CN111205332A - Oxaliplatin-flavone pharmaceutical co-crystal and preparation method and application thereof - Google Patents
Oxaliplatin-flavone pharmaceutical co-crystal and preparation method and application thereof Download PDFInfo
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- CN111205332A CN111205332A CN202010118569.3A CN202010118569A CN111205332A CN 111205332 A CN111205332 A CN 111205332A CN 202010118569 A CN202010118569 A CN 202010118569A CN 111205332 A CN111205332 A CN 111205332A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
Abstract
The invention relates to an oxaliplatin-flavone pharmaceutical co-crystal and a preparation method and application thereof. Specifically, the invention discloses oxaliplatin-flavone pharmaceutical co-crystals which have excellent stability in artificial gastrointestinal fluids and can effectively reduce toxic and side effects in practical application.
Description
Technical Field
The invention relates to the field of medicines, in particular to oxaliplatin-flavone pharmaceutical co-crystals and a preparation method and application thereof.
Background
Oxaliplatin (OXA), known by the chemical name (trans-1R, 2R-diaminocyclohexane) platinum (ii) oxalate (compound of formula I), also known as levofloxacin, platinum oxalate, has the following chemical structural formula:
oxaliplatin was developed by Debiopharm, Switzerland, produced and sold by the company Sannofy, France, and was first marketed in France 10 months in 1996. Oxaliplatin for injection was approved by the FDA in 2004 for use in combination with 5-fluorouracil and folinic acid for first-line treatment of advanced colorectal cancer. Oxaliplatin has an alkylating effect and can form an adduct with DNA to cause cross-linking among DNA strands, in the strand and between DNA-protein molecules, so that the DNA double strands cannot be separated in the process of transcription and translation, and finally, the cell apoptosis is caused. However, oxaliplatin exhibits high cytotoxicity, produces certain toxic and side effects on the hematopoietic system, the digestive system and the nervous system, and these side effects are significantly increased when used in combination with 5-fluorouracil.
In addition, oxaliplatin is a water-soluble drug that is chemically active, poorly stable in the gastrointestinal tract, susceptible to chemical degradation, and produces inactive or toxic compounds that may present toxic or unknown side effects.
Therefore, the research direction of oxaliplatin is to enhance the stability of oxaliplatin in solution, so as to further improve the drug effect and reduce the toxic and side effects of oxaliplatin.
Disclosure of Invention
The invention aims to provide an oxaliplatin-flavone pharmaceutical co-crystal, and a preparation method and application thereof. The pharmaceutical co-crystal has excellent stability in artificial gastrointestinal fluids.
In a first aspect of the invention, an oxaliplatin-flavone pharmaceutical co-crystal is provided, wherein the pharmaceutical co-crystal is a co-crystal of oxaliplatin and a flavonoid compound.
In another preferred embodiment, the flavonoid is selected from the group consisting of: naringenin, baicalein, kaempferol, quercetin, myricetin, fisetin, luteolin, apigenin, dihydromyricetin, or combinations thereof.
In another preferred embodiment, the pharmaceutical co-crystal comprises oxaliplatin and a flavonoid compound in a molar ratio of 0.1 to 8, preferably 0.2 to 6, more preferably 0.25 to 4.
In another preferred example, the pharmaceutical co-crystal is an oxaliplatin-naringenin pharmaceutical co-crystal or an oxaliplatin-baicalein pharmaceutical co-crystal.
In another preferred embodiment, the oxaliplatin-naringenin pharmaceutical co-crystals have one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the oxaliplatin-naringenin medicament eutectic has characteristic peaks at the following 2 theta values: 7.1 +/-0.2 degrees, 10.8 +/-0.2 degrees, 14.2 +/-0.2 degrees, 21.7 +/-0.2 degrees, 25.6 +/-0.2 degrees, 25.8 +/-0.2 degrees and 26.6 +/-0.2 degrees;
2) the eutectic space group of the oxaliplatin-naringenin pharmaceutical cocrystal is a monoclinic system;
3) the eutectic space group of the oxaliplatin-naringenin pharmaceutical cocrystal is P21；
4) The oxaliplatin-naringenin pharmaceutical co-crystal
5) The oxaliplatin-naringenin pharmaceutical co-crystal is α degrees, β degrees, 95.724(1 degree) and gamma is 90 degrees;
6) the DSC spectrum of the oxaliplatin-naringenin medicament eutectic has an endothermic peak at the temperature of 270-300 ℃.
In another preferred embodiment, the XRPD pattern of the oxaliplatin-naringenin drug cocrystal has characteristic peaks at the following 2 theta 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 ± 0.7 +/-0.2 °, 31.3 +/-0.2 °, 32.4 +/-0.2 °, 34.2 ± 0.2 °.
In another preferred embodiment, the XRPD pattern of the oxaliplatin-naringenin drug cocrystal has characteristic peaks at the following 2 theta 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 °.
In another preferred embodiment, the XRPD pattern of the oxaliplatin-naringenin drug cocrystal is substantially as shown in figure 2.
In another preferred embodiment, the DSC pattern of the oxaliplatin-naringenin pharmaceutical cocrystal is basically shown as 3.
In another preferred embodiment, the TGA profile of the oxaliplatin-naringenin pharmaceutical co-crystal is substantially as shown in 4.
In another preferred embodiment, the oxaliplatin-baicalein pharmaceutical co-crystal has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the oxaliplatin-baicalein pharmaceutical co-crystal has characteristic peaks at the following 2 theta values: 7.8 +/-0.2 degrees, 11.5 +/-0.2 degrees, 15.3 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.1 +/-0.2 degrees and 35.3 +/-0.2 degrees;
2) the eutectic space group of the oxaliplatin-baicalein pharmaceutical co-crystal is a triclinic crystal system;
3) the eutectic space group of the oxaliplatin-baicalein pharmaceutical cocrystal is
4) The oxaliplatin-baicalein pharmaceutical co-crystal
5) α ═ 85.450(1) ° of the oxaliplatin-baicalein pharmaceutical co-crystal, β ═ 84.324(1) ° and gamma ═ 86.311(1) °;
6) the DSC spectrum of the oxaliplatin-baicalein drug cocrystal has an endothermic peak at the temperature of 270-300 ℃.
In another preferred example, the XRPD pattern of the oxaliplatin-baicalein pharmaceutical co-crystal has characteristic peaks at the following 2 theta 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 °, 24.3 +/-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 +/-0.2 °, 27.7 +/-0.7 ± 0.2 °, 39.7 +/-0.2 °, 39.3 ± 0.2.2 °, 39.3 ± 0.2 °, 2.3 ± 0.7 +/-0.2 °.
In another preferred example, the XRPD pattern of the oxaliplatin-baicalein pharmaceutical co-crystal has characteristic peaks at the following 2 theta 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 °.
In another preferred embodiment, the XRPD pattern of the oxaliplatin-baicalein pharmaceutical co-crystal is substantially as shown in figure 6.
In another preferred embodiment, the DSC pattern of the oxaliplatin-baicalein pharmaceutical co-crystal is basically shown as 7.
In another preferred embodiment, the TGA spectrum of the oxaliplatin-baicalein pharmaceutical co-crystal is substantially as shown in 8.
In a second aspect of the invention, a preparation method of the oxaliplatin-flavone pharmaceutical cocrystal is provided, which comprises the following steps:
1) providing a solid mixture of oxaliplatin and a flavonoid, 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 the oxaliplatin and the flavonoid compound;
3) and (3) preparing the oxaliplatin-flavone pharmaceutical co-crystal from the mixed solution obtained in the step (a) by a solvent volatilization method.
In another preferred embodiment, the molar ratio of oxaliplatin to flavonoid is 0.1 to 8, preferably 0.2 to 6, more preferably 0.25 to 4.
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-dimethylformamide, or a combination thereof.
In another preferred embodiment, in step 2), the mixing ratio of the solid mixture and the first solvent is 1mg/mL-10mg/mL, preferably 4mg/mL-6 mg/mL.
In another preferred embodiment, the solvent evaporation process is carried out at 10-40 deg.C (preferably 15-35 deg.C, more preferably 20-30 deg.C).
In another preferred embodiment, the solvent evaporation method is performed for 0.3 to 35 days, preferably 0.5 to 30 days, more preferably 0.8 to 15 days.
In a third aspect of the invention, a pharmaceutical composition is provided, which comprises the oxaliplatin-flavone pharmaceutical cocrystal of the first aspect of the invention and a pharmaceutically acceptable carrier.
In a fourth aspect of the invention there is provided a use of the oxaliplatin-flavone pharmaceutical co-crystals of the first aspect of the invention for the preparation of a medicament for the prevention and/or treatment of a cancer selected from the group consisting of: colorectal cancer, gastric cancer, breast cancer.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
Fig. 1 shows the structural unit of oxaliplatin-naringenin pharmaceutical co-crystal prepared in example 1.
FIG. 2 is an XRPD pattern of oxaliplatin-naringenin pharmaceutical co-crystals prepared in example 1.
FIG. 3 is a DSC of oxaliplatin-naringenin pharmaceutical co-crystals prepared in example 1.
FIG. 4 is a TGA spectrum of oxaliplatin-naringenin pharmaceutical co-crystals prepared in example 1.
Fig. 5 shows structural units of oxaliplatin-baicalein pharmaceutical co-crystals prepared in example 2.
FIG. 6 is an XRPD pattern of oxaliplatin-baicalein pharmaceutical co-crystals prepared in example 2.
FIG. 7 is a DSC chart of oxaliplatin-baicalein pharmaceutical co-crystal prepared in example 2.
FIG. 8 is a TGA spectrum of oxaliplatin-baicalein pharmaceutical co-crystals prepared in example 2.
Fig. 9 is a dissolution curve of oxaliplatin, oxaliplatin-naringenin pharmaceutical co-crystal and oxaliplatin-baicalein pharmaceutical co-crystal in artificial gastric juice.
Fig. 10 is a dissolution curve of oxaliplatin, oxaliplatin-naringenin pharmaceutical co-crystal and oxaliplatin-baicalein pharmaceutical co-crystal in an artificial intestinal fluid.
Detailed Description
The inventor has conducted long-term and intensive studies and unexpectedly prepared an oxaliplatin-flavone pharmaceutical co-crystal having excellent stability in artificial gastrointestinal fluids. The pharmaceutical co-crystal takes flavonoid compounds as co-crystal ligands of oxaliplatin for the first time and is prepared by a volatilization method which is easy to implement. On this basis, the inventors have completed the present invention.
The pharmaceutical cocrystal technology is a method of changing the physicochemical properties of pharmaceutically active molecules by selecting cocrystal ligands or cocrystal formers (CCFs) and pharmaceutically active molecules (APIs) that can self-assemble into new solid forms under the induction of intermolecular weak forces such as hydrogen bonding, pi-pi stacking, van der waals forces, etc. Such as solubility, dissolution rate, melting point, pharmacological activity and stability, etc. The maximum application value of the pharmaceutical co-crystal is that the pharmaceutical co-crystal not only changes the molecular structure of the API, but also improves the physicochemical properties of the API, and different co-crystal ligands can generate different degrees of influence on the properties of pharmaceutical active ingredients. The appearance of pharmaceutical co-crystals opens a wider prospect for realizing the practical application of API in the pharmaceutical field.
Based on the consideration, natural flavonoid compounds with anti-tumor activity, such as naringenin and baicalein, are selected as ligands and form pharmaceutical co-crystals with oxaliplatin, aiming at reducing hydrophilicity, reducing dissolution rate, relieving degradation in digestive tract, increasing gastrointestinal tract stability and reducing toxicity.
The invention provides two new pharmaceutical co-crystals of oxaliplatin, which are respectively named as oxaliplatin-naringenin and oxaliplatin-baicalein, and the structural formulas of the two new pharmaceutical co-crystals are shown in the table I.
TABLE-oxaliplatin pharmaceutical cocrystal structure
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of and intermixing with the co-crystals of the present invention without significantly reducing the potency of the co-crystals. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The medicine composition is injection, capsule, tablet, pill, powder or granule.
The mode of administration of the pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the co-crystals 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, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the compound or compounds in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise 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 nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compositions 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 which may be required if necessary.
The composition of the invention can be used for independent administration or combined administration with other pharmaceutically acceptable compounds (such as antitumor drugs).
Compared with the prior art, the invention has the following main advantages:
(1) the oxaliplatin-flavone pharmaceutical co-crystal has excellent stability in artificial gastrointestinal fluids;
(2) the oxaliplatin-flavone pharmaceutical co-crystal has the characteristics of small toxic and side effects and high drug effect;
(3) the oxaliplatin-flavone pharmaceutical co-crystal has the characteristics of simple preparation method, low cost and easiness for large-scale production.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1 preparation of oxaliplatin-naringenin pharmaceutical co-crystals
1.1 placing oxaliplatin and naringenin in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 10mL of acetonitrile, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, filtering, placing the solvent at room temperature for volatilization, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.2 placing oxaliplatin and naringenin in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 10mL of ethanol, placing a glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.3 placing oxaliplatin and naringenin in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 10mL of water, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.4 placing oxaliplatin and naringenin in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in a mixed solvent of 3mL of water, 5mL of ethanol and 2mL of acetone, placing a glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, after the powder is completely dissolved, placing the solvent at room temperature for volatilization, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.5 placing oxaliplatin and naringenin in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 10mL of methanol solvent, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.6 placing oxaliplatin and naringenin in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 10mL of ethyl acetate solvent, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.7 placing oxaliplatin and naringenin in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 3mL of trifluoroethanol solvent, placing a glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.8 putting oxaliplatin and naringenin in a transparent glass instrument according to the molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 10mL of tetrahydrofuran solvent, putting the glass container containing the mixed solution on a stirrer for stirring or putting the glass container in an ultrasonic instrument for ultrasonic treatment, after the powder is completely dissolved, putting the solvent at room temperature for volatilization, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.9 placing oxaliplatin and naringenin in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 3mL of dimethyl sulfoxide solvent, placing a glass container containing the mixed solution on a stirrer to stir or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature to volatilize after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.10 placing oxaliplatin and naringenin in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 8mL of isopropanol solvent, placing a glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.11 placing oxaliplatin and naringenin in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 6mL of methanol and 4mL of ethyl acetate solvent, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.12 placing oxaliplatin and naringenin in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and naringenin together in 8mL of N, N-dimethylformamide solvent, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.13, dropping an isopropanol solvent to assist grinding for 10min, placing a product in a transparent glass instrument, then dissolving the product in 3mL of water, 5mL of ethanol and 2mL of acetone solvent together, placing a glass container containing the mixed solution on a stirrer to stir or placing the glass container in an ultrasonic instrument for ultrasonic treatment, volatilizing the solvent at room temperature after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
1.14 adding an ethanol solvent dropwise to assist grinding for 20min, placing the product in a transparent glass instrument, dissolving the product in a mixed solvent of 3mL of methanol and 3mL of acetonitrile, placing a glass container containing the mixed solution on a stirrer to stir or placing the glass container in an ultrasonic instrument for ultrasonic treatment, after the powder is completely dissolved, placing the solvent at room temperature to volatilize, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-naringenin pharmaceutical co-crystal.
The X-ray powder diffraction, operation and analysis steps of the invention are as follows:
using a Rigaku Ultima IV powder diffractometer illuminated with Cu-K α (40kV, 40mA) at room temperature using a D/tex Ultra detector, the scanning range was from 3 DEG to 45 DEG in the 2 theta interval and the scanning speed was 20 DEG/min
The differences in measurements associated with such X-ray powder diffraction analysis results arise from a number of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors in determining peak position), and (e) properties of the substance (e.g., preferred orientation errors). Calibration errors and sample height errors often result in a shift of all peaks in the same direction. When a flat holder is used, small differences in sample height will result in large shifts in XRPD peak positions. Systematic studies show that sample height differences of 1mm can result in peak shifts of 2 θ up to 1 °. These shifts can be identified from the X-ray diffraction patterns and can be eliminated by compensating for them (using the system calibration factor for all peak position values) or recalibrating the instrument. As described above, measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent.
The oxaliplatin-naringenin pharmaceutical eutectic structural unit prepared by the invention is shown in figure 1, a eutectic space group is a monoclinic system, and the space group is P21，
α ° 90 °, β ° 95.724(1) ° γ 90 °. XRPD pattern having diffraction peaks at 2 θ values of about 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 °, with an error range of 2 θ values of ± 0.2, and a derivative of the twoAs shown in fig. 2, the diffraction peaks of the XRPD pattern of the oxaliplatin-naringenin pharmaceutical cocrystal are listed in the following table two:
table two oxaliplatin-naringenin pharmaceutical co-crystals XRPD diffraction peaks
Differential Scanning Calorimetry (DSC) analysis was performed on the oxaliplatin-naringenin pharmaceutical co-crystals of example 1, with the following operating and analytical steps:
using a TA Q2000 differential scanning calorimeter with N2The temperature rise rate is 10 ℃/min under the atmosphere.
A DSC diagram of the oxaliplatin-naringenin pharmaceutical co-crystal is shown in fig. 3, in which an endothermic peak corresponds to a melting process.
As can be seen from fig. 3: the oxaliplatin-naringenin pharmaceutical co-crystal has an endothermic peak at the temperature of 270-300 ℃.
Thermogravimetric (TGA) analysis of the oxaliplatin-naringenin drug cocrystal of example 1 was performed with the following operating and analytical steps:
using TA Q500 thermogravimetric analyzer and N2The temperature rise rate is 10 ℃/min under the atmosphere.
The TGA of the oxaliplatin-naringenin pharmaceutical co-crystal is shown in fig. 4, and it is understood from the graph that there is substantially no weight loss before decomposition.
Example 2 preparation of oxaliplatin-baicalein pharmaceutical co-crystals
2.1 placing oxaliplatin and baicalein in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein together in 10mL of acetonitrile, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, filtering, placing the solvent at room temperature for volatilization, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.2 placing oxaliplatin and baicalein in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein together in 10mL of ethanol, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.3 placing oxaliplatin and baicalein in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein in 10mL of water together, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.4 placing oxaliplatin and baicalein in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein together in a mixed solvent of 3mL of water, 5mL of ethanol and 2mL of acetone, placing a glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, after the powder is completely dissolved, placing the solvent at room temperature for volatilization, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.5 placing oxaliplatin and baicalein in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein together in 10mL of methanol solvent, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.6 placing oxaliplatin and baicalein in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein together in 10mL of ethyl acetate solvent, placing a glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.7 placing oxaliplatin and baicalein in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein together in 3mL of trifluoroethanol solvent, placing a glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.8 putting oxaliplatin and baicalein in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein together in 10mL of tetrahydrofuran solvent, putting the glass container containing the mixed solution on a stirrer for stirring or putting the glass container in an ultrasonic instrument for ultrasonic treatment, after the powder is completely dissolved, putting the solvent at room temperature for volatilization, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.9 placing oxaliplatin and baicalein in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein in 3mL of dimethyl sulfoxide solvent together, placing a glass container containing the mixed solution on a stirrer to stir or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature to volatilize after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.10 placing oxaliplatin and baicalein in a transparent glass instrument according to a molar ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein together in 8mL of isopropanol solvent, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.11 placing oxaliplatin and baicalein in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein in 6mL of methanol and 4mL of ethyl acetate solvent together, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.12 placing oxaliplatin and baicalein in a transparent glass instrument according to the mol ratio of 4: 1-1: 4, then dissolving the oxaliplatin and the baicalein in 8mL of N, N-dimethylformamide solvent together, placing the glass container containing the mixed solution on a stirrer for stirring or placing the glass container in an ultrasonic instrument for ultrasonic treatment, placing the solvent at room temperature for volatilization after the powder is completely dissolved, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
2.13 according to the mol ratio of 4: 1-1: 4, adding an isopropanol solvent dropwise to assist grinding for 10min, placing the product in a transparent glass instrument, then dissolving the product in 3mL of water, 5mL of ethanol and 2mL of acetone solvent together, placing a glass container containing the mixed solution on a stirrer to stir or placing the glass container in an ultrasonic instrument for ultrasonic treatment, after the powder is completely dissolved, placing the solvent at room temperature to volatilize, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical cocrystal crystal.
2.14 according to the mol ratio of 4: 1-1: 4, adding an ethanol solvent dropwise to assist grinding for 20min, placing the product in a transparent glass instrument, then dissolving the product in a mixed solvent of 3mL of methanol and 3mL of acetonitrile, placing a glass container containing the mixed solution on a stirrer to stir or placing the glass container in an ultrasonic instrument for ultrasonic treatment, after the powder is completely dissolved, placing the solvent at room temperature to volatilize, and generating crystals after 1-30 days by a solvent volatilization method, namely the oxaliplatin-baicalein pharmaceutical co-crystal.
The oxaliplatin-baicalein pharmaceutical cocrystal structural unit prepared by the invention is shown in figure 5, the cocrystal space group is a triclinic crystal system, and the space group is
α 85.450(1) ° β 84.324(1) ° and γ 86.311(1) ° with XRPD pattern at 2 θ values of about 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, 32.8, 27.8Diffraction peaks at 0, 32.5, 34.7, 35.3, 39.0, 39.2, 39.7, 41.7 and 42.0 degrees with 2 theta error within ± 0.2 are shown in figure 6, and the XRPD pattern of oxaliplatin-baicalein pharmaceutical co-crystals shows the diffraction peaks in the following table three:
XRPD diffraction peak of Epstein-Barr drug cocrystal
Differential Scanning Calorimetry (DSC) analysis was performed on the oxaliplatin-baicalein pharmaceutical co-crystals of example 2, with the following operating and analytical steps:
using TA, Q2000 differential scanning calorimeter and N2The temperature rise rate is 10 ℃/min under the atmosphere.
The DSC chart of the oxaliplatin-baicalein pharmaceutical co-crystal is shown in figure 7, wherein an endothermic peak corresponds to a melting process.
As can be seen from fig. 7: the oxaliplatin-baicalein drug cocrystal has an endothermic peak at the temperature of 270-300 ℃.
Thermogravimetric (TGA) analysis of the oxaliplatin-baicalein pharmaceutical co-crystal of example 2 was performed with the following operating and analytical steps:
using TA, Q500 thermogravimetric analyzer and N2The temperature rise rate is 10 ℃/min under the atmosphere.
The TGA profile of the oxaliplatin-baicalein pharmaceutical co-crystal is shown in fig. 8, and it can be seen that there is substantially no weight loss before decomposition.
Example 3 dissolution Rate of oxaliplatin drug cocrystals
The instrument comprises the following steps: agilent 1260 high performance liquid chromatograph; a chromatographic column: AHMADZU VP-ODS C18 column (5 μm,250 mm. times.4.6 mm); mobile phase: a is water, B is methanol; 90/10 (V/V); detection wavelength: 230 nm; flow rate: 1 mL/min; sample introduction amount: 20 mu L of the solution; column temperature: 25 deg.C
Grinding the oxaliplatin pharmaceutical co-crystal and the oxaliplatin raw material per se, sieving the ground material with a 100-mesh sieve, weighing oxaliplatin 10mg and the oxaliplatin pharmaceutical co-crystal with corresponding content, respectively dissolving the oxaliplatin pharmaceutical co-crystal and the oxaliplatin pharmaceutical co-crystal in an artificial gastric juice and an artificial intestinal juice dissolution medium, sampling at intervals, filtering through a 0.45-micrometer microporous filter membrane, monitoring the solution concentration at each time point by using a high-efficiency liquid phase, and calculating the retention rate after the oxaliplatin generates a degradation phenomenon. Due to the hydrophilicity of oxaliplatin, oxaliplatin rapidly dissolves in simulated gastric and intestinal fluids and undergoes extreme degradation. Wherein, the degradation phenomenon of oxaliplatin in artificial gastric juice is serious, and the content of oxaliplatin is only 3.91 percent after 3 hours. The oxaliplatin pharmaceutical co-crystal is slowly dissolved in the artificial gastric juice, so that the dissolution rate is reduced, the content of oxaliplatin is obviously improved after 3 hours, and the retention rate of the oxaliplatin-naringenin pharmaceutical co-crystal reaches 22.4 percent. Although the stability of the oxaliplatin in the artificial intestinal juice is higher than that of the oxaliplatin in the artificial gastric juice, the oxaliplatin is also degraded obviously, the concentration of the oxaliplatin is 63.73% after 8 hours, and the concentration and retention rate of the oxaliplatin in the formed novel pharmaceutical cocrystal are higher than that of the oxaliplatin per se, and the retention rate can reach more than 90%, which is detailed in the following table four.
TABLE-oxaliplatin and retention rate of co-crystal thereof in artificial gastrointestinal fluids
Example 4 cell proliferation-toxicity test of oxaliplatin drug cocrystals
The oxaliplatin-baicalein pharmaceutical co-crystal and the oxaliplatin-naringenin pharmaceutical co-crystal prepared by the method are used for cell proliferation-toxicity determination, and the cells to be screened comprise: human gastric mucosal epithelial cells GES-1 and human gastric adenocarcinoma cells SGC-7901. The specific experimental method is as follows:
1. digesting, counting and preparing the cells to the concentration of 5X 104Cell suspension/mL, 100. mu.L of cell suspension per well in a 96-well cell culture plate (5X 10 per well)3Individual cells);
2. placing human gastric mucosal epithelial cells and human gastric adenocarcinoma cells in RPMI-1640 medium containing 10% by volume fetal bovine serum at 37 deg.C and 5% CO2Culturing in an incubator;
3. adding 100 mu L of corresponding working solution into each hole, and setting 3 holes for each concentration;
4. cells were incubated at 37 ℃ with 5% CO2Culturing for 24h in an incubator, then discarding the supernatant, and washing the cells for 1 time by the culture solution;
5. the 96-well plate was stained with CCK-8, and 100. mu.L of CCK-8 working solution (V) was added to each wellCulture solution：VCCK-8 stock solution10: 1) continuously culturing for 3 hours in the incubator; and setting lambda to 450nm, reading the absorbance A value of each hole by using a microplate reader, and calculating the cell proliferation rate.
Cell proliferation rate (%). test group A value/control group A value 100%
The half Inhibitory Concentration (IC) was calculated using SPSS software50) Value, IC of oxaliplatin and co-crystals thereof50The values are detailed in table five below.
TABLE WU oxaliplatin and half maximal inhibitory concentration values of co-crystals thereof
The experimental results show that:
1) the oxaliplatin-naringenin pharmaceutical co-crystal prepared by the method has half Inhibitory Concentration (IC) on human gastric mucosal epithelial cell GES-150) The value is 1063.5mg/L, the cytotoxicity is far lower than that of oxaliplatin (489.1mg/L), the inhibition effect on human gastric adenocarcinoma cells SGC-7901 is slightly better than that of oxaliplatin, wherein IC of oxaliplatin and oxaliplatin-naringenin drug cocrystal on the cells50The values were 208.9mg/L and 186.1mg/L, respectively.
2) The oxaliplatin-baicalein pharmaceutical co-crystal has an inhibition effect on both human gastric adenocarcinoma cells SGC-7901 and human gastric mucosa epithelial cells GES-1, has a more obvious inhibition effect on human gastric adenocarcinoma cells, and realizes the reduction of toxicity on the basis of achieving the same inhibition effect with oxaliplatin.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. The oxaliplatin-flavone pharmaceutical co-crystal is characterized by being a co-crystal of oxaliplatin and a flavonoid compound.
2. The pharmaceutical co-crystal of claim 1, wherein the flavonoid is selected from the group consisting of: naringenin, baicalein, kaempferol, quercetin, myricetin, fisetin, luteolin, apigenin, dihydromyricetin, or combinations thereof.
3. The pharmaceutical co-crystal according to claim 1, wherein the molar ratio of oxaliplatin to flavonoids in the pharmaceutical co-crystal is from 0.1 to 8.
4. The pharmaceutical co-crystal of claim 1, wherein the pharmaceutical co-crystal is an oxaliplatin-naringenin pharmaceutical co-crystal or an oxaliplatin-baicalein pharmaceutical co-crystal.
5. The pharmaceutical co-crystal of claim 4, wherein the oxaliplatin-naringenin pharmaceutical co-crystal has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the oxaliplatin-naringenin medicament eutectic has characteristic peaks at the following 2 theta values: 7.1 +/-0.2 degrees, 10.8 +/-0.2 degrees, 14.2 +/-0.2 degrees, 21.7 +/-0.2 degrees, 25.6 +/-0.2 degrees, 25.8 +/-0.2 degrees and 26.6 +/-0.2 degrees;
2) the eutectic space group of the oxaliplatin-naringenin pharmaceutical cocrystal is a monoclinic system;
3) the oxaliplatin-naringenin drugThe eutectic space group of the eutectic crystal is P21；
4) The oxaliplatin-naringenin pharmaceutical co-crystal
5) The oxaliplatin-naringenin pharmaceutical co-crystal is α degrees, β degrees, 95.724(1 degree) and gamma is 90 degrees;
6) the DSC spectrum of the oxaliplatin-naringenin medicament eutectic has an endothermic peak at the temperature of 270-300 ℃.
6. The pharmaceutical co-crystal of claim 4, wherein the oxaliplatin-baicalein pharmaceutical co-crystal has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the oxaliplatin-baicalein pharmaceutical co-crystal has characteristic peaks at the following 2 theta values: 7.8 +/-0.2 degrees, 11.5 +/-0.2 degrees, 15.3 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.1 +/-0.2 degrees and 35.3 +/-0.2 degrees;
2) the eutectic space group of the oxaliplatin-baicalein pharmaceutical co-crystal is a triclinic crystal system;
3) the eutectic space group of the oxaliplatin-baicalein pharmaceutical cocrystal is P1A;
4) the oxaliplatin-baicalein pharmaceutical co-crystal
5) α ═ 85.450(1) ° of the oxaliplatin-baicalein pharmaceutical co-crystal, β ═ 84.324(1) ° and gamma ═ 86.311(1) °;
6) the DSC spectrum of the oxaliplatin-baicalein drug cocrystal has an endothermic peak at the temperature of 270-300 ℃.
7. A method of preparing oxaliplatin-flavone pharmaceutical co-crystals as claimed in claim 1, comprising the steps of:
1) providing a solid mixture of oxaliplatin and a flavonoid, 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 the oxaliplatin and the flavonoid compound;
3) and (3) preparing the oxaliplatin-flavone pharmaceutical co-crystal from the mixed solution obtained in the step (a) by a solvent volatilization method.
8. The method of claim 7, wherein the first solvent is selected from the group consisting of: water, acetonitrile, methanol, ethanol, trifluoroethanol, propanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, or a combination thereof.
9. A pharmaceutical composition comprising the oxaliplatin-flavone pharmaceutical co-crystals of claim 1 and a pharmaceutically acceptable carrier.
10. Use of oxaliplatin-flavone pharmaceutical co-crystals according to claim 1 for the preparation of a medicament for the prevention and/or treatment of a cancer selected from the group consisting of: colorectal cancer, gastric cancer, breast cancer.
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| WO2021170001A1 (en) * | 2020-02-25 | 2021-09-02 | 华东理工大学 | Oxaliplatin-flavonoid drug eutectic crystal, preparation method therefor and use thereof |
| CN114681465A (en) * | 2020-12-25 | 2022-07-01 | 华东理工大学 | Lobaplatin-flavone pharmaceutical co-crystal as well as preparation method and application thereof |
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| WO2006105725A1 (en) * | 2005-04-05 | 2006-10-12 | Shanghai Gloriayx Biopharmaceuticals Co., Ltd | A combination of luteolin and one of pt chemotherapeutics |
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| CN1915232A (en) * | 2005-08-12 | 2007-02-21 | 吴一心 | Combination of baicalin and medication of chemical treatment in platinum family |
| CN103494838B (en) * | 2013-09-30 | 2016-05-11 | 武汉大学 | A kind of chemotherapy medicine composition |
| CN116854745A (en) * | 2015-06-25 | 2023-10-10 | 新纳特产品公司 | Pharmaceutical co-crystal composition and use thereof |
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| WO2021170001A1 (en) * | 2020-02-25 | 2021-09-02 | 华东理工大学 | Oxaliplatin-flavonoid drug eutectic crystal, preparation method therefor and use thereof |
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