WO2022222205A1 - Amoxicillin capsule and preparation method therefor - Google Patents

Abstract

Provided in the present invention are an amoxicillin capsule and a preparation method therefor, belonging to the technical field of drug preparation. 10-35 wt% of light amoxicillin powder with a particle size of less than 0.180 mm and 10-40 wt% of heavy amoxicillin powder with a particle size of 0.600-0.850 mm are mixed with the balance of heavy amoxicillin powder with a particle size of 0.180-0.600 mm, then the mixture and magnesium stearate are fed alternately for mixing, and filling and polishing are performed to obtain an amoxicillin capsule. According to the present invention, the particle size ratio of the amoxicillin powder is adjusted, the amount of the light amoxicillin powder is increased, and the minimum particle size of the light powder is no longer limited whereas the maximum particle size of the heavy powder is limited, so that an amoxicillin capsule with a high stability and good dissolution rate is obtained.

Description

Amoxicillin capsules and preparation method thereof technical field

The invention relates to the preparation of capsules, in particular to an amoxicillin capsule and a preparation method thereof.

Background technique

Amoxicillin, also known as amoxicillin or amoxicillin, is one of the most commonly used semi-synthetic penicillin broad-spectrum beta-lactam antibiotics, clinically used for the treatment of tonsillitis, laryngitis, pneumonia, chronic bronchitis, urinary Systemic infections, skin and soft tissue infections, purulent pleurisy, hepatobiliary system infections, sepsis, typhoid fever, dysentery, etc. At present, the oral dosage forms of amoxicillin mainly include tablets, capsules, granules, etc., and amoxicillin capsules are mainly used clinically as therapeutic drugs.

Due to the poor solubility of amoxicillin, it is slightly soluble in water and insoluble in ethanol, resulting in the problem of poor dissolution of the amoxicillin capsules made. The poor dissolution rate further limits the in vivo absorption of amoxicillin. Therefore, improving the dissolution rate of amoxicillin capsules has always been a research hotspot. In addition, amoxicillin itself is sensitive to humidity and heat. High temperature and high humidity will lead to the production of polymers and impurities. The reduction of the content of polymers and impurities is also one of the important factors to be investigated in the preparation of amoxicillin capsules.

The Chinese invention patent with the announcement number CN107875136 B discloses a pharmaceutical preparation of amoxicillin and a preparation method thereof. Amoxicillin capsules are prepared by mixing amoxicillin and magnesium stearate, which reduces the types of excipients, thereby reducing the cost of amoxicillin. Security risks. However, in order to ensure the stability of the drug, the technical solution uses amoxicillin heavy powder to prepare capsules, but due to the relatively large relative particle size of the amoxicillin heavy powder, there is a phenomenon of uneven mixing, and the technical solution lacks disintegrants, etc. Excipients, resulting in poor dissolution of the prepared amoxicillin capsules.

A Chinese invention patent application with publication number CN109172539 A discloses a kind of amoxicillin capsule and its production method and application. In order to improve the dissolution rate of amoxicillin, the technical scheme adjusts the ratio of amoxicillin heavy powder and light powder , the amount of light powder is increased, but the amount of light powder and the minimum particle size are clearly limited. This is because in the mixing process, there is the phenomenon of light powder floating up and heavy powder sinking, and heavy powder and light powder are very different. It is difficult to mix, and the increase of the amount of light powder will make it more difficult to mix the light powder and the heavy powder, and the light powder will aggregate, and the specific surface area of the light powder aggregated part will be larger, and the increase of the specific surface area will cause it to come into contact with water. The probability increases, so that the impurities increase, and the stability of the prepared amoxicillin capsules is poor.

The Chinese invention patent application with publication number CN109953971 A discloses a preparation method of amoxicillin capsules, which selects 20-60 mesh amoxicillin heavy powder and more than 60 mesh amoxicillin light powder to mix, although the surface increases The dosage of amoxicillin light powder above 60 mesh is not limited and the minimum particle size is not limited, but it defines amoxicillin powder above 60 mesh as light powder, and uses 20 and 60 mesh sieves as rotary vibrating sieves in the granulation process. The number of sieve meshes, the amount of light powder above 80 meshes contained in the amoxicillin light powder prepared in this way will be substantially reduced, and the technical solution reduces the difficulty of mixing heavy powder and light powder in this way, thereby improving The stability of amoxicillin capsules, but its dissolution rate needs to be improved.

SUMMARY OF THE INVENTION

In view of the above problems, the present invention provides an amoxicillin capsule and a preparation method thereof.

For achieving the above object, the technical scheme adopted in the present invention is:

An amoxicillin capsule, the raw materials for making its active ingredients, include: 100 parts by weight of amoxicillin medicinal powder and 0.2-0.5 parts by weight of magnesium stearate;

The amoxicillin medicinal powder is composed of 10-35wt% amoxicillin light powder with a particle size of less than 0.180mm (passing an 80-mesh sieve), and 10-40wt% with a particle size of 0.600-0.850mm (passing a 20-mesh sieve and failing to pass a 30-mesh sieve). ) of the amoxicillin heavy powder and the balance of the amoxicillin heavy powder with a particle size of 0.180 to 0.600 mm (passing a 30-mesh sieve and not passing an 80-mesh sieve).

Further, the amoxicillin powder is obtained by using a dry granulator with a roller pressure of 6.0-10.0 MPa.

Further, in the granulation process of the dry granulator, the ambient humidity is 52-58%.

Further, the technological parameters of the dry granulator are: the stirring speed is 15-20 rpm, the screw feeding speed is 50-60 rpm, the pressing roller speed is 10-15 rpm, the pressing roller temperature is 20-30 ℃, and the granulation speed is 100～130rpm, the mesh size of the whole grain screen is 0.80～0.84mm, and the mesh number of the rotary vibrating screen is 20 mesh, 30 mesh and 80 mesh.

Further, the particle size of magnesium stearate is 0.180-0.850 mm (passed through 20 mesh sieve, but failed to pass through 80 mesh sieve).

A preparation method of amoxicillin capsules is to take amoxicillin medicinal powder and mix with heavy powder, then alternately feed and mix with magnesium stearate, and then fill and polish to obtain the amoxicillin capsules.

Further, the humidity of the heavy powder mixing and the mixing material are both 52-58%.

Further, the rotating speed of the heavy powder mixing is 12-15 r/min, and the time is 11-15 min; the rotating speed of the mixing is 12-15 r/min, and the time is 2-5 min.

Further, after the mixing of the heavy powder is stopped, the obtained amoxicillin powder needs to stand for 5-10 minutes, and then is taken out and alternately fed with magnesium stearate.

Further, the humidity of the filling and polishing are both 30-43%.

The beneficial effects of the preparation method of amoxicillin capsules of the present invention are:

By adjusting the particle size ratio of the amoxicillin medicinal powder, the dosage of the amoxicillin light powder is increased, and the minimum particle size of the light powder is no longer limited, but the maximum particle size of the heavy powder is limited, thereby obtaining a kind of high stability and dissolution Good Amoxicillin Capsules;

The present invention reduces the adverse reactions caused by pharmaceutical excipients by reducing the dosage of magnesium stearate;

The present invention reduces the granulation pressure by adjusting the process parameters of dry granulation, thereby reducing the decomposition of amoxicillin; by controlling the humidity in the granulation process, while ensuring the stability of the amoxicillin powder (non-polymerization, non-hydrolysis, No impurities), reduce the flying of amoxicillin light powder;

In the present invention, the amoxicillin medicinal powder is mixed with the heavy powder first, and the process parameters such as humidity and rotational speed in the heavy powder mixing process are controlled, so as to ensure the stability of the amoxicillin medicinal powder, and effectively suppress the heavy powder from sinking and the light powder on the light powder. The floating phenomenon achieves the purpose of fully mixing heavy powder and light powder;

The present invention shortens the mixing time of the magnesium stearate and the amoxicillin powder and improves the drug dissolution rate by first mixing the amoxicillin medicinal powder uniformly, and then mixing with the magnesium stearate in batches alternately. The improvement of the dissolution rate here may be due to the reason that the excessive mixing of magnesium stearate and the powder will affect the dissolution rate of the drug;

Increase drug stability by adjusting the humidity during filling and polishing.

Description of drawings

1 to 4 are the dissolution curves of the amoxicillin capsules prepared in Examples 1 to 6 and Comparative Examples 1 to 13 in Experimental Example 1 of the present invention in a pH 4.0 acetate buffer;

Figures 5 to 8 are the dissolution curves of the amoxicillin capsules prepared in Examples 1 to 6 and Comparative Examples 1 to 13 in Experimental Example 1 of the present invention in a pH 6.8 phosphate buffer;

9-12 are the dissolution curves of the amoxicillin capsules in water prepared by Examples 1-6 and Comparative Examples 1-13 in Experimental Example 1 of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Many specific details are set forth in the following description to facilitate a full understanding of the present invention, but the present invention can also be implemented in other ways different from those described herein, and those skilled in the art can do so without departing from the connotation of the present invention. Similar promotion, therefore, the present invention is not limited by the specific embodiments disclosed below.

Embodiment 1 A kind of preparation method of amoxicillin capsule

The present embodiment is a preparation method of amoxicillin capsules, and the specific preparation process includes the following steps performed in sequence:

1) Set the equipment parameters of the dry granulator: the stirring speed is 17 rpm, the screw feeding speed is 56 rpm, the pressure of the pressing roller is 6.8 MPa, the rotational speed of the pressing roller is 13 rpm, the temperature of the pressing roller is 25 ℃, the granulating speed is 130 rpm, and the granulating speed is 130 rpm. The aperture of the particle screen is 0.84mm, and the mesh number of the rotary vibrating screen is 20 mesh, 30 mesh and 80 mesh.

Under the conditions of a temperature of 25°C and a humidity of 52%, the amoxicillin crude drug was dried in nitrogen at 25°C for 30s, then added to the hopper of a dry granulator for granulation, and collected through a 20-mesh sieve and failed to pass. Amoxicillin heavy powder (particle size is 0.600～0.850mm) with 30 mesh sieve, amoxicillin heavy powder (particle size is 0.180～0.600mm) passed through 30 mesh sieve and not passed through 80 mesh sieve, and amoxicillin heavy powder (particle size is 0.180～0.600mm) passed through 80 mesh sieve For the amoxicillin light powder (particle size less than 0.180mm), the amoxicillin API that did not pass the 20-mesh sieve was added to the dry granulator for simultaneous granulation.

2) Under the conditions of a temperature of 25°C and a humidity of 52%, weigh 56.5g of amoxicillin light powder with a particle size of less than 0.180mm (accounting for 22.6wt%) and 75g of amoxicillin with a particle size of 0.600-0.850mm. Heavy powder (accounting for 30wt%) and 118.5g of amoxicillin heavy powder (accounting for 47.4wt%) with a particle size of 0.180-0.600mm were added to a multi-directional motion mixer, maintained at 25°C, humidity of 52%, controlled The mixing speed was 14 r/min, and the mixing was performed for 11 min. After the mixer was automatically shut down, the power was cut off and left to stand for 8 min, and the amoxicillin powder was taken out.

3) under the condition that temperature is 25 ℃, humidity is 52%, get 250g amoxicillin powder and 0.5g magnesium stearate alternately feed and mix (the weight ratio of amoxicillin powder and magnesium stearate is 100 : 0.2), maintain 25 ℃, humidity is 52%, control mixing speed to be 14r/min, mix material 2min, obtain mixed medicine powder;

Wherein, alternate feeding refers to first put in 50g amoxicillin powder, then put in 0.1g magnesium stearate, then put in 50g amoxicillin powder, then put in 0.1g magnesium stearate, and then alternately feed the above-mentioned dosage until the feeding is completed, also That is to say, the amoxicillin powder and the magnesium stearate are cross-feeding, and each material is divided into five feedings. Although the present embodiment is divided into five feedings, it is not limited to being divided into five feedings.

4) under the condition that the temperature is 25°C and the humidity is 40%, get the mixed medicinal powder and pour it into the gelatin hollow capsule with a capsule filling machine for filling and polishing to obtain 1000 amoxicillin capsules;

The obtained amoxicillin capsules also need to be aluminum-plasticized and packaged.

Embodiment 2～6 The preparation method of amoxicillin capsule

Embodiments 2 to 6 are respectively a preparation method of amoxicillin capsules, and their steps are basically the same as those of embodiment 1, and the difference is only in the amount of raw materials and process parameters. For details, see Table 1:

Table 1 List of various process parameters in Examples 2 to 6

The contents of other parts of Examples 2 to 6 are the same as those of Example 1.

The amoxicillin capsules prepared in Examples 1-6 have good stability and high dissolution rate.

Experimental Example 1 Dissolution Determination of Amoxicillin Capsules

Comparative Examples 1 to 10 are comparative tests of the preparation process of amoxicillin capsules in Example 1, and the differences are only:

In Comparative Example 1, 100 g of amoxicillin light powder with a particle size of less than 0.180 mm (40 wt %), 75 g of amoxicillin heavy powder with a particle size of 0.600 to 0.850 mm (30 wt %) and 75 g of amoxicillin with a particle size of 0.180 to 0.600 mm were used Amoxicillin heavy powder prepared amoxicillin powder (accounting for 30wt%);

In Comparative Example 2, 12.5g of amoxicillin light powder with a particle size of less than 0.180mm (5wt%), 75g of amoxicillin heavy powder with a particle size of 0.600-0.850mm (30wt%) and 162.5g of amoxicillin with a particle size of 0.180- Amoxicillin powder (accounting for 65wt%) is prepared from 0.600mm amoxicillin heavy powder;

In the granulation process of Comparative Example 3, the pressure of the pressing roller was set to 11.0 MPa;

The humidity in the granulation process of Comparative Example 4 was 63%;

The humidity in the granulation process of Comparative Example 5 was 48%;

The humidity in the heavy powder mixing process of Comparative Example 6 was 63%;

The humidity in the heavy powder mixing process of Comparative Example 7 was 48%;

Comparative example 8 no longer distinguishes heavy powder mixing and compounding and carries out two-step mixing, but mixes magnesium stearate with the amoxicillin powder of each particle size together;

In the step 3 of comparative example 9), mixing time is 8min;

The humidity during filling and polishing of Comparative Example 10 was 50%;

In Comparative Example 11, amoxicillin capsules were prepared according to the preparation method disclosed in the Chinese invention patent with the publication number of CN107875136B;

In Comparative Example 12, amoxicillin capsules were prepared according to the preparation method disclosed in the Chinese invention patent application with the publication number of CN109172539A;

Comparative Example 13 Amoxicillin capsules were prepared according to the preparation method disclosed in the Chinese invention patent application with the publication number of CN109953971A.

It should be noted that the experiment found that in the granulation process, when the pressure is lower than 6.0MPa, the granulation cannot be carried out well, so no more comparative examples are added here;

Take the amoxicillin capsules prepared in Examples 1 to 6 and Comparative Examples 1 to 13, according to the provisions of the first method in "Chinese Pharmacopoeia" (2015 edition four parts 0931), respectively in pH4.0 acetate buffer, pH6. 8 The in vitro release comparison test was carried out in phosphate buffer and water, and the test results are shown in Tables 2 to 4 and accompanying drawings 1 to 12:

Table 2 Summary of dissolution data in pH 4.0 acetate buffer

time (min)	5	10	15	20	30	45	60	90
Example 1	38.61	54.27	65.35	75.14	86.19	97.1	100.09	100.1
Example 2	39.27	56.72	68.14	78.25	88.14	99.62	100.02	100.02

Example 3	37.41	52.12	63.59	74.15	85.11	96.75	99.98	99.98
Example 4	38.21	53.79	64.85	74.67	85.45	96.96	100.07	100.03
Example 5	38.19	55.11	65.98	75.37	86.57	98.28	100.01	100.02
Example 6	39.02	55.41	67.66	76.45	85.79	98.79	100.04	100.03
Comparative Example 1	38.99	56.42	68.76	77.91	87.64	96.75	98.77	98.77
Comparative Example 2	12.1	27.54	40.67	50.12	59.89	64.18	70.21	80.16
Comparative Example 3	36.44	51.85	63.27	74.39	85.21	96.43	99.88	99.87
Comparative Example 4	32.45	50.97	60.27	72.44	81.69	92.74	99.63	99.6
Comparative Example 5	25.31	38.64	48.63	55.68	66.72	78.01	85.29	96.11
Comparative Example 6	30.21	47.64	54.95	68.72	79.81	89.01	98.79	98.98
Comparative Example 7	20.26	34.83	46.52	54.34	66.12	76.35	83.92	94.59
Comparative Example 8	23.15	42.05	50.82	69.11	80.59	93.11	99.75	99.74
Comparative Example 9	21.58	43.15	48.97	58.64	72.33	89.64	96.58	99.67
Comparative Example 10	37.22	52.63	63.28	74.54	85.36	96.98	99.87	99.87
Comparative Example 11	16.85	31.33	45.25	52.69	62.35	71.11	80.25	90.26
Comparative Example 12	36.56	51.98	63.87	75.12	86.25	97.9	99.67	99.69
Comparative Example 13	30.21	50.26	60.25	70.85	80.24	90.63	96.89	99.87

Table 3 Summary of dissolution data in pH 6.8 phosphate buffer

time (min)	5	10	15	20	30	45	60	90
Example 1	53.43	72.64	83.59	93.56	99.9	100.06	100.08	100.07
Example 2	55.15	74.56	85.61	94.25	99.96	100.02	100.01	100.02
Example 3	54.63	73.01	84.26	93.75	99.91	100	99.98	99.98
Example 4	53.68	73.56	83.26	93.98	99.89	100.06	100.07	100.03
Example 5	53.16	73.59	84.53	94.2	99.92	100.01	100.01	100.02
Example 6	54.16	73.12	84.98	93.45	99.94	100.3	100.04	100.03
Comparative Example 1	56.21	74.86	85.99	94.56	98.74	98.73	98.74	98.74
Comparative Example 2	20.01	49.58	66.74	74.28	84.01	95.04	99.67	99.66
Comparative Example 3	50.54	70.63	81.36	91.58	98.89	99.87	99.88	99.87
Comparative Example 4	49.59	68.56	77.99	90.15	97.45	99.62	99.63	99.6
Comparative Example 5	39.54	57.99	70.59	86.89	92.93	96.11	98.14	98.13
Comparative Example 6	48.69	68.12	76.82	91.01	97.25	98.97	98.99	98.98
Comparative Example 7	35.56	54.36	68.25	88.66	93.56	98.79	98.79	98.8
Comparative Example 8	36.86	56.54	69.63	87.91	93.45	99.73	99.75	99.74
Comparative Example 9	34.77	52.01	64.69	85.36	90.11	99.67	99.67	99.67
Comparative Example 10	51.25	72.59	83.01	92.99	99.87	99.87	99.86	99.87
Comparative Example 11	22.56	50.21	65.97	75.65	84.56	95.16	99.25	99.25
Comparative Example 12	52.1	72.04	82.69	92.64	99.67	99.66	99.67	99.68
Comparative Example 13	45.96	67.24	78.69	91.66	98.65	99.87	99.87	99.87

Table 4 List of dissolution data in water

According to the dissolution data in Tables 2-4, the amoxicillin capsules prepared in Examples 1-6 and Comparative Examples 1-13 were drawn in pH4.0 acetate buffer, pH6.8 phosphate buffer and water, respectively. For the dissolution profiles, see Figures 1-12 for details.

It can be seen from Tables 2 to 4 and Figures 1 to 12 that the dissolution rate of the amoxicillin capsules prepared in Examples 1 to 6 is significantly better than that of Comparative Examples 1 to 13, indicating that the amoxicillin capsules prepared by the present invention are in different media. All have good dissolution.

Experimental Example 2 Stability determination of amoxicillin capsules

Take the amoxicillin capsules (specification 0.5g) prepared in Examples 1 to 6 and Comparative Examples 1 to 13, and place them for 6 months under the conditions of 40±2° C. and RH75±5% respectively. Sampling at 2, 3 and 6 months, tested according to the stability check items, and compared with the 0-day data.

Amoxicillin Capsules were tested in accordance with the indicators and determination methods of sample content, moisture, related substances, dissolution rate, etc. stipulated in the 2015 edition of the Chinese Pharmacopoeia. The specific test results are shown in the following table:

Table 5 List of stability test results

As can be seen from Table 5, the amoxicillin capsules prepared in Comparative Examples 1-13 cannot have both good dissolution and stability at the same time, and the content of related substances is relatively high, while the amoxicillin capsules prepared in Examples 1-6 of the present invention Xilin capsules have good stability and dissolution, and the content of related substances is low. The above experiments show that the present invention produces less impurities in the process of preparing amoxicillin capsules, which is more conducive to the preparation and storage of amoxicillin capsules.

To sum up, the amoxicillin capsules prepared by the present invention can have both good dissolution and stability, and the content of related substances is low.

Obviously, the described embodiments are only some, but not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Claims (10)

1. An amoxicillin capsule, characterized in that the raw materials for making its active ingredients include: 100 parts by weight of amoxicillin medicinal powder and 0.2-0.5 parts by weight of magnesium stearate;

   The amoxicillin medicinal powder is composed of 10-35wt% amoxicillin light powder with a particle size of less than 0.180mm, 10-40wt% amoxicillin heavy powder with a particle size of 0.600-0.850mm, and the remainder with a particle size of 0.180-0.600mm Amoxicillin heavy powder composition.
2. The amoxicillin capsule according to claim 1, wherein the amoxicillin medicinal powder is prepared by using a dry granulator with a roller pressure of 6.0-10.0 MPa.
3. The amoxicillin capsule according to claim 2, wherein in the granulation process of the dry granulator, the ambient humidity is 52-58%.
4. The amoxicillin capsule according to claim 2 or 3, wherein the technological parameters of the dry granulator are: the stirring speed is 15～20rpm, the screw feeding speed is 50～60rpm, and the pressing roller speed is 10～20rpm 15rpm, the temperature of the pressing roller is 20~30℃, the granulation speed is 100~130rpm, the granulation screen aperture is 0.80~0.84mm, and the mesh number of the rotary vibrating screen is 20 mesh, 30 mesh and 80 mesh.
5. The amoxicillin capsule according to any one of claims 1-3, wherein the granularity of magnesium stearate is 0.180-0.850 mm.
6. The preparation method of the amoxicillin capsule described in any one of claims 1-5, it is characterised in that the preparation method is to take the amoxicillin medicinal powder and mix with the heavy powder, and then mix with magnesium stearate alternately for feeding After filling and polishing, the amoxicillin capsules are obtained.
7. The method for preparing amoxicillin capsules according to claim 6, wherein the humidity of the heavy powder mixing and the mixing is 52-58%.
8. The method for preparing amoxicillin capsules according to claim 6 or 7, wherein the mixing speed of the heavy powder is 12-15 r/min and the time is 11-15 min; the mixing speed is 12-15 min. 15r/min, time is 2～5min.
9. The method for preparing amoxicillin capsules according to claim 6 or 7, characterized in that, after the heavy powder mixing is stopped, the obtained amoxicillin powder needs to stand for 5 to 10 minutes, and then take out and alternate with magnesium stearate. Feeding.
10. The preparation method of amoxicillin capsules according to claim 6 or 7, characterized in that, the humidity of the filling and polishing is both 30-43%.

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