.084, and 38.

707. More preferably, the powder X-ray diffraction pattern of the cabazitaxel-pinene eutectic is shown in Figure 11.

6. A method for preparing a co-crystal of cabazitaxel and active plant essential oil components as described in any one of claims 1-5, characterized in that: Cabazitaxel and active ingredients from plant essential oils are mixed to form a material to be crystallized; then crystallization is performed to obtain a co-crystal of cabazitaxel and active ingredients from plant essential oils.

7. The method for preparing the cocrystal of cabazitaxel and plant essential oil active ingredients according to claim 6, characterized in that: The molar ratio of cabazitaxel to the active ingredient of plant essential oil is 50:1-1:50; preferably, the molar ratio of cabazitaxel to the active ingredient of plant essential oil is 10:1-1:10; more preferably, the molar ratio of cabazitaxel to the active ingredient of plant essential oil is 3:1-1:

3.

8. The method for preparing the co-crystal of cabazitaxel and plant essential oil active ingredients according to claim 6, characterized in that: The crystallization process of the cabazitaxel and the active ingredients of the plant essential oil is selected from the following methods: Method a: Crystallize the material to be crystallized by volatilization or vacuum evaporation concentration; preferably, the volume of the concentrated material is 10%-60% of the volume of the material to be crystallized, more preferably 20%-40%; or, Method b: Cool the material to be crystallized and then crystallize it; preferably, cool it below the crystallization point; preferably, the cooling temperature range is from 40-80℃ to below the crystallization point; or, Method c: Grind the material to be crystallized, and allow it to stand to evaporate. Preferably, the grinding frequency is 15-30Hz, more preferably 20-30Hz; the grinding time is preferably 10-120min, and more preferably 30-60min; or... Method d: The material to be crystallized is stirred. Preferably, the stirring temperature is 20-50℃ and the stirring time is 24-72h.

9. The use of a cocrystal of cabazitaxel and plant essential oil active ingredients as described in any one of claims 1-5 in the preparation of an anticancer drug.

10. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a cocrystal of cabazitaxel and a plant essential oil active ingredient as described in any one of claims 1-5, and a medically acceptable carrier.

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