Risperidone drug composition and preparation method thereof

Abstract

The present application relates to a lurasidone hydrochloride pharmaceutical composition and a preparation method thereof. The present application discloses a lurasidone hydrochloride pharmaceutical composition, which comprises lurasidone hydrochloride and a stabilizer, wherein the lurasidone hydrochloride is in nanoscale. The prepared lurasidone hydrochloride pharmaceutical composition can improve the solubility and bioavailability of the drug, and reduce the influence of food effect. The preparation method of the present application is simple in operation, low in production cost and easy to realize industrialized scale-up production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a lurasidone hydrochloride pharmaceutical composition and its preparation method. Background Technology

[0002] Lurasidone hydrochloride, chemically named (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methylene-2H-isoindole-1,3-dione hydrochloride, is a novel second-generation antipsychotic drug developed by Sumitomo Pharmaceutical Co., Ltd. of Dai Nippon. In October 2010, the U.S. FDA approved lurasidone hydrochloride tablets. It was marketed for the treatment of schizophrenia. In June 2013, the FDA approved it for the treatment of bipolar disorder. In March 2014, it was approved for marketing in the European Union for the treatment of schizophrenia. In January 2019, it received NMPA import drug registration approval for the treatment of psychiatric patients. Lurasidone hydrochloride is a bidirectional inhibitor of central dopamine receptor 2 (D2) and serotonin 2 (5-HT2A).

[0003] The FDA instructions state that lurasidone hydrochloride should be taken with at least 350 kcal of food, as its bioavailability is low (9%–19%). When taken with food, the blood concentration (C) is... max The area under the curve (AUC) for both the drug and time was 3 times and 2 times that of the drug taken on an empty stomach, respectively. The positive effect of food on the bioavailability of lurasidone may be attributed to delayed gastric emptying and altered gastrointestinal pH. However, the requirement for postprandial administration is challenging for patients taking medication for psychiatric disorders; therefore, developing a drug that improves the bioavailability of lurasidone and reduces the food effect remains a pressing challenge for pharmaceutical researchers.

[0004] Lurasidone hydrochloride is a Class II biopharmaceutical system drug (BCS). Its low solubility and dissolution rate are the main reasons for its low oral bioavailability.

[0005] Drug nanocrystal technology refers to the process of dispersing or precipitating micron-sized drug particles through grinding, dispersion, or crystallization, reducing the particle size to the nanometer scale and ensuring their stability with the aid of stabilizers. Techniques for preparing nanocrystals can be categorized into top-down methods (such as high-pressure homogenization or media grinding) and bottom-up methods (such as good solvent-antisolvent addition and supercritical fluid methods). Bottom-up methods involve a physicochemical process of drug dissolution (solvent) and precipitation, making them unsuitable for commercial production. They suffer from solvent residue issues, difficulty in process control, and high costs. Top-down methods, on the other hand, utilize mechanical grinding to reduce drug particle size to the nanometer scale, making them suitable for commercial production.

[0006] Advantages of oral drug administration using nanocrystalline materials: The surface area of ​​poorly soluble drugs is closely related to their bioavailability. Reducing particle size can significantly increase the saturated solubility and dissolution rate of drugs, enabling rapid absorption and onset of action, thereby significantly improving drug bioavailability. Eliminating the food effect: Oral administration of conventional formulations of poorly soluble drugs is greatly affected by food. After eating, due to bile secretion and increased surfactant concentration, solubility increases, and the physiological environment at this time is conducive to improved bioavailability. Conversely, bioavailability is usually reduced in a fasting state, resulting in large differences in oral absorption. Nanocrystalline formulations can reduce the variability in drug absorption in the gastrointestinal tract and significantly reduce the food effect.

[0007] Patent application CN109998991A discloses a long-acting intramuscular injection nanosuspension of lurasidone hydrochloride and its preparation method. The method involves high-speed dispersion combined with wet media milling to prepare a nanosuspension of lurasidone hydrochloride for intramuscular injection. However, it is a long-acting injectable solution, not an oral formulation, and does not involve solidification or reconstitution. Therefore, the nanosuspension has poor stability and is difficult to store for extended periods. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of the prior art and provide a stable and effective lurasidone hydrochloride pharmaceutical composition and its preparation method, so as to improve the solubility and bioavailability of the drug, while reducing the influence of food effects.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] A pharmaceutical composition of lurasidone hydrochloride, comprising lurasidone hydrochloride and a stabilizer, wherein the lurasidone hydrochloride is nanoscale, preferably crystalline.

[0011] In this invention, the initial particle size of lurasidone hydrochloride is d90 < 300 μm, d90 < 200 μm, d90 < 160 μm, d90 < 120 μm, d90 < 80 μm, d90 < 50 μm, d90 < 20 μm, d90 < 10 μm, or a combination of several particle size ranges. When the particle size is d90 < 10 μm, the grinding efficiency can be greatly improved.

[0012] In this invention, the stabilizer is selected from one or more of cellulose, polymers, surfactants, and natural stabilizers; preferably, the cellulose is selected from one or more of methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, and hydroxypropyl methylcellulose; the polymer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers, povidone, polyvinyl alcohol-polyoxyethylene castor oil, and polyethylene glycol succinate; the surfactant is selected from one or more of sodium dodecylbenzenesulfonate, cisplatin, Tween, Span, and sodium dodecyl sulfate; and the natural stabilizer is selected from one or more of sodium alginate, dextran, gum arabic, mannitol, lecithin, and chitosan; more preferably, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyoxyethylene-polyoxypropylene block copolymers, povidone, mannitol, Span, and Tween; further preferably, hydroxypropylcellulose, hydroxypropyl methylcellulose, Tween, and Span; and even more preferably, a combination of hydroxypropyl methylcellulose and Tween.

[0013] In this invention, the percentage of component weight calculated based on the total weight of the prescription is calculated based on the total weight of the prescription of the solvent-free pharmaceutical composition.

[0014] In this invention, the weight percentage of the stabilizer is 10-80% based on the total weight of the prescription, preferably 10-70%, more preferably 20-60%, and even more preferably 40-60%.

[0015] In this invention, hydroxypropyl methylcellulose is selected from one or more combinations of hydroxypropyl methylcellulose with different viscosity ranges; preferably, the viscosity range is 1 to 6500 mPa·s, more preferably, the viscosity range is 1 to 4000 mPa·s; further preferably, the viscosity range is 1 to 400 mPa·s; even more preferably, the viscosity range is 3 to 50 mPa·s; and most preferably, the viscosity range is 3 to 15 mPa·s.

[0016] The viscosity of this invention refers to the apparent viscosity of a 2% hydroxypropyl methylcellulose aqueous solution at 20°C. This includes various commercially available hydroxypropyl methylcellulose grades such as K100LVP, K4M, E4MP, E10, E3, E5, E6, E15, E50, K3, SL, SSL, EF, and ELF that meet the specified conditions.

[0017] In this invention, Tween is selected from one or more of Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 80, Tween 81 and Tween 85; preferably Tween 40, Tween 60 and 80; more preferably Tween 80.

[0018] In this invention, the stabilizer is a combination of hydroxypropyl methylcellulose and Tween. The weight percentage of hydroxypropyl methylcellulose is 10-60%, preferably 20-55%, more preferably 30-55%, and even more preferably 40-55%, based on the total weight of the formulation. The weight percentage of Tween is 0-10%, preferably 0-5%, and more preferably 0.1-3%.

[0019] In this invention, the weight percentage of lurasidone hydrochloride is 20-90%, preferably 30-90%, more preferably 40-80%, and even more preferably 40-60% based on the total weight of the prescription.

[0020] In this invention, the solvent is water, including ultrapure water, water for injection, or distilled water.

[0021] In this invention, the stabilizer can be prepared into a solution with a concentration of 0.1% to 15%, preferably a solution with a concentration of 0.1% to 10%, more preferably a solution with a concentration of 0.1% to 5%, and then further prepared into a nanocrystal suspension with the active ingredient.

[0022] In this invention, the particle size of lurasidone hydrochloride nanocrystal suspension is d90 < 1000 nm, d90 < 800 nm, d90 < 600 nm, d90 < 300 nm, d90 < 200 nm, d90 < 100 nm, d90 < 50 nm, or a combination of several particle size ranges. The smaller the particle size, the greater the increase in drug saturation solubility and dissolution rate, allowing for rapid drug absorption and onset of action, thereby significantly improving drug bioavailability. Considering both grinding efficiency and energy consumption, a particle size of d90 < 300 nm for the lurasidone hydrochloride nanocrystal suspension is preferable.

[0023] The present invention also provides a pharmaceutical composition of lurasidone hydrochloride, wherein a redispersant and a filler are added to the above-mentioned nanocrystal suspension to prepare a nanocrystal solidified product.

[0024] In this invention, the redispersant is sucrose, trehalose, mannitol, lactose, glucose, maltose, povidone, polyethylene glycol, dextran, albumin, ethylene glycol, glycerol, dimethyl sulfoxide, dimethylformamide, Tween, L-serine, monosodium glutamate, alanine, glycine, sarcosine, acetate, citrate, tartrate, phosphate, microcrystalline cellulose, starch, sodium chloride, benzoate, benzenesulfonate; preferably sucrose or trehalose; more preferably sucrose.

[0025] In this invention, the weight percentage of the redispersant, based on the total weight of the prescription, is 1-40%, or 1-30%, or 1-25%, or 1-20%, or 5-20%, or 10-25%.

[0026] In this invention, the filler is one or more of the following: anhydrous α-lactose, α-lactose monohydrate, β-lactose, corn starch, wheat starch, potato starch, pregelatinized starch, dextrin, microcrystalline cellulose, mannitol, sucrose, powdered sugar, erythrose, xylitol, sorbitol, calcium sulfate, dicalcium phosphate, calcium carbonate, calcium sulfate dihydrate, calcium sulfate, magnesium oxide, aluminum hydroxide, microcrystalline cellulose pellet core, sucrose pellet core, starch microspheres, and tartaric acid pellet core; preferably lactose, starch, and mannitol; more preferably lactose.

[0027] In this invention, the weight percentage of lactose, based on the total weight of the prescription, is 20-90%, or 30-90%, or 40-90%, or 30-80%, or 50-80%, or 60-70%.

[0028] To ensure the nanocrystalline particle size of the finished formulation, the particle size of the lurasidone hydrochloride nanocrystal composition after resolidation following solidification and granulation was monitored. After resolidation, the particle size of the lurasidone hydrochloride nanocrystal solidified product was d90 < 1000 nm, d90 < 800 nm, d90 < 600 nm, d90 < 400 nm, d90 < 200 nm, or a combination of several particle size ranges; preferably, the particle size was d90 < 600 nm.

[0029] The present invention also provides a composition of lurasidone hydrochloride comprising the above-described lurasidone hydrochloride nanocrystal solidified material and one or more pharmaceutically acceptable excipients.

[0030] In this invention, pharmaceutically acceptable excipients are all commonly used excipients, including one or more of diluents, disintegrants, and lubricants.

[0031] In this invention, the diluent includes one or more of lactose, starch, microcrystalline cellulose, mannitol, pregelatinized starch, and sucrose; microcrystalline cellulose is preferred.

[0032] In this invention, the weight percentage of the diluent is 1-30% based on the total weight of the prescription, preferably 1-20%, more preferably 1-15%, and even more preferably 5-15%.

[0033] In this invention, the disintegrant includes one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, starch, modified starch, microcrystalline cellulose, sodium alginate, carboxymethyl starch, or sodium carboxymethyl starch; preferably crospovidone sodium carboxymethyl cellulose.

[0034] In this invention, the weight percentage of the disintegrant is 1-15% based on the total weight of the prescription, preferably 1-10%, and more preferably 1-5%.

[0035] In this invention, the lubricant includes one or more of talc, micronized silica gel, hydrogenated vegetable oil, sodium stearate fumarate, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol, or magnesium stearate; preferably magnesium stearate.

[0036] In this invention, the weight percentage of the lubricant, based on the total weight of the prescription, is 0 to 5%, preferably 0 to 3%, and more preferably 0.1 to 2%.

[0037] In this invention, each unit dose of the lurasidone hydrochloride pharmaceutical composition contains 1-500 mg, 5-400 mg, 5-300 mg, 5-200 mg, 5-150 mg, 5-120 mg, 10-100 mg, or 20-80 mg of lurasidone hydrochloride; preferably, each unit dose of the lurasidone hydrochloride nanocrystal oral solid dosage form contains 5-150 mg of active ingredient, more preferably 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride.

[0038] In one embodiment of the present invention, the pharmaceutical composition comprises the following components:

[0039] Components percentage Lurasidone Hydrochloride 20～90％ stabilizer 10～80％ ;

[0040] or,

[0041] Components percentage Lurasidone Hydrochloride 30～90％ stabilizer 10～70％ ;

[0042] or,

[0043]

[0044]

[0045] or,

[0046] Components percentage Lurasidone Hydrochloride 40～80％ Hydroxypropyl methylcellulose 20～60％ ;

[0047] or,

[0048] Components percentage Lurasidone Hydrochloride 40～80％ Hydroxypropyl methylcellulose 30～55％ Twain 0～5％ ;

[0049] or,

[0050] Components percentage Lurasidone Hydrochloride 40～60％ Hydroxypropyl methylcellulose 40～55％ Twain 0.1～3％ .

[0051] In another embodiment of the present invention, the pharmaceutical composition comprises the following components:

[0052] Components percentage Nanocrystal suspension 1～40％ redispersant 1～30％ filler 40～90％ ;

[0053] or,

[0054] Components percentage Nanocrystal suspension 5～35％ redispersant 1～25％ filler 50～80％ ;

[0055] or,

[0056] Components percentage Nanocrystal suspension 10～30％ redispersant 5～25％ filler 60～75％ ;

[0057] or,

[0058] Components percentage Nanocrystal suspension 10～25％ sucrose 10～25％ lactose 60～70％ .

[0059] In another embodiment of the present invention, the pharmaceutical composition comprises the following components:

[0060] Components percentage Nanocrystal solidified material 60～95％ diluent 1～30％ Disintegrant 1～15％ lubricant 0～5％ ;

[0061] or,

[0062] Components percentage Nanocrystal solidified material 70～95％ diluent 1～20％ Disintegrant 1～10％ lubricant 0～3％ ;

[0063] or,

[0064] Components percentage Nanocrystal solidified material 80～95％ diluent 1～15％ Disintegrant 1～5％ lubricant 0～3％ ;

[0065] or,

[0066] Components percentage Nanocrystal solidified material 80～95％ microcrystalline cellulose 1～15％ Disintegrant 1～5％ lubricant 0～3％ ;

[0067] or,

[0068] Components percentage Nanocrystal solidified material 80～95％ microcrystalline cellulose 1～15％ Cross-linked carboxymethyl cellulose sodium 1～5％ lubricant 0～3％ ;

[0069] or,

[0070] Components percentage Nanocrystal solidified material 80～95％ microcrystalline cellulose 1～15％ Cross-linked carboxymethyl cellulose sodium 1～5％ magnesium stearate 0.1～2％ .

[0071] In another embodiment of the present invention, the pharmaceutical composition comprises the following components:

[0072] Components percentage Lurasidone Hydrochloride 1～25％ stabilizer 1～25％ redispersant 1～30％ filler 40～80％ diluent 1～25％ Disintegrant 1～15％ lubricant 0～5％ ;

[0073] or,

[0074] Components percentage Lurasidone Hydrochloride 1～20％ stabilizer 1～20％ redispersant 1～25％ filler 45～75％ diluent 1～20％ Disintegrant 1～10％ lubricant 0～3％ ;

[0075] or,

[0076] Components percentage Lurasidone Hydrochloride 1～15％ stabilizer 1～20％ redispersant 1～25％ filler 50～75％ diluent 1～15％ Disintegrant 1～6％ lubricant 0～3％ ;

[0077] or,

[0078] Components percentage Lurasidone Hydrochloride 1～15％ stabilizer 1～15％ redispersant 10～20％ filler 50～65％ diluent 1～15％ Disintegrant 1～5％ lubricant 0.1～2％ .

[0079] In another embodiment of the present invention, the pharmaceutical composition comprises the following components:

[0080] Components percentage Lurasidone Hydrochloride 1～15％ Hydroxypropyl methylcellulose 1～15％ Twain 0～1％ redispersant 10～20％ filler 50～65％ diluent 1～15％ Disintegrant 1～5％ lubricant 0～2％ ;

[0081] or,

[0082] Components percentage Lurasidone Hydrochloride 1～15％ Hydroxypropyl methylcellulose 1～15％ Twain 0～1％ sucrose 10～20％ filler 50～65％ diluent 1～15％ Disintegrant 1～5％ lubricant 0～2％ ;

[0083] or,

[0084]

[0085]

[0086] or,

[0087] Components percentage Lurasidone Hydrochloride 1～15％ Hydroxypropyl methylcellulose 1～15％ Twain 0～1％ sucrose 10～20％ lactose 50～65％ microcrystalline cellulose 1～15％ Disintegrant 1～5％ lubricant 0～2％ ;

[0088] or,

[0089] Components percentage Lurasidone Hydrochloride 1～15％ Hydroxypropyl methylcellulose 1～15％ Twain 0～1％ sucrose 10～20％ lactose 50～65％ microcrystalline cellulose 1～15％ Cross-linked carboxymethyl cellulose sodium 1～5％ lubricant 0～2％ ;

[0090] or,

[0091]

[0092]

[0093] This invention also provides a method for preparing a lurasidone hydrochloride pharmaceutical composition, characterized by comprising the following steps:

[0094] (1) Prepare a nanocrystal suspension by combining lurasidone hydrochloride, stabilizer and solvent;

[0095] (2) Add redispersant and filler to nanocrystal suspension and granulate to obtain nanocrystal solidified product;

[0096] (3) Nanocrystal compositions are prepared by adding diluents, disintegrants and lubricants to nanocrystal solids;

[0097] (4) The nanocrystal composition is prepared into an oral solid dosage form.

[0098] In this invention, the nanocrystal suspension can be prepared by one or more of the following methods: precipitation, emulsification, high-pressure homogenization, media grinding, or high-pressure microfluidic jetting, with media grinding being the preferred method.

[0099] In this invention, the lurasidone hydrochloride nanocrystal suspension is prepared by a wet grinding process, with water as the solvent.

[0100] In this invention, the preparation method specifically includes the following steps:

[0101] Step 1: Mix water, lurasidone hydrochloride and stabilizer evenly, then add to a ball mill and wet grind to obtain a lurasidone hydrochloride nanocrystal suspension.

[0102] Step 2: Take the lurasidone hydrochloride nanocrystal suspension obtained in Step 1, filter it, add redispersant and filler, and granulate it to obtain lurasidone hydrochloride nanocrystal solidified product.

[0103] Step 3: Take the solidified material obtained in Step 2 and add diluent, disintegrant, and lubricant in sequence to obtain a lurasidone hydrochloride nanocrystal composition.

[0104] Step 4: Take the composition obtained in Step 3 and prepare it into an oral formulation.

[0105] In this invention, the stabilizer is first dissolved in water to prepare an aqueous stabilizer solution, then lurasidone hydrochloride is added and stirred thoroughly. The resulting lurasidone hydrochloride suspension is then added to a ball mill and wet-milled to obtain a lurasidone hydrochloride nanocrystal suspension with the target particle size.

[0106] In this invention, the active pharmaceutical ingredient, lurasidone hydrochloride, is added to a grinding chamber for grinding to prepare a lurasidone hydrochloride nanocrystal suspension. Both excessively high and low proportions of the active pharmaceutical ingredient affect the grinding efficiency and the resulting nanocrystal size. Therefore, in the preparation of the lurasidone hydrochloride nanocrystal suspension, the preferred weight percentage of lurasidone hydrochloride is 40-80%.

[0107] In this invention, the lurasidone hydrochloride nanocrystal suspension is solidified and granulated. The process can be fluidized bed granulation, spray drying or freeze drying, with fluidized bed granulation being preferred.

[0108] In this invention, the pharmaceutical composition can be prepared into various dosage forms, including tablets, granules, capsules, nasal administration preparations, or transdermal preparations; oral solid dosage forms, including granules, capsules, and tablets, are preferred based on medication compliance.

[0109] In one embodiment of the present invention, the pharmaceutical composition can be directly prepared into granules.

[0110] In another embodiment of the invention, the pharmaceutical composition may be further compressed into tablets, optionally coated, to obtain lurasidone hydrochloride nanocrystal tablets.

[0111] In another embodiment of the present invention, the composition can be filled into capsule shells to obtain lurasidone hydrochloride capsules.

[0112] In addition, the lurasidone hydrochloride pharmaceutical composition prepared by the present invention can also be used to prepare drugs for treating mental illnesses, preferably schizophrenia.

[0113] The lurasidone hydrochloride pharmaceutical composition prepared by this invention has the following advantages:

[0114] (1) The present invention uses fewer excipients, reducing costs, and has little impact on particle size after reconstitution;

[0115] (2) The drug crystals prepared by this invention have small particle size, which can better improve bioavailability;

[0116] (3) The nano-formulation prepared by the present invention reduces the variability of oral drug absorption in the gastrointestinal tract and significantly reduces the food effect;

[0117] (4) In addition, the preparation process of the present invention is simple and easy to scale up for industrial production. Attached Figure Description

[0118] Figure 1 This is a dissolution test curve of the lurasidone hydrochloride pharmaceutical composition in Example 3. Detailed Implementation

[0119] The present invention will be further described in detail below with reference to embodiments, but is not limited to the embodiments described below. Equivalent substitutions or modifications made by those skilled in the art based on the present invention, without departing from the essential content of the present invention, are also within the protection scope of the present invention.

[0120] Experiment 1: Screening of Stabilizers

[0121] This invention uses a ball mill for wet grinding to prepare nanocrystals. To further reduce the particle size, a stabilizer needs to be added. This experiment selected one or more different types of stabilizer compositions and conducted tests under the same ball mill parameters (linear velocity 10 m / s, peristaltic pump speed 40 rpm, grinding time 4 h) to determine the optimal composition, with the smallest final particle size of the lurasidone hydrochloride nanocrystal suspension being considered the best. The particle size distribution was measured using a Malvern 3000 laser particle size analyzer, and D50 and D90 were selected as measurement parameters with a weighting of 1:1. The score (S) was calculated using the following formula, with a higher score indicating a better stabilizer composition: Score (S) = 1 / D50 + 1 / D90.

[0122] The experimental design is as follows:

[0123] Table 1 Screening of Stabilizer Types

[0124]

[0125] As can be seen from the data above, when prescription 4 uses a combination of hydroxypropyl methylcellulose E5 and Tween 80 as stabilizers, the resulting lurasidone hydrochloride nanocrystal suspension has a smaller particle size.

[0126] Experiment 2: Screening of redispersants and fillers

[0127] The lurasidone hydrochloride nanocrystal suspension prepared using formula 4 in the stabilizer screening was solidified and granulated using fluidized bed granulation technology. Different redispersants and fillers were tested to determine the optimal composition, with the smallest particle size of the final lurasidone hydrochloride nanocrystal composition being considered the best. The particle size distribution was measured using a Malvern 3000 laser particle size analyzer, with D50 and D90 selected as measurement parameters, weighted at 1:1. The score (S) was calculated using the following formula: Score (S) = 1 / D50 + 1 / D90.

[0128] The experimental design is as follows:

[0129] Table 2 Screening of Redispersants and Composition Fillers

[0130]

[0131] As can be seen from the data above, sucrose was selected as the redispersant and lactose as the filler in Formula 7. After the lurasidone hydrochloride nanocrystal suspension was solidified and granulated, it had little effect on the particle size after reconstitution.

[0132] Example 1

[0133] Preparation of nanocrystal suspension: Hydroxypropyl methylcellulose E5 and Tween 80 were dissolved in water to prepare a stabilizer aqueous solution. Lurasidone hydrochloride was added and stirred thoroughly. The resulting lurasidone hydrochloride suspension was added to a ball mill, and 0.3 mm zirconia beads were added. The peristaltic pump was turned on at a speed of 44 rpm, the grinding chamber speed was 10 m / s, and wet grinding was carried out for 4 h to obtain lurasidone hydrochloride nanocrystal suspension.

[0134]

[0135] Preparation of solidified nanocrystals: The lurasidone hydrochloride nanocrystal suspension obtained in the above steps was filtered through a 300-mesh sieve, sucrose was added as a redispersant and stirred evenly, and lactose was used as a filler as a carrier. The solidified lurasidone hydrochloride nanocrystals were obtained by fluidized bed granulation.

[0136]

[0137]

[0138] Nanocrystal composition: Take the prepared nanocrystal solidified material, add diluent microcrystalline cellulose, disintegrant croscarmellose sodium cellulose, lubricant magnesium stearate in sequence, mix evenly, and further prepare granules, capsules or tablets.

[0139]

[0140] Example 2

[0141] Preparation of nanocrystal suspension: Hydroxypropyl methylcellulose E5 and Tween 80 were dissolved in water to prepare a stabilizer aqueous solution. Lurasidone hydrochloride was added and stirred thoroughly. The resulting lurasidone hydrochloride suspension was added to a ball mill, and 0.3 mm zirconia beads were added. The peristaltic pump was turned on at a speed of 22 rpm, the grinding chamber speed was 10 m / s, and wet grinding was carried out for 4 h to obtain lurasidone hydrochloride nanocrystal suspension.

[0142]

[0143] The nanocrystal solidified material was prepared in a manner similar to that described in Example 1.

[0144]

[0145] The nanocrystal composition was prepared in a manner similar to that described in Example 1.

[0146]

[0147]

[0148] Example 3

[0149] The nanocrystal suspension was prepared in a manner similar to that described in Example 2.

[0150]

[0151] The nanocrystal solidified material was prepared in a manner similar to that described in Example 1.

[0152]

[0153] The nanocrystal composition was prepared in a manner similar to that described in Example 1.

[0154]

[0155] Example 4

[0156] Preparation of nanocrystal suspension: Hydroxypropyl methylcellulose E5 and Tween 80 were dissolved in water to prepare a stabilizer aqueous solution. Lurasidone hydrochloride was added and stirred thoroughly. The resulting lurasidone hydrochloride suspension was added to a ball mill, and 0.3 mm zirconia beads were added. The peristaltic pump was turned on at a speed of 22 rpm, the grinding chamber speed was 10 m / s, and wet grinding was carried out for 1 h to obtain lurasidone hydrochloride nanocrystal suspension.

[0157]

[0158] The nanocrystal solidified material was prepared in a manner similar to that described in Example 1.

[0159]

[0160] The nanocrystal composition was prepared in a manner similar to that described in Example 1.

[0161]

[0162] Experimental Example 3: Particle Size Determination

[0163] Approximately 1 mL of nanocrystal suspension or approximately 2 g of nanocrystal composition was placed in a sample cell, and the particle size distribution was measured using a Malvern 3000 laser particle size analyzer, with D50 and D90 selected as the measurement parameters. The particle size determination results for each embodiment are shown in the table below:

[0164]

[0165] The above results indicate that the particle size D90 of the lurasidone hydrochloride nanocrystal suspension prepared in Example 3 is less than 300 nm and the particle size distribution is uniform; the increase in D90 of the nanocrystal solidified product is the smallest.

[0166] Experimental Example 4: Particle Size Stability Study

[0167] The lurasidone hydrochloride nanocrystal suspension prepared in Example 3 was refrigerated at 2–8°C. After solidification, the powder was placed at room temperature, and samples from different batches were taken at 1, 3, 7, and 14 days. The particle size distribution was measured using a Malvern 3000 laser particle size analyzer, with D50 and D90 selected as the measurement parameters. The experimental results are shown in the table below.

[0168]

[0169] The results showed that the nanocrystal suspension could maintain stable particle size for 7 days under refrigeration conditions of 2–8℃, and the particle size increased after 14 days; the nanocrystal solidified material could maintain stable particle size for 14 days under room temperature conditions.

[0170] Experimental Example 5: Dissolution Test

[0171] Dissolution tests were conducted on different solid dosage forms (granules, tablets, and capsules) prepared from the lurasidone hydrochloride nanocrystal composition in Example 3. According to the dissolution determination method in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the paddle method was used at 50 rpm / min, with an acetate-sodium acetate buffer solution at pH 4.5 as the dissolution medium (900 mL volume) and the temperature maintained at 37 ± 0.5℃. Commercially available lurasidone hydrochloride tablets were also tested. As a control group, 10 mL of solution was collected at 5, 10, 20, 30, 45, and 60 minutes, and an equal volume of isothermal dissolution medium was added simultaneously. The collected dissolution solution was filtered through a 0.45 μm filter membrane, 8 mL of the initial filtrate was discarded, and the subsequent filtrate was collected. The content of lurasidone hydrochloride was determined by high performance liquid chromatography.

[0172] Determination method: High performance liquid chromatography (HPLC) was performed using an Xselect CSH C18 column. The mobile phase was phosphate buffer (pH 4.0)-acetonitrile = 40:60, and the flow rate was 1.0 mL / min. The detection wavelength was 230 nm. The release rate results are as follows:

[0173]

[0174]

[0175] The results showed that, at 60 min, the cumulative release rate of the granules prepared in Example 3 under the dissolution condition of pH 4.5 reached 94%, while the cumulative release rate of commercially available tablets was only 62%.

[0176] Experimental Example 6: Stability Study

[0177] The granules prepared in Example 3 were packaged in composite film bags (40 mg specification) and their stability was investigated under accelerated conditions of 40°C / RH 75%.

[0178] Determination method: High performance liquid chromatography (HPLC) was performed using an XBridge C18 column, with mobile phase A being phosphate buffer (pH 7.0)-acetonitrile = 80:20 and mobile phase B being acetonitrile, at a flow rate of 1.0 mL / min; the detection wavelength was 210 nm. The results are shown in the table below:

[0179]

[0180] Example 3 of the present invention - the granules were stored under accelerated conditions for 6 months, and the related substances showed no significant changes, indicating good stability.

Claims

1. A pharmaceutical composition of lurasidone hydrochloride, characterized in that, It includes the following components: Lurasidone hydrochloride is nanoscale and crystalline. The stabilizer is selected from a combination of hydroxypropyl methylcellulose and Tween, with Tween being Tween 80 and the viscosity range of hydroxypropyl methylcellulose being 3–15 mPa·s. The redispersant is sucrose, and the filler is lactose; The diluent is microcrystalline cellulose, the disintegrant is sodium croscarmellose, and the lubricant is magnesium stearate; The method for preparing the pharmaceutical composition includes the following steps: (1) Prepare a nanocrystal suspension by combining lurasidone hydrochloride, stabilizer and solvent; (2) Add redispersant and filler to nanocrystal suspension and granulate to obtain nanocrystal solidified product; (3) Nanocrystal compositions are prepared by adding diluents, disintegrants and lubricants to nanocrystal solids; The solvent is water; the particle size of lurasidone hydrochloride in the nanocrystal suspension is d90 < 300 nm; after redissolution of the nanocrystal solids, the particle size of lurasidone hydrochloride is d90 < 600 nm.

2. The pharmaceutical composition according to claim 1, characterized in that, Each unit dose of the drug composition contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride.

3. The pharmaceutical composition according to claim 2, characterized in that, It includes the following components: 。 4. A method for preparing the lurasidone hydrochloride pharmaceutical composition according to any one of claims 1 to 3, characterized in that, Includes the following steps: (1) Prepare a nanocrystal suspension by combining lurasidone hydrochloride, stabilizer and solvent; (2) Add redispersant and filler to nanocrystal suspension and granulate to obtain nanocrystal solidified product; (3) Nanocrystal compositions are prepared by adding diluents, disintegrants and lubricants to nanocrystal solids; (4) The nanocrystal composition is prepared into an oral solid dosage form; Step (1) uses the media grinding method.

5. The preparation method according to claim 4, characterized in that, Includes the following steps: Step 1: Mix water, lurasidone hydrochloride and stabilizer evenly, then add to a ball mill and wet grind to obtain a lurasidone hydrochloride nanocrystal suspension. Step 2: Take the lurasidone hydrochloride nanocrystal suspension obtained in Step 1, filter it, add redispersant and filler, and granulate it to obtain lurasidone hydrochloride nanocrystal solidified product. Step 3: Take the solidified material obtained in Step 2 and add diluent, disintegrant, and lubricant in sequence to obtain a lurasidone hydrochloride nanocrystal composition. Step 4: Take the composition obtained in Step 3 and prepare it into an oral solid dosage form; The granulation method is fluidized bed granulation; Oral solid dosage forms include tablets, capsules, or granules.

6. The use of the lurasidone hydrochloride pharmaceutical composition according to any one of claims 1 to 3 in the preparation of a medicament for treating mental disorders, wherein the mental disorder is schizophrenia.

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