阅读说明：本技术 含依维莫司的组合物及其制备方法 (Everolimus-containing composition and preparation method thereof ) 是由 汤文星 苏焕鹏 张现涛 何盛江 谭斌 于 2020-12-18 设计创作，主要内容包括：本发明公开了一种含依维莫司的组合物的制备方法,包括以下步骤：将依维莫司、抗氧剂、羟丙甲纤维素及有机溶剂混合,得到第一混合物；将所述第一混合物与乳糖混合得到第二混合物；对所述第二混合物进行动态真空干燥,所述动态真空干燥为使得所述第三混合物在非静止状态下进行真空干燥；其中,所述依维莫司、所述抗氧剂、所述羟丙甲纤维素、所述乳糖的质量份数依次分别为1～5份、0.01～0.05份、5～15份、1～5份。(The invention discloses a preparation method of a composition containing everolimus, which comprises the following steps: mixing everolimus, an antioxidant, hydroxypropyl methylcellulose and an organic solvent to obtain a first mixture; mixing the first mixture with lactose to obtain a second mixture; dynamically vacuum-drying the second mixture such that the third mixture is vacuum-dried in a non-static state; the weight parts of the everolimus, the antioxidant, the hydroxypropyl methylcellulose and the lactose are respectively 1-5 parts, 0.01-0.05 part, 5-15 parts and 1-5 parts in sequence.)

1. A preparation method of a composition containing everolimus is characterized by comprising the following steps:

mixing everolimus, an antioxidant, hydroxypropyl methylcellulose and an organic solvent to obtain a first mixture;

mixing the first mixture with lactose to obtain a second mixture;

dynamically vacuum-drying the second mixture such that the third mixture is vacuum-dried in a non-static state;

the weight parts of the everolimus, the antioxidant, the hydroxypropyl methylcellulose and the lactose are respectively 1-5 parts, 0.01-0.05 part, 5-15 parts and 1-5 parts in sequence.

2. The method of preparing a composition comprising everolimus according to claim 1, wherein the apparent viscosity of the 2% solution of hypromellose at 20 ℃ is from 2.3 to 3.3 mPa-s.

3. The method for preparing an everolimus-containing composition according to claim 1, wherein the organic solvent is used in an amount of 70 to 150 parts by mass.

4. The method of claim 1, wherein the non-resting state comprises any one or more of stirring and rotation.

5. The process for preparing an everolimus-containing composition according to claim 4, wherein the step of dynamic vacuum drying of the second mixture comprises: adding the second mixture into a vacuum homogenizing emulsifying machine, removing the organic solvent, and transferring the materials into a double-cone rotary vacuum drying machine for vacuum drying when the materials are dried until no jelly is formed.

6. The method for preparing a composition comprising everolimus according to claim 5,

the vacuum degree of the vacuum homogenizing emulsifying machine is less than or equal to-0.085 MPa, and the drying temperature is less than or equal to 55 ℃.

7. The method for preparing the everolimus-containing composition according to claim 5, wherein the vacuum degree of the vacuum homogenizing and emulsifying machine is less than or equal to-0.090 MPa, and the drying temperature is less than or equal to 45 ℃.

8. The method for preparing the everolimus-containing composition according to claim 5, wherein the stirring speed of the vacuum homogenizer is 50rpm to 80rpm, and the homogenizing speed is 1500rpm to 2000 rpm.

9. The method for producing an everolimus-containing composition according to any one of claims 1 to 8, comprising the step of pulverizing the second mixture after dynamic vacuum drying, wherein the pulverized median particle diameter D50 is 60 μm or less.

10. The method for preparing a composition containing everolimus according to any one of claims 1 to 8, wherein the organic solvent is one or more selected from the group consisting of absolute ethanol, acetone, methanol, dichloromethane and acetonitrile.

11. The method for preparing an everolimus-containing composition according to any one of claims 1 to 8, wherein the antioxidant includes, but is not limited to, one or more of propyl gallate, ascorbyl palmitate, t-butyl-p-hydroxyanisole, and di-t-butyl-p-cresol.

12. Everolimus-containing composition obtained by the process for preparing an everolimus-containing composition according to any one of claims 1 to 11.

13. The everolimus-containing composition of claim 12, wherein the everolimus-containing composition is a solid dispersant.

Technical Field

The invention relates to the field of medicinal preparations, in particular to an everolimus-containing composition and a preparation method thereof.

Background

Everolimus is a derivative of rapamycin, pioneered by the company novartis, switzerland under the certian or Afinitor trade name, which has been approved for marketing in the united states and the european union. Certian is used clinically mainly to prevent rejection after kidney and heart transplantation surgeries. With the intensive research, everolimus shows a positive treatment effect in the field of tumor treatment, and the Afiniiter which is subsequently marketed is used for treating renal cell carcinoma, treating the subarachnoid giant cell astrocytoma and the like which are associated with nodular brain sclerosis and are partially new indications at present in the clinical stage, and all the Afiniferation medicines aim at VEGF targets to treat various cancers. Everolimus is a selective mTOR kinase inhibitor, and the action mechanism is mainly to form a complex with FKBP-12 protein, so that the activity of mTOR kinase is inhibited, the growth, differentiation and metabolism of cancer cells are interfered, and the antitumor effect is achieved.

The solubility of everolimus is low, and everolimus is difficult to dissolve in solutions with various pH values and only dissolves in organic solvents, so that the everolimus is suitable for preparing solid dispersions by adopting a solvent method, and the dissolution rate is improved, so that the bioavailability after oral administration is improved. Everolimus has the characteristics of heat sensitivity, photosensitivity, easy oxidation and the like, so that the temperature, illumination and oxygen are controlled in the preparation process, and the stability of the medicine is ensured. In addition, everolimus generates a large amount of isomers in water, and the presence of moisture further exacerbates the oxidation, so the use of aqueous solutions should be avoided in the preparation process.

Patent ZL201110065075.4 adjusts the pH value of everolimus and excipient and reasonable prescription proportion, and utilizes fluidized bed wrapping technology to uniformly disperse main drug to obtain a preparation with high bioavailability and non-micronized property, which overcomes the defects of solubility and stability. The acid-base regulator and water are added in the preparation process of the patent, and the problem of stability of the medicine is difficult to overcome due to instability of medicine molecules under acidic and aqueous solution conditions. As can be seen from the examples, the overall impurities are higher, although the dissolution rate is faster.

Hydroxypropyl methylcellulose is one of nonionic cellulose mixed ethers, belongs to a high molecular compound, is dissolved in water and insoluble in an organic solvent, can expand to form a uniform colloidal solution after being stirred for a long time in the organic solvent, and can be layered after standing. In the microwave drying technology disclosed in patent CN106265525A, the prepared hypromellose solution is spread in a sample tray of a dryer, and the organic solvent is removed by controlling the microwave drying parameters. However, the hypromellose colloidal solution can be layered after standing, and static drying can form a high molecular film on the surface of the material, which affects the volatilization of the internal organic solvent, inevitably results in the extension of drying time, and needs to consume more energy in industrial mass production, thereby improving the production cost.

Patent CN105616365A discloses drying techniques such as rotary evaporation and vacuum drying oven to prepare solid dispersion. The method can prevent the direct contact of the medicine and air through vacuum operation, and can effectively avoid the oxidative degradation of everolimus. However, the vacuum drying oven is static drying, and the drying efficiency is low. The glass bottle used for rotary evaporation is generally laboratory equipment, large-scale production is difficult to realize, materials are difficult to collect, and the obtained materials have high hardness and are difficult to crush.

Disclosure of Invention

Therefore, it is necessary to provide a composition containing everolimus and a preparation method thereof, aiming at the problems of low drying efficiency, difficult material collection, poor drug stability, high hardness of dried materials, difficult processing and the like in the prior art.

A method for preparing an everolimus-containing composition, comprising the steps of:

mixing everolimus, an antioxidant, hydroxypropyl methylcellulose and an organic solvent to obtain a first mixture;

mixing the first mixture with lactose to obtain a second mixture;

dynamically vacuum-drying the second mixture such that the third mixture is vacuum-dried in a non-static state;

the weight parts of the everolimus, the antioxidant, the hydroxypropyl methylcellulose and the lactose are respectively 1-5 parts, 0.01-0.05 part, 5-15 parts and 1-5 parts in sequence.

In some of these embodiments, the apparent viscosity of the 2% solution of hypromellose at 20 ℃ is from 2.3 to 3.3mPa · s.

In some embodiments, the organic solvent is 70 to 150 parts by weight.

In some embodiments, the non-static state includes any one or more of stirring and rotation.

In some of these embodiments, the step of dynamically vacuum drying the second mixture comprises: adding the second mixture into a vacuum homogenizing emulsifying machine, removing the organic solvent, and transferring the materials into a double-cone rotary vacuum drying machine for vacuum drying when the materials are dried until no jelly is formed.

In some of the embodiments, the vacuum degree of the vacuum homogenizing emulsifying machine is less than or equal to-0.085 MPa, and the drying temperature is less than or equal to 55 ℃.

In some of these embodiments, the vacuum homogenizer is at a vacuum of ≦ -0.090MPa and a drying temperature of ≦ 45 deg.C.

In some embodiments, the stirring speed of the vacuum homogenizing emulsifying machine is 50rpm to 80rpm, and the homogenizing speed is 1500rpm to 2000 rpm.

In some embodiments, the method comprises the step of crushing the product of the dynamic vacuum drying of the second mixture, wherein the value of the median particle diameter D50 after crushing is less than or equal to 60 mu m.

In some of these embodiments, the organic solvent is selected from one or more of absolute ethanol, acetone, methanol, dichloromethane, acetonitrile.

In some of these embodiments, the antioxidant includes, but is not limited to, one or more of propyl gallate, ascorbyl palmitate, t-butyl p-hydroxyanisole, di-t-butyl p-cresol.

The composition containing everolimus obtained by the preparation method.

In some of these embodiments, the everolimus-containing composition is a solid dispersant.

The preparation method of the everolimus-containing composition provided by the invention adopts a vacuum drying method, the operation process is simple, the drying rate is high, the influence of oxygen and moisture is avoided in the drying process, and stable preparation conditions are provided, so that the stability of the product in the preparation and storage processes is ensured. Traditional wet granulation material is easy to be crystallized in the preparation process, and the vacuum drying preparation method of the application can enable hydroxypropyl methylcellulose and lactose to be wrapped on the surface of everolimus, so that the everolimus keeps the state of amorphous raw materials in the whole preparation process, and the chemical stability of the everolimus in the preparation process is improved. The composition prepared from everolimus prepared by the method disclosed by the invention is good in brittleness, easy to crush and process, and capable of being produced in a process amplification manner, and the production cost is favorably reduced.

Furthermore, according to the preparation method, everolimus and hydroxypropyl methylcellulose are mixed, so that the hydroxypropyl methylcellulose automatically swells and wraps the surface of everolimus. Because the hydroxypropyl methylcellulose is easy to shrink in the drying process and is not easy to open when meeting water, if the surface only contains the hydroxypropyl methylcellulose, the everolimus product is not easy to dissolve out in the using process, on the basis, the lactose is added after the hydroxypropyl methylcellulose is mixed for mixing, so that the lactose is inserted into gaps of the hydroxypropyl methylcellulose, and the lactose is easy to dissolve in water after being dried, thereby improving the speed of dissolving out the everolimus in the product.

Detailed Description

In order that the invention may be more fully understood, reference will now be made to the following description. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

The lactose can be anhydrous lactose or lactose monohydrate. The lactose monohydrate is monohydrate C formed by crystallizing lactose in water₁₂H₂₂O₁₁·H₂O, when heated at 120 deg.C, can be converted into anhydrous lactose.

Hypromellose, also known as hydroxypropyl methylcellulose, also known as hypromellose, cellulose hypromellose. The high-purity cotton cellulose can be selected as a raw material and is prepared by special etherification under the alkaline condition. The hydroxypropyl methyl cellulose HPMC has thermal gelation property, the product water solution forms gel precipitation after being heated, and is dissolved after being cooled, and the gel temperature of the products with different specifications is different. The solubility varies with viscosity, the lower the viscosity, the greater the solubility, and the different specifications of hydroxypropylmethylcellulose HPMC have certain differences in their properties.

The embodiment of the invention provides a preparation method of a composition containing everolimus, which comprises the following steps:

mixing everolimus, an antioxidant, hydroxypropyl methylcellulose and an organic solvent to obtain a first mixture;

mixing the first mixture with lactose to obtain a second mixture;

dynamically vacuum-drying the second mixture such that the third mixture is vacuum-dried in a non-static state;

the mass fractions of the everolimus, the antioxidant, the hydroxypropyl methylcellulose and the lactose are respectively part, part and part in sequence.

The preparation method of the everolimus-containing composition provided by the invention adopts a vacuum drying method, the operation process is simple, the drying rate is high, the influence of oxygen and moisture is avoided in the drying process, and stable preparation conditions are provided, so that the stability of the product in the preparation and storage processes is ensured. Traditional wet granulation material is easy to be crystallized in the preparation process, and the vacuum drying preparation method of the application can enable hydroxypropyl methylcellulose and lactose to be wrapped on the surface of everolimus, so that the everolimus keeps the state of amorphous raw materials in the whole preparation process, and the chemical stability of the everolimus in the preparation process is improved. The composition prepared from everolimus prepared by the method disclosed by the invention is good in brittleness, easy to crush and process, and capable of being produced in a process amplification manner, and the production cost is favorably reduced.

Furthermore, according to the preparation method, everolimus and hydroxypropyl methylcellulose are mixed, so that the hydroxypropyl methylcellulose automatically swells and wraps the surface of everolimus. Because the hydroxypropyl methylcellulose is easy to shrink in the drying process and is not easy to open when meeting water, if the surface only contains the hydroxypropyl methylcellulose, the everolimus product is not easy to dissolve out in the using process, on the basis, the lactose is added after the hydroxypropyl methylcellulose is mixed for mixing, so that the lactose is inserted into gaps of the hydroxypropyl methylcellulose, and the lactose is easy to dissolve in water after being dried, thereby improving the speed of dissolving out the everolimus in the product.

The everolimus starting material of the present invention may be present in any of the crystalline forms, or in the form of a hydrate, or a solvate, or in the form of an amorphous form.

In some embodiments, everolimus may be mixed with an antioxidant prior to being mixed with hypromellose and lactose to provide an antioxidant environment for subsequent processing.

In some embodiments, the apparent viscosity of the 2% solution of hypromellose at 20 ℃ is from 2.3mPa · s to 3.3m Pa · s.

In some embodiments, the organic solvent is 70 to 150 parts by mass. For example, 70, 80, 90, 100, 110, 120, 130, 140, 150 parts may be used.

In some embodiments, the non-stationary state includes any one or more of stirring, rotation.

In some embodiments, the step of dynamically vacuum drying the second mixture comprises: adding the second mixture into a vacuum homogenizing emulsifying machine, removing the organic solvent, and transferring the materials into a double-cone rotary vacuum drying machine for vacuum drying when the materials are dried until no jelly is formed.

In some embodiments, the vacuum homogenizer is at a vacuum of ≦ -0.085MPa and a drying temperature of ≦ 55 ℃. More preferably, the vacuum degree of the vacuum homogenizing emulsifying machine is less than or equal to-0.090 MPa, and the drying temperature is less than or equal to 45 ℃.

In some embodiments, the stirring speed of the vacuum homogeneous emulsifying machine is 50rpm to 80 rpm. Specifically, the rotation speed may be 50rpm, 60rpm, 70rpm, or 80 rpm. More preferably 70 to 80 rpm.

In some embodiments, the homogenizing rotation speed of the vacuum homogenizing and emulsifying machine is 1500rpm to 2000rpm, and specifically 1500rpm, 1600rpm, 1700rpm, 1800rpm, 1900rpm, 2000 rpm. More preferably 1800rpm to 2000 rpm.

In the vacuum homogenizing emulsifying machine, the materials are stirred while being dried in vacuum so as to accelerate the drying. But the materials can not be completely dried due to the structural characteristics of the vacuum homogenizing emulsifying machine, so that the materials dried in the vacuum homogenizing drier can be transferred to the next drier for continuous and thorough drying.

In the double-cone rotary vacuum drying machine, the materials can be overturned while being dried in vacuum, so that the drying is more uniform and thorough. In some embodiments, the double-cone rotary vacuum dryer has a vacuum degree of less than or equal to-0.085 MPa and a drying temperature of less than or equal to 55 ℃. More preferably, the vacuum degree of the double-cone rotary vacuum drier is less than or equal to-0.090 MPa, and the drying temperature is less than or equal to 45 ℃.

In some embodiments, the equipment used for drying the vacuum homogenizing emulsifying machine can comprise a stirring system, a heating system and a vacuum system. In addition, a feed system, a temperature reduction system or a nitrogen charging system can be included.

In some embodiments, the method further comprises the step of comminuting the product of the dynamic vacuum drying of the second mixture. The preferable value of the median particle diameter D50 after grinding is less than or equal to 60 μm. More preferably, the D50 value is ≦ 45 μm.

Wherein, the crushing device can be any one of a mechanical crusher, a hammer crusher, a grinding type crusher or a jet mill, and more preferably is a hammer crusher.

The product dosage form prepared by the invention can be used as a solid dispersing agent, or the solid dispersing agent is packaged into capsules.

In some embodiments, the organic solvent is selected from one or more of absolute ethanol, acetone, methanol, dichloromethane, acetonitrile. Preferably absolute ethyl alcohol, acetone or a mixed solvent of absolute ethyl alcohol and acetone. Further preferred is absolute ethanol.

In some embodiments, the antioxidant includes, but is not limited to, one or more of propyl gallate, ascorbyl palmitate, t-butyl p-hydroxyanisole, di-t-butyl p-cresol.

Everolimus-containing composition obtained by the preparation method.

The following is a detailed description of specific embodiments.

Example 1

The preparation method of the everolimus-containing composition of this example is as follows:

adding 100 parts of absolute ethyl alcohol into a vacuum homogenizing emulsifying machine, setting the stirring speed to be 50rpm, the homogenizing speed to be 1500rpm and the heating temperature to be 55 ℃.

② adding 1 part of everolimus and 0.01 part of ditert-butyl-p-cresol into the absolute ethyl alcohol in the step (i), stirring and dissolving. 10 parts of hypromellose (VLV from Dow) is added and stirring is continued to expand the hypromellose. Finally, 1 part of lactose monohydrate (G200 from Mei-Kong Co.) was added and stirring was continued.

Starting a vacuum pump, controlling the vacuum degree to be less than or equal to-0.085 MPa, starting to remove the organic solvent, and finishing the drying of the emulsifying machine when the material is in a dry state (no jelly exists).

Discharging, placing the material in a double-cone vacuum drier, setting the drying temperature at 55 deg.C and the vacuum degree at-0.085 MPa, and continuously removing organic solvent.

Discharging, and pulverizing to obtain solid dispersion with median particle diameter D50 value not more than 60 μm.

Example 2

The preparation method of the everolimus-containing composition of this example is as follows:

adding 100 parts of absolute ethyl alcohol into a vacuum homogenizing emulsifying machine, setting the stirring speed to be 80rpm, the homogenizing speed to be 2000rpm and the heating temperature to be 45 ℃.

② adding 1 part of everolimus and 0.01 part of ditert-butyl-p-cresol into the absolute ethyl alcohol in the step (i), stirring and dissolving. 10 parts of hypromellose (VLV from Dow) is added and stirring is continued to expand the hypromellose. Finally, 1 part of lactose monohydrate (G200 from Mei-Kong Co.) was added and stirring was continued.

Starting a vacuum pump, controlling the vacuum degree to be less than or equal to-0.090 MPa, starting to remove the organic solvent, and ending the drying of the emulsifying machine when the material is in a dry state (no jelly exists).

Discharging, placing the material in a double-cone vacuum drier, setting the drying temperature at 45 ℃ and the vacuum degree at less than or equal to-0.090 MPa, and continuously removing the organic solvent.

Discharging, and pulverizing to obtain solid dispersion with median particle diameter D50 value not more than 60 μm.

Example 3

The preparation method of the everolimus-containing composition of this example is as follows:

adding 100 parts of absolute ethyl alcohol into a vacuum homogenizing emulsifying machine, setting the stirring speed to be 80rpm, the homogenizing speed to be 2000rpm and the heating temperature to be 45 ℃.

② adding 1 part of everolimus and 0.01 part of ditert-butyl-p-cresol into the absolute ethyl alcohol in the step (i), stirring and dissolving. 10 parts of hypromellose (VLV from Dow) is added and stirring is continued to expand the hypromellose. Finally, 1 part of lactose monohydrate (F100 from Mei-Kong Co.) was added and stirring was continued.

Starting a vacuum pump, controlling the vacuum degree to be less than or equal to-0.090 MPa, starting to remove the organic solvent, and ending the drying of the emulsifying machine when the material is in a dry state (no jelly exists).

Discharging, placing the material in a vacuum drying oven, setting the drying temperature at 55 deg.C and the vacuum degree at less than or equal to-0.090 MPa, and continuously removing organic solvent.

Discharging, and pulverizing to obtain solid dispersion with median particle diameter D50 value not more than 45 μm.

Comparative example 1 (Rotary evaporator drying)

The preparation method of the everolimus-containing composition of this comparative example was as follows:

adding 100 parts of absolute ethyl alcohol into a beaker, and starting magnetic stirring.

② adding 1 part of everolimus and 0.01 part of ditert-butyl-p-cresol into the absolute ethyl alcohol in the step (i), stirring and dissolving. 10 parts of hypromellose (VLV from Dow) is added and stirring is continued to expand the hypromellose. Finally, 1 part of lactose monohydrate (F100 from Mei-Kong Co.) was added and stirring was continued.

Thirdly, transferring the material obtained in the second step into a rotary evaporator, setting the water bath temperature to be 55 ℃, starting a vacuum pump, controlling the vacuum degree to be less than or equal to-0.085 MPa, starting to remove the organic solvent, and stopping operation after drying for 4 hours.

Discharging and grinding to obtain the solid dispersion.

Comparative example 2 (vacuum drying oven drying)

The preparation method of the everolimus-containing composition of this comparative example was as follows:

adding 100 parts of absolute ethyl alcohol into a beaker, and starting magnetic stirring.

② adding 1 part of everolimus and 0.01 part of ditert-butyl-p-cresol into the absolute ethyl alcohol in the step (i), stirring and dissolving. 10 parts of hypromellose (VLV from Dow) is added and stirring is continued to expand the hypromellose. Finally, 1 part of lactose monohydrate (F100 from Mei-Kong Co.) was added and stirring was continued.

Evenly spreading the material obtained in the second step in a sample tray of a vacuum drying oven, setting the drying temperature to be 55 ℃, starting a vacuum pump, controlling the vacuum degree to be less than or equal to-0.085 MPa, starting to remove the organic solvent, and stopping operation after drying for 48 hours.

Discharging and grinding to obtain the solid dispersion.

COMPARATIVE EXAMPLE 3 (fluid bed drying)

The preparation method of the everolimus-containing composition of this comparative example was as follows:

adding 100 parts of absolute ethyl alcohol into a beaker, and starting magnetic stirring.

② adding 1 part of everolimus and 0.01 part of ditert-butyl-p-cresol into the absolute ethyl alcohol in the step (i), stirring and dissolving. 10 parts of hypromellose (VLV from Dow) is added and stirring is continued to expand the hypromellose. Finally, 1 part of lactose monohydrate (F100 from Mei-Kong Co.) was added and stirring was continued.

Thirdly, the material obtained in the second step is added into a fluidized bed for drying through a peristaltic pump and a sprayer, the drying temperature is set to be 55 ℃, and the organic solvent is removed.

Discharging and grinding to obtain the solid dispersion.

COMPARATIVE EXAMPLE 4 (reduction of lactose monohydrate dosage)

The preparation method of the everolimus-containing composition of this comparative example was as follows:

adding 100 parts of absolute ethyl alcohol into a vacuum homogenizing emulsifying machine, setting the stirring speed to be 50rpm, the homogenizing speed to be 1500rpm and the heating temperature to be 55 ℃.

② adding 1 part of everolimus and 0.01 part of ditert-butyl-p-cresol into the absolute ethyl alcohol in the step (i), stirring and dissolving. 10 parts of hypromellose (VLV from Dow) is added and stirring is continued to expand the hypromellose. Finally, 0.5 part of lactose monohydrate (G200 from Mei-Kong Co.) was added and stirring was continued.

Starting a vacuum pump, controlling the vacuum degree to be less than or equal to-0.085 MPa, starting to remove the organic solvent, and finishing the drying of the emulsifying machine when the material is in a dry state (no jelly exists).

Discharging, placing the material in a double-cone vacuum drier, setting the drying temperature at 55 deg.C and the vacuum degree at-0.085 MPa, and continuously removing organic solvent.

Discharging and crushing to obtain the solid dispersion.

Comparative example 5 (increasing the amount of hypromellose)

The preparation method of the everolimus-containing composition of this comparative example was as follows:

adding 100 parts of absolute ethyl alcohol into a vacuum homogenizing emulsifying machine, setting the stirring speed to be 50rpm, the homogenizing speed to be 1500rpm and the heating temperature to be 55 ℃.

② adding 1 part of everolimus and 0.01 part of ditert-butyl-p-cresol into the absolute ethyl alcohol in the step (i), stirring and dissolving. 20 parts of hypromellose (VLV from Dow) was added and stirring was continued to expand the hypromellose. Finally, 1 part of lactose monohydrate (G200 from Mei-Kong Co.) was added and stirring was continued.

Starting a vacuum pump, controlling the vacuum degree to be less than or equal to-0.085 MPa, starting to remove the organic solvent, and finishing the drying of the emulsifying machine when the material is in a dry state (no jelly exists).

Discharging, placing the material in a double-cone vacuum drier, setting the drying temperature at 55 deg.C and the vacuum degree at-0.085 MPa, and continuously removing organic solvent.

Discharging and crushing to obtain the solid dispersion.

The compositions obtained in example 1 and comparative examples 1 to 5 were collected and the yields calculated while comparing the material properties, the specific results are shown in table 1.

TABLE 1

The "rate at which everolimus is completely dissolved" means the rate at which everolimus is completely dissolved in water in each of the examples or comparative example dosage forms, and the more "+" indicates the shorter time required for complete dissolution.

As can be seen from Table 1, the drying efficiency of the example 1 which adopts the vacuum homogenizing emulsifying machine for drying is high, the obtained material has good brittleness and is easy to crush, and thus the quality and the yield of the product are ensured. Comparative example 1, which was prepared using a rotary evaporator, had a long drying time, and the material was strongly adhered to the wall, and the bottle mouth was narrow and small, making sampling difficult. The intermediate material prepared by the vacuum drying oven is statically dried in the drying process, and the hydroxypropyl methylcellulose forms a high-molecular film after being dried on the surface of the material, so that the volatilization of an organic solvent of the internal material is influenced, and the intermediate material cannot be thoroughly dried. In the fluidized bed drying process, because the intermediate material is heterogeneous colloidal solution, phase separation is generated in the conveying process by using a peristaltic pump, only a small amount of solute enters the fluidized bed through a spray nozzle, and most of solute is blocked in a peristaltic pump pipeline, so that thorough drying cannot be realized. Furthermore, everolimus in the product prepared in the example of the present invention is most easily eluted.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.