CN116035908A - Atomization system for preparing spherical drug microcrystals and application thereof - Google Patents
Atomization system for preparing spherical drug microcrystals and application thereof Download PDFInfo
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Abstract
The invention relates to an atomization system for preparing medicine microspheres, which comprises a heating chamber 2, an atomizer 5, a condensation chamber 14 and a cyclone separator 16, wherein the heating chamber 2 is communicated with the atomizer 5 through a liquid conveying pipe 8, a vertical air inlet pipe 9, a horizontal air inlet pipe 10 and an atomization nozzle 12 are arranged on the atomizer 5, the atomizer 5 is communicated with the condensation chamber 14 through the atomization nozzle 12, the condensation chamber 14 is communicated with the cyclone separator 16, and the condensation chamber 14 is communicated with a gas condenser 13 through a low-temperature drying gas inlet pipe 15. Compared with the traditional mode, the atomization system shortens the condensation time, the sphericity of the prepared microsphere is improved, the particle size range can be reduced to 0.2-0.5, and the yield is more than 80%.
Description
Technical Field
The invention relates to the field of medicines, in particular to an atomization system for preparing medicine microspheres and application thereof.
Background
The drug microsphere is a sphere with the particle size of 5-500 μm formed by dissolving or dispersing drugs into a polymer material. After spherical microcrystal is administrated, the polymer material is gradually degraded to release the medicine, so that the administration dosage is reduced, the abrupt release of the medicine is reduced, the peak-valley phenomenon of blood concentration is reduced or even avoided, the administration times of the treatment period are reduced, the bioavailability and the administration compliance of patients are improved, and the spherical microcrystal has very broad market prospect. The drug loading, morphology, particle size and particle size distribution of the drug microspheres can influence the dispersion state of the drug and the degradation and porosity of the framework material to influence the release of the drug.
The preparation method of the medicine microsphere comprises an emulsifying solvent diffusion method, a spray drying method, a hot melt extrusion method, an aerosol method and the like. The emulsion solvent diffusion method has the defects of wide particle size distribution, low encapsulation efficiency, abrupt drug release and the like. The spray drying method has organic solvent residues which affect the health of human body and the safety of medicines. The products prepared by the hot melt extrusion method are mostly irregular spheres, and have the defects of low drug loading (about 10-20%), abrupt release (about 10-40% of accumulated release rate in 1 h), organic reagent residues and the like. The high-speed high-pressure medium flow is generated by the gas atomization method through an atomization nozzle, the medicine melt is dispersed into tiny liquid drops, and then the tiny liquid drops are condensed, solidified and dried to form the medicine microsphere. The medicine microsphere prepared by the air atomization method has the advantages of large medicine carrying quantity, uniform dispersion, high encapsulation efficiency, avoiding using an organic solvent, reducing abrupt release of the medicine, reducing clinical dosage, wide application range and the like. But the defects of poor condensation effect, uneven surface roundness of the medicine microspheres and the like are easy to occur. Therefore, research and development of new atomizing systems is needed to solve the foregoing problems.
Disclosure of Invention
The invention aims to provide an atomization system for preparing medicine microspheres, which comprises a heating chamber 2, an atomizer 5, a condensation chamber 14 and a cyclone separator 16, wherein the heating chamber 2 is communicated with the atomizer 5 through a liquid conveying pipe 8, a vertical air inlet pipe 9, a horizontal air inlet pipe 10 and an atomization nozzle 12 are arranged on the atomizer 5, the atomizer 5 is communicated with the condensation chamber 14 through the atomization nozzle 12, the condensation chamber 14 is communicated with the cyclone separator 16, low-temperature drying gas is fed into the condensation chamber 14 through a low-temperature drying gas inlet pipe 15 by a gas condenser 13, the gas condenser 13 is communicated with a gas dryer 19, the gas dryer 19 is communicated with a gas storage tank 20, and the gas storage tank 20 is communicated with a gas compressor 21.
In a preferred embodiment of the present invention, the bottom of the heating chamber 2 is tapered.
In a preferred embodiment of the present invention, a stirrer 3 is disposed in the heating chamber 2.
In a preferred embodiment of the present invention, the heating chamber 2 is connected to the infusion tube 8 by a peristaltic pump 11, wherein the peristaltic pump 11 is any one selected from a speed-regulating peristaltic pump, a flow-rate peristaltic pump, and a distribution peristaltic pump.
In a preferred embodiment of the present invention, the heating means of the heating chamber 2 is selected from any one of or a combination of resistance heating, electromagnetic induction heating, infrared heating wire, microwave heating, and arc heating.
In a preferred embodiment of the present invention, the atomizer 5 is selected from any one of a rotary atomizer, a parallel flow type two-fluid nozzle atomizer, a fountain type two-fluid nozzle atomizer, a pressure type nozzle atomizer, and a combination type nozzle atomizer.
In a preferred embodiment of the present invention, the atomizer 5 is preheated first, and the preheating mode is selected from any one of resistance heating, electromagnetic induction heating, arc heating, winding of a heating wire around the periphery of the atomizer, a heating jacket, and oil bath heating, or a combination thereof.
In a preferred technical scheme of the invention, an oil inlet 4 and an oil outlet 6 are arranged on the atomizer 5.
In a preferred embodiment of the present invention, the aperture of the atomizing nozzle 12 is 0.5-5mm, preferably 0.8-3mm.
In a preferred embodiment of the present invention, the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 simultaneously feed high-pressure inert gas into the atomizer 5.
In a preferred embodiment of the present invention, the cyclone 16 is two cyclones connected in series, and the coarse powder collecting tank 17 and the fine powder collecting tank 18 are respectively connected.
In a preferred embodiment of the present invention, a temperature control panel 1 is further disposed in the atomization system, for setting a heating temperature of the heating chamber 2.
In a preferred technical scheme of the invention, a control panel 7 is further arranged in the atomization system and is used for controlling a preheating device of the infusion tube 8, the vertical air inlet tube 9 and the horizontal air inlet tube 10, and the preheating device is selected from any one or combination of resistance heating, electromagnetic induction heating, electric arc heating and heating wire winding heating.
It is another object of the present invention to provide a method for preparing pharmaceutical microspheres using the nebulization system of the present invention, comprising in particular the steps of:
(1) Uniformly mixing the medicines or the mixture of the medicines and the carrier materials according to the ratio of 1:1-1:20, then putting the mixture into a heating chamber, and heating the mixture under the protection of inert gas at 50-200rpm to prepare molten liquid medicine;
(2) Feeding the molten liquid medicine into an atomizer preheated to a temperature 20-30deg.C higher than the melting point of the medicine at a flow rate of 1000-2000mL/h, and pulverizing into fogdrops with 0.05-5Mpa of high-pressure inert gas;
(3) And (3) sending the prepared fog drops into a condensing chamber, carrying out cold solidification to form spherical microcrystals under the action of low-temperature drying gas at the temperature of-80 ℃ to 0 ℃, and sending the spherical microcrystals into a cyclone separator for separation after drying.
In a preferred embodiment of the invention, the weight ratio of the drug to the carrier material is 1:1.5-1:10, preferably 1:2-1:5.
In a preferred embodiment of the present invention, the stirring speed in the step (1) is 80-120rpm/min.
In a preferred embodiment of the present invention, the heating mode of the heating chamber in the step (1) may be any one or a combination of resistance heating, electromagnetic induction heating, infrared heating wire, microwave heating, and arc heating.
In a preferred embodiment of the present invention, the inert gas in the step (1) is selected from any one of argon, nitrogen and helium or a combination thereof.
In a preferred embodiment of the present invention, the viscosity of the molten liquid medicine in the step (1) is 50pa.s-28000pa.s, preferably 100pa.s-15000pa.s.
In a preferred technical scheme of the invention, the flow rate of the molten liquid medicine in the step (2) is 1200-1800mL/h.
In a preferred embodiment of the present invention, the preheating mode of the atomizer in the step (2) is selected from any one of resistance heating, electromagnetic induction heating, arc heating, winding heating wire, and hot oil heating, or a combination thereof.
In a preferred embodiment of the present invention, the atomizer in the step (2) is selected from any one of a rotary atomizer, a parallel flow type two-fluid nozzle atomizer, a fountain type two-fluid nozzle atomizer, a pressure type nozzle atomizer, and a combination type nozzle atomizer.
In a preferred technical scheme of the invention, the atomizer in the step (2) comprises an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe, wherein the aperture of the atomizing nozzle is 0.5-5mm, preferably 0.8-3mm.
In a preferred embodiment of the present invention, the high-pressure inert gas in the step (2) is selected from any one or a combination of argon, nitrogen and helium, and the pressure of the high-pressure inert gas is 0.1-3Mpa, preferably 0.5-1.5Mpa.
In a preferred embodiment of the present invention, the low-temperature drying gas in the step (3) may be selected from any one of nitrogen, helium, argon, neon, carbon monoxide, carbon dioxide, or a combination thereof.
In a preferred embodiment of the present invention, the temperature of the low temperature drying gas in the step (3) is-50 ℃ to-20 ℃, preferably-40 ℃ to-25 ℃.
In a preferred embodiment of the present invention, the drying in the step (3) is selected from any one of reduced pressure drying and vacuum drying or a combination thereof, and the drying temperature is 35 ℃ to 65 ℃, preferably 40 ℃ to 50 ℃.
In the preferred technical scheme of the invention, the cyclone separator in the step (3) is two cyclone separators connected in series, and the coarse powder collecting tank and the fine powder collecting tank are respectively communicated.
In a preferred embodiment of the present invention, the drug is selected from any one of a poorly soluble drug, a slightly soluble drug, a soluble drug, and a readily soluble drug having a melting point of 60 ℃ to 300 ℃.
In a preferred embodiment of the present invention, the carrier material is selected from any one of a slow release material, a water-soluble carrier material, a poorly soluble carrier material, an enteric carrier material, or a combination thereof.
In a preferred embodiment of the present invention, the drug spherical microspheres are any one of spheroids, spheres, or a combination thereof.
In a preferred embodiment of the present invention, the average particle size of the drug microspheres is 20 μm to 250. Mu.m, preferably 50 μm to 200. Mu.m, more preferably 100 μm to 150. Mu.m.
In the preferred technical scheme of the invention, the porosity of the drug microsphere is less than or equal to 10 percent.
In the preferred technical scheme of the invention, the bulk density of the drug microsphere is 0.25g/cm 3 -0.86g/cm 3 Preferably 0.40g/cm 3 -0.65g/cm 3 More preferably 0.5g/cm 3 -0.6g/cm 3 。
In a preferred technical scheme of the invention, the drug microsphere is a solid sphere, preferably a compact round solid sphere.
In a preferred technical scheme of the invention, the medicine is selected from any one of progesterone, megestrol acetate and indomethacin.
In a preferred technical scheme of the invention, the melting point of the medicine is 80-200 ℃.
In a preferred technical scheme of the invention, the slow-release material is any one or combination of polyester slow-release material, polyanhydride slow-release material and polyamide slow-release material, preferably the polyester slow-release material is selected from any one or combination of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polylactic acid-glycolic acid copolymer (50:50), polylactic acid-glycolic acid copolymer (75:25), polylactic acid-glycolic acid copolymer (85:15) and polyorthoester, and the molecular weight of the polyester slow-release material is 10000-50000 daltons.
In a preferred embodiment of the present invention, the water-soluble carrier material is selected from any one of poloxamer, polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, aminoalkyl methacrylate copolymer E, polyvinyl alcohol/polyethylene glycol graft copolymer, ethylene-vinyl acetate copolymer, acrylic resin, polyoxyethylene, polyvinyl alcohol, povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, polyvinyl acetate povidone mixture, or a combination thereof.
In a preferred embodiment of the present invention, the poorly soluble carrier material is selected from any one of Ethyl Cellulose (EC), polyacrylic resin Eudragit containing quaternary ammonium groups, polymethacrylic resin, or a combination thereof.
In a preferred embodiment of the present invention, the enteric carrier is selected from any one of carboxymethylcellulose (CNEC), hypromellose phthalate (HPMCP), polyacrylate (Eudragit L and S) or a combination thereof.
In a preferred embodiment of the present invention, the pharmaceutical microsphere further comprises a plasticizer.
In a preferred embodiment of the present invention, the plasticizer is selected from any one of polyethylene glycol 400, polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, vitamin E polyethylene glycol succinate, polyethylene glycol-15 hydroxystearate, stearic acid and its salts, glyceryl stearate, polysorbates, castor oil polyoxyethylene ethers, sodium dodecyl sulfate, polyoxyethylene polyoxypropylene ether block copolymers, sucrose, glucose, sorbitol, maltitol, xylitol, isomalt, mannitol, lactitol, erythritol, tartaric acid, fumaric acid, malic acid, maleic acid, ethanol, propylene glycol, glycerin, or a combination thereof.
In a preferred embodiment of the present invention, the weight ratio of plasticizer to carrier material in the pharmaceutical microsphere is 1:1-1:30, preferably 1:2-1:20, more preferably 1:3-1:10.
In a preferred embodiment of the present invention, the pharmaceutical microsphere further comprises a glidant.
In a preferred technical scheme of the invention, the glidant is selected from any one or combination of silicon dioxide, colloidal silicon dioxide, micro silica gel, aluminum magnesium silicate, halloysite and light calcium carbonate.
In a preferred technical scheme of the invention, the weight ratio of the glidant to the carrier material in the drug microsphere is 1:1-1:10, preferably 1:2-1:5.
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
The invention is tested, unless otherwise indicated, using the following method:
1. the particle size distribution of the spherical crystals was detected by laser diffraction: the Mastersizer 2000Mu laser particle sizer (Malvern, uk) uses water as the dispersion medium, the pump speed of the cell is set to 2200rpm, and the analysis mode selects the universal mode. After the light and background measurement is completed, the suspension is taken and stirred uniformly and added into a sample injector until the shading degree is stabilized at 15+/-1%, and the particle size measurement is started.
2. The surface morphology of the sample to be measured is observed by adopting a JSM-7900F thermal field emission scanning electron microscope (JEOL corporation, japan) and is subjected to metal spraying treatment, and the scanning voltage is 30kV.
3. Raman spectrum imaging is carried out by adopting a microscopic confocal laser Raman spectrometer (Renisshaw, england), and 785nm excitation light source is selected for imaging.
Compared with the prior art, the invention has the following beneficial technical effects:
1. according to the atomization system for preparing the drug microspheres, the atomization gun body is preheated through the oil bath, so that the temperature difference between the gun body and the liquid medicine is reduced, solidification in the flowing process of the liquid medicine is avoided, the gun body is blocked, and the liquid medicine is maintained to achieve a continuous atomization state; and meanwhile, the vertical air inlet and the horizontal air inlet are combined, so that the liquid medicine can be smashed in a maximized and omnibearing manner, uneven stress and insufficient stress of the liquid medicine are avoided, the adhesion phenomenon of microspheres is reduced, and the roundness of the microspheres is improved.
2. The atomization system of the invention is wholly sealed and dried, so that atomized liquid medicine is quickly condensed into balls, the influence of water vapor caused by cold-heat exchange on the interior and surface morphology of the microspheres is avoided, compared with the traditional mode, the condensation time is shortened, the sphericity of the prepared microspheres is improved, the particle size range can be reduced to 0.2-0.5, and the yield is more than 80%.
3. The atomizing nozzle can be replaced in real time according to the requirements to prepare spherical powder with different particle diameters, for example, the pressure type nozzle is suitable for obtaining microspheres with narrow particle diameter distribution and larger particle diameter, the parallel flow type double-fluid nozzle is suitable for preparing microspheres with smaller particle diameter, and the combined type nozzle is suitable for obtaining microspheres with narrower particle diameter distribution and smaller particle diameter, and the like. The cyclone separation system can pre-screen the prepared microspheres with different particle sizes, and the subsequent screening workload is reduced.
4. The atomization system can be applied to the medical field, can prepare bulk drugs with any surface morphology into round spherical drug microspheres, can achieve good needle penetrating property and slow release effect, delays drug release, improves the oral bioavailability of the drug, the effectiveness and the safety of the drug, obviously reduces the administration times of patients and reduces the toxic and side effects of the drug. The operation is simple and safe, and the industrial production is realized.
Drawings
FIG. 1 is a block diagram of an atomizing system according to the present disclosure, wherein FIG. 1 (a) is a main diagram of the atomizing system, and comprises: the device comprises a temperature control panel 1, a heating chamber 2, a stirrer 3, an oil inlet 4, an atomizer 5, an oil outlet 6, a control panel 7, a liquid conveying pipe 8, a vertical air inlet pipe 9, a horizontal air inlet pipe 10, a peristaltic pump 11, an atomizing nozzle 12, a condensing chamber 14, a low-temperature drying gas inlet pipe 15, a cyclone separator 16, a coarse powder collecting tank 17 and a fine powder collecting tank 18; fig. 1 (b) is a schematic diagram of a low-temperature dry gas generating system connected to a low-temperature dry gas inlet pipe 15, comprising a gas condenser 13, a gas dryer 19, a gas storage tank 20, and a gas compressor 21;
FIG. 2 is a scanning electron microscope image of a progesterone sustained release microsphere;
FIG. 3 shows a particle size distribution of progesterone-releasing microspheres;
fig. 4 raman imaging of progesterone sustained release microspheres;
FIG. 5 investigation of the release of progesterone sustained release microspheres of examples 1-5;
figure 6 example 7 in vitro release studies of megestrol acetate microspheres;
FIG. 7 dissolution investigation of indomethacin solid dispersible tablets of example 9.
Detailed Description
The invention is illustrated by the following examples, which are given solely for the purpose of further illustration and are not intended to limit the scope of the invention. Some insubstantial modifications and adaptations of the invention by others are within the scope of the invention.
The invention relates to an atomization system for preparing medicine microspheres, which is shown in figure 1, and comprises a heating chamber 2, an atomizer 5, a condensation chamber 14 and a cyclone separator 16, wherein the heating chamber 2 is communicated with the atomizer 5 through a liquid conveying pipe 8, a vertical air inlet pipe 9, a horizontal air inlet pipe 10 and an atomization nozzle 12 are arranged on the atomizer 5, the atomizer 5 is communicated with the condensation chamber 14 through the atomization nozzle 12, the condensation chamber 14 is communicated with the cyclone separator 16, and the condensation chamber 14 is communicated with a gas condenser 13 through a low-temperature drying gas inlet pipe 15.
The bottom of the heating chamber 2 is conical, the stirrer 3 is arranged in the heating chamber 2, so that the medicine is heated uniformly in the heating process, the temperature control panel 1 is used for setting the heating temperature of the heating chamber 2, and the heating chamber 2 is communicated with the infusion tube 8 through the peristaltic pump 11.
The atomizer 5 is provided with the oil inlet 4 and the oil outlet 6, hot oil enters the atomizer 5 through the oil inlet 4, so that the hot oil preheats the atomizer, and the hot oil is discharged from the oil outlet 6, so that the temperature of the atomizing gun is preheated to 20-30 ℃ higher than the melting point of the medicine, the temperature difference between the gun body and the medicine is reduced, solidification of the medicine in the flowing process is avoided, the gun body is blocked, and the medicine liquid is maintained to achieve a continuous atomizing state.
The aperture of the atomizing nozzle 12 is 0.5-5mm. The atomizing nozzle 12 can be replaced in real time according to the requirement to prepare microspheres with different particle diameters, such as a pressure nozzle is suitable for obtaining microspheres with narrow particle diameter distribution and larger particle diameter, a parallel flow type double-fluid nozzle is suitable for preparing microspheres with smaller particle diameter, and a combined nozzle is suitable for obtaining microspheres with narrower particle diameter distribution and smaller particle diameter.
The vertical air inlet pipe 9 and the horizontal air inlet pipe 10 simultaneously feed high-pressure inert gas into the atomizer 5. The combination of the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 can maximize and crush the liquid medicine in all directions, avoid uneven stress and insufficient stress of the liquid medicine, reduce microsphere adhesion phenomenon and improve the roundness of microspheres. When the medicine is in a near-melting state, a heater switch of the control panel 7 is started to preheat the infusion tube 8, the vertical air inlet tube 9 and the horizontal air inlet tube 10, so that the problem that when the medicine flows through, a channel is blocked due to a large temperature difference to influence the atomization of the medicine is avoided.
The gas condenser 13 is connected to a gas dryer 19, the gas dryer 19 is connected to a gas storage tank 20, the gas storage tank 20 is connected to a gas compressor 21, and a low-temperature dry gas is produced and fed into the condensing chamber 14 through a low-temperature dry gas inlet pipe 15.
The cyclone separator 16 is two cyclone separators connected in series, and is respectively communicated with the coarse powder collecting tank 17 and the fine powder collecting tank 18, so that the prepared microspheres with different particle sizes are pre-screened, and the subsequent screening workload is reduced.
EXAMPLE 1 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone with 20g of PLGA (molecular weight is 10000 daltons), putting into a heating chamber 2, starting a stirrer 3, and heating to 140 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine; the viscosity of the molten liquid medicine is 275.16Pa.s
(2) Conveying the molten liquid medicine into an atomizer 5 at the speed of 1000mL/h, wherein an atomizing nozzle 12, a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 on the atomizer 5 are all preheated to 160 ℃; the molten medicine is smashed and atomized by 0.5Mpa high-pressure nitrogen entering from a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 at an atomizing nozzle 12 to form fog drops, and the atomizing time depends on the total amount of the medicine;
(3) The fog drops fall into the condensing chamber 14 due to self gravity and are quickly solidified into spherical microcrystals at the temperature of minus 20 ℃ after encountering low-temperature dry air of 0.2 Mpa; the spherical microcrystals are sent to a cyclone separation system 16, wherein spherical microcrystals with larger particle size fall into a coarse powder collection tank 17, and spherical microcrystals with smaller particle size fall into a fine powder collection tank 18; the off-white dry powder in the coarse powder collecting tank 17 is collected to obtain the progesterone sustained-release microspheres with the yield of 82.68 percent.
The scanning electron microscope image of the progesterone sustained-release microsphere is shown in figure 2, and the particle size distribution diagram is shown in figure 3. Spherical microcrystalline raman imaging is shown in fig. 4. The content uniformity was 9.01, the encapsulation efficiency was 83.09%, and the porosity was 3.34%.
EXAMPLE 2 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone with 20g of PLGA (molecular weight of 30000 daltons), putting into a heating chamber 2, starting a stirrer 3, and heating to 140 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer 5 at the speed of 1000mL/h, wherein an atomizing nozzle 12, a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 on the atomizer 5 are all preheated to 160 ℃; the molten medicine is smashed and atomized by 1Mpa high-pressure nitrogen entering from a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 at an atomizing nozzle 12 to form fog drops, and the atomizing time depends on the total amount of the medicine;
(3) The fog drops fall into the condensing chamber 14 due to self gravity and are quickly solidified into microspheres at the temperature of minus 20 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent to a cyclone separation system 16, wherein the microspheres with larger particle size fall into a coarse powder collection tank 17, and the microspheres with smaller particle size fall into a fine powder collection tank 18; collecting off-white dry powder in coarse powder collecting tank 17 to obtain progesterone sustained-release microsphere.
EXAMPLE 3 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone with 20g of PLGA (molecular weight of 50000 daltons), putting into a heating chamber 2, starting a stirrer 3, and heating to 140 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer 5 at the speed of 1000mL/h, wherein an atomizing nozzle 12, a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 on the atomizer 5 are all preheated to 160 ℃; the molten medicine is smashed and atomized by 1.5Mpa high-pressure nitrogen entering from a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 at an atomizing nozzle 12 to form fog drops, and the atomizing time depends on the total amount of the medicine;
(3) The fog drops fall into the condensing chamber 14 due to self gravity and are quickly solidified into microspheres at the temperature of minus 20 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent to a cyclone separation system 16, wherein the microspheres with larger particle size fall into a coarse powder collection tank 17, and the microspheres with smaller particle size fall into a fine powder collection tank 18; collecting off-white dry powder in coarse powder collecting tank 17 to obtain progesterone sustained-release microsphere.
EXAMPLE 4 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone and 20g of PLA (molecular weight 10000 daltons), putting into a heating chamber 2, starting a stirrer 3, and heating to 180 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer 5 at the speed of 1000mL/h, wherein an atomizing nozzle 12, a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 on the atomizer 5 are all preheated to 160 ℃; the molten medicine is smashed and atomized by 1.5Mpa high-pressure nitrogen entering from a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 at an atomizing nozzle 12 to form fog drops, and the atomizing time depends on the total amount of the medicine;
(3) The fog drops fall into the condensing chamber 14 due to self gravity and are quickly solidified into microspheres at the temperature of minus 30 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent to a cyclone separation system 16, wherein the microspheres with larger particle size fall into a coarse powder collection tank 17, and the microspheres with smaller particle size fall into a fine powder collection tank 18; collecting off-white dry powder in coarse powder collecting tank 17 to obtain progesterone sustained-release microsphere.
EXAMPLE 5 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone and 20g of PCL (molecular weight is 10000 daltons), putting into a heating chamber 2, starting a stirrer 3, and heating to 160 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer 5 at the speed of 1000mL/h, wherein an atomizing nozzle 12, a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 on the atomizer 5 are all preheated to 160 ℃; the molten medicine is smashed and atomized by 1.5Mpa high-pressure nitrogen entering from a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 at an atomizing nozzle 12 to form fog drops, and the atomizing time depends on the total amount of the medicine;
(3) The fog drops fall into the condensing chamber 14 due to self gravity and are quickly solidified into microspheres at the temperature of minus 25 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent to a cyclone separation system 16, wherein the microspheres with larger particle size fall into a coarse powder collection tank 17, and the microspheres with smaller particle size fall into a fine powder collection tank 18; collecting off-white dry powder in coarse powder collecting tank 17 to obtain progesterone sustained-release microsphere.
Test example 1 in vitro Release study of Progesterone sustained-release microspheres
Placing 10mg of progesterone sustained release microspheres prepared in examples 1-5 into a flow cell filled with 1mm glass beads at the conical part by using circulation system of flow cell method, and using phosphate buffer solution (pH 7.34) containing 0.5% Tween 80 as dissolution medium at 37deg.C and flow rate of 4ml min -1 1mL (released on-line through a 0.45 μm filter) was sampled at 1h,2h,3h,4h,6h,8h,10h,12h,24h,48h,72h,96h,120h,144h,168h,192h,240h,268 h. The results are shown in FIG. 5.
EXAMPLE 6 preparation of Progesterone sustained-release microsphere injection
The prescription of the progesterone sustained-release microsphere injection is as follows:
the preparation method of the progesterone sustained-release microsphere injection comprises the following steps:
weighing required amount of mannitol, dissolving in sterilized injectable water at 60deg.C, adding sodium carboxymethylcellulose and Tween 80, stirring at 100rpm, and sterilizing with high pressure steam for 20 min.
EXAMPLE 7 preparation of medroxyprogesterone acetate microspheres
(1) Uniformly mixing 10g of megestrol acetate and 30g of polypropylene resin, putting into a heating chamber 2, starting a stirrer 3, and heating to 210 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer 5 at the speed of 1000mL/h, wherein an atomizing nozzle 12, a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 on the atomizer 5 are all preheated to 230 ℃; the molten medicine is smashed and atomized by 0.5Mpa high-pressure nitrogen entering from a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 at an atomizing nozzle 12 to form fog drops, and the atomizing time depends on the total amount of the medicine;
(3) The fog drops fall into the condensing chamber 14 due to self gravity and are quickly solidified into microspheres at the temperature of minus 40 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent to a cyclone separation system 16, wherein the microspheres with larger particle size fall into a coarse powder collection tank 17, and the microspheres with smaller particle size fall into a fine powder collection tank 18; and collecting pale yellow dry powder in a coarse powder collecting tank 17, namely the megestrol acetate microspheres.
Test example 2
The megestrol acetate microsphere prepared in example 7 was compared to the release of commercially available product (megestrol acetate dispersible tablet, trade name of the beneficial agent) in vitro, and the results are shown in fig. 6. In vitro release assay method using a rotor blade method, dissolution medium was phosphate buffer (pH 4) containing 1.0% Tween 80, dissolution medium volume was 900mL, rotation speed was 75rpm temperature was 37℃and 5mL (release had passed through 0.45 μm filter membrane) at 5min,10min,15min,30min,1h,2h,4h,6h,8h,12h,24 h.
Example 8 preparation of Indometacin microspheres
(1) Uniformly mixing 10g of indomethacin and 20g of poloxamer 188, putting into a heating chamber 2, starting a stirrer 3, and heating to 165 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer 5 at the speed of 1150mL/h, wherein an atomizing nozzle 12, a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 on the atomizer 5 are all preheated to 180 ℃; the molten medicine is smashed and atomized by 0.6Mpa high-pressure nitrogen entering from a vertical air inlet pipe 9 and a horizontal air inlet pipe 10 at an atomizing nozzle 12 to form fog drops, and the atomizing time depends on the total amount of the medicine;
(3) The fog drops fall into the condensing chamber 14 due to self gravity and are quickly solidified into microspheres at the temperature of minus 30 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent to a cyclone separation system 16, wherein the microspheres with larger particle size fall into a coarse powder collection tank 17, and the microspheres with smaller particle size fall into a fine powder collection tank 18; collecting the white dry powder in coarse powder collecting tank 17 to obtain indometacin microsphere with bulk density of 0.47g/cm 3 。
EXAMPLE 9 preparation of Indometacin Dispersion tablets
The indomethacin dispersible tablet comprises the following components:
the preparation method of the indomethacin dispersible tablet comprises the following steps:
the indomethacin microsphere prepared in the example 8 is fully mixed with spherical microcrystalline cellulose, crosslinked povidone and methylcellulose, pressed into blocks, crushed into 40 meshes, granulated, fully mixed with magnesium stearate, and pressed into tablets under the pressure of 75N to obtain the indomethacin dispersible tablet.
Test example 3
The dissolution rate of indomethacin drug substance (commercially available from the company limited by the pharmaceutical industry of the stone medicine group) and indomethacin dispersible tablet of example 9 in phosphate buffer saline with pH of 6.8 was measured by the same particle size distribution, and the result is shown in FIG. 7.
The above description of the embodiments of the present invention is not intended to limit the present invention, and those skilled in the art can make various changes or modifications according to the present invention without departing from the spirit of the present invention, and shall fall within the scope of the claims of the present invention.
Claims (10)
1. An atomization system for preparing medicine microspheres is characterized by comprising a heating chamber 2, an atomizer 5, a condensing chamber 14 and a cyclone separator 16, wherein the heating chamber 2 is communicated with the atomizer 5 through a liquid conveying pipe 8, a vertical air inlet pipe 9, a horizontal air inlet pipe 10 and an atomizing nozzle 12 are arranged on the atomizer 5, the atomizer 5 is communicated with the condensing chamber 14 through the atomizing nozzle 12, the condensing chamber 14 is communicated with the cyclone separator 16, low-temperature drying gas is fed into the condensing chamber 14 through a low-temperature drying gas inlet pipe 15 by a gas condenser 13, the gas condenser 13 is communicated with a gas dryer 19, the gas dryer 19 is communicated with a gas storage tank 20, and the gas storage tank 20 is communicated with a gas compressor 21.
2. An atomising system according to claim 1 wherein the bottom of the heating chamber 2 is tapered.
3. The atomizing system according to any one of claims 1 to 2, wherein the atomizer 5 is preheated by any one or a combination of resistive heating, electromagnetic induction heating, arc heating, heating wire wound around the atomizer, heating jacket, and oil bath heating.
4. A system according to any one of claims 1-3, characterized in that the vertical inlet pipe 9 and the horizontal inlet pipe 10 feed high-pressure inert gas simultaneously to the atomizer 5.
5. A method for preparing pharmaceutical microspheres using an atomisation system according to any of the claims 1-4, characterized in that the method comprises in particular the steps of:
(1) Uniformly mixing the medicines or the mixture of the medicines and the carrier materials according to the ratio of 1:1-1:20, then putting the mixture into a heating chamber, and heating the mixture under the protection of inert gas at 50-200rpm to prepare molten liquid medicine;
(2) Feeding the molten liquid medicine into an atomizer preheated to a temperature 20-30deg.C higher than the melting point of the medicine at a flow rate of 1000-2000mL/h, and pulverizing into fogdrops with 0.05-5Mpa of high-pressure inert gas;
(3) And (3) sending the prepared fog drops into a condensing chamber, carrying out cold solidification to form spherical microcrystals under the action of low-temperature drying gas at the temperature of-80 ℃ to 0 ℃, and sending the spherical microcrystals into a cyclone separator for separation after drying.
6. The method according to claim 5, wherein the atomizer in step (2) comprises an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe, and the diameter of the atomizing nozzle is 0.5-5mm, preferably 0.8-3mm.
7. The method according to any one of claims 5 to 6, wherein the high pressure inert gas in step (2) is selected from any one or a combination of argon, nitrogen and helium, and the pressure of the high pressure inert gas is 0.1 to 3Mpa, preferably 0.5 to 1.5Mpa.
8. The method according to any one of claims 5-7, wherein the temperature of the low temperature drying gas in step (3) is from-50 ℃ to-20 ℃, preferably from-40 ℃ to-25 ℃.
9. A method according to any one of claims 5 to 8, wherein the drug microspheres have an average particle size of 20 μm to 250 μm, preferably 50 μm to 200 μm, more preferably 100 μm to 150 μm.
10. The method of any one of claims 5-9, wherein the pharmaceutical microspheres have a bulk density of 0.25g/cm 3 -0.86g/cm 3 Preferably 0.40g/cm 3 -0.65g/cm 3 More preferably 0.5g/cm 3 -0.6g/cm 3 。
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