Oxaliplatin-flavonoid drug cocrystal and preparation method and application thereof

Abstract

The present invention relates to oxaliplatin-flavonoid drug cocrystals and preparation methods and applications thereof. Specifically, the present invention discloses a class of oxaliplatin-flavonoid drug cocrystals, which have excellent stability in artificial gastrointestinal fluid and can effectively reduce toxic side effects in practical applications.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to an oxaliplatin-flavonoid drug cocrystal and a preparation method and application thereof. Background Art

[0002] Oxaliplatin (OXA), chemically known as (trans-1R, 2R-diaminocyclohexane) oxalate platinum (II) (compound of formula I), is also known as oxalidine and oxalate platinum. Its chemical structure is as follows:

[0003]

[0004] Oxaliplatin was developed by Swiss company Debiopharm and produced and sold by French company Sanofi. It was first launched in France in October 1996. In 2004, the FDA approved the use of oxaliplatin for injection in combination with 5-fluorouracil and folinic acid as a first-line treatment for advanced colorectal cancer. Oxaliplatin has an alkylating effect and is an alkylating agent. It can form adducts with DNA, causing cross-linking between DNA chains, within DNA chains, and between DNA and protein molecules, making it impossible for the DNA double helix to be untied during transcription and translation, ultimately leading to cell apoptosis. However, oxaliplatin exhibits high cytotoxicity and has certain toxic side effects on the hematopoietic system, digestive system, and nervous system. When used in combination with 5-fluorouracil, these side effects increase significantly.

[0005] In addition, oxaliplatin is a water-soluble drug with active chemical properties. It has poor stability in the gastrointestinal tract and is easily chemically degraded to produce inactive or toxic compounds, which may have toxic or unknown side effects.

[0006] Therefore, the current research direction of oxaliplatin is to enhance its stability in solution, thereby further improving its efficacy and reducing its toxic side effects. Summary of the invention

[0007] The object of the present invention is to provide a class of oxaliplatin-flavonoid drug co-crystals and a preparation method and application thereof. The drug co-crystal has excellent stability in artificial gastrointestinal fluid.

[0008] In a first aspect of the present invention, an oxaliplatin-flavonoid drug co-crystal is provided, wherein the drug co-crystal is a co-crystal of oxaliplatin and a flavonoid compound.

[0009] In another preferred embodiment, the flavonoid compound is selected from the group consisting of naringenin, baicalein, kaempferol, quercetin, myricetin, fisetin, luteolin, apigenin, dihydromyricetin, or a combination thereof.

[0010] In another preferred embodiment, in the drug co-crystal, the molar ratio of oxaliplatin to flavonoid compound is 0.1-8, preferably 0.2-6, and more preferably 0.25-4.

[0011] In another preferred embodiment, the drug cocrystal is oxaliplatin-naringenin drug cocrystal or oxaliplatin-baicalein drug cocrystal.

[0012] In another preferred embodiment, the oxaliplatin-naringenin drug cocrystal has one or more characteristics selected from the following group:

[0013] 1) The XRPD spectrum of the oxaliplatin-naringenin drug cocrystal has characteristic peaks at the following 2θ values: 7.1±0.2°, 10.8±0.2°, 14.2±0.2°, 21.7±0.2°, 25.6±0.2°, 25.8±0.2°, 26.6±0.2°;

[0014] 2) The cocrystal space group of the oxaliplatin-naringenin drug cocrystal is monoclinic;

[0015] 3) The cocrystal space group of the oxaliplatin-naringenin drug cocrystal is P21;

[0016] 4) The oxaliplatin-naringenin drug cocrystal

[0017] 5) The oxaliplatin-naringenin drug cocrystal has α=90°, β=95.724(1)°, and γ=90°;

[0018] 6) The DSC spectrum of the oxaliplatin-naringenin drug cocrystal has an endothermic peak between 270-300°C.

[0019] In another preferred embodiment, the XRPD spectrum of the oxaliplatin-naringenin drug cocrystal has characteristic peaks at the following 2θ values: 7.1±0.2°, 10.8±0.2°, 11.3±0.2°, 12.8±0.2°, 14.2±0.2°, 14.6±0.2°, 16.5±0.2°, 16.9±0.2°, 18.6±0.2°, 19.0±0.2°, 19.5±0.2°, 21.0±0.2°, 21.7±0.2°, 22.3±0.2°, 22.5±0.2°, 25.6±0.2°, 25.8±0.2°, 26.2±0.2°, 26.6±0.2°, 27.8±0.2°, 29.4±0.2°, 31.3±0.2°, 32.4±0.2°, 34.0±0.2°, 34.6±0.2°, 35.4±0.2°, 36.2±0.2°, 37.7±0.2°, 40.4±0.2°, 43.2±0.2°.

[0020] In another preferred embodiment, the XRPD spectrum of the oxaliplatin-naringenin drug cocrystal has characteristic peaks at the following 2θ values: 7.1, 10.8, 11.3, 12.8, 14.2, 14.6, 16.5, 16.9, 18.6, 19.0, 19.5, 21.0, 21.7, 22.3, 22.5, 25.6, 25.8, 26.2, 26.6, 27.8, 29.4, 31.3, 32.4, 34.0, 34.6, 35.4, 36.2, 37.7, 40.4, 43.2°.

[0021] In another preferred embodiment, the XRPD pattern of the oxaliplatin-naringenin drug cocrystal is substantially as follows Figure 2 shown.

[0022] In another preferred embodiment, the DSC spectrum of the oxaliplatin-naringenin drug cocrystal is substantially as shown in Figure 3.

[0023] In another preferred embodiment, the TGA spectrum of the oxaliplatin-naringenin drug cocrystal is substantially as shown in Figure 4.

[0024] In another preferred embodiment, the oxaliplatin-baicalein drug cocrystal has one or more characteristics selected from the following group:

[0025] 1) The XRPD spectrum of the oxaliplatin-baicalein drug cocrystal has characteristic peaks at the following 2θ values: 7.8±0.2°, 11.5±0.2°, 15.3±0.2°, 17.8±0.2°, 19.1±0.2°, 35.3±0.2°;

[0026] 2) The cocrystal space group of the oxaliplatin-baicalein drug cocrystal is triclinic system;

[0027] 3) The cocrystal space group of the oxaliplatin-baicalein drug cocrystal is

[0028] 4) The oxaliplatin-baicalein drug cocrystal

[0029] 5) The oxaliplatin-baicalein drug cocrystal has α=85.450(1)°, β=84.324(1)°, and γ=86.311(1)°;

[0030] 6) The DSC spectrum of the oxaliplatin-baicalein drug cocrystal has an endothermic peak between 270-300°C.

[0031] In another preferred embodiment, the XRPD spectrum of the oxaliplatin-baicalein drug cocrystal has characteristic peaks at the following 2θ values: 7.8±0.2°, 11.5±0.2°, 11.6±0.2°, 15.3±0.2°, 15.4±0.2°, 17.7±0.2°, 17.8±0.2°, 18.5±0.2°, 19.1±0.2°, 20.4±0.2°, 20.6±0.2°, 21.2±0.2°, 21.4±0.2°, 21.8±0.2°, 22.8±0.2°, 23.2±0.2°, 24.8±0.2°, 25.8±0.2°, 26.8±0.2°, 27.8±0.2°, 28.8±0.2°, 29.8±0.2°, 30.8±0.2°, 31.3±0.2°, 32.3±0.2°, 33.3±0.2°, 34.3±0.2°, 35.3±0.2°, 36.3±0.2°, 37.3±0.2°, 38.3±0.2°, 39.4±0.2°, 40.5±0.2°, 41. 0.2°, 24.3±0.2°, 24.8±0.2°, 25.3±0.2°, 26.8±0.2°, 27.1±0.2°, 27.8±0.2°, 28.6±0.2°, 29.9±0.2°, 30.7±0.2°, 31.8±0.2°, 32.0±0.2°, 32.5±0.2°, 34.7±0.2°, 35.3±0.2°, 39.0±0.2°, 39.2±0.2°, 39.7±0.2°, 41.7±0.2°, 42.0°±0.2°.

[0032] In another preferred embodiment, the XRPD spectrum of the oxaliplatin-baicalein drug cocrystal has characteristic peaks at the following 2θ values: 7.8, 11.5, 11.6, 15.3, 15.4, 17.7, 17.8, 18.5, 19.1, 20.4, 20.6, 21.2, 21.4, 21.8, 22.8, 23.2, 24.3, 24.8, 25.3, 26.8, 27.1, 27.8, 28.6, 29.9, 30.7, 31.8, 32.0, 32.5, 34.7, 35.3, 39.0, 39.2, 39.7, 41.7, 42.0°.

[0033] In another preferred embodiment, the XRPD pattern of the oxaliplatin-baicalein drug cocrystal is substantially as follows Figure 6 shown.

[0034] In another preferred embodiment, the DSC spectrum of the oxaliplatin-baicalein drug cocrystal is substantially as shown in FIG7 .

[0035] In another preferred embodiment, the TGA spectrum of the oxaliplatin-baicalein drug cocrystal is substantially as shown in FIG8 .

[0036] The second aspect of the present invention provides a method for preparing the oxaliplatin-flavonoid drug cocrystal according to the first aspect of the present invention, comprising the following steps:

[0037] 1) providing a solid mixture of oxaliplatin and flavonoids and a first solvent;

[0038] 2) mixing the solid mixture and the first solvent to obtain a first mixed solution, and stirring and / or ultrasonically treating the first mixed solution to completely dissolve oxaliplatin and flavonoids;

[0039] 3) The mixed solution obtained in the above step is subjected to a solvent volatilization method to obtain the oxaliplatin-flavonoid drug co-crystal.

[0040] In another preferred embodiment, the molar ratio of oxaliplatin to flavonoids is 0.1-8, preferably 0.2-6, and more preferably 0.25-4.

[0041] In another preferred embodiment, the first solvent is selected from the group consisting of water, acetonitrile, methanol, ethanol, trifluoroethanol, propanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.

[0042] In another preferred embodiment, in step 2), the mixing ratio of the solid mixture and the first solvent is 1 mg / mL-10 mg / mL, preferably 4 mg / mL-6 mg / mL.

[0043] In another preferred embodiment, the solvent volatilization method is carried out at 10-40°C (preferably 15-35°C, more preferably 20-30°C).

[0044] In another preferred embodiment, the solvent volatilization method is carried out for 0.3-35 days, preferably 0.5-30 days, and more preferably 0.8-15 days.

[0045] The third aspect of the present invention provides a pharmaceutical composition comprising the oxaliplatin-flavonoid drug cocrystal according to the first aspect of the present invention and a pharmaceutically acceptable carrier.

[0046] The fourth aspect of the present invention provides a use of the oxaliplatin-flavonoid drug cocrystal according to the first aspect of the present invention for preparing a drug for preventing and / or treating a cancer selected from the following group: colorectal cancer, gastric cancer, and breast cancer.

[0047] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 It is the structural unit of the oxaliplatin-naringenin drug cocrystal prepared in Example 1.

[0049] Figure 2 This is the XRPD spectrum of the oxaliplatin-naringenin drug cocrystal prepared in Example 1.

[0050] Figure 3 This is the DSC spectrum of the oxaliplatin-naringenin drug cocrystal prepared in Example 1.

[0051] Figure 4 This is the TGA spectrum of the oxaliplatin-naringenin drug cocrystal prepared in Example 1.

[0052] Figure 5 It is the structural unit of the oxaliplatin-baicalein drug cocrystal prepared in Example 2.

[0053] Figure 6 This is the XRPD spectrum of the oxaliplatin-baicalein drug cocrystal prepared in Example 2.

[0054] Figure 7 This is the DSC spectrum of the oxaliplatin-baicalein drug cocrystal prepared in Example 2.

[0055] Figure 8 This is the TGA spectrum of the oxaliplatin-baicalein drug cocrystal prepared in Example 2.

[0056] Fig. 9 These are the dissolution curves of oxaliplatin, oxaliplatin-naringenin drug cocrystal and oxaliplatin-baicalin drug cocrystal in artificial gastric juice.

[0057] Fig.10 These are the dissolution curves of oxaliplatin, oxaliplatin-naringenin drug cocrystal and oxaliplatin-baicalin drug cocrystal in artificial intestinal fluid. DETAILED DESCRIPTION

[0058] After long and in-depth research, the inventor unexpectedly prepared an oxaliplatin-flavonoid drug co-crystal with excellent stability in artificial gastrointestinal fluid. The drug co-crystal uses flavonoid compounds as co-crystal ligands of oxaliplatin for the first time and is prepared by an easy-to-implement volatilization method. On this basis, the inventor completed the present invention.

[0059] Pharmaceutical cocrystal technology refers to a method of changing the physicochemical properties of active pharmaceutical molecules by selecting cocrystal ligands or cocrystal formers (CCF) and active pharmaceutical ingredients (API) to self-assemble into a new solid form under the induction of weak intermolecular forces such as hydrogen bonds, π-π stacking, and van der Waals forces. Such as solubility, dissolution rate, melting point, pharmacological activity, and stability. The greatest application value of pharmaceutical cocrystals is that they not only change the molecular structure of API itself, but also improve the physicochemical properties of API, and different cocrystal ligands will have different degrees of influence on the properties of active pharmaceutical ingredients. The emergence of pharmaceutical cocrystals has opened up a broader prospect for the practical application of API in the pharmaceutical field.

[0060] Based on the above considerations, natural flavonoid compounds with anti-tumor activity, such as naringenin and baicalein, were selected as ligands to form drug co-crystals with oxaliplatin, aiming to reduce hydrophilicity, reduce dissolution rate, alleviate degradation in the digestive tract, increase gastrointestinal stability, and reduce toxicity.

[0061] The present invention provides two new oxaliplatin drug co-crystals, which are respectively named oxaliplatin-naringenin and oxaliplatin-baicalein, and their structural formulas are shown in Table 1.

[0062] Table 1 Oxaliplatin drug cocrystal structure

[0063]

[0064] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the co-crystal of the present invention and with each other without significantly reducing the efficacy of the co-crystal. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0065] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0066] There is no particular limitation on the administration of the pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0067] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the cocrystals are mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizing agents, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0068] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0069] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0070] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0071] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0072] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0073] The dosage forms of the composition of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required when necessary.

[0074] The composition of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0075] Compared with the prior art, the present invention has the following main advantages:

[0076] (1) The oxaliplatin-flavonoid drug cocrystal has excellent stability in artificial gastrointestinal fluid;

[0077] (2) The oxaliplatin-flavonoid drug co-crystal has the characteristics of small toxic side effects and high efficacy;

[0078] (3) The oxaliplatin-flavonoid drug co-crystal has the characteristics of simple preparation method, low cost and easy scalability.

[0079] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for which specific conditions are not specified in the following examples are usually performed under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0080] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0081] Example 1 Preparation of Oxaliplatin-Naringenin Drug Cocrystal

[0082] 1.1 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of acetonitrile. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication, filtered, and the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0083] 1.2 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of ethanol. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0084] 1.3 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of water. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0085] 1.4 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in a mixed solvent of 3 mL of water, 5 mL of ethanol and 2 mL of acetone. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0086] 1.5 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of methanol solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0087] 1.6 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of ethyl acetate solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0088] 1.7 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 3 mL of trifluoroethanol solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0089] 1.8 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of tetrahydrofuran solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0090] 1.9 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 3 mL of dimethyl sulfoxide solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0091] 1.10 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 8 mL of isopropanol solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0092] 1.11 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 6 mL of methanol and 4 mL of ethyl acetate solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0093] 1.12 Oxaliplatin and naringenin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 8 mL of N,N-dimethylformamide solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-naringenin drug cocrystals.

[0094] 1.13 Oxaliplatin and naringenin are in a molar ratio of 4:1 to 1:4. Isopropanol solvent is added dropwise to assist grinding for 10 minutes. The product is placed in a transparent glass apparatus and then dissolved in 3 mL of water, 5 mL of ethanol and 2 mL of acetone solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are oxaliplatin-naringenin drug cocrystals.

[0095] 1.14 Oxaliplatin and naringenin are in a molar ratio of 4:1 to 1:4. Ethanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in a mixed solvent of 3 mL of methanol and 3 mL of acetonitrile. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are oxaliplatin-naringenin drug cocrystals.

[0096] The X-ray powder diffraction, operation and analysis steps in the present invention are as follows:

[0097] The diffractometer was a Rigaku Ultima IV powder diffractometer, which was irradiated with Cu-Kα (40 kV, 40 mA) and a D / tex Ultra detector at room temperature. The scanning range was from 3° to 45° in the 2θ interval, and the scanning speed was 20° / min.

[0098] The measurement differences associated with such X-ray powder diffraction analysis results are caused by a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors that occur when determining peak positions), and (e) the nature of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in displacements of all peaks in the same direction. When a flat support is used, small differences in sample height will result in large displacements of XRPD peak positions. Systematic studies have shown that sample height differences of 1 mm can result in peak displacements of up to 1° of 2θ. These displacements can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the displacements (applying the system calibration factor to all peak position values) or recalibrating the instrument. As described above, by applying the system calibration factor to make the peak positions consistent, measurement errors from different instruments can be corrected.

[0099] The oxaliplatin-naringenin drug cocrystal structural unit prepared by the present invention is as follows Figure 1 As shown, the eutectic space group is monoclinic, and the space group is P21. α=90°,β=95.724(1)°,γ=90°。 Its XRPD spectrum has diffraction peaks at 2θ values ​​of approximately 7.1, 10.8, 11.3, 12.8, 14.2, 14.6, 16.5, 16.9, 18.6, 19.0, 19.5, 21.0, 21.7, 22.3, 22.5, 25.6, 25.8, 26.2, 26.6, 27.8, 29.4, 31.3, 32.4, 34.0, 34.6, 35.4, 36.2, 37.7, 40.4, 43.2°, wherein the 2θ value error range is ±0.2, and the diffraction pattern is as follows Figure 2 As shown, the diffraction peaks of the XRPD pattern of oxaliplatin-naringenin drug cocrystal are listed in the following Table 2:

[0100] Table 2 XRPD diffraction peaks of oxaliplatin-naringenin drug cocrystals

[0101]

[0102]

[0103] The oxaliplatin-naringenin drug cocrystal in Example 1 was subjected to differential scanning calorimetry (DSC) analysis, and the operation and analysis steps were as follows:

[0104] A TA Q2000 differential scanning calorimeter was used with a N2 atmosphere and a heating rate of 10°C / min.

[0105] The DSC image of oxaliplatin-naringenin drug cocrystal is shown below: Figure 3 As shown, the endothermic peak corresponds to the melting process.

[0106] from Figure 3 It can be seen that the oxaliplatin-naringenin drug cocrystal has an endothermic peak between 270-300°C.

[0107] Thermogravimetric (TGA) analysis was performed on the oxaliplatin-naringenin drug cocrystal in Example 1, and the operation and analysis steps were as follows:

[0108] A TA Q500 thermogravimetric analyzer was used with a N2 atmosphere and a heating rate of 10°C / min.

[0109] The TGA image of oxaliplatin-naringenin drug cocrystal is shown below: Figure 4 As shown, it can be seen from the figure that there is basically no weight loss before decomposition.

[0110] Example 2 Preparation of Oxaliplatin-Baicalein Drug Cocrystal

[0111] 2.1 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of acetonitrile. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for ultrasonication, filtered, and the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-baicalein drug cocrystals.

[0112] 2.2 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of ethanol. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are the oxaliplatin-baicalein drug cocrystals.

[0113] 2.3 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of water. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are the oxaliplatin-baicalein drug cocrystals.

[0114] 2.4 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in a mixed solvent of 3 mL of water, 5 mL of ethanol and 2 mL of acetone. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are the oxaliplatin-baicalein drug cocrystals.

[0115] 2.5 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of methanol solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are the oxaliplatin-baicalein drug cocrystals.

[0116] 2.6 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of ethyl acetate solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are the oxaliplatin-baicalein drug cocrystals.

[0117] 2.7 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 3 mL of trifluoroethanol solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are the oxaliplatin-baicalein drug cocrystals.

[0118] 2.8 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 10 mL of tetrahydrofuran solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are the oxaliplatin-baicalein drug cocrystals.

[0119] 2.9 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 3 mL of dimethyl sulfoxide solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-baicalein drug cocrystals.

[0120] 2.10 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 8 mL of isopropanol solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are the oxaliplatin-baicalein drug cocrystals.

[0121] 2.11 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 6 mL of methanol and 4 mL of ethyl acetate solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are the oxaliplatin-baicalein drug cocrystals.

[0122] 2.12 Oxaliplatin and baicalein are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 8 mL of N,N-dimethylformamide solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are oxaliplatin-baicalein drug cocrystals.

[0123] 2.13 Oxaliplatin and baicalein are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added to assist grinding for 10 minutes. The product is placed in a transparent glass apparatus and then dissolved in 3 mL of water, 5 mL of ethanol and 2 mL of acetone solvent. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are the oxaliplatin-baicalein drug cocrystals.

[0124] 2.14 Oxaliplatin and baicalein are mixed in a molar ratio of 4:1 to 1:4, and ethanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in a mixed solvent of 3 mL of methanol and 3 mL of acetonitrile. The glass container containing the mixed solution is placed on a stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at room temperature. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are the oxaliplatin-baicalein drug cocrystals.

[0125] The oxaliplatin-baicalein drug cocrystal structural unit prepared by the present invention is as follows Figure 5 As shown, its eutectic space group is triclinic, and the space group is α=85.450(1)°, β=84.324(1)°, γ=86.311(1)°. Its XRPD spectrum has diffraction peaks at 2θ values ​​of approximately 7.8, 11.5, 11.6, 15.3, 15.4, 17.7, 17.8, 18.5, 19.1, 20.4, 20.6, 21.2, 21.4, 21.8, 22.8, 23.2, 24.3, 24.8, 25.3, 26.8, 27.1, 27.8, 28.6, 29.9, 30.7, 31.8, 32.0, 32.5, 34.7, 35.3, 39.0, 39.2, 39.7, 41.7, and 42.0°, wherein the 2θ value error range is ±0.2, and the diffraction pattern is as follows: Figure 6 As shown, the diffraction peaks of the XRPD pattern of oxaliplatin-baicalein drug cocrystal are listed in the following Table 3:

[0126] Table 3 XRPD diffraction peaks of oxaliplatin-baicalein drug cocrystal

[0127]

[0128]

[0129]

[0130] The oxaliplatin-baicalein drug cocrystal in Example 2 was subjected to differential scanning calorimetry (DSC) analysis, and the operation and analysis steps were as follows:

[0131] A TA, Q2000 differential scanning calorimeter was used with a N2 atmosphere and a heating rate of 10°C / min.

[0132] The DSC graph of oxaliplatin-baicalein drug cocrystal is shown below: Figure 7 As shown, the endothermic peak corresponds to the melting process.

[0133] from Figure 7 It can be seen that the oxaliplatin-baicalein drug cocrystal has an endothermic peak between 270-300℃.

[0134] The oxaliplatin-baicalein drug cocrystal in Example 2 was subjected to thermogravimetric (TGA) analysis, and the operation and analysis steps were as follows:

[0135] A TA,Q500 thermogravimetric analyzer was used with a N2 atmosphere and a heating rate of 10°C / min.

[0136] The TGA image of oxaliplatin-baicalein drug cocrystal is shown below: Figure 8 As shown, it can be seen from the figure that there is basically no weight loss before decomposition.

[0137] Example 3 Dissolution rate of oxaliplatin drug cocrystal

[0138] Instrument: Agilent 1260 high performance liquid chromatograph; Chromatographic column: AHMADZU VP-ODS C18 column (5μm, 250mm×4.6mm); Mobile phase: A: water, B: methanol; A / B=90 / 10 (V / V); Detection wavelength: 230nm; Flow rate: 1mL / min; Injection volume: 20μL; Column temperature: 25℃

[0139] After grinding the oxaliplatin drug cocrystal and the oxaliplatin raw material itself, they were passed through a 100-mesh sieve, and 10 mg of oxaliplatin and oxaliplatin drug cocrystals with corresponding contents were weighed and dissolved in artificial gastric juice and artificial intestinal juice dissolution media, respectively. Samples were taken at regular intervals, filtered through a 0.45 μm microporous filter membrane, and the solution concentration at each time point was monitored by high-performance liquid chromatography. When oxaliplatin was degraded, the retention rate was calculated. Due to the hydrophilicity of oxaliplatin, oxaliplatin dissolves rapidly in artificial simulated gastric juice and intestinal juice, and extremely degraded. Among them, the degradation of oxaliplatin in artificial gastric juice is more serious, and the content of oxaliplatin is only 3.91% after 3 hours. The drug cocrystal of oxaliplatin dissolves slowly in artificial gastric juice, reducing its dissolution rate. After 3 hours, the content of oxaliplatin has a more obvious increase, and the retention rate of oxaliplatin-naringenin drug cocrystal reaches 22.4%. Although the stability of oxaliplatin in artificial intestinal fluid is higher than that in artificial gastric fluid, it also undergoes significant degradation. After 8 hours, the concentration of oxaliplatin is 63.73%. The concentration and retention rate of oxaliplatin in the formed new drug cocrystal are higher than that of oxaliplatin itself, and both can reach a retention rate of more than 90%, as shown in Table 4 below.

[0140] Table 4 Retention rate of oxaliplatin and its cocrystal in artificial gastrointestinal fluid

[0141]

[0142] Example 4 Cell proliferation-toxicity experiment of oxaliplatin drug cocrystal

[0143] The oxaliplatin-baicalein drug cocrystal and oxaliplatin-naringenin drug cocrystal prepared by the method of the present invention were used to perform cell proliferation-toxicity assays, and the screened cells included: human gastric mucosal epithelial cells GES-1 and human gastric adenocarcinoma cells SGC-7901. The specific experimental method is as follows:

[0144] 1. Digest, count and prepare the cells to a concentration of 5×10 4 100 μL of cell suspension (5×10 cells / mL) was added to each well of a 96-well cell culture plate. 3 cells);

[0145] 2. Human gastric epithelial cells and human gastric adenocarcinoma cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum by volume at 37°C in a 5% CO2 incubator;

[0146] 3. Add 100 μL of the corresponding working solution to each well, and set up 3 replicate wells for each concentration;

[0147] 4. After the cells were cultured in a 37°C, 5% CO2 incubator for 24 hours, the supernatant was discarded and the cells were washed once with culture medium;

[0148] 5. Stain the 96-well plate with CCK-8 and add 100 μL CCK-8 working solution (V 培养液 :V CCK-8原液 =10:1), and continue culturing in the incubator for 3 hours; set λ=450nm, read the absorbance A value of each well with an enzyme-labeled instrument, and calculate the cell proliferation rate.

[0149] Cell proliferation rate (%) = A value of experimental group / A value of control group * 100%

[0150] SPSS software was used to calculate the half inhibitory concentration (IC 50 ) value, IC of oxaliplatin and its cocrystal 50 The values ​​are shown in Table 5 below.

[0151] Table 5 Half inhibitory concentration values ​​of oxaliplatin and its cocrystals

[0152]

[0153] The experimental results show that:

[0154] 1) The half inhibitory concentration (IC50) of the oxaliplatin-naringenin drug cocrystal prepared by the method of the present invention on human gastric mucosal epithelial cells GES-1 50 ) value is 1063.5mg / L, and its cytotoxicity is much lower than that of oxaliplatin (489.1mg / L). Its inhibitory effect on human gastric adenocarcinoma cell SGC-7901 is slightly better than that of oxaliplatin. The IC values ​​of oxaliplatin and oxaliplatin-naringenin cocrystal on this cell are 50 The values ​​are 208.9 mg / L and 186.1 mg / L respectively.

[0155] 2) Oxaliplatin-baicalein drug cocrystal has inhibitory effects on human gastric adenocarcinoma cells SGC-7901 and human gastric mucosal epithelial cells GES-1. Its inhibitory effect on human gastric adenocarcinoma cells is more obvious. On the basis of achieving the same inhibitory effect as oxaliplatin, its toxicity is reduced.

[0156] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. Oxaliplatin-flavonoid drug cocrystal, characterized in that: The drug co-crystal is an oxaliplatin-naringenin drug co-crystal or an oxaliplatin-baicalin drug co-crystal; Among them, the XRPD spectrum of the oxaliplatin-naringenin drug cocrystal has characteristic peaks at the following 2θ values: 7.1±0.2°, 10.8±0.2°, 14.2±0.2°, 21.7±0.2°, 25.6±0.2°, 25.8±0.2°, 26.6±0.2°; The XRPD spectrum of oxaliplatin-baicalein drug cocrystal has characteristic peaks at the following 2θ values: 7.8±0.2°, 11.5±0.2°, 15.3±0.2°, 17.8±0.2°, 19.1±0.2°, and 35.3±0.2°.

2. The pharmaceutical co-crystal according to claim 1, characterized in that The oxaliplatin-naringenin drug co-crystal has one or more characteristics selected from the following group: 1) The cocrystal space group of the oxaliplatin-naringenin drug cocrystal is a monoclinic system; 2) The cocrystal space group of the oxaliplatin-naringenin drug cocrystal is P21; 3) The oxaliplatin-naringenin drug cocrystal 4) The oxaliplatin-naringenin drug cocrystal has α=90°, β=95.724(1)°, and γ=90°; 5) The DSC spectrum of the oxaliplatin-naringenin drug cocrystal has an endothermic peak between 270-300°C.

3. The pharmaceutical co-crystal according to claim 1, characterized in that The oxaliplatin-baicalein drug co-crystal has one or more characteristics selected from the following group: 1) The cocrystal space group of the oxaliplatin-baicalein drug cocrystal is triclinic system; 2) The cocrystal space group of the oxaliplatin-baicalein drug cocrystal is 3) The oxaliplatin-baicalein drug cocrystal 4) The oxaliplatin-baicalein drug cocrystal has α=85.450(1)°, β=84.324(1)°, γ=86.311(1)°; 5) The DSC spectrum of the oxaliplatin-baicalein drug cocrystal has an endothermic peak between 270-300°C.

4. A method for preparing the oxaliplatin-naringenin drug cocrystal according to claim 1, characterized in that: The steps include: 1) providing a solid mixture of oxaliplatin and naringenin and a first solvent; 2) mixing the solid mixture and the first solvent to obtain a first mixed solution, and stirring and / or ultrasonically treating the first mixed solution to completely dissolve oxaliplatin and naringenin; 3) The mixed solution obtained in the above steps is subjected to a solvent volatilization method to obtain the oxaliplatin-naringenin drug cocrystal.

5. A method for preparing the oxaliplatin-baicalein drug cocrystal according to claim 1, characterized in that: The steps include: 1) providing a solid mixture of oxaliplatin and baicalein and a first solvent; 2) mixing the solid mixture and the first solvent to obtain a first mixed solution, and stirring and / or ultrasonically treating the first mixed solution to completely dissolve oxaliplatin and baicalein; 3) The mixed solution obtained in the above step is subjected to a solvent volatilization method to obtain the oxaliplatin-baicalein drug cocrystal.

6. The preparation method according to claim 4, characterized in that: The molar ratio of oxaliplatin to naringenin is 0.1-8.

7. The preparation method according to claim 5, characterized in that: The molar ratio of oxaliplatin to baicalein is 0.1-8.

8. The method according to claim 4 or 5, characterized in that The first solvent is selected from the group consisting of water, acetonitrile, methanol, ethanol, trifluoroethanol, propanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.

9. A pharmaceutical composition, characterized in that It comprises the oxaliplatin-flavonoid drug cocrystal according to claim 1 and a pharmaceutically acceptable carrier.

10. A use of the oxaliplatin-flavonoid drug cocrystal according to claim 1, characterized in that: Used for preparing a drug for preventing and / or treating cancer, wherein the cancer is selected from the following group: colorectal cancer, gastric cancer, and breast cancer.

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