Metoclopramide hydrochloride oral liquid and preparation method thereof

Abstract

The invention belongs to the technical field of medicine, and discloses metoclopramide hydrochloride oral liquid and a preparation method thereof.The metoclopramide hydrochloride oral liquid is prepared from 0.5 mg / ml to 1.5 mg / ml of metoclopramide hydrochloride, 1 mg / ml to 3 mg / ml of bacteriostatic agent, 1 mg / ml to 4 mg / ml of hydroxyethyl cellulose, 0.2 mg / ml to 1 mg / ml of sweetening agent, essence and water; the bacteriostatic agent is a mixture of hydroxypropyl methyl ester and propyl hydroxybenzoate; the sweetening agent is a mixture of stevioside and saccharin sodium salt. The metoclopramide hydrochloride oral solution prepared by the invention is simple in process, suitable for large-scale production and high in control degree of product quality, the stability and taste of the obtained product are better than those of commercially available products, and the effectiveness and compliance of taking medicines by patients are improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a metoclopramide hydrochloride oral solution and its preparation method. Background Technology

[0002] The statements herein merely provide background information related to the present invention and do not necessarily constitute prior art.

[0003] Metoclopramide dihydrochloride, an antiemetic, is a dopamine 2 (D2) receptor antagonist. Its chemical name is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide hydrochloride monohydrate. Clinically, it is primarily used as an injection, although syrup (oral solution) formulations are available in some countries.

[0004] Metoclopramide hydrochloride may cause serious neurological adverse reactions, including acute extrapyramidal symptoms and irreversible tardive dyskinesia. High doses increase the risk of acute dystonia, with higher risk in children than adults, and long-term use in the elderly increases the risk of tardive dyskinesia. There are numerous cases of overdose in children, therefore accurate administration is crucial. Oral solutions are more suitable for pediatric patients, facilitating precise dosing, and their palatable taste can improve medication adherence.

[0005] The formulation of metoclopramide hydrochloride oral solution includes metoclopramide hydrochloride, hydroxyethyl cellulose, sodium cyclamate, sodium saccharin, methylparaben, propylparaben, citric acid, apricot flavor, and purified water. However, during the stability period, the related substances in the above-mentioned metoclopramide hydrochloride oral solution increased significantly, and the content of these substances, as well as the content of preservatives and pH value, decreased to varying degrees, posing safety and efficacy risks to the product itself. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the purpose of this invention is to provide a metoclopramide hydrochloride oral solution and its preparation method.

[0007] To achieve the above objectives, the present invention is implemented through the following technical solution: In a first aspect, the present invention provides a metoclopramide hydrochloride oral solution, comprising the following components: metoclopramide hydrochloride 0.5-1.5 mg / ml, antibacterial agent 1-3 mg / ml, hydroxyethyl cellulose 1-4 mg / ml, sweetener 0.2-1 mg / ml, flavoring and water; The antibacterial agent is a mixture of methyl hydroxypropyl and propylparaben; The sweetener is a mixture of steviol glycosides and sodium saccharin.

[0008] Secondly, the present invention provides a method for preparing the metoclopramide hydrochloride oral solution, comprising the following steps: Under stirring conditions, the dispersion of hydroxyethyl cellulose was added to the antibacterial agent solution. After adjusting the pH value, sweetener, flavoring and metoclopramide hydrochloride were added in sequence, and the remaining water was added. Continue stirring until metoclopramide hydrochloride is completely dissolved to obtain metoclopramide hydrochloride oral solution.

[0009] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows: This invention provides a novel metoclopramide hydrochloride oral solution and its preparation method. Compared with existing compositions and preparation methods, the metoclopramide hydrochloride oral solution prepared by this invention has a simple process, is suitable for mass production, allows for high-level quality control, and the resulting product has better stability and taste than commercially available products, thus improving patient efficacy and compliance.

[0010] This invention conducts a systematic acidity study on reagents included in pharmacopoeias of various countries to determine the optimal pH range, thereby maximizing product stability. In addition, by comparing the materials of different packaging containers, the most cost-effective packaging container that can effectively guarantee product quality was identified.

[0011] By controlling the proportions of excipients methylparaben, propylparaben, and hydroxyethyl cellulose solvents during the production process, the antibacterial agent is completely dissolved, ensuring the product has high antibacterial efficacy. Furthermore, the dispersed solution is uniform and does not form clumps, thus avoiding the clogging of filter cartridges by insoluble matter during later filling, which would increase filtration pressure and affect production efficiency. This fundamentally improves product quality control and production efficiency.

[0012] In addition, by comparing and examining the storage time limits in different containers, it was determined that the product is not limited to a single container material, thus increasing the options available. Detailed Implementation

[0013] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0014] To address the issues of significant increases in related substances and varying degrees of decrease in content, preservative content, and pH value during the stability period of existing metoclopramide hydrochloride oral solutions, posing safety and efficacy risks, this invention provides a metoclopramide hydrochloride oral solution comprising the following components: metoclopramide hydrochloride 0.5-1.5 mg / ml, antibacterial agent 1-3 mg / ml, hydroxyethyl cellulose 1-4 mg / ml, sweetener 0.2-1 mg / ml, flavoring, and water; The antibacterial agent is a mixture of methyl hydroxypropyl and propylparaben; The sweetener is a mixture of steviol glycosides and sodium saccharin.

[0015] In some embodiments, the concentration of metoclopramide hydrochloride is 0.7-1.3 mg / ml, such as 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, etc.

[0016] In some embodiments, the mass ratio of propylparaben to methylparaben is 0.1-0.5:1-4.

[0017] Preferably, the mass ratio of propylparaben to hydroxyethylcellulose is 0.1-0.4:1-2.

[0018] More preferably, the concentration of propylparaben is 0.1-0.3 mg / ml, and the concentration of methylparaben is 1-1.5 mg / ml. For example, the concentration of propylparaben can be 0.1 mg / ml, 0.11 mg / ml, 0.12 mg / ml, 0.13 mg / ml, 0.14 mg / ml, 0.15 mg / ml, 0.16 mg / ml, 0.17 mg / ml, 0.18 mg / ml, 0.19 mg / ml, 0.20 mg / ml, 0.21 mg / ml, 0.22 mg / ml, 0.23 mg / ml, 0.24 mg / ml, 0.25 mg / ml, 0.26 mg / ml, 0.27 mg / ml, 0.28 mg / ml, 0.29 mg / ml, or 0.3 mg / ml.

[0019] The concentration of methylparaben can be 1 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml or 1.5 mg / ml.

[0020] More preferably, the concentration of propylparaben is 0.2 mg / ml and the concentration of methylparaben is 1.3 mg / ml.

[0021] In some embodiments, the concentration of hydroxyethyl cellulose is 2-3 mg / ml. For example, the concentration of hydroxyethyl cellulose can be 2 mg / ml, 2.1 mg / ml, 2.2 mg / ml, 2.3 mg / ml, 2.4 mg / ml, 2.5 mg / ml, 2.6 mg / ml, 2.7 mg / ml, 2.8 mg / ml, 2.9 mg / ml, or 3 mg / ml.

[0022] Preferably, the concentration of hydroxyethyl cellulose is 2.5 mg / ml.

[0023] In some embodiments, the mass ratio of steviol glycosides to sodium saccharin is 1-5:1-5.

[0024] Preferably, the mass ratio of steviol glycosides to sodium saccharin is 2-4:2-4.

[0025] More preferably, the concentration of steviol glycosides is 0.2-0.3 mg / ml, and the concentration of sodium saccharin is 0.2-0.3 mg / ml. For example, the concentration of steviol glycosides can be 0.2 mg / ml, 0.21 mg / ml, 0.22 mg / ml, 0.23 mg / ml, 0.24 mg / ml, 0.25 mg / ml, 0.26 mg / ml, 0.27 mg / ml, 0.28 mg / ml, 0.29 mg / ml, or 0.3 mg / ml; and the concentration of sodium saccharin can be 0.2 mg / ml, 0.21 mg / ml, 0.22 mg / ml, 0.23 mg / ml, 0.24 mg / ml, 0.25 mg / ml, 0.26 mg / ml, 0.27 mg / ml, 0.28 mg / ml, 0.29 mg / ml, or 0.3 mg / ml.

[0026] In some embodiments, the flavoring includes orange powder flavoring and apricot powder flavoring, wherein the concentration of orange powder flavoring is 0.02-0.04 mg / ml, and the concentration of apricot powder flavoring is 0.02-0.04 mg / ml. For example, the concentration of orange powder flavoring can be 0.02 mg / ml, 0.03 mg / ml, or 0.04 mg / ml; and the concentration of apricot powder flavoring can be 0.02 mg / ml, 0.03 mg / ml, or 0.04 mg / ml.

[0027] In some embodiments, a pH adjuster, wherein the pH adjuster is citric acid, is also included.

[0028] Preferably, citric acid is used to adjust the pH of the oral solution to 2-3, more preferably 2.4-3, and even more preferably 2.8-3. For example, the pH value can be 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.7, 2.8, 2.9, or 3; preferably 2.8, 2.9, or 3.

[0029] Secondly, the present invention provides a method for preparing the metoclopramide hydrochloride oral solution, comprising the following steps: Under stirring conditions, the dispersion of hydroxyethyl cellulose was added to the antibacterial agent solution, and sweetener, flavoring and metoclopramide hydrochloride were added in sequence, followed by the remaining water. Continue stirring until metoclopramide hydrochloride is completely dissolved, then adjust the pH value to obtain metoclopramide hydrochloride oral solution.

[0030] In some embodiments, the amount of water in the antibacterial agent solution is 20-40% of the total water volume of the oral liquid, preferably 25-35%. For example, it can be 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%.

[0031] Preferably, when preparing the antibacterial agent solution, the antibacterial agent is added to water, heated to 75-85℃, and stirred to dissolve for 30-50 minutes to obtain the antibacterial agent solution.

[0032] Optimizing the dissolution temperature and time of the antibacterial agent ensures complete dissolution, giving the product a high antibacterial efficacy.

[0033] In some embodiments, the amount of water in the hydroxyethyl cellulose dispersion is 60-70% of the total water volume of the oral liquid, such as 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70%.

[0034] Preferably, the amount of water in the hydroxyethyl cellulose dispersion is 65% of the total water volume of the oral solution.

[0035] Specifically, the prescription for the metoclopramide hydrochloride oral solution of the present invention is shown in Table 1: Table 1

[0036] The present invention will be further described below with reference to the embodiments.

[0037] Example 1 The composition of a batch of 12L metoclopramide hydrochloride oral solution is shown in Table 2 below: Table 2. Prescription composition of Example 1

[0038] The preparation method of the above-mentioned metoclopramide hydrochloride oral solution includes the following steps: (1) Add the antibacterial agents methylparaben and propylparaben sequentially to 30% purified water (water temperature 80±5 ℃), stir at 500 rpm for about 40 minutes to dissolve, and obtain solution one; (2) Add hydroxyethyl cellulose to 65% purified water outside the tank and stir at 700 rpm for about 25 minutes to disperse the hydroxyethyl cellulose evenly, to obtain dispersion one; (3) While stirring, add dispersion one to solution one, add sweetener, flavoring, raw materials, etc. in sequence, and add purified water to close to the predetermined amount. Continue stirring to make metoclopramide hydrochloride completely dissolved. (4) Divide the solution into 8 equal portions, and then add citric acid solution to adjust the pH value to the target value (2.0-2.5: 2.0 / 2.2 / 2.4; 2.5-6.0: 2.8 / 3.0 / 4.0 / 5.0 / 6.0) and finally bring the volume to a final level; (5) The water loss rate of the oral solution of metoclopramide hydrochloride was investigated by placing it in containers of different materials to determine the packaging material.

[0039] In each table, "high temperature" refers to placing the oral solution of metoclopramide hydrochloride at 60°C.

[0040] Illumination refers to applying the following illumination to the oral solution of metoclopramide hydrochloride: illuminance: 4500 Lx ± 500 Lx; total illuminance of the light source not less than 1,200,000 lux·hours; total energy of the near-ultraviolet lamp not less than 200 W·hr / m². 2 .

[0041] The content (%) refers to the amount of metoclopramide hydrochloride (C) in this product. 14 H 22 The mass percentage of ClN3O2HCl in the labeled amount should be 90.0%-110.0%.

[0042] Table 3 Results of oral solution content detection

[0043] Table 4. Results of pH test of oral solution

[0044] Table 5-1 Results of Related Substances Detection in Oral Solutions

[0045] Table 5-2 Results of Related Substances Detection in Oral Solutions

[0046] Table 6. Changes in water loss rate of oral solutions in different packaging containers under high temperature conditions (pH 2.8)

[0047] Example 2 The composition of a batch of 3L metoclopramide hydrochloride oral solution is shown in Table 7 below: Table 7. Prescription composition of Example 2

[0048] The preparation method of the above-mentioned metoclopramide hydrochloride oral solution includes the following steps: (1) Add the antibacterial agents methylparaben and propylparaben sequentially to 30% purified water (water temperature 80±5 ℃), stir at 500 rpm for about 40 minutes to dissolve, and obtain solution one; (2) Add hydroxyethyl cellulose to 65% purified water outside the tank and stir with a stirring paddle at 700 rpm to disperse the hydroxyethyl cellulose evenly, to obtain dispersion one; (3) While stirring, add dispersion one to solution one, add sweetener, flavoring, raw materials, etc. in sequence, and add purified water to close to the predetermined amount. Continue stirring to make metoclopramide hydrochloride completely dissolved.

[0049] (4) Divide into 4 equal parts, and add citric acid solution as a pH adjuster to adjust the pH value to the target value to each part.

[0050] Table 8 Results of Composition Content Detection

[0051] Table 9 pH test results of the composition

[0052] As can be seen from the preparation processes of the compositions in each embodiment, the compositions prepared in different batches can stably produce qualified products.

[0053] The results of the investigation of the influencing factors of the compositions of Examples 1 and 2 (with different acidities) under different conditions show that high temperature has a greater impact on the stability of the main components and antibacterial agents, while the effect of light is relatively small. In addition, the samples with higher pH values ​​have better stability at high temperatures.

[0054] High temperature significantly affects the stability of the main components and antibacterial agents, while the effect of light is relatively small (there is a slight decrease, but the magnitude is smaller than that under high temperature conditions). Samples with higher pH values ​​have better stability at high temperatures. Samples with pH 2.8-pH 3.0 even showed no change in content after light exposure. However, low pH samples (pH 2.0) are close to the lower limit of the standard and have potential risks. The stability of low pH samples needs to be monitored.

[0055] According to research, from a stability perspective, formulations with higher pH values ​​(such as pH 2.8-pH 3.0) should be preferred; considering cost, polyethylene packaging containers should be the preferred choice. If a lower pH formulation (such as pH 2.0) must be used, special attention should be paid to its stability under high-temperature storage conditions, especially the antibacterial agent content, and stricter storage conditions or stability monitoring should be ensured.

[0056] Comparative Example 1 To ensure complete dissolution of the antibacterial agent and guarantee product quality, the amount of solvent used was increased. A batch of 20L metoclopramide hydrochloride oral solution was prepared, and its composition is shown in the table below. Table 10 Comparative Example 1 Prescription Composition

[0057] The preparation method of the above-mentioned metoclopramide hydrochloride oral solution includes the following steps: (1) Add the antibacterial agents methylparaben and propylparaben sequentially to 70% of the prepared purified water (water temperature 80±5 ℃), stir at 500 rpm for 30 minutes to dissolve, and obtain solution one; (2) Add hydroxyethyl cellulose to approximately 25% purified water outside the tank, and slowly add it while stirring at 1200 rpm for about 100 minutes to disperse the hydroxyethyl cellulose evenly, to obtain dispersion one; (3) While stirring, add dispersion one to solution one, then add citric acid solution as a pH adjuster to adjust the pH value to the target value of 2.8. Then perform sieving.

[0058] (3) Add sweeteners, flavorings, raw materials, etc. in sequence, and add purified water to close to the predetermined amount. Continue stirring to dissolve metoclopramide hydrochloride completely, and finally adjust the volume.

[0059] Comparative Example 2 The composition of a batch of 20L metoclopramide hydrochloride oral solution is shown in the table below: Table 11. Composition of the prescription in Comparative Example 2

[0060] The preparation method of the above-mentioned metoclopramide hydrochloride oral solution includes the following steps: (1) Add the antibacterial agents methylparaben and propylparaben sequentially to 65% purified water (water temperature 80±5 ℃), stir at 500 rpm for 40 minutes to dissolve, and obtain solution one; (2) Add hydroxyethyl cellulose to 30% purified water outside the tank and stir at 1500 rpm for about 120 minutes to disperse the hydroxyethyl cellulose evenly, to obtain dispersion one; (3) While stirring, add dispersion one to solution one, then add citric acid solution as a pH adjuster to adjust the pH value to the target value of 2.8. Then perform sieving.

[0061] (3) Add sweeteners, flavorings, raw materials, etc. in sequence, and add purified water to close to the predetermined amount. Continue stirring to dissolve metoclopramide hydrochloride completely, and finally adjust the volume.

[0062] Table 12 Results of content and antibacterial agent content in Comparative Examples 1 and 2

[0063] Table 13 Results of the storage time observation of Comparative Example 1 in containers of different materials

[0064] Compared to Examples 1 and 2, the antibacterial agent content in Comparative Examples 1 and 2 did not differ significantly after increasing the amount of solvent. However, the amount of solvent used to dissolve hydroxyethyl cellulose was affected by the total volume. When dispersed in purified water, a large number of clumps formed, and the dispersion time was long. Even with increased rotation speed and slow stirring, transparent, insoluble, fine clumps still existed. Without sieving, the final metoclopramide hydrochloride oral solution would contain obvious clumps, affecting the product's properties. Sieving is feasible, but the process is relatively complex.

[0065] This process offers greater flexibility compared to different dispensing equipment (considering the characteristics of the excipients, the amount of solvent used to dissolve the key excipients is also crucial).

[0066] As can be seen from the examples and comparative examples, stable metoclopramide hydrochloride oral solutions can be prepared in Examples 1 and 2, Comparative Examples 1 and 2, and they have different selectivity for different dispensing equipment and a wider range of dispensing container materials.

[0067] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A metoclopramide hydrochloride oral solution, characterized in that: It includes the following components: metoclopramide hydrochloride 0.5-1.5 mg / ml, antibacterial agent 1-3 mg / ml, hydroxyethyl cellulose 1-4 mg / ml, sweetener 0.2-1 mg / ml, flavoring and water; The antibacterial agent is a mixture of methyl hydroxypropyl and propylparaben; The sweetener is a mixture of steviol glycosides and sodium saccharin.

2. The metoclopramide hydrochloride oral solution according to claim 1, characterized in that: The concentration of metoclopramide hydrochloride is 0.7-1.3 mg / ml.

3. The metoclopramide hydrochloride oral solution according to claim 1, characterized in that: The mass ratio of propylparaben to methylparaben is 0.1-0.5:1-4; Preferably, the mass ratio of propylparaben to hydroxyethylcellulose is 0.1-0.4:1-2; Preferably, the concentration of propylparaben is 0.1-0.3 mg / ml, and the concentration of methylparaben is 1-1.5 mg / ml; Preferably, the concentration of propylparaben is 0.2 mg / ml and the concentration of methylparaben is 1.3 mg / ml.

4. The metoclopramide hydrochloride oral solution according to claim 1, characterized in that: The concentration of hydroxyethyl cellulose is 2-3 mg / ml, preferably 2.5 mg / ml.

5. The metoclopramide hydrochloride oral solution according to claim 1, characterized in that: The mass ratio of steviol glycosides to sodium saccharin is 1-5:1-5; Preferably, the mass ratio of steviol glycosides to sodium saccharin is 2-4:2-4. Preferably, the concentration of steviol glycosides is 0.2-0.3 mg / ml, and the concentration of sodium saccharin is 0.2-0.3 mg / ml.

6. The metoclopramide hydrochloride oral solution according to claim 1, characterized in that: The flavorings include orange powder flavoring and apricot powder flavoring, with the concentration of orange powder flavoring being 0.02-0.04 mg / ml and the concentration of apricot powder flavoring being 0.02-0.04 mg / ml.

7. The metoclopramide hydrochloride oral solution according to claim 1, characterized in that: It also includes a pH adjuster, wherein the pH adjuster is citric acid, and the pH of the oral solution is adjusted to 2-3, preferably 2.4-3, and more preferably 2.8-3, using citric acid.

8. The method for preparing the metoclopramide hydrochloride oral solution according to any one of claims 1-7, characterized in that: Includes the following steps: Under stirring conditions, the dispersion of hydroxyethyl cellulose was added to the antibacterial agent solution, and sweetener, flavoring and metoclopramide hydrochloride were added in sequence, followed by the remaining water. Continue stirring until metoclopramide hydrochloride is completely dissolved, then adjust the pH value to obtain metoclopramide hydrochloride oral solution.

9. The method for preparing metoclopramide hydrochloride oral solution according to claim 8, characterized in that: The amount of water in the antibacterial agent solution is 20-40% of the total water volume of the oral liquid, preferably 25-35%.

10. The method for preparing metoclopramide hydrochloride oral solution according to claim 8, characterized in that: The amount of water in the hydroxyethyl cellulose dispersion is 60-70% of the total water volume of the oral solution. Preferably, the amount of water in the hydroxyethyl cellulose dispersion is 65% of the total water volume of the oral solution.

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