Compound amoxicillin powder as well as preparation method and application thereof

Abstract

The invention relates to compound amoxicillin powder and a preparation method and application thereof.According to the compound amoxicillin powder, an amoxicillin inclusion compound, a potassium clavulanate solid dispersion and a stabilizer serve as raw materials, all the components in the amoxicillin powder are reasonably matched, amoxicillin and potassium clavulanate are compounded, and the compound amoxicillin powder is prepared. According to the compound amoxicillin powder disclosed by the invention, sodium dihydrogen phosphate, disodium hydrogen phosphate, EDTA-4Na, sodium hydrogen sulfite, beta-cyclodextrin, a carrier material PEG-6000 and 15-hydroxystearic acid polyethylene glycol ester are added at the same time, and all the components have a synergistic effect, so that after the compound amoxicillin powder is prepared, the water solubility and stability of the product can be improved, and the quality of the product can be improved. Furthermore, the preparation method disclosed by the invention is simple and efficient, is beneficial to industrial production, and has great application potential.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and more particularly to a preparation method and application of a compound amoxicillin powder for improving the water solubility and stability of the compound amoxicillin powder. Background Art

[0002] Amoxicillin (AMO) is a broad-spectrum penicillin antibiotic and a semi-synthetic β-lactam antibiotic. It is a white or off-white crystalline powder. It tastes slightly bitter and has good antibacterial and bactericidal effects. It is widely used in clinical practice. However, amoxicillin also has problems with stability and poor water solubility: amoxicillin is slightly soluble in water, which is far from meeting the needs of dosing devices in today's large-scale farming, because amoxicillin soluble powder must be dissolved in a high concentration under the condition of 1:50 times; in addition, since the β-lactam ring in the molecule of amoxicillin is unstable, the β-lactam ring can be opened under the action of acids, alkalis, certain metal ions and oxidants, thereby damaging the stability of amoxicillin.

[0003] Potassium clavulanate has only weak antibacterial activity, but it can firmly bind to most β-lactamases to form irreversible conjugates. It not only has effects on the enzymes of Staphylococcus, but also on the enzymes produced by a variety of Gram-negative bacteria. It is an effective β-lactamase inhibitor. Potassium clavulanate is ineffective when used alone. It is often used in combination with penicillins to overcome the drug resistance caused by the production of β-lactamases by microorganisms and improve the efficacy of penicillins. In clinical practice, potassium clavulanate and amoxicillin form a compound preparation that can inhibit the destruction of amoxicillin by β-lactamases produced by microorganisms such as Staphylococcus aureus, Haemophilus influenzae, Catarrhalis, Escherichia coli, Klebsiella, Proteus mirabilis, Proteus vulgaris, Neisseria gonorrhoeae, Legionella, and Bacteroides fragilis. However, potassium clavulanate is extremely unstable, easily oxidized, and easily loses efficacy due to moisture absorption.

[0004] At present, it is still difficult to maintain good stability and water solubility of amoxicillin and potassium clavulanate after the combination, and maintain good product quality. In summary, how to maintain good stability and water solubility after compounding amoxicillin and potassium clavulanate to prepare compound amoxicillin powder is a problem that needs to be solved urgently. Summary of the invention

[0005] Based on this, it is necessary to provide a compound amoxicillin powder and a preparation method and application thereof. After the compound amoxicillin powder is prepared using amoxicillin inclusion complex, potassium clavulanate solid dispersion and stabilizer as raw materials, the water solubility and stability of the product can be improved, thereby improving the product quality.

[0006] The technical solution is as follows:

[0007] The first aspect of the present invention provides a compound amoxicillin powder, comprising an amoxicillin inclusion compound, a potassium clavulanate solid dispersion and a stabilizer;

[0008] The raw materials of the amoxicillin inclusion compound include amoxicillin and β-cyclodextrin;

[0009] The raw materials of the potassium clavulanate solid dispersion include potassium clavulanate, a carrier material and 15-hydroxystearate polyethylene glycol;

[0010] The stabilizer includes one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, EDTA-4Na and sodium bisulfite;

[0011] The carrier material is PEG-6000.

[0012] In one embodiment, the raw materials of the amoxicillin inclusion compound include the following components by weight: 80-100 parts of amoxicillin and 200-300 parts of β-cyclodextrin; and / or

[0013] The raw materials of the potassium clavulanate solid dispersion include the following components by weight: 8-50 parts of potassium clavulanate, 24-200 parts of carrier material and 3-10 parts of 15-hydroxystearate polyethylene glycol; and / or

[0014] The stabilizer comprises the following components by weight: 0.5-2 parts of sodium dihydrogen phosphate, 5-20 parts of disodium hydrogen phosphate, 1-3 parts of EDTA-4Na and 1-3 parts of sodium bisulfite.

[0015] In one embodiment, the β-cyclodextrin is sulfobutyl-β-cyclodextrin.

[0016] In one embodiment, in the compound amoxicillin powder, the weight ratio of amoxicillin to potassium clavulanate is (2-10):1.

[0017] The second aspect of the present invention provides a method for preparing the compound amoxicillin powder as described above, comprising the following steps:

[0018] The amoxicillin, β-cyclodextrin and solvent are stirred, dried and crushed to prepare an amoxicillin inclusion compound;

[0019] The carrier material, 15-hydroxystearate polyethylene glycol and potassium clavulanate are stirred and mixed, frozen, and crushed to prepare a potassium clavulanate solid dispersion;

[0020] The stabilizer, amoxicillin inclusion compound and potassium clavulanate solid dispersion are mixed and packaged to prepare compound amoxicillin powder.

[0021] In one embodiment, in the step of preparing the amoxicillin inclusion compound, the solvent is water; and / or

[0022] The stirring temperature is 70°C-80°C; and / or

[0023] The stirring time is 2 hours to 3 hours.

[0024] In one embodiment, in the step of preparing the solid dispersion of potassium clavulanate, the mixing and stirring time is 1 hour to 2 hours; and / or

[0025] The freezing time is 5 to 10 hours; and / or

[0026] The freezing temperature is -10℃--30℃.

[0027] In one embodiment, in the step of preparing the compound amoxicillin powder, the mixing time is 25 minutes to 45 minutes.

[0028] In one embodiment, the step of preparing the compound amoxicillin powder further includes a packaging step after mixing, and the packaging production environment meets at least one of the following characteristics:

[0029] (1) Temperature is 18℃-26℃;

[0030] (2) Humidity ≤ 25%.

[0031] The third aspect of the present invention provides use of the compound amoxicillin powder as described above in the preparation of antibacterial or bactericidal drugs.

[0032] Compared with the prior art, this application has the following beneficial effects:

[0033] The compound amoxicillin powder of the present application uses amoxicillin inclusion complex, potassium clavulanate solid dispersion and stabilizer as raw materials. By reasonably matching the components in amoxicillin powder, amoxicillin and potassium clavulanate are compounded, and stabilizers, β-cyclodextrin, carrier materials PEG-6000, 15-hydroxystearate polyethylene glycol ester are added at the same time. The components work synergistically to prepare the compound amoxicillin powder. The inventor has experimentally verified that in some embodiments, the compound amoxicillin powder can make the solubility of amoxicillin in 1L drinking water reach more than 30g at 25°C, and the solubility of 10% amoxicillin soluble powder reaches 300g / L, which is about 30 times that of amoxicillin. At the same time, the stability reaches 36 months, which is higher than the 18 months of the national pharmacopoeia standard, further improving the water solubility and stability of the compound amoxicillin.

[0034] Furthermore, the present application utilizes inclusion technology to form a β-cyclodextrin amoxicillin inclusion complex, utilizes solid dispersion technology to form a potassium clavulanate solid dispersion, and then adds a stabilizer and adjusts the reaction conditions to prepare a compound amoxicillin powder. The preparation method is simple and efficient, is conducive to industrial production, and has great application potential. DETAILED DESCRIPTION

[0035] The present application will be further described in detail below in conjunction with specific embodiments. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thoroughly understood.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0037] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0038] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

[0039] Herein, the optional scope of "and / or", "or / and", and "and / or" includes any one of two or more relevant listed items, and also includes any and all combinations of the relevant listed items, wherein said any and all combinations include any two relevant listed items, any more relevant listed items, or a combination of all relevant listed items. (It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in the present application, the technical solution undoubtedly includes technical solutions that are all connected by "logical AND", and also undoubtedly includes technical solutions that are all connected by "logical OR". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For another example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, technical solutions that are all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, a combination of any two or any three of A, B, C, and D, and also includes a combination of four items of A, B, C, and D (that is, a technical solution that is all connected by "logical AND").)

[0040] Herein, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0041] Herein, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used for descriptive purposes only and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. In addition, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present application, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0042] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0043] Specifically, only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form an undefined range; and any lower limit can be combined with other lower limits to form an undefined range, and any upper limit can be combined with any other upper limit to form an undefined range. In addition, each individually disclosed point or single value itself can be combined with any other point or single value as a lower limit or upper limit or with other lower limits or upper limits to form an undefined range. The use of numerical ranges represented by endpoints includes all numbers within the range and any range within the range, for example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4 and 5, etc.

[0044] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

[0045] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0046] The temperature parameters in this application, unless otherwise specified, allow both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±2°C, ±1°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, and ±0.1°C are allowed. Normal temperature or room temperature in this application refers to no temperature control operation, generally 4°C~35°C, preferably 20±5°C.

[0047] Cyclodextrin (CD) is a cyclic oligosaccharide formed by connecting 6-12 glucose molecules obtained by enzymatic cyclization of starch. It has a special annular hollow cylindrical structure with a hydrophobic inner layer and a hydrophilic outer layer. Common cyclodextrins include α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. Among them, β-cyclodextrin is widely used in veterinary medicine due to its large output and low cost. Various inclusion compounds generated by β-CD and organic compounds have special adsorption properties, and also have multiple functions such as stabilization, sustained release, emulsification, enhanced solubility and dispersibility.

[0048] At present, due to the instability and poor water solubility of amoxicillin, the application scope is limited and the efficacy is poor. Therefore, in order to expand the application scope of amoxicillin and improve its stability, it is necessary to study the preparations with improved water solubility and stability of amoxicillin and related preparation methods. At present, the methods for forming β-CD inclusion complexes mainly include saturated solution method, freeze drying method, grinding method, spray drying method, liquid-liquid method or gas-liquid method, solid phase inclusion method, etc., and cyclodextrin inclusion complexes can not only exist in solid form, but also exist in water and some organic solvents. Based on this, the present application forms β-cyclodextrin amoxicillin inclusion complexes by adding β-cyclodextrin to amoxicillin and using inclusion technology; carrier materials PEG-6000 and 15-hydroxystearic acid polyethylene glycol ester are added to potassium clavulanate, and potassium clavulanate solid dispersion is formed by solid dispersion technology, and then a stabilizer is added and the reaction conditions are adjusted to prepare compound amoxicillin powder. Through the preparation method of the present application, the solubility of amoxicillin in 1L of drinking water at 25°C can reach more than 30g (the solubility of 10% amoxicillin soluble powder reaches 300g / L), and the stability can reach 36 months, which is higher than the national pharmacopoeia standard of 18 months. The problems of instability and poor water solubility of compound amoxicillin powder are solved from the source, and the sensitivity of amoxicillin is improved.

[0049] The first aspect of the present invention provides a compound amoxicillin powder, comprising an amoxicillin inclusion compound, a potassium clavulanate solid dispersion and a stabilizer;

[0050] The raw materials of the amoxicillin inclusion compound include amoxicillin and β-cyclodextrin;

[0051] The raw materials of the potassium clavulanate solid dispersion include potassium clavulanate, a carrier material and 15-hydroxystearate polyethylene glycol;

[0052] The stabilizer includes one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, EDTA-4Na and sodium bisulfite;

[0053] The carrier material is PEG-6000.

[0054] Amoxicillin belongs to the β-lactam class of broad-spectrum antibacterial drugs. Its antibacterial effect originates from interfering with the biosynthesis of peptidoglycan in bacterial cell walls. Bacteria are often in a hypotonic environment. Due to the osmotic pressure difference between the inside and outside, water will enter the bacteria, causing the bacteria to burst and die after taking in too much water. However, in actual situations, the peptidoglycan in the bacterial cell wall can prevent the bacteria from being swollen and burst by water, and peptidoglycan can prevent the bacteria from spontaneously absorbing too much water. β-lactam antibiotics can act on the bacterial cell wall, inhibit the formation of peptidoglycan in its cell wall, and then cause defects in the bacterial cell wall, and external water enters the bacteria, causing the bacteria to swell, lyse, and die. However, when bacteria produce β-lactamase that can hydrolyze the β-lactam ring of penicillin, β-lactam drugs become ineffective. Potassium clavulanate is ineffective when used alone, and is often used in combination with penicillins to overcome the drug resistance caused by the production of β-lactamase by microorganisms and improve the efficacy of penicillins. However, potassium clavulanate is extremely unstable and easily loses its efficacy due to moisture absorption. Since PEG has good water solubility and can be dissolved in a variety of organic solvents, it can disperse certain drugs in a molecular state, thereby preventing drug aggregation. It is often used as a water-soluble carrier material in solid dispersion materials to increase the dissolution rate of drugs. Therefore, solid dispersion technology is used, PEG6000 is used as a carrier material, and the shielding effect of the PEG6000 carrier is used to delay the hydrolysis of potassium clavulanate and improve the stability of potassium clavulanate.

[0055] In some of the examples, the raw materials of the amoxicillin inclusion compound include the following components by weight: 80-100 parts of amoxicillin and 200-300 parts of β-cyclodextrin.

[0056] In some of the examples, the raw materials of the potassium clavulanate solid dispersion include the following components by weight: 8-50 parts of potassium clavulanate, 24-200 parts of carrier material and 3-10 parts of 15-hydroxystearate polyethylene glycol.

[0057] In some of the examples, the stabilizer includes the following components by weight: 0.5-2 parts of sodium dihydrogen phosphate, 5-20 parts of disodium hydrogen phosphate, 1-3 parts of EDTA-4Na and 1-3 parts of sodium bisulfite.

[0058] In some of the examples, the β-cyclodextrin is sulfobutyl-β-cyclodextrin. Sulfobutyl-β-cyclodextrin has higher water solubility than β-cyclodextrin, and its water solubility at room temperature is generally more than 50%, and its inclusion capacity is stronger. In one specific example, the present application uses inclusion technology to form an amoxicillin-sulfobutyl-β-cyclodextrin inclusion complex, which improves the water solubility and stability of amoxicillin, and at the same time, a stabilizer is added to the formula to further improve the stability of amoxicillin.

[0059] In some examples, the weight ratio of amoxicillin to potassium clavulanate in the compound amoxicillin powder is (2-10): 1. It can be understood that the weight ratio of amoxicillin to potassium clavulanate in the compound amoxicillin powder includes but is not limited to 2: 1, 2.5: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1, 5.5: 1, 6: 1, 6.5: 1, 7: 1, 7.5: 1, 8: 1, 8.5: 1, 9: 1, 9.5: 1, 10: 1.

[0060] The second aspect of the present invention provides a method for preparing the compound amoxicillin powder as described above, comprising the following steps:

[0061] The amoxicillin, β-cyclodextrin and solvent are stirred, dried and crushed to prepare an amoxicillin inclusion compound;

[0062] The carrier material, 15-hydroxystearate polyethylene glycol and potassium clavulanate are stirred and mixed, frozen, and crushed to prepare a potassium clavulanate solid dispersion;

[0063] The stabilizer, amoxicillin inclusion compound and potassium clavulanate solid dispersion are mixed and packaged to prepare compound amoxicillin powder.

[0064] In some of the examples, in the step of preparing the amoxicillin inclusion compound, the solvent is water.

[0065] In some of the examples, in the step of preparing the amoxicillin inclusion compound, the stirring temperature is 70° C.-80° C. It can be understood that in the step of preparing the amoxicillin inclusion compound, the stirring temperature includes but is not limited to 70° C., 72° C., 74° C., 76° C., 78° C., and 80° C.

[0066] In some of these examples, in the step of preparing the amoxicillin inclusion compound, the stirring time is 2 hours to 3 hours. It is understandable that in the step of preparing the amoxicillin inclusion compound, the stirring time includes but is not limited to 2 hours, 2.2 hours, 2.4 hours, 2.6 hours, 2.8 hours, and 3 hours.

[0067] In some of the examples, in the step of preparing the solid dispersion of potassium clavulanate, the mixing and stirring time is 1 hour to 2 hours. It can be understood that in the step of preparing the solid dispersion of potassium clavulanate, the mixing and stirring time includes but is not limited to 1 hour, 1.2 hours, 1.4 hours, 1.6 hours, 1.8 hours, and 2 hours.

[0068] In some of the examples, in the step of preparing the solid dispersion of potassium clavulanate, the freezing time is 5 hours to 10 hours. It can be understood that in the step of preparing the solid dispersion of potassium clavulanate, the freezing time includes but is not limited to 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, and 10 hours.

[0069] In some of the examples, in the step of preparing the potassium clavulanate solid dispersion, the freezing temperature is -10°C to -30°C. It can be understood that in the step of preparing the potassium clavulanate solid dispersion, the freezing temperature includes but is not limited to -10°C, -15°C, -20°C, -25°C, and -30°C.

[0070] In some of these examples, in the step of preparing the compound amoxicillin powder, the mixing time is 25 minutes to 45 minutes. It is understandable that in the step of preparing the compound amoxicillin powder, the mixing time includes but is not limited to 25 minutes, 28 minutes, 31 minutes, 34 minutes, 37 minutes, 40 minutes, 42 minutes, and 45 minutes.

[0071] In some of the examples, the steps of preparing compound amoxicillin powder include a packaging step after mixing, and the packaging production environment meets the following characteristics: the temperature is 18°C-26°C. It can be understood that the packaging production environment meets the following characteristics: the temperature includes but is not limited to 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C

[0072] In some of the examples, the steps for preparing compound amoxicillin powder include a packaging step after mixing, and the packaging production environment meets the following characteristics: humidity ≤ 25%.

[0073] The third aspect of the present invention provides use of the compound amoxicillin powder as described above in the preparation of antibacterial or bactericidal drugs.

[0074] The following is further described in conjunction with specific embodiments. The raw materials involved in the following specific embodiments, unless otherwise specified, can all be commercially available; the instruments used, unless otherwise specified, can all be commercially available; the processes involved, unless otherwise specified, are all routinely selected by those skilled in the art.

[0075] The following are specific embodiments.

[0076] Example 1

[0077] This embodiment provides a preparation method for improving the water solubility and stability of compound amoxicillin, which is as follows:

[0078] The compound amoxicillin powder comprises the following components: 100 parts by mass of amoxicillin, 25 parts by mass of potassium clavulanate, 0.5 parts by mass of sodium dihydrogen phosphate, 5 parts by mass of disodium hydrogen phosphate, 1 part by mass of EDTA-4Na, 1.5 parts by mass of sodium bisulfite, 300 parts by mass of sulfobutyl-β-cyclodextrin, 100 parts by mass of PEG-6000, and 3 parts by mass of polyethylene glycol hydroxystearate.

[0079] The preparation method is as follows:

[0080] (1) The reaction kettle is heated to 70°C, sulfobutyl-β-cyclodextrin is stirred and dissolved in drinking water, amoxicillin is added and stirred for 2 hours, and then dried and crushed to obtain an amoxicillin inclusion compound;

[0081] (2) heating and melting PEG-6000 and 15-hydroxystearate polyethylene glycol in a reaction kettle, adding potassium clavulanate, stirring for 1 hour, freezing in a -20°C freezer for 5 hours, and low-temperature grinding to obtain a potassium clavulanate solid dispersion;

[0082] (3) Add sodium dihydrogen phosphate, disodium hydrogen phosphate, EDTA-4Na, sodium bisulfite, amoxicillin inclusion compound and potassium clavulanate solid dispersion into a mixer and mix for 30 minutes;

[0083] (4) Under a production environment with a temperature of 26°C and a humidity of ≤25%, compound amoxicillin powder (amoxicillin: potassium clavulanate = 4:1) can be obtained by packaging.

[0084] Comparative Example 1

[0085] Comparative Example The compound amoxicillin powder comprises the following components: 4 parts by mass of amoxicillin, 1 part by mass of potassium clavulanate, and 5 parts by mass of anhydrous glucose.

[0086] The preparation method is as follows:

[0087] (1) Add amoxicillin, potassium clavulanate and anhydrous glucose into the mixer and mix for 30 minutes;

[0088] (2) The compound amoxicillin powder (amoxicillin: potassium clavulanate = 4:1) is obtained by packaging.

[0089] The solubility and stability performance tests of the compound amoxicillin powder prepared in Example 1 and Comparative Example 1 were performed, and the test results are shown below.

[0090] 1. Solubility test

[0091] The method is: take 15g of the test sample and place it in a Nessler colorimetric tube, add water to make a 50mL solution (the concentration is twice the high-dose concentration in clinical use), turn it upside down 10 times at 25℃+2℃, the test sample should be completely dissolved, let it stand for 30 minutes, and no turbidity or precipitation should be generated.

[0092] Results: The experimental results show that according to commercial packaging, at 25°C + 2°C, the solubility of the compound amoxicillin powder of Example 1 reaches 300g / L. The solubility of the compound amoxicillin powder of Comparative Example 1 is 10g / L.

[0093] 2. Stability test

[0094] Method: Long-term stability test

[0095] This test is conducted under accelerated conditions. Its purpose is to explore the stability of drugs by accelerating the chemical or physical changes of drugs, and to provide necessary information for formulation design, packaging, transportation and storage. Three batches of test products are required, which are packaged according to market conditions and placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 36 months. The equipment used should be able to control the temperature ±2℃ and the relative humidity ±5%, and be able to monitor the actual temperature and humidity. During the test period, samples are taken once at the 0th month, 1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, 24th month and 36th month, respectively, and tested according to the key stability inspection items. For accelerated tests, it is recommended to use a water-insulated electric constant temperature incubator (20-60℃). A dryer with a saturated salt solution with a certain relative humidity is placed in the box. The equipment should be able to control the required temperature, and the temperature of each part of the equipment should be uniform and suitable for long-term use. A constant humidity and constant temperature box or other suitable equipment can also be used.

[0096] Results: The experimental results show that according to the commercial packaging, three batches of samples were placed for 36 months at a temperature of 40℃±2℃ and a relative humidity of 75%±5%. Samples were taken once at 0th month, 1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, 24th month and 36th month respectively. The samples at 1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, 24th month and 36th month were compared with the samples at 0th month. The properties of the samples did not change, and the moisture content and content were all within the qualified range, indicating that the product stability was reliable. The stability test result of the compound amoxicillin powder of comparative example 1 was 18 months.

[0097] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0098] The above-described embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be construed as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent application shall be subject to the attached claims, and the description may be used to interpret the content of the claims.

Claims

1. A compound amoxicillin powder, characterized in that: It includes amoxicillin inclusion compound, potassium clavulanate solid dispersion and stabilizer; The raw materials of the amoxicillin inclusion compound include amoxicillin and β-cyclodextrin; The raw materials of the potassium clavulanate solid dispersion include potassium clavulanate, a carrier material and 15-hydroxystearate polyethylene glycol; The stabilizer includes one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, EDTA-4Na and sodium bisulfite; The carrier material is PEG-6000.

2. The compound amoxicillin powder according to claim 1, characterized in that: The raw materials of the amoxicillin inclusion compound include the following components by weight: 80-100 parts of amoxicillin and 200-300 parts of β-cyclodextrin; and / or The raw materials of the potassium clavulanate solid dispersion include the following components by weight: 8-50 parts of potassium clavulanate, 24-200 parts of carrier material and 3-10 parts of 15-hydroxystearate polyethylene glycol; and / or The stabilizer comprises the following components by weight: 0.5-2 parts of sodium dihydrogen phosphate, 5-20 parts of disodium hydrogen phosphate, 1-3 parts of EDTA-4Na and 1-3 parts of sodium bisulfite.

3. The compound amoxicillin powder according to claim 1 or 2, characterized in that: The β-cyclodextrin is sulfobutyl-β-cyclodextrin.

4. The compound amoxicillin powder according to claim 1 or 2, characterized in that: In the compound amoxicillin powder, the weight ratio of amoxicillin to potassium clavulanate is (2-10):

1.

5. A method for preparing the compound amoxicillin powder according to any one of claims 1 to 4, characterized in that: The following steps are involved: The amoxicillin, β-cyclodextrin and solvent are stirred, dried and crushed to prepare an amoxicillin inclusion compound; The carrier material, 15-hydroxystearate polyethylene glycol and potassium clavulanate are stirred and mixed, frozen, and crushed to prepare a potassium clavulanate solid dispersion; The stabilizer, the amoxicillin inclusion compound and the potassium clavulanate solid dispersion are mixed to prepare the compound amoxicillin powder.

6. The method for preparing the compound amoxicillin powder according to claim 5, characterized in that: In the step of preparing the amoxicillin inclusion compound, the solvent is water; and / or The stirring temperature is 70°C-80°C; and / or The stirring time is 2 hours to 3 hours.

7. The method for preparing the compound amoxicillin powder according to claim 5, characterized in that: In the step of preparing the potassium clavulanate solid dispersion, the mixing and stirring time is 1 hour to 2 hours; and / or The freezing time is 5 to 10 hours; and / or The freezing temperature is -10℃--30℃.

8. The method for preparing the compound amoxicillin powder according to claim 5, characterized in that: In the step of preparing the compound amoxicillin powder, the mixing time is 25 minutes to 45 minutes.

9. The method for preparing the compound amoxicillin powder according to any one of claims 5 to 8, characterized in that: After mixing, the step of subpackaging is also included, and the production environment of subpackaging meets at least one of the following characteristics: (1) Temperature is 18℃-26℃; (2) Humidity ≤ 25%.

10. Use of the compound amoxicillin powder according to any one of claims 1 to 4 in the preparation of antibacterial or bactericidal drugs.