WO2022148005A1

WO2022148005A1 - Medicinal solid dispersion and preparation method therefor

Info

Publication number: WO2022148005A1
Application number: PCT/CN2021/108305
Authority: WO
Inventors: 胡双华; 张世喜; 杜松; 郑琴香; 陈丽平
Original assignee: 湖南南新制药股份有限公司
Priority date: 2021-01-08
Filing date: 2021-07-24
Publication date: 2022-07-14
Also published as: CN112587485A

Abstract

A 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-formamide or a hydrate, a solvate, or a pharmaceutically acceptable salt of same, or a solid dispersion of a crystal thereof. The solid dispersion comprises a medicinal active ingredient and a pharmaceutically acceptable substrate. The substrate is selected from one or more of polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methyl cellulose, and comprises no surfactant. The present invention has the advantages of excellent stability, increased safeness, a high dissolution rate, and high bioavailability.

Description

A kind of medicine solid dispersion and preparation method thereof

technical field

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical solid dispersion and a preparation method thereof.

Background technique

4-{4-[3-(4-Chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide, the structure is as follows:

English name: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-picolinamide, CAS number: 1343498-72-5, is an effective VEGF and RAF The kinase inhibitor belongs to a multi-targeted antitumor drug. Vascular endothelial growth factor (VEGF) is one of the most important cell growth factors in tumor angiogenesis. In addition, the Raf/MEK/ERK transduction pathway exists in all eukaryotic cells, and the specific cascade phosphorylation signals of Ras, Raf, MEK and ERK are transferred from the extracellular to the nucleus. Many tumor cells have up-regulation of this pathway. Once this pathway is over-activated, the acceleration of cell proliferation and the prolongation of cell survival will lead to the formation and development of tumors.

As 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide was found in methanol, acetone, acetonitrile and methanol/acetonitrile ( 1/1) It is very slightly soluble in mixed solvents, and almost insoluble in water and aqueous pH solutions, which makes it difficult to make effective pharmaceutical preparations. Therefore, how to prepare stable, high dissolution and high bioavailability 4-{4 The pharmaceutical formulation of -[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide is an unsolved problem at present.

To solve the problem of insoluble pharmaceutical preparations, there are mainly solid dispersion technology, micronization technology, inclusion technology, etc. Usually, after the drug is micronized, the particle size decreases, the surface area increases, and the dissolution rate increases, but after the particle size decreases to a certain extent, there is a tendency to spontaneously aggregate during storage or after entering the body, and the dissolution rate decreases instead. However, the inclusion technology has problems such as low success rate and low drug loading due to factors such as drug molecular weight and spatial structure.

Solid dispersion is the preparation technology of insoluble drugs and polymer raw materials by hot melt extrusion, spray drying or other methods. Due to the many types and preparation methods of solid dispersions, such as solid solution - the drug is dissolved in a solid carrier in a molecular state to form a homogeneous system, the dispersity of the drug in the solid solution is often higher than that in the eutectic mixture; Precipitate--a non-crystalline amorphous substance formed by solid drug and carrier in proper proportion, the commonly used carrier is polyhydroxy compound; eutectic mixture--drug and carrier are co-melted into a completely miscible liquid, stirred evenly and quickly It is cooled and solidified to become a dispersion, and the drug is dispersed in the carrier in the form of crystallites to become a physical mixture. Moreover, the solid dispersions prepared by different methods also have different properties. What type or method is used to prepare 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorobenzene Oxy}pyridine-2-carboxamide stable, highly bioavailable solid dispersions remain an unsolved problem.

For example, solid dispersions also have the problems of complex process and low drug loading. For poorly soluble substances, a large amount of carrier is often added, resulting in a decrease in drug loading, which is not suitable for clinical application. CN101039657A discloses a pharmaceutical composition containing a solid dispersion and a polymer matrix. The method adopts polydextrose and another polymer as a carrier to prepare the solid dispersion by hot melt extrusion. Only two carriers including polydextrose can achieve the desired effect, and the drug load is not high.

In order to solve the problem of low drug loading, surfactants are usually added in the preparation of solid dispersions to solve the above problems. for example:

CN106456539A discloses a solid dispersion, which is composed of at least one hydrophobic basic compound (API), a pharmaceutically acceptable water-soluble carrier and an enteric carrier. The solid dispersion can selectively add at least one a pharmaceutically acceptable surfactant. However, the use of only one polymer as a carrier in the preparation of solid dispersions may make it difficult to address API solubility issues. For example, the solid dispersion obtained by dispersing API in a water-soluble carrier may cause the supersaturation of the API in the aqueous solution due to the rapid dissolution of the water-soluble carrier from the skeleton, which in turn leads to the recrystallization of the API in the dissolution medium, and finally reduces the bioavailability. The pharmaceutically acceptable surfactant in the present invention refers to a pharmaceutically acceptable ionic or nonionic surfactant. In the present invention, the surfactant is an amphoteric compound, which can solubilize the API in the solution and improve the wettability and solubility of the API in the preparation.

CN1822843A discloses a method of preparing particles containing coprecipitates surrounding a neutral hydrophilic carrier, the method comprising spraying an organic solution on the neutral hydrophilic carrier, the solution comprising at least one HIV-containing Inhibitory properties of the triazine or pyrimidine active ingredient, a surfactant and a hydrophilic polymer. In some cases, solid dispersions by themselves are not sufficient to ensure adequate levels of bioavailability and effectiveness of the active ingredient to be administered. Many improvements have been proposed for this purpose such as the addition of surfactants.

CN1367683A discloses a non-crystalline cefuroxime acetoxyethyl ester solid dispersion, which contains cefuroxime acetoxyethyl ester, surfactant and water-insoluble inorganic carrier.

Therefore, surfactants are usually added to the current solid dispersions, but the surfactants are usually cytotoxic, and there are potential hidden dangers for the safe application of drugs.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present application is to provide a kind of suitable for 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-methyl The solid dispersion of amide preferably provides a solid dispersion with excellent stability, higher safety, high dissolution rate and high bioavailability.

In order to solve the above-mentioned technical problems, the technical scheme adopted in the present invention is as follows:

The present invention provides a pharmaceutical solid dispersion comprising 0.1-5 parts by weight of Compound 1 or its hydrate, solvate, or its pharmaceutically acceptable salt, or its crystalline form

and 2-30 parts by weight of a pharmaceutically acceptable matrix selected from one or more of polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose, the solid dispersion does not include Surfactant.

The matrix is selected from polyvinylpyrrolidone, preferably one or more of povidone K15, povidone K25, povidone K30, povidone K90 and copovidone S630, preferably copovidone S630.

The solid dispersion contains 0.5-5 parts by weight of compound 1 and 2-25 parts of copovidone S630, preferably 1 part by weight of compound 1 and 4-6 parts of copovidone S630, more preferably 1 part by weight of Compound 1 and 4.5 parts of copovidone S630.

The solid dispersion also contains microcrystalline cellulose and croscarmellose sodium, preferably 1-10 parts by weight of microcrystalline cellulose and 1-10 parts by weight of croscarmellose sodium, preferably Contains 1-4 parts by weight of microcrystalline cellulose and 1-4 parts by weight of croscarmellose sodium, preferably 2 parts by weight of microcrystalline cellulose and 2 parts by weight of croscarmellose sodium .

The solid dispersion of the present invention is obtained by mixing compound 1 and copovidone S630 and then granulating in a fluidized bed, preferably after mixing compound 1 and copovidone S630, spraying the above-mentioned microcrystalline cellulose and cross-linked carboxymethyl It is made of cellulose sodium after fluidized bed granulation.

The present invention also provides a pharmaceutical tablet comprising the above-mentioned pharmaceutical solid dispersion.

The pharmaceutical tablet of the present invention comprises the above-mentioned pharmaceutical solid dispersion, 1-10 parts by weight of microcrystalline cellulose (extra), 1-5 parts by weight of croscarmellose sodium (extra), preferably including 1 -4 parts by weight of microcrystalline cellulose (extra), 1-2 parts by weight of croscarmellose sodium (extra).

For the tablet of the present invention, it is preferable to add the above-mentioned microcrystalline cellulose and croscarmellose sodium in the solid dispersion, and then add the above-mentioned microcrystalline cellulose and croscarmellose sodium after granulation, and then press piece.

The pharmaceutical tablet of the present invention further comprises lubricants and glidants, preferably 0.1-0.5 parts by weight of silicon dioxide and 0.01-0.2 parts by weight of magnesium stearate.

The pharmaceutical solid dispersible tablet of the present invention comprises 0.1-2 parts by weight of compound 1, 2-20 parts by weight of copovidone S630, 1-10 parts by weight of microcrystalline cellulose, and 1-10 parts by weight of croscarmellose cellulose sodium, and 0.1-0.5 parts by weight of silicon dioxide and 0.01-0.2 parts by weight of magnesium stearate.

The pharmaceutical solid dispersible tablet of the present invention preferably comprises 1 part by weight of compound 1, 4-6 parts by weight of copovidone S630, 5 parts by weight of microcrystalline cellulose, 4 parts by weight of croscarmellose sodium, And 0.2 parts by weight of silicon dioxide and 0.1 part by weight of magnesium stearate.

The present invention also provides a method for preparing a solid dispersion, comprising:

(1) Dissolve the mixture of compound 1 and matrix in the mixed solution of acetone and ethanol, stir to dissolve;

(2) Then the fluidized bed top spray granulation.

The preparation method is preferably: it includes

(2) Then, microcrystalline cellulose and croscarmellose sodium are top-sprayed into the mixed solution prepared in step (1) for fluidized bed granulation.

The present invention also provides a method for preparing a pharmaceutical tablet, which comprises the following steps:

(2) then spray granulation from the top of the fluidized bed to make a solid dispersion;

(3) Add auxiliary materials to the above-mentioned solid dispersion granules to prepare tablets.

Preferably, it includes the following steps:

(3) after sieving the external croscarmellose sodium, microcrystalline cellulose and silicon dioxide, mix with the above-mentioned solid dispersion particles;

(4) The magnesium stearate is then sieved, mixed with the above-mentioned particles, and compressed into tablets.

Preferably, in step (2), microcrystalline cellulose and croscarmellose sodium are added to perform fluidized bed granulation to prepare a solid dispersion.

For the tablet of the present invention, when preparing a solid dispersion, firstly add the above-mentioned microcrystalline cellulose and croscarmellose sodium to make solid dispersion particles, and then add the above-mentioned cross-linked carboxymethyl cellulose to the particles. It is made of plain sodium and microcrystalline cellulose, as well as glidants and lubricants.

Beneficial effects:

1. The present invention does not use surfactant, which not only improves the dissolution rate of compound 1, but also reduces the side effects brought by the surfactant.

2. The solid dispersion of the present invention is more stable, can effectively reduce impurities such as related substances, and improves the safety of drug clinical application.

3. The solid dispersion preparation of the present invention significantly improves the dissolution rate and bioavailability of the drug, and improves the therapeutic effect of the drug.

Detailed ways

The following examples are used to illustrate the present invention, but do not limit the invention itself.

Example 1

Screening of solid dispersion preparation technology

Hot-melt extrusion process: According to the types and amounts of raw and auxiliary materials in Table 1, compound 1 and auxiliary materials were passed through an 80-mesh sieve respectively.

Then, the sieved API and auxiliary materials are sieved and mixed evenly, then hot-melt extruded at the temperature in the table, and the hot-melt extruded product is pulverized.

Table 1 Solid dispersion hot melt extrusion process recipe

spray drying process

Experimental procedure

According to the types and amounts of raw and auxiliary materials in Table 2, weigh compound 1 and copovidone S630. The mixture of compound 1 and copovidone S630 was dissolved in a mixed solution of acetone and ethanol, and stirred in a water bath at 70-80° C. until dissolved. The above solution was spray-dried using a B-290/B-295 spray dryer from Buchi, Switzerland, with an inlet air temperature of 78° C., an outlet air temperature of 59° C., a pump of 25 mL/min, and cleaning 3 times/min.

Table 2 Spray drying process prescription of solid dispersion

Fluidized bed granulation process

Experimental procedure

1) According to the types and amounts of raw and auxiliary materials in Table 3, weigh compound 1 and povidone S630.

2) Dissolve the mixture of raw drug compound 1 and copovidone S630 in a mixed solution of acetone and ethanol, and stir in a water bath at 70-80° C. until dissolved.

3) croscarmellose sodium and microcrystalline cellulose are placed in the fluidized bed granulator (Midi-Gallt), top spray is sprayed into the solution of compound 1 and copovidone S630 prepared in step (2) Granulate.

Table 3 Fluidized bed granulation process recipe

The solid dispersions prepared by different processes are investigated for related substances, and the results are shown in Table 4

Table 4 Results of related substances in different preparation processes

The experimental results show that the hot-melt extrusion method leads to a serious increase in the related substances of the solid dispersion of the present invention, and the total impurity of the solid dispersion prepared by the spray drying process is controlled at 0.23%, but the density of the solid dispersion obtained by spray drying is very small, The particle size is very small and the static electricity is serious, so it is not suitable for direct compression of powder. In addition, the production process of the sprayed organic solvent is easy to block and the efficiency is low. In order to improve the production efficiency, it is finally determined to use the fluidized bed granulation to prepare the solid dispersion process.

Example 2

Solid Dispersion Formulation Screening

Four different dosages of solid dispersion carrier copovidone S630 were selected, and the mass ratios of the main drug and copovidone S630 were 1:4.5, 1:6, 1:10, and 1:12, respectively, to prepare solid dispersion tablets. agent.

Table 5. The dosage prescription of different solid dispersion carriers

Experimental procedure

1) According to the types and amounts of raw and auxiliary materials in the table, weigh compound 1 and copovidone S630.

2) Dissolve the mixture of compound 1 and copovidone S630 in a mixed solution of acetone and ethanol, and stir in a water bath at 70-80° C. until dissolved.

3) Under the condition of 50-60°C water bath, rotate and evaporate to dryness to obtain a solid dispersion, which is pulverized and sieved to obtain solid dispersion particles.

4) Pass the added croscarmellose sodium and silicon dioxide through a 60-mesh sieve, and the microcrystalline cellulose through a 30-mesh sieve, and manually mix with the solid dispersion particles for 20 minutes.

5) Pass the extra magnesium stearate through a 60-mesh sieve, and mix with the above-mentioned particles for 5 min.

6) Compress tablets using a rotary tablet press. The tablet shape is 19mm*10mm, and the tablet hardness is controlled at 80-150N. Then above-mentioned product is carried out dissolution test investigation, the result is shown in Table 6

Table 6 Dissolution of formulations with different solid dispersion carrier dosages

It can be seen from the above dissolution results that the four formulations can make the preparation reach the release platform, that is, the release is complete, indicating that the solid dispersion prepared by the poorly soluble drug compound 1 significantly improves the dissolution rate of the drug. Comparing the four prescriptions, the formula F1 with a low proportion of copovidone S630 reached the release platform faster, while the tablet with a high proportion of the prescription disintegrated slowly, making it difficult to achieve rapid release.

Example 3

The mass ratio of the main drug and copovidone S630 was 1:4.5 and 1:6 to prepare the product, and the fluidized bed granulation process was used. After granulation, the tablet was pressed for dissolution test.

Table 7 Different solid dispersion carrier formulations

Experimental procedure

1) According to the type and dosage of raw and auxiliary materials in the table, weigh the raw drug compound 1 and copovidone S630.

3) The added croscarmellose sodium and microcrystalline cellulose are placed in the fluidized bed granulator (Midi-Gallt), and the top spray is sprayed into compound 1 and copovidone prepared in step (2). The solution of S630 was granulated.

4) Pass the added croscarmellose sodium and silicon dioxide through a 60-mesh sieve, and the microcrystalline cellulose through a 30-mesh sieve, and mix with the above-mentioned solid dispersion particles in a Tubular mixer for 20 minutes.

5) Pass the extra magnesium stearate through a 60-mesh sieve, and mix with the above-mentioned particles for 5 min. Tablets were compressed using a rotary tablet press.

Then a dissolution test was carried out, and the results are shown in Table 8. It can be seen from the above dissolution results that the product with a mass ratio of the main drug and copovidone S630 of 1:4.5 is released faster than the 1:6 product.

Example 4

Animal PK experiments of two batches of F10 and F11 formulations

The F10 and F11 tablets were orally administered to beagle dogs, and the bioavailability of the two batches of formulations of F10 and F11 was determined. The results are shown in Table 8. Wherein preparation 1: the solution preparation is PEG400/PG=9/1 (the drug is dissolved in the mixed solvent of PEG400/PG (9:1) to prepare a clear solution), and the dosage is 3 mg/kg; solid dispersible tablet F10 , Dosage of F11: 40mg/only. The experimental results show that the solid dispersible tablet of the present invention significantly improves the bioavailability.

Table 8 PK experiments of prescriptions with different solid dispersion carrier dosages

Example 5

Solid dispersion formulation:

Preparation method Referring to the preparation method in Example 3, tablets were prepared.

Example 6

Solid dispersion formulation:

Example 7

Solid dispersion formulation:

Example 8

Solid dispersion formulation:

The preparation method refers to the preparation method in Example 3.

Example 9

Solid dispersion formulation:

Example 10

Solid dispersion formulation:

Example 11

Accelerated stability experiments, comparative studies on related substances

The F10 tablets (40mg specification, 3 batches) samples in Example 3 of the three batches of pilot scales were investigated in detail. The three batches of pilot scale samples accelerated the related substances of the six-month stability samples. The measurement results are shown in the table. 9-11. The results showed that the related substances of the self-made preparations were qualified, and the content of the related substances in the three batches of pilot samples under the existing packaging changed little.

Table 9 Test results of related substances in samples of batch 1 pilot preparation accelerated test (40℃/RH75%)

Table 10 Test results of related substances in the sample of batch 2 pilot preparation accelerated test (40℃/RH75%)

Table 11 Test results of related substances in samples of batch 3 pilot preparation accelerated test (40℃/RH75%)

Dissolution profile studies

The F10 tablet sample (40 mg specification, batch 1) in Example 3 of the pilot scale was determined in 4 dissolution media (pH 1.0 hydrochloric acid solution containing 0.5% Tween-80, pH 4 containing 0.5% Tween-80). .5 dissolution profiles in acetate buffer, 0.3% Tween-80 in water, and 0.5% Tween-80 in pH 6.8 phosphate buffer). In addition, the dissolution profiles of two other batches of F10 tablet samples in Example 3 (40 mg strength, batches 1 and 2) in pH 1.0 hydrochloric acid solution supplemented with 0.5% Tween-80 were determined. The measurement conditions are shown in Table 12. The measurement results are shown in Tables 13 and 14. The experimental results show that the solid dispersion of the present invention is industrially controllable and stable in quality and has stable reproducibility.

Table 12 Dissolution Determination Conditions

Table 13 Four dissolution profile data for batch 1 tablets (n=6)

Claims

A pharmaceutical solid dispersion, characterized in that: the solid dispersion comprises 0.1-5 parts by weight of Compound 1 or a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof

and 2-30 parts by weight of a pharmaceutically acceptable matrix selected from one or more of polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose, the solid dispersion does not include Surfactant.
The solid dispersion according to claim 1, wherein the matrix is selected from polyvinylpyrrolidone.
The solid dispersion according to claim 1, wherein the polyvinylpyrrolidone is selected from the group consisting of Povidone K15, Povidone K25, Povidone K30, Povidone K90 and Copovidone S630 or more, preferably copovidone S630.
The solid dispersion according to claim 3, characterized in that: the solid dispersion comprises 0.5-5 parts by weight of compound 1 and 2-25 parts by weight of copovidone S630, preferably 1 part by weight of compounds 1 and 4 - 6 parts of Copovidone S630.
The solid dispersion according to any one of claims 1-4, characterized in that: the preparation step comprises the steps of mixing compound 1 and copovidone S630 and then fluidized bed granulation.
A pharmaceutical tablet is characterized in that: it comprises the pharmaceutical solid dispersion described in any one of claims 1-5.
The pharmaceutical tablet according to claim 6, characterized in that: it further comprises 2-10 parts by weight of microcrystalline cellulose and 1-5 parts by weight of croscarmellose sodium.
A pharmaceutical solid dispersible tablet is characterized in that: it comprises 0.1-2 parts by weight of compound 1, 2-20 parts by weight of copovidone S630, 1-10 parts by weight of microcrystalline cellulose, 1-10 parts by weight of Croscarmellose sodium, and 0.1-0.5 parts by weight of silicon dioxide and 0.01-0.2 parts by weight of magnesium stearate.
The preparation method of solid dispersion according to any one of claims 1-5, is characterized in that:

which includes

(1) Dissolve the mixture of compound 1 and matrix in the mixed solution of acetone and ethanol, stir and dissolve;

(2) Then the fluidized bed top spray granulation.
The pharmaceutical tablet preparation method according to any one of claims 6-7, characterized in that:

(1) Dissolve the mixture of compound 1 and matrix in the mixed solution of acetone and ethanol, stir and dissolve;

(2) then top-spray granulation of fluidized bed to make solid dispersion;

(3) Add auxiliary materials to the above-mentioned solid dispersion granules to prepare tablets.