CN118339144A - Cabozantinib eutectic and preparation method and application thereof as medicine or in pharmaceutical preparation - Google Patents

Cabozantinib eutectic and preparation method and application thereof as medicine or in pharmaceutical preparation Download PDF

Info

Publication number
CN118339144A
CN118339144A CN202280079796.7A CN202280079796A CN118339144A CN 118339144 A CN118339144 A CN 118339144A CN 202280079796 A CN202280079796 A CN 202280079796A CN 118339144 A CN118339144 A CN 118339144A
Authority
CN
China
Prior art keywords
crystal
xrpd
steps
acid
crystals
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202280079796.7A
Other languages
Chinese (zh)
Inventor
刘晓忠
郑和校
李郡
靳奇峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medoncare Pharmaceutical Co ltd
Original Assignee
Medoncare Pharmaceutical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medoncare Pharmaceutical Co ltd filed Critical Medoncare Pharmaceutical Co ltd
Publication of CN118339144A publication Critical patent/CN118339144A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Relates to a co-crystal of cabozatinib, a preparation method thereof and application thereof as a medicine or in a medicine preparation, and more particularly to application of the co-crystal of cabozatinib in treating progressive metastatic Medullary Thyroid Cancer (MTC), renal cancer and prostatic cancer. The eutectic has good solubility, good stability, process developability and the like, and the preparation method is simple, low in cost and has important value for optimizing and developing the medicine in the future.

Description

Cabozantinib eutectic and preparation method and application thereof as medicine or in pharmaceutical preparation Technical Field
The invention relates to a co-crystal formed by cabatinib, a preparation method thereof and application thereof as a medicament or in a pharmaceutical preparation for treating progressive, metastatic Medullary Thyroid Cancer (MTC) patients, renal cancer and prostatic cancer.
Technical Field
Cabatinib (cabozantinib) is an anticancer drug developed by Exelixis company, and its indication for treating metastatic medullary thyroid cancer and renal cancer is FDA approved in 11 2012 and 4 2016 respectively, and in addition, its indication for treating liver cancer is FDA approved in 1 2019. Cabozantinib is marketed as (S) -malate.
Chinese patent application CN102388024A from the company elsamili Ai Kexi discloses 1:1 malate salt of cabitinib. In 2012, the U.S. FDA approved the company's cabitinib malate (1:1) for sale under the trade name COMETRIQ. WO2015177758 A1 discloses forms 1,2, 3 and 4 of compound I, wherein form 4 is the preferred form, but the form also has the problems of low solubility, flowability, compressibility, tensile strength, adhesion. Thus, there is still a need for extensive experimental research to provide more crystalline forms and forms with better properties to support drug development.
The cabatinib code XL184 is a multi-target small molecule tyrosine kinase inhibitor and comprises nine targets of MET, VEGFR 123, ROS1 and RET, AXL, NTRK, KIT. The most common adverse reactions of cabotinib include: diarrhea (63%), stomatitis (51%), PPES, hand and foot syndrome (50%), weight loss (48%), anorexia (46%), nausea (43%), fatigue (41%), oral pain (36%), hair color change (34%), dysgesia (34%), hypertension (33%), constipation (27%), abdominal pain (27%), vomiting (24%), weakness (21%), dysphonia (20%), rash (19%), dry skin (19%), headache (18%), hair loss (16%), dizziness (14%), joint pain (14%), dysphagia (13%), muscle cramps (12%), erythema (11%), dyspepsia (11%),
Wherein the 3-4 level adverse reaction comprises: diarrhea (16%), PPES, hand and foot syndrome (13%), fatigue (9%), hypertension (8%), weakness (6%), stomatitis (5%), weight loss (5%), anorexia (5%), dysphagia (4%), abdominal pain (3%), oral pain (2%), nausea (2%), dehydration (2%), erythema (1%), hypotension (1%), rash (1%), joint pain (1%), musculoskeletal chest pain (1%), nausea (1%).
The most common laboratory anomaly data for the cabotinib group include: AST elevation (86%), ALT elevation (86%), lymphocyte decrease (53%), ALP elevation (52%), hypocalcemia (52%), neutropenia (35%), thrombocytopenia (35%), hypophosphatemia (28%), hyperbilirubin (25%), hypomagnesemia (19%), hypokalemia (18%), hyponatremia (10%).
Because of the numerous side effects of the cabozantinib and the high occurrence probability, the therapeutic effect and the safety are greatly influenced. Thus, the use of eutectic techniques improves the basic structure of a cabozantinib drug, while improving its properties such as solubility, stability, permeability and bioavailability. The invention relates to a series of eutectic crystals of cabozantinib, gallic acid, DL-tartaric acid, maleic acid and piperazine serving as eutectic precursors. The co-crystals of the present invention may meet one or more objectives such as, but not limited to, improved solubility, stability and bioavailability, and better safety in pharmaceutical applications.
Disclosure of Invention
The invention relates to a co-crystal of cabatinib and gallic acid, DL-tartaric acid, maleic acid and piperazine.
In some embodiments, the active is selected from cabozantinib, in some embodiments, the co-crystal precursor is selected from the group consisting of fazilic acid, DL-tartaric acid, maleic acid, piperazine.
The co-crystals of the present invention are formed when cabatinib (active pharmaceutical ingredient API) and gallic acid, DL-tartaric acid, maleic acid, piperazine (co-crystal precursor) are bonded together by hydrogen bonds. In some embodiments, other non-covalent bonds and covalent interactions may also be present in the co-crystal.
One aspect of the present invention contemplates a cabozantinib-based co-crystal that provides a sufficient level of bioavailability that is therapeutically effective and maintains levels in a pharmaceutical application for a therapeutically effective period of time.
Compared with the cabozantinib, the cabozantinib eutectic has better solubility and stability, and is convenient to store and use; and can be directly used for preparing solid preparations, and has good powder properties.
Drawings
Figure 1 shows an X-ray powder diffraction (XRPD) pattern of a co-crystal of cabatinib and gallic acid.
Figure 2 shows the X-ray powder diffraction (XRPD) pattern of a co-crystal of cabatinib and DL-tartaric acid.
Figure 3 shows an X-ray powder diffraction (XRPD) pattern of a co-crystal of cabatinib and maleic acid.
Figure 4 shows an X-ray powder diffraction (XRPD) pattern of a co-crystal of cabatinib and piperazine.
Figure 5 shows the effect of cabatinib co-crystals on the viability of medullary thyroid cancer cells.
FIG. 6 shows the effect of cabatinib co-crystals on the survival of renal cancer cells 786-O.
Figure 7 shows the effect of cabatinib co-crystals on the survival rate of prostate cancer cells PC-3.
The invention relates to a cabozantinib eutectic crystal and a preparation method thereof. The co-crystal comprises cabatinib and a co-crystal precursor gallic acid, DL-tartaric acid, maleic acid and piperazine.
In some embodiments, the cabozantinib and the gallic acid are combined in a 1:1 ratio. The co-crystal comprises an X-ray diffraction pattern as shown in figure 1. In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in fig. 1.
In some embodiments, the cabozantinib and DL-tartaric acid are combined in a 1:1 ratio. The co-crystal had an XRPD pattern comprised at 10.280 °,11.380 °,13.860 °,15.801 °,17.901 °,20.639 °,22.960 °, and 27.881 ° (rounded to 10.3 °,11.4 °,13.9 °,15.8 °,17.9 °,20.6 °,23.0 °, and 27.9 °, respectively) (corresponding to, respectively D-spacing of (2) x 0.2 degrees. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2θ of 10.280 °,11.380 °,13.860 °,15.801 °,17.901 °,20.639 °,22.960 °, and 27.881 ° ± 0.1 °. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2θ of 10.280 °,11.380 °,13.860 °,15.801 °,17.901 °,20.639 °,22.960 °, and 27.881 ° ± 0.05 °. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in figure 2. In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in fig. 2.
In some embodiments, the cabozantinib and maleic acid co-crystals are combined in a 1:1 ratio. The co-crystal had an XRPD pattern comprised at 6.999 °,8.760 °,10.159 °,11.919 °,13.939 °,17.460 °,23.381 ° and 25.359 ° (rounded to 7.0 °,8.8 °,10.2 °,11.9 °,13.9 °,17.5 °,23.4 and 25.4 °), respectively (corresponding to, respectively) D-spacing of (2) x 0.2 degrees. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2θ of 6.999 °,8.760 °,10.159 °,11.919 °,13.939 °,17.460 °,23.381 °, and 25.359 ° ± 0.1 °. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2θ of 6.999 °,8.760 °,10.159 °,11.919 °,13.939 °,17.460 °,23.381 °, and 25.359 ° ± 0.05 °. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in fig. 3. In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in fig. 3.
In some embodiments, the cabozantinib and piperazine co-crystals are combined in a 1:2 ratio. The co-crystal has an XRPD pattern. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in fig. 4. In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in fig. 4.
The co-crystal of the present invention comprises: gallic acid, DL-tartaric acid, maleic acid, piperazine as co-precursor; and cabozatinib as co-crystal precursors (co-precursors) and Active Pharmaceutical Ingredients (APIs).
In some embodiments, the cabozantinib and the gallic acid, DL-tartaric acid, and maleic acid are combined in a 1:1 ratio.
In some embodiments, the cabozantinib and maleic acid are combined in a 1:2 ratio.
The solid state of the co-crystals of the present invention is any crystalline polymorph or other mixture. The co-crystals may also be made in amorphous form, which may be combined with any of the crystalline forms. In other embodiments, the solid state of the co-crystals is an amorphous form, different forms of the co-crystals of the invention may be obtained by different crystallization processes, and the co-crystals may be made amorphous by known techniques.
The co-crystals of the present invention may be prepared by a process comprising:
(a) Dissolving or suspending the gallic acid, DL-tartaric acid, maleic acid, piperazine in a solvent, respectively, optionally heating the solution or dispersion to a temperature above room temperature and below the boiling point of the solution or dispersion;
preferably, for said gallic acid, the solvent used is selected from ethanol; for the DL-tartaric acid, the solvent used is selected from isopropanol; for the maleic acid, the solvent used is selected from water; for the piperazine, the solvent used is selected from ethanol;
(b) Adding cabozantinib to dissolve or suspend in a solvent together with or after step (a), respectively;
(c) The reaction time is selected to be 0.1 to 24 hours, and the temperature of the step (a) is kept and stirred;
(d) Cooling the solution or dispersion of steps (a), (b), (c) to ambient temperature or below;
(e) Optionally evaporating part or all of the solvent; and
(F) The resulting co-crystals were filtered off.
In some embodiments, the specific conditions of the process may be adjusted, with the appropriate ratio being in the molar range ：1:0.1-1:20、1:0.2-1:20、1:0.3-1:20、1:0.4-1:20、1:0.5-1:20、1:0.6-1:20、1:0.7-1:20、1:0.8-1:20、1:0.9-1:20、1:1-1:20、1:2-1:20、1:3-1:20、1:4-1:20、1:5-1:20、1:6-1:18、1:7-1:15、1:8-1:13、1:9-1:12 or 1:10-1:11 described below. In some embodiments, a suitable ratio is about 1:1 (mole). In some embodiments, the period of time for slurrying or stirring the mixture may be within the following ranges: 0.1-24 hours, 0.2-12 hours, 0.25-6 hours, 0.3-2 hours, 0.4-1 hours or 0.5-1 hour. In some embodiments, the period of time for slurrying or stirring the mixture may be about 0.5 hours. In some embodiments, the eutectic compound may be obtained by drying, filtering, centrifuging, pipetting, or a combination thereof. In some embodiments, the eutectic compound may be obtained by centrifugation.
Example 1
84.8Mg (0.5 mmol) of gallic acid and 5ml of ethanol are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour for dissolution, 50mg (0.1 mmol) of cabatinib is added, the mixture is heated to 70 ℃, the heating is stopped after stirring for 4 hours, the mixture is cooled to room temperature, the solvent is dried in a spin-drying mode, the mixture is dried at the temperature of 40 ℃ in vacuum, and a eutectic crude product is obtained, and the eutectic crude product is detected to be amorphous through XRPD.
Example 2
33.92Mg (0.2 mmol) of gallic acid and 12ml of ethanol are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour to dissolve, 100mg (0.2 mmol) of cabatinib is added, heated to 70 ℃, stirred for 4 hours, naturally cooled to room temperature, the solvent is dried by spin, 5ml of ethanol is added, stirred for 3 hours, filtered to obtain a crude crystal product, the crude crystal product is treated by ethanol and heptane, and the crude crystal product is dried at the vacuum 40 ℃ to obtain 109.95mg of co-crystal. The amorphous form was determined to be 1:1 by XRPD and HPLC detection.
Example 3
67.84Mg (0.4 mmol) of gallic acid and 22ml of ethanol are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour to dissolve, 200mg (0.4 mmol) of cabatinib is added, heated to 70 ℃, stirred for 4 hours, naturally cooled to room temperature, the solvent is dried by spin, 5ml of ethanol is added, stirred for 3 hours, filtered to obtain a crude crystal product, the crude crystal product is treated by ethanol and heptane, and the crude crystal product is dried at the vacuum 40 ℃ to obtain 231.14mg of co-crystal. The amorphous form was determined to be 1:1 by XRPD and HPLC detection.
Example 4
101.76Mg (0.6 mmol) of gallic acid and 30ml of ethanol are added into a 50ml eggplant-shaped bottle, stirred for 0.5 hour to dissolve, 300mg (0.6 mmol) of cabatinib is added, the mixture is heated to 70 ℃ and stirred for 4 hours, then the mixture is naturally cooled to room temperature, the solvent is dried by spin, 5ml of ethanol is added, the mixture is stirred for 3 hours, filtration is carried out to obtain a crude crystal product, the crude crystal product is treated by ethanol and heptane, and 357.90mg of co-crystal is obtained after drying at 40 ℃ in vacuum. The amorphous form was determined to be 1:1 by XRPD and HPLC detection.
Example 5
149.64Mg (1.0 mmol) of DL-tartaric acid and 10ml of isopropanol are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour, 50mg (0.1 mmol) of cabotinib is added, the mixture is heated to 70 ℃ and stirred for 4 hours, then the mixture is naturally cooled to room temperature, the solvent is dried in a spinning way, and the mixture is dried at a vacuum of 40 ℃ to obtain a crude eutectic product, and the crude product has a characteristic peak through XRPD detection.
Example 6
29.93Mg (0.2 mmol) of DL-tartaric acid and 5ml of isopropanol are added into a 25ml eggplant-shaped bottle, heated to 70 ℃, stirred for 0.5 hour for dissolution, 100mg (0.2 mmol) of cabatinib is added, stirred for 6 hours, naturally cooled to room temperature, the reactants are ice-bathed to 0-5 ℃ and stirred for 3 hours, filtered to obtain crude crystals, treated with isopropanol and heptane, and dried at 40 ℃ in vacuum to obtain 110.39mg of co-crystals. The crystal form and the ratio were determined to be 1:1 by XRPD and HPLC detection.
Example 7
89.78Mg (0.6 mmol) of DL-tartaric acid and 11ml of isopropanol are added into a 25ml eggplant-shaped bottle, heated to 70 ℃, stirred for 0.5 hour for dissolution, 300mg (0.6 mmol) of cabatinib is added, stirred for 6 hours, naturally cooled to room temperature, the reactants are ice-bathed to 0-5 ℃ and stirred for 3 hours, filtration is carried out, crude crystals are obtained, the crude crystals are treated by isopropanol and heptane, and 329.09mg of co-crystals are obtained after drying at 40 ℃ in vacuum. The crystal form and the ratio were determined to be 1:1 by XRPD and HPLC detection.
Example 8
115.72Mg (1.0 mmol) of maleic acid and 5ml of water are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour, 50mg (0.1 mmol) of cabotinib is added, the mixture is heated to 70 ℃ and stirred for 4 hours, then the mixture is naturally cooled to room temperature, the solvent is dried in a spinning way, and the mixture is dried at the vacuum of 40 ℃ to obtain a eutectic crude product, and the eutectic crude product has a characteristic peak through XRPD detection.
Example 9
23.14Mg (0.2 mmol) of maleic acid and 5ml of water are added into a 25ml eggplant-shaped bottle, heated to 70 ℃, stirred for 0.5 hour for dissolution, 100mg (0.2 mmol) of cabatinib is added, stirred for 6 hours, naturally cooled to room temperature, the reactants are ice-bathed to 0-5 ℃ and stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried at 40 ℃ in vacuum to obtain 101.77mg of co-crystals. The crystal form and the ratio were determined to be 1:1 by XRPD and HPLC detection.
Example 10
69.43Mg (0.6 mmol) of maleic acid and 15ml of water are added into a 50ml eggplant-shaped bottle, heated to 70 ℃, stirred for 0.5 hour for dissolution, 300mg (0.6 mmol) of cabotinib is added, stirred for 6 hours, naturally cooled to room temperature, the reactants are ice-bathed to 0-5 ℃ and stirred for 3 hours, the filtration is carried out to obtain a crude crystal product, the crude crystal product is treated by water and heptane, and the crude crystal product is dried at the vacuum of 40 ℃ to obtain 326.61mg of co-crystal. The crystal form and the ratio were determined to be 1:1 by XRPD and HPLC detection.
Example 11
85.88Mg (1.0 mmol) of piperazine and 8ml of ethanol are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour, 50mg (0.1 mmol) of cabatinib is added, the mixture is heated to 70 ℃, stirred for 4 hours, naturally cooled to room temperature, the solvent is dried in a spinning way, and the mixture is dried at a vacuum of 40 ℃ to obtain a eutectic crude product, and the eutectic crude product is detected to be amorphous by XRPD.
Example 12
34.34Mg (0.4 mmol) of piperazine and 10ml of ethanol are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour to dissolve, 100mg (0.2 mmol) of cabatinib is added, heated to 70 ℃, stirred for 4 hours, naturally cooled to room temperature, the solvent is dried by spin, 5ml of ethanol is added, stirred for 3 hours, filtered to obtain a crude crystal product, the crude crystal product is treated by ethanol and heptane, and dried at the vacuum of 40 ℃ to obtain 114.83mg of co-crystal. The amorphous form was determined to be 1:2 by XRPD and HPLC detection.
Example 13
68.68Mg (0.8 mmol) of piperazine and 15ml of ethanol are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour to dissolve, 200mg (0.4 mmol) of cabatinib is added, heated to 70 ℃, stirred for 4 hours, naturally cooled to room temperature, the solvent is dried by spin, 5ml of ethanol is added, stirred for 3 hours, filtered to obtain a crude crystal product, treated by ethanol and heptane, and dried at the vacuum of 40 ℃ to obtain 223.54mg of co-crystal. The amorphous form was determined to be 1:2 by XRPD and HPLC detection.
Example 14
103.06Mg (0.12 mmol) of piperazine and 27ml of ethanol are added into a 50ml eggplant-shaped bottle, stirred for 0.5 hour to dissolve, 300mg (0.6 mmol) of cabatinib is added, the mixture is heated to 70 ℃ and stirred for 4 hours, then the mixture is naturally cooled to room temperature, the solvent is dried by spin, 10ml of ethanol is added, the mixture is stirred for 3 hours, filtration is carried out to obtain a crude crystal product, the crude crystal product is treated by ethanol and heptane, and 339.22mg of co-crystal is obtained after the drying under vacuum at 40 ℃. The amorphous form was determined to be 1:2 by XRPD and HPLC detection.
Example 15
The MTT method is used for detecting the inhibition effect of the cabatinib eutectic on the proliferation of medullary thyroid cancer cells, renal cancer cells 786-O and prostate cancer cells PC-3, as shown in figures 5, 6 and 7, the cabatinib eutectic can effectively enhance the inhibition effect on the medullary thyroid cancer cells, the renal cancer cells 786-O and the prostate cancer cells PC-3, the natural effect of Yu Kabo is strong, and the killing power of the cabatinib eutectic on the three cells is stronger, which indicates that the cabatinib eutectic enhances the anti-tumor effect of the medicine and shows stronger anti-tumor effect.
Comparative example 1
68.85Mg (0.5 mmol) of salicylic acid and 5ml of water are added into a 25ml eggplant-shaped bottle, heated to 70 ℃, stirred for 0.5 hours, 50mg (0.1 mmol) of cabotinib is added, stirred for 6 hours, naturally cooled to room temperature, the reactants are ice-bathed to 0-5 ℃ and stirred for 3 hours, filtration is carried out to obtain a crude product, isopropanol and heptane are used for treatment, and the obtained product is dried at a vacuum of 40 ℃ to obtain 102.56mg of a sample. The sample pattern was detected by XRPD to overlap with the cabotinib pattern, and no co-crystals were formed.
Comparative example 2
84.8Mg (0.5 mmol) of gallic acid and 5ml of toluene are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour for dissolution, 50mg (0.1 mmol) of cabotinib is added, the mixture is heated to 70 ℃, the heating is stopped after stirring for 4 hours, the mixture is cooled to room temperature, the solvent is dried in a spin-drying mode, the mixture is dried at the vacuum temperature of 40 ℃ to obtain a crude eutectic product, and an XRPD detection sample pattern is overlapped with the cabotinib pattern to form no eutectic.
Comparative example 3
149.64Mg (1.0 mmol) of DL-tartaric acid and 10ml of isopropanol are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour, 50mg (0.1 mmol) of cabotinib is added, the mixture is reacted at room temperature (25 ℃) for 4 hours, the mixture is naturally cooled to room temperature after stirring, the solvent is dried by spin, and the mixture is dried at a vacuum of 40 ℃ to obtain a crude eutectic product, and an XRPD detection sample pattern is overlapped with the DL-tartaric acid pattern, so that the eutectic is not formed.
Comparative example 4
17.17Mg (0.2 mmol) of piperazine and 10ml of ethanol are added into a 25ml eggplant-shaped bottle, stirred for 0.5 hour to dissolve, 200mg (0.4 mmol) of cabatinib is added, heated to 70 ℃, stirred for 4 hours, naturally cooled to room temperature, the solvent is dried by spin, 5ml of ethanol is added, stirred for 3 hours, filtered to obtain a crude crystal product, the crude crystal product is treated by ethanol and heptane, and then dried at a vacuum of 40 ℃ to obtain 180.96mg of co-crystal. The sample pattern was detected by XRPD to overlap with the cabotinib pattern, and no co-crystals were formed.
Test for inhibiting prostate cancer transplantation tumor of nude mice by cabatinib co-crystal
PC-3m cells in the logarithmic growth phase were treated with 0.25% trypsin digest, washed 2 times with PBS, and the cell suspension density of the serum-free medium was adjusted to 1X 10 7/ml. Preserving in a sterile centrifuge tube, and keeping the temperature until reaching an animal room. On an ultra clean bench, 0.2 ml/mouse cell fluid was inoculated under Ji Lepi on the right hand of a nude mouse, with the cell number of 2X 10 6, by using a 1ml disposable sterile syringe. Subcutaneous nodules were visible to the naked eye 7 days after inoculation. About 5mm 2 of transplanted tumor can be seen 14 days after inoculation, and the successful molding is achieved.
Rats were randomly divided into 3 groups of 20 rats each. ① Treatment groups of 20 rats were continuously perfused with 30mg/kg (calculated as cabotinib) of cabotinib and the cabotinib co-crystal, respectively, for 14 d. ② Model group 20 rats were continuously perfused with 14d normal saline (30 mg/kg) after successful molding. ③ The control group of 20 rats was not subjected to molding, and only 14d of normal saline (30 mg/kg) was continuously perfused. Animals were sacrificed at the end of treatment, tumor tissues were dissected, the tumor tissues of three groups of rats were weighed and their tumor inhibition rates were calculated. Measuring the short diameter (W) and the long diameter (L) of the transplanted tumor by using a vernier caliper, and calculating the volume of the tumor body, wherein V=W2×L×0.52; tumor inhibition rate (%) = (average tumor mass of blank tumor-bearing group-average tumor mass of each experimental group)/average tumor mass of blank tumor-bearing group x 100%.
Compared with the control group, the weight of the model group, the treatment group and the tumor body are obviously increased, and the tumor body volume is obviously increased; compared with the model group, the quality of the treated group tumor is reduced, and the tumor inhibition rate is obviously increased. In the treatment group, the inhibition tumor rate of the cabozantinib eutectic is obviously higher than that of Yu Kabo-group and L-malic acid cabozantinib group.
Solubility test
The solubility test data are shown in table 1.
TABLE 1
Stability test
Stability test data are shown in tables 2 to 3.
TABLE 2
TABLE 3 Table 3

Claims (15)

  1. A co-crystal formed by cabotinib as an active substance and other compounds as co-crystal precursors; wherein the eutectic precursor is selected from one or more of the following compounds: DL-tartaric acid, gallic acid, maleic acid, piperazine.
  2. The co-crystal of claim 1, wherein the cabozatinib and the co-crystal precursor DL-tartaric acid, gallic acid, maleic acid are combined in a 1:1 ratio, wherein the cabozatinib and the co-crystal precursor piperazine are combined in a 1:2 ratio.
  3. The co-crystal of claim 1, selected from the group consisting of:
    Comprises the following steps of 1:1 co-crystals of the cabozatinib and the DL-tartaric acid combined in proportion,
    Comprises the following steps of 1: 1a co-crystal of cabozitinib and gallic acid combined in proportion,
    Comprises the following steps of 1:1 co-crystals of combretastatin and maleic acid combined in proportion, and
    Comprises the following steps of 1:2 co-crystals of combretastatin and piperazine in proportion.
  4. The co-crystal of claim 1, comprising a ratio of 1: a co-crystal of cabatinib and DL-tartaric acid combined in a ratio of 1 having an X-ray diffraction powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2Θ of 10.280 °,11.380 °,13.860 °,15.801 °,17.901 °,20.639 °,22.960 °, and 27.881 ° ± 0.2 °.
  5. The co-crystal of claim 1, comprising a co-crystal of cabozantinib and gallic acid combined in a 1:1 ratio, having an amorphous X-ray diffraction powder diffraction (XRPD) pattern.
  6. The co-crystal of claim 1, comprising a ratio of 1:1 ratio of co-crystals of combined cabatinib and maleic acid having an X-ray diffraction powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.999 °,8.760 °,10.159 °,11.919 °,13.939 °,17.460 °,23.381 ° and 25.359 ° ± 0.2 °.
  7. The co-crystal of claim 1, comprising a ratio of 1:2 co-crystals of combrettinib and piperazine in proportions having an amorphous X-ray diffraction powder diffraction (XRPD) pattern.
  8. A pharmaceutical composition comprising a co-crystal compound according to any one of claims 1 to 7, optionally together with a pharmaceutically acceptable carrier.
  9. The pharmaceutical composition of claim 8, wherein the compound is present in a solid state in any crystalline polymorphic or amorphous form or mixtures thereof.
  10. A process for preparing the co-crystal of claim 9, comprising the steps of:
    (a) Dissolving or suspending the co-crystal precursor gallic acid, DL-tartaric acid, maleic acid, piperazine in a solvent, respectively, optionally heating the solution or dispersion to a temperature above room temperature and below the boiling point of the solution or dispersion;
    preferably, for said gallic acid, the solvent used is selected from ethanol; for the DL-tartaric acid, the solvent used is selected from isopropanol; for the maleic acid, the solvent used is selected from water; for the piperazine, the solvent used is selected from ethanol;
    (b) Adding cabozantinib to dissolve or suspend in a solvent together with or after step (a), respectively;
    (c) The reaction time is selected to be 0.1 to 24 hours, and the temperature of the step (a) is kept and stirred;
    (d) Cooling the solution or dispersion of steps (a), (b), (c) to ambient temperature or below;
    (e) Optionally evaporating part or all of the solvent; and
    (F) The resulting co-crystals were filtered off.
  11. The method of claim 10 comprising the steps of: 1 and having an XRPD pattern as shown in figure 1.
  12. The method of claim 10 comprising the steps of: 1 and DL-tartaric acid, and has an XRPD pattern as shown in figure 2.
  13. The method of claim 10 comprising the steps of: 1 and maleic acid, and has an XRPD pattern as shown in figure 3.
  14. The method of claim 10 comprising the steps of: 2 and having an XRPD pattern as shown in figure 4.
  15. Use of the co-crystal of any one of claims 1-7 or the pharmaceutical composition of any one of claims 8-9 in the manufacture of a medicament for the treatment of progressive metastatic Medullary Thyroid Cancer (MTC), renal cancer, and prostate cancer.
CN202280079796.7A 2021-12-03 2022-12-02 Cabozantinib eutectic and preparation method and application thereof as medicine or in pharmaceutical preparation Pending CN118339144A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2021114701929 2021-12-03
CN202111470192 2021-12-03
PCT/CN2022/136101 WO2023098853A1 (en) 2021-12-03 2022-12-02 Cocrystal of cabozantinib, preparation method therefor and application thereof as drug or in pharmaceutical preparation

Publications (1)

Publication Number Publication Date
CN118339144A true CN118339144A (en) 2024-07-12

Family

ID=86611551

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202280079796.7A Pending CN118339144A (en) 2021-12-03 2022-12-02 Cabozantinib eutectic and preparation method and application thereof as medicine or in pharmaceutical preparation

Country Status (2)

Country Link
CN (1) CN118339144A (en)
WO (1) WO2023098853A1 (en)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2612853A1 (en) * 2003-09-26 2013-07-10 Exelixis Inc. c-Met modulators and methods of use
TWI447108B (en) * 2009-01-16 2014-08-01 Exelixis Inc Malate salts of n-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof
CN104109124B (en) * 2013-04-19 2016-08-31 正大天晴药业集团股份有限公司 The rich crystal for Buddhist nun 0.5 malate of card
EP3274332B1 (en) * 2015-03-25 2018-12-19 Sandoz AG Crystalline forms of cabozantinib phosphate and cabozantinib hydrochloride
CN108341773A (en) * 2017-01-21 2018-07-31 南京华威医药科技开发有限公司 The rich crystal form II for Buddhist nun's malate of card
CN112638880B (en) * 2018-09-20 2022-03-25 苏州科睿思制药有限公司 Cabotinib malate crystal form and preparation method and application thereof

Also Published As

Publication number Publication date
WO2023098853A1 (en) 2023-06-08

Similar Documents

Publication Publication Date Title
KR101347522B1 (en) Stabile active ingredient complex of salts of the o-acetylsalicylic acid with basic amino acids and glycine
US20170050982A1 (en) New crystalline form of cefamandole sodium compound, formulation and preparation method thereof
US10323035B2 (en) Co-crystal of a CDK inhibitor and an MEK inhibitor and process of preparation thereof
JPH05148274A (en) Gallium compound
AU2022211878B1 (en) Targeting Degradable Nano-Drug Carrier for Chemo/Photothermal Synergistic Therapy and Preparation Method Thereof
CN111116462A (en) Regorafenib and wogonin co-crystal and application thereof
CN112999169A (en) Regorafenib-coated nano porous hydroxyapatite sustained-release microsphere as well as preparation method and application thereof
CN110054606B (en) Dihydromyricetin-berberine hydrochloride pharmaceutical co-crystal and preparation method thereof
JPS60190742A (en) Phenylmethylphenoxy compound, manufacture and medicinal composition
CN118339144A (en) Cabozantinib eutectic and preparation method and application thereof as medicine or in pharmaceutical preparation
CN106117214A (en) According to Shandong for Buddhist nun's novel crystal forms and preparation method thereof
JP2004504390A (en) Novel form of (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide
JP3472261B2 (en) Pharmaceutical suspension containing nevirapine hemihydrate
US9834567B1 (en) Crystalline form of cefamandole nafate compound, preparation and preparing method thereof
CN102180785A (en) Synthesis and application of ibuprofen lysine
CN105753869B (en) A kind of eutectic and preparation method thereof of CDK inhibitor and mek inhibitor
WO2023098848A1 (en) Osimertinib co-crystal, preparation method, and application as drug or in pharmaceutical formulation
CN111378002A (en) Novel cycloastragenol crystal form A and preparation method thereof
CN108484635A (en) 4H- thienos [2,3-b] thiapyran -4- ketone compounds and its application
CN112842990B (en) Preparation method of temperature-controlled double-drug preparation and application of temperature-controlled double-drug preparation in postoperative treatment of tumors
CN113372332B (en) Novel crystal form of octreotide
CN107556304A (en) A kind of new nitroimidazoles medicine and its production and use
CN87106966A (en) New 2,6-diamino-3-halogeno-benzyl pyridine compounds and their and preparation method thereof and pharmaceutical use
TW200815455A (en) Organic compounds
CN101011396A (en) Sustained release microcapsule of licardipine hydrochloride and its preparing process

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination