CN117679372A - Controlled release composite microsphere and preparation method and application thereof - Google Patents
Controlled release composite microsphere and preparation method and application thereof Download PDFInfo
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- CN117679372A CN117679372A CN202311460176.0A CN202311460176A CN117679372A CN 117679372 A CN117679372 A CN 117679372A CN 202311460176 A CN202311460176 A CN 202311460176A CN 117679372 A CN117679372 A CN 117679372A
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- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
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- XSMMCTCMFDWXIX-UHFFFAOYSA-N zinc silicate Chemical compound [Zn+2].[O-][Si]([O-])=O XSMMCTCMFDWXIX-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
-
- 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)
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a controlled release composite microsphere, a preparation method and application thereof, wherein the controlled release composite microsphere comprises the following components: the drug-loaded mesoporous material comprises a magnetic nanoparticle and an inner core of the drug-loaded mesoporous material, wherein the drug-loaded mesoporous material comprises a mesoporous material loaded with a therapeutic agent; the inner core sequentially coats the first coating layer and the second coating layer; the first coating layer comprises a polydopamine layer and/or a gel layer, and the second coating layer comprises a degradable polyester layer. The controlled release composite microsphere has long-acting drug release performance, and the drug release period can reach more than 80 days; the magnetic field-driven slow-release preparation has the advantages of accelerating slow-release effect of the medicine, stronger controlled-release capacity of the medicine, good biocompatibility and bioactivity, and capability of being used as a scaffold material for supporting cell adhesion and proliferation and effectively promoting tissue repair and reconstruction.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a controlled release composite microsphere, and a preparation method and application thereof.
Background
The materials currently applied to the microspheres mainly comprise inorganic materials, natural polymers and synthetic polymers, and are classified into degradable materials and non-degradable materials according to degradation performance. Polyesters are the most widely studied biodegradable synthetic polymeric materials such as polylactic acid, polyglycolic acid, polyepsilon caprolactone, poly beta hydroxybutyric acid, poly beta hydroxyvaleric acid and copolymers thereof. Water-soluble polymers such as chitosan, sodium alginate, hyaluronic acid and gelatin are also used as carrier materials of medicines, but the degradation behavior of the water-soluble polymers is uncontrollable, so that slow release of medicines is not facilitated due to excessively high burst release; or hydrophobic polymers such as polylactic acid, polyglycolic acid, poly epsilon-caprolactone, poly beta-hydroxybutyric acid, poly beta-hydroxyvaleric acid and copolymers thereof are adopted as carrier materials of medicines, but the medicine release curve of the material prepared from the pure hydrophobic polymers is single, and the effect of controlling release according to the needs is difficult to achieve. Therefore, the microsphere preparation prepared by combining the water-soluble polymer and the hydrophobic polymer can better regulate and control the release curve of the drug, but still can not achieve the aim of controlling the release of the drug according to the requirement.
In recent years, the magnetic response nanocomposite has become an excellent bone tissue engineering scaffold material due to good biocompatibility, biological absorbability, mechanical properties, magnetic response and the like. It has been found that magnetic materials can be used to treat bone diseases such as fractures, bone defects, osteotomies, osteoporosis, etc. by modulating osteoblast behavior (e.g., cell adhesion, migration, proliferation, differentiation, etc.) under static or pulsed electromagnetic fields. It is speculated that the enhanced osteogenic differentiation of cells under magnetic stimulation may be mainly due to magneto-mechanical force stimulation, i.e. the deformation of the magnetic coating under the action of a magnetic field acts on the cells, further activating the mechanical transduction signaling channels and thus promoting the osteogenic differentiation of cells. Meanwhile, the magnetic responsive material can deform or move by applying an external magnetic field to the magnetic responsive material, so that the active regulation and control of the drug release performance of the material is facilitated.
Disclosure of Invention
The present invention aims to solve at least one of the above technical problems in the prior art. Therefore, the invention aims to provide a controlled release composite microsphere, a preparation method and application thereof, and the controlled release composite microsphere has the functions of drug controlled release and magnetic response.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided a controlled release composite microsphere comprising:
the drug-loaded mesoporous material comprises a magnetic nanoparticle and an inner core of the drug-loaded mesoporous material, wherein the drug-loaded mesoporous material comprises a mesoporous material loaded with a therapeutic agent;
the inner core sequentially coats the first coating layer and the second coating layer;
the first coating layer comprises a polydopamine layer and/or a gel layer, and the second coating layer comprises a degradable polyester layer.
In some embodiments of the invention, the mass ratio of the therapeutic agent to mesoporous material is 1: (0.8-2000); preferably 1: (1-2000); preferably 1: (0.8-1000); the method comprises the following steps: 1. 1: 5. 1: 20. 7: 20. 4: 5. 1: 500. 1: 1000. 1:1500, etc.
In some embodiments of the present invention, the mass ratio of the drug-loaded mesoporous material, the magnetic nanoparticle and the polydopamine is (40-150): (40-100): 1.
in some embodiments of the invention, the mass ratio of the drug-loaded mesoporous material, the magnetic nanoparticle and the gel is (6-12): (4-13): 1.
in some embodiments of the invention, the mass ratio of the first cladding layer clad core to the second cladding layer is 1: (2.5-25); preferably 1: (2.5-20).
In some embodiments of the invention, the mesoporous material is particulate; preferably, the average particle size of the mesoporous material is 40 nm-120 nm; and/or the specific surface area of the mesoporous material is 200m 2 /g～2000m 2 /g; and/or the average pore diameter of the mesoporous material is 2 nm-40 nm.
In some embodiments of the invention, the degradable polyester has a molecular weight of 2 to 15 kilodaltons.
In some embodiments of the invention, the controlled release composite microsphere has an average particle size of 0.05mm to 2mm.
In some embodiments of the invention, the release period of the therapeutic agent in the controlled release composite microsphere is at least 80 days; preferably, the release period of the therapeutic agent in the controlled release composite microsphere is 80 to 95 days, such as 81 to 91 days.
In some embodiments of the invention, the therapeutic agents include, but are not limited to, chemotherapeutic agents, biotherapeutic agents, such as antineoplastic agents, antibodies, anti-inflammatory agents, and immunotherapeutic agents, as well as other natural or artificial drugs with specific functions, such as vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor, keratinocyte growth factor, nerve growth factor, ertapenem, imipenem, meropenem, piperacillin/tazobactam, amikacin, colistin, polymyxin B, para-linezolid, vancomycin, tetracycline, tigecycline, fluorouracil, amphotericin B, caspofungin, voriconazole, berberine hydrochloride, gentamicin, resveratrol, vitamin D, melatonin, naringin, rifampicin, triclosan, chlorhexidine, bone morphogenic protein, platelet derived factors, transforming growth factors, insulin-like growth factors, parathyroid hormone, growth hormone, interleukin, alendronate sodium, sodium phosphate, strontium phosphate, sodium phosphate, and at least one of the group of sodium phosphate, and sodium phosphate.
In some embodiments of the invention, the magnetic nanoparticles comprise at least one of iron, cobalt, nickel, and/or metal oxides thereof; such as at least one of ferric oxide and ferric oxide.
In some embodiments of the invention, the mesoporous material comprises at least one of mesoporous silicon, mesoporous calcium silicate, mesoporous magnesium silicate, mesoporous zinc silicate, mesoporous strontium silicate, mesoporous bioglass, mesoporous hydroxyapatite.
In some embodiments of the invention, the gel layer comprises a natural polymer comprising at least one of alginate, silk fibroin, hyaluronic acid, chondroitin sulfate, chitosan quaternary ammonium salt, carboxymethyl chitosan, dextran, polyvinyl alcohol, polyethylene glycol-polypropylene glycol-polyethylene glycol, sericin, degummed silk, polyethylene glycol, gelatin, collagen, cyclodextrin, serum albumin.
In some embodiments of the invention, the degradable polyester comprises at least one of polylactic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, poly 3-hydroxyalkanoate, poly (3-hydroxybutyrate), poly 3-hydroxybutyrate-co-3-hydroxyvalerate, polytrimethylene carbonate, polybutylene succinate.
In a second aspect of the present invention, a method for preparing the controlled release composite microsphere is provided, comprising the following steps:
s1: dispersing the mesoporous material in an aqueous solution containing a therapeutic agent, and drying to obtain a drug-loaded mesoporous material;
s2: dispersing the magnetic nano particles and the drug-loaded mesoporous material in dopamine and/or gel water solution, and drying to obtain a polydopamine and/or gel coated inner core;
s3: dispersing the polydopamine and/or gel coated inner core in an organic solvent containing degradable polyester to form a blend;
s4: adding the blend into water phase containing emulsifier, dispersing to obtain the controlled release composite microsphere.
In the invention, a plurality of methods for preparing the drug-loaded microspheres comprise an emulsifying solvent volatilization method, a phase separation method, an emulsifying solvent extraction method, a spray drying method, a melting method and the like, wherein the emulsifying solvent volatilization method can be further subdivided into an O/W emulsifying method and an O 1 /O 2 Emulsification, multiple emulsion-in-liquid drying, and the like. The drug-loaded microsphere prepared by the invention uses degradable polyester as a shell layer for coating the magnetic nano-particles, so that the preparation by an O/W emulsion method is more suitable. For the purposes of the present invention, the O/W emulsion method is to divide magnetic nanoparticlesDispersing in aqueous solution containing therapeutic agent, and drying to obtain magnetic nanoparticle with therapeutic agent pre-loaded; dispersing magnetic nano-particles of the pre-loaded therapeutic agent in a dopamine-containing and/or gel water solution, and drying to obtain a polydopamine-and/or gel-coated inner core; dispersing the polydopamine and/or gel coated inner core in an organic solvent containing degradable polyester to form a blend; and adding the blend into a water phase containing an emulsifier, and dispersing to form the intelligent controlled-release composite microsphere. The microspheres formed may optionally be collected by centrifugation, washing, sieving, etc. as is commonly practiced in the art, and further optionally by vacuum drying and/or freeze drying to obtain dry powders of the microspheres.
In some embodiments of the present invention, in S3, the organic solvent comprises a volatile organic solvent of at least one of dichloromethane, chloroform, ethyl acetate, ethanol, methanol, acetone, and the like; preferably dichloromethane. The solubility of the organic solvent in the aqueous phase and other properties are related to the particle size, encapsulation efficiency and drug loading of the formed controlled release composite microspheres.
In some embodiments of the invention, the concentration of the emulsifier is from 2mg/mL to 15mg/mL; and/or the emulsifier comprises at least one of polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium polyacrylate, gelatin, tween, span and sodium polymethacrylate. The type and concentration of the emulsifier are related to the size of liquid drops in the formed emulsion, the dispersion degree of the magnetic nano particles and the therapeutic agent and the water phase, and the entrapment rate and the drug loading rate in the intelligent controlled release composite microsphere can be improved to a certain extent by adopting polyvinyl alcohol and sodium carboxymethyl cellulose as the emulsifier and selecting a specific concentration.
In some embodiments of the invention, in S1, the speed of rotation of the dispersion is 150rpm to 1000rpm; preferably 200rpm to 1000rpm; preferably 150rpm to 800rpm; and/or the dispersing time is 4-24 hours; preferably 8 to 24 hours; and/or the dispersing temperature is 0-40 ℃.
In some embodiments of the invention, in S2, the degree of rotation of the dispersion is from 100rpm to 800rpm; preferably 200rpm to 500rpm; and/or, the dispersing time is 2-24 hours; preferably 6 to 24 hours; and/or, the dispersing temperature is 0-40 ℃; preferably from 4℃to 40 ℃.
In some embodiments of the invention, in S3, the temperature of the dispersion is from 0 ℃ to 40 ℃.
In some embodiments of the invention, in S4, the degree of rotation of the dispersion is 150rpm to 800rpm; preferably 150rpm to 700rpm; and/or, the dispersing time is 6-32 h; preferably 6 to 30 hours; and/or, the dispersing temperature is 0-40 ℃; preferably from 10℃to 40 ℃.
In the invention, the dispersion method adopted in the process of forming emulsion and evaporating the organic solvent has a certain influence on the formation of the microsphere, and the particle size and the encapsulation rate of the obtained intelligent controlled-release composite microsphere can be increased by adopting the dispersion method.
In a third aspect of the invention, a medical composition is provided comprising the controlled release composite microsphere.
By utilizing the intelligent controlled release composite microsphere, a further medical composition can be obtained, and the medical purpose (such as tissue injury repair and regeneration) based on a specific therapeutic agent is realized through the magnetic effect and the drug controlled release effect of the microsphere. For example, a scaffold, dressing, or other composite material comprising the intelligent controlled release composite microspheres described above, and the like.
In a fourth aspect of the invention, a medical device is provided comprising said controlled release composite microsphere and/or said pharmaceutical composition. In the invention, the tissue injury repair is realized by using the controlled release composite microsphere based on an implantable device of a drug controlled release system or a combined device of the drug controlled release system and magnetic field generating equipment.
The beneficial effects of the invention are as follows:
1. the intelligent controlled release composite microsphere takes the degradable polyester as a matrix material and is combined with polydopamine and/or gel and magnetic nano particles and drug-loaded mesoporous materials in sequence, so that the intelligent controlled release composite microsphere has long-acting drug release performance, and the drug release period can reach more than 80 days; the magnetic field-driven slow-release preparation has the advantages of accelerating slow-release effect of the medicine, stronger controlled-release capacity of the medicine, good biocompatibility and bioactivity, and capability of being used as a scaffold material for supporting cell adhesion and proliferation and effectively promoting tissue repair and reconstruction.
2. In the invention, the preparation is carried out by an emulsion solvent volatilization method, the method is simpler, the requirement on equipment is not high, the raw material sources are easy to obtain, the cost is low, and the industrialization is easy to realize.
Drawings
FIG. 1 shows the results of the detection of the drug release properties outside the microspheres of examples 1 to 5 and comparative examples 1 to 4.
FIG. 2 shows the results of the detection of the drug release properties outside the microspheres of examples 6 to 10 and comparative examples 5 to 8.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The starting materials, reagents or apparatus used in the examples and comparative examples were either commercially available from conventional sources or may be obtained by prior art methods unless specifically indicated. Unless otherwise indicated, assays or testing methods are routine in the art.
Example 1
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous hydroxyapatite in 0.1mL of aqueous solution containing 0.05mg of vascular endothelial growth factor at 0 ℃, stirring at 200rpm for 24min, and freeze-drying to obtain a drug-loaded mesoporous material; dispersing 60mg of nano ferric oxide particles and 40mg of drug-loaded mesoporous material in 4mL of aqueous solution containing 10mg of dopamine at 4 ℃, stirring at 200rpm for 18min, and freeze-drying to obtain a polydopamine-coated inner core; dispersing 100mg of the polydopamine-coated core powder into 10mL of trichloromethane solution containing 1g of polytrimethylene carbonate (with a molecular weight of 15 ten thousand daltons) at 4 ℃ to form a blend; 600mL of aqueous solution containing 1.8g of methylcellulose is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 0 ℃, and after continuous stirring for 30 hours at 500rpm, the intelligent controlled-release dopamine-containing composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Example 2
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous calcium silicate in 1.5mL of aqueous solution containing 100mg of alendronate sodium at 40 ℃, stirring at 500rpm for 12min, and freeze-drying to obtain a drug-loaded mesoporous material; dispersing 60mg of nano ferroferric oxide particles and 60mg of drug-loaded mesoporous material in 8mL of aqueous solution containing 12mg of dopamine at 0 ℃, stirring at 800rpm for 2min, and freeze-drying to obtain a polydopamine-coated inner core; dispersing 40mg of the drug-loaded mesoporous material wrapped by polydopamine and magnetic nanoparticle powder in 10mL of dichloromethane solution containing 1g of polylactic acid (with the molecular weight of 5 ten thousand daltons) at 20 ℃ to form a blend; 400mL of aqueous solution containing 3.5g of polyvinyl alcohol is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 20 ℃, and after continuous stirring for 18 hours at 250rpm, the intelligent controlled-release dopamine-containing composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Example 3
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous silicon in 0.9mL of aqueous solution containing 35mg of resveratrol at 4 ℃, stirring at 1000rpm for 4min, and freeze-drying to obtain a drug-loaded mesoporous material; dispersing 30mg of nano ferric oxide particles and 70mg of drug-loaded mesoporous material in 5mL of aqueous solution containing 10mg of dopamine at 40 ℃, stirring at 400rpm for 15min, and freeze-drying to obtain a polydopamine-coated inner core; dispersing 150mg of the polydopamine-coated core powder in 10mL of chloroform solution containing 1g of poly (3-hydroxybutyrate) -co-3-hydroxyvalerate (with a molecular weight of 6 ten thousand daltons) at 0 ℃ to form a blend solution; preparing 500mL of aqueous solution containing 4g of gelatin as an aqueous phase containing an emulsifier, slowly dripping the blend into the aqueous phase at 40 ℃, continuously stirring at 150rpm for 24 hours, and then depositing, separating, cleaning and freeze-drying to obtain the intelligent controlled-release dopamine-containing composite microsphere.
Example 4
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous bioglass in 1.2mL of aqueous solution containing 80mg of dexamethasone at 15 ℃, stirring at 400rpm for 8min, and freeze-drying to obtain a drug-loaded mesoporous material; dispersing 50mg of nano ferroferric oxide particles and 150mg of drug-loaded mesoporous material in 6mL of aqueous solution containing 20mg of dopamine at 20 ℃, stirring at 250rpm for 12min, and freeze-drying to obtain a polydopamine-coated inner core; dispersing 200mg of the polydopamine-coated core powder into 10mL of ethyl acetate solution containing 1g of polylactic acid-glycolic acid copolymer (with a molecular weight of 2 ten thousand daltons) at 40 ℃ to form a blend; preparing 300mL of aqueous solution containing 4.5g of polyvinyl alcohol as an aqueous phase containing an emulsifier, slowly dripping the blending solution into the aqueous phase at 15 ℃, continuously stirring at 700rpm for 6 hours, and then depositing, separating, cleaning and freeze-drying to obtain the intelligent controlled-release dopamine-containing composite microsphere.
Example 5
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous magnesium silicate in 0.6mL of aqueous solution containing 20mg of vancomycin at 20 ℃, stirring at 300rpm for 18min, and freeze-drying to obtain a drug-loaded mesoporous material; dispersing 100mg of nano ferroferric oxide particles and 150mg of drug-loaded mesoporous material in 11mL of aqueous solution containing 15mg of dopamine at 15 ℃, stirring at 100rpm for 24min, and freeze-drying to obtain a polydopamine-coated inner core; dispersing 400mg of the polydopamine-coated core powder into 10mL of tetrahydrofuran solution containing 1g of polycaprolactone (with a molecular weight of 6 ten thousand daltons) at 35 ℃ to form a blend; preparing 300mL of aqueous solution containing 3g of methylcellulose as an aqueous phase containing an emulsifier, slowly dripping the blending solution into the aqueous phase at 25 ℃, continuously stirring for 12 hours at 300rpm, and then depositing, separating, cleaning and freeze-drying to obtain the intelligent controlled-release dopamine-containing composite microsphere.
Example 6
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous calcium silicate in 0.7ml of aqueous solution containing 30mg of gentamicin at 30 ℃, stirring at 300rpm for 15 hours, and freeze-drying to obtain a mesoporous material loaded with a therapeutic agent; dispersing 1000mg of nano ferric oxide particles and 1000mg of mesoporous material loaded with a therapeutic agent in 15ml of aqueous solution containing 100mg of gelatin at 40 ℃, stirring at 500rpm for 6min, and freeze-drying to obtain gel-coated drug-loaded mesoporous material and magnetic nanoparticles; dispersing 200mg of the gel-coated drug-loaded mesoporous material and magnetic nanoparticle powder in 10ml of tetrahydrofuran solution containing 1g of polytrimethylene carbonate (with the molecular weight of 7 kilodaltons) at 18 ℃ to form a blend solution; preparing 500ml of aqueous solution containing 3g of polyvinyl alcohol as an aqueous phase containing an emulsifier, slowly dripping the blending solution into the aqueous phase at 40 ℃, continuously stirring for 12 hours at 500rpm, and then depositing, separating, cleaning and freeze-drying to obtain the intelligent controlled-release gel-containing composite microsphere.
Example 7
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous silicon in 1ml of aqueous solution containing 125mg of alendronate sodium at 40 ℃, stirring at 200rpm for 12 hours, and freeze-drying to obtain a mesoporous material loaded with a therapeutic agent; dispersing 2600mg of nano ferric oxide particles and 1400mg of mesoporous material loaded with a therapeutic agent in 15ml of aqueous solution containing 200mg of hyaluronic acid at 25 ℃, stirring at 400rpm for 12min, and freeze-drying to obtain gel-coated drug-loaded mesoporous material and magnetic nanoparticles; dispersing 150mg of the gel-coated drug-loaded mesoporous material and magnetic nanoparticle powder in 10ml of tetrahydrofuran solution containing 1g of polylactic acid-glycolic acid copolymer (with the molecular weight of 6 ten thousand daltons) at the temperature of 40 ℃ to form a blend solution; 600ml of aqueous solution containing 12g of gelatin is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 20 ℃, and after continuous stirring for 32 hours at 180rpm, the intelligent controlled-release gel-containing composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Example 8
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous bioglass in 0.1ml of aqueous solution containing 0.1mg of bone morphogenetic protein at 0 ℃, stirring at 150rpm for 24 hours, and freeze-drying to obtain a mesoporous material loaded with a therapeutic agent; dispersing 400mg of nano ferroferric oxide particles and 1200mg of mesoporous material loaded with a therapeutic agent in 8ml of aqueous solution containing 100mg of silk fibroin at 4 ℃, stirring at 200rpm for 18min, and freeze-drying to obtain gel-coated drug-loaded mesoporous material and magnetic nanoparticles; dispersing 50mg of the gel-coated drug-loaded mesoporous material and magnetic nanoparticle powder in 10ml of trichloromethane solution containing 1g of polylactic acid (with the molecular weight of 2 ten thousand daltons) at the temperature of 0 ℃ to form a blend solution; 400ml of aqueous solution containing 12g of polyvinyl alcohol is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 25 ℃, and after continuous stirring for 24 hours at 200rpm, the intelligent controlled-release gel-containing composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Example 9
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous hydroxyapatite in 0.5ml of aqueous solution containing 50mg of resveratrol at 15 ℃, stirring at 350rpm for 8 hours, and freeze-drying to obtain a mesoporous material loaded with a therapeutic agent; dispersing 600mg of nano ferroferric oxide particles and 300mg of mesoporous material loaded with a therapeutic agent in 6ml of aqueous solution containing 50mg of collagen at 30 ℃, stirring at 350rpm for 15min, and freeze-drying to obtain gel-coated drug-loaded mesoporous material and magnetic nanoparticles; dispersing 400mg of the gel-coated drug-loaded mesoporous material and magnetic nanoparticle powder in 10ml of dichloromethane solution containing 1g of poly 3-hydroxybutyrate-co-3-hydroxyvalerate (with a molecular weight of 15 ten thousand daltons) at 20 ℃ to form a blend solution; 300ml of aqueous solution containing 4.5g of methyl cellulose is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 10 ℃, and after continuous stirring for 6 hours at 800rpm, the intelligent controlled-release gel-containing composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Example 10
The embodiment prepares a controlled release composite microsphere, which comprises the following specific processes:
dispersing 100mg of mesoporous strontium silicate in 0.6ml of aqueous solution containing 40mg of vancomycin at 20 ℃, stirring at 800rpm for 4 hours, and freeze-drying to obtain a mesoporous material loaded with a therapeutic agent; dispersing 400mg of nano ferric oxide particles and 880mg of mesoporous material loaded with a therapeutic agent in 10ml of aqueous solution containing 80mg of carboxymethyl chitosan at 15 ℃, stirring at 300rpm for 24min, and freeze-drying to obtain gel-coated drug-loaded mesoporous material and magnetic nanoparticles; dispersing 300mg of the gel-coated drug-loaded mesoporous material and magnetic nanoparticle powder in 10ml of ethyl acetate solution containing 1g of polybutylene succinate (with the molecular weight of 8 ten thousand daltons) at 25 ℃ to form a blend solution; preparing 300ml of aqueous solution containing 3g of methylcellulose as an aqueous phase containing an emulsifier, slowly dripping the blending solution into the aqueous phase at 30 ℃, continuously stirring for 24 hours at 300rpm, and then depositing, separating, cleaning and freeze-drying to obtain the intelligent controlled-release gel-containing composite microsphere.
Comparative example 1
This comparative example produced a microsphere that differed from example 2 in that it did not contain magnetic nanoparticles, specifically by:
dispersing 100mg of mesoporous calcium silicate in 1.5mL of aqueous solution containing 100mg of alendronate sodium at 40 ℃, stirring at 500rpm for 12min, and freeze-drying to obtain a drug-loaded mesoporous material; dispersing 60mg of drug-loaded mesoporous material in 8mL of aqueous solution containing 12mg of dopamine at 0 ℃, stirring at 800rpm for 2min, and freeze-drying to obtain a polydopamine-coated drug-loaded mesoporous material; dispersing 40mg of the drug-loaded mesoporous material powder wrapped by polydopamine in 10mL of dichloromethane solution containing 1g of polylactic acid (with a molecular weight of 5 ten thousand daltons) at 20 ℃ to form a blend; 400mL of aqueous solution containing 3.5g of polyvinyl alcohol is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 20 ℃, and after continuous stirring for 18 hours at 250rpm, the dopamine-containing composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Comparative example 2
The comparative example prepared a microsphere, which differs from example 2 in that it does not contain mesoporous materials, and the specific process is:
dispersing 60mg of nano ferroferric oxide particles and 30mg of alendronate sodium in 8mL of aqueous solution containing 12mg of dopamine at 0 ℃, stirring at 800rpm for 2min, and freeze-drying to obtain a polydopamine-coated therapeutic agent and magnetic nanoparticles; dispersing 40mg of the polydopamine-coated therapeutic agent and magnetic nanoparticle powder in 10mL of dichloromethane solution containing 1g of polylactic acid (with a molecular weight of 5 ten thousand daltons) at 20 ℃ to form a blend; 400mL of aqueous solution containing 3.5g of polyvinyl alcohol is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 20 ℃, and after continuous stirring for 18 hours at 250rpm, the intelligent controlled-release dopamine-containing composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Comparative example 3
The comparative example produced a microsphere differing from example 2 in that it did not contain polydopamine, and the specific procedure was:
dispersing 100mg of mesoporous calcium silicate in 1.5mL of aqueous solution containing 100mg of alendronate sodium at 40 ℃, stirring at 500rpm for 12min, and freeze-drying to obtain a drug-loaded mesoporous material; dispersing 20mg of nano ferroferric oxide particles and 20mg of drug-loaded mesoporous material in 10mL of dichloromethane solution containing 1g of polylactic acid (with a molecular weight of 5 ten thousand daltons) at 20 ℃ to form a blend; 400mL of aqueous solution containing 3.5g of polyvinyl alcohol is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 20 ℃, and after continuous stirring for 18 hours at 250rpm, the intelligent controlled-release composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Comparative example 4
The comparative example prepared a microsphere, which is different from example 2 in that it does not contain mesoporous material and polydopamine, and specifically comprises the following steps:
dispersing 20mg of nano ferroferric oxide particles and 30mg of alendronate sodium in 10mL of dichloromethane solution containing 1g of polylactic acid (with a molecular weight of 5 ten thousand daltons) at 20 ℃ to form a blend; 400mL of aqueous solution containing 3.5g of polyvinyl alcohol is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 20 ℃, and after continuous stirring for 18 hours at 250rpm, the intelligent controlled-release composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Comparative example 5
This comparative example produced a microsphere that differed from example 9 in that it did not contain magnetic nanoparticles, specifically by:
dispersing 100mg of mesoporous hydroxyapatite in 0.5ml of aqueous solution containing 50mg of resveratrol at 15 ℃, stirring at 350rpm for 8 hours, and freeze-drying to obtain a mesoporous material loaded with a therapeutic agent; dispersing 300mg of mesoporous material loaded with therapeutic agent in 6ml of aqueous solution containing 50mg of collagen at 30 ℃, stirring at 350rpm for 15min, and freeze-drying to obtain gel-coated mesoporous material loaded with the drug; dispersing 400mg of the gel-coated medicine-carrying mesoporous material powder in 10ml of dichloromethane solution containing 1g of poly 3-hydroxybutyrate-co-3-hydroxyvalerate (with a molecular weight of 15 ten thousand daltons) at 20 ℃ to form a blend solution; 300ml of an aqueous solution containing 4.5g of methylcellulose is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 10 ℃, and after continuous stirring for 6 hours at 800rpm, the gel-containing composite microsphere is obtained by deposition, separation, washing and freeze drying.
Comparative example 6
The comparative example produced a microsphere, which differs from example 9 in that it does not contain mesoporous materials, and the specific process is:
dispersing 600mg of nano ferroferric oxide particles and 100mg of resveratrol in 6ml of aqueous solution containing 50mg of collagen at 30 ℃, stirring at 350rpm for 15min, and freeze-drying to obtain gel-coated drug-loaded magnetic nano particles; dispersing 400mg of the gel-coated drug-loaded magnetic nanoparticle powder in 10ml of dichloromethane solution containing 1g of poly 3-hydroxybutyrate-co-3-hydroxyvalerate (with a molecular weight of 15 ten thousand daltons) at 20 ℃ to form a blend solution; 300ml of aqueous solution containing 4.5g of methyl cellulose is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 10 ℃, and after continuous stirring for 6 hours at 800rpm, the intelligent controlled-release gel-containing composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Comparative example 7
This comparative example produced a microsphere that differed from example 9 in that it did not contain a gel, specifically by:
dispersing 100mg of mesoporous hydroxyapatite in 0.5ml of aqueous solution containing 50mg of resveratrol at 15 ℃, stirring at 350rpm for 8 hours, and freeze-drying to obtain a mesoporous material loaded with a therapeutic agent; 267mg of nano ferroferric oxide particles and 133mg of mesoporous material loaded with a therapeutic agent are dispersed in 10ml of dichloromethane solution containing 1g of poly 3-hydroxybutyrate-co-3-hydroxyvalerate (molecular weight of 15 ten thousand daltons) at 20 ℃ to form a blend solution; 300ml of aqueous solution containing 4.5g of methyl cellulose is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 10 ℃, and after continuous stirring for 6 hours at 800rpm, the intelligent controlled-release composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Comparative example 8
The comparative example produced a microsphere, which differs from example 9 in that it does not contain mesoporous material and gel, and the specific process is:
267mg of nano ferroferric oxide particles and 44mg of resveratrol are dispersed in 10ml of methylene chloride solution containing 1g of poly 3-hydroxybutyrate-co-3-hydroxyvalerate (molecular weight of 15 ten thousand daltons) at 20 ℃ to form a blend solution; 300ml of aqueous solution containing 4.5g of methyl cellulose is prepared as an aqueous phase containing an emulsifier, the blend is slowly dripped into the aqueous phase at 10 ℃, and after continuous stirring for 6 hours at 800rpm, the intelligent controlled-release composite microsphere is obtained through deposition, separation, cleaning and freeze drying.
Test example 1
The products of examples 1 to 10 and comparative examples 1 to 8 were evaluated for cytotoxicity in vitro and drug release performance in vitro, respectively.
In vitro cytotoxicity evaluation was evaluated with reference to the requirements of GB/T16886.5.
The in vitro drug release performance evaluation method comprises the following steps: the cumulative release rate of the therapeutic agent was calculated by immersing 500mg of the product in 200mL of PBS (ph=7.4) in a constant temperature shaker at 37 ℃ and 60rpm, periodically collecting the test solution and supplementing the same amount of PBS, measuring the content of the therapeutic agent in the collected test solution by High Performance Liquid Chromatography (HPLC), and comparing the total amount of the therapeutic agent loaded in the product. Wherein, in order to study the effect on the release performance of microsphere drugs under the action of a magnetic field. The product of example 1 immersed in PBS was placed in a magnetic coil of a low frequency dynamic magnetic field device, and the magnetic field intensity distribution in the magnetic coil was uniform, at 10mt.
The results are shown in tables 1, 2, fig. 1 and 2.
TABLE 1
Remarks: the cell viability of the blank, negative and positive control groups was 100%, 82.43%, 14.37%, respectively.
The results of in vitro cytotoxicity evaluation are shown in tables 1 and 2, and as can be seen from the tables, the intelligent controlled release dopamine-containing composite microsphere prepared by the preparation method provided by the application has no cytotoxicity.
TABLE 2
Remarks: the cell viability of the blank, negative and positive control groups was 100%, 82.43%, 14.37%, respectively.
The results of in vitro drug release performance tests of examples 1 to 5 and comparative examples 1 to 4 are shown in FIG. 1 and Table 3.
TABLE 3 cumulative Release Rate (%)
The results of the in vitro drug release performance tests of examples 6 to 10 and comparative examples 5 to 8 are shown in FIG. 2 and Table 4.
TABLE 4 cumulative Release Rate (%)
Comparative examples 1 to 4 are composite microspheres containing alendronate sodium; example 2-magnetic field effect microspheres were placed in an alternating magnetic field when evaluating drug release properties, no magnetic nanoparticles were used in comparative example 1, no mesoporous material was used in comparative example 2, no polydopamine was used in comparative example 3, and no mesoporous material and polydopamine were used in comparative example 4. As can be seen from the figure, the drug release rate is significantly faster in the example 2-magnetic field action group under the action of alternating magnetic field compared with the example 2. The microsphere obtained in the comparative example can solve the problem of burst release to a certain extent without using magnetic nano particles, and the slow release period is close to that of the intelligent controlled release dopamine-containing composite microsphere provided in the example 2; the mesoporous material is not used in the comparative example 2, so that the drug release rate is obviously accelerated and is close to that of the magnetic field action group in the example 2; in comparative example 3, polydopamine was not used, and the drug release rate was accelerated, which was intermediate between example 2 and comparative example 2; the mesoporous material and polydopamine were not used in comparative example 4, and the drug release rate was the fastest.
Comparative examples 5 to 8 are composite microspheres containing alendronate sodium; however, example 9-magnetic field effect microspheres were placed in an alternating magnetic field when evaluating drug release properties, no magnetic nanoparticles were used in comparative example 5, no mesoporous material was used in comparative example 6, no gel was used in comparative example 7, and no mesoporous material and gel were used in comparative example 8. As can be seen from the figure, the example 9-magnetic field effect group showed significantly faster drug release rate under alternating magnetic field compared to example 9. The microsphere obtained in the comparative example can solve the problem of burst release to a certain extent without using magnetic nano particles, and the slow release period is close to that of the intelligent controlled release gel-containing composite microsphere provided in the example 9; the comparative example 6, in which no mesoporous material was used, had significantly faster drug release rates, between example 9 and the example 9-magnetic field active group; in comparative example 7, no gel was used, and the drug release rate was accelerated, which was intermediate between example 9 and comparative example 6; the release rate of the drug was significantly faster without the use of mesoporous materials and gels in comparative example 8, which is similar to that of the magnetic field active set of example 9.
From the above results, it can be seen that the controlled release composite microsphere of the present invention can 1) maintain good biocompatibility after compositing magnetic nanoparticles, mesoporous materials, polydopamine and/or gel, and degradable polyester, 2) provide the materials with good long-acting slow release function, and 2) provide the materials with good magnetic response controlled release function, so that the controlled release composite microsphere is more suitable for repairing and regenerating tissues, and is also more suitable for treating diseases such as bacterial infection, inflammation, etc.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. A controlled release composite microsphere, characterized in that: comprising the following steps:
the drug-loaded mesoporous material comprises a magnetic nanoparticle and an inner core of the drug-loaded mesoporous material, wherein the drug-loaded mesoporous material comprises a mesoporous material loaded with a therapeutic agent;
the inner core sequentially coats the first coating layer and the second coating layer;
the first coating layer comprises a polydopamine layer and/or a gel layer, and the second coating layer comprises a degradable polyester layer.
2. The controlled release composite microsphere according to claim 1, wherein: the mass ratio of the therapeutic agent to the mesoporous material is 1: (0.8-2000).
3. The controlled release composite microsphere according to claim 1, wherein: the mass ratio of the drug-loaded mesoporous material to the magnetic nano particles to the polydopamine is (40-150): (40-100): 1.
4. the controlled release composite microsphere according to claim 1, wherein: the mass ratio of the drug-loaded mesoporous material to the magnetic nano particles to the gel is (6-12): (4-13): 1.
5. the controlled release composite microsphere according to claim 1, wherein: the mass ratio of the inner core coated by the first coating layer to the second coating layer is 1: (2.5-25).
6. The controlled release composite microsphere according to claim 1, wherein: the average particle diameter of the controlled release composite microsphere is 0.05 mm-2 mm.
7. The controlled release composite microsphere according to claim 1, wherein: the release period of the therapeutic agent in the controlled release composite microsphere is at least 80 days.
8. A method for preparing the controlled release composite microsphere according to any one of claims 1 to 7, wherein: the method comprises the following steps:
s1: dispersing the mesoporous material in an aqueous solution containing a therapeutic agent, and drying to obtain a drug-loaded mesoporous material;
s2: dispersing the magnetic nano particles and the drug-loaded mesoporous material in dopamine and/or gel water solution, and drying to obtain a polydopamine coated inner core;
s3: dispersing the polydopamine coated inner core in an organic solvent containing degradable polyester to form a blend;
s4: adding the blend into water phase containing emulsifier, dispersing to obtain the controlled release composite microsphere.
9. A medical composition characterized by: comprising a controlled release composite microsphere according to any one of claims 1 to 7.
10. A medical device, characterized by: comprising the controlled release composite microsphere according to any one of claims 1 to 7 and/or the pharmaceutical composition.
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| CN119349524A (en) * | 2024-12-20 | 2025-01-24 | 上海摩漾生物科技有限公司 | A raspberry-shaped biodegradable porous microsphere with high mesoporosity and its preparation method and application |
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Cited By (1)
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| CN119349524A (en) * | 2024-12-20 | 2025-01-24 | 上海摩漾生物科技有限公司 | A raspberry-shaped biodegradable porous microsphere with high mesoporosity and its preparation method and application |
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