CN106309371B - Cefixime nano dispersion and preparation method thereof - Google Patents
Cefixime nano dispersion and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a cefixime nano dispersion, which comprises cefixime nano particles and pharmaceutical excipients, wherein the pharmaceutical excipients comprise one or more of a surfactant, a filling agent, a polymer, cellulose and derivatives thereof, and the average particle size of the cefixime nano particles is 50-900 nm. The nano dispersion has high solubility in water and excellent dissolution performance. Meanwhile, the invention also provides a method for preparing the nano dispersion, which is characterized in that cefixime nano particles are prepared by reducing the particle size of the raw material, and then are mixed with auxiliary materials to prepare the cefixime nano dispersion through spray drying or freeze drying. The preparation method is simple, is easy for industrial large-scale production, and has good industrial prospect.
Description
Technical Field
The invention relates to a cefixime nano-dispersion and a preparation method thereof, belonging to the field of pharmaceutical preparations.
Background
Cefixime, its chemical name is: (6R, 7R) -7- ((2Z) - (2-amino-4-thiazolyl) -2- (carboxymethoxyimino) acetamido) -3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0]-octyl-2-ene-2-carboxylic acid trihydrate having the molecular formula C16H15N5O7S2·3H2O, molecular weight 507.50, structural formula as follows:
cefixime is a third generation oral cephalosporin, first developed by Japan Tengze drug industry, Inc. in the early 80 s of the last century, and was released to the market in 1985 after completion of phase III clinical trials in Japan. Cefixime has obvious antibacterial action on gram-positive bacteria and gram-negative bacteria, is mainly used for clinically treating bronchitis, respiratory diseases, cystitis, urethritis, scarlet fever, otitis media and the like caused by sensitive strains, has high clinical curative effect, small dosage and less adverse drug reactions, and is widely applied.
Cefixime belongs to a medicine which is difficult to dissolve in water, has extremely low solubility in water, seriously influences the dissolution and absorption of the medicine and has poor oral bioavailability.
The cefixime preparation on the market at present comprises capsules, tablets, dispersible tablets, chewable tablets, granules and dry suspensions, and is a traditional oral administration preparation, because the cefixime has extremely low solubility in water, the disintegration and dissolution speed of the medicine in vivo is slow, the absorption and distribution of the medicine in vivo are influenced, the bioavailability of the medicine is poor, and the curative effect of the medicine is influenced.
In the prior art, the particle size of cefixime medicament is reduced by utilizing a micronization technology, and the dissolution of cefixime is attempted to be improved. For example, patent CN101889987B discloses a method for preparing cefixime and capsules, which comprises the steps of jet milling cefixime, solubilizer and water-soluble auxiliary materials, mixing with the rest of the auxiliary materials, and dry granulating. Patent CN102670536A discloses a method for preparing cefixime dispersible tablets, which comprises micronizing cefixime, reducing the particle size to 20-120 μm, mixing with other adjuvants such as solubilizer, filler, lubricant, binder and disintegrant, and granulating. Although the method can reduce the particle size of cefixime to a certain extent through the action of a physical method, the particle size is uncontrollable and is not uniformly distributed, and the effect of improving the dissolution of cefixime is not obvious.
In order to improve the bioavailability of cefixime, submicron technologies such as microemulsion, microspheres, liposome and the like are applied to cefixime preparations.
Patent CN101711741B discloses a cefixime submicron emulsion solid preparation, which consists of cefixime submicron emulsion particles and other auxiliary materials, wherein the submicron emulsion consists of 1 part of cefixime, 2.5-10 parts of emulsifier and 0.8-5 parts of auxiliary emulsifier. The dissolution rate of cefixime is improved by using a microemulsion technology, but the auxiliary emulsifier is an essential component in the formation of the microemulsion, and the auxiliary emulsifier has the defect of 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 comprises the following steps: adding stearic acid and lauric acid into an organic solvent, stirring for dissolving, adding cefixime, and stirring to form an organic phase; dissolving Tween 80 and hydrogenated castor oil polyoxyethylene ether 40 in water, and stirring to form a water phase; adding the organic phase into the stirred water phase, and removing the organic solvent to obtain primary emulsion; the colostrum is quickly added into cold water under the stirring condition, high-pressure homogenization and emulsification are carried out to obtain nanometer suspension, and finally, the solid lipid nanometer particle is obtained after drying. The liposome technology has the disadvantages of complex preparation process, harsh preparation conditions, higher requirements on equipment and high production cost, and in addition, the liposome is influenced by electrolytes and polar compounds and has the defects of instability in vivo and in vitro, easy leakage of medicines and the like.
In conclusion, it is still necessary to provide a cefixime preparation with good dissolution effect and high bioavailability.
Disclosure of Invention
The invention provides a cefixime nano dispersion with small particle size, narrow distribution and controllable particle morphology, wherein the average particle size of cefixime nano particles in the nano dispersion is 50-900nm, the particle morphology is regular, the specific surface area and the solubility of a medicament in water can be effectively increased, and the bioavailability and the curative effect of the medicament are improved. Meanwhile, the invention also provides a method for preparing the cefixime nano dispersion, which is simple and easy to operate, has low cost, is easy to amplify and industrially produce and has good industrial prospect.
The cefixime nano dispersion comprises cefixime nano particles and pharmaceutical excipients, wherein the pharmaceutical excipients comprise one or more of a surfactant, a filler, a polymer, cellulose and derivatives thereof; the cefixime nano-particles have an average particle size of 50-900nm, preferably an average particle size of 50-260 nm.
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, polyvinyl alcohol and polyethylene glycol; the cellulose and its derivatives are selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose, ethyl cellulose, and ethyl methylcellulose.
The cefixime nano dispersion has high content of main drugs, the mass percentage of cefixime nano particles is 70-95%, and the mass percentage of pharmaceutical excipients is 5-30%.
The invention also provides a preparation method of the cefixime nano dispersion, which comprises the following steps: reducing the particle size of the cefixime bulk drug to prepare cefixime nano particles, mixing the cefixime nano particles with pharmaceutical excipients, and preparing the nano dispersion through spray drying or freeze drying. Which 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) and (4) spray drying or freeze drying the mixture obtained in the step (4) to obtain the cefixime nano dispersion.
The crude product of the bulk drug sold in the market is generally prepared by purifying the crude product through an acid-base neutralization process, for example, in patent CN101544660A, the crude product is added with an alkali solution, or the crude product is dissolved in an organic solvent and then added with the alkali solution, the pH of the solution is adjusted to 6-9, the reaction is fully performed until the solution is clarified to obtain a cefixime salt solution, the acid is added into the filtered filtrate to adjust the pH to 2-5, and the refined product is obtained by crystallization, filtration and drying. The refined product prepared by the method has good fluidity, but large particles, and the average particle size is more than 100 mu m.
According to the Nernst-Noyes-Whitney equation, the specific surface area of the medicine is increased, the dissolution rate of the medicine can be improved, and the bioavailability of the medicine is improved. The specific surface area of the drug particles is affected by the particle size of the particles, the particle morphology, and the like, and the smaller the particle size, the larger the specific surface area.
In the step (2), the cefixime nano particles with small particle size, narrow distribution and controllable morphology are prepared by fully mixing the components through a supergravity rotary packed bed or a microchannel reactor, improving an acid-base neutralization process and combining the acid-base neutralization process with the supergravity rotary packed bed or the microchannel reactor, wherein the average particle size of the cefixime nano particles is 50-900nm, and preferably 50-260 nm.
The high-gravity rotating packed bed replaces the conventional gravity field by utilizing a centrifugal force field which is generated by high-speed rotation and is hundreds to thousands of times of gravity. Under the supergravity field, the liquid is highly sheared and dispersed to be in a very fine liquid drop or liquid filament state, the contact specific surface area is increased, the micromixing and the micrometric mass transfer are greatly enhanced, the distribution is more uniform, and the reaction time is greatly shortened. The particle size of the particles can be controlled by changing the rotating speed and further changing the gravity acceleration, and the large and uncontrollable particle size caused by the problems of uneven mixing, local supersaturation and the like can be avoided.
When the hypergravity rotating packed bed is used for fully mixing, the process operation parameters of the hypergravity rotating packed bed reactor, such as the rotating speed, the mixing temperature, the concentration of the drug solution, the flow rate of the acid solution, the flow rate of the drug solution, the flow rate ratio of the acid solution and the drug solution, and the like, are groped and adjusted, the concentration of the drug solution is determined to be 1-200mg/ml, the flow rate of the drug solution is 1-20L/min, the flow rate of the acid solution is 1-20L/min, the mixing temperature is 0-50 ℃, and the rotating speed is 100 plus 2800 rpm.
The flow ratio of the acid solution and the medicine solution is related to the supersaturation degree of the system, and has important influence on the particle size of the cefixime particles. As the flow ratio of the acid solution to the drug solution is increased, the supersaturation degree of the system is increased, and the nucleation rate is increased. In order to further obtain cefixime nano-particles with smaller particle size, narrower distribution and more controllable appearance, the flow ratio of the acid solution to the medicine solution is preferably 1: 20-1.
Microchannel reactors are microreactors with fluidic channel sizes on the order of microns. Due to the internal microstructure, the material has a large specific surface area which can reach hundreds of times or even thousands of times of the specific surface area of the stirring kettle. The fluid flows in the microchannel in a laminar flow state, the mixing is carried out by diffusion, the molecular diffusion distance is short, and the instant uniform mixing and the efficient heat and mass transfer of the materials are realized.
When the microchannel reactor is used for fully mixing, the process operation parameters of the microchannel reactor, such as the inner diameter of the reactor, the mixing temperature, the concentration of a drug solution, the flow rate of the drug solution, the flow rate of an acid solution, the flow rate ratio of the acid solution to the drug solution and the like, are groped and adjusted, the mixing temperature is determined to be 0-50 ℃, 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 flow rate of the acid solution is 0.01-0.5L/min.
In order to further obtain cefixime nano-particles with smaller particle size, narrower distribution and more controllable appearance, the flow ratio of the acid solution to the medicine solution is preferably 1: 50-1.
The acid and the base used in the preparation process of the cefixime nano-particles are the acid and the base which are commonly used in laboratories. Preferably, the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate; the acid is one or more of hydrochloric acid, acetic acid, oxalic acid, sulfuric acid, phosphoric acid, phosphorous 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 to 4, more preferably 1 to 1.9.
The cefixime nano-particles prepared in the step (3) of the method have an average particle size of 50-900nm, preferably 50-260 nm.
The cefixime nano-particles prepared by the method have large specific surface area and surface energy, and are easy to agglomerate after being placed for a long time to form micro-particles, so that the bioavailability of a medicinal preparation is influenced. In order to avoid agglomeration of the cefixime nano-particles, the cefixime nano-particles are dispersed into water containing pharmaceutical excipients, and the cefixime nano-dispersion is obtained by spray drying or freeze drying. Spray drying or freeze drying can effectively reduce the phenomena of mutual adhesion and agglomeration among the nano dispersions.
In the step (5), the preferred inlet temperature of spray drying is 100-140 ℃, the outlet temperature is 45-75 ℃, the feeding speed is 5-40mL/min, and the compressed air pressure is 0.4-0.8 MPa. The freeze drying preferably has a prefreezing temperature of-45 deg.C, a prefreezing time of 2-3h, a vacuum degree of 0.1mbar, and a drying time of 12-48 h.
The cefixime nano-dispersion prepared by the invention has higher stability and solubility, and can be widely applied to injections, tablets, capsules, soft capsules, emulsions, oral solutions or suspensions.
Drawings
Fig. 1 is a scanning electron micrograph of cefixime nanoparticles of example 3;
fig. 2 is a scanning electron micrograph of cefixime nanoparticles of example 5;
fig. 3 is a scanning electron micrograph of cefixime nanoparticles of example 7;
fig. 4 is a scanning electron micrograph of cefixime nanoparticles of example 11;
fig. 5 is a scanning electron microscope image of cefixime refined product of comparative example.
As can be seen from the scanning electron microscope image, the cefixime nano-particles in fig. 1 have a particle size of less than 500nm and an average particle size of 260 nm; fig. 2 shows that the particle size of cefixime nano-particles is less than 100nm, and the average particle size is 50 nm; fig. 3 shows that the particle size of cefixime nano-particles is less than 1 μm, and the average particle size is 640 nm; fig. 4 shows that the particle size of cefixime nano-particles is less than 100nm, and the average particle size is 54 nm; FIG. 5 shows that the cefixime refined product has a particle size of more than 100 μm and an average particle size of 125 μm. The particles in FIG. 3 are uniformly distributed, the morphology is controllable, and the particle size distribution is narrow; the particles in the images 1, 2 and 4 are more uniform in distribution, regular and uniform in appearance and narrower in particle size distribution.
Detailed Description
Example 1
Dissolving 20.0g of cefixime bulk drug in 500mL of 0.5mol/L sodium hydroxide solution to prepare a drug solution with the concentration of 40 mg/mL. Respectively adding acid and a drug solution into a supergravity rotating packed bed reactor, wherein the acid is sulfuric acid and phosphoric acid, adjusting the flow rate of the acid solution to be 20.0L/min, the flow rate of the drug solution to be 1.0L/min, the rotating speed to be 100rpm, the temperature to be 30 ℃, and mixing to obtain a cefixime nano suspension with the pH value of 1.9; the nano suspension is filtered and washed to obtain 19.8g of cefixime nano particles, and the yield is 99.0%. The average particle size of the cefixime nano-particles is 900 nm.
Dispersing the cefixime nano-particles obtained in the above manner into 300mL of water containing 1.1g of sodium dodecyl sulfate and 1.1g of lecithin, controlling the inlet temperature of a spray dryer to be 100 ℃, the outlet temperature to be 45 ℃, the feeding speed to be 5mL/min and the compressed air pressure to be 0.4MPa, and performing spray drying to obtain the cefixime nano-dispersion.
Example 2
50.0g of cefixime bulk drug is dissolved in a mixed solution of 200mL of 1mol/L sodium acetate solution and 300mL of 1mol/L sodium hydroxide solution to prepare a drug solution with the concentration of 100 mg/mL. Respectively adding an acid solution and a drug solution into a supergravity rotating packed bed reactor, wherein the acid is oxalic acid, adjusting the flow rate of the acid solution to be 18.0L/min, the flow rate of the drug solution to be 9.0L/min, the rotating speed to be 1000rpm, the temperature to be 25 ℃, and mixing to obtain the cefixime nano suspension with the pH value of 1.5; the nano suspension is filtered and washed to obtain 49.4g of cefixime nano particles, and the yield is 98.8%. The average particle size of the cefixime nano-particles is 520 nm.
Dispersing the obtained cefixime nano particles into 300ml of water containing 1.3g of chitosan and 1.3g of ethyl cellulose, subpackaging the cefixime nano particles into freeze-drying bottles, controlling the pre-freezing temperature of a freeze-drying machine to be 45 ℃ below zero, the pre-freezing time to be 2.5h, the vacuum degree to be 0.1mbar, and the drying time to be 24h, and freeze-drying to obtain the cefixime nano dispersion.
Example 3
Dissolving 20.0g of cefixime bulk drug in 100mL of 2.0mol/L sodium carbonate solution to prepare a drug solution with the concentration of 200 mg/mL. Respectively adding an acid solution and a drug solution into a supergravity rotating packed bed reactor, wherein the acid is formic acid, adjusting the flow rate of the acid solution to be 10.0L/min, the flow rate of the drug solution to be 10.0L/min, the rotating speed to be 500rpm, the temperature to be 0 ℃, and mixing to obtain a cefixime nano suspension with the pH value of 4.0; the nano suspension is filtered and washed to obtain 19.2g of cefixime nano particles, and the yield is 96.0%. The average particle size of the cefixime nano-particles is 260nm, and a scanning electron micrograph is shown in figure 1.
Dispersing the obtained cefixime nano particles into 300ml of water containing 1.6g of starch, 1.6g of sodium oleate and 1.6g of polyvinylpyrrolidone, subpackaging the cefixime nano particles into freeze-drying bottles, controlling the pre-freezing temperature of a freeze-drying machine to be-45 ℃, the pre-freezing time to be 2 hours, the vacuum degree to be 0.1mbar and the drying time to be 12 hours, and freeze-drying to obtain the cefixime nano dispersion.
Example 4
16.0g of cefixime bulk drug is dissolved in a 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 drug solution with the concentration of 160 mg/mL. Respectively adding an acid solution and a drug solution into a supergravity rotating packed bed reactor, wherein the acid is hydrochloric acid and citric acid, adjusting the flow rate of the acid solution to be 2.0L/min, the flow rate of the drug solution to be 12.0L/min, the rotating speed to be 1500rpm, the temperature to be 10 ℃, and mixing to obtain a cefixime nano suspension with the pH value of 3.0; the nano suspension is filtered and washed to obtain 15.3g of cefixime nano particles, and the yield is 95.6%. The average particle size of the cefixime nano-particles is 150 nm.
Dispersing the obtained cefixime nano particles into 300ml of water containing 1.4g of polyvinylpyrrolidone and 1.3g of polyvinyl alcohol, subpackaging the cefixime nano particles into freeze-drying bottles, controlling the pre-freezing temperature of a freeze-drying machine to be 45 ℃ below zero, the pre-freezing time to be 3 hours, the vacuum degree to be 0.1mbar and the drying time to be 48 hours, and freeze-drying to obtain the cefixime nano dispersion.
Example 5
1.0g of cefixime bulk drug is dissolved in 1000mL of 0.5mol/L sodium bicarbonate solution to prepare a drug solution with the concentration of 1 mg/mL. Respectively adding an acid solution and a drug solution into a supergravity rotating packed bed reactor, wherein the acid is hydrochloric acid, adjusting the flow rate of the acid solution to be 1.0L/min, the flow rate of the drug solution to be 20.0L/min, the rotating speed to be 2800rpm, the temperature to be 20 ℃, and mixing to obtain a cefixime nano suspension with the pH value of 1; and filtering and washing the nano suspension to obtain 0.98g of cefixime nano particles, wherein the yield is 98.0%. The cefixime nano-particles have the average particle size of 50nm, and a scanning electron microscope image is shown in figure 2.
Dispersing the obtained cefixime nano particles into 200mL of water containing 0.42g of poloxamer, controlling the inlet temperature of a spray dryer to be 120 ℃, the outlet temperature to be 50 ℃, the feeding speed to be 20mL/min and the compressed air pressure to be 0.6MPa, and performing spray drying to obtain the cefixime nano dispersion.
Example 6
Dissolving 15.0g of cefixime bulk drug in 100mL of 2mol/L sodium carbonate solution to prepare 150mg/mL drug solution. Respectively adding an acid solution and a drug solution into a supergravity rotating packed bed reactor, wherein the acid is acetic acid, adjusting the flow rate of the acid solution to be 1.5L/min, the flow rate of the drug solution to be 15.0L/min, the rotating speed to be 2000rpm, the temperature to be 50 ℃, and mixing to obtain a cefixime nano suspension with the pH value of 1.6; the nano suspension is filtered and washed to obtain 14.25g of cefixime nano particles, and the yield is 95.0%. The average particle size of the cefixime nano-particles is 54 nm.
Dispersing the obtained cefixime nano particles into 200mL of water containing 2.75g of lactose and 2g of cyclodextrin, controlling the inlet temperature of a spray dryer to be 140 ℃, the outlet temperature to be 75 ℃, the feeding speed to be 40mL/min and the compressed air pressure to be 0.8MPa, and performing spray drying to obtain the cefixime nano dispersion.
Example 7
Dissolving 12.0g of cefixime bulk drug in 100mL of 1mol/L sodium hydroxide solution to prepare a drug solution with the concentration of 120 mg/mL. Respectively adding an acid solution and a drug solution into a microchannel reactor with the inner diameter of 0.5mm, wherein the acid is acetic acid and sulfuric acid, adjusting the flow rate of the acid solution to be 0.5L/min, the flow rate of the drug solution to be 0.01L/min and the temperature to be 10 ℃, and mixing to obtain a cefixime nano suspension with the pH value of 1.9; the nano suspension is filtered and washed to obtain 11.6g of cefixime nano particles, and the yield is 96.7%. The average particle size of the cefixime nano-particles is 640nm, and a scanning electron microscope picture is shown in figure 3.
Dispersing the obtained cefixime nano particles into 200ml of water containing 1.4g of methylcellulose and 1.5g of sodium carboxymethylcellulose, subpackaging the cefixime nano particles into freeze-drying bottles, controlling the pre-freezing temperature of a freeze-drying machine to be-45 ℃, the pre-freezing time to be 2.5h, the vacuum degree to be 0.1mbar, and the drying time to be 24h, and freeze-drying to obtain the cefixime nano dispersion.
Example 8
18.0g of cefixime bulk drug is dissolved 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 the concentration of 180 mg/mL. Respectively adding an acid solution and a drug solution into a microchannel reactor with the inner diameter of 0.8mm, wherein the acid is formic acid and phosphoric acid, adjusting the flow of the acid solution to be 0.2L/min, the flow of the drug solution to be 0.05L/min and the temperature to be 0 ℃, and mixing to obtain a cefixime nano suspension with the pH value of 1.2; the nano suspension is filtered and washed to obtain 17.5g of cefixime nano particles, and the yield is 97.2%. The average particle size of the cefixime nano-particles is 500 nm.
Dispersing the cefixime nano-particles into 300mL of water containing 3.6g of polyethylene glycol and 3.9g of hydroxypropyl cellulose, controlling the inlet temperature of a spray dryer to be 120 ℃, the outlet temperature to be 55 ℃, the feeding speed to be 15mL/min and the compressed air pressure to be 0.6MPa, and performing spray drying to obtain the cefixime nano-dispersion.
Example 9
50.0g of cefixime bulk drug is dissolved 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 prepare a drug solution with the concentration of 100 mg/mL. Respectively adding an acid solution and a drug solution into a microchannel reactor with the inner diameter of 0.6mm, wherein the acid is acetic acid, phosphorous acid and phosphoric acid, adjusting the flow rate of the acid solution to be 0.03L/min, adjusting the flow rate of the drug solution to be 0.3L/min, and mixing at the temperature of 15 ℃ to obtain a cefixime nano suspension with the pH value of 3.5; the nano suspension is filtered and washed to obtain 47.5g of cefixime nano particles, and the yield is 95.0%. The average particle size of the cefixime nano-particles is 250 nm.
Dispersing the cefixime nano-particles obtained in the above into 300mL of water containing 0.5g of hydroxypropyl methyl cellulose, 1.0g of microcrystalline cellulose and 1.0g of tween 80, controlling the inlet temperature of a spray dryer to be 140 ℃, the outlet temperature to be 75 ℃, the feeding speed to be 40mL/min and the compressed air pressure to be 0.8MPa, and performing spray drying to obtain the cefixime nano-dispersion.
Example 10
1.0g of cefixime bulk drug is dissolved in 1000mL of 0.1mol/L sodium hydroxide solution to prepare a drug solution with the concentration of 1 mg/mL. Respectively adding an acid solution and a drug solution into a microchannel reactor with the inner diameter of 1mm, wherein the acid is hydrochloric acid, adjusting the flow of the acid solution to be 0.1L/min, the flow of the drug solution to be 0.1L/min and the temperature to be 25 ℃, and mixing to obtain a cefixime nano suspension with the pH value of 4; the nano suspension is filtered and washed to obtain 0.96g of cefixime nano particles, and the yield is 96.0%. The average particle size of the cefixime nano-particles is 210 nm.
Dispersing the obtained cefixime nano particles into 200ml of water containing 0.24g of mannitol, subpackaging the cefixime nano particles into freeze-drying bottles, controlling the pre-freezing temperature of a freeze-drying machine to be-45 ℃, the pre-freezing time to be 3h, the vacuum degree to be 0.1mbar and the drying time to be 48h, and freeze-drying to obtain the nano cefixime dispersion.
Example 11
Dissolving 20.0g of cefixime bulk drug in 100mL of 1mol/L potassium hydroxide solution to prepare a drug solution with the concentration of 200 mg/mL. Respectively adding an acid solution and a drug solution into a microchannel reactor with the inner diameter of 0.1mm, wherein the acid is hydrochloric acid, adjusting the flow of the acid solution to be 0.01L/min, the flow of the drug solution to be 0.5L/min and the temperature to be 0 ℃, and mixing to obtain a cefixime nano suspension with the pH of 1.0; the nano suspension is filtered and washed to obtain 19.8g of cefixime nano particles, and the yield is 99.0%. The cefixime nano-particles have the average particle size of 54nm, and a scanning electron micrograph is shown in figure 4.
Dispersing the obtained cefixime nano particles into 200ml of water containing 2.2g of polyethylene glycol, subpackaging the cefixime nano particles into freeze-drying bottles, controlling the pre-freezing temperature of a freeze dryer to be-45 ℃, the pre-freezing time to be 2 hours, the vacuum degree to be 0.1mbar and the drying time to be 12 hours, and freeze-drying to obtain the cefixime nano dispersion.
Example 12
Dissolving 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 the concentration of 80 mg/mL. Respectively adding the acid mixed solution and the drug solution into a microchannel reactor with the inner diameter of 0.3mm, wherein the acid is acetic acid and oxalic acid, adjusting the flow of the acid solution to be 0.02L/min, adjusting the flow of the drug solution to be 0.4L/min, and mixing at 50 ℃ to obtain the cefixime nano suspension with the pH value of 1.7; the nano suspension is filtered and washed to obtain 15.77g of cefixime nano particles, and the yield is 98.6%. The average particle size of the cefixime nano-particles is 60 nm.
Dispersing the obtained cefixime nano particles into 200mL of water containing 0.83g of hydroxypropyl methyl cellulose, controlling the inlet temperature of a spray dryer to be 100 ℃, the outlet temperature to be 45 ℃, the feeding speed to be 5mL/min and the compressed air pressure to be 0.4MPa, and performing spray drying to obtain the cefixime nano dispersion.
Comparative example (reference CN101544660A preparation method)
Dissolving 1.0g of cefixime bulk drug in 10% sodium bicarbonate solution, adjusting the pH value to 7.8, fully reacting to be clear to obtain cefixime sodium salt solution, adding activated carbon for adsorption, filtering, adding 1.0mol/L hydrochloric acid solution into filtrate, adjusting the pH value to 3.6, separating out crystals, filtering, washing with water, and drying under reduced pressure at 50 ℃ to obtain 0.92g of cefixime refined product with the yield of 92.0%. The scanning electron microscope image of the cefixime refined product is shown in figure 5.
Contrast investigation of solubility
Taking excessive cefixime nano dispersion of examples 1-12 and the cefixime refined product of the comparative example, placing the cefixime nano dispersion and the cefixime refined product of the comparative example in water, oscillating the mixture to be balanced under the condition of constant temperature of 37 ℃, centrifuging the mixture, filtering the supernatant liquid through a 0.1 mu m filter membrane, taking filtrate for analysis, measuring the actual concentration of the drug in the solution, and calculating the saturation solubility, wherein the specific data is as follows:
from the solubility data, the solubility of the cefixime nano dispersion prepared by the invention is obviously improved compared with that of a cefixime refined product, and is more than 19 times that of the cefixime refined 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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