A preparation method of artificial bezoar metronidazole capsules

Abstract

The invention provides a preparation method of artificial bezoar-metronidazole capsules. The capsules contain 2 parts of artificial bezoar, 80 parts of metronidazole, and 30-40 parts of starch in parts by weight. The preparation method comprises the steps of preparing raw materials and auxiliary materials, premixing, wet processing, and filling. The prepared artificial bezoar-metronidazole capsules have small weight variation, high content uniformity, and stable quality after accelerated storage for 6 months.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to a preparation method of artificial bezoar metronidazole capsules. Background Art

[0002] Artificial bezoar metronidazole is a compound medication, primarily in capsule form, used to treat pericoronitis of wisdom teeth, localized alveolar abscesses, and pulpitis. Metronidazole effectively inhibits periodontitis-causing anaerobic bacteria, while artificial bezoar alleviates gum swelling and pain. The synergistic effect of these two enhances the therapeutic effect.

[0003] Heze Food and Drug Inspection and Testing Institute conducted random inspections on artificial bezoar metronidazole capsules from 25 manufacturers and found significant differences in the dissolution behavior of metronidazole. Figure 1 As shown, it seriously affects the quality and efficacy of the product.

[0004] Therefore, it is necessary to further study the prescription and preparation process of artificial bezoar metronidazole capsules to provide a drug with stable quality, high solubility and stability. Summary of the Invention

[0005] The present invention provides a preparation method of artificial bezoar and metronidazole capsules. The capsules contain 2 parts of artificial bezoar, 80 parts of metronidazole, and 30-40 parts of starch in parts by weight. The preparation method comprises the following steps:

[0006] (1) Preparation of raw materials and auxiliary materials;

[0007] Artificial bezoar, metronidazole and starch were micronized and the particle size was controlled as follows:

[0008] Raw materials <![CDATA[D 90 ]]> <![CDATA[D 50 ]]> <![CDATA[D 10 ]]> Artificial bezoar ≤32μm ≤12μm ≤5μm Metronidazole ≤50μm ≤30μm ≤10μm starch ≤120μm ≤70μm ≤40μm

[0009] (2) Premixing and mixing

[0010] Premixing: Add artificial bezoar, 1 / 3-1 / 2 of metronidazole, and 1 / 2-3 / 5 of starch to a mixer and premix; the mixer speed is 10-13 rpm and the premixing time is 18-26 minutes;

[0011] Mixing: Add the remaining metronidazole and starch into the mixer at a speed of 14-18 rpm and premix for 8-10 minutes;

[0012] (3) Filling: Filling into capsules.

[0013] Preferably, the starch is potato starch.

[0014] Preferably, the contents of the capsule are 2 parts of artificial bezoar, 80 parts of metronidazole and 32-35 parts of starch in parts by weight.

[0015] More preferably, the contents of the capsule are 2 parts of artificial bezoar, 80 parts of metronidazole and 34 parts of starch in parts by weight.

[0016] Furthermore, in step (1), the particle sizes of artificial bezoar, metronidazole, and starch are preferably as follows:

[0017] Raw materials <![CDATA[D 90 ]]> <![CDATA[D 50 ]]> <![CDATA[D 10 ]]> Artificial bezoar ≥25μm ≥8μm ≥2μm Metronidazole ≥40μm ≥22μm ≥5μm starch ≥80μm ≥50μm ≥25μm

[0018] Furthermore, in step (2), the premixing step is preferably: artificial bezoar, 4 / 10 metronidazole, and 1 / 2 starch are added to a mixer for premixing; the mixer speed is 12 rpm, and the premixing time is 22 minutes.

[0019] Furthermore, in step (2), the mixing step is preferably: adding the remaining metronidazole and starch into a mixer, the mixer speed is 17 rpm, and the premixing time is 10 minutes.

[0020] Furthermore, in step (3), each capsule contains 5 mg of artificial bezoar and 200 mg of metronidazole.

[0021] Furthermore, in step (3), the weight of the contents of each capsule is 0.25-0.35 g, preferably 0.29 g.

[0022] The artificial bezoar metronidazole capsules prepared by the present invention are reasonably prepared by controlling the particle sizes of artificial bezoar, metronidazole and auxiliary material starch. The weight difference of the prepared artificial bezoar metronidazole capsules is small, the content uniformity is high, and the quality is stable after accelerated storage for 6 months. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 : Dissolution results of metronidazole in artificial bezoar metronidazole capsules from 25 manufacturers. DETAILED DESCRIPTION

[0024] The present invention discloses a method for preparing artificial bezoar metronidazole capsules. Those skilled in the art can refer to the contents of the present invention, combine the relevant principles of pharmaceutical preparation, and appropriately improve the process parameters to achieve the present invention. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of the present invention. The application of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0025] For a better understanding of the present invention and not to limit the scope of the present invention, all numerals expressing amounts, percentages, and other numerical values ​​used in this application should be understood as being modified by the word "about" in all cases. Each numerical parameter should at least be considered to be obtained in light of the number of reported significant digits and by conventional rounding methods.

[0026] The present invention is further described below by way of examples, which, however, do not limit the present invention in any way.

[0027] The artificial bezoar, metronidazole, and potato starch used in the embodiments of the present invention were micronized to have particle sizes as shown in the following table:

[0028]

[0029] Weight difference:

[0030] Take 20 capsules, accurately weigh each, pour out the contents, and clean the capsule shell with a small brush. Then accurately weigh the hard capsule shells and calculate the filling amount per capsule and the average filling amount. The filling amount per capsule should differ by ±10% compared to the theoretical filling amount.

[0031] Artificial bezoar content uniformity inspection: according to the "0941 content uniformity inspection method" in the 2020 edition of the Chinese Pharmacopoeia

[0032] Determination of Metronidazole Dissolution Curve

[0033] Dissolution medium: pH 1.2 hydrochloric acid solution; 900ml

[0034] Speed: 50 rpm

[0035] Sampling time: 10min, 15min, 20min, 30min, 45min, 60min;

[0036] Among them: the dissolution rate in 30 minutes is not less than 80%; the dissolution rate in 60 minutes is not less than 90%; the RSD of dissolution at the first time point of 10 minutes is not higher than 20%, and the RSD of dissolution at the second time point of 15 minutes to 60 minutes is not higher than 10%.

[0037] Example 1-20: Artificial Bezoar Metronidazole Capsules

[0038] 1. Prescription composition:

[0039]

[0040] The artificial bezoar, metronidazole and potato starch used are shown in Tables 1 to 4.

[0041] Table 1: Table of artificial bezoar, metronidazole, and potato starch used in Examples 1-5

[0042] Artificial bezoar starch Metronidazole Example 1 Artificial bezoar 1 Potato starch1 Metronidazole 1 Example 2 Artificial bezoar 2 Potato starch1 Metronidazole 1 Example 3 Artificial bezoar 3 Potato starch1 Metronidazole 1 Example 4 Artificial bezoar 4 Potato starch1 Metronidazole 1 Example 5 Artificial bezoar 5 Potato starch1 Metronidazole 1

[0043] Table 2: Table 2: Table 2: Table 2: Table 2: Table 2: Table 2: Table 2

[0044]

[0045]

[0046] Table 3: Table 3: Table 3 of artificial bezoar, metronidazole, and starch used in Examples 11-15

[0047] Artificial bezoar starch Metronidazole Example 11 Artificial bezoar 2 Potato starch 2 Metronidazole 1 Example 12 Artificial bezoar 2 Potato starch1 Metronidazole 2 Example 13 Artificial bezoar 1 Potato starch1 Metronidazole 3 Example 14 Artificial bezoar 1 Potato starch1 Metronidazole 4 Example 15 Artificial bezoar 1 Potato starch1 Metronidazole 5

[0048] Table 4: Table 4: Table 4: Table 4: Table 4: Table 4: Table 4: Table 4: Table 4: Table 4: Table 4:

[0049] Artificial bezoar starch Metronidazole Example 16 Artificial bezoar 1 Potato starch 3 Metronidazole 3 Example 17 Artificial bezoar 1 Potato starch 4 Metronidazole 4 Example 18 Artificial bezoar 1 Potato starch 5 Metronidazole 5 Example 19 Artificial bezoar 1 Potato starch 4 Metronidazole 3 Example 20 Artificial bezoar 1 Potato starch 5 Metronidazole 4

[0050] 2. Preparation method:

[0051] (1) Premixing and mixing:

[0052] Premixing: Add artificial bezoar, 4 / 10 metronidazole, and 1 / 2 potato starch to a mixer and premix; the mixer speed is 12 rpm and the premixing time is 22 minutes;

[0053] Mixing: Add the remaining metronidazole and potato starch into the mixer at a speed of 17 rpm and premix for 10 minutes.

[0054] (2) Filling: Fill into capsules, each capsule weighing 0.29 g.

[0055] 3. Test results:

[0056] 1. The prepared artificial bezoar metronidazole capsules were tested for artificial bezoar content uniformity and weight difference. The results are shown in Table 5.

[0057] Table 5: Content uniformity and weight difference results of artificial bezoar metronidazole capsules prepared in Examples 1-20

[0058]

[0059] 2. The dissolution curve of artificial bezoar metronidazole capsules that meet the requirements for content uniformity and weight variation was measured in a pH 1.2 hydrochloric acid solution. The results are shown in Table 6.

[0060]

[0061] Comparative analysis of Examples 1-20 revealed that:

[0062] (1) Artificial bezoar metronidazole capsules prepared from artificial bezoar, potato starch, and metronidazole within a characteristic particle size range (such as Examples 1-2, Examples 6-7, and Examples 11-12) not only meet the requirements for the uniformity of the content of artificial bezoar and the weight difference of the capsules, but also have high metronidazole solubility (30 min dissolution rate is not less than 80%; 60 min dissolution rate is not less than 90%), and the dissolution is stable within the same batch (the RSD of the dissolution at the first time point of 10 min is not higher than 20%, and the RSD of the dissolution at the second time point of 15 min to 60 min is not higher than 10%).

[0063] (2) When only artificial bezoar of other particle sizes is used, as shown in Examples 3-5, the content uniformity of the artificial bezoar in the prepared artificial bezoar metronidazole capsules does not meet the requirements.

[0064] (3) When only potato starch of other particle sizes was used, as shown in Examples 8-10, the weight difference of the prepared artificial bezoar metronidazole capsules did not meet the requirements (Examples 9-10) or the dissolution stability was poor (Example 8, the RSD of dissolution at the second time point of 15 min was higher than 10%), which did not meet the requirements and had a large difference in product quality.

[0065] (3) When only potato starch of other particle sizes was used, as shown in Examples 13-15, the weight difference of the prepared artificial bezoar metronidazole capsules did not meet the requirements (Example 14) or the metronidazole solubility was low (30 min dissolution was less than 80%; 60 min dissolution was less than 90%) or the dissolution stability was poor (the RSD of the dissolution at the first time point of 10 min was greater than 20%, and the RSD of the dissolution at the second time point of 15 min was greater than 10%), which did not meet the requirements and resulted in large differences in product quality.

[0066] (4) When potato starch and metronidazole of other particle size ranges were used simultaneously, as shown in Examples 16-20, the weight difference of the prepared artificial bezoar metronidazole capsules did not meet the requirements, and the product quality varied greatly.

[0067] Comparative Examples 1-4: Effects of Premixing and Mixing Steps

[0068] 1. Prescription composition: Same as Example 1.

[0069] 2. Preparation method: The premixing and mixing steps are shown in the following table. The remaining steps are the same as those in Example 1.

[0070]

[0071] 3. Test results:

[0072] 1. The prepared artificial bezoar metronidazole capsules were tested for artificial bezoar content uniformity and weight difference. The results are shown in Table 7.

[0073] Table 7: Content uniformity and weight difference results of artificial bezoar metronidazole capsules prepared in Comparative Examples 1-4

[0074]

[0075] 2. The dissolution curve of the artificial bezoar metronidazole capsules of Comparative Example 3 was measured in a pH 1.2 hydrochloric acid solution. The results are shown in Table 8:

[0076] Table 8: Dissolution curve of artificial bezoar metronidazole capsules of Comparative Example 3 in pH 1.2 hydrochloric acid solution

[0077]

[0078] A comparative analysis of Example 1 and Comparative Examples 1-4 revealed that the process parameters of the premixing and mixing steps affected the content uniformity, weight variation, and dissolution stability of the artificial bezoar. First, the artificial bezoar-metronidazole capsules provided by the present invention (e.g., Example 1) not only met the requirements for content uniformity and weight variation of the artificial bezoar, but also had high metronidazole solubility (30-minute dissolution rate not less than 80%; 60-minute dissolution rate not less than 90%) and stable dissolution within the same batch (RSD of dissolution at the first time point of 10 minutes was not greater than 20%, and RSD of dissolution at the second time point of 15 minutes to 60 minutes was not greater than 10%). Second, artificial bezoar-metronidazole capsules prepared by premixing and mixing without the process parameters of the present invention (e.g., Comparative Examples 1-4) showed that the content uniformity of the artificial bezoar and the weight variation of the capsules did not meet the requirements, and the dissolution of metronidazole within the same batch was unstable (RSD of dissolution at the first time point of 10 minutes was greater than 20%, and RSD of dissolution at the second time point of 15 minutes to 60 minutes was greater than 10%).

[0079] Comparative Examples 5-6: Effect of Starch Composition

[0080] 1. Prescription composition: Starch is shown in the following table, and the rest is the same as Example 1 (including starch particle size)

[0081] Comparative Example starch Comparative Example 5 wheat starch Comparative Example 6 Soluble starch

[0082] 2. Preparation method: Same as Example 1.

[0083] 3. Test results:

[0084] 1. The prepared artificial bezoar metronidazole capsules were tested for artificial bezoar content uniformity and weight difference. The results are shown in Table 9.

[0085] Table 9: Content uniformity and weight difference results of artificial bezoar metronidazole capsules prepared in Comparative Examples 5-6

[0086]

[0087] 2. The dissolution curve of the artificial bezoar metronidazole capsules of Comparative Examples 5-6 was measured in a pH 1.2 hydrochloric acid solution. The results are shown in Table 8:

[0088] Table 8: Dissolution curve of artificial bezoar metronidazole capsules of comparative examples 5-6 in pH 1.2 hydrochloric acid solution

[0089]

[0090] A comparative analysis of Example 1 and Comparative Examples 5-6 found that the composition of starch affects the dissolution behavior of artificial bezoar metronidazole capsules. When other types of starch were used, such as commonly used soluble starch and wheat starch, the prepared artificial bezoar metronidazole capsules were unstable in dissolution (as shown in Comparative Examples 5 and 6, the RSD of the dissolution result at the first time point of 10 min was higher than 20%; or the RSD of the dissolution result at the second time point of 20 min was higher than 10%), and the product quality varied greatly, which did not meet the requirements.

Claims

1. A method for preparing an artificial bezoar and metronidazole capsule, wherein the capsule contents are 2 parts of artificial bezoar, 80 parts of metronidazole, and 30-40 parts of starch in parts by weight; the preparation method comprises the following steps: (1) Preparation of raw materials and auxiliary materials: Artificial bezoar, metronidazole and starch were micronized and the particle size was controlled as follows: Artificial bezoar: D 90 Greater than or equal to 25μm and less than or equal to 32μm, D 50 Greater than or equal to 8μm and less than or equal to 12μm, D 10 Greater than or equal to 2μm and less than or equal to 5μm; Metronidazole: D90 greater than or equal to 40 μm and less than or equal to 50 μm, D50 greater than or equal to 22 μm and less than or equal to 30 μm, D10 greater than or equal to 5 μm and less than or equal to 10 μm; Starch: D90 greater than or equal to 80 μm and less than or equal to 120 μm, D50 greater than or equal to 50 μm and less than or equal to 70 μm, D10 greater than or equal to 25 μm and less than or equal to 40 μm; The starch is potato starch; (2) Premixing and mixing: Premixing: Add artificial bezoar, 1 / 3-1 / 2 of metronidazole, and 1 / 2-3 / 5 of starch to a mixer and premix; the mixer speed is 10-13 rpm and the premixing time is 18-26 minutes; Mixing: Add the remaining metronidazole and starch into the mixer at a speed of 14-18 rpm and premix for 8-10 minutes; (3) Filling: Filling into capsules.

2. The preparation method according to claim 1, wherein Calculated by weight, the contents of the capsule are 2 parts of artificial bezoar, 80 parts of metronidazole and 32-35 parts of starch.

3. The preparation method according to claim 1, wherein Calculated by weight, the contents of the capsule are 2 parts of artificial bezoar, 80 parts of metronidazole and 34 parts of starch.

4. The preparation method according to claim 1, wherein In step (2), the premixing step is as follows: artificial bezoar, 4 / 10 metronidazole, and 1 / 2 starch are added to a mixer for premixing; the mixer speed is 12 rpm, and the premixing time is 22 minutes.

5. The preparation method according to claim 1, wherein In step (2), the mixing step is as follows: the remaining metronidazole and starch are added into the mixer, the mixer speed is 17 rpm, and the premixing time is 10 minutes.

6. The preparation method according to claim 1, wherein In step (3), each capsule contains 5 mg of artificial bezoar and 200 mg of metronidazole.

7. The preparation method according to claim 1, wherein In step (3), the weight of the contents of each capsule is 0.25-0.35 g.

8. The preparation method according to claim 1, wherein In step (3), the weight of the contents of each capsule is 0.29 g.

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