WO2023138366A1 - Solid dispersion, preparation method for same, and pharmaceutical composition containing same - Google Patents

Abstract

A solid dispersion, a preparation method for same, and a pharmaceutical composition containing same. The preparation method for the solid dispersion comprises: after mixing an active pharmaceutical ingredient with a solubilizing matrix, carrying out hot-melt extrusion, and carrying out low-temperature crushing on an extrudate, thereby obtaining the solid dispersion. The D90 of the solid dispersion is less than or equal to 100 µm. The solid dispersion has a small particle size, has good fluidity, and can be smoothly tableted after being mixed with a small amount of adjuvants or can be used for filling in a capsule after being mixed with a small amount of adjuvants, so that the use amount of the adjuvant is greatly reduced, the mass of a tablet or capsule can then be reduced, the size of the tablet or capsule is reduced, and it is easier for a patient to swallow; and it is also conducive to improving the formulation specification.

Description

Solid dispersion, its preparation method and pharmaceutical composition containing it

References to related applications

The present invention claims the priority of the invention patent application entitled "Solid Dispersion and Its Preparation Method and Pharmaceutical Composition Containing It" filed in China on January 19, 2022, with application number 202210060860.9, and the entire content of the patent application is incorporated herein by reference.

technical field

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

Background technique

Hypromellose acetate succinate (HPMCAS), hypromellose (HPMC), and hypromellose phthalate (HPMCP) are commonly used cellulose solubilization matrices for the preparation of solid dispersions, and have been widely used in the development of pharmaceutical preparations, such as enzalutamide tablets, telaprevir tablets, apalutamide, tacrolimus, etc.

There are three main techniques for preparing solid dispersion particles: 1) spray drying technique; 2) coprecipitation technique; 3) hot melt extrusion technique.

The spray drying technology uses the high pressure of the high-pressure pump to atomize the organic solution of the material into mist droplets through the atomizer, and then directly contacts with the hot air for heat exchange, and completes the drying in a short time. Due to the very small spray drying technology, the atomized liquid droplets are very small, and the solid dispersion particles obtained by direct drying are very fine, so the dissolution is fast. Disadvantages of spray drying technology include: 1) A large amount of flammable and explosive organic solvents need to be used, and they are also easy to leak and pollute the environment. 2) The particles obtained by spray drying are fine, fluffy, poor in fluidity, and poor in compressibility. They need to be mixed with more external auxiliary materials or granulated to improve fluidity. For example, patent WO2014043208 discloses that the enzalutamide solid dispersion particle Carr coefficient prepared by spray drying is 33.3%, and its fluidity is very poor. Excipients such as 316 are mixed many times and sieved many times to obtain tablet powder with general fluidity, which is extremely cumbersome. The preparation prescription of this patent uses more than 40% of auxiliary materials except hypromellose acetate succinate. It can be seen that in order to improve its fluidity and facilitate direct tablet compression, a large amount of auxiliary materials and glidants with good fluidity need to be added; and none of them can be directly mixed for tablet compression, and grinding or dry granulation is required to improve fluidity. 3) Spray granules use a large amount of excipients to improve fluidity, which will inevitably lead to large tablet weight. At the same time, the granules are too fine, the specific surface area is large, there is more air, and the compression space is limited, which will inevitably lead to excessive tablet size. Larger tablets have poor medication compliance for the elderly and children who have difficulty swallowing.

Co-precipitation to prepare solid dispersed particles is to deposit the organic solution of the raw material drug and the solubilizing matrix on the surface of the excipients through spraying and hot air drying. The advantage of this process is that the equipment requirements are low, and the fluidized bed can meet the requirements. The obtained particles are fluffy, have a large surface area, and can be dissolved quickly. The disadvantage is that a large amount of auxiliary materials need to be added as co-precipitation carriers in the fluidized bed granulation. Patent WO2021064123 discloses the preparation of enzalutamide solid dispersion granules by fluidized bed granulation, which needs to add a large amount of microcrystalline cellulose and croscarmellose sodium to granulate, and at the same time, dry granulate with external excipients to obtain granules that meet the requirements of fluidity and can be used for tableting. The use of a large number of excipients will inevitably make it difficult to reduce the size of the tablet, and the size of the tablet is too large for the elderly and children who have difficulty swallowing and poor medication compliance.

Hot-melt extrusion is a technology in which drugs and solubilized matrix materials are added to a screw machine to obtain extrudates with uniform shapes through heating-melting-mixing-extrusion processes. Compared with the spray drying and co-precipitation methods, this process has the advantages of continuous production, no use of organic solvents, more environmental protection, and the obtained extrudates are compact, compact, small in size and high in bulk density. Although the extrudate is dense and compact, it is very difficult to crush the extrudate of the cellulose-containing solid dispersion, and it is easy to generate a large amount of heat during the crushing, which may even cause the solid dispersion to melt in the crushing equipment. Patent CN104983701A discloses the preparation of posaconazole-containing cellulose-containing hot-melt extruded solid dispersion particles, which are sieved through 200 mesh and 75 mesh to obtain particles with a particle size distribution between 75 microns and 300 microns, and the pulverization of hot-melt extruded particles below 100 μm has not been studied. Patent WO2014043208 discloses using a mortar and pestle to manually grind the extrudate, and then sieve it to obtain hot-melt extrudate particles with D90≤100μm. None of the above methods is suitable for industrial production, and it does not actually solve the problem of difficult crushing of cellulose-containing solid dispersions. Patent WO2019030691 discloses the preparation of enzalutamide-containing hypromellose acetate succinate solid dispersion particles by hot-melt extrusion. After crushing, the solid dispersion particles need to be dry granulated with auxiliary materials, and finally compressed into tablets. The purpose of the dry granulation is to improve the fluidity of the crushed solid dispersion particles.

The particle size of the cellulose-containing solid dispersion obtained by the spray-drying technology and co-precipitation technology reported at present is fine or fluffy, but the fluidity is poor. It needs to add a large amount of excipients to granulate, or to improve the fluidity after multiple times of mixing and sieving. The operation is cumbersome, which is not conducive to direct compression and direct filling of capsules. At the same time, the use of a large number of excipients will inevitably lead to large tablet weight, and it is difficult to reduce the size of the tablet. If the tablet size is too large, the medication compliance of the elderly and children with dysphagia will be poor. However, the cellulose-containing solid dispersion prepared by hot-melt extrusion is difficult to pulverize. The solid dispersion particles with D ₉₀ ≤ 100 μm cannot be directly pulverized and must be sieved. At the same time, the cellulose-containing solid dispersion particles need to be granulated to improve fluidity. A large number of excipients are required, which will also lead to large tablet weight and large tablet size, which is not conducive to medication for the elderly and children who have difficulty swallowing. It is also not conducive to direct compression and direct filling of capsules.

Patent WO2014043208 discloses cellulose-containing solid dispersion particles of enzalutamide. The particle size affects its supersaturation maintenance capacity. The finer the particle size, the better the supersaturation maintenance capacity, which in turn promotes drug absorption. Therefore, the preparation of fine particle size solid dispersion particles can be used to improve the bioavailability of drugs, which is of positive significance for drug development. The fluidity of powder is part of the development of solid preparations. Good fluidity can ensure uniform mixing, smooth feeding during tablet compression and stable tablet weight. At the same time, materials with good fluidity can be used for direct tablet compression, and can also be directly filled into capsules, which simplifies the process.

Therefore, the preparation of cellulose-containing solid dispersion particles with fine particle size and good fluidity not only helps to improve the bioavailability of drugs, but also facilitates the process of direct compression and direct filling of capsules, which is of great significance in drug development and production.

Contents of the invention

The first aspect of the present invention is to provide a method for preparing a solid dispersion, which comprises the following steps: after the active pharmaceutical ingredient is mixed with a solubilizing matrix, hot-melt extrusion is performed, and the extruded product is pulverized at a low temperature to obtain the solid dispersion, and the solubilizing matrix is selected from a cellulose solubilizing matrix and/or a non-cellulose solubilizing matrix.

In some embodiments of the first aspect of the present invention, the low-temperature pulverization is pulverization by mixing the extrudate with a low-temperature medium, for example, the low-temperature medium is dry ice or liquid nitrogen, preferably liquid nitrogen.

In some embodiments of the first aspect of the present invention, the pharmaceutically active ingredient is selected from enzalutamide, ARN-509 or posaconazole.

In some embodiments of the first aspect of the present invention, the solubilization matrix comprises a cellulosic solubilization matrix and a non-cellulosic solubilization matrix.

In some embodiments of the first aspect of the present invention, the solubilization matrix is a cellulosic solubilization matrix.

In some embodiments of the first aspect of the present invention, the cellulose-based solubilizing matrix is selected from one or more of hypromellose acetate succinate, hypromellose or hypromellose phthalate.

In some embodiments of the first aspect of the present invention, the non-cellulosic solubilizing matrix is selected from one or more of povidone, copovidone or polyethylene glycol.

In some embodiments of the first aspect of the present invention, the mass ratio of the active pharmaceutical ingredient to the solubilizing matrix is 1:2-1:5, such as 1:2, 1:2.5, 1:2.7, 1:3, 1:4, 1:5, especially 1:2, 1:2.5, 1:2.7, 1:3, 1:4 or 1:5.

In some embodiments of the first aspect of the present invention, the rotational speed of the low-temperature pulverization is above 10,000 rpm; preferably, the rotational speed of the low-temperature pulverization is above 12,000 rpm; for example, above 16,000 rpm, such as 16,000 rpm, 18,000 rpm, 20,000 rpm, especially 16,000 rpm, 18,000 rpm or 20,000 rpm.

In some embodiments of the first aspect of the present invention, the number of low-temperature pulverization is more than 1 time; preferably, the number of times of low-temperature pulverization is more than 1 time and less than 4 times, such as 1 time, 2 times or 3 times.

In some embodiments of the first aspect of the present invention, the temperature of the hot melt extrusion is 140-200° C., and the screw speed is 200-600 rpm. For example, the temperature of the hot melt extrusion is 140°C, 150°C, 160°C, 170°C, 175°C, 180°C, 185°C, 190°C, 195°C, especially 140°C, 150°C, 160°C, 170°C, 175°C, 180°C, 185°C, 190°C or 195°C; the screw speed of the hot melt extrusion is 200rpm, 300rpm, 400rpm, 500rpm and 600rpm, especially 200rpm, 300rpm, 400rpm, 500rpm or 600rpm.

The second aspect of the present invention is to provide a solid dispersion, which is obtained by the preparation method of the first aspect of the present invention, comprising a pharmaceutical active ingredient and a solubilizing matrix, the solubilizing matrix is selected from cellulose solubilizing matrix and/or non-cellulose solubilizing matrix, the _D90 of the solid dispersion is 50-100 μm; preferably, the _D50 of the solid dispersion is 25-60 μm, and the _D10 is 8-30 μm.

In some embodiments of the second aspect of the present invention, the solubilization matrix comprises a cellulosic solubilization matrix and a non-cellulosic solubilization matrix.

In some embodiments of the second aspect of the present invention, the solubilization matrix is a cellulosic solubilization matrix.

In some embodiments of the second aspect of the present invention, the pharmaceutically active ingredient is selected from enzalutamide, ARN-509 or posaconazole.

In some embodiments of the second aspect of the present invention, the mass ratio of the active pharmaceutical ingredient to the solubilizing matrix is 1:2-1:5, such as 1:2, 1:2.5, 1:2.7, 1:3, 1:4, 1:5, especially 1:2, 1:2.5, 1:2.7, 1:3, 1:4 or 1:5.

In some embodiments of the second aspect of the present invention, the cellulose-based solubilizing matrix is selected from one or more of hypromellose acetate succinate, hypromellose or hypromellose phthalate.

In some embodiments of the second aspect of the present invention, the non-cellulosic solubilizing matrix is selected from one or more of povidone, copovidone or polyethylene glycol.

A third aspect of the present invention provides a pharmaceutical composition, which includes the solid dispersion of the second aspect of the present invention; preferably, the pharmaceutical composition also includes a disintegrant and a lubricant, the disintegrator is selected from one or more of croscarmellose sodium, crospovidone or sodium starch glycolate, and the lubricant is selected from one or more of magnesium stearate, calcium stearate or sodium stearyl fumarate.

In some embodiments of the third aspect of the present invention, the pharmaceutical composition further includes one or more of fillers, glidants or binders. Preferably, the filler is selected from microcrystalline cellulose or silicified microcrystalline cellulose; the glidant is selected from silicon dioxide or colloidal silicon dioxide; and the binder is selected from hydroxypropyl cellulose.

In some embodiments of the third aspect of the present invention, the pharmaceutical composition includes the following components by mass: 10-30 parts of active ingredients (especially active pharmaceutical ingredients), 55-80 parts of cellulose solubilizing base, 3-12 parts of disintegrant, 0.1-2 parts of lubricant, especially 10-30 parts of active pharmaceutical ingredient, 55-80 parts of cellulose solubilizing base, 3-12 parts of disintegrating agent and 0.1-2 parts of lubricant.

Compared with the prior art, the present invention has the following beneficial effects:

The preparation method of the solid dispersion of the present invention adopts hot-melt extrusion and low-temperature pulverization to directly pulverize to obtain a solid dispersion with a D ₉₀ ≤ 100 μm, and has a relatively high yield. The method can be applied to the pulverization of solid dispersions of enzalutamide, posaconazole, and ARN-509. At the same time, the method can also realize the pulverization of hot-melt extrusion solid dispersions with different ratios of cellulose solubilizing matrix and active ingredients. The method has strong durability and is suitable for industrialization.

The D ₉₀ of the solid dispersion prepared by the invention is less than or equal to 100 μm, and has a finer particle size, and the prepared pharmaceutical composition shows faster dissolution. Therefore, the solid dispersion prepared by the invention can improve the bioavailability of the drug.

The D ₉₀ of the solid dispersion prepared by the present invention is ≤100 μm, and has a finer particle size. At the same time, because the particle size distribution of the solid dispersion prepared by the present invention is relatively concentrated, the D ₅₀ is 25-60 μm, and the D ₁₀ is 8-30 μm. Therefore, the particles have good fluidity at the same time.

Because the solid dispersion prepared by the present invention has good fluidity, it can be smoothly compressed into tablets or filled into capsules by mixing with a small amount of auxiliary materials, which can greatly reduce the amount of auxiliary materials, thereby reducing the quality of tablets or capsules and reducing the size of tablets or capsules, which is more conducive to swallowing by patients; meanwhile, it is also conducive to improving the specifications of the preparation.

Description of drawings

Fig. 1 is the dissolution curve of the posaconazole tablet obtained in Example 4 and Comparative Example 1.

Fig. 2 is the dissolution curve of ARN-509 tablets obtained in Example 5 and Comparative Example 2.

Detailed ways

The above content of the present invention will be further described in detail below through specific examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technical solutions realized based on the above content of the present invention belong to the scope of the present invention.

Test method for the angle of repose: slowly add powder from the top of the funnel, and the material leaked from the bottom of the funnel forms the inclination angle of a conical pile on the horizontal plane.

The particle size distribution was detected by a Malvern laser particle size analyzer.

Example 1:

2kg of enzalutamide and 6kg of hypromellose acetate succinate were hot-melt extruded at 195°C and the screw speed was 300rpm. After the extrudate was cooled, thin slices were prepared by cold roll, and the material was crushed to obtain a primary crushed extrudate.

Example 1-1: Take 1.2 kg of the primary crushed extrudate and mix it with dry ice, and crush it twice with a pulverizer at a rotation speed of 16000 rpm to obtain 1.06 kg of a solid dispersion with D ₉₀ =163 μm, D ₅₀ =95 μm, D ₁₀ =31 μm, and an angle of repose of 32°. Take 300 g of the solid dispersion and sieve it with a 150-mesh sieve to obtain 143.4 g of undersize, with a yield of 47.8%. The obtained undersize is a solid dispersion of enzalutamide with D ₉₀ =97 μm, D ₅₀ =59 μm, D ₁₀ =27 μm, and an angle of repose of 36°.

Example 1-2: Take 1.2 kg of primary pulverized extrudates and mix them with liquid nitrogen, and use a pulverizer to pulverize twice at a rotational speed of 10,000 rpm to obtain 1.14 kg of enzalutamide solid dispersion with D ₉₀ =131 μm, D ₅₀ =72 μm, D ₁₀ =21 μm, and an angle of repose of 34°.

Example 1-3: Take 1.2 kg of the primary crushed extrudate and mix it with liquid nitrogen, and use a pulverizer at a speed of 16,000 rpm to co-powder once to obtain 1.13 kg of enzalutamide solid dispersion with D ₉₀ = 89 μm, D ₅₀ = 46 μm, D ₁₀ = 22 μm, and an angle of repose of 36°.

Example 1-4: Take 1.2 kg of the primary crushed extrudate and mix it with liquid nitrogen, and co-pulverize it twice with a pulverizer at a rotational speed of 16,000 rpm to obtain 1.10 kg of enzalutamide solid dispersion with D ₉₀ =75 μm, D ₅₀ =40 μm, D ₁₀ =18 μm, and an angle of repose of 38°.

Example 1-5: Take 1.2 kg of the primary crushed extrudate and mix it with liquid nitrogen, and use a pulverizer at a speed of 18,000 rpm to pulverize it twice to obtain 1.08 kg of enzalutamide solid dispersion with D ₉₀ =51 μm, D ₅₀ =25 μm, D ₁₀ =8 μm, and an angle of repose of 38°.

Examples 1-6: The pulverized solid dispersion in the above-mentioned Examples 1-4 was further mixed with liquid nitrogen, and pulverized twice with a pulverizer at a rotational speed of 18,000 rpm to obtain a solid dispersion of enzalutamide with D ₉₀ =35 μm, D ₅₀ =14 μm, D ₁₀ =5 μm, and an angle of repose of 46°.

Example 2:

0.5kg of enzalutamide, 1.35kg of hypromellose acetate succinate and 0.15kg of copovidone were hot-melt extruded at 195°C at a screw speed of 300rpm. After the extrudate was cooled, it was cold-rolled to prepare flakes. After crushing the material, it was mixed with liquid nitrogen and crushed once with a pulverizer at a speed of 16,000rpm to obtain D ₉₀ =87 μm, D ₅₀ =47 μm, and D ₁₀ =21 μm, enzalutamide solid dispersion with an angle of repose of 35°.

Example 3:

0.5kg of enzalutamide, 1.35kg of hypromellose acetate succinate and 0.15kg of hypromellose were hot-melt extruded at 195°C at a screw speed of 300rpm. After the extrudate was cooled, it was cold-rolled to prepare flakes. After crushing the material, it was mixed with liquid nitrogen and crushed once with a pulverizer at a speed of 16,000rpm to obtain D ₉₀ =82 μm, D ₅₀ =43 μm, and D ₁₀ =19 μm, enzalutamide solid dispersion with an angle of repose of 37°.

Example 4:

Premix 1.0 kg of posaconazole and 3.0 kg of hypromellose acetate succinate for 5 minutes, and carry out hot-melt extrusion at 140°C and a screw speed of 300 rpm. After the extrudate is cooled, it is cold rolled to prepare thin slices. After crushing the material, 3.62 kg of primary pulverized particles are obtained. Take 2.5 kg of primary pulverized particles and mix them with liquid nitrogen, and pulverize once with a pulverizer at a rotational speed of 16,000 rpm to obtain a solid dispersion of posaconazole with D ₉₀ =93 μm, D ₅₀ =50 μm, D ₁₀ =24 μm, and an angle of repose of 36°.

Take 2.0kg of posaconazole solid dispersion, 0.1925kg of hypromellose acetate succinate, 0.25kg of microcrystalline cellulose, 0.2kg of low-substituted hydroxypropyl cellulose, and 0.11kg of silicon dioxide and mix for 5 minutes, then add 12.5g of magnesium stearate, mix for 1 minute, and press into tablets, with a tablet weight of 550mg.

Comparative example 1:

Take 1 kg of the primary pulverized particles in Example 4 and sieve, collect particles between 50 mesh and 250 mesh, and obtain posaconazole solid dispersion particles with D ₉₀ =260 μm, D ₅₀ =143 μm, and D ₁₀ =46 μm. Take 0.2 kg of the pulverized solid dispersion of posaconazole, and prepare tablets with the same prescription as in Example 4, with a tablet weight of 550 mg.

Example 5:

Premix 1.0kg of ARN-509 and 3.0kg of hypromellose acetate succinate for 5 minutes, and carry out hot-melt extrusion at 195°C and a screw speed of 300rpm. After the extrudate is cooled, it is prepared into thin slices by cold roll, and the material is crushed to obtain 3.72kg of primary crushed particles. Take 2.82 kg of primary pulverized particles and mix them with liquid nitrogen, and pulverize once with a pulverizer at a rotational speed of 16,000 rpm to obtain an ARN-509 solid dispersion with D ₉₀ =97 μm, D ₅₀ =52 μm, D ₁₀ =26 μm, and an angle of repose of 38°.

Take 240g of ARN-509 solid dispersion, 9.1g of colloidal silicon dioxide, 35g of croscarmellose sodium, 412.4g of silicified microcrystalline cellulose, mix for 5min, add 3.5g of magnesium stearate, mix for 1min, compress into tablets, the tablet weight is 690mg.

Comparative example 2:

Take 0.9 kg of primary pulverized particles in Example 5, sieve with a sieve with a pore size of 250 μm, and collect the undersize to obtain an ARN-509 solid dispersion with D ₉₀ =200 μm, D ₅₀ =129 μm, and D ₁₀ =50 μm.

Take 240 g of ARN-509 solid dispersion after sieving, and prepare tablets according to the prescription in Example 5, with a tablet weight of 690 mg.

Embodiment 6:

Premix 1.0 kg of enzalutamide and 3.0 kg of hypromellose for 5 minutes, and carry out hot-melt extrusion at 195°C and a screw speed of 300 rpm. After the extrudate is cooled, it is cold-rolled to prepare flakes. After crushing the material, it is mixed with liquid nitrogen and crushed twice with a pulverizer at a speed of 16,000 rpm to obtain D ₉₀ =89 μm, D ₅₀ =45 μm, D ₁₀ =22 μm, and an angle of repose of 37°. Enzalutamide solid dispersion.

Embodiment 7:

Premix 1.0kg enzalutamide and 3.0kg hypromellose phthalate for 5 minutes, and perform hot-melt extrusion at 195°C at a screw speed of 300rpm. After the extrudate is cooled, it is cooled and rolled to prepare flakes. After crushing the material, it is mixed with liquid nitrogen and crushed once with a pulverizer at a speed of 16000rpm to obtain D ₉₀ = 91 μm, D ₅₀ = 43 μm, D ₁₀ = 24 μm, angle of repose Enzalutamide solid dispersion at 34°.

Embodiment 8:

Take 1.995 kg of the enzalutamide solid dispersion in Example 6, add 5 g of magnesium stearate, mix for 1 min, and fill the capsules with a capsule filling machine. The target filling volume is 321.6 mg, and the filling volume difference during the filling process is within 5%, and the filling is smooth.

Embodiment 9:

Take 0.998 kg of the enzalutamide solid dispersion (D ₉₀ =89 μm, D ₅₀ =46 μm, D ₁₀ =22 μm) in Example 1-3, add 2.5 g of magnesium stearate, mix for 1 min, and fill the capsules with a capsule filling machine. The target filling volume is 321.6 mg. The filling volume difference during the filling process is within 5%, and the filling is smooth.

Example 10:

Take 320g of enzalutamide solid dispersion (D ₉₀ = 51 μm, D ₅₀ = 25 μm, D ₁₀ = 8 μm) in Example 1-5, 27 g of croscarmellose sodium and 2 g of silicon dioxide, mix for 5 min, add 1 g of magnesium stearate, mix for 1 min, and press into tablets. The tablet size is 13×6 mm, the tablet weight is 350 mg, and the specification is 80 mg.

Example 11:

Premix 0.5 kg of enzalutamide and 1.0 kg of hypromellose acetate succinate for 5 minutes, and perform hot-melt extrusion at 195°C and a screw speed of 300 rpm. After the extrudate is cooled, it is cooled and rolled to prepare thin slices. After crushing, it is mixed with liquid nitrogen and crushed once with a pulverizer at 16,000 rpm to obtain enzalutamide solids with D ₉₀ = 89 μm, D ₅₀ = 43 μm, and D ₁₀ = 24 μm dispersion.

Mix 240 g of enzalutamide solid dispersion and 29 g of croscarmellose sodium for 5 minutes, add 1.0 g of magnesium stearate, mix for 1 minute, and press into tablets.

Example 12:

Premix 0.5kg of enzalutamide and 2.0kg of hypromellose acetate succinate for 5 minutes, and carry out hot-melt extrusion at 195°C at a screw speed of 300rpm. After the extrudate is cooled, it is rolled into thin slices, crushed, mixed with liquid nitrogen, and crushed twice with a pulverizer at a speed of 16,000rpm to obtain D ₉₀ = 85 μm, D ₅₀ = 46 μm, D ₁₀ = 19 μm, and the angle of repose is Enzalutamide solid dispersion at 39°.

Example 13:

Take 240 g of the ARN-509 solid dispersion (D ₉₀ =97 μm, D ₅₀ =52 μm, D ₁₀ =26 μm) in Example 5, add 10.125 g of croscarmellose sodium and 0.5 g of silicon dioxide, mix for 5 min, add 0.375 g of magnesium stearate, mix for 1 min, and press into tablets. The tablet weight is 251 mg, and the specification is 60 mg. Within 5%, tablet compression is smooth.

Another part of the above blended granules was taken and compressed into tablets with a tablet weight of 502 mg and a specification of 120 mg. The difference in tablet weight during tablet compression was within 5%, and the tablet compression was smooth.

Example 14:

Take 240 g of the ARN-509 solid dispersion (D ₉₀ =97 μm, D ₅₀ =52 μm, D ₁₀ =26 μm) in Example 5, add 10 g of crospovidone, mix for 5 min, add 0.5 g of sodium stearyl fumarate, mix for 1 min, and press into tablets. The tablet weight is 250.5 mg, and the specification is 60 mg.

Example 15:

Take 240 g of the ARN-509 solid dispersion (D ₉₀ =97 μm, D ₅₀ =52 μm, D ₁₀ =26 μm) in Example 5, add 10 g of sodium starch glycolate, mix for 5 minutes, add 0.5 g of magnesium stearate, mix for 1 minute, and press into tablets. The tablet weight is 250.5 mg, and the specification is 60 mg.

Comparative example 3:

Dissolve 16g of enzalutamide and 48g of hypromellose acetate succinate in 320g of acetone, perform fluidized bed granulation with 50.84g of microcrystalline cellulose and 8.8g of croscarmellose sodium, and obtain fluidized bed granules after drying. The particle angle of repose is 45°.

Comparative example 4:

Dissolve 16g of enzalutamide and 48g of hypromellose acetate succinate in 320g of acetone, and spray-dry to obtain spray-dried granules. The particle angle of repose is 46°.

Comparative example 5:

0.5kg enzalutamide and 2.5kg hypromellose acetate succinate were hot-melt extruded at 185°C and the screw speed was 400rpm. After the extrudate was cooled, it was cold-rolled to prepare thin slices. ₉₀=243μm, D ₅₀= 151 μm, D ₁₀=59μm, the angle of repose is 30°; take another 0.8kg of primary crushed extrudate, and crush it twice with a pulverizer at a speed of 16000rpm, D ₉₀=203μm, D ₅₀=138μm, D ₁₀=46 μm, the angle of repose is 32°.

The extrudates of Example 1, Example 2, Example 3 and Comparative Example 5 were all transparent strips, and were all amorphous through X-ray diffraction analysis, indicating that the solid dispersion prepared by this method was amorphous.

Solid dispersion particle size and fluidity comparison:

Comparing Example 1 and Comparative Example 5, it can be seen that the extrudate is pulverized at room temperature, even if the pulverizer is used to pulverize twice at a higher rotational speed, the D ₉₀ of the obtained solid dispersion is still greater than 200 μm, and a solid dispersion with D ₉₀ ≤ 100 μm cannot be obtained. However, by low-temperature pulverization, especially mixing with liquid nitrogen and pulverizing once or twice, a solid dispersion with D ₉₀ ≤ 100 μm can be obtained.

The comparison of Example 1 and Comparative Example 3-4 shows that the fluidity of the solid dispersion obtained in Examples 1-1 to 1-5 is better than that of the particles of Comparative Examples 3 and 4, indicating that the solid dispersion obtained by the preparation method of the present invention has good fluidity.

The _D90 of the solid dispersion of the present invention is 50-100 μm, and has good fluidity. The reason is that the particle size distribution of the solid dispersion of the present invention is relatively concentrated. Compared with conventional materials, the solid dispersion of the present invention has greater _D50 and _D10 under the same _D90 , ensuring the fluidity of the product. Therefore, in order to ensure that the solid dispersion has good fluidity while taking into account relatively rapid dissolution, the _D90 of the solid dispersion of the present invention is preferably 50-100 μm, the _D50 is preferably 25-60 μm, and the _D10 is preferably 8-30 μm.

Comparison of tablet weight and tablet size:

The solid dispersion of the present invention has good fluidity, does not need granulation, repeated sieving and mixing, can greatly simplify the process, and only needs to add a small amount of additional auxiliary materials to meet the needs of powder direct compression, thus greatly reducing the amount of auxiliary materials.

Comparing the enzalutamide tablet of Example 10 with the tablet of Example 16 in CN105358535A, it can be seen that the tablet weight and size of the tablet prepared by using the solid dispersion of the present invention can be significantly reduced.

the	Example 16 in CN105358535A		Experiment 10
Specification	80mg	80mg
sheet shape	14.8mm*7.8mm	13*6mm
Sheet weight	540mg	350mg
Proportion of excipients in tablet except solubilizing matrix	40.7%	8.6%

Comparing the ARN-509 tablet of Example 13 with the tablet of Example 5.2 in CN106999431A, the tablet weight of the ARN-509 tablet (60 mg specification) of Example 13 is 251 mg, which is 690 mg compared to the tablet weight 690 mg of the tablet of Example 5.2 (60 mg specification) in CN106999431A, which greatly reduces the amount of auxiliary materials and the size of the tablet. The tablet weight of the 120 mg tablet in Example 13 is 502 mg, which is still lower than the 690 mg tablet weight of the 60 mg tablet in Example 5.2 of CN106999431A, which can reduce the number of tablets taken by patients and improve medication compliance.

Dissolution rate comparison:

According to the second method of dissolution determination (paddle method) of the Chinese Pharmacopoeia 2015 edition, the dissolution curves of the posaconazole tablets obtained in Example 4 and Comparative Example 1 and the ARN-509 tablets obtained in Example 5 and Comparative Example 2 were compared, as shown in Fig. 1 and Fig. 2 for details. The results show that Example 4 dissolves faster than Comparative Example 1, and Example 5 dissolves faster than Comparative Example 2, indicating that the tablet prepared by the solid dispersion of the present invention can accelerate the dissolution rate.

The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, they should be considered as within the scope of this specification.

The above-mentioned embodiments only represent several implementation modes of the present invention, which are convenient for a specific and detailed understanding of the technical solutions of the present invention, but should not be construed as limiting the protection scope of the invention. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. It should be understood that technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are within the protection scope of the appended claims of the present invention. Therefore, the protection scope of the present invention should be determined by the contents of the appended claims, and the description can be used to interpret the contents of the claims.

Claims (10)

1. A method for preparing a solid dispersion, the preparation method comprising the following steps: after mixing an active pharmaceutical ingredient with a solubilizing matrix, hot-melt extruding, and crushing the extruded product at a low temperature to obtain the solid dispersion, and the solubilizing matrix is selected from a cellulose solubilizing matrix and/or a non-cellulose solubilizing matrix.
2. The preparation method according to claim 1, characterized in that the low-temperature pulverization is performed by mixing the extrudate with a low-temperature medium, for example, the low-temperature medium is dry ice or liquid nitrogen, preferably liquid nitrogen.
3. The preparation method according to claim 1 or 2, characterized in that, one or more of the following conditions are met:

   The pharmaceutical active ingredient is selected from enzalutamide, ARN-509 or posaconazole; or,

   The solubilization matrix includes a cellulose solubilization matrix and a non-cellulose solubilization matrix, or, the solubilization matrix is a cellulose solubilization matrix; or,

   The cellulose solubilizing matrix is selected from one or more of hypromellose acetate succinate, hypromellose or hypromellose phthalate; or,

   The non-cellulose solubilizing matrix is selected from one or more of povidone, copovidone or polyethylene glycol; or

   The mass ratio of the active pharmaceutical ingredient to the solubilizing matrix is 1:2-1:5, for example 1:2, 1:2.5, 1:2.7, 1:3, 1:4 or 1:5.
4. The preparation method according to any one of claims 1-3, wherein one or more of the following conditions are met:

   The rotation speed of the low temperature grinding is above 10000rpm; preferably, the rotation speed of the low temperature grinding is above 12000rpm; for example above 16000rpm, such as 16000rpm, 18000rpm or 20000rpm; or,

   The number of low-temperature pulverization is more than 1 time; preferably, the number of low-temperature pulverization is more than 1 time and less than 4 times, preferably 1 time, 2 times or 3 times; or,

   The temperature of the hot-melt extrusion is 140-200°C, and the screw speed is 200-600rpm; preferably, the temperature of the hot-melt extrusion is 140°C, 150°C, 160°C, 170°C, 175°C, 180°C, 185°C, 190°C or 195°C; the screw speed of the hot-melt extrusion is 200rpm, 300rpm, 400rpm, 500rpm or 600 rpm.
5. A solid dispersion obtained by the preparation method according to any one of claims 1-4, comprising an active pharmaceutical ingredient and a solubilizing matrix, the solubilizing matrix being selected from cellulose solubilizing matrix and/or non-cellulose solubilizing matrix, the _D90 of the solid dispersion is 50-100 μm; preferably, the _D50 of the solid dispersion is 25-60 μm, and the _D10 is 8-30 μm.
6. The solid dispersion according to claim 5, wherein the solubilization matrix comprises a cellulose solubilization matrix and a non-cellulose solubilization matrix; or, the solubilization matrix is a cellulose solubilization matrix.
7. The solid dispersion according to claim 5 or 6, characterized in that, one or more of the following conditions are met:

   The pharmaceutical active ingredient is selected from enzalutamide, ARN-509 or posaconazole; or,

   The mass ratio of the pharmaceutically active ingredient to the solubilizing matrix is 1:2-1:5, such as 1:2, 1:2.5, 1:2.7, 1:3, 1:4 or 1:5; or,

   The cellulose solubilizing matrix is selected from one or more of hypromellose acetate succinate, hypromellose or hypromellose phthalate; or,

   The non-cellulose solubilizing matrix is selected from one or more of povidone, copovidone or polyethylene glycol.
8. A kind of pharmaceutical composition, described pharmaceutical composition comprises solid dispersion according to any one of claim 5-7; Preferably, described pharmaceutical composition also comprises disintegrating agent and lubricant, and described disintegrating agent is selected from one or more in croscarmellose sodium, crospovidone or carboxymethyl starch sodium, and described lubricant is selected from one or more in magnesium stearate, calcium stearate or sodium stearyl fumarate.
9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition also includes one or more of a filler, a glidant or a binder; preferably, the filler is selected from microcrystalline cellulose or silicified microcrystalline cellulose; the glidant is selected from silicon dioxide or colloidal silicon dioxide; and the binder is selected from hydroxypropyl cellulose.
10. The pharmaceutical composition according to claim 8 or 9, characterized in that the pharmaceutical composition comprises the following components by mass: 10-30 parts of pharmaceutical active ingredients, 55-80 parts of cellulose solubilizing matrix, 3-12 parts of disintegrant and 0.1-2 parts of lubricant.

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