A mosapride citrate syrup and a method for preparing the same

Abstract

The present application relates to a kind of syrup containing mosapride citrate, belong to the field of pharmaceutical preparations, the syrup of the present application contains mosapride citrate, flavouring agent, β-cyclodextrin, stabilizer, aromatic agent, bacteriostatic agent and purified water composition, preparation method is: first β-cyclodextrin is dissolved in water, stirring dissolves, then mosapride citrate is added, stirring dissolves, obtains solution I, standby;Stabilizer, bacteriostatic agent, aromatic agent are dissolved in water, then flavouring agent is added, obtains solution II standby;Solution I, solution II are mixed, obtain immediately.The syrup prepared in the present application, stability is improved, child is convenient, safe characteristics of taking.For industrial production, it is convenient for market promotion that preparation process is simple.

Description

TECHNICAL FIELD

[0001] The present application relates to a Mosapride Citrate syrup and its preparation method, belonging to the field of pharmaceutical preparations BACKGROUND

[0002] It is a selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist, which promotes the release of acetylcholine by exciting the 5-HT4 receptors of the cholinergic interneurons and the myenteric plexus of the gastrointestinal tract, thus enhancing the motility of the gastrointestinal tract and improving the gastrointestinal symptoms of patients with functional dyspepsia without affecting the secretion of gastric acid. It has no affinity for dopamine D2, 5-HT1 and 5-HT2 receptors on the synaptic membranes of the brain, and thus has no extrapyramidal side effects caused by the blockade of these receptors.

[0003] The clinically selected dosage forms of Mosapride Citrate include tablets and oral solutions. Since Mosapride Citrate has poor water solubility, the drug is difficult to dissolve in solid preparations such as tablets, so that the drug cannot achieve the desired therapeutic effect. Liquid preparations such as syrup and oral solution have high bioavailability and are particularly suitable for children and patients with difficulty in swallowing.

[0004] Chinese patent CN101273973B discloses a pharmaceutical composition containing Mosapride Citrate prepared by directly compressing powder and its preparation method

[0005] At present, the existing Mosapride Citrate preparations in China mainly include tablets and oral solution preparations. The present application provides a syrup preparation that can increase patient adaptability, which meets the needs of a wide range of patients. SUMMARY

[0006] The present application aims to provide a high-quality oral Mosapride Citrate syrup that overcomes the shortcomings of the prior art, greatly improves the stability of the preparation and the degradation impurities, and provides a safer Mosapride Citrate syrup for children and its preparation method.

[0007] The purpose of the present application is achieved by the following technical solution: a Mosapride Citrate syrup preparation, wherein the Mosapride Citrate contains Mosapride Citrate, a flavoring agent, β-cyclodextrin, a stabilizer, an aromatic agent, a bacteriostatic agent and purified water.

[0008] The β-cyclodextrin is water-soluble β-cyclodextrin, and the water-soluble β-cyclodextrin is one or more of hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, 2,6-dimethoxy-β-cyclodextrin and hydroxyethyl-β-cyclodextrin; preferably, the water-soluble β-cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0009] The flavoring agent is one or more of glucose, maltose and sucrose.

[0010] The stabilizer is one or more of glycerin, sodium alginate, pregelatinized starch, povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, sodium citrate, hydroxypropyl methyl cellulose.

[0011] The fragrance is one or more of lemon essence, orange essence, peach essence, raspberry essence.

[0012] The bacteriostatic agent is one or more of benzoic acid, sodium benzoate, hydroxybenzoic acid ester, hydroxyphenyl ethyl ester, potassium sorbate.

[0013] The citric acid mosapride syrup, in terms of weight ratio,

[0014]

[0015] The stabilizer is glycerin, sodium alginate, and further preferably, the ratio of the two is 1:1.

[0016] The bacteriostatic agent is sodium benzoate.

[0017] The second object of the present application is to provide a preparation method of citric acid mosapride syrup, which comprises the following steps:

[0018] Step 1): first dissolve β-cyclodextrin in water, stir to dissolve, then add citric acid mosapride, stir to dissolve, to obtain solution I, ready for use;

[0019] Step 2): dissolve the stabilizer, bacteriostatic agent, and fragrance in water, then add the flavoring agent to obtain solution II, ready for use;

[0020] Step 3): mix solution I and solution II to obtain the product.

[0021] Further, in order to achieve the object of the present application, the inventors have screened the prescription composition and dosage, optimized the process operation and process parameters through a large number of experiments, and finally obtained the technical solution solving the technical problems of the present application.

[0022] A preparation method of citric acid mosapride syrup as described above, the preparation method comprises the following steps:

[0023] (1) Dissolve water-soluble β-cyclodextrin in an appropriate amount of water;

[0024] (2) Dissolve citric acid mosapride in the solution of step (1)

[0025] (3) Dissolve the fragrance, stabilizer, and bacteriostatic agent in an appropriate amount of water, and then dissolve the sucrose;

[0026] (4) Mix the two solutions of step (2) and step (3), make the solution clear, stir it evenly and add water to the full amount

[0027] The preferred scheme of the present application is that in the step:

[0028] In step (1), hydroxypropyl-β-cyclodextrin is added into water for injection above 80℃ under stirring, and is dissolved by stirring;

[0029] In step (2), mosapride citrate is dissolved in the solution of step (1);

[0030] In step (3), glycerol, sodium benzoate, peach flavor are dissolved in water, and sucrose is added and stirred to dissolve;

[0031] In step (4), step (2) and step (3) are slowly mixed together under stirring, the solution is made clear, stirred evenly, and water is added to the full amount, and filtered.

[0032] Compared with the prior art, the technical scheme of the present application has the advantages of:

[0033] (1) The syrup of the present application contains mosapride citrate, flavoring agent, stabilizer and bacteriostatic agent, and through the optimal combination of the auxiliary materials, especially the optimal hydroxypropyl-β-cyclodextrin, the bitter taste of mosapride can be significantly eliminated.

[0034] (2) The preparation method of the present application is: dissolving water-soluble β-cyclodextrin in water; then adding flavoring agent, aromatic agent, stabilizer and bacteriostatic agent into the water solution after stirring and dissolving mosapride citrate in water, and stirring, dissolving, filtering, filling and packaging. The syrup prepared by the present application has improved stability, is convenient and safe for children to take, and has simple preparation process, which is suitable for industrial production and market promotion. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 : HPLC chart of Example 1 of the present application at the 0th month

[0036] Figure 2 : HPLC chart of Example 1 of the present application after 6 months of accelerated test

[0037] Figure 3 : HPLC chart of Example 4 of the present application at the 0th month

[0038] Figure 4 : HPLC chart of Example 4 of the present application after 6 months of accelerated test

[0039] Figure 5 : HPLC chart of Comparative Example 3 of the present application at the 0th month

[0040] Figure 6 HPLC chart of Comparative Example 3 of the present application after 6 months of accelerated test DETAILED DESCRIPTION

[0041] Example 1: A syrup of Mosapride Citrate, the content of each component is as follows (1000 mL) by weight ratio:

[0042]

[0043]

[0044] The specific preparation process is as follows:

[0045] In step (1), hydroxypropyl-β-cyclodextrin is added into water for injection above 80°C under stirring to dissolve;

[0046] In step (2), Mosapride Citrate is dissolved in the solution of step (1);

[0047] In step (3), glycerol, sodium benzoate, peach flavor are dissolved in water, and sucrose is added to dissolve under stirring;

[0048] In step (4), steps (2) and (3) are slowly mixed together under stirring to make the solution clear, uniform and to add water to the total amount, and the pH value is measured to be 5.0-6.0, and then filtered to obtain the product.

[0049] Example 2: A syrup of Mosapride Citrate, the content of each component is as follows (1000 mL) by weight ratio:

[0050]

[0051] The preparation process is the same as that of Example 1.

[0052] Example 3: A syrup of Mosapride Citrate, the content of each component is as follows (1000 mL) by weight ratio:

[0053]

[0054] The preparation process is the same as that of Example 1.

[0055] Example 4: A syrup of Mosapride Citrate, the content of each component is as follows (1000 mL) by weight ratio:

[0056]

[0057] The preparation process is the same as that of Example 1.

[0058] Comparative Example 1: A syrup of Mosapride Citrate, the ingredients are as follows (1000 mL) by weight ratio

[0059]

[0060] The preparation process is the same as Example 1.

[0061] Comparative Example 2: A syrup of Mosapride Citrate, the ingredients are as follows (1000 mL) by weight ratio

[0062]

[0063] The preparation process is the same as Example 1.

[0064] Comparative Example 3: A syrup of Mosapride Citrate, the ingredients are as follows (1000 mL) by weight ratio

[0065]

[0066] The preparation process is the same as Example 1.

[0067] Comparative Example 4: A syrup of Mosapride Citrate, the ingredients are as follows (1000 mL) by weight ratio

[0068]

[0069] The preparation process is the same as Example 1.

[0070] Comparative Example 5: A syrup of Mosapride Citrate, the ingredients are as follows (1000 mL) by weight ratio

[0071]

[0072] The preparation process is the same as Example 1.

[0073] Comparative Example 6: A syrup of Mosapride Citrate, the ingredients are as follows (1000 mL) by weight ratio

[0074]

[0075]

[0076] Preparation method:

[0077] (1) Mosapride Citrate is dissolved in water;

[0078] (2) Hydroxypropyl-β-cyclodextrin, glycerol, sodium benzoate are added to an appropriate amount of water, stirred to dissolve, and sucrose is added and stirred to dissolve;

[0079] (3) Slowly add step (1) into step (2) under stirring, make the solution clear, then add peach flavor, stir until uniform, and add water to the full amount, and circulate filtration

[0080] Technical effects of the verification examples:

[0081] 1. Taste test

[0082] In the field of food science and pharmacy, the evaluation method of taste is mainly based on human taste. In recent years, although there have been studies on using instruments to evaluate taste, due to technical problems, they have not been widely applied. Therefore, the evaluation of taste still adopts the method of scoring the taste after human tasting, and considering the particularity of the compound Chinese medicine syrup provided by the present application, after consulting and referring to the literature, the present application formulates a set of scoring standard system for taste, as shown in Table 1:

[0083] Table 1: Taste evaluation scoring table of syrup

[0084] Taste level Judging criteria Score 1 Poor taste, noticeable bitterness or off-taste 1-2 2 Average taste, only weak bitterness or off-taste 3-4 3 Average taste, no bitterness or off-taste 5-6 4 Good taste, only weak bitterness and off-taste 7-8 5 Good taste, no bitterness or off-taste 9-10

[0085] The taste test adopts a double-blind method, and the test personnel taste to determine the level and score according to the level, with a full score of 10 points. The sensitivity of taste is related to age, and young children are very sensitive to bitterness, while the elderly are relatively dull. The total number of taste bud cells reaches the maximum at the age of 20, and the taste is relatively sensitive. Therefore, the age of the test subjects is controlled at 20-25 years old. A total of 110 people (Lu'nan Pharmaceutical Group employees) were recruited for the test, half male and half female. The blank control group does not contain active substances, and the others are the same as Example 1. Before the experiment, the test subjects should first rinse their mouths with warm water, then taste each solution in order, keep each solution in the mouth for about 10 seconds, spit out the liquid, immediately select the bitterness level, then rinse the mouth with warm water until there is no taste of the previous liquid in the mouth. The relevant taste parameters are statistically analyzed by SPSS 17.0

[0086] Table 2: Taste evaluation of syrup of each example

[0087]

[0088] Note: ** Compared with Comparative Example 1, there is a significant difference

[0089] From the results in Table 2, it can be seen that the addition of flavoring agents is not random, and the amount and type are strictly limited. In Comparative Example 5, although both are flavoring agents, they cannot achieve the same technical effect, and the taste test is actually not good. In terms of amount, the addition of flavoring agents is not the more the better. As can be seen from Table 2, the addition of flavoring agents in Comparative Example 1, which is not in the proportion of the present application, does not achieve the technical effect of the present application.

[0090] 2. Stability test

[0091] The stability of the syrup of Examples 1-10 was determined, and retested after 6 months of accelerated testing at 40°C ± 2°C and 75% ± 5% relative humidity, and sampled at 0, 3, and 6 months for analysis. The content of related substances was observed, and the results are shown in Table 3.

[0092] Table 3 Stability evaluation of the syrup of each example

[0093]

[0094]

[0095] As shown in Table 5, the stability of the syrup was good when the mixture of glycerol and sodium alginate was used as a stabilizer. The stability test results showed that the Mosapride citrate syrup of the present application did not significantly change in appearance and content after 6 months of accelerated and long-term testing. The total related substances did not increase during the 6 months of accelerated stability testing.​

Claims

1. A syrup of mosapride citrate, characterized by, The mosapride citrate syrup contains mosapride citrate, flavoring agent, β-cyclodextrin, stabilizer, aromatic agent, bacteriostatic agent and purified water; the weight ratio is as follows: Mosapride citrate 50 parts Flavoring agent 100 parts β-cyclodextrin 50-200 parts Stabilizer 5-20 parts Aromatic agent 5-15 parts Bacteriostatic agent 1-5 parts Purified water appropriate amount The stabilizer is a combination of glycerol and sodium alginate. The preparation method is as follows: step 1) first dissolve β-cyclodextrin in water, stir and dissolve, then add mosapride citrate, stir and dissolve to obtain solution I for standby; step 2) dissolve stabilizer, bacteriostatic agent and aromatic agent in water, then add flavoring agent to obtain solution II for standby; step 3) mix solution I and solution II to obtain the product.

2. The mosapride citrate syrup as set forth in claim 1, characterized by The β-cyclodextrin is water-soluble β-cyclodextrin.

3. The mosapride citrate syrup as set forth in claim 2, characterized by The water-soluble β-cyclodextrin is one or more of hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, 2,6-dimethoxy-β-cyclodextrin and hydroxyethyl-β-cyclodextrin.

4. The mosapride citrate syrup as set forth in claim 3, characterized by The β-cyclodextrin is hydroxypropyl-β-cyclodextrin.

5. The mosapride citrate syrup as set forth in claim 1, characterized by The flavoring agent is one or more of glucose, maltose and sucrose.

6. The mosapride citrate syrup as set forth in claim 1, characterized by The aromatic agent is one or more of lemon essence, sweet orange essence, juicy peach essence and raspberry essence.

7. The mosapride citrate syrup as set forth in claim 1, characterized by The bacteriostatic agent is one or more of benzoic acid, sodium benzoate, hydroxybenzoic acid ester, hydroxyphenyl ethyl ester and potassium sorbate.

8. The mosapride citrate syrup as set forth in claim 7, characterized by The bacteriostatic agent is sodium benzoate.

Images