WO2022087763A1 - Co-cristal contenant une base libre de sorafénib et du 5-fluorouracile, composition pharmaceutique et leurs utilisations - Google Patents

Co-cristal contenant une base libre de sorafénib et du 5-fluorouracile, composition pharmaceutique et leurs utilisations Download PDF

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WO2022087763A1
WO2022087763A1 PCT/CN2020/123526 CN2020123526W WO2022087763A1 WO 2022087763 A1 WO2022087763 A1 WO 2022087763A1 CN 2020123526 W CN2020123526 W CN 2020123526W WO 2022087763 A1 WO2022087763 A1 WO 2022087763A1
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crystal
sorafenib
cancer
fluorouracil
present
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Chinese (zh)
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钱锋
刘程宇
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愈磐生物科技（苏州）有限公司
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil

Definitions

  • the present invention relates to the field of medicine, in particular, the present invention relates to a co-crystal containing sorafenib free base and 5-fluorouracil, a pharmaceutical composition and use thereof.
  • Sorafenib is a tyrosine kinase inhibitor, angiogenesis inhibitor and vascular endothelial growth inhibitor that has been approved for the treatment of liver cancer, thyroid cancer and kidney cancer.
  • the marketed drug of sorafenib is its salt form, namely sorafenib tosylate.
  • the oral administration dose of the drug is relatively large, and the toxic and side effects are relatively serious.
  • 5-fluorouracil is a pyrimidine fluoride, which is an antimetabolite and antitumor drug. It can inhibit thymidine nucleotide synthase, block the conversion of deoxypyrimidine nucleotides into thymidine nucleus, interfere with DNA synthesis, and inhibit RNA. The synthesis also has a certain inhibitory effect. It is widely used clinically for solid tumors of digestive tract. The combination of 5-fluorouracil and some other drugs can often obtain higher response rate and survival rate.
  • an object of the present invention is to provide a co-crystal of sorafenib and 5-fluorouracil, which can effectively improve the bioavailability of sorafenib, and potentially further demonstrate that sorafenib and Synergistic effect of 5-fluorouracil.
  • the present invention is accomplished by the inventors based on the following findings:
  • the inventor has conducted in-depth research on the preparation of sorafenib. CCF) program.
  • CCF sorafenib.
  • the inventors of the present invention unexpectedly discovered that 5-fluorouracil (FU) can be used as CCF to form a drug-drug co-crystal structure with sorafenib free base , the co-crystal can effectively improve the dissolution rate of sorafenib, thereby improving the bioavailability of sorafenib.
  • the co-crystal can potentially exert the pharmacological synergistic effect of sorafenib and 5-fluorouracil. , so as to further improve the therapeutic effect of cancer, especially liver cancer and other original indications.
  • the present invention provides a co-crystal, according to an embodiment of the present invention, the co-crystal comprising: sorafenib free base; and 5-fluorouracil.
  • the co-crystal can effectively improve the dissolution rate of sorafenib, thereby improving the bioavailability of sorafenib.
  • the co-crystal can potentially exert the pharmacological effects of sorafenib and 5-fluorouracil.
  • the synergistic effect on cancer can further improve the therapeutic effect on the original indications such as cancer, especially liver cancer.
  • the above-mentioned co-crystal may further have at least one of the following additional technical features:
  • the molar ratio of the sorafenib free base and the 5-fluorouracil is about 1:1.
  • the co-crystals have X-ray powders at 2 ⁇ of about 9.1, about 13.4, about 15.7, about 17.2, about 18.2, about 18.7, about 20.2, about 21.0, about 22.0, about 23.8, and about 27.4 Diffraction peaks, preferably, the co-crystal has substantially the same X-ray powder diffraction of the SOR-FU co-crystal as in FIG. 3 .
  • the DSC thermogram of the co-crystal exhibits a single melting point at about 225.4°C.
  • the present invention provides a pharmaceutical composition
  • the pharmaceutical composition contains the aforementioned co-crystal.
  • the co-crystal can effectively improve the dissolution rate of sorafenib, thereby improving the bioavailability of sorafenib.
  • the co-crystal can potentially exert the pharmacological effects of sorafenib and 5-fluorouracil.
  • the synergistic effect on cancer can further improve the therapeutic effect on the original indications such as cancer, especially liver cancer.
  • the pharmaceutical composition further comprises at least one of a diluent, a solvent, an excipient, a carrier or a solubilizer.
  • the present invention also provides a method for preparing the aforementioned co-crystal, according to an embodiment of the present invention, the method comprises: mixing a stoichiometric proportion of sorafenib and 5-fluorouracil with The organic solvents are mixed; the resulting mixture is recrystallized to obtain the co-crystal.
  • the formation of drug co-crystals, especially drug-drug co-crystals has always been a technical difficulty in the pharmaceutical field.
  • the inventors of the present invention through arduous efforts, found that 5-fluorouracil can be used as a co-crystal of sorafenib.
  • the crystal former also forms a co-crystal with sorafenib as an active pharmaceutical ingredient, and as mentioned above, the co-crystal can effectively improve the dissolution rate of sorafenib, thereby improving the bioavailability of sorafenib.
  • the co-crystal can potentially exert the pharmacological synergistic effect of sorafenib and 5-fluorouracil, thereby further improving the therapeutic effect on the original indications such as cancer, especially liver cancer.
  • the above-mentioned method for preparing a co-crystal may further have at least one of the following additional technical features:
  • the organic solvent includes at least one of methanol, ethanol, isopropanol, dichloromethane, chloroform and acetonitrile.
  • the recrystallization is performed at a temperature of 4-40°C and a stirring speed of 5-2000 RPM for 40-50 hours.
  • the present invention proposes the use of the aforementioned co-crystal in the preparation of a medicament for the treatment of cancer.
  • the medicament is used to treat at least one selected from the group consisting of colon cancer, rectal cancer, gastric cancer, breast cancer, ovarian cancer, choriocarcinoma, malignant mole, head and neck squamous cell carcinoma, Skin cancer, liver cancer, bladder cancer, preferably liver cancer.
  • Fig. 1 is a PXRD pattern of a precipitate obtained by co-stirring Sorafenib and a 5-fluorouracil structural analog in methanol according to an embodiment of the present invention.
  • Fig. 2 is a PXRD pattern of the precipitate obtained by co-stirring sorafenib with aspirin, piperazine, urea and other compounds in methanol according to an embodiment of the present invention.
  • Figure 3 is a DSC curve of SOR free base, drug FU and SOR-FU co-crystal according to one embodiment of the present invention.
  • Figure 4 is a TGA curve of SOR free base, drug FU and SOR-FU co-crystal according to one embodiment of the present invention.
  • 5 is a PXRD pattern of SOR free base, drug FU and SOR-FU co-crystal according to one embodiment of the present invention.
  • FIG. 6 is a schematic structural diagram of a SOR-FU cocrystal according to an embodiment of the present invention, wherein (A) the unit cell structure of the cocrystal and each atomic label; (B) the two-dimensional crystal structure of the SOR-FU cocrystal face each other Interaction hydrogen bonding display; (C) side display of the two-dimensional crystal structure of the SOR-FU co-crystal; (D) three-dimensional crystal structure of the SOR-FU co-crystal and interaction hydrogen bonding display.
  • Figure 7 is a DVS curve of SOR-FU co-crystal and SOR salt according to one embodiment of the present invention.
  • Figure 8 is an intrinsic dissolution rate of SOR salts and SOR-FU co-crystals in 0.1 M HCl (0.1% Tween 80) according to one embodiment of the present invention.
  • Figure 9 is a USPII dissolution result of SOR salt and SOR-FU co-crystal in 0.1M HCl (0.1% Tween 80) according to one embodiment of the present invention.
  • Sorafenib is a tyrosine kinase inhibitor, an angiogenesis inhibitor and a vascular endothelial growth inhibitor. It has been approved for the treatment of liver, thyroid and kidney cancers.
  • the marketed drug of sorafenib is its salt form, namely sorafenib tosylate.
  • 5-Fluorouracil (FU) is a broad-spectrum anticancer drug, which is widely used clinically to treat colon cancer, rectal cancer, gastric cancer, breast cancer, ovarian cancer, choriocarcinoma, malignant mole, head and neck squamous cell carcinoma. , skin cancer, liver cancer, bladder cancer and other solid tumors.
  • 5-Fluorouracil is a pyrimidine fluoride. It is an antimetabolite and antitumor drug. It can inhibit thymidine nucleotide synthase, block the conversion of deoxypyrimidine nucleotides into thymidine nucleus, interfere with DNA synthesis, and inhibit RNA synthesis. There is also a certain inhibitory effect. It is widely used clinically for solid tumors of digestive tract. The combination of 5-fluorouracil and some other drugs can often obtain higher response rate and survival rate.
  • co-crystal and “co-crystal” are used interchangeably and refer to an active pharmaceutical ingredient (API) and a co-crystal former (CCF) in a hydrogen bond, A crystal formed by a fixed stoichiometric ratio under the action of ⁇ - ⁇ stacking, van der Waals force or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature.
  • co-crystal means a unique solid form of a crystalline substance composed of two or more unique compounds, wherein the two or more unique compounds form a new chemical entity. Co-crystals are solids at room temperature and have different physical and chemical characteristics than the respective two or more compounds.
  • the co-crystals of the present invention can be analyzed by methods well known in the art to characterize solid or crystalline materials. Examples of characterization methods include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and the like. TGA can be used to study residual solvents present in co-crystal samples and to identify the temperature at which decomposition of each co-crystal sample occurs. DSC can be used to observe the thermal-transitions that occur in eutectic samples as a function of temperature and to determine the melting point of each eutectic sample. XRPD can be used for structural characterization of co-crystals.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • XRPD X-ray powder diffraction
  • API is molecular or ionic
  • CCF is a physiologically acceptable acid, alkali, and non-ionic compound, which can be excipients, vitamins, minerals, amino acids, and food additives.
  • some API molecules can also be used as CCF, and the two APIs in this type of co-crystal generally have similar indications or have synergistic effects.
  • the formation of co-crystals does not necessarily improve the physicochemical properties of the API.
  • CN102816079 discloses 10 organic acid co-crystals of agomelatine, among which 5 kinds of co-crystals have higher dissolution rates than agomelatine, and 5 kinds of co-crystals have lower dissolution rates. It can be seen that the solubility of co-crystals is related to CCF. Selecting a suitable CCF helps to improve the solubility of drugs, while some will reduce the solubility of drugs. The stability of the co-crystal is also related to the type of CCF. It should be noted that the drug-drug co-crystal structure has long been a technical difficulty in the field. If there is a drug co-crystal that can satisfy the performance of improving dissolution and bioavailability, it can further satisfy the combined administration, which will have significant advantages. economic and social benefits.
  • the term "about” means that the specified numerical value may vary within a reasonable range, eg, within a range of not more than 5%, preferably not more than 1%.
  • bioavailability as used herein relates to a measure of the amount of active ingredient absorbed into the bloodstream after ingestion by the human body.
  • the composition of the formulation can affect the bioavailability of the active ingredient. Although the same active ingredient may be used in both formulations, the bioavailability of the active ingredient is not necessarily the same. Thus, the bioavailability of the active ingredient can vary significantly depending on formulation composition such as excipient ingredients and their amounts and grades.
  • the present invention successfully prepared a sorafenib-fluorouracil co-crystal (SOR-FU), and unexpectedly found that the co-crystal can produce further improved properties compared with existing active compounds, especially involving but not limited to: solubility, Dissolution, bioavailability, stability, Cmax, Tmax and processability, in addition, the co-crystal may play a pharmacological synergistic effect while improving the dissolution rate and bioavailability of sorafenib, and improve the treatment of cancer. Especially in the treatment of liver cancer.
  • the present invention is accomplished by the inventors based on the following findings:
  • the inventor has conducted in-depth research on the preparation of sorafenib. CCF) program.
  • CCF sorafenib.
  • the inventors of the present invention unexpectedly discovered that 5-fluorouracil (FU) can be used as CCF to form a drug-drug co-crystal structure with sorafenib free base , the co-crystal can effectively improve the dissolution rate of sorafenib, thereby improving the bioavailability of sorafenib.
  • the co-crystal can potentially exert the pharmacological synergistic effect of sorafenib and 5-fluorouracil. , so as to further improve the therapeutic effect of cancer, especially liver cancer and other original indications.
  • the present invention provides a co-crystal, according to an embodiment of the present invention, the co-crystal comprising: sorafenib free base; and 5-fluorouracil.
  • the co-crystal can effectively improve the dissolution rate of sorafenib, thereby improving the bioavailability of sorafenib.
  • the co-crystal can potentially exert the pharmacological effects of sorafenib and 5-fluorouracil.
  • the synergistic effect on cancer can further improve the therapeutic effect on the original indications such as cancer, especially liver cancer.
  • a sorafenib-fluorouracil co-crystal (SOR-FU) was prepared, which unexpectedly found that the co-crystal could yield further improved properties over existing active compounds, in particular but not limited to: solubility, dissolution, Bioavailability, stability, Cmax, Tmax and processability, in addition, the co-crystal may play a pharmacological synergistic effect while improving the dissolution rate and bioavailability of sorafenib, and improve the treatment of cancer, especially liver cancer. the therapeutic effect.
  • SOR-FU sorafenib-fluorouracil co-crystal
  • the co-crystal may play a pharmacological synergistic effect while improving the dissolution rate and bioavailability of sorafenib, and improve the therapeutic effect on cancer, especially liver cancer.
  • sorafenib is administered alone for a period of time, cancer cells will quickly develop drug resistance, so combination therapy is recommended in clinical practice.
  • the use of the co-crystal of the present invention can effectively avoid the drug resistance of cancer cells to the single administration of sorafenib.
  • the molar ratio of the sorafenib free base and the 5-fluorouracil is about 1:1.
  • the co-crystals have X-ray powders at 2 ⁇ of about 9.1, about 13.4, about 15.7, about 17.2, about 18.2, about 18.7, about 20.2, about 21.0, about 22.0, about 23.8, and about 27.4 Diffraction peaks, preferably, the co-crystal has substantially the same X-ray powder diffraction of the SOR-FU co-crystal as in FIG. 5 .
  • the DSC thermogram of the co-crystal exhibits a single melting point at about 225.4°C.
  • the present invention provides a pharmaceutical composition
  • the pharmaceutical composition contains the aforementioned co-crystal.
  • the co-crystal can effectively improve the dissolution rate of sorafenib, thereby improving the bioavailability of sorafenib.
  • the co-crystal can potentially exert the pharmacological effects of sorafenib and 5-fluorouracil.
  • the synergistic effect on cancer can further improve the therapeutic effect on the original indications such as cancer, especially liver cancer.
  • the co-crystals or pharmaceutical compositions (eg, cells) of the present invention may be administered to a subject in need thereof by any method that allows the co-crystals to be delivered, eg, by oral, intravenous or parenteral delivery. , tissue or patient (including animals or humans).
  • administration can be by pills, tablets, aerosols, suppositories, liquid formulations for ingestion or injection or as eye or ear drops, dietary supplements, and topical formulations.
  • the pharmaceutical composition further comprises at least one of a diluent, solvent, excipient, carrier or solubilizer.
  • the content of the active ingredient in the pharmaceutical composition can be lower than that of the conventional sorafenib tosylate tablet formulation, and the dosage of its administration Alternatively, the frequency of administration may be lower than that of the existing sorafenib tosylate tablets.
  • the present invention proposes a tablet containing a co-crystal according to an embodiment of the present invention, which is taken as a single dose, one tablet per day, and each tablet of the tablet contains free sorafenib
  • the content of the base is lower than the daily administered dose of existing sorafenib tosylate tablets.
  • the dosage of the tablet containing the co-crystal according to the embodiment of the present invention may be 350-760 mg/day.
  • the present invention also provides a method for preparing the aforementioned co-crystal, according to an embodiment of the present invention, the method comprises: mixing a stoichiometric proportion of sorafenib and 5-fluorouracil with The organic solvents are mixed; the resulting mixture is recrystallized to obtain the co-crystal.
  • the formation of drug co-crystals, especially drug-drug co-crystals has always been a technical difficulty in the pharmaceutical field.
  • the inventors of the present invention through arduous efforts, found that 5-fluorouracil can be used as a co-crystal of sorafenib.
  • the crystal former also forms a co-crystal with sorafenib as an active pharmaceutical ingredient, and as mentioned above, the co-crystal can effectively improve the dissolution rate of sorafenib, thereby improving the bioavailability of sorafenib, In addition, the co-crystal can potentially exert the pharmacological synergistic effect of sorafenib and 5-fluorouracil, thereby further improving the therapeutic effect on the original indications such as cancer, especially liver cancer.
  • the organic solvent includes at least one of methanol, ethanol, isopropanol, dichloromethane, chloroform and acetonitrile.
  • the recrystallization is performed at a temperature of 4-40° C. and a stirring speed of 5-2000 RPM for 40-50 hours.
  • the temperature can be 5, 8, 10, 15, 20, 25, 30, 35°C
  • the stirring speed can be 50, 100, 300, 500, 800, 1000, 1300, 1500, 1800 RPM.
  • the present invention proposes the use of the aforementioned co-crystal in the preparation of a medicament for the treatment of cancer.
  • the medicament is used to treat at least one selected from the group consisting of colon cancer, rectal cancer, gastric cancer, breast cancer, ovarian cancer, choriocarcinoma, malignant mole, head and neck squamous cell carcinoma, Skin cancer, liver cancer, bladder cancer, preferably liver cancer.
  • Sora Fini-fluorouracil co-crystal Sora Fini-fluorouracil co-crystal
  • Sora Fini-fluorouracil co-crystal SOR-FU, in the following Examples and its corresponding figures, the Sorafenib-fluorouracil co-crystal is denoted as SOR-FU).
  • Example 1 and Example 2 obtained the same co-crystal.
  • the above compounds are structural analogs of 5-fluorouracil. Although these substances are similar in structure to 5-fluorouracil, they cannot form co-crystals with sorafenib.
  • the precipitate obtained by co-stirring Sorafenib and 5-fluorouracil in methanol was characterized by PXRD. As shown in Figure 1, the PXRD pattern was in the range of 8-15°, 18-20°, and 22-27°. PXRD of the pure drug of fenib basically showed that no new co-crystal was formed between sorafenib and these substances, which indicated that such a co-crystal was not easily obtained.
  • PXRD was determined by co-stirring sorafenib with aspirin, piperazine, urea, tartaric acid, fumaric acid, maleic acid, metformin hydrochloride and other compounds in methanol.
  • the drug PXRD showed that no new co-crystals were formed between sorafenib and these substances, which further indicated that the formation of co-crystals between sorafenib and 5-fluorouracil was very difficult to find.
  • Example 1 or 2 The melting points of SOR (sorafenib free base), FU (5-fluorouracil) and SOR-FU (sorafenib-fluorouracil co-crystal) in Example 1 or 2 were determined by DSC by heating at 10°C/min. The Tonsets of their three melting points are 209.1°C, 281.2°C, and 225.4°C, respectively. Exemplary results are shown in Figure 3. From the results in this figure, it can be seen that the melting points of the three are obviously different, and the eutectic has a single melting point, so it shows that the eutectic prepared in Example 1 and Example 2 is indeed a kind of eutectic. new crystalline substance.
  • the degradation curves of SOR (sorafenib free base), FU (5-fluorouracil) and SOR-FU (sorafenib-fluorouracil co-crystal) in Example 1 or 2 were determined by using TGA at a temperature of 10°C/min.
  • the results show that the degradation curves of the three are significantly different, and the weight percentages after the degradation equilibrium are also significantly different.
  • the exemplary results are shown in Figure 4, indicating that the three are significantly different. Therefore, it is indicated that the co-crystal prepared in Example 1 and Example 2 is indeed a new crystalline substance.
  • SOR sinafenib free base
  • FU fluorouracil
  • SOR-FU sinafenib-fluorouracil co-crystal
  • SOR-FU Siliconefenib-Fluorouracil co-crystal
  • SOR-FU has basically the same diffraction peaks as the simulated diffraction peaks of the co-crystal. Therefore, it shows that the co-crystal prepared in Example 1 and Example 2 is indeed a new type of co-crystal. crystalline substance.
  • the present invention also conducts structural characterization of the SOR-FU single crystal obtained by the methanol evaporation method in Example 1, and specific, exemplary results are shown in FIG. 6 .
  • Sorafenib-fluorouracil co-crystal belongs to the triclinic crystal system, P-1 space point group. Its unit cell contains one SOR molecule and one FU molecule. The ordering of all atomic numbers of SOR and FU in the asymmetric unit is shown in Fig. 6(A).
  • the SOR-FU co-crystal and the SOR tosylate powder were placed in the DVS instrument, respectively, and the adsorption curves were measured. Exemplary results are shown in Figure 7. The results show that the water absorption results of the SOR-FU co-crystal and the SOR-listed tosylate show that the SOR-FU co-crystal is more hydrophobic than the SOR tosylate. Reduced hygroscopicity of SOR-FU co-crystals during drug storage.
  • sorafenib tosylate tablets and SOR-FU are prepared, the difference is that sorafenib tosylate is replaced with an equal weight of SOR-FU co-crystal, briefly Then, SOR-FU and SOR toluenesulfonic acid salt were added with 20% PVP, and then prepared into tablets under the condition of 800kgf 15s using a carver tablet machine. The obtained tablets were separately dissolved in 20 mL of 0.1 M HCl (0.1% tween80) solution for intrinsic tablet dissolution. Samples were taken at different time points to determine drug concentration after centrifugation, and exemplary results are shown in Figure 8. The SOR-FU co-crystal was found to have a similar intrinsic dissolution rate to the SOR salt.
  • the dissolution profile of the drug is shown in Figure 9, that is, the USPII dissolution of SOR salt and SOR-FU co-crystal in 0.1M HCl (0.1% Tween 80), and it can be seen that SOR-FU co-crystal has better performance than SOR salt. Dissolution effect.

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Abstract

La présente invention concerne un co-cristal contenant une base libre de sorafénib et du 5-fluorouracile, une composition pharmaceutique et leurs utilisations. Le co-cristal comprend : la base libre de sorafénib ; et du 5-fluorouracile. Le co-cristal selon la présente invention est capable d'augmenter de manière efficace la vitesse de dissolution du sorafénib, augmentant ainsi la biodisponibilité du sorafénib ; en outre, le co-cristal est potentiellement apte à fournir un effet pharmacologiquement synergique de sorafénib et de 5-fluorouracile, augmentant ainsi davantage l'effet thérapeutique vis-à-vis du cancer, et notamment des indications originales telles que le cancer du foie.
PCT/CN2020/123526 2020-10-26 2020-10-26 Co-cristal contenant une base libre de sorafénib et du 5-fluorouracile, composition pharmaceutique et leurs utilisations WO2022087763A1 (fr)

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