A composition containing mosapride citrate and a method for preparing the same

Abstract

The present application provides a novel mosapride citrate composition, which is prepared by a specially optimized fluidized bed granulation process, has good content uniformity, and can keep the dissolution of the finished product from decreasing and the related substances from increasing for a long time, so that the drug effectiveness and safety of the mosapride citrate composition after long-term storage are more guaranteed.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a composition containing mosapride citrate and a method for preparing the same. Background Technology

[0002] Mosapride citrate is a selective 5-HT4 receptor agonist. It enhances upper gastrointestinal motility by stimulating 5-HT4 receptors in gastrointestinal cholinergic interneurons and the myenteric plexus, thereby promoting acetylcholine release. It is a third-generation prokinetic drug developed by Nippon Pharmaceutical Co., Ltd. Clinically, it is mainly used for patients with functional dyspepsia accompanied by gastrointestinal symptoms such as heartburn, belching, nausea, vomiting, early satiety, and upper abdominal distension. Its chemical name is (±)-4-amino-5-chloro-2-ethoxy-N-{4-(4-fluorobenzyl)-2-morphonel]methyl}toluamide citrate dihydrate, with the molecular formula C63. 21 H 25 ClFN3O3·C6H8O7·2H2O, with a molecular weight of 650.05, has the following structural formula:

[0003]

[0004] Mosapride citrate is a BCS Class II drug with extremely low solubility in water. For solid dosage forms of this type of drug, the rate of dissolution is often the rate-limiting step affecting bioavailability. Current national standards clearly stipulate that mosapride citrate tablets must achieve a dissolution rate of no less than 75% in 0.1 mol / L hydrochloric acid solution (simulating gastric juice) after 30 minutes to ensure effective release and absorption of the drug in the patient's stomach. However, for some patients with low gastric acid, the dissolution of mosapride citrate in the stomach may be significantly reduced, leading to decreased bioavailability and failing to achieve effective therapeutic effects. Furthermore, because mosapride citrate is a heat-sensitive compound, industrially produced mosapride citrate formulations exhibit significant stability issues during long-term transportation and storage, especially when exposed to humid and hot environments. This can lead to an increase in related substances, posing safety risks and hindering clinical application. Therefore, controlling related substances in its formulation composition remains a challenging problem that needs to be continuously addressed in this field. In addition, the commonly used formulation of mosapride citrate in clinical treatment is 5mg, such as "Gassing" produced by the original manufacturer, Sumitomo Pharmaceuticals of Japan. Therefore, the proportion of active ingredient in the formulation is often low, which can easily lead to problems with content uniformity. This can result in unstable efficacy during clinical application. Therefore, meeting the requirements for content uniformity is also very important to ensure the stable efficacy of mosapride citrate formulations. Summary of the Invention

[0005] To address some key issues that still exist in the existing technology, one of the objectives of this invention is to provide a novel composition containing mosapride citrate, which has good content uniformity and can maintain the dissolution of the finished product without decreasing and the related substances without increasing over a long period of time, thus ensuring the efficacy and safety of the drug after long-term storage of the mosapride citrate composition.

[0006] This invention provides a composition containing mosapride citrate, which contains mosapride citrate, mannitol, and hydroxypropyl methylcellulose (HPMC), and is prepared by fluidized bed granulation process.

[0007] According to the above composition containing mosapride citrate, the fluidized bed granulation process includes the following steps:

[0008] (1) Prepare hydroxypropyl methylcellulose into a hydroxypropyl methylcellulose solution, add mosapride citrate, disperse and dissolve it to make an adhesive solution;

[0009] (2) Spray the above adhesive onto mannitol for granulation.

[0010] Specifically, in step (1) above, the hydroxypropyl methylcellulose solution is prepared using an aqueous ethanol solution as the solvent;

[0011] The volume concentration of the ethanol-water solution is 20-60% (v / v), preferably 30-40% (v / v), and more preferably 40% (v / v).

[0012] The mass / volume concentration of the hydroxypropyl methylcellulose solution is 2-10% (w / v), preferably 3-5% (w / v), and more preferably 3% (w / v).

[0013] According to the above-mentioned composition containing mosapride citrate, the components of the composition further contain other pharmaceutically acceptable excipients.

[0014] According to the above-mentioned compositions containing mosapride citrate, other pharmaceutically acceptable excipients include fillers, disintegrants, glidants, and lubricants.

[0015] Specifically, according to the above-mentioned composition containing mosapride citrate, the preparation steps of said composition include:

[0016] (1) Hydroxypropyl methylcellulose was dissolved in an ethanol aqueous solution to prepare a hydroxypropyl methylcellulose solution. Mosapride citrate was added and stirred to fully disperse and dissolve the solution, which served as an adhesive solution.

[0017] (2) Place mannitol in a fluidized bed granulator and spray the above-mentioned binder onto the mannitol for granulation.

[0018] (3) Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, flow aid and lubricant according to the prescription amount, mix evenly, compress into tablets, and the product is obtained.

[0019] According to the above-mentioned composition containing mosapride citrate, the content of mosapride citrate is 1.0 to 10.0 parts, the content of mannitol is 10.0 to 100.0 parts, the content of hydroxypropyl methylcellulose is 0.5 to 3.0 parts, the content of filler is 16.5 to 33.0 parts, the content of disintegrant is 13.2 to 36.3 parts, the content of glidant is 0 to 1.65 parts, and the content of lubricant is 0 to 1.65 parts.

[0020] According to the above-mentioned composition containing mosapride citrate, the filler is selected from one or more of pregelatinized starch, corn starch, dicalcium phosphate, and microcrystalline cellulose, preferably microcrystalline cellulose.

[0021] According to the above-mentioned composition containing mosapride citrate, the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl methylcellulose, crospovidone sodium carboxymethyl cellulose and sodium carboxymethyl starch, preferably a combination of low-substituted hydroxypropyl methylcellulose and crospovidone sodium carboxymethyl cellulose.

[0022] According to the above-mentioned composition containing mosapride citrate, the flow aid is selected from one or more of micronized silica gel and talc, preferably micronized silica gel.

[0023] According to the above-mentioned composition containing mosapride citrate, the lubricant is selected from one or more of magnesium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, and sodium lauryl sulfate, preferably magnesium stearate.

[0024] More specifically, the present invention provides a composition containing mosapride citrate, comprising the following components:

[0025]

[0026] It is prepared using the following fluidized bed granulation process:

[0027] (1) Dissolve hydroxypropyl methylcellulose in a 30-40% ethanol aqueous solution to prepare a 3-5% hydroxypropyl methylcellulose solution, add mosapride citrate, stir to fully disperse and dissolve it, and use it as an adhesive solution;

[0028] (2) Place mannitol in a fluidized bed granulator, control the temperature at 30-40℃, spray the above-mentioned binder solution onto the mannitol for granulation, and continue drying after granulation.

[0029] (3) Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, flow aid and lubricant according to the prescription amount, mix evenly, compress into tablets, and the product is obtained.

[0030] More specifically, the present invention provides a composition containing mosapride citrate, comprising the following components:

[0031]

[0032] It is prepared using the following fluidized bed granulation process:

[0033] (1) Dissolve hydroxypropyl methylcellulose in 40% ethanol aqueous solution to prepare 3% hydroxypropyl methylcellulose solution, add mosapride citrate, stir to fully disperse and dissolve it, and use it as an adhesive solution;

[0034] (2) Place mannitol in a fluidized bed granulator, control the temperature at 35°C, spray the above-mentioned binder solution onto the mannitol for granulation, and continue drying after granulation.

[0035] (3) Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, flow aid and lubricant according to the prescription amount, mix evenly, compress into tablets, and the product is obtained.

[0036] More specifically, the present invention provides a composition containing mosapride citrate, comprising the following components:

[0037]

[0038] It is prepared using the following fluidized bed granulation process:

[0039] (1) Dissolve hydroxypropyl methylcellulose in 40% ethanol aqueous solution to prepare 3% hydroxypropyl methylcellulose solution, add mosapride citrate, stir to fully disperse and dissolve it, and use it as an adhesive solution;

[0040] (2) Place mannitol in a fluidized bed granulator, control the temperature at 35°C, spray the above-mentioned binder solution onto the mannitol for granulation, and continue drying after granulation.

[0041] (3) Remove the dry granules from the fluidized bed, granulate them, add microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, micronized silica gel and magnesium stearate according to the prescription amount, mix evenly, compress into tablets, and the product is obtained.

[0042] The mosapride citrate composition provided by this invention has the following advantages:

[0043] (1) The wet granulation process solves the problem that the dry granulation process in industrial production has high requirements for the quality of raw materials or requires strict pretreatment.

[0044] (2) The uniformity of the content of the finished product is significantly improved, the dissolution is fast, and the effect is rapid.

[0045] (3) The finished product has better stability after long-term storage under accelerated simulation, with no significant decrease in dissolution and no significant increase in related substances. This means that the therapeutic effect is maintained, safety is guaranteed, and the quality is more stable. Detailed Implementation

[0046] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the present invention.

[0047] The methods for determining the indicators involved in this invention and the information on the original research products are as follows:

[0048] 1. Information on the original drug: Mosapride Citrate Tablets (trade name: ), specification 5mg, manufacturer: Dainippon Sumitomo Pharma Co., Ltd., repackaging company: Sumitomo Pharmaceutical (Suzhou) Co., Ltd., product batch number: 2757c.

[0049] 2. Content uniformity determination: Take 10 tablets of sample and determine the relative content of each tablet with the labeled amount as 100. Calculate the mean X and standard deviation S of the relative content, as well as the absolute value A of the difference between the labeled amount and the mean (i.e., A = |100-X|). Finally, calculate the value of A+1.80S. The smaller the value, the higher the content uniformity.

[0050] 3. Dissolution determination before and after acceleration, and stability test under extreme acceleration conditions: temperature 60℃, humidity 92.5%, samples were taken and analyzed after 0 days and 10 days. Dissolution determination method: Take the test sample and perform dissolution determination according to the method (Chinese Pharmacopoeia 2015 Edition, General Chapter 0931, Method II), using 900 ml of 0.1 mol / L hydrochloric acid solution as solvent, rotating at 50 rpm. Operate according to the method, and after the specified time, take an appropriate amount of solution, filter, and take the filtrate for determination by high performance liquid chromatography. Use octadecylsilane-bonded silica gel as the stationary phase; use acetonitrile-methanol-citrate buffer (7:9:24, dissolve 8.82 g of sodium citrate dihydrate in 800 ml of water, adjust the pH to 3.3 with dilute hydrochloric acid, and add water to 1000 ml) as the mobile phase; the detection wavelength is 274 nm; the column temperature is 40℃; adjust the flow rate so that the retention time of the mosapride peak is about 9 minutes, and calculate the mosapride content by external standard method based on the peak area.

[0051] 4. Determination of related substances before and after acceleration, and stability test under extreme acceleration conditions: At 60℃ and 92.5% humidity, samples were taken for analysis after 0 days and 10 days. An appropriate amount of the fine sample powder (approximately equivalent to 10 mg of mosapride citrate) was placed in a 10 ml volumetric flask, and an appropriate amount of diluent (citrate buffer) was added. The mixture was shaken for 20 minutes, diluted to the mark with the diluent, and filtered. The filtrate was used as the test solution. 1 ml of the test solution was accurately measured and placed in a 200 ml volumetric flask. The solution was diluted to the mark with the diluent and mixed to prepare a control solution. An appropriate amount of mosapride citrate reference standard was also prepared and diluted with the diluent to prepare a mixed solution containing approximately 2 μg per ml as the system suitability solution. The test was performed according to the high-performance liquid chromatography method (General Chapter 0512, Part IV, Chinese Pharmacopoeia 2015 Edition), using octadecyl bonded silica gel as the stationary phase (XSelect CSHTM C). 18 5μm, 4.6mm×250mm); using citrate buffer solution (dissolve 8.82g of sodium citrate in 800ml of water, adjust the pH to 4.0 with dilute hydrochloric acid, and then add water to 1000ml) as mobile phase A, and acetonitrile as mobile phase B, gradient elution was performed according to the table below; the detection wavelength was 274nm; the column temperature was 40℃; and the flow rate was 1.0ml per minute.

[0052]

[0053] Accurately measure 10 μl of the system suitability solution and inject it into the liquid chromatograph. Perform six consecutive injections. The relative standard deviation of the mosapride peak area should not exceed 3.0%, and the theoretical plate number, calculated based on the mosapride peak, should not be less than 4000. Accurately measure 10 μl each of the test solution and the control solution and inject them separately into the liquid chromatograph. Record the chromatograms until twice the retention time of the main component peak. Calculate the total related substances content using the following formula:

[0054] Total related substances content % = (Total peak area - Principal component peak area) × 100 / Self-reference peak area × 200. The experimental materials and equipment used in this invention are as follows:

[0055] Table 1 Main Experimental Materials

[0056]

[0057] Table 2 List of Main Equipment and Instruments

[0058]

[0059] Comparative Example 1

[0060]

[0061] Preparation process:

[0062] 1. Weigh the prescribed amount of filler and disintegrant, and mix them evenly using a suitable mixer.

[0063] 2. Weigh out the prescribed amount of mosapride citrate raw material and add it to the above mixed excipients by equal incremental dilution. Mix thoroughly through a 40-mesh sieve each time until completely and evenly mixed.

[0064] 3. Add 3% HPMC ethanol aqueous solution to prepare soft material, and sieve through 18 mesh to form wet granules.

[0065] 4. The wet granules obtained above are dried at 50°C for 2 hours, and then sieved through an 18-mesh sieve to obtain dry granules.

[0066] 5. Weigh out the prescribed amount of silicon dioxide and magnesium stearate, mix them thoroughly with the above dry granules, and compress them into tablets to obtain the final product.

[0067] Comparative Example 2

[0068]

[0069] Preparation process:

[0070] 1. Weigh the prescribed amount of filler and disintegrant, and mix them evenly using a suitable mixer.

[0071] 2. Weigh out the prescribed amount of mosapride citrate raw material and add it to the above mixed excipients by equal incremental dilution. Mix thoroughly through a 40-mesh sieve each time until completely and evenly mixed.

[0072] 3. Add 3% HPMC ethanol aqueous solution to prepare soft material, and sieve through 18 mesh to form wet granules.

[0073] 4. The wet granules obtained above are dried at 50°C for 2 hours, and then sieved through an 18-mesh sieve to obtain dry granules.

[0074] 5. Weigh out the prescribed amount of silicon dioxide and magnesium stearate, mix them thoroughly with the above dry granules, and compress them into tablets to obtain the final product.

[0075] Comparative Example 3

[0076]

[0077] Preparation process:

[0078] 1. Dissolve HPMC in purified water, add mosapride citrate, stir to disperse, and prepare an adhesive solution for later use.

[0079] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0080] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0081] The content uniformity of the original drug and comparative examples 1-3 was determined. Accelerated tests were conducted according to the aforementioned accelerated testing method, and the dissolution rate and content of related substances were measured before and after acceleration. The results are as follows:

[0082] Table 3. Test results of the original drug and comparative examples 1-3

[0083]

[0084] According to the results in the table above, after accelerated testing, the dissolution rate of the compositions of Comparative Examples 1-3 and the original product decreased significantly, and the content of related substances increased significantly. This indicates that the quality of the compositions of Comparative Examples 1-3 and the original product decreased significantly after long-term storage, which is not conducive to long-term transportation and storage.

[0085] Comparative tests of different excipients in particles in Examples 1-6

[0086]

[0087] Preparation process:

[0088] 1. Dissolve HPMC in an ethanol-water solution, add mosapride citrate, stir to disperse, and prepare an adhesive solution for later use.

[0089] 2. Place dicalcium phosphate (or lactose, microcrystalline cellulose, starch, dextrin, mannitol) in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0090] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0091] To determine the uniformity of product content, an accelerated test was conducted according to the aforementioned accelerated test method. The dissolution rate and the content of related substances were measured before and after acceleration. The results are as follows:

[0092] Table 4. Sample measurement results of Examples 1-6

[0093]

[0094] Examples 7-10: Comparative Tests of Different Adhesives

[0095]

[0096] Preparation process:

[0097] 1. Dissolve CMC-Na (or PVP, HPC, HPMC) in an ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare an adhesive solution for later use.

[0098] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0099] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0100] To determine the uniformity of product content, an accelerated test was conducted according to the aforementioned accelerated test method. The dissolution rate was measured before and after acceleration, and the results are as follows:

[0101] Table 5. Sample measurement results of Examples 7-10

[0102]

[0103] Examples 11-14: Comparative Tests of Adhesive Solutions with Different Ethanol Concentrations

[0104]

[0105] Preparation process:

[0106] 1. Dissolve HPMC in an ethanol-water solution, add mosapride citrate, stir to disperse, and prepare an adhesive solution for later use.

[0107] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0108] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0109] To determine the uniformity of product content, an accelerated test was conducted according to the aforementioned accelerated test method. The dissolution rate was measured before and after acceleration, and the results are as follows:

[0110] Table 6. Sample measurement results from Examples 11-14

[0111]

[0112] Examples 15-18: Comparative Tests of Different HPMC Concentrations in Adhesive Solutions

[0113]

[0114] Preparation process:

[0115] 1. Dissolve HPMC in an ethanol-water solution, add mosapride citrate, stir to disperse, and prepare an adhesive solution of the appropriate concentration for later use.

[0116] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0117] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0118] To determine the uniformity of product content, an accelerated test was conducted according to the aforementioned accelerated test method. The dissolution rate was measured before and after acceleration, and the results are as follows:

[0119] Table 7. Sample measurement results from Examples 15-18

[0120]

[0121] Example 19

[0122]

[0123] Preparation process:

[0124] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0125] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0126] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0127] Example 20

[0128]

[0129] Preparation process:

[0130] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0131] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0132] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0133] Example 21

[0134]

[0135] Preparation process:

[0136] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0137] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0138] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0139] Example 22

[0140]

[0141] Preparation process:

[0142] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0143] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0144] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0145] Example 23

[0146]

[0147] Preparation process:

[0148] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0149] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0150] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0151] Example 24

[0152]

[0153] Preparation process:

[0154] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0155] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0156] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and magnesium stearate according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0157] Example 25

[0158]

[0159]

[0160] Preparation process:

[0161] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0162] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0163] 3. Remove the dry granules from the fluidized bed, granulate them, and then add filler, disintegrant, silica, and magnesium stearate according to the prescribed amount. Mix well, compress into tablets, and the product is ready.

[0164] Example 26

[0165]

[0166] Preparation process:

[0167] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0168] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 30°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0169] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, and talc according to the prescription amount, mix well, and compress into tablets to obtain the final product.

[0170] Example 27

[0171]

[0172] Preparation process:

[0173] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0174] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 35°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0175] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and sodium lauryl sulfate according to the prescription amount, mix well, compress into tablets, and the product is obtained.

[0176] Example 28

[0177]

[0178] Preparation process:

[0179] 1. Dissolve HPMC in a 40% ethanol aqueous solution, add mosapride citrate, stir to disperse, and prepare a 3% adhesive solution for later use.

[0180] 2. Place mannitol in a fluidized bed granulator, turn on the hot air, and control the temperature at 40°C to make the material boil. Atomize the above-mentioned binder solution through a spray gun and spray it onto the mannitol for granulation. After obtaining the granules, continue to dry them with hot air.

[0181] 3. Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, silica and stearic acid according to the prescription amount, mix well, compress into tablets, and the product is ready.

[0182] The content uniformity of Examples 19-28 was determined by conducting accelerated tests according to the aforementioned accelerated testing method, and the dissolution rate before and after acceleration was measured. The results are as follows:

[0183] Table 8. Sample measurement results of Examples 19-28

[0184]

Claims

1. A non-coated tablet containing mosapride citrate, characterized in that, This product is composed of mosapride citrate, mannitol, hydroxypropyl methylcellulose, and other pharmaceutically acceptable excipients. These other pharmaceutically acceptable excipients include one or more of fillers, disintegrants, flow aids, and lubricants. The fillers are selected from one or more of pregelatinized starch, corn starch, dicalcium phosphate, and microcrystalline cellulose. The disintegrants are selected from one or more of crospovidone, low-substituted hydroxypropyl methylcellulose, crospovidone carboxymethyl cellulose sodium, and sodium carboxymethyl starch. The flow aids are selected from one or more of micronized silica gel and talc. The lubricants are selected from magnesium stearate, stearic acid, and hydrogenated plant... The tablet contains one or more of the following: animal oil, polyethylene glycol, and sodium lauryl sulfate; the content of mosapride citrate is 1.0–10.0 parts; the content of mannitol is 10.0–100.0 parts; the content of hydroxypropyl methylcellulose is 0.5–3.0 parts; the content of filler is 16.5–33.0 parts; the content of disintegrant is 13.2–36.3 parts; the content of glidant is 0–1.65 parts; and the content of lubricant is 0–1.65 parts. The uncoated tablet is prepared using a fluidized bed granulation process, which includes the following steps: (1) Prepare hydroxypropyl methylcellulose into a hydroxypropyl methylcellulose solution, add mosapride citrate, disperse and dissolve it to make an adhesive solution; (2) Spray the above-mentioned adhesive onto mannitol for granulation. In step (1), the hydroxypropyl methylcellulose solution is prepared using an aqueous ethanol solution as a solvent, wherein the concentration of the aqueous ethanol solution is 30-40% and the concentration of the hydroxypropyl methylcellulose solution is 3-5%.

2. The non-coated tablet containing mosapride citrate according to claim 1, characterized in that, In step (1), the hydroxypropyl methylcellulose solution is prepared using an aqueous ethanol solution as the solvent, wherein the concentration of the aqueous ethanol solution is 40% and the concentration of the hydroxypropyl methylcellulose solution is 3%.

3. A non-coated tablet containing mosapride citrate according to claim 2, characterized in that, The preparation steps of the uncoated tablets include: (1) Hydroxypropyl methylcellulose was dissolved in an ethanol aqueous solution to prepare a hydroxypropyl methylcellulose solution. Mosapride citrate was added and stirred to fully disperse and dissolve the solution, which served as an adhesive solution. (2) Place mannitol in a fluidized bed granulator and spray the above-mentioned binder onto the mannitol for granulation. (3) Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, flow aid and lubricant according to the prescription amount, mix evenly, compress into tablets, and the product is obtained.

4. A non-coated tablet containing mosapride citrate according to claim 1, characterized in that, The filler is microcrystalline cellulose; the disintegrant is a combination of low-substituted hydroxypropyl methylcellulose and croscarmellose sodium; the flow aid is micronized silica gel; and the lubricant is magnesium stearate.

5. A non-coated tablet containing mosapride citrate according to any one of claims 1-4, characterized in that, It contains the following components: And it is prepared by the following fluidized bed granulation process: (1) Hydroxypropyl methylcellulose is dissolved in 30-40% ethanol aqueous solution to prepare 3-5% hydroxypropyl methylcellulose solution, mosapride citrate is added, and it is stirred to fully disperse and dissolve it as a binder solution; (2) Place mannitol in a fluidized bed granulator, control the temperature at 30-40℃, spray the above-mentioned binder solution onto the mannitol for granulation, and continue drying after granulation. (3) Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, flow aid and lubricant according to the prescription amount, mix evenly, compress into tablets, and the product is obtained.

6. A non-coated tablet containing mosapride citrate according to claim 5, characterized in that, It contains the following components: It is prepared using the following fluidized bed granulation process: (1) Dissolve hydroxypropyl methylcellulose in 40% ethanol aqueous solution to prepare 3% hydroxypropyl methylcellulose solution, add mosapride citrate, stir to fully disperse and dissolve it, and use it as an adhesive solution; (2) Place mannitol in a fluidized bed granulator, control the temperature at 35°C, spray the above-mentioned binder solution onto the mannitol for granulation, and continue drying after granulation. (3) Remove the dry granules from the fluidized bed, granulate them, add filler, disintegrant, flow aid and lubricant according to the prescription amount, mix evenly, compress into tablets, and the product is obtained.

7. A non-coated tablet containing mosapride citrate according to claim 6, characterized in that, It contains the following components: The filler is microcrystalline cellulose, the disintegrant is low-substituted hydroxypropyl methylcellulose and croscarmellose sodium, the flow aid is micronized silica gel, and the lubricant is magnesium stearate. It is prepared using the following fluidized bed granulation process: (1) Dissolve hydroxypropyl methylcellulose in 40% ethanol aqueous solution to prepare 3% hydroxypropyl methylcellulose solution, add mosapride citrate, stir to fully disperse and dissolve it, and use it as an adhesive solution; (2) Place mannitol in a fluidized bed granulator, control the temperature at 35°C, spray the above-mentioned binder solution onto the mannitol for granulation, and continue drying after granulation. (3) Remove the dry granules from the fluidized bed, granulate them, add microcrystalline cellulose, low-substituted hydroxypropyl methylcellulose, croscarmellose sodium, micronized silica gel and magnesium stearate according to the prescription amount, mix evenly, compress into tablets, and the product is obtained.

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