Solid composition containing ceftizoxime sodium microcapsules as well as preparation method and application of solid composition

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a solid composition containing ceftizoxime sodium microcapsules as well as a preparation method and application of the solid composition. The invention provides a solid composition containing ceftizoxime sodium microcapsules. The solid composition comprises the ceftizoxime sodium microcapsules, sorbitol, microcrystalline cellulose and povidone, the ceftizoxime sodium micro-capsule comprises a capsule core and a capsule wall material wrapping the capsule core, and the capsule core comprises ceftizoxime sodium. The solid composition containing the ceftizoxime sodium microcapsules provided by the invention is high in ceftizoxime sodium active ingredient content, long in storage period, accurate in dosage and convenient to orally take and use, and can be stably released in an acidic or alkaline environment.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a solid composition containing cefuroxime sodium microcapsules, a preparation method and an application thereof. 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] The dosage of existing cefuroxime sodium intermediates is inaccurate and the dosage cannot be precisely controlled. When cefuroxime sodium is made into solid preparations, it degrades, resulting in less active ingredients, and there will also be a large number of impurities, short storage period, poor in vivo bioavailability and other problems. Summary of the invention

[0004] Therefore, the technical problem to be solved by the present invention is to overcome the inaccurate dosage of the cefuroxime sodium intermediate in the prior art, and the inability to accurately control the dosage; when the cefuroxime sodium is made into a solid preparation, the degradation of the cefuroxime sodium leads to a small amount of active ingredients, and there will also be a large amount of impurities, a short storage period, and poor in vivo bioavailability. The present invention thus provides a solid composition containing cefuroxime sodium microcapsules, a preparation method and an application.

[0005] To this end, the present invention provides the following technical solutions.

[0006] The invention provides a solid composition containing ceftizoxime sodium microcapsules, comprising ceftizoxime sodium microcapsules, sorbitol, microcrystalline cellulose and povidone; the ceftizoxime sodium microcapsules comprise a capsule core and a capsule material wrapping the capsule core, and the capsule core comprises ceftizoxime sodium.

[0007] In an optional embodiment, the mass ratio of the cefuroxime sodium microcapsules, sorbitol, microcrystalline cellulose, and povidone is (6-18):(4-12):(2-6):(1-3).

[0008] In an optional embodiment, the solid composition further comprises sodium carboxymethyl starch and talc.

[0009] In an optional embodiment, the mass ratio of the cefuroxime sodium microcapsules, sodium carboxymethyl starch and talc is (6-18):(1-3):(0.6-1.8).

[0010] In an optional embodiment, the capsule material comprises an inner coating and an outer coating, wherein the inner coating wraps the capsule core; the inner coating comprises carboxymethyl dextran; and the outer coating comprises monolinoleyl glycerol;

[0011] Preferably, the mass ratio of cefuroxime sodium, carboxymethyl dextran and monolinoleyl glycerol is (1-3):(0.5-1.5):(0.5-1.5);

[0012] Preferably, the particle size of the cefuroxime sodium is 80-120 μm;

[0013] Preferably, the monolinoleic acid glyceride includes at least one of monolinoleic acid glyceride, monolinoleic acid diglyceride and monolinoleic acid triglyceride;

[0014] Preferably, the carboxymethyl glucan is carboxymethylated yeast glucan;

[0015] Preferably, the outer coating further comprises at least one of an antioxidant and a suspending agent.

[0016] In an optional embodiment, the monolinoleylglycerol comprises monolinoleylglycerol, monolinoleylglycerol dilinoleylglycerol and monolinoleylglycerol trilinoleylglycerol in a volume ratio of (2-2.5):(1-1.5):(1-1.5);

[0017] In an optional embodiment, the mass ratio of the monolinoleyl glyceride, the antioxidant and the suspending agent is (0.5-1.5):(0.2-0.6):(0.2-0.6);

[0018] In an optional embodiment, the antioxidant includes at least one of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ) and vitamin E;

[0019] In an optional embodiment, the suspending agent includes at least one of sodium carboxymethyl cellulose, dimethicone, carbomer and Tween 80.

[0020] In an optional embodiment, the antioxidant includes vitamin E;

[0021] In an alternative embodiment, the suspending agent comprises Tween 80.

[0022] The present invention also provides a method for preparing a solid composition containing cefuroxime sodium microcapsules, comprising the following steps:

[0023] The cefuroxime sodium microcapsules are uniformly mixed with sorbitol, microcrystalline cellulose and povidone.

[0024] In an optional embodiment, sodium carboxymethyl starch and talc are also added.

[0025] The preparation method of the cefuroxime sodium microcapsules comprises the following steps:

[0026] (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;

[0027] (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.

[0028] In an optional embodiment, the step (1) further comprises suspending and fluidizing the cefuroxime sodium at 30-55° C. before the spraying;

[0029] In an optional embodiment, the suspension fluidization of cefuroxime sodium is carried out under hot air;

[0030] In an optional embodiment, in step (1), the concentration of the carboxymethyl dextran solution is 10-20wt%;

[0031] 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;

[0032] In an optional embodiment, in step (2), the concentration of the monolinoleylglycerol solution is 5-15wt%;

[0033] 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 %;

[0034] 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.

[0035] 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;

[0036] 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.

[0037] In an optional embodiment, the step (1) further comprises a first drying step after the spraying;

[0038] In an optional embodiment, the first drying temperature is 30-55°C;

[0039] In an optional embodiment, the first drying time is 30-60s;

[0040] In an optional embodiment, the step (2) further comprises a second drying step after the spraying;

[0041] In an optional embodiment, the second drying temperature is 30-55°C;

[0042] In an optional embodiment, the second drying time is 30-60 seconds.

[0043] The present invention also provides a preparation comprising a solid composition containing ceftizoxime sodium microcapsules, wherein the preparation comprises the solid composition containing ceftizoxime sodium microcapsules or the solid composition containing ceftizoxime sodium microcapsules prepared by the above preparation method. Preferably, the dosage form of the preparation is selected from tablets or capsules.

[0044] The technical solution of the present invention has the following advantages:

[0045] 1. The solid composition containing ceftizoxime sodium microcapsules provided by the present invention comprises ceftizoxime sodium microcapsules, sorbitol, microcrystalline cellulose and povidone; the ceftizoxime sodium microcapsules comprise a capsule core and a capsule material wrapping the capsule core, wherein the capsule core comprises ceftizoxime sodium. The solid composition containing ceftizoxime sodium microcapsules provided by the present invention has accurate dosage and is convenient for oral use. The solid composition contains high active ingredients of ceftizoxime sodium, has a long storage period, and can be stably released in an acidic or alkaline environment. Sorbitol contains six hydroxyl groups, which can effectively bind free water. Microcrystalline cellulose forms a gel when it meets water to improve adhesion. Sorbitol can adsorb microcrystalline cellulose to form a reinforced interface film to wrap the ceftizoxime sodium microcapsules, thereby protecting the active ingredients of ceftizoxime sodium from degradation in different application environments, having good drug efficacy, and not generating a large amount of impurities to cause allergic reactions and other adverse reactions. The formed reinforced interface film can also prolong the storage period of the solid composition, which is convenient for storage and can be taken orally, and is convenient for use. Povidone can modify, wrap and slowly release ceftizoxime sodium, thereby making the active ingredients less likely to degrade. In the prior art, although the solid preparation of ceftizoxime sodium has the advantages of convenience, many problems still occur, such as the inability to exert the performance of ceftizoxime sodium itself, and problems such as degradation and decreased stability will occur, and the drug utilization rate will be reduced. The present invention can solve the problem of decreased stability when ceftizoxime sodium is made into a solid preparation in the prior art, and sorbitol, microcrystalline cellulose and povidone are used to make it into solid preparations such as tablets and capsules, which not only improves the convenience of application, but also can make full use of the drug properties. The solid composition containing ceftizoxime sodium microcapsules provided by the present invention is more accurate in dosage than ceftizoxime sodium microcapsules, which is convenient for users to accurately control the dosage of active ingredients, and has high in vivo bioavailability after use.

[0046] 2. The method for preparing a solid composition containing cefuroxime sodium microcapsules provided by the present invention uses dry mixing during the preparation of the solid composition, thereby avoiding the degradation of cefuroxime sodium after contact with moisture and heat, better ensuring the stability of the prepared solid composition, and having a higher bioavailability in the body. DETAILED DESCRIPTION

[0047] 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.

[0048] 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.

[0049] The cefuroxime sodium microcapsules used in the following examples were prepared by the following method:

[0050] (1) 125 g of 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; 125 g of carboxymethyl dextran is mixed with 500 mL of water, atomized through the nozzle of the bottom-spray fluidized bed, and continuously added to the fluidized bed. The mass of carboxymethyl dextran sprayed per minute is 0.1 to 0.2 wt % based on the mass of cefuroxime sodium; after spraying, hot air drying is performed at 30° C. for 30 to 60 s to obtain a pre-microcapsule product.

[0051] (2) 125 g of monolinoleyl glycerol, 50 g of Tween 80, 50 g of vitamin E and 200 mL of water were mixed into a solution, atomized through a nozzle of a bottom spray fluidized bed, and continuously added into the fluidized bed. The total mass of monolinoleyl glycerol, Tween 80 and vitamin E in the solution sprayed per minute was 0.1-0.2 wt % based on the mass of the previous microcapsule product. After the spraying was completed, hot air drying was used at 30° C. for 30-60 s, and the material was cooled to obtain cefuroxime sodium microcapsules.

[0052] Example 1

[0053] This embodiment provides a method for preparing a solid composition containing ceftizoxime sodium microcapsules. The raw materials and dosage of the solid composition containing ceftizoxime sodium microcapsules are shown in Table 1.

[0054] Table 1

[0055] composition Dosage Cefuroxime Sodium Microcapsules 600g Sorbitol 400g Microcrystalline Cellulose 200g Povidone K30 100g Sodium carboxymethyl starch 100g talcum powder 60g

[0056] The preparation method is as follows: (1) sorbitol and microcrystalline cellulose are sieved through a 120-mesh sieve, povidone K30 and sodium carboxymethyl starch are sieved through a 24-mesh sieve, and talc is sieved through a 40-mesh sieve;

[0057] (2) The cefuroxime sodium microcapsules are uniformly mixed with sorbitol, microcrystalline cellulose, povidone K30, sodium carboxymethyl starch and talc, and tabletted to obtain tablets.

[0058] Example 2

[0059] This embodiment provides a method for preparing a solid composition containing 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.

[0060] Table 2

[0061] composition Dosage Cefuroxime Sodium Microcapsules 600g Sorbitol 400g Microcrystalline Cellulose 200g Povidone K30 100g Sodium carboxymethyl starch 100g talcum powder 60g

[0062] The preparation method is as follows: (1) sorbitol and microcrystalline cellulose are sieved through a 120-mesh sieve, povidone K30 and sodium carboxymethyl starch are sieved through a 24-mesh sieve, and talc is sieved through a 40-mesh sieve;

[0063] (2) The cefuroxime sodium microcapsules are uniformly mixed with sorbitol, microcrystalline cellulose, povidone K30, sodium carboxymethyl starch and talc, and filled into hollow capsules to obtain capsules.

[0064] Example 3

[0065] This embodiment provides a method for preparing a solid composition containing ceftizoxime 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 3.

[0066] Table 3

[0067] composition Dosage Cefuroxime Sodium Microcapsules 1800g Sorbitol 1200g Microcrystalline Cellulose 600g Povidone K30 300g Sodium carboxymethyl starch 300g talcum powder 180g

[0068] Example 4

[0069] This embodiment provides a method for preparing a solid composition containing ceftizoxime sodium microcapsules. Compared with Example 2, the only difference is that the amount of raw materials is different. The amount of raw materials is shown in Table 4.

[0070] Table 4

[0071] composition Dosage Cefuroxime Sodium Microcapsules 1800g Sorbitol 1200g Microcrystalline Cellulose 600g Povidone K30 300g Sodium carboxymethyl starch 300g talcum powder 180g

[0072] Comparative Example 1

[0073] This comparative example provides a method for preparing a solid composition containing ceftizoxime sodium microcapsules. Compared with Example 1, the only difference is that sucrose of equal mass is used to replace the sorbitol in Example 1, and the amounts of other raw materials are the same as those in Example 1.

[0074] Comparative Example 2

[0075] This comparative example provides a method for preparing a solid composition containing ceftizoxime sodium microcapsules. Compared with Example 1, the only difference is that calcium hydrogen phosphate of the same quality is used to replace the microcrystalline cellulose in Example 1, and the amounts of other raw materials are the same as those in Example 1.

[0076] Comparative Example 3

[0077] This comparative example provides a method for preparing a solid composition containing ceftizoxime sodium microcapsules. Compared with Example 1, the only difference is that sorbitol is not added, and the amounts of other raw materials are the same as those in Example 1.

[0078] Experimental Example 1

[0079] In this experimental example, an accelerated stability test was conducted on the solid composition containing cefuroxime sodium microcapsules prepared in Examples 1-4 and Comparative Examples 1-3, as follows.

[0080] (1) The solid compositions containing ceftizoxime sodium microcapsules prepared in Examples 1-4 and Comparative Examples 1-3 and commercially available preparations (manufacturer: Southwest Pharmaceutical Co., Ltd.) 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 ceftizoxime sodium content in the sample was detected using the parameters in Table 5 of the high performance liquid chromatography method; the impurity content in the sample was detected using the parameters in Table 6 of the high performance liquid chromatography method; and the retention rates of ceftizoxime sodium and related substances were calculated. The results are shown in Tables 8-9.

[0081] Table 5 HPLC parameters 1

[0082]

[0083]

[0084] Note: This table is used to detect the content of cefuroxime sodium.

[0085] Table 6 HPLC parameters 2

[0086]

[0087] Note: This table is used to detect the content of impurities.

[0088] Table 7

[0089] 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

[0090] 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%.

[0091] Table 8 Retention rate of cefuroxime sodium

[0092] Sample name 1M 2M 3M Example 1 99.8％ 98.7％ 96.9％ Example 2 99.5％ 98.2％ 97.0％ Example 3 99.5％ 98.8％ 97.1％ Example 4 99.6％ 99.1％ 97.7％ Comparative Example 1 85.3％ 71.9％ 65.5％ Comparative Example 2 74.7％ 66.9％ 58.4％ Comparative Example 3 95.8％ 82.5％ 74.3％ Commercially available samples 98.5％ 96.8％ 93.2％

[0093] 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.

[0094] Table 9 Retention rate of impurities

[0095] Sample name 1M 2M 3M Example 1 0.09％ 0.16％ 0.28％ Example 2 0.10％ 0.21％ 0.33％ Example 3 0.05％ 0.14％ 0.23％ Example 4 0.11％ 0.20％ 0.29％ Comparative Example 1 1.25％ 2.01％ 3.99％ Comparative Example 2 1.61％ 2.84％ 3.43％ Comparative Example 3 0.35％ 1.98％ 3.32％ Commercially available samples 0.21％ 0.34％ 0.65％

[0096] 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.

[0097] It can be seen from Tables 8-9 that the solid composition containing ceftizoxime sodium microcapsules provided by the present invention has fewer impurities and a higher retention rate of ceftizoxime sodium compared with commercially available preparations. Adverse reactions or allergic reactions that occur in clinical practice are mostly related to the impurity content. Therefore, the solid composition containing ceftizoxime sodium microcapsules provided by the present invention can reduce the probability of adverse reactions and allergic reactions.

[0098] Experimental Example 2

[0099] In this experimental example, the solid composition containing ceftizoxime sodium microcapsules prepared in Examples 1-4 and Comparative Examples 1-3 was subjected to a dissolution test in multiple media, as follows.

[0100] The solid compositions containing ceftizoxime sodium microcapsules prepared in Examples 1-4 and Comparative Examples 1-3 were placed in hydrochloric acid solution (pH 1.2), acetate solution (pH 4.5), phosphate solution (pH 6.8) and water, respectively. The release amount of the solid compositions containing ceftizoxime sodium microcapsules was detected by high performance liquid chromatography using the parameters in Table 5 at 2, 4, 8, 12 and 24 h, and the retention rate and dissolution rate of ceftizoxime sodium were calculated at this time. The results are shown in Table 10.

[0101] The retention rate of ceftizoxime sodium = the content of ceftizoxime sodium sampled / 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 solid composition;

[0102] Dissolution rate of ceftizoxime sodium: dissolution rate = 1-retention rate of ceftizoxime sodium;

[0103] Table 10 Dissolution rate of ceftizoxime sodium

[0104]

[0105]

[0106] As can be seen from Table 10, the solid composition containing ceftizoxime sodium microcapsules prepared by the present invention shows a gradient release in four common solutes, the release is gentle and stable, and the dissolution rate in 24 hours is also relatively thorough, indicating that the solid composition containing ceftizoxime sodium microcapsules provided by the present invention can better ensure the in vivo bioavailability, and ceftizoxime sodium is less degraded and has good efficacy under the common in vivo acidic environment.

[0107] 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 solid composition containing cefuroxime sodium microcapsules, characterized in that: The invention comprises cefuroxime sodium microcapsules, sorbitol, microcrystalline cellulose and povidone; the cefuroxime sodium microcapsules comprise a capsule core and capsule materials wrapping the capsule core, and the capsule core comprises cefuroxime sodium.

2. The solid composition according to claim 1, characterized in that The mass ratio of the cefuroxime sodium microcapsules, sorbitol, microcrystalline cellulose and povidone is (6-18):(4-12):(2-6):(1-3).

3. The solid composition according to claim 1 or 2, characterized in that The solid composition further comprises sodium carboxymethyl starch and talc.

4. The solid composition according to claim 3, characterized in that The mass ratio of the cefuroxime sodium microcapsules, sodium carboxymethyl starch and talc is (6-18):(1-3):(0.6-1.8).

5. The solid composition according to any one of claims 1 to 4, characterized in that The capsule material comprises an inner coating and an outer coating, wherein the inner coating wraps the capsule core; the inner coating comprises carboxymethyl dextran; and the outer coating comprises monolinoleyl glycerol; Preferably, the mass ratio of cefuroxime sodium, carboxymethyl dextran and monolinoleyl glycerol is (1-3):(0.5-1.5):(0.5-1.5); Preferably, the particle size of the cefuroxime sodium is 80-120 μm; Preferably, the monolinoleic acid glyceride includes at least one of monolinoleic acid glyceride, monolinoleic acid diglyceride and monolinoleic acid triglyceride; Preferably, the carboxymethyl glucan is carboxymethylated yeast glucan; Preferably, the outer coating further comprises at least one of an antioxidant and a suspending agent.

6. The solid composition according to claim 5, characterized in that The monolinoleic acid glyceride comprises monolinoleic acid glyceride, monolinoleic acid diglyceride and monolinoleic acid triglyceride in a volume ratio of (2-2.5):(1-1.5):(1-1.5); and / or, 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); and / or, The antioxidant comprises at least one of butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone and vitamin E; and / or, The suspending agent includes at least one of sodium carboxymethylcellulose, dimethicone, carbomer and Tween 80.

7. The solid composition according to claim 6, characterized in that The antioxidant includes vitamin E; and / or, The suspending agent includes Tween 80.

8. A method for preparing a solid composition containing cefuroxime sodium microcapsules, characterized in that: The steps include: The cefuroxime sodium microcapsules are uniformly mixed with sorbitol, microcrystalline cellulose and povidone.

9. The preparation method according to claim 8, characterized in that: It also includes the addition of sodium carboxymethyl starch and talc.

10. A preparation comprising a solid composition containing microcapsules of cefuroxime sodium, characterized in that: The preparation comprises the solid composition containing ceftizoxime sodium microcapsules according to any one of claims 1 to 7 or the solid composition containing ceftizoxime sodium microcapsules prepared by the preparation method according to any one of claims 8 to 9; Preferably, the dosage form of the preparation is selected from tablets or capsules.

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