Pharmaceutical composition containing cefcapene pivoxil hydrochloride and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical compositions, and discloses a pharmaceutical composition containing cefcapene pivoxil hydrochloride and a preparation method thereof.The pharmaceutical composition is prepared from, by mass, 10%-70% of cefcapene pivoxil hydrochloride, 5%-30% of filler, 0.5%-10% of disintegrating agent, 0.1%-3% of lubricant, 3%-10% of sodium alginate and 30%-45% of beta-cyclodextrin. According to the cefcapene pivoxil hydrochloride capsule, the dosage of each component is controlled, particularly the ratio of sodium alginate to beta-cyclodextrin is controlled, a micelle protection layer is formed on the surface of cefcapene pivoxil hydrochloride by using sodium alginate, and then the clathration effect on cefcapene pivoxil hydrochloride is realized by using a cavity structure of beta-cyclodextrin, so that the stability of cefcapene pivoxil hydrochloride is greatly improved, and the stability of cefcapene pivoxil hydrochloride is improved. And the dissolution rate is far superior to that of the original developed preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical compositions, and in particular to a pharmaceutical composition containing cefcapone hydrochloride and a preparation method thereof. Background Art

[0002] Cefuroxime hydrochloride is a third-generation oral cephalosporin antibiotic. Cefuroxime hydrochloride tablets are mainly suitable for respiratory tract infections (such as pneumonia, bronchitis, pharyngitis, tonsillitis, etc.), otitis media, sinusitis, urinary tract infections (such as gonorrhea, pyelonephritis, cystitis, etc.), skin and skin tissue infections, biliary tract infections, etc. caused by sensitive bacteria. Cefuroxime hydrochloride contains β-lactam bonds and ester bonds in its molecular structure. It is sensitive to moisture, heat, and light, and is very easy to degrade. In the preparation process of solid preparations, it is necessary to strictly control the environmental temperature and humidity and packaging materials, and the production convenience is poor, resulting in a high waste of production resources. In addition, cefuroxime hydrochloride is difficult to dissolve in water, and its solubility in water is only 83.89μg / ml (37±0.5℃), so the solubility is low. Therefore, there is an urgent need for a way to solve its poor stability characteristics, while being able to improve the solubility, simplify the preparation process, and reduce production costs.

[0003] The patent application with publication number CN102552198A discloses a cefoperazone hydrochloride composition tablet, in which lactose is added to increase the tablet hardness, improve the smoothness of the tablet surface, and significantly improve the drug efficacy. The main feature of this patent is that the tablet hardness is improved, but the problem of poor stability is not solved. At the same time, the drug efficacy is mainly exerted by the pharmacological effect of the cefoperazone hydrochloride drug itself, and this patent does not highlight obvious advantages.

[0004] The patent application with publication number CN104188932A discloses a cefcapene pivoxil hydrochloride composition, which is obtained by tableting cefcapene pivoxil hydrochloride, starch, hydroxypropyl cellulose, sodium carboxymethyl starch, magnesium stearate, and pharmaceutical film coating premix excipients. The dissolution rate of the tablet can reach more than 90%, which improves the use effect of cefcapene pivoxil hydrochloride tablets and can effectively expand the utilization rate of drugs. The patent can improve the drug dissolution rate well, but still does not solve the problem of poor stability of cefcapene pivoxil hydrochloride.

[0005] The patent application with publication number CN102138923A discloses a cefcapene pivoxil hydrochloride composition and a preparation method thereof, wherein the cefcapene pivoxil hydrochloride particle size is crushed to less than 100 μm, and starch fillers, disintegrants, and lubricants are used in the tablet core, and anti-adhesive agents such as micro-powdered silica gel that exceed the conventional dosage are added, and a certain amount of soluble excipients such as sucrose are used in combination, which can significantly improve the dissolution of cefcapene pivoxil hydrochloride tablets. This patent can improve the drug dissolution rate, but cefcapene pivoxil hydrochloride has poor stability, heat generation during the crushing process exacerbates the degradation of impurities, and the raw materials after crushing are easy to re-agglomerate under the action of surface free energy due to the increased surface area, and the process preparation is difficult to make it well dispersed, resulting in the improvement of dissolution rate. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a pharmaceutical composition containing cefcapene pivoxil hydrochloride and a preparation method thereof. By adding sodium alginate and β-cyclodextrin as stabilizers, the cefcapene pivoxil hydrochloride pharmaceutical composition has stable chemical properties and improved solubility. By adopting inclusion technology and direct mixing process, the process is simple and controllable, and the stability of the prepared solid preparation is significantly improved, and the quality is better than that of the original commercially available product.

[0007] The purpose of the present invention is achieved through the following technical solutions: In a first aspect, the present invention provides a pharmaceutical composition containing cefcapene hydrochloride, wherein the raw materials thereof include, by mass percentage: 10-70% of cefcapene hydrochloride, 5-30% of a filler, 0.5-10% of a disintegrant, 0.1-3% of a lubricant, 3-10% of sodium alginate and 30-45% of β-cyclodextrin.

[0008] Cefuroxime hydrochloride tablets are prepared by using inclusion technology and direct tableting process, using sodium alginate to form a micellar protective film on the surface of cefuroxime hydrochloride to avoid the introduction of adverse factors such as temperature and moisture, and then using the inclusion effect of β-cyclodextrin to achieve the purpose of enhancing the stability of the preparation and improving the solubility. This preparation process is simple and convenient, and the obtained preparation not only has significantly improved the stability of related substances, but also has significantly improved solubility.

[0009] In addition, the cefcapone hydrochloride tablets prepared by the process disclosed in the present invention can be further prepared into coated tablets, granules, dry suspensions or powders. The tablets prepared by the method disclosed in the present invention can significantly reduce the special requirements for the particle size of raw materials in the traditional preparation process, reduce costs, and improve production efficiency and drug stability.

[0010] Preferably, the raw materials include, by mass percentage: 15-50% of cefcapone hydrochloride, 5-20% of filler, 0.5-5% of disintegrant, 0.1-1% of lubricant, 3-5% of sodium alginate and 35-45% of β-cyclodextrin.

[0011] Preferably, the raw materials include, by mass percentage: 35-40% of cefcapene pivoxil hydrochloride, 10-20% of filler, 0.5-5% of disintegrant, 0.1-1% of lubricant, 3-5% of sodium alginate and 35-45% of β-cyclodextrin.

[0012] Preferably, the raw materials include, by mass percentage: 35-40% of cefcapene pivoxil hydrochloride, 10-20% of filler, 0.5-2% of disintegrant, 0.1-1% of lubricant, 4% of sodium alginate and 40-45% of β-cyclodextrin.

[0013] Compared with Y-cyclodextrin and γ-cyclodextrin, only β-cyclodextrin has a spatial size that can embed the caprine coated with sodium alginate on the surface, thus having a better effect of improving stability and increasing solubility.

[0014] Preferably, the filler is one or more of mannitol, microcrystalline cellulose and lactose; more preferably, the filler is mannitol and / or lactose.

[0015] Preferably, the disintegrant is one or more of carboxymethylcellulose calcium, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose sodium and sodium carboxymethyl starch; more preferably, the disintegrant is carboxymethylcellulose calcium.

[0016] Preferably, the lubricant is one or more of magnesium stearate, micro-powdered silica gel and talc; more preferably, the lubricant is magnesium stearate.

[0017] In a second aspect, the present invention also provides a method for preparing a pharmaceutical composition containing cefcapone hydrochloride, comprising the following steps: 1. Micronizing sodium alginate, and then uniformly mixing the sodium alginate with cefcapone hydrochloride to prepare a premix; II. Prepare β-cyclodextrin into a saturated aqueous solution, add the premix, heat and stir, filter, and dry to obtain a drug-containing solid powder; III. Mixing the drug-containing solid powder with a filler, a disintegrant and a lubricant to obtain a pharmaceutical composition.

[0018] Preferably, the particle size D90 of the sodium alginate after micronization is no more than 10 μm, and the particle size D50 is no more than 3 μm.

[0019] Preferably, the pulverization gas pressure during the micronization treatment is 0.2 to 0.6 MPa.

[0020] Preferably, the mixing speed is 2 to 15 rpm, and the mixing time is 5 to 30 min.

[0021] Preferably, the heating and stirring is heating to 40-50° C. and stirring for 0.5-2 h.

[0022] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention significantly improves the stability of the solid preparation by controlling the dosage of each component, especially controlling the ratio of the stabilizer (sodium alginate and β-cyclodextrin); at the same time, sodium alginate is first used to form a micelle protective layer on the surface of cefcapone hydrochloride, and then the cefcapone hydrochloride is encapsulated by the cavity structure of β-cyclodextrin, so as to achieve the effect of preventing moisture and resisting temperature, thereby greatly improving the stability of cefcapone hydrochloride, and the solubility is far better than that of the original preparation.

[0023] (2) The pharmaceutical composition containing cefcapone hydrochloride prepared by the present invention not only has good stability, but can also be prepared into tablets, granules, powders, dry suspensions, etc., and can achieve the taste masking effect by virtue of the cyclodextrin inclusion effect. It is not only suitable for adults, but also for children and adults with dysphagia.

[0024] (3) The preparation process of the cefcapone hydrochloride pharmaceutical composition of the present invention is simple, does not require special equipment, and the finished product is stable and controllable. There is no need to control the ambient temperature and humidity, so it is suitable for large-scale production and has high commercial value. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is described below with specific embodiments, but the protection scope of the present invention is not limited thereto: Example 1 As shown in Table 1, the pharmaceutical composition containing cefcapone hydrochloride in this example includes the following raw material components and is made into tablets.

[0026] Table 1 The preparation method thereof comprises the following steps: I. The sodium alginate used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.5 μm, and D50 is 1.08 μm.

[0027] II. The micronized sodium alginate and cefcapone hydrochloride were first mixed at a mixing speed of 10 rpm for 20 min to prepare a premix.

[0028] III. Prepare a saturated aqueous solution of β-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 1 hour, filter, and dry to obtain a drug-containing solid powder.

[0029] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0030] V. The pharmaceutical composition is tableted using a fully automatic high-speed tablet press, with a punch type of 8 mm round punch, and the tablet weight difference is controlled to be ±7.5% to obtain plain tablets. After calculating the average tablet weight of the plain tablets, a high-efficiency coating machine is used for coating, with a target weight gain of 3% (range: 2-5%). After reaching the target coating weight gain, the liquid spraying is stopped, and the operation is continued for 10 minutes. The heating is turned off, and the material is discharged when the outlet air temperature drops to room temperature to obtain coated tablets.

[0031] Example 2 As shown in Table 2, the pharmaceutical composition containing cefcapone hydrochloride in this example includes the following raw material components and is made into tablets.

[0032] Table 2 raw material Amount per piece (g) Mass ratio (%) Cefcapene Pivoxil Hydrochloride 95 35 Sodium alginate 10 4 β-Cyclodextrin 115 43 Bulking agent (mannitol) 40 15 Disintegrant (Carboxymethylcellulose calcium) 5 2 Lubricant (magnesium stearate) 3 1 total 268 100 The preparation method thereof comprises the following steps: I. The sodium alginate used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.5 μm, and D50 is 1.08 μm.

[0033] II. The micronized sodium alginate and cefcapone hydrochloride were first mixed at a mixing speed of 10 rpm for 20 min to prepare a premix.

[0034] III. Prepare a saturated aqueous solution of β-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 1 hour, filter, and dry to obtain a drug-containing solid powder.

[0035] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0036] V. Tableting and coating the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0037] Example 3 As shown in Table 3, the pharmaceutical composition containing cefcapone hydrochloride in this example includes the following raw material components and is made into tablets.

[0038] Table 3 raw material Amount per piece (g) Mass ratio (%) Cefcapene Pivoxil Hydrochloride 101 38 Sodium alginate 12 5 β-Cyclodextrin 107 40 Bulking agent (mannitol) 40 14 Disintegrant (Carboxymethylcellulose calcium) 5 2 Lubricant (magnesium stearate) 3 1 total 268 100 The preparation method thereof comprises the following steps: I. The sodium alginate used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.5 μm, and D50 is 1.08 μm.

[0039] II. The micronized sodium alginate and cefcapone hydrochloride were first mixed at a mixing speed of 10 rpm for 20 min to prepare a premix.

[0040] III. Prepare a saturated aqueous solution of β-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 1 hour, filter, and dry to obtain a drug-containing solid powder.

[0041] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0042] V. Tableting and coating the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0043] Comparative Example 1 The difference from Example 1 is that sodium alginate is replaced by an equal mass of β-cyclodextrin.

[0044] As shown in Table 4, the pharmaceutical composition containing cefcapene hydrochloride in this comparative example includes the following raw material components and is made into tablets.

[0045] Table 4 raw material Amount per piece (g) Mass ratio (%) Cefcapene Pivoxil Hydrochloride 100 37 β-Cyclodextrin 120 45 Bulking agent (mannitol) 40 15 Disintegrant (Carboxymethylcellulose calcium) 5 2 Lubricant (magnesium stearate) 3 1 total 268 100 The preparation method thereof comprises the following steps: I. Prepare a saturated aqueous solution of β-cyclodextrin in the formula amount, add cefcapone hydrochloride thereto, control the water temperature to 45° C., stir thoroughly for 1 h, filter, and dry to obtain a drug-containing solid powder.

[0046] II. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0047] III. The pharmaceutical composition is tableted and coated (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0048] Comparative Example 2 The difference from Example 1 is that β-cyclodextrin is replaced by an equal mass of sodium alginate.

[0049] As shown in Table 5, the pharmaceutical composition containing cefcapene hydrochloride in this comparative example includes the following raw material components and is made into tablets.

[0050] Table 5 raw material Amount per piece (g) Mass ratio (%) Cefcapene Pivoxil Hydrochloride 100 37 Sodium alginate 120 45 Bulking agent (mannitol) 40 15 Disintegrant (Carboxymethylcellulose calcium) 5 2 Lubricant (magnesium stearate) 3 1 total 268 100 The preparation method thereof comprises the following steps: I. The sodium alginate used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.5 μm, and D50 is 1.08 μm.

[0051] II. The micronized sodium alginate and cefcapone hydrochloride were first mixed at a mixing speed of 15 rpm for a mixing time of 40 min to prepare a premix.

[0052] III. The premix and the filler, disintegrant and lubricant in the formula amount are placed in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0053] IV. Compress and coat the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0054] Comparative Example 3 The difference from Example 1 is that the added mass ratio of β-cyclodextrin in each preparation is too large.

[0055] As shown in Table 6, the pharmaceutical composition containing cefcapene hydrochloride in this comparative example includes the following raw material components and is made into tablets.

[0056] Table 6 raw material Amount per piece (g) Mass ratio (%) Cefcapene Pivoxil Hydrochloride 100 26 Sodium alginate 10 3 β-Cyclodextrin 220 58 Bulking agent (mannitol) 40 11 Disintegrant (Carboxymethylcellulose calcium) 5 1.3 Lubricant (magnesium stearate) 3 0.7 total 378 100 The preparation method thereof comprises the following steps: I. The sodium alginate used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.5 μm, and D50 is 1.08 μm.

[0057] II. The micronized sodium alginate and cefcapone hydrochloride were first mixed at a mixing speed of 10 rpm for 20 min to prepare a premix.

[0058] III. Prepare a saturated aqueous solution of β-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 2 hours, filter, and dry to obtain a drug-containing solid powder.

[0059] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0060] V. Tableting and coating the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0061] Comparative Example 4 The difference from Example 1 is that the added mass proportion of sodium alginate in each preparation is too small.

[0062] As shown in Table 7, the pharmaceutical composition containing cefcapene hydrochloride in this comparative example includes the following raw material components and is made into tablets.

[0063] Table 7 raw material Amount per piece (g) Mass ratio (%) Cefcapene Pivoxil Hydrochloride 100 38 Sodium alginate 5 2 β-Cyclodextrin 110 42 Bulking agent (mannitol) 40 15 Disintegrant (Carboxymethylcellulose calcium) 5 2 Lubricant (magnesium stearate) 3 1 total 263 100 The preparation method thereof comprises the following steps: I. The sodium alginate used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.5 μm, and D50 is 1.08 μm.

[0064] II. The micronized sodium alginate and cefcapone hydrochloride were first mixed at a mixing speed of 10 rpm for 20 min to prepare a premix.

[0065] III. Prepare a saturated aqueous solution of β-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 1 hour, filter, and dry to obtain a drug-containing solid powder.

[0066] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0067] V. Tableting and coating the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0068] Comparative Example 5 The difference from Example 1 is that the added mass proportion of sodium alginate in each preparation is too large.

[0069] As shown in Table 8, the pharmaceutical composition containing cefcapone hydrochloride in this comparative example includes the following raw material components and is made into tablets.

[0070] Table 8 raw material Amount per piece (g) Mass ratio (%) Cefcapene Pivoxil Hydrochloride 100 36 Sodium alginate 16 6 β-Cyclodextrin 110 40 Bulking agent (mannitol) 40 15 Disintegrant (Carboxymethylcellulose calcium) 5 2 Lubricant (magnesium stearate) 3 1 total 274 100 The preparation method thereof comprises the following steps: I. The sodium alginate used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.5 μm, and D50 is 1.08 μm.

[0071] II. The micronized sodium alginate and cefcapone hydrochloride were first mixed at a mixing speed of 10 rpm for 30 min to prepare a premix.

[0072] III. Prepare a saturated aqueous solution of β-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 1 hour, filter, and dry to obtain a drug-containing solid powder.

[0073] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0074] V. Tableting and coating the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0075] Comparative Example 6 The difference from Example 1 is that according to the raw material composition ratio in Table 1, only sodium alginate is replaced by corn gum of the same mass.

[0076] The preparation method comprises the following steps: I. The corn gum used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.2 μm, and D50 is 1.03 μm.

[0077] II. The micronized corn gum and cefoperazone hydrochloride were first mixed at a mixing speed of 10 rpm for 20 min to prepare a premix.

[0078] III. Prepare a saturated aqueous solution of β-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 1 hour, filter, and dry to obtain a drug-containing solid powder.

[0079] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0080] V. Tableting and coating the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0081] Comparative Example 7 The difference from Example 1 is that according to the raw material component ratio in Table 1, only sodium alginate is replaced by an equal mass of carboxymethyl cellulose.

[0082] The preparation method comprises the following steps: I. The carboxymethyl cellulose in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.4 μm, and D50 is 1.05 μm.

[0083] II. The micronized carboxymethyl cellulose and cefcapone hydrochloride were first mixed at a mixing speed of 10 rpm for 20 min to prepare a premix.

[0084] III. Prepare a saturated aqueous solution of β-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 1 hour, filter, and dry to obtain a drug-containing solid powder.

[0085] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0086] V. Tableting and coating the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0087] Comparative Example 8 The difference from Example 1 is that according to the raw material composition ratio in Table 1, only β-cyclodextrin is replaced by an equal mass of γ-cyclodextrin.

[0088] The preparation method thereof comprises the following steps: I. The sodium alginate used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, and the particle size D90 is 3.5 μm and D50 is 1.08 μm.

[0089] II. The micronized sodium alginate and cefcapone hydrochloride were first mixed at a mixing speed of 10 rpm for 20 min to prepare a premix.

[0090] III. Prepare a saturated aqueous solution of Y-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 1 hour, filter, and dry to obtain a drug-containing solid powder.

[0091] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0092] V. Tableting and coating the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0093] Comparative Example 9 The difference from Example 1 is that according to the raw material composition ratio in Table 1, only β-cyclodextrin is replaced by γ-cyclodextrin of equal mass.

[0094] The preparation method thereof comprises the following steps: I. The sodium alginate used in the formula is micronized by a jet mill, the grinding pressure is 0.4 MPa, the particle size D90 is 3.5 μm, and D50 is 1.08 μm.

[0095] II. The micronized sodium alginate and cefcapone hydrochloride were first mixed at a mixing speed of 10 rpm for 20 min to prepare a premix.

[0096] III. Prepare a saturated aqueous solution of γ-cyclodextrin in the formula amount, add the premix into it, control the water temperature to 45°C, stir thoroughly for 1 hour, filter, and dry to obtain a drug-containing solid powder.

[0097] IV. Place the drug-containing solid powder and the prescribed amount of filler, disintegrant and lubricant in a square cone hopper for mixing at a mixing speed of 10 rpm for 30 min to obtain a pharmaceutical composition.

[0098] V. Tableting and coating the pharmaceutical composition (according to the tableting and coating steps in Example 1) to obtain coated tablets.

[0099] Effect Experiment 1. Stability The samples of Examples 1-3, Comparative Examples 1-9 and the original preparation (commercially available 100 mg cefcapone hydrochloride tablets, trade name: Flomox) were taken for stability study.

[0100] According to the "Technical Guidelines for Stability Research of Chemical Drugs (APIs and Preparations) (Revised)" promulgated by the State Food and Drug Administration in February 2015 and the "Chinese Pharmacopoeia" 2020 Edition Part IV General Chapter 9001 "Guidelines for Stability Testing of APIs and Preparations", including accelerated tests (40℃±2℃, 75% RH±5%RH) and long-term tests (30℃±2℃, 65% RH±5%RH), the results of accelerated stability tests and long-term stability tests are shown in Tables 9 and 10.

[0101] 1.1 Accelerated stability test Table 9 Accelerated stability results 1.2 Long-term stability test Table 10 Long-term stability results 2. Dissolution Take examples 1-3, comparative examples 1-4, and 100 mg commercially available tablet samples produced by Shionogi Co., Ltd. and number them respectively, take 6 bags of samples in each group, use 900 ml of purified water as the dissolution medium, rotate at 50 revolutions per minute, operate by the paddle method, after 30 minutes, take an appropriate amount of the solution, filter, accurately measure an appropriate amount of the filtrate, and quantitatively dilute it with the dissolution medium to prepare a solution containing 10 μg of cefoperazone per 1 ml, and measure the absorbance at a wavelength of 265 nm according to the ultraviolet-visible spectrophotometry (General Rule 0401), and calculate the solubility of each tablet. The results are shown in Table 11.

[0102] Dissolution calculation formula: Dissolution % = (A 样品 ×W 对照 ×Control Purity×V 溶出介质体积 × average tablet weight) / (A 对照 ×W 样品 ×V 对照品稀释倍数 × labeled amount) × 100%.

[0103] Where: A represents absorbance; W represents drug mass (mg); V represents volume (mL).

[0104] Table 11 Dissolution results * The standard is greater than 75%.

[0105] The results show that compared with comparative examples 1-9, examples 1-3 of the present invention show good stability in both accelerated and long-term tests, and each impurity has no obvious growth in accelerated tests and long-term tests, and has better stability and is better than the original preparation. In addition, the dissolution rate in examples 1-3 is much higher than that of the original preparation, the bioavailability is greatly improved, and the clinical application is safer.

[0106] Specifically, the comparison between Example 1 and Comparative Examples 1-5 shows that the addition amount of β-cyclodextrin and sodium alginate has a greater impact on the stability of the preparation, and can have a higher stability of cefcapene hydrochloride within the addition amount range defined by the present invention. In addition, relative to the single addition of equal proportions of β-cyclodextrin / sodium alginate in Comparative Examples 1-2, and relative to the addition of too much / too little β-cyclodextrin and sodium alginate in Comparative Examples 3-4, Example 1 has a higher solubility, indicating that the synergistic effect of β-cyclodextrin and sodium alginate can also improve the solubility of the preparation. The comparison between Example 1 and Comparative Examples 6-7 shows that sodium alginate can better wrap cefcapene hydrochloride relative to corn gum and carboxymethyl cellulose, and a micellar protective film with higher stability can be formed on the surface, thereby achieving the purpose of enhancing the stability of the preparation. Comparison between Example 1 and Comparative Examples 8-9 shows that, compared with Y-cyclodextrin and γ-cyclodextrin, the three-dimensional space size of β-cyclodextrin is just enough to embed the carpine ester coated with sodium alginate on the surface, so the effect of improving the stability of the preparation is better, and the solubility is also better.

[0107] The above are only preferred embodiments of the present invention, and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the specification of the present invention, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A pharmaceutical composition containing cefcapone hydrochloride, characterized in that: Calculated by mass percentage, the raw materials include: 10-70% of cefuroxime hydrochloride, 5-30% of filler, 0.5-10% of disintegrant, 0.1-3% of lubricant, 3-5% of sodium alginate and 30-45% of beta-cyclodextrin.

2. The pharmaceutical composition containing cefcapene hydrochloride according to claim 1, characterized in that: Calculated by mass percentage, the raw materials include: 35-40% of cefcapene hydrochloride, 10-20% of filler, 0.5-5% of disintegrant, 0.1-1% of lubricant, 3-5% of sodium alginate and 35-45% of beta-cyclodextrin.

3. The pharmaceutical composition containing cefcapene hydrochloride according to claim 2, characterized in that: Calculated by mass percentage, the raw materials include: 35-40% of cefuroxime hydrochloride, 10-20% of filler, 0.5-2% of disintegrant, 0.1-1% of lubricant, 4% of sodium alginate and 40-45% of beta-cyclodextrin.

4. The pharmaceutical composition containing cefcapene hydrochloride according to claim 1, characterized in that: The filler is one or more of mannitol, microcrystalline cellulose and lactose.

5. The pharmaceutical composition containing cefcapene pivoxil hydrochloride according to any one of claims 1 to 4, characterized in that: The disintegrant is one or more of carboxymethylcellulose calcium, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose sodium and sodium carboxymethyl starch.

6. The pharmaceutical composition containing cefcapene hydrochloride according to any one of claims 1 to 4, characterized in that: The lubricant is one or more of magnesium stearate, micro powder silica gel and talcum powder.

7. A method for preparing a pharmaceutical composition containing cefcapone hydrochloride as claimed in any one of claims 1 to 6, characterized in that: The steps include:

1. Micronizing sodium alginate, and then mixing it with cefcapone hydrochloride to obtain a premix; II. Prepare β-cyclodextrin into a saturated aqueous solution, add the premix, heat and stir, filter, and dry to obtain a drug-containing solid powder; III. Mixing the drug-containing solid powder with a filler, a disintegrant and a lubricant to obtain a pharmaceutical composition.

8. The preparation method according to claim 7, characterized in that: The particle size D90 of the sodium alginate after micronization is no more than 10 μm.

9. The preparation method according to claim 7 or 8, characterized in that: The heating and stirring is heating to 40-50° C. and stirring for 0.5-2 h.

10. The preparation method according to claim 7 or 8, characterized in that: The mixing speed is 2-15 rpm, and the mixing time is 5-30 min.

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