Apalutamide nanoparticle and preparation method therefor

Abstract

An apalutamide nanoparticle and preparation method therefor relating to the field of pharmaceutical preparations. The nanoparticle comprises an active ingredient and a stabilizer. The active ingredient is amorphous apalutamide or a pharmaceutically acceptable salt thereof, and the stabilizer comprises an ionic stabilizer and a steric stabilizer. The provided nanoparticle has a stable physical form, is able to stably maintain an amorphous crystal form, has good dissolution speed and dissolution rate, possesses good stability in terms of dissolution, content, related substances, crystal form, etc., and has good bioavailability.

Description

Apalutamide nanoparticles and preparation method thereof

[0001] This application claims priority to and the benefits of Chinese Patent Application No. 202311849613.8 filed with the State Intellectual Property Office of China on December 29, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of pharmaceutical preparations, and in particular to apalutamide nanoparticles and a preparation method thereof. Background Art

[0003] The chemical name of apalutamide is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide, and its chemical structure is shown below:

[0004] Apalutamide is almost insoluble in aqueous media within the pH range of 1-12. It is a BCS Class II drug and is a poorly soluble drug. If it is directly prepared into oral solid preparations such as tablets or capsules without special treatment, the drug dissolution rate is slow and incomplete, and the bioavailability is low, which limits the therapeutic effect of its oral preparation. ) is a 60mg tablet, taken once daily, but requires four tablets for a total of 240mg. Because the original formulation used solid dispersion technology for solubilization, coupled with its larger size and high carrier ratio, the final product weighed a significant amount. Each 60mg tablet weighed over 720mg, and four tablets were required at a time. This limited the use of medication for elderly patients with swallowing difficulties, significantly reducing patient compliance.

[0005] Currently, the disclosed technologies for solubilizing apalutamide preparations all utilize solid dispersions for solubilization. Patent applications CN106999430A, CN106999431A, and CN106999432A utilize spray drying technology to prepare apalutamide solid dispersions using dichloromethane, methanol, and / or acetone as solvents. Other excipients are then added to prepare tablets. Because solid dispersion solubilization requires a high carrier ratio, and the solid dispersions prepared using spray drying are fluffy and have poor fluidity, the prepared solid dispersions must be dry granulated to obtain granules with good fluidity, followed by the addition of a large amount of excipients and tablet compression, resulting in low drug loading. Each 60mg apalutamide tablet weighs over 700mg; each 120mg apalutamide tablet weighs as much as 1400mg (see Example 6.2 of CN106999431A, Example 3.2 of CN106999430A, and Example 3.2 of CN106999432A). The heavy tablets significantly increase swallowing difficulty and severely reduce patient compliance. Furthermore, the spray-drying process in this patent uses a large amount of organic solvent, increasing production risks and adversely affecting the environment.

[0006] In addition, patent applications CN106999430A, CN106999431A, and CN106999432A also utilize hot-melt extrusion to prepare apalutamide solid dispersions, which are then further formulated into tablets by adding other excipients. Apalutamide has a high melting point of 194-196°C, which results in high operating temperatures for hot-melt extrusion, which can easily lead to degradation of the active ingredient, increasing stability risks, and placing high demands on the workshop cooling system during the extrusion process.

[0007] Drug nanocrystals are made by grinding micron-sized drug particles into dispersed or crystallized particles, reducing their particle size to submicron (100-1000nm) or even nanometer (1-100nm). Drug nanocrystals do not require special carrier materials and incorporate fewer stabilizing inactive substances, most of which are safe and less likely to cause toxic side effects.

[0008] But, on the one hand, the drug nanocrystal drug delivery system belongs to thermodynamic and kinetic unstable system, and coalescence and crystal growth take place easily, causing dissolution rate to slack off. Whether nanocrystal solidification still is nano state after the redispersion on the other hand, is also a problem demanding urgent solution. Nanocrystal solid preparation only has to take the back and still be nano state in gastrointestinal fluid redispersion, could improve wettability, saturated solubility and dissolution rate of medicine. If caking polymerization after its redissolution, just can not reach the technical effect that improves solubility and dissolution rate. No matter adopt solidification methods such as freeze drying, spray drying, fluidized bed drying or vacuum drying, in the nanocrystal suspension solidification process, because the loss of moisture, all can produce various stresses, produce " solidification damage ", can cause irreversible aggregation of drug nanoparticles, and then cause caking polymerization after redissolution, can not improve the technical effect of solubility and dissolution rate.

[0009] In summary, apalutamide has low solubility, resulting in low bioavailability. Therefore, bioavailability can be significantly improved after solubilization. Existing solubilization technologies for apalutamide are all solid dispersion technologies. Solid dispersion solubilization, whether through spray drying or hot-melt extrusion, requires a carrier at least several times the volume of apalutamide, resulting in low drug loading. This, in turn, leads to heavy tablets, large particle weight, or bulky apalutamide preparations, restricting medication use for elderly patients with swallowing difficulties and significantly reducing patient compliance. Nanocrystal technology, on the other hand, presents challenges such as proneness to aggregation, crystal growth, slowed dissolution, and the loss of nanocrystal density upon solidification and subsequent dispersion.

[0010] Therefore, there is still a need to develop an apalutamide composition with high drug loading, small tablet weight, particle weight or formulation volume, fast dissolution rate and high bioavailability. Summary of the Invention

[0011] SUMMARY OF THE INVENTION

[0012] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0013] In a first aspect, the present invention provides nanoparticles. The active ingredient is amorphous apalutamide or a pharmaceutically acceptable salt thereof, and the stabilizer comprises an ionic stabilizer and a steric stabilizer. The nanoparticles provided by the present invention have a stable morphology, can stably maintain an amorphous state, exhibit good dissolution rate and dissolution rate, and exhibit excellent stability in dissolution, content, related substances, and amorphous state. Furthermore, they have good bioavailability and exhibit unexpected technical benefits.

[0014] In a second aspect, the present invention provides a pharmaceutical preparation comprising the nanoparticles described in the first aspect.

[0015] In a third aspect, the present invention provides a method for preparing a suspension containing the nanoparticles described in the first aspect.

[0016] In a fourth aspect, a method for preparing the pharmaceutical preparation according to the second aspect of the present invention.

[0017] Detailed Description of the Invention

[0018] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0019] In a first aspect, the present invention provides a nanoparticle.

[0020] A nanoparticle comprises an active ingredient and a stabilizer, wherein the active ingredient is amorphous apalutamide or a pharmaceutically acceptable salt thereof, and the stabilizer comprises an ionic stabilizer and a steric stabilizer.

[0021] In some embodiments, the nanoparticles have a particle size D90 of less than 1000 nm. In some embodiments, the nanoparticles have a particle size D90 of less than 800 nm. In some embodiments, the nanoparticles have a particle size D90 of less than 600 nm. In some embodiments, the nanoparticles have a particle size D90 of less than 500 nm.

[0022] In some embodiments, the ionic stabilizer comprises one or more of sodium lauryl sulfate, sodium lauryl sulfonate, sodium dioctyl sulfosuccinate, benzethonium chloride, docusate sodium, arginine salts, and lecithin. In some embodiments, the ionic stabilizer comprises at least one of sodium lauryl sulfate, docusate sodium, and lecithin.

[0023] In some embodiments, the steric stabilizer comprises one or more of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone (i.e., vinyl pyrrolidone-vinyl acetate copolymer), and povidone (i.e., polyvinyl pyrrolidone). In some embodiments, the steric stabilizer comprises at least one of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, copovidone, hydroxypropyl methylcellulose, and povidone. In some embodiments, the steric stabilizer comprises at least one of hydroxypropyl cellulose, copovidone, hydroxypropyl methylcellulose, and povidone.

[0024] In some embodiments, the ionic stabilizer is at least one of sodium lauryl sulfate, docusate sodium, and lecithin, and the steric stabilizer includes at least one of hypromellose acetate succinate, hydroxypropyl cellulose, copovidone, hydroxypropyl methylcellulose, and povidone. In some embodiments, the ionic stabilizer is at least one of sodium lauryl sulfate, docusate sodium, and lecithin, and the steric stabilizer includes at least one of hypromellose acetate succinate, hydroxypropyl cellulose, copovidone VA64, hydroxypropyl methylcellulose E3, and povidone K30.

[0025] In some embodiments, the ionic stabilizer is sodium lauryl sulfate, and the steric stabilizer is hypromellose acetate succinate.

[0026] In some embodiments, the ionic stabilizer is sodium lauryl sulfate, and the steric stabilizer is hydroxypropyl cellulose.

[0027] In some embodiments, the active ingredient is present in an amount of 1.00 wt% to 80.00 wt% based on the total mass of the nanoparticles. In some embodiments, the active ingredient is present in an amount of 5.00 wt% to 79.00 wt% based on the total mass of the nanoparticles. In some embodiments, the active ingredient is present in an amount of 5.00 wt%, 10.00 wt%, 15.00 wt%, 20.00 wt%, 25.00 wt%, 30.00 wt%, 35.00 wt%, 40.00 wt%, 45.00 wt%, 50.00 wt%, 55.00 wt%, 60.00 wt%, 65.00 wt%, 70.00 wt%, 75.00 wt%, 79.00 wt% or 80.00 wt% based on the total mass of the nanoparticles.

[0028] In some embodiments, the mass ratio of the steric stabilizer to the active ingredient is 1:6 to 2:1. In some embodiments, the mass ratio of the steric stabilizer to the active ingredient is 1:2 to 2:1. In some embodiments, the mass ratio of the steric stabilizer to the active ingredient is 1:6, 1:5, 1:4, 1:3, 1:2, 1:1 or 2:1.

[0029] In some embodiments, the mass ratio of the ionic stabilizer to the active ingredient is 1:100 to 1:1. In some embodiments, the mass ratio of the ionic stabilizer to the active ingredient is 1:100, 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1:15, 1:12, 1:10, 1:5, 1:4, 1:3, 1:2 or 1:1. In some embodiments, the mass ratio of the ionic stabilizer to the active ingredient is 1:5 to 1:2.

[0030] In some embodiments, the nanoparticles are prepared by a combination of one or more methods selected from the group consisting of precipitation, emulsification, high-pressure homogenization, media milling, and high-pressure microfluidization. In some preferred embodiments, the nanoparticles are prepared by media milling.

[0031] In a second aspect, the present invention provides a pharmaceutical preparation.

[0032] A pharmaceutical preparation comprising the nanoparticles described in the first aspect.

[0033] In some embodiments, the pharmaceutical preparation is a granule, a suspension, a capsule or a tablet.

[0034] In some embodiments, the pharmaceutical preparation is a granule, which comprises the nanoparticles described in the first aspect and a pharmaceutically acceptable excipient.

[0035] In some embodiments, the pharmaceutical preparation is a suspension, which comprises the nanoparticles described in the first aspect and water.

[0036] In some embodiments, the pharmaceutical preparation is a suspension, which comprises the nanoparticles described in the first aspect, a protective agent and water.

[0037] In some embodiments, the pharmaceutical preparation is a capsule, and the contents of the capsule contain drug pellets, and the drug pellets contain the nanoparticles and pellet cores described in the first aspect.

[0038] In some embodiments, the pharmaceutical preparation is a capsule, the contents of the capsule include the upper drug pellets and an enteric layer on the upper drug pellets, the upper drug pellets contain the nanoparticles and pellet cores described in the first aspect, and the enteric layer is made of enteric material.

[0039] In some embodiments, the drug preparation is a capsule, the contents of which include the upper drug micropills, an isolation layer outside the upper drug micropills, and an enteric layer on the upper drug micropills. The upper drug micropills contain the nanoparticles and pill cores described in the first aspect, and the enteric layer is an enteric material.

[0040] In some embodiments, the pellet core comprises a sucrose pellet core, a microcrystalline cellulose pellet core, a starch pellet core, a tartaric acid pellet core, or a mannitol pellet core.

[0041] In some embodiments, the pharmaceutical preparation is a tablet, which comprises the nanoparticles described in the first aspect and other pharmaceutically acceptable excipients.

[0042] In some embodiments, the material of the isolation layer in the capsule includes at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, acrylic resin No. IV, and polyvinyl acetal diethylaminoacetic acid.

[0043] In some embodiments, the enteric material in the capsule includes at least one of hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, acrylic resin, alginate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and cellulose acetate phthalate.

[0044] In some embodiments, the mass ratio of the nanoparticles to the pellet core in the above-mentioned micropills in the capsule is 1:3.97-8:1 or 1:4 to 8:1. In some embodiments, the mass ratio of the nanoparticles to the pellet core in the above-mentioned micropills in the capsule is 1:4, 1:3, 1:2, 2:5, 24:41, 1:1, 96:50, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1.

[0045] In some embodiments, in the capsule, the ratio of the total mass of the upper drug pellets and the isolation layer to the mass of the upper drug pellets, calculated based on the total mass of the pharmaceutical preparation, is 1.03:1.00 to 1.30:1.00. In some embodiments, in the capsule, the ratio of the total mass of the upper drug pellets and the isolation layer to the mass of the upper drug pellets, calculated based on the total mass of the pharmaceutical preparation, is 1.03:1.00, 1.10:1.00, 1.15:1.00, 1.20:1.00, 1.25:1.00, or 1.30:1.00.

[0046] In some embodiments, the contents of the capsule contain the upper drug pellets and an enteric layer outside the upper drug pellets, the upper drug pellets contain the nanoparticles and pellet cores described in the first aspect, the enteric layer is an enteric material, and in the capsule, the ratio of the total mass of the upper drug pellets and the enteric layer to the mass of the upper drug pellets, calculated based on the total mass of the pharmaceutical preparation, is 1.1:1.0 to 1.3:1.0. In some embodiments, the contents of the capsule contain the upper drug pellets and the enteric layer outside the upper drug pellets, the upper drug pellets contain the nanoparticles and pellet cores described in the first aspect, the enteric layer is an enteric material, and in the capsule, the ratio of the total mass of the upper drug pellets and the enteric layer to the mass of the upper drug pellets, calculated based on the total mass of the pharmaceutical preparation, is 1.1:1.0, 1.2:1.0, or 1.3:1.0.

[0047] In some embodiments, the contents of the capsule contain the upper drug pellets, the isolation layer outside the upper drug pellets, and the enteric layer outside the upper drug pellets, the upper drug pellets contain the nanoparticles and pellet cores described in the first aspect, the enteric layer is an enteric material, and in the capsule, the total mass of the upper drug pellets, the isolation layer, and the enteric layer to the total mass of the upper drug pellets and the isolation layer is 1.1:1.0 to 1.3:1.0, calculated based on the total mass of the pharmaceutical preparation. In some embodiments, the contents of the capsule contain the upper drug pellets, the isolation layer outside the upper drug pellets, and the enteric layer outside the upper drug pellets, the upper drug pellets contain the nanoparticles and pellet cores described in the first aspect, the enteric layer is an enteric material, and in the capsule, the total mass of the upper drug pellets, the isolation layer, and the enteric layer to the total mass of the upper drug pellets and the isolation layer is 1.1:1.0, 1.2:1.0, or 1.3:1.0, calculated based on the total mass of the pharmaceutical preparation.

[0048] In some embodiments, the other pharmaceutically acceptable excipients in the tablet include at least one of a disintegrant, a filler, a glidant, and a lubricant.

[0049] In some embodiments, the disintegrant in the tablet includes at least one selected from corn starch, starch, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, light anhydrous silicic acid, calcium silicate, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, and sodium carboxymethyl starch.

[0050] In some embodiments, the filler in the tablet comprises at least one selected from the group consisting of microcrystalline cellulose, mannitol, lactose, starch, corn starch, dibasic calcium phosphate hydrate, dibasic calcium phosphate, monocalcium phosphate, magnesium carbonate, calcium carbonate, purified sucrose, and glucose.

[0051] In some embodiments, the glidant in the tablet comprises micronized silica gel.

[0052] In some embodiments, the lubricant in the tablet includes at least one of magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid.

[0053] In some embodiments, the mass ratio of the protective agent to the active ingredient is 4:1 to 1:6. In some embodiments, the mass ratio of the protective agent to the active ingredient is 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5 or 1:6.

[0054] In some embodiments, the protective agent includes a polymer compound or a sugar alcohol.

[0055] In some embodiments, the sugar alcohol protective agent includes at least one of mannitol, lactose, fructose, glycine, glucose, sucrose, maltose, trehalose, sorbitol, xylitol, polydextrose, oligofructose, oligomaltose, oligogalactose, and dextrin.

[0056] In some embodiments, the mass ratio of the sugar alcohol protective agent to the active ingredient is 4:1 to 1:6. In some embodiments, the mass ratio of the sugar alcohol protective agent to the active ingredient is 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5 or 1:6.

[0057] In some embodiments, the polymer protective agent includes at least one of hypromellose acetate succinate, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, vinyl pyrrolidone-vinyl acetate copolymer, or polyvinyl pyrrolidone. In some embodiments, the polymer compound is hypromellose acetate succinate.

[0058] In some embodiments, the mass ratio of the polymer protective agent to the active ingredient is 4:1 to 1:6. In some embodiments, the mass ratio of the polymer protective agent to the active ingredient is 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5 or 1:6.

[0059] In a third aspect, the present invention provides a method for preparing a suspension containing the nanoparticles described in the first aspect.

[0060] In some embodiments, a method for preparing a suspension containing the nanoparticles described in the first aspect comprises: dissolving a steric stabilizer and an ionic stabilizer with a grinding solvent, adding an active ingredient, stirring to obtain a suspension, and grinding to obtain a suspension containing the nanoparticles described in the first aspect.

[0061] In some embodiments, the grinding comprises mixing the suspension with grinding beads and then grinding.

[0062] In some embodiments, the grinding solvent comprises water or a pH 6.8 buffered saline solution.

[0063] In some embodiments, the buffer salt in the pH 6.8 buffered saline solution comprises phosphate.

[0064] In some embodiments, the steric stabilizer comprises hypromellose acetate succinate and / or the polymer compound is hypromellose acetate succinate, and the grinding solvent is a buffered saline solution with a pH of 6.8.

[0065] In some embodiments, the phosphate salt comprises at least one of sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0066] In some embodiments, the pH of the pH 6.8 buffered saline solution is adjusted using sodium hydroxide or phosphoric acid during preparation. In some embodiments, the buffer salt concentration in the pH 6.8 buffered saline solution is 0.021 mol / L-0.50 mol / L. In some embodiments, the buffer salt concentration in the pH 6.8 buffered saline solution is 0.02 mol / L-0.10 mol / L. In some embodiments, the buffer salt concentration in the pH 6.8 buffered saline solution is 0.01 mol / L, 0.02 mol / L, 0.03 mol / L, 0.04 mol / L, 0.05 mol / L, 0.06 mol / L, 0.07 mol / L, 0.08 mol / L, 0.09 mol / L, 0.10 mol / L, 0.15 mol / L, 0.20 mol / L, 0.25 mol / L, 0.30 mol / L, 0.35 mol / L, 0.40 mol / L, 0.45 mol / L or 0.50 mol / L.

[0067] In a fourth aspect, a method for preparing the pharmaceutical preparation according to the second aspect of the present invention.

[0068] In some embodiments, a method for preparing the drug preparation described in the first aspect, wherein the drug preparation is a capsule, comprises: mixing the suspension prepared by the preparation method described in the third aspect with a protective agent and solidifying the mixture onto a pellet core to obtain drug-coated micropills, and then pouring the drug-coated micropills into a capsule to obtain the capsule.

[0069] In some embodiments, a method for preparing the drug preparation of the first aspect, wherein the drug preparation is a capsule, comprises: mixing the suspension prepared by the preparation method of the third aspect with a protective agent and solidifying the mixture onto a pellet core to obtain drug-coated micropills, then coating the micropills with the enteric material to obtain coated drug-coated micropills, and then pouring the coated drug-coated micropills into capsules to obtain the capsules.

[0070] In some embodiments, a method for preparing the drug preparation of the first aspect, wherein the drug preparation is a capsule, comprises: mixing the suspension prepared by the preparation method of the third aspect with a protective agent and solidifying the mixture onto a pellet core to obtain drug-coated micropills, then wrapping the drug-coated micropills with the material of the isolation layer, and then coating them with the enteric material, and then filling the pellets into capsules to obtain the capsules.

[0071] In some embodiments, the solidification in the method for preparing the capsule comprises solidification by drug loading in a fluidized bed.

[0072] In some embodiments, a method for preparing the pharmaceutical preparation of the first aspect, wherein the pharmaceutical preparation is a tablet, comprises: mixing the suspension prepared by the preparation method of the third aspect with a protective agent and then solidifying the mixture, then mixing the mixture with a pharmaceutically acceptable excipient, and tableting the mixture to obtain the tablet.

[0073] In some embodiments, the solidification in the method for preparing the tablet comprises solidification by spray drying or freeze drying.

[0074] In some embodiments, the solidification in the tablet preparation method is performed by freeze drying, and the preparation method further comprises grinding and screening after solidification, and then mixing with pharmaceutically acceptable excipients.

[0075] In some embodiments, a method for preparing the pharmaceutical preparation of the first aspect, wherein the pharmaceutical preparation is a granule, comprises: mixing the suspension prepared by the preparation method of the third aspect with a protective agent and then solidifying the mixture; then adding other pharmaceutically acceptable excipients, mixing, dry granulating, and then mixing with a lubricant and / or a flavoring agent to obtain the granule.

[0076] In some embodiments, a method for preparing the pharmaceutical preparation of the first aspect, wherein the pharmaceutical preparation is a granule, the suspension prepared by the preparation method and the protective agent are solidified by a spray drying process, and then other pharmaceutically acceptable excipients are added, mixed, dry granulated, and then mixed with a lubricant and / or a flavoring agent to obtain the granule.

[0077] In some embodiments, other pharmaceutically acceptable excipients of the granules include at least one of a filler, a lubricant, and a flavoring agent.

[0078] In some embodiments, the filler in the granules includes at least one of sucrose, lactose, mannitol, sorbitol, maltitol, xylitol, erythritol, glucose, starch, and dextrin;

[0079] In some embodiments, the lubricant in the granules includes at least one of magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc, and magnesium oxide;

[0080] In some embodiments, the flavoring agent in the granules includes at least one of sucralose, aspartame, saccharin sodium, sucrose, strawberry flavor, orange flavor, mint flavor, peach flavor, and banana flavor.

[0081] In some embodiments, the solidification in the preparation method of the granules comprises spray drying, freeze drying or fluidized bed granulation. Beneficial effects

[0082] Compared with the prior art, the present invention has at least one of the following beneficial effects:

[0083] The nanoparticle material provided by the present invention has a stable morphology, can stably maintain an amorphous state, has a good dissolution rate and dissolution rate, and has good stability in dissolution, content, related substances, amorphous state, etc., and has good bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] FIG1 is an XRD pattern of the spray-dried powder of Formulation 1 in Example 1 after ball milling with ball milling solution.

[0085] FIG2 is an XRD pattern of the spray-dried powder of the ball-milled solution of Recipe 1 in Example 1 after being placed for 24 hours.

[0086] FIG3 is an XRD pattern of the spray-dried powder of the ball-milled solution of Recipe 1 in Example 1 after being placed for 48 hours.

[0087] FIG4 is an XRD pattern of the spray-dried powder of the ball-milled liquid of Recipe 1 in Example 1 after being placed for 72 hours.

[0088] Figure 5 is a comparison of the XRD test results of the pellets obtained after curing of Prescription 59, Prescription 60, Prescription 61, and Prescription 62 in Example 26. Figure 5 shows, from top to bottom, the XRD patterns of the apalutamide Form B API, the XRD patterns of the pellets obtained after curing of Prescription 59, the XRD patterns of the pellets obtained after curing of Prescription 60, the XRD patterns of the pellets obtained after curing of Prescription 61, and the XRD patterns of the pellets obtained after curing of Prescription 62.

[0089] Figure 6 shows XRD patterns of samples of apalutamide nanoparticle capsules obtained from Prescription 74, Prescription 75, Comparative Prescription 29, and Comparative Prescription 30 in Example 38, which were stored under accelerated conditions for 6 months. From top to bottom in Figure 6 , the XRD pattern of apalutamide Form B, the XRD pattern of sample A6M of Comparative Prescription 30, the XRD pattern of sample A6M of Prescription 74, the XRD pattern of sample A6M of Prescription 75, and the XRD pattern of sample A6M of Comparative Prescription 29 are shown.

[0090] Definition of terms

[0091] The term "D90" refers to the particle size at which the 90th percentile of a sample's cumulative particle size distribution is reached. Its physical meaning is that 90% of the particles are smaller than this value. For example, "D90 ≤ 100 μm" means "90% of the particles are ≤ 100 μm." D10 refers to the particle size at which the 10th percentile of a sample's cumulative particle size distribution is reached; D50 refers to the particle size at which the 50th percentile of a sample's cumulative particle size distribution is reached.

[0092] The term "comprising" and variations thereof, such as "including" and "comprising" are to be construed as open ended, i.e., "including but not limited to." When used to define compositions and methods, "consisting essentially of" or grammatical variations thereof shall mean the exclusion of other elements of any significance to the compositions and methods of preparation, but shall not exclude factors that have no substantial effect on the compositions and methods of preparation. "Consisting of" or grammatical variations thereof shall mean the exclusion of elements not expressly enumerated. Embodiments defined by each of these transition terms are within the scope of the present invention. For example, when a formulation is described as comprising ingredients A, B, and C, a formulation consisting essentially of A, B, and C and a formulation consisting of A, B, and C are independently within the scope of the present invention.

[0093] Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents. For example, reference to "a stabilizer" includes one or more stabilizers.

[0094] In the foregoing text of the present invention, all numerical values ​​disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. Based on the disclosed numbers, the value of each numerical value may vary by less than ±10% or by a reasonable difference deemed by a person skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0095] "Pharmaceutically acceptable" means a substance or compound that is, within the scope of adequate medical judgment, suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions or similar reactions, and has a reasonable benefit / risk ratio.

[0096] Recitation of ranges of values ​​herein is intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if it were individually recited herein.

[0097] The term "weight percent" or "percent by weight" or "wt%" is defined as the weight of a single component in a composition divided by the total weight of all components of the composition and then multiplied by 100%. In some cases, if the composition has an outer coating, the weight of the coating may be included or excluded from the total weight. DETAILED DESCRIPTION

[0098] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0099] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0100] Unless otherwise specified, the reference preparation (RLD) described in the examples and comparative examples: the manufacturer is Xi'an Janssen; the specification is 60 mg; and the batch number is 19LG0585.

[0101] The term "strength" refers to the weight of the active ingredient in a single dose of a preparation. For example, a 60 mg apalutamide tablet or apalutamide capsule means that each apalutamide tablet or each apalutamide capsule contains 60 mg of apalutamide.

[0102] The grinding solvent in the embodiments of the present invention can be a buffered saline solution with a pH of 6.8 ± 0.02 or water. Unless otherwise specified, the grinding solvent in the following embodiments of the present invention is a buffered saline solution with a pH of 6.8, which contains 0.05 mol / L sodium dihydrogen phosphate and is adjusted to pH 6.8 with sodium hydroxide or phosphoric acid.

[0103] The apalutamide crystal form B of the present invention is sourced from: manufacturer: Dr. Reddy's Laboratories Limited; product name: Apalutamide (Micronized); batch number: APA / OPT / 4-250.

[0104] The apalutamide crystalline form B, apalutamide (crystalline form B), and crystalline form B apalutamide described in the present invention all represent the same substance.

[0105] The preparation method of the amorphous apalutamide of the present invention comprises dissolving apalutamide crystalline form B in a mixed solvent of methanol and dichloromethane (the volume ratio of methanol to dichloromethane is 5:1-1:1), and then spray drying to obtain the amorphous apalutamide.

[0106] Comparative Example 1:

[0107] Crystalline nanocrystal technology The patent WO2022166701A1 discloses a scheme for preparing apalutamide nanocrystalline composition, which uses a crystalline raw material. The optimal formulation (comparative formulation 2) was investigated using different dissolution methods. There were certain differences in the data under different dissolution methods, among which the in situ optical fiber had a stronger in vitro and in vivo correlation. However, the pharmacokinetic performance of the optimal formulation 47 in WO2022166701A1 (i.e., comparative formulation 2 of the present invention) in animals still could not reach the same or higher level as the reference preparation.

[0108] Table 1: Apalutamide Nanocrystal Tablet Formulation

[0109] Preparation method: see prescription 46 and prescription 47 in WO2022166701A1 (the comparative prescription 1 described in the present invention is prescription 46 in WO2022166701A1, and the comparative prescription 2 described in the present invention is prescription 47 in WO2022166701A1).

[0110] Table 2: Dissolution results of comparative formulation 1-comparative formulation 2 and reference preparation (%, n=3)

[0111] Example 1: Active ingredient in different forms

[0112] Prescription: as shown in Table 3.

[0113] Preparation method of prescription 1: weigh the steric stabilizer and the ionic stabilizer separately, add the grinding solvent and stir until the solution is clear, then add amorphous apalutamide and stir evenly to obtain a suspension; add grinding beads and the suspension into the grinding chamber and grind to obtain an amorphous apalutamide nanoparticle suspension.

[0114] Preparation method of prescription 2: weigh the steric stabilizer and the ionic stabilizer separately, add the grinding solvent and stir until the solution is clear, then add the amorphous apalutamide, stir evenly to obtain a suspension; add grinding beads and the suspension into the grinding chamber and grind to obtain a nanoparticle suspension, add a protective agent to the nanoparticle suspension to obtain a suspension containing the protective agent and nanoparticles, use a fluidized bed layer to apply the drug, use sucrose pellet cores as a substrate, spray the suspension containing the protective agent and nanoparticles onto the substrate, solidify to obtain drug-coated micropills, and fill the drug-coated micropills into capsules to obtain amorphous apalutamide nanoparticle capsules.

[0115] Preparation method of comparative prescription 3: Prepared according to the preparation method of prescription 1, but replacing amorphous apalutamide with crystalline form B apalutamide to obtain apalutamide nanocrystalline suspension.

[0116] Preparation method of comparative prescription 4: Prepare according to the preparation method of prescription 1, but replace amorphous apalutamide with crystalline form B apalutamide to obtain apalutamide nanoparticle capsules.

[0117] Table 3: Ball milling study of different active ingredient forms

[0118] Stability investigation of the ball milling solution: The ball milling solution was placed for different periods of time and then solidified by spray drying. The crystal form of the solidified particles was determined.

[0119] Table 4 Stability data of ball milling solution after different time

[0120] Conclusion: As shown in Figures 1 to 4, amorphous apalutamide will slowly crystallize as the storage time increases. Therefore, there are technical difficulties in crystallization when ball milling amorphous apalutamide.

[0121] Example 2: Dissolution Test

[0122] In vitro dissolution testing was conducted on the formulations obtained from Example Formulations 1-2 and Comparative Formulations 3-4 using a paddle method at 50 rpm, using a dissolution medium with a pH of 6.8, a volume of 900 mL, and a temperature of 37.0±0.5°C. Dissolution sampling was performed at 5, 10, 15, 20, 30, and 60 minutes. Sampling was performed at the midpoint between the paddle tip and the liquid level, 10 mm from the inner wall of the dissolution vessel. In vitro dissolution measurements were performed using an inline fiber optic. The test results are shown in Table 5.

[0123] Table 5: Dissolution results of prescription 1-2 and comparative prescription 3-4 (%, n=3)

[0124] Analysis of results: Compared with the ball-milling of apalutamide in crystalline form B, the dissolution of amorphous apalutamide was faster but unstable after ball-milling, and dissolution regression occurred. Amorphous apalutamide was unstable and easily transformed into crystals during storage after ball-milling. Moreover, it can be seen from Formulation 2 and Comparative Formulation 4 that the solidification damage caused by amorphous apalutamide during the solidification process was greater than that of crystalline apalutamide.

[0125] Comparative Example 2: In vivo pharmacokinetic study in animals (nanosuspension)

[0126] Dosing regimen: Sixteen healthy Beagle dogs, half male and half female, were divided into four groups of four, administered on an empty stomach. (To ensure fasting conditions similar to those in humans, all groups received an intramuscular injection of pentagastrin 0.5 hours before dosing to promote gastric acid secretion.)

[0127] Experimental group: Group A: reference preparation (manufacturer: Xi'an Janssen; specification: 60 mg; batch number: 19LG0585) apalutamide tablets (specification: 60 mg / tablet) once a day, 1 tablet each time.

[0128] Group B: The amorphous apalutamide nanoparticle suspension obtained in Prescription 1 of Example 1 was administered once a day. The amorphous apalutamide nanoparticle suspension was administered within 24 hours of its preparation. Each dose of the amorphous apalutamide nanoparticle suspension contained 60 mg of apalutamide.

[0129] Group C: The apalutamide nanocrystal suspension obtained from Comparative Prescription 3 in Example 1 was administered once a day. The apalutamide nanoparticle suspension was prepared and administered within 24 hours. Each dose of the apalutamide nanocrystal suspension contained 60 mg of apalutamide.

[0130] Group D: Apalutamide nanoparticle capsules prepared according to Prescription 2 in Example 1 (specification: 60 mg / capsule, the amorphous nanosuspension was prepared and the drug application process was completed within 24 hours) were administered once a day, 1 capsule each time.

[0131] After administration under fasting conditions, blood samples were collected at 0, 0.25, 0.5, 1, 2, 5, 8, 24, 48, 96 and 144 hours to determine blood drug concentrations.

[0132] Table 6 lists the pharmacokinetic data of 60 mg apalutamide suspension, capsules and reference preparations prepared by Prescription 1, Comparative Prescription 3 and Prescription 2 in Beagle dogs.

[0133] Table 6: Results of in vivo pharmacokinetic studies in animals

[0134] Analysis of results: According to the results of the in vivo pharmacokinetic study of animals in Table 6, this animal experiment adopted a 4-crossover experimental design to compare prescription 3 and RLD. There were significant differences. The highest blood drug concentration and the area under the blood drug concentration-time curve of prescription 3 were 55.40% and 58.84% of the reference, respectively. The bioavailability was significantly lower than that of the reference preparation. The efficacy of taking this preparation could not be guaranteed. The highest blood drug concentration and the area under the blood drug concentration-time curve of prescription 1 were 116.90% and 107.75% of the reference, respectively. The bioavailability was closer to the reference preparation, and there was no significant difference. This shows that the mixed ball mill has good dispersion and remains stable in gastric acid. It will not cause apalutamide to crystallize and is well absorbed. Prescription 1 and comparative prescription 3 are the same in ingredients, but the difference is the form of the active ingredient. The active ingredient used in prescription 1 contains an amorphous state, while the active ingredient used in comparative prescription 3 is crystalline form B. This shows that the absorption of different forms of active ingredients in animals is different. There is a big difference between the two groups, and the amorphous active ingredient is better absorbed in the body; however, the in vivo data of animals after solidification of Prescription 2 were significantly different from those of Prescription 1. The maximum blood drug concentration and the area under the blood drug concentration-time curve of Prescription 2 were 53.42% and 62.95% of those of Prescription 1, respectively, indicating that damage may have occurred during the solidification process. After solidification, it is very sensitive to acid. When gastric acid penetrates into the upper drug layer, the amorphous state of apalutamide is destroyed, resulting in a decrease in solubilization ability, which leads to poor absorption in animals. Therefore, it is necessary to optimize the ball milling prescription and solidification and examine the protective layer in the future.

[0135] Example 3: Screening of steric stabilizer types

[0136] Prescription: as shown in Table 7.

[0137] Preparation method: Referring to the preparation method of Prescription 2 in Example 1, a suspension containing a protective agent and nanoparticles was prepared, and the suspension containing the protective agent and nanoparticles was spray dried and solidified. The solidification was completed within 24 hours of obtaining the nanosuspension (an appropriate amount of the particles obtained after solidification was taken to determine the crystal form, the results are shown in Table 8), and then the additional excipients microcrystalline cellulose, cross-linked polyvinylpyrrolidone and micropowdered silica were added and mixed. Finally, magnesium stearate was added, mixed, and tableted to obtain apalutamide amorphous nanoparticle tablets.

[0138] Table 7: Screening formula for steric stabilizer types

[0139] Table 8 Nanoparticle suspension particle size and crystal form data after spray drying and solidification

[0140] Conclusion: Compared with other stabilizers, the use of at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, copovidone, hydroxypropyl methylcellulose, and povidone is more conducive to improving the crystalline stability of amorphous apalutamide during the spray-drying solidification process, and has unexpected technical effects.

[0141] Example 6: Dissolution Test

[0142] Dissolution tests were performed on apalutamide amorphous nanoparticle tablets prepared from Prescriptions 3 to 8 and Comparative Prescriptions 5 to 7 in Example 5, respectively. The dissolution procedure was the same as in Example 2. The test results are shown in Table 9.

[0143] Table 9: Dissolution results of prescriptions 3-8 and comparative prescriptions 5-7 (%, n=3)

[0144] Result analysis:

[0145] Under the same conditions, the amorphous apalutamide nanoparticles of Formulations 3 to 8, which respectively use hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, copovidone, hydroxypropyl methylcellulose and povidone as steric stabilizers, have higher solubility and faster dissolution rate in a pH 6.8 medium than the apalutamide nanoparticles of Comparative Formulations 5 to Comparative Formulations 7, which respectively use Tween-80, poloxamer P188 and polyethylene glycol 6000 as steric stabilizers, and have unexpected technical effects; therefore, the steric stabilizer is preferably at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, copovidone, hydroxypropyl methylcellulose and povidone, which has unexpected technical effects.

[0146] Example 7: Screening of steric stabilizer ratios

[0147] Prescription: as shown in Table 10 and Table 11.

[0148] Preparation method: Prepare by referring to the preparation method in Example 3 to obtain apalutamide amorphous nanoparticle tablets.

[0149] Table 10: Screening formula for steric stabilizer ratio

[0150] Table 11: Screening formula for steric stabilizer ratio

[0151] Example 8: Dissolution Test

[0152] Amorphous nanoparticle tablets prepared from Prescriptions 9 to 18 in Example 7 and Comparative Prescriptions 8 and 9 were subjected to dissolution tests. The dissolution operation was the same as in Example 2. The dissolution results are shown in Table 12.

[0153] Table 12: Dissolution results of Prescription 9-Prescription 18, Comparative Prescription 8-Comparative Prescription 9 (%, n=3)

[0154] Analysis of results: The amorphous apalutamide nanoparticles ball-milled solutions (Formulations 9-13) using hydroxypropyl cellulose as a steric stabilizer and having a weight ratio of the steric stabilizer to amorphous apalutamide in the range of 1:6 to 2:1 had high solubility and fast dissolution rate in a dissolution medium of pH 6.8; the amorphous apalutamide nanoparticles ball-milled solutions (Formulations 14-18) using hydroxypropyl methylcellulose acetate succinate as a steric stabilizer and having a weight ratio of the steric stabilizer to amorphous apalutamide in the range of 1:6 to 2:1 had high solubility and fast dissolution rate in a dissolution medium of pH 6.8, with unexpected technical effects.

[0155] In the ball-milling solution of apalutamide nanoparticles, the selected steric stabilizer achieves inter-particle stabilization within the system primarily by providing a steric hindrance effect. Excessive steric stabilizer will increase the viscosity of the grinding system, making it difficult to obtain nanoscale particles in a short period of time and may even result in a decrease in dissolution. Excessive steric stabilizer is insufficient to form an ideal inter-particle steric hindrance effect, making it easy for particles to agglomerate, which is also detrimental to the physical stability of the final preparation. Therefore, a weight ratio of steric stabilizer to apalutamide within 1:6 to 2:1 can improve the dissolution rate of apalutamide nanoparticles, demonstrating unexpected technical effects.

[0156] Example 9 Screening of Ionic Stabilizer Types

[0157] Prescription: as shown in Table 13.

[0158] Prescription 19-Prescription 20, Comparative Prescription 10-Comparative Prescription 14 Preparation method: Prepare with reference to the preparation method of Example 3 to obtain apalutamide amorphous nanoparticle tablets.

[0159] Table 13: Ionic stabilizer type screening formula table

[0160] Example 10: Dissolution Test

[0161] Dissolution tests were performed on amorphous nanoparticle tablets prepared according to Prescription 15, Prescription 19-Prescription 20, and Comparative Prescription 10-Comparative Prescription 14 in Example 9, respectively. The dissolution operation was the same as in Example 2. The test results are shown in Table 14.

[0162] Table 14: Dissolution results of Prescriptions 19-21, Comparative Prescriptions 9-13 (%, n=3)

[0163] Result analysis: Compared with the use of non-ionic stabilizers, the present invention uses at least one of ionic surfactants such as sodium lauryl sulfate, sodium docusate, and lecithin as a stabilizer, and the resulting amorphous nanoparticles dissolve faster, with unexpected technical effects.

[0164] Example 11 Screening of the ratio of ionic stabilizers

[0165] Prescription: as shown in Table 15.

[0166] Preparation method of Prescription 21-Prescription 26, Comparative Prescription 16-Comparative Prescription 17: Prepare by referring to the preparation method of Example 3 to obtain apalutamide amorphous nanoparticle tablets.

[0167] Preparation method of comparative prescription 15: Prepared according to the preparation method of Example 3, but without adding the ionic stabilizer, to obtain apalutamide amorphous nanoparticle tablets.

[0168] Table 15: Ionic stabilizer ratio screening formula table

[0169] Example 12 Dissolution Experiment

[0170] The nanoparticle ball-milling solutions prepared by Prescriptions 21 to 26 and Comparative Prescriptions 15 to 17 in Example 16 were respectively subjected to dissolution tests. The dissolution operation was the same as that in Example 2. The test results are shown in Table 16.

[0171] Table 16: Dissolution results of Prescriptions 21-26, Comparative Prescriptions 15-17 (%, n=3)

[0172] Analysis of Results: The above dissolution results demonstrate that when the weight ratio of sodium lauryl sulfate (sodium lauryl sulfate) as an ionic stabilizer to apalutamide is within the range of 1:100-1:1, the resulting apalutamide nanoparticle tablets exhibit high solubility and rapid dissolution in a dissolution medium at pH 6.8. In the apalutamide nanoparticle composition, the ionic stabilizer primarily stabilizes the particles within the system through a potential effect; it also has a certain solubilizing effect on apalutamide. However, excessive addition of ionic stabilizer can lead to the generation of numerous bubbles during milling, hindering milling. Excessive use can also lead to toxicity issues. Therefore, the preferred range for the weight ratio of ionic stabilizer to apalutamide is 1:100-1:1, preferably 1:5-1:2, which exhibits unexpected technical benefits.

[0173] Example 13: Screening of protective agent types

[0174] Prescription: as shown in Table 17.

[0175] Preparation Methods for Prescriptions 27-32: Prepared according to the preparation method of Prescription 2 in Example 1, amorphous apalutamide nanoparticle capsules were obtained. In the preparation method, the crystal form of the pellets was determined after the pellets were obtained. The results are shown in Table 18.

[0176] Comparative Preparation Method 18 (No Preservative Added): Apalutamide nanoparticle capsules were prepared using the method described in Example 1, Preparation Method 2 (no preservative added). In this preparation method, an appropriate amount of the ball-milled nanosuspension was used to determine the crystalline form. The results are shown in Table 18.

[0177] Table 17: Prescription table for screening of protective agent types

[0178] Table 18: Ball milling liquid particle size and crystal form test data

[0179] Conclusion: The protective agent provided by the present invention is beneficial to improving the crystal stability of the product and has unexpected technical effects.

[0180] Example 14: Dissolution Test

[0181] Dissolution tests were performed on the amorphous apalutamide nanoparticles prepared by ball-milling solutions of formulations 27 to 32 in Example 13 and comparative formulation 18. The test results are shown in Table 19.

[0182] Table 19: Dissolution results of prescriptions 27-32 and comparative prescription 18 (%, n=3)

[0183] Conclusion: The protective agent provided by the present invention is beneficial to improving the solubility and dissolution rate of the product, and has unexpected technical effects.

[0184] Example 15: Screening of protective agent ratios

[0185] Prescription: as shown in Table 20.

[0186] Preparation Method for Prescriptions 33-41: Prepared according to the preparation method of Prescription 2 in Example 1, to obtain apalutamide amorphous nanoparticle capsules. After obtaining the above-mentioned pellets, an appropriate amount of the above-mentioned pellets was collected to determine the crystal form. The results are shown in Table 21.

[0187] Table 20: Prescription table for screening protective agent ratio

[0188] Table 21 Crystal form detection data:

[0189] Example 16: Dissolution Test

[0190] Dissolution tests were performed on apalutamide amorphous nanoparticle capsules prepared according to Formulations 33 to 42 in Example 15. The test results are shown in Table 22.

[0191] Table 22: Dissolution results of Formulations 33-42 (%, n=3)

[0192] Analysis of results: The above dissolution results show that the amorphous apalutamide nanoparticle capsules obtained when the weight ratio of the protective agent to amorphous apalutamide is in the range of 4:1 to 1:6 have high solubility and fast dissolution rate in the dissolution medium of pH 6.8, and have unexpected technical effects.

[0193] In amorphous apalutamide nanoparticle compositions, the addition of a suitable protective agent is crucial to reduce damage during the solidification process and maintain the redispersibility of the nanoparticles. Excessive amounts of protective agent can lead to excessive tablet weight. Insufficient or no protective agent can cause instantaneous water loss during solidification, disrupting the nanoparticle structure and promoting particle agglomeration. This poor redispersibility and negatively impacts the physical stability of the apalutamide nanoparticle composition. In the present invention, the weight ratio of protective agent to apalutamide is preferably between 4:1 and 1:6. This achieves both high dissolution rate and rapid dissolution rate while reducing particle weight and improving the physical stability of the apalutamide nanoparticle composition, resulting in unexpected technical benefits.

[0194] Example 17: Screening of curing process - spray drying

[0195] Prescription: as shown in Table 23.

[0196] Preparation method: Prepare according to the preparation method of Example 3 to obtain apalutamide amorphous nanoparticle tablets.

[0197] Table 23 Amorphous apalutamide nanoparticles spray-dried formulation after ball milling

[0198] Example 18 Dissolution Test

[0199] Dissolution tests were performed on apalutamide amorphous nanoparticle tablets prepared according to Prescriptions 43 to 46 in Example 17, respectively. The dissolution procedures were the same as in Example 2. The test results are shown in Table 24.

[0200] Table 24: Dissolution results of Formulations 43-46 (%, n=3)

[0201] Example 19: Screening of solidification process - freeze drying

[0202] Prescription: as shown in Table 25.

[0203] Preparation method of Prescription 47-Prescription 50: Prepare a suspension containing a protective agent and nanoparticles according to the preparation method of Example 3, freeze-dry to obtain a lyophilized material; grind the lyophilized material through a 30-mesh sieve, add the prescribed amount of additional excipients microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and micropowder silica gel, mix, then add magnesium stearate, mix, and tablet to obtain apalutamide amorphous nanoparticle tablets.

[0204] Table 25: Formulation of amorphous apalutamide nanoparticles after ball milling and spray drying

[0205] Example 20 Dissolution Test

[0206] Dissolution tests were performed on amorphous apalutamide nanoparticle tablets prepared according to Formulations 47 to 50 in Example 19, respectively. The dissolution procedures were the same as in Example 2. The test results are shown in Table 26.

[0207] Table 26: Dissolution results of Formulations 47-50 (%, n=3)

[0208] Example 21: Screening of Solidification Process in Apalutamide Nanoparticle Tablets - Fluidized Bed (Pellets Coating / Granulation)

[0209] Prescription: See Table 27.

[0210] Preparation method of Prescription 51-Prescription 52: Prepare according to the preparation method of Prescription 2 in Example 1 to obtain apalutamide amorphous nanoparticle capsules.

[0211] Preparation method of comparative prescription 19: Prepare a suspension containing a protective agent and nanoparticles according to the preparation method of prescription 2 in Example 1. Use microcrystalline cellulose (microcrystalline cellulose is added in powder form, not as a pellet) as a substrate and perform top spray granulation. After obtaining drug-containing granules, capsules are filled to obtain apalutamide nanoparticle capsules.

[0212] Preparation method of comparative prescription 20: A suspension containing a protective agent and nanoparticles was prepared according to the preparation method of prescription 2 in Example 1. Mannitol (mannitol was added in powder form, not as a pellet) was used as a substrate for top spray granulation. After obtaining drug-containing granules, capsules were filled to obtain apalutamide nanoparticle capsules.

[0213] Table 27: Screening formula for apalutamide nanocuring process

[0214] Example 22: Dissolution Test

[0215] Dissolution tests were performed on apalutamide amorphous nanoparticle capsules prepared from Prescriptions 51 and 52 in Example 21 and Comparative Prescriptions 19 and 20, respectively. The dissolution operation was the same as in Example 2. The test results are shown in Table 28.

[0216] Table 28: Dissolution results of Prescription 51-Prescription 52 and Comparative Prescription 19-Comparative Prescription 20 (%, n=3)

[0217] Conclusion: The dissolution results in Tables 24, 26 and 28 above indicate that the formulation of the present invention and the solidification processes of spray drying, fluidized bed loading and freeze drying can all produce apalutamide preparations with a fast dissolution rate.

[0218] Example 23: Investigation of the weight gain range of pellets

[0219] Prescription: as shown in Table 29.

[0220] Preparation method of Prescription 53-Prescription 58, Comparative Prescription 21-Comparative Prescription 22: Prepare according to the preparation method of Prescription 2 in Example 1 to obtain apalutamide amorphous nanoparticle capsules.

[0221] Table 29: Prescription table for screening the proportion of protective agents in the nano-curing process of apalutamide

[0222] Example 24: Dissolution Test

[0223] Apalutamide nanoparticle capsules prepared according to Prescriptions 53 to 58 in Example 23 and Comparative Prescriptions 21 to 22 were subjected to dissolution tests. The dissolution operation was the same as in Example 2. The test results are shown in Table 30.

[0224] Table 30: Dissolution results of Prescriptions 53-58 and Comparative Prescriptions 21-22 (%, n=3)

[0225] Result analysis:

[0226] The mass ratio of the nanoparticles to the sucrose pellet cores (1:3.97-8:1) provided by the present invention is beneficial to improving the dissolution rate and dissolution rate of the product.

[0227] Example 25: Particle size distribution before and after curing

[0228] The apalutamide oral nanoparticle preparations prepared according to Prescriptions 43 to 52 and Comparative Prescriptions 19 to 22 in the aforementioned Examples were used. The particle size distribution of the nanoparticle suspension before solidification and after solidification and reconstitution in purified water was measured using a laser particle size analyzer. The test results are shown in Table 31.

[0229] Table 31: Particle size distribution before and after curing

[0230] Analysis of the results: The particle size of the apalutamide nanoparticles obtained using the formulations and preparation methods described in Formulations 43 to 52 did not change significantly before and after curing, while the apalutamide nanoparticles obtained from Comparative Formulations 19 to 22 had a larger particle size after curing. This indicates that when the steric stabilizer, protective agent, or dosage and type are inappropriate, it is impossible to obtain an apalutamide amorphous nanoparticle preparation with an ideal particle size or a stable particle size. However, the use of the steric stabilizer, protective agent, or dosage and type provided by the present invention is conducive to obtaining an apalutamide amorphous nanoparticle preparation with an ideal particle size or a stable particle size, and has unexpected technical effects.

[0231] Example 26: Mixed steric stabilizer (HPC+LF)

[0232] Prescription: as shown in Table 32.

[0233] Preparation method of Prescription 59-Prescription 62: Prepare according to the preparation method of Prescription 2 in Example 1 to obtain amorphous apalutamide nanoparticle capsules.

[0234] Table 32: Mixed space stabilizer prescription

[0235] Example 27: Dissolution Test

[0236] Dissolution tests were performed on apalutamide amorphous nanoparticle capsules prepared according to Formulations 59 to 62 in Example 26, respectively. The dissolution procedures were the same as in Example 2. The test results are shown in Table 33.

[0237] Table 33: Dissolution results of Formulations 58-62 (%, n=3)

[0238] Example 28: Crystal form data

[0239] The drug-coated micropellets obtained after curing of prescriptions 59 to 62 were respectively subjected to XRD testing, and the results are shown in Figure 5.

[0240] Result analysis: Figure 5 shows, from top to bottom, the crystal form of apalutamide Form B API, and the XRD patterns of Formulations 59, 60, 61, and 62 after solidification. After solidification, apalutamide is all amorphous.

[0241] As can be seen from Figure 5 and Table 33, the use of the mixed steric stabilizer provided by the present invention is beneficial for making the entire system more stable, improving the crystal stability of the product, maintaining the amorphous form of apalutamide after solidification, and improving the dissolution stability of the amorphous apalutamide nanoparticle capsules obtained after solidification, which has unexpected technical effects.

[0242] Example 29: Investigation of isolation layer coating materials

[0243] Prescription: See Table 34.

[0244] Preparation method of Prescription 63-Prescription 65: Prepare the medicated micropills according to the preparation method of Prescription 2 in Example 1; dissolve the isolation layer material in the prescription in water to form a coating solution, and perform isolation layer coating through a fluidized bed; first dissolve triethyl citrate, glyceryl monostearate, and Tween 80 in water, and then add the prescribed amount of Eudragit L30D-55 and stir until homogeneous to obtain an enteric coating solution, perform enteric layer coating through a fluidized bed, and finally put the coated micropills into capsules to obtain enteric amorphous nanoparticle capsules.

[0245] Preparation method of comparative prescription 23: Prepare the above-mentioned micropills according to the preparation method of prescription 2 in reference example 1; first dissolve triethyl citrate, glyceryl monostearate, and Tween 80 in water, then add the prescribed amount of Eudragit L30D-55 and stir until homogeneous to obtain an enteric coating solution, perform enteric layer coating through a fluidized bed, and finally put the coated micropills into capsules to obtain enteric amorphous nanoparticle capsules.

[0246] Table 34: Seal Coating Formulation

[0247] Example 30: Dissolution Data

[0248] Dissolution tests were conducted on enteric-coated amorphous nanoparticle capsules prepared in Formulations 63-65 of Example 29, Comparative Example 20, and a reference preparation (19LG0585). The capsules were acid-resistant for 2 hours in 500 mL of 0.1 M HCl at a temperature of 37.0 ± 0.5°C using a paddle method at 75 rpm. After the acid-resistant period, the medium was adjusted to pH 6.8 with a pH 6.8 buffered saline solution and sodium hydroxide. The volume of the medium was reduced to 900 mL. In vitro dissolution testing was conducted at a temperature of 37.0 ± 0.5°C using a paddle method at 75 rpm. Dissolution sampling was performed at 5, 10, 15, 20, 30, and 60 minutes. Sampling was performed at the midpoint between the paddle tip and the liquid level, 10 mm from the inner wall of the dissolution cup. In vitro dissolution measurements were performed using an in-line optical fiber. The test results are shown in Table 35.

[0249] Table 35: Dissolution results of Prescription 63-Prescription 65 and Comparative Prescription 23 and Reference Preparation (19LG0585) (%, n=3)

[0250] Result analysis: Without the blocking effect of the isolation layer, the medium will slowly enter the upper drug layer during the acid resistance process, causing the amorphous apalutamide to be unstable and thus causing a decrease in dissolution.

[0251] Example 31: Seal Coating Weight Gain Range

[0252] Prescription: as shown in Table 36.

[0253] Preparation method of Prescription 66-Prescription 68, Comparative Prescription 24-Comparative Prescription 25: Prepare according to the preparation method of Prescription 63-Prescription 65 in Example 29 to obtain enteric-coated amorphous nanoparticle capsules.

[0254] Table 36: Seal Coating Formulation

[0255] Example 32: Dissolution Data

[0256] Dissolution tests were performed on enteric-coated amorphous nanoparticle capsules prepared from Prescriptions 66 to 68 and Comparative Prescriptions 24 to 25 in Example 33. The dissolution operation was the same as in Example 30. The test results are shown in Table 37.

[0257] Table 37: Dissolution results of formulations 66-68 and 23-24 (%, n=3)

[0258] Analysis of results: If the blocking ability of the isolation layer is too strong, the dissolution will be slowed down in the dissolution medium of pH 6.8. If the blocking ability is too low, the medium entering the layered drug layer will also destroy the amorphous state of apalutamide. When the ratio of the total mass of the drug pellets and the isolation layer to the mass of the drug pellets is 1.03:1-1.3:1, the isolation layer has a protective effect and will not reduce the dissolution rate in the dissolution medium of pH 6.8.

[0259] Example 33: Enteric Coating Solution

[0260] Prescription: as shown in Table 38.

[0261] Preparation method of prescription 69: prepare the medicated micropills according to the preparation method of prescription 2 in Example 1; dissolve the isolation layer material in the prescription in water to form a coating solution, and perform isolation layer coating through a fluidized bed; first dissolve triethyl citrate, glyceryl monostearate, and Tween 80 in water, and then add the prescribed amount of Eudragit L30D-55 and stir until homogeneous to obtain an enteric coating solution, perform enteric layer coating through a fluidized bed, and finally, place the coated micropills into capsules to obtain enteric-coated amorphous nanoparticle capsules.

[0262] Preparation method of Prescription 70: Prepare the medicated micropills according to the preparation method of Prescription 2 in Example 1; dissolve the isolation layer material in the prescription in water to form a coating solution, and perform isolation layer coating through a fluidized bed; add triethyl citrate, hydroxypropyl methylcellulose acetate succinate, and glyceryl monostearate to a solution containing ethanol and water, stir and disperse, and then homogenize, and perform enteric layer coating through a fluidized bed. Finally, the coated micropills are placed in capsules to obtain enteric-coated amorphous nanoparticle capsules.

[0263] Table 38: Enteric Coating Formulation

[0264] Example 34: Dissolution Test

[0265] Amorphous apalutamide nanoparticle capsules prepared according to Prescriptions 69 and 70 in Example 33 were subjected to dissolution tests respectively. The dissolution procedures were the same as those in Example 30. The test results are shown in Table 39.

[0266] Table 39: Dissolution results of formulations 60-61 and (%, n=3)

[0267] Example 35: Enteric Coating Weight Gain Range

[0268] Prescription: as shown in Table 40.

[0269] Preparation method of Prescription 71-Prescription 73, Comparative Prescription 26-Comparative Prescription 27: Prepare according to the preparation method of Prescription 70 in Example 33 to obtain enteric-coated amorphous nanoparticle capsules.

[0270] Preparation method of comparative prescription 28: Prepare the medicated micropellets according to the preparation method of prescription 2 in reference example 1; dissolve the isolation layer material in the prescription in water to form a coating solution, and apply the isolation layer coating through a fluidized bed; put the coated micropellets into capsules to obtain amorphous nanoparticle capsules.

[0271] Table 40: Enteric Coating Formulation

[0272] Example 36: Dissolution Test

[0273] Dissolution tests were performed on amorphous apalutamide nanoparticle capsules prepared from Prescriptions 71 to 73 in Example 35, Comparative Prescriptions 26 to 28, and nanoparticle capsules prepared from Comparative Prescription 28. The dissolution operation was the same as in Example 30. The test results are shown in Table 41.

[0274] Table 41: Dissolution results of prescriptions 71-73 and comparative prescriptions 26-28 (%, n=3)

[0275] Analysis of results: Without enteric coating or if the enteric coating is too thin, hydrochloric acid medium will penetrate through the isolation layer and enter the layered drug layer, resulting in the destruction of the amorphous state of apalutamide and a decrease in dissolution. If the enteric coating is too thick, the medium will enter too slowly, resulting in slow dissolution and incomplete dissolution. When the ratio of the total mass of the drug pellets, isolation layer and enteric layer to the total mass of the drug pellets and isolation layer is 1.1:1 to 1.3:1, the enteric coating has sufficient protective effect and will not reduce the dissolution rate in the dissolution medium of pH 6.8, which has unexpected technical effects.

[0276] Example 37: Stability Study

[0277] Preparation method of Prescription 74-Prescription 75, Comparative Prescription 29-Comparative Prescription 30: Prepare according to the preparation method of Prescription 70 in Example 33 to obtain enteric-coated amorphous nanoparticle capsules.

[0278] Prescription 74, Prescription 75, Comparative Prescription 29, and Comparative Prescription 30 were placed under accelerated conditions (40°C ± 2°C, 75% RH ± 5% RH) for 6 months (A6M). The samples at 0 day and those placed under accelerated conditions for 6 months were tested for dissolution in a dissolution medium of pH 6.8 (the dissolution conditions were the same as in Example 2), and the samples were tested for acid resistance in 0.1M HCl and then in a dissolution medium of pH 6.8 (the dissolution conditions were the same as in Example 30). The content, related substances, and crystal form were tested. The results are shown in Tables 42 to 45 and Figure 6.

[0279] Table 42: Stability Study Formulation

[0280] Example 38: Stability Data

[0281] Table 43: pH 6.8 dissolution results during stability of Formulations 74-75 and Comparative Formulations 29-30 (%, n=3)

[0282] Table 44: Dissolution results of 0.1M HCl-pH 6.8 during the stability process of Formulation 74-Formulation 75 and Comparative Formulation 29-Comparative Formulation 30 (%, n=3)

[0283] Table 45: Content and related substance data during the stability process of Prescription 74-Prescription 75 and Comparative Prescription 29-Comparative Prescription 30

[0284] Note: LOQ means limit of quantification (0.05%), and ND means not detected.

[0285] FIG6 shows, from top to bottom, the XRD patterns of apalutamide Form B, the XRD patterns of sample A6M of comparative prescription 30, the XRD patterns of sample A6M of comparative prescription 74, the XRD patterns of sample A6M of comparative prescription 75, and the XRD patterns of sample A6M of comparative prescription 29.

[0286] Result analysis: The dissolution, related substances and content data of target prescriptions 74 and 75 were stable during the stability process, with unexpected technical effects. In contrast, prescription 29 used poloxamer P188 as a non-ionic stabilizer. Although the content and related substances did not change significantly during the entire stability process, the dissolution may have decreased significantly due to crystal transformation. In contrast, prescription 30 did not add a protective agent. Its dissolution platform decreased significantly on day 0. This may be due to the curing damage dissolution caused by the lack of a protective agent during the curing process, which caused the dissolution to decrease. The dissolution further decreased during the stability process.

[0287] Example 39: In vivo pharmacokinetic study in animals (enteric-coated amorphous nanoparticle capsules)

[0288] Dosing regimen: Three-dose, three-cross (12 healthy Beagle dogs, half male and half female, divided into three groups, 4 dogs each). Administer the drug on an empty stomach. (To ensure fasting conditions similar to those in humans, all groups received an intramuscular injection of pentagastrin 0.5 hours before dosing to promote gastric acid secretion.)

[0289] Experimental group: Group A: reference preparation (manufacturer: Xi'an Janssen; specification: 60 mg; batch number: 19LG0585) apalutamide tablets (specification: 60 mg / tablet) once a day, 1 tablet each time.

[0290] Group B: Apalutamide amorphous nanoparticle capsules (enteric-coated micropellet capsules, specification: 60 mg / capsule) obtained from prescription 74 in Example 37 were taken once a day, 1 capsule each time.

[0291] Group C: Apalutamide amorphous nanoparticle capsules (enteric-coated micropellet capsules, specification: 60 mg / capsule) obtained from comparative prescription 28 in Example 37 were taken once a day, 1 capsule each time.

[0292] After administration under fasting conditions, blood samples were collected at 0, 0.25, 0.5, 1, 2, 5, 8, 24, 48, 96, 144, 220 and 360 hours to determine blood drug concentrations.

[0293] Table 46 lists the pharmacokinetic data of 60 mg apalutamide amorphous nanoparticle capsules prepared by formulation 74, comparative formulation 28, and the reference preparation in Beagle dogs.

[0294] Table 46: Results of in vivo pharmacokinetic studies in animals

[0295] Analysis of results: According to the in vivo pharmacokinetic study results of animals in Table 46, this animal experiment adopted a 3-way crossover design. There were still differences between Prescription 28 and RLD. The maximum blood drug concentration and the area under the blood drug concentration-time curve of Prescription 28 were 71.06% and 69.41% of the reference, respectively. The bioavailability was still lower than that of the reference preparation. The efficacy of taking this preparation could not be guaranteed. Prescription 28 and Prescription 2 both used amorphous apalutamide. The maximum blood drug concentration and the area under the blood drug concentration-time curve of Prescription 2 were 62.44% and 67.65% of the reference, respectively. This shows that it is very sensitive to acid after solidification. The presence of the isolation layer can still slightly delay the penetration of gastric acid into the upper drug layer and reduce the crystal conversion rate. The maximum blood drug concentration and the area under the blood drug concentration-time curve of group B were 103.03% and 105.88% of the reference, respectively. The bioavailability was closer to that of the reference preparation, and there was no significant difference. Combined with the experiments of prescription 1 and comparative prescription 3, the absorption of different forms of active ingredients in animals showed great differences. The amorphous active ingredient was better absorbed in the body. This shows that the preparation of nanoparticles with amorphous apalutamide can achieve equivalence to the reference without causing curing damage during the curing process and under the protection of the enteric coating film, which has unexpected technical effects.

[0296] While the present invention has been described through preferred embodiments, it is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope and content of the present invention to implement and apply the present invention. Those skilled in the art may, drawing upon the present invention, appropriately modify the process parameters to implement the present invention. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A nanoparticle, characterized in that, It includes an active ingredient and a stabilizer. The active ingredient is amorphous apalutamide or a pharmaceutically acceptable salt thereof, and the stabilizer includes an ionic stabilizer and a steric stabilizer.

2. The nanoparticles according to claim 1, wherein the D90 particle size of the nanoparticles is less than 1000 nm, or the D90 particle size of the nanoparticles is less than 800 nm, or the D90 particle size of the nanoparticles is less than 600 nm, or the D90 particle size of the nanoparticles is less than 500 nm.

3. The nanoparticles according to claim 1, wherein the ionic stabilizer includes one or more of sodium dodecyl sulfate, sodium dodecyl sulfonate, dioctyl sodium sulfosuccinate, benzethonium chloride, sodium docusate, arginine salt, and lecithin; the steric stabilizer includes one or more of hypromellose acetate succinate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, and povidone; the ionic stabilizer is sodium dodecyl sulfate and the steric stabilizer is hypromellose acetate succinate; or the ionic stabilizer is sodium dodecyl sulfate and the steric stabilizer is hydroxypropyl cellulose.

4. The nanoparticles according to claim 1, calculated based on the total mass of the nanoparticles, the content of the active ingredient is 1.00 wt% - 80.00 wt% or 5.00 wt% - 79.00 wt%; and / or the mass ratio of the steric stabilizer to the active ingredient is 1:6 - 2:1, preferably 1:2 - 2:1; and / or the mass ratio of the ionic stabilizer to the active ingredient is 1:100 - 1:

1.

5. The nanoparticles according to claim 1, the nanoparticles are prepared by using one or more of the methods of precipitation method, emulsification method, high-pressure homogenization method, media milling method or high-pressure microfluidization method in combination, preferably the media milling method.

6. The nanoparticle according to claim 1, wherein the preparation method of the nanoparticle comprises: Dissolve the steric stabilizer and the ionic stabilizer with a milling solvent, then add the active ingredient, stir to obtain a suspension, and mill to obtain a suspension containing the nanoparticles according to claim 1; Optionally, the milling includes milling after mixing the suspension and milling beads; Optionally, the milling solvent includes water or a buffered saline solution with a pH of 6.8; and / or Optionally, the buffer salt in the buffered saline solution with a pH of 6.8 includes phosphate.

7. A pharmaceutical preparation, the pharmaceutical preparation includes the nanoparticles according to claim 1; Optionally, the pharmaceutical preparation is a granule, a suspension, a capsule or a tablet.

8. The pharmaceutical preparation according to claim 7, the pharmaceutical preparation is a granule, and the granule includes the nanoparticles according to claim 1 and pharmaceutically acceptable excipients.

9. The pharmaceutical preparation according to claim 7, the pharmaceutical preparation is a suspension, and the suspension includes the nanoparticles according to claim 1 and water.

10. The pharmaceutical preparation according to claim 9, the suspension further includes a protective agent.

11. The pharmaceutical preparation according to claim 7, wherein the pharmaceutical preparation is a capsule, wherein the contents of the capsule contain the upper medicine pellets, and the upper medicine pellets contain the nanoparticles and pellet cores according to claim 1; or The pharmaceutical preparation is a capsule, the contents of the capsule include the upper medicine pellets and an enteric layer outside the upper medicine pellets, the upper medicine pellets contain the nanoparticles and pellet cores according to claim 1, and the enteric layer is made of enteric material; or The pharmaceutical preparation is a capsule, the contents of which include the upper medicine pellets, an isolation layer outside the upper medicine pellets and an enteric layer outside the upper medicine pellets, the upper medicine pellets contain the nanoparticles and pellet cores according to claim 1, and the enteric layer is an enteric material.

12. The pharmaceutical preparation according to claim 11, wherein the material of the isolation layer in the capsule comprises at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, acrylic resin No. IV, and polyvinyl acetal diethylaminoacetic acid; and / or The enteric material in the capsule comprises at least one of hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, acrylic resin, alginate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and cellulose acetate phthalate; and / or The mass ratio of the nanoparticles to the pellet core in the upper medicine pellets in the capsule is 1:3.97 to 8:1 or 1:4 to 8:1; and / or In the capsule, the ratio of the total mass of the upper drug pellets and the isolation layer to the mass of the upper drug pellets is 1.03:1.00-1.30:1.00, calculated based on the total mass of the drug preparation; and / or The contents of the capsule include the upper medicine pellets and the enteric layer outside the upper medicine pellets. In the capsule, the ratio of the total mass of the upper medicine pellets and the enteric layer to the mass of the upper medicine pellets is 1.1:1.0-1.3:1.0, calculated based on the total mass of the drug preparation; and / or The contents of the capsule include upper medicine pellets, an isolation layer outside the upper medicine pellets and an enteric layer outside the upper medicine pellets. In the capsule, calculated based on the total mass of the drug preparation, the ratio of the total mass of the upper medicine pellets, the isolation layer and the enteric layer to the total mass of the upper medicine pellets and the isolation layer is 1.1:1.0 to 1.3:1.

0.

13. The pharmaceutical preparation according to claim 7, which is a tablet, comprising the nanoparticles according to claim 1 and other pharmaceutically acceptable excipients.

14. The pharmaceutical preparation according to claim 13, wherein the other pharmaceutically acceptable excipients in the tablet include at least one of a disintegrant, a filler, a glidant, and a lubricant; and / or The disintegrant in the tablet comprises at least one selected from corn starch, starch, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, light anhydrous silicic acid, calcium silicate, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, and sodium carboxymethyl starch; and / or The filler in the tablet includes at least one selected from microcrystalline cellulose, mannitol, lactose, starch, corn starch, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate, calcium dihydrogen phosphate, magnesium carbonate, calcium carbonate, purified sucrose, and glucose; and / or The glidant in the tablet includes colloidal silicon dioxide; and / or The lubricant in the tablet includes at least one of magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc powder, and stearic acid.

15. The pharmaceutical preparation according to claim 10, wherein the mass ratio of the protective agent to the active ingredient is 4:1 to 1:6; and / or The protective agent includes a high molecular compound or a sugar alcohol; and / or The sugar alcohol protective agent includes at least one of mannitol, lactose, fructose, glycine, glucose, sucrose, maltose, trehalose, sorbitol, xylitol, polydextrose, fructooligosaccharide, maltooligosaccharide, galactooligosaccharide, and dextrin. The mass ratio of the sugar alcohol protective agent to the active ingredient is 4:1 to 1:6; and / or The high molecular protective agent includes at least one of hypromellose acetate succinate, copovidone VA64, hydroxypropyl cellulose, hydroxymethyl cellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, vinylpyrrolidone-vinyl acetate copolymer, or polyvinylpyrrolidone; and / or The mass ratio of the high molecular protective agent to the active ingredient is 4:1 to 1:6; and / or Preferably, the high molecular compound is hypromellose acetate succinate.

16. The pharmaceutical preparation according to claim 7, wherein the pharmaceutical preparation is a capsule, and the preparation method of the pharmaceutical preparation comprises: Dissolve the spatial stabilizer and the ionic stabilizer in a grinding solvent, then add the active ingredient, stir to obtain a suspension, and grind to obtain a suspension containing the nanoparticles according to claim 1; mix the obtained suspension with the protective agent and then solidify it onto the pill core to obtain coated pellets, and then fill the coated pellets into a capsule to obtain the capsule; Or The pharmaceutical preparation is a capsule, and the preparation method includes: dissolving the spatial stabilizer and the ionic stabilizer in a grinding solvent, then adding the active ingredient, stirring to obtain a suspension, and grinding to obtain a suspension containing the nanoparticles according to claim 1; mixing the obtained suspension with the protective agent and then solidifying it onto the pill core to obtain coated pellets, then coating the coated pellets with the enteric material to obtain enteric-coated coated pellets, and then filling the enteric-coated coated pellets into a capsule to obtain the capsule; Or The pharmaceutical preparation is a capsule, and the preparation method includes: dissolving the spatial stabilizer and the ionic stabilizer in a grinding solvent, then adding the active ingredient, stirring to obtain a suspension, and grinding to obtain a suspension containing the nanoparticles according to claim 1; mixing the obtained suspension with the protective agent and then solidifying it onto the pill core to obtain coated pellets, then wrapping the coated pellets with the material of the isolating layer, then coating with the enteric material, and then filling into a capsule to obtain the capsule; Optionally, the grinding includes grinding after mixing the suspension and grinding beads; Optionally, the grinding solvent includes water or a buffered saline solution with a pH of 6.8; Optionally, the buffer salt in the buffer saline solution with pH 6.8 includes phosphate.

17. The pharmaceutical preparation according to claim 16, wherein the curing in the preparation method of the capsule includes curing by using a fluidized bed layer-by-layer coating process.

18. The pharmaceutical preparation according to claim 7, wherein the pharmaceutical preparation is a tablet, and the preparation method comprises: Dissolve the spatial stabilizer and the ionic stabilizer in a grinding solvent, then add the active ingredient, stir to obtain a suspension, grind to obtain a suspension containing the nanoparticles as claimed in claim 1; mix the obtained suspension with a protective agent and then carry out curing, and then mix with other pharmaceutically acceptable excipients, and tableting to obtain the tablets; Optionally, the grinding includes grinding after mixing the suspension and grinding beads. Optionally, the grinding solvent includes water or a buffer saline solution with pH 6.

8. Optionally, the buffer salt in the buffer saline solution with pH 6.8 includes phosphate. Optionally, the curing in the preparation method of the tablets includes curing by using spray drying or freeze drying. Optionally, the curing in the preparation method of the tablets is carried out by freeze drying, and the preparation method further includes grinding and sieving after curing, and then mixing with other pharmaceutically acceptable excipients.

19. The pharmaceutical preparation according to claim 7, wherein the pharmaceutical preparation is a granule, and the preparation method of the pharmaceutical preparation comprises: Dissolve the spatial stabilizer and the ionic stabilizer in a grinding solvent, then add the active ingredient, stir to obtain a suspension, grind to obtain a suspension containing the nanoparticles as claimed in claim 1; mix the obtained suspension with a protective agent and then carry out curing, then add other pharmaceutically acceptable excipients, mix, dry granulate, and then mix with a lubricant and / or a flavoring agent to obtain the granules; Optionally, the grinding includes grinding after mixing the suspension and grinding beads. Optionally, the grinding solvent includes water or a buffer saline solution with pH 6.

8. Optionally, the buffer salt in the buffer saline solution with pH 6.8 includes phosphate. Optionally, the other pharmaceutically acceptable excipients of the granules include at least one of a filler, a lubricant, and a flavoring agent; Optionally, the filler in the granules includes at least one of sucrose, lactose, mannitol, sorbitol, maltitol, xylitol, erythritol, glucose, starch, and dextrin; Optionally, the lubricant in the granules includes at least one of magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc powder, and magnesium oxide; Optionally, the flavoring agent in the granules includes at least one of sucralose, aspartame, sodium saccharin, sucrose, strawberry essence, orange essence, mint essence, peach essence, and banana essence; Optionally, the curing in the preparation method of the pharmaceutical preparation includes spray drying, freeze drying, or fluidized bed granulation.

20. The pharmaceutical preparation according to claim 7, wherein the pharmaceutical preparation is a granule, and the preparation method of the pharmaceutical preparation comprises: Dissolve the spatial stabilizer and the ionic stabilizer in a grinding solvent, then add the active ingredient, stir to obtain a suspension, grind to obtain a suspension containing the nanoparticles as claimed in claim 1; adopt a fluidized bed granulation process for the obtained suspension and spray it on a filler substrate to prepare granules, and then mix with a lubricant and / or a flavoring agent to obtain the granules; Optionally, the grinding includes grinding after mixing the suspension and grinding beads; Optionally, the grinding solvent includes water or a buffered saline solution with a pH of 6.8; Optionally, the buffer salt in the buffered saline solution with a pH of 6.8 includes phosphate; Optionally, the filler in the granule includes at least one of sucrose, lactose, mannitol, sorbitol, maltitol, xylitol, erythritol, glucose, starch, and dextrin; Optionally, the lubricant in the granule includes at least one of magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc, and magnesium oxide; Optionally, the flavoring agent in the granule includes at least one of sucralose, aspartame, sodium saccharin, sucrose, strawberry essence, orange essence, mint essence, peach essence, and banana essence; Optionally, the solidification in the preparation method of the pharmaceutical preparation includes spray drying, freeze drying, or fluidized bed granulation.

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