HK1166005B - Tolvaptan solid dispersion and its preparation method - Google Patents

Description

Tolvaptan solid dispersion and preparation method thereof

Technical Field

The invention belongs to the field of chemical pharmacy, and particularly relates to a tolvaptan solid dispersion containing cross-linked polyvinylpyrrolidone.

Background

Tolvaptan (tolvaptan) vasopressin receptor antagonist, chemical name 7-chloro-5-hydroxy-1- [ 2-methyl-4- (2-methylbenzamido) benzoyl ] -2, 3, 4, 5-tetrahydropyran-1H-benzazepine, structural formula as follows:

the united states food and drug administration approved new drug marketing application of tolvaptan (vasopressin V2 receptor antagonist) produced by tsukamur pharmaceutical company of japan, and in a heart failure model, tolvaptan only showed a water-draining diuretic effect, significantly reduced cardiac preload, and had no effect on afterload and renal function. Many clinical trials for treating heart failure and hyponatremia have demonstrated that tolvaptan is effective in reducing fluid retention and correcting hyponatremia in heart failure patients with volume overload. Tolvaptan can effectively relieve pulmonary congestion symptoms and physical signs of patients with heart failure, and also can reduce weight and protect renal function without serious adverse reactions. Tolvaptan related compounds have proven useful for the treatment of: high or isovolumetric hyponatremia with heart failure, liver cirrhosis, and antidiuretic hormone secretion disorder syndrome.

Tolvaptan is a white crystal or crystalline powder, and is hardly soluble in water, and thus its bioavailability is inevitably low when tolvaptan, which is water-insoluble, is orally administered.

To overcome this problem, japanese patent publication No. JP11021241A discloses a method for preparing a tolvaptan solid preparation composition, the method comprising the steps of: dissolving tolvaptan and hydroxypropyl cellulose in an organic solvent according to a certain proportion, removing the organic solvent according to a spray drying method to obtain a tolvaptan solid dispersion composition, and adding other pharmaceutic adjuvants to prepare a solid preparation.

Disclosure of Invention

The present inventors have unexpectedly found that a tolvaptan solid dispersion prepared by combining tolvaptan with a carrier comprising crospovidone (i.e., crospovidone) exhibits higher solubility and stability of the active ingredient than prior art tolvaptan formulations comprising hydroxypropyl cellulose; the compound is also more convenient to prepare into a common solid preparation, and further research shows that the dissolution efficiency of the medicine can be further improved by adding other water-soluble polymers on the basis of the crosslinked polyvinylpyrrolidone.

An object of the present invention is to provide a tolvaptan solid dispersion exhibiting higher water solubility and bioavailability than conventional tolvaptan formulations, and a preparation method thereof.

It is another object of the present invention to provide a pharmaceutical composition comprising a solid dispersion of tolvaptan for oral administration.

According to one aspect of the present invention, there is provided a solid dispersion comprising an amorphous form of the active ingredient tolvaptan or a salt thereof, cross-linked polyvinylpyrrolidone. In a preferred embodiment, the weight ratio of the active ingredient tolvaptan or the salt thereof to the crosslinked polyvinylpyrrolidone is controlled to be 1: 0.05-20; preferably in a weight ratio of 1: 0.1 to 10, preferably 2: 1.

The solid dispersion of the present invention may consist of the active ingredient and the cross-linked polyvinylpyrrolidone only. Further, the solid dispersion of the present invention may further contain a water-soluble polymer. The invention further improves the physical properties of the solid dispersion by adding one or more water-soluble polymers. The water-soluble polymer is a water-soluble polymer commonly used in solid dispersions, and can be selected from the following polymers:

alkyl celluloses such as methyl cellulose;

hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose;

hydroxyalkyl alkylcelluloses, such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose;

carboxyalkyl celluloses, such as carboxymethyl cellulose;

alkali metals of carboxyalkyl celluloses, such as sodium carboxymethyl cellulose;

carboxyalkylalkylcelluloses, such as carboxymethylethylcellulose;

carboxyalkyl cellulose esters;

pectins, such as sodium carboxymethyl amylopectin;

chitin derivatives, such as chitosan;

polysaccharides such as alginic acid, its alkali metal and ammonium salts, carrageenan (caraganan), galactomannan, xanthan gum, agar, gum arabic, guar gum and xanthan gum;

polymethacrylic acid and salts thereof;

polymethacrylic acid and salts thereof, methacrylate copolymers, aminoalkyl methacrylate copolymers;

polyvinyl acetal and diethylaminoacetate;

sugar-type surfactants such as sucrose distearate, sucrose mono/distearate and sucrose monopalmitate;

polyvinyl alcohol;

polyvinylpyrrolidone and polyvinylpyrrolidone-vinyl acetate copolymer;

polyalkylene oxides such as polyethylene oxide and polypropylene oxide;

or ethylene oxide-propylene oxide copolymers.

Among the above-mentioned water-soluble polymers, alkylcellulose, hydroxyalkylcellulose, carboxyalkylalkylcellulose or their alkali metal salts, polyvinylpyrrolidone are preferable, and hydroxypropylmethylcellulose, polyvinylpyrrolidone are more preferable. Among them, the preferred embodiment is to use the water-soluble polymer and the crosslinked polyvinylpyrrolidone in a weight ratio of 1: 5 to 20, preferably 1: 8 to 15, and most preferably 1: 10.

It has been found through studies that the amount of the water-soluble polymer added thereto is not particularly limited since the water-soluble polymer can further improve the properties of the solid dispersion, and can be selected by those skilled in the art according to the actual production, and it has been found through actual studies that the improvement effect exhibited when the amount of the water-soluble polymer is 1: 5 to 20 relative to the amount of the crosslinked polyvinylpyrrolidone has a statistical significance, preferably 1: 8 to 15, and most preferably 1: 10.

In addition, the compositions described in the examples of the present invention may be referred to as preferable illustrations of the effects of the present invention. A preferred embodiment of the solid dispersion of the present invention is a solid dispersion comprising the following components and proportions:

wherein the water soluble polymer is polyvinylpyrrolidone, hydroxypropylcellulose, hydroxyethylcellulose or methylcellulose, with polyvinylpyrrolidone or hydroxypropylcellulose embodiments being most effective.

For solutions containing water-soluble polymers, the solid dispersion may contain no further components, i.e. only the active ingredient, the crosslinked polyvinylpyrrolidone and the water-soluble polymer.

In the preparation of the amorphous tolvaptan solid dispersion of the present invention, crosslinked polyvinylpyrrolidone alone or a combination of a water-soluble polymer and crosslinked polyvinylpyrrolidone may be used as a carrier. In the specific operation, the operation can be carried out according to the following steps:

(1) dissolving tolvaptan or a salt thereof in an organic solvent;

(2) for solid dispersions containing no water soluble polymer, the crosslinked polyvinylpyrrolidone is dissolved or dispersed in an organic solvent;

for the solid dispersion containing the water-soluble polymer, the cross-linked polyvinylpyrrolidone and the water-soluble polymer can be directly dissolved or dispersed in the organic solvent at the same time to form a solution, or the cross-linked polyvinylpyrrolidone and the water-soluble polymer can be respectively dissolved or dispersed in the two organic solvents to form two solutions, and the organic solvent can contain water according to the dissolving or dispersing requirements of the drug or the solid dispersion carrier;

(3) mixing the above solutions of the drug and the solid dispersion carrier, and removing the organic solvent to obtain a solid dispersion mixture.

The method of removing the organic solvent to obtain a solid dispersion can be carried out according to a conventional operation in the art, such as evaporation, spray drying or fluidized bed drying, and for the present invention, spray drying is preferably used.

In the present invention, as the organic solvent for dissolving the drug or the solid dispersion carrier, a solvent which can dissolve the above-mentioned substance or can be dispersed relatively easily, and is selected from lower alcohols such as methanol, ethanol, and isopropyl alcohol; ketones such as acetone and methyl ethyl ketone; and halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, and mixed solvents thereof. Meanwhile, water can be added according to the requirement. Such as methanol, ethanol, isopropanol, acetone, butanone, dichloromethane, dichloroethane, chloroform or carbon tetrachloride. Among these organic solvents, a mixed solvent of a lower alcohol and a halogenated hydrocarbon is preferable from the viewpoint of solubility and removal by distillation, and specifically includes a mixed solution of methanol or ethanol and methylene chloride. The preferred embodiments in the specific implementation are: dissolving tolvaptan or a salt thereof using a mixture of ethanol and dichloromethane; the crosslinked polyvinylpyrrolidone and the water-soluble polymer are dissolved using a mixture of ethanol and dichloromethane or ethanol.

The particle size of the amorphous tolvaptan solid dispersion is in the range of 0.01-400 μm, preferably 0.1-300 μm, and more preferably 1-200 μm.

The amorphous tolvaptan solid dispersion of the present invention does not show any endothermic peak in its DSC scan, nor crystalline refractive peak in its powder X-ray diffraction spectrum, indicating that tolvaptan contained in the dispersion of the present invention is a stable amorphous form.

In addition, the present invention provides a pharmaceutical composition for oral administration comprising the solid dispersion together with pharmaceutically acceptable carriers, excipients and additives. The pharmaceutical composition may be formulated in the form of powder, granules, tablets, soft or hard capsules, pills or coated preparations according to any conventional method. For example, the solid dispersion in the form of powder or granules may be filled into a hard capsule together with a lubricant or other pharmaceutical additives, or made into a tablet form together with pharmaceutical additives for tableting, and then optionally coated according to any conventional method to obtain a coated formulation.

The formulations of the present invention may be administered orally in individual doses or in divided doses.

In the present invention, one or more pharmaceutically acceptable excipients may be optionally added during the preparation of the orally administrable composition comprising the solid dispersion to improve the flowability and other physical properties of the solid dispersion. The medicinal excipient can be selected from lactose, starch, sodium starch glycolate, polyvinylpyrrolidone, croscarmellose sodium, maltodextrin, microcrystalline cellulose, calcium phosphate, calcium bicarbonate and microcrystalline cellulose. Additionally, lubricants such as stearic acid, magnesium stearate and talc may be employed in the present invention.

Drawings

The above and other objects and features of the present invention will become apparent when taken in conjunction with the following drawings, each of which shows:

FIG. 1: example 1 spectrum of powder X-ray diffraction;

FIG. 2: in vitro release profiles of examples 1-10, comparative examples 1-2;

FIG. 3: in vivo bioavailability profiles for drug substance, example 4, comparative example 2.

Detailed Description

The following examples are given without limiting the scope of the invention in any way.

Example 1

Adding 20g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 10g of crospovidone into the ethanol, uniformly dispersing, then mixing the tolvaptan solution and the crospovidone dispersion, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-400 microns, and the average particle size of the tolvaptan solid dispersion is 52 microns.

Example 2

Adding 20g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 2g of crospovidone into the ethanol, uniformly dispersing, then mixing the tolvaptan solution and the crospovidone dispersion, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-400 microns, and the average particle size of the tolvaptan solid dispersion is 52 microns.

Example 3

Adding 20g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 200g of crospovidone into the ethanol, uniformly dispersing, then mixing the tolvaptan solution and the crospovidone dispersion liquid, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-400 mu m, and the average particle size of the tolvaptan solid dispersion is 52 mu m.

Example 4

Adding 20g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 1g of polyvinylpyrrolidone into the mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 10g of crosslinked polyvinylpyrrolidone into the mixture of dichloromethane and ethanol, uniformly dispersing, mixing the tolvaptan solution with other additive dispersion liquid, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-100 microns, and the average particle size of the tolvaptan solid dispersion is 25 microns.

Example 5

Adding 20g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 1g of hydroxypropyl methylcellulose into the mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 10g of cross-linked polyvinylpyrrolidone into the mixture of dichloromethane and ethanol, uniformly dispersing, mixing the tolvaptan solution with other additive dispersion liquid, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-100 mu m, and the average particle size of the tolvaptan solid dispersion is 25 mu m.

Example 6

Adding 20g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 1g of hydroxyethyl cellulose into the mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 10g of crosslinked polyvinylpyrrolidone into the mixture of dichloromethane and ethanol, uniformly dispersing, mixing the tolvaptan solution with other additive dispersion liquid, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-100 microns, and the average particle size of the tolvaptan solid dispersion is 25 microns.

Example 7

Adding 20g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 1g of sodium carboxymethylcellulose into the mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 10g of crosslinked polyvinylpyrrolidone into the mixture of dichloromethane and ethanol, uniformly dispersing, mixing the tolvaptan solution with other additive dispersion liquid, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-100 microns, and the average particle size of the tolvaptan solid dispersion is 25 microns.

Example 8

Adding 20g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 1g of methylcellulose into the mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 10g of crosslinked polyvinylpyrrolidone into the mixture of dichloromethane and ethanol, uniformly dispersing, mixing the tolvaptan solution with other additive dispersion liquid, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-100 microns, and the average particle size of the tolvaptan solid dispersion is 25 microns.

Example 9

Adding 20g of tolvaptan to a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 2g of sucrose ester to the mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 10g of crosslinked polyvinylpyrrolidone to the mixture of dichloromethane and ethanol, uniformly dispersing, mixing the tolvaptan solution with other additive dispersion liquid, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-100 microns, and the average particle size of the tolvaptan solid dispersion is 25 microns.

Example 10

Adding 20g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 0.5g of polyvinyl alcohol into the mixture of dichloromethane and ethanol, stirring until the solution becomes clear, adding 10g of crosslinked polyvinylpyrrolidone into the mixture of dichloromethane and ethanol, uniformly dispersing, mixing the tolvaptan solution with other additive dispersion liquid, and performing spray drying to obtain a tolvaptan solid dispersion, wherein the particle size distribution of the tolvaptan solid dispersion is 1-100 mu m, and the average particle size of the tolvaptan solid dispersion is 25 mu m.

Comparative example 1

Adding 10g of tolvaptan into a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, and directly carrying out spray drying to obtain tolvaptan amorphous powder, wherein the particle size distribution of the tolvaptan amorphous powder is 0.01-200 mu m, and the average particle size of the tolvaptan amorphous powder is 28 mu m.

Comparative example 2

Adding 20g of tolvaptan to a mixture of dichloromethane and ethanol, stirring until the solution becomes clear, then adding 10g of hydroxypropyl cellulose, uniformly dispersing, and carrying out spray drying to obtain a tolvaptan solid dispersion with the particle size distribution of 1-400 mu m and the average particle size of 56 mu m.

Dissolution test

An appropriate amount (corresponding to 100mg of tolvaptan) of each of the powders of examples 1 to 10, comparative examples, and control samples (particle size distribution of the crystal starting material is 1 to 400 μm, average particle size is 83 μm) was weighed, and the weighed amount was added to a dissolution apparatus, 900ml of 0.2% (W/V) aqueous sodium lauryl sulfate solution was used as a solvent, and the paddle method, rotation speed: the dissolution test was performed at 100 rpm. Samples were taken at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, and 45 minutes, respectively, as test solutions, and the dissolution rates were measured and calculated.

The dissolution (%) was calculated by dissolving a certain amount of tolvaptan in methanol, transferring into a 5ml to 100ml measuring flask, diluting with 0.2% (W/V) aqueous sodium lauryl sulfate solution to make a solution having a concentration of 20. mu.g/ml as a standard solution, and measuring the absorbance in the standard solution and the test solution at a wavelength of 269mm and 330 mm. The dissolution rate was obtained from the obtained ratio of the absorbance difference. The results are shown in table 1 below:

TABLE 1

According to the above experimental results, it can be seen that:

(1) the cross-linked polyvinylpyrrolidone is used as the carrier of the tolvaptan solid dispersion, so that the release characteristic of the drug can be obviously improved, and the effect is obviously improved when hydroxypropyl cellulose is used as the carrier of the solid dispersion in the prior art. The ratio between drug and crospovidone may be selected over a wide range, with a better release profile in the range of 1: 0.1-10, with a best effect at about 1: 0.5.

(2) On the basis of taking the cross-linked polyvinylpyrrolidone as a carrier of the tolvaptan solid dispersion, other water-soluble polymers and the cross-linked polyvinylpyrrolidone can be added to be simultaneously used as a carrier of the solid dispersion. As a result of comparison, it was found that since the water-soluble polymer can further improve the properties of the solid dispersion, the amount of the water-soluble polymer added thereto is not particularly limited, and the enhancing effect exhibited when the amount of the water-soluble polymer is 1: 5 to 20 relative to the amount of the crosslinked polyvinylpyrrolidone is statistically significant, and the 1: 10 effect is the best. Of these water-soluble polymers, hydroxypropyl cellulose and polyvinylpyrrolidone, hydroxyethyl cellulose and methyl cellulose are the most effective.

Example 11

Sieving the solid dispersion raw material with a 40-mesh sieve, sieving the auxiliary material with a 80-mesh sieve, weighing the raw and auxiliary materials according to the prescription amount, uniformly mixing, granulating with a proper amount of 5% hydroxypropyl cellulose solution, carrying out ventilation drying at about 50 ℃, grading the dry granules with a 20-mesh sieve, adding the crospovidone and the magnesium stearate, uniformly mixing, and filling into capsules.

Example 12

Sieving the solid dispersion raw material with a 40-mesh sieve, sieving the auxiliary material with a 80-mesh sieve, weighing the raw and auxiliary materials according to the prescription amount, uniformly mixing, granulating with a proper amount of 5% hydroxypropyl cellulose solution, carrying out ventilation drying at about 50 ℃, grading the dried granules with a 20-mesh sieve, adding the crosslinked carboxymethyl cellulose and the magnesium stearate, uniformly mixing, tabletting and coating to obtain the finished product.

Example 13

Sieving the solid dispersion raw material with a 40-mesh sieve, sieving the auxiliary material with a 80-mesh sieve, weighing the raw and auxiliary materials according to the prescription amount, uniformly mixing, granulating with a proper amount of 5% povidone solution, carrying out ventilation drying at about 50 ℃, grading the dried granules with a 20-mesh sieve, adding the low-substituted hydroxypropyl cellulose and magnesium stearate, uniformly mixing, and tabletting to obtain the low-substituted hydroxypropyl cellulose and magnesium stearate dispersible tablet.

Claims (23)

1. A solid dispersion characterized by: the active ingredient tolvaptan preparation comprises an amorphous active ingredient tolvaptan or salt thereof and cross-linked polyvinylpyrrolidone, wherein the weight ratio of the active ingredient to the cross-linked polyvinylpyrrolidone is 1: 0.1-10.

2. The solid dispersion of claim 1, wherein the weight ratio of active ingredient to cross-linked polyvinylpyrrolidone is 2: 1.

3. the solid dispersion of claim 1 or 2, wherein the solid dispersion consists of an active ingredient and cross-linked polyvinylpyrrolidone.

4. The solid dispersion according to any one of claims 1 or 2, wherein the solid dispersion further contains a water-soluble polymer.

5. The solid dispersion of claim 4, wherein the solid dispersion consists of the active ingredient with cross-linked polyvinylpyrrolidone and a water-soluble polymer.

6. The solid dispersion of claim 4, wherein the water soluble polymer is selected from one or more of: alkyl cellulose, hydroxyalkyl cellulose or their alkali metal salts, hydroxyalkyl alkyl cellulose, carboxyalkyl alkyl cellulose, carboxyalkyl cellulose ester, starch, pectin, sucrose ester, polyvinylpyrrolidone.

7. The solid dispersion of claim 4, wherein the water soluble polymer is selected from one or more of: hydroxypropyl cellulose or polyvinylpyrrolidone.

8. The solid dispersion of any one of claims 5-7, wherein the weight ratio of the water-soluble polymer to the cross-linked polyvinylpyrrolidone is in the range of 1: 5-20.

9. The solid dispersion of claim 8, wherein the weight ratio of the water-soluble polymer to the cross-linked polyvinylpyrrolidone is 1: 8-15.

10. The solid dispersion of claim 8, wherein the weight ratio of the water-soluble polymer to the cross-linked polyvinylpyrrolidone is 1: 10.

11. the solid dispersion according to claim 4, which contains tolvaptan: crosslinked polyvinylpyrrolidone: the weight ratio of the water-soluble polymer is 2: 1: 0.1, wherein the water-soluble polymer is polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, or methyl cellulose.

12. The solid dispersion according to claim 11, consisting of tolvaptan, cross-linked polyvinylpyrrolidone and a water-soluble polymer.

13. A method for preparing a solid dispersion according to any one of claims 1 to 3, comprising the steps of:

1) dissolving tolvaptan or a salt thereof in an organic solvent;

2) dissolving or dispersing the cross-linked polyvinylpyrrolidone in an organic solvent, wherein the organic solvent optionally contains water according to the dissolving or dispersing requirement;

3) mixing the above solutions, and removing the organic solvent to obtain solid dispersion mixture.

14. A method for preparing a solid dispersion according to any one of claims 4 to 12, comprising the steps of:

1) dissolving tolvaptan or a salt thereof in an organic solvent;

2) dissolving or dispersing the crosslinked polyvinylpyrrolidone and the water-soluble polymer in an organic solvent, or dissolving or dispersing the crosslinked polyvinylpyrrolidone and the water-soluble polymer in an organic solvent, respectively, the organic solvent optionally containing water according to the need of dissolution or dispersion;

3) mixing the above solutions, and removing the organic solvent to obtain solid dispersion mixture.

15. The method of claim 13, wherein the method of removing the organic solvent is selected from the group consisting of evaporation, spray drying, and fluidized bed drying.

16. The method of claim 13, wherein the method of removing organic solvent is a spray drying method.

17. The method according to claim 13, wherein the organic solvent in step 1) or 2) is selected from methanol, ethanol, isopropanol, acetone, butanone, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.

18. The process of claim 17, wherein the organic solvent in step 1) is a mixture of ethanol and dichloromethane; and/or the organic solvent in the step 2) is a mixture of ethanol and dichloromethane or ethanol.

19. The method of claim 14, wherein the method of removing the organic solvent is selected from the group consisting of evaporation, spray drying, or fluidized bed drying.

20. The method of claim 14, wherein the method of removing organic solvent is a spray drying method.

21. The method according to claim 14, wherein the organic solvent in step 1) or 2) is selected from methanol, ethanol, isopropanol, acetone, butanone, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.

22. The process of claim 21, wherein the organic solvent in step 1) is a mixture of ethanol and dichloromethane; and/or the organic solvent in the step 2) is a mixture of ethanol and dichloromethane or ethanol.

23. A pharmaceutical composition comprising the solid dispersion according to any one of claims 1-12.