Solid dispersion containing macrocyclic compound and preparation thereof

Abstract

The invention discloses a solid dispersion containing a macrocyclic compound as well as a preparation method and application of the solid dispersion. The solid dispersion comprises a compound shown in a formula I, and / or a stereoisomer and / or a pharmaceutically acceptable salt of the compound, and / or a solvate of the compound, a carrier material and a surfactant. The solid dispersion prepared by adjusting the types and proportions of the carrier material and the surfactant and combining a spray drying method can improve the solubility of the macrocyclic compound under media with different pH conditions and improve the oral bioavailability of the macrocyclic compound in animal bodies.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a solid dispersion containing a macrocyclic compound and a preparation thereof, and further discloses a preparation method and application thereof. BACKGROUND

[0002] The macrocyclic compound has the structure shown in the following formula I, is a light yellow to yellow-green powder, is easily soluble in acetic acid, is slightly soluble in methanol, ethanol and acetonitrile, and is almost insoluble in water.

[0003]

[0004] The compound of formula I is a macrocyclic kinase inhibitor, has good tropomyosin-related kinase (Trk kinase) inhibitory activity and selectivity. Trk kinase is a type of nerve growth factor receptor, and the family thereof is composed of highly homologous TrkA, TrkB and TrkC, which are respectively encoded by NTRK1, NTRK2 and NTRK3 genes. Under normal physiological conditions, Trk protein is a high-affinity receptor for nerve growth factor. In the process of organ formation, Trk protein is expressed in neuronal tissue, and plays a key role in the development of central and peripheral nervous systems. When chromosomal variation occurs NTRK gene fusion, leading to high expression of chimeric Trk protein, the regulation of the downstream signal pathway of Trk kinase is abnormal, and the overactivation of the pathway can lead to the occurrence of cancer. NTRK gene fusion occurs in various adult and pediatric solid tumors, including breast cancer, colorectal cancer, non-small cell lung cancer, and various sarcomas. There are various new drugs in clinical research targeting NTRK fusion genes at present, which all have Trk kinase inhibitory activity, and most of them achieve inhibition of kinase catalytic activity by competing with ATP binding sites. The prior art discloses that the compound of formula I has good in vivo tumor growth inhibition effect, and can be used for treating patients with NTRK or ROS1 gene fusion solid tumors.

[0005] In view of the almost insoluble nature of the compound of formula I in water and its clinical use, it is of great significance to improve the solubility and oral bioavailability of the compound of formula I by solid dispersion technology for the development of oral solid preparations of the compound of formula I. SUMMARY

[0006] The present application aims to at least solve one of the above-mentioned technical problems in the prior art. To this end, the object of the present application is to provide a preparation method and application of a solid dispersion containing a macrocyclic compound and a preparation thereof, to improve the solubility of the compound of formula I and improve its oral bioavailability.

[0007] In order to achieve the above-mentioned object, the technical solution adopted by the present application is: In a first aspect, the present application provides a solid dispersion containing a macrocyclic compound, comprising a compound of Formula I and / or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, a carrier material and a surfactant;

[0008] wherein R1is selected from hydrogen, halogen; X is selected from CR2, N; R2is selected from hydrogen, halogen, -CN, -C(O)R a , -C(O)OR a , -C(O)NR a R b ; R a , R b are each independently selected from hydrogen, C 1～6 alkyl; L is selected from C 1～6 alkylene; Y is selected from O; is selected from a benzene ring, a pyridine ring; n, r are each independently selected from any natural number from 1 to 3.

[0009] In some embodiments of the present application, the halogen includes any one of F, Cl, Br, I.

[0010] In some embodiments of the present application, n is 1 or 2; r is 1.

[0011] In some embodiments of the present application, the compound of Formula I has a structure as shown in the following Formula (1): (1).

[0012] In some embodiments of the present application, the compound of Formula I has an X-ray diffraction pattern with characteristic peaks at 2θ values of 9.49±0.2, 10.60±0.2, 11.54±0.2, 14.10±0.2, 17.09±0.2, 19.15±0.2, 20.30±0.2, 22.85±0.2, 23.89±0.2 and 27.74±0.2.

[0013] In some embodiments of the present application, the compound of Formula I has an X-ray powder diffraction (XRPD) pattern as shown in Figure 1 .

[0014] In some embodiments of the present application, the compound of Formula I has a differential scanning calorimetry (DSC) pattern as shown in Figure 2 , wherein the endothermic peak (Onset: 233.65℃) should be the melting peak of the compound.

[0015] In some embodiments of the present invention, the solid dispersion containing the macrocyclic compound has the following characteristics: Figure 3 or Figure 4 The XRPD diagram shown.

[0016] In some embodiments of the present invention, the solid dispersion containing the macrocyclic compound has the following characteristics: Figure 5 or Figure 6 The DSC diagram shown.

[0017] In some embodiments of the present invention, the compound of formula I exists in the solid dispersion in an amorphous form.

[0018] In some embodiments of the present invention, the mass ratio of the compound of formula I, the carrier material, and the surfactant is 1:(3~7):(0.2~1).

[0019] In some embodiments of the present invention, the mass ratio of the compound of Formula I and / or its stereoisomers and / or its pharmaceutically acceptable salts, the carrier material and the surfactant is 1:3:0.5 to 1:7:0.5.

[0020] In some embodiments of the present invention, the mass ratio of the compound of Formula I and / or its stereoisomers and / or its pharmaceutically acceptable salts, the carrier material and the surfactant is 1:7:0.5.

[0021] In some embodiments of the present invention, the carrier material is selected from one or more of the following: methacrylic acid-ethyl acrylate copolymer, copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, and polyacrylic acid resin.

[0022] In some embodiments of the present invention, the carrier material is selected from one or more of copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

[0023] In some embodiments of the present invention, the carrier material is selected from one or more of copovidone and hydroxypropyl methylcellulose.

[0024] In some embodiments of the present invention, the surfactant is selected from one or more of sodium dodecyl sulfate, vitamin E polyethylene glycol succinate, 15-hydroxystearic acid polyethylene glycol ester, polyoxyethylene and polyoxypropylene block copolymer, and polyethylene glycol glycerol laurate.

[0025] In some embodiments of the present invention, the surfactant is vitamin E polyethylene glycol succinate.

[0026] In some embodiments of the present invention, the solid dispersion comprises a compound of formula I, hydroxypropyl methylcellulose, and vitamin E polyethylene glycol succinate.

[0027] In some embodiments of the present invention, the mass ratio of compound of formula I, hydroxypropyl methylcellulose, and vitamin E polyethylene glycol succinate in the solid dispersion is 1:7:0.5.

[0028] In some embodiments of the present invention, the solid dispersion comprises a compound of formula I, hydroxypropyl methylcellulose, copolyvinylpyrrolidone, and vitamin E polyethylene glycol succinate.

[0029] In some embodiments of the present invention, the mass ratio of the compound of formula I, hydroxypropyl methylcellulose, copovidone, and vitamin E polyethylene glycol succinate in the solid dispersion is 1:3.5:3.5:0.5.

[0030] In a second aspect, the present invention provides a method for preparing a solid dispersion of the compound of formula I described in the first aspect of the present invention, comprising the following steps: S1: Mix the compound of formula I with a solvent to form a first mixed solution; S2: Add the carrier material and surfactant to the first mixed solution to form a second mixed solution; S3: Spray dry the second mixed solution to obtain the final product.

[0031] In some embodiments of the present invention, in step S1, the solvent includes one or more of methanol, acetone, tetrahydrofuran, and dichloromethane. Preferably, the solvent includes dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is 2:1.

[0032] In some embodiments of the present invention, in step S3, the parameters of the spray drying step include: inlet air temperature 70~85℃, outlet air temperature 40~55℃, air flow rate 35-45mm, peristaltic pump speed 30~50%, and nozzle size 0.6-0.8mm.

[0033] In some embodiments of the present invention, in step S3, the parameters of the spray drying step include: inlet air temperature 75~80℃, outlet air temperature 45~50℃, air flow rate 40mm, peristaltic pump speed 35~45%, and nozzle size 0.7mm.

[0034] In some embodiments of the present invention, the method for preparing the solid dispersion of the compound of formula I further includes the step of dissolving the second mixed solution with ultrasonic assistance or with heating assistance.

[0035] A third aspect of the present invention provides a formulation comprising a solid dispersion of a compound of formula I as described in the first aspect of the present invention or a solid dispersion of a compound of formula I prepared by the method described in the second aspect of the present invention, the formulation further comprising other pharmaceutically acceptable excipients.

[0036] In some embodiments of the present invention, the pharmaceutically acceptable excipients include fillers, disintegrants, binders, lubricants, etc.

[0037] In some embodiments of the present invention, the filler includes at least one of mannitol, microcrystalline cellulose, lactose, pregelatinized starch, and dicalcium phosphate.

[0038] In some embodiments of the present invention, the disintegrant includes at least one of croscarmellose sodium, croscarmellose polyvinylpyrrolidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0039] In some embodiments of the present invention, the adhesive comprises at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, sodium alginate, or povidone.

[0040] In some embodiments of the present invention, the lubricant includes at least one of magnesium stearate, stearic acid, talc, sodium stearate fumarate, or micronized silica gel.

[0041] A fourth aspect of the present invention provides the use of a solid dispersion of a compound of formula I as described in the first aspect of the present invention, a solid dispersion of a compound of formula I prepared by the method described in the second aspect of the present invention, or a formulation as described in the third aspect of the present invention in the preparation of a medicament for treating diseases related to abnormal kinase activity.

[0042] In some embodiments of the present invention, the disease associated with abnormal kinase activity is a disease associated with abnormal Trk kinase activity.

[0043] In some embodiments of the present invention, the disease associated with abnormal Trk kinase activity is any one or more of the following: neurodegenerative diseases, pain, cancer, and inflammation.

[0044] In some embodiments of the present invention, the disease is multiple sclerosis, Parkinson's disease, Alzheimer's disease, inflammatory pain, neuropathic pain, surgical pain, neurocytoma, melanoma, breast cancer, gastric cancer, asthma, inflammatory bowel disease, or atopic dermatitis.

[0045] The term "pharmaceutically acceptable salt" refers to acidic and / or basic salts formed by the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-mentioned compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0046] The beneficial effects of this invention are achieved by screening and optimizing the ratio of carrier materials and surfactants in the appropriate excipients to obtain the solid dispersion of the compound of formula I. Compared with the compound of formula I, the solubility in gastric and small intestinal fluids under simulated fasting conditions is significantly improved, and it exhibits higher oral bioavailability in rats after gavage at the same dose. The solid dispersion of the compound of formula I of this invention improves the solubility of the macrocyclic compound and enhances its in vivo bioavailability. The preparation method of this invention is standardized and reliable, and the solid dispersion has good physicochemical properties and stability, showing potential for development into a drug for treating the above-mentioned diseases. Attached Figure Description

[0047] Figure 1 This is the X-ray powder diffraction (XRPD) pattern of the compound of formula I described in this invention; Figure 2 This is the differential scanning calorimetry (DSC) spectrum of the compound of formula I described in this invention; Figure 3 These are the X-ray powder diffraction patterns of formulations F1 and F2 in Example 1 of this invention; Figure 4 This is the differential scanning calorimetry spectrum of prescription F1 in Embodiment 1 of the present invention; Figure 5 This is the differential scanning calorimetry spectrum of prescription F2 in Embodiment 1 of the present invention; Figure 6 This is the X-ray powder diffraction pattern of formulation F1 in Example 1 of the present invention after being stored at 2~8℃ for 4 months; Figure 7 This is the X-ray powder diffraction pattern of prescription F2 in Example 1 of the present invention after being stored at 2~8℃ for 4 months; Figure 8This is the differential scanning calorimetry spectrum of prescription F1 in Example 1 of the present invention after being stored at 2~8℃ for 4 months; Figure 9 This is the differential scanning calorimetry spectrum of prescription F2 in Example 1 of the present invention after being stored at 2~8℃ for 4 months. Detailed Implementation

[0048] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials, reagents, or apparatus used in the embodiments and comparative examples are all available from conventional commercial sources or can be obtained by existing technical methods. Unless otherwise specified, the test or experimental methods are conventional methods in the art.

[0049] In this embodiment of the invention, unless specific experimental steps or conditions are specified, the procedures or conditions can be performed according to the conventional experimental steps or conditions described in the literature in this field. Reagents used without specified manufacturers are all commercially available conventional reagent products.

[0050] In this embodiment of the invention, the experimental reagent information involved is shown in Table 1.

[0051] Table 1. Experimental Raw Materials and Reagents

[0052] Determination of XRPD and DSC of Compound I XRPD measurements: The X-ray source was a Cu~Kα target (1.54056 Å); the minimum operating voltage and current of the photodiode were 40 kV and 30 mA, respectively; the 2-Theta value of the sample scanning range was from 2... o up to 50 o The scan rate was 5 deg / min. Results are shown below. Figure 1 XRPD spectra show that compound I has distinct and sharp diffraction peaks, indicating that it is a crystalline compound.

[0053] DSC determination: A temperature program was set up, ranging from 30-300℃, at a rate of 20℃ / min, to measure the DSC curve of the samples. Gas source: Nitrogen, 50 mL / min. Results are shown below. Figure 2 According to the DSC spectrum, the compound of formula I has a distinct endothermic peak, which (Onset: 233.65℃) should be the melting peak of the compound.

[0054] Screening of carrier materials In this embodiment, the micro-rotary evaporation method is used to screen the carrier material.

[0055] The compound stock solution and polymer stock solution were prepared using dichloromethane and methanol (volume ratio 2:1). After thorough mixing according to the ratio, the solvent was removed by rotary evaporation, and the mixture was then dried under reduced pressure in a vacuum drying oven to obtain the solid dispersion. The concentration of compound I was 1 mg / mL. The solubility of the sample in FaSSIF medium at pH 6.8 was measured. The sample information and solubility measurement results are shown in Table 2 below.

[0056] Table 2 Screening of carrier materials

[0057] In a pH 6.8 FaSSGF medium, the solid dispersions prepared using Kollidon V464, HPMC 2910 606, and HPC LF as support materials showed a significant improvement in solubility compared to the compound of Formula I in this medium.

[0058] Surfactant screening In this embodiment, the micro-rotary evaporation method is used to screen surfactants.

[0059] Dichloromethane and methanol (volume ratio 2:1) were used to prepare stock solutions for the compound, polymer, and surfactant. The solutions were mixed thoroughly according to the specified ratios, and the solvent was removed by rotary evaporation. The resulting solid dispersions were then dried under reduced pressure in a vacuum drying oven. Compound I was added at a concentration of 10 mg / mL, and the solubility of the samples in FaSSIF medium at pH 6.8 was determined. Sample information and solubility measurement results are shown in Table 3 below.

[0060] Table 3 Screening of Surfactants

[0061] Note: " / " indicates not detected.

[0062] In FaSSGF medium at pH 6.8, the solid dispersions prepared by formulations 11 and 16 showed significantly improved solubility compared to the compound of formula I in this medium.

[0063] Screening of carrier materials In this embodiment, the micro-volume rotary evaporation method is used to screen for the co-use of carrier materials.

[0064] Dichloromethane and methanol (volume ratio 2:1) were used to prepare stock solutions for the compound, polymer, and surfactant. The solutions were mixed thoroughly according to the specified ratios, and the solvent was removed by rotary evaporation. The resulting solid dispersions were then dried under reduced pressure in a vacuum drying oven. The concentration of compound I was 10 mg / mL, and the solubility of the sample in FaSSIF medium at pH 6.8 was determined. Sample information and solubility measurement results are shown in Table 4 below.

[0065] Table 4 Screening of carrier materials for co-use

[0066] In pH 6.8 FaSSGF medium, the combined use of Kollidon VA64 and HPMC 2910 606 can effectively improve solubility.

[0067] Screening of surfactant combinations In this embodiment, a micro-volume rotary evaporation method is used to screen for the combined use of surfactants.

[0068] Dichloromethane and methanol (volume ratio 2:1) were used to prepare stock solutions for the compound, polymer, and surfactant. The solutions were mixed thoroughly according to the specified ratios, and the solvent was removed by rotary evaporation. The resulting solid dispersions were then dried under reduced pressure in a vacuum drying oven. The concentration of compound I was 10 mg / mL, and the solubility of the sample in FaSSIF medium at pH 6.8 was determined. Sample information and solubility measurement results are shown in Table 5 below.

[0069] Table 5 Screening of surfactant combinations

[0070] Screening of the ratio of carrier materials used in combination In this embodiment, a micro-volume rotary evaporation method is used to screen for increasing the proportion of carrier materials.

[0071] Dichloromethane and methanol (volume ratio 2:1) were used to prepare stock solutions for the compound, polymer, and surfactant. The solutions were mixed thoroughly according to the specified ratios, and the solvent was removed by rotary evaporation. The resulting solid dispersions were then dried under reduced pressure in a vacuum drying oven. The concentration of compound I was 10 mg / mL, and the solubility of the sample in FaSSIF medium at pH 6.8 was determined. Sample information and solubility measurement results are shown in Table 6 below.

[0072] Table 6 Screening of Carrier Material Proportions

[0073] In FaSSGF medium at pH 6.8, increasing the polymer ratio can maintain solubility while also improving solution stability.

[0074] Example 1: Preparation of spray-dried samples of solid dispersion of compound I Taking the preparation methods of prescription batch F1 and prescription batch F2 as examples: weigh the prescription amount of the active pharmaceutical ingredient and dissolve it in a mixed solvent of dichloromethane and methanol (dichloromethane:methanol = 2:1 (v / v)). Then dissolve the prescription amounts of HPMC 2910 606 and TPGS in the above solvent, mix them evenly, and dissolve them by ultrasonication or heating at 60°C. Then spray dry them according to the set parameters to prepare a solid dispersion. The prescription and solubility results of the solid dispersion are shown in Tables 7-9 below.

[0075] Table 7 Preparation of solid dispersion samples for formulation F1 (spray drying method)

[0076] Table 8 Preparation of solid dispersion samples of formulation F2 (spray drying method)

[0077] Table 9. Information on spray-dried samples and results of dynamic solubility determination.

[0078] The solid fractions F1 and F2 prepared by spray drying also promoted the dissolution of compound I in media at pH 1.6 and pH 6.8, while maintaining good solubility after 6 hours.

[0079] Example 2: Determination of XRPD and DSC of solid dispersion of compound I XRPD and DSC tests were performed on samples from prescription batches F1 and F2, and the results are as follows: Figures 3 to 5 As shown. The XRPD results of both batches of solid dispersions showed no diffraction peaks characteristic of the active pharmaceutical ingredient (API) of Formula I, indicating that there were no characteristic peaks of the API in either batch of solid dispersions. The DSC results of both batches of solid dispersions showed no characteristic endothermic peak at the melting point (233.65℃) of the API, indicating that the API existed in an amorphous form in the solid dispersion formulation.

[0080] After the solid dispersion of compound I was stored at 2-8°C for four months, its XRPD and DSC were analyzed, as shown in the figures below. Figures 6 to 9 ,from Figures 6-9 As can be seen, the solid dispersion of Formula I obtained by the present invention has good stability. After being stored under these conditions for four months, the Formula I compound can still exist in the solid dispersion formulation in an amorphous form.

[0081] Example 3: Pharmacokinetic Experiment in Rats Test samples: were selected from the solid dispersion formulation F1 of compound I prepared in Example 1 and compound I, respectively.

[0082] Experimental Methods: Male SD rats were used, with three rats per group. Three administration groups were established: intravenous injection of compound I (intravenous administration group), single oral gavage administration of compound I (oral administration group 1), and single oral gavage administration of the solid dispersion formulation F1 of compound I provided in this invention (oral administration group 2). The intravenous group dose was 2 mg / kg, and the oral group dose was 20 mg / kg. Sampling time points were 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24, and 48 hours. A standard curve was established based on the sample concentration within an appropriate range. The concentration of the test sample in plasma samples was measured, and quantitative analysis and pharmacokinetic parameters were calculated. The results are shown in Table 10. In Table 10, C... max AUC represents the peak concentration of the drug. last The area under the curve when the drug is applied, T max T represents the peak time of drug action. 1 / 2 is the half-peak time of drug action, and F is the oral bioavailability.

[0083] Table 10 Results of pharmacokinetic experiments in rats

[0084] Note: "NA" represents maladaptive.

[0085] The formula for calculating oral bioavailability is: .

[0086] As shown in Table 10, the experiments demonstrate that the solid dispersion provided by this invention can improve the oral bioavailability of Formula I compound in rats, while also exhibiting a longer half-life and good pharmacokinetic properties.

[0087] The above examples and experimental results demonstrate that, compared to the compound of formula I, the solid dispersion obtained by screening and optimizing the ratio of carrier materials and surfactants in the appropriate excipients exhibits significantly improved solubility in gastric and small intestinal fluids under simulated fasting conditions. Furthermore, it demonstrates higher oral bioavailability in rats after gavage administration at the same dose. The solid dispersion of formula I provided by this invention improves the solubility of macrocyclic compounds and enhances in vivo bioavailability. Moreover, the preparation method of the solid dispersion of formula I provided by this invention is standardized and reliable, and the solid dispersion exhibits good physicochemical properties and stability, showing broad application potential in drugs for diseases related to abnormal kinase activity.

Claims

1. A solid dispersion containing a macrocyclic compound, characterized in that: Includes compounds of formula I, and / or their stereoisomers, and / or their pharmaceutically acceptable salts, and / or their solvates, as well as carrier materials and surfactants. R1 is selected from hydrogen and halogens; X is selected from CR2 and N; R2 is selected from hydrogen, halogens, -CN, and -C(O)R. a -C(O)OR a -C(O)NR a R b ; R a R b Selected separately from hydrogen and C 1～6 alkyl; L is selected from C 1～6 Alkylene; Y is selected from O; Selected from benzene ring and pyridine ring; n and r are each independently selected from any natural number from 1 to 3.

2. The solid dispersion according to claim 1, characterized in that, The mass ratio of the compound of Formula I, the carrier material, and the surfactant is 1:(3~7):(0.2~1).

3. The solid dispersion according to claim 1, characterized in that, The carrier material includes one or more of the following: methacrylic acid-ethyl acrylate copolymer, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, and polyacrylic acid resin.

4. The solid dispersion according to claim 1, characterized in that, The surfactant includes one or more of sodium dodecyl sulfate, vitamin E polyethylene glycol succinate, 15-hydroxystearic acid polyethylene glycol ester, poloxamer 188, and glyceryl laurate.

5. The solid dispersion according to any one of claims 1-4, characterized in that, The solid dispersion comprises a compound of formula I, hydroxypropyl methylcellulose, and vitamin E polyethylene glycol succinate; or, The solid dispersion comprises a compound of formula I, hydroxypropyl methylcellulose, copolyvinylpyrrolidone, and vitamin E polyethylene glycol succinate.

6. A method for preparing the solid dispersion according to any one of claims 1-5, characterized in that, Includes the following steps: S1: Mix the compound of formula I with a solvent to form a first mixed solution; S2: Add carrier material and surfactant to the first mixed solution to form a second mixed solution; S3: Spray dry the second mixed solution to obtain the final product.

7. The method for preparing a solid dispersion according to claim 6, characterized in that, The solvent includes one or more of methanol, acetone, tetrahydrofuran, and dichloromethane.

8. The method for preparing a solid dispersion according to claim 6 or 7, characterized in that, Step S2 further includes the step of dissolving the second mixed solution with ultrasound or heating.

9. A formulation comprising the solid dispersion according to any one of claims 1-5 or the solid dispersion prepared by the method according to any one of claims 6-8, characterized in that, The formulation also includes other pharmaceutically acceptable excipients.

10. Use of the solid dispersion of any one of claims 1-5, the solid dispersion prepared by the method of any one of claims 6-8, or the formulation of claim 9 in the preparation of a medicament for treating diseases associated with abnormal kinase activity.

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