CN116036022A - Preparation and application of novel drug microsphere containing carrier material - Google Patents

Preparation and application of novel drug microsphere containing carrier material Download PDF

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Publication number
CN116036022A
CN116036022A CN202111600117.XA CN202111600117A CN116036022A CN 116036022 A CN116036022 A CN 116036022A CN 202111600117 A CN202111600117 A CN 202111600117A CN 116036022 A CN116036022 A CN 116036022A
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drug
microsphere
carrier material
microspheres
combination
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郑爱萍
张慧
程艺
王玥
高静
刘楠
高翔
王增明
李蒙
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Academy of Military Medical Sciences AMMS of PLA
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Academy of Military Medical Sciences AMMS of PLA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a drug microsphere containing a carrier material, wherein the weight ratio of drug to the carrier material in the drug microsphere is 1:1-1:20, and the drug is selected from insoluble drug, slightly soluble drug, soluble drug and soluble drug with the melting point of 60-300 ℃The carrier material is selected from one or a combination of slow release materials, water-soluble carrier materials, insoluble carrier materials and enteric carrier materials, the drug microspheres are sphere-like, spherical or a combination thereof, the average particle size of the drug microspheres is 20-250 mu m, the porosity of the drug microspheres is less than or equal to 10%, and the bulk density of the drug microspheres is 0.25g/cm 3 ‑0.86g/cm 3 . The drug microsphere has the advantages of uniform particle size distribution, large drug loading rate, high encapsulation efficiency (more than or equal to 80%), stable and smooth release curve, high bioavailability, reduced drug burst, contribution to reducing the dosage of drugs and avoiding organic solvent residues. And has controllable dissolution, and can improve the solubility and bioavailability of insoluble drugs.

Description

Preparation and application of novel drug microsphere containing carrier material
Technical Field
The invention belongs to the field of medicines, and in particular relates to a drug microsphere containing a carrier material, a preparation method and application thereof.
Background
The drug microsphere is a sphere with the particle size of 5-500 μm formed by dissolving or dispersing drugs into a polymer material. After microsphere administration, the polymer material gradually degrades and releases the drug, reduces the administration dosage, reduces the drug burst release, reduces or even avoids the peak-valley phenomenon of blood concentration, reduces the administration times of the treatment period, improves the bioavailability and the administration compliance of patients, and has very broad market prospect.
The drug loading, morphology, particle size and particle size distribution of the drug microspheres can influence the dispersion state of the drug and the degradation and porosity of the framework material to influence the release of the drug. The preparation method of the microsphere comprises an emulsifying solvent diffusion method, a spray drying method, a hot melt extrusion method and the like. The emulsion solvent diffusion method has the defects of wide particle size distribution, low encapsulation efficiency, abrupt drug release and the like. The spray drying method has organic solvent residues which affect the health of human body and the safety of medicines. The products prepared by the hot melt extrusion method are mostly irregular spheres, and have the defects of low drug loading (about 10-20%), abrupt release (about 10-40% of accumulated release rate in 1 h), organic reagent residues and the like. Therefore, there is a need to study drug microspheres with higher drug loading, more uniform microsphere particle size, no organic reagent residue, and reduced burst release, and a method for preparing the same.
Disclosure of Invention
The invention aims to provide a drug microsphere containing a carrier material, wherein the weight ratio of drug to the carrier material in the drug microsphere is 1:1-1:20, the drug is selected from any one of insoluble drug, slightly soluble drug, soluble drug and easily soluble drug with the melting point of 60-300 ℃, the carrier material is selected from any one of a slow release material, a water soluble carrier material, a slightly soluble carrier material and an enteric carrier material or a combination thereof, the drug microsphere is any one of a spheroid shape and a sphere shape or a combination thereof, and the average particle size of the drug microsphere is 20-250 mu m.
In the preferred technical scheme of the invention, the porosity of the drug microsphere is less than or equal to 10%.
In a preferred technical scheme of the invention, the bulk density of the drug microsphere is 0.25g/cm 3 -0.86g/cm 3 Preferably 0.40g/cm 3 -0.65g/cm 3 More preferably 0.5g/cm 3 -0.6g/cm 3 。
In a preferred embodiment of the present invention, the average particle size of the drug microsphere is 50-200 μm, preferably 100-150 μm.
In a preferred technical scheme of the invention, the drug microsphere is a solid sphere, preferably a compact round solid sphere.
In the preferred technical scheme of the invention, the weight ratio of the medicine in the medicine microsphere to the carrier material is 1:1.5-1:10, preferably 1:2-1:5.
In a preferred technical scheme of the invention, the medicine is selected from any one of progesterone, megestrol acetate and indomethacin.
In a preferred technical scheme of the invention, the melting point of the medicine is 80-200 ℃.
In a preferred technical scheme of the invention, the slow-release material is any one or combination of polyester slow-release material, polyanhydride slow-release material and polyamide slow-release material, preferably the polyester slow-release material is selected from any one or combination of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polylactic acid-glycolic acid copolymer (50:50), polylactic acid-glycolic acid copolymer (75:25), polylactic acid-glycolic acid copolymer (85:15) and polyorthoester, and the molecular weight of the polyester slow-release material is 10000-50000 daltons.
In a preferred embodiment of the present invention, the water-soluble carrier material is selected from any one of poloxamer, polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, aminoalkyl methacrylate copolymer E, polyvinyl alcohol/polyethylene glycol graft copolymer, ethylene-vinyl acetate copolymer, acrylic resin, polyoxyethylene, polyvinyl alcohol, povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, polyvinyl acetate povidone mixture, or a combination thereof.
In a preferred embodiment of the present invention, the poorly soluble carrier material is selected from any one of Ethyl Cellulose (EC), polyacrylic resin Eudragit containing quaternary ammonium groups, polymethacrylic resin, or a combination thereof.
In a preferred embodiment of the present invention, the enteric carrier is selected from any one of carboxymethylcellulose (CNEC), hypromellose phthalate (HPMCP), polyacrylate (Eudragit L and S) or a combination thereof.
In a preferred embodiment of the present invention, the pharmaceutical microsphere further optionally comprises a plasticizer.
In a preferred embodiment of the present invention, the plasticizer is selected from any one of polyethylene glycol 400, polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, vitamin E polyethylene glycol succinate, polyethylene glycol-15 hydroxystearate, stearic acid and its salts, glyceryl stearate, polysorbates, castor oil polyoxyethylene ethers, sodium dodecyl sulfate, polyoxyethylene polyoxypropylene ether block copolymers, sucrose, glucose, sorbitol, maltitol, xylitol, isomalt, mannitol, lactitol, erythritol, tartaric acid, fumaric acid, malic acid, maleic acid, ethanol, propylene glycol, glycerin, or a combination thereof.
In a preferred embodiment of the present invention, the weight ratio of plasticizer to carrier material in the pharmaceutical microsphere is 1:1-1:30, preferably 1:2-1:20, more preferably 1:3-1:10.
In a preferred embodiment of the present invention, the pharmaceutical microsphere further optionally comprises a glidant.
In a preferred technical scheme of the invention, the glidant is selected from any one or combination of silicon dioxide, colloidal silicon dioxide, micro silica gel, aluminum magnesium silicate, halloysite and light calcium carbonate.
In a preferred technical scheme of the invention, the weight ratio of the glidant to the carrier material in the drug microsphere is 1:1-1:10, preferably 1:2-1:5.
In a preferred embodiment of the present invention, the pharmaceutical microsphere further optionally comprises an antioxidant.
In a preferred embodiment of the present invention, the antioxidant is selected from any one of sodium bisulfite, t-butyl-p-cresol, sodium metabisulfite, vitamin E, disodium edetate, vitamin C, glutathione or a combination thereof.
In a preferred technical scheme of the invention, the weight ratio of the antioxidant to the carrier material in the drug microsphere is 1:1-1:10, preferably 1:2-1:5.
The invention also aims to provide a method for preparing the drug microsphere, wherein the weight ratio of the drug to the carrier material in the drug microsphere is 1:1-1:20, the drug is selected from any one of insoluble drug, slightly soluble drug, soluble drug and easily soluble drug with the melting point of 60-300 ℃, the carrier material is selected from any one of slow release material, water soluble carrier material, slightly soluble carrier material and enteric carrier material or the combination thereof, the drug microsphere is any one of spheroid and sphere or the combination thereof, the average particle size of the drug microsphere is 20-250 mu m, and the preparation method comprises the following steps:
(1) Uniformly mixing the medicine and the carrier material according to a ratio of 1:1-1:20, then putting the mixture into a heating chamber, and heating the mixture under the protection of inert gas at 50-200rpm to prepare molten liquid medicine;
(2) Feeding the molten liquid medicine into an atomizer preheated to a temperature 20-30deg.C higher than the melting point of the medicine at a flow rate of 1000-2000mL/h, and pulverizing into fogdrops with 0.05-5Mpa of high-pressure inert gas;
(3) And (3) sending the prepared fog drops into a condensing chamber, condensing and solidifying the fog drops into microspheres under the action of low-temperature drying gas at the temperature of-80 ℃ to 0 ℃, and sending the microspheres into a cyclone separator for separation after drying.
In a preferred embodiment of the invention, the weight ratio of the drug to the carrier material is 1:1.5-1:10, preferably 1:2-1:5.
In a preferred embodiment of the present invention, the stirring speed in the step (1) is 80-120rpm/min.
In a preferred embodiment of the present invention, the heating mode of the heating chamber in the step (1) may be any one or a combination of resistance heating, electromagnetic induction heating, infrared heating wire, microwave heating, and arc heating.
In a preferred embodiment of the present invention, the inert gas in the step (1) is selected from any one of argon, nitrogen and helium or a combination thereof.
In a preferred embodiment of the present invention, the viscosity of the molten liquid medicine in the step (1) is 50pa.s-28000pa.s, preferably 100pa.s-15000pa.s.
In a preferred technical scheme of the invention, the flow rate of the molten liquid medicine in the step (2) is 1200-1800mL/h.
In a preferred embodiment of the present invention, the preheating mode of the atomizer in the step (2) is selected from any one of resistance heating, electromagnetic induction heating, arc heating, winding heating wire, and hot oil heating, or a combination thereof.
In a preferred embodiment of the present invention, the atomizer in the step (2) is selected from any one of a rotary atomizer, a parallel flow type two-fluid nozzle atomizer, a fountain type two-fluid nozzle atomizer, a pressure type nozzle atomizer, and a combination type nozzle atomizer.
In a preferred technical scheme of the invention, the atomizer in the step (2) comprises an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe, wherein the aperture of the atomizing nozzle is 0.5-5mm, preferably 0.8-3mm.
In a preferred embodiment of the present invention, the high-pressure inert gas in the step (2) is selected from any one or a combination of argon, nitrogen and helium, and the pressure of the high-pressure inert gas is 0.1-3Mpa, preferably 0.5-1.5Mpa.
In a preferred embodiment of the present invention, the low-temperature drying gas in the step (3) may be selected from any one of nitrogen, helium, argon, neon, carbon monoxide, carbon dioxide, or a combination thereof.
In a preferred embodiment of the present invention, the temperature of the low temperature drying gas in the step (3) is-50 ℃ to-20 ℃, preferably-40 ℃ to-25 ℃.
In a preferred embodiment of the present invention, the drying in the step (3) is selected from any one of reduced pressure drying and vacuum drying or a combination thereof, and the drying temperature is 35 ℃ to 65 ℃, preferably 40 ℃ to 50 ℃.
In the preferred technical scheme of the invention, the cyclone separator in the step (3) is two cyclone separators connected in series, and the coarse powder collecting tank and the fine powder collecting tank are respectively communicated.
It is another object of the present invention to provide a pharmaceutical microsphere formulation comprising the pharmaceutical microsphere of the present invention comprising a carrier material and a pharmaceutically acceptable carrier.
In a preferred embodiment of the present invention, the formulation is selected from any one of injection, tablet, capsule, pill, granule, and patch.
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, flavoring agents.
Another object of the present invention is to provide a progesterone sustained-release microsphere injection, which is composed of progesterone sustained-release microspheres with particle size of 20-100 μm and pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is any one of osmotic pressure regulator, stabilizer, pH value regulator, solvent or their combination.
In a preferred embodiment of the present invention, the particle size of the progesterone sustained-release microsphere is 20-100 μm, preferably 50-200 μm, more preferably 100-150 μm.
In the preferred technical scheme of the invention, the porosity of the progesterone microsphere is less than or equal to 10 percent.
In a preferred embodiment of the present invention, the bulk density of the progesterone microsphere is 0.25g/cm 3 -0.86g/cm 3 Preferably 0.40g/cm 3 -0.65g/cm 3 More preferably 0.5g/cm 3 -0.6g/cm 3 。
In a preferred technical scheme of the invention, the progesterone sustained-release microsphere is a solid sphere, preferably a compact and round solid sphere.
In a preferred technical scheme of the invention, the progesterone sustained-release microsphere is a progesterone sustained-release microsphere containing sustained-release materials.
In a preferred embodiment of the present invention, the slow release material is polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA) with a molecular weight peak value of 5000-100000 dalton, preferably 10000-50000 dalton, preferably the polylactic acid and its copolymer is any one of polylactic acid-glycolic acid copolymer (50:50), polylactic acid-glycolic acid copolymer (75:25), polylactic acid-glycolic acid copolymer (85:15) or their combination.
In a preferred embodiment of the present invention, the content of progesterone microsphere in the injection is 1% -10% (w/v), preferably 2% -8% (w/v).
In a preferred embodiment of the present invention, the solvent content of the injection is 60% -95% (w/w), preferably 70% -90% (w/w).
In a preferred embodiment of the present invention, the solvent is selected from any one of water, glycerin, propylene glycol, ethanol, ethyl acetate, or a combination thereof.
In a preferred embodiment of the present invention, the osmotic pressure regulator is contained in the injection in an amount of 0.05% -10% (w/v), preferably 0.1% -6% (w/v).
In a preferred embodiment of the present invention, the osmotic pressure regulator is selected from any one of sodium chloride, glucose, mannitol, trehalose, sucrose, or a combination thereof.
In a preferred embodiment of the present invention, the stabilizer is present in the injection in an amount of 0.01% -5% (w/v), preferably 0.02-2% (w/v).
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, acacia, polysorbate 20, polysorbate 80, and poloxamer.
In a preferred embodiment of the present invention, the content of the pH regulator in the injection is 0.05% -5% (w/v), preferably 0.1% -2% (w/v).
In a preferred embodiment of the present invention, the pH adjustor 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.
In the preferred technical scheme of the invention, the content of the progesterone microsphere in the injection is 1-10% (w/w), 0.01-5% (w/w) of sodium hydroxymethyl cellulose, 0.05-10% (w/w) of mannitol, 20.01-5% of polysorbate and 60-95% (w/w) of water for injection.
In the preferred technical scheme of the invention, the content of the progesterone microsphere in the injection is 2-8% (w/w), 0.02-2% (w/w) of sodium hydroxymethyl cellulose, 0.1-6% (w/w) of mannitol, 20.02-2% of polysorbate and 70-90% (w/w) of water for injection.
The invention also aims to protect the indomethacin solid dispersible tablet, which is prepared by mixing indomethacin microspheres with the particle size of 20-250 mu m with a pharmaceutically acceptable carrier, granulating, drying and tabletting, wherein the pharmaceutically acceptable carrier is any one or combination of a filler, an adhesive, a lubricant and a disintegrating agent.
In a preferred embodiment of the present invention, the content of indomethacin microsphere in the dispersion tablet is 50-80% (w/w), preferably 60-70% (w/w).
In a preferred embodiment of the present invention, the particle size of the indomethacin microsphere is 50-200 μm, preferably 100-150 μm.
In a preferred technical scheme of the invention, the indomethacin microspheres are solid spheres, and are preferably compact and round solid spheres.
In the preferred technical scheme of the invention, the porosity of the indometacin microsphere is less than or equal to 10%.
In a preferred technical scheme of the invention, the bulk density of the indometacin microsphere is 0.25g/cm 3 -0.86g/cm 3 Preferably 0.40g/cm 3 -0.65g/cm 3 More preferably 0.5g/cm 3 -0.6g/cm 3 。
In a preferred technical scheme of the invention, the indomethacin microsphere is a microsphere containing a carrier material.
In a preferred technical scheme of the invention, the carrier material is any one or combination of poloxamer, polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, aminoalkyl methacrylate copolymer E, polyvinyl alcohol/polyethylene glycol graft copolymer, ethylene-vinyl acetate copolymer, acrylic resin, polyoxyethylene, polyvinyl alcohol, povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer and polyvinyl acetate povidone mixture.
In a preferred embodiment of the present invention, the filler content of the dispersible tablet is 10% -50% (w/w), preferably 20% -40% (w/w).
In a preferred embodiment of the present invention, the filler is selected from any one of starch, pregelatinized starch, microcrystalline cellulose, sucrose, dextrin, sorbitol, mannitol, maltitol, or a combination thereof.
In a preferred embodiment of the present invention, the binder content of the dispersible tablet is 1% -10% (w/w), preferably 2% -5% (w/w).
In a preferred embodiment of the present invention, the binder is selected from any one of starch slurry, methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, pregelatinized starch, povidone, hypromellose, ethylcellulose, polyethylene glycol, gelatin, and sodium alginate, or a combination thereof.
In a preferred embodiment of the present invention, the content of the disintegrant in the dispersible tablet is 1% to 10% (w/w), preferably 2% to 5% (w/w).
In a preferred embodiment of the present invention, the disintegrant is selected from any one of sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and calcium carboxymethyl cellulose, or a combination thereof.
In a preferred embodiment of the present invention, the lubricant content of the dispersible tablet is 0.1% -10% (w/w), preferably 0.5% -5% (w/w).
In a preferred embodiment of the present invention, the lubricant is one or more selected from magnesium stearate, silica and talc, or a combination thereof.
In the preferred technical scheme of the invention, the content of indometacin microspheres in the dispersible tablet is 50-80% (w/w), 10-50% (w/w) of microcrystalline cellulose, 1-10% (w/w) of crospovidone, 0.1-10% of magnesium stearate and 1-10% (w/w) of methylcellulose.
In the preferred technical scheme of the invention, the content of indometacin microspheres in the dispersible tablet is 60-70% (w/w), 20-40% (w/w) of microcrystalline cellulose, 2-5% (w/w) of crospovidone, 0.5-5% of magnesium stearate and 2-5% (w/w) of methylcellulose.
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
The invention is tested, unless otherwise indicated, using the following method:
1. the particle size distribution of the spherical crystals was detected by laser diffraction: the Mastersizer 2000Mu laser particle sizer (Malvern, uk) uses water as the dispersion medium, the pump speed of the cell is set to 2200rpm, and the analysis mode selects the universal mode. After the light and background measurement is completed, the suspension is taken and stirred uniformly and added into a sample injector until the shading degree is stabilized at 15+/-1%, and the particle size measurement is started.
2. The surface morphology of the sample to be measured is observed by adopting a JSM-7900F thermal field emission scanning electron microscope (JEOL corporation, japan) and is subjected to metal spraying treatment, and the scanning voltage is 30kV.
3. Raman spectrum imaging is carried out by adopting a microscopic confocal laser Raman spectrometer (Renisshaw, england), and 785nm excitation light source is selected for imaging.
Compared with the prior art, the invention has the following beneficial effects:
1. the drug microsphere has the advantages of uniform particle size distribution, large drug loading rate, high encapsulation efficiency (more than or equal to 80%), stable and smooth release curve, high bioavailability, reduced drug burst, contribution to reducing the dosage of drugs and avoiding organic solvent residues. And has controllable dissolution, and can improve the solubility and bioavailability of insoluble drugs.
2. The preparation method of the drug microsphere does not need wet grinding, prepares the spherical shape with regular shape, controls the grain size range and the drug loading capacity of the drug to control release, and has the characteristics of simple operation, better cost, suitability for industrial production and the like.
3. The atomization method of the medicine microsphere is wholly sealed and dried, so that atomized liquid medicine is quickly condensed into balls, the influence of water vapor caused by cold and heat exchange on the interior and surface morphology of the microsphere is avoided, compared with the traditional mode, the condensation time is shortened, the sphericity of the prepared microsphere is improved, the particle size range can be reduced to 0.2-0.5, the yield is more than 80%, and the sphericity of the microsphere is improved.
Drawings
FIG. 1 is a scanning electron microscope image of a progesterone sustained release microsphere;
FIG. 2 shows a particle size distribution diagram of progesterone-releasing microspheres;
fig. 3 raman imaging of progesterone sustained release microspheres;
FIG. 4 investigation of the release of progesterone sustained release microspheres of examples 1-5;
figure 5 example 7 in vitro release studies of megestrol acetate microspheres;
FIG. 6 dissolution investigation of indomethacin solid dispersible tablets of example 9.
Detailed Description
The invention is further illustrated in the following in connection with specific examples which are intended to be illustrative only and are not intended to limit the scope of the invention in any way.
Experimental material PLGA (polylactic acid-glycolic acid copolymer): the molar ratio of lactic acid to glycolic acid was 75:25, available from Shandong, biotech Co., ltd.
PCL (polycaprolactone), PLA (polylactic acid) were purchased from Shandong Dai, biotech Inc. Polypropylene resin (Eudragit RS PO) was purchased from Ashland and poloxamer 188 was purchased from BASF (China) Company Ltd.
EXAMPLE 1 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone with 20g of PLGA (molecular weight is 10000 daltons), putting into a heating chamber, starting a stirrer, and heating to 140 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain a molten liquid medicine; the viscosity of the molten liquid medicine is 275.16Pa.s;
(2) Conveying the molten liquid medicine into an atomizer 5 at the speed of 1000mL/h, wherein an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe on the atomizer are all preheated to 160 ℃; the molten medicine is smashed and atomized at the atomizing nozzle by 0.5Mpa high-pressure nitrogen entering from the vertical air inlet pipe and the horizontal air inlet pipe to form fog drops, and the atomizing time depends on the total amount of the medicine;
(3) The fog drops fall into the condensing chamber due to self gravity and are quickly solidified into microspheres at the temperature of minus 20 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent into a cyclone separation system, wherein the microspheres with larger particle size fall into a coarse powder collecting tank, and the microspheres with smaller particle size fall into a fine powder collecting tank; collecting off-white dry powder in coarse powder collecting tank to obtain progesterone sustained-release microsphere.
The scanning electron microscope image of the progesterone sustained-release microsphere is shown in figure 1, and the particle size distribution diagram is shown in figure 2. Microsphere Raman imaging is shown in figure 3. The content uniformity was 9.01, the encapsulation efficiency was 83.09%, and the porosity was 3.34%.
EXAMPLE 2 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone and 20g of PLGA (molecular weight of 30000 daltons), putting into a heating chamber, starting a stirrer, and heating to 140 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer at the speed of 1000mL/h, wherein an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe on the atomizer are all preheated to 160 ℃; the molten liquid medicine is smashed and atomized at the atomizing nozzle by 1Mpa high-pressure nitrogen entering from the vertical air inlet pipe and the horizontal air inlet pipe to form fog drops, and the atomizing time is determined according to the total amount of the medicine;
(3) The fog drops fall into the condensing chamber due to self gravity and are quickly solidified into microspheres at the temperature of minus 20 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent into a cyclone separation system, wherein the microspheres with larger particle size fall into a coarse powder collecting tank, and the microspheres with smaller particle size fall into a fine powder collecting tank; collecting off-white dry powder in coarse powder collecting tank to obtain progesterone sustained-release microsphere.
EXAMPLE 3 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone with 20g of PLGA (molecular weight of 50000 daltons), putting into a heating chamber, starting a stirrer, and heating to 140 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer at the speed of 1000mL/h, wherein an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe on the atomizer are all preheated to 160 ℃; the molten liquid medicine is smashed and atomized at an atomizing nozzle by 1.5Mpa high-pressure nitrogen entering from a vertical air inlet pipe and a horizontal air inlet pipe to form fog drops, and the atomizing time is determined according to the total amount of the medicine;
(3) The fog drops fall into the condensing chamber due to self gravity and are quickly solidified into microspheres at the temperature of minus 20 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent into a cyclone separation system, wherein the microspheres with larger particle size fall into a coarse powder collecting tank, and the microspheres with smaller particle size fall into a fine powder collecting tank; collecting off-white dry powder in coarse powder collecting tank to obtain progesterone sustained-release microsphere.
EXAMPLE 4 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone and 20g of PLA (molecular weight is 10000 daltons), putting into a heating chamber, starting a stirrer, and heating to 180 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer at the speed of 1000mL/h, wherein an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe on the atomizer are all preheated to 160 ℃; the molten liquid medicine is smashed and atomized at an atomizing nozzle by 1.5Mpa high-pressure nitrogen entering from a vertical air inlet pipe and a horizontal air inlet pipe to form fog drops, and the atomizing time is determined according to the total amount of the medicine;
(3) The fog drops fall into the condensing chamber due to self gravity and are quickly solidified into microspheres at the temperature of minus 30 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent into a cyclone separation system, wherein the microspheres with larger particle size fall into a coarse powder collecting tank, and the microspheres with smaller particle size fall into a fine powder collecting tank; collecting off-white dry powder in coarse powder collecting tank to obtain progesterone sustained-release microsphere.
EXAMPLE 5 preparation of Progesterone sustained-release microspheres
(1) Uniformly mixing 10g of progesterone and 20g of PCL (molecular weight is 10000 daltons), putting into a heating chamber, starting a stirrer, and heating to 160 ℃ under the protection of nitrogen at a rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer at the speed of 1000mL/h, wherein an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe on the atomizer are all preheated to 160 ℃; the molten liquid medicine is smashed and atomized at an atomizing nozzle by 1.5Mpa high-pressure nitrogen entering from a vertical air inlet pipe and a horizontal air inlet pipe to form fog drops, and the atomizing time is determined according to the total amount of the medicine;
(3) The fog drops fall into the condensing chamber due to self gravity and are quickly solidified into microspheres at the temperature of minus 25 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent into a cyclone separation system, wherein the microspheres with larger particle size fall into a coarse powder collecting tank, and the microspheres with smaller particle size fall into a fine powder collecting tank; collecting off-white dry powder in coarse powder collecting tank to obtain progesterone sustained-release microsphere.
Test example 1 in vitro Release study of Progesterone sustained-release microspheres
Placing 10mg of progesterone sustained release microspheres prepared in examples 1-5 into a flow cell filled with 1mm glass beads at the conical part by using circulation system of flow cell method, and using phosphate buffer solution (pH 7.34) containing 0.5% Tween 80 as dissolution medium at 37deg.C and flow rate of 4ml min -1 1mL (released on-line through a 0.45 μm filter) was sampled at 1h,2h,3h,4h,6h,8h,10h,12h,24h,48h,72h,96h,120h,144h,168h,192h,240h,268 h. The results are shown in FIG. 4.
EXAMPLE 6 preparation of Progesterone sustained-release microsphere injection
The prescription of the progesterone sustained-release microsphere injection is as follows:
Figure BDA0003432852140000161
Figure BDA0003432852140000171
the preparation method of the progesterone sustained-release microsphere injection comprises the following steps:
weighing required amount of mannitol, dissolving in sterilized injectable water at 60deg.C, adding sodium carboxymethylcellulose and Tween 80, stirring at 100rpm, and sterilizing with high pressure steam for 20 min.
EXAMPLE 7 preparation of medroxyprogesterone acetate microspheres
(1) Uniformly mixing 10g of megestrol acetate and 30g of polypropylene resin, putting into a heating chamber, starting a stirrer, and heating to 210 ℃ under the protection of nitrogen at the rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer at the speed of 1000mL/h, wherein an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe on the atomizer are all preheated to 230 ℃; the molten medicine is smashed and atomized at the atomizing nozzle by 0.5Mpa high-pressure nitrogen entering from the vertical air inlet pipe and the horizontal air inlet pipe to form fog drops, and the atomizing time depends on the total amount of the medicine;
(3) The fog drops fall into the condensing chamber due to self gravity and are quickly solidified into microspheres at the temperature of minus 40 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent into a cyclone separation system, wherein the microspheres with larger particle size fall into a coarse powder collecting tank, and the microspheres with smaller particle size fall into a fine powder collecting tank; and (5) collecting pale yellow dry powder in a coarse powder collecting tank, namely the megestrol acetate microspheres.
Test example 2
The megestrol acetate microsphere prepared in example 7 was compared to the release of commercially available product (megestrol acetate dispersible tablet, trade name of the beneficial agent) in vitro, and the results are shown in fig. 5. In vitro release assay method using a rotor blade method, dissolution medium was phosphate buffer (pH 4) containing 1.0% Tween 80, dissolution medium volume was 900mL, rotation speed was 75rpm temperature was 37℃and 5mL (release had passed through 0.45 μm filter membrane) at 5min,10min,15min,30min,1h,2h,4h,6h,8h,12h,24 h.
Example 8 preparation of Indometacin microspheres
(1) Uniformly mixing 10g of indomethacin and 20g of poloxamer 188, putting into a heating chamber, starting a stirrer, and heating to 165 ℃ under the protection of nitrogen at the rotating speed of 75rpm to obtain molten liquid medicine;
(2) Conveying the molten liquid medicine into an atomizer at the speed of 1150mL/h, wherein an atomizing nozzle, a vertical air inlet pipe and a horizontal air inlet pipe on the atomizer are all preheated to 180 ℃; the molten liquid medicine is smashed and atomized at an atomizing nozzle by 0.6Mpa high-pressure nitrogen entering from a vertical air inlet pipe and a horizontal air inlet pipe to form fog drops, and the atomizing time is determined according to the total amount of the medicine;
(3) The fog drops fall into the condensing chamber due to self gravity and are quickly solidified into microspheres at the temperature of minus 30 ℃ after encountering low-temperature dry nitrogen; the microspheres are sent into a cyclone separation system, wherein the microspheres with larger particle size fall into a coarse powder collecting tank, and the microspheres with smaller particle sizeThe balls fall into a fine powder collecting tank; collecting white dry powder in coarse powder collecting tank to obtain indometacin microsphere with bulk density of 0.47g/cm 3 。
EXAMPLE 9 preparation of Indometacin Dispersion tablets
The indomethacin dispersible tablet comprises the following components:
Figure BDA0003432852140000191
the preparation method of the indomethacin dispersible tablet comprises the following steps:
the indomethacin microsphere prepared in the example 8 is fully mixed with microsphere cellulose, crosslinked povidone and methylcellulose, pressed into blocks, crushed into 40 meshes, granulated, fully mixed with magnesium stearate, and pressed into tablets under the pressure of 75N to obtain the indomethacin dispersible tablet.
Test example 3
The dissolution rate of indomethacin drug substance (commercially available from the company limited by the pharmaceutical industry of the stone medicine group) and indomethacin dispersible tablet of example 9 in phosphate buffer saline with pH of 6.8 was measured, and the result is shown in FIG. 6.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.

Claims (10)

1. The drug microsphere containing the carrier material is characterized in that the weight ratio of the drug to the carrier material in the drug microsphere is 1:1-1:20, the drug is selected from any one of insoluble drug, slightly soluble drug, soluble drug and easily soluble drug with the melting point of 60-300 ℃, the carrier material is selected from any one of slow release material, water soluble carrier material, slightly soluble carrier material and enteric carrier material or the combination thereof, the drug microsphere is any one of spheroid and sphere or the combination thereof, and the average particle size of the drug microsphere is 20-250 mu m.
2. The pharmaceutical microsphere of claim 1, wherein the bulk density of the pharmaceutical microsphere is 0.25g/cm 3 -0.86g/cm 3 Preferably 0.40g/cm 3 -0.65g/cm 3 More preferably 0.5g/cm 3 -0.6g/cm 3 。
3. The pharmaceutical microsphere of any one of claims 1-2, wherein the drug is selected from any one of progesterone, megestrol acetate, indomethacin.
4. A pharmaceutical microsphere according to any one of claims 1-3, wherein the slow release material is any one of or a combination of polyester-based slow release materials, polyanhydride-based slow release materials, polyamide-based slow release materials, preferably the polyester-based slow release materials are selected from any one of 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), polyorthoester with a molecular weight of 5000-50000 daltons.
5. The pharmaceutical microsphere of any one of claims 1-4, wherein the water soluble carrier material is selected from any one of poloxamer, polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, aminoalkyl methacrylate copolymer type E, polyvinyl alcohol/polyethylene glycol graft copolymer, ethylene-vinyl acetate copolymer, acrylic resin, polyoxyethylene, polyvinyl alcohol, povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, polyvinyl acetate povidone mixture, or combinations thereof.
6. A method for preparing the drug microsphere according to any one of claims 1 to 5, wherein the weight ratio of the drug to the carrier material in the drug microsphere is 1:1 to 1:20, the drug is selected from any one of insoluble drug, slightly soluble drug, soluble drug and easily soluble drug with the melting point of 60 ℃ to 300 ℃, the carrier material is selected from any one of slow release material, water soluble carrier material, slightly soluble carrier material and enteric carrier material or a combination thereof, the drug microsphere is any one of spheroid and sphere or a combination thereof, and the average particle size of the drug microsphere is 20 μm to 250 μm, and the specific preparation method comprises the following steps:
(1) Uniformly mixing the medicine and the carrier material according to a ratio of 1:1-1:20, then putting the mixture into a heating chamber, and heating the mixture under the protection of inert gas at 50-200rpm to prepare molten liquid medicine;
(2) Feeding the molten liquid medicine into an atomizer preheated to a temperature 20-30deg.C higher than the melting point of the medicine at a flow rate of 1000-2000mL/h, and pulverizing into fogdrops with 0.05-5Mpa of high-pressure inert gas;
(3) And (3) sending the prepared fog drops into a condensing chamber, condensing and solidifying the fog drops into microspheres under the action of low-temperature drying gas at the temperature of-80 ℃ to 0 ℃, and sending the microspheres into a cyclone separator for separation after drying.
7. The process according to claim 6, wherein the atomizer in step (2) comprises an atomizing nozzle having a pore diameter of 0.5 to 5mm, preferably 0.8 to 3mm, a vertical air inlet pipe and a horizontal air inlet pipe.
8. A pharmaceutical microsphere formulation, characterized in that it consists of a pharmaceutical microsphere according to any one of claims 1-5 or a pharmaceutical microsphere prepared by the method according to any one of claims 6-7 and a pharmaceutically acceptable carrier.
9. The pharmaceutical microsphere formulation according to claim 8, wherein the pharmaceutical microsphere formulation is a progesterone sustained release microsphere injection, wherein the progesterone sustained release microsphere injection consists of progesterone sustained release microspheres with particle size of 20-100 μm and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is any one of osmotic pressure regulator, stabilizer, pH regulator, solvent or a combination thereof.
10. The pharmaceutical microsphere preparation according to claim 8, wherein the pharmaceutical microsphere preparation is a indomethacin solid dispersible tablet, and the dispersible tablet is prepared by mixing indomethacin microspheres with the particle size of 20-250 μm with a pharmaceutically acceptable carrier, granulating, drying and tabletting, wherein the pharmaceutically acceptable carrier is any one of a filler, an adhesive, a lubricant and a disintegrating agent or a combination thereof.
CN202111600117.XA 2021-12-24 2021-12-24 Preparation and application of novel drug microsphere containing carrier material Pending CN116036022A (en)

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