Lobaplatin-flavonoid drug cocrystal and preparation method and application thereof

Abstract

The present invention provides a class of lobaplatin-flavonoid drug cocrystals and a preparation method and application thereof. Specifically, the drug cocrystal is selected from the following group: lobaplatin-fisetin drug cocrystal, lobaplatin-myricetin drug cocrystal, lobaplatin-naringenin drug cocrystal, lobaplatin-luteolin drug cocrystal, lobaplatin-kaempferol drug cocrystal, or lobaplatin-quercetin drug cocrystal. In the drug cocrystal of the present invention, the dissolution rate of lobaplatin in intestinal fluid and gastric fluid is significantly slowed down, and the stability of lobaplatin in gastrointestinal fluid is significantly improved, which provides the possibility for the preparation of lobaplatin oral preparations. In addition, the lobaplatin-flavonoid drug cocrystal of the present invention can improve the anti-cancer effect of lobaplatin, reduce the dosage of lobaplatin, and thus reduce the side effects caused by lobaplatin.

Description

Technical Field

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

[0002] Lobaplatin (D219466, LBP) is 1,2-diamino-cyclobutane-lactic acid platinum (compound of formula I), and its chemical structure is as follows:

[0003]

[0004] Lobaplatin is a third-generation platinum anticancer drug innovatively developed by Asta Medica AG of Germany. In 2003, the State Food and Drug Administration approved lobaplatin as a national Class I new drug for marketing. Lobaplatin has an alkylating effect and is an alkylating agent. Alkylating agents can form carbon cations or other electrophilic group compounds in vivo, and then covalently bind to electron-rich groups (such as amino, sulfhydryl, hydroxyl, carboxyl, phosphate, etc.) in biological macromolecules (such as DNA, RNA, enzymes, etc.) in cells, causing them to lose their activity or break DNA molecules, thereby leading to tumor cell death. Lobaplatin is mainly used to treat breast cancer, small cell lung cancer and chronic myeloid leukemia, and has a similar and stronger inhibitory effect to cisplatin.

[0005] According to data released by the State Food and Drug Administration, the commercially available preparations of lobaplatin are mainly freeze-dried powder injections, which are generally administered intravenously with 5% glucose solution as the solvent in clinical practice. Oral administration is ineffective. So far, all platinum anti-tumor drugs on the market are administered by injection, and there is no orally effective platinum anti-tumor drug available for clinical use. Therefore, the development of oral preparations of platinum anti-tumor drugs is an important direction for anti-cancer chemotherapy research.

[0006] Lobaplatin is a water-soluble drug with active chemical properties. It has poor stability in the gastrointestinal tract and is prone to chemical degradation, which affects the oral absorption of the drug. Different crystal forms and salt forms of the drug may affect its dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent.

[0007] Therefore, there is an urgent need in the art to develop a new form of lobaplatin that reduces the hydrophilicity of lobaplatin, reduces the dissolution rate, increases gastrointestinal stability, and reduces digestive tract degradation. Summary of the invention

[0008] The object of the present invention is to provide a lobaplatin drug cocrystal which reduces the hydrophilicity of lobaplatin, reduces the dissolution rate, increases the gastrointestinal stability and reduces the digestive tract degradation.

[0009] In a first aspect, the present invention provides a lobaplatin-flavonoid drug cocrystal, wherein the drug cocrystal is selected from the following group: lobaplatin-fisetin drug cocrystal, lobaplatin-myricetin drug cocrystal, lobaplatin-naringenin drug cocrystal, lobaplatin-luteolin drug cocrystal, lobaplatin-kaempferol drug cocrystal, or lobaplatin-quercetin drug cocrystal.

[0010] In another preferred embodiment, the lobaplatin-filaxanthin drug cocrystal has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 12.3±0.2°, 17.4±0.2°, 17.6±0.2°, 25.4±0.2°, and 26.9±0.2°.

[0011] In another preferred embodiment, the lobaplatin-filaxanthin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 8.7±0.2°, 11.2±0.2°, 12.7±0.2°, 14.7±0.2°, 30.7±0.2°.

[0012] In another preferred embodiment, the lobaplatin-filaxanthin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 17±0.2°, 18.5±0.2°, 24.1±0.2°, 26.1±0.2°, 27.9±0.2°.

[0013] In another preferred embodiment, the lobaplatin-fisetin drug cocrystal has one or more of the following characteristics:

[0014] (a) the molar ratio of lobaplatin to fisetin in the lobaplatin-fisetin drug cocrystal is 1:1;

[0015] (b) the differential scanning calorimetry spectrum of the lobaplatin-fisetin drug cocrystal has a maximum peak at 169.2°C±2°C (or ±1°C, or ±0.5°C); and / or

[0016] (c) The thermogravimetric spectrum of the lobaplatin-fisetin drug cocrystal is between 40 and 150° C., with a weight loss of 2.73%±0.3% (or ±0.2%, or ±0.1%).

[0017] In another preferred embodiment, the lobaplatin-fisetin drug cocrystal has one or more of the following characteristics:

[0018] (a) The X-ray powder diffraction spectrum of the lobaplatin-fisetin drug cocrystal is substantially as follows Figure 8 As shown;

[0019] (b) The lobaplatin-fisetin drug co-crystal has substantially Figure 3 The differential scanning calorimetry (DSC) spectrum shown in curve (c); and / or

[0020] (c) The lobaplatin-fisetin drug co-crystal has substantially Fig. 9 Thermogravimetric spectra (TGA) are shown.

[0021] In another preferred embodiment, the lobaplatin-myricetin drug cocrystal has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 8.8±0.2°, 16.9±0.2°, 17.7±0.2°, 21±0.2°, 25±0.2°, and 25.5±0.2°.

[0022] In another preferred embodiment, the lobaplatin-myricetin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 11.5±0.2°, 17.3±0.2°, 25.9±0.2°, 29.3±0.2°, 33±0.2°.

[0023] In another preferred embodiment, the lobaplatin-myricetin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 9.1±0.2°, 10.2±0.2°, 13.3±0.2°, 20.5±0.2°, 22.6±0.2°.

[0024] In another preferred embodiment, the lobaplatin-myricetin drug cocrystal has one or more of the following characteristics:

[0025] (a) the molar ratio of lobaplatin to myricetin in the lobaplatin-myricetin drug co-crystal is 1:1;

[0026] (b) the differential scanning calorimetry spectrum of the lobaplatin-myricetin drug cocrystal has a maximum peak at 172.6°C ± 2°C (or ± 1°C, or ± 0.5°C); and / or

[0027] (c) The thermogravimetric spectrum of the lobaplatin-myricetin drug cocrystal is between 30 and 150° C., with a weight loss of 2.89%±0.3% (or ±0.2%, or ±0.1%).

[0028] In another preferred embodiment, the lobaplatin-myricetin drug cocrystal has one or more of the following characteristics:

[0029] (a) The lobaplatin-myricetin drug co-crystal has substantially Fig.14 The X-ray powder diffraction spectrum shown;

[0030] (b) The lobaplatin-myricetin drug co-crystal has substantially Figure 3 The differential scanning calorimetry (DSC) spectrum shown in curve (f); and / or

[0031] (c) The lobaplatin-myricetin drug co-crystal has substantially Fig.15 Thermogravimetric spectra (TGA) are shown.

[0032] In another preferred example, the lobaplatin-naringenin drug cocrystal has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 7.9±0.2°, 10.9±0.2°, 14.9±0.2°, 17.9±0.2°, 22.2±0.2°, and 25.5±0.2°.

[0033] In another preferred embodiment, the lobaplatin-naringenin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 12.6±0.2°, 16.8±0.2°, 22.7±0.2°, 23.2±0.2°.

[0034] In another preferred embodiment, the lobaplatin-naringenin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 19.7±0.2°, 24.5±0.2°, 26.2±0.2°, 29.2±0.2°, 33.5±0.2°.

[0035] In another preferred embodiment, the lobaplatin-naringenin drug cocrystal has one or more of the following characteristics:

[0036] (a) the molar ratio of lobaplatin to naringenin in the lobaplatin-naringenin drug cocrystal is 1:1;

[0037] (b) the differential scanning calorimetry spectrum of the lobaplatin-naringenin drug cocrystal has a maximum peak at 181.2°C ± 2°C (or ± 1°C, or ± 0.5°C);

[0038] (c) the thermogravimetric spectrum of the lobaplatin-naringenin drug cocrystal is between 40° C. and 150° C., with a weight loss of 2.7%±0.3% (or ±0.2%, or ±0.1%); and / or

[0039] (d) the space group of the lobaplatin-naringenin drug cocrystal is monoclinic, and the space group is P21 / c, α=90°, β=103.772(2)°, γ=90°.

[0040] In another preferred embodiment, the lobaplatin-naringenin drug cocrystal has one or more of the following characteristics:

[0041] (a) The lobaplatin-naringenin drug co-crystal has substantially Figure 2 The X-ray powder diffraction spectrum shown;

[0042] (b) The lobaplatin-naringenin drug co-crystal has substantially Figure 3 The differential scanning calorimetry (DSC) spectrum shown in curve (a); and / or

[0043] (c) The lobaplatin-naringenin drug co-crystal has substantially Figure 4 Thermogravimetric spectra (TGA) are shown.

[0044] In another preferred embodiment, the lobaplatin-luteolin drug cocrystal has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 9.3±0.2°, 11.6±0.2°, 17.1±0.2°, 18.8±0.2°, 21.3±0.2°, and 26±0.2°.

[0045] In another preferred embodiment, the lobaplatin-luteolin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 9.7±0.2°, 10±0.2°, 14±0.2°, 19.4±0.2°, 27.8±0.2°.

[0046] In another preferred embodiment, the lobaplatin-luteolin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 12.2±0.2°, 18.1±0.2°, 24±0.2°, 25.6±0.2°, 27±0.2°.

[0047] In another preferred embodiment, the lobaplatin-luteolin drug cocrystal has one or more of the following characteristics:

[0048] (a) the molar ratio of lobaplatin to luteolin in the lobaplatin-luteolin drug co-crystal is 1:1;

[0049] (b) the differential scanning calorimetry spectrum of the lobaplatin-luteolin drug cocrystal has a maximum peak at 185.6°C±2°C (or ±1°C, or ±0.5°C);

[0050] (c) the thermogravimetric spectrum of the lobaplatin-luteolin drug cocrystal is between 50 and 150° C., with a weight loss of 2.49%±0.3% (or ±0.2%, or ±0.1%); and / or

[0051] (d) the space group of the lobaplatin-luteolin drug cocrystal is monoclinic, and the space group is P 21 / n, α=90°, β=95.046(2)°, γ=90.

[0052] In another preferred embodiment, the lobaplatin-luteolin drug cocrystal has one or more of the following characteristics:

[0053] (a) The lobaplatin-luteolin drug co-crystal has substantially Figure 6 The X-ray powder diffraction spectrum shown;

[0054] (b) The lobaplatin-luteolin drug co-crystal has substantially Figure 3 The differential scanning calorimetry (DSC) spectrum shown in curve (b); and / or

[0055] (c) The lobaplatin-luteolin drug co-crystal has substantially Figure 7 Thermogravimetric spectra (TGA) are shown.

[0056] In another preferred embodiment, the lobaplatin-kaempferol drug cocrystal has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 6.9±0.2°, 8.7±0.2°, 11.6±0.2°, 13.8±0.2°, and 27.9±0.2°.

[0057] In another preferred embodiment, the lobaplatin-kaempferol drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 19.1±0.2°, 19.7±0.2°, 22.7±0.2°, 24±0.2°, 25.1±0.2°.

[0058] In another preferred embodiment, the lobaplatin-kaempferol drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 17.4±0.2°, 17.8±0.2°, 29.3±0.2°, 32.3±0.2°, 35±0.2°, 35.4±0.2°.

[0059] In another preferred embodiment, the lobaplatin-kaempferol drug cocrystal has one or more of the following characteristics:

[0060] (a) the molar ratio of lobaplatin to kaempferol in the lobaplatin-kaempferol drug cocrystal is 1:1;

[0061] (b) the differential scanning calorimetry spectrum of the lobaplatin-kaempferol drug cocrystal has a maximum peak at 220.9°C±2°C (or ±1°C, or ±0.5°C); and / or

[0062] (c) The thermogravimetric spectrum of the lobaplatin-kaempferol drug cocrystal shows a weight loss of 8.62%±0.3% (or ±0.2%, or ±0.1%) between 30°C and 150°C.

[0063] In another preferred embodiment, the lobaplatin-kaempferol drug cocrystal has one or more of the following characteristics:

[0064] (a) The lobaplatin-kaempferol drug co-crystal has substantially Fig.10 The X-ray powder diffraction spectrum shown;

[0065] (b) The lobaplatin-kaempferol drug co-crystal has substantially Figure 3 The differential scanning calorimetry (DSC) spectrum shown in curve (d); and / or

[0066] (c) The lobaplatin-kaempferol drug co-crystal has substantially Fig.11Thermogravimetric spectra (TGA) are shown.

[0067] In another preferred embodiment, the lobaplatin-quercetin drug cocrystal has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 11.6±0.2°, 17.8±0.2°, 23.7±0.2°, 24.3±0.2°, and 26.4±0.2°.

[0068] In another preferred embodiment, the lobaplatin-quercetin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 13.7±0.2°, 21.2±0.2°, 25.2±0.2°, 27.1±0.2°, 27.4±0.2°.

[0069] In another preferred embodiment, the lobaplatin-quercetin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 16.7±0.2°, 17±0.2°, 17.3±0.2°, 20.9±0.2°, 21.7±0.2°.

[0070] In another preferred embodiment, the lobaplatin-quercetin drug cocrystal has one or more of the following characteristics:

[0071] (a) the molar ratio of lobaplatin to quercetin in the lobaplatin-quercetin drug cocrystal is 1:1;

[0072] (b) the differential scanning calorimetry spectrum of the lobaplatin-quercetin drug cocrystal has a maximum peak at 180.1°C ±2°C (or ±1°C, or ±0.5°C);

[0073] (c) The thermogravimetric spectrum of the lobaplatin-quercetin drug cocrystal is between 30 and 150° C., with a weight loss of 2.77%±0.3% (or ±0.2%, or ±0.1%).

[0074] In another preferred embodiment, the lobaplatin-quercetin drug cocrystal has one or more of the following characteristics:

[0075] (a) the lobaplatin-quercetin drug co-crystal has substantially Fig.12 The X-ray powder diffraction spectrum shown;

[0076] (b) the lobaplatin-quercetin drug co-crystal has substantially Figure 3 Differential scanning calorimetry (DSC) spectrum shown in curve (e);

[0077] (c) the lobaplatin-quercetin drug co-crystal has substantially Fig.13 Thermogravimetric spectra (TGA) are shown.

[0078] The second aspect of the present invention provides a pharmaceutical composition comprising:

[0079] (a) active ingredient: lobaplatin-flavonoid drug cocrystal, wherein the drug cocrystal is selected from the group consisting of lobaplatin-fisetin drug cocrystal, lobaplatin-myricetin drug cocrystal, lobaplatin-naringenin drug cocrystal, lobaplatin-luteolin drug cocrystal, lobaplatin-kaempferol drug cocrystal, or lobaplatin-quercetin drug cocrystal, or a combination thereof; and

[0080] (b) a pharmaceutically acceptable carrier.

[0081] In another preferred embodiment, among the active ingredients, the weight percentage of the lobaplatin-fisetin drug cocrystal is 50-100wt%, preferably 80-99.99wt%; more preferably, 90-99.5wt%.

[0082] In another preferred embodiment, among the active ingredients, the weight percentage of the lobaplatin-luteolin drug cocrystal is 50-100wt%, preferably 80-99.99wt%; more preferably, 90-99.5wt%.

[0083] In another preferred embodiment, the pharmaceutical composition is an oral preparation.

[0084] In another preferred embodiment, the oral preparation is a solid preparation or a liquid preparation.

[0085] In another preferred embodiment, the solid preparation is selected from: capsules, tablets, pills, powders, or granules.

[0086] The third aspect of the present invention provides a use of the lobaplatin-flavonoid drug cocrystal as described in the first aspect of the present invention or the pharmaceutical composition as described in the second aspect of the present invention for preparing a drug or preparation for preventing and / or treating cancer.

[0087] In another preferred embodiment, the cancer is selected from the group consisting of breast cancer, small cell lung cancer, chronic myeloid leukemia or cecal cancer.

[0088] In a fourth aspect, the present invention provides a method for preparing the drug co-crystal according to the first aspect of the present invention, comprising the steps of: dissolving lobaplatin and a flavonoid compound in an inert solvent, and volatilizing and crystallizing the resulting solution to obtain the drug co-crystal.

[0089] In another preferred embodiment, the flavonoid compound is selected from the following group: fisetin, myricetin, naringenin, luteolin, kaempferol or quercetin.

[0090] In another preferred embodiment, the molar ratio of lobaplatin to flavonoids is 1-5:1-5, preferably, 1-4:1-4, more preferably, 1-2:1-2.

[0091] In another preferred embodiment, the inert solvent is selected from the group consisting of water, ethanol, acetone, isopropanol, methanol, n-propanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, benzyl alcohol, n-butanol, or a combination thereof.

[0092] In another preferred embodiment, the temperature of the volatilization and crystallization is room temperature.

[0093] In another preferred embodiment, the volatilization and crystallization time is 1-30 days, preferably, 1-15 days.

[0094] In another preferred embodiment, the method for preparing the lobaplatin-fisetin drug cocrystal comprises the steps of: dissolving lobaplatin and fisetin in an inert solvent, and volatilizing and crystallizing the obtained solution, thereby obtaining the lobaplatin-fisetin drug cocrystal.

[0095] In another preferred embodiment, the molar ratio of lobaplatin to fisetin is 1-5:1-5, preferably, 1-4:1-4, more preferably, 1-2:1-2.

[0096] In another preferred embodiment, in the method for preparing lobaplatin-fisetin drug cocrystal, the temperature of the volatilization and crystallization is room temperature.

[0097] In another preferred embodiment, in the method for preparing lobaplatin-fisetin drug cocrystal, the volatilization crystallization time is 1-30 days, preferably, 1-15 days.

[0098] In another preferred embodiment, the method for preparing the lobaplatin-myricetin drug cocrystal comprises the steps of: dissolving lobaplatin and myricetin in an inert solvent, and volatilizing and crystallizing the obtained solution, thereby obtaining the lobaplatin-myricetin drug cocrystal.

[0099] In another preferred embodiment, the molar ratio of lobaplatin to myricetin is 1-5:1-5, preferably, 1-4:1-4, more preferably, 1-2:1-2.

[0100] In another preferred embodiment, in the method for preparing lobaplatin-myricetin drug cocrystal, the temperature of the volatilization and crystallization is room temperature.

[0101] In another preferred embodiment, in the method for preparing lobaplatin-myricetin drug cocrystal, the volatilization crystallization time is 1-30 days, preferably, 1-15 days.

[0102] In another preferred embodiment, the method for preparing the lobaplatin-naringenin drug cocrystal comprises the steps of: dissolving lobaplatin and naringenin in an inert solvent, and volatilizing and crystallizing the obtained solution, thereby obtaining the lobaplatin-naringenin drug cocrystal.

[0103] In another preferred embodiment, the molar ratio of lobaplatin to naringenin is 1-5:1-5, preferably, 1-4:1-4, more preferably, 1-2:1-2.

[0104] In another preferred embodiment, in the method for preparing lobaplatin-naringenin drug cocrystal, the temperature of the volatilization and crystallization is room temperature.

[0105] In another preferred embodiment, in the method for preparing lobaplatin-naringenin drug cocrystal, the volatilization crystallization time is 1-30 days, preferably, 1-15 days.

[0106] In another preferred embodiment, the preparation method of lobaplatin-luteolin drug co-crystal comprises the steps of: dissolving lobaplatin and luteolin in an inert solvent, and volatilizing and crystallizing the obtained solution, thereby obtaining the lobaplatin-luteolin drug co-crystal.

[0107] In another preferred embodiment, the molar ratio of lobaplatin to luteolin is 1-5:1-5, preferably, 1-4:1-4, and more preferably, 1-2:1-2.

[0108] In another preferred embodiment, in the method for preparing lobaplatin-luteolin drug cocrystal, the temperature of the volatilization crystallization is room temperature.

[0109] In another preferred embodiment, in the method for preparing lobaplatin-luteolin drug cocrystal, the volatilization crystallization time is 1-30 days, preferably, 1-15 days.

[0110] In another preferred embodiment, the method for preparing the lobaplatin-kaempferol drug cocrystal comprises the steps of: dissolving lobaplatin and kaempferol in an inert solvent, and volatilizing and crystallizing the obtained solution, thereby obtaining the lobaplatin-kaempferol drug cocrystal.

[0111] In another preferred embodiment, the molar ratio of lobaplatin to kaempferol is 1-5:1-5, preferably, 1-4:1-4, more preferably, 1-2:1-2.

[0112] In another preferred embodiment, in the method for preparing lobaplatin-kaempferol drug cocrystal, the temperature of the volatilization crystallization is room temperature.

[0113] In another preferred embodiment, in the method for preparing lobaplatin-kaempferol drug cocrystal, the volatilization crystallization time is 1-30 days, preferably, 1-15 days.

[0114] In another preferred embodiment, the method for preparing the lobaplatin-quercetin drug cocrystal comprises the steps of: dissolving lobaplatin and quercetin in an inert solvent, and volatilizing and crystallizing the obtained solution, thereby obtaining the lobaplatin-quercetin drug cocrystal.

[0115] In another preferred embodiment, the molar ratio of lobaplatin to quercetin compound is 1-5:1-5, preferably, 1-4:1-4, more preferably, 1-2:1-2.

[0116] In another preferred embodiment, in the method for preparing lobaplatin-quercetin drug cocrystal, the temperature of the volatilization crystallization is room temperature.

[0117] In another preferred embodiment, in the method for preparing lobaplatin-quercetin drug cocrystal, the volatilization crystallization time is 1-30 days, preferably, 1-15 days.

[0118] 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

[0119] Figure 1 Structural unit diagram of lobaplatin-naringenin drug cocrystal.

[0120] Figure 2 XRPD pattern of lobaplatin-naringenin drug cocrystal.

[0121] Figure 3 DSC graph of lobaplatin drug cocrystal.

[0122] Figure 4 TGA chart of lobaplatin-naringenin.

[0123] Figure 5 Structural unit diagram of lobaplatin-luteolin drug co-crystal.

[0124] Figure 6 XRPD pattern of lobaplatin-luteolin drug cocrystal.

[0125] Figure 7 TGA diagram of lobaplatin-luteolin drug cocrystal.

[0126] Figure 8 XRPD pattern of lobaplatin-fisetin drug cocrystal.

[0127] Fig. 9 TGA graph of lobaplatin-fisetin drug cocrystal.

[0128] Fig.10 XRPD pattern of lobaplatin-kaempferol drug cocrystal.

[0129] Fig.11 TGA graph of lobaplatin-kaempferol drug cocrystal.

[0130] Fig.12 XRPD pattern of lobaplatin-quercetin drug cocrystal.

[0131] Fig.13 TGA graph of lobaplatin-quercetin drug cocrystal.

[0132] Fig.14XRPD pattern of lobaplatin-myricetin drug cocrystal.

[0133] Fig.15 TGA graph of lobaplatin-myricetin drug cocrystal.

[0134] Fig.16 Dissolution profile of lobaplatin drug cocrystal in artificial gastric fluid.

[0135] Fig.17 Dissolution profile of lobaplatin drug cocrystal in artificial intestinal fluid. DETAILED DESCRIPTION

[0136] The inventors have conducted extensive and in-depth research, and through a large number of screenings and tests, provided a class of lobaplatin-flavonoid drug cocrystals. Surprisingly, compared with lobaplatin, the dissolution rate of lobaplatin in the drug cocrystal of the present invention in the gastrointestinal fluid is significantly slowed down, and the stability of lobaplatin in the gastrointestinal fluid is significantly improved, which provides a possibility for preparing lobaplatin oral preparations. In addition, the drug cocrystal of the present invention can improve the anti-cancer effect of lobaplatin, reduce the dosage of lobaplatin, and thus reduce the side effects caused by lobaplatin. On this basis, the present invention was completed.

[0137] the term

[0138] 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 to which this invention belongs.

[0139] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0140] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0141] As used herein, the terms "lobaplatin" or "compound of Formula I" are used interchangeably to refer to a compound having the structure of Formula I.

[0142] As used herein, the terms "pharmaceutical co-crystal of the present invention" or "lobaplatin-flavonoid pharmaceutical co-crystal of the present invention" are used interchangeably to refer to the lobaplatin-flavonoid pharmaceutical co-crystal of the present invention.

[0143] In another preferred embodiment, the term "inert solvent" refers to a solvent that does not react with the dissolved compound, including (but not limited to): water, ethanol, acetone, isopropanol, methanol, n-propanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, benzyl alcohol, n-butanol, or a combination thereof.

[0144] Unless otherwise specified, the term "room temperature" or "normal temperature" refers to a temperature of 4-32°C, preferably 25±5°C.

[0145] As used herein, the term "n or more" refers to any positive integer including n and greater than n (e.g., n, n+1, ...), wherein the upper limit Nup is the number of all values ​​in the group. For example, "1 or more" includes not only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ... each positive integer of the upper limit Nup, but also includes "2 or more", "3 or more", "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more", etc.

[0146] Drug Cocrystals

[0147] Pharmaceutical cocrystals refer to the formation of supramolecular crystals with a fixed stoichiometric ratio by self-assembling with active pharmaceutical ingredients (API) under the induction of weak intermolecular forces such as hydrogen bonds, π-π stacking, and van der Waals forces by introducing cocrystal ligands (CCF). Pharmaceutical cocrystal technology can change many physical and chemical properties of active pharmaceutical ingredients by selecting appropriate cocrystal ligands, such as improving solubility, improving pharmacological activity, increasing stability, or lowering the melting point. More importantly, after the cocrystal ligand forms a supramolecular cocrystal compound with the active pharmaceutical ingredient through non-covalent bonds such as hydrogen bonds, it can also improve the pharmacological activity of the original active pharmaceutical molecule, thereby providing a new solution for the development of new drugs with greater clinical application value.

[0148] The drug co-crystal of the present invention is a lobaplatin-flavonoid drug co-crystal, including: lobaplatin-fisetin drug co-crystal, lobaplatin-myricetin drug co-crystal, lobaplatin-naringenin drug co-crystal, lobaplatin-luteolin drug co-crystal, lobaplatin-kaempferol drug co-crystal, or lobaplatin-quercetin drug co-crystal. Preferably, in the lobaplatin-flavonoid drug co-crystal, the molar ratio of lobaplatin to flavonoid is about 1:1.

[0149] crystallization

[0150] The pharmaceutical co-crystals of the present invention can be prepared by methods commonly used in the art.

[0151] The solubility limit of the compound of interest can be exceeded by operating the solution, thereby completing production-scale crystallization. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature and then cooling the solution to below the saturation limit. Alternatively, the liquid volume can be reduced by boiling, atmospheric evaporation, vacuum drying or by some other methods. The solubility of the compound of interest can be reduced by adding an antisolvent or a solvent in which the compound has a low solubility or a mixture of such solvents. Another alternative method is to adjust the pH value to reduce solubility. For a detailed description of the crystallization aspect, see Crystallization, the third edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN0750611294.

[0152] If it is desired that salt formation and crystallization occur simultaneously, the addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting materials. Likewise, completion of the synthesis reaction in a medium in which the final desired form is less soluble than the reactants may result in direct crystallization of the final product.

[0153] Optimization of crystallization can include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One embodiment is to dissolve the compound of interest in a solvent at an elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner to bring the system just below the saturation level. At this point, seeds of the desired form can be added (while maintaining the integrity of the seeds), and the system is cooled to complete crystallization.

[0154] Pharmaceutical composition and use

[0155] The pharmaceutical composition of the present invention comprises a safe and effective amount of the pharmaceutical co-crystal of the present invention and a pharmaceutically acceptable carrier.

[0156] In the drug co-crystal of the present invention, lobaplatin is an anticancer active substance.

[0157] The flavonoid compounds fisetin, myricetin, naringenin, luteolin, kaempferol and quercetin used in the pharmaceutical co-crystal of the present invention are all common flavonoid compounds that can be safely used, and their properties can be foreseen by those skilled in the art.

[0158] The pharmaceutical composition of the present invention can be used to prevent and / or treat cancers, including (but not limited to): breast cancer, small cell lung cancer, chronic myeloid leukemia, and cecal cancer.

[0159] The "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the pharmaceutical co-crystal of the present invention per dose, and more preferably, contains 10-500 mg of the pharmaceutical co-crystal of the present invention per dose. Preferably, the "one dose" is one capsule or tablet.

[0160] "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 drug co-crystal of the present invention and with each other without significantly reducing the efficacy of the drug 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 Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0161] The administration route of the pharmaceutical co-crystal or pharmaceutical composition of the present invention is not particularly limited, and representative administration routes include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0162] Compared with lobaplatin, the lobaplatin-flavonoid drug co-crystal of the present invention has better stability in gastrointestinal fluid, so the pharmaceutical composition of the present invention is particularly preferably an oral preparation.

[0163] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the pharmaceutical cocrystals of the present invention 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.

[0164] 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 opacifying agents, and the release of the pharmaceutical co-crystals of the present invention or the active compound in such compositions may 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 pharmaceutical co-crystals of the present invention can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0165] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the pharmaceutical cocrystals of the present invention, the liquid dosage form may contain inert diluents 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.

[0166] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0167] In addition to the pharmaceutical co-crystals of the present invention, the suspension may contain suspending agents such 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.

[0168] 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.

[0169] The dosage forms of the pharmaceutical co-crystals 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.

[0170] The pharmaceutical cocrystals of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds, such as anticancer agents. In certain embodiments, the pharmaceutical cocrystals of the present invention are administered to a subject suffering from cancer in combination with other conventional cancer treatments, such as radiotherapy or surgery. Radiotherapy is well known in the art and includes X-ray therapy, such as gamma radiation, and radiopharmaceutical therapy.

[0171] A general range of therapeutically effective doses of the pharmaceutical co-crystals of the present invention will be about 1-2000 mg / day, about 10-about 1000 mg / day, about 10-about 500 mg / day, about 10-about 250 mg / day, about 10-about 100 mg / day, or about 10-about 50 mg / day. Or the dosage is determined based on the amount of lobaplatin contained in the pharmaceutical co-crystal of the present invention. The therapeutically effective dose will be administered in one or more doses. However, it should be understood that the specific dose of the pharmaceutical co-crystal of the present invention for any particular patient will depend on a variety of factors, such as the age, sex, weight, general health, diet, individual response of the patient to be treated, the time of administration, the severity of the disease to be treated, the activity of the specific pharmaceutical co-crystal administered, the dosage form, the mode of application, and concomitant medications. The therapeutically effective amount for a given situation can be determined by routine experimentation and is within the ability and judgment of the clinician or physician. In any case, the pharmaceutical co-crystal or composition will be administered in multiple doses based on the individual situation of the patient and in a manner that allows the delivery of a therapeutically effective amount.

[0172] The main advantages of the present invention include:

[0173] 1. The present invention provides a novel class of lobaplatin-flavonoid drug co-crystals, including lobaplatin-fisetin drug co-crystals, lobaplatin-myricetin drug co-crystals, lobaplatin-naringenin drug co-crystals, lobaplatin-luteolin drug co-crystals, lobaplatin-kaempferol drug co-crystals, and lobaplatin-quercetin drug co-crystals.

[0174] 2. The dissolution rate of lobaplatin in the lobaplatin-flavonoid drug cocrystal of the present invention in the gastrointestinal fluid is significantly slowed down, and the stability of lobaplatin in the gastrointestinal fluid is significantly improved, which is very suitable for preparing lobaplatin oral preparations.

[0175] 3. The lobaplatin-flavonoid drug co-crystal of the present invention can improve the anti-cancer effect of lobaplatin, reduce the dosage of lobaplatin, and thus reduce the side effects caused by lobaplatin.

[0176] 4. The lobaplatin-flavonoid drug co-crystal of the present invention provides a possibility for preparing an effective lobaplatin oral preparation, which enables patients to take the medicine more simply and conveniently.

[0177] The present invention will be further described below in conjunction with specific implementation. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0178] Reagents

[0179] Lobaplatin (purity>98%), naringenin, quercetin (purchased from Shanghai Adamas Reagent Co., Ltd., purity>98%), luteolin, fisetin (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., purity>98%), kaempferol, myricetin (Shanghai MacLean Biochemical Technology Co., Ltd.)

[0180] X-ray powder diffraction

[0181] The diffractometer was a Rigaku Ultima IV, 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.

[0182] Differential Scanning Calorimetry (DSC) Analysis

[0183] A TA Q2000 differential scanning calorimeter was used with a N2 atmosphere and a heating rate of 10°C / min.

[0184] Thermogravimetric (TGA) analysis

[0185] A TA, Q500 thermogravimetric analyzer was used with a N2 atmosphere, a heating rate of 10°C / min, and a temperature range of 30°C-350°C.

[0186] High performance liquid chromatography

[0187] Instrument: Agilent 1260 HPLC; Chromatographic column: AHMADZU VP-ODS C18 column (5 μm, 250 mm × 4.6 mm); Mobile phase: A: water, B: methanol; A / B = 60 / 40 (V / V); Detection wavelength: 210 nm; Flow rate: 1 mL / min; Injection volume: 20 μL; Column temperature: 35 °C

[0188] Nuclear Magnetic Resonance

[0189] The sample was dissolved in deuterated DMSO and measured by 400M NMR spectrometer. 1 H-NMR spectrum, the number and attribution of each hydrogen atom in the spectrum were analyzed using MestReNova 9.0 software.

[0190] Example 1

[0191] Preparation of Lobaplatin-naringenin drug cocrystal

[0192] 1.1 Lobaplatin 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, filtered, and the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are lobaplatin-naringenin drug cocrystals.

[0193] 1.2 Lobaplatin 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 lobaplatin-naringenin drug cocrystals.

[0194] 1.3 Lobaplatin 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 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-naringenin drug cocrystals.

[0195] 1.4 Lobaplatin 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 2 mL of water, 4 mL of ethanol and 1 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-naringenin drug cocrystals.

[0196] 1.5 Lobaplatin 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 2 mL of water, 4 mL of ethanol and 1 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-naringenin drug cocrystals.

[0197] 1.6 Lobaplatin 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 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-naringenin drug cocrystals.

[0198] 1.7 Lobaplatin 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 together in 5 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-naringenin drug cocrystals.

[0199] 1.8 Lobaplatin and naringenin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 10 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 4 mL of ethanol 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 lobaplatin-naringenin drug cocrystals.

[0200] 1.9 Lobaplatin and naringenin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 10 minutes. The product is placed in a transparent glass apparatus and then dissolved in 5 mL of n-propanol 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-naringenin drug cocrystals.

[0201] 1.10 Lobaplatin 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 7 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 by solvent evaporation method after 1 to 30 days, which are lobaplatin-naringenin drug cocrystals.

[0202] 1.11 Lobaplatin and naringenin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 10 minutes. The product is placed in a transparent glass apparatus and then dissolved in 7 mL of n-butanol 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 lobaplatin-naringenin drug cocrystals.

[0203] 1.12 Lobaplatin 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 together in a mixed solvent of 3 mL of methanol and 3 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 lobaplatin-naringenin drug cocrystals.

[0204] 1.13 Lobaplatin and naringenin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 10 minutes. The product is placed in a transparent glass apparatus and then dissolved in 2 mL of ethanol solvent. The glass container containing the mixed solution is placed on a 50°C stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at 6°C. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are lobaplatin-naringenin drug cocrystals.

[0205] 1.14 Lobaplatin and naringenin are in a molar ratio of 1:1, and the 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 ethanol. The glass container containing the mixed solution is placed on a 50°C stirrer and stirred. After the powder is completely dissolved, the solvent is volatilized at 6°C. After 10 days, colorless block crystals are generated by the solvent volatilization method, which is the lobaplatin-naringenin drug cocrystal. Its X-ray powder diffraction pattern is shown in the figure.

[0206] The lobaplatin-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 P 21 / c. α=90°, β=103.772(2)°, γ=90°.

[0207] XRPD diffraction pattern of lobaplatin-naringenin drug cocrystal Figure 2 As shown, the diffraction peaks of the XRPD pattern of lobaplatin-naringenin are listed in Table 1:

[0208] Table 1

[0209]

[0210]

[0211] Hydrogen NMR spectrum of lobaplatin-naringenin drug cocrystal: 1H NMR ppm (dimethyl sulfoxide-d6, 400 MHz, 25 ° C), lobaplatin: 5.03, 4.87, 4.77, 4.56 (4H, brs, -NH2), 3.83-3.78 (1H, m, H-7), 2.69 (4H, s, 5,6-CH2), 2.33 (2H, s, 3,4-CH), 1.89-1.87 (2H, d, 1,2-CH2, a bond), 1.58 (2H, d, 1,2-CH2, e bond), 1.06-1.04 (3H, s, -CH3); naringenin: 12.16(1H,s,5-OH), 10.85(1H,s,7-OH), 9.60(1H,s,3'-OH), 7.33-7.31(2H,d,H-2',H-6'), 6.81-6.77(2H,d,H-3' , H-5'), 5.88 (2H, s, H-8, H-6), 5.46-5.22 (1H, dd, H-2), 3.30-3.23 (1H, dd, H-3trans), 2.71-2.76 (1H, dd, H-3cis).

[0212] The DSC graph of lobaplatin-naringenin drug cocrystal is shown below: Figure 3 As shown in the curve (a), the endothermic peak corresponds to the melting process and has a maximum peak at about 181.2°C.

[0213] The TGA image of lobaplatin-naringenin drug cocrystal is shown below: Figure 4 As shown in the figure, it can be seen that the drug cocrystal loses 2.7% of its weight between 40 and 150°C due to partial loss of water molecules, and the theoretical value is 2.62%, and then decomposes.

[0214] Example 2

[0215] Preparation of Lobaplatin-Luteolin Drug Cocrystal

[0216] 2.1 Lobaplatin and luteolin 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, filtered, and the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are lobaplatin-luteolin drug cocrystals.

[0217] 2.2 Lobaplatin and luteolin 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 lobaplatin-luteolin drug cocrystals.

[0218] 2.3 Lobaplatin and luteolin 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 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 lobaplatin-luteolin drug cocrystals.

[0219] 2.4 Lobaplatin and luteolin 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 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 lobaplatin-luteolin drug cocrystals.

[0220] 2.5 Lobaplatin and luteolin 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 N,N-dimethylformamide. 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 lobaplatin-luteolin drug cocrystals.

[0221] 2.6 Lobaplatin and luteolin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 5 mL of dimethyl sulfoxide. 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 lobaplatin-luteolin drug cocrystals.

[0222] 2.7 Lobaplatin and luteolin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 5 mL of acetonitrile and 5 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 lobaplatin-luteolin drug cocrystals.

[0223] 2.8 Lobaplatin and luteolin 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 2 mL of water, 4 mL of ethanol and 1 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 lobaplatin-luteolin drug cocrystals.

[0224] 2.9 Lobaplatin and luteolin 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 together in 5 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-luteolin drug cocrystals.

[0225] 2.10 Lobaplatin and luteolin 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 together in 4 mL of ethanol 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 lobaplatin-luteolin drug cocrystals.

[0226] 2.11 Lobaplatin and luteolin 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 together in 5 mL of n-propanol 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 lobaplatin-luteolin drug cocrystals.

[0227] 2.12 Lobaplatin and luteolin 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 together in 7 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-luteolin drug cocrystals.

[0228] 2.13 Lobaplatin and luteolin 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 together in 7 mL of n-butanol 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 lobaplatin-luteolin drug cocrystals.

[0229] 2.14 Lobaplatin and luteolin 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 together in 3 mL of ethanol solvent. The glass container containing the mixed solution is placed on a 50°C stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at 6°C. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are lobaplatin-luteolin drug cocrystals.

[0230] 2.15 Lobaplatin and luteolin are in a molar ratio of 1:1. Grind for 10 minutes with the aid of isopropanol solvent. Place the product in a transparent glass apparatus and then dissolve them together in 10 mL of ethanol. Stir the glass container containing the mixed solution on a stirrer. After the powder is completely dissolved, place the solvent at room temperature to evaporate. Crystals are generated after 15 days by the solvent evaporation method, which is the lobaplatin-luteolin drug cocrystal. Its XRPD diffraction pattern is as follows Figure 6 shown.

[0231] The lobaplatin-luteolin drug co-crystal structural unit prepared by the present invention is as follows Figure 5 As shown, its eutectic space group is monoclinic, and the space group is P 21 / n. α=90°, β=95.046(2)°, γ=90°.

[0232] like Figure 6 As shown, the diffraction peaks of the XRPD pattern of lobaplatin-luteolin drug cocrystal are listed in Table 2:

[0233] Table 2

[0234]

[0235]

[0236] The nuclear magnetic resonance hydrogen spectrum of lobaplatin-luteolin drug cocrystal: 1H NMR ppm (dimethyl sulfoxide-d6, 400MHz, 25℃), lobaplatin: 5.03, 4.87, 4.76, 4.56 (4H, brs, -NH2), 3.84-3.79 (1H, m, H-7), 2.68 (4H, s, 5,6-CH2), 2.33 (2H, s, 3,4-CH), 1.88-1.87 (2H, d, 1,2-CH2, a bond), 1.58-1.57 (2H, d, 1,2-CH2, e bond), 1.08-1.04 ( 3H, s, -CH3); luteolin: 12.98 (1H, s, 5-OH), 10.82 (1H, s, 7-OH), 9.90 (1H, s, 4'-OH), 9.43 (1H, s, 3'-OH), 7.43 (1H, d, H-2'), 7.39 (1H, dd, H-6'), 6.89-6.87 (1H, d, H-5'), 6.67 (1H, s, H-3), 6.45 (1H, d, H-8), 6.19 (1H, d, H-6).

[0237] The DSC graph of lobaplatin-luteolin drug cocrystal is shown below: Figure 3 As shown in the curve (b), the endothermic peak corresponds to the melting process, and the endothermic peak has a maximum peak at about 185.6°C.

[0238] The TGA diagram of lobaplatin-luteolin drug cocrystal is shown below: Figure 7 As shown in the figure, it can be seen that the drug cocrystal loses 2.49% of its weight between 50 and 150°C due to partial loss of water molecules, and the theoretical value is 2.57%, and then decomposes.

[0239] Example 3

[0240] Preparation of Lobaplatin-Fisetin Cocrystal

[0241] 3.1 Lobaplatin and fisetin 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, filtered, and the solvent is evaporated at room temperature. Crystals are generated after 1 to 30 days by the solvent evaporation method, which are lobaplatin-fisetin drug cocrystals.

[0242] 3.2 Lobaplatin and fisetin 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 lobaplatin-fisetin drug cocrystals.

[0243] 3.3 Lobaplatin and fisetin 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 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 lobaplatin-fisetin drug cocrystals.

[0244] 3.4 Lobaplatin and fisetin 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 benzyl alcohol. 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 lobaplatin-fisetin drug cocrystals.

[0245] 3.5 Lobaplatin and fisetin 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 N,N-dimethylformamide. 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 lobaplatin-fisetin drug cocrystals.

[0246] 3.6 Lobaplatin and fisetin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 5 mL of dimethyl sulfoxide. 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 lobaplatin-fisetin drug cocrystals.

[0247] 3.7 Lobaplatin and fisetin 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. 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 lobaplatin-fisetin drug cocrystals.

[0248] 3.8 Lobaplatin and fisetin 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 2 mL of water, 4 mL of ethanol and 1 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 lobaplatin-fisetin drug cocrystals.

[0249] 3.9 The molar ratio of lobaplatin and fisetin is 4:1 to 1:4. Isopropanol solvent is added dropwise to assist grinding for 15 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 6 mL of ethanol 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 lobaplatin-fisetin drug cocrystals.

[0250] 3.10 The molar ratio of lobaplatin and fisetin is 4:1 to 1:4. Isopropanol solvent is added dropwise to assist grinding for 15 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 7 mL of n-propanol 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 lobaplatin-fisetin drug cocrystals.

[0251] 3.11 The molar ratio of lobaplatin and fisetin is 4:1 to 1:4. Isopropanol solvent is added dropwise to assist grinding for 15 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 12 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-fisetin drug cocrystals.

[0252] 3.12 The molar ratio of lobaplatin and fisetin is 4:1 to 1:4. Isopropanol solvent is added to assist grinding for 15 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 11 mL of n-butanol 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 lobaplatin-fisetin drug cocrystals.

[0253] 3.13 The molar ratio of lobaplatin and fisetin is 4:1 to 1:4. Isopropanol solvent is added to assist grinding for 15 minutes. The product is placed in a transparent glass apparatus and then dissolved in 7 mL of ethanol solvent. The glass container containing the mixed solution is placed on a 50°C stirrer or ultrasonicated in an ultrasonic instrument. 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 lobaplatin-fisetin drug cocrystals.

[0254] 3.14 The molar ratio of lobaplatin and fisetin is 4:1 to 1:4. Isopropanol solvent is added to assist grinding for 15 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 5 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 6°C. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are lobaplatin-fisetin drug cocrystals.

[0255] 3.15 Lobaplatin and fisetin are in a molar ratio of 1:1, and the 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 ethanol. The glass container containing the mixed solution is placed on a 50°C stirrer and stirred. After the powder is completely dissolved, the solvent is placed at 6°C to evaporate. After 10 days, a dark orange powder is generated by the solvent evaporation method, which is the lobaplatin-fisetin drug cocrystal. Its XRPD diffraction pattern is as follows Figure 8 shown.

[0256] The diffraction peaks of the XRPD pattern of lobaplatin-fisetin drug cocrystal are listed in Table 3:

[0257] Table 3

[0258] 2-Theta d(A) I(Height)% 8.7 10.1361 23.5 9.2 9.5622 11.9 11.2 7.9172 25.2 12.3 7.1788 61.5 12.7 6.9857 30.8 14.7 6.0296 22.2 17.0 5.1974 15.7 17.4 5.1044 100 17.6 5.0368 40.3 18.3 4.837 10.3 18.5 4.7879 18.6 19.1 4.6385 7.5 20.5 4.3236 10.2 22.4 3.9682 8.7 24.1 3.6909 16.1 25.1 3.5446 10.2 25.4 3.5029 100 26.1 3.416 15 26.9 3.3139 43.5 27.9 3.1976 19.3 29.5 3.0273 5.3 30.7 2.9132 24.2 31.5 2.839 10.1 33.0 2.7152 4.7 34.6 2.5918 9.1 35.2 2.5446 3.9 36.3 2.4754 3.5 38.5 2.3375 4.7 39.8 2.263 4.8

[0259] H NMR spectrum of lobaplatin-fisetin drug cocrystal: 1 H NMR ppm (dimethyl sulfoxide-d6, 400 MHz, 25 ° C), lobaplatin: 5.06, 4.91, 4.80, 4.60 (4H, brs, -NH2), 3.83-3.80 (1H, m, H-7), 2.70 (4H, s, 5,6-CH2), 2.33 (2H, s, 3,4-CH), 1.88 (2H, d, 1,2-CH2, a bond), 1.57 (2H, d, 1,2-CH2, e bond), 1.07-1.05 (3H, s, -CH3); Flavin: 10.73 (1H, s, 7-OH), 9.50 (1H, s, 3-OH), 9.26 (1H, s, 4'-OH), 9.04 (1H, s, 3'-OH), 7.92-7.89 (1H, d, H-5), 7. 69-7.68 (1H, d, H-2'), 7.55-7.52 (1H, dd, H-6'), 6.90 (1H, d, H-6), 6.88 (1H, d, H-8), 6.87-6.89 (1H, d, H-5').

[0260] The DSC graph of lobaplatin-fisetin drug cocrystal is shown below: Figure 3 As shown in the curve (c), the endothermic peak corresponds to the melting process, and the endothermic peak has a maximum peak at about 169.2°C.

[0261] The TGA diagram of lobaplatin-fisetin drug cocrystal is shown below: Fig. 9 As shown in the figure, it can be seen that the drug cocrystal loses 2.73% of its weight between 40 and 150°C due to partial loss of water molecules, and the theoretical value is 2.57%, and then decomposes.

[0262] Example 4

[0263] Preparation of Lobaplatin-Kaempferol Cocrystal

[0264] 4.1 Loplatin and kaempferol 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. 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 loplatin-kaempferol drug cocrystals.

[0265] 4.2 Loplatin and kaempferol 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 by the solvent evaporation method after 1 to 30 days, which are loplatin-kaempferol drug cocrystals.

[0266] 4.3 Loplatin and kaempferol 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 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 by the solvent evaporation method after 1 to 30 days, which are loplatin-kaempferol drug cocrystals.

[0267] 4.4 Loplatin and kaempferol 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 benzyl alcohol. 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 by the solvent evaporation method after 1 to 30 days, which are loplatin-kaempferol drug cocrystals.

[0268] 4.5 Loplatin and kaempferol 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 N,N-dimethylformamide. 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 loplatin-kaempferol drug cocrystals.

[0269] 4.6 Loplatin and kaempferol are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 5 mL of dimethyl sulfoxide. 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 loplatin-kaempferol drug cocrystals.

[0270] 4.7 Loplatin and kaempferol 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 2 mL of water, 4 mL of ethanol and 1 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 loplatin-kaempferol drug cocrystals.

[0271] 4.8 Loplatin and kaempferol are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 5 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 by the solvent evaporation method after 1 to 30 days, which are loplatin-kaempferol drug cocrystals.

[0272] 4.9 Loplatin and kaempferol are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 4 mL of ethanol 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 loplatin-kaempferol drug cocrystals.

[0273] 4.10 Loplatin and kaempferol are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 6 mL of n-propanol 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 loplatin-kaempferol drug cocrystals.

[0274] 4.11 Loplatin and kaempferol are prepared in a molar ratio of 4:1 to 1:4. Isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 6 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 loplatin-kaempferol drug cocrystals.

[0275] 4.12 Loplatin and kaempferol are in a molar ratio of 4:1 to 1:4. Isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 10 mL of n-butanol 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 loplatin-kaempferol drug cocrystals.

[0276] 4.13 Loplatin and kaempferol are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 2 mL of ethanol solvent. The glass container containing the mixed solution is placed on a 50°C stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at 6°C. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are loplatin-kaempferol drug cocrystals.

[0277] 4.14 Loplatin and kaempferol were ground in a molar ratio of 1:1, and isopropanol solvent was added to assist grinding for 30 minutes. The product was placed in a transparent glass apparatus and then dissolved in 2 mL of ethanol. The glass container containing the mixed solution was placed on a 50°C stirrer and stirred. After the powder was completely dissolved, the solvent was evaporated at 6°C. After 15 days, a yellow powder was generated by the solvent evaporation method, which was the loplatin-kaempferol drug cocrystal. Its XRPD diffraction pattern is shown as follows Fig.10 shown.

[0278] The diffraction peaks of the XRPD pattern of lobaplatin-kaempferol drug cocrystal are listed in Table 4:

[0279] Table 4

[0280]

[0281]

[0282] H NMR spectrum of lobaplatin-kaempferol drug cocrystal: 1H NMR ppm (dimethyl sulfoxide-d6, 400 MHz, 25 ° C), lobaplatin: 5.02, 4.86, 4.76, 4.54 (4H, brs, -NH2), 3.83-3.78 (1H, m, H-7), 2.68 (4H, s, 5,6-CH2), 2.33 (2H, s, 3,4-CH), 1.88-1.87 (2H, d, 1,2-CH2, a bond), 1.57-1.58 (2H, d, 1,2-CH2, e bond), 1.05-1.03 (3H, s, -CH3); kaempferol: 12.47 (1 H, s, 5-OH), 10.77 (1H, brs, 7-OH), 10.09 (1H, brs, 3-OH), 9.41 (1H, s, 4'-OH), 8.05-8.03 (2H, d, H-2', H-6'), 6.93-6.91 (2 H, d, H-3', H-5'), 6.42 (1H, d, H-8), 6.17 (1H, d, H-6); Ethanol: 4.34 (1H, s, -OH), 3.43-4.45 (2H, q, -CH2), 1.4-1.7 (3H, t, -CH3).

[0283] The DSC graph of lobaplatin-kaempferol drug cocrystal is shown below: Figure 3 As shown in the curve (d), the endothermic peak corresponds to the melting process, and the endothermic peak has a maximum peak at about 220.9°C.

[0284] The TGA image of lobaplatin-kaempferol drug cocrystal is shown below: Fig.11 As shown in the figure, it can be seen that the eutectic loses 8.62% of its weight between 30 and 150°C, which is due to the partial loss of water molecules and ethanol molecules, and the theoretical value is 8.57%, and then decomposes.

[0285] Example 5

[0286] Preparation of Lobaplatin-Quercetin Cocrystal

[0287] 5.1 Lobaplatin and quercetin 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. 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 lobaplatin-quercetin drug cocrystals.

[0288] 5.2 Lobaplatin and quercetin 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-quercetin drug cocrystals.

[0289] 5.3 Lobaplatin and quercetin 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 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-quercetin drug cocrystals.

[0290] 5.4 Lobaplatin and quercetin 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 benzyl alcohol. 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-quercetin drug cocrystals.

[0291] 5.5 Lobaplatin and quercetin 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 N,N-dimethylformamide. 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 lobaplatin-quercetin drug cocrystals.

[0292] 5.6 Lobaplatin and quercetin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 5 mL of dimethyl sulfoxide. 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 lobaplatin-quercetin drug cocrystals.

[0293] 5.7 Lobaplatin and quercetin 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 2 mL of water, 4 mL of ethanol and 1 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-quercetin drug cocrystals.

[0294] 5.8 Lobaplatin and quercetin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 5 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-quercetin drug cocrystals.

[0295] 5.9 Lobaplatin and quercetin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 4 mL of ethanol 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 lobaplatin-quercetin drug cocrystals.

[0296] 5.10 Lobaplatin and quercetin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 5 mL of n-propanol 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-quercetin drug cocrystals.

[0297] 5.11 Lobaplatin and quercetin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 7 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-quercetin drug cocrystals.

[0298] 5.12 Lobaplatin and quercetin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 10 mL of n-butanol 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 lobaplatin-quercetin drug cocrystals.

[0299] 5.13 Lobaplatin and quercetin are mixed in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 3 mL of ethanol solvent. The glass container containing the mixed solution is placed on a 50°C stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at 6°C. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are lobaplatin-quercetin drug cocrystals.

[0300] 5.14 Lobaplatin and quercetin were ground in a molar ratio of 1:1, and isopropanol solvent was added to assist grinding for 10 minutes. The product was placed in a transparent glass apparatus and then dissolved in 2.5 mL of ethanol. The glass container containing the mixed solution was placed on a 50°C stirrer and stirred. After the powder was completely dissolved, the solvent was evaporated at 6°C. After 10 days, a yellow powder was generated by the solvent evaporation method, which was the lobaplatin-quercetin drug cocrystal. Its XRPD diffraction pattern is as follows Fig.12 shown.

[0301] The diffraction peaks of the XRPD pattern of lobaplatin-quercetin drug cocrystal are listed in Table 5:

[0302] Table 5

[0303]

[0304]

[0305] H NMR spectrum of lobaplatin-quercetin drug cocrystal: 1 H NMR ppm (dimethyl sulfoxide-d6, 400 MHz, 25 °C), lobaplatin: 5.02, 4.87, 4.76, 4.56 (4H, brs, -NH2), 3.84-3.79 (1H, m, H-7), 2.68 (4H, s, 5,6-CH2), 2.33 (2H, s, 3,4-CH), 1.88-1.87 (2H, d, 1,2-CH2, a bond), 1.58-1.56 (2H, d, 1,2-CH2, e bond), 1.06-1.04 (3H, s, -CH3); Quercetin: 12.48 (1H, s, 5-OH), 10.76 (1H, s, 7-OH), 10.09 (1H, s, 3-OH), 9.37 (1H, s, 4'-OH), 9.31 (1H, s, 3'- OH), 7.67 (1H, d, H-2'), 7.55-7.52 (1H, dd, H-6'), 6.87-6.89 (1H, d, H-5'), 6.39 (1H, d, H-8), 6.17 (1H, d, H-6).

[0306] The DSC diagram of lobaplatin-quercetin drug cocrystal is shown below: Figure 3As shown in the curve (e), the endothermic peak corresponds to the melting process, and the endothermic peak has a maximum peak at about 180.1°C.

[0307] The TGA image of lobaplatin-quercetin drug cocrystal is shown below: Fig.13 As shown in the figure, it can be seen that the drug cocrystal loses 2.77% of its weight between 30 and 150°C due to partial loss of water molecules, and the theoretical value is 2.51%, and then decomposes.

[0308] Example 6

[0309] Preparation of Lobaplatin-Myricetin Cocrystal

[0310] 6.1 Lobaplatin and myricetin 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. 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 lobaplatin-myricetin drug cocrystals.

[0311] 6.2 Lobaplatin and myricetin 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-myricetin drug cocrystals.

[0312] 6.3 Lobaplatin and myricetin 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 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-myricetin drug cocrystals.

[0313] 6.4 Lobaplatin and myricetin 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 benzyl alcohol. 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-myricetin drug cocrystals.

[0314] 6.5 Lobaplatin and myricetin 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 N,N-dimethylformamide. 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-myricetin drug cocrystals.

[0315] 6.6 Lobaplatin and myricetin are placed in a transparent glass container at a molar ratio of 4:1 to 1:4, and then dissolved together in 5 mL of dimethyl sulfoxide. 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 by the solvent evaporation method after 1 to 30 days, which are lobaplatin-myricetin drug cocrystals.

[0316] 6.7 Loplatin and myricetin 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 2 mL of water, 4 mL of ethanol and 1 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 by the solvent evaporation method after 1 to 30 days, which are loplatin-myricetin drug cocrystals.

[0317] 6.8 Loplatin and myricetin are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 6 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 by the solvent evaporation method after 1 to 30 days, which are loplatin-myricetin drug cocrystals.

[0318] 6.9 Loplatin and myricetin are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 7 mL of ethanol 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 loplatin-myricetin drug cocrystals.

[0319] 6.10 Loplatin and myricetin are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 8 mL of n-propanol 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 loplatin-myricetin drug cocrystals.

[0320] 6.11 Loplatin and myricetin are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 12 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 by the solvent evaporation method after 1 to 30 days, which are loplatin-myricetin drug cocrystals.

[0321] 6.12 Lobaplatin and myricetin are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added dropwise to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 10 mL of n-butanol 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 lobaplatin-myricetin drug cocrystals.

[0322] 6.13 Lobaplatin and myricetin are in a molar ratio of 4:1 to 1:4, and isopropanol solvent is added to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved together in 6 mL of ethanol solvent. The glass container containing the mixed solution is placed on a 50°C stirrer for stirring or placed in an ultrasonic instrument for sonication. After the powder is completely dissolved, the solvent is evaporated at 6°C. Crystals are generated by the solvent evaporation method after 1 to 30 days, which are lobaplatin-myricetin drug cocrystals.

[0323] 6.14 Lobaplatin and myricetin are in a molar ratio of 1:1, and the isopropanol solvent is added to assist grinding for 20 minutes. The product is placed in a transparent glass apparatus and then dissolved in 6 mL of ethanol. The glass container containing the mixed solution is placed on a 50°C stirrer and stirred. After the powder is completely dissolved, the solvent is placed at 6°C to evaporate. After 15 days, an orange powder is generated by the solvent evaporation method, which is the lobaplatin-myricetin drug cocrystal. Its XRPD diffraction pattern is as follows Fig.14 shown.

[0324] The diffraction peaks of the XRPD pattern of lobaplatin-myricetin drug cocrystal are listed in Table 6:

[0325] Table 6

[0326]

[0327]

[0328] H NMR spectrum of lobaplatin-myricetin drug cocrystal: 1 H NMR ppm (dimethyl sulfoxide-d6, 400 MHz, 25 °C), lobaplatin: 5.11, 4.97, 4.85, 4.66 (4H, brs, -NH2), 3.91-3.86 (1H, m, H-7), 2.76 (4H, s, 5,6-CH2), 2.39 (2H, s, 3,4-CH), 1.94 (2H, d, 1,2-CH2, a bond), 1.64 (2H, d, 1,2-CH2, e bond), 1. 13-1.11 (3H, s, -CH3); Myricetin: 12.57 (1H, s, 5-OH), 10.76 (1H, s, 7-OH), 9.35 (1H, s, 4'-OH), 9.22 (2H, s, 3'-OH, 5'-OH), 8.81 (1H, s, 3-OH), 7.31 (2H, s, H-2', H-6'), 6.44 (1H, d, H-8), 6.24 (1H, d, H-6).

[0329] The DSC graph of lobaplatin-myricetin drug cocrystal is shown below: Figure 3 As shown in curve (f), the endothermic peak corresponds to the melting process, and the endothermic peak has a maximum peak at about 172.6°C.

[0330] The TGA image of lobaplatin-myricetin drug cocrystal is shown below: Fig.15 As shown in the figure, it can be seen that the drug co-crystal loses 2.89% of its weight between 30 and 150°C, which is due to the partial loss of water molecules, and the theoretical value is 2.50%, and then decomposes.

[0331] The structural formula of the lobaplatin-flavonoid drug co-crystal prepared by the present invention is shown in Table 7:

[0332] Table 7

[0333]

[0334]

[0335] Example 7

[0336] Dissolution rate test of lobaplatin drug cocrystal

[0337] Preparation of artificial gastric juice: Add 800 mL of water and 10 g of pepsin to 16.4 mL of dilute hydrochloric acid, shake well to fully dissolve, adjust pH to 1.2, and dilute with water to 1000 mL to obtain artificial gastric juice.

[0338] Preparation of artificial intestinal fluid: weigh 6.8 g of potassium dihydrogen phosphate and dissolve it in 500 mL of water, and adjust the pH to 6.8 with 0.1 mol / L sodium hydroxide solution; weigh 10 g of trypsin and dissolve it in water, mix the two solutions evenly, and add water to make up to 1000 mL to obtain artificial intestinal fluid.

[0339] Lobaplatin drug cocrystal and lobaplatin raw material were ground and passed through a 100-mesh sieve. 5 mg of lobaplatin and lobaplatin drug cocrystal with corresponding content were weighed and dissolved in artificial gastric juice and artificial intestinal juice dissolution medium, 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. The results are as follows: Fig.16 and Fig.17 The final retention rate of lobaplatin in lobaplatin and its drug co-crystal after 8 h is shown and summarized in Table 8: Retention rate = final drug concentration of lobaplatin / peak concentration of lobaplatin×100%.

[0340] Table 8 Retention rate of lobaplatin and its cocrystal in artificial gastrointestinal fluid

[0341]

[0342] from Fig.16 , 17 It can be seen that due to the hydrophilicity of lobaplatin, lobaplatin dissolves rapidly in artificial gastric juice and artificial intestinal juice, and undergoes severe degradation; while the drug cocrystals of lobaplatin-flavonoids dissolve slowly in artificial gastric juice and artificial intestinal juice, and the dissolution rate decreases. After 8 hours, the concentration and retention rate of each drug cocrystal are higher than those of lobaplatin itself ( Fig.16 , 17 , Table 8). This indicates that the drug co-crystal formed by lobaplatin and flavonoid compounds significantly improves the stability of lobaplatin in gastrointestinal fluid, so the drug co-crystal of the present invention is suitable for preparing oral preparations of lobaplatin, which is convenient for patients to take the medicine.

[0343] Example 8

[0344] Cytotoxicity experiment of lobaplatin drug cocrystal

[0345] The lobaplatin drug co-crystal prepared by the method of the present invention was used to perform cytotoxicity assay, and the screened cells were human ileocecal cancer cells HCT-8. The specific experimental method is as follows:

[0346] 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);

[0347] 2. Human ileocecal cancer cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum by volume at 37°C in a 5% CO2 incubator;

[0348] 3. Add 100 μL of the corresponding working solution to each well, and set up 3 replicate wells for each concentration;

[0349] 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;

[0350] 5. Perform CCK-8 staining on the 96-well plate 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.

[0351] Cell proliferation rate (%) = A value of experimental group / A value of control group

[0352] The half maximal inhibitory concentration (IC50) value was calculated using SPSS software. The IC50 values ​​of lobaplatin and its cocrystals are shown in Table 9 below.

[0353] Table 9 Half inhibitory concentration values ​​(IC 50 ±SD, μM)

[0354]

[0355] The experimental results showed that the IC 50 The value is 208 μM, while for the drug cocrystal of the present invention, the half inhibition concentration of the lobaplatin-naringenin drug cocrystal with the worst inhibition effect is 322 μM, wherein the lobaplatin content is only 194 μM. It can be seen that when treating cancer, the drug cocrystal of the present invention can reduce the dosage of lobaplatin, thereby reducing its side effects.

[0356] In addition, the use of the drug cocrystals of the present invention, especially the lobaplatin-fisetin drug cocrystals, lobaplatin-luteolin drug cocrystals, etc., significantly reduced the half inhibitory concentration of cecal cancer cells, which suggests that lobaplatin and the flavonoid ligands of the present invention have a synergistic effect in inhibiting cancer (especially lobaplatin-fisetin or lobaplatin-luteolin).

[0357] In summary, the drug cocrystal provided by the present invention can effectively improve the stability of lobaplatin in the gastrointestinal tract, and surprisingly, can also improve its anti-cancer effect, and is very suitable as an alternative active ingredient of lobaplatin for use in pharmaceutical preparations, especially in oral preparations.

[0358] 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. A lobaplatin-flavonoid drug cocrystal, wherein: The drug co-crystal is selected from the following group: lobaplatin-fisetin drug co-crystal or lobaplatin-luteolin drug co-crystal; Wherein, the molar ratio of lobaplatin to fisetin in the lobaplatin-fisetin drug cocrystal is 1:1, and the lobaplatin-fisetin drug cocrystal has the following group of X-ray powder diffraction characteristic peaks: 12.3±0.2º, 17.4±0.2º, 17.6±0.2º, 25.4±0.2º and 26.9±0.2º; The molar ratio of lobaplatin to luteolin in the lobaplatin-luteolin drug co-crystal is 1:1; and the lobaplatin-luteolin drug co-crystal has the following group of X-ray powder diffraction characteristic peaks: 9.3±0.2º, 11.6±0.2º, 17.1±0.2º, 18.8±0.2º, 21.3±0.2º and 26±0.2º.

2. The lobaplatin-flavonoid drug co-crystal according to claim 1, characterized in that The co-crystal is lobaplatin-fisetin drug co-crystal.

3. The lobaplatin-flavonoid drug co-crystal according to claim 1, characterized in that: The lobaplatin-fisetin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 8.7±0.2º, 11.2±0.2º, 12.7±0.2º, 14.7±0.2º, 30.7±0.2º.

4. The lobaplatin-flavonoid drug co-crystal according to claim 1, characterized in that The lobaplatin-fisetin drug cocrystal has one or more of the following characteristics: (a) the differential scanning calorimetry spectrum of the lobaplatin-fisetin drug cocrystal has a maximum peak at 169.2°C ± 2°C; and / or (b) The thermogravimetric spectrum of the lobaplatin-fisetin drug cocrystal is between 40 and 150° C., with a weight loss of 2.73%±0.3%.

5. The lobaplatin-flavonoid drug co-crystal according to claim 1, characterized in that: The lobaplatin-fisetin drug cocrystal has one or more of the following characteristics: (a) The X-ray powder diffraction spectrum of the lobaplatin-fisetin drug cocrystal is substantially as shown in FIG8 ; (b) the lobaplatin-fisetin drug cocrystal has a differential scanning calorimetry (DSC) spectrum substantially as shown in curve (c) of FIG. 3 ; and / or (c) The lobaplatin-fisetin drug co-crystal has a thermogravimetric spectrum (TGA) substantially as shown in FIG. 9 .

6. The lobaplatin-flavonoid drug co-crystal according to claim 1, characterized in that: The lobaplatin-luteolin drug cocrystal also has one or more X-ray powder diffraction characteristic peaks selected from the following group: 9.7±0.2º, 10±0.2º, 14±0.2º, 19.4±0.2º, 27.8±0.2º.

7. The lobaplatin-flavonoid drug co-crystal according to claim 1, characterized in that: The lobaplatin-luteolin drug co-crystal has one or more of the following characteristics: The lobaplatin-luteolin drug co-crystal has an X-ray powder diffraction spectrum substantially as shown in FIG6 ; (b) the lobaplatin-luteolin drug co-crystal has a differential scanning calorimetry (DSC) spectrum substantially as shown in curve (b) in FIG. 3 ; and / or (c) The lobaplatin-luteolin drug co-crystal has a thermogravimetric spectrum (TGA) substantially as shown in FIG. 7 .

8. A pharmaceutical composition, characterized in that Include: (a) Active ingredient: the lobaplatin-flavonoid drug co-crystal according to any one of claims 1 to 7, wherein the drug co-crystal is selected from the group consisting of lobaplatin-fisetin drug co-crystal, lobaplatin-luteolin drug co-crystal or a combination thereof; and (b) a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, characterized in that The pharmaceutical composition is an oral preparation.

10. Use of the lobaplatin-flavonoid drug co-crystal according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 or 9 in the preparation of a drug or preparation for preventing and / or treating ileocecal cancer.

11. A method for preparing the pharmaceutical co-crystal according to claim 1, characterized in that: Includes steps: Lobaplatin and luteolin were mixed in a molar ratio of 1:1, and isopropanol solvent was added dropwise to assist grinding for 10 minutes. The product was placed in a transparent glass apparatus and then dissolved in 10 mL of ethanol. The glass container containing the mixed solution was placed in a stirrer and stirred. After the powder was completely dissolved, the solution was placed at 4-32°C for evaporation. Crystals were generated after 15 days by the solvent evaporation method, which was the lobaplatin-luteolin drug cocrystal. or The molar ratio of lobaplatin and fisetin was 1:1, and isopropanol solvent was added dropwise to assist grinding for 10 minutes. The product was placed in a transparent glass apparatus and then dissolved in 3 mL of ethanol. The glass container containing the mixed solution was placed on a 50°C stirrer and stirred. After the powder was completely dissolved, the solution was evaporated at 6°C. After 10 days, a dark orange powder was generated by the solvent evaporation method, which was the lobaplatin-fisetin drug cocrystal.

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