Lurasidone orally disintegrating tablet and preparation method thereof

Abstract

The invention provides a lurasidone orally disintegrating tablet and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The lurasidone orally disintegrating tablet is prepared from the following components in parts by mass: 15 to 23 parts of lurasidone hydrochloride, 60 to 70 parts of a filling agent, 1.5 to 3.5 parts of an adhesive, 9 to 12 parts of a disintegrating agent, 0.1 to 1 part of a sweetening agent and 0.5 to 2 parts of a lubricating agent, the filling agent comprises mannitol and microcrystalline cellulose; the mass ratio of the mannitol to the microcrystalline cellulose is 1: (1-5). The lurasidone orally disintegrating tablet prepared by the preparation method disclosed by the invention is fast in disintegration, high in dissolution rate and better in stability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a lurasidone orally disintegrating tablet and a preparation method thereof. Background Art

[0002] Schizophrenia is a common mental disorder. The etiology of schizophrenia is complex and has not been fully elucidated. It mostly occurs in young and middle-aged adults, manifested as multiple disorders in perception, thinking, emotion, will behavior, etc. The mental activities are inconsistent with the surrounding environment and inner experience, being divorced from reality. Generally, there is no disturbance of consciousness and obvious intellectual impairment, but there may be cognitive function impairments in aspects such as attention, working memory, abstract thinking, and information integration. The course of the disease is mostly protracted and recurrent, and some patients have mental activity decline and varying degrees of social function deficits.

[0003] Lurasidone is a new type of atypical antipsychotic drug with high affinity for dopamine D2 receptor, 5-HT2A receptor and 5-HT7 receptor, and has been approved by the FDA for the treatment of adult schizophrenia and major depressive episodes of bipolar disorder. Currently, the only lurasidone preparations on the market are ordinary tablets, which need to be swallowed with water. Dysphagia is one of the common adverse symptoms of schizophrenia patients, so there is an urgent need to develop a dosage form that is convenient to take to improve the compliance of psychiatric patients.

[0004] Compared with ordinary tablets, the orally disintegrating tablet of this dosage form does not require water or chewing. The drug is placed on the tongue and quickly disintegrates and disperses into fine particles when encountering saliva, and enters the stomach through swallowing action to take effect. It can also be placed under the tongue, and after rapid disintegration, the drug is absorbed through the mucosa to take effect. The drug dissolution is accelerated, and it has a large area of distribution in the gastrointestinal tract, with the characteristics of rapid onset and high bioavailability. Zhu Qiang, Liu Lang, etc., "Comparative study on in vitro dissolution of lurasidone hydrochloride orally disintegrating tablets and ordinary tablets" (Chinese Journal of New Drugs, Vol. 25, No. 14, 2016); it has been publicly reported that the lurasidone hydrochloride orally disintegrating tablet has a faster dissolution rate than ordinary tablets while avoiding the behavior of hiding drugs by mental illness patients, and the selection of the orally disintegrating tablet dosage form is better. However, lurasidone hydrochloride not only has poor fluidity but also has a bitter taste. If developed into an orally disintegrating tablet, not only the problems of low in vitro dissolution rate and poor fluidity during preparation molding need to be solved, but also the problem of poor taste after disintegration in the oral cavity needs to be solved, which has great technical difficulties.

[0005] Chinese Patent CN 107854446 A discloses a lurasidone hydrochloride orally disintegrating tablet and its preparation method. The prescription is composed of pharmaceutical excipients with good compatibility with the drug, including fillers, disintegrants, wetting agents and binders, flavoring agents, lubricants, etc. Calculated by weight percentage, the proportions of each component are as follows: lurasidone hydrochloride 1-15%, filler 20-90%, disintegrant 5-20%, wetting agent and binder 1-10%, flavoring agent 2-6%, lubricant 0.5-5%. The preparation method adopts the wet granulation and tabletting method. However, this patent does not disclose the effect data such as disintegration time limit, dissolution rate and stability.

[0006] Chinese Patent CN103054824A discloses a lurasidone hydrochloride orally disintegrating tablet preparation and its preparation method. The components and their mass percentages of the orally disintegrating tablet are as follows: lurasidone hydrochloride 5%-60%, filler 25%-80%, disintegrant 5%-20%, wetting agent 0.02%-0.15%, flavoring agent 0.2%-5%, lubricant 0.5%-2%. This preparation can be completely disintegrated within 60 s, disintegrated into extremely fine powder, the drug dissolution is accelerated, the absorption is fast, and for poorly soluble drugs such as lurasidone hydrochloride, its bioavailability can be improved. However, its stability is not high and there are potential safety hazards.

[0007] In summary, it is of great significance for researchers in this field to develop a lurasidone hydrochloride orally disintegrating tablet with fast disintegration, high dissolution rate and better stability. Summary of the Invention

[0008] In view of the above problems, the present invention provides a lurasidone hydrochloride orally disintegrating tablet and its preparation method. By optimizing the components, ratios and preparation methods, the obtained lurasidone hydrochloride orally disintegrating tablet has fast disintegration, high dissolution rate and better stability.

[0009] To achieve the above object, the technical solution adopted by the present invention is as follows: On the one hand, the present invention provides a lurasidone hydrochloride orally disintegrating tablet, which contains the following components in parts by mass: 15 parts - 23 parts of lurasidone hydrochloride, 60 parts - 70 parts of filler, 1.5 parts - 3.5 parts of binder, 9 parts - 12 parts of disintegrant, 0.1 part - 1 part of sweetener and 0.5 - 2 parts of lubricant; The filler contains mannitol and microcrystalline cellulose; the mass ratio of mannitol to microcrystalline cellulose is 1:1 - 5.

[0010] Preferably, it contains the following components in parts by mass: 18 parts - 22 parts of lurasidone hydrochloride, 65 parts - 69 parts of filler, 1.6 parts - 3.2 parts of binder, 9 parts - 10 parts of disintegrant, 0.5 part - 1 part of sweetener and 0.6 - 1.5 parts of lubricant; Further preferably, by mass parts, it comprises the following components: 19 parts - 21 parts of lurasidone hydrochloride, 66 parts - 68 parts of filler, 1.5 parts - 2 parts of binder, 9 parts - 10 parts of disintegrant, 0.6 parts - 1 part of sweetener and 1 - 1.3 parts of lubricant; Preferably, the binder is selected from at least one of povidone, methylcellulose, hypromellose, hydroxypropylcellulose or sodium carboxymethylcellulose.

[0011] Further preferably, the binder is hypromellose.

[0012] Preferably, the disintegrant is selected from at least one of crosslinked polyvinylpyrrolidone, croscarmellose sodium or carboxymethylcellulose.

[0013] Further preferably, the disintegrant is carboxymethylcellulose.

[0014] Preferably, the carboxymethylcellulose is added in two portions, namely internal addition carboxymethylcellulose and external addition carboxymethylcellulose; Further preferably, the mass ratio of the internal addition carboxymethylcellulose to the external addition carboxymethylcellulose is: 1 - 2:1 - 2.

[0015] More preferably, the mass ratio of the internal addition carboxymethylcellulose to the external addition carboxymethylcellulose is: 1 - 1.5:1 - 1.5.

[0016] Preferably, the microcrystalline cellulose is added in two portions, namely internal addition microcrystalline cellulose and external addition microcrystalline cellulose.

[0017] Preferably, the mass ratio of the internal addition microcrystalline cellulose to the external addition microcrystalline cellulose is 1:1.5 - 4.

[0018] Preferably, the mass of the external addition microcrystalline cellulose is greater than 33% of the total mass of the raw materials of the lurasidone orally disintegrating tablets.

[0019] Preferably, the sweetener is selected from at least one of sucrose, sucralose, aspartame, fructose, stevioside, mannitol or sorbitol. Further preferably, the sweetener is sucralose.

[0020] Preferably, the lubricant is selected from at least one of magnesium stearate, calcium stearate or sodium fumarate; further preferably, the lubricant is magnesium stearate.

[0021] Preferably, the particle size D90 of the lurasidone hydrochloride ≤ 10 μm. Further preferably, the particle size D90 of the lurasidone hydrochloride ≤ 5 μm.

[0022] On the other hand, the present invention provides a preparation method of the above-mentioned lurasidone orally disintegrating tablets, comprising the following steps: 1) Mix lurasidone hydrochloride, mannitol, added microcrystalline cellulose, binder, and added carboxymethyl cellulose, granulate, wet screen the granules, dry, and dry screen the granules to obtain dry-screened granules; 2) Mix the dry-screened granules obtained in step 1), added microcrystalline cellulose, added carboxymethyl cellulose, sweetener, and lubricant, and press into tablets. Preferably, the preparation method is carried out in a wet granulator.

[0023] Preferably, in step 1), before mixing lurasidone hydrochloride, mannitol, and added microcrystalline cellulose, they need to be sieved through a 20 - 60 mesh sieve first.

[0024] Preferably, in step 1), the parameters for mixing are: stirring speed 80 - 120 rpm, shear speed 800 - 1200 rpm, and mixing for 3 - 6 min.

[0025] Preferably, in step 1), the parameters for granulating are: stirring speed 130 - 180 rpm, shear speed 1300 - 1800 rpm, and time 1 - 2 min.

[0026] Preferably, in step 1), the parameters for wet screening the granules are: rotation speed 400 - 600 rpm.

[0027] Preferably, in step 1), the parameters for drying are: inlet air temperature 50 - 70 °C, air volume 150 - 350 m 3 / h, dry until the material temperature reaches 40 - 60 °C, and stop discharging when the loss on drying is < 3%.

[0028] Preferably, in step 1), the parameters for dry screening the granules are: rotation speed 400 - 600 rpm.

[0029] Compared with the prior art, the present invention has the following beneficial effects: By optimizing the combination of the filler as mannitol and microcrystalline cellulose and defining the ratio between the two, and by adding microcrystalline cellulose and disintegrant in the form of internal addition and external addition, the lurasidone orally disintegrating tablets prepared under the preparation method of the present invention have fast disintegration, high dissolution rate, and better stability. Detailed implementation manners

[0030] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the following specific embodiments are used to further clarify the present invention. However, the following embodiments are only the preferred embodiments of the present invention, not all of them. Based on the embodiments in the implementation manner, other embodiments obtained by those skilled in the art without creative efforts all fall within the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all ordinary commercially available products, and no specific limitation is made on their sources. The technical and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0031] Example 1 A lurasidone orally disintegrating tablet, and its formulation is shown in Table 1 below: Table 1. Formulation of Example 1

[0032] Preparation method: (1) Sieving: The raw drug and the internal addition of microcrystalline cellulose are roughly mixed and sieved through a 30-mesh sieve, and mannitol is sieved through a 30-mesh sieve for standby; the particle size D90 of the raw drug is 4.81 μm.

[0033] (2) Premixing: Lurasidone hydrochloride, mannitol, internal addition of microcrystalline cellulose, hypromellose, and internal addition of carboxymethyl cellulose are poured into a wet granulator, and the stirring speed is set at 100 rpm, the shearing speed is set at 1000 rpm, and mixed for 5 min.

[0034] (3) Preparing soft materials: The stirring speed is 100 rpm, the shearing speed is 1000 rpm, the atomization pressure is 1.5 bar, the peristaltic pump speed is 150 rpm, and a wetting agent (purified water, about 3 g / 1000 tablets) is sprayed to granulate.

[0035] (4) Granulating: Set the stirring speed at 150 rpm, the shearing speed at 1500 rpm, and run for 1 min.

[0036] (5) Wet screening: Use a 4*4 sieve mesh and screen at 500 rpm.

[0037] (6) Drying: Place the wet-screened granules in a preheated fluidized bed pot, set the inlet air temperature at 60 ± 5 °C, the air volume at 250 ± 50 m 3 / h, dry until the material temperature is 50 ± 5 °C, and stop discharging when the loss on drying is < 3%.

[0038] (7) Dry screening: After drying, use a granulator, a screen mesh with a pore diameter of 0.8 mm, and set the rotation speed at 500 rpm for screening.

[0039] (8) Weighing: Calculate and weigh the additional excipients.

[0040] (9) Mixing: Add about 1 / 2 of the dry whole granules, externally added microcrystalline cellulose, externally added carboxymethyl cellulose, sucralose, and the remaining dry whole granules into a mixer, with a rotation speed of 10 rpm and mix for 10 min. Then add magnesium stearate, with a rotation speed of 10 rpm and mix for 5 min.

[0041] (10) Tabletting: Adjust the tablet weight to 0.200 g and tablet with a hardness of about 30 - 50 N.

[0042] Example 2 A lurasidone orally disintegrating tablet, and its formula is shown in Table 2 below: Table 2. Formula of Example 2

[0043] The preparation method is the same as that of Example 1.

[0044] Example 3 A lurasidone orally disintegrating tablet, and its formula is shown in Table 3 below: Table 3. Formula of Example 3

[0045] The preparation method is the same as that of Example 1.

[0046] Example 4 A lurasidone orally disintegrating tablet, and its formula is shown in Table 4 below: Table 4. Formula of Example 4

[0047] The preparation method is the same as that of Example 1.

[0048] Example 5 A lurasidone orally disintegrating tablet, and its formula is shown in Table 5 below: Table 5. Formula of Example 5

[0049] The preparation method is the same as that of Example 1.

[0050] Example 6 A lurasidone orally disintegrating tablet, and its formula is shown in Table 6 below: Table 6. Formula of Example 6

[0051] The preparation method is the same as that of Example 1.

[0052] Example 7 A lurasidone orally disintegrating tablet, and its formula is shown in Table 7 below: Table 7. Formula of Example 7

[0053] The preparation method is the same as that of Example 1.

[0054] Example 8 A lurasidone orally disintegrating tablet, the formulation of which is shown in Table 8 below: Table 8. Formulation of Example 8

[0055] The preparation method is the same as that of Example 1.

[0056] Comparative Example 1 A lurasidone orally disintegrating tablet, the formulation of which is shown in Table 9 below: Table 9. Formulation of Comparative Example 1

[0057] The preparation method is as follows: (1) Sieving: The raw drug is sieved through a 30-mesh sieve, and mannitol is sieved through a 30-mesh sieve for standby; the particle size D90 of the raw drug is 4.81 μm.

[0058] (2) Premixing: Lurasidone hydrochloride, mannitol, and internal cross-linked carboxymethyl cellulose sodium are poured into a wet granulator, and the stirring speed is set at 100 rpm, the shearing speed is set at 1000 rpm, and mixed for 5 min.

[0059] (3) Preparing soft material: The stirring speed is 100 rpm, the shearing speed is 1000 rpm, the atomizing pressure is 1.5 bar, the peristaltic pump speed is 150 rpm, and a wetting agent (purified water, about 3 g / 1000 tablets) is sprayed to granulate.

[0060] (4) Granulating: The stirring speed is set at 150 rpm, the shearing speed is set at 1500 rpm, and run for 1 min.

[0061] (5) Wet screening: Use a 4*4 sieve mesh and screen at 500 rpm.

[0062] (6) Drying: Place the wet-screened granules in a preheated fluidized bed pot, set the inlet air temperature at 60 ± 5 °C, the air volume at 250 ± 50 m 3 / h, dry until the material temperature is 50 ± 5 °C, and stop discharging when the loss on drying is < 3%.

[0063] (7) Dry screening: After drying, use a granulator, a sieve mesh with a pore diameter of 0.8 mm, and set the speed at 500 rpm for screening.

[0064] (8) Weighing: Calculate and weigh the additional excipients.

[0065] (9) Mixing: Add about 1 / 2 of the dry granulated particles, externally added cross-linked sodium carboxymethylcellulose, sucralose, and the remaining dry granulated particles into a mixer, with a rotation speed of 10 rpm and mix for 10 min. Then add magnesium stearate, with a rotation speed of 10 rpm and mix for 5 min.

[0066] (10) Tabletting: Adjust the tablet weight to 0.200 g and tablet with a hardness of about 30 - 50 N.

[0067] Comparative Example 2 An orally disintegrating tablet of lurasidone, and its formulation is shown in Table 10 below: Table 10. Formulation Table of Comparative Example 2

[0068] Preparation method: (1) Sieving: The raw drug passes through a 30-mesh sieve, and mannitol passes through a 30-mesh sieve for standby; the particle size D90 of the raw drug is 4.81 μm.

[0069] (2) Premixing: Pour lurasidone hydrochloride, internally added mannitol, and internally added cross-linked sodium carboxymethylcellulose into a wet granulator, set the stirring speed at 100 rpm, the shearing speed at 1000 rpm, and mix for 5 min.

[0070] (3) Preparing soft material: The stirring speed is 100 rpm, the shearing speed is 1000 rpm, the atomizing pressure is 1.5 bar, the peristaltic pump speed is 150 rpm, and a wetting agent (purified water, about 3 g / 1000 tablets) is sprayed to granulate.

[0071] (4) Granulating: Set the stirring speed at 150 rpm, the shearing speed at 1500 rpm, and run for 1 min.

[0072] (5) Wet screening: Use a 4*4 sieve mesh and screen at 500 rpm.

[0073] (6) Drying: Place the wet-screened particles in a preheated fluidized bed pot, set the inlet air temperature at 60 ± 5 °C, the air volume at 250 ± 50 m 3 / h, dry until the material temperature reaches 50 ± 5 °C, and stop discharging when the loss on drying is < 3%.

[0074] (7) Dry screening: After drying, use a granulator, a sieve mesh with a pore diameter of 0.8 mm, and set the rotation speed at 500 rpm for screening.

[0075] (8) Weighing: Calculate and weigh the externally added excipients.

[0076] (9) Mixing: Add about 1 / 2 of the dry granulated particles, mannitol added externally, croscarmellose sodium added externally, sucralose, and the remaining dry granulated particles into a mixer, with a rotation speed of 10 rpm and mix for 10 min. Then add magnesium stearate, with a rotation speed of 10 rpm and mix for 5 min.

[0077] (10) Tabletting: Adjust the tablet weight to 0.200 g and tablet with a hardness of about 30 - 50 N.

[0078] Comparative Example 3 An orally disintegrating tablet of lurasidone, and its formula is shown in Table 11 below: Table 11. Formula Table of Comparative Example 3

[0079] Preparation method: (1) Sieving: Coarsely mix the active pharmaceutical ingredient with microcrystalline cellulose and sieve through a 30 - mesh sieve, and sieve mannitol through a 30 - mesh sieve for standby; the D90 particle size of the active pharmaceutical ingredient is 4.81 μm.

[0080] (2) Premixing: Pour lurasidone hydrochloride, mannitol added internally, microcrystalline cellulose added internally, and croscarmellose sodium added internally into a wet granulator, set the stirring speed at 100 rpm, the shear speed at 1000 rpm, and mix for 5 min.

[0081] (3) Preparing soft material: Stirring speed 100 rpm, shear speed 1000 rpm, atomization pressure 1.5 bar, peristaltic pump speed 150 rpm, spray and add wetting agent (purified water, about 3 g / 1000 tablets) for granulation.

[0082] (4) Granulation: Set the stirring speed at 150 rpm, the shear speed at 1500 rpm, and run for 1 min.

[0083] (5) Wet screening: Use a 4*4 sieve mesh and screen at 500 rpm.

[0084] (6) Drying: Place the wet screened particles in a pre - heated fluidized bed pot, set the inlet air temperature at 60 ± 5 °C, the air volume at 250 ± 50 m 3 / h, dry until the material temperature reaches 50 ± 5 °C, and stop discharging when the loss on drying is < 3%.

[0085] (7) Dry screening: After drying, use a granulator, a sieve mesh with a pore diameter of 0.8 mm, and set the rotation speed at 500 rpm for screening.

[0086] (8) Weighing: Calculate and weigh the externally added excipients; (9) Mixing: Add about 1 / 2 of the dry granulated particles, mannitol added externally, cross-linked sodium carboxymethylcellulose added externally, sucralose, and the remaining dry granulated particles into a mixer, with a rotation speed of 10 rpm and mix for 10 min. Then add magnesium stearate, with a rotation speed of 10 rpm and mix for 5 min.

[0087] (10) Tabletting: Adjust the tablet weight to 0.200 g and tablet with a hardness of about 30 - 50 N.

[0088] Comparative Example 4 An orally disintegrating tablet of lurasidone, the formulation is shown in Table 12 below: Table 12. Formulation Table of Comparative Example 4

[0089] Preparation method: (1) Sieving: After the crude mixing of the active pharmaceutical ingredient, sieve it through a 30-mesh sieve, and sieve mannitol through a 30-mesh sieve for standby; the particle size D90 of the active pharmaceutical ingredient is 4.81 μm.

[0090] (2) Premixing: Pour lurasidone hydrochloride, mannitol, hypromellose, and carboxymethylcellulose added internally into a wet granulator, set the stirring speed at 100 rpm, the shearing speed at 1000 rpm, and mix for 5 min.

[0091] (3) Preparing soft material: With a stirring speed of 100 rpm, a shearing speed of 1000 rpm, an atomization pressure of 1.5 bar, and a peristaltic pump speed of 150 rpm, spray and add a wetting agent (purified water, about 3 g / 1000 tablets) to granulate.

[0092] (4) Granulating: Set the stirring speed at 150 rpm, the shearing speed at 1500 rpm, and run for 1 min.

[0093] (5) Wet screening: Use a 4*4 sieve mesh and screen at 500 rpm.

[0094] (6) Drying: Place the wet-screened particles in a preheated fluidized bed pot, set the inlet air temperature at 60 ± 5 °C, the air volume at 250 ± 50 m 3 / h, dry until the material temperature reaches 50 ± 5 °C, and stop discharging when the loss on drying is < 3%.

[0095] (7) Dry screening: After drying, use a granulator with a screen mesh diameter of 0.8 mm and a rotation speed of 500 rpm for screening.

[0096] (8) Weighing: Calculate and weigh the externally added excipients; (9) Mixing: Add about 1 / 2 of the dry whole granules, additional microcrystalline cellulose, additional carboxymethyl cellulose, sucralose, and the remaining dry whole granules into a mixer, set the rotation speed at 10 rpm, and mix for 10 min. Then add magnesium stearate, set the rotation speed at 10 rpm, and mix for 5 min.

[0097] (10) Tabletting: Adjust the tablet weight to 0.200 g and tablet at a hardness of about 30 - 50 N.

[0098] Comparative Example 5 A lurasidone orally disintegrating tablet, and its formulation is shown in Table 13 below: Table 13. Formulation of Comparative Example 5

[0099] The preparation method is the same as that of Example 1.

[0100] Comparative Example 6 A lurasidone orally disintegrating tablet, and its formulation is shown in Table 14 below: Table 14. Formulation of Comparative Example 6

[0101] The preparation method is the same as that of Example 1.

[0102] Comparative Example 7 A lurasidone orally disintegrating tablet, and its formulation is shown in Table 15 below: Table 15. Formulation of Comparative Example 7

[0103] Preparation method: (1) Sieving: The raw drug and the internal added microcrystalline cellulose are roughly mixed and then sieved through a 30 - mesh sieve, and mannitol is sieved through a 30 - mesh sieve for standby; the particle size D90 of the raw drug is 4.81 μm.

[0104] (2) Premixing: Pour lurasidone hydrochloride, mannitol, internal added microcrystalline cellulose, hypromellose, and internal added crospovidone into a wet granulator, set the stirring speed at 100 rpm, the shear speed at 1000 rpm, and mix for 5 min.

[0105] (3) Preparing soft material: Set the stirring speed at 100 rpm, the shear speed at 1000 rpm, the atomization pressure at 1.5 bar, and the peristaltic pump speed at 150 rpm, and spray the wetting agent (purified water, about 3 g / 1000 tablets) to granulate.

[0106] (4) Granulating: Set the stirring speed at 150 rpm, the shear speed at 1500 rpm, and run for 1 min.

[0107] (5) Wet screening: Use a 4*4 sieve mesh and screen at 500 rpm.

[0108] (6) Drying: Place the wet-sized granules in the preheated fluidized bed pan, set the inlet air temperature at 60 ± 5 °C and the air volume at 250 ± 50 m 3 / h, dry until the material temperature reaches 50 ± 5 °C, and stop discharging when the loss on drying is < 3%.

[0109] (7) Dry sizing: After drying, use a granulator with a 0.8 mm sieve mesh diameter and set the rotation speed at 500 rpm for sizing.

[0110] (8) Weighing: Calculate and weigh the added excipients; (9) Mixing: Add about 1 / 2 of the dry-sized granules, added microcrystalline cellulose, added cross-linked povidone, sucralose, and the remaining dry-sized granules into the mixer, set the rotation speed at 10 rpm, and mix for 10 min. Then add magnesium stearate, set the rotation speed at 10 rpm, and mix for 5 min.

[0111] (10) Tabletting: Adjust the tablet weight to 0.200 g and tablet at a hardness of about 30 - 50 N.

[0112] Comparative Example 8 An orally disintegrating tablet of lurasidone, the formulation table of which is shown in Table 16 below: Table 16. Formulation table of Comparative Example 8

[0113] Preparation method: (1) Sieving: After the crude mixing of the active ingredient and the added microcrystalline cellulose, pass through a 30-mesh sieve, and pass mannitol through a 30-mesh sieve for standby; the particle size D90 of the active ingredient is 4.81 μm.

[0114] (2) Premixing: Pour lurasidone hydrochloride, mannitol, added microcrystalline cellulose, hypromellose, and hypromellose into a wet granulator, set the stirring speed at 100 rpm, the shearing speed at 1000 rpm, and mix for 5 min.

[0115] (3) Preparing soft material: Set the stirring speed at 100 rpm, the shearing speed at 1000 rpm, the atomization pressure at 1.5 bar, the peristaltic pump speed at 150 rpm, and spray the wetting agent (purified water, about 3 g / 1000 tablets) for granulation.

[0116] (4) Granulation: Set the stirring speed at 150 rpm, the shearing speed at 1500 rpm, and run for 1 min.

[0117] (5) Wet sizing: Use a 4*4 sieve mesh and size at 500 rpm.

[0118] (6) Drying: Place the wet-sized granules in the preheated fluidized bed pan, set the inlet air temperature at 60 ± 5 °C and the air volume at 250 ± 50 m3 / h, dry until the material temperature reaches 50 ± 5 °C, and stop discharging after the loss on drying is < 3%.

[0119] (7)Dry granulation: After drying, use a granulator with a screen mesh diameter of 0.8 mm and set the rotation speed to 500 rpm for granulation.

[0120] (8)Weighing: Calculate and weigh the additional excipients; (9)Mixing: Add about 1 / 2 of the granules after dry granulation, additional microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sucralose, and the remaining granules after dry granulation into the mixer, with a rotation speed of 10 rpm and mix for 10 min. Then add magnesium stearate, with a rotation speed of 10 rpm and mix for 5 min.

[0121] (10)Tablet pressing: Adjust the tablet weight to 0.200 g and press tablets with a hardness of about 30 - 50 N.

[0122] Comparative Example 9 A lurasidone orally disintegrating tablet, and its formulation is shown in Table 17 below: Table 17. Formulation of Comparative Example 9

[0123] The preparation method is the same as that of Example 1.

[0124] Comparative Example 10 A lurasidone orally disintegrating tablet, and its formulation is shown in Table 18 below: Table 18. Formulation of Comparative Example 10

[0125] The preparation method is the same as that of Example 1.

[0126] Comparative Example 11 A lurasidone orally disintegrating tablet, compared with Example 1, only the particle size of the active pharmaceutical ingredient is changed to D90 = 11.1 μm, and the rest is the same as Example 1.

[0127] Comparative Example 12 Prepare a lurasidone orally disintegrating tablet according to the formulation and preparation method of Example 1 of CN103054824A.

[0128] Comparative Example 13 A lurasidone orally disintegrating tablet, compared with Example 1, only mannitol is replaced with lactose. Its formulation is shown in Table 19 below: Table 19. Formulation of Comparative Example 13

[0129] Preparation method: (1)Sieving: After the crude mixing of the active pharmaceutical ingredient and the added microcrystalline cellulose, sieve through a 30-mesh sieve, and sieve lactose through a 30-mesh sieve for standby; the particle size D90 of the active pharmaceutical ingredient is 4.81 μm.

[0130] (2)Premixing: Pour lurasidone hydrochloride, lactose, added microcrystalline cellulose, hypromellose, and added carboxymethyl cellulose into a wet granulator, set the stirring speed at 100 rpm, the shearing speed at 1000 rpm, and mix for 5 min.

[0131] (3)Preparing soft material: Stirring speed 100 rpm, shearing speed 1000 rpm, atomization pressure 1.5 bar, peristaltic pump speed 150 rpm, spray and add wetting agent (purified water, about 3 g / 1000 tablets) to granulate.

[0132] (4)Granulating: Set the stirring speed at 150 rpm, the shearing speed at 1500 rpm, and run for 1 min.

[0133] (5)Wet screening: Use a 4*4 sieve mesh and screen at 500 rpm.

[0134] (6)Drying: Place the wet-screened granules in a preheated fluidized bed pot, set the inlet air temperature at 60 ± 5 °C, the air volume for lactose at 250 ± 50 m 3 / h, dry until the material temperature reaches 50 ± 5 °C, and stop discharging when the loss on drying is < 3%.

[0135] (7)Dry screening: After drying, use a granulator, a sieve mesh with a pore diameter of 0.8 mm, and set the speed at 500 rpm for screening.

[0136] (8)Weighing: Calculate and weigh the added excipients; (9)Mixing: Add about 1 / 2 of the dry-screened granules, added microcrystalline cellulose, added carboxymethyl cellulose, sucralose, and the remaining dry-screened granules into a mixer, rotate at 10 rpm, and mix for 10 min. Then add magnesium stearate, rotate at 10 rpm, and mix for 5 min.

[0137] (10)Tabletting: Adjust the tablet weight to 0.200 g and tablet at a hardness of about 30 - 50 N.

[0138] Comparative Example 14 A lurasidone orally disintegrating tablet, compared with Example 1, only replaces microcrystalline cellulose with lactose. Its formulation table is shown in Table 20 below: Table 20. Formulation Table of Comparative Example 14

[0139] Preparation method: (1)Sieving: After the crude mixture of the active pharmaceutical ingredient and internal lactose is sieved through a 30-mesh sieve, mannitol is sieved through a 30-mesh sieve and reserved; the particle size D90 of the active pharmaceutical ingredient is 4.81 μm.

[0140] (2)Premixing: Ziprasidone hydrochloride, lactose, internal lactose, hypromellose, and internal carboxymethyl cellulose are poured into a wet granulator, and the stirring speed is set at 100 rpm, the shearing speed is set at 1000 rpm, and the mixture is stirred for 5 minutes.

[0141] (3)Soft mass preparation: The stirring speed is 100 rpm, the shearing speed is 1000 rpm, the atomization pressure is 1.5 bar, the peristaltic pump speed is 150 rpm, and a wetting agent (purified water, about 3 g / 1000 tablets) is sprayed to granulate.

[0142] (4)Granulation: The stirring speed is set at 150 rpm, the shearing speed is set at 1500 rpm, and it runs for 1 minute.

[0143] (5)Wet screening: Use a 4*4 sieve mesh and screen at 500 rpm.

[0144] (6)Drying: The wet-screened granules are placed in a preheated fluidized bed pot, and the inlet air temperature is set at 60 ± 5 °C, the air volume is 250 ± 50 m 3 / h, and drying is stopped and the product is discharged when the material temperature reaches 50 ± 5 °C and the loss on drying is < 3%.

[0145] (7)Dry screening: After drying, use a granulator, a sieve mesh with a pore diameter of 0.8 mm, and set the speed at 500 rpm for screening.

[0146] (8)Weighing: Calculate and weigh the external excipients; (9)Mixing: Add about 1 / 2 of the dry-screened granules, external lactose, external carboxymethyl cellulose, sucralose, and the remaining dry-screened granules into a mixer, with a speed of 10 rpm, and mix for 10 minutes. Then add magnesium stearate, with a speed of 10 rpm, and mix for 5 minutes.

[0147] (10)Tablet pressing: Adjust the tablet weight to 0.200 g and press tablets with a hardness of about 30 - 50 N.

[0148] Comparative Example 15: A ziprasidone orally disintegrating tablet, and its formulation table is shown in Table 21 below: Table 21. Formulation table of Comparative Example 15

[0149] The preparation method is as follows: S1. Mix 20% ziprasidone hydrochloride (D90 ≤ 10 μm), 10.5% mannitol 50C, 10.0% microcrystalline cellulose, and 1.0% crospovidone evenly and reserve.

[0150] S2. Add 1.5% hydroxypropyl methylcellulose to water and mix to obtain a hydroxypropyl methylcellulose solution. Add the mixture in S1 to the above hydroxypropyl methylcellulose solution for granulation. After observing the particle state, perform wet screening, fluidized bed drying, and dry screening in sequence to obtain Component A.

[0151] S3. Add 21.1% mannitol 200SD, 27.65% microcrystalline cellulose 102, 2.5% crospovidone, 1.0% stevioside, 4% sodium carbonate, and 0.75% magnesium stearate to Component A in S2 in sequence, then mix well and press tablets to obtain orally disintegrating tablets.

[0152] Comparative Example 16 An orally disintegrating tablet of lurasidone was prepared according to the formula and preparation method in Example 5 of Chinese Patent Application CN116077451A. Its formula is shown in Table 22 below: Table 22. Formula Table of Comparative Example 16

[0153] Test Example 1 Hardness test: Take n = 10 tablets for testing. Hardness tester: Huanghai Pharmaceutical Inspection, Model SY-2D.

[0154] Disintegration time: According to the disintegration limit (orally disintegrating tablets) inspection method in General Chapter 0921 of ChP2020, at 37°C ± 1°C, about 900 mL of water, take n = 6 tablets for testing, with the limit ≤ 60 seconds. Orally disintegrating tablet tester: TianDa TianFa, Model KB-1.

[0155] Table 23. Hardness Results

[0156] Test Example 2 Stability test: Dissolution: In pH 3.8 medium, paddle method, 75 rpm / 900 mL, 37°C ± 0.5°C. Limit: Not less than 75% of the labeled amount in 20 min.

[0157] Dissolution curve: In pH 3.8 medium, paddle method, 75 rpm / 900 mL, 37°C ± 0.5°C.

[0158] Table 24. Stability Results of Example 1 and Comparative Example 12

[0159] Table 25. Dissolution Curve Results of Example 1 and Comparative Example 11

[0160] Table 26. Dissolution of Example 1, Examples 5 - 6 and Comparative Example 10

[0161] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than limiting the protection scope of the present invention. Any simple modification or equivalent replacement made by those of ordinary skill in the art to the technical solution of the present invention shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A lurasidone orally disintegrating tablet, characterized in that, By mass parts, it comprises the following components: 15 parts - 23 parts of lurasidone hydrochloride, 60 parts - 70 parts of filler, 1.5 parts - 3.5 parts of binder, 9 parts - 12 parts of disintegrant, 0.1 part - 1 part of sweetener, and 0.5 - 2 parts of lubricant; The filler comprises mannitol and microcrystalline cellulose; the mass ratio of mannitol to microcrystalline cellulose is 1:1 - 5.

2. The lurasidone orally disintegrating tablet according to claim 1, wherein By mass parts, it comprises the following components: 18 parts - 22 parts of lurasidone hydrochloride, 65 parts - 69 parts of filler, 1.6 parts - 3.2 parts of binder, 9 parts - 10 parts of disintegrant, 0.5 part - 1 part of sweetener, and 0.6 - 1.5 parts of lubricant.

3. The orally disintegrating tablet of lurasidone according to claim 1, wherein The binder is selected from at least one of povidone, methylcellulose, hypromellose, hydroxypropylcellulose or sodium carboxymethylcellulose; The disintegrant is selected from at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose or carboxymethylcellulose.

4. The lurasidone orally disintegrating tablet according to claim 3, wherein The binder is hypromellose; the disintegrant is carboxymethylcellulose.

5. The lurasidone orally disintegrating tablet according to claim 4, wherein The carboxymethylcellulose is added in two portions, namely internal addition carboxymethylcellulose and external addition carboxymethylcellulose; the mass ratio of internal addition carboxymethylcellulose to external addition carboxymethylcellulose is: 1 - 2:1 - 2.

6. The lurasidone orally disintegrating tablet according to claim 4, wherein The microcrystalline cellulose is added in two portions, namely internal addition microcrystalline cellulose and external addition microcrystalline cellulose; the mass ratio of internal addition microcrystalline cellulose to external addition microcrystalline cellulose is 1:1.5 - 4, and the mass of the external addition microcrystalline cellulose is greater than 33% of the total mass of the raw materials of the orally disintegrating tablet of lurasidone.

7. The lurasidone orally disintegrating tablet according to claim 1, wherein The sweetener is selected from at least one of sucrose, sucralose, aspartame, fructose, stevioside, mannitol or sorbitol; the lubricant is selected from at least one of magnesium stearate, calcium stearate or sodium stearyl fumarate.

8. The lurasidone orally disintegrating tablet according to claim 1, wherein The particle size D90 of the lurasidone hydrochloride ≤ 10 μm.

9. The preparation method of the lurasidone orally disintegrating tablets according to any one of claims 1-8, characterized in that, It comprises the following steps: 1) Mix lurasidone hydrochloride, mannitol, internal addition microcrystalline cellulose, binder and internal addition carboxymethylcellulose, granulate, wet size, dry, and dry size to obtain dry sized granules; 2) Mix the dry sized granules obtained in step 1), external addition microcrystalline cellulose, external addition carboxymethylcellulose, sweetener and lubricant, and press tablets.

10. The preparation method according to claim 9, characterized in that, Meet at least one of the following conditions: In step 1), the parameters of the mixing are: stirring speed 80 - 120 rpm, shear speed 800 - 1200 rpm, mixing for 3 - 6 min; The parameters of the granulation are: stirring speed 130 - 180 rpm, shear speed 1300 - 1800 rpm, time 1 - 2 min; The parameters of the wet sizing are: speed 400 - 600 rpm; The parameters of the drying are as follows: the inlet air temperature is 50 - 70 °C, the air volume is 150 - 350 m 3 / h, drying until the material temperature reaches 40 - 60 °C, and stopping the machine for discharging when the loss on drying is < 3%; The parameters of the dry sizing are: speed 400 - 600 rpm.

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