A sustained-release preparation of mosapride citrate, a method for preparing the same, and use thereof

Abstract

The application provides a mosapride citrate sustained-release preparation, a preparation method thereof and application thereof. The mosapride citrate sustained-release preparation comprises first immediate-release granules, second immediate-release granules and sustained-release granules with a mass ratio of (1-2):(1-2):(1-2). The application can make the obtained preparation have a sustained-release effect by using the first immediate-release granules, the second immediate-release granules and the sustained-release granules in combination, and introducing mosapride citrate co-grinding materials into the second immediate-release granules. The test shows that the mosapride citrate sustained-release preparation provided by the application can be released smoothly within 2-12 hours without burst release effect. Meanwhile, the preparation process of the mosapride citrate sustained-release preparation provided by the application is simple, easy to realize, high in production efficiency, good in stability, and suitable for large-scale industrialized or industrialized production.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a mosapride citrate sustained-release formulation, 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] After oral administration, mosapride is rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentration in 0.5–1 hour. Its short half-life (1.4–2 hours) results in a relatively short duration of action. Therefore, it is necessary to formulate mosapride into a long-acting, sustained-release formulation to prolong the duration of therapeutic effect, maintain a stable required concentration of mosapride in patients, reduce the frequency of dosing, and improve patient compliance.

[0005] Patent CN102548544A discloses a pharmaceutical composition that simultaneously possesses immediate-release and long-acting properties. However, this composition is prone to burst release, which is not conducive to the long-term use of the drug. Summary of the Invention

[0006] In view of this, the purpose of this invention is to provide a mosapride citrate sustained-release formulation, its preparation method, and its application. The mosapride citrate sustained-release formulation provided by this invention has a smooth release and no burst release effect.

[0007] To achieve this objective, the present invention adopts the following technical solution:

[0008] In a first aspect, the present invention provides a sustained-release formulation of mosapride citrate, comprising a first immediate-release granule, a second immediate-release granule, and a sustained-release granule;

[0009] 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);

[0010] The first immediate-release granules comprise, by weight:

[0011] Mosapride citrate 10-20 parts

[0012] 5-10 parts of the first solubilizing agent

[0013] 5-150 parts of the first filler;

[0014] The second immediate-release granules comprise, by weight:

[0015] 30-60 parts of mosapride citrate co-ground powder

[0016] 50-150 parts of the second filler

[0017] 5-10 parts of disintegrant

[0018] 5-10 parts of the second solubilizing agent;

[0019] The sustained-release granules comprise, by weight:

[0020] Mosapride citrate 30-60 parts

[0021] 50-100 parts of the third filler

[0022] 50-100 parts of sustained-release ingredients.

[0023] Preferably, the mosapride citrate co-ground material is obtained by co-grinding mosapride citrate, hydrophilic polymeric excipients, and polyvinyl alcohol.

[0024] Preferably, the mass ratio of mosapride citrate, hydrophilic polymeric excipients, and polyvinyl alcohol is (15~45):(35~55):(10~35).

[0025] Preferably, the hydrophilic polymeric excipient is selected from any one or more of cyclodextrin, starch, or gelatin.

[0026] Preferably, the molecular weight of the polyvinyl alcohol is 20,000 to 300,000.

[0027] Preferably, the first solubilizing agent is selected from meglumine.

[0028] Preferably, the second solubilizing agent comprises meglumine and triethanolamine, wherein the mass ratio of meglumine to triethanolamine is (5~10):1.

[0029] Preferably, the sustained-release component comprises ethyl cellulose and hydroxyethyl cellulose in a mass ratio of 1:(5~10).

[0030] 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.

[0031] 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.

[0032] Preferably, the mass ratio of the first immediate-release granules, the second immediate-release granules, and the sustained-release granules is (1.2~1.5):(1.2~1.5):(1.2~1.5).

[0033] Preferably, the mass ratio of mosapride citrate, hydrophilic polymeric excipients, and polyvinyl alcohol is (18~40):(36~50):(10~30).

[0034] Preferably, the first immediate-release granules comprise, by weight:

[0035] Mosapride citrate 12-15 parts

[0036] 5-8 parts of the first solubilizing agent

[0037] 10-100 parts of the first filler;

[0038] The second immediate-release granules comprise, by weight:

[0039] 35-50 parts of mosapride citrate co-ground powder

[0040] 60-100 parts of the second filler

[0041] 5-8 parts of disintegrant

[0042] 5-8 parts of the second solubilizing agent;

[0043] The sustained-release granules comprise, by weight:

[0044] Mosapride citrate 35-50 parts

[0045] 60-90 parts of the third filler

[0046] Sustained-release component 60-90 parts.

[0047] Preferably, the dosage form of the mosapride citrate sustained-release formulation is selected from any one of tablets, capsules, oral solutions, or granules.

[0048] Secondly, the present invention provides a method for preparing the above-mentioned mosapride citrate sustained-release formulation, comprising:

[0049] The first immediate-release granules, the second immediate-release granules, and the sustained-release granules were mixed evenly in a certain proportion to obtain a sustained-release formulation of mosapride citrate.

[0050] Thirdly, the present invention provides the application of the mosapride citrate sustained-release formulation involved in the above-mentioned technical solution in the preparation of a drug for relieving gastrointestinal discomfort.

[0051] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0052] This invention provides a sustained-release formulation of mosapride citrate, 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 by introducing a co-ground mosapride citrate compound into the second immediate-release granule, the resulting formulation exhibits a sustained-release effect. Testing shows that the sustained-release formulation of mosapride citrate provided by this invention releases gradually within 2~12 hours, without a burst release effect.

[0053] In addition, the preparation process of the mosapride citrate sustained-release 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. Attached Figure Description

[0054] Figure 1 The sustained-release curves of the granules obtained in Examples 1-3 and Comparative Examples 1-3 are shown. 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 sustained-release formulation of mosapride citrate, 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 for the second immediate-release particles to better release mosapride citrate.

[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 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.

[0089] In this invention, the dosage form of the mosapride citrate sustained-release formulation can be selected from any one of tablets, capsules, oral solutions or granules, or other common medical dosage forms, as needed.

[0090] The present invention also provides a method for preparing the above-mentioned mosapride citrate sustained-release formulation, comprising:

[0091] The first immediate-release granules, the second immediate-release granules, and the sustained-release granules were mixed evenly in a certain proportion to obtain a sustained-release formulation of mosapride citrate.

[0092] In some embodiments of the present invention, the method for preparing the mosapride citrate sustained-release formulation preferably includes:

[0093] 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.

[0094] After mixing all the raw materials except triethanolamine for 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.

[0095] 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.

[0096] 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 sustained-release formulation of mosapride citrate.

[0097] After being mixed evenly according to the specified proportions, the mosapride citrate sustained-release formulation can be prepared into the appropriate dosage form according to actual needs.

[0098] 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.

[0099] In some embodiments of the present invention, the dissolution rate of the obtained mosapride citrate sustained-release 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 smooth release within 2-12 hours without any burst release. Therefore, the mosapride citrate sustained-release formulation 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.

[0100] Based on this, the present invention also provides the application of the above-mentioned mosapride citrate sustained-release formulation in the preparation of a drug for relieving gastrointestinal discomfort.

[0101] 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.

[0102] Preparation Example 1

[0103] 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.

[0104] Preparation Example 2

[0105] 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.

[0106] Preparation Example 3

[0107] 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.

[0108] Comparative Preparation Example 1

[0109] 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.

[0110] Comparative Preparation Example 2

[0111] 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.

[0112] Comparative preparation example 3

[0113] 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.

[0114] Verification Example

[0115] 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.

[0116] Table 1

[0117]

[0118] Examples 1-3

[0119] Weigh the corresponding raw materials according to the formula in Table 2;

[0120] 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;

[0121] Table 2

[0122]

[0123] The specific preparation method is as follows:

[0124] First immediate-release granules: According to Table 2, after mixing the raw materials, a soft material was prepared using a 50 vol% ethanol solution as a binder, wet granulation was performed, and after fluidized bed drying, 40-60 mesh dry granules were collected to obtain the first immediate-release granules.

[0125] Second instant-release granules: According to Table 2, after mixing all raw materials except triethanolamine, 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, dry 40-60 mesh granules are collected to obtain the second instant-release granules.

[0126] Slow-release granules: According to Table 2, 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 slow-release granules.

[0127] 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.

[0128] Comparative Examples 1-3

[0129] 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.

[0130] Verification Example

[0131] Dissolution determination: The granules obtained in Examples 1-3 and Comparative Examples 1-3 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 h, 4 h, 6 h, 8 h, 10 h, and 12 h, 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 well to obtain the reference solution. Both solutions were analyzed by HPLC, and the cumulative release rate was calculated. The results are shown in Table 3. Figure 1 .

[0132] Table 3

[0133]

[0134] Depend on Figure 1 As shown in Table 1, the dissolution of the mosapride citrate co-ground materials obtained in Examples 1-3 of the present invention can be released slowly within 2-12 h without a burst release effect, while Comparative Examples 1-3 all showed burst release phenomena.

[0135] 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 sustained-release formulation of mosapride citrate, 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 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 is a combination of meglumine and triethanolamine in a mass ratio of (5~10):1; The disintegrant is 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 sustained-release component is a combination of ethyl cellulose and hydroxyethyl cellulose in a mass ratio of 1:(5~10); The mosapride citrate co-ground material was obtained by co-grinding mosapride citrate, hydrophilic polymer excipients, and polyvinyl alcohol. The mass ratio of mosapride citrate, hydrophilic polymeric excipient, and polyvinyl alcohol is (15~45):(35~55):(10~35); the hydrophilic polymeric excipient is β-cyclodextrin.

2. The mosapride citrate sustained-release formulation according to claim 1, wherein the polyvinyl alcohol has a molecular weight of 20,000 to 300,000.

3. The mosapride citrate sustained-release formulation according to claim 1 or 2, 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.

4. The mosapride citrate sustained-release formulation according to any one of claims 1 to 3, characterized in that, The mass ratio of the first immediate-release granule, the second immediate-release granule, and the sustained-release granule is (1.2~1.5):(1.2~1.5):(1.2~1.5); The mass ratio of mosapride citrate, hydrophilic polymer excipients, and polyvinyl alcohol is (18~40):(36~50):(10~30).

5. The mosapride citrate sustained-release formulation according to any one of claims 1 to 4, 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 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 sustained-release granules comprise, by weight: Mosapride citrate 35-50 parts 60-90 parts of the third filler Sustained-release component 60-90 parts.

6. The mosapride citrate sustained-release formulation according to any one of claims 1 to 5, characterized in that, The dosage form of the mosapride citrate extended-release formulation is selected from any one of tablets, capsules, oral solutions, or granules.

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

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

Images