Glucocorticoid-baicalein and / or baicalin co-amorphous substance and application thereof

Abstract

The invention discloses a glucocorticoid-baicalein and / or baicalin co-amorphous substance and application thereof.The co-amorphous substance is formed by glucocorticoid, baicalein and / or baicalin in a non-covalent bond mode, the molar ratio of glucocorticoid to baicalein and / or baicalin is 1: 10-10: 1, powder X-ray diffraction analysis of CuK alpha radiation is adopted, and by taking 2 theta as the unit, the ratio of the glucocorticoid to the baicalein to the baicalein is 1: 10-1: 1. A powder X-ray diffraction pattern of the co-amorphous substance has a dispersion diffraction peak at a position of 15.0 + / -0.3 degrees to 27.0 + / -0.3 degrees. According to the application, glucocorticoid is combined with baicalein and / or baicalin according to a specific proportion, so that the pharmaceutical composition is used for treating or preventing thymoma. The composition is prepared by a mechanochemical method, forms a co-amorphous substance, and has the potential of improving the solubility of the medicine and improving the curative effect. Besides, the pharmaceutical composition can be prepared into various dosage forms, is convenient for clinical application, provides a new treatment choice for treating the thymoma, and particularly has remarkable clinical significance for patients with poor traditional treatment effects.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a glucocorticoid-baicalein and / or baicalin co-amorphous substance and application thereof. Background Art

[0002] Thymoma (TET) is a disease with a low incidence rate but no specific treatment. Thymoma is often associated with severe autoimmune diseases, such as myasthenia gravis. At present, surgical resection is the main means of treating thymoma. For unresectable and metastatic thymomas, radiotherapy and chemotherapy are mainly used for treatment, but systemic chemotherapy and local radiotherapy are not effective for advanced thymomas. At present, no effective targeted drug for the treatment of thymoma has been found. For patients with unresectable and metastatic thymomas, there is no clinically proven effective treatment method so far. Therefore, there is an urgent clinical need for the preparation of drugs for the treatment or prevention of thymoma.

[0003] Drug combination refers to two or more active drug molecules and / or related active compounds in a certain proportion, through the intermolecular non-covalent interaction force to form a specific state, and work together to treat diseases. The combination of drugs in a certain proportion can improve their physical and chemical properties and enhance their clinical therapeutic effects on the one hand, and enrich their clinical application forms on the other hand. When drugs are used in combination, when the active drug molecules and the combined ligands form a specific state (a composition in a specific state) through intermolecular non-covalent interaction forces in a certain proportion, it will produce a better therapeutic effect. For chemical drugs, through the study of the composition, better therapeutic effects can be achieved, and the purpose of more effectively treating or preventing diseases can be achieved. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a glucocorticoid-baicalein and / or baicalin co-amorphous substance and its application. Starting from the study of the existence state of glucocorticoid solid matter, through combined screening technology and biological activity evaluation technology, on the basis of new drug uses, the combined solid matter is discovered, and the combined substance is combined with pharmacodynamic research to provide basic scientific data for finding, discovering and developing a medicinal combined solid matter of glucocorticoids with the best clinical efficacy; at the same time, it also provides a theoretical and material basis for the research on therapeutic drugs for thymoma based on glucocorticoid solid drug raw materials.

[0005] The technical problem to be solved by the present invention is achieved through the following technical solutions:

[0006] A glucocorticoid-baicalein and / or baicalin co-amorphous substance, wherein the co-amorphous substance is formed by glucocorticoid, baicalein and / or baicalin by non-covalent bonds, the molar ratio of the two is 1:10-10:1, and the powder X-ray diffraction analysis using CuKα radiation shows that, in units of 2θ, a powder X-ray diffraction spectrum of the co-amorphous substance has diffuse diffraction peaks at 15.0±0.3° to 27.0±0.3°.

[0007] Preferably, in the above technical solution, the molar ratio of the glucocorticoid, baicalein and / or baicalin is 1:5-5:1, preferably 1:2-2:1, and more preferably 1:1.

[0008] Preferably, in the above technical solution, the glucocorticoid is a natural glucocorticoid or an artificial semi-synthetic or synthetic glucocorticoid; preferably, the glucocorticoid is cortisone, hydrocortisone, prednisone, prednisone acetate, prednisolone, methylprednisolone, betamethasone, beclomethasone propionate or dexamethasone; more preferably, the glucocorticoid is hydrocortisone, prednisone acetate or prednisone; preferably, the glucocorticoid is hydrocortisone, and the powder X-ray diffraction analysis using CuKα radiation, in units of 2θ, the powder X-ray diffraction spectrum of the co-amorphous substance has a diffuse diffraction peak at 15.6±0.3°; preferably, the glucocorticoid is prednisone acetate, and the powder X-ray diffraction analysis using CuKα radiation, in units of 2θ, the powder X-ray diffraction spectrum of the co-amorphous substance has diffuse diffraction peaks at 15.9±0.3° and 26.4±0.3°.

[0009] A method for preparing a glucocorticoid-baicalein and / or baicalin co-amorphous product, specifically comprising:

[0010] The glucocorticoid and baicalein and / or baicalin are added in a molar ratio of 1:10-10:1, preferably 1:5-5:1, more preferably 1:2-2:1, particularly preferably 1:1, and prepared by a mechanochemical method.

[0011] Preferably, in the above technical solution, the mechanochemical method is a ball milling method or a liquid-added ball milling method, wherein the ball milling method is to mix the glucocorticoids with baicalein and / or baicalin in a molar ratio of 1:10-10:1 in a mortar or a ball mill, the ball-to-material ratio is 1:1-10:1, the ball milling speed is 20r / min-400r / min, and the grinding time is 0.1-72 hours; the liquid-added ball milling method is to mix the glucocorticoids with baicalein and / or baicalin in a molar ratio of 1:10-1 0:1 is put into a ball mill for mixing, an organic solvent is added, and the mixture is collected after grinding at room temperature; the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane or cyclohexane; the ball mill speed is 20 r / min-400 r / min, the liquid addition amount is 0.01-100 ml; and the grinding time is 0.1-72 hours.

[0012] A method for preparing a glucocorticoid-baicalein and / or baicalin co-amorphous product, specifically comprising:

[0013] Glucocorticoid and baicalein and / or baicalin are added in a molar ratio of 1:10-10:1, and an organic solvent is added. The mixture is stirred at 10-80° C. for 0.1-2 days, filtered, concentrated, and vacuum dried at low temperature to obtain a solid substance.

[0014] Preferably, in the above technical scheme, the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, and cyclohexane; the ratio of the total mass of the glucocorticoid and baicalein and / or baicalin to the volume of the organic solvent is 1 mg / ml-500 mg / ml, the drying temperature is 40-80°C, and the drying time is 1-10 hours.

[0015] Use of a co-amorphous compound in a drug for treating or preventing thymoma.

[0016] A pharmaceutical composition comprises a co-amorphous substance and a pharmaceutically acceptable excipient or carrier; the pharmaceutical composition is prepared as a tablet, a capsule, a pill, or an injection; or the pharmaceutical composition is prepared as a sustained-release preparation or a controlled-release preparation.

[0017] Preferably, in the above technical solution, the thymoma is an anterior superior mediastinal tumor originating from thymic epithelial cells; preferably, the thymoma is a type B thymoma; more preferably, the thymoma is a type B1, type B2, or type B3 thymoma; particularly preferably, the thymoma is a type B2 thymoma; the glucocorticoid is prepared as a preparation with a dosage of 10 mg / day to 300 mg / day, and the baicalein and / or baicalin are prepared as a preparation with a dosage of 20 mg / day to 200 mg / day; the molar ratio of the glucocorticoid to baicalein and / or baicalin is 1:10-10:1, preferably 1:5-5:1, more preferably 1:2-2:1, and particularly preferably 1:1.

[0018] The above technical solution of the present invention has the following beneficial effects:

[0019] The present application provides a novel pharmaceutical composition, which is used to treat or prevent thymoma by combining glucocorticoids with baicalein (and / or baicalin) in a specific ratio. The composition is prepared by a mechanochemical method to form a co-amorphous substance, which has the potential to improve drug solubility and efficacy. In addition, the pharmaceutical composition can be prepared into a variety of dosage forms, which is convenient for clinical application, and provides a new treatment option for thymoma treatment, especially for patients with poor traditional treatment effects. It has significant clinical significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention.

[0021] Figure 1 This is the chest CT image of patient Yang Moumou in Example 1.

[0022] Figure 2 This is the chest CT image of patient Liu in Example 2.

[0023] Figure 3 This is the chest CT image of patient Huang in Example 3.

[0024] Figure 4 This is the chest CT image of patient Han in Example 4.

[0025] Figure 5 This is the chest CT image of patient Guo Moumou in Example 5.

[0026] Figure 6 This is the powder X-ray diffraction pattern of the co-amorphous product of hydrocortisone and baicalein (molar ratio 1:1).

[0027] Figure 7 It is the powder X-ray diffraction pattern of the physical mixture of hydrocortisone and baicalein (molar ratio 1:1).

[0028] Figure 8 This is the infrared absorption spectrum of the co-amorphous compound of hydrocortisone and baicalein (molar ratio 1:1).

[0029] Fig. 9 This is the differential scanning calorimetry spectrum of the co-amorphous product of hydrocortisone and baicalein (molar ratio 1:1).

[0030] Fig.10 It is the differential scanning calorimetry spectrum of the co-amorphous product of hydrocortisone and baicalein (molar ratio 1:1) and baicalein and hydrocortisone raw materials.

[0031] Fig.11 This is the powder X-ray diffraction pattern of the co-amorphous product of prednisolone acetate and baicalein (molar ratio 1:1).

[0032] Fig.12 The powder X-ray diffraction pattern of the physical mixture of prednisolone acetate and baicalein (molar ratio 1:1).

[0033] Fig.13 This is the infrared absorption spectrum of the co-amorphous product of prednisolone acetate and baicalein (molar ratio 1:1).

[0034] Fig.14 This is the differential scanning calorimetry spectrum of the co-amorphous product of prednisolone acetate and baicalein (molar ratio 1:1).

[0035] Fig.15 It is the differential scanning calorimetry spectrum of the co-amorphous product of prednisone acetate and baicalein (molar ratio 1:1) and baicalein and prednisone acetate raw materials.

[0036] Fig.16 This is the equilibrium solubility result of the co-amorphous product of hydrocortisone and baicalein and the hydrocortisone raw material in pH 6.8 medium.

[0037] Fig.17 These are the equilibrium solubility results of the co-amorphous product of prednisone acetate and baicalein and the raw material of prednisone acetate in a pH 6.8 medium. DETAILED DESCRIPTION

[0038] Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be noted that the relative arrangement of components and steps, numerical expressions and numerical values ​​set forth in these embodiments do not limit the scope of the present invention unless otherwise specifically stated.

[0039] One or more embodiments of the present application provide technical methods and materials for preparing drugs for treating or preventing thymoma, and provide new materials and technologies for preparing new drugs for treating or preventing thymoma.

[0040] One or more embodiments of the present application provide a composition for treating or preventing thymoma, the composition comprising or consisting of a glucocorticoid and baicalein (and / or baicalin).

[0041] In one or more embodiments, the molar ratio of the glucocorticoid to baicalein (and / or baicalin) is 1:10-10:1, for example, 1:5-5:1, 1:4-4:1, 1:3-3:1, 1:2-2:1.

[0042] In one or more embodiments, the molar ratio of glucocorticoid to baicalein (and / or baicalin) is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0043] In one or more embodiments, the molar ratio of the glucocorticoid to baicalein (and / or baicalin) is 1:1.

[0044] One or more embodiments of the present application provide a co-amorphous substance, which is formed by a glucocorticoid and baicalein (and / or baicalin) by non-covalent bonds, and is analyzed by powder X-ray diffraction using CuKα radiation. In units of 2θ, the powder X-ray diffraction pattern of the co-amorphous substance has a diffuse diffraction peak at 15.0±0.3° to 27.0±0.3°.

[0045] In one or more embodiments, the molar ratio of the glucocorticoid to baicalein (and / or baicalin) is 1:10-10:1.

[0046] In one or more embodiments, the molar ratio of the glucocorticoid to baicalein (and / or baicalin) is 1:5-5:1, 1:4-4:1, 1:3-3:1, 1:2-2:1.

[0047] In one or more embodiments, the molar ratio of glucocorticoid to baicalein (and / or baicalin) is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0048] In one or more embodiments, the molar ratio of the glucocorticoid to baicalein (and / or baicalin) is 1:1.

[0049] In one or more embodiments, the powder X-ray diffraction analysis using CuKα radiation shows that the powder X-ray diffraction pattern of the co-amorphous material has diffuse diffraction peaks at 15.9±0.3° and 26.4±0.3° in units of 2θ.

[0050] In one or more embodiments, the powder X-ray diffraction analysis using CuKα radiation shows that the powder X-ray diffraction pattern of the co-amorphous material has a diffuse diffraction peak at 15.6±0.3° in units of 2θ.

[0051] In one or more embodiments, the glucocorticoid is a natural glucocorticoid or an artificial semi-synthetic or synthetic glucocorticoid.

[0052] In one or more embodiments, the glucocorticoid is cortisone, hydrocortisone, prednisone, prednisone acetate, prednisolone, methylprednisolone, betamethasone, beclomethasone dipropionate, or dexamethasone.

[0053] In one or more embodiments, the glucocorticoid is hydrocortisone, prednisolone acetate, or prednisone.

[0054] In one or more embodiments, the baicalein (and / or baicalin) is one or more flavonoid compounds derived from Scutellaria baicalensis.

[0055] In one or more embodiments, the baicalein (and / or baicalin) is baicalein;

[0056] In one or more embodiments, the glucocorticoid is hydrocortisone, the baicalein (and / or baicalin) is baicalein, and powder X-ray diffraction analysis using CuKα radiation is performed, and in units of 2θ, the powder X-ray diffraction pattern of the co-amorphous material has a diffuse diffraction peak at 15.6±0.3°.

[0057] In one or more embodiments, the glucocorticoid is hydrocortisone, the baicalein (and / or baicalin) is baicalein, and the powder X-ray diffraction analysis using CuKα radiation, in units of 2θ, the powder X-ray diffraction pattern of the co-amorphous material is as follows: Figure 6 shown.

[0058] In one or more embodiments, the glucocorticoid is prednisone acetate, the baicalein (and / or baicalin) is baicalein, and powder X-ray diffraction analysis using CuKα radiation is performed, and in units of 2θ, the powder X-ray diffraction pattern of the co-amorphous material has diffuse diffraction peaks at 15.9±0.3° and 26.4±0.3°.

[0059] In one or more embodiments, the glucocorticoid is prednisone acetate, the baicalein (and / or baicalin) is baicalein, and the powder X-ray diffraction analysis using CuKα radiation, in units of 2θ, the powder X-ray diffraction pattern of the co-amorphous material is as follows: Fig.11 shown.

[0060] In one or more embodiments, the co-amorphous substance is prepared by the following method: glucocorticoid and baicalein (and / or baicalin) are added in a molar ratio of 1:10-10:1 and prepared by a mechanochemical method.

[0061] In one or more embodiments, the molar ratio of the glucocorticoid to baicalein (and / or baicalin) is 1:5-5:1, 1:4-4:1, 1:3-3:1, 1:2-2:1.

[0062] In one or more embodiments, the molar ratio of glucocorticoid to baicalein (and / or baicalin) is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0063] In one or more embodiments, the mechanochemical method is a ball milling method, wherein the glucocorticoid and baicalein (and / or baicalin) are mixed in a mortar or a ball mill at a molar ratio of 1:10-10:1, the ball-to-material ratio is 1:1-10:1 (e.g., 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10), the ball milling speed is 20r / min-400r / min (e.g., 100r / min, 200r / min, 300r / min), and the grinding time is 0.1-72 hours (e.g., 1, 10, 20, 30, 40, 40, 50, 60 hours);

[0064] In one or more embodiments, the mechanochemical method is a liquid-adding ball milling method, wherein a glucocorticoid and baicalein (and / or baicalin) having a molar ratio of 1:10-10:1 (e.g., 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20) are placed in a ball mill for mixing, an organic solvent is added, and the mixture is ground at room temperature and collected.

[0065] In one or more embodiments, the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane or cyclohexane.

[0066] In one or more embodiments, the ball mill speed is 20r / min-400r / min (e.g., 100r / min, 200r / min, 300r / min), the liquid addition amount is 0.01-100ml (e.g., 1, 10, 20, 30, 40, 40, 50, 60, 70, 80, 90ml); the grinding time is 0.1-72 hours (e.g., 1, 10, 20, 30, 40, 40, 50, 60 hours).

[0067] In one or more embodiments, the co-amorphous material is prepared by the following method: glucocorticoid and baicalein (and / or baicalin) are added in a molar ratio of 1:10-10:1 (e.g., 10:1, 1:1, 1:10), an organic solvent is added, and the mixture is stirred at a temperature of 10-80°C (e.g., 20, 40, 70°C) for 0.1-2 days (e.g., 1 day), filtered, concentrated, and dried in a low-temperature vacuum to obtain a solid substance.

[0068] In one or more embodiments, the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, and cyclohexane.

[0069] In one or more embodiments, the ratio of the total mass of the glucocorticoid and baicalein (and / or baicalin) to the volume of the organic solvent is 1 mg / ml-500 mg / ml (e.g., 50, 100, 200, 300, 400 mg / ml), the drying temperature is 40-80°C (e.g., 50, 60, 70°C), and the drying time is 1-10 hours (e.g., 2, 5, 7 hours).

[0070] In one or more embodiments, glucocorticoid and baicalein (and / or baicalin) are added in a molar ratio of 1:10-10:1 and prepared by a mechanochemical method.

[0071] In one or more embodiments, the molar ratio of glucocorticoid to baicalein (and / or baicalin) is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0072] In one or more embodiments, the mechanochemical method is a ball milling method, and the glucocorticoid and baicalein (and / or baicalin) are mixed in a molar ratio of 1:10-10:1 (e.g., 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20) are put into a mortar or ball mill for mixing, the ball-to-material ratio is 1:1-10:1 (for example, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1), the ball mill speed is 20r / min-400r / min (for example, 100r / min, 200r / min, 300r / min), and the grinding time is 0.1-72 hours (for example, 1, 10, 50 hours).

[0073] In one or more embodiments, the mechanochemical method is a liquid-adding ball milling method, wherein a glucocorticoid and baicalein (and / or baicalin) having a molar ratio of 1:10-10:1 (e.g., 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20) are placed in a ball mill for mixing, an organic solvent is added, and the mixture is ground at room temperature and collected.

[0074] In one or more embodiments, the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane or cyclohexane.

[0075] In one or more embodiments, the ball mill speed is 20r / min-400r / min (e.g., 100r / min, 200r / min, 300r / min), the liquid addition amount is 0.01-100ml (e.g., 1, 20, 50ml); the grinding time is 0.1-72 hours (e.g., 1, 10, 50 hours).

[0076] One or more embodiments of the present application provide a method for preparing the co-amorphous substance of the present application, wherein the molar ratio of glucocorticoid to baicalein (and / or baicalin) is 1:10-10:1 (e.g., 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:10-10:1). :4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20) are added, an organic solvent is added, and the mixture is stirred at a temperature of 10-80° C. (e.g., 50, 60, 70° C.) for 0.1-2 days (e.g., 1 day), filtered, concentrated, and dried in a low-temperature vacuum to obtain a solid substance.

[0077] In one or more embodiments, the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, and cyclohexane.

[0078] In one or more embodiments, the ratio of the total mass of the glucocorticoid and baicalein (and / or baicalin) to the volume of the organic solvent is 1 mg / ml-500 mg / ml (e.g., 50, 100, 200, 300, 400 mg / ml), the drying temperature is 40-80°C (e.g., 50, 60, 70°C), and the drying time is 1-10 hours (e.g., 2, 5, 7 hours).

[0079] One or more embodiments of the present application provide a pharmaceutical composition, which contains a therapeutically or prophylactically effective amount of the composition or co-amorphous substance of the present application and a pharmaceutically acceptable excipient or carrier.

[0080] In one or more embodiments, the pharmaceutical composition is prepared as tablets, capsules, pills, or injections.

[0081] In one or more embodiments, the pharmaceutical composition is prepared as a sustained-release formulation or a controlled-release formulation.

[0082] One or more embodiments of the present application provide use of the composition or co-amorphous substance of the present application or the pharmaceutical composition of the present application in the preparation of a drug for treating or preventing thymoma.

[0083] In one or more embodiments, the thymoma is an anterior superior mediastinal tumor arising from thymic epithelial cells.

[0084] In one or more embodiments, the thymoma is a type B thymoma.

[0085] In one or more embodiments, the thymoma is a type B1, type B2, or type B3 thymoma.

[0086] In one or more embodiments, the thymoma is a type B2 thymoma.

[0087] One or more embodiments of the present application provide the use of a combination of glucocorticoid and baicalein (and / or baicalin) in the preparation of a medicament for treating or preventing thymoma.

[0088] In one or more embodiments, the glucocorticoid is prepared as a preparation with a dosage of 10 mg / day-300 mg / day (50, 100, 200 mg / day), and the baicalein (and / or baicalin) is prepared as a preparation with a dosage of 20 mg / day-200 mg / day (50, 100, 150 mg / day).

[0089] In one or more embodiments, the glucocorticoid and baicalein (and / or baicalin) are as described above.

[0090] In one or more embodiments, the molar ratio of the glucocorticoid to baicalein (and / or baicalin) is 1:10-10:1.

[0091] In one or more embodiments, the molar ratio of glucocorticoid to baicalein (and / or baicalin) is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0092] In one or more embodiments, glucocorticoids and baicalein (and / or baicalin) compounds are used as active substances, and through a large number of experimental studies, especially through the understanding based on the biological characteristics and occurrence and development process of thymoma, the regulation process is explored. Without being limited to any theory, it is proved that glucocorticoids can play an intervention role in the occurrence and development process of thymoma through their specific receptors. This invention breaks through the traditional understanding of the immunosuppression of glucocorticoid drugs and the regulation of thymic immune function. On this basis, after a large number of studies, the substances and compositions that improve and stabilize glucocorticoids for treating or preventing thymoma are explored. It is found that baicalein (and / or baicalin) can produce the effect of improving glucocorticoids for treating or preventing thymoma. The structural formulas of glucocorticoids and baicalein (and / or baicalin) are shown below.

[0093] Chemical structure of glucocorticoid drugs:

[0094]

[0095] Molecular structure of baicalin (and / or baicalin) compounds:

[0096]

[0097] One or more embodiments of the present application provide the use of a combination or joint use of glucocorticoids and baicalein (and / or baicalin) in the preparation of a drug for preventing or treating or preventing thymoma.

[0098] One or more embodiments of the present application provide a composition state of glucocorticoid and baicalein (and / or baicalin) and a preparation method thereof.

[0099] One or more embodiments of the present application provide a pharmaceutical composition comprising a pure composition of glucocorticoid and baicalein (and / or baicalin), or a mixed solid substance containing a composition of glucocorticoid and baicalein (and / or baicalin) in any non-zero ratio and a pharmaceutically acceptable carrier.

[0100] One or more embodiments of the present application provide a pharmaceutical composition using a combination of glucocorticoid and baicalein (and / or baicalin) as a pharmaceutical active ingredient, wherein the daily adult dosage of glucocorticoid via the digestive tract is 10 mg-300 mg, and the total amount of baicalein (and / or baicalin) is 20 mg-200 mg.

[0101] One or more embodiments of the present application provide a combination of glucocorticoids and baicalein (and / or baicalin) which, during the treatment or prevention of a disease, changes the blood drug concentration in a living organism due to the combination, thereby exerting an effective therapeutic or preventive effect of the drug. Specifically, the glucocorticoid in the composition selected after research and screening dissolves faster than ordinary glucocorticoids, and dissolves more per unit time, thereby ensuring that the glucocorticoid can exert its effect faster and better.

[0102] One or more embodiments of the present application provide a combination substance of glucocorticoid and baicalein (and / or baicalin), which, during the treatment or prevention of a disease, changes the blood drug concentration in a living organism due to the combined substance, thereby exerting an effective therapeutic or preventive effect of the drug. Specifically, the baicalein (and / or baicalin) in the composition selected after research and screening has a slower dissolution rate than ordinary baicalein (and / or baicalin), and the amount of baicalein (and / or baicalin) dissolved per unit time is less. Under the same dose, the dissolution and stable drug concentration can be maintained for a longer time, which effectively compensates for the short half-life of baicalein (and / or baicalin) drugs and ensures that baicalein (and / or baicalin) can continue to exert its effect for a longer time.

[0103] One or more embodiments of the present application provide the use of a combination of glucocorticoid and baicalein (and / or baicalin) as an effective pharmaceutical ingredient in the preparation of a drug for treating or preventing thymoma.

[0104] In one or more embodiments, the composition or co-amorphous product of glucocorticoid and baicalein (and / or baicalin) is a composition of glucocorticoid and baicalein (and / or baicalin) in a certain molar ratio, wherein the total amount of glucocorticoid is 10 mg-300 mg, and the total amount of baicalein (and / or baicalin) is 20 mg-200 mg.

[0105] In one or more embodiments, the co-amorphous substance of glucocorticoid and baicalein (and / or baicalin) presents a co-amorphous substance state. When powder X-ray diffraction analysis using CuKα radiation is performed, the powder X-ray diffraction pattern of the co-amorphous substance has a diffuse diffraction peak at 15.0±0.3° to 27.0±0.3° in units of 2θ.

[0106] In one or more embodiments, the powder X-ray diffraction pattern of the co-amorphous material is as follows: Figure 6 , Fig.11 shown.

[0107] In one or more embodiments, the powder X-ray diffraction patterns of the co-amorphous forms of glucocorticoids and baicalein (and / or baicalin) are compared (e.g.: Figure 6 , Fig.11 ), the powder X-ray diffraction pattern of the physical mixture of glucocorticoid and baicalein (and / or baicalin) (for example: Figure 7 , Fig.12 ) It can be seen that there are obvious differences in the number of diffraction peaks, diffraction peak positions, diffraction peak intensities, diffraction peak topological patterns, etc., indicating that the composition of glucocorticoid and baicalein (and / or baicalin) and the physical mixture of glucocorticoid and baicalein (and / or baicalin) are different substances. The co-amorphous substance of glucocorticoid and baicalein (and / or baicalin) of the present application forms a new solid material state.

[0108] In one or more embodiments, the method for preparing a co-amorphous substance of glucocorticoid and baicalein (and / or baicalin) comprises: adding glucocorticoid and baicalein (and / or baicalin) in a certain molar ratio, 10 mg-300 mg of glucocorticoid, and 20 mg-200 mg of baicalein (and / or baicalin) in total, and preparing the co-amorphous substance of glucocorticoid and baicalein (and / or baicalin) by a mechanochemical method with controlled pressure and temperature.

[0109] In one or more embodiments, the mechanochemical method may be a ball milling method, i.e., glucocorticoids and baicalein (and / or baicalin) are mixed in a mortar or a ball mill in a certain molar ratio, with a ball-to-material ratio of 1:1-10:1, preferably 6:1-10:1; the ball milling speed is 20r / min-400r / min; and the grinding time is 0.1-72 hours.

[0110] In one or more embodiments, the mechanochemical method can be a liquid-adding ball milling method, in which an organic solvent is added, ground at room temperature and collected. The organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane or cyclohexane; the ball milling speed is 20r / min-400r / min, the liquid addition amount is 0.01-100ml; the grinding time is 0.1-72 hours.

[0111] In one or more embodiments, the preparation method of the co-amorphous product of glucocorticoid and baicalein (and / or baicalin) includes: adding glucocorticoid and baicalein (and / or baicalin) in a certain molar ratio into a clean container, the total amount of glucocorticoid is 10mg-300mg, the total amount of baicalein (and / or baicalin) is 20mg-200mg, adding an organic solvent to form a suspension, stirring at room temperature, and filtering the obtained suspension to obtain the co-amorphous product of glucocorticoid and baicalein (and / or baicalin). The composite organic solvent is selected from any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, and cyclohexane, and is prepared as a mixed solvent by combining them in different proportions; the volume ratio of the total mass of glucocorticoid and baicalein (and / or baicalin) to the organic solvent is 1 mg / ml-500 mg / ml; the drying temperature is 40-80°C; and the drying time is 1-10 hours.

[0112] In one or more embodiments, the composition or co-amorphous product of glucocorticoid and baicalein (and / or baicalin) prepared by the above method is mixed with other chemical substances in any non-zero ratio and in a conventional manner to obtain a pharmaceutical composition comprising glucocorticoid and baicalein (and / or baicalin).

[0113] In one or more embodiments, a pharmaceutical composition comprising a glucocorticoid and baicalein (and / or baicalin), a composition comprising a glucocorticoid and baicalein (and / or baicalin), and a pharmaceutically acceptable carrier.

[0114] In one or more embodiments, the pharmaceutical composition comprising a glucocorticoid and baicalein (and / or baicalin) comprises a co-amorphous substance of a glucocorticoid and baicalein (and / or baicalin) and a pharmaceutically acceptable carrier.

[0115] In one or more embodiments, for the pharmaceutical composition of the present application, the daily human dosage of glucocorticoids via the digestive tract is 10 mg / day-300 mg / day, and the daily human dosage of baicalein (and / or baicalin) via the digestive tract is 20 mg / day-200 mg / day.

[0116] In one or more embodiments, the pharmaceutical composition of the present application can be prepared as a tablet, a capsule, a pill, an injection preparation, a sustained-release preparation or a controlled-release preparation.

[0117] In one or more embodiments, the present application provides a composition of a glucocorticoid and baicalein (and / or baicalin), a co-amorphous product of a glucocorticoid and baicalein (and / or baicalin), or a pharmaceutical composition comprising the composition or the co-amorphous product, and their use in the preparation of a medicament for the treatment or prevention of thymoma.

[0118] In one or more embodiments, the thymoma may be a type B thymoma.

[0119] In one or more embodiments, the thymoma is an anterior superior mediastinal tumor arising from thymic epithelial cells.

[0120] In one or more embodiments, the type B thymoma includes type B1, type B2 or type B3.

[0121] In one or more embodiments, the type B thymoma is type B1 or type B2.

[0122] In one or more embodiments, the type B thymoma is type B2.

[0123] In one or more embodiments, a pharmaceutical composition is provided, which comprises a combination or a co-amorphous product of a glucocorticoid and baicalein (and / or baicalin) as an active ingredient.

[0124] In one or more embodiments, the pharmaceutical composition can be prepared according to methods known in the art.

[0125] In one or more embodiments, any dosage form suitable for human or animal use can be prepared by combining a composition or co-amorphous product of a glucocorticoid and baicalein (and / or baicalin) with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants.

[0126] In one or more embodiments, the content of the combination or co-amorphous product of glucocorticoid and baicalein (and / or baicalin) in the pharmaceutical composition is 10 wt % to 90 wt %.

[0127] In one or more embodiments, the pharmaceutical composition of the present application can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0128] In one or more embodiments, the dosage form of the pharmaceutical composition of the present application is a solid dosage form. The solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, drop pills, suppositories, films, patches, aerosols (powders), sprays, etc.

[0129] In one or more embodiments, the pharmaceutical composition of the present application can be prepared into a common preparation, or a sustained-release preparation, a controlled-release preparation, a targeted preparation, and various microparticle delivery systems.

[0130] In one or more embodiments, in order to prepare the pharmaceutical composition of the present application into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0131] In one or more embodiments, the tablet may also be a coated tablet, such as a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, or a double-layer tablet and a multi-layer tablet.

[0132] In one or more embodiments, the administration unit may be a capsule, and the active ingredients of glucocorticoid and baicalein (and / or baicalin) may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredients of glucocorticoid and baicalein (and / or baicalin) may also be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets may also be used to prepare the capsules of the present application.

[0133] In one or more embodiments, colorants, preservatives, fragrances, flavoring agents or other additives may also be added to the pharmaceutical preparations as desired.

[0134] In one or more embodiments, in order to achieve the purpose of medication and enhance the therapeutic effect, the pharmaceutical composition of the present application can be administered by any known administration method.

[0135] In one or more embodiments, the dosage of the pharmaceutical composition of the present application can vary widely according to the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form, etc. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other treatment means.

[0136] In one or more embodiments, the pharmaceutical composition of the present application can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the pharmaceutical composition of the present application has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0137] In one or more embodiments, the composition or co-amorphous product of glucocorticoid and baicalein (and / or baicalin) of the present application or the pharmaceutical composition thereof provides an active substance for preparing a drug for treating or preventing thymoma.

[0138] In one or more embodiments, the composition or co-amorphous product of glucocorticoid and baicalein (and / or baicalin) of the present application or the pharmaceutical composition thereof can be used as an active substance for preparing a drug for treating or preventing thymoma.

[0139] In one or more embodiments, the composition or co-amorphous product of glucocorticoid and baicalein (and / or baicalin) of the present application or the pharmaceutical composition thereof exhibits a solubility advantage over glucocorticoid in a system of pH 6.8.

[0140] In one or more embodiments, the drug developed with the composition or co-amorphous substance of the glucocorticoid and baicalein (and / or baicalin) of the present application or its pharmaceutical composition as the active ingredient has a biological absorption effect after oral administration, quickly reaches the maximum concentration value in the gastrointestinal tract or blood, and plays a superior role and application in the treatment or prevention of diseases.

[0141] In one or more embodiments, the composition or co-amorphous substance of the glucocorticoid and baicalein (and / or baicalin) of the present application or its pharmaceutical composition combined with a solid substance increases the blood concentration of the drug in the organism to prolong the effective action time of the drug, thereby exerting a more effective therapeutic effect of the drug.

[0142] In one or more embodiments, there are many factors affecting the dosage of the active ingredient of the pharmaceutical composition of glucocorticoids and baicalein (and / or baicalin), for example, the patient's age, body surface area, route of administration, number of administrations, and different treatment purposes result in different dosages for each medication; different absorption and blood drug concentrations between samples, etc., so that the appropriate dosage range for each use of the pharmaceutical composition of glucocorticoids and baicalein (and / or baicalin) is 0.1-20 mg / kg body weight, preferably 2-10 mg / kg body weight. When used, different total dosage plans of the active ingredients of glucocorticoids and baicalein (and / or baicalin) should be formulated according to the actual treatment requirements of different situations, and can be divided into multiple or one-time administration methods.

[0143] Scutellaria baicalensis is the dried root and rhizome of Scutellaria baicalensis Georgi, a plant of the Lamiaceae family.

[0144] Example 1

[0145] Combination of glucocorticoids and baicalein (and / or baicalin) in the treatment of thymoma case 1.

[0146] Patient Yang XX, male, 52 years old, was diagnosed with thymoma type B1. He underwent right anterior mediastinal thymoma removal by right thoracoscopic surgery in a tertiary hospital in 2017. Two years later, multiple metastases occurred in the right chest cavity. He was given 50-100 mg / day of glucocorticoids and 200 mg / day of baicalein for 30 consecutive days, and the multiple metastases in the right chest cavity were significantly reduced. The remaining multiple metastases in the right chest cavity were removed by right thoracoscopic surgery and hot perfusion of the right chest cavity was performed. The results are as follows Figure 1 .

[0147] Example 2

[0148] Combination therapy of glucocorticoids and baicalein (and / or baicalin) in the treatment of thymoma case 2.

[0149] Patient Liu XX, 64 years old, was diagnosed with mixed thymoma B2 and B3, which engulfed the superior vena cava and the left and right innominate veins. He was given glucocorticoids 100 mg / day and baicalein 200 mg / day for 30 consecutive days, and the multiple metastatic lesions in the right chest cavity were significantly reduced. Figure 2 .

[0150] Example 3

[0151] Combination therapy of glucocorticoids and baicalein (and / or baicalin) in the treatment of thymoma case 3.

[0152] Patient Huang XX, male, 72 years old, was diagnosed with thymoma type B1, with a cyst in the right anterior mediastinum and a huge mass in the left anterior mediastinum, which engulfed the left pulmonary artery and the first branch of the left pulmonary artery. He was given glucocorticoids 100mg / day and baicalein 100mg / day for 30 consecutive days, and the huge mass in the left anterior mediastinum was significantly reduced. The mass was completely removed through the median sternotomy approach. The results are as follows Figure 3 .

[0153] Example 4

[0154] Combination therapy of glucocorticoids and baicalein (and / or baicalin) in the treatment of thymoma case 4.

[0155] Patient Han X, male, 55 years old, was diagnosed with thymoma type B2, located in the right anterior mediastinum, with right thoracic metastasis. He was given glucocorticoid 100 mg / day and baicalein 200 mg / day for 30 consecutive days. The primary lesion showed cystic changes and the right thoracic metastasis was significantly reduced. Figure 4 .

[0156] Example 5

[0157] Combination therapy of glucocorticoids and baicalein (and / or baicalin) in the treatment of thymoma case 5.

[0158] Patient Guo XX, female, 62 years old, had adenoma type B2. Three years after surgery, a metastasis appeared in the left chest cavity. She was treated with glucocorticoid 100 mg / day and baicalein 200 mg / day for 19 consecutive days, and the metastasis in the left chest cavity was significantly reduced. Figure 5 .

[0159] Example 6

[0160] Amorphous compound of hydrocortisone and baicalein and its preparation method 1.

[0161] As shown in the table below, baicalein and hydrocortisone are put into a ball mill at a molar ratio of 1:1 (mass ratio of 43:57), and an appropriate ball-to-material ratio is selected, an appropriate rotation speed is set, and an appropriate grinding time is applied. Hydrocortisone and baicalein form a co-amorphous substance at a molar ratio of 1:1. When powder X-ray diffraction analysis is performed using CuKα radiation experimental conditions, the powder X-ray diffraction spectrum shows a diffuse diffraction peak, and the 2-Theta value diffraction peak position is 15.6±0.3°. The diffraction spectrum is shown in FIG. Figure 6 , indicating that the obtained sample is amorphous compound of baicalein and hydrocortisone (molar ratio 1:1). Specific examples are shown in Table 1.

[0162] Table 1 Specific example of the preparation method of the co-amorphous compound of hydrocortisone and baicalein (molar ratio 1:1)

[0163]

[0164]

[0165] Hydrocortisone and baicalein are amorphous (molar ratio 1:1), do not contain crystallization solvent or crystal water components, when using powder X-ray diffraction analysis, using CuKα radiation experimental conditions, the performance of the diffraction peak position: 2-Theta value (°) or d value The relative intensity peak height value (Height%) or peak area value (Area%) of the diffraction peak has the following characteristic peak values ​​for the solid substance (Table 2, Figure 6 ). The powder X-ray diffraction spectrum data of the physical mixture of hydrocortisone and baicalein can be found in Figure 7 , Table 2. The powder X-ray diffraction patterns of the co-amorphous product of hydrocortisone and baicalein in a molar ratio of 1:1 and the physical mixture of hydrocortisone and baicalein (molar ratio 1:1) showed obvious differences in the number of diffraction peaks, diffraction peak positions, diffraction peak intensities, and diffraction peak topological patterns, indicating that the co-amorphous product of hydrocortisone and baicalein (molar ratio 1:1) and the physical mixture of hydrocortisone and baicalein are different substances.

[0166] Table 2 Powder X-ray diffraction peak data of the co-amorphous product (molar ratio 1:1) and the physical mixture of hydrocortisone and baicalein (and / or baicalin) A

[0167]

[0168]

[0169] The co-amorphous product of hydrocortisone and baicalein (molar ratio 1:1) was analyzed by attenuated total reflection Fourier transform infrared spectroscopy at 3402, 2931, 1710, 1656, 1651, 1614, 1583, 1506, 1493, 1470, 1450, 1366, 1338, 1304, 1274, 1233, 1187, 1161, 1131, 1078, 1 There are characteristic peaks of infrared spectrum at 054, 1034, 1022, 1002, 942, 915, 899, 865, 845, 816, 778, 766, 745, 719, 687, 658, 641, 615, 600, 575, 525, 514, 504, 483, 459, 434, 426, 419 cm-1, and the allowable deviation of the characteristic peaks of infrared spectrum is ±2 cm -1 ( Figure 8 ).

[0170] The co-amorphous product of hydrocortisone and baicalein (molar ratio 1:1) was analyzed by differential scanning calorimetry. In the range of 30-250°C, when the heating rate was 10°C per minute, its DSC spectrum showed four absorption peaks at 69°C±3°C, 102°C±3°C, 119°C±3°C, and 194°C±3°C ( Fig. 9 ). The DSC spectra of the co-amorphous product of hydrocortisone and baicalein in a molar ratio of 1:1 are significantly different from those of baicalein and hydrocortisone in terms of the number and position of the absorption / exothermic peaks, indicating that the co-amorphous product of hydrocortisone and baicalein (molar ratio 1:1) is a different substance from the raw materials of baicalein and hydrocortisone ( Fig.10 ).

[0171] Example 7

[0172] Amorphous compound of prednisolone acetate and baicalein and preparation method thereof

[0173] As shown in the table below, baicalein and prednisone acetate are taken and put into a ball mill according to a molar ratio of 1:1 (mass ratio is 40:60), and an appropriate ball-to-material ratio is selected, an appropriate rotation speed is set, and an appropriate grinding time is applied. Prednisone acetate and baicalein are formed into a co-amorphous substance in a molar ratio of 1:1. When powder X-ray diffraction analysis is performed using CuKα radiation experimental conditions, its powder X-ray diffraction spectrum shows diffuse diffraction peaks, and the 2-Theta value diffraction peak positions are 15.9±0.3° and 26.4±0.3°. Its diffraction spectrum is shown in Fig.11 , indicating that the obtained sample is a co-amorphous compound of baicalein and prednisolone acetate (molar ratio 1:1). Specific examples are shown in Table 3.

[0174] Table 3 Specific examples of the preparation method of the co-amorphous compound of prednisone acetate and baicalein (and / or baicalin) A (molar ratio 1:1)

[0175]

[0176] The co-amorphous product of prednisolone acetate and baicalein (molar ratio 1:1) does not contain crystallization solvent or crystal water. When analyzed by powder X-ray diffraction under CuKα radiation experimental conditions, it is manifested as the diffraction peak position: 2-Theta value (°) or d value The relative intensity peak height value (Height%) or peak area value (Area%) of the diffraction peak has the following characteristic peak values ​​for the solid substance (Table 4, Fig.11 ). The powder X-ray diffraction spectrum data of the physical mixture of prednisolone acetate and baicalein can be found in Fig.12, Table 4. The powder X-ray diffraction patterns of the co-amorphous product of prednisone acetate and baicalein (molar ratio 1:1) and the physical mixture of prednisone acetate and baicalein have obvious differences in the number of diffraction peaks, diffraction peak positions, diffraction peak intensities, and diffraction peak topological patterns, indicating that the co-amorphous product of prednisone acetate and baicalein (molar ratio 1:1) and the physical mixture of prednisone acetate and baicalein are different substances.

[0177] Table 4 Powder X-ray diffraction peak data of prednisolone acetate and baicalein co-amorphous product (molar ratio 1:1) and physical mixture

[0178]

[0179] The co-amorphous product of prednisolone acetate and baicalein (molar ratio 1:1) was analyzed by attenuated total reflection Fourier transform infrared spectroscopy at 3397, 3092, 2944, 1704, 1654, 1615, 1585, 1505, 1492, 1470, 1449, 1410, 1369, 1340, 1306, 1282, 1266, 1231, 1202, 1185, 1161, 1133 There are characteristic peaks of infrared spectrum at 1121, 1101, 1080, 1044, 1022, 1000, 947, 917, 896, 887, 869, 843, 823, 778, 766, 719, 707, 688, 658, 614, 600, 574, 557, 538, 506, 481, 458, and 420 cm-1, and the allowable deviation of the characteristic peaks of infrared spectrum is ±2 cm-1( Fig.13 ).

[0180] When the co-amorphous product of prednisolone acetate and baicalein (molar ratio 1:1) was analyzed by differential scanning calorimetry, in the range of 30-250°C, when the heating rate was 10°C per minute, its DSC spectrum had an endothermic peak at 62°C±3°C, 110°C±3°C, 186°C±3°C, and 213°C±3°C ( Fig.14 The DSC spectra of the co-amorphous product of prednisone acetate and baicalein (molar ratio 1:1) and baicalein and prednisone acetate have obvious differences in the number and position of absorption / exothermic peaks, indicating that the co-amorphous product of prednisone acetate and baicalein (molar ratio 1:1) and baicalein and prednisone acetate are different substances ( Fig.15 ).

[0181] Example 8

[0182] Equilibrium solubility of the co-amorphous product of hydrocortisone and baicalein

[0183] The equilibrium solubility of hydrocortisone and baicalein co-amorphous substance and raw material in a solution system with a pH value of 6.8 was investigated. Accurately weigh 30 mg of hydrocortisone and baicalein co-amorphous substance and raw material, 2 ml of dissolution medium, and experiment for 72 hours at 37°C and 160 r / min. The percentage of solubility was calculated by high performance liquid chromatography and external standard method. The solubility comparison diagram was drawn with the experimental sample as the horizontal axis and the substance concentration in the medium as the vertical axis ( Fig.16 ).

[0184] Detection conditions: Detection system: Aligent 1200, chromatographic column: Agilent Eclipse XDB-C18 (4.6×250mm, 5μm); mobile phase: methanol-0.1% phosphoric acid water (60:40, v / v); flow rate: 1ml / min; column temperature: 30℃; detection wavelength: hydrocortisone: 237nm, injection volume: 10μl.

[0185] The dissolution amount of hydrocortisone in the co-amorphous material in pH 6.8 medium is 655.77 μg / ml. Compared with 441.89 μg / ml of hydrocortisone raw material, the dissolution of glucocorticoid is significantly improved, which is 1.48 times of the raw material. The f2 value is -17, indicating a significant difference, that is, the solubility of glucocorticoid in the co-amorphous material is significantly improved, and an unexpected technical effect is achieved.

[0186] Example 9

[0187] Equilibrium solubility of the co-amorphous product of prednisolone acetate and baicalein

[0188] The equilibrium solubility of prednisone acetate and baicalein co-amorphous substance and raw materials in a solution system with a pH value of 6.8 was investigated. 30 mg of prednisone acetate and baicalein co-amorphous substance and raw materials were accurately weighed, and 2 ml of dissolution medium was added. The experiment was carried out at 37°C and 160 r / min for 72 hours. The percentage of solubility was calculated by high performance liquid chromatography and the external standard method. The solubility comparison diagrams were drawn with the experimental sample as the horizontal axis and the substance concentration in the medium as the vertical axis ( Fig.17 ).

[0189] Detection conditions: Detection system: Aligent 1200, chromatographic column: Agilent Eclipse XDB-C18 (4.6×250mm, 5μm); mobile phase: methanol-0.1% phosphoric acid water (60:40, v / v); flow rate: 1ml / min; column temperature: 30℃; detection wavelength: prednisolone acetate: 237nm; injection volume: 10μL.

[0190] The dissolution amount of prednisone acetate in the co-amorphous material in pH 6.8 medium is 26.00 μg / ml, which is significantly improved compared with 18.25 μg / ml of the prednisone acetate raw material, which is 1.42 times that of the raw material. The two have a significant difference, that is, the solubility of glucocorticoids in the co-amorphous material is improved, and an unexpected technical effect is achieved.

[0191] Example 10

[0192] Preparation method of combined pharmaceutical preparation 1 (tablets)

[0193] Preparation method of drug tablets: take glucocorticoids and baicalein (and / or baicalin), use several excipients as auxiliary ingredients for preparing tablets, and prepare tablet samples containing 30-500 mg (30 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 500 mg) of glucocorticoids and baicalein (and / or baicalin) per tablet in a certain ratio. Table 5 gives the tablet formula.

[0194] Table 5 Preparation formula of glucocorticoid and baicalein (and / or baicalin) tablets

[0195] Name of raw materials and auxiliary materials Glucocorticoids and baicalein (and / or baicalin) lactose starch Low substituted hydroxypropyl cellulose Microcrystalline Cellulose talcum powder Magnesium Stearate

[0196] The method of preparing a tablet preparation using glucocorticoids and baicalein (and / or baicalin) as raw materials is as follows: several excipients are mixed evenly with the raw materials and directly tableted; or the excipients are mixed with dry granules and then mixed evenly with the raw materials and then tableted.

[0197] Embodiment 11

[0198] Preparation method 2 of combined pharmaceutical preparation (tablets):

[0199] Preparation method of drug tablets: take glucocorticoids and baicalein (and / or baicalin), use several excipients as auxiliary ingredients for preparing drug tablets, and prepare tablet samples containing 30-500 mg (30 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg) of glucocorticoids and baicalein (and / or baicalin) per tablet in a certain ratio. Table 6 gives the tablet formula.

[0200] Table 6 Preparation formula of glucocorticoid and baicalein (and / or baicalin) tablets

[0201] Name of raw materials Glucocorticoids and baicalein (and / or baicalin) lactose starch Low substituted hydroxypropyl cellulose Microcrystalline Cellulose talcum powder Magnesium Stearate 1% Sodium Carboxymethylcellulose

[0202] The method for preparing a tablet preparation using glucocorticoid and baicalein (and / or baicalin) as raw materials is as follows: uniformly mixing several excipients with the raw materials, adding an appropriate amount of 1% sodium hydroxymethylcellulose solution to prepare a soft material, sieving granules, drying the wet granules, sieving whole granules, adding magnesium stearate and talcum powder, mixing uniformly, and tableting to obtain the tablet preparation.

[0203] Example 12

[0204] Preparation method of combined pharmaceutical preparation 3 (capsules)

[0205] Preparation method of drug capsules: glucocorticoids and baicalein (and / or baicalin) are used as raw materials, and several excipients are used as auxiliary ingredients for preparing combined drug capsules. Capsule samples with a drug content of 30-500 mg (30 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 500 mg) per tablet are prepared in a certain proportion. The capsule formula is given in Table 7.

[0206] Table 7 API and excipient formula of the drug capsule preparation of glucocorticoid and baicalein (and / or baicalin)

[0207] Name of raw materials Glucocorticoids and baicalein (and / or baicalin) lactose starch Microcrystalline Cellulose Magnesium Stearate 1% Sodium Carboxymethylcellulose

[0208] The method for preparing capsules using glucocorticoids and baicalein (and / or baicalin) as raw materials is as follows: several excipients are mixed evenly with the raw materials, an appropriate amount of 1% sodium hydroxymethylcellulose solution is added to prepare wet granules, the granules are dried and sieved, magnesium stearate is added to mix evenly, and the granules are inserted into capsules; or the granulation step is omitted, and the glucocorticoids and baicalein (and / or baicalin) raw materials are directly mixed evenly with several excipients and auxiliary materials, the granules are sieved, and the granules are directly loaded into capsules.

[0209] Embodiment 13

[0210] Dosage of the pharmaceutical composition comprising glucocorticoid and baicalein (and / or baicalin) 1 (tablet)

[0211] The pharmaceutical composition developed using glucocorticoids and baicalein (and / or baicalin) as active pharmaceutical ingredients has a daily dosage of 500 mg and can be prepared into 250 mg ordinary tablets, one tablet twice a day, or 500 mg tablets, one tablet once a day.

[0212] Dosage 2 of the pharmaceutical composition comprising glucocorticoid and baicalein (and / or baicalin) (capsule)

[0213] The pharmaceutical composition developed using glucocorticoids and baicalein (and / or baicalin) as active pharmaceutical ingredients has a daily dosage of 600 mg and can be prepared into 2 100 mg capsules 3 times a day or 1 300 mg capsule 2 times a day.

[0214] Although the present invention has been disclosed as above by the embodiments, it is not intended to limit the present invention. Any person skilled in the art may make various choices and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention is limited by the claims and their equivalents.

Claims

1. A glucocorticoid-baicalein and / or baicalin co-amorphous substance, characterized in that: The co-amorphous substance is formed by glucocorticoid, baicalein and / or baicalin by non-covalent bonds, and the molar ratio of the two is 1:10-10:

1. The powder X-ray diffraction analysis using CuKα radiation shows that, in units of 2θ, the powder X-ray diffraction spectrum of the co-amorphous substance has diffuse diffraction peaks at 15.0±0.3° to 27.0±0.3°.

2. The glucocorticoid-baicalein and / or baicalin co-amorphous substance according to claim 1, characterized in that: The molar ratio of the glucocorticoid, baicalein and / or baicalin is 1:5-5:1, preferably 1:2-2:1, and more preferably 1:

1.

3. The glucocorticoid-baicalein and / or baicalin co-amorphous substance according to claim 1, characterized in that: The glucocorticoid is a natural glucocorticoid or an artificial semi-synthetic or synthetic glucocorticoid; preferably, the glucocorticoid is cortisone, hydrocortisone, prednisone, prednisone acetate, prednisolone, methylprednisolone, betamethasone, beclomethasone dipropionate or dexamethasone; more preferably, the glucocorticoid is hydrocortisone, prednisone acetate or prednisone; Preferably, the glucocorticoid is hydrocortisone, and the powder X-ray diffraction analysis using CuKα radiation shows that the powder X-ray diffraction pattern of the co-amorphous substance has a diffuse diffraction peak at 15.6±0.3° in units of 2θ; Preferably, the glucocorticoid is prednisolone acetate, and the powder X-ray diffraction analysis using CuKα radiation shows that, in units of 2θ, the powder X-ray diffraction pattern of the co-amorphous material has diffuse diffraction peaks at 15.9±0.3° and 26.4±0.3°.

4. A method for preparing a glucocorticoid-baicalein and / or baicalin co-amorphous product, characterized in that: Specifically: The glucocorticoid and baicalein and / or baicalin are added in a molar ratio of 1:10-10:1, preferably 1:5-5:1, more preferably 1:2-2:1, particularly preferably 1:1, and prepared by a mechanochemical method.

5. The preparation method according to claim 4, characterized in that: The mechanochemical method is a ball milling method or a liquid-added ball milling method. The ball milling method is to mix the glucocorticoids and baicalein and / or baicalin in a molar ratio of 1:10-10:1 in a mortar or a ball mill, the ball-to-material ratio is 1:1-10:1, the ball milling speed is 20r / min-400r / min, and the grinding time is 0.1-72 hours; the liquid-added ball milling method is to mix the glucocorticoids and baicalein and / or baicalin in a molar ratio of 1:10-10:1 in a mortar or a ball mill. The method comprises the following steps: mixing the raw materials in a mill, adding an organic solvent, grinding at room temperature and collecting the raw materials; the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane or cyclohexane; the ball milling speed is 20 r / min-400 r / min, the liquid addition amount is 0.01-100 ml; and the grinding time is 0.1-72 hours.

6. The method for preparing the glucocorticoid-baicalein and / or baicalin co-amorphous product according to any one of claims 1 to 3, characterized in that: Specifically: Glucocorticoid and baicalein and / or baicalin are added in a molar ratio of 1:10-10:1, an organic solvent is added, and the mixture is stirred at 10-80° C. for 0.1-2 days. After filtering, the mixture is concentrated and vacuum dried at low temperature to obtain a solid substance.

7. The preparation method according to claim 6, characterized in that: The organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, and cyclohexane; the ratio of the total mass of the glucocorticoid and baicalein and / or baicalin to the volume of the organic solvent is 1 mg / ml-500 mg / ml, the drying temperature is 40-80°C, and the drying time is 1-10 hours.

8. Use of the co-amorphous substance according to any one of claims 1 to 3 or the co-amorphous substance prepared according to any one of claims 4 to 7 in a drug for treating or preventing thymoma.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the co-amorphous material described in any one of claims 1-3 or the co-amorphous material prepared according to any one of claims 4-7 and a pharmaceutically acceptable excipient or carrier; the pharmaceutical composition is prepared as a tablet, capsule, pill, injection; or the pharmaceutical composition is prepared as a sustained-release preparation or a controlled-release preparation.

10. Use of the pharmaceutical composition according to claim 9 in treating or preventing thymoma, characterized in that: The thymoma is an anterior superior mediastinal tumor originating from thymic epithelial cells; preferably, the thymoma is a type B thymoma; more preferably, the thymoma is a type B1, type B2, or type B3 thymoma; particularly preferably, the thymoma is a type B2 thymoma; The glucocorticoid is prepared as a preparation with a dosage of 10 mg / day to 300 mg / day, and the baicalein and / or baicalin are prepared as a preparation with a dosage of 20 mg / day to 200 mg / day; the molar ratio of the glucocorticoid to baicalein and / or baicalin is 1:10-10:1, preferably 1:5-5:1, more preferably 1:2-2:1, and particularly preferably 1:1.

Images