High-stability erythromycin cyclic ester dry suspension and preparation method thereof

Abstract

The invention provides a high-stability erythromycin cyclic ester 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, and uniformly stirring and mixing to prepare a mixture A; s2, adding low-substituted hydroxypropyl cellulose, lauryl sodium sulfate, acesulfame potassium and vanillin into the xanthan gum solution, and uniformly stirring and mixing to prepare a mixture B; s3, uniformly stirring and mixing erythromycin cydocarbonate with the mixture A and the mixture B to prepare a mixture; and S4, preparing a soft material from the mixture, sieving and granulating to obtain wet particles, drying, finishing the particles, and sub-packaging to obtain the high-stability erythromycin cydocarbonate dry suspension. According to the method disclosed by the invention, the erythromycin cyclamate, the mixture A and the mixture B are stably adsorbed to form a stable medicine mixture, the stable medicine mixture is easy to disperse and stabilize in water, meanwhile, rapid degradation of the erythromycin cyclamate in the later storage process is also effectively avoided, the storage stability is improved, and the bioavailability is also high.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a high-stability cyclic erythromycin dry suspension and a preparation method thereof. Background Art

[0002] Influenza is an acute respiratory disease caused by influenza virus, which is common in winter and spring. Influenza generally presents with acute onset, fatigue symptoms in the prodromal period, and systemic poisoning symptoms such as high fever (up to 39℃~40℃), chills, chills, headache, and sore muscles and joints all over the body will soon appear, which may be accompanied by or without local symptoms such as nasal congestion, runny nose, sore throat, dry cough, discomfort behind the sternum, facial flushing, and conjunctival congestion. The course of influenza is usually 4 to 7 days, and a few patients may have coughs for several weeks. Influenza can affect the respiratory tract and may cause inflammation of the tonsils, throat, lungs, etc., thereby inducing tonsillitis, pneumonia, etc. Cyclic erythromycin is erythromycin ring 11,12-carbonate, a semi-synthetic derivative of erythromycin, which can treat bacterial pneumonia, tonsillitis, pharyngitis, mycoplasma pneumonia, etc. Appropriate use of cyclic erythromycin can effectively relieve the above symptoms. Currently, the drug dosage forms of cyclic erythromycin on the market include tablets, capsules, and dry suspensions. Tablets and capsules are difficult for children to swallow and can taste bitter, so they are not well accepted. Dry suspensions are suitable for children and people with difficulty swallowing. They can be taken after being dissolved in water, which is convenient to use. However, due to unreasonable process conditions, the current dry suspensions have poor stability, are easily degraded during storage, and have poor dispersion in water, and are prone to agglomeration, which makes them inconvenient to take. Summary of the invention

[0003] In view of this, the present invention provides a high-stability cyclic erythromycin dry suspension and a preparation method thereof.

[0004] The technical solution of the present invention is achieved in this way:

[0005] A method for preparing a high-stability cyclic erythromycin dry suspension comprises the following steps:

[0006] S1. Prepare polyvinyl alcohol into a polyvinyl alcohol solution, add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir at a speed of 100-150 r / min for 5-7 min, then add mannitol, sucrose and lactose and stir at a speed of 300-500 r / min to mix, dry, and grind through an 80-100 mesh sieve to obtain a mixture A;

[0007] S2, preparing xanthan gum into a xanthan gum solution, taking low-substituted hydroxypropyl cellulose and sodium lauryl sulfate and adding them into the xanthan gum solution, stirring at a speed of 200-300 r / min for 4-6 min, then adding acesulfame potassium and vanillin, stirring and mixing at a speed of 500-600 r / min, drying, crushing, and passing through an 80-100 mesh sieve to obtain a mixture B;

[0008] S3, stirring and mixing erythromycin cyclohexetate with mixture A and mixture B at a rotation speed of 800-1000 r / min, drying, crushing, and passing through an 80-100 mesh sieve to obtain a mixture;

[0009] S4. The mixture is uniformly moistened with ethanol solution to obtain a soft material, and then granulated through a 20-30 mesh sieve to obtain wet granules. The wet granules are dried, sieved through a 30-40 mesh sieve to obtain whole granules, and packaged 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 step S1 and step S2, the drying temperature is 40-50°C.

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

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

[0014] Furthermore, in step S4, the drying is first performed at 35-40°C for 1-1.5 hours, and then the temperature is raised to 45-60°C and dried until the moisture content is ≤1.2%.

[0015] The high-stability cyclic erythromycin dry suspension prepared by the preparation method of the invention.

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

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] The present invention prepares mixture A and mixture B according to reasonable process conditions, and then lowers the cyclic erythromycin drug and mixes with mixture A and mixture B at a suitable stirring speed, so that cyclic erythromycin is stably adsorbed with mixture A and mixture B to form a stable drug mixture, effectively avoiding the rapid degradation of cyclic erythromycin in the later storage process, improving stability, and being conducive to long-term storage. In addition, mixture A and mixture B are first prepared under suitable ultrasonic process conditions, which can reduce the surface energy of cyclic erythromycin pharmaceutical excipients, and finally reduce the adsorption between cyclic erythromycin dry suspension drug particles, effectively avoiding aggregation and sedimentation between cyclic erythromycin dry suspension drug particles, making the suspension easier to be evenly dispersed in water, and also making the suspension more stable, which is convenient for taking. The cyclic erythromycin dry suspension prepared by the method of the present invention can also effectively cover its bitter taste and improve the compliance of drug taking. DETAILED DESCRIPTION

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

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

[0021] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0022] Example 1

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

[0024] The preparation method of the high-stability cyclic erythromycin dry suspension comprises the following steps:

[0025] S1, polyvinyl alcohol is prepared into a polyvinyl alcohol solution with a concentration of 45wt%, hydroxypropyl-β-cyclodextrin is added to the polyvinyl alcohol solution and stirred at a speed of 100r / min for 5min, then mannitol, sucrose and lactose are added and stirred at a speed of 400r / min, dried at a temperature of 50°C, and crushed through a 100-mesh sieve to obtain a mixture A;

[0026] S2, preparing xanthan gum into a xanthan gum solution with a concentration of 40wt%, adding low-substituted hydroxypropyl cellulose and sodium lauryl sulfate to the xanthan gum solution and stirring at a speed of 300r / min for 5min, then adding acesulfame potassium and vanillin and stirring and mixing at a speed of 500r / min, drying at a temperature of 45°C, crushing, and passing through a 100-mesh sieve to obtain a mixture B;

[0027] S3, stirring and mixing erythromycin cyclohexetate with mixture A and mixture B at a rotation speed of 900 r / min, drying at a temperature of 50° C., crushing, and passing through an 80-mesh sieve to obtain a mixture;

[0028] S4. The mixture is uniformly moistened with 60wt% ethanol solution to obtain a soft material, and then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 40°C for 1.5h, and then dried at 50°C to a moisture content of ≤1.2%. The granules are sieved through a 40-mesh sieve and packaged to obtain a high-stability cyclic erythromycin dry suspension.

[0029] Example 2

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

[0031] The preparation method of the high-stability cyclic erythromycin dry suspension comprises the following steps:

[0032] S1. Prepare a polyvinyl alcohol solution with a concentration of 43 wt %, add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir at a speed of 150 r / min for 6 min, then add mannitol, sucrose and lactose and stir and mix at a speed of 300 r / min, dry at a temperature of 45° C., and crush through an 80-mesh sieve to obtain a mixture A;

[0033] S2, preparing xanthan gum into a xanthan gum solution with a concentration of 48 wt%, taking low-substituted hydroxypropyl cellulose and sodium lauryl sulfate and adding them to the xanthan gum solution, stirring at a speed of 200 r / min for 4 min, then adding acesulfame potassium and vanillin and stirring and mixing at a speed of 550 r / min, drying at a temperature of 50° C., crushing, and passing through an 80-mesh sieve to obtain a mixture B;

[0034] S3, stirring and mixing erythromycin cyclohexetate with mixture A and mixture B at a rotation speed of 800 r / min, drying at a temperature of 40° C., crushing, and passing through an 80-mesh sieve to obtain a mixture;

[0035] S4. The mixture is uniformly moistened with an ethanol solution having a concentration of 58 wt% to obtain a soft material, and then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35° C. for 1.5 h, and then heated to 60° C. and dried to a moisture content of ≤1.2%. The granules are sieved through a 40-mesh sieve and packaged to obtain a high-stability cyclic erythromycin dry suspension.

[0036] Example 3

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

[0038] The preparation method of the high-stability cyclic erythromycin dry suspension comprises the following steps:

[0039] S1, polyvinyl alcohol is prepared into a polyvinyl alcohol solution with a concentration of 45wt%, hydroxypropyl-β-cyclodextrin is added to the polyvinyl alcohol solution and stirred at a speed of 100r / min for 7min, and then mannitol, sucrose and lactose are added and stirred at a speed of 450r / min, dried at a temperature of 45°C, and crushed through a 100-mesh sieve to obtain a mixture A;

[0040] S2, preparing xanthan gum into a xanthan gum solution with a concentration of 45wt%, adding low-substituted hydroxypropyl cellulose and sodium lauryl sulfate to the xanthan gum solution, stirring at a speed of 250r / min for 6min, then adding acesulfame potassium and vanillin, stirring and mixing at a speed of 500r / min, drying at a temperature of 45°C, crushing, and passing through a 100-mesh sieve to obtain a mixture B;

[0041] S3, stirring and mixing erythromycin cyclohexetate, mixed material A and mixed material B at a rotation speed of 950 r / min, drying at a temperature of 45° C., crushing, and passing through an 80-mesh sieve to obtain a mixture;

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

[0043] Example 4

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

[0045] The preparation method of the high-stability cyclic erythromycin dry suspension comprises the following steps:

[0046] S1. Prepare polyvinyl alcohol into a polyvinyl alcohol solution with a concentration of 50 wt%, add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir at a speed of 150 r / min for 6 min, then add mannitol, sucrose and lactose and stir and mix at a speed of 500 r / min, dry at a temperature of 40° C., and crush through an 80-mesh sieve to obtain a mixture A;

[0047] S2, preparing xanthan gum into a xanthan gum solution with a concentration of 45wt%, taking low-substituted hydroxypropyl cellulose and sodium lauryl sulfate and adding them to the xanthan gum solution, stirring at a speed of 280r / min for 5min, then adding acesulfame potassium and vanillin, stirring and mixing at a speed of 600r / min, drying at a temperature of 40°C, crushing, and passing through an 80-mesh sieve to obtain a mixture B;

[0048] S3, stirring and mixing erythromycin cyclohexetate with mixture A and mixture B at a rotation speed of 1000 r / min, drying at a temperature of 50° C., crushing, and passing through an 80-mesh sieve to obtain a mixture;

[0049] S4. The mixture is uniformly moistened with an ethanol solution having a concentration of 55wt% to obtain a soft material, and then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35°C for 1.0h, and then dried at 50°C to a moisture content of ≤1.2%, and granulated through a 40-mesh sieve, and packaged to obtain a high-stability cyclic erythromycin dry suspension.

[0050] Comparative Example 1

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

[0052] The preparation method of the high-stability cyclic erythromycin dry suspension of this comparative example comprises the following steps:

[0053] S1. Prepare xanthan gum into a xanthan gum solution with a concentration of 45 wt%, add low-substituted hydroxypropyl cellulose and sodium lauryl sulfate into the xanthan gum solution and stir at a speed of 280 r / min for 5 min, then add acesulfame potassium and vanillin and stir at a speed of 600 r / min to mix, dry at a temperature of 40° C., grind, and pass through an 80-mesh sieve to obtain a mixture B;

[0054] S2, stirring and mixing erythromycin cycloester, hydroxypropyl-β-cyclodextrin, mannitol, sucrose, lactose, polyvinyl alcohol and mixed material B at a speed of 700 r / min, drying at a temperature of 50° C., crushing, and passing through an 80-mesh sieve to obtain a mixture;

[0055] S3. The mixture is uniformly moistened with an ethanol solution having a concentration of 55 wt% to obtain a soft material, and then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35° C. for 1.0 h, and then dried at 50° C. to a moisture content of ≤1.2%. The granules are sieved through a 40-mesh sieve and packaged to obtain a high-stability cyclic erythromycin dry suspension.

[0056] Comparative Example 2

[0057] The difference between this comparative example and Example 4 is that the preparation steps of S2 are changed, and the rest are consistent with Example 4.

[0058] The preparation method of the high-stability cyclic erythromycin dry suspension of this comparative example comprises the following steps:

[0059] S1. Prepare polyvinyl alcohol into a polyvinyl alcohol solution with a concentration of 50 wt%, add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir at a speed of 150 r / min for 6 min, then add mannitol, sucrose and lactose and stir and mix at a speed of 500 r / min, dry at a temperature of 40° C., and crush through an 80-mesh sieve to obtain a mixture A;

[0060] S2, stirring and mixing erythromycin cyclohexyl, mixed material A, xanthan gum, low-substituted hydroxypropyl cellulose, sodium lauryl sulfate, acesulfame potassium and vanillin at a speed of 600 r / min, drying at a temperature of 50° C., crushing, and passing through an 80-mesh sieve to obtain a mixture;

[0061] S3. The mixture is uniformly moistened with an ethanol solution having a concentration of 55 wt% to obtain a soft material, and then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35° C. for 1.0 h, and then dried at 50° C. to a moisture content of ≤1.2%. The granules are sieved through a 40-mesh sieve and packaged to obtain a high-stability cyclic erythromycin dry suspension.

[0062] Comparative Example 3

[0063] The difference between this comparative example and Example 4 is that the entire preparation process is changed, and the rest is consistent with Example 4.

[0064] The preparation method of the high-stability cyclic erythromycin dry suspension of this comparative example comprises the following steps:

[0065] S1. Stirring and mixing erythromycin cycloester, hydroxypropyl-β-cyclodextrin, mannitol, sucrose, lactose, polyvinyl alcohol, xanthan gum, low-substituted hydroxypropyl cellulose, sodium lauryl sulfate, acesulfame potassium and vanillin at a speed of 1000 r / min, drying at a temperature of 50° C., crushing and passing through an 80-mesh sieve to obtain a mixture;

[0066] S2. The mixture is uniformly moistened with an ethanol solution having a concentration of 55 wt% to obtain a soft material, and then granulated through a 20-mesh sieve to obtain wet granules. The wet granules are first dried at 35° C. for 1.0 h, and then dried at 50° C. to a moisture content of ≤1.2%. The granules are sieved through a 40-mesh sieve and packaged to obtain a high-stability cyclic erythromycin dry suspension.

[0067] The high-stability cyclic erythromycin dry suspension prepared in the above Examples 1-4 and Comparative Examples 1-3 was subjected to performance tests.

[0068] After the cyclic erythromycin dry suspensions prepared in Examples 1-4 of the present invention and Comparative Examples 1-3 were packaged with aluminum-plastic film, they were placed at a temperature of 40±2°C and a relative humidity of 75±5% for 6 months, and the volume sedimentation ratio and the loss on drying after 6 months of placement were tested by sampling at 0 days, the 3rd month and the 6th month. The volume sedimentation ratio was determined with reference to Part IV of the 2020 edition of the Chinese Pharmacopoeia-"0123 Oral Solution, Oral Suspension, Oral Emulsion". In the test sample, the dry suspension and water liquid ratio g / mL was 1:50. The loss on drying was determined with reference to Part IV of the 2020 edition of the Chinese Pharmacopoeia-"0831 Loss on Drying Method". The results are shown in Table 1 below.

[0069] Table 1 Performance test of erythromycin cyclic ester dry suspension

[0070]

[0071] The above results show that the erythromycin cycloester dry suspension prepared by the method of Examples 1-4 of the present invention has high stability, and the drying loss after being placed for 6 months also meets the corresponding requirements. Compared with Example 4, Comparative Examples 1-3 change the preparation steps of the erythromycin cycloester dry suspension, which affects the dispersion performance between erythromycin cycloester 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 drying loss do not meet the requirements.

[0072] In addition, the in vitro dissolution of the erythromycin cyclohexetate dry suspension prepared in Examples 1-4 of the present invention all met the requirements and had high bioavailability.

[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 in the protection scope of the present invention.

Claims

1. A method for preparing a high-stability cyclic erythromycin dry suspension, characterized in that: The following steps are involved: S1. Prepare polyvinyl alcohol into a polyvinyl alcohol solution, add hydroxypropyl-β-cyclodextrin to the polyvinyl alcohol solution and stir at a speed of 100-150 r / min for 5-7 min, then add mannitol, sucrose and lactose and stir at a speed of 300-500 r / min to mix, dry, and grind through an 80-100 mesh sieve to obtain a mixture A; S2, preparing xanthan gum into a xanthan gum solution, taking low-substituted hydroxypropyl cellulose and sodium lauryl sulfate and adding them into the xanthan gum solution, stirring at a speed of 200-300 r / min for 4-6 min, then adding acesulfame potassium and vanillin, stirring and mixing at a speed of 500-600 r / min, drying, crushing, and passing through an 80-100 mesh sieve to obtain a mixture B; S3, stirring and mixing erythromycin cyclohexetate with mixture A and mixture B at a rotation speed of 800-1000 r / min, drying, crushing, and passing through an 80-100 mesh sieve to obtain a mixture; S4. The mixture is uniformly moistened with ethanol solution to obtain a soft material, and then granulated through a 20-30 mesh sieve to obtain wet granules. The wet granules are dried, sieved through a 30-40 mesh sieve to obtain whole granules, and packaged to obtain a high-stability cyclic erythromycin dry suspension.

2. The method for preparing the high stability cyclic ester erythromycin dry suspension according to claim 1, characterized in that: In step S1, the concentration of the polyvinyl alcohol solution is 40-50 wt%.

3. The method for preparing the high stability cyclic ester erythromycin dry suspension according to claim 1, characterized in that: In step S1 and step S2, the drying temperature is 40-50°C.

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

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

6. The method for preparing the high-stability cyclic ester erythromycin dry suspension according to claim 1, characterized in that: In step S4, the drying is first performed at 35-40° C. for 1-1.5 hours, and then the temperature is raised to 45-60° C. and dried until the moisture content is ≤1.2%.

7. A high-stability cyclic erythromycin dry suspension prepared by the preparation method according to any one of claims 1 to 6.

8. The high stability cyclic erythromycin dry suspension according to claim 7, characterized in that: The invention comprises the following raw materials in parts by weight: 7-9 parts of erythromycin cycloester, 10-13 parts of hydroxypropyl-β-cyclodextrin, 5-8 parts of mannitol, 4-7 parts of polyvinyl alcohol, 6-10 parts of xanthan gum, 5-8 parts of low-substituted hydroxypropyl cellulose, 0.8-1.2 parts of sodium lauryl sulfate, 60-72 parts of sucrose, 7-9 parts of lactose, 1-3 parts of acesulfame potassium and 0.2-1.0 parts of vanillin.

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