Preparation and application of a novel drug microsphere containing a carrier material

Abstract

This invention relates to a drug microsphere containing a carrier material. The weight ratio of drug to carrier material in the drug microsphere is 1:1 to 1:20. The drug is selected from any one of the following: poorly soluble drugs, slightly soluble drugs, soluble drugs, and readily soluble drugs with a melting point of 60℃ to 300℃. The carrier material is selected from any one or a combination of sustained-release materials, water-soluble carrier materials, poorly soluble carrier materials, and enteric-coated carrier materials. The drug microspheres are spherical, near-spherical, or a combination thereof. The average particle size of the drug microspheres is 20μm to 250μm, the porosity of the drug microspheres is ≤10%, and the bulk density of the drug microspheres is 0.25g / cm³. 3 -0.86g / cm 3 The drug microspheres of this invention have uniform particle size distribution, high drug loading capacity, high encapsulation efficiency (≥80%), smooth and stable release curve, and high bioavailability. They reduce drug burst release, which is beneficial for reducing drug dosage and avoiding organic solvent residue. Furthermore, they exhibit controllable dissolution, which can improve the solubility and bioavailability of poorly soluble drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to a drug microsphere containing a carrier material, its preparation method, and its application. Background Technology

[0002] Drug microspheres are spheres with a particle size of 5μm-500μm formed by dissolving or dispersing drugs in polymer materials. After drug administration, the polymer material gradually degrades to release the drug, reducing the dosage, reducing drug burst release, reducing or even avoiding peak and trough phenomena in blood drug concentration, reducing the number of dosing cycles, improving bioavailability and patient compliance, and thus having a very broad market prospect.

[0003] The drug loading, morphology, particle size, and particle size distribution of drug microspheres affect the drug dispersion and the degradation and porosity of the matrix material, thus influencing drug release. Microsphere preparation methods include emulsion solvent diffusion, spray drying, and hot-melt extrusion. Emulsion solvent diffusion suffers from drawbacks such as wide particle size distribution, low encapsulation efficiency, and burst release. Spray drying leaves organic solvent residues, affecting human health and drug safety. Hot-melt extrusion produces products that are mostly irregular spherical and have drawbacks such as low drug loading (approximately 10-20%), burst release (cumulative release rate of approximately 10-40% within 1 hour), and organic reagent residues. Therefore, there is a need to research drug microspheres with higher drug loading, more uniform particle size, no organic reagent residues, and reduced burst release, as well as their preparation methods. Summary of the Invention

[0004] The purpose of this invention is to provide a drug microsphere containing a carrier material, wherein the weight ratio of drug to carrier material in the drug microsphere is 1:1 to 1:20. The drug is selected from any one of poorly soluble drugs, slightly soluble drugs, soluble drugs, and readily soluble drugs with a melting point of 60℃-300℃. The carrier material is selected from any one or a combination of sustained-release materials, water-soluble carrier materials, poorly soluble carrier materials, and enteric carrier materials. The drug microsphere is any one or a combination of spherical or near-spherical shapes. The average particle size of the drug microsphere is 20μm-250μm.

[0005] In a preferred embodiment of the present invention, the porosity of the drug microspheres is ≤10%.

[0006] In a preferred embodiment of the present invention, the bulk density of the drug microspheres is 0.25 g / cm³. 3 -0.86g / cm 3 The preferred value is 0.40 g / cm³. 3 -0.65g / cm 3 More preferably 0.5 g / cm³ 3 -0.6g / cm 3 .

[0007] In a preferred embodiment of the present invention, the average particle size of the drug microspheres is 50-200 μm, preferably 100-150 μm.

[0008] In a preferred embodiment of the present invention, the drug microspheres are solid spheres, preferably dense and round solid spheres.

[0009] In a preferred embodiment of the present invention, the weight ratio of drug to carrier material in the drug microspheres is 1:1.5-1:10, preferably 1:2-1:5.

[0010] In a preferred embodiment of the present invention, the drug is selected from any one of progesterone, megestrol acetate, and indomethacin.

[0011] In a preferred embodiment of the present invention, the melting point of the drug is 80℃-200℃.

[0012] In a preferred embodiment of the present invention, the sustained-release material is any one or a combination of polyester sustained-release materials, polyanhydride sustained-release materials, and polyamide sustained-release materials. Preferably, the polyester sustained-release material is selected from any one or a 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 polyorthoesters with a molecular weight of 5,000-100,000 Daltons. The molecular weight of the polyester sustained-release material is 10,000-50,000 Daltons.

[0013] In a preferred embodiment of the present invention, the water-soluble carrier material is selected from any one or a combination of poloxamer, polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, aminoalkyl methacrylate copolymer E type, polyvinyl alcohol / polyethylene glycol graft copolymer, ethylene-vinyl acetate copolymer, acrylic resin, polyoxyethylene, polyvinyl alcohol, povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, dimethylamine methacrylate-butyl methacrylate-methyl methacrylate copolymer, and polyvinyl acetate-povidone mixture.

[0014] In a preferred embodiment of the present invention, the poorly soluble carrier material is selected from any one or a combination of ethyl cellulose (EC), quaternary ammonium-containing polyacrylic acid resin Eudragit, and polymethyl methacrylate resin.

[0015] In a preferred embodiment of the present invention, the enteric carrier is selected from any one or a combination of carboxymethyl cellulose (CNEC), hydroxypropyl methyl cellulose phthalate (HPMCP), and polyacrylic acid resins (Eudragit L and S).

[0016] In a preferred embodiment of the present invention, the drug microspheres optionally further include a plasticizer.

[0017] In a preferred embodiment of the present invention, the plasticizer is selected from any one or a 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 lauryl 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 glycerin.

[0018] In a preferred embodiment of the present invention, the weight ratio of plasticizer to carrier material in the drug microspheres is 1:1-1:30, preferably 1:2-1:20, and more preferably 1:3-1:10.

[0019] In a preferred embodiment of the present invention, the drug microspheres optionally further include a flow aid.

[0020] In a preferred embodiment of the present invention, the flow aid is selected from any one or a combination of silica, colloidal silica, micronized silica gel, magnesium aluminum silicate, red ochre, and light calcium carbonate.

[0021] In a preferred embodiment of the present invention, the weight ratio of the flow aid to the carrier material in the drug microspheres is 1:1-1:10, preferably 1:2-1:5.

[0022] In a preferred embodiment of the present invention, the drug microspheres optionally further include an antioxidant.

[0023] In a preferred embodiment of the present invention, the antioxidant is selected from any one or a combination of sodium bisulfite, tert-butyl-p-cresol, sodium metabisulfite, vitamin E, disodium ethylenediaminetetraacetate, vitamin C, and glutathione.

[0024] In a preferred embodiment of the present invention, the weight ratio of antioxidant to carrier material in the drug microspheres is 1:1-1:10, preferably 1:2-1:5.

[0025] Another object of the present invention is to provide a method for preparing drug microspheres, wherein the weight ratio of drug to carrier material in the drug microspheres is 1:1 to 1:20, the drug is selected from any one of poorly soluble drugs, slightly soluble drugs, soluble drugs, and readily soluble drugs with a melting point of 60℃-300℃, the carrier material is selected from any one or a combination of sustained-release materials, water-soluble carrier materials, poorly soluble carrier materials, and enteric-coated carrier materials, the drug microspheres are any one or a combination of spherical or near-spherical shapes, and the average particle size of the drug microspheres is 20μm-250μm. The specific preparation method includes the following steps:

[0026] (1) Mix the drug and carrier material evenly at a ratio of 1:1 to 1:20 and then put them into the heating chamber. Heat the mixture at 50-200 rpm under inert gas protection to obtain a molten drug solution.

[0027] (2) The molten drug solution is fed into an atomizer that has been preheated to a temperature 20-30°C higher than the melting point of the drug at a flow rate of 1000-2000 mL / h, and is broken into droplets by high-pressure inert gas at a pressure of 0.05-5 MPa.

[0028] (3) The prepared droplets are sent into the condensation chamber and solidified into microspheres under the action of low temperature dry gas from -80℃ to 0℃. After drying, they are sent into a cyclone separator for separation to obtain the product.

[0029] In a preferred embodiment of the present invention, the weight ratio of the drug to the carrier material is 1:1.5-1:10, preferably 1:2-1:5.

[0030] In a preferred embodiment of the present invention, the stirring speed in step (1) is 80-120 rpm / min.

[0031] In a preferred embodiment of the present invention, the heating method of the heating chamber in step (1) can be selected from any one or a combination of resistance heating, electromagnetic induction heating, infrared heating, microwave heating, and electric arc heating.

[0032] In a preferred embodiment of the present invention, the inert gas in step (1) is selected from any one or a combination of argon, nitrogen, and helium.

[0033] In a preferred embodiment of the present invention, the viscosity of the molten liquid in step (1) is 50 Pa·s-28000 Pa·s, preferably 100 Pa·s-15000 Pa·s.

[0034] In a preferred embodiment of the present invention, the flow rate of the molten liquid in step (2) is 1200-1800 mL / h.

[0035] In a preferred embodiment of the present invention, the preheating method of the atomizer in step (2) is selected from any one or a combination of resistance heating, electromagnetic induction heating, electric arc heating, winding heating wire, and hot oil heating.

[0036] In a preferred embodiment of the present invention, the atomizer in step (2) 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.

[0037] In a preferred embodiment of the present invention, the atomizer in step (2) includes an atomizing nozzle, a vertical air inlet pipe, and a horizontal air inlet pipe. The aperture of the atomizing nozzle is 0.5-5mm, preferably 0.8-3mm.

[0038] In the preferred embodiment of the present invention, 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 0.1-3 MPa, preferably 0.5-1.5 MPa.

[0039] In a preferred embodiment of the present invention, the low-temperature drying gas in step (3) may be selected from any one or a combination of nitrogen, helium, argon, neon, carbon monoxide, and carbon dioxide.

[0040] In a preferred embodiment of the present invention, the temperature of the low-temperature drying gas in step (3) is -50°C to -20°C, preferably -40°C to -25°C.

[0041] In the preferred embodiment of the present invention, 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℃, preferably 40℃-50℃.

[0042] In a preferred embodiment of the present invention, the cyclone separator in step (3) consists of two cyclone separators connected in series, which are respectively connected to the coarse powder collection tank and the fine powder collection tank.

[0043] Another object of the present invention is to provide a pharmaceutical microsphere formulation comprising pharmaceutical microspheres containing the carrier material described in the present invention and a pharmaceutically acceptable carrier.

[0044] In a preferred embodiment of the present invention, the dosage form is selected from any one of injection, tablet, capsule, pill, granule, or patch.

[0045] In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or a combination of surfactants, suspending agents, isotonic agents, preservatives, fillers, disintegrants, binders, lubricants, and flavoring agents.

[0046] Another object of the present invention is to provide a progesterone sustained-release microsphere injection, wherein the progesterone sustained-release microsphere injection comprises progesterone sustained-release microspheres with a particle size of 20-100 μm and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is any one or a combination of an osmotic pressure regulator, a stabilizer, a pH regulator, and a solvent.

[0047] In a preferred embodiment of the present invention, the particle size of the progesterone sustained-release microspheres is 20-100 μm, preferably 50-200 μm, and more preferably 100-150 μm.

[0048] In a preferred embodiment of the present invention, the porosity of the progesterone microspheres is ≤10%.

[0049] In a preferred embodiment of the present invention, the bulk density of the progesterone microspheres is 0.25 g / cm³. 3 -0.86g / cm 3 The preferred value is 0.40 g / cm³. 3 -0.65g / cm 3 More preferably 0.5 g / cm³ 3 -0.6g / cm 3 .

[0050] In a preferred embodiment of the present invention, the progesterone sustained-release microspheres are solid spheres, preferably dense and round solid spheres.

[0051] In a preferred embodiment of the present invention, the progesterone sustained-release microspheres are progesterone sustained-release microspheres containing sustained-release materials.

[0052] In a preferred embodiment of the present invention, the sustained-release material is polylactic acid (PLA), polyglycolic acid (PGA), or polylactic-glycolic acid copolymer (PLGA) with a peak molecular weight of 5,000-100,000 Daltons, preferably 10,000-50,000 Daltons. Preferably, the polylactic acid and its copolymers are any one or a combination of polylactic-glycolic acid copolymer (50:50), polylactic-glycolic acid copolymer (75:25), and polylactic-glycolic acid copolymer (85:15).

[0053] In a preferred embodiment of the present invention, the content of progesterone microspheres in the injection is 1%-10% (w / v), preferably 2%-8% (w / v).

[0054] In a preferred embodiment of the present invention, the solvent content in the injection is 60%-95% (w / w), preferably 70%-90% (w / w).

[0055] In a preferred embodiment of the present invention, the solvent is selected from any one or a combination of water, glycerol, propylene glycol, ethanol, and ethyl acetate.

[0056] In a preferred embodiment of the present invention, the content of the osmotic pressure regulator in the injection is 0.05%-10% (w / v), preferably 0.1%-6% (w / v).

[0057] In a preferred embodiment of the present invention, the osmotic pressure regulator is selected from any one or a combination of sodium chloride, glucose, mannitol, trehalose, and sucrose.

[0058] In a preferred embodiment of the present invention, the stabilizer content in the injection is 0.01%-5% (w / v), preferably 0.02-2% (w / v).

[0059] In a preferred embodiment of the present invention, the stabilizer is selected from any one or a combination of sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, glycerin, gum arabic, polysorbate 20, polysorbate 80, and poloxamer.

[0060] In a preferred embodiment of the present invention, the content of pH adjuster in the injection is 0.05%-5% (w / v), preferably 0.1%-2% (w / v).

[0061] In a preferred embodiment of the present invention, the pH adjuster is selected from any one or a combination of citric acid, lactic acid, acetic acid, adipic acid, sodium hydroxide, potassium carbonate, sodium citrate, potassium citrate, and sodium citrate.

[0062] In a preferred embodiment of the present invention, the contents of progesterone microspheres in the injection are 1-10% (w / w), sodium carboxymethyl cellulose 0.01-5% (w / w), mannitol 0.05-10% (w / w), polysorbate 20 0.01-5%, and water for injection 60%-95% (w / w).

[0063] In a preferred embodiment of the present invention, the contents of the injection are 2-8% (w / w) progesterone microspheres, 0.02-2% (w / w) sodium carboxymethyl cellulose, 0.1-6% (w / w) mannitol, 0.02-2% polysorbate 20, and 70%-90% (w / w) water for injection.

[0064] Another object of the present invention is to protect an indomethacin solid dispersion tablet, wherein the dispersion tablet is obtained by mixing, granulating, drying and compressing indomethacin microspheres with a particle size of 20-250 μm with a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is any one or a combination of fillers, binders, lubricants and disintegrants.

[0065] In a preferred embodiment of the present invention, the content of the indomethacin microspheres in the dispersion is 50-80% (w / w), preferably 60-70% (w / w).

[0066] In a preferred embodiment of the present invention, the particle size of the indomethacin microspheres is 50-200 μm, preferably 100-150 μm.

[0067] In a preferred embodiment of the present invention, the indomethacin microspheres are solid spheres, preferably dense and round solid spheres.

[0068] In a preferred embodiment of the present invention, the porosity of the indomethacin microspheres is ≤10%.

[0069] In a preferred embodiment of the present invention, the bulk density of the indomethacin microspheres is 0.25 g / cm³. 3 -0.86g / cm 3 The preferred value is 0.40 g / cm³. 3 -0.65g / cm 3 More preferably 0.5 g / cm³ 3 -0.6g / cm 3 .

[0070] In a preferred embodiment of the present invention, the indomethacin microspheres are microspheres containing a carrier material.

[0071] In a preferred embodiment of the present invention, the carrier material is any one or a combination of poloxamer, polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, aminoalkyl methacrylate copolymer E type, polyvinyl alcohol / polyethylene glycol graft copolymer, ethylene-vinyl acetate copolymer, acrylic resin, polyoxyethylene, polyvinyl alcohol, povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, dimethylamine ethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, and polyvinyl acetate-povidone mixture.

[0072] In a preferred embodiment of the present invention, the filler content in the dispersible tablet is 10%-50% (w / w), preferably 20%-40% (w / w).

[0073] In a preferred embodiment of the present invention, the filler is selected from any one or a combination of starch, pregelatinized starch, microcrystalline cellulose, sucrose, dextrin, sorbitol, mannitol, and maltitol.

[0074] In a preferred embodiment of the present invention, the binder content in the dispersion sheet is 1%-10% (w / w), preferably 2%-5% (w / w).

[0075] In a preferred embodiment of the present invention, the adhesive is selected from any one or a combination of starch paste, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, pregelatinized starch, povidone, hydroxypropyl methylcellulose, ethylcellulose, polyethylene glycol, gelatin, and sodium alginate.

[0076] In a preferred embodiment of the present invention, the disintegrant content in the dispersible tablet is 1%-10% (w / w), preferably 2%-5% (w / w).

[0077] In a preferred embodiment of the present invention, the disintegrant is selected from any one or a combination of sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, and calcium carboxymethyl cellulose.

[0078] In a preferred embodiment of the present invention, the lubricant content in the dispersion tablet is 0.1%-10% (w / w), preferably 0.5%-5% (w / w).

[0079] In a preferred embodiment of the present invention, the lubricant is selected from one or more of magnesium stearate, silicon dioxide, and talc, or a combination thereof.

[0080] In a preferred embodiment of the present invention, the dispersible tablet contains 50-80% (w / w) indomethacin microspheres, 10-50% (w / w) microcrystalline cellulose, 1%-10% (w / w) crospovidone, 0.1-10% magnesium stearate, and 1%-10% (w / w) methylcellulose.

[0081] In a preferred embodiment of the present invention, the dispersible tablet contains 60-70% (w / w) indomethacin microspheres, 20-40% (w / w) microcrystalline cellulose, 2%-5% (w / w) crospovidone, 0.5-5% magnesium stearate, and 2%-5% (w / w) methylcellulose.

[0082] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; the remainder is weight / weight percentage.

[0083] Unless otherwise stated, the present invention uses the following method for detection:

[0084] 1. Particle size distribution of spherical crystals was determined using laser diffraction: A Mastersizer 2000Mu laser particle size analyzer (Malvern, UK) was used, with water as the dispersion medium. The sample cell pump speed was set to 2200 rpm, and the analysis mode was set to general mode. After the light and background measurements were completed, the suspension was stirred thoroughly and added to the sample injector. The light occlusion was stabilized at 15±1% before particle size measurement began.

[0085] 2. The surface morphology of the sample was observed using a JSM-7900F thermal field emission scanning electron microscope (JEOL Corporation, Japan). The sample was treated with gold sputtering, and the scanning voltage was 30kV.

[0086] 3. Raman spectroscopy imaging was performed using a microconfocal laser Raman spectrometer (Renishaw, UK), with a 785nm excitation source selected for imaging.

[0087] Compared with the prior art, the present invention has the following beneficial effects:

[0088] 1. The drug microspheres of the present invention have uniform particle size distribution, large drug loading capacity, high encapsulation efficiency (≥80%), smooth and stable release curve, and high bioavailability, reducing drug burst release, which is beneficial for reducing drug dosage and avoiding organic solvent residue. Furthermore, they have controllable dissolution, which can improve the solubility and bioavailability of poorly soluble drugs.

[0089] 2. The preparation method of the drug microspheres of the present invention does not require wet grinding, and produces spheres with regular shapes. The release can be controlled by controlling the particle size range and the drug loading. It has the characteristics of simple operation, lower cost, and suitability for industrial production.

[0090] 3. The atomization method of the drug microspheres of the present invention is a completely sealed and dry process, which allows the atomized drug liquid to condense into spheres quickly, avoiding water vapor caused by heat exchange that affects the internal and surface morphology of the microspheres. Compared with the traditional method, 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, the yield is greater than 80%, and the roundness of the microspheres is improved. Attached Figure Description

[0091] Figure 1 Scanning electron microscope image of progesterone sustained-release microspheres;

[0092] Figure 2 Particle size distribution diagram of progesterone sustained-release microspheres;

[0093] Figure 3 Raman imaging of progesterone sustained-release microspheres;

[0094] Figure 4 Examples 1-5: Release investigation of progesterone sustained-release microspheres;

[0095] Figure 5Example 7: In vitro release study of megestrol acetate microspheres;

[0096] Figure 6 Example 9: Dissolution study of indomethacin solid dispersible tablets. Detailed Implementation

[0097] The present invention will be further described in detail below with reference to specific embodiments. These embodiments are only used to illustrate the present invention and do not limit the scope of the present invention in any way.

[0098] Experimental material PLGA (polylactic acid-glycolic acid copolymer): the molar ratio of lactic acid to glycolic acid was 75:25, and it was purchased from Shandong Daigang Biotechnology Co., Ltd.

[0099] PCL (polycaprolactone) and PLA (polylactic acid) were purchased from Shandong Daigang Biotechnology Co., Ltd. Polypropylene resin (Eudragit RS PO) was purchased from Ashland, and poloxamer 188 was purchased from BASF (China) Company Ltd.

[0100] Example 1: Preparation of progesterone sustained-release microspheres

[0101] (1) Mix 10g of progesterone with 20g of PLGA (molecular weight of 10000 Daltons) evenly and put it into the heating chamber. Turn on the stirrer and heat it to 140°C at 75 rpm under nitrogen protection to obtain a molten drug solution; the viscosity of the molten drug solution is 275.16 Pa·s.

[0102] (2) The molten drug solution is delivered into the nebulizer 5 at a rate of 1000 mL / h. The nebulizer nozzle, vertical air inlet pipe and horizontal air inlet pipe are all preheated to 160°C. The molten drug solution is atomized by 0.5 MPa high-pressure nitrogen gas entering from the vertical air inlet pipe and horizontal air inlet pipe at the nebulizer nozzle to form droplets. The atomization time depends on the total amount of drug.

[0103] (3) Due to their own gravity, the droplets fall into the condensation chamber and, upon encountering low-temperature dry nitrogen, rapidly solidify into microspheres at -20°C. The microspheres are then sent to the cyclone separation system, where the larger microspheres fall into the coarse powder collection tank and the smaller microspheres fall into the fine powder collection tank. The off-white dry powder collected in the coarse powder collection tank is the progesterone sustained-release microsphere.

[0104] Scanning electron microscopy image of progesterone sustained-release microspheres is shown below. Figure 1 See particle size distribution diagram. Figure 2 Microsphere Raman imaging is shown in [reference needed]. Figure 3 The content uniformity was 9.01, the encapsulation efficiency was 83.09%, and the porosity was 3.34%.

[0105] Example 2 Preparation of progesterone sustained-release microspheres

[0106] (1) Mix 10g progesterone with 20g PLGA (molecular weight of 30,000 Daltons) evenly and put it into the heating chamber. Turn on the stirrer and heat it to 140°C at 75 rpm under nitrogen protection to obtain a molten drug solution.

[0107] (2) The molten drug solution is delivered into the nebulizer at a rate of 1000 mL / h. The nebulizer nozzle, vertical air inlet pipe and horizontal air inlet pipe are all preheated to 160°C. The molten drug solution is atomized by 1 MPa high-pressure nitrogen gas entering from the vertical air inlet pipe and horizontal air inlet pipe at the nebulizer nozzle to form droplets. The atomization time depends on the total amount of drug.

[0108] (3) Due to their own gravity, the droplets fall into the condensation chamber and, upon encountering low-temperature dry nitrogen, rapidly solidify into microspheres at -20°C. The microspheres are then sent to the cyclone separation system, where the larger microspheres fall into the coarse powder collection tank and the smaller microspheres fall into the fine powder collection tank. The off-white dry powder collected in the coarse powder collection tank is the progesterone sustained-release microsphere.

[0109] Example 3 Preparation of progesterone sustained-release microspheres

[0110] (1) Mix 10g progesterone with 20g PLGA (molecular weight of 50,000 Daltons) evenly and put it into the heating chamber. Turn on the stirrer and heat it to 140°C at 75 rpm under nitrogen protection to obtain a molten drug solution.

[0111] (2) The molten drug solution is delivered into the nebulizer at a rate of 1000 mL / h. The nebulizer nozzle, vertical air inlet pipe and horizontal air inlet pipe are all preheated to 160°C. The molten drug solution is atomized by 1.5 MPa high-pressure nitrogen gas entering from the vertical air inlet pipe and horizontal air inlet pipe at the nebulizer nozzle to form droplets. The atomization time depends on the total amount of drug.

[0112] (3) Due to their own gravity, the droplets fall into the condensation chamber and, upon encountering low-temperature dry nitrogen, rapidly solidify into microspheres at -20°C. The microspheres are then sent to the cyclone separation system, where the larger microspheres fall into the coarse powder collection tank and the smaller microspheres fall into the fine powder collection tank. The off-white dry powder collected in the coarse powder collection tank is the progesterone sustained-release microsphere.

[0113] Example 4: Preparation of progesterone sustained-release microspheres

[0114] (1) Mix 10g of progesterone with 20g of PLA (molecular weight of 10000 Daltons) evenly and put it into the heating chamber. Turn on the stirrer and heat it to 180°C at 75 rpm under nitrogen protection to obtain a molten drug solution.

[0115] (2) The molten drug solution is delivered into the nebulizer at a rate of 1000 mL / h. The nebulizer nozzle, vertical air inlet pipe and horizontal air inlet pipe are all preheated to 160°C. The molten drug solution is atomized by 1.5 MPa high-pressure nitrogen gas entering from the vertical air inlet pipe and horizontal air inlet pipe at the nebulizer nozzle to form droplets. The atomization time depends on the total amount of drug.

[0116] (3) Due to their own gravity, the droplets fall into the condensation chamber and, upon encountering low-temperature dry nitrogen, rapidly solidify into microspheres at -30°C. The microspheres are then sent to the cyclone separation system, where the larger microspheres fall into the coarse powder collection tank and the smaller microspheres fall into the fine powder collection tank. The off-white dry powder collected in the coarse powder collection tank is the progesterone sustained-release microsphere.

[0117] Example 5: Preparation of progesterone sustained-release microspheres

[0118] (1) Mix 10g progesterone with 20g PCL (molecular weight of 10000 Daltons) evenly and put it into the heating chamber. Turn on the stirrer and heat it to 160°C at 75 rpm under nitrogen protection to obtain a molten drug solution.

[0119] (2) The molten drug solution is delivered into the nebulizer at a rate of 1000 mL / h. The nebulizer nozzle, vertical air inlet pipe and horizontal air inlet pipe are all preheated to 160°C. The molten drug solution is atomized by 1.5 MPa high-pressure nitrogen gas entering from the vertical air inlet pipe and horizontal air inlet pipe at the nebulizer nozzle to form droplets. The atomization time depends on the total amount of drug.

[0120] (3) Due to their own gravity, the droplets fall into the condensation chamber and, upon encountering low-temperature dry nitrogen, rapidly solidify into microspheres at -25°C. The microspheres are then sent to the cyclone separation system, where the larger microspheres fall into the coarse powder collection tank and the smaller microspheres fall into the fine powder collection tank. The off-white dry powder collected in the coarse powder collection tank is the progesterone sustained-release microsphere.

[0121] Example 1: In vitro release rate study of progesterone sustained-release microspheres

[0122] A flow-through circulation system was used. 10 mg of the progesterone sustained-release microspheres prepared in Examples 1-5 were placed in a flow-through cell with a conical section filled with 1 mm glass beads. Phosphate buffer (pH 7.34) containing 0.5% Tween 80 was used as the dissolution medium. The temperature was 37°C and the flow rate was 4 ml / min. -11 mL samples were 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 (releasing the material that had passed through a 0.45 μm filter membrane online). Results are shown below. Figure 4 .

[0123] Example 6: Preparation of Progesterone Sustained-Release Microsphere Injection

[0124] The prescription for progesterone sustained-release microsphere injection is as follows:

[0125]

[0126]

[0127] The preparation steps for progesterone sustained-release microsphere injection are as follows:

[0128] Weigh the required amount of mannitol, dissolve it in sterile water for injection at 60°C, then add sodium carboxymethyl cellulose and Tween 80, stir at 100 rpm until completely dispersed, and then autoclave for 20 minutes to obtain the final product.

[0129] Example 7 Preparation of medroxyprogesterone acetate microspheres

[0130] (1) Mix 10g of megestrol acetate and 30g of polypropylene resin evenly and put them into the heating chamber. Turn on the stirrer and heat the mixture to 210°C at 75 rpm under nitrogen protection to obtain a molten drug solution.

[0131] (2) The molten drug solution is delivered into the nebulizer at a rate of 1000 mL / h. The nebulizer nozzle, vertical air inlet pipe and horizontal air inlet pipe are all preheated to 230°C. The molten drug solution is atomized by 0.5 MPa high-pressure nitrogen gas entering from the vertical air inlet pipe and horizontal air inlet pipe at the nebulizer nozzle to form droplets. The atomization time depends on the total amount of drug.

[0132] (3) Due to their own gravity, the droplets fall into the condensation chamber and, upon encountering low-temperature dry nitrogen, rapidly solidify into microspheres at -40°C. The microspheres are then sent to the cyclone separation system, where the larger microspheres fall into the coarse powder collection tank and the smaller microspheres fall into the fine powder collection tank. The pale yellow dry powder collected in the coarse powder collection tank is the megestrol acetate microsphere.

[0133] Experimental Example 2

[0134] The in vitro release of the medroxyprogesterone acetate microspheres prepared in Example 7 was compared with that of a commercially available product (medroxyprogesterone acetate dispersible tablets, trade name Yilizhi). The results are shown in the figure. Figure 5The in vitro release assay was performed using a paddlewheel method. The dissolution medium was phosphate buffer (pH 4) containing 1.0% Tween 80, with a volume of 900 mL. The paddlewheel rotation was 75 rpm, and the temperature was 37 °C. Samples of 5 mL were 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 (the release had passed through a 0.45 μm filter membrane).

[0135] Example 8 Preparation of indomethacin microspheres

[0136] (1) Mix 10g indomethacin and 20g poloxamer 188 evenly and put them into the heating chamber. Turn on the stirrer and heat to 165°C at 75 rpm under nitrogen protection to obtain a molten drug solution.

[0137] (2) The molten drug solution is delivered into the nebulizer at a rate of 1150 mL / h. The nebulizer nozzle, vertical air inlet pipe and horizontal air inlet pipe are all preheated to 180°C. The molten drug solution is atomized by 0.6 MPa high-pressure nitrogen gas entering from the vertical air inlet pipe and horizontal air inlet pipe at the nebulizer nozzle to form droplets. The atomization time depends on the total amount of drug.

[0138] (3) Due to their own gravity, the droplets fall into the condensation chamber and, upon encountering low-temperature dry nitrogen gas, rapidly solidify into microspheres at -30°C. The microspheres are then fed into a cyclone separation system, where larger microspheres fall into a coarse powder collection tank, and smaller microspheres fall into a fine powder collection tank. The white, dry powder collected in the coarse powder collection tank is indomethacin microspheres, with a bulk density of 0.47 g / cm³. 3 .

[0139] Example 9 Preparation of Indomethacin Dispersible Tablets

[0140] The formula for indomethacin dispersible tablets is as follows:

[0141]

[0142] The preparation method of indomethacin dispersible tablets includes the following steps:

[0143] The indomethacin microspheres prepared in Example 8 were thoroughly mixed with microsphere cellulose, crospovidone, 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.

[0144] Experimental Example 3

[0145] 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 6 .

[0146] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A progesterone sustained-release microsphere containing a carrier material, wherein the progesterone sustained-release microsphere is made of progesterone and carrier material in a weight ratio of 1:2 to 1:5, wherein 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, wherein the microsphere is selected from any one of spherical or near-spherical shapes, wherein the microsphere is a dense, round, solid sphere, wherein the average particle size of the microsphere is 20 μm-100 μm, the porosity of the microsphere is ≤10%, and the bulk density of the microsphere is 0.25 g / cm³. 3 -0.86g / cm 3 The preparation of microspheres includes the following steps: (1) After mixing progesterone and carrier material at a ratio of 1:2 to 1:5, the mixture is placed in a heating chamber and heated at 50-200 rpm under inert gas protection to obtain a molten drug solution. (2) The molten drug solution is fed into an atomizer that has been 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 with a pressure of 0.5-1.5 MPa entering from the vertical and horizontal air inlets. (3) The prepared droplets are sent into the condensation chamber and solidified into microspheres under the action of low temperature dry gas at -50℃ to -20℃. After drying, they are sent into a cyclone separator for separation. The cyclone separator consists of two cyclone separators connected in series, which are respectively connected to a coarse powder collection tank and a fine powder collection tank. The microspheres with larger particle sizes fall into the coarse powder collection tank, and the microspheres with smaller particle sizes fall into the fine powder collection tank. The off-white dry powder collected in the coarse powder collection tank is the progesterone sustained-release microsphere.

2. The progesterone sustained-release microspheres as described in claim 1, wherein the inert gas in step (1) is selected from any one or a combination of argon, nitrogen, and helium.

3. The progesterone sustained-release microspheres as described in claim 1, wherein the flow rate of the molten drug solution in step (2) is 1200-1800 mL / h.

4. The progesterone sustained-release microspheres as described in claim 1, wherein the atomizer in step (2) 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, or a combined nozzle atomizer.

5. The progesterone sustained-release microspheres as described in claim 1, wherein the low-temperature drying gas in step (3) is selected from any one or a combination of nitrogen, helium, argon, neon, carbon monoxide, and carbon dioxide.

6. The progesterone sustained-release microspheres as described in claim 1, wherein the temperature of the low-temperature drying gas in step (3) is -40°C to -25°C.

7. The progesterone sustained-release microspheres as described in claim 1, 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℃.

8. The progesterone sustained-release microspheres according to claim 7, wherein the drying temperature is 40℃-50℃.

9. The progesterone sustained-release microspheres according to claim 1, wherein the bulk density of the progesterone sustained-release microspheres is 0.40 g / cm³. 3 -0.65g / cm 3 .

10. The progesterone sustained-release microspheres according to claim 9, wherein the bulk density of the progesterone sustained-release microspheres is 0.5 g / cm³. 3 -0.6g / cm 3 .

11. A method for preparing progesterone sustained-release microspheres containing a carrier material as described in any one of claims 1-10, comprising the following steps: (1) After mixing progesterone and carrier material at a ratio of 1:2 to 1:5, the mixture is placed in a heating chamber and heated at 50-200 rpm under inert gas protection to obtain a molten drug solution. (2) The molten drug solution is fed into an atomizer that has been 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 with a pressure of 0.5-1.5 MPa entering from the vertical and horizontal air inlets. (3) The prepared droplets are sent into the condensation chamber and solidified into microspheres under the action of low temperature dry gas at -50℃ to -20℃. After drying, they are sent into a cyclone separator for separation. The cyclone separator consists of two cyclone separators connected in series, which are respectively connected to a coarse powder collection tank and a fine powder collection tank. The microspheres with larger particle sizes fall into the coarse powder collection tank, and the microspheres with smaller particle sizes fall into the fine powder collection tank. The off-white dry powder collected in the coarse powder collection tank is the progesterone sustained-release microsphere.

12. The method as described in claim 11, wherein the heating method of the heating chamber in step (1) can be selected from any one or a combination of resistance heating, electromagnetic induction heating, infrared heating wire, microwave heating, and electric arc heating.

13. The method of claim 11, wherein the inert gas in step (1) is selected from any one or a combination of argon, nitrogen, and helium.

14. The method according to claim 11, wherein the flow rate of the molten drug solution in step (2) is 1200-1800 mL / h.

15. The method as described in claim 11, wherein the preheating method of the atomizer in step (2) is selected from any one or a combination of resistance heating, electromagnetic induction heating, electric arc heating, winding heating wire, and hot oil heating.

16. The method as described in claim 11, wherein the atomizer in step (2) 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.

17. The method of claim 11, wherein the high-pressure inert gas in step (2) is selected from any one or a combination of argon, nitrogen, and helium.

18. The method of claim 11, wherein the low-temperature drying gas in step (3) may be selected from any one or a combination of nitrogen, helium, argon, neon, carbon monoxide, and carbon dioxide.

19. The method as described in claim 11, characterized in that, The temperature of the low-temperature drying gas in step (3) is -40℃ to -25℃.

20. The method as described in claim 11, characterized in that, In step (3), the drying process is selected from either reduced pressure drying or vacuum drying or a combination thereof, and the drying temperature is 35℃-65℃.

21. The method as described in claim 20, characterized in that, In step (3), the drying process is selected from either reduced pressure drying or vacuum drying or a combination thereof, and the drying temperature is 40℃-50℃.

22. A progesterone sustained-release microsphere injection, characterized in that, The injection is composed of progesterone sustained-release microspheres containing a carrier material as described in any one of claims 1-10 and a pharmaceutically acceptable carrier; the progesterone sustained-release microsphere injection is composed of progesterone sustained-release microspheres with a particle size of 20-100 μm and a pharmaceutically acceptable carrier, wherein the progesterone sustained-release microspheres are progesterone sustained-release microspheres containing a carrier material, the content of progesterone sustained-release microspheres in the injection is 1%-10% (w / v), the pharmaceutically acceptable carrier is a combination of an osmotic pressure regulator, a stabilizer, a pH adjuster, and a solvent, the content of the solvent in the injection is 60%-95% (w / w), the content of the osmotic pressure regulator in the injection is 0.05%-10% (w / v), the content of the stabilizer in the injection is 0.01%-5% (w / v), and the content of the pH adjuster in the injection is 0.05%-5% (w / v).

23. The progesterone sustained-release microsphere injection as described in claim 22, wherein the content of progesterone sustained-release microspheres in the injection is 2%-8% (w / v).

24. The progesterone sustained-release microsphere injection as described in claim 22, wherein the solvent content in the injection is 70%-90% (w / w).

25. The progesterone sustained-release microsphere injection of claim 22, wherein the solvent is selected from any one or a combination of water, glycerol, propylene glycol, ethanol, and ethyl acetate.

26. The progesterone sustained-release microsphere injection as described in claim 22, wherein the content of the osmotic pressure regulator in the injection is 0.1%-6% (w / v).

27. The progesterone sustained-release microsphere injection of claim 22, wherein the osmotic pressure regulator is selected from any one or a combination of sodium chloride, glucose, mannitol, trehalose, and sucrose.

28. The progesterone sustained-release microsphere injection as described in claim 22, wherein the stabilizer content in the injection is 0.02-2% (w / v).

29. The progesterone sustained-release microsphere injection of claim 22, wherein the stabilizer is selected from any one or a combination of sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, glycerin, gum arabic, polysorbate 20, polysorbate 80, and poloxamer.

30. The progesterone sustained-release microsphere injection as described in claim 22, wherein the pH adjuster content in the injection is 0.1%-2% (w / v).

31. The progesterone sustained-release microsphere injection according to claim 22, wherein the pH adjuster is selected from any one or a combination of citric acid, lactic acid, acetic acid, adipic acid, sodium hydroxide, potassium carbonate, sodium citrate, potassium citrate, and sodium citrate.

32. The progesterone sustained-release microsphere injection as described in claim 22, wherein the progesterone sustained-release microspheres in the injection contain 1-10% (w / w), sodium carboxymethyl cellulose 0.01-5% (w / w), mannitol 0.05-10% (w / w), polysorbate 200.01-5%, and water for injection 60%-95% (w / w).

33. The progesterone sustained-release microsphere injection as described in claim 32, wherein the progesterone sustained-release microspheres in the injection contain 2-8% (w / w), sodium carboxymethyl cellulose 0.02-2% (w / w), mannitol 0.1-6% (w / w), polysorbate 20 0.02-2%, and water for injection 70%-90% (w / w).

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