An atomization system for preparing spherical drug microcrystals and application thereof

Abstract

The present application relates to a kind of atomization system for preparing pharmaceutical microspheres, including heating chamber (2), atomizer (5), condensing chamber (14), cyclone (16), heating chamber (2) is communicated with atomizer (5) by infusion tube (8), atomizer (5) is provided with vertical air inlet pipe (9), horizontal air inlet pipe (10), atomization nozzle (12), atomizer (5) is communicated with condensing chamber (14) by atomization nozzle (12), condensing chamber (14) is communicated with cyclone (16), condensing chamber (14) is communicated with gas condensing machine (13) by low-temperature drying gas inlet pipe (15).The atomization system of the present application, compared with the condensing time of traditional mode shortens, the sphericity of the microspheres prepared is improved, and the particle size range can be reduced to 0.2-0.5, and the yield is greater than 80%.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a kind of atomization system for preparing drug microspheres and application thereof. BACKGROUND

[0002] Drug microspheres are dissolved or dispersed into polymer materials to form spherical particles with a particle size of 5 μm-500 μm. After administration, the polymer material gradually degrades to release the drug, reducing the dosage, reducing drug burst, reducing or even avoiding the peak-trough phenomenon of blood drug concentration, reducing the number of medication in the treatment cycle, improving the bioavailability and patient medication compliance, and having a very broad market prospect. The drug loading, morphology, particle size and particle size distribution of drug microspheres affect the dispersion state of the drug and the degradation and porosity of the matrix material, thereby affecting the drug release.

[0003] The preparation methods of drug microspheres include emulsion solvent diffusion method, spray drying method, hot melt extrusion method and aerosol method. The emulsion solvent diffusion method has the defects of wide particle size distribution, low encapsulation efficiency and drug burst. The spray drying method has the defect of residual organic solvent affecting human health and drug safety. The hot melt extrusion method produces irregular spherical products, and has the defects of low drug loading (about 10-20%), drug burst (cumulative release rate within 1 h is about 10-40%) and residual organic reagent. The aerosolization method generates high-speed high-pressure medium flow through an atomizing nozzle, disperses the drug melt into fine droplets, and then condenses and dries the fine droplets into drug microspheres. The drug microspheres prepared by the aerosolization method have the advantages of high drug loading, uniform dispersion, high encapsulation efficiency, avoidance of the use of organic solvents, reduction of drug burst, reduction of clinical medication dosage and wide application range. However, the aerosolization method has the defects of poor condensation effect and uneven roundness of the surface of the drug microspheres. Therefore, it is urgent to develop a new atomization system to solve the above problems. SUMMARY

[0004] The present application aims to provide an atomization system for preparing drug microspheres, which comprises a heating chamber 2, an atomizer 5, a condensing chamber 14 and a cyclone separator 16. The heating chamber 2 is connected to the atomizer 5 through a liquid inlet pipe 8. The atomizer 5 is provided with a vertical air inlet pipe 9, a horizontal air inlet pipe 10 and an atomizing nozzle 12. The atomizer 5 is connected to the condensing chamber 14 through the atomizing nozzle 12. The condensing chamber 14 is connected to the cyclone separator 16. Low-temperature drying gas is sent into the condensing chamber 14 through a low-temperature drying gas inlet pipe 15 by a gas condensing machine 13. The gas condensing machine 13 is connected to a gas drying machine 19. The gas drying machine 19 is connected to a gas storage tank 20. The gas storage tank 20 is connected to a gas compressor 21.

[0005] In a preferred technical solution of the present application, the bottom of the heating chamber 2 is conical.

[0006] In the preferred technical scheme of the present application, the heating chamber 2 is provided with a stirrer 3.

[0007] In the preferred technical scheme of the present application, the heating chamber 2 is communicated with the infusion pipe 8 through a peristaltic pump 11, wherein the peristaltic pump 11 is selected from any one of a speed-regulating peristaltic pump, a flow-regulating peristaltic pump and a dispensing peristaltic pump.

[0008] In the preferred technical scheme of the present application, the heating mode of the heating chamber 2 is selected from any one of resistance heating, electromagnetic induction heating, infrared heating line, microwave heating and electric arc heating or a combination thereof.

[0009] In the preferred technical scheme of the present application, the atomizer 5 is selected from any one of a rotary atomizer, a co-current two-fluid nozzle atomizer, a fountain two-fluid nozzle atomizer, a pressure nozzle atomizer and a combined nozzle atomizer.

[0010] In the preferred technical scheme of the present application, the atomizer 5 is preheated, and the preheating mode is selected from any one of resistance heating, electromagnetic induction heating, electric arc heating, winding a heating wire around the periphery of the atomizer, a heating jacket and oil bath heating or a combination thereof.

[0011] In the preferred technical scheme of the present application, the atomizer 5 is provided with an oil inlet 4 and an oil outlet 6.

[0012] In the preferred technical scheme of the present application, the atomizing nozzle 12 has a pore diameter of 0.5-5 mm, preferably 0.8-3 mm.

[0013] In the preferred technical scheme of the present application, the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 simultaneously send high-pressure inert gas into the atomizer 5.

[0014] In the preferred technical scheme of the present application, the cyclone separator 16 is two cyclone separators connected in series and respectively communicated with a coarse powder collection tank 17 and a fine powder collection tank 18.

[0015] In the preferred technical scheme of the present application, the atomizing system is further provided with a temperature control panel 1 for setting the heating temperature of the heating chamber 2.

[0016] In the preferred technical scheme of the present application, the atomizing system is further provided with a control panel 7 for controlling the preheating device of the infusion pipe 8, the vertical air inlet pipe 9 and the horizontal air inlet pipe 10, wherein the preheating device is selected from any one of resistance heating, electromagnetic induction heating, electric arc heating and heating wire winding heating or a combination thereof.

[0017] Another object of the present application is to provide a method for preparing drug microspheres using the atomizing system.

[0018] (1) the drug or mixture of the drug and carrier material is mixed uniformly at 1:1-1:20, and then is put into a heating chamber to prepare a molten drug solution under heating and temperature rising at 50-200 rpm and inert gas protection;

[0019] (2) the molten drug solution is sent into an atomizer preheated to a temperature 20-30 DEG C higher than the melting point of the drug at a flow rate of 1000-2000 mL / h, and is broken into mist droplets by high-pressure inert gas at a pressure of 0.05-5 MPa;

[0020] (3) the prepared mist droplets are sent into a condensing chamber, and are condensed and solidified into spherical microcrystals under the action of low-temperature drying gas at-80 DEG C to 0 DEG C, and then are sent into a cyclone separator for separation to obtain the drug microcrystals.

[0021] In the preferred technical scheme of the present application, the weight ratio of the drug to the carrier material is 1:1.5-1:10, preferably 1:2-1:5.

[0022] In the preferred technical scheme of the present application, the stirring speed in step (1) is 80-120 rpm / min.

[0023] In the preferred technical scheme of the present application, the heating mode of the heating chamber in step (1) can be selected from any one or combination of resistance heating, electromagnetic induction heating, infrared heating wire, microwave heating and electric arc heating.

[0024] In the preferred technical scheme of the present application, the inert gas in step (1) is selected from any one or combination of argon, nitrogen and helium.

[0025] In the preferred technical scheme of the present application, the viscosity of the molten drug solution in step (1) is 50 Pa.s-28000 Pa.s, preferably 100 Pa.s-15000 Pa.s.

[0026] In the preferred technical scheme of the present application, the flow rate of the molten drug solution in step (2) is 1200-1800 mL / h.

[0027] In the preferred technical scheme of the present application, the preheating mode of the atomizer in step (2) is selected from any one or combination of resistance heating, electromagnetic induction heating, electric arc heating, winding heating wire and hot oil heating.

[0028] In the preferred technical scheme of the present application, the atomizer in step (2) is selected from any one of rotary atomizer, co-current double-fluid nozzle atomizer, fountain double-fluid nozzle atomizer, pressure nozzle atomizer and combined nozzle atomizer.

[0029] In the preferred technical scheme of the present application, the atomizer in step (2) comprises an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe, and the pore diameter of the atomizing nozzle is 0.5-5mm, preferably 0.8-3mm.

[0030] In the preferred technical scheme of the present application, the high-pressure inert gas in step (2) is selected from any one or combination of argon, nitrogen and helium, and the pressure of the high-pressure inert gas is 0.1-3Mpa, preferably 0.5-1.5Mpa.

[0031] In the preferred technical scheme of the present application, the low-temperature drying gas in step (3) is selected from any one or combination of nitrogen, helium, argon, neon, carbon monoxide and carbon dioxide.

[0032] In the preferred technical scheme of the present application, the temperature of the low-temperature drying gas in step (3) is-50℃ to-20℃, preferably-40℃ to-25℃.

[0033] In the preferred technical scheme of the present application, the drying in step (3) is selected from any one or combination of reduced-pressure drying and vacuum drying, and the drying temperature is 35℃-65℃, preferably 40℃-50℃.

[0034] In the preferred technical scheme of the present application, the cyclone separator in step (3) is two cyclone separators connected in series, which are connected to a coarse powder collection tank and a fine powder collection tank, respectively.

[0035] In the preferred technical scheme of the present application, 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℃-300℃.

[0036] In the preferred technical scheme of the present application, the carrier material is selected from any one or combination of a sustained-release material, a water-soluble carrier material, a poorly soluble carrier material and an enteric carrier material.

[0037] In the preferred technical scheme of the present application, the drug spherical microspheres are any one or combination of spheroidal and spherical.

[0038] In the preferred technical scheme of the present application, the average particle size of the drug microspheres is 20μm-250μm, preferably 50-200μm, and more preferably 100-150μm.

[0039] In the preferred technical scheme of the present application, the porosity of the drug microspheres is ≤10%.

[0040] In the preferred technical scheme of the present application, the bulk density of the drug microspheres 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 .

[0041] In the preferred technical solution of the present application, the drug microspheres are solid spheres, preferably dense and round solid spheres.

[0042] In the preferred technical solution of the present application, the drug is selected from any one of progesterone, megestrol acetate, indomethacin.

[0043] In the preferred technical solution of the present application, the melting point of the drug is 80-200℃.

[0044] In the preferred technical solution of the present application, the sustained-release material is any one of polyester sustained-release material, polyanhydride sustained-release material, polyamide sustained-release material or a combination thereof, preferably the polyester sustained-release material is selected from any one of polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(lactic-co-glycolic acid) (50:50), poly(lactic-co-glycolic acid) (75:25), poly(lactic-co-glycolic acid) (85:15), polyorthoester or a combination thereof, the molecular weight of the polyester sustained-release material is 10000-50000 Dalton.

[0045] In the preferred technical solution of the present application, the water-soluble carrier material is selected from any one of poloxamer, polyethylene glycol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methacrylic acid amine alkyl ester copolymer type E, polyvinyl alcohol / polyethylene glycol graft copolymer, ethylene-vinyl acetate copolymer, acrylic resin, polyoxyethylene, polyvinyl alcohol, povidone, copovidone, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, polyvinyl acetate povidone mixture or a combination thereof.

[0046] In the preferred technical solution of the present application, the water-soluble carrier material is selected from any one of poloxamer, polyethylene glycol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methacrylic acid amine alkyl ester copolymer type E, polyvinyl alcohol / polyethylene glycol graft copolymer, ethylene-vinyl acetate copolymer, acrylic resin, polyoxyethylene, polyvinyl alcohol, povidone, copovidone, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, polyvinyl acetate povidone mixture or a combination thereof.

[0047] In the preferred technical solution of the present application, the enteric carrier is selected from any one of carboxymethyl cellulose (CNEC), hydroxypropyl methyl cellulose phthalate (HPMCP), polyacrylic acid resin (Eudragit L and S) or a combination thereof.

[0048] In the preferred technical solution of the present application, the drug microspheres further comprise a plasticizer.

[0049] In the preferred technical solution of the present application, the plasticizer is selected from any one or combination 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, isomaltitol, mannitol, lactitol, erythritol, tartaric acid, fumaric acid, malic acid, maleic acid, ethanol, propylene glycol, and glycerol.

[0050] In the preferred technical solution of the present application, the weight ratio of the plasticizer to the carrier material in the drug microspheres is 1:1-1:30, preferably 1:2-1:20, and more preferably 1:3-1:10.

[0051] In the preferred technical solution of the present application, the drug microspheres further comprise a glidant.

[0052] In the preferred technical solution of the present application, the glidant is selected from any one or combination of silicon dioxide, colloidal silicon dioxide, microfine silica, magnesium aluminum silicate, red ointment, and light calcium carbonate.

[0053] In the preferred technical solution of the present application, the weight ratio of the glidant to the carrier material in the drug microspheres is 1:1-1:10, preferably 1:2-1:5.

[0054] Unless otherwise specified, the percentage referred to in the present application between liquids is a volume / volume percentage; the percentage referred to in the present application between a liquid and a solid is a volume / weight percentage; the percentage referred to in the present application between a solid and a liquid is a weight / volume percentage; and the rest is a weight / weight percentage.

[0055] Unless otherwise specified, the present application is detected by the following method:

[0056] 1. Laser diffraction method is used to detect the particle size distribution of spherical crystals: Mastersizer 2000Mu laser particle size analyzer (Malvern, UK), with water as the dispersion medium, the sample cell pump speed is set to 2200 rpm, and the analysis mode is selected as the general mode. After the light and background measurement is completed, the suspension is stirred uniformly and added into the sample injector until the light intensity is stable at 15±1%, and the particle size measurement is started.

[0057] 2. JSM-7900F hot field emission scanning electron microscope (JEOL, Japan) is used to observe the surface morphology of the sample, which is treated by sputtering, and the scanning voltage is 30kV.

[0058] 3. Raman spectrum imaging was performed by using a micro confocal laser Raman spectrometer (Renishaw, UK) with 785 nm excitation light source.

[0059] Compared with the prior art, the present application has the following beneficial technical effects:

[0060] 1. The atomization system for preparing drug microspheres of the present application preheats the atomization gun body by oil bath, reduces the temperature difference between the gun body and the drug solution, avoids the freezing and clogging of the gun body during the flow of the drug solution, and maintains the continuous atomization state of the drug solution; meanwhile, the combination of vertical air inlet and horizontal air inlet can maximize and omnidirectionally break the drug solution, avoid uneven and insufficient stress of the drug solution, and reduce the adhesion of microspheres and improve the roundness of microspheres.

[0061] 2. The atomization system of the present application is overall airtight and dry, which can quickly condense the atomized drug solution into balls, avoid the water vapor caused by heat exchange, affect the internal and surface morphology of microspheres, shorten the condensation time compared with the traditional method, improve the sphericity of the prepared microspheres, and reduce the particle size range to 0.2-0.5, with a yield of more than 80%.

[0062] 3. The atomization nozzle of the present application can be replaced in real time according to the requirements, and different spherical powders with different particle sizes can be prepared, such as pressure nozzles suitable for obtaining microspheres with narrow particle size distribution and large particle size, and flow type double fluid nozzles suitable for the preparation of microspheres with small particle size, and combined nozzles suitable for obtaining microspheres with narrow particle size distribution and small particle size, etc. The cyclone separation system can pre-screen the microspheres with different particle sizes prepared, and reduce the subsequent screening workload.

[0063] 4. The atomization system of the present application can be applied to the medical field, and can prepare drug microspheres with any surface morphology into round and spherical drug microspheres, which can achieve good needle passing property and sustained release effect, delay drug release, improve the oral bioavailability, effectiveness and safety of drugs, significantly reduce the frequency of drug administration of patients, and reduce the toxic and side effects of drugs. The operation is simple and safe, and is beneficial to realize industrialized production. BRIEF DESCRIPTION OF DRAWINGS

[0064] Figure 1 is a structure diagram of the atomization system of the present application, wherein Figure 1(a) is a main body diagram of the atomization system, which 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 delivery tube 8, a vertical air inlet tube 9, a horizontal air inlet tube 10, a peristaltic pump 11, an atomization nozzle 12, a condensation chamber 14, a low-temperature drying gas inlet tube 15, a cyclone separator 16, a coarse powder collection tank 17, and a fine powder collection tank 18; Figure 1(b) is a schematic diagram of a low-temperature drying gas generation system connected to the low-temperature drying gas inlet tube 15, which comprises a gas condensing machine 13, a gas drying machine 19, a gas storage tank 20, and a gas compressor 21.

[0065] Figure 2 Scanning electron microscope image of progesterone sustained-release microspheres;

[0066] Figure 3 Particle size distribution diagram of progesterone sustained-release microspheres;

[0067] Figure 4 Raman imaging of progesterone sustained-release microspheres;

[0068] Figure 5 Examples 1-5: Release investigation of progesterone sustained-release microspheres;

[0069] Figure 6 Example 7: In vitro release study of megestrol acetate microspheres;

[0070] Figure 7 Example 9: Dissolution study of indomethacin solid dispersible tablets. Detailed Implementation

[0071] The following specific embodiments illustrate the present invention. It should be noted that these specific embodiments are only for further explanation and do not represent a limitation on the scope of protection of the present invention. Non-essential modifications and adjustments made by others based on the present invention still fall within the scope of protection of the present invention.

[0072] The present invention provides an atomization system for preparing drug microspheres, as shown in Figure 1. It includes a heating chamber 2, an atomizer 5, a condenser 14, and a cyclone separator 16. The heating chamber 2 is connected to the atomizer 5 via an infusion pipe 8. The atomizer 5 is equipped with a vertical air inlet pipe 9, a horizontal air inlet pipe 10, and an atomizing nozzle 12. The atomizer 5 is connected to the condenser 14 via the atomizing nozzle 12. The condenser 14 is connected to the cyclone separator 16. The condenser 14 is connected to a gas condenser 13 via a low-temperature drying gas inlet pipe 15.

[0073] The bottom of the heating chamber 2 is conical. A stirrer 3 is installed in the heating chamber 2 to ensure that the drug is heated evenly during the heating process. The temperature control panel 1 is used to set the heating temperature of the heating chamber 2. The heating chamber 2 is connected to the infusion tube 8 through a peristaltic pump 11.

[0074] The atomizer 5 is provided with an oil inlet 4 and an oil outlet 6. Hot oil enters the atomizer 5 through the oil inlet 4 to preheat the atomizer. The hot oil is then discharged from the oil outlet 6, which preheats the temperature of the atomizing gun to 20-30°C higher than the melting point of the drug. This reduces the temperature difference between the gun body and the drug, prevents the drug from solidifying during the flow process, and avoids clogging the gun body, thus maintaining the continuous atomization of the drug.

[0075] The orifice diameter 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 sizes. For example, the pressure nozzle is suitable for obtaining microspheres with narrow particle size distribution and large particle size, the flow double-fluid nozzle is suitable for preparing microspheres with small particle size, the combined nozzle is suitable for obtaining microspheres with narrow particle size distribution and small particle size, etc.

[0076] The vertical gas inlet pipe 9 and the horizontal gas inlet pipe 10 simultaneously send high-pressure inert gas into the atomizer 5. The combination of the vertical gas inlet pipe 9 and the horizontal gas inlet pipe 10 can maximize and fully break the drug solution, avoid uneven stress and insufficient stress on the drug solution, reduce the adhesion of microspheres, and improve the roundness of the microspheres. When the drug is in a near-melting state, the heater switch of the control panel 7 is turned on to preheat the infusion pipe 8, the vertical gas inlet pipe 9, and the horizontal gas inlet pipe 10, so as to avoid channel blockage caused by large temperature difference when the drug flows through, and affect the atomization of the drug.

[0077] The gas condensing machine 13 is connected with the gas drying machine 19, the gas drying machine 19 is connected with the gas storage tank 20, and the gas storage tank 20 is connected with the gas compressor 21 to produce low-temperature dry gas, which is sent into the condensing chamber 14 through the low-temperature dry gas inlet pipe 15.

[0078] The cyclone separator 16 is two cyclone separators connected in series, which are respectively connected with the coarse powder collection tank 17 and the fine powder collection tank 18 to realize pre-screening of the microspheres with different particle sizes prepared, and reduce the subsequent screening workload.

[0079] Example 1: Preparation of progesterone sustained-release microspheres

[0080] (1) 10g progesterone and 20g PLGA (molecular weight 10000 Dalton) were uniformly mixed and put into the heating chamber 2, the stirrer 3 was turned on, and the temperature was raised to 140℃ under nitrogen protection at a speed of 75rpm to obtain a molten drug solution; the viscosity of the molten drug solution was 275.16Pa.s

[0081] (2) The molten drug solution was delivered into the atomizer 5 at a speed of 1000mL / h, wherein the atomizing nozzle 12, the vertical gas inlet pipe 9, and the horizontal gas inlet pipe 10 on the atomizer 5 were preheated to 160℃; the molten drug solution was broken and atomized by 0.5Mpa high-pressure nitrogen gas entering from the vertical gas inlet pipe 9 and the horizontal gas inlet pipe 10 at the atomizing nozzle 12 to form mist droplets, and the atomization time was determined according to the total amount of the drug;

[0082] (3) The mist drops fall into the condensing chamber 14 due to their own gravity, and are rapidly solidified into spherical microcrystals at -20°C after encountering 0.2 MPa low-temperature dry air; the spherical microcrystals are sent into the cyclone separation system 16, in which the spherical microcrystals with a larger particle size fall into the coarse powder collection tank 17, and the spherical microcrystals with a smaller particle size fall into the fine powder collection tank 18; the white-like dry powder collected in the coarse powder collection tank 17 is the progesterone sustained-release microspheres, and the yield is 82.68%.

[0083] The scanning electron microscope image of the progesterone sustained-release microspheres is shown in Figure 2 , and the particle size distribution diagram is shown in Figure 3 . The Raman imaging of the spherical microcrystals is shown in Figure 4 . The content uniformity is 9.01, the encapsulation rate is 83.09%, and the porosity is 3.34%.

[0084] Example 2 Preparation of progesterone sustained-release microspheres

[0085] (1) 10 g of progesterone and 20 g of PLGA (molecular weight 30000 Dalton) are uniformly mixed and put into the heating chamber 2, the stirrer 3 is turned on, and the temperature is raised to 140°C under the protection of nitrogen gas at a speed of 75 rpm to obtain a molten drug solution;

[0086] (2) The molten drug solution is delivered into the atomizer 5 at a speed of 1000 mL / h, wherein the atomizing nozzle 12, the vertical air inlet pipe 9, and the horizontal air inlet pipe 10 on the atomizer 5 are preheated to 160°C; the molten drug solution is atomized by 1 MPa high-pressure nitrogen gas entering from the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 at the atomizing nozzle 12 to form mist drops, and the atomizing time is determined according to the total amount of the drug;

[0087] (3) The mist drops fall into the condensing chamber 14 due to their own gravity, and are rapidly solidified into microspheres at -20°C after encountering low-temperature dry nitrogen gas; the microspheres are sent into the cyclone separation system 16, in which the microspheres with a larger particle size fall into the coarse powder collection tank 17, and the microspheres with a smaller particle size fall into the fine powder collection tank 18; the white-like dry powder collected in the coarse powder collection tank 17 is the progesterone sustained-release microspheres.

[0088] Example 3 Preparation of progesterone sustained-release microspheres

[0089] (1) 10 g of progesterone and 20 g of PLGA (molecular weight 50000 Dalton) are uniformly mixed and put into the heating chamber 2, the stirrer 3 is turned on, and the temperature is raised to 140°C under the protection of nitrogen gas at a speed of 75 rpm to obtain a molten drug solution;

[0090] (2) The molten drug solution is delivered into the atomizer 5 at a speed of 1000 mL / h, wherein the atomizing nozzle 12, the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 of the atomizer 5 are preheated to 160℃; the molten drug solution is broken and atomized at the atomizing nozzle 12 by 1.5 Mpa high-pressure nitrogen gas entering from the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 to form mist droplets, and the atomizing time is determined according to the total amount of the drug;

[0091] (3) The mist droplets fall into the condensing chamber 14 due to their own gravity, and rapidly solidify into microspheres at -20℃ after encountering low-temperature dry nitrogen gas; the microspheres are sent into the cyclone separation system 16, wherein the microspheres with a larger particle size fall into the coarse powder collection tank 17, and the microspheres with a smaller particle size fall into the fine powder collection tank 18; the white-like dry powder collected in the coarse powder collection tank 17 is the progesterone sustained-release microspheres.

[0092] Example 4 Preparation of progesterone sustained-release microspheres

[0093] (1) 10 g of progesterone and 20 g of PLA (molecular weight: 10000 Dalton) are uniformly mixed and put into the heating chamber 2, the stirrer 3 is turned on, and the temperature is raised to 180℃ under nitrogen protection at a stirring speed of 75 rpm to obtain a molten drug solution;

[0094] (2) The molten drug solution is delivered into the atomizer 5 at a speed of 1000 mL / h, wherein the atomizing nozzle 12, the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 of the atomizer 5 are preheated to 160℃; the molten drug solution is broken and atomized at the atomizing nozzle 12 by 1.5 Mpa high-pressure nitrogen gas entering from the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 to form mist droplets, and the atomizing time is determined according to the total amount of the drug;

[0095] (3) The mist droplets fall into the condensing chamber 14 due to their own gravity, and rapidly solidify into microspheres at -30℃ after encountering low-temperature dry nitrogen gas; the microspheres are sent into the cyclone separation system 16, wherein the microspheres with a larger particle size fall into the coarse powder collection tank 17, and the microspheres with a smaller particle size fall into the fine powder collection tank 18; the white-like dry powder collected in the coarse powder collection tank 17 is the progesterone sustained-release microspheres.

[0096] Example 5 Preparation of progesterone sustained-release microspheres

[0097] (1) 10 g of progesterone and 20 g of PCL (molecular weight: 10000 Dalton) are uniformly mixed and put into the heating chamber 2, the stirrer 3 is turned on, and the temperature is raised to 160℃ under nitrogen protection at a stirring speed of 75 rpm to obtain a molten drug solution;

[0098] (2) The molten drug solution is delivered into the atomizer 5 at a speed of 1000 mL / h, wherein the atomizing nozzle 12, the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 of the atomizer 5 are preheated to 160°C; the molten drug solution is atomized by the 1.5 MPa high-pressure nitrogen gas from the vertical air inlet pipe 9 and the horizontal air inlet pipe 10 at the atomizing nozzle 12 to form mist droplets, and the atomizing time is determined according to the total amount of the drug;

[0099] (3) The mist droplets fall into the condensing chamber 14 due to their own gravity, and are rapidly frozen into microspheres at -25°C after meeting the low-temperature dry nitrogen; the microspheres are sent into the cyclone separation system 16, wherein the microspheres with a larger particle size fall into the coarse powder collection tank 17, and the microspheres with a smaller particle size fall into the fine powder collection tank 18; the white dry powder collected in the coarse powder collection tank 17 is the progesterone sustained-release microspheres.

[0100] Test Example 1: In-vitro release rate study of progesterone sustained-release microspheres

[0101] The circulating system of the flow cell method is used, 10 mg of the progesterone sustained-release microspheres prepared in Examples 1-5 are placed in the flow cell with the conical part filled with 1 mm glass beads, 0.5% Tween 80-containing phosphate buffer (pH 7.34) is used as the dissolution medium, the temperature is 37°C, and the flow rate is 4 mL / min -1 , 1 mL of sample is taken at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 192 h, 240 h, and 268 h (the release has been on-line through a 0.45 μm filter membrane). The results are shown in Table 1. Figure 5 .

[0102] Example 6: Preparation of progesterone sustained-release microsphere injection

[0103] The prescription of the progesterone sustained-release microsphere injection is as follows:

[0104]

[0105] The preparation steps of the progesterone sustained-release microsphere injection are as follows:

[0106] The required amount of mannitol is weighed and dissolved in sterilized water for injection at a temperature of 60°C, then sodium carboxymethyl cellulose and Tween 80 are added, and the mixture is stirred at 100 rpm until it is completely dispersed, and then high-pressure steam sterilization is performed for 20 min to obtain the product.

[0107] Example 7: Preparation of medroxyprogesterone acetate microspheres

[0108] (1) 10 g of medroxyprogesterone acetate and 30 g of polypropylene resin are uniformly mixed and put into the heating chamber 2, the stirrer 3 is turned on, and the temperature is raised to 210°C under the protection of nitrogen gas at a stirring speed of 75 rpm to obtain a molten drug solution;

[0109] (2) The molten drug solution is delivered into the atomizer 5 at a speed of 1000 mL / h, wherein the atomizing nozzle 12, the vertical inlet tube 9 and the horizontal inlet tube 10 of the atomizer 5 are preheated to 230°C; the molten drug solution is atomized at the atomizing nozzle 12 by the 0.5 MPa high-pressure nitrogen gas from the vertical inlet tube 9 and the horizontal inlet tube 10 to form mist droplets, and the atomizing time is determined according to the total amount of the drug;

[0110] (3) The mist droplets fall into the condensing chamber 14 due to their own gravity, and rapidly solidify into microspheres at -40°C after encountering the low-temperature dry nitrogen gas; the microspheres are sent into the cyclone separation system 16, wherein the microspheres with a larger particle size fall into the coarse powder collection tank 17, and the microspheres with a smaller particle size fall into the fine powder collection tank 18; the light yellow dry powder collected in the coarse powder collection tank 17 is the megestrol acetate microspheres.

[0111] Test Example 2

[0112] The megestrol acetate microspheres prepared in Example 7 are compared with the marketed product (megestrol acetate dispersible tablets, trade name Yilizhi) in terms of in vitro release, and the results are shown in Table 2. Figure 6 The in vitro release determination method adopts the paddle method, the dissolution medium is 1.0% Tween 80-containing phosphate buffer (pH 4), the volume of the dissolution medium is 900 mL, the rotation speed is 75 rpm, the temperature is 37°C, and 5 mL of the sample (the release has passed through a 0.45 μm filter) is taken at 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h.

[0113] Preparation of indomethacin microspheres

[0114] (1) 10 g of indomethacin is uniformly mixed with 20 g of poloxamer 188 and put into the heating chamber 2, the stirrer 3 is turned on, the rotation speed is 75 rpm, and the temperature is increased to 165°C under the protection of nitrogen to obtain a molten drug solution;

[0115] (2) The molten drug solution is delivered into the atomizer 5 at a speed of 1150 mL / h, wherein the atomizing nozzle 12, the vertical inlet tube 9 and the horizontal inlet tube 10 of the atomizer 5 are preheated to 180°C; the molten drug solution is atomized at the atomizing nozzle 12 by the 0.6 MPa high-pressure nitrogen gas from the vertical inlet tube 9 and the horizontal inlet tube 10 to form mist droplets, and the atomizing time is determined according to the total amount of the drug;

[0116] (3) Due to their own gravity, the droplets fall into the condensation chamber 14, where they rapidly solidify into microspheres at -30°C upon encountering low-temperature dry nitrogen gas. The microspheres are then fed into the cyclone separation system 16, where larger microspheres fall into the coarse powder collection tank 17, and smaller microspheres fall into the fine powder collection tank 18. The white dry powder collected in the coarse powder collection tank 17 is indomethacin microspheres with a bulk density of 0.47 g / cm³. 3 .

[0117] Example 9: Preparation of Indomethacin Dispersible Tablets

[0118] The formula for indomethacin dispersible tablets is as follows:

[0119]

[0120] The preparation method of indomethacin dispersible tablets includes the following steps:

[0121] The indomethacin microspheres prepared in Example 8 were thoroughly mixed with spherical microcrystalline cellulose, cross-linked polyvinyl ketone, and methylcellulose, compressed into blocks, pulverized to 40 mesh, granulated, and then magnesium stearate was added and thoroughly mixed. The mixture was then compressed into tablets under a pressure of 75 N to obtain indomethacin dispersible tablets.

[0122] Experimental Example 3

[0123] Dissolution rates of indomethacin raw material (commercially purchased from CSPC Pharmaceutical Group Ouyi Pharmaceutical Co., Ltd.) and indomethacin dispersible tablets from Example 9 with the same particle size distribution were determined in a phosphate buffer solution at pH 6.8. The results are shown below. Figure 7 .

[0124] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing progesterone sustained-release microspheres containing a carrier material using an atomization system, characterized in that, The sustained-release microspheres are made of progesterone and carrier material in a weight ratio of 1:2 to 1:

5. The carrier material is selected from any one or a combination of polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), and polycaprolactone (PCL) with a molecular weight of 10,000-50,000 Daltons. The microspheres are selected from either spherical or near-spherical shapes, and are dense, round, solid spheres with an average particle size of 20 μm-100 μm, a porosity ≤10%, and a bulk density of 0.25 g / cm³. 3 -0.86g / cm 3 , The atomization system includes a heating chamber (2), an atomizer (5), a condenser (14), and a cyclone separator (16). The heating chamber (2) is connected to the atomizer (5) through a liquid inlet pipe (8). The atomizer (5) is equipped with a vertical air inlet pipe (9), a horizontal air inlet pipe (10), and an atomizing nozzle (12). The atomizer (5) is connected to the condenser (14) through the atomizing nozzle (12). The condenser (14) is connected to the cyclone separator (16). Low-temperature dry gas is sent into the condenser (14) by a gas condenser (13) through an air inlet pipe (15). 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). The method specifically includes the following steps: (1) After the mixture of drug and carrier material is mixed evenly, it is put into the heating chamber and heated at 50-200 rpm under inert gas protection to obtain molten drug solution; (2) The molten drug solution is fed into the nebulizer, which is preheated to a temperature 20-30°C higher than the melting point of the drug, at a flow rate of 1000-2000 mL / h. The solution is then broken into droplets by high-pressure inert gas at a pressure of 0.5-1.5 MPa. High-pressure inert gas is simultaneously introduced into the nebulizer (5) through the vertical air inlet pipe (9) and the horizontal air inlet pipe (10). (3) The prepared droplets are sent into the condensation chamber and solidified into spherical microcrystals under the action of low temperature dry gas at -50℃ to -20℃. After drying, they are sent into a cyclone separator for separation to obtain the final product.

2. The method as described in claim 1, wherein the bottom of the heating chamber (2) is conical.

3. The method as described in claim 1, wherein a stirrer (3) is provided in the heating chamber (2).

4. The method as described in claim 1, wherein the heating chamber (2) is connected to the infusion tube (8) via a peristaltic pump (11), wherein, The peristaltic pump (11) is selected from any one of the following: speed-regulating peristaltic pump, flow-type peristaltic pump, and distribution type peristaltic pump.

5. The method as described in claim 1, wherein the heating method of the heating chamber (2) is selected from any one or a combination of resistance heating, electromagnetic induction heating, infrared heating wire, microwave heating, and electric arc heating.

6. The method as described in claim 1, wherein the atomizer (5) is selected from any one of a rotary atomizer, a parallel flow dual-fluid nozzle atomizer, a fountain-type dual-fluid nozzle atomizer, a pressure nozzle atomizer, and a combined nozzle atomizer.

7. The method as described in claim 1, wherein the atomizer (5) is preheated first, and the preheating method is selected from any one or a combination of resistance heating, electromagnetic induction heating, electric arc heating, heating wire wound around the atomizer, heating sleeve, and oil bath heating.

8. The method as described in claim 1, wherein the atomizer (5) is provided with an oil inlet (4) and an oil outlet (6).

9. The method as described in claim 1, wherein the aperture of the atomizing nozzle (12) is 0.5-5 mm.

10. The method of claim 9, wherein the aperture of the atomizing nozzle (12) is 0.8-3 mm.

11. The method as described in claim 1, wherein the cyclone separator (16) is two cyclone separators connected in series, respectively connected to the coarse powder collection tank (17) and the fine powder collection tank (18).

12. The method as described in claim 1, wherein the atomization system is further provided with a temperature control panel (1) for setting the heating temperature of the heating chamber (2).

13. The method as described in claim 1, wherein the atomization system is further provided with a control panel (7) for controlling the preheating devices of the infusion tube (8), the vertical air inlet tube (9), and the horizontal air inlet tube (10), wherein the preheating device is selected from any one or a combination of resistance heating, electromagnetic induction heating, electric arc heating, and heating wire winding heating.

14. The method according to any one of claims 1-13, wherein the stirring speed in step (1) is 80-120 rpm.

15. The method according to any one of claims 1-13, wherein the inert gas in step (1) is selected from any one or a combination of argon, nitrogen, and helium.

16. The method according to any one of claims 1-13, wherein the flow rate of the molten drug solution in step (2) is 1200-1800 mL / h.

17. The method according to any one of claims 1-13, characterized in that, The low-temperature drying gas in step (3) can be any one or a combination of nitrogen, helium, argon, neon, carbon monoxide, and carbon dioxide.

18. The method according to any one of claims 1-13, wherein the temperature of the low-temperature drying gas in step (3) is -40°C to -25°C.

19. The method according to any one of claims 1-13, wherein the drying in step (3) is selected from any one or a combination of reduced pressure drying and vacuum drying, and the drying temperature is 35℃-65℃.

20. The method as described in claim 19, wherein the drying temperature in step (3) is 40°C-50°C.

21. The method according to any one of claims 1-13, wherein the bulk density of the microspheres is 0.40 g / cm³. 3 -0.65g / cm 3 .

22. The method of claim 21, wherein the packing density of the microspheres is 0.5 g / cm³. 3 -0.6g / cm 3 .

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