Solid dispersion of zyz384 and method of preparation and use thereof

Abstract

The application discloses a solid dispersion of ZYZ384 and a preparation method and application thereof, wherein the solid dispersion is prepared from raw materials including ZYZ384 and a carrier, the carrier is povidone K30, and the mass ratio of the ZYZ384 and the carrier is 1:4-20. The solid dispersion of the application significantly improves the solubility of the raw material drug ZYZ384, improves the in-vivo exposure amount and peak concentration of the drug, and has a significant advantage in improving in-vivo absorption of the drug and improving bioavailability; and a good antitumor effect can be achieved at a lower dose, the main organs have no obvious toxicity, and the solid dispersion has good biological safety. The preparation process is simple, the conditions are mild, and the operation is easy; the used organic solvent is easy to remove, there is no toxic solvent residue, and the solid dispersion is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically to the field of pharmaceutical formulation technology, and more specifically, to a solid dispersion of ZYZ384, its preparation method, and its application. Background Technology

[0002] ZYZ384 is a compound with potential medicinal activity, and its molecular formula is C0. 25 H 24 N2O2, structural formula is Preliminary studies have shown promising application prospects in relevant pharmacological models. However, ZYZ384 suffers from poor water solubility, resulting in low in vitro dissolution and limited in vivo absorption, which in turn affects its bioavailability. This, to some extent, limits its further clinical development and application.

[0003] Solid dispersion technology is a formulation technique that uniformly disperses drugs in a molecular, amorphous, or microcrystalline state within a water-soluble carrier. It is an effective means to improve the solubility and dissolution rate of poorly soluble drugs. By preparing solid dispersions of poorly soluble drugs with hydrophilic carriers (such as polyethylene glycol, polyvinylpyrrolidone, poloxamer, etc.), the wettability of the drug can be significantly improved, the particle size of the drug can be reduced, and the drug can even exist in an amorphous form, thereby improving the solubility and dissolution rate of the drug, and ultimately improving its bioavailability.

[0004] There are existing reports on using solid dispersion technology to improve the dissolution of poorly soluble drugs, but for the specific compound ZYZ384, there is no research on preparing it into a solid dispersion.

[0005] In addition, some existing solid dispersion preparation processes have problems such as residual organic solvents. Summary of the Invention

[0006] Based on this, the purpose of this invention is to improve the solubility and bioavailability of the active pharmaceutical ingredient ZYZ384.

[0007] The specific technical solutions for achieving the above-mentioned objectives are as follows.

[0008] A first aspect of the present invention provides a solid dispersion comprising a component having the structural formula as shown below. It is prepared from ZYZ384 and a carrier, wherein the carrier is polyvinyl ketone K30, and the mass ratio of ZYZ384 to the carrier is 1:3~20.

[0009] A second aspect of the present invention provides a method for preparing the above-mentioned solid dispersion, comprising the following steps:

[0010] (1) After mixing ZYZ384 and the carrier, add anhydrous ethanol and stir in a water bath at 30℃~60℃ until a clear solution is obtained;

[0011] (2) After evaporating the clarified solution in step (1) to dryness, vacuum dry it, grind and sieve it to obtain the final product.

[0012] A third aspect of the present invention provides the use of the above-described solid dispersion in the preparation of antitumor drugs.

[0013] In a fourth aspect, the present invention provides an antitumor drug, wherein the active ingredient is the above-mentioned solid dispersion.

[0014] The inventors of this invention have discovered that using povidone K30 as a carrier and preparing a solid dispersion with the active pharmaceutical ingredient ZYZ384 at a specific mass ratio under a specific process can significantly improve the solubility of ZYZ384, increase the in vivo exposure and peak concentration of the drug, and has significant advantages in improving drug absorption and bioavailability. Furthermore, in vivo pharmacodynamic studies have shown that the solid dispersion achieves good antitumor effects at lower doses, has no significant toxicity to major organs, and exhibits good biocompatibility. Therefore, the solid dispersion of this invention has good economic benefits and broad application prospects.

[0015] The preparation process of the solid dispersion of the present invention is simple, mild, and easy to operate. The organic solvent used is easy to remove and leaves no toxic solvent residue, making it suitable for industrial production. Attached Figure Description

[0016] Figure 1 SEM images of the active pharmaceutical ingredient ZYZ384, its solid dispersion ZYZ384@SD, carrier PVP K30, and a physical mixture of the active pharmaceutical ingredient ZYZ384 and carrier PVP K30.

[0017] Figure 2 XRD results of the active pharmaceutical ingredient ZYZ384, its solid dispersion ZYZ384@SD, carrier PVP K30, and physical mixture of active pharmaceutical ingredient ZYZ384 and carrier PVP K30.

[0018] Figure 3 This report presents the in vivo antitumor efficacy study results of the active pharmaceutical ingredient ZYZ384 and its solid dispersion ZYZ384@SD. A: Establishment of a tumor-bearing nude mouse model and treatment methods; B: Changes in body weight of nude mice during treatment; C: Changes in tumor volume of nude mice during treatment.

[0019] Figure 4 Photos of tumors removed at the end of an in vivo antitumor drug efficacy study, along with the average tumor weight.

[0020] Figure 5This is the histopathological examination result of major organs after the completion of the in vivo anti-tumor drug efficacy study.

[0021] Figure 6 The results show the solubility of solid dispersions made from different carriers.

[0022] Figure 7 The concentration results of ZYZ384 in different carriers are shown.

[0023] Figure 8 The effect of different drug loading ratios on the encapsulation efficiency of ZYZ384 solid dispersions is shown.

[0024] Figure 9 The effect of different stirring temperatures on the encapsulation efficiency of solid dispersions of ZYZ384 is shown. Detailed Implementation

[0025] To facilitate understanding of the present invention, a more complete description will be provided below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0026] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used in this invention includes any and all combinations of one or more of the associated listed items.

[0027] Unless otherwise specified, all examples were performed under standard experimental conditions, such as those described in Sambrook et al., Molecular Cloning: a Laboratory Manual (Sambrook J & Russell DW, 2013), or as recommended by the manufacturer.

[0028] The inventors of this invention discovered that the active pharmaceutical ingredient ZYZ384 exhibits significant precipitation upon reaching supersaturation in aqueous solutions of various common polymeric carriers. However, it remains stable without significant precipitation only upon reaching supersaturation in an aqueous solution of povidone K30. Therefore, povidone K30 can serve as a carrier for ZYZ384, effectively inhibiting its crystallization and maintaining its supersaturated concentration. Furthermore, the inventors prepared a solid dispersion by mixing the active pharmaceutical ingredient ZYZ384 and povidone K30 at a specific mass ratio under specific processes (specific solvents and specific stirring temperatures). They found that the encapsulation efficiency of ZYZ384 was high, and it existed in an amorphous form within the solid dispersion, overcoming the inherent poor water solubility of ZYZ384. Compared to the active pharmaceutical ingredient ZYZ384, the solubility of its solid dispersion is significantly improved. Pharmacokinetic studies show that the solid dispersion significantly increases the in vivo exposure and peak concentration of the drug, while the elimination behavior remains largely consistent, demonstrating the significant advantages of solid dispersion in improving drug absorption and bioavailability. In vivo pharmacodynamic studies show that the solid dispersion achieves good antitumor effects at lower doses. Histopathological examination results indicate that the solid dispersion has no significant toxicity to major organs and exhibits good biocompatibility. Therefore, the solid dispersion of this invention has good economic benefits and broad application prospects.

[0029] In some embodiments of the present invention, a solid dispersion is disclosed, which is prepared from raw materials including ZYZ384 and a carrier, wherein the carrier is polyvinyl ketone K30, and the mass ratio of ZYZ384 to the carrier is 1:4~20.

[0030] In one embodiment, the mass ratio of ZYZ384 to the carrier is 1:6~20.

[0031] In one embodiment, the mass ratio of ZYZ384 to the carrier is 1:6~15.

[0032] In one embodiment, the mass ratio of ZYZ384 to the carrier is 1:8~15.

[0033] In one embodiment, the mass ratio of ZYZ384 to the carrier is 1:8~10.

[0034] In other embodiments of the present invention, a method for preparing the above-mentioned solid dispersion is disclosed, comprising the following steps:

[0035] (1) After mixing ZYZ384 and the carrier, add anhydrous ethanol and stir in a water bath at 30℃~60℃ until a clear solution is obtained;

[0036] (2) After evaporating the clarified solution in step (1) to dryness, vacuum dry it, grind and sieve it to obtain the final product.

[0037] In one embodiment, the temperature of the water bath in step (1) is 35°C to 45°C.

[0038] In one embodiment, the stirring in step (1) is magnetic stirring, the stirring time is 15 min to 25 min, and the stirring speed is 300 rpm to 600 rpm.

[0039] In one embodiment, the mass-to-volume ratio of ZYZ384 to anhydrous ethanol in step (1) is 1 mg: 4 mL ~ 6 mL.

[0040] In one embodiment, the evaporation in step (2) is vacuum evaporation, and the vacuum evaporation temperature is 35°C to 45°C.

[0041] In one embodiment, the temperature of vacuum drying in step (2) is 45℃~55℃, and the vacuum degree of vacuum drying is -0.08 MPa~-0.1 MPa.

[0042] In one embodiment, the temperature of vacuum drying in step (2) is 48℃~52℃, and the vacuum degree of vacuum drying is -0.085 MPa~-0.095 MPa.

[0043] In one embodiment, the mesh size of the sieve in step (2) is 80 to 100 mesh.

[0044] In other embodiments of the present invention, the use of the above-described solid dispersion in the preparation of antitumor drugs is disclosed.

[0045] In one embodiment, the tumor is liver cancer, lung cancer, human colon cancer, human breast cancer, or human pancreatic adenocarcinoma.

[0046] In other embodiments of the present invention, an antitumor drug is disclosed, the active ingredient of which is the above-mentioned solid dispersion.

[0047] In one embodiment, the tumor is liver cancer, lung cancer, human colon cancer, human breast cancer, or human pancreatic adenocarcinoma.

[0048] In the following embodiments of the present invention, ZYZ384 active pharmaceutical ingredient was synthesized according to the method of Example 1 of patent CN202111337495.3.

[0049] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0050] Example 1: Preparation of a solid dispersion of ZYZ384

[0051] This embodiment prepares a solid dispersion of ZYZ384, including the following steps:

[0052] 1. Weigh out drug ZYZ384 (2 mg) and carrier PVP K30 (12 mg) in a mass ratio of 1:6 and place them in a container;

[0053] 2. Add 5 mL of anhydrous ethanol and stir magnetically for 20 minutes (600 rpm) in a 40°C water bath to completely dissolve the drug and carrier and form a clear solution.

[0054] 3. Transfer the obtained clear solution to a rotary evaporator and evaporate it to dryness under reduced pressure at 40°C to obtain a solid material;

[0055] 4. Transfer the solid material to a vacuum drying oven and vacuum dry overnight at 50°C and -0.09 MPa to ensure complete solvent removal;

[0056] 5. Place the dried solid material in a mortar and grind it thoroughly. Pass it through an 80-mesh sieve and collect the portion that passes through the sieve to obtain the solid dispersion of ZYZ384 (represented as ZYZ384@SD).

[0057] Figure 1 For the active pharmaceutical ingredient ZYZ384 ( Figure 1 a) Its solid dispersion ZYZ384@SD ( Figure 1 c) Carrier PVPK30 ( Figure 1 (b) A physical mixture of active pharmaceutical ingredient ZYZ384 and carrier PVP K30 ( Figure 1 The SEM results are shown in d). The ZYZ384 active pharmaceutical ingredient particles are in a crystalline state. When prepared into a solid dispersion, the sharp corners and facets of the active pharmaceutical ingredient are obviously gone, indicating that the drug forms a co-precipitate in an amorphous form under the action of the carrier. The physical mixture can be seen to be a simple mixture of multiple substances.

[0058] Figure 2 The X-ray diffraction (XRD) results are shown for the active pharmaceutical ingredient (API) ZYZ384, its solid dispersion ZYZ384@SD, the carrier PVP K30, and a physical mixture of API ZYZ384 and carrier PVP K30. Significant diffraction peaks are observed around 16° for ZYZ384, but these peaks disappear after preparation as a solid dispersion. In the physical mixture, the same series of diffraction peaks largely overlap with those of the API. This indicates that the distribution state of ZYZ384 within the carrier changes in the solid dispersion, possibly existing in a molecular or amorphous form.

[0059] Example 2: Pharmacokinetic Study of Solid Dispersion of ZYZ384

[0060] This embodiment compares the differences in in vivo pharmacokinetic behavior between the active pharmaceutical ingredient ZYZ384 and its solid dispersion (prepared in Example 1, denoted as ZYZ384@SD), and systematically evaluates the main pharmacokinetic parameters of the two formulations after administration. The steps include:

[0061] 1. Take a number of male SD rats and randomly divide them into two groups. They are given ZYZ384 raw material (n=6) and ZYZ384 solid dispersion (n=6) by gavage, respectively. The dosage is 50 mg / kg (calculated as ZYZ384).

[0062] 2. Blood samples were collected at different time points after administration. After processing, the concentration of ZYZ384 in plasma was determined by liquid chromatography-tandem mass spectrometry, and the main pharmacokinetic parameters (mean ± SD) were calculated.

[0063] The results are shown in Table 1.

[0064] Table 1

[0065]

[0066] Table 1 shows that, compared with the active pharmaceutical ingredient ZYZ384, its solid dispersion exhibited a significantly higher level of drug exposure in vivo. The AUC of the active pharmaceutical ingredient... 0-t and AUC 0-∞ The AUC values ​​were 260.23 ± 49.51 h·ng / mL and 253.38 ± 40.95 h·ng / mL, respectively. However, after preparation as a solid dispersion, these parameters significantly increased to 1822.85 ± 755.47 h·ng / mL (**P < 0.01) and 1906.09 ± 772.67 h·ng / mL (*P < 0.05). Compared with the active pharmaceutical ingredient ZYZ384, the AUC of its solid dispersion was significantly higher. 0-t and AUC 0-∞ The increases of approximately 7.0-fold and 7.5-fold, respectively, indicate that solid dispersions can significantly increase the overall drug exposure in vivo.

[0067] Meanwhile, the peak concentration (Cmax) of the solid dispersion of ZYZ384 was significantly higher than that of the active pharmaceutical ingredient (API) ZYZ384. The Cmax of the API was 28.64 ± 1.84 ng / mL, while the Cmax of the solid dispersion reached 260.72 ± 131.40 ng / mL (*P < 0.05), approximately 9.1 times that of the API, suggesting that the solid dispersion significantly enhanced the extent and rate of drug absorption. In comparison, the elimination half-life (t) of the two formulations was significantly different. 1 / 2 The difference was not significant; the t of the active pharmaceutical ingredient was... 1 / 2The time to elimination was 5.45 ± 0.70 min for the solid dispersion and 4.99 ± 0.43 min for the solid dispersion, indicating that the change in formulation did not significantly affect the elimination process of the drug in vivo.

[0068] Based on the results of this embodiment, the in vivo drug exposure and peak concentration of drug ZYZ384 were significantly increased after being prepared as a solid dispersion, while the elimination behavior remained basically the same, demonstrating that solid dispersions have significant advantages in improving drug absorption and bioavailability in vivo.

[0069] Example 3: In vivo antitumor efficacy study of solid dispersion of ZYZ384

[0070] This embodiment studies the in vivo antitumor efficacy of the active pharmaceutical ingredient ZYZ384 and its solid dispersion (prepared in Example 1, denoted as ZYZ384@SD). The steps include (see flowchart). Figure 3 A in the middle):

[0071] 1. Purchase nude mice aged 4-6 weeks. One week later, administer 1×10⁻⁶ mice. 7 Ten male BALB / C-nu nude mice (16-18 g each) were subcutaneously inoculated into the right upper limb as the primary tumor. After approximately 15 days of observation, the mice were sacrificed, and the subcutaneous tumor tissue was dissected and cleaned of blood with pre-cooled PBS. The tumor tissue was cut into 1-3 mm pieces using a scalpel and placed at one end of a puncture needle. The skin of the right upper limb of the mouse was wiped with an alcohol swab, and the puncture needle was inserted subcutaneously to inject the tumor tissue, thus constructing a HepG-2 hepatocellular carcinoma BALB / C-nu nude mouse xenograft model. The mice were then observed until the tumor volume reached 50-100 mm². 3 The experiment can begin at this time.

[0072] 2. After constructing the HepG-2 nude mouse model, when the tumor volume reaches 80 mm... 3 Nude mice were randomly divided into 7 groups of 6 mice each. Saline was used as the control group, and the other groups were sorafenib (100 mg / kg, positive control, MCE), EPZ031686 (100 mg / kg, SMYD3 inhibitor, positive control, MCE), ZYZ384 (100 mg / kg), ZYZ384@SD (50 mg / kg), ZYZ384@SD (75 mg / kg), and ZYZ384@SD (100 mg / kg).

[0073] The drug was administered by gavage at a dose of 400 μL on days 1, 3, 5, 7, 9, 11 and 13, for a total of 7 administrations.

[0074] 3. After administration, continue to feed nude mice normally, observe their survival status and weigh them daily, measure the long axis and short axis of the nude mice with vernier calipers, calculate the tumor volume (V) and relative tumor volume (RTV) according to the formula (long axis * short axis * short axis) / 2, and plot the nude mouse tumor volume-time curve and weight-time change curve.

[0075] Nude mice were sacrificed on day 15 after drug administration. Subcutaneous tumors were completely dissected, tumor mass was measured, and ex vivo tumor images were taken to calculate tumor inhibition rate (TGI).

[0076] After the in vivo antitumor drug efficacy experiment, nude mice in each group were euthanized, and major organs such as the heart, liver, spleen, lungs, and kidneys were immediately dissected and separated. The tissues were rinsed with physiological saline to remove blood contamination and fixed in 10% neutral formalin solution for 24 hours. The fixed tissues were dehydrated, embedded in paraffin, sectioned (approximately 5 μm thick), stained with hematoxylin and eosin (H&E), and the pathological morphological changes of each organ tissue were observed under an optical microscope.

[0077] 4. Experimental Results

[0078] (1) During the in vivo tumor suppression experiment, the body weight of mice in the sorafenib group was significantly different from that in the control group (*P < 0.05), while there was no statistically significant difference in body weight between the other treatment groups and the control group. Figure 3 (B in the text). Tumor volume change results showed that both the ZYZ384@SD 75 mg / kg group and the positive control group were significantly different from the control group (*P <0.05), indicating that ZYZ384@SD has a good tumor-suppressing effect at a dose of 75 mg / kg. Figure 3 (C in the middle).

[0079] (2) After 14 days of treatment, tumor tissue was removed. There was a highly significant difference between the ZYZ384@SD 75 mg / kg group and the control group (**P < 0.01), and there was no significant difference between this group and the sorafenib 100 mg / kg group. This indicates that ZYZ384@SD 75 mg / kg can achieve tumor-suppressing efficacy comparable to positive control drugs at a lower dose. Figure 4 ).

[0080] (3) Histopathological examination results showed that the heart, liver, spleen, lungs, and kidneys of nude mice in each treatment group had normal tissue structure and no obvious pathological changes were observed. Figure 5 ).

[0081] Example 4: Comparison of solubility of solid dispersions made from different carriers

[0082] This example compares the solubility of solid dispersions made from ZYZ384 and different supports. Except for the supports in step 1 being PEG2000, PEG4000, PEG6000, PVP K30, PVP VA64 and poloxamer 188, the other steps are the same as in Example 1.

[0083] After sieving each solid dispersion sample through a 60-mesh sieve, 1 mg of powder (equivalent to 1 mg ZYZ384) was mixed with 5 mL of purified water and shaken at 37 ℃ for 24 hours. After shaking, the mixture was filtered through a 0.45 μm microporous membrane, and the filtrate was appropriately diluted and its solubility was determined.

[0084] The results are as follows Figure 6 As shown, the solubility of ZYZ384 active pharmaceutical ingredient in water is less than 50 μg / mL. Solid dispersions prepared from ZYZ384 with carriers PEG2000, PEG4000, PEG6000, PVP VA64, and poloxamer 188 exhibit a solubility of up to 165 μg / mL; while the solubility of a solid dispersion prepared from ZYZ384 with carrier PVP K30 reaches 361.97 μg / mL, significantly higher, indicating that ZYZ384 is almost completely dissolved in carrier PVP K30. Therefore, PVP K30, as a carrier, can maximize the solubility of ZYZ384.

[0085] Example 5: Comparison of the inhibitory effects of different carriers on ZYZ384 crystallization

[0086] This embodiment uses a solvent evaporation method to compare the inhibitory effects of different polymer carriers on the crystallization of the drug ZYZ384. The steps include:

[0087] 1. Dissolve ZYZ384 in dimethyl sulfoxide to prepare a ZYZ384-dimethyl sulfoxide solution with a concentration of 1 mg / mL.

[0088] 2. Prepare aqueous solutions of six polymers, each with a concentration of 2 mg / mL, namely PEG2000, PEG4000, PEG6000, PVP K30, PVP VA64 and poloxamer 188.

[0089] 3. Mix the ZYZ384-dimethyl sulfoxide solution from step 1 with equal volumes of the six polymer aqueous solutions from step 2. Stir the mixture at 100 r / min at 37 °C. Take 0.5 mL samples at time points of 0.1 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 10 h to determine the concentration of ZYZ384 in the solution.

[0090] The results are as follows Figure 7As shown, crystallization and precipitation were observed in mixtures (supersaturated solutions) of ZYZ384-dimethyl sulfoxide solution with aqueous solutions of PEG2000, PEG4000, PEG6000, PVP VA64, and poloxamer 188. However, the supersaturated solution concentration of ZYZ384-dimethyl sulfoxide solution and PVP K30 aqueous solution remained stable, with no significant precipitation. Therefore, PVP K30 can serve as a carrier for ZYZ384, both improving its solubility and effectively inhibiting its crystallization.

[0091] Example 6: Comparison of the effects of different drug loading ratios on the properties of solid dispersions

[0092] This embodiment compares the effects of different drug-to-carrier mass ratios on the solid dispersion properties of ZYZ384. Except for the mass ratios of drug ZYZ384 to carrier PVP K30 being 1:3, 1:4, 1:6, 1:8, 1:10, 1:15, and 1:20, the other steps are the same as in Example 1.

[0093] Take appropriate amounts of each solid dispersion and determine the encapsulation efficiency by centrifugation.

[0094] The results are as follows Figure 8 As shown, the results indicate that the dissolution rate of ZYZ384 gradually increases with the increase of the PVP K30 ratio. When the drug-to-feed ratio is 1:3, the proportion of drug molecules in a dispersed state is relatively low, possibly due to insufficient polymer content leading to molecular aggregation. Within the drug-to-feed ratio range of 1:6 to 1:20, the encapsulation efficiency is consistently high, exceeding 60%. The highest encapsulation efficiency, exceeding 80%, is achieved at a drug-to-feed ratio of 1:8.

[0095] Example 7: Comparison of the effects of different stirring temperatures on the encapsulation efficiency of solid dispersions

[0096] This embodiment compares the effect of different stirring temperatures on the encapsulation efficiency of solid dispersions during the preparation of ZYZ384. Except for the stirring temperatures in step 2 (30℃, 40℃, 50℃, 60℃, and 70℃), all other steps are the same as in Example 1. Appropriate amounts of each solid dispersion were taken, and the encapsulation efficiency was determined by centrifugation.

[0097] The results are as follows Figure 9 As shown in the figure, the encapsulation efficiency is at a high level when the stirring temperature is between 30℃ and 50℃, and the encapsulation efficiency is significantly higher at a stirring temperature of 40℃, reaching 86%.

[0098] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0099] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A solid dispersion, characterized in that, Its structure is as follows It was prepared from ZYZ384 and a carrier, wherein the carrier is polyvinyl ketone K30, and the mass ratio of ZYZ384 to the carrier is 1:6~20. The method for preparing the solid dispersion includes the following steps: (1) After mixing ZYZ384 and the carrier, add anhydrous ethanol and stir in a water bath at 30℃~60℃ until a clear solution is obtained; (2) After evaporating the clarified solution in step (1) to dryness, vacuum dry it, grind and sieve it to obtain the final product.

2. The solid dispersion according to claim 1, characterized in that, The mass ratio of ZYZ384 to the carrier is 1:6~15.

3. The solid dispersion according to claim 2, characterized in that, The mass ratio of ZYZ384 to the carrier is 1:8~15.

4. The solid dispersion according to claim 3, characterized in that, The mass ratio of ZYZ384 to the carrier is 1:8~10.

5. A method for preparing the solid dispersion according to any one of claims 1 to 4, characterized in that, Includes the following steps: (1) After mixing ZYZ384 and the carrier, add anhydrous ethanol and stir in a water bath at 30℃~60℃ until a clear solution is obtained; (2) After evaporating the clarified solution from step (1) to dryness, vacuum dry it, grind and sieve it to obtain the final product.

6. The method for preparing the solid dispersion according to claim 5, characterized in that, The temperature of the water bath in step (1) is 35℃~45℃.

7. The method for preparing the solid dispersion according to claim 5, characterized in that, The stirring in step (1) is magnetic stirring, the stirring time is 15 min to 25 min, and the stirring speed is 300 rpm to 600 rpm; And / or, the mass-to-volume ratio of ZYZ384 to anhydrous ethanol in step (1) is 1 mg: 4 mL to 6 mL.

8. The method for preparing the solid dispersion according to claim 5, characterized in that, The evaporation described in step (2) is vacuum evaporation, and the temperature of vacuum evaporation is 35℃~45℃; And / or, the temperature of the vacuum drying in step (2) is 45℃~55℃; the vacuum degree of the vacuum drying is -0.08MPa~-0.1 MPa; And / or, the mesh size of the sieve described in step (2) is 80 mesh to 100 mesh.

9. The method for preparing a solid dispersion according to claim 8, characterized in that, The temperature of vacuum drying in step (2) is 48℃~52℃; the vacuum degree of vacuum drying is -0.085 MPa~-0.095 MPa.

10. The use of the solid dispersion according to any one of claims 1 to 4 in the preparation of antitumor drugs.

11. The application according to claim 10, characterized in that, The tumor is liver cancer, lung cancer, human colon cancer, human breast cancer, or human pancreatic adenocarcinoma.

12. An antitumor drug, characterized in that, Its active ingredients include the solid dispersion described in any one of claims 1 to 4.

13. The antitumor drug according to claim 12, characterized in that, The tumor is liver cancer, lung cancer, human colon cancer, human breast cancer, or human pancreatic adenocarcinoma.

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