A gastroretentive formulation of mosapride citrate, a method for preparing the same, and use thereof

Abstract

The application provides a mosapride citrate stomach floating preparation, a preparation method thereof and application thereof. The mosapride citrate stomach floating preparation comprises first immediate-release particles, second immediate-release particles and sustained-release particles with a mass ratio of (1-2):(1-2):(1-2). The application uses the first immediate-release particles, the second immediate-release particles and the sustained-release particles in combination, and introduces mosapride citrate co-grinding materials into the second immediate-release particles and the sustained-release particles, so that the obtained preparation has a sustained-release effect. In addition, the application introduces a gas production layer coating and a retardation layer coating into the second immediate-release particles and the sustained-release particles in sequence, so that the mosapride citrate is prepared into a stomach floating preparation, the absorption of the mosapride citrate in the stomach and the upper part of the small intestine is prolonged, the blood drug concentration is stabilized, and the frequency of taking medicine is reduced. According to tests, the mosapride citrate stomach floating preparation provided by the application can be released smoothly within 2-12 hours, and has no burst release effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation, specifically relating to a mosapride citrate gastric floating preparation, its preparation method, and its application. Background Technology

[0002] Mosapride is a drug that is a selective 5-HT4 receptor agonist. It promotes the release of acetylcholine, stimulates the gastrointestinal tract and exerts a prokinetic effect, thereby improving gastrointestinal symptoms in patients with functional dyspepsia, but does not affect gastric acid secretion.

[0003] Mosapride has no affinity for dopamine D2 receptors, adrenaline α1 receptors, 5-HT1 and 5-HT2 receptors on the synaptic membrane of brain nerve cells, and therefore will not cause extrapyramidal syndrome or adverse cardiovascular reactions.

[0004] Gastric floating drug delivery systems are significant for improving the bioavailability of drugs that are primarily absorbed or exert their effects in the stomach because they prolong the residence time of drugs at the site of absorption or action. Therefore, preparing mosapride citrate into a gastric floating formulation is important for prolonging its absorption in the stomach and upper small intestine, stabilizing blood drug concentrations, and reducing the frequency of dosing. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide a mosapride citrate gastric flotation formulation, its preparation method, and its application. The mosapride citrate gastric flotation formulation provided by this invention has a slow release and no burst release effect.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides a mosapride citrate gastric floating formulation, comprising a first immediate-release granule, a second immediate-release granule, and a sustained-release granule;

[0008] The mass ratio of the first immediate-release granule, the second immediate-release granule, and the sustained-release granule is (1~2):(1~2):(1~2);

[0009] The first immediate-release granules comprise, by weight:

[0010] Mosapride citrate 10-20 parts

[0011] 5-10 parts of the first solubilizing agent

[0012] 5-150 parts of the first filler;

[0013] The second immediate-release granules comprise, by weight:

[0014] 30-60 parts of mosapride citrate co-ground powder

[0015] 50-150 parts of the second filler

[0016] 5-10 parts of disintegrant

[0017] 5-10 parts of the second solubilizing agent;

[0018] The sustained-release granules comprise, by weight:

[0019] Mosapride citrate 30-60 parts

[0020] 50-100 parts of the third filler

[0021] 50-100 parts of sustained-release ingredient;

[0022] The mosapride citrate co-ground material is obtained by co-grinding mosapride citrate, hydrophilic polymer excipients and polyvinyl alcohol; the mass ratio of mosapride citrate, hydrophilic polymer excipients and polyvinyl alcohol is (15~45):(35~55):(10~35);

[0023] The second immediate-release particles and the sustained-release particles are coated sequentially with a gas-generating layer coating liquid and a barrier layer coating liquid, respectively. The gas-generating layer coating liquid includes sodium bicarbonate, hydroxypropyl methylcellulose and water; the barrier layer coating liquid includes triethyl citrate, silica and coating material.

[0024] Preferably, the mass ratio of sodium bicarbonate, hydroxypropyl methylcellulose and water is (3~5):1:(20~50).

[0025] Preferably, the mass ratio of triethyl citrate, silica, and coating material is (3~6):(5~12):(20~40):100.

[0026] Preferably, the hydrophilic polymeric excipient is selected from any one or more of cyclodextrin, starch, or gelatin.

[0027] Preferably, the molecular weight of the polyvinyl alcohol is 20,000 to 300,000.

[0028] Preferably, the first solubilizing agent is selected from meglumine.

[0029] Preferably, the second solubilizing agent comprises meglumine and triethanolamine, wherein the mass ratio of meglumine to triethanolamine is (5~10):1.

[0030] Preferably, the sustained-release component comprises ethyl cellulose and hydroxyethyl cellulose in a mass ratio of 1:(5~10).

[0031] Preferably, the first filler, the second filler, and the third filler are each independently selected from any one or more of microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, lactose, sucrose, mannitol, sorbitol, or dextrin.

[0032] Preferably, the disintegrant is selected from any one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, or sodium carboxymethyl cellulose.

[0033] Preferably, the first filler and the second filler are selected from lactose.

[0034] Preferably, the third filler is selected from lactose and microcrystalline cellulose, wherein the mass ratio of lactose to microcrystalline cellulose is (0.8~1.5):1.

[0035] Preferably, the disintegrant is selected from sodium carboxymethyl cellulose.

[0036] Preferably, the first immediate-release granules comprise, by weight:

[0037] Mosapride citrate 12-15 parts

[0038] 5-8 parts of the first solubilizing agent

[0039] 10-100 parts of the first filler;

[0040] The second immediate-release granules comprise, by weight:

[0041] 35-50 parts of mosapride citrate co-ground powder

[0042] 60-100 parts of the second filler

[0043] 5-8 parts of disintegrant

[0044] 5-8 parts of the second solubilizing agent;

[0045] The sustained-release granules comprise, by weight:

[0046] Mosapride citrate 35-50 parts

[0047] 60-90 parts of the third filler

[0048] Sustained-release component 60-90 parts.

[0049] Secondly, the present invention provides a method for preparing the above-mentioned mosapride citrate gastric floating formulation, comprising:

[0050] The first immediate-release granules, the coated second immediate-release granules, and the coated sustained-release granules were mixed evenly in a certain proportion to obtain the mosapride citrate gastric floating formulation.

[0051] Thirdly, the present invention provides the application of the above-mentioned mosapride citrate gastric floating formulation in the preparation of a drug for relieving gastrointestinal discomfort.

[0052] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0053] This invention provides a mosapride citrate gastric floating formulation, comprising a first immediate-release granule, a second immediate-release granule, and a sustained-release granule in a mass ratio of (1~2):(1~2):(1~2). By using the first immediate-release granule, the second immediate-release granule, and the sustained-release granule in combination, and introducing a co-ground mosapride citrate into the second immediate-release granule and the sustained-release granule, the resulting formulation exhibits a sustained-release effect. Furthermore, by sequentially introducing a gas-generating layer coating and a blocking layer coating into the second immediate-release granule, this invention prepares mosapride citrate into a gastric floating formulation, prolonging its absorption in the stomach and upper small intestine, stabilizing blood drug concentration, and reducing the frequency of dosing. Testing shows that the mosapride citrate gastric floating formulation provided by this invention provides a smooth release within 2~12 hours, without a burst release effect.

[0054] In addition, the preparation process of the mosapride citrate gastric floating formulation provided by the present invention is simple, easy to implement, has high production efficiency, and good stability, making it suitable for large-scale industrial or commercial production. Detailed Implementation

[0055] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0056] This invention provides a mosapride citrate gastric flotation formulation, comprising a first immediate-release granule, a second immediate-release granule, and a sustained-release granule. In this invention, the mass ratio of the first immediate-release granule, the second immediate-release granule, and the sustained-release granule is (1~2):(1~2):(1~2), preferably (1.2~1.5):(1.2~1.5):(1.2~1.5). In some embodiments of this invention, the mass ratio of the first immediate-release granule, the second immediate-release granule, and the sustained-release granule can be 1:1:1, 1:1:2, 1:1.5:1, 1:1.5:2, 1:2:1, 1:2:2, 2:1:1.5, 2:1:2, 2:1.5:1, or 2:1.5:2, etc. The values ​​listed above are merely illustrative and not limiting; other values ​​within the range are also applicable.

[0057] In some embodiments of the present invention, the first immediate-release granules comprise, by weight:

[0058] Mosapride citrate 10-20 parts

[0059] 5-10 parts of the first solubilizing agent

[0060] The first filler is 5 to 150 parts.

[0061] In some preferred embodiments of the present invention, the first immediate-release granules comprise, by weight:

[0062] Mosapride citrate 12-15 parts

[0063] 5-8 parts of the first solubilizing agent

[0064] The first filler is 10 to 100 parts.

[0065] In this invention, the first solubilizing agent is selected from meglumine; the first filler is selected from any one or more of microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, lactose, sucrose, mannitol, sorbitol or dextrin, preferably any one or more of microcrystalline cellulose, lactose, mannitol or sorbitol.

[0066] In some embodiments of the present invention, the second immediate-release granules comprise, by weight:

[0067] 30-60 parts of mosapride citrate co-ground powder

[0068] 50-150 parts of the second filler

[0069] 5-10 parts of disintegrant

[0070] 5-10 parts of the second solubilizing agent.

[0071] In some preferred embodiments of the present invention, the second immediate-release granules comprise, by weight:

[0072] 35-50 parts of mosapride citrate co-ground powder

[0073] 60-100 parts of the second filler

[0074] 5-8 parts of disintegrant

[0075] 5-8 parts of the second solubilizing agent.

[0076] In this invention, the mosapride citrate co-milled material is obtained by co-milling mosapride citrate, a hydrophilic polymeric excipient, and polyvinyl alcohol; the mass ratio of mosapride citrate, the hydrophilic polymeric excipient, and polyvinyl alcohol is (15~45):(35~55):(10~35), preferably (18~40):(36~50):(10~30), more preferably (20~38):(38~50):(12~28). The hydrophilic polymeric excipient is selected from any one or more of cyclodextrin, starch, or gelatin, preferably cyclodextrin, which can be α-cyclodextrin or β-cyclodextrin, preferably β-cyclodextrin. The molecular weight of the polyvinyl alcohol is 20,000 to 300,000, preferably 50,000 to 250,000, more preferably 100,000 to 200,000. It should be noted that the present invention co-grinds mosapride citrate, hydrophilic polymeric excipients, and polyvinyl alcohol to obtain mosapride citrate co-grind, which allows mosapride citrate to be released better without burst release, thus facilitating its better absorption in the individual's stomach and intestines.

[0077] In this invention, the selection of the second filler is as described above for the selection of the first filler, and will not be repeated here. The second solubilizing agent includes meglumine and triethanolamine, wherein the mass ratio of meglumine to triethanolamine is (5~10):1, preferably (6~9):1, and more preferably (6.5~8.5):1. It should be noted that, through screening, this invention selects the combination of meglumine and triethanolamine as the second solubilizing agent, which is beneficial to obtaining a better sustained-release effect in the formulation.

[0078] In this invention, the disintegrant is selected from any one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, or sodium carboxymethyl cellulose, preferably sodium carboxymethyl cellulose.

[0079] In some embodiments of the present invention, the sustained-release particles comprise, by weight:

[0080] Mosapride citrate 30-60 parts

[0081] 50-100 parts of the third filler

[0082] 50-100 parts of sustained-release ingredients.

[0083] In some preferred embodiments of the present invention, the sustained-release particles comprise, by weight:

[0084] Mosapride citrate 35-50 parts

[0085] 60-90 parts of the third filler

[0086] Sustained-release component 60-90 parts.

[0087] In this invention, the third filler is selected as described above for the first filler, and will not be repeated here.

[0088] In some embodiments of the present invention, the first and second fillers are preferably lactose; the third filler is selected from lactose and microcrystalline cellulose, wherein the mass ratio of lactose to microcrystalline cellulose is (0.8~1.5):1, preferably (0.9~1.3):1, and more preferably 1.2:1. The disintegrant is preferably sodium carboxymethyl cellulose.

[0089] In this invention, the sustained-release component includes ethyl cellulose and hydroxyethyl cellulose, wherein the mass ratio of ethyl cellulose to hydroxyethyl cellulose is 1:(5~10), preferably 1:(6~9), and more preferably 1:(6.5~8.5). It should be noted that this invention, through screening, uses a combination of ethyl cellulose and hydroxyethyl cellulose as the sustained-release component, which results in a better sustained-release effect in the prepared mosapride citrate sustained-release formulation and effectively avoids the occurrence of burst release.

[0090] It should be noted that in this invention, after screening, the second immediate-release particles and the sustained-release particles are respectively coated with a gas-generating layer coating liquid and a barrier layer coating liquid in sequence. The gas-generating layer coating liquid preferably includes sodium bicarbonate, hydroxypropyl methylcellulose, and water; the mass ratio of sodium bicarbonate, hydroxypropyl methylcellulose, and water is (3~5):1:(20~50), preferably (3~4):1:(25~45), and more preferably 3:1:30; the barrier layer coating liquid preferably includes triethyl citrate, silica, and a coating material. The coating material can be a material well known to those skilled in the art, such as Eudragit RL 30D. The mass ratio of triethyl citrate, silica, and the coating material is (3~6):(5~12):(20~40):100, preferably (3.5~5.5):(6~10):(25~30):100, and more preferably 5:10:25:100. In this invention, by specifically selecting sodium bicarbonate, hydroxypropyl methylcellulose, and water as the gas-generating coating layer and sodium bicarbonate, hydroxypropyl methylcellulose, and water as the blocking coating layer, and sequentially coating the second immediate-release granules and the sustained-release granules, mosapride citrate can be prepared into a gastric floating formulation, which better prolongs its absorption in the stomach and upper small intestine, better stabilizes blood drug concentration, and reduces the frequency of dosing.

[0091] In some embodiments of the present invention, the second immediate-release particles are coated in the gas-generating layer coating solution, increasing their weight by 8-15%, preferably 9-12%, more preferably 10%; after drying, they are coated a second time in the retardation layer coating solution, increasing their weight by 3-8%, preferably 4-6%, more preferably 5%.

[0092] In some embodiments of the present invention, the slow-release particles are coated in a gas-generating layer coating solution, increasing their weight by 12-25%, preferably 14-20%, and more preferably 15%; after drying, they are coated a second time in a barrier layer coating solution, increasing their weight by 5-15%, preferably 6-10%, and more preferably 8%.

[0093] In this invention, the dosage form of the mosapride citrate gastric floating preparation can be selected from any one of tablets, capsules, oral solutions or granules, or other common medical dosage forms, as needed.

[0094] The present invention also provides a method for preparing the above-mentioned mosapride citrate gastric floating formulation, comprising:

[0095] The first immediate-release granules, the second immediate-release granules, and the sustained-release granules were mixed evenly in a certain proportion to obtain the mosapride citrate gastric floating formulation.

[0096] In some embodiments of the present invention, the method for preparing the mosapride citrate gastric floating formulation preferably includes:

[0097] After mixing the raw materials of the first immediate-release granules, a binder is added to prepare a soft material, which is then wet-granulated, fluidized bed dried, and 40-60 mesh dry granules are collected to obtain the first immediate-release granules.

[0098] After mixing all the raw materials except triethanolamine in the second immediate-release granules, a binder and triethanolamine are added to prepare a soft material. The material is then wet-granulated, dried in a fluidized bed, and 40-60 mesh dry granules are collected to obtain the second immediate-release granules.

[0099] The first-release particles are coated in the gas-generating layer coating solution, increasing their weight by 8-15%. After drying, they are coated a second time in the retardation layer coating solution, increasing their weight by 3-8%.

[0100] After mixing the raw materials for the sustained-release granules, a binder is added to prepare a soft material. The material is then wet-granulated, dried in a fluidized bed, and the 40-60 mesh dry granules are collected to obtain the sustained-release granules.

[0101] The slow-release particles are coated in the gas-generating layer coating solution, increasing their weight by 12-25%. After drying, they are coated a second time in the retardation layer coating solution, increasing their weight by 5-15%.

[0102] Then, the first immediate-release granules, the second immediate-release granules, and the sustained-release granules were mixed evenly in a certain proportion to obtain the mosapride citrate gastric floating formulation.

[0103] After being mixed evenly according to the specified proportions, the mosapride citrate gastric floating preparation can be prepared into the corresponding dosage form according to actual needs.

[0104] In this invention, the adhesive can be a substance commonly used by those skilled in the art. In some embodiments of this invention, a 50 vol% ethanol solution is used as the adhesive.

[0105] In summary, the preparation process of the mosapride citrate gastric floating formulation provided by this invention is simple, easy to implement, has high production efficiency, and good stability, making it suitable for large-scale industrial or commercial production.

[0106] In some embodiments of the present invention, the dissolution rate of the obtained mosapride citrate gastric floating granules was determined according to the "Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II". The results showed that the granules achieved a gradual release within 2-12 hours without any sudden release. Therefore, the mosapride citrate gastric floating granules provided by the present invention can achieve long-acting sustained release, prolong the duration of therapeutic effect, maintain a stable required concentration of mosapride in the patient's body, reduce the frequency of medication administration, and improve patient compliance.

[0107] In some embodiments of the present invention, microspheres made from mosapride citrate gastric floating granules are placed in 900 mL of 0.1 mol / L hydrochloric acid solution at 37 ± 0.5 °C and a stirring speed of 75 rpm. The floating rate is calculated after 8 hours according to the formula: floating rate = number of floating microspheres / total number of microspheres × 100%. The results show that the mosapride citrate gastric floating formulation provided by the present invention has good flocculation properties, thus prolonging its absorption in the stomach and upper small intestine, stabilizing blood drug concentration, and reducing the frequency of administration.

[0108] Based on this, the present invention also provides the application of the above-mentioned mosapride citrate gastric floating formulation in the preparation of a drug for relieving gastrointestinal discomfort.

[0109] To further illustrate the present invention, the following examples provide a detailed description. All experimental materials used in the following examples are commercially available products. The molecular weight of the polyvinyl alcohol involved is 20,000 to 300,000.

[0110] Preparation Example 1

[0111] 7.50 g of mosapride citrate, 17.6 g of β-cyclodextrin, and 6.8 g of polyvinyl alcohol were divided into three portions and placed in a ball mill. First, one-third of the mixture was added to a dry mixer and mixed at 15 r / min for 7 min. Then, the second portion of the mixture was added to the dry mixer and mixed at 15 r / min for 7 min. Finally, the remaining mixture was added to the dry mixer and dry-mixed at 15 r / min for 7 min to obtain the mosapride citrate co-milled product.

[0112] Preparation Example 2

[0113] 8.60 g of mosapride citrate, 19.3 g of β-cyclodextrin, and 7.34 g of polyvinyl alcohol were divided into three portions and placed in a ball mill. First, one-third of the mixture was added to a dry mixer and mixed at 19 r / min for 8 min. Then, the second portion of the mixture was added to the dry mixer and mixed at 19 r / min for 8 min. Finally, the remaining mixture was added to the dry mixer and dry-mixed at 19 r / min for 8 min to obtain the mosapride citrate co-milled product.

[0114] Preparation Example 3

[0115] 7.90 g of mosapride citrate, 18.7 g of β-cyclodextrin, and 7.23 g of polyvinyl alcohol were divided into three portions and placed in a ball mill. First, one-third of the mixture was added to a dry mixer and mixed at 17 r / min for 10 min. Then, the second portion of the mixture was added to the dry mixer and mixed at 17 r / min for 10 min. Finally, the remaining mixture was added to the dry mixer and dry-mixed at 17 r / min for 10 min to obtain the mosapride citrate co-milled product.

[0116] Comparative Preparation Example 1

[0117] Compared with Preparation Example 1, no polyvinyl alcohol was added, but the remaining parameters and steps were the same as those in Preparation Example 1.

[0118] Comparative Preparation Example 2

[0119] Compared with Preparation Example 1, polyvinyl alcohol was replaced with polyethylene glycol in equal amounts, while the remaining parameters and steps remained the same as in Preparation Example 1.

[0120] Comparative preparation example 3

[0121] Compared with Preparation Example 1, 6.8 g of polyvinyl alcohol was replaced with 4.5 g of polyvinyl alcohol, while the remaining parameters and steps were the same as in Preparation Example 1.

[0122] Verification Example

[0123] According to Method 2 of General Chapter 0931 in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the dissolution of the mosapride citrate co-ground products obtained in Preparation Examples 1-3 and Comparative Preparation Examples 1-3 was determined, and the results are shown in Table 1.

[0124] Table 1

[0125]

[0126] Examples 1-3

[0127] Weigh the corresponding raw materials according to the formula in Table 2;

[0128] Among them, the mosapride citrate co-milled products corresponding to Examples 1-3 are the mosapride citrate co-milled products obtained in Examples 1-3, respectively;

[0129] Table 2

[0130]

[0131] The gas-generating layer coating fluid consists of sodium bicarbonate, hydroxypropyl methylcellulose, and water in a mass ratio of 3:1:30;

[0132] The barrier coating solution comprises triethyl citrate, silica, Eudragit RL 30D, and water in a mass ratio of 5:10:25:100;

[0133] The specific preparation method is as follows:

[0134] First immediate-release granules: After mixing the raw materials, a soft material was prepared using a 50 vol% ethanol solution as a binder. The material was then wet-granulated, dried in a fluidized bed, and the 40-60 mesh dry granules were collected to obtain the first immediate-release granules.

[0135] Second instant-release granules: After mixing the raw materials, the resulting mixture is mixed with a mixture of 50 vol% ethanol solution of binder and triethanolamine to prepare a soft material. After wet granulation and fluidized bed drying, 40-60 mesh dry granules are collected to obtain the second instant-release granules.

[0136] The second fast-release particles were coated in the gas-generating layer coating solution, resulting in a 10% weight gain. After drying, they were coated a second time in the retardation layer coating solution, resulting in a 5% weight gain.

[0137] Slow-release granules: After mixing the raw materials, a soft material is prepared using a 50 vol% ethanol solution as a binder. The material is then wet-granulated, dried in a fluidized bed, and the 40-60 mesh dry granules are collected to obtain slow-release granules.

[0138] The slow-release particles were coated in the gas-generating layer coating solution, resulting in a 15% increase in weight. After drying, they were coated a second time in the retardation layer coating solution, resulting in an 8% increase in weight.

[0139] The first immediate-release granules, the second immediate-release granules, and the sustained-release granules are mixed evenly in a mass ratio of 1:1:2 and then packaged to obtain granules.

[0140] Comparative Examples 1-3

[0141] Compared with Example 1, the only difference is that the mosapride citrate co-milled material was replaced in equal amounts with the mosapride citrate co-milled material obtained in Comparative Preparation Examples 1-3, while the other parameters and steps remained the same as in Example 1.

[0142] Comparative Example 4

[0143] Compared with Example 1, the difference is that the first immediate-release particles are coated in the gas-generating layer coating solution to increase the weight by 10%, and after drying, they are coated a second time in the retardation layer coating solution to increase the weight by 5%, while the second immediate-release particles and the sustained-release particles are not coated. The remaining parameters and steps are the same as in Example 1.

[0144] Comparative Example 5

[0145] Compared with Example 1, the difference is that the second immediate-release particles are not coated, while the other parameters and steps are the same as in Example 1.

[0146] Comparative Example 6

[0147] Compared with Example 1, the difference is that the sustained-release particles are not coated, while the other parameters and steps are the same as in Example 1.

[0148] Verification Example

[0149] Dissolution determination: The granules obtained in Examples 1-3 and Comparative Examples 1-5 were determined according to the General Chapter 0931, Method II, Part IV of the Chinese Pharmacopoeia 2020. 900 mL of 0.1 mol / L hydrochloric acid solution was used as the dissolution medium, and the rotation speed was 75 rpm. The procedure was followed, and after 2, 4, 6, 8, 10, and 12 hours, 10 mL of the solution was collected, filtered, and the filtrate was used as the test solution. Simultaneously, 10 mL of 0.1 mol / L hydrochloric acid was added. Separately, 65 mg of mosapride citrate reference standard was accurately weighed and placed in a 100 mL volumetric flask. Methanol was added to dilute to the final volume. 5 mL of this solution was accurately pipetted into the 100 mL volumetric flask, diluted to the final volume with methanol, and then mixed thoroughly. This was used as the reference solution. Both solutions were analyzed by HPLC, and the cumulative release rate was calculated. The results are shown in Table 3.

[0150] Table 3

[0151]

[0152] As shown in Table 3, the mosapride citrate gastric floating formulation provided by this invention has a slow release and no burst release effect.

[0153] Floating performance test

[0154] 100 microspheres prepared from the granules obtained in Examples 1-3 and Comparative Examples 1-6 were placed in 900 mL of 0.1 mol / L hydrochloric acid solution at 37±0.5℃ and the stirring speed was 75 rpm. The floating rate of the microspheres was calculated after 8 hours according to the formula: floating rate = number of floating microspheres / total number of microspheres × 100%.

[0155] The test results are shown in Table 4 below (each group was tested 3 times, and the average value was taken):

[0156] Table 4

[0157]

[0158] As shown in Table 4, the mosapride citrate gastric flotation formulation provided by this invention has good flotation performance compared with the comparative example.

[0159] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A mosapride citrate gastric flotation formulation, characterized in that, Includes first-release granules, second-release granules, and sustained-release granules; The mass ratio of the first immediate-release granule, the second immediate-release granule, and the sustained-release granule is (1~2):(1~2):(1~2); The first immediate-release granules comprise, by weight: Mosapride citrate 10-20 parts 5-10 parts of the first solubilizing agent 5-150 parts of the first filler; The first solubilizing agent is selected from meglumine; The second immediate-release granules comprise, by weight: 30-60 parts of mosapride citrate co-ground powder 50-150 parts of the second filler 5-10 parts of disintegrant 5-10 parts of the second solubilizing agent; The second solubilizing agent includes meglumine and triethanolamine, wherein the mass ratio of meglumine to triethanolamine is (5~10):1; The disintegrant is selected from sodium carboxymethyl cellulose; The sustained-release granules comprise, by weight: Mosapride citrate 30-60 parts 50-100 parts of the third filler 50-100 parts of sustained-release ingredient; The mosapride citrate co-ground compound is obtained by co-grinding mosapride citrate, a hydrophilic polymeric excipient, and polyvinyl alcohol; the mass ratio of mosapride citrate, the hydrophilic polymeric excipient, and polyvinyl alcohol is (15~45):(35~55):(10~35); the hydrophilic polymeric excipient is β-cyclodextrin; The sustained-release components include ethyl cellulose and hydroxyethyl cellulose in a mass ratio of 1:(5~10); The second immediate-release particles and the sustained-release particles are coated sequentially with a gas-generating layer coating solution and a barrier layer coating solution, respectively. The gas-generating layer coating solution includes sodium bicarbonate, hydroxypropyl methylcellulose and water; the barrier layer coating solution includes triethyl citrate, silica and coating material. The second immediate-release particles are coated in the gas-generating layer coating solution, resulting in a weight gain of 8-15%. After drying, they are coated a second time in the retardation layer coating solution, resulting in a weight gain of 3-8%. The slow-release particles are coated in the gas-generating layer coating solution, increasing their weight by 12-25%; after drying, they are coated a second time in the retardation layer coating solution, increasing their weight by 5-15%.

2. The mosapride citrate gastric flotation formulation according to claim 1, characterized in that, The mass ratio of sodium bicarbonate, hydroxypropyl methylcellulose and water is (3~5):1:(20~50); The mass ratio of triethyl citrate, silica, and coating material is (3~6):(5~12):(20~40):

100.

3. The mosapride citrate gastric flotation formulation according to claim 1 or 2, characterized in that, The molecular weight of the polyvinyl alcohol is 20,000 to 300,000.

4. The mosapride citrate gastric flotation formulation according to claim 1, characterized in that, The first filler, the second filler, and the third filler are each independently selected from any one or more of microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, lactose, sucrose, mannitol, sorbitol, or dextrin.

5. The mosapride citrate gastric flotation formulation according to claim 4, characterized in that, The first filler and the second filler are selected from lactose; The third filler is selected from lactose and microcrystalline cellulose, wherein the mass ratio of lactose to microcrystalline cellulose is (0.8~1.5):

1.

6. The mosapride citrate gastric flotation formulation according to claim 1, characterized in that, The first immediate-release granules comprise, by weight: Mosapride citrate 12-15 parts 5-8 parts of the first solubilizing agent 10-100 parts of the first filler; The first solubilizing agent is selected from meglumine; The second immediate-release granules comprise, by weight: 35-50 parts of mosapride citrate co-ground powder 60-100 parts of the second filler 5-8 parts of disintegrant 5-8 parts of the second solubilizing agent; The second solubilizing agent includes meglumine and triethanolamine, wherein the mass ratio of meglumine to triethanolamine is (5~10):1; The disintegrant is selected from sodium carboxymethyl cellulose; The sustained-release granules comprise, by weight: Mosapride citrate 35-50 parts 60-90 parts of the third filler Sustained-release ingredient: 60-90 parts; The mosapride citrate co-ground compound is obtained by co-grinding mosapride citrate, a hydrophilic polymeric excipient, and polyvinyl alcohol; the mass ratio of mosapride citrate, the hydrophilic polymeric excipient, and polyvinyl alcohol is (15~45):(35~55):(10~35); the hydrophilic polymeric excipient is β-cyclodextrin; The sustained-release components include ethyl cellulose and hydroxyethyl cellulose in a mass ratio of 1:(5~10); The second immediate-release particles and the sustained-release particles are coated sequentially with a gas-generating layer coating solution and a barrier layer coating solution, respectively. The gas-generating layer coating solution includes sodium bicarbonate, hydroxypropyl methylcellulose and water; the barrier layer coating solution includes triethyl citrate, silica and coating material. The second immediate-release particles are coated in the gas-generating layer coating solution, resulting in a weight gain of 8-15%. After drying, they are coated a second time in the retardation layer coating solution, resulting in a weight gain of 3-8%. The slow-release particles are coated in the gas-generating layer coating solution, increasing their weight by 12-25%; after drying, they are coated a second time in the retardation layer coating solution, increasing their weight by 5-15%.

7. A method for preparing a mosapride citrate gastric floating formulation as described in any one of claims 1 to 6, characterized in that, include: The first immediate-release granules, the coated second immediate-release granules, and the coated sustained-release granules were mixed evenly in a certain proportion to obtain the mosapride citrate gastric floating formulation.

8. The mosapride citrate gastric flotation formulation according to any one of claims 1 to 6 or The application of the mosapride citrate gastric floating formulation prepared by the method according to claim 7 in the preparation of drugs for relieving gastrointestinal discomfort.

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