Mosapride composition as well as preparation method and application thereof

Abstract

The invention provides a mosapride composition. The mosapride composition is obtained by reacting mosapride citrate, tartaric acid and glutamic acid in a solvent according to a molar ratio of 1: (0.1-0.2): (0.3-0.4). The mosapride composition prepared by the method is high in dissolution rate, good in stability and low in content of related substances.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a mosapride composition, a preparation method thereof and use thereof. Background Art

[0002] Mosapride is a drug that is a selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist that can promote the release of acetylcholine, stimulate the gastrointestinal tract and exert a prokinetic effect, thereby improving the gastrointestinal symptoms of patients with functional dyspepsia, but does not affect the secretion of gastric acid.

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

[0004] Mosapride citrate is a poorly soluble drug. The prior art 201510041610.0 improves its solubility by co-grinding it with hydrophilic excipients such as β-cyclodextrin, hydroxypropyl methylcellulose, povidone, and polyethylene glycol 6000, but it also leads to an increase in the content of related substances, which is as high as more than 0.25%. Summary of the invention

[0005] In view of this, the technical problem to be solved by the present invention is to provide a mosapride composition, and the mosapride composition provided by the present invention has good solubility in gastric acid.

[0006] The invention provides a mosapride composition. The mosapride composition is obtained by reacting mosapride citrate, tartaric acid and glutamic acid in a solvent at a molar ratio of 1:0.1-0.2:0.3-0.4.

[0007] Preferably, the solvent comprises ethanol and acetone in a ratio of 2 to 5:1.

[0008] The present invention provides a method for preparing a mosapride composition, comprising the following steps:

[0009] The product is obtained by placing mosapride citrate, tartaric acid and glutamic acid in a solvent for reaction.

[0010] Preferably, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.1-0.2:0.3-0.4;

[0011] The solvent includes ethanol and acetone in a ratio of 2 to 5:1.

[0012] Preferably, the reaction temperature is 30-40° C., and the reaction time is 20-60 min.

[0013] Preferably, the preparation method further comprises filtering and concentrating by rotary evaporation.

[0014] The present invention provides the use of the mosapride composition or the mosapride composition prepared by the preparation method described in any one of the above technical schemes in preparing a drug for treating functional dyspepsia and gastric disease.

[0015] The present invention provides a mosapride oral preparation, comprising the mosapride composition described in any one of the above technical solutions or the mosapride composition prepared by the preparation method described in any one of the above technical solutions.

[0016] The present invention provides a mosapride tablet, comprising the following raw materials in percentage by mass:

[0017] 10 to 20 parts of the mosapride composition described in the above technical solution

[0018] Microcrystalline cellulose 50~70 parts

[0019] Lactose 50~70 parts

[0020] Povidone 0.5~1.5 parts

[0021] 4-6 parts of sodium carboxymethyl cellulose

[0022] 0.5~1.5 parts of magnesium stearate

[0023] 2~4 parts of silicon dioxide.

[0024] The present invention provides a pharmaceutical composition, comprising the mosapride composition described in any one of the above technical solutions or the mosapride composition prepared by the preparation method described in any one of the above technical solutions.

[0025] Compared with the prior art, the present invention provides a mosapride composition, which is obtained by reacting mosapride citrate, tartaric acid and glutamic acid in a solvent at a molar ratio of 1:0.1-0.2:0.3-0.4. The mosapride composition prepared by the method has high solubility, good stability and low content of related substances. DETAILED DESCRIPTION

[0026] The present invention provides a mosapride composition, a preparation method thereof and its use. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the method and application of this article without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention.

[0027] In this application, the term "and / or" describes the association relationship of associated objects, indicating that there may be three relationships. For example, A and / or B can represent: A exists alone, A and B exist at the same time, and B exists alone. A and B can be singular or plural.

[0028] In this application, "at least one" means one or more, "more than one" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single or plural items.

[0029] The invention provides a mosapride composition. The mosapride composition is obtained by reacting mosapride citrate, tartaric acid and glutamic acid in a solvent at a molar ratio of 1:0.1-0.2:0.3-0.4.

[0030] The mosapride of the present invention can be obtained from commercial sources or prepared according to a synthesis method disclosed in the prior art.

[0031] The inventors creatively discovered that the mosapride composition formed by mosapride citrate, tartaric acid and glutamic acid has better solubility, high dissolution rate and good stability.

[0032] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.1~0.2:0.3~0.4.

[0033] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.1:0.4;

[0034] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.2:0.3;

[0035] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.1:0.3;

[0036] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.2:0.4.

[0037] The solvent of the present invention comprises ethanol and acetone in a ratio of 2 to 5:1; preferably, the ratio of ethanol and acetone can be 2:1, 3:1, 4:1 or 5:1; or any value between the above two.

[0038] The reaction temperature of the present invention is 30-40° C., and the reaction time is 20-60 min.

[0039] In some specific embodiments, the reaction temperature is 32-38°C and the reaction time is 20-50 min;

[0040] In some specific embodiments, the reaction temperature is 34-36° C., and the reaction time is 20-40 min;

[0041] In some specific embodiments, the reaction temperature is 35°C and the reaction time is 30 min;

[0042] The present invention provides a method for preparing a mosapride composition, comprising the following steps:

[0043] The product is obtained by placing mosapride citrate, tartaric acid and glutamic acid in a solvent for reaction.

[0044] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.1~0.2:0.3~0.4.

[0045] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.1:0.4;

[0046] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.2:0.3;

[0047] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.1:0.3;

[0048] In some preferred embodiments of the present invention, the molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.2:0.4.

[0049] The solvent of the present invention comprises ethanol and acetone in a ratio of 2 to 5:1; preferably, the ratio of ethanol and acetone can be 2:1, 3:1, 4:1 or 5:1; or any value between the above two.

[0050] The reaction temperature of the present invention is 30-40° C., and the reaction time is 20-60 min.

[0051] In some specific embodiments, the reaction temperature is 32-38° C. and the reaction time is 20-50 min. ;

[0052] In some specific embodiments, the reaction temperature is 34-36° C., and the reaction time is 20-40 min;

[0053] In some specific embodiments, the reaction temperature is 35°C and the reaction time is 30 min;

[0054] According to the present invention, the preparation method further comprises filtering and rotary evaporation concentration.

[0055] The present invention does not limit the specific method and parameters of the filtration, which are well known to those skilled in the art.

[0056] The temperature of the rotary evaporation concentration of the present invention is preferably 40-50°C; preferably 42-48°C; more preferably 43-46°C; most preferably 44-45°C.

[0057] The invention provides the use of the mosapride composition described in the above technical scheme or the mosapride composition prepared by the preparation method described in any one of the above technical schemes in the preparation of drugs for treating functional dyspepsia and gastric diseases.

[0058] The present invention provides a mosapride oral preparation, comprising the mosapride composition described in any one of the above technical solutions or the mosapride composition prepared by the preparation method described in any one of the above technical solutions.

[0059] The pharmaceutical composition of the present invention can be prepared as follows: using standard and conventional techniques, the compound of the present invention is combined with a pharmaceutically acceptable solid or liquid carrier, and optionally combined with pharmaceutically acceptable auxiliary agents and excipients to prepare a usable dosage form.

[0060] The oral preparation of the present invention comprises the mosapride composition and pharmaceutically acceptable excipients.

[0061] In one embodiment of the present application, the pharmaceutical compositions are in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or sterile injections, and can be prepared and used according to conventional methods, but are not limited thereto.

[0062] In one embodiment of the present application, when formulating the pharmaceutical composition, a diluent or excipient may be used, such as a commonly used filler, extender, binder, wetting agent, disintegrant or surfactant, but not limited thereto.

[0063] In one embodiment of the present application, the solid preparation for oral administration includes tablets, pills, powders, granules or capsules, and such solid preparations include at least one excipient in the dead cells of Lactobacillus acidophilus. For example, it can be prepared in the following manner: mixed starch, calcium carbonate, sucrose, lactose or gelatin. In addition, for example, in addition to simple excipients, lubricants such as magnesium stearate and talc can also be used, but it may not be limited thereto.

[0064] In one embodiment of the present application, liquid preparations for oral administration include suspensions, oral preparations, emulsions, syrups, etc., in addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as wetting agents, sweeteners, and may include flavors, preservatives, etc., but are not limited to these.

[0065] The present invention provides a mosapride tablet, comprising the following raw materials in percentage by mass:

[0066] 10 to 20 portions of the mosapride composition described in the above technical solution

[0067] Microcrystalline cellulose 50~70 parts

[0068] Lactose 50~70 parts

[0069] Povidone 0.5~1.5 parts

[0070] 4-6 parts of sodium carboxymethyl cellulose

[0071] 0.5~1.5 parts of magnesium stearate

[0072] 2~4 parts of silicon dioxide.

[0073] In some specific embodiments of the present invention, the mosapride tablets include the following raw materials in percentage by mass:

[0074] 12-18 parts of Mosapride composition

[0075] Microcrystalline cellulose 55~65 parts

[0076] Lactose 55~65 parts

[0077] Povidone 0.8~1.3 parts

[0078] 4.5~5.5 parts of sodium carboxymethyl cellulose

[0079] 0.8~1.3 parts of magnesium stearate

[0080] 2.5~3.5 parts of silicon dioxide.

[0081] In a specific embodiment of the present invention, the mosapride composition is 10 to 20 parts

[0082] 15 parts of Mosapride Citrate Composition

[0083] Microcrystalline cellulose 60 parts

[0084] Lactose 60 parts

[0085] 1 part of Povidone

[0086] 5 parts of sodium carboxymethyl cellulose

[0087] 1 part magnesium stearate

[0088] 3 parts of silicon dioxide.

[0089] The present invention provides a pharmaceutical composition, comprising the mosapride composition described in any one of the above technical solutions or the mosapride composition prepared by the preparation method described in any one of the above technical solutions.

[0090] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution, some or all of the steps can be executed in parallel or sequentially, and the execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0091] The numerical ranges and parameters involved in the present invention have presented the relevant numerical values ​​in the specific embodiments as accurately as possible. However, any numerical value essentially inevitably contains standard deviations due to individual testing methods. Therefore, unless otherwise explicitly stated, it should be understood that all numerical ranges or specific data used in this disclosure may have certain reasonable deviations within a certain range, for example: within 1% or 0.5%.

[0092] Some cases are recorded in the embodiments and comparative examples of the present invention, wherein the embodiments show certain implementation modes of the present invention. However, this does not mean that the effects of the present invention can only be achieved in these cases.

[0093] In order to further illustrate the present invention, a mosapride composition, a preparation method thereof and uses thereof provided by the present invention are described in detail below in conjunction with examples.

[0094] Example 1

[0095] Mosapride citrate, tartaric acid and glutamic acid were weighed in a molar ratio of 1:0.1:0.4 and added into a mixed solution of ethanol and acetone in a mass ratio of 3:1, heated to 35°C, dissolved, filtered, and rotary evaporated at 45°C to obtain a mosapride citrate composition.

[0096] Example 2

[0097] Mosapride citrate, tartaric acid and glutamic acid were weighed in a molar ratio of 1:0.2:0.3 and added into a mixed solution of ethanol and acetone in a mass ratio of 4:1, heated to 35°C, dissolved, filtered, and rotary evaporated at 45°C to obtain a mosapride citrate composition.

[0098] Example 3

[0099] Mosapride citrate, tartaric acid and glutamic acid were weighed in a molar ratio of 1:0.1:0.3 and added into a mixed solution of ethanol and acetone in a mass ratio of 2:1, heated to 35°C, dissolved, filtered, and rotary evaporated at 45°C to obtain a mosapride citrate composition.

[0100] Embodiment 4-6

[0101] The co-grinded mosapride citrate of Examples 1 to 3 of the present invention is mixed with auxiliary materials and then tableted to obtain mosapride citrate tablets.

[0102] The formula of Mosapride Citrate Tablets is as follows:

[0103] Mosapride citrate composition 15g

[0104] Microcrystalline cellulose 60g

[0105] Lactose 60g

[0106] Povidone 1g

[0107] Sodium carboxymethyl cellulose 5g

[0108] Magnesium stearate 1g

[0109] Silicon dioxide 3g

[0110] 1000 pieces

[0111] Verification Example

[0112] Dissolution determination: According to the "Chinese Pharmacopoeia 2020 Edition Four General Rules 0931 Second Method", 900mL of 0.1mol / L hydrochloric acid solution was used as the dissolution medium, the speed was 75rpm per minute, and the operation was carried out according to the law. After 5, 30, and 45min, 10mL of the solution was taken, filtered, and the filtrate was taken as the test solution, and 10mL of 0.1mol / L hydrochloric acid was added at the same time; another mosapride citrate reference substance was taken, 65mg was accurately weighed, placed in a 100mL volumetric flask, methanol was added to dilute and fix the volume, 5mL of the solution was accurately transferred to a 100mL volumetric flask with a pipette, methanol was added to dilute and fix the volume, 5mL of the solution was accurately transferred to a volumetric flask with a pipette, methanol was added to dilute and fix the volume, and shaken well as the reference solution. Take the above two solutions, detect them by HPLC, and calculate the cumulative release. The results are shown in Table 1.

[0113] The test results are shown in Table 1.

[0114] Table 1

[0115]

[0116] The mosapride citrate tablets prepared in Example 6 were placed at 60° C., relative humidity 75% and light (4500±500 lx) for 10 days. The results are shown in Tables 2, 3 and 4.

[0117] Table 2 60℃ high temperature

[0118]

[0119] Table 3 75% high humidity

[0120]

[0121] Table 4 Lighting

[0122]

[0123] The above are only preferred embodiments of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A mosapride composition, characterized in that: The mosapride composition is obtained by reacting mosapride citrate, tartaric acid and glutamic acid in a solvent at a molar ratio of 1:0.1-0.2:0.3-0.

4.

2. The mosapride composition according to claim 1, characterized in that The solvent includes ethanol and acetone in a ratio of 2 to 5:

1.

3. A method for preparing a mosapride composition, characterized in that: The steps include: The product is obtained by placing mosapride citrate, tartaric acid and glutamic acid in a solvent for reaction.

4. The preparation method according to claim 1, characterized in that: The molar ratio of mosapride citrate, tartaric acid and glutamic acid is 1:0.1-0.2:0.3-0.4; The solvent includes ethanol and acetone in a ratio of 2 to 5:

1.

5. The preparation method according to claim 1, characterized in that: The reaction temperature is 30-40° C., and the reaction time is 20-60 min.

6. The preparation method according to claim 1, characterized in that: The preparation further comprises filtering and concentrating by rotary evaporation.

7. Use of the mosapride composition according to any one of claims 1 to 2 or the mosapride composition prepared by the preparation method according to any one of claims 3 to 6 in preparing a drug for treating functional dyspepsia and gastric disease.

8. A mosapride oral preparation, characterized in that: The mosapride composition comprises the mosapride composition according to any one of claims 1 to 2 or the mosapride composition prepared by the preparation method according to any one of claims 3 to 6.

9. A mosapride tablet, characterized in that: The raw materials include the following mass percentages: 10 to 20 parts of the mosapride composition according to any one of claims 1 to 2 Microcrystalline cellulose 50~70 parts Lactose 50~70 parts Povidone 0.5~1.5 parts 4-6 parts of sodium carboxymethyl cellulose 0.5~1.5 parts of magnesium stearate 2~4 parts of silicon dioxide.

10. A pharmaceutical composition, characterized in that The invention comprises the mosapride composition according to any one of claims 1 to 2 or the mosapride composition prepared by the preparation method according to any one of claims 3 to 7.

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