CN106309371B - Cefixime nano dispersion and preparation method thereof - Google Patents

Abstract

The invention relates to a cefixime nano-dispersion. The nano-dispersion comprises cefixime nanoparticles and pharmaceutical excipients, and the pharmaceutical excipients include one or more of surfactants, fillers, polymers, cellulose and derivatives thereof. The average particle size of the cefixime nanoparticles is 50-900 nm. The nanodispersion has high solubility in water and excellent dissolution properties. At the same time, the present invention also provides a method for preparing the nano-dispersion. The cefixime nano-particles are prepared by reducing the particle size of the raw material itself, and then mixed with auxiliary materials to prepare the cefixime nano-dispersion by spray drying or freeze drying. The preparation method is simple, easy to scale up in industrialized production, and has a good industrialization prospect.

Description

A kind of cefixime nano-dispersion and preparation method thereof

technical field

The invention relates to a cefixime nano-dispersion and a preparation method thereof, belonging to the field of pharmaceutical preparations.

Background technique

Cefixime, its chemical name is: (6R,7R)-7-((2Z)-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetamido)-3-ethene Base-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid trihydrate, the molecular formula is C ₁₆ H ₁₅ N ₅ O ₇ S ₂ · 3H ₂ O, the molecular weight is 507.50, and the structural formula is as follows:

Cefixime is a third-generation oral cephalosporin, first developed by Japan's Fujisawa Pharmaceutical Co., Ltd. in the early 1980s, and put on the market in 1985 after completing the Phase III clinical trial in Japan. Cefixime has significant antibacterial effect on both Gram-positive bacteria and negative bacteria. It is mainly used in the clinical treatment of bronchitis, respiratory diseases, cystitis, urethritis, scarlet fever, otitis media, etc. caused by sensitive strains. Its clinical efficacy It is widely used because of its high dosage, small dosage and few adverse drug reactions.

Cefixime is a poorly water-soluble drug with extremely low solubility in water, which seriously affects the dissolution and absorption of the drug, and has poor oral bioavailability.

The currently listed cefixime preparations include capsules, tablets, dispersible tablets, chewable tablets, granules, and dry suspensions, all of which are traditional oral dosage forms. The disintegration and dissolution rate of the drug is slow, which affects the absorption and distribution of the drug in the body, resulting in poor bioavailability of the drug and affecting the efficacy of the drug.

In the prior art, micronization technology is used to reduce the particle size of cefixime in an attempt to improve the dissolution of cefixime. For example, patent CN101889987B discloses a preparation method of cefixime and capsules. In the method, cefixime, a solubilizer and water-soluble auxiliary materials are subjected to jet pulverization, and then mixed with other auxiliary materials for dry granulation. Patent CN102670536A discloses a preparation method of cefixime dispersible tablets, which micronizes cefixime to reduce the particle size to 20-120 μm, and then mixes it with other auxiliary materials such as solubilizers, fillers, lubricants, adhesives and The disintegrant is mixed for granulation. The above method can reduce the particle size of cefixime to a certain extent through the action of physical methods, but its particle size is uncontrollable and unevenly distributed, and the effect of improving the dissolution of cefixime is not significant.

In order to improve the bioavailability of cefixime, submicron technologies such as microemulsion, microspheres, and liposomes have been applied to cefixime preparations.

Patent CN101711741B discloses a cefixime submicroemulsion solid preparation, which is composed of cefixime submicroemulsion particles and other auxiliary materials. component composition. The patent utilizes the microemulsion technology to improve the dissolution rate of cefixime, but the co-emulsifier is an indispensable component in the formation of the microemulsion, and the co-emulsifier often has the disadvantage of having relatively large toxic and side effects.

Patent CN102327235B discloses a cefixime solid lipid nanoparticle, which is composed of cefixime, stearic acid, lauric acid, Tween 80 and hydrogenated castor oil polyoxyethylene ether. The preparation method is as follows: adding stearic acid and lauric acid into an organic solvent, stirring and dissolving, adding cefixime and stirring to form an organic phase; then dissolving Tween 80 and hydrogenated castor oil polyoxyethylene ether 40 in water, stirring to form water The organic phase is added to the stirring water phase, and the organic solvent is removed to obtain colostrum; the colostrum is quickly added to cold water under stirring conditions, and the high-pressure homogeneous emulsification is performed to obtain a nano-suspension, which is finally dried to obtain solid lipid nanoparticles . The preparation process of liposome technology is complex, the preparation conditions are harsh, the requirements for equipment are high, and the production cost is high. In addition, liposomes are also affected by electrolytes and polar compounds, which are unstable in vivo and in vitro, and easy to leak drugs. and other shortcomings.

In conclusion, how to provide a cefixime preparation with good dissolution effect and high bioavailability is still very necessary.

SUMMARY OF THE INVENTION

The invention provides a cefixime nano-dispersion with small particle size, narrow distribution and controllable particle morphology. The average particle diameter of the cefixime nanoparticles in the nano-dispersion is 50-900 nm, and the particle morphology is regular. , can effectively increase the specific surface area of the drug and the solubility of the drug in water, and improve the bioavailability and efficacy of the drug. At the same time, the present invention also provides a method for preparing cefixime nano-dispersion, which is simple and easy to operate, low in cost, easy to scale up and industrialized production, and has a good industrialization prospect.

The cefixime nano-dispersion of the present invention includes cefixime nanoparticles and pharmaceutical excipients, wherein the pharmaceutical excipients include one or more of surfactants, fillers, polymers, cellulose and derivatives thereof; cefixime The average particle size of the nanoparticles is 50-900 nm, preferably the average particle size is 50-260 nm.

Above-mentioned surface agent is selected from one or more of poloxamer, sodium lauryl sulfate, Tween, lecithin, sodium oleate, Span; filler is selected from lactose, starch, microcrystalline cellulose , mannitol, cyclodextrin, one or more of chitosan; polymer is selected from one or more of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol; cellulose and its derivatives are selected from One or more of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, and ethyl methyl cellulose.

The cefixime nano-dispersion has a high content of the main drug, the mass percentage content of the cefixime nano particles is 70%-95%, and the mass percentage content of the pharmaceutical auxiliary materials is 5-30%.

The present invention also provides a method for preparing the above-mentioned cefixime nanodispersion: reducing the particle size of the cefixime crude drug itself, preparing cefixime nanoparticles, mixing with pharmaceutical excipients, and preparing the nanodispersion by spray drying or freeze drying . It includes the following steps:

(1) Dissolve cefixime in an alkaline solution to obtain a drug solution;

(2) The drug solution and the acid solution are fully mixed to obtain the cefixime nano suspension;

(3) filtering and washing the nano suspension to obtain cefixime nanoparticles;

(4) Disperse cefixime nanoparticles into water containing pharmaceutical excipients to obtain a mixture;

(5) The mixture in step (4) is spray-dried or freeze-dried to obtain a cefixime nano-dispersion.

The crude drug sold on the market is generally obtained by purifying the crude product through an acid-base neutralization process. As disclosed in patent CN101544660A, the crude product is added to an alkali solution, or the crude product is dissolved in an organic solvent and then added to the alkali solution to adjust its pH to 6-9. , Fully react to clarification to obtain cefixime salt solution, add acid to the filtered filtrate to adjust pH to 2-5, crystallize, filter and dry to obtain refined products. The refined product prepared by the method has good fluidity, but the particles are large, and the average particle size is greater than 100 μm.

According to the Nernst-Noyes-Whitney equation, increasing the specific surface area of the drug can improve the dissolution rate of the drug, thereby improving the bioavailability of the drug. The specific surface area of drug particles is also affected by factors such as particle size and particle shape. The smaller the particle size, the larger the specific surface area.

The above method step (2) is fully mixed by the supergravity rotating packed bed or the microchannel reactor, and by improving the acid-base neutralization process, the acid-base neutralization process is combined with the supergravity rotating packed bed or the microchannel reactor, Cefixime nanoparticles with small particle size, narrow distribution and controllable morphology are prepared, and the average particle size is 50-900 nm, preferably 50-260 nm.

The hypergravity rotating packed bed replaces the conventional gravity field with a centrifugal force field that is hundreds to thousands of times of gravity generated by high-speed rotation. Under the hypergravity field, the liquid is highly sheared and dispersed in the state of very fine droplets or liquid filaments, and the specific surface area of the contact increases, which greatly strengthens the microscopic mixing and microscopic mass transfer, making the distribution more uniform and the reaction time greatly shortened. By changing the rotational speed and then changing the acceleration of gravity, the particle size of the particles can be controlled to avoid problems such as uneven mixing and local supersaturation that cause the particle size to be large and uncontrollable.

When the supergravity rotating packed bed is used for sufficient mixing, the process operating parameters of the hypergravity rotating packed bed reactor, such as rotational speed, mixing temperature, drug solution concentration, flow rate of acid solution, flow rate of drug solution, acid solution and drug solution Adjust the flow ratio of the drug solution, determine the concentration of the drug solution to be 1-200mg/ml, the flow rate of the drug solution to be 1-20L/min, the flow rate of the acid solution to be 1-20L/min, and the mixing temperature to be 0-50°C. The rotational speed is 100-2800rpm.

The flow ratio of the acid solution and the drug solution is related to the supersaturation of the system, which has an important influence on the particle size of cefixime. With the increase of the flow ratio of the acid solution to the drug solution, the supersaturation of the system increases and the nucleation rate increases. In order to further obtain cefixime nanoparticles with smaller particle size, narrower distribution and more controllable morphology, the flow ratio of acid solution to drug solution is preferably 1:20-1.

Microchannel reactors are microreactors with fluid channel dimensions in the micrometer scale. Due to the internal microstructure, it has a large specific surface area, which can reach hundreds or even thousands of times that of the stirred tank. The fluid flows in a laminar flow state in the microchannel, the mixing is carried out by diffusion, and the molecular diffusion distance is short, which realizes instant uniform mixing of materials and efficient heat and mass transfer.

When using the microchannel reactor for thorough mixing, the process operating parameters of the microchannel reactor, such as the inner diameter of the reactor, the mixing temperature, the concentration of the drug solution, the flow rate of the drug solution, the flow rate of the acid solution, the acid solution and the drug solution The flow ratio of the reactor is adjusted by groping, and the mixing temperature is determined to be 0-50 °C, the inner diameter of the reactor is 0.1-1mm, the concentration of the drug solution is 1-200mg/ml, the flow rate of the drug solution is 0.01-0.5L/min, and the acid solution is 0.01-0.5L/min. The flow rate is 0.01-0.5L/min.

In order to further obtain cefixime nanoparticles with smaller particle size, narrower distribution and more controllable morphology, the flow ratio of acid solution to drug solution is preferably 1:50-1.

The acids and bases used in the preparation of cefixime nanoparticles are those commonly used in laboratories. The preferred base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate; the acid is hydrochloric acid, acetic acid, oxalic acid, sulfuric acid, phosphoric acid, One or more of phosphoric acid, formic acid and citric acid.

When the acid is mixed with the drug solution in step (2) of the above method, the pH of the suspension is preferably 1-4, and more preferably the pH is 1-1.9.

The cefixime nanoparticles prepared in step (3) of the above method have an average particle size of 50-900 nm, preferably 50-260 nm.

The cefixime nanoparticles prepared above, due to their large specific surface area and surface energy, are prone to agglomeration when placed for a long time to form micro-particles, which affects the bioavailability of the pharmaceutical preparation. In order to avoid the agglomeration of cefixime nanoparticles, the cefixime nanoparticles are dispersed in water containing pharmaceutical excipients, and the cefixime nanodispersion is obtained by spray drying or freeze drying. Spray drying or freeze drying can effectively reduce the mutual adhesion and agglomeration of nanodispersions.

In the above step (5), the preferred inlet temperature of spray drying is 100-140°C, the outlet temperature is 45-75°C, the feed rate is 5-40mL/min, and the compressed air pressure is 0.4-0.8Mpa. The preferred pre-freezing temperature for freeze-drying is -45°C, the pre-freezing time is 2-3 hours, the vacuum degree is 0.1 mbar, and the drying time is 12-48 hours.

The cefixime nano-dispersion prepared by the invention has high stability and solubility, and can be widely used in injections, tablets, capsules, soft capsules, emulsions, oral solutions or suspensions.

Description of drawings

Fig. 1 is the scanning electron microscope picture of the cefixime nanoparticle of embodiment 3;

Fig. 2 is the scanning electron microscope picture of the cefixime nanoparticle of embodiment 5;

Fig. 3 is the scanning electron microscope picture of the cefixime nanoparticle of embodiment 7;

Fig. 4 is the scanning electron microscope picture of the cefixime nanoparticle of embodiment 11;

Fig. 5 is a scanning electron microscope image of a refined cefixime product of a comparative example.

It can be seen from the above scanning electron microscope images that the particle size of the cefixime nanoparticles in Figure 1 is less than 500nm, and the average particle size is 260nm; the particle size of the cefixime nanoparticles in Figure 2 is less than 100nm, and the average particle size is 50nm; Figure 3 Cefixime nanoparticles The particle size of the nanoparticles is less than 1 μm, and the average particle size is 640 nm; the particle size of the cefixime nanoparticles in Figure 4 is less than 100 nm, and the average particle size is 54 nm; the particle size of the refined cefixime product in Figure 5 is greater than 100 μm, and its average particle size is 125 μm. Figure 3 shows uniform particle distribution, controllable morphology, and narrow particle size distribution; Figure 1, Figure 2 and Figure 4 show more uniform particle distribution, regular and uniform morphology, and narrower particle size distribution.

Detailed ways

Example 1

Dissolve 20.0 g of cefixime bulk drug in 500 ml of 0.5 mol/L sodium hydroxide solution to prepare a drug solution with a concentration of 40 mg/mL. The acid and the drug solution are respectively added to the supergravity rotating packed bed reactor, wherein the acid is sulfuric acid and phosphoric acid, the flow rate of the acid solution is adjusted to be 20.0L/min, the flow rate of the drug solution is 1.0L/min, the rotating speed is 100rpm, and the temperature is 30° C., mixing to obtain a cefixime nano-suspension with a pH of 1.9; filtering and washing the nano-suspension to obtain 19.8 g of cefixime nanoparticles, with a yield of 99.0%. The average particle size of the cefixime nanoparticles is 900 nm.

The cefixime nanoparticles obtained above were dispersed in 300ml of water containing 1.1g of sodium lauryl sulfate and 1.1g of lecithin, and the inlet temperature of the spray dryer was controlled to be 100°C, the outlet temperature was 45°C, and the feed rate was 5mL /min, the compressed air pressure is 0.4MPa, and the cefixime nano-dispersion is obtained by spray drying.

Example 2

Dissolve 50.0 g of cefixime bulk drug in a mixed solution of 200 ml of 1 mol/L sodium acetate solution and 300 ml of 1 mol/L sodium hydroxide solution to prepare a drug solution with a concentration of 100 mg/mL. The acid solution and the drug solution were respectively added to the supergravity rotating packed bed reactor, wherein the acid was oxalic acid, the flow rate of the adjusted acid solution was 18.0L/min, the flow rate of the drug solution was 9.0L/min, the rotating speed was 1000rpm, and the temperature was 1000 rpm. At 25° C., mixing to obtain a cefixime nano-suspension with a pH of 1.5; filtering and washing the nano-suspension to obtain 49.4 g of cefixime nanoparticles, with a yield of 98.8%. The average particle size of the cefixime nanoparticles is 520 nm.

The cefixime nanoparticles obtained above were dispersed in 300 ml of water containing 1.3 g of chitosan and 1.3 g of ethyl cellulose, and then packed into freeze-drying bottles. The freezing time is 2.5h, the vacuum degree is 0.1mbar, and the drying time is 24h. After freeze-drying, the cefixime nano-dispersion is obtained.

Example 3

Dissolve 20.0 g of cefixime bulk drug in 100 ml of 2.0 mol/L sodium carbonate solution to prepare a drug solution with a concentration of 200 mg/mL. The acid solution and the drug solution were respectively added to the supergravity rotating packed bed reactor, wherein the acid was formic acid, the flow rate of the adjusted acid solution was 10.0L/min, the flow rate of the drug solution was 10.0L/min, the rotating speed was 500rpm, and the temperature was 0 ℃, mixing to obtain a cefixime nano suspension with a pH of 4.0; filtering and washing the nano suspension to obtain 19.2 g of cefixime nanoparticles with a yield of 96.0%. The average particle size of the cefixime nanoparticles is 260 nm, and the scanning electron microscope image is shown in FIG. 1 .

The cefixime nanoparticles obtained above were dispersed into 300 ml of water containing 1.6 g of starch, 1.6 g of sodium oleate and 1.6 g of polyvinylpyrrolidone, and then packed into freeze-dried bottles, and the freeze-drier pre-freezing temperature was controlled to -45 ℃, the pre-freezing time is 2h, the vacuum degree is 0.1mbar, the drying time is 12h, and the cefixime nano-dispersion is obtained by freeze-drying.

Example 4

Dissolve 16.0g of cefixime bulk drug in the mixed solution of 20ml of 1mol/L potassium acetate solution, 30ml of 1mol/L potassium hydroxide solution and 50ml of 1mol/L sodium carbonate solution, to prepare a concentration of 160mg /mL of drug solution. The acid solution and the drug solution were respectively added to the supergravity rotating packed bed reactor, wherein the acid was hydrochloric acid and citric acid, the flow rate of the acid solution was adjusted to be 2.0L/min, the flow rate of the drug solution was 12.0L/min, and the rotational speed was 1500rpm, The temperature is 10° C., and the mixture is mixed to obtain a cefixime nano-suspension with a pH of 3.0; the nano-suspension is filtered and washed to obtain 15.3 g of cefixime nanoparticles, with a yield of 95.6%. The average particle size of the cefixime nanoparticles is 150 nm.

The cefixime nanoparticles obtained above were dispersed into 300ml of water containing 1.4g of polyvinylpyrrolidone and 1.3g of polyvinyl alcohol, and then packed into freeze-drying bottles. Time 3h, vacuum degree 0.1mbar, drying time 48h, freeze-drying to obtain cefixime nano-dispersion.

Example 5

Dissolve 1.0 g of cefixime bulk drug in 1000 ml of 0.5 mol/L sodium bicarbonate solution to prepare a drug solution with a concentration of 1 mg/mL. The acid solution and the drug solution were respectively added to the supergravity rotating packed bed reactor, wherein the acid was hydrochloric acid, the flow rate of the adjusted acid solution was 1.0L/min, the flow rate of the drug solution was 20.0L/min, the rotating speed was 2800rpm, and the temperature was 20 ℃, mixing to obtain a cefixime nano suspension with a pH of 1; filtering and washing the nano suspension to obtain 0.98 g of cefixime nanoparticles with a yield of 98.0%. The average particle size of the cefixime nanoparticles is 50 nm, and the scanning electron microscope image is shown in FIG. 2 .

The cefixime nanoparticles obtained above were dispersed in 200ml of water containing 0.42g of poloxamer, the inlet temperature of the control spray dryer was 120°C, the outlet temperature was 50°C, the feed rate was 20mL/min, and the compressed air pressure was 0.6MPa, spray-dried to obtain cefixime nano-dispersion.

Example 6

Dissolve 15.0g of cefixime bulk drug in 100ml of 2mol/L sodium carbonate solution to prepare a drug solution with a concentration of 150mg/mL. The acid solution and the drug solution were respectively added to the supergravity rotating packed bed reactor, wherein the acid was acetic acid, the flow rate of the adjusted acid solution was 1.5L/min, the flow rate of the drug solution was 15.0L/min, the rotating speed was 2000rpm, and the temperature was 50 ℃. ℃, mixing to obtain a cefixime nano suspension with a pH of 1.6; filtering and washing the nano suspension to obtain 14.25 g of cefixime nanoparticles with a yield of 95.0%. The average particle size of the cefixime nanoparticles is 54 nm.

The cefixime nanoparticles obtained above were dispersed into 200ml of water containing 2.75g lactose and 2g cyclodextrin, the inlet temperature of the spray dryer was controlled to be 140°C, the outlet temperature was 75°C, the feed rate was 40mL/min, and the compressed air The pressure is 0.8MPa, and the cefixime nano-dispersion is obtained by spray drying.

Example 7

Dissolve 12.0g of cefixime bulk drug in 100ml of 1mol/L sodium hydroxide solution to prepare a drug solution with a concentration of 120mg/mL. The acid solution and the drug solution were respectively added to a microchannel reactor with an inner diameter of 0.5 mm, wherein the acid was acetic acid and sulfuric acid, the flow rate of the acid solution was adjusted to 0.5L/min, the flow rate of the drug solution was 0.01L/min, and the temperature was 10 ℃, mixing to obtain a cefixime nano-suspension with a pH of 1.9; filtering and washing the nano-suspension to obtain 11.6 g of cefixime nanoparticles with a yield of 96.7%. The average particle size of the cefixime nanoparticles is 640 nm, and the scanning electron microscope image is shown in FIG. 3 .

Disperse the cefixime nanoparticles obtained above into 200 ml of water containing 1.4 g of methylcellulose and 1.5 g of sodium carboxymethyl cellulose, pack it into a freeze-drying bottle, and control the pre-freezing temperature of the freeze-drying machine to -45 ℃, the pre-freezing time is 2.5h, the vacuum degree is 0.1mbar, the drying time is 24h, and the cefixime nanodispersion is obtained by freeze-drying.

Example 8

Dissolve 18.0g of cefixime bulk drug in a mixed solution of 50ml of 1mol/L potassium bicarbonate solution and 50ml of 1mol/L potassium hydroxide solution to prepare a drug solution with a concentration of 180mg/mL. The acid solution and the drug solution were respectively added to a microchannel reactor with an inner diameter of 0.8 mm, wherein the acid was formic acid and phosphoric acid, the flow rate of the acid solution was adjusted to 0.2L/min, the flow rate of the drug solution was 0.05L/min, and the temperature was 0 ℃, mixing to obtain a cefixime nano-suspension with a pH of 1.2; filtering and washing the nano-suspension to obtain 17.5 g of cefixime nanoparticles with a yield of 97.2%. The average particle size of the cefixime nanoparticles is 500 nm.

The cefixime nanoparticles obtained above were dispersed in 300ml water containing 3.6g polyethylene glycol and 3.9g hydroxypropyl cellulose, and the control spray dryer inlet temperature was 120°C, the outlet temperature was 55°C, and the feed rate was 15mL /min, the compressed air pressure is 0.6MPa, and the cefixime nano-dispersion is obtained by spray drying.

Example 9

Dissolve 50.0g of cefixime bulk drug in a mixed solution of 200ml of 1mol/L sodium hydroxide solution, 150ml of 1mol/L sodium bicarbonate solution and 150ml of 1mol/L potassium hydroxide solution to form a concentration of 100mg/mL drug solution. The acid solution and the drug solution were respectively added to a microchannel reactor with an inner diameter of 0.6 mm, wherein the acid was acetic acid, phosphorous acid and phosphoric acid, and the flow rate of the acid solution was adjusted to be 0.03L/min, and the flow rate of the drug solution was 0.3L/min. The temperature is 15° C., and the mixture is mixed to obtain a cefixime nano-suspension with a pH of 3.5; the nano-suspension is filtered and washed to obtain 47.5 g of cefixime nanoparticles with a yield of 95.0%. The average particle size of the cefixime nanoparticles is 250 nm.

The cefixime nanoparticles obtained above are dispersed in 300ml water containing 0.5g hydroxypropyl methylcellulose, 1.0g microcrystalline cellulose and 1.0g Tween 80, and the control spray dryer inlet temperature is 140°C, and the outlet temperature is 140°C. The temperature is 75° C., the feeding rate is 40 mL/min, the compressed air pressure is 0.8 MPa, and the cefixime nano-dispersion is obtained by spray drying.

Example 10

Dissolve 1.0 g of cefixime API in 1000 ml of 0.1 mol/L sodium hydroxide solution to prepare a drug solution with a concentration of 1 mg/mL. The acid solution and the drug solution were respectively added to a microchannel reactor with an inner diameter of 1 mm, wherein the acid was hydrochloric acid, the flow rate of the acid solution was adjusted to 0.1L/min, the flow rate of the drug solution was 0.1L/min, the temperature was 25 ° C, and the mixing was performed. A cefixime nano-suspension with pH 4 was obtained; the nano-suspension was filtered and washed to obtain 0.96 g of cefixime nano-particles, and the yield was 96.0%. The average particle size of the cefixime nanoparticles is 210 nm.

The cefixime nanoparticles obtained above were dispersed into 200ml of water containing 0.24g of mannitol, and then packed into freeze-dried bottles. , the drying time was 48h, and the nano-cefixime dispersion was obtained by freeze-drying.

Example 11

Dissolve 20.0 g of cefixime bulk drug in 100 ml of 1 mol/L potassium hydroxide solution to prepare a drug solution with a concentration of 200 mg/mL. The acid solution and the drug solution were respectively added to a microchannel reactor with an inner diameter of 0.1 mm, wherein the acid was hydrochloric acid, the flow rate of the acid solution was adjusted to be 0.01L/min, the flow rate of the drug solution was 0.5L/min, and the temperature was 0°C, Mixing to obtain a cefixime nano-suspension with a pH of 1.0; filtering and washing the nano-suspension to obtain 19.8 g of cefixime nanoparticles with a yield of 99.0%. The average particle size of the cefixime nanoparticles is 54 nm, and the scanning electron microscope image is shown in FIG. 4 .

The cefixime nanoparticles obtained above were dispersed into 200ml of water containing 2.2g polyethylene glycol, and then packed into freeze-drying bottles. 0.1mbar, drying time 12h, freeze-drying to obtain cefixime nano-dispersion.

Example 12

Dissolve 16.0g of cefixime bulk drug in a mixed solution of 100ml of 1mol/L sodium acetate solution and 100ml of 1mol/L sodium bicarbonate solution to prepare a drug solution with a concentration of 80mg/mL. The acid mixed solution and the drug solution were respectively added to a microchannel reactor with an inner diameter of 0.3 mm, wherein the acid was acetic acid and oxalic acid, and the flow rate of the acid solution was adjusted to be 0.02L/min, and the flow rate of the drug solution was 0.4L/min. The temperature was 50° C., and mixed to obtain a cefixime nano-suspension with a pH of 1.7; the nano-suspension was filtered and washed to obtain 15.77 g of cefixime nanoparticles, with a yield of 98.6%. The average particle size of the cefixime nanoparticles is 60 nm.

The cefixime nanoparticles obtained above were dispersed into 200ml of water containing 0.83g of hydroxypropyl methylcellulose, the inlet temperature of the spray dryer was controlled to be 100°C, the outlet temperature was 45°C, the feed rate was 5mL/min, and the compression was performed. The air pressure is 0.4MPa, and the cefixime nano-dispersion is obtained by spray drying.

Comparative example (refer to the preparation method of CN101544660A)

Dissolve 1.0 g of cefixime in 10% sodium bicarbonate solution, adjust the pH value to 7.8, fully react to clarification to obtain cefixime sodium salt solution, add activated carbon for adsorption, filter, add 1.0mol/L to the filtrate The hydrochloric acid solution was adjusted to pH 3.6, crystals were precipitated, filtered, washed with water, and dried under reduced pressure at 50°C to obtain 0.92 g of cefixime refined product with a yield of 92.0%. The scanning electron microscope image of its refined cefixime product is shown in Figure 5.

Solubility comparative study

Take the excess cefixime nano-dispersion of Examples 1-12 and the cefixime refined product of the comparative example, put them in water, shake them to equilibrium at a constant temperature of 37°C, and filter the upper layer liquid through a 0.1 μm filter after centrifugation. The filtrate is analyzed, the actual concentration of the drug in the solution is determined, and the saturated solubility is calculated. The specific data are as follows:

It can be seen from the above solubility data that the cefixime nano-dispersion prepared by the present invention has a significantly higher solubility than the refined cefixime product, and is more than 19 times that of the refined cefixime product.

Claims (13)

1. A cefixime nano dispersion is characterized by comprising cefixime nano particles and pharmaceutical excipients, wherein the pharmaceutical excipients are selected from one or more of surfactants, fillers, polymers, cellulose and derivatives thereof; the surfactant is one or more selected from poloxamer, sodium dodecyl sulfate, tween, lecithin, sodium oleate and span; the filler is selected from one or more of lactose, starch, microcrystalline cellulose, mannitol, cyclodextrin and chitosan; the polymer is selected from one or more of polyvinylpyrrolidone, polyethylene glycol and polyvinyl alcohol; the cellulose and its derivatives are selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose, and ethyl cellulose; the average particle size of the cefixime nano particles is 50-900 nm; the preparation method of the cefixime nano dispersion comprises the following steps:

(1) dissolving cefixime in an aqueous alkali to obtain a medicinal solution;

(2) fully mixing the medicine solution and the acid solution to obtain cefixime nano suspension;

(3) filtering and washing the nano suspension to obtain cefixime nano particles;

(4) dispersing the cefixime nano particles into water containing pharmaceutical excipients to obtain a mixture;

(5) spray drying or freeze drying the mixture obtained in the step (4) to obtain cefixime nano dispersion;

wherein, the step (2) is fully mixed by a supergravity rotating packed bed or a microchannel reactor.

2. Cefixime nanodispersion according to claim 1, wherein the cefixime nanoparticles have an average particle size of 50-260 nm.

3. The cefixime nano-dispersion according to claim 1, wherein the mass percentage of cefixime nano-particles in the nano-dispersion is 70-95%, and the mass percentage of pharmaceutical excipients is 5-30%.

4. The cefixime nano-dispersion as claimed in claim 1, wherein the flow rate of the acid solution is 1-20L/min, the flow rate of the drug solution is 1-20L/min, and the rotation speed is 100-2800rpm when the mixing is fully carried out by the supergravity rotating packed bed.

5. Cefixime nanodispersion according to claim 4, wherein the flow ratio of acid solution to drug solution is 1: 20-1.

6. Cefixime nanodispersion according to claim 1, wherein the inner diameter of the microchannel reactor is 0.1-1.0mm, the flow rate of the acid solution is 0.01-0.5L/min and the flow rate of the drug solution is 0.01-0.5L/min.

7. Cefixime nanodispersion according to claim 6, wherein the flow ratio of acid solution to drug solution is 1: 50-1.

8. Cefixime nanodispersion according to claim 1, wherein the concentration of the cefixime drug solution in step (1) is 1-200 mg/ml.

9. Cefixime nano-dispersion according to claim 1, wherein the base in step (1) is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate.

10. Cefixime nano-dispersion according to claim 1, wherein the acid in step (2) is one or more of hydrochloric acid, acetic acid, oxalic acid, sulfuric acid, phosphoric acid, phosphorous acid, formic acid, citric acid.

11. Cefixime nanodispersion according to claim 1, wherein the pH of the suspension after mixing in step (2) is 1-4.

12. Cefixime nanodispersion according to claim 1, wherein the mixing temperature in step (2) is 0-50 ℃.

13. A pharmaceutical composition comprising cefixime nanodispersion according to any one of claims 1-12 and pharmaceutically acceptable excipients.

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