A high-stability cycloester erythromycin dry suspension and a preparation method thereof

Abstract

The application provides a high-stability cycloester erythromycin dry suspension and a preparation method thereof. The preparation method comprises the following steps: S1, adding hydroxypropyl-beta-cyclodextrin, mannitol, sucrose and lactose into a polyvinyl alcohol solution, stirring and uniformly mixing to prepare a mixture A; S2, adding low-substitution hydroxypropyl cellulose, sodium dodecyl sulfate, acesulfame potassium and vanillin into a xanthan gum solution, stirring and uniformly mixing to prepare a mixture B; S3, stirring and uniformly mixing the cycloester erythromycin, the mixture A and the mixture B to prepare a mixture; S4, preparing a soft material from the mixture, sieving, granulating, drying, whole-granulating and sub-packaging to obtain the high-stability cycloester erythromycin dry suspension. Through the method, the cycloester erythromycin is stably adsorbed with the mixture A and the mixture B to form a stable drug mixture, which is easy to disperse and stable in water, and the degradation of the cycloester erythromycin in the later storage process is effectively avoided, the storage stability is improved, and the bioavailability is high.

Description

Technical Field

[0001] This invention relates to the field of drug preparation technology, and in particular to a highly stable cyclic erythromycin dry suspension and its preparation method. Background Technology

[0002] Influenza is an acute respiratory illness caused by the influenza virus, and it is more prevalent in winter and spring. Influenza typically presents with an acute onset, with fatigue in the prodromal period, quickly followed by high fever (39℃~40℃), chills, headache, and systemic symptoms such as muscle and joint pain. It may or may not be accompanied by local symptoms such as nasal congestion, runny nose, sore throat, dry cough, retrosternal discomfort, facial flushing, and conjunctival congestion. The course of influenza is usually 4–7 days, but in a few patients, the cough may persist for several weeks. Influenza can affect the respiratory tract, potentially causing inflammation of the tonsils, throat, and lungs, leading to conditions such as tonsillitis and pneumonia. Cycloerythromycin ester, an 11,12-carbonate derivative of erythromycin, is a semi-synthetic derivative of erythromycin and can treat bacterial pneumonia, tonsillitis, pharyngitis, and mycoplasma pneumonia. Appropriate use of cycloerythromycin ester can effectively relieve these symptoms. Currently, cycloerythromycin ester is available in tablet, capsule, and dry suspension formulations. Tablets and capsules are difficult for children to swallow and have a noticeable bitter taste, making them less acceptable. Dry suspensions are suitable for children and those with swallowing difficulties. They can be taken by dissolving the medication in water, making them convenient. However, current dry suspensions suffer from poor stability due to inadequate manufacturing processes. They are prone to degradation during storage and have poor dispersibility in water, easily agglomerating, which makes them inconvenient to take. Summary of the Invention

[0003] In view of this, the present invention proposes a highly stable cyclic erythromycin dry suspension and its preparation method.

[0004] The technical solution of this invention is implemented as follows:

[0005] A method for preparing a highly stable cyclic erythromycin dry suspension includes the following steps:

[0006] S1. Prepare a polyvinyl alcohol solution by preparing polyvinyl alcohol. Add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir for 5-7 minutes at a speed of 100-150 r / min. Then add mannitol, sucrose, and lactose and stir and mix at a speed of 300-500 r / min. Dry and pulverize through an 80-100 mesh sieve to obtain mixture A.

[0007] S2. Prepare xanthan gum solution. Add low-substituted hydroxypropyl cellulose and sodium dodecyl sulfate to xanthan gum solution and stir for 4-6 minutes at a speed of 200-300 r / min. Then add acesulfame potassium and vanillin and stir and mix at a speed of 500-600 r / min. Dry, pulverize and pass through an 80-100 mesh sieve to obtain mixture B.

[0008] S3. Mix cyclic erythromycin with mixture A and mixture B at a speed of 800-1000 r / min, dry, pulverize, and pass through an 80-100 mesh sieve to obtain a mixture;

[0009] S4. Wet the mixture evenly with ethanol solution to obtain a soft material, then granulate it through a 20-30 mesh sieve to obtain wet granules. Dry the wet granules, granulate them through a 30-40 mesh sieve, and package them to obtain a high-stability cyclic erythromycin dry suspension.

[0010] Furthermore, in step S1, the concentration of the polyvinyl alcohol solution is 40-50 wt%.

[0011] Furthermore, in steps S1 and S2, the drying temperature is 40-50°C.

[0012] Furthermore, in step S2, the concentration of the xanthan gum solution is 40-50 wt%.

[0013] Furthermore, in step S4, the concentration of the ethanol solution is 50-60 wt%.

[0014] Furthermore, in step S4, the drying process involves first drying at 35-40℃ for 1-1.5 hours, and then raising the temperature to 45-60℃ to dry until the moisture content is ≤1.2%.

[0015] A highly stable cyclic erythromycin dry suspension prepared by the preparation method described in this invention.

[0016] Furthermore, the highly stable cyclic erythromycin dry suspension comprises the following raw materials in parts by weight: 7-9 parts cyclic erythromycin, 10-13 parts hydroxypropyl-β-cyclodextrin, 5-8 parts mannitol, 4-7 parts polyvinyl alcohol, 6-10 parts xanthan gum, 5-8 parts low-substituted hydroxypropyl cellulose, 0.8-1.2 parts sodium dodecyl sulfate, 60-72 parts sucrose, 7-9 parts lactose, 1-3 parts acesulfame potassium, and 0.2-1.0 parts vanillin.

[0017] Compared with the prior art, the beneficial effects of the present invention are:

[0018] This invention prepares mixture A and mixture B according to reasonable process conditions, and then mixes cyclic erythromycin with mixtures A and B at a suitable stirring speed. This allows cyclic erythromycin to be stably adsorbed into mixtures A and B, forming a stable drug mixture. This effectively avoids rapid degradation of cyclic erythromycin during later storage, improves stability, and is beneficial for long-term storage. Furthermore, preparing mixtures A and B under suitable ultrasonic processing conditions reduces the surface energy of the pharmaceutical excipients for cyclic erythromycin, ultimately reducing the adsorption between cyclic erythromycin dry suspension drug particles. This effectively prevents aggregation and sedimentation of cyclic erythromycin dry suspension drug particles, making the suspension easier to disperse evenly in water, and also making the suspension more stable and easier to take. The cyclic erythromycin dry suspension prepared by the method of this invention can also effectively mask its bitterness, improving drug compliance. Detailed Implementation

[0019] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0020] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0021] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0022] Example 1

[0023] The high-stability cyclic erythromycin dry suspension of this embodiment comprises the following raw materials in parts by weight: 8.5 parts cyclic erythromycin, 12 parts hydroxypropyl-β-cyclodextrin, 7 parts mannitol, 7 parts polyvinyl alcohol, 9 parts xanthan gum, 7 parts low-substituted hydroxypropyl cellulose, 1.0 part sodium dodecyl sulfate, 72 parts sucrose, 8 parts lactose, 3 parts acesulfame potassium, and 0.8 parts vanillin.

[0024] The preparation method of this highly stable cyclic erythromycin dry suspension includes the following steps:

[0025] S1. Prepare a 45wt% polyvinyl alcohol solution. Add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir for 5 minutes at 100 r / min. Then add mannitol, sucrose, and lactose and stir at 400 r / min until well mixed. Dry at 50℃ and pulverize through a 100-mesh sieve to obtain mixture A.

[0026] S2. Prepare a xanthan gum solution with a concentration of 40 wt%. Add low-substituted hydroxypropyl cellulose and sodium dodecyl sulfate to the xanthan gum solution and stir for 5 min at a speed of 300 r / min. Then add acesulfame potassium and vanillin and stir and mix at a speed of 500 r / min. Dry at a temperature of 45℃, pulverize, and pass through a 100-mesh sieve to obtain mixture B.

[0027] S3. Mix cycloerythromycin with mixture A and mixture B at a speed of 900 r / min, dry at a temperature of 50℃, pulverize, and pass through an 80-mesh sieve to obtain a mixture;

[0028] S4. The mixture is wetted evenly with a 60wt% ethanol solution to obtain a soft material, which is then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 40℃ for 1.5h, and then the temperature is raised to 50℃ to dry until the moisture content is ≤1.2%. The granules are then sieved through a 40-mesh sieve for granulation and packaged to obtain a high-stability cyclic erythromycin dry suspension.

[0029] Example 2

[0030] The high-stability cyclic erythromycin dry suspension of this embodiment comprises the following raw materials in parts by weight: 8.1 parts cyclic erythromycin, 13 parts hydroxypropyl-β-cyclodextrin, 5 parts mannitol, 4 parts polyvinyl alcohol, 8 parts xanthan gum, 6 parts low-substituted hydroxypropyl cellulose, 0.9 parts sodium dodecyl sulfate, 68 parts sucrose, 7 parts lactose, 2 parts acesulfame potassium, and 1.0 part vanillin.

[0031] The preparation method of this highly stable cyclic erythromycin dry suspension includes the following steps:

[0032] S1. Prepare a 43wt% polyvinyl alcohol solution. Add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir for 6 minutes at 150 r / min. Then add mannitol, sucrose, and lactose and stir at 300 r / min until well mixed. Dry at 45℃ and pulverize through an 80-mesh sieve to obtain mixture A.

[0033] S2. Prepare a xanthan gum solution with a concentration of 48wt%. Add low-substituted hydroxypropyl cellulose and sodium dodecyl sulfate to the xanthan gum solution and stir for 4 minutes at a speed of 200 r / min. Then add acesulfame potassium and vanillin and stir and mix at a speed of 550 r / min. Dry at a temperature of 50℃, pulverize, and pass through an 80-mesh sieve to obtain mixture B.

[0034] S3. Mix cycloerythromycin with mixture A and mixture B at a speed of 800 r / min, dry at a temperature of 40℃, pulverize, and pass through an 80-mesh sieve to obtain a mixture;

[0035] S4. The mixture is wetted evenly with a 58wt% ethanol solution to obtain a soft material, which is then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35℃ for 1.5h, and then the temperature is raised to 60℃ to dry until the moisture content is ≤1.2%. The granules are then sieved through a 40-mesh sieve, packaged, and the highly stable cyclic erythromycin dry suspension is obtained.

[0036] Example 3

[0037] The high-stability cyclic erythromycin dry suspension of this embodiment comprises the following raw materials in parts by weight: 8 parts cyclic erythromycin, 11.5 parts hydroxypropyl-β-cyclodextrin, 8 parts mannitol, 5 parts polyvinyl alcohol, 7 parts xanthan gum, 8 parts low-substituted hydroxypropyl cellulose, 1.2 parts sodium dodecyl sulfate, 60 parts sucrose, 8 parts lactose, 3 parts acesulfame potassium, and 0.5 parts vanillin.

[0038] The preparation method of this highly stable cyclic erythromycin dry suspension includes the following steps:

[0039] S1. Prepare a 45wt% polyvinyl alcohol solution. Add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir for 7 minutes at 100 r / min. Then add mannitol, sucrose, and lactose and stir at 450 r / min until well mixed. Dry at 45℃ and pulverize through a 100-mesh sieve to obtain mixture A.

[0040] S2. Prepare a xanthan gum solution with a concentration of 45 wt%. Add low-substituted hydroxypropyl cellulose and sodium dodecyl sulfate to the xanthan gum solution and stir for 6 min at a speed of 250 r / min. Then add acesulfame potassium and vanillin and stir and mix at a speed of 500 r / min. Dry at a temperature of 45℃, pulverize, and pass through a 100-mesh sieve to obtain mixture B.

[0041] S3. Mix cycloerythromycin with mixture A and mixture B at a speed of 950 r / min, dry at a temperature of 45℃, pulverize, and pass through an 80-mesh sieve to obtain a mixture;

[0042] S4. The mixture is wetted evenly with a 50wt% ethanol solution to obtain a soft material, which is then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 40℃ for 1 hour, and then the temperature is raised to 45℃ to dry until the moisture content is ≤1.2%. The granules are then sieved through a 40-mesh sieve for granulation and packaged to obtain a high-stability cyclic erythromycin dry suspension.

[0043] Example 4

[0044] The high-stability cyclic erythromycin dry suspension of this embodiment comprises the following raw materials in parts by weight: 8.2 parts cyclic erythromycin, 10 parts hydroxypropyl-β-cyclodextrin, 6 parts mannitol, 6 parts polyvinyl alcohol, 10 parts xanthan gum, 5 parts low-substituted hydroxypropyl cellulose, 1.0 part sodium dodecyl sulfate, 65 parts sucrose, 9 parts lactose, 1 part acesulfame potassium, and 0.9 parts vanillin.

[0045] The preparation method of this highly stable cyclic erythromycin dry suspension includes the following steps:

[0046] S1. Prepare a 50wt% polyvinyl alcohol solution. Add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir for 6 minutes at 150 r / min. Then add mannitol, sucrose, and lactose and stir at 500 r / min until well mixed. Dry at 40℃ and pulverize through an 80-mesh sieve to obtain mixture A.

[0047] S2. Prepare a xanthan gum solution with a concentration of 45wt%. Add low-substituted hydroxypropyl cellulose and sodium dodecyl sulfate to the xanthan gum solution and stir for 5 minutes at a speed of 280 r / min. Then add acesulfame potassium and vanillin and stir and mix at a speed of 600 r / min. Dry at a temperature of 40℃, pulverize, and pass through an 80-mesh sieve to obtain mixture B.

[0048] S3. Mix cycloerythromycin with mixture A and mixture B at a speed of 1000 r / min, dry at a temperature of 50℃, pulverize, and pass through an 80-mesh sieve to obtain a mixture;

[0049] S4. The mixture is wetted evenly with a 55wt% ethanol solution to obtain a soft material, which is then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35℃ for 1.0h, and then the temperature is raised to 50℃ to dry until the moisture content is ≤1.2%. The granules are then sieved through a 40-mesh sieve, packaged, and the highly stable cyclic erythromycin dry suspension is obtained.

[0050] Comparative Example 1

[0051] The difference between this comparative example and Example 4 is that the preparation steps of S1 are changed, while the rest are the same as in Example 4.

[0052] The preparation method of the highly stable cyclic erythromycin dry suspension in this comparative example includes the following steps:

[0053] S1. Prepare a xanthan gum solution with a concentration of 45wt%. Add low-substituted hydroxypropyl cellulose and sodium dodecyl sulfate to the xanthan gum solution and stir for 5 minutes at a speed of 280 r / min. Then add acesulfame potassium and vanillin and stir and mix at a speed of 600 r / min. Dry at a temperature of 40℃, pulverize, and pass through an 80-mesh sieve to obtain mixture B.

[0054] S2. Cycloerythromycin ester is mixed with hydroxypropyl-β-cyclodextrin, mannitol, sucrose, lactose, polyvinyl alcohol, and mixture B at a speed of 700 r / min, dried at 50℃, pulverized, and passed through an 80-mesh sieve to obtain the mixture.

[0055] S3. The mixture is wetted evenly with a 55wt% ethanol solution to obtain a soft material, which is then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35℃ for 1.0h, and then the temperature is raised to 50℃ to dry until the moisture content is ≤1.2%. The granules are then sieved through a 40-mesh sieve, packaged, and the highly stable cyclic erythromycin dry suspension is obtained.

[0056] Comparative Example 2

[0057] The difference between this comparative example and Example 4 is that the preparation steps of S2 are changed, while the rest remains the same as in Example 4.

[0058] The preparation method of the highly stable cyclic erythromycin dry suspension in this comparative example includes the following steps:

[0059] S1. Prepare a 50wt% polyvinyl alcohol solution. Add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir for 6 minutes at 150 r / min. Then add mannitol, sucrose, and lactose and stir at 500 r / min until well mixed. Dry at 40℃ and pulverize through an 80-mesh sieve to obtain mixture A.

[0060] S2. Erythromycin cyclophosphamide, mixed with mixture A, xanthan gum, low-substituted hydroxypropyl cellulose, sodium lauryl sulfate, acesulfame potassium, and vanillin are stirred and mixed at a speed of 600 r / min, dried at a temperature of 50℃, pulverized, and passed through an 80-mesh sieve to obtain the mixture.

[0061] S3. The mixture is wetted evenly with a 55wt% ethanol solution to obtain a soft material, which is then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35℃ for 1.0h, and then the temperature is raised to 50℃ to dry until the moisture content is ≤1.2%. The granules are then sieved through a 40-mesh sieve, packaged, and the highly stable cyclic erythromycin dry suspension is obtained.

[0062] Comparative Example 3

[0063] The difference between this comparative example and Example 4 is that the entire preparation process has been changed, while the rest remains the same as Example 4.

[0064] The preparation method of the highly stable cyclic erythromycin dry suspension in this comparative example includes the following steps:

[0065] S1. Erythromycin cyclophosphamide, hydroxypropyl-β-cyclodextrin, mannitol, sucrose, lactose, polyvinyl alcohol, xanthan gum, low-substituted hydroxypropyl cellulose, sodium lauryl sulfate, acesulfame potassium, and vanillin are stirred and mixed at 1000 r / min, dried at 50℃, pulverized, and passed through an 80-mesh sieve to obtain a mixture.

[0066] S2. The mixture is wetted evenly with a 55wt% ethanol solution to obtain a soft material, which is then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35℃ for 1.0h, and then the temperature is raised to 50℃ to dry until the moisture content is ≤1.2%. The granules are then sieved through a 40-mesh sieve, packaged, and the highly stable cyclic erythromycin dry suspension is obtained.

[0067] The high-stability cyclic erythromycin dry suspensions prepared in Examples 1-4 and Comparative Examples 1-3 were subjected to performance tests.

[0068] The cyclic erythromycin dry suspensions prepared in Examples 1-4 and Comparative Examples 1-3 of this invention were packaged in aluminum-plastic film and placed at a temperature of 40±2℃ and a relative humidity of 75±5% for 6 months. Samples were taken at day 0, month 3, and month 6 to test the volumetric sedimentation ratio and the loss on drying after 6 months. The volumetric sedimentation ratio was determined according to the Chinese Pharmacopoeia 2020 Edition, Part IV - "0123 Oral Solutions, Oral Suspensions, Oral Emulsions", with a dry suspension to water ratio of 1:50 g / mL in the test samples. The loss on drying was determined according to the Chinese Pharmacopoeia 2020 Edition, Part IV - "0831 Loss on Drying Determination Method". The results are shown in Table 1 below.

[0069] Table 1 Performance test results of erythromycin cyclophosphamide dry suspension

[0070]

[0071] The above results indicate that the cyclic erythromycin dry suspensions prepared by the methods of Examples 1-4 of this invention have high stability, and the loss on drying after 6 months of storage also meets the corresponding requirements. Compared with Example 4, Comparative Examples 1-3 changed the preparation steps of the cyclic erythromycin dry suspensions, affecting the dispersion performance between cyclic erythromycin and raw materials such as hydroxypropyl-β-cyclodextrin, mannitol, polyvinyl alcohol, xanthan gum, and low-substituted hydroxypropyl cellulose, resulting in decreased stability, and the sedimentation volume ratio and loss on drying did not meet the requirements.

[0072] In addition, the in vitro dissolution rates of the cyclic erythromycin dry suspensions prepared in Examples 1-4 of this invention all met the requirements, and the bioavailability was high.

[0073] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of a high stability cyciic ester erythromycin dry suspension characterized in that, Includes the following steps: S1. Prepare a polyvinyl alcohol solution by preparing polyvinyl alcohol. Add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir for 5-7 minutes at a speed of 100-150 r / min. Then add mannitol, sucrose, and lactose and stir and mix at a speed of 300-500 r / min. Dry and pulverize through an 80-100 mesh sieve to obtain mixture A. S2. Prepare xanthan gum solution. Add low-substituted hydroxypropyl cellulose and sodium dodecyl sulfate to xanthan gum solution and stir for 4-6 minutes at a speed of 200-300 r / min. Then add acesulfame potassium and vanillin and stir and mix at a speed of 500-600 r / min. Dry, pulverize and pass through an 80-100 mesh sieve to obtain mixture B. S3. Mix cyclic erythromycin with mixture A and mixture B at a speed of 800-1000 r / min, dry, pulverize, and pass through an 80-100 mesh sieve to obtain a mixture; S4. Wet the mixture evenly with ethanol solution to obtain a soft material, then granulate it through a 20-30 mesh sieve to obtain wet granules. Dry the wet granules, granulate them through a 30-40 mesh sieve, and package them to obtain a high-stability cyclic erythromycin dry suspension.

2. A process for the preparation of a high stability suspension of a cyclic ester erythromycin as claimed in claim 1, characterized in that, In step S1, the concentration of the polyvinyl alcohol solution is 40-50 wt%.

3. A process for the preparation of a high stability suspension of a cyclic ester erythromycin as claimed in claim 1, characterized in that, In steps S1 and S2, the drying temperature is 40-50℃.

4. The method for preparing the highly stable cyclic erythromycin dry suspension according to claim 1, characterized in that, In step S2, the concentration of the xanthan gum solution is 40-50 wt%.

5. The method for preparing the highly stable cyclic erythromycin dry suspension according to claim 1, characterized in that, In step S4, the concentration of the ethanol solution is 50-60 wt%.

6. The method for preparing the highly stable cyclic erythromycin dry suspension according to claim 1, characterized in that, In step S4, the drying process involves first drying at 35-40℃ for 1-1.5 hours, and then raising the temperature to 45-60℃ to dry until the moisture content is ≤1.2%.

7. The method for preparing the highly stable cyclic erythromycin dry suspension according to any one of claims 1-6, characterized in that, The cyclic erythromycin dry suspension comprises the following raw materials in parts by weight: 7-9 parts cyclic erythromycin, 10-13 parts hydroxypropyl-β-cyclodextrin, 5-8 parts mannitol, 4-7 parts polyvinyl alcohol, 6-10 parts xanthan gum, 5-8 parts low-substituted hydroxypropyl cellulose, 0.8-1.2 parts sodium dodecyl sulfate, 60-72 parts sucrose, 7-9 parts lactose, 1-3 parts acesulfame potassium, and 0.2-1.0 parts vanillin.

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