Trimebutine Maleate Resin Complex Sustained Release Suspension and Its Preparation Method

Abstract

The present invention discloses a sustained-release suspension of trimebutine maleate resin complex, and its raw materials by weight include: 190-210 parts of trimebutine maleate resin complex, 18-22 parts of xanthan gum, 0-20 parts of tragacanth gum, 15-17 parts of citric acid, 4-6 parts of propylene glycol, and 240-260 parts of water. The present invention also discloses a preparation method of the above-mentioned sustained-release suspension of trimebutine maleate resin complex, which comprises the following steps: dissolving xanthan gum and tragacanth gum in water, then successively adding citric acid and propylene glycol and mixing evenly, and then adding trimebutine maleate resin complex and stirring evenly to obtain the sustained-release suspension of trimebutine maleate resin complex. The sustained-release suspension of trimebutine maleate resin complex of the present invention can achieve site-specific sustained release in the human intestine, continuously exert its drug effect, and the suspension has good stability and no bitter taste, improving the compliance of patients in taking the medicine.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a sustained-release suspension of trimebutine maleate resin complex and a preparation method thereof. Background Art

[0002] Trimebutine maleate is a gastrointestinal rhythm regulator, which is mainly used clinically to treat gastrointestinal symptoms caused by chronic gastritis and irritable bowel syndrome. Most of the trimebutine maleate on the market is film-coated tablets. Due to the short biological half-life of the drug, the dosage of general ordinary preparations is three times a day, which causes certain troubles for the elderly and children to take. The pellets coating material used in the sustained-release capsules is easy to break in aqueous media, with the risk of drug sudden release, and the poor control of particle size affects the stability of the drug. Moreover, the capsules also cause certain troubles for people with difficulty in swallowing. Summary of the Invention

[0003] Based on the technical problems existing in the background art, the present invention proposes a sustained-release suspension of trimebutine maleate resin complex and a preparation method thereof. The sustained-release suspension of trimebutine maleate resin complex of the present invention can achieve site-specific sustained release in the human intestine, continuously exert its medicinal effect, and the suspension has good stability, no bitter taste, and improves the compliance of patients taking the medicine.

[0004] The present invention proposes a sustained-release suspension of trimebutine maleate resin complex, and its raw materials include, by weight: 190-210 parts of trimebutine maleate resin complex, 18-22 parts of xanthan gum, 0-20 parts of tragacanth gum, 15-17 parts of citric acid, 4-6 parts of propylene glycol, and 240-260 parts of water.

[0005] Preferably, the resin used in the trimebutine maleate resin complex is a cation exchange resin.

[0006] Preferably, the resin used in the trimebutine maleate resin complex is IRP88 resin.

[0007] Preferably, the particle size of the IRP88 resin is 400-600 μm.

[0008] Preferably, in the preparation process of the trimebutine maleate resin complex, the trimebutine maleate solution is mixed with the resin, stirred at 37-40 °C for 0.8-1.2 h, solid-liquid separated, washed, and dried to obtain the trimebutine maleate resin complex.

[0009] Preferably, in the preparation process of the trimebutine maleate resin complex, the weight ratio of trimebutine maleate to the resin is 3-5:0.5.

[0010] Preferably, in the preparation process of the trimebutine maleate resin complex, the concentration of the trimebutine maleate solution is 30 - 50 mg / ml.

[0011] Preferably, in the preparation process of the trimebutine maleate resin complex, the solvent of the trimebutine maleate solution is an aqueous acetonitrile solution with a volume fraction of 15 - 25%.

[0012] Preferably, the raw materials of the suspension further include: sweeteners, preservatives, flavors, and pigments.

[0013] Preferably, the weight ratio of xanthan gum to sweeteners, preservatives, flavors, and pigments is 18 - 22:4 - 6:0.5 - 1.5:0.5 - 1.5:0.5 - 1.5.

[0014] The above-mentioned sweeteners can be aspartame, etc. The above-mentioned preservatives can be methylparaben, etc. The above-mentioned flavors can be lemon flavor, etc. The above-mentioned pigments can be tartrazine, etc.

[0015] The present invention also provides a preparation method of the above-mentioned sustained-release suspension of trimebutine maleate resin complex, which includes the following steps: dissolving xanthan gum and tragacanth in water, then sequentially adding citric acid and propylene glycol and mixing evenly, and then adding the trimebutine maleate resin complex and stirring evenly to obtain the sustained-release suspension of trimebutine maleate resin complex.

[0016] Preferably, when adding the trimebutine maleate resin complex, stir for 20 - 40 min at a speed of 250 - 350 rpm to mix evenly.

[0017] The above-mentioned water can be deionized water, etc.

[0018] 1. The present invention selects a cation exchange resin to form a complex with trimebutine maleate. Due to the characteristics of the ion exchange resin, the release of the drug depends on the type and strength of the ions. In a non-ion aqueous medium, the drug cannot be released, ensuring the stability of the suspension; it can isolate the influence of the external environment on the drug to a certain extent and improve the stability of the drug and the suspension; and it will not undergo ion exchange in gastric juice and can gradually exchange with sodium ions, potassium ions, etc. in the intestine, achieving a targeted sustained-release effect in the intestine and reducing the dosing frequency.

[0019] 2. The present invention selects a cation exchange resin to form a complex with trimebutine maleate, which can mask the bitter taste of trimebutine maleate. Formulating it into a suspension can further mask the bitter taste and improve the compliance of taking; and the particle size of the cation exchange resin is controllable, which can avoid the problem that the existing pellets have different particle sizes and it is easy to sediment when made into a suspension, improving the stability of the suspension; and the preparation process of the present invention is simple and the cost is low, which is suitable for industrial production.

[0020] The sustained-release suspension of trimebutine maleate resin complex of the present invention can achieve site-specific sustained release in the human intestine, continuously exert its medicinal effect, and the suspension has good stability and no bitter taste, improving the compliance of patients in taking the medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Results of drug loading amounts of different resins.

[0022] Figure 2 Results of drug loading amounts at different temperatures.

[0023] Figure 3 Results of drug loading amounts with different dosages of trimebutine maleate.

[0024] Figure 4 Dissolution curves of Examples 4 - 6. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0025] Hereinafter, the technical solutions of the present invention will be described in detail through specific examples.

[0026] Example 1

[0027] A preparation method of a trimebutine maleate resin complex includes the following steps:

[0028] Add 3 g of trimebutine maleate raw material to 100 ml of an acetonitrile aqueous solution with a volume fraction of 20%, prepare three portions in parallel, and respectively add 0.5 g of IRP64 resin, IRP69 resin, IRP88 resin. Stir and react at 25°C for static drug loading. Sampling is carried out at different time points, filtered and diluted, and the absorbance is measured by UV-vis to calculate the drug concentration and the drug loading amount Q∞ (mg·mg -1 ). The results are as Figure 1 shown. Figure 1 Results of drug loading amounts of different resins.

[0029] From Figure 1 it can be seen that: The drug loading amount of IRP88 resin is the highest, and the rate of reaching drug loading equilibrium is the fastest.

[0030] Example 2

[0031] A preparation method of a trimebutine maleate resin complex includes the following steps:

[0032] Add 3 g of trimebutine maleate raw material and 0.5 g of IRP64 resin was prepared in three parallel portions and stirred and reacted at 25 °C, 37 °C, and 40.0 °C respectively for static drug loading. Samples were taken at different time points, filtered and diluted, and the absorbance was measured by UV-vis to calculate the drug concentration and the drug loading amount Q∞ (mg·mg -1 ). The results are as Figure 2 shown. Figure 2 The drug loading results at different temperatures are shown.

[0033] It can be seen from Figure 2 that when the temperature is 40.0 °C, the drug loading amount and the drug loading rate are relatively fast.

[0034] Example 3

[0035] A preparation method of a trimebutine maleate resin complex comprises the following steps:

[0036] 0.5 g of IRP64 resin was added to 100 ml of an aqueous acetonitrile solution with a volume fraction of 20%. Three parallel portions were prepared and 1 g, 3 g, and 5 g of trimebutine maleate raw materials were added respectively. They were all stirred and reacted at 40.0 °C for static drug loading. Samples were taken at different time points, filtered and diluted, and the absorbance was measured by UV-vis to calculate the drug concentration and the drug loading amount Q∞ (mg·mg -1 ). The results are as Figure 3 shown. Figure 3 The drug loading results with different dosages of trimebutine maleate are shown.

[0037] It can be seen from Figure 3 that when the concentration of trimebutine maleate is 30 mg / ml, the drug loading amount and the drug loading rate are relatively high; when the concentration is 50 mg / ml, the drug loading amount and the drug loading efficiency are basically the same as those at 30 mg / ml.

[0038] It can be seen from Examples 1 - 3 that the conditions for preparing the trimebutine maleate resin complex are: the concentration of trimebutine maleate is 30 - 50 mg / ml, the resin is IRP88 resin, the temperature is 37 - 40 °C, and the weight ratio of trimebutine maleate to resin is 3 - 5:0.5.

[0039] Example 4

[0040] A sustained-release suspension of a trimebutine maleate resin complex, the raw materials of which include, by weight: 200 parts of trimebutine maleate resin complex, 20 parts of xanthan gum, 16 parts of citric acid, 5 parts of propylene glycol, 5 parts of aspartame, 1 part of methylparaben, 1 part of lemon essence, 1 part of tartrazine, and 250 parts of water.

[0041] The preparation method of the above-mentioned trimebutine maleate resin complex sustained-release suspension comprises the following steps: adding xanthan gum into water, stirring to dissolve it to form a viscous liquid, then successively adding citric acid, propylene glycol, aspartame, methylparaben, lemon essence, and tartrazine and mixing them evenly, then adding the trimebutine maleate resin complex, stirring at a speed of 300 rpm for 30 min to mix evenly, filling into HDPE bottles, and capping to obtain the trimebutine maleate resin complex sustained-release suspension.

[0042] Example 5

[0043] A trimebutine maleate resin complex sustained-release suspension, the raw materials of which include, by weight: 200 parts of trimebutine maleate resin complex, 22 parts of xanthan gum, 10 parts of tragacanth gum, 17 parts of citric acid, 6 parts of propylene glycol, 6 parts of aspartame, 1.5 parts of methylparaben, 0.5 part of lemon essence, 0.5 part of tartrazine, and 250 parts of water.

[0044] The preparation method of the above-mentioned trimebutine maleate resin complex sustained-release suspension comprises the following steps: adding xanthan gum and tragacanth gum into water, stirring to dissolve them to form a viscous liquid, then successively adding citric acid, propylene glycol, aspartame, methylparaben, lemon essence, and tartrazine and mixing them evenly, then adding the trimebutine maleate resin complex, stirring at a speed of 300 rpm for 30 min to mix evenly, filling into HDPE bottles, and capping to obtain the trimebutine maleate resin complex sustained-release suspension.

[0045] Example 6

[0046] A trimebutine maleate resin complex sustained-release suspension, the raw materials of which include, by weight: 200 parts of trimebutine maleate resin complex, 18 parts of xanthan gum, 20 parts of tragacanth gum, 15 parts of citric acid, 4 parts of propylene glycol, 4 parts of aspartame, 0.5 part of methylparaben, 1.5 parts of lemon essence, 1.5 parts of tartrazine, and 250 parts of water.

[0047] The preparation method of the above-mentioned trimebutine maleate resin complex sustained-release suspension comprises the following steps: adding xanthan gum and tragacanth gum into water, stirring to dissolve them to form a viscous liquid, then successively adding citric acid, propylene glycol, aspartame, methylparaben, lemon essence, and tartrazine and mixing them evenly, then adding the trimebutine maleate resin complex, stirring at a speed of 300 rpm for 30 min to mix evenly, filling into HDPE bottles, and capping to obtain the trimebutine maleate resin complex sustained-release suspension.

[0048] Comparative Example 1

[0049] Replace xanthan gum with gelatin, and the others are the same as in Example 4.

[0050] Comparative Example 2

[0051] Replace xanthan gum with guar gum, and the others are the same as in Example 4.

[0052] Comparative Example 3

[0053] Replace xanthan gum with gelatin, and the others are the same as in Example 5.

[0054] Comparative Example 4

[0055] Replace xanthan gum with guar gum, and the others are the same as in Example 6.

[0056] Take the sustained-release suspension of trimebutine maleate resin complex prepared in Examples 4-6 and Comparative Examples 1-4, and investigate its wall adhesion phenomenon, particle aggregation phenomenon and sedimentation volume ratio.

[0057] 1. Wall adhesion experiment: Let the suspensions prepared in Examples 4-6 and Comparative Examples 1-4 stand for 3 h, turn them upside down 7-8 times, place them on a horizontal table, and observe whether there are particles hanging on the inner wall of the inner packaging bottle and whether the particles hanging on the inner wall will flow into the suspension.

[0058] It was observed that: There were some particles hanging on the inner wall of the suspension of Example 4 and flowed into the suspension within 1 min. There was no obvious wall adhesion phenomenon in the suspensions of Examples 5-6; There were more particles hanging on the inner wall of the suspensions of Comparative Examples 1-4, and there were still more particles that did not flow into the suspension within 1 min.

[0059] 2. Particle aggregation in the suspension will cause the instability of the system and inaccurate content detection. Therefore, it is necessary to detect whether there are loose aggregates in the suspension. The specific steps include: Take the suspensions prepared in Examples 4-6 and Comparative Examples 1-4, turn them upside down 7-8 times, stand for 3 h, and use a light source to enhance the visibility of the visual method. Use the light source to illuminate the suspension in the inner packaging bottle and observe whether there are loose aggregates.

[0060] It was observed that: There was no particle aggregation phenomenon in the suspensions of Examples 4-6; There was particle aggregation phenomenon in Comparative Examples 1-4.

[0061] 3. Detect the sedimentation volume ratio: Take 25 mL of each group of suspensions and add them to a stoppered graduated cylinder, shake well, record the height H0 at this time, stand for 3 h at 25 °C, record the height of the sedimentation surface in the graduated cylinder, calculate the sedimentation volume ratio, measure three times in parallel, and record the average value.

[0062] The results were as follows: The sedimentation volume ratios of Examples 4-6 were 0.90, 0.93, and 0.98 in sequence, all of which met the requirements of the pharmacopoeia (sedimentation volume ratio ≥ 0.90), while the sedimentation volume ratios of Comparative Examples 1-4 were all less than 0.90 and did not meet the requirements of the pharmacopoeia.

[0063] It can be seen from the above results that xanthan gum can be used to formulate the trimebutine maleate resin complex into a suspension and maintain a stable suspension state; and the combination of xanthan gum and tragacanth can further improve the stability of the suspension state.

[0064] Take the trimebutine maleate resin complex sustained-release suspension prepared in Examples 4-6 for dissolution test.

[0065] The dissolution method is as follows: paddle method at 50 rpm, sampling times are 2, 4, 6, 8, 10 and 12 h, the dissolution medium is 0.15 M NaCl aqueous solution, the medium volume is 900 ml, and the temperature is 37°C. Start timing when the sample is put in, take 10 ml of the sample at the set time points, and supplement the dissolution medium with the same temperature and volume at the same time. Filter the sample to obtain the test solution, and detect the content of trimebutine. The results are as Figure 4 shown.

[0066] Figure 4 are the dissolution curves of Examples 4-6.

[0067] From Figure 4 it can be seen that: the trimebutine maleate resin complex sustained-release suspension prepared by the present invention has no burst release phenomenon. From the perspective of cumulative release, the release curve is relatively flat, approaching "zero-order release"; the overall release time is about 10-12 h. Compared with the conventional trimebutine preparation, its drug release period is significantly prolonged.

[0068] The above is only the preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and should be covered within the protection scope of the present invention.

Claims

1. A trimebutine maleate resin complex sustained-release suspension, characterized in that: The raw materials include, by weight: 190-210 parts of trimebutine maleate resin complex, 18-22 parts of xanthan gum, 10-20 parts of tragacanth gum, 15-17 parts of citric acid, 4-6 parts of propylene glycol, and 240-260 parts of water; The resin used in trimebutine maleate resin complex is Amberlite ® IRP88 resin; Amberlite ® The particle size of IRP88 resin is 400-600 μm; In the preparation process of the trimebutine maleate resin complex, the trimebutine maleate solution and the resin are mixed, stirred at 37-40° C. for 0.8-1.2 hours, solid-liquid separation, washing, and drying to obtain the trimebutine maleate resin complex; In the preparation process of trimebutine maleate resin complex, the weight ratio of trimebutine maleate to resin is 3-5:0.5; During the preparation of trimebutine maleate resin complex, the concentration of trimebutine maleate solution was 30-50 mg / ml; In the preparation process of trimebutine maleate resin complex, the solvent of trimebutine maleate solution is acetonitrile aqueous solution with a volume fraction of 15-25%; The raw materials of the suspension also include: sweeteners, preservatives, flavors, and pigments; The weight ratio of xanthan gum to sweetener, preservative, flavor and pigment is 18-22:4-6:0.5-1.5:0.5-1.5:0.5-1.

5.

2. A method for preparing the trimebutine maleate resin complex sustained-release suspension according to claim 1, characterized in that: The method comprises the following steps: dissolving xanthan gum and tragacanth gum in water, then sequentially adding citric acid and propylene glycol and mixing evenly, then adding trimebutine maleate resin complex, and stirring at a speed of 250-350 rpm for 20-40 minutes to obtain a trimebutine maleate resin complex sustained-release suspension.

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