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CN-121991009-A - Eutectic crystal of cabazitaxel and plant essential oil active ingredients, and preparation method and application thereof

CN121991009ACN 121991009 ACN121991009 ACN 121991009ACN-121991009-A

Abstract

The invention discloses a co-crystal of cabazitaxel and plant essential oil active ingredients, and a preparation method and application thereof. The eutectic crystal is formed by self-assembly of raw materials including cabazitaxel and plant essential oil active ingredients. Mixing cabazitaxel and plant essential oil to form a material to be crystallized, and crystallizing to obtain the eutectic crystal of active components of cabazitaxel and plant essential oil. The co-crystal of the active ingredients of the cabazitaxel-plant essential oil solves the problems that the cabazitaxel solvate is easy to remove solvent in the process of heating or long-term storage to change the ingredients or to convert the crystal form and the cabazitaxel is easy to absorb moisture in the process of long-term storage in a solvent-free form, and improves the stability of the cabazitaxel. Meanwhile, the inhibition effect of the eutectic crystal on tumor cells is obviously improved, and the anti-tumor activity of cabazitaxel can be further improved. In conclusion, the co-crystal of the cabazitaxel and the plant essential oil active ingredient has good stability, no solvent toxicity and high safety, and can better meet the requirements of patent medicine in the aspects of production, quality control, clinical application and the like.

Inventors

  • YANG JINGXIANG
  • NIU XIAOFANG
  • MA HUAN

Assignees

  • 南开大学

Dates

Publication Date
20260508
Application Date
20241104

Claims (10)

  1. 1. A co-crystal of cabazitaxel and plant essential oil active ingredients, characterized in that: The eutectic crystal is formed by self-assembly of raw materials including cabazitaxel and plant essential oil active ingredients.
  2. 2. The co-crystal of cabazitaxel and plant essential oil active ingredient of claim 1, characterized in that: The plant essential oil active ingredient is selected from at least one of alcohols, phenols, aldehydes, ketones, esters or olefins compounds, and/or, In the eutectic, the mol ratio of the cabazitaxel to the plant essential oil active ingredient is 3:1-1:3; Preferably, the method comprises the steps of, The alcohol compound is selected from at least one of menthol, patchouli alcohol, eucalyptol, linalool, citronellol, geraniol, nerol, purple eugenol, terpineol, camphol, eugenol, vanillyl alcohol or perillyl alcohol, and/or, The phenolic compound is selected from at least one of eugenol, methyl eugenol, carvacrol, paeonol or thymol, and/or, The aldehyde compound is selected from at least one of citral, citronellal, cinnamaldehyde, trans-cinnamaldehyde, perillaldehyde, cumin aldehyde, anisaldehyde, vanillin, cinnamaldehyde or cyclocitral, and/or, The ketone compound is selected from at least one of menthone, carvone, elsholtzia ketone, camphene ketone, ma Bianxi ketone, flavanone, biotone, patchouli ketone or grapefruit ketone, and/or, The ester compound is at least one selected from methyl salicylate, cinnamyl acetate, geranyl acetate, linalyl acetate, citronellyl acetate or nepetalactone, and/or, The olefin compound is at least one selected from limonene, elemene, pinene, camphene, sabinene, carene, caryophyllene, terpinene, ocimene, myrcene, elemene, perillene, cymene, dipentene, bisabolene, farnesene, gingerol or phellandrene.
  3. 3. The co-crystal of cabazitaxel and plant essential oil active ingredient according to claim 1, wherein the plant essential oil active ingredient is selected from menthol, wherein the cabazitaxel-menthol co-crystal comprises a powder X-ray diffraction pattern expressed in terms of 2 theta + -0.2 DEG diffraction angles exhibiting characteristic peaks at 7.417, 8.936, 10.250, 12.585, 14.552, 15.413, 16.990, 17.791, 18.469, 20.518, 21.995; preferably, the cabazitaxel-menthol co-crystal also has one or more additional peaks at 21.192, 23.632, 25.172, 26.914, 29.006, 29.478 of powder X-ray diffraction patterns expressed in terms of 2 theta ± 0.2 ° diffraction angle; further preferably, the cabazitaxel-menthol co-crystal also has one or more additional peaks 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、39.255 of the powder X-ray diffraction pattern expressed in terms of 2 theta +0.2 deg. diffraction angle; Still more preferably, the powder X-ray diffraction pattern of the cabazitaxel-menthol co-crystal is shown in fig. 1; and/or the number of the groups of groups, The plant essential oil active ingredient is selected from eucalyptol, wherein the cabazitaxel-eucalyptol eutectic comprises powder X-ray diffraction pattern expressed by 2 theta plus or minus 0.2 degree diffraction angle and has 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 co-crystal also has one or more additional peaks at 10.574, 11.376, 12.300, 12.912, 14.964, 15.739, 16.216, 17.215, 18.020, 20.028, 21.767 of powder X-ray diffraction patterns expressed in terms of 2 theta ± 0.2 ° diffraction angles; Further preferably, the cabazitaxel-eucalyptol co-crystal also has one or more additional peaks at 9.284, 13.117, 13.628, 19.305, 22.587, 22.979, 23.448, 23.881, 24.271, 29.009, 32.920 of powder X-ray diffraction patterns expressed in terms of 2 theta ± 0.2 ° diffraction angles; Still more preferably, the cabazitaxel-eucalyptol co-crystal also has one or more additional peaks 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、37.268 of the powder X-ray diffraction pattern expressed in terms of 2 theta + 0.2 deg. diffraction angle; Still further preferably, the powder X-ray diffraction pattern of the cabazitaxel-eucalyptol co-crystal is shown in fig. 3; and/or the number of the groups of groups, The plant essential oil active ingredient is selected from linalool, wherein the cabazitaxel-linalool cocrystal comprises powder X-ray diffraction patterns expressed by diffraction angles of 2 theta plus or minus 0.2 degrees, and the powder X-ray diffraction patterns show 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 co-crystal also has one or more additional peaks at 11.148, 11.806, 12.462, 12.728, 13.115, 16.909, 17.448, 17.713, 20.091, 21.539, 23.965 of powder X-ray diffraction patterns expressed in terms of 2θ±0.2° diffraction angles; Further preferably, the cabazitaxel-linalool co-crystal also has one or more additional peaks at 14.223, 15.415, 20.664, 23.265, 24.521, 25.012, 25.253, 25.979, 30.520, 31.995, 32.959, 35.503 of the powder X-ray diffraction pattern expressed in terms of 2 theta ± 0.2 ° diffraction angle; Still more preferably, the cabazitaxel-linalool cocrystal also has one or more additional peaks at 10.509, 28.469, 29.289, 32.386, 33.800, 34.191, 34.623, 36.217, 38.227 of powder X-ray diffraction pattern expressed in terms of 2θ±0.2° diffraction angle; Still further preferably, the powder X-ray diffraction pattern of the cabazitaxel-linalool cocrystal is shown in fig. 4.
  4. 4. The co-crystal of cabazitaxel and plant essential oil active ingredient according to claim 1, wherein the plant essential oil active ingredient is selected from eugenol, wherein the cabazitaxel-eugenol co-crystal comprises a powder X-ray diffraction pattern expressed in terms of 2 theta + -0.2 DEG diffraction angles exhibiting characteristic peaks at 7.174, 8.958, 10.617, 10.986, 11.850, 12.585, 15.045, 16.722, 19.085, 20.824; Preferably, the cabazitaxel-eugenol co-crystal also has one or more additional peaks at 9.614, 11.665, 15.598, 16.134, 17.691, 20.397, 21.543, 21.933, 22.566, 25.521, 26.340 of powder X-ray diffraction patterns expressed in terms of 2θ±0.2°; Further preferably, the cabazitaxel-eugenol co-crystal also has one or more additional peaks expressed in terms of 2 theta ± 0.2 ° diffraction angles of the powder X-ray diffraction pattern at 13.124, 14.120, 14.346, 17.954, 18.552, 19.658, 23.471, 23.841, 25.274, 26.811, 27.221, 36.300; Still more preferably, the cabazitaxel-eugenol co-crystal also has one or more additional peaks 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、39.440 of the powder X-ray diffraction pattern expressed in terms of 2 theta + 0.2 deg. diffraction angle; Still further preferably, the powder X-ray diffraction pattern of the cabazitaxel-eugenol co-crystal is shown in fig. 5; and/or the number of the groups of groups, The plant essential oil active ingredient is selected from carvacrol, wherein the carvacrol-carvacrol co-crystal comprises powder X-ray diffraction patterns expressed in terms of 2 theta + -0.2 DEG diffraction angles and show 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, 22.260; The cabazitaxel-carvacrol co-crystal also has one or more additional peaks at 13.449, 20.583, 20.785, 20.999, 22.852, 23.351, 26.770 of powder X-ray diffraction patterns expressed in terms of 2θ±0.2°; Preferably, the cabazitaxel-carvacrol co-crystal also has one or more additional peaks at 15.619, 16.845, 18.831, 23.842, 25.063, 25.276, 27.059, 28.512, 29.205, 29.544 of powder X-ray diffraction patterns expressed in terms of 2θ±0.2°; further preferably, the powder X-ray diffraction pattern of the cabazitaxel-carvacrol co-crystal is shown in fig. 6; and/or the number of the groups of groups, The plant essential oil active ingredient is selected from citral, wherein the cabazitaxel-citral co-crystal comprises a powder X-ray diffraction pattern expressed in terms of 2θ±0.2° diffraction angles, showing 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, 22.018; Preferably, the cabazitaxel-citral co-crystal also has one or more additional peaks 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、27.384 of the powder X-ray diffraction pattern expressed in terms of 2 theta + 0.2 deg. diffraction angle; Further preferably, the cabazitaxel-citral co-crystal also has one or more additional peaks 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、37.739 of the powder X-ray diffraction pattern expressed in terms of 2 theta +0.2 deg. diffraction angle; still more preferably, the powder X-ray diffraction pattern of the cabazitaxel-citral co-crystal is shown in fig. 7.
  5. 5. The co-crystal of cabazitaxel and plant essential oil active ingredient according to claim 1, wherein the plant essential oil active ingredient is selected from menthone, wherein the cabazitaxel-menthone co-crystal comprises a powder X-ray diffraction pattern expressed in terms of 2 theta + -0.2 DEG diffraction angles exhibiting 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, 22.671; preferably, the cabazitaxel-menthone co-crystal also has one or more additional peaks expressed in terms of 2 theta ± 0.2 ° diffraction angles of the powder X-ray diffraction pattern 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, 30.501; further preferably, the cabazitaxel-menthone co-crystal also has one or more additional peaks 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、38.558 of the powder X-ray diffraction pattern expressed in terms of 2 theta +0.2 deg. diffraction angle; Still more preferably, the powder X-ray diffraction pattern of the cabazitaxel-menthone co-crystal is as shown in fig. 8, and/or, The plant essential oil active ingredient is selected from methyl salicylate, wherein the cabazitaxel-methyl salicylate eutectic comprises powder X-ray diffraction patterns expressed in terms of 2 theta plus or minus 0.2 degree diffraction angles, and the powder X-ray diffraction patterns show characteristic peaks at 7.537, 9.387, 12.072, 15.187, 15.417, 17.749 and 18.924; Preferably, the cabazitaxel-methyl salicylate co-crystal also has one or more additional peaks in powder X-ray diffraction patterns expressed in terms of 2 theta ± 0.2 ° diffraction angles 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, 31.155; Further preferably, the cabazitaxel-methyl salicylate co-crystal also has one or more additional peaks 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、35.155 of the powder X-ray diffraction pattern expressed in terms of 2 theta + 0.2 deg. diffraction angle; Still more preferably, the cabazitaxel-methyl salicylate co-crystal also has one or more additional peaks at 14.361, 14.610, 16.043, 19.458, 26.542, 27.120, 29.036, 31.467, 31.828, 33.211, 34.500 of powder X-ray diffraction patterns expressed in terms of 2 theta ± 0.2 ° diffraction angles; still further preferably, the powder X-ray diffraction pattern of the cabazitaxel-methyl salicylate co-crystal is shown in fig. 9; and/or the number of the groups of groups, The plant essential oil active ingredient is selected from limonene, wherein the cabazitaxel-limonene eutectic comprises powder X-ray diffraction pattern expressed by 2 theta plus or minus 0.2 degree diffraction angle and has 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 co-crystal also has one or more additional peaks expressed in terms of 2 theta ± 0.2 ° diffraction angles of the powder X-ray diffraction pattern at 5.227, 6.520, 7.032, 11.009, 11.750, 12.420, 18.348, 19.309, 20.086, 22.119, 30.378, 31.893; Further preferably, the cabazitaxel-limonene co-crystal also has one or more additional peaks expressed in terms of 2 theta ± 0.2 ° diffraction angles of the powder X-ray diffraction pattern 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, 35.445; Still more preferably, the cabazitaxel-limonene co-crystal also has one or more additional peaks 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、37.186 of the powder X-ray diffraction pattern expressed in terms of 2 theta +0.2 deg. diffraction angle; Still further preferably, the powder X-ray diffraction pattern of the cabazitaxel-limonene co-crystal is shown in fig. 10; and/or the number of the groups of groups, The plant essential oil active ingredient is selected from pinene, wherein the cabazitaxel-pinene eutectic comprises a powder X-ray diffraction pattern expressed in terms of 2 theta + -0.2 deg. diffraction angle, and the powder X-ray diffraction pattern shows 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, 22.097; preferably, the cabazitaxel-pinene co-crystal also has one or more additional peaks of powder X-ray diffraction patterns expressed in terms of 2 theta ± 0.2 ° diffraction angles at 5.247, 11.049, 11.316, 13.054, 16.071, 16.829, 17.591, 18.450, 21.313, 30.458; further preferably, the cabazitaxel-pinene co-crystal also has one or more additional peaks in powder X-ray diffraction patterns expressed in terms of 2 theta ± 0.2 ° diffraction angles 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, 38.707; Still more preferably, the powder X-ray diffraction pattern of the cabazitaxel-pinene co-crystal is shown in fig. 11.
  6. 6. A process for the preparation of a co-crystal of cabazitaxel and a plant essential oil active ingredient as claimed in any one of claims 1 to 5, characterised in that: Mixing cabazitaxel and plant essential oil active ingredients to form a material to be crystallized, and then carrying out crystallization treatment to obtain a eutectic crystal of cabazitaxel and plant essential oil active ingredients.
  7. 7. The method for preparing the co-crystal of cabazitaxel and plant essential oil active ingredients according to claim 6, characterized in that: The feeding molar ratio of the cabazitaxel to the plant essential oil active ingredient is 50:1-1:50, preferably, the feeding molar ratio of the cabazitaxel to the plant essential oil active ingredient is 10:1-1:10, and further preferably, the feeding molar ratio of the cabazitaxel to the plant essential oil active ingredient is 3:1-1:3.
  8. 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 treatment of the cabazitaxel and the plant essential oil active ingredient is selected from the following methods: the method a comprises evaporating the material to be crystallized or concentrating under reduced pressure, preferably, the volume of the concentrated material is 10% -60%, preferably 20% -40%, of the volume of the material to be crystallized, or The method b comprises cooling the material to be crystallized, crystallizing, preferably cooling to below crystallization point, preferably cooling from 40-80deg.C to below crystallization point, or Method c comprises grinding the material to be crystallized, standing for volatilizing, preferably at a frequency of 15-30Hz, more preferably 20-30Hz, for a time of 10-120min, more preferably 30-60min, or The method d comprises stirring the material to be crystallized, wherein the temperature of the stirring is preferably 20-50 ℃, and the stirring time is 24-72h.
  9. 9. Use of a co-crystal of cabazitaxel and a plant essential oil active ingredient according to any one of claims 1 to 5 for the preparation of an anticancer drug.
  10. 10. A pharmaceutical composition comprising a co-crystal of cabazitaxel and a plant essential oil active ingredient according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

Description

Eutectic crystal of cabazitaxel and plant essential oil active ingredients, and preparation method and application thereof Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to a co-crystal of active ingredients of cabazitaxel and plant essential oil, and a preparation method and application thereof. Background Cabazitaxel (Cabazitaxel) belongs to taxane antitumor drugs, has remarkable anticancer and anti-leukemia activities, and is approved by the FDA to be marketed in month 6 and 17 of 2010. The chemical name of the catalyst is 4-acetoxyl-2 alpha-benzoyloxy-5 beta, 20-epoxy-1-hydroxy-7 beta, 10 beta-dimethoxy-9-oxo-11-alkene-13 alpha-yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, the molecular formula is C 45H57NO14, and the structural formula is as follows: The solid form of cabazitaxel has been widely studied due to its good therapeutic effect, and many solvates, anhydrous crystalline forms, hydrates, amorphous forms and the like have been found. Patent WO2005028462 a in the company of ambrette medicine reports an acetone solvate of cabazitaxel (containing 6.5% by mass of acetone). WO2009115655 ambet pharmaceutical company again discloses 5 anhydrous crystalline forms, 3 ethanolate polymorphs, ethanol/water binary solvates and 2 hydrates (monohydrate and dihydrate) of cabazitaxel. Patent WO2014067207A1,CN103058960B,CN103450119A,WO2013088335A1,CN102746258A,CN103910697A,CN103910696A,WO2013111157A1,CN103044364B et al discloses various anhydrous crystalline, solvated and amorphous forms of cabazitaxel. The above results indicate that cabazitaxel forms solvates easily and polymorphic forms exist, and that different crystallization processes may result in cabazitaxel of different crystalline forms or containing different solvents. Acetone solvate is the only pharmaceutical form currently approved by the FDA for marketing, but is unstable and is susceptible to partial removal of acetone either on prolonged storage or at elevated temperatures. The anhydrous form of cabazitaxel has poor stability and changes to the corresponding hydrate when left for a period of time at different humidities, and forms the monohydrate and the dihydrate at ambient temperature at 10% and 60% relative humidities, respectively. The solvate is easy to remove solvent in the process of heating or long-term storage to generate component change or crystal form conversion, thereby negatively affecting the medicinal effect of cabazitaxel. In addition, the clinical medication has definite limit requirement on solvent residue, and the solvent contained in the solvate certainly exceeds the limit of the national relevant standard, thus generating hidden trouble on the safety of medicines. In view of the wide prospect of cabazitaxel in medicine, the novel solid form of cabazitaxel with high safety and good stability has very important application value, and is easy to develop and prepare. Disclosure of Invention Aiming at the defects of the prior art, the invention provides a co-crystal of cabazitaxel and plant essential oil active ingredients, and a preparation method and application thereof. The invention provides a novel eutectic crystal of active ingredients of cabazitaxel and plant essential oil, which is based on the fact that the eutectic crystal of active ingredients of cabazitaxel and plant essential oil does not need to be added with a solvent in the preparation process, so that solvent residues do not exist, plant essential oil is used as a plant source substance, the novel eutectic crystal has the advantages of being friendly to human bodies and environment, various in biological activity and the like, is widely applied to the fields of medicines and foods, can solve the toxicity problem of cabazitaxel solvate in the prior art, and in addition, the eutectic crystal of active ingredients of cabazitaxel and plant essential oil is good in stability, can not be converted into any other solid form of cabazitaxel under various humidity conditions, solves the problem that the existing anhydrous form of cabazitaxel is easy to absorb moisture, and finally, the eutectic crystal of active ingredients of cabazitaxel and plant essential oil has obvious inhibition effect on tumor cells, and the antitumor activity is remarkably improved. A first aspect of the present invention provides a co-crystal of cabazitaxel and a plant essential oil active ingredient, which is a co-crystal formed by self-assembly of raw materials including cabazitaxel and a plant essential oil active ingredient. Cabazitaxel is used as taxane antitumor medicine, and its molecular structure contains taxane, acetyl, benzoyloxy, hydroxyl, dimethoxy, amido, ester, etc. and may form hydrogen bond or other non-covalent interaction with hydroxyl, aldehyde, carbonyl, ester, etc. functional group in plant essential oil molecule to form eutectic via self-assembly under proper crystallization condition. The co-cr