Ceftizoxime sodium micro-capsule, preparation method and ceftizoxime sodium micro-capsule preparation

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a ceftizoxime sodium micro-capsule, a preparation method and a ceftizoxime sodium micro-capsule preparation. The invention provides a ceftizoxime sodium micro-capsule. The ceftizoxime sodium micro-capsule comprises a capsule core and a capsule wall material wrapping the capsule core, the capsule material comprises an inner coating and an outer coating, the inner coating wraps the capsule core, and the capsule core comprises ceftizoxime sodium; the inner coating comprises carboxymethyl glucan; the outer coating comprises glyceryl monolinoleate; the mass ratio of the ceftizoxime sodium to the carboxymethyl glucan to the glyceryl monolinoleate is (1 to 3): (0.5 to 1.5): (0.5 to 1.5). The prepared ceftizoxime sodium micro-capsule is high in stability, long in storage period and good in slow release effect.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a ceftizoxime sodium microcapsule and a preparation method thereof, and a ceftizoxime sodium microcapsule preparation. Background Art

[0002] Cefuroxime sodium, chemical name: (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-8-oxo-5-thia-1-aminobicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, is a semi-synthetic third-generation cephalosporin with a broad antibacterial spectrum, similar to cefotaxime. It has moderate antibacterial effects on some Gram-positive bacteria; it has stronger antibacterial effects on Gram-negative bacteria; some Gram-negative bacteria resistant to first-generation cephalosporins and gentamicin may also be sensitive to Cefuroxime sodium; but fecal streptococci and methicillin-resistant Staphylococci are not sensitive to Cefuroxime sodium. Cefuroxime sodium is mainly used to treat various infections caused by sensitive bacteria, including sepsis, respiratory system infections, urinary and reproductive system infections, pleurisy, peritonitis, cholecystitis, intrauterine infection, adnexitis, meningitis, and secondary infections such as trauma and burns; in addition, because cefuroxime sodium is mainly excreted through the kidneys, it is particularly effective in treating pyelonephritis and urinary tract infections.

[0003] Cefuroxime Sodium Powder for Injection is one of the antibiotic drugs widely used in clinical practice, and its preparations are all prepared by aseptic packaging of Cefuroxime Sodium raw materials. However, the existing Cefuroxime Sodium Powder for Injection needs to be stored at low temperatures to prevent the drug from changing color. It is prone to degradation and polymerization reactions during storage, which leads to pH fluctuations, and then causes problems such as a decrease in the content of active ingredients in the drug and an increase in impurities, affecting the quality and stability of the drug. It has also become the main cause of many allergic reactions in clinical practice. In order to improve the stability of Cefuroxime Sodium for Injection, people store it in nitrogen-filled inner packaging materials, but due to the inability to accurately control the nitrogen filling level in the aseptic packaging process, the risk of preparation stability is increased.

[0004] In the prior art, the crystal form of cefuroxime sodium is changed to improve the thermal stability of cefuroxime sodium compounds, but the obtained cefuroxime sodium compounds have poor fluidity and poor stability after being configured into solutions. The prior art also improves its stability by preparing cefuroxime sodium liposome injections, but the equipment requirements are high and industrialization is difficult. The prior art also provides a sustained-release preparation containing cephalosporin, but the use of toxic substances in the preparation process is harmful to the human body and the environment, and the drug loading is limited, which is easy to clog, and has poor injectability and stability when administered in large doses; the cefuroxime sodium preparation in the prior art is a rapid-release preparation, and the administration frequency is large, which will produce drug resistance and increase additional costs, and further drug-resistant strains will appear. The effective dose must be continuously increased to produce an effect, resulting in a vicious cycle, and the peak-to-valley fluctuations of blood drug concentrations become higher. Summary of the invention

[0005] Therefore, the technical problem to be solved by the present invention is to overcome the defects of the prior art ceftizoxime sodium preparations, such as poor stability and short storage period, and the prior preparations are rapid-release preparations that require frequent use, resulting in a continuous increase in the effective dose and large peak-to-trough fluctuations in blood drug concentration during administration, thereby providing a ceftizoxime sodium microcapsule and a preparation method, and a ceftizoxime sodium microcapsule preparation.

[0006] To this end, the present invention provides the following technical solutions.

[0007] The present invention provides a ceftizoxime sodium microcapsule, wherein the ceftizoxime sodium microcapsule comprises a capsule core and a capsule material wrapping the capsule core; the capsule material comprises an inner coating and an outer coating, the inner coating wraps the capsule core, and the capsule core comprises ceftizoxime sodium; the inner coating comprises carboxymethyl dextran; and the outer coating comprises monolinoleyl glycerol;

[0008] The mass ratio of cefuroxime sodium, carboxymethyl dextran and monolinoleyl glycerol is (1-3):(0.5-1.5):(0.5-1.5).

[0009] In an optional embodiment, the capsule core is in powder form;

[0010] In an optional embodiment, the particle size of the cefuroxime sodium is 80-120 μm;

[0011] In an optional embodiment, the monolinoleic acid glyceride includes at least one of monolinoleic acid glyceride, monolinoleic acid diglyceride and monolinoleic acid triglyceride;

[0012] In an alternative embodiment, the carboxymethyl glucan is carboxymethylated yeast glucan.

[0013] In an optional embodiment, the monolinoleylglycerol comprises monolinoleylglycerol, dilinoleylglycerol and trilinoleylglycerol in a volume ratio of (2-2.5):(1-1.5):(1-1.5).

[0014] In an optional embodiment, the outer coating further comprises at least one of an antioxidant and a suspending agent;

[0015] Preferably, the mass ratio of the monolinoleylglycerol, the antioxidant and the suspending agent is (0.5-1.5):(0.2-0.6):(0.2-0.6);

[0016] Preferably, the antioxidant comprises at least one of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ) and vitamin E; more preferably, the antioxidant is vitamin E;

[0017] Preferably, the suspending agent comprises at least one of sodium carboxymethylcellulose, dimethicone, carbomer and Tween 80; more preferably, the suspending agent is Tween 80.

[0018] The present invention also provides a method for preparing cefuroxime sodium microcapsules, comprising the following steps:

[0019] (1) preparing a carboxymethyl dextran solution, and spraying the carboxymethyl dextran solution on cefuroxime sodium by a spraying method to obtain a pre-microcapsule product;

[0020] (2) preparing a monolinoleic acid glyceryl solution, and spraying the monolinoleic acid glyceryl solution on the pre-microcapsule product by a spraying method to obtain cefuroxime sodium microcapsules.

[0021] In an optional embodiment, the step (1) further comprises suspending and fluidizing the cefuroxime sodium at 30-55° C. before the spraying;

[0022] In an optional embodiment, the suspension fluidization of cefuroxime sodium is carried out under hot air;

[0023] In an optional embodiment, in step (1), the concentration of the carboxymethyl dextran solution is 10-20wt%;

[0024] The solvent of the solution is a well-known solvent in the art, such as an organic solvent and water. Considering the safety to the human body, the solvent is preferably water;

[0025] In an optional embodiment, in step (2), the concentration of the monolinoleylglycerol solution is 5-15wt%;

[0026] In an optional embodiment, in the step (1), based on the mass of the ceftizoxime sodium, the mass of the carboxymethyl dextran added per minute is 0.1-0.2 wt %;

[0027] In an optional embodiment, in step (2), based on the mass of the pre-microcapsule product, the mass of the dispersed phase in the monolinoleic acid glyceryl solution added per minute is 0.1-0.2 wt %. It should be noted that the monolinoleic acid glyceryl solution is a dispersion, which includes a dispersed phase and a dispersion medium, and the dispersed phase includes monolinoleic acid glyceryl.

[0028] The dispersion medium of the dispersion is a solvent known in the art, such as an organic solvent and water. Considering the safety to the human body, the dispersion medium is preferably water;

[0029] In an optional embodiment, the monolinoleylglycerol solution further comprises at least one of an antioxidant and a suspending agent. It should be noted that the dispersed phase further comprises at least one of an antioxidant and a suspending agent.

[0030] In an optional embodiment, the step (1) further comprises a first drying step after the spraying;

[0031] In an optional embodiment, the first drying temperature is 30-55°C;

[0032] In an optional embodiment, the first drying time is 30-60s;

[0033] In an optional embodiment, the step (2) further comprises a second drying step after the spraying;

[0034] In an optional embodiment, the second drying temperature is 30-55°C;

[0035] In an optional embodiment, the second drying time is 30-60 seconds.

[0036] The present invention also provides a preparation containing ceftizoxime sodium microcapsules, wherein the preparation comprises the ceftizoxime sodium microcapsules or the ceftizoxime sodium microcapsules prepared by the preparation method.

[0037] The technical solution of the present invention has the following advantages:

[0038] 1. The ceftizoxime sodium microcapsules provided by the present invention include a capsule core and a capsule material wrapping the capsule core; the capsule material includes an inner coating and an outer coating, the inner coating wraps the capsule core, and the capsule core includes ceftizoxime sodium; the inner coating includes carboxymethyl dextran; the outer coating includes monolinoleyl glyceride; the mass ratio of ceftizoxime sodium, carboxymethyl dextran and monolinoleyl glyceride is (1-3):(0.5-1.5):(0.5-1.5). The ceftizoxime sodium microcapsules prepared by the present invention have high stability, long storage period and good sustained release effect. The present invention adopts a double-layer coating design. The carboxymethyl glucan used in the inner coating is carboxymethylated yeast glucan. Yeast glucan has an immune enhancement effect, but it is insoluble in water and difficult to use. Carboxymethylating it can retain the spiral structure of the glucan, ensure biological activity and have excellent solubility; the outer coating uses monolinoleic acid glyceride, which is a mixture of monolinoleic acid monoglyceride, monolinoleic acid diglyceride and monolinoleic acid triglyceride; monolinoleic acid glyceride can stimulate bile secretion, form a micellar solution, and maintain the stability of the microcapsule in the body. Its double bonds and long carbon chains can also stimulate the secretion of chylomicrons, which are transported and absorbed through the lymphatic system, thereby reducing the first-pass effect of the liver and improving safety; chylomicrons are also combined with carboxymethyl glucan, and chylomicrons are used as carriers to transport drugs across the intestinal epithelial barrier, with efficient transmembrane transport without destroying the drug structure, further improving the stability of the microcapsule. The ceftizoxime sodium microcapsules of the present invention are sustained-release preparations, which can stably release ceftizoxime sodium within 24 hours after use, reduce the number of administrations, avoid the adverse phenomenon of drug resistance, and also reduce the risks of increasing the effective dose and large peak-to-trough fluctuations in blood drug concentration during administration.

[0039] 2. The preparation method of the ceftizoxime sodium microcapsules provided by the present invention, the present invention preferably adds carboxymethyl dextran in the form of an aqueous solution, and adds monolinoleic acid glyceride in the form of an aqueous dispersion, only water is needed without adding an organic solvent, and the solvent residue is avoided from causing harm to the human body. All the excipients used in the preparation of the ceftizoxime sodium microcapsules of the present invention are pharmaceutical grade and in reasonable amounts, which are safer for the human body. In addition, the preparation time of the ceftizoxime sodium microcapsules prepared by the present invention is short, the production cost is low, and there is no need to frequently change the production equipment. The capsule core is preferably in powder form, which greatly reduces the risk of poor stability caused by deformation and rupture of the capsule wall. DETAILED DESCRIPTION

[0040] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0041] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0042] The monolinolein glyceryl in the following examples and comparative examples is a mixture of monolinolein glyceryl, dilinolein glyceryl and trilinolein glyceryl in a volume ratio of 2:1:1.

[0043] Example 1

[0044] This embodiment provides a method for preparing ceftizoxime sodium microcapsules. The raw materials and dosage of ceftizoxime sodium microcapsules are shown in Table 1.

[0045] Table 1

[0046] composition Dosage Cefuroxime Sodium 125g Carboxymethyl dextran 125g Monolinoleylglycerol 125g Twain 80 50g Vitamin E 50g

[0047] The preparation method of cefuroxime sodium microcapsules comprises the following steps:

[0048] (1) placing cefuroxime sodium in a bottom spray fluidized bed, introducing hot air, controlling the hot air temperature to 30° C., and suspending and fluidizing the cefuroxime sodium; mixing carboxymethyl dextran with 500 mL of water, atomizing through a nozzle of the bottom spray fluidized bed, and continuously adding the fluidized bed, with the mass of the carboxymethyl dextran sprayed per minute being 0.1 to 0.2 wt % based on the mass of cefuroxime sodium; and drying by hot air after spraying at 30° C. for 30 to 60 s to obtain a pre-microcapsule product.

[0049] (2) Mix monolinoleylglycerol, Tween 80, vitamin E and 200 mL of water into a solution, atomize it through the nozzle of the bottom spray fluidized bed, and continuously add it into the fluidized bed. The total mass of monolinoleylglycerol, Tween 80 and vitamin E in the solution sprayed per minute is 0.1-0.2 wt % based on the mass of the previous microcapsule product. After spraying, dry it at 30° C. for 30-60 s by hot air drying, cool the material, and obtain cefuroxime sodium microcapsules.

[0050] Example 2

[0051] This embodiment provides a method for preparing ceftizoxime sodium microcapsules. Compared with Example 1, the only difference is that the amount of raw materials used is different. The amount of raw materials used is shown in Table 2.

[0052] Table 2

[0053] composition Dosage Cefuroxime Sodium 125g Carboxymethyl dextran 187.5g Monolinoleylglycerol 187.5g Twain 80 75g Vitamin E 75g

[0054] Example 3

[0055] This embodiment provides a method for preparing cefuroxime sodium microcapsules. Compared with Example 1, the only difference is that butylated hydroxyanisole is used instead of vitamin E in Example 1.

[0056] Table 3

[0057]

[0058]

[0059] Example 4

[0060] This embodiment provides a method for preparing cefuroxime sodium microcapsules. Compared with Example 1, the only difference is that dimethicone is used instead of Tween 80 in Example 1.

[0061] Table 4

[0062] composition Dosage Cefuroxime Sodium 125g Carboxymethyl dextran 125g Monolinoleylglycerol 125g Dimethicone 50g Vitamin E 50g

[0063] Example 5

[0064] This embodiment provides a method for preparing ceftizoxime sodium microcapsules. The raw materials and dosage of ceftizoxime sodium microcapsules are shown in Table 5.

[0065] Table 5

[0066] composition Dosage Cefuroxime Sodium 125g Carboxymethyl dextran 31.25g Monolinoleylglycerol 31.25g Sodium Carboxymethyl Cellulose 12.5g Butylated Hydroxytoluene (BHT) 12.5g

[0067] The preparation method of cefuroxime sodium microcapsules comprises the following steps:

[0068] (1) placing cefuroxime sodium in a bottom spray fluidized bed, introducing hot air, controlling the hot air temperature to 55° C., and suspending and fluidizing the cefuroxime sodium; mixing carboxymethyl dextran with 500 mL of water, atomizing through a nozzle of the bottom spray fluidized bed, and continuously adding the fluidized bed, with the mass of the carboxymethyl dextran sprayed per minute being 0.1 to 0.2 wt % based on the mass of cefuroxime sodium; and drying by hot air after spraying at 55° C. for 30 to 60 s to obtain a pre-microcapsule product.

[0069] (2) Mixing monolinoleic acid glyceryl, sodium carboxymethyl cellulose, butylated hydroxytoluene and 200 mL of water into a solution, atomizing it through the nozzle of the bottom spray fluidized bed, and continuously adding it into the fluidized bed. The total mass of monolinoleic acid glyceryl, sodium carboxymethyl cellulose and butylated hydroxytoluene in the solution sprayed per minute is 0.1-0.2 wt % based on the mass of the previous microcapsule product. After the spraying is completed, the solution is dried at 55° C. for 30-60 s by hot air drying, and the material is cooled to obtain cefuroxime sodium microcapsules.

[0070] Comparative Example 1

[0071] This comparative example provides a method for preparing cefuroxime sodium microcapsules. Compared with Example 1, the only difference is that the amount of raw materials is different. The amount of raw materials is shown in Table 6.

[0072] Table 6

[0073] composition Dosage Cefuroxime Sodium 125g Carboxymethyl dextran 250g Monolinoleylglycerol 250g Twain 80 125g Vitamin E 125g

[0074] Comparative Example 2

[0075] This comparative example provides a method for preparing cefuroxime sodium microcapsules. Compared with Example 1, the only difference is that the amount of raw materials is different. The amount of raw materials is shown in Table 7.

[0076] Table 7

[0077] composition Dosage Cefuroxime Sodium 125g Carboxymethyl dextran 12.5g Monolinoleylglycerol 12.5g Twain 80 12.5g Vitamin E 12.5g

[0078] Comparative Example 3

[0079] This comparative example provides a method for preparing cefuroxime sodium microcapsules. Compared with Example 1, the only difference is that gum arabic is used instead of the carboxymethyl dextran in Example 1.

[0080] Table 8

[0081] composition Dosage Cefuroxime Sodium 125g Gum Arabic 125g Monolinoleylglycerol 125g Twain 80 50g Vitamin E 50g

[0082] Comparative Example 4

[0083] This comparative example provides a method for preparing cefuroxime sodium microcapsules. Compared with Example 1, the difference is that lecithin is used instead of monolinoleylglycerol in Example 1.

[0084] Table 9

[0085] composition Dosage Cefuroxime Sodium 125g Carboxymethyl dextran 125g Lecithin 125g Twain 80 50g Vitamin E 50g

[0086] Comparative Example 5

[0087] This comparative example provides a method for preparing cefuroxime sodium microcapsules, which is different from Example 1 only in that monolinoleyl glycerol is not added.

[0088] Table 10

[0089] composition Dosage Cefuroxime Sodium 125g Carboxymethyl dextran 125g Twain 80 50g Vitamin E 50g

[0090] Comparative Example 6

[0091] This comparative example provides a method for preparing cefuroxime sodium microcapsules. The raw materials and amounts are shown in Table 11.

[0092] Table 11

[0093]

[0094]

[0095] The preparation method of cefuroxime sodium microcapsules comprises the following steps:

[0096] Cefuroxime sodium is placed in a bottom spray fluidized bed, hot air is introduced, and the hot air temperature is controlled to be 30°C to suspend and fluidize the cefuroxime sodium; monolinoleylglycerol, Tween 80, vitamin E and 200 mL of water are mixed into a solution, atomized through a nozzle of the bottom spray fluidized bed, and continuously added into the fluidized bed; based on the mass of cefuroxime sodium, the total mass of monolinoleylglycerol, Tween 80 and vitamin E in the solution sprayed per minute is 0.1-0.2wt%; after spraying, hot air drying is adopted, drying is carried out at 55°C for 30-60s, and the material is cooled and discharged to obtain cefuroxime sodium microcapsules.

[0097] Experimental Example 1

[0098] In this experimental example, the cefuroxime sodium microcapsules prepared in Examples 1-5 and Comparative Examples 1-6 were subjected to a release experiment in artificial intestinal fluid, as follows.

[0099] (1) Prepare artificial intestinal fluid (refer to Chinese Pharmacopoeia): Take 6.8 g of potassium dihydrogen phosphate and add 500 ml of water to dissolve it. Adjust the pH value to 6.8 with 0.1 mol / L sodium hydroxide solution. Take 10 g of pancreatic enzyme and add appropriate amount of water to dissolve it. Mix the two solutions and dilute with water to 1000 ml.

[0100] (2) The tablet was measured using a four-in-one measuring instrument. The measuring instrument was started and preheated, and the temperature was set to 37° C. The basket shaft and the basket body were installed, and the positioning ball was used to position the basket. The dissolution cup was placed and fixed (900 ml of the prepared artificial intestinal fluid was poured into each dissolution cup). The cefuroxime sodium microcapsules prepared in Examples 1-5 and Comparative Examples 1-6 containing an equal amount of cefuroxime sodium were respectively taken, wrapped with gauze, and placed in the corresponding basket body, and the rotation speed was controlled at 100 r / min.

[0101] (3) After 2, 4, 8, 12, and 24 hours, a portion of each basket of Examples 1-5 and Comparative Examples 1-6 was taken, and the content of ceftizoxime sodium in the corresponding basket was detected by HPLC, and the retention rate and dissolution rate of ceftizoxime sodium at this time were calculated. The results are shown in Tables 13-14. The parameters of HPLC are shown in Table 12.

[0102] Table 12 HPLC parameters 1

[0103]

[0104] Note: This table is used to detect the content of cefuroxime sodium.

[0105] The retention rate of ceftizoxime sodium = the content of ceftizoxime sodium sampled in the basket / the theoretical embedding amount of ceftizoxime sodium in the sample; the theoretical embedding amount of ceftizoxime sodium in the sample is the actual added mass of ceftizoxime sodium in the microcapsule;

[0106] Dissolution rate of ceftizoxime sodium: dissolution rate = 1-retention rate of ceftizoxime sodium;

[0107] Table 13 Retention rate of cefuroxime sodium

[0108]

[0109]

[0110] Table 14 Dissolution rate of ceftizoxime sodium

[0111] Sample name Dissolution rate after 2 hours Dissolution rate after 4 hours Dissolution rate after 8 hours Dissolution rate after 12h Dissolution rate after 24 hours Example 1 46.1％ 58.7％ 71.4％ 94.7％ 99.2％ Example 2 49.0％ 60.2％ 80.9％ 95.5％ 99.5％ Example 3 52.7％ 64.5％ 77.7％ 94.9％ 98.1％ Example 4 47.9％ 59.9％ 80.7％ 93.4％ 97.4％ Example 5 50.8％ 59.5％ 80.1％ 94.3％ 98.9％ Comparative Example 1 74.7％ 90.3％ 96.4％ 100％ 100％ Comparative Example 2 82.4％ 99.9％ 100％ 100％ 100％ Comparative Example 3 22.6％ 30.9％ 48.4％ 63.7％ 80.3％ Comparative Example 4 49.8％ 88.6％ 94.7％ 99.6％ 100％ Comparative Example 5 51.2％ 88.2％ 92.8％ 99.9％ 100％ Comparative Example 6 67.5％ 95.4％ 99.9％ 100％ 100％

[0112] It can be seen from Tables 13-14 that the ceftizoxime sodium microcapsules prepared by the present invention have good sustained-release effect and can be released steadily within 24 hours, reducing the number of administrations; the retention rate and dissolution rate of the ceftizoxime sodium microcapsules prepared in Examples 1-5 are comparable, indicating that the selection of antioxidants and suspending agents does not affect the release of the microcapsules.

[0113] It can be seen from Examples 1-5 and Comparative Examples 1-2 that the sustained-release effect of the cefuroxime sodium microcapsules prepared when the mass ratio of cefuroxime sodium, carboxymethyl dextran and monolinoleyl glycerol is not within the range defined by the present invention is poor.

[0114] It can be seen from Examples 1-5 and Comparative Example 3 that in Comparative Example 3, gum arabic was used instead of carboxymethyl dextran, and the dissolution rate was 48.4% after 4 hours, and the release time was too long, indicating that the cefuroxime sodium microcapsules made of gum arabic had a poor release effect in artificial intestinal fluid.

[0115] It can be seen from Examples 1-5 and Comparative Example 4 that in Comparative Example 4, lecithin is used instead of monolinolein glyceryl, and the dissolution rate is 88.6% after 4 hours, which is less than 65% of the dissolution rate of Examples 1-5 in the same period, and the sustained release effect is not good, indicating that the combined use of carboxymethyl dextran and monolinolein glyceryl can effectively improve the sustained release effect of the prepared cefuroxime sodium microcapsules.

[0116] It can be seen from Examples 1-5 and Comparative Examples 5-6 that Comparative Example 5 shows that using monolinoleylglycerol as an outer coating makes the release of cefuroxime sodium more gradual in an artificial intestinal fluid environment; Comparative Example 6 shows that using carboxymethyl dextran as an inner coating allows for a gradual release of cefuroxime sodium.

[0117] In summary, the present invention adopts a double-layer coating of carboxymethyl dextran and monolinoleyl glycerol to coat cefuroxime sodium, which can effectively improve the sustained-release effect of the prepared cefuroxime sodium microcapsules.

[0118] Experimental Example 2

[0119] In this experimental example, an accelerated stability test was conducted on the cefuroxime sodium microcapsules prepared in Examples 1-5 and Comparative Examples 1-6, as follows.

[0120] (1) The cefuroxime sodium microcapsules and commercially available preparations (manufacturer: Southwest Pharmaceutical Co., Ltd.) prepared in Examples 1-5 and Comparative Examples 1-6 (250 mg per portion, calculated as cefuroxime sodium) were placed in vials and placed in an acceleration box (40° C., 75% humidity). Product stability tests were performed on each sample for 1 month, 2 months, and 3 months. After the expiration, the cefuroxime sodium content in the sample was detected using the parameters in Table 12 of the high performance liquid chromatography method; the impurity content in the sample was detected using the parameters in Table 15 of the high performance liquid chromatography method; and the retention rates of cefuroxime sodium and impurities were calculated, respectively. The results are shown in Tables 17-18.

[0121] Table 15 HPLC parameters 2

[0122]

[0123]

[0124] Note: This table is used to detect the content of impurities.

[0125] Table 16

[0126] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 97 3 10 85 15 20 40 60 25 40 60 26 97 3 35 97 3

[0127] The retention rate of cefuroxime sodium = the content of cefuroxime sodium in each time period of the sample / the detection content in the sample at month 0; the sample at month 0 is the sample just prepared, and the retention rate at month 0 is regarded as 100%.

[0128] Table 17 Retention rate of cefuroxime sodium

[0129] Sample name 1M 2M 3M Example 1 99.3％ 96.5％ 95.9％ Example 2 99.1％ 97.1％ 95.2％ Example 3 98.7％ 97.0％ 95.4％ Example 4 99.3％ 98.4％ 96.7％ Example 5 99.0％ 97.5％ 95.6％ Comparative Example 1 98.8％ 93.6％ 90.1％ Comparative Example 2 99.2％ 95.3％ 92.0％ Comparative Example 3 98.0％ 92.8％ 89.4％ Comparative Example 4 98.7％ 94.6％ 93.3％ Comparative Example 5 98.5％ 96.9％ 94.6％ Comparative Example 6 98.2％ 95.2％ 91.3％ Commercially available samples 98.5％ 96.8％ 93.2％

[0130] Note: 1M, 2M and 3M correspond to the test results after the samples have been placed for 1 month, 2 months and 3 months respectively.

[0131] Table 18 Retention rate of impurities

[0132]

[0133]

[0134] Note: 1M, 2M and 3M correspond to the test results after the samples have been placed for 1 month, 2 months and 3 months respectively.

[0135] After 3 months of accelerated stability test, the retention rate of the ceftizoxime sodium microcapsules prepared in Examples 1-5 was greater than 95%, which was better than the commercially available particles, indicating good stability. At the same time, there were fewer impurities, which could reduce the probability of adverse reactions and allergic reactions.

[0136] It can be seen from Examples 1-5 and Comparative Examples 1-2 that the cefuroxime sodium microcapsules prepared when the mass ratio of cefuroxime sodium, carboxymethyl dextran and monolinoleyl glycerol is not within the range defined by the present invention have poor stability.

[0137] It can be seen from Examples 1-5 and Comparative Example 3 that in Comparative Example 3, gum arabic was used instead of carboxymethyl dextran. After 3 months of accelerated stability experiment, the retention rate of cefuroxime sodium had dropped to 89.4%, indicating that the stability of the cefuroxime sodium microcapsules made with gum arabic was poor; further indicating that the inner coating containing carboxymethyl dextran can improve the stability of the microcapsules.

[0138] It can be seen from Examples 1-5 and Comparative Example 4 that in Comparative Example 4, lecithin is used instead of monolinoleylglycerol. After 2 months of accelerated stability experiment, the retention rate of cefuroxime sodium has dropped to 94.6%, compared with the retention rate of Examples 1-5 which is greater than 96% in the same period, indicating that the combination of carboxymethyl dextran and monolinoleylglycerol can effectively improve the stability of the prepared cefuroxime sodium microcapsules and can be stored for a long time.

[0139] Comparative Example 5 uses carboxymethyl dextran to form a coating, and its retention rate of cefuroxime sodium and the retention rate of impurities are roughly equivalent to those of commercially available samples. It can be seen from Examples 1-5 and Comparative Example 5 that after the introduction of the outer coating containing monolinoleyl glyceride into the microcapsule, the stability of cefuroxime sodium is further improved. Comparative Example 6 shows that the double-layer coating formed by carboxymethyl dextran and monolinoleyl glyceride has higher stability than that of the coating using only carboxymethyl dextran.

[0140] In summary, the present invention adopts a double-layer coating of carboxymethyl dextran and monolinoleyl glycerol to coat cefuroxime sodium, which can effectively improve the stability of the prepared cefuroxime sodium microcapsules.

[0141] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the scope of protection of the invention.

Claims

1. A cefuroxime sodium microcapsule, characterized in that: The cefuroxime sodium microcapsule comprises a capsule core and a capsule material wrapping the capsule core; the capsule material comprises an inner coating and an outer coating, the inner coating wraps the capsule core, and the capsule core comprises cefuroxime sodium; the inner coating comprises carboxymethyl dextran; and the outer coating comprises monolinoleyl glycerol; The mass ratio of cefuroxime sodium, carboxymethyl dextran and monolinoleyl glycerol is (1-3):(0.5-1.5):(0.5-1.5).

2. The cefuroxime sodium microcapsule according to claim 1, characterized in that: The particle size of the cefuroxime sodium is 80-120 μm; and / or, The monolinoleic acid glyceride includes at least one of monolinoleic acid glyceride, monolinoleic acid diglyceride and monolinoleic acid triglyceride; and / or, Carboxymethyl glucan is carboxymethylated yeast glucan.

3. The cefuroxime sodium microcapsule according to claim 1, characterized in that: The monolinoleic acid glyceride includes monolinoleic acid monoglyceride, monolinoleic acid diglyceride and monolinoleic acid triglyceride in a volume ratio of (2-2.5):(1-1.5):(1-1.5).

4. The ceftizoxime sodium microcapsule according to any one of claims 1 to 3, characterized in that: The outer coating further comprises at least one of an antioxidant and a suspending agent; Preferably, the mass ratio of the monolinoleylglycerol, the antioxidant and the suspending agent is (0.5-1.5):(0.2-0.6):(0.2-0.6); Preferably, the antioxidant comprises at least one of butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone and vitamin E; more preferably, the antioxidant is vitamin E; Preferably, the suspending agent comprises at least one of sodium carboxymethylcellulose, dimethicone, carbomer and Tween 80; more preferably, the suspending agent is Tween 80.

5. A method for preparing cefuroxime sodium microcapsules, characterized in that: The steps include: (1) preparing a carboxymethyl dextran solution, and spraying the carboxymethyl dextran solution on cefuroxime sodium by a spraying method to obtain a pre-microcapsule product; (2) preparing a monolinoleic acid glyceryl solution, and spraying the monolinoleic acid glyceryl solution on the pre-microcapsule product by a spraying method to obtain cefuroxime sodium microcapsules.

6. The preparation method according to claim 5, characterized in that: The step (1) further comprises suspending and fluidizing the cefuroxime sodium at 30-55° C. before spraying; and / or, In the step (1), the concentration of the carboxymethyl dextran solution is 10-20 wt %; and / or, In the step (2), the concentration of the monolinoleylglycerol solution is 5-15wt%.

7. The preparation method according to claim 6, characterized in that: In the step (1), based on the mass of the ceftizoxime sodium, the mass of the carboxymethyl dextran added per minute is 0.1-0.2 wt %; and / or, In the step (2), based on the mass of the pre-microcapsule product, the mass of the dispersed phase in the monolinoleyl glycerol solution added per minute is 0.1-0.2 wt %.

8. The preparation method according to claim 5, characterized in that: The monolinoleylglycerol solution further comprises at least one of an antioxidant and a suspending agent; and / or, The step (1) further comprises a first drying step after the spraying; and / or, The step (2) further comprises a second drying step after the spraying.

9. The preparation method according to claim 8, characterized in that: The first drying temperature is 30-55°C; and / or, The first drying time is 30-60s; and / or, The second drying temperature is 30-55°C; and / or, The second drying time is 30-60s.

10. A preparation containing cefuroxime sodium microcapsules, characterized in that: The preparation comprises the cefuroxime sodium microcapsules described in any one of claims 1 to 4 or the cefuroxime sodium microcapsules prepared by the preparation method described in any one of claims 5 to 9.

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