Compound amoxicillin and potassium clavulanate powder and its preparation method

Abstract

The application relates to the technical field of veterinary medicine preparations, and particularly discloses a compound amoxicillin and clavulanate potassium powder and a preparation method thereof.A compound amoxicillin and clavulanate potassium powder comprises the following components in parts by weight: 5-20 parts by weight of amoxicillin, 1.25-5 parts by weight of clavulanate potassium and 20-50 parts by weight of a clathrate agent, wherein the clathrate agent is porous starch treated by alcohol-alkali.A preparation method of the compound amoxicillin and clavulanate potassium powder is characterized by comprising the following steps: mixing and stirring formula amount of amoxicillin, clavulanate potassium and a clathrate agent for 20-30 minutes, then adding formula amount of an antioxidant and a diluent, mixing for 15-20 minutes and then distributing.The compound amoxicillin and clavulanate potassium powder has the advantages of good water solubility and good stability.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of veterinary medicine preparations, in particular to a compound amoxicillin and clavulanate potassium powder and a preparation method thereof. BACKGROUND

[0002] Amoxicillin is a semi-synthetic penicillin beta-lactam antibiotic, which is a white or white-like crystalline powder, is one of the most widely used oral semi-synthetic penicillins at present, belongs to a reproductive period bactericide (class I), is a penicillin with an amino side chain; but is several times stronger than penicillin in efficacy, has small toxic and side effects, can hinder the synthesis of cell wall muropeptide, cause the cell wall of bacteria to be defective, the bacteria to swell and lyse and die, and is mainly used for infectious diseases caused by gram-positive bacteria such as staphylococcus aureus and streptococcus and gram-negative bacteria such as escherichia coli and bacillus pasteurii. In veterinary clinics, it is often used for infections caused by gram-positive bacteria such as staphylococcus aureus, streptococcus and gram-negative bacteria such as escherichia coli and bacillus pasteurii.

[0003] Potassium clavulanate is a beta-lactamase inhibitor, which can combine with beta-lactamase to form an irreversible combination, and has weak antibacterial activity itself. Potassium clavulanate combined with amoxicillin can significantly improve the antibacterial activity of amoxicillin and its penetration ability to the cell membrane, the curative effect can be increased by several times or even dozens of times, and the drug resistance of drug-resistant strains can be restored to sensitivity, overcoming the bacterial drug resistance problem existing in single amoxicillin. Amoxicillin and potassium clavulanate are used in combination, which is suitable for lower respiratory tract infections, otitis media, sinusitis caused by microorganisms producing beta-lactamase haemophilus influenzae and moraxella catarrhalis, urinary tract and skin soft tissue infections caused by microorganisms producing beta-lactamase 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 beta-lactam ring in the molecular structure, which is extremely unstable in chemical properties and is easily degraded under acid or alkaline conditions to form inactive molecules; amoxicillin is difficult to dissolve in water, and has extremely low solubility in water, which is not conducive to the absorption in the animal body, seriously affecting the curative effect of amoxicillin; and amoxicillin is easy to discolor when heated or stored for a long time, so that the content of the effective ingredient is reduced, and the drug efficacy is reduced. In addition, the existing amoxicillin and potassium clavulanate raw materials are unstable under conditions such as high temperature and high humidity, are easy to absorb moisture and degrade, thereby causing poor quality stability of the preparation product, especially the aqueous solution, the effective content degrades rapidly, which is not conducive to long-term storage, and brings hidden dangers to the safety and effectiveness in clinical use.

[0005] Since amoxicillin is mainly in the form of soluble powder in veterinary medicine, it is convenient for transportation and liquid preparation and administration. Therefore, it is urgent to improve the water solubility and stability of the compound amoxicillin and clavulanate potassium preparation. SUMMARY

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

[0007] In a first aspect, the application provides a compound amoxicillin and clavulanate potassium powder.

[0008] The compound amoxicillin and clavulanate 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 a clathrate agent, wherein the clathrate agent is porous starch treated by alcohol-alkali.

[0009] By using the above technical scheme, since amoxicillin and potassium clavulanate are unstable, the porous starch is used for embedding, and the amoxicillin and potassium clavulanate enter the porous structure of the porous starch, thereby improving the stability; and the porous starch is treated by alcohol-alkali, so that the water solubility of the porous starch is further improved, thereby improving the water solubility of the pharmaceutical composition.

[0010] Preferably, the alcohol-alkali treatment specifically comprises the following steps: starch milk with a mass concentration of 12-15% is prepared by mixing the porous starch and 80% ethanol, stirring is performed at 40-50°C for 1h, NaOH solution is added at a uniform speed, after the addition is completed, reaction is performed for 20-50min, suction filtration is performed, 95% ethanol is added, neutralization is performed to pH 7.0 by using hydrochloric acid ethanol, suction filtration is performed, the obtained product is washed twice by using 95% ethanol and once by using anhydrous ethanol, and drying, crushing and sieving are performed.

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

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

[0013] Preferably, the modification treatment is specifically performed as follows: the porous starch, the polysaccharide and the sodium gluconate solution are uniformly mixed according to a mass ratio of (0.1-0.25):(0.02-0.05):(0.5-1.0), reaction is performed at 120-130°C for 1-2h, precipitation is washed, drying is performed, and crushing and sieving are performed.

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

[0015] By adopting the technical scheme, after the porous starch is treated by alcohol-alkali, although the porous structure is increased, the particle structure becomes unstable and the strength is greatly reduced, and the porous starch is easy to collapse, so the sodium gluconate and polysaccharide are used for cross-linking modification to improve the mechanical strength of the porous starch. The sodium gluconate cross-linking treatment still maintains the pore structure of the porous starch, so that the adsorption performance is not affected, and the mechanical structure is strengthened, and the carrying capacity for the adsorbate is also improved. The cross-linked polysaccharide structure contains rich hydroxyl groups, so that the water solubility of the porous starch is further improved, and the water solubility of the compound preparation is improved.

[0016] When the polysaccharide is white psammosilica, the white psammosilica has biological activities such as anti-inflammatory and antioxidant, and can inhibit the growth of various bacteria, so that the antibacterial effect of the compound preparation is improved; the white psammosilica also has an alpha-helix structure, so it also has certain inclusion properties, and the adsorption capacity of the porous starch is further improved.

[0017] Preferably, the compound amoxicillin and potassium clavulanate 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 metabisulfite and sodium bisulfite; and the diluent is one or more of anhydrous dextrose, mannitol, anhydrous lactose and soluble starch.

[0019] In a second aspect, the application further provides a preparation method of the compound amoxicillin and potassium clavulanate powder.

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

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

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

[0023] 1. The application uses the porous starch treated by alcohol-alkali as an inclusion agent to improve the water solubility and stability of the compound amoxicillin and potassium clavulanate powder;

[0024] 2. The application further cross-links and modifies the porous starch treated by alcohol-alkali to be used as an inclusion agent, so as to further improve the water solubility and stability of the compound amoxicillin and potassium clavulanate powder;

[0025] 3、The application adopts a new inclusion agent, and only simple preparation process is needed to obtain high water solubility and high stability of the compound amoxicillin and potassium clavulanate powder. DETAILED DESCRIPTION

[0026] The application will be further described in detail below in conjunction with examples, and it is particularly stated that: in the following examples, the specific conditions not noted are carried out according to the conventional conditions or the conditions suggested by the manufacturers, and the raw materials used in the following examples can be sourced from the ordinary market unless otherwise specified.

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

[0028] Take 50 g (dry basis) of porous potato starch and place it in a container, add an 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 with constant stirring; and add a certain amount of 3 mol / L NaOH at a uniform speed of 4 mL / min to the starch milk, after the addition is completed, react for 40 min to make it fully react; after the reaction is completed, the starch milk is filtered, then pour in an appropriate amount of 95% ethanol, and neutralize 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, sieve, and obtain.

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

[0030] Take 50 g (dry basis) of porous potato starch and place it in a container, add an 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 with constant stirring; and add a certain amount of 3 mol / L NaOH at a uniform speed of 4 mL / min to the starch milk, after the addition is completed, react for 40 min to make it fully react; after the reaction is completed, the starch milk is filtered, then pour in an appropriate amount of 95% ethanol, and neutralize 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, sieve, and obtain.

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

[0032] Weigh 50g (dry basis) of porous corn starch and place it in a container. Add an appropriate amount of water and ethanol to make a starch slurry with a mass concentration of 13%. Then place the container in a water bath and keep it at 45℃ while stirring continuously. Add a certain amount of 3mol / L NaOH dropwise to the starch slurry at a rate of 4mL / min. After the addition is complete, allow the reaction to proceed for 40min to allow for complete reaction. After the reaction is complete, filter the starch slurry and add an appropriate amount of 95% ethanol. Neutralize the solution with 3% (V / V) hydrochloric acid ethanol to pH 7.0. Filter the solution, wash it twice with 95% ethanol, and finally wash it once with anhydrous ethanol. Dry the solution at 80℃, pulverize it, and sieve it to obtain the final product.

[0033] Preparation Example 4

[0034] The porous potato starch treated with alcohol and alkali in Preparation Example 1, sodium gluconate, and Bletilla striata polysaccharide were mixed evenly at a mass ratio of 0.1:0.02:0.5, reacted at 120°C for 2 hours, the precipitate was washed twice, dried at 80°C, ground and sieved to obtain the final 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 mixed evenly at a mass ratio of 0.25:0.05:1.0, reacted at 120°C for 2 hours, the precipitate was washed twice, dried at 80°C, ground and sieved to obtain the final 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 at a mass ratio of 0.15:0.04:0.8, reacted at 120°C for 2 hours, the precipitate was washed twice, dried at 80°C, ground and sieved to obtain the final product.

[0039] Preparation Example 7

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

[0041] Example 1

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

[0043] Preparation method: (1) Take the prescription amount of amoxicillin, potassium clavulanate, and the inclusion agent into the mixer, start the mixer and mix for 30 minutes, then add the prescription amount of antioxidant sodium pyrosulfite and anhydrous glucose, mix for 15 minutes, and then perform packaging after the intermediate product is qualified.

[0044] Quality inspection: The obtained soluble powder is white or white-like powder; all inspections meet the requirements of the Chinese Veterinary Pharmacopoeia for soluble powder.

[0045] Example 2

[0046] Each 100 g of the compound amoxicillin potassium clavulanate powder contains 10 g of amoxicillin, 2.5 g of potassium clavulanate, 35 g of inclusion agent, 0.8 g 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.

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

[0048] Example 3

[0049] Each 100 g of the compound amoxicillin potassium clavulanate powder contains 20 g of amoxicillin, 5 g of potassium clavulanate, 50 g of inclusion agent, 1 g 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 alcohol-alkali treated porous cassava starch in Preparation Example 2.

[0053] Example 5

[0054] Compared with Example 3, the only difference is that the inclusion agent is the alcohol-alkali treated porous corn starch 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] The difference from Example 3 is that the inclusion agent is the modified starch prepared in Preparation Example 7.

[0063] Comparative Example 1

[0064] The difference from Example 3 is that the inclusion agent is porous potato starch.

[0065] Comparative Example 2

[0066] The difference from Example 3 is that the inclusion agent is β-cyclodextrin.

[0067] Comparative Example 3

[0068] The difference from Example 3 is that no inclusion agent is contained.

[0069] Performance test test

[0070] 1. Solubility test

[0071] Specific method: According to the relevant provisions of Amoxicillin soluble powder in Chinese Veterinary Pharmacopoeia, 50 mg of the soluble powder prepared in the examples and comparative examples was weighed, 100 mL of tap water was added to prepare a solution, the dissolution was observed, and the dissolution time was recorded.

[0072] Accelerated condition: The accelerated experiment was carried out under the condition of temperature 40±2℃, relative humidity 65±5%RH, the dissolution of the sample was observed, and the dissolution time was recorded.

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

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

[0075] Table 1 Solubility time of each example and comparative example

[0076]

[0077]

[0078] 2. Determination of the content of amoxicillin and potassium clavulanate in soluble powder by high performance liquid chromatography

[0079] Mobile phase A: 0.05 mol / L phosphate buffer (take 0.05 mol / L potassium dihydrogen phosphate solution, adjust 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: An appropriate amount of soluble powder of each example and comparative example in the present application was precisely weighed, dissolved and quantitatively diluted with mobile phase A to prepare a solution containing about 2.0 mg of amoxicillin (calculated as C16H19N3O5S) per 1 ml.

[0082] Reference solution: An appropriate amount of amoxicillin reference substance was precisely weighed, dissolved and quantitatively diluted with mobile phase A to prepare a solution containing about 20 μg of amoxicillin (calculated as C16H19N3O5S) per 1 ml.

[0083] System suitability solution: An appropriate amount of amoxicillin system suitability reference substance was dissolved and diluted with mobile phase A to prepare a solution containing about 2.0 mg per 1 ml.

[0084] Chromatographic conditions: octadecylsilane-bonded silica gel was used as the filler; 0.05 mol / L phosphate buffer (0.05 mol / L potassium dihydrogen phosphate solution was adjusted to pH 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 (pH 5.0)-acetonitrile (80:20) was used as mobile phase B; first, isocratic elution was performed with mobile phase A-mobile phase B (92:8), and then linear gradient elution was performed according to the table below as soon as the amoxicillin peak was eluted; the detection wavelength was 254 nm; the injection volume was 20 μl.

[0085] Table 2 Chromatographic conditions

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

[0087] Accelerated conditions: 50 mg of soluble powder prepared in each example and comparative example was weighed and dissolved in 100 mL of tap water. The accelerated experiment was performed under the conditions of temperature 40±2℃ and relative humidity 65±5% RH.

[0088] Detection results: the content of related substances of compound amoxicillin and potassium clindamycin powder in examples 1-9 and comparative examples 1-3 was determined at 0 (when the product was prepared), 1, 3 and 6 months, and the determination results are shown in Table 3.

[0089] Table 3 Detection results of related substances of each example and comparative example

[0090]

[0091]

[0092] It can be seen from Examples 1-5 and Comparative Examples 1-3 and Table 1 that the solubility time of the soluble powder is reduced by adding the inclusion agent β-cyclodextrin or porous potato starch, and the solubility time of the soluble powder is further reduced by adding the alcohol-alkali treated porous potato starch as the inclusion agent (Examples 1-5). It can be found that the solubility time of Examples 1-5 increases little and is basically stable after 6 months of accelerated test.

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

[0094] It can be seen from Example 3 and Examples 6-9 that the solubility of the soluble powder is further improved by further modifying the alcohol-alkali treated porous starch with sodium gluconate and polysaccharide.

[0095] It can be seen from Examples 1-5 and Comparative Examples 1-3 and Table 3 that the stability of amoxicillin and potassium clavulanate in Comparative Example 3 is poor because no inclusion agent is added, and the stability of amoxicillin and potassium clavulanate is improved in Comparative Example 1 and Comparative Example 2 by adding the inclusion agent porous potato starch and β-cyclodextrin respectively, but still cannot reach the ideal value.

[0096] The stability of amoxicillin and potassium clavulanate is greatly improved in Examples 1-5 by adding the alcohol-alkali treated porous potato starch as the inclusion agent, and the stability of potassium clavulanate is more obviously improved after 6 months of accelerated test.

[0097] It can be seen from Examples 3-5 that the alcohol-alkali treated porous potato starch as the inclusion agent has better effect than the porous tapioca starch and the porous corn starch on the stability of amoxicillin and potassium clavulanate.

[0098] It can be seen from Example 3 and Examples 6-9 that the stability of amoxicillin and potassium clavulanate is further improved by further modifying the alcohol-alkali treated porous starch with sodium gluconate and polysaccharide. It can be seen from Examples 6-8 and Example 9 that the improvement effect of the stability of amoxicillin and potassium clavulanate by using the cross-linking modification with bletilla striata polysaccharide is better than that by using the modification with 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. Some improvements and decorations 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 and potassium clavulanate powder, characterized by: The compound comprises the following components by weight: amoxicillin 5-20 parts by weight, potassium clavulanate 1.25-5 parts by weight, and a clathrate agent 20-50 parts by weight, wherein the clathrate agent is porous starch treated by alcohol-alkali, The clathrate agent is further modified by cross-linking modification treatment of the porous starch treated by alcohol-alkali with sodium gluconate and bletilla striata polysaccharide; the porous starch treated by alcohol-alkali, bletilla striata polysaccharide and sodium gluconate solution are mixed uniformly at a mass ratio of (0.1-0.25):(0.02-0.05):(0.5-1.0), and then reacted at 120-130℃ for 1-2h, precipitated, washed, dried and ground and sieved.

2. The compound amoxicillin and potassium clavulanate powder according to claim 1, characterized by, The alcohol-alkali treatment is as follows: the porous starch and 80% ethanol are configured into a starch milk with a mass concentration of 12-15%, stirred at 40-50℃ for 1h, and then NaOH solution is added dropwise at a uniform speed, and after the dropwise addition is completed, the reaction is carried out for 20-50min, and then 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, and then dried, crushed and sieved. The porous starch is one or more of porous potato starch and porous tapioca starch.

3. The compound amoxicillin and potassium clavulanate powder according to any one of claims 1 or 2, characterized in that, The compound amoxicillin and potassium clavulanate powder further comprises 0.5-1 parts by weight of an antioxidant and 20-75 parts by weight of a diluent. The antioxidant is one or more of sodium thiosulfate, sodium metabisulfite and sodium bisulfite; and the diluent is one or more of anhydrous glucose, mannitol and anhydrous lactose.

4. The compound amoxicillin and potassium clavulanate powder according to claim 1, wherein the compound amoxicillin and potassium clavulanate powder is a powder comprising 0.5 to 5% by weight of the potassium clavulanate. The method comprises the following steps: mixing and stirring the formula amount of amoxicillin, potassium clavulanate and clathrate agent for 20-30min, then adding the optional formula amount of antioxidant and diluent, and mixing for 15-20min, and then dispensing. ​ 5. The compound amoxicillin and potassium clavulanate powder according to claim 4, characterized by, ​ ​ 6. The method of preparing the complex amoxicillin and potassium clavulanate powder according to any one of claims 1 to 5, wherein, ​

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