Trimebutine maleate resin compound sustained-release suspension and preparation method thereof

Abstract

The trimebutine maleate resin compound slow-release suspension is prepared from the following raw materials in parts by weight: 190 to 210 parts of trimebutine maleate resin compound, 18 to 22 parts of xanthan gum, 0 to 20 parts of tragacanth gum, 15 to 17 parts of citric acid, 4 to 6 parts of propylene glycol and 240 to 260 parts of water. The invention also discloses a preparation method of the trimebutine maleate resin compound slow-release suspension, which comprises the following steps: dissolving xanthan gum and tragacanth gum in water, then sequentially adding citric acid and propylene glycol, uniformly mixing, then adding the trimebutine maleate resin compound, uniformly stirring and mixing to obtain the trimebutine maleate resin compound slow-release suspension. The trimebutine maleate resin compound slow-release suspension is obtained. The trimebutine maleate resin compound sustained-release suspension disclosed by the invention can realize positioned sustained release in the intestinal tract of a human body and continuously exert the drug effect, has good stability and no bitter taste, and improves the taking compliance of a patient.

Description

Technical Field

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

[0002] Trimebutine maleate is a gastrointestinal rhythm agent, 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 general dosage of ordinary preparations is three times a day, which causes certain troubles for the elderly and children. The micro-pellet coating material used in sustained-release capsules is easy to rupture in aqueous media, which has the risk of causing sudden drug release, and the poor control of particle size affects the stability of the drug. The capsules also cause certain troubles for people with difficulty swallowing. Summary of the invention

[0003] Based on the technical problems existing in the background technology, the present invention proposes a trimebutine maleate resin complex sustained-release suspension and a preparation method thereof. The trimebutine maleate resin complex sustained-release suspension of the present invention can achieve localized sustained release in the human intestine and continuously exert its drug efficacy. In addition, the suspension has good stability and no bitterness, thereby improving the patient's compliance with taking the drug.

[0004] The invention provides a trimebutine maleate resin complex sustained-release suspension, wherein the raw materials thereof comprise, 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 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 separation, washing, and drying are performed to obtain the trimebutine maleate resin complex.

[0009] Preferably, in the preparation process of trimebutine maleate resin complex, the weight ratio of trimebutine maleate to 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 trimebutine maleate resin complex, the solvent of trimebutine maleate solution is acetonitrile aqueous solution with a volume fraction of 15-25%.

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

[0013] Preferably, 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.

[0014] The sweetener may be aspartame, etc. The preservative may be methylparaben, etc. The flavor may be lemon flavor, etc. The pigment may be lemon yellow, etc.

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

[0016] Preferably, the trimebutine maleate resin complex is added and stirred at a speed of 250-350 rpm for 20-40 min to mix.

[0017] The water mentioned above can be deionized water or the like.

[0018] 1. The present invention uses 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 an ion-free aqueous medium, the drug cannot be released, thereby ensuring the stability of the suspension; the influence of the external environment on the drug can be isolated to a certain extent, thereby improving the stability of the drug and the suspension; and no ion exchange occurs in the gastric juice, but it can gradually exchange with sodium ions, potassium ions, etc. in the intestine, thereby achieving a localized sustained-release effect in the intestine and reducing the frequency of administration;

[0019] 2. The present invention uses a cation exchange resin to form a complex with trimebutine maleate, which can mask the bitterness of trimebutine maleate. The suspension can further mask the bitterness and improve the compliance of taking. The particle size of the cation exchange resin is controllable, which can avoid the problem that the particle size of the existing micropills is different, and the micropills are easily sedimented when made into a suspension, thereby improving the stability of the suspension. The preparation process of the present invention is simple, the cost is low, and it is suitable for industrial production.

[0020] The trimebutine maleate resin complex sustained-release suspension of the present invention can achieve localized sustained release in the human intestine and continuously exert its drug efficacy. The suspension has good stability and no bitterness, thereby improving the patient's compliance with taking the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The drug loading results of different resins are shown in Figure 2.

[0022] Figure 2 The drug loading results at different temperatures.

[0023] Figure 3 The drug loading results of different trimebutine maleate dosages.

[0024] Figure 4 This is the dissolution curve of Example 4-6. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is described in detail below through specific embodiments.

[0026] Example 1

[0027] A method for preparing a trimebutine maleate resin complex comprises the following steps:

[0028] Add 3 g of trimebutine maleate raw material to 100 ml of 20% acetonitrile aqueous solution, prepare three portions in parallel, and add 0.5 g of IRP64 resin, IRP69 resin, IRP88 resin was stirred at 25°C for static drug loading. Samples were taken at different time points, filtered and diluted, and the absorbance was measured by UV-vis. The drug concentration and drug loading Q∞ (mg·mg -1 ). The result is Figure 1 shown. Figure 1 The drug loading results of different resins are shown in Figure 2.

[0029] Depend on Figure 1 It can be seen that: IRP88 resin has the highest drug loading capacity and reaches drug loading equilibrium the fastest.

[0030] Example 2

[0031] A method for preparing a trimebutine maleate resin complex comprises the following steps:

[0032] Add 3 g of trimebutine maleate raw material and 0.5 g of IRP64 resin was prepared in triplicate and stirred at 25°C, 37°C, and 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 drug loading Q∞ (mg·mg -1 ). The result is Figure 2 shown. Figure 2 The drug loading results at different temperatures.

[0033] Depend on Figure 2 It can be seen that when the temperature is 40.0℃, the drug loading amount and drug loading rate are faster.

[0034] Example 3

[0035] A method for preparing a trimebutine maleate resin complex comprises the following steps:

[0036] Add 0.5 g of IRP64 resin was prepared in triplicate, and 1 g, 3 g, and 5 g of trimebutine maleate raw material were added, respectively. The mixture was stirred 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. The drug concentration and drug loading Q∞ (mg·mg -1 ). The result is Figure 3 shown. Figure 3 The drug loading results of different trimebutine maleate dosages.

[0037] Depend on Figure 3 It can be seen that when the concentration of trimebutine maleate is 30 mg / ml, the drug loading amount and loading rate are higher; when the concentration is 50 mg / ml, the drug loading amount and loading efficiency are basically the same as those of 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, temperature of 37-40°C, trimebutine maleate, and resin in a weight ratio of 3-5:0.5.

[0039] Example 4

[0040] A trimebutine maleate resin complex sustained-release suspension, 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 to water, stirring to dissolve it to form a viscous liquid, then sequentially adding citric acid, propylene glycol, aspartame, methylparaben, lemon essence, and tartrazine to mix evenly, then adding the trimebutine maleate resin complex, stirring at a speed of 300 rpm for 30 minutes to mix evenly, filling into a HDPE bottle, 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 parts of lemon essence, 0.5 parts 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 to water, stirring to dissolve them to form a viscous liquid, then sequentially adding citric acid, propylene glycol, aspartame, methylparaben, lemon essence, and tartrazine to mix evenly, then adding the trimebutine maleate resin complex, stirring at a speed of 300 rpm for 30 minutes to mix evenly, filling into an HDPE bottle, and capping to obtain a 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 parts 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 to water, stirring to dissolve them to form a viscous liquid, then sequentially adding citric acid, propylene glycol, aspartame, methylparaben, lemon essence, and tartrazine to mix evenly, then adding the trimebutine maleate resin complex, stirring at a speed of 300 rpm for 30 minutes to mix evenly, filling into an HDPE bottle, and capping to obtain a trimebutine maleate resin complex sustained-release suspension.

[0048] Comparative Example 1

[0049] The xanthan gum was replaced with gelatin, and the rest was the same as in Example 4.

[0050] Comparative Example 2

[0051] The xanthan gum was replaced by guar gum, and the rest was the same as in Example 4.

[0052] Comparative Example 3

[0053] The xanthan gum was replaced with gelatin, and the rest was the same as in Example 5.

[0054] Comparative Example 4

[0055] The xanthan gum was replaced by guar gum, and the rest was the same as in Example 6.

[0056] The trimebutine maleate resin complex sustained-release suspensions prepared in Examples 4-6 and Comparative Examples 1-4 were taken to investigate their wall adhesion phenomenon, particle aggregation phenomenon and sedimentation volume ratio.

[0057] 1. Wall hanging experiment: The suspensions prepared in Examples 4-6 and Comparative Examples 1-4 were allowed to stand for 3 h, turned over 7-8 times, and placed on a horizontal table to observe whether there were particles hanging on the inner wall of the inner packaging bottle and whether the particles hanging on the inner wall would flow into the suspension.

[0058] It was observed that: the suspension of Example 4 had some particles hanging on the inner wall, which flowed into the suspension within 1 minute, while Examples 5-6 had no obvious wall hanging phenomenon; the suspensions of Comparative Examples 1-4 had more particles hanging on the inner wall, and more particles did not flow into the suspension within 1 minute.

[0059] 2. Aggregation of particles in the suspension will cause instability of the system and inaccurate content detection, so whether loose aggregates are generated in the suspension is detected. The specific steps include: taking the suspensions prepared in Examples 4-6 and Comparative Examples 1-4, turning them over 7-8 times, and letting them stand for 3 hours. A light source can be used to enhance the visibility of the visual method, and the light source is used to illuminate the suspension in the inner packaging bottle to observe whether there are loose aggregates.

[0060] It was found through observation that the suspensions of Examples 4-6 had no particle aggregation phenomenon, while the suspensions of Comparative Examples 1-4 had particle aggregation phenomenon.

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

[0062] The results are as follows: the sedimentation volume ratios of Examples 4-6 are 0.90, 0.93, and 0.98, respectively, all of which meet the requirements of the Pharmacopoeia (sedimentation volume ratio ≥ 0.90), while the sedimentation volume ratios of Comparative Examples 1-4 are all less than 0.90, which do not meet the requirements of the Pharmacopoeia.

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

[0064] The trimebutine maleate resin composite sustained-release suspension according to Examples 4-6 was subjected to a dissolution test.

[0065] The dissolution method is: paddle method 50rpm, sampling time is 2, 4, 6, 8, 10 and 12h, dissolution medium is 0.15M NaCl aqueous solution, medium volume is 900ml, temperature is 37℃. The timing starts when the sample is added, 10ml is sampled at the set time point, and the dissolution medium is added at the same temperature and volume. The sample is filtered to obtain the test solution, and the trimebutine content is detected. The results are as follows Figure 4 shown.

[0066] Figure 4 This is the dissolution curve of Example 4-6.

[0067] Depend on 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 gentle, close to "zero-order release"; the overall release time is about 10-12h, and the drug release period is significantly prolonged compared with conventional trimebutine preparations.

[0068] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by 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, 0-20 parts of tragacanth gum, 15-17 parts of citric acid, 4-6 parts of propylene glycol and 240-260 parts of water.

2. The trimebutine maleate resin complex sustained-release suspension according to claim 1, characterized in that: The resin used in the trimebutine maleate resin complex is a cation exchange resin.

3. The trimebutine maleate resin complex sustained-release suspension according to claim 1 or 2, characterized in that: The resin used in trimebutine maleate resin complex is IRP88 resin; preferably, The particle size of IRP88 resin is 400-600 μm.

4. The trimebutine maleate resin complex sustained-release suspension according to any one of claims 1 to 3, characterized in that: 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 separation, washing, and drying are performed to obtain the trimebutine maleate resin complex.

5. The trimebutine maleate resin complex sustained-release suspension according to claim 4, characterized in that: In the preparation process of trimebutine maleate resin complex, the weight ratio of trimebutine maleate to resin is 3-5:0.

5.

6. The trimebutine maleate resin complex sustained-release suspension according to claim 4, characterized in that: In the preparation process of trimebutine maleate resin complex, the concentration of trimebutine maleate solution is 30-50 mg / ml.

7. The trimebutine maleate resin complex sustained-release suspension according to claim 4, characterized in that: 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%.

8. The trimebutine maleate resin complex sustained-release suspension according to any one of claims 1 to 7, characterized in that: The raw materials of the suspension also include: sweetener, preservative, flavor and pigment.

9. The trimebutine maleate resin complex sustained-release suspension according to claim 8, characterized in that: 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.

10. A method for preparing the trimebutine maleate resin complex sustained-release suspension according to any one of claims 1 to 9, 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, then adding trimebutine maleate resin complex, stirring and mixing, and obtaining a trimebutine maleate resin complex sustained-release suspension; preferably, adding the trimebutine maleate resin complex, stirring and mixing at a speed of 250-350 rpm for 20-40 min.

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