Compound amoxicillin tablet, preparation method and use

Abstract

The application belongs to the technical field of medicine, and particularly relates to a compound amoxicillin tablet, a preparation method and application. The compound amoxicillin tablet comprises, in terms of mass fraction, 12.5-62.5% of amoxicillin, 2.5-6.5% of centella asiatica, 24.0-83.9% of starch, 1.0-6.0% of sodium carboxymethyl starch, and 0.1-1.0% of magnesium stearate. Through optimization of the prescription and preparation process, the antibacterial ability and efficacy of amoxicillin are improved, the stability of the amoxicillin tablet is improved, the efficacy of the amoxicillin tablet is stable, and the clinical application of the amoxicillin tablet can be further expanded.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a compound amoxicillin tablet, a preparation method and use. BACKGROUND

[0002] Amoxicillin is an organic compound with a chemical formula of C 16 H 19 N3O5S, which is an antibiotic drug, also known as amoxicillin, and belongs to the ampicillin family of penicillins. It is a white or white crystalline powder with a slight special odor and bitter taste, is a major variety of the second generation of penicillins, is a broad-spectrum semi-synthetic antibiotic, can inhibit the synthesis of bacterial cell walls, has high-efficiency broad-spectrum antibacterial effect, and has very small toxic and side effects, and is commonly used for treating bacterial infections, such as middle ear infection, streptococcal laryngitis, pneumonia, skin infection and urinary tract infection. The World Health Organization recommends the product as the first choice of beta-lactam oral antibiotic, and the product occupies an important position in oral antibiotics.

[0003] Amoxicillin preparations include capsules, tablets, granules, dispersible tablets and the like. The maximum solubility of standard amoxicillin is very limited (2g / l), and during use, it is easy to complex with ions (Ca 2+ , Mg 2+ , etc.) in water to form a precipitate. In addition, due to the beta-lactam ring in the molecular structure of amoxicillin, the chemical property is extremely unstable, and under acid or alkali conditions, it is easy to degrade to form an inactive molecule. The solubility and chemical stability of amoxicillin in water are contradictory to each other: the solubility of amoxicillin in an alkaline environment is increased, but the stability is poor, in addition, amoxicillin is easy to discolor when heated or stored for a long time, which leads to a decrease in effective components and further reduces the drug efficacy. SUMMARY

[0004] In view of the deficiencies of the prior art, the application provides a compound amoxicillin tablet with high safety, high stability and strong efficacy, which overcomes the defect that amoxicillin is easy to decompose by optimizing the prescription and preparation process, improves the antibacterial capacity of amoxicillin, and further improves the safety of drug use.

[0005] Specifically, the technical scheme of the application is as follows:

[0006] A first object of the application is to provide a prescription of a compound amoxicillin tablet, in which each component is calculated in terms of mass fraction as follows: 12.5% to 62.5% of amoxicillin, 2.5% to 6.5% of centella asiatica, 24.0% to 83.9% of starch, 1.0% to 6.0% of sodium carboxymethyl starch, and 0.1% to 1.0% of magnesium stearate.

[0007] The second object of the present application is to provide a preparation method of the compound amoxicillin tablet, comprising the following steps:

[0008] (1) The Centella asiatica is washed, dried, cut, soaked in a 5.0-10.0% sodium bicarbonate aqueous solution, dried after being taken out, ground, sieved, and then obtained as Centella asiatica powder for use;

[0009] (2) The amoxicillin and the Centella asiatica powder of step (1) are ground according to the prescription amount, respectively, and then sieved through a 100-mesh sieve, mixed uniformly, and then added with sodium carboxymethyl starch, starch and magnesium stearate sieved through an 80-mesh sieve, mixed uniformly, and then the powder is directly compressed into tablets.

[0010] The Centella asiatica is used as whole herb, bitter and pungent in taste, and cold in nature, and usually has the effects of clearing heat and dampness, detoxifying and swelling, relieving jaundice and stranguria, and activating blood and relieving pain, and is clinically used for treating damp-heat jaundice, carbuncle and swelling, injury, poisoning diarrhea, sore throat, and gallstone, etc., and the prior art does not find that it can assist in improving the efficacy of antibiotic drugs.

[0011] In one of the embodiments, the compound amoxicillin tablet is calculated by mass fraction as follows: 31.25% of amoxicillin, 4.5% of Centella asiatica, 61.25% of starch, 2.5% of sodium carboxymethyl starch, and 0.5% of magnesium stearate.

[0012] In one of the embodiments, the compound amoxicillin tablet is calculated by mass fraction as follows: 12.5% of amoxicillin, 2.5% of Centella asiatica, 83.9% of starch, 1.0% of sodium carboxymethyl starch, and 0.1% of magnesium stearate.

[0013] In one of the embodiments, the compound amoxicillin tablet is calculated by mass fraction as follows: 62.5% of amoxicillin, 6.5% of Centella asiatica, 24.0% of starch, 6.0% of sodium carboxymethyl starch, and 1.0% of magnesium stearate.

[0014] Further, in some embodiments, the compound amoxicillin tablet can be coated to cover the bad smell of the drug and improve the compliance of taking the medicine, and the coating material is Opadry, and the coating weight is 2.0-4.0%.

[0015] The third object of the present application is to provide the use of the compound amoxicillin tablet in preparing antibiotic drugs.

[0016] Compared with the prior art, the present application has the following beneficial effects:

[0017] The application creatively adds pure natural traditional Chinese medicine Centella asiatica in the prescription of amoxicillin tablets, and pretreats the Centella asiatica with a certain concentration of sodium bicarbonate aqueous solution, after the pretreatment, the Centella asiatica is added to the prescription of amoxicillin tablets, which not only plays a synergistic auxiliary role in improving the bacteriostatic ability of amoxicillin, but also improves the stability of amoxicillin tablets, reduces the decomposition rate of the effective components, and stabilizes the drug efficacy. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 Content change of accelerated test of compound amoxicillin tablets of examples 1-3 and compound amoxicillin tablets of comparative examples 1-3

[0019] Figure 2 Content change of accelerated test of compound amoxicillin tablets of examples 4-6, compound amoxicillin tablets of comparative examples 4 and 5, and commercially available preparation (amoxicillin tablets, GMP code H13021771) DETAILED DESCRIPTION

[0020] In order to make the purpose, technical scheme of the application more clear, the following examples are combined to further illustrate the application, but the protection scope of the application is not limited to these examples, and the examples are only used to explain the application. Those skilled in the art should understand that any change or equivalent replacement without departing from the concept of the application is included in the protection scope of the application.

[0021] Example 1 compound amoxicillin tablet

[0022] Formula:

[0023] Mass fraction (%) Amoxicillin 31.25 Centella asiatica 4.5 Starch 61.25 Sodium carboxymethyl starch 2.5 Magnesium stearate 0.5

[0024] Preparation method:

[0025] (1) wash, dry, and cut the Centella asiatica, soak it in a 6.5% sodium bicarbonate aqueous solution for 5-10 hours, dry it after taking it out, crush it, sieve it, obtain the Centella asiatica powder, and reserve it for use;

[0026] (2) according to the prescription amount, grind the amoxicillin and the Centella asiatica powder of step (1) respectively, sieve them through a 100-mesh sieve, mix them uniformly, add the ground sodium carboxymethyl starch and starch sieved through an 80-mesh sieve, mix them again, add the magnesium stearate sieved through an 80-mesh sieve, mix them again, and directly compress the powder into tablets.

[0027] Example 2 compound amoxicillin tablet

[0028] Formula:

[0029] Mass fraction (%) Amoxicillin 12.5 Centella asiatica 2.5 Starch 83.9 Sodium carboxymethyl starch 1.0 Magnesium stearate 0.1

[0030] Preparation method:

[0031] (1) Yunnan snow lotus is washed, dried, cut into pieces, and soaked in a 5.0% sodium bicarbonate aqueous solution for 5-10 hours. After being taken out, it is dried, crushed, sieved, and obtained as Yunnan snow lotus powder for standby use;

[0032] (2) Amoxicillin and the Yunnan snow lotus powder of step (1) are respectively ground into powder, sieved through a 100-mesh sieve, mixed uniformly, and then carboxymethyl starch sodium, starch, and magnesium stearate sieved through an 80-mesh sieve are added and mixed uniformly. The powder is directly compressed into tablets to obtain the compound amoxicillin tablets.

[0033] Example 3 Compound Amoxicillin Tablets

[0034] Formulation:

[0035] Mass fraction (%) Amoxicillin 62.5 Centella asiatica 6.5 Starch 24.0 Sodium carboxymethyl starch 6.0 Magnesium stearate 1.0

[0036] Preparation method:

[0037] (1) Yunnan snow lotus is washed, dried, cut into pieces, and soaked in a 10.0% sodium bicarbonate aqueous solution for 5-10 hours. After being taken out, it is dried, crushed, sieved, and obtained as Yunnan snow lotus powder for standby use;

[0038] (2) Amoxicillin and the Yunnan snow lotus powder of step (1) are respectively ground into powder, sieved through a 100-mesh sieve, mixed uniformly, and then carboxymethyl starch sodium, starch, and magnesium stearate sieved through an 80-mesh sieve are added and mixed uniformly. The powder is directly compressed into tablets to obtain the compound amoxicillin tablets.

[0039] Example 4 Compound Amoxicillin Tablets

[0040] Formulation:

[0041] Mass fraction (%) Amoxicillin 31.25 Centella asiatica 4.5 Starch 61.25 Sodium carboxymethyl starch 2.5 Magnesium stearate 0.5

[0042] Preparation method:

[0043] (1) Yunnan snow lotus is washed, dried, cut into pieces, and soaked in a 6.5% sodium bicarbonate aqueous solution for 5-10 hours. After being taken out, it is dried, crushed, sieved, and obtained as Yunnan snow lotus powder for standby use;

[0044] (2) Amoxicillin and the Yunnan snow lotus powder of step (1) are respectively ground into powder, sieved through a 100-mesh sieve, mixed uniformly, and then carboxymethyl starch sodium, starch, and magnesium stearate sieved through an 80-mesh sieve are added and mixed uniformly. The powder is directly compressed into tablets to obtain the compound amoxicillin tablets.

[0045] (3) Opadry coating premix is prepared, and the compound amoxicillin tablets of step (2) are coated. The coating weight is increased by 3.0%.

[0046] Example 5 Compound Amoxicillin Tablets

[0047] Formula:

[0048]

[0049] Preparation method:

[0050] (1) The Centella asiatica is washed, dried, cut into pieces, soaked in a 6.5% sodium bicarbonate aqueous solution for 5-10 hours, dried after taking out, crushed, sieved, to obtain Centella asiatica powder, for use;

[0051] (2) The amoxicillin and the Centella asiatica powder of step (1) are respectively ground to fine powder, sieved through a 100-mesh sieve, mixed uniformly, the carboxymethyl starch sodium and the starch ground to fine powder through an 80-mesh sieve are added, mixed uniformly, the magnesium stearate sieved through an 80-mesh sieve is added, mixed uniformly, and the powder is directly compressed into tablets, to obtain the compound amoxicillin tablet.

[0052] (3) The compound amoxicillin tablet obtained in step (2) is coated with an Opadry coating premix, and the coating weight is increased by 2.0%.

[0053] Example 6 Compound amoxicillin tablet

[0054] Formula:

[0055] Mass fraction (%) Amoxicillin 62.5 Centella asiatica 6.5 Starch 24.0 Sodium carboxymethyl starch 6.0 Magnesium stearate 1.0

[0056] Preparation method:

[0057] (1) The Centella asiatica is washed, dried, cut into pieces, soaked in a 6.5% sodium bicarbonate aqueous solution for 5-10 hours, dried after taking out, crushed, sieved, to obtain Centella asiatica powder, for use;

[0058] (2) The amoxicillin and the Centella asiatica powder of step (1) are respectively ground to fine powder, sieved through a 100-mesh sieve, mixed uniformly, the carboxymethyl starch sodium and the starch ground to fine powder through an 80-mesh sieve are added, mixed uniformly, the magnesium stearate sieved through an 80-mesh sieve is added, mixed uniformly, and the powder is directly compressed into tablets, to obtain the compound amoxicillin tablet.

[0059] (3) The compound amoxicillin tablet obtained in step (2) is coated with an Opadry coating premix, and the coating weight is increased by 4.0%.

[0060] Comparative example 1 Compound amoxicillin tablet

[0061] Formula:

[0062]

[0063] Preparation method:

[0064] The amoxicillin is taken by prescription amount, ground, passed through a 100 mesh sieve, carboxymethyl starch sodium and starch ground through an 80 mesh sieve are added, mixed, and then magnesium stearate passed through an 80 mesh sieve is added, mixed, and the powder is directly compressed into tablets.

[0065] Comparative Example 2 Compound Amoxicillin Tablets

[0066] Formula:

[0067] Mass fraction (%) Amoxicillin 31.25 Forsythia extract 4.5 Starch 61.25 Sodium carboxymethyl starch 2.5 Magnesium stearate 0.5

[0068] Preparation Method:

[0069] (1) Forsythia extract: dry forsythia is taken, 7-8 times the weight of forsythia is added, and then the mixture is placed in a 95-100℃ water bath for 4-5h, and then concentrated under reduced pressure to obtain the extract. The extract is filtered through a 0.22μm filter to obtain the forsythia extract, which is reserved;

[0070] (2) The amoxicillin is taken by prescription amount, ground, passed through a 100 mesh sieve, the forsythia extract of step (1), carboxymethyl starch sodium and starch ground through an 80 mesh sieve are added, and the mixture is made into soft material, dried, and then magnesium stearate passed through an 80 mesh sieve is added, mixed, and compressed into tablets.

[0071] Comparative Example 3 Compound Amoxicillin Tablets

[0072] Formula:

[0073] Mass fraction (%) Amoxicillin 31.25 Centella asiatica 8.5 Starch 57.25 Sodium carboxymethyl starch 2.5 Magnesium stearate 0.5

[0074] Preparation Method:

[0075] (1) The gotu kola is washed, dried, cut, soaked in a 6.5% sodium bicarbonate aqueous solution for 5-10h, dried, ground, and sieved to obtain gotu kola powder, which is reserved;

[0076] (2) The amoxicillin and the gotu kola powder of step (1) are taken by prescription amount, ground, passed through a 100 mesh sieve, mixed, carboxymethyl starch sodium and starch ground through an 80 mesh sieve are added, mixed, and then magnesium stearate passed through an 80 mesh sieve is added, mixed, and the powder is directly compressed into tablets.

[0077] Comparative Example 4 Compound Amoxicillin Tablets

[0078] Formula:

[0079] Mass fraction (%) Amoxicillin 31.25 Centella asiatica extract 4.5 Starch 61.25 Sodium carboxymethyl starch 2.5 Magnesium stearate 0.5

[0080] Preparation Method:

[0081] (1) The gotu kola is washed, dried, ground, and sieved to obtain gotu kola powder, which is reserved;

[0082] (2) Grind amoxicillin and the Centella asiatica powder described in step (1) according to the prescribed amount, pass through a 100-mesh sieve, mix evenly, add sodium starch glycolate and starch that have been finely ground through an 80-mesh sieve, mix evenly, then add magnesium stearate that has been passed through an 80-mesh sieve, mix evenly, and directly compress the powder into tablets to obtain the product.

[0083] Comparative Example 5 Compound Amoxicillin Tablets

[0084] formula:

[0085] Figure 1 Figure 2 31.25 Mass fraction (%) 4.5 Amoxicillin 61.25 Centella asiatica 2.5 Starch 0.5

[0086] Preparation method:

[0087] (1) Wash, dry, and chop Centella asiatica, add 7 to 8 times the weight of Centella asiatica in water, and then extract in a 95 to 100° C. water bath for 4 to 5 hours. Then, concentrate under reduced pressure to obtain an extract, filter through a 0.22 μm filter membrane to obtain a Centella asiatica extract for later use. The Centella asiatica extract contains 0.9 to 1.3% of asiaticoside and madecassoside.

[0088] (2) According to the prescribed amount, amoxicillin passed through a 100-mesh sieve, sodium carboxymethyl starch ground through an 80-mesh sieve, starch, and the Centella asiatica powder extract of step (1) are mixed evenly, a soft material is prepared, and the material is dried. Magnesium stearate passed through an 80-mesh sieve is then added, the mixture is mixed evenly, and the powder is pressed into tablets to obtain the product.

[0089] Verification Example

[0090] 1. In vitro antibacterial test of the compound amoxicillin tablets of the present invention

[0091] To compare the in vitro antibacterial effects of the compound amoxicillin tablets of Examples 1 to 3 of the present invention, the compound amoxicillin tablets of Comparative Examples 1 to 5, and commercially available amoxicillin tablets (National Medicine Standard No. H13021771) on Pasteurella, Salmonella, and Pseudomonas aeruginosa, the minimum inhibitory concentrations (MICs) for each bacterial species were determined using the microbroth dilution method. Pasteurella, Salmonella, and Pseudomonas aeruginosa isolates were inoculated into MH broth medium and cultured in a 37°C incubator for 24 hours. The proliferated bacteria were counted by the McFarland standard turbidimetric method until the growth turbidity reached 3 to 6×10 8 cfu / mL. Then dilute the bacteria to 3-6×10 6The bacteria solution with the concentration of cfu / mL is prepared for standby. 96 sterile plastic culture plates are taken respectively, 50 μL of M-H broth medium is added into the first to the 24th wells, 50 μL of the mixed solution is sucked out and added into the second well, and the same method is used to dilute to the 22th well, and 50 μL is discarded. The 23th well is a negative control well with only the drug solution without the bacteria. The 24th well is a positive control well with only the bacteria without the drug solution. The drug concentration of each example in each well is respectively 10000, 5000, 2500, 1250, 625, 312.5, 156.25, 78.125, 39.0625, 19.5313, 9.7656, 4.8828, 2.4414, 1.2207, 0.6104, 0.3052, 0.1526, 0.0763, 0.03815, 0.01907, 0.0095, 0.0048 μg / mL. The bacteria culture plates are respectively cultured in a 37℃ incubator for 24 hours, and the results are observed. The minimum inhibitory concentration (MIC) value is determined by the microdilution method (the minimum drug concentration inhibiting more than 80% of the bacteria growth is the MIC value), and the results are shown in Table 1.

[0092] Table 1 Minimum inhibitory concentration (MIC) value of each example for each bacteria

[0093]

[0094] Table 1 shows that the compound amoxicillin tablets have strong inhibitory ability, and have good inhibitory effect on Pasteurella, Salmonella, Pneumococcus and Escherichia coli. Compared with the compound amoxicillin tablets of Comparative Examples 1-5 and the commercially available amoxicillin tablets, the compound amoxicillin tablets have strong drug efficacy.

[0095] 2. Stability verification of the compound amoxicillin tablets of the present application

[0096] The amoxicillin content is determined by the accelerated test of high performance liquid chromatography at the 1st month, the 2nd month, the 3rd month and the 6th month, and the determination method is as follows:

[0097] Test solution: an appropriate amount of the product (about equivalent to amoxicillin, C 16 H 19N3O5S, accurately weigh, place in a 50 ml volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well. Reference solution: take amoxicillin reference substance, accurately weigh, add mobile phase to dissolve and dilute to the mark to prepare a solution containing about 0.5 mg of amoxicillin (calculated as C16H19N3O5S) per 1 ml. System suitability solution: take about 25 mg of amoxicillin system suitability reference substance, place in a 50 ml volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well. Chromatographic conditions: use octadecylsilane bonded silica gel as the filler; use 0.05 mol / L potassium dihydrogen phosphate solution (adjust the pH value to 5.0 with 2 mol / L potassium hydroxide solution)-acetonitrile (97.5:2.5) as the mobile phase; the detection wavelength is 254 nm; the injection volume is 20 μl. System suitability requirements: the chromatogram of the system suitability solution should be consistent with the standard chromatogram. Determination method: accurately measure the test sample solution and the reference solution, respectively inject into the liquid chromatograph, and record the chromatogram. Calculate by the external standard method with peak area.

[0098] Sodium carboxymethyl starch The content changes of the compound amoxicillin tablets of examples 1-3 and the compound amoxicillin tablets of comparative examples 1-3 in the accelerated test, Magnesium stearate Mass fraction (%) Amoxicillin Centella asiatica Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Centella asiatica Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Centella asiatica Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Forsythia extract Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Centella asiatica Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Centella asiatica extract Starch Sodium carboxymethyl starch Magnesium stearate Figure 1 Figure 2 Mass fraction (%) Amoxicillin Centella asiatica Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Centella asiatica Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Centella asiatica Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Centella asiatica Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Forsythia extract Starch Sodium carboxymethyl starch Magnesium stearate Mass fraction (%) Amoxicillin Centella asiatica Starch Sodium carboxym The content changes of the compound amoxicillin tablets of examples 4-6, the compound amoxicillin tablets of comparative examples 4 and 5, and the commercially available amoxicillin tablets in the accelerated test, and the comparison shows that the content of the compound amoxicillin tablets of examples 1-6 is stable, the content of amoxicillin remains unchanged after 6 months of accelerated test, and the drug efficacy is stable.

Claims

1. A compound amoxicillin tablet, characterized in that: The compound amoxicillin tablets are calculated by mass fraction as follows: 12.5-62.5% amoxicillin, 2.5-6.5% Centella asiatica, 24.0-83.9% starch, 1.0-6.0% sodium starch glycolate, and 0.1-1.0% magnesium stearate; The preparation method of the compound amoxicillin tablets comprises the following steps: (1) Wash, dry, and chop Centella asiatica, soak it in a 5.0-10.0% sodium bicarbonate aqueous solution for 5-10 hours, take it out, dry it, crush it, and sieve it to obtain Centella asiatica powder for later use; (2) Grind amoxicillin and the Centella asiatica powder described in step (1) according to the prescribed amount, pass through a 100-mesh sieve, mix well, add sodium starch glycolate and starch that have been finely ground through an 80-mesh sieve, mix well, then add magnesium stearate that has been passed through an 80-mesh sieve, mix well, and directly compress the powder into tablets to obtain the product.

2. The compound amoxicillin tablet according to claim 1, characterized in that The compound amoxicillin tablets are calculated by mass fraction as follows: 31.25% amoxicillin, 4.5% Centella asiatica, 61.25% starch, 2.5% sodium starch glycolate, and 0.5% magnesium stearate.

3. The compound amoxicillin tablet according to claim 1, characterized in that The compound amoxicillin tablets are calculated by mass fraction as follows: 12.5% ​​amoxicillin, 2.5% Centella asiatica, 83.9% starch, 1.0% sodium starch glycolate, and 0.1% magnesium stearate.

4. The compound amoxicillin tablet according to claim 1, characterized in that The compound amoxicillin tablets are calculated by mass fraction as follows: 62.5% amoxicillin, 6.5% Centella asiatica, 24.0% starch, 6.0% sodium starch glycolate, and 1.0% magnesium stearate.

5. The compound amoxicillin tablet according to any one of claims 1 to 4, characterized in that The compound amoxicillin tablets can also be coated.

6. The compound amoxicillin tablet according to claim 5, characterized in that The coating weight gain is 2.0-4.0%.

7. The compound amoxicillin tablet according to claim 5, characterized in that The coating material is Opadry.

8. The compound amoxicillin tablet according to claim 5, characterized in that The mass fraction of the sodium bicarbonate aqueous solution is 6.5%.

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