High-stability piperaspirone hydrochloride pharmaceutical preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a high-stability piperaspirone hydrochloride pharmaceutical preparation and a preparation method thereof. The piperaspirone hydrochloride pharmaceutical preparation provided by the invention comprises the following components in percentage by mass: 1-10% of piperaspirone hydrochloride or pharmaceutically acceptable salt thereof and 3-7% of polyvinyl alcohol, in the preparation process of the piperaspirone hydrochloride medicinal preparation, the polyvinyl alcohol is added in batches in a powder form and a solution form. By improving the adding mode of the polyvinyl alcohol, the stabilizing effect of the polyvinyl alcohol is exerted to the greatest extent, and the prepared piperaspirone hydrochloride pharmaceutical preparation has excellent dissolution stability, ensures the quality stability of the product, has the characteristics of short preparation period, simple process, high reproducibility and the like, and is suitable for large-batch production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a highly stable perospirone hydrochloride pharmaceutical preparation and a preparation method thereof. Background Art

[0002] Perospirone Hydrochloride, English name: Perospirone Hydrochloride, chemical name is N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2-cis-cyclohexanedicarboximide-hydrochloride dihydrate, CAS: 192052-81-6, molecular formula is C 23 H 30 N4O2S·HCl·2H2O, and the chemical structural formula is as follows:

[0003]

[0004] The perospirone hydrochloride raw material drug has poor hydrophilicity and is slightly soluble in water (about 10 mg / mL), and there are great challenges in the dissolution and stability of the preparation.

[0005] The drug dissolution test is an important technical means to reflect the drug quality. Especially for oral solid preparations, the study of the drug dissolution curve is very important. Before the drug is launched on the market, by studying the dissolution behavior of the drug in vitro through the dissolution curve, the inherent characteristics of the preparation can be understood, and the in vivo dissolution situation can be predicted; it can provide guidance for clinical bioequivalence tests and improve the success rate of bioequivalence tests; it can be used to establish the dissolution test method in the quality standard and provide guarantee for drug quality control. After the drug is launched on the market, the dissolution curve test with discrimination ability can be used for quality control in the drug production process, and can reflect the quality status of the preparation to a certain extent; it can be used to investigate the stability within and between batches of the drug and provide guidance for the quality evaluation before and after the prescription and process changes.

[0006] Chinese Patent Application CN102302468A discloses a perospirone hydrochloride rapid-release tablet and a preparation method thereof. Through the powder direct compression process, the production efficiency is improved, the drug disintegrates quickly, the dissolution time is short, and the dissolution rate is 15% higher than that of the drugs prepared by ordinary wet or dry granulation methods. However, it is found in actual application that there is a problem of reduced dissolution during the stability investigation of this composition, and there is a certain difference from the quality of the original research preparation "Lullan".

[0007] Chinese Patent Application for Invention CN116549452A discloses a perospirone hydrochloride pharmaceutical composition and its preparation method. The composition includes perospirone hydrochloride and / or its derivatives, a binder, a disintegrant, a diluent, and a lubricant. The weight percentage of perospirone hydrochloride and / or its derivatives in the composition is 1 - 20%, the weight percentage of the binder is 3 - 7%, the weight percentage of the disintegrant is 3 - 7%, the weight percentage of the diluent is 30 - 90%, and the weight percentage of the lubricant is 0.01 - 5%. This pharmaceutical composition has good formability, small differences in dissolution rate, high quality uniformity, and few related substance impurities, providing technical guarantee for the safety of clinical medication. However, there is still a lack of research on improving the stability of the preparation.

[0008] In summary, in the prior art, the preparation of perospirone hydrochloride tablets all have the problem of reduced dissolution during the stability study, that is, poor dissolution stability, which in turn affects the product quality. Therefore, there is an urgent need to improve and optimize from the aspects of the prescription composition and preparation process to solve the above problems existing in perospirone hydrochloride tablets. Summary of the Invention

[0009] Aiming at the problem that the dissolution of the solid preparation of perospirone hydrochloride drug is likely to decrease during the stability study, the specific phenomenon is that the raw material powder floats on the liquid surface of the dissolution medium, resulting in incomplete dissolution. In order to solve the problem of reduced dissolution during the stability study of perospirone hydrochloride tablets in the prior art, the present invention provides a perospirone hydrochloride pharmaceutical preparation with good preparation process reproducibility, high dissolution rate, and good dissolution stability, and its preparation method.

[0010] To achieve the above object, the present invention adopts the following technical solutions:

[0011] The first aspect of the present invention is to provide a perospirone hydrochloride pharmaceutical preparation with high stability. The perospirone hydrochloride pharmaceutical preparation includes, by mass percentage: 1 - 10% of perospirone hydrochloride or its pharmaceutically acceptable salt and 3 - 7% of polyvinyl alcohol; during the preparation process of the perospirone hydrochloride pharmaceutical preparation, polyvinyl alcohol is added in batches in powder form and solution form.

[0012] Further, the mass ratio of polyvinyl alcohol in powder form to polyvinyl alcohol in solution form is 1:1 - 3:1.

[0013] Further, the perospirone hydrochloride pharmaceutical preparation further includes one or more of a filler, a disintegrant, and a lubricant.

[0014] Further, the filler is selected from one or more of lactose, corn starch, microcrystalline cellulose, mannitol, and anhydrous calcium hydrogen phosphate; preferably lactose, corn starch, and microcrystalline cellulose.

[0015] Further, the disintegrant is selected from one or more of calcium carboxymethylcellulose, sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethylcellulose; preferably calcium carboxymethylcellulose.

[0016] Further, the lubricant is selected from one or more of magnesium stearate, talc powder, and colloidal silica; preferably magnesium stearate.

[0017] Further, the perospirone hydrochloride pharmaceutical preparation comprises, by mass percentage: 1-10% of perospirone hydrochloride or a pharmaceutically acceptable salt thereof, 3-7% of a binder, 74-85% of a filler, 5-7% of a disintegrant, and 0.5-2% of a lubricant.

[0018] In some specific embodiments of the present invention, the perospirone hydrochloride pharmaceutical preparation comprises, by mass percentage: 1-10% of perospirone hydrochloride or a pharmaceutically acceptable salt thereof, 3-7% of polyvinyl alcohol, 52-57% of lactose, 11-14% of corn starch, 11-14% of microcrystalline cellulose, 5-7% of calcium carboxymethylcellulose, and 0.5-2% of magnesium stearate.

[0019] Even further, the perospirone hydrochloride pharmaceutical preparation further comprises: a film coating premix.

[0020] Even further, the mass percentage of the film coating premix in the perospirone hydrochloride pharmaceutical preparation is 1-3%.

[0021] Even further, the gastric-soluble film coating premix is selected from one or more of hydroxypropyl methylcellulose, titanium dioxide, glycerol, magnesium stearate, and yellow iron oxide.

[0022] The second aspect of the present invention lies in: providing a preparation method of the perospirone hydrochloride pharmaceutical preparation as described in any one of the above, comprising the following steps:

[0023] (1) Premixing: Mixing perospirone hydrochloride or a pharmaceutically acceptable salt thereof, a filler, a disintegrant, and polyvinyl alcohol added in powder form to obtain a premixed material;

[0024] (2) Solution preparation: Dissolving the remaining polyvinyl alcohol in water to prepare a polyvinyl alcohol solution, i.e., obtaining polyvinyl alcohol in solution form, for standby;

[0025] (3) Granulation and sizing: Spraying the polyvinyl alcohol solution into a fluidized bed containing the premixed material for granulation, and after the spraying is completed, drying and sizing;

[0026] (4) Total mixing: Mixing the sized granules with a lubricant uniformly to obtain the product.

[0027] Further, the mass concentration of the polyvinyl alcohol solution is 5-10%.

[0028] Further, the fluidized bed granulation is specifically as follows: the inlet air temperature is 50 - 70°C, the inlet air volume is 1000 - 3000 m 3 / h, and the atomization pressure is 0.2 - 0.4 MPa.

[0029] Further, in step (3), it is dried until the water content ≤ 3%.

[0030] Further, the preparation method further includes: tableting and coating the preparation obtained by total mixing; specifically: tableting the total mixing powder with a Ф7mm round shallow concave punch die; and coating with a film coating premix.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] (1) The inventor unexpectedly found during the research and development of the perospirone hydrochloride pharmaceutical preparation that the dosage of polyvinyl alcohol has a significant impact on the dissolution stability of this product. By selecting the dosage of the binder, the problem that the raw material powder floats on the liquid surface of the dissolution medium and causes incomplete dissolution is improved;

[0033] (2) During the preparation process of the perospirone hydrochloride pharmaceutical preparation, when further dividing polyvinyl alcohol into powder form and solution form and adding them in two batches during the premixing and fluidized bed granulation steps, the prepared tablets show good dissolution properties. The dissolution curve is similar to that of the original preparation "Lullan", and during the stability investigation process, the problem that the raw material powder floats on the surface of the dissolution medium can be avoided, and the dissolution stability is good, further improving the quality stability of the product;

[0034] (3) At the same time, the preparation process provided by the present invention has a short cycle, a simple process, high reproducibility, and is suitable for large-scale production. Description of the Drawings

[0035] Figure 1 It is the dissolution curve graph of each preparation at 0 day;

[0036] Figure 2 It is the dissolution curve graph of each preparation after accelerating for 3 months. Detailed Embodiments

[0037] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the embodiments of the invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts shall fall within the protection scope of the present invention.

[0038] Example 1

[0039] A perospirone hydrochloride coated tablet, based on 1000 tablets, its formulation composition and dosage are shown in Table 1.

[0040] Table 1

[0041]

[0042]

[0043] Note: The composition of the film coating premix (mass percentage) is: hypromellose 78.5%, titanium dioxide 15%, glycerol 5%, yellow iron oxide 1% and magnesium stearate 0.5%. The same applies hereinafter.

[0044] The preparation method is as follows:

[0045] (1) Premixing: Add perospirone hydrochloride, microcrystalline cellulose, carboxymethylcellulose calcium, and polyvinyl alcohol (in powder form) into a mixer, set the mixing rotation speed at 10 rpm, and mix for 10 min; after mixing, granulate with a granulator and pass through a 0.8 mm sieve 3 times under the condition of a cutter rotation speed of 800 rpm; then add lactose and corn starch into the mixer, set the mixing rotation speed at 10 rpm, and mix for 10 min.

[0046] (2) Preparation of polyvinyl alcohol solution: Add polyvinyl alcohol (in solution form) into an appropriate amount of water, stir and dissolve at 80 ± 5 °C, and then cool to room temperature to prepare a polyvinyl alcohol solution with a mass concentration of 6%.

[0047] (3) Granulation: Add the premixed materials into a fluidized bed, set the inlet air temperature at 60 ± 10 °C, the inlet air volume at 1000 - 1500 m 3 / h, preheat the materials to 42 - 45 °C and start spraying the liquid, adjust the atomization pressure to 0.3 ± 0.1 MPa, the peristaltic pump rotation speed to 70 rpm, so that the liquid spraying speed is 0.4 kg / min. After the liquid spraying is stable, the material temperature is 30 - 35 °C. After the liquid spraying is completed, keep the inlet air temperature unchanged and continue drying until the moisture content ≤ 3%.

[0048] (4) Granule sizing: Size the dried granules with a mobile granulator using a 1.0 mm sieve under the condition of a rotation speed of 500 rpm.

[0049] (5) Total mixing: Add the sized granules after dry granulation and magnesium stearate into a mixer, set the rotation speed at 10 rpm, and mix for 10 min to obtain the total mixed powder.

[0050] (6) Tabletting: Tablet the total mixed powder with a Ф7 mm round shallow concave punch die, and the hardness is 3 - 6 kgf.

[0051] (7) Coating: Coat with the film coating premix, and the coating weight gain is 2.2%.

[0052] Example 2

[0053] A perospirone hydrochloride coated tablet, and the dosage of its formulation components is shown in Table 2.

[0054] Table 2

[0055] Component Dosage g Mass percentage % Perospirone Hydrochloride 8.62 7.0 Lactose 66.99 54.3 Corn Starch 15.24 12.3 Microcrystalline Cellulose 15.30 12.4 Carboxymethylcellulose Calcium 7.38 6.0 Polyvinyl Alcohol (powder form) 2.46 2.0 Polyvinyl Alcohol (solution form) 1.23 1.0 Magnesium Stearate 1.24 1.0 Total weight of tablet core 120.93 97.8 Film coating premix 2.69 2.2 Total weight of coated tablet 123.62 100.0

[0056] The preparation method is the same as that of Example 1.

[0057] Example 3

[0058] A perospirone hydrochloride coated tablet, and the formulation components and dosage are shown in Table 3.

[0059] Table 3

[0060]

[0061]

[0062] The preparation method is the same as that of Example 1.

[0063] Example 4

[0064] A perospirone hydrochloride coated tablet, and the formulation components and dosage are shown in Table 4.

[0065] Table 4

[0066] Component Dosage g Mass percentage % Perospirone Hydrochloride 8.62 7.0 Mannitol 72.30 58.5 Corn Starch 15.24 12.3 Calcium Hydrogen Phosphate Anhydrous 10.00 8.1 Carboxymethylcellulose Calcium 7.38 6.0 Polyvinyl Alcohol (powder form) 3.69 3.0 Polyvinyl Alcohol (solution form) 2.46 2.0 Magnesium Stearate 1.24 1.0 Total weight of tablet core 120.93 97.8 Film coating premix 2.69 2.2 Total weight of coated tablet 123.62 100.0

[0067] The preparation method is as follows:

[0068] (1) Premixing: Add perospirone hydrochloride, anhydrous calcium hydrogen phosphate, calcium carboxymethylcellulose, and polyvinyl alcohol (in powder form) into a mixer, set the mixing speed at 10 rpm, and mix for 10 min; after mixing, granulate with a granulator and pass through a 0.8 mm sieve 3 times under the condition of a cutter speed of 800 rpm; then add mannitol and corn starch into the mixer, set the mixing speed at 10 rpm, and mix for 10 min.

[0069] (2) Preparation of polyvinyl alcohol solution: Add polyvinyl alcohol (in solution form) into an appropriate amount of water, stir and dissolve at 80 ± 5 °C, and then cool to room temperature to prepare a polyvinyl alcohol solution with a mass concentration of 6%.

[0070] (3) Granulation: Add the premixed materials into a fluidized bed, set the inlet air temperature at 60 ± 10 °C, the inlet air volume at 1000 - 1500 m 3 / h, preheat the materials to 42 - 45 °C and start spraying the liquid, adjust the atomization pressure to 0.3 ± 0.1 MPa, the peristaltic pump speed to 70 rpm, so that the liquid spraying speed is 0.4 kg / min, after the liquid spraying is stable, the material temperature is 30 - 35 °C, after the liquid spraying is completed, keep the inlet air temperature unchanged, and continue drying until the moisture content ≤ 3%.

[0071] (4) Granulation: The dried granules are granulated dry using a mobile granulator with a 1.0 mm sieve at a rotational speed of 500 rpm.

[0072] (5) Total mixing: The granules after dry granulation and magnesium stearate are added to a mixer, the rotational speed is set at 10 rpm, and mixed for 10 min to obtain the total mixed powder.

[0073] (6) Tabletting: The total mixed powder is tabletted using a Ф7 mm round shallow concave punch die with a hardness of 3 - 6 kgf.

[0074] (7) Coating: Coated with a film coating premix with a coating weight gain of 2.2%.

[0075] Example 5

[0076] A perospirone hydrochloride coated tablet, the formulation composition and dosage are shown in Table 5.

[0077] Table 5

[0078]

[0079]

[0080] The preparation method is as follows:

[0081] (1) Premixing: Perospirone hydrochloride, anhydrous calcium hydrogen phosphate, sodium carboxymethyl starch, and polyvinyl alcohol (in powder form) are added to a mixer, the mixing rotational speed is set at 10 rpm, and mixed for 10 min; after mixing, granulation is carried out using a granulator and passed through a 0.8 mm sieve 3 times at a cutter rotational speed of 800 rpm; then mannitol and corn starch are added to the mixer, the mixing rotational speed is set at 10 rpm, and mixed for 10 min.

[0082] (2) Preparation of polyvinyl alcohol solution: Polyvinyl alcohol (in solution form) is added to an appropriate amount of water, stirred and dissolved at 80 ± 5 °C, and then cooled to room temperature to prepare a polyvinyl alcohol solution with a mass concentration of 6%.

[0083] (3) Granulation: The premixed material is added to a fluidized bed, the inlet air temperature is set at 60 ± 10 °C, the inlet air volume is 1000 - 1500 m 3 / h, the material is preheated to 42 - 45 °C and then spraying of the liquid starts, the atomization pressure is adjusted to 0.3 ± 0.1 MPa, the peristaltic pump rotational speed is 70 rpm, so that the liquid spraying speed is 0.4 kg / min, after the liquid spraying is stable, the material temperature is 30 - 35 °C, after the liquid spraying is completed, the inlet air temperature remains unchanged, and continue drying until the moisture content ≤ 3%.

[0084] (4) Granulation: The dried granules are granulated dry using a mobile granulator with a 1.0 mm sieve at a rotational speed of 500 rpm.

[0085] (5) Total mixing: Add the granulated particles after dry sizing and talc powder into the mixer, set the rotation speed at 10 rpm, mix for 10 min to obtain the total mixed powder.

[0086] (6) Tableting: Tablet the total mixed powder using a Ф7mm round shallow concave punch die, with a hardness of 3 - 6 kgf.

[0087] (7) Coating: Coat with a film coating premix, with a coating weight gain of 2.2%.

[0088] Example 6

[0089] A perospirone hydrochloride coated tablet, and its formulation composition and dosage are shown in Table 6.

[0090] Table 6

[0091] Component Dosage g Mass percentage % Perospirone Hydrochloride 8.62 7.0 Mannitol 67.00 54.2 Corn Starch 15.24 12.3 Calcium Hydrogen Phosphate Anhydrous 15.30 12.4 Crosslinked Polyvinylpyrrolidone 7.38 6.0 Polyvinyl Alcohol (powder form) 3.69 3.0 Polyvinyl Alcohol (solution form) 2.46 2.0 Colloidal Silicon Dioxide 1.24 1.0 Total weight of tablet core 120.93 97.8 Film coating premix 2.69 2.2 Total weight of coated tablet 123.62 100.0

[0092] The preparation method is as follows:

[0093] (1) Premixing: Add perospirone hydrochloride, anhydrous calcium hydrogen phosphate, crosslinked polyvinylpyrrolidone, and polyvinyl alcohol (in powder form) into the mixer, set the mixing rotation speed at 10 rpm, and mix for 10 min; after mixing, size the particles using a granulator and pass through a 0.8 mm sieve 3 times under the condition of a cutter rotation speed of 800 rpm; then add mannitol and corn starch into the mixer, set the mixing rotation speed at 10 rpm, and mix for 10 min.

[0094] (2) Preparation of polyvinyl alcohol solution: Add polyvinyl alcohol (in solution form) into an appropriate amount of water, stir and dissolve at 80 ± 5 °C, and then cool to room temperature to prepare a polyvinyl alcohol solution with a mass concentration of 6%.

[0095] (3) Granulation: Add the premixed materials into the fluidized bed, set the inlet air temperature at 60 ± 10 °C, the inlet air volume at 1000 - 1500 m 3 / h, preheat the materials to 42 - 45 °C and start spraying the liquid, adjust the atomization pressure to 0.3 ± 0.1 MPa, and the peristaltic pump rotation speed to 70 rpm to make the liquid spraying speed 0.4 kg / min. After the liquid spraying is stable, the material temperature is 30 - 35 °C. After the liquid spraying is completed, keep the inlet air temperature unchanged and continue drying until the moisture content ≤ 3%.

[0096] (4) Sizing: Size the dried particles using a mobile granulator with a 1.0 mm sieve under the condition of a rotation speed of 500 rpm for dry sizing.

[0097] (5) Total mixing: Add the sized particles after dry sizing and colloidal silicon dioxide into the mixer, set the rotation speed at 10 rpm, and mix for 10 min to obtain the total mixed powder.

[0098] (6) Tabletting: Tabletting the total mixed powder using a Ф7mm round shallow concave punch die, with a hardness of 3 - 6 kgf.

[0099] (7) Coating: Coating with a film coating premix, with a coating weight gain of 2.2%.

[0100] Comparative Example 1

[0101] A perospirone hydrochloride coated tablet, the formulation composition and dosage are shown in Table 7.

[0102] Table 7

[0103] Component Dosage g Mass percentage % Perospirone Hydrochloride 8.62 7.0 Lactose 67.00 54.2 Corn Starch 15.24 12.3 Microcrystalline Cellulose 15.30 12.4 Carboxymethylcellulose Calcium 7.38 6.0 Polyvinyl Alcohol 6.15 5.0 Magnesium Stearate 1.24 1.0 Total weight of tablet core 120.93 97.8 Film coating premix 2.69 2.2 Total weight of coated tablet 123.62 100.0

[0104] The preparation method is as follows:

[0105] (1) Premixing: Add perospirone hydrochloride, microcrystalline cellulose, and calcium carboxymethylcellulose to a mixer, set the mixing speed at 10 rpm, and mix for 10 min; after mixing, pass through a 0.8 mm sieve 3 times using a granulating machine at a granulating cutter speed of 8000 rpm; then add lactose and corn starch to the mixer, set the mixing speed at 10 rpm, and mix for 10 min.

[0106] (2) Preparation of polyvinyl alcohol solution: Add polyvinyl alcohol to an appropriate amount of water, stir and dissolve at 80 ± 5 °C, and then cool to room temperature to prepare a polyvinyl alcohol solution with a mass concentration of 6%.

[0107] (3) Granulation: Add the premixed material to a fluidized bed, set the inlet air temperature at 60 ± 10 °C, the inlet air volume at 1000 - 3000 m 3 / h, preheat the material to 42 - 45 °C and start spraying the liquid, adjust the atomization pressure to 0.3 ± 0.1 MPa, the peristaltic pump speed to 70 rpm, so that the spraying speed is 0.4 kg / min, and the material temperature is 30 - 35 °C after the spraying is stable. After spraying, keep the inlet air temperature unchanged and continue drying until the moisture content ≤ 3%.

[0108] (4) Granule sizing: Size the dried granules using a mobile granule sizing machine with a 1.0 mm sieve at a speed of 500 rpm for dry granule sizing.

[0109] (5) Total mixing: Add the sized granules and magnesium stearate to a mixer, set the speed at 10 rpm, and mix for 10 min to obtain the total mixed powder.

[0110] (6) Tabletting: Tabletting the total mixed powder using a Ф7mm round shallow concave punch die, with a hardness of 3 - 6 kgf.

[0111] (7) Coating: Coating with a film coating premix, with a coating weight gain of 2.2%.

[0112] Comparative Example 2

[0113] A perospirone hydrochloride coated tablet, and its formulation composition and dosage are shown in Table 8.

[0114] Table 8

[0115] Component Dosage g Mass percentage % Perospirone Hydrochloride 8.62 7.0 Lactose 70.69 57.2 Corn Starch 15.24 12.3 Microcrystalline Cellulose 15.30 12.4 Carboxymethylcellulose Calcium 7.38 6.0 Polyvinyl Alcohol (powder form) 1.476 1.2 Polyvinyl Alcohol (solution form) 0.984 0.8 Magnesium Stearate 1.24 1.0 Total weight of tablet core 120.93 97.8 Film coating premix 2.69 2.2 Total weight of coated tablet 123.62 100.0

[0116] The preparation method is the same as that of Example 1.

[0117] Comparative Example 3

[0118] A perospirone hydrochloride coated tablet, and its formulation composition and dosage are shown in Table 9.

[0119] Table 9

[0120] Component Dosage g Mass percentage % Perospirone Hydrochloride 8.62 7.0 Lactose 63.31 51.2 Corn Starch 15.24 12.3 Microcrystalline Cellulose 15.30 12.4 Carboxymethylcellulose Calcium 7.38 6.0 Polyvinyl Alcohol (powder form) 5.094 4.8 Polyvinyl Alcohol (solution form) 3.936 3.2 Magnesium Stearate 1.24 1.0 Total weight of tablet core 120.93 97.8 Film coating premix 2.69 2.2 Total weight of coated tablet 123.62 100.0

[0121] The preparation method is the same as that of Example 1.

[0122] Comparative Example 4

[0123] A perospirone hydrochloride coated tablet, and its formulation composition and dosage are shown in Table 10.

[0124] Table 10

[0125] Component Dosage g Mass percentage % Perospirone Hydrochloride 8.62 7.0 Lactose 67.00 54.2 Corn Starch 15.24 12.3 Microcrystalline Cellulose 15.30 12.4 Carboxymethylcellulose Calcium 7.38 6.0 Polyvinyl Alcohol 6.15 5.0 Magnesium Stearate 1.24 1.0 Total weight of tablet core 120.93 97.8 Film coating premix 2.69 2.2 Total weight of coated tablet 123.62 100.0

[0126] The preparation method is as follows:

[0127] (1) Premixing: Add perospirone hydrochloride, microcrystalline cellulose, carboxymethylcellulose calcium, and polyvinyl alcohol into a mixer, set the mixing rotation speed at 10 rpm, and mix for 10 min; after mixing, granulate with a granulator and pass through a 0.8 mm sieve 3 times at a cutter rotation speed of 800 rpm; then add lactose and corn starch into the mixer, set the mixing rotation speed at 10 rpm, and mix for 10 min.

[0128] (2) Total mixing: Add magnesium stearate into the mixer, set the mixing rotation speed at 10 rpm, and mix for 10 min to obtain the total mixing powder.

[0129] (3) Tabletting: Tablet the total mixing powder with a Ф7 mm round shallow concave punch die, and the hardness is 3 - 6 kgf.

[0130] (4) Coating: Coat with a film coating premix, and the coating weight gain is 2.2%.

[0131] Comparative Example 5

[0132] A perospirone hydrochloride coated tablet, and its formulation composition and dosage are shown in Table 11.

[0133] Table 11

[0134] Component Dosage g Mass percentage % Perospirone Hydrochloride 8.62 7.0 Lactose 67.00 54.2 Corn Starch 15.24 12.3 Microcrystalline Cellulose 15.30 12.4 Carboxymethylcellulose Calcium 7.38 6.0 Polyvinyl Alcohol (powder form) 2.46 2.0 Polyvinyl Alcohol (solution form) 3.69 3.0 Magnesium Stearate 1.24 1.0 Total weight of tablet core 120.93 97.8 Film coating premix 2.69 2.2 Total weight of coated tablet 123.62 100.0

[0135] The preparation method was the same as that of Example 1.

[0136] Comparative Example 6

[0137] A perospirone hydrochloride coated tablet, the formulation composition and dosage are shown in Table 12.

[0138] Table 12

[0139] Component Dosage g Mass percentage % Perospirone Hydrochloride 8.62 7.0 Lactose 67.00 54.2 Corn Starch 15.24 12.3 Microcrystalline Cellulose 15.30 12.4 Carboxymethylcellulose Calcium 7.38 6.0 Polyvinyl Alcohol (powder form) 4.92 4.0 Polyvinyl Alcohol (solution form) 1.23 1.0 Magnesium Stearate 1.24 1.0 Total weight of tablet core 120.93 97.8 Film coating premix 2.69 2.2 Total weight of coated tablet 123.62 100.0

[0140] The preparation method was the same as that of Example 1.

[0141] Test Example

[0142] The dissolution stability of the above-mentioned examples and comparative examples was tested. According to the general rules of Part IV of the Chinese Pharmacopoeia 2020 Edition, the dissolution and release determination method II (paddle method) was carried out. pH 6.8 phosphate buffer solution was selected as the dissolution medium, the medium volume was 1000 mL, the rotation speed was 50 rpm, and the dissolution at 5, 10, 15, 30, 45, and 60 min was measured. The accelerated test conditions were a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. The experimental results are shown in Table 13.

[0143] Table 13 Dissolution stability results of examples and comparative examples

[0144]

[0145]

[0146] From the above results, it can be known that the dissolution curves of the perospirone hydrochloride coated tablets prepared in Examples 1-6 were all similar to the original preparation Lullan on the 0th day (both satisfied that the dissolution at 15 min was greater than 85%). After 3 months of acceleration, there was no significant change in dissolution compared with the 0th day, and the dissolution stability was good.

[0147] In Comparative Example 1 and Comparative Example 4, polyvinyl alcohol was used in the form of solution (fluidized bed granulation) and powder form (powder direct compression process) respectively. The dissolution stability of the perospirone hydrochloride coated tablets prepared decreased significantly after 3 months of acceleration. It can be seen that during the preparation process of perospirone hydrochloride coated tablets, the addition method of polyvinyl alcohol has a great influence on the dissolution stability of the preparation.

[0148] In Comparative Example 2, the dosage of polyvinyl alcohol was 2%, and its dissolution after 3 months of acceleration decreased significantly compared with the 0th day, and the dissolution stability was poor; in Comparative Example 3, the dosage of polyvinyl alcohol was 8%. After 3 months of acceleration, although the cumulative dissolution at 60 min was equivalent, the dissolution in the early stage was slower, that is, the dissolution consistency with the original preparation Lullan became worse after 3 months of acceleration.

[0149] Comparing Comparative Examples 5 and 6 with Example 1, it was found that the ratio of the polyvinyl alcohol in powder form to that in solution form also had a certain degree of influence on the dissolution stability of the preparation. During the preparation of the perospirone hydrochloride coated tablets of the present invention, the ratio (mass ratio) of the polyvinyl alcohol in powder form to that in solution form is preferably 1:1 - 3:1.

[0150] In summary, through the improvement of the dosage of polyvinyl alcohol and the preparation process, the dissolution stability of the preparation is effectively improved. In addition, through the adjustment of the ratio of the polyvinyl alcohol in powder form to that in solution form, the dissolution stability is further enhanced, greatly improving the product quality stability.

[0151] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent substitution on some of the technical features. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A highly stable perospirone hydrochloride pharmaceutical preparation, characterized in that, The perospirone hydrochloride pharmaceutical preparation comprises, by mass percentage: 1-10% of perospirone hydrochloride or its pharmaceutically acceptable salt and 3-7% of polyvinyl alcohol; in the preparation process of the perospirone hydrochloride pharmaceutical preparation, the polyvinyl alcohol is added in batches in powder form and solution form.

2. The perospirone hydrochloride pharmaceutical preparation according to claim 1, characterized in that, The mass ratio of the polyvinyl alcohol in powder form and solution form is 1:1 - 3:

1.

3. The perospirone hydrochloride pharmaceutical preparation according to claim 1, wherein It further comprises one or more of a filler, a disintegrant and a lubricant.

4. The perospirone hydrochloride pharmaceutical preparation according to claim 3, characterized in that, The filler is selected from one or more of lactose, corn starch, microcrystalline cellulose, mannitol and anhydrous calcium hydrogen phosphate; the disintegrant is selected from one or more of calcium carboxymethylcellulose, sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked carboxymethylcellulose sodium; the lubricant is selected from one or more of magnesium stearate, talc powder and colloidal silicon dioxide.

5. The perospirone hydrochloride pharmaceutical preparation according to claim 4, characterized in that, The filler is lactose, corn starch and microcrystalline cellulose; the disintegrant is calcium carboxymethylcellulose; the lubricant is magnesium stearate.

6. The perospirone hydrochloride pharmaceutical preparation according to any one of claims 3-5, characterized in that, It comprises, by mass percentage: 1-10% of perospirone hydrochloride or its pharmaceutically acceptable salt, 3-7% of a binder, 74-85% of a filler, 5-7% of a disintegrant and 0.5-2% of a lubricant.

7. The preparation method of the perospirone hydrochloride pharmaceutical preparation according to any one of claims 3-6, characterized in that, It comprises the following steps: (1) Premixing: Mixing perospirone hydrochloride or its pharmaceutically acceptable salt, the filler, the disintegrant and the polyvinyl alcohol added in powder form to obtain a premixed material. (2) Solution preparation: Dissolving the remaining polyvinyl alcohol in water to prepare a polyvinyl alcohol solution, namely obtaining the polyvinyl alcohol in solution form for standby. (3) Granulation and sizing: Spraying the polyvinyl alcohol solution into a fluidized bed filled with the premixed material for granulation, and after the spraying is completed, drying and sizing. (4) Total mixing: Mixing the sized granules and the lubricant evenly to obtain the product.

8. The preparation method according to claim 7, characterized in that, The mass concentration of the polyvinyl alcohol solution is 5-10%.

9. The preparation method according to claim 7, wherein The fluidized bed granulation is specifically as follows: the inlet air temperature is 50 - 70 °C, the inlet air volume is 1000 - 3000 m 3 / h, and the atomization pressure is 0.2 - 0.4 MPa.

10. The preparation method according to claim 7, wherein In step (3), drying is carried out until the water content ≤ 3%.

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