Compound amoxicillin, clindamycin and potassium tretinate powder and preparation method thereof

Abstract

The invention relates to the technical field of veterinary drug preparations, and particularly discloses compound amoxicillin, clindamycin and potassium tretinate powder and a preparation method thereof. The compound amoxicillin, clavulanate potassium powder is prepared from the following components in parts by weight: 5 to 20 parts of amoxicillin, 1.25 to 5 parts of clavulanate potassium and 20 to 50 parts of an inclusion agent, and the inclusion agent is porous starch subjected to alcohol-alkali treatment. The preparation method of the compound amoxicillin-clavulanate potassium powder is characterized by comprising the following steps: mixing and stirring amoxicillin, clavulanate potassium and an inclusion agent according to the formula ratio for 20-30 minutes, then adding an antioxidant and a diluent according to the formula ratio, mixing for 15-20 minutes, and sub-packaging. The compound amoxicillin, clindamycin and potassium tretinate powder disclosed by the invention has the advantages of good water solubility and good stability.

Description

Technical Field

[0001] The present application relates to the technical field of veterinary drug preparations, and in particular to a compound amoxicillin-clindamycin potassium powder and a preparation method thereof. Background Art

[0002] Amoxicillin is a semi-synthetic penicillin β-lactam antibiotic. It is a white or off-white crystalline powder. It is one of the most widely used oral semi-synthetic penicillins. It belongs to the reproductive period bactericide (Class I) and is a penicillin with an amino side chain. However, it is several times more potent than penicillin and has fewer toxic side effects. It can hinder the synthesis of cell wall mucopeptides, causing bacterial cell wall defects, bacterial swelling, lysis and death. It is mainly used for infections caused by Gram-positive bacteria and some Gram-negative bacteria. In veterinary clinical practice, it is often used for infections caused by Gram-positive bacteria such as Staphylococcus aureus and Streptococcus, and Gram-negative bacteria such as Escherichia coli and Pasteurella.

[0003] Potassium clavulanate is a β-lactamase inhibitor that can combine with β-lactamase to form an irreversible conjugate, and its own antibacterial activity is weak. Potassium clavulanate combined with amoxicillin can significantly improve the antibacterial activity of amoxicillin and its ability to penetrate cell membranes, increase the efficacy by several times or even dozens of times, and can restore the sensitivity of resistant strains to drugs, overcoming the problem of bacterial resistance to amoxicillin alone. The combined use of amoxicillin and potassium clavulanate is suitable for lower respiratory tract infections, otitis media, sinusitis caused by microbial β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis, urinary tract and skin soft tissue infections caused by microbial β-lactamase-producing Staphylococcus aureus and enzyme-producing Enterobacteriaceae such as Escherichia coli and Klebsiella; it can also be used for mild and moderate infections caused by enterococci.

[0004] However, amoxicillin contains a β-lactam ring in its molecular structure, which is extremely unstable in chemical properties and easily degraded under acidic or alkaline conditions to form inactive molecules; amoxicillin is poorly soluble in water and has extremely low solubility in water, which is not conducive to absorption in animals, seriously affecting the efficacy of amoxicillin; and amoxicillin is prone to discoloration when exposed to heat or stored for a long time, which reduces the content of active ingredients and thus reduces the efficacy. In addition, the existing raw materials of amoxicillin and potassium clavulanate are unstable under conditions of high temperature and high humidity, and are prone to moisture absorption and degradation, resulting in poor quality stability of the preparation products, especially aqueous solutions, where the effective content degrades rapidly, which is not conducive to long-term storage, bringing hidden dangers to the safety and effectiveness in clinical use.

[0005] Since amoxicillin is mainly in the form of soluble powder in veterinary drugs, it is convenient to transport and prepare liquid for administration. Therefore, improving the water solubility and stability of compound amoxicillin and clavulanate potassium preparations is an urgent problem to be solved. Summary of the invention

[0006] In view of the poor water solubility and stability of the existing compound amoxicillin-clavulanate potassium powder, the present application proposes a compound amoxicillin-clavulanate potassium powder and a preparation method thereof.

[0007] In the first aspect, the present application proposes a compound amoxicillin-clindamycin potassium powder, which adopts the following technical solution.

[0008] A compound amoxicillin-clinamide potassium powder comprises the following components in parts by weight: 5-20 parts by weight of amoxicillin, 1.25-5 parts by weight of potassium clavulanate, and 20-50 parts by weight of an inclusion agent, wherein the inclusion agent is porous starch treated with alcohol and alkali.

[0009] By adopting the above technical solution, since amoxicillin and potassium clavulanate are unstable, porous starch is used for embedding, and amoxicillin and potassium clavulanate enter the porous structure of the porous starch, thereby improving stability; and the water solubility of the porous starch can be further improved by subjecting the porous starch to alcohol-alkali treatment, thereby improving the water solubility of the porous starch, thereby improving the water solubility of the pharmaceutical composition.

[0010] Preferably, the alcohol-alkali treatment is specifically as follows: porous starch and 80% ethanol are configured into starch milk with a mass concentration of 12-15%, stirred at 40-50°C for 1h, NaOH solution is added dropwise at a uniform rate, reacted for 20-50min after the addition is complete, filtered, 95% ethanol is added, neutralized to pH 7.0 with hydrochloric acid ethanol, filtered, washed twice with 95% ethanol and once with anhydrous ethanol, dried, crushed and sieved.

[0011] Preferably, the porous starch is one or more of porous potato starch and porous cassava starch.

[0012] Preferably, the inclusion agent is further subjected to the following modification treatment: the porous starch subjected to alcohol-alkali treatment is cross-linked with sodium gluconate and polysaccharide.

[0013] Preferably, the specific operation of the modification treatment is: uniformly mix the porous starch, polysaccharide and sodium gluconate solution in a mass ratio of (0.1-0.25):(0.02-0.05):(0.5-1.0), react at 120-130°C for 1-2h, precipitate, wash, dry, grind and sieve.

[0014] Preferably, the polysaccharide is Bletilla striata polysaccharide.

[0015] By adopting the above technical solution, after the porous starch is treated with alcohol-alkali, although the porous structure increases, the particle structure becomes unstable, the strength is greatly reduced, and it is easy to collapse. Therefore, sodium gluconate and polysaccharide are needed to be cross-linked and modified to improve the mechanical strength of the porous starch. The pore structure of the porous starch is still maintained after the sodium gluconate cross-linking treatment, so it will not affect the adsorption performance, and because the mechanical structure is strengthened, the carrying capacity of the adsorbate is also improved. The cross-linked polysaccharide structure can further improve the water solubility of the porous starch because it contains rich hydroxyl groups, thereby improving the water solubility of the compound preparation.

[0016] When the polysaccharide used is Bletilla striata polysaccharide, it has biological activities such as anti-inflammatory and antioxidant, and can inhibit the growth of various bacteria, which can improve the antibacterial effect of the compound preparation; Bletilla striata polysaccharide also has an α-helical structure, and therefore has certain inclusion properties, which can further improve the adsorption capacity of porous starch.

[0017] Preferably, the compound amoxicillin-clindamycin potassium powder further comprises 0.5-1 parts by weight of an antioxidant and 20-75 parts by weight of a diluent.

[0018] Preferably, the antioxidant is one or more of sodium thiosulfate, sodium pyrosulfite, and sodium bisulfite; and the diluent is one or more of anhydrous glucose, mannitol, anhydrous lactose, and soluble starch.

[0019] In the second aspect, the present application also proposes a method for preparing compound amoxicillin-clindamycin potassium powder, and adopts the following technical scheme.

[0020] A preparation method of compound amoxicillin-clavulanate potassium powder comprises the following steps: mixing and stirring amoxicillin, potassium clavulanate and a inclusion agent in a formula amount for 20-30 minutes, then adding an optional antioxidant and a diluent in a formula amount, mixing for 15-20 minutes, and packaging.

[0021] By adopting the above technical solution, a compound amoxicillin-clindamycin potassium powder with good water solubility and stability can be prepared by a relatively simple process.

[0022] In summary, this application has the following beneficial effects:

[0023] 1. The present application improves the water solubility and stability of compound amoxicillin-clindamycin potassium powder by using porous starch treated with alcohol and alkali as inclusion agent;

[0024] 2. The present application further improves the water solubility and stability of the compound amoxicillin-clindamycin potassium powder by further cross-linking and modifying the porous starch treated with alcohol and alkali and then using it as an inclusion agent;

[0025] 3. The present application adopts a new inclusion agent, and only a simple preparation process is required to obtain a highly water-soluble and highly stable compound amoxicillin-clindamycin potassium powder. DETAILED DESCRIPTION

[0026] The present application is further described in detail below in conjunction with the examples. It is particularly noted that if no specific conditions are specified in the following examples, the experiments are carried out according to conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following examples can be obtained from common commercial sources.

[0027] Preparation Example 1 - Alcohol-alkali treated porous potato starch

[0028] Weigh 50g (dry basis) of porous potato starch and place it in a container, add appropriate amount of water and ethanol to make starch milk with a mass concentration of 13%, then place the container in a water bath and keep it at 45°C, keep stirring continuously; and uniformly add a certain amount of 3mol / L NaOH to the starch milk at a speed of 4mL / min, and after the addition is completed, react for 40min to fully react; after the reaction is completed, filter the starch milk, pour an appropriate amount of 95% ethanol, and neutralize it with 3% (V / V) hydrochloric acid ethanol to pH 7.0; filter, wash twice with 95% ethanol, and finally wash once with anhydrous ethanol; dry at 80°C, crush, and sieve to obtain.

[0029] Preparation Example 2 - Alcohol-alkali treated porous cassava starch

[0030] Weigh 50g (dry basis) of porous cassava starch and place it in a container, add appropriate amount of water and ethanol to make starch milk with a mass concentration of 13%, then place the container in a water bath and keep it at 45°C, keep stirring continuously; and uniformly add a certain amount of 3mol / L NaOH to the starch milk at a speed of 4mL / min, and react for 40min to fully react it after the addition is completed; after the reaction is completed, filter the starch milk, pour an appropriate amount of 95% ethanol, and neutralize it with 3% (V / V) hydrochloric acid ethanol to pH7.0; filter, wash with 95% ethanol twice, and finally wash with anhydrous ethanol once; dry at 80°C, crush, and sieve to obtain the product.

[0031] Preparation Example 3 - Alcohol-alkali treated porous corn starch

[0032] Weigh 50 g (dry basis) of porous corn starch and place it in a container, add appropriate amount of water and ethanol to make a starch milk with a mass concentration of 13%, then place the container in a water bath and keep it at 45°C, keep stirring continuously; and uniformly add a certain amount of 3 mol / L NaOH to the starch milk at a speed of 4 mL / min, and after the addition is completed, react for 40 minutes to fully react; after the reaction is completed, filter the starch milk, pour in an appropriate amount of 95% ethanol, and neutralize it to pH 7.0 with 3% (V / V) hydrochloric acid ethanol; filter, wash twice with 95% ethanol, and finally wash once with anhydrous ethanol; dry at 80°C, crush, and sieve to obtain the product.

[0033] Preparation Example 4

[0034] The alcohol-alkali treated porous potato starch of Preparation Example 1, sodium gluconate and Bletilla striata polysaccharide were mixed evenly in a mass ratio of 0.1:0.02:0.5, reacted at 120° C. for 2 h, precipitated and washed twice, dried at 80° C., and ground and sieved to obtain the product.

[0035] Preparation Example 5

[0036] The porous potato starch treated with alcohol and alkali in Preparation Example 1, sodium gluconate and Bletilla striata polysaccharide were uniformly mixed in a mass ratio of 0.25:0.05:1.0, reacted at 120° C. for 2 h, precipitated and washed twice, dried at 80° C., and ground and sieved to obtain the product.

[0037] Preparation Example 6

[0038] The porous potato starch treated with alcohol and alkali in Preparation Example 1, sodium gluconate and Bletilla striata polysaccharide were mixed evenly in a mass ratio of 0.15:0.04:0.8, reacted at 120° C. for 2 h, precipitated and washed twice, dried at 80° C., and ground and sieved to obtain the product.

[0039] Preparation Example 7

[0040] The porous potato starch treated with alcohol and alkali in Preparation Example 1, sodium gluconate and seaweed polysaccharide were uniformly mixed in a mass ratio of 0.15:0.04:0.8, reacted at 130° C. for 1 h, precipitated and washed twice, dried at 80° C., and ground and sieved to obtain the product.

[0041] Example 1

[0042] Each 100g of the compound amoxicillin-clindamycin potassium powder contains 5g of amoxicillin, 1.25g of potassium clavulanate, 20g of inclusion agent, 0.5g of antioxidant sodium pyrosulfite, and the rest is anhydrous glucose. The inclusion agent is the alcohol-alkali treated porous potato starch in Preparation Example 1.

[0043] Preparation method: (1) Take the prescribed amount of amoxicillin and potassium clavulanate, put the inclusion agent into a mixer, turn on the mixer and mix for 30 minutes, then add the prescribed amount of antioxidant sodium metabisulfite and anhydrous glucose, mix for 15 minutes, and package after the intermediate product passes the inspection.

[0044] Quality inspection: The obtained soluble powder is white powder or off-white powder; all inspections are in compliance with the provisions of the Chinese Veterinary Pharmacopoeia on soluble powder.

[0045] Example 2

[0046] Each 100g of the compound amoxicillin-clindamycin potassium powder contains 10g of amoxicillin, 2.5g of potassium clavulanate, 35g of inclusion agent, 0.8g of antioxidant sodium pyrosulfite, and the rest is anhydrous glucose. The inclusion agent is the porous potato starch treated with alcohol-alkali in Preparation Example 1.

[0047] The preparation method is the same as that in Example 1.

[0048] Example 3

[0049] Each 100g of the compound amoxicillin-clindamycin potassium powder contains 20g of amoxicillin, 5g of potassium clavulanate, 50g of inclusion agent, 1g of antioxidant sodium pyrosulfite, and the rest is anhydrous glucose. The inclusion agent is the alcohol-alkali treated porous potato starch in Preparation Example 1.

[0050] The preparation method is the same as that in Example 1.

[0051] Example 4

[0052] Compared with Example 3, the only difference is that the inclusion agent is the porous cassava starch treated with alcohol and alkali in Preparation Example 2.

[0053] Example 5

[0054] Compared with Example 3, the only difference is that the inclusion agent is the porous corn starch treated with alcohol and alkali in Preparation Example 3.

[0055] Example 6

[0056] Compared with Example 3, the only difference is that the inclusion agent is the modified starch prepared in Preparation Example 4.

[0057] Example 7

[0058] Compared with Example 3, the only difference is that the inclusion agent is the modified starch prepared in Preparation Example 5.

[0059] Example 8

[0060] Compared with Example 3, the only difference is that the inclusion agent is the modified starch prepared in Preparation Example 6.

[0061] Example 9

[0062] Compared with Example 3, the only difference is that the inclusion agent is the modified starch prepared in Preparation Example 7.

[0063] Comparative Example 1

[0064] Compared with Example 3, the only difference is that the inclusion agent is porous potato starch.

[0065] Comparative Example 2

[0066] Compared with Example 3, the only difference is that the inclusion agent is β-cyclodextrin.

[0067] Comparative Example 3

[0068] Compared with Example 3, the only difference is that the inclusion agent is not contained.

[0069] Performance testing

[0070] 1. Solubility test

[0071] Specific method: According to the relevant provisions of the "Chinese Veterinary Pharmacopoeia" on amoxicillin soluble powder, weigh 50 mg of the soluble powder prepared in the example and the comparative example, add 100 mL of tap water to make a solution, observe the dissolution, and record the dissolution time.

[0072] Acceleration conditions: Carry out the accelerated test at a temperature of 40±2℃ and a relative humidity of 65±5%RH, observe the dissolution of the sample, and record the dissolution time.

[0073] Results: The dissolution of the soluble powders of the examples and comparative examples in tap water was investigated at 0 (when the product was prepared), 1, 3, and 6 months.

[0074] The above embodiments and comparative examples were tested three times in parallel, and the results were averaged. The experimental results are shown in Table 1.

[0075] Table 1 Dissolution time of each embodiment and comparative example

[0076]

[0077]

[0078] 2. Determination of amoxicillin and potassium clavulanate in soluble powder by HPLC

[0079] Mobile phase A: 0.05 mol / L phosphate buffer (take 0.05 mol / L potassium dihydrogen phosphate solution, adjust the pH value to 5.0 with 2 mol / L potassium hydroxide solution)-acetonitrile (99:1).

[0080] Mobile phase B: 0.05 mol / L phosphate buffer (pH 5.0)-acetonitrile (80:20).

[0081] Test solution: Take an appropriate amount of the soluble powder of each embodiment and comparative example of the present application, accurately weigh it, add mobile phase A to dissolve it and quantitatively dilute it to prepare a solution containing about 2.0 mg of amoxicillin (calculated as C16H19N3O5S) per 1 ml.

[0082] Reference solution: Take an appropriate amount of amoxicillin reference substance, weigh it accurately, add mobile phase A to dissolve it and quantitatively dilute it to make a solution containing approximately 20 μg of amoxicillin (calculated as C16H19N3O5S) per 1 ml.

[0083] System suitability solution: Take an appropriate amount of amoxicillin system suitability reference substance, dissolve it in mobile phase A and dilute it to make a solution containing approximately 2.0 mg per 1 ml.

[0084] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; 0.05 mol / L phosphate buffer (take 0.05 mol / L potassium dihydrogen phosphate solution, adjust the pH value to 5.0 with 2 mol / L potassium hydroxide solution)-acetonitrile (99:1) was used as mobile phase A, and 0.05 mol / L phosphate buffer (pH5.0)-acetonitrile (80:20) was used as mobile phase B; firstly, isocratic elution was performed with mobile phase A-mobile phase B (92:8), and after the elution of amoxicillin peak was completed, linear gradient elution was performed immediately according to the table below; the detection wavelength was 254 nm; the injection volume was 20 μl.

[0085] Table 2 Chromatographic conditions

[0086] Time (min) Liquidity A(%) Liquidity B (%) 0 92 8 25 0 100 40 0 100 41 92 8 55 92 8

[0087] Acceleration conditions: Weigh 50 mg of the soluble powder obtained in the examples and comparative examples, add 100 mL of tap water to prepare a solution, and conduct the acceleration test at a temperature of 40±2°C and a relative humidity of 65±5%RH.

[0088] Test results: The contents of related substances in the compound amoxicillin-clindamycin potassium powder of Examples 1-9 and Comparative Examples 1-3 were measured at 0 (when preparing the product), 1, 3, and 6 months. The measurement results are shown in Table 3.

[0089] Table 3 Test results of related substances in various embodiments and comparative examples

[0090]

[0091]

[0092] Combining Examples 1-5 and Comparative Examples 1-3 and Table 1, it can be seen that the dissolution time of the soluble powder is reduced by adding the inclusion agent β-cyclodextrin or potato porous starch compared to no inclusion agent, and the dissolution time of the soluble powder is further reduced by adding the potato porous starch treated with alcohol-alkali as the inclusion agent (Examples 1-5). It can also be found that after 6 months of accelerated testing, the dissolution time of Examples 1-5 increases very little and remains basically stable.

[0093] It can be seen from Examples 3-5 that, in terms of the solubility of soluble powder, the alcohol-alkali treated porous potato starch as an inclusion agent has a better effect than porous cassava starch and porous corn starch.

[0094] Combining Example 3 with Examples 6-9, it can be seen that modifying the porous starch after alcohol-alkali treatment with sodium gluconate and polysaccharide again can further improve the dissolution time of the soluble powder.

[0095] Combining Examples 1-5 and Comparative Examples 1-3 and Table 3, it can be seen that in Comparative Example 3, since no inclusion agent was added, the stability of amoxicillin and potassium clavulanate was relatively poor, while after the inclusion agents porous potato starch and β-cyclodextrin were added to Comparative Example 1 and Comparative Example 2, respectively, the stability of amoxicillin and potassium clavulanate was improved, but still could not reach the ideal value.

[0096] After adding the potato porous starch treated with alcohol-alkali as the inclusion agent in Examples 1-5, the stability of amoxicillin and potassium clavulanate was greatly improved, especially after 6 months of accelerated test, the stability of potassium clavulanate was improved more significantly.

[0097] In combination with Examples 3-5, it can be seen that the alcohol-alkali treated porous potato starch as an inclusion agent has a better stabilizing effect on amoxicillin and potassium clavulanate than porous cassava starch and porous corn starch.

[0098] Combining Example 3 with Examples 6-9, it can be seen that modifying the porous starch after alcohol-alkali treatment with sodium gluconate and polysaccharide again can further improve the stability of amoxicillin and potassium clavulanate. Comparing Examples 6-8 with Example 9, it can be seen that the cross-linking modification using Bletilla striata polysaccharide has a better effect on improving the stability of amoxicillin and potassium clavulanate than the modification using seaweed polysaccharide.

[0099] The above are only some embodiments of the present application, and the protection scope of the present application is not limited to the above embodiments. For ordinary technicians in this technical field, some improvements and modifications without departing from the creative design of the present application should also fall within the protection scope of the present application.

Claims

1. A compound amoxicillin-clindamycin potassium powder, characterized in that: The invention comprises the following components in parts by weight: 5-20 parts by weight of amoxicillin, 1.25-5 parts by weight of potassium clavulanate, and 20-50 parts by weight of an inclusion agent, wherein the inclusion agent is porous starch treated with alcohol and alkali.

2. The compound amoxicillin-clindamycin potassium powder according to claim 1, characterized in that: The alcohol-alkali treatment is specifically: The porous starch and 80% ethanol are prepared into a starch milk with a mass concentration of 12-15%, stirred at 40-50°C for 1 hour, and the NaOH solution is added dropwise at a uniform rate. After the addition is completed, the mixture is reacted for 20-50 minutes, filtered, 95% ethanol is added, and the mixture is neutralized to pH 7.0 with hydrochloric acid ethanol, filtered, washed twice with 95% ethanol and once with anhydrous ethanol, dried, crushed, and sieved to obtain the product.

3. The compound amoxicillin-clindamycin potassium powder according to any one of claims 1 or 2, characterized in that: The porous starch is one or more of porous potato starch and porous cassava starch.

4. The compound amoxicillin-clindamycin potassium powder according to claim 3, characterized in that: The inclusion agent is also subjected to the following modification treatment: the porous starch treated with alcohol and alkali is cross-linked and modified with sodium gluconate and polysaccharide.

5. The compound amoxicillin-clindamycin potassium powder according to claim 4, characterized in that: The specific operation of the modification treatment is: The porous starch, polysaccharide and sodium gluconate solution are uniformly mixed in a mass ratio of (0.1-0.25):(0.02-0.05):(0.5-1.0), reacted at 120-130° C. for 1-2 hours, precipitated, washed, dried, ground and sieved.

6. The compound amoxicillin-clindamycin potassium powder according to claim 5, characterized in that: The polysaccharide is Bletilla striata polysaccharide.

7. The compound amoxicillin-clindamycin potassium powder according to claim 1, characterized in that: The compound amoxicillin-clindamycin potassium powder further comprises 0.5-1 parts by weight of an antioxidant and 20-75 parts by weight of a diluent.

8. The compound amoxicillin-clindamycin potassium powder according to claim 7, characterized in that: The antioxidant is one or more of sodium thiosulfate, sodium pyrosulfite, and sodium bisulfite; the diluent is one or more of anhydrous glucose, mannitol, and anhydrous lactose.

9. The method for preparing the compound amoxicillin-clindamycin potassium powder according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: mixing and stirring amoxicillin, potassium clavulanate and a inclusion agent in a formula amount for 20-30 minutes, then adding an optional antioxidant and a diluent in a formula amount, mixing for 15-20 minutes, and packaging.

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