CN111904960A - Solid dispersion and medicinal composition - Google Patents
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- CN111904960A CN111904960A CN202010425327.9A CN202010425327A CN111904960A CN 111904960 A CN111904960 A CN 111904960A CN 202010425327 A CN202010425327 A CN 202010425327A CN 111904960 A CN111904960 A CN 111904960A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a solid dispersion and a medicinal composition, and relates to the technical field of medicines, wherein the solid dispersion contains an active medicament and a carrier material; the active drug is a compound of formula 1 or a compound of formula 2; the carrier material is hydroxypropyl methylcellulose acetate succinate,
Any one of hypromellose phthalate. The solid dispersion of the present invention can improve the solubility and absorption properties of the compound of formula 1 or formula 2, and thus can reduce the clinical doseAmount of the compound (A). The compounds of formula 1 or formula 2 are characterized in that they are dispersed in the carrier material in amorphous form and are stable when placed under accelerated conditions (40 ℃/75% RH) for 3 months. The preparation prepared by the invention can greatly reduce the influence of the temperature and the humidity of the environment on the dissolution and the bioavailability of the product in the processes of production, transportation, storage and the like of the medicine.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a solid dispersion and a medicinal composition.
Background
N- (4-methyl-3- (1-isonicotinate piperidine-4-yl) oxy) phenyl) -3- (trifluoromethyl) benzamide (formula 1) is a developed high-selectivity C-KIT tyrosine kinase inhibitor, can strongly inhibit phosphorylation of kinase C-KIT, shows no inhibition effect on BCR-abl and FLT3 kinase, shows a small off-target effect in a selective test of 468 human kinases, and can be used for treating CD117 positive gastrointestinal stromal tumors. The compound of formula 1 has been disclosed in patent CN107286077A and shows potentially valuable pharmaceutical properties.
N- { 4-methyl-3- [4- (5-morpholinyl-3-pyridyl) -1H-pyrazol-1-yl ] phenyl } -3-trifluoromethyl-benzamide (formula 2) is a third-generation Pan-BRAF kinase small molecule inhibitor in research and development, and is mainly used for treating cancers such as BRAF mutation, RAS mutated melanoma, non-small cell lung cancer and colorectal cancer; it not only can inhibit the tumor of Braf mutation, but also has strong inhibition effect on the activation of signal path caused by Ras protein mutation, and shows that the protein is a potential valuable drug property. And the tumor is a serious disease seriously harming human health, and in all tumors, RAS mutation accounts for about 30 percent, and BRAF mutation accounts for about 8 percent, so the tumor has great clinical requirements.
Compounds with low solubility in water may have low dissolution and thus exhibit poor bioavailability. Poorly bioavailable compounds can cause problems in patient treatment, often due to unpredictability of the dosing/therapeutic effect of the compound by patient's erratic absorption; for example, diet can affect a patient's ability to absorb compounds of the aforementioned poor bioavailability, and thus may require a dosing regimen that takes into account the effects of food. Furthermore, due to unpredictable administration effects, the dosage may require a large safety margin, while a large dose of the compound may be required to achieve the desired therapeutic effect, which also increases the side effects of the drug. The compound of formula 1 and the compound of formula 2 both have the problem of poor bioavailability caused by low solubility, and in order to improve the solubility of the compound of formula 1 and the compound of formula 2 in the whole gastrointestinal tract environment and improve the bioavailability of the preparation, the development of an insoluble drug into a drug preparation product stably existing in an amorphous form is of great significance.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a solid dispersion and a medicinal composition, wherein the compound of formula 1 or formula 2 in the solid dispersion is changed from a crystalline form to an amorphous form and is dispersed in the solid dispersion, so that the solubility and the dissolution rate of an active medicament are obviously improved, and the bioavailability is effectively improved.
The solid dispersion provided by the invention contains an active medicament and a carrier material; the active drug is a compound of formula 1 or a compound of formula 2;
the carrier material is selected from hypromellose acetate succinate,
One or more of hydroxypropyl methylcellulose phthalate.
Preferably, the carrier material is hypromellose acetate succinate or
Of these, hypromellose acetate succinate (HPMCAS, trade name: Aqoat, available from Shin-Etsu Chemical Industry Co., Ltd. or other vendors) is an enteric solid dispersion material, and is currently available in a variety of grades, such AS AS-LF, AS-LG, AS-MF, AS-MG, AS-HF, and AS-HG; the hydroxypropyl methylcellulose acetate succinate with different levels can control the triggering release of the drug at different pH parts of the gastrointestinal tract, and can be adjusted within the range of pH 5.2-pH 6.5.
The (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) is a novel amphiphilic nonionic medicinal high polymer material, has the glass transition temperature (Tg) of about 70 ℃, is high in safety, has the effects of solubilization, crystal inhibition, space stability, suspension, heat sensitivity, film formation and the like, and has good application prospects in the aspects of improving the dissolution rate and bioavailability of insoluble medicines.
The solid dispersion provided by the invention has the following weight ratio of the active medicament to the carrier material of 1: 1-5; preferably 1: 2 to 4.
The solid dispersion proposed by the present invention may further comprise a solubilizer; the solubilizer is any one or more of sodium dodecyl sulfate, polysorbate 80 and poloxamer 188.
Preferably, the weight percentage of the solubilizer in the solid dispersion is 0.5-10%. The HLB value of the solubilizer is within the range of 12-18, the solubilizer has the functions of wetting and solubilizing, the use of the solubilizer in the solid dispersion increases the solubility of the insoluble drug on one hand, and the solubilizer can play a role in auxiliary crystal inhibition by being matched with a carrier material on the other hand, so that the storage stability of the solid dispersion is effectively ensured.
The invention also provides a preparation method of the solid dispersion, which can adopt any one of a solvent method, a coprecipitation method and a melting method;
when the preparation method adopts a solvent method, the specific steps are as follows: dissolving active drug and carrier material in organic solvent, stirring for dissolving, removing solvent, drying, and pulverizing to obtain solid dispersion;
when the preparation method adopts a coprecipitation method, the preparation method comprises the following specific steps: dissolving active drug and carrier material in organic solvent, stirring to dissolve, adding into poor solvent, filtering, drying, and pulverizing to obtain solid dispersion.
When the solid dispersion further comprises a solubilizer, the solubilizer may be added together with the active drug and the carrier to be dissolved in the organic solvent in the process for producing the solid dispersion, or may be added in the pulverizing step before the solid dispersion is produced.
The drying method in the preparation method can adopt any one of vacuum drying, rotary evaporation, spray drying, boiling fluidized drying, freeze drying and microwave drying; preferably vacuum drying or spray drying.
The organic solvent used in the preparation method is one or more of ethanol, acetone, ethyl acetate, methanol, isopropanol, N-dimethylformamide, dichloromethane, N-dimethylacetamide and N-methylpyrrolidone; the poor solvent used in the preparation method is purified water or ethanol, and preferably purified water.
Preferably, when a solvent method preparation process is used, the organic solvent is selected from any one or more of acetone and ethanol, and the weight ratio of the active drug to the organic solvent is 1: 50-200 parts of;
preferably, when the coprecipitation method is used, the organic solvent is selected from one or more of N, N-Dimethylformamide (DMF) and N, N-Dimethylacetamide (DMA), and the weight ratio of the active drug to the solvent is 1: 5 to 25.
The invention also provides a composition containing the solid dispersion as a main drug.
The invention also provides a pharmaceutical composition containing the composition and a pharmaceutically acceptable excipient. The solid dispersion prepared by the invention can be used as a composition containing a main drug, and can be matched with at least one pharmaceutically acceptable other excipient according to the dosage form required by product development. Pharmaceutically common excipients include, but are not limited to, fillers, lubricants, glidants, binders, disintegrants, and are prepared using formulation processing techniques well known to those skilled in the art of pharmaceutical formulation to enhance the dissolution and bioavailability of poorly soluble pharmaceutical formulations.
Preferably, the pharmaceutical composition is provided in a dosage form. Such formulations include, but are not limited to, tablets, capsules, granules, and suspensions.
The invention also provides the use of the solid dispersion or the composition or the medicinal composition, and the solid dispersion or the composition or the medicinal composition of the formula 1 is used for treating gastrointestinal stromal tumors; the solid dispersion or the composition or the pharmaceutical composition of the formula 2 is used for treating melanoma, non-small cell lung cancer, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer and thyroid cancer.
Has the advantages that: the solid dispersion of the present invention can improve the solubility and absorption properties of the compound of formula 1 or formula 2, thereby reducing the clinical dose, and is characterized in that the compound of formula 1 or formula 2 is dispersed in the carrier material in an amorphous form. The amorphous raw material of the conventional solid dispersion is crystallized during long-term storage to cause the solid dispersion to lose efficacy, and the dissolution rate and bioavailability are affected, but the solid dispersion prepared by the present invention is still in an amorphous state and stable performance is shown by the compound of formula 1 or formula 2 after being placed under accelerated conditions (40 ℃/75% RH) for 3 months. The preparation prepared by the invention can greatly reduce the influence of the temperature and humidity of the environment on the dissolution and bioavailability of the product in the processes of production, transportation, storage and the like of the medicine.
Drawings
FIG. 1 is a graph comparing solubility curves of a compound of formula 1, a solid dispersion 1 of formula 1, and a solid dispersion 2 of formula 1 prepared in example 1 of the present invention in a phosphate medium at pH 6.8;
FIG. 2 is a DTG comparison of solid dispersion 2 of formula 1, a blend of formula 1, and a compound of formula 1 prepared in example 1 of the present invention; wherein, a: a compound of formula 1, b: formula 1 blend, c: formula 1 solid dispersion 2;
FIG. 3 is a comparative XRD pattern of solid dispersion 1 of formula 1 prepared in example 1 of the present invention, solid dispersion of formula 1 prepared in example 3 and compound of formula 1; wherein, a: a compound of formula 1, b: solid dispersion 1, c of formula 1 of example 1: the solid dispersion of formula 1 of example 3;
FIG. 4 is a comparative XRD pattern of the solid dispersion of formula 1 prepared in example 2 of the present invention after being left for 3 months at 40 ℃ and 65% RH;
FIG. 5 is a comparative XRD pattern of the compounds of formula 2, formula 2 solid dispersion 1, formula 2 solid dispersion 2, formula 2 solid dispersion 3, formula 2 prepared in example 4 of the present invention; a: a compound of formula 1, b: formula 2 solid dispersion 1, c: formula 2 solid dispersion 2, d: formula 2 solid dispersion 3;
FIG. 6 is a graph comparing the solubility curves of the solid dispersion of formula 2 prepared in example 5 of the present invention and the compound of formula 2 in phosphate medium at pH 6.8;
FIG. 7 is a comparative XRD plot of the solid dispersion of formula 2 prepared in example 5 of the present invention after 3 months of storage under accelerated conditions (40 deg.C/75% RH).
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
1) Formula 1 solid dispersion 1 preparation: adding 1g of the compound of formula 1 into 100mL of 95% ethanol, stirring to dissolve to obtain a clear solution, and adding 4g
Stirring to dissolve; vacuum drying at 40 ℃ for 24 hours, and sieving with a 60-mesh sieve to obtain solid dispersion 1 (the compound + of formula 1)
)。
2) Formula 1 solid dispersion 2 preparation: adding 1g of the compound shown as the formula 1 into 100mL of propanol, and stirring to dissolve the compound to obtain a clear solution; 0.4g SDS was added and 4g was added
Stirring to be uniform; vacuum drying at 40 deg.C for 24 hr, and sieving with 60 mesh sieve to obtain solidDispersion 2 (compound of formula 1 +
+SDS)。
3) Preparation of a blend of formula 1: 1g of the compound of formula 1, 0.4g of SDS, 4g
Mixing uniformly to obtain a physical mixture (the blend of the formula 1).
Example 2
Adding 1g of the compound shown as the formula 1 into 100mL of propanol, and stirring to dissolve the compound to obtain a clear solution; 0.4g SDS was added, and 3g was added
Stirring to be uniform; removing solvent by fluidized bed spray drying method, and sieving with 60 mesh sieve to obtain solid dispersion.
Example 3
Adding 1g of the compound shown in the formula 1 into 15mL of DMA, stirring to dissolve, adding 4g of HPMCAS, and stirring to dissolve to obtain an organic phase solution; slowly dropping the organic phase solution into 150ml of purified water under high shear condition, filtering, vacuum drying at 40 ℃ for 12 hours, and sieving with a 80-mesh sieve to obtain the solid dispersion.
Example 4
1) Formula 2 solid dispersion 1 preparation: adding 1g of the compound shown in the formula 2 into 15mL of DMF, stirring to dissolve, adding 2g of HPMCAS, and stirring to dissolve to obtain an organic phase solution; the organic phase solution was added dropwise to 150ml of purified water under high shear conditions, filtered, vacuum-dried at 40 ℃ for 12 hours, and passed through a 60-mesh sieve to obtain a solid dispersion (compound of formula 2: HPMCAS ═ 1: 2).
2) Formula 2 solid dispersion 2 preparation: adding 1g of the compound shown in the formula 2 into 15mL of DMF, stirring to dissolve, adding 3g of HPMCAS, and stirring to dissolve to obtain an organic phase solution; the organic phase solution was added dropwise to 150ml of purified water under high shear conditions, filtered, vacuum-dried at 40 ℃ for 12 hours, and passed through a 60-mesh sieve to obtain a solid dispersion (compound of formula 2: HPMCAS ═ 1: 3).
3) Formula 2 solid dispersion 3 preparation: adding 1g of the compound shown in the formula 2 into 15mL of DMF, stirring to dissolve, adding 4g of HPMCAS, and stirring to dissolve to obtain an organic phase solution; the organic phase solution was added dropwise to 150ml of purified water under high shear conditions, filtered, vacuum-dried at 40 ℃ for 12 hours, and passed through a 60-mesh sieve to obtain a solid dispersion (compound of formula 2: HPMCAS ═ 1: 4).
Example 5
Example 6
Adding 1g of the compound shown as the formula 2 into 150mL of propanol, and stirring to dissolve the compound to obtain a clear solution; 0.4g SDS was added, and 3g was added
Stirring to be uniform; removing solvent by fluidized bed spray drying method, and sieving with 60 mesh sieve to obtain solid dispersion.
Example 7
45g of solid dispersion of the formula 1 is prepared according to the example 2, 20g of microcrystalline cellulose (PH102) as filler and 2.5g of crospovidone as disintegrant are added, the mixture is mixed uniformly, 0.5g of magnesium stearate as lubricant is added, the mixture is pressed into tablets by using a 9.0mm punch die after the mixture is mixed uniformly, the weight of the tablets is controlled to be 340mg (+ -5%), and the hardness is controlled to be 70 +/-10N.
Example 8
41g of solid dispersion of the formula 2 was prepared in the same manner as in example 5, and 17g of lactose (Flowac 100) as a filler and 3.5g of low-substituted hydroxypropylcellulose as a disintegrant were added thereto, followed by mixing uniformly, adding 0.5g of sodium stearyl fumarate as a lubricant, mixing uniformly, and tabletting with a 7.5mm die, wherein the tablet weight was controlled to 155. + -. 5 mg and the hardness was controlled to 80. + -.10N.
The solid dispersions prepared in the examples of the present invention were examined by the characterization means of solubility measurement, differential thermal gravimetric analysis (DTG), and X-ray powder diffraction (XRD), respectively.
Firstly, solubility:
FIG. 1 is a graph comparing solubility curves of a compound of formula 1, a solid dispersion 1 of formula 1, and a solid dispersion 2 of formula 1 prepared in example 1 of the present invention in a phosphate medium at pH 6.8. As can be seen from fig. 1, the compound of formula 1 alone has a lower solubility and dissolution rate in phosphate sustained release formulation at ph 6.8; solid dispersion 1 of formula 1 (compound of formula 1 +
) The solubility and the dissolution rate are greatly improved, which shows that the solubility and the dissolution rate of the compound of the formula 1 dispersed in the carrier material by amorphous crystallization can be obviously improved; formula 1 solid dispersion 2 (compound of formula 1 +
+ SDS) is more improved than the solid dispersion 1 of formula 1, indicating that the solubilizer not only has the effect of increasing solubility and dissolution rate, but also has the effect of further inhibiting possible crystallization of amorphous raw material during dissolution because it can reduce the surface free energy of poorly soluble raw material.
FIG. 6 is a graph comparing the solubility curves of the solid dispersion of formula 2 prepared in example 5 of the present invention and the compound of formula 2 in phosphate medium at pH6.8, the compound of formula 2 having lower solubility and dissolution rate; the solubility and the dissolution rate of the solid dispersion shown in the formula 2 are obviously improved compared with those of the compound shown in the formula 1, which shows that the solid dispersion has the function of obviously improving the solubility of raw materials. This is because the carrier material in the solid dispersion can encapsulate the drug and reduce the particle size of the starting material; simultaneously, reaggregation and agglomeration of the drug are reduced, thereby inhibiting crystallization of the drug; in addition, the specific surface area of the drug particles is increased, so that the wettability of the drug is increased; the solubility of the drug in the carrier diffusion layer can be increased, the higher solubility of the carrier can also increase the moisture of the drug to promote dissolution and absorption, and the dissolution rate and the bioavailability of the drug are improved.
Characterization of the solid dispersion:
1) differential thermal thermogravimetric (DTG) analysis: for the samples and sources of the present inventionThe adjuvants were subjected to DTG analysis. FIG. 3(a) is a DTG scan of a compound of formula 1, showing a distinct crystalline endotherm at 170 ℃; FIG. 3(b) is a DTG scan of the blend of formula 1 of example 1, from which it can be seen that a crystalline endotherm is visible at 170 deg.C, indicating
Simple mixing with the compound of formula 1 does not disperse the drug in an amorphous form. FIG. 3(c) is a DTG scan of the solid dispersion 2 of formula 1 prepared in example 1 showing no crystalline endothermic peak, indicating
The compound of formula 1 is fully dispersed, and the drug is transformed from a crystalline form with a compact structure into an amorphous state.
2) X-ray diffraction (XRD) analysis:
XRD analysis is carried out on the sample and the raw and auxiliary materials in the invention. FIG. 3(a) is an XRD scan of the compound of formula 1 having a strong diffraction peak at 8 to 40 degrees, FIG. 3(b) is an XRD scan of the solid dispersion 1 of formula 1 in example 1 having no characteristic diffraction peak, indicating that the compound of formula 1 exists in an amorphous state
Is a solid dispersion of a carrier material; FIG. 3(c) is an XRD scan of the solid dispersion of formula 1 of example 3, without characteristic diffraction peaks, illustrating the presence of the compound of formula 1 in amorphous form in a solid dispersion with HPMCAS as support material;
FIG. 5(a) is an XRD scan of the compound of formula 2 having a strong diffraction peak at 10-30 ℃; FIG. 5 (b) is an XRD scan of solid dispersion 1 of formula 2 prepared in example 4, without characteristic diffraction peaks, illustrating the presence of the compound of formula 2 in amorphous state in the solid dispersion; FIG. 5(c) is an XRD scan of solid dispersion 2 of formula 2 prepared in example 4, without characteristic diffraction peaks, illustrating the presence of the compound of formula 2 in amorphous state in the solid dispersion; FIG. 5(d) is an XRD scan of solid dispersion 3 of formula 2 prepared in example 4, without characteristic diffraction peaks, illustrating the presence of the compound of formula 2 in an amorphous state in the solid dispersion; the mass ratio of the compound of formula 2 to the carrier material is shown to be 1: 2-1: 4, the compounds of formula 2 are in an amorphous state; therefore, during actual production, the dosage of the carrier material in the invention can be greatly reduced on the premise of ensuring the stability, thereby reducing the production cost.
3) Solid dispersion stability characterization:
the solid dispersion of formula 1 in example 2 of the present invention was placed at 40 ℃ and 60% RH for 3 months under accelerated conditions, and XRD was used to examine whether or not crystallization occurred, and the test results are shown in FIG. 4. In comparison with 0 month, no diffraction peak was observed after 3 months, indicating that the compound of formula 1 was still present in the solid dispersion in an amorphous state, indicating that the solid dispersion was stable during long-term storage.
The solid dispersion of formula 2 in example 5 of the present invention was placed at 40 ℃ and 60% RH for 3 months under accelerated conditions, and XRD was used to examine whether or not crystallization occurred, and the test results are shown in FIG. 7. In comparison with 0 month, no diffraction peak was observed after 3 months, indicating that the compound of formula 2 was still present in the solid dispersion in an amorphous state, indicating that the solid dispersion was stable during long-term storage.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and equivalent substitutions or changes according to the technical solution and the inventive concept of the present invention should be covered by the scope of the present invention.
Claims (10)
1. A solid dispersion comprising an active agent and a carrier material; the active drug is a compound of formula 1 or a compound of formula 2;
the carrier material is selected from hypromellose acetate succinate,
One or more of hydroxypropyl methylcellulose phthalate.
2. The solid dispersion of claim 1, wherein the weight ratio of active drug to carrier material is 1: 1-5; preferably 1: 2 to 4.
3. The solid dispersion of claim 1 or 2, further comprising a solubilizer; the solubilizer is any one or more of sodium dodecyl sulfate, polysorbate 80 and poloxamer 188.
4. The solid dispersion of claim 3, wherein the solubilizer is present in the solid dispersion in an amount of 0.5 to 10% by weight.
5. A method for preparing a solid dispersion according to any one of claims 1 to 4, wherein any one of a solvent method, a coprecipitation method, and a melting method is used; the solvent method comprises the following specific steps: dissolving active drug and carrier material in organic solvent, stirring for dissolving, removing solvent, drying, and pulverizing to obtain solid dispersion; the coprecipitation method comprises the following specific steps: dissolving active drug and carrier material in organic solvent, stirring to dissolve, adding into poor solvent, filtering, drying, and pulverizing to obtain solid dispersion.
6. The method for producing a solid dispersion according to claim 5, wherein the organic solvent is one or more selected from the group consisting of ethanol, acetone, ethyl acetate, methanol, isopropanol, N-dimethylformamide, dichloromethane, N-dimethylacetamide, and N-methylpyrrolidone; the poor solvent is purified water or ethanol.
7. A composition comprising the solid dispersion of any one of claims 1 to 4 as a principal agent.
8. A pharmaceutical composition comprising the composition of claim 7 and a pharmaceutically acceptable excipient.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is provided in a dosage form selected from the group consisting of tablets, capsules, granules, and suspensions.
10. A solid dispersion according to any one of claims 1 to 4 or a composition according to claims 7 to 9, wherein the solid dispersion or composition or pharmaceutical composition of formula 1 is for use in the treatment of gastrointestinal stromal tumors; the solid dispersion or the composition or the pharmaceutical composition of the formula 2 is used for treating melanoma, non-small cell lung cancer, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer and thyroid cancer.
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