CN115120562A - Drug-loaded nanofiber scaffold particle and preparation method and application thereof - Google Patents

Drug-loaded nanofiber scaffold particle and preparation method and application thereof Download PDF

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CN115120562A
CN115120562A CN202110315674.0A CN202110315674A CN115120562A CN 115120562 A CN115120562 A CN 115120562A CN 202110315674 A CN202110315674 A CN 202110315674A CN 115120562 A CN115120562 A CN 115120562A
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drug
nanofiber scaffold
loaded
loaded nanofiber
preparation
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邵莹华
梁阿辉
陈苗苗
聂礼绵
曲洪媛
赵芳
宋德利
吴昌琳
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SUZHOU BOCHUANG TONGKANG BIOLOGICAL ENGINEERING CO LTD
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SUZHOU BOCHUANG TONGKANG BIOLOGICAL ENGINEERING CO LTD
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    • 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
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    • 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
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract

The invention provides a drug-loaded nanofiber scaffold particle as well as a preparation method and application thereof, wherein the drug-loaded nanofiber scaffold particle is a three-dimensional network structure particle formed by drug-loaded nanofibers; the raw materials of the drug-loaded nanofiber comprise high polymer materials; and the drug-loaded nanofiber scaffold particles are prepared by crushing drug-loaded nanofiber scaffold membranes. The invention also provides a preparation method of the drug-loaded nanofiber scaffold particle, which comprises the following steps: preparing a drug-loaded nanofiber scaffold membrane from a high polymer material and a drug, and crushing to obtain the drug-loaded nanofiber scaffold particles. The drug-loaded nanofiber scaffold particles are good in stability and high in biocompatibility, and can realize accurate positioning of drugs and adjust release rate and period; the preparation method is simple and efficient, has various administration modes and has extremely high application value.

Description

Drug-loaded nanofiber scaffold particle and preparation method and application thereof
Technical Field
The invention belongs to the technical field of preparation of drug carriers, and particularly relates to a drug-loaded nanofiber scaffold particle as well as a preparation method and application thereof.
Background
The drug carrier can change the mode of entering the human body and the distribution of the drug in the human body, can convey the drug to a target organ, and controls the release speed of the drug, thereby improving the utilization rate, effectiveness and safety of the drug, and having wide application value.
Currently, the common drug carriers include microspheres, nanoparticles, and liposomes. CN106389356A discloses a controllable preparation method of paclitaxel-loaded PLGA porous microspheres, which adopts a multiple emulsion solvent volatilization method, takes BSA as a pore-forming agent and PLGA as a carrier, wraps paclitaxel in the microspheres, and obtains the paclitaxel-loaded PLGA porous microspheres after washing precipitates by centrifugation, freeze drying. The porous microsphere structure prepared by the method has larger specific surface area and pore volume, and the controllable release of the medicament can be realized by regulating and controlling the size and the pore diameter of the microsphere. However, in the preparation process, an animal-derived pore-forming agent is used, so that certain potential safety hazards exist, the pore-forming agent is difficult to completely remove and has residual risks, the preparation method is complex, and the application of the product is limited.
CN109010926A discloses a method for preparing a porous micro-scaffold and a composite system thereof, wherein a method of chemical cross-linking reaction and then freeze-drying is used to prepare the porous micro-scaffold, but the method can only be used for specific materials and has a narrow application range; meanwhile, the micro-scaffold fiber prepared by the method is thick, and the problem of uneven gaps possibly exists; in addition, the problems of incomplete impurity removal, long process time and the like in the cross-linking reaction exist.
At present, the drug carriers on the market often have the problems of complex preparation method, poor biocompatibility or potential safety hazard. How to provide a novel drug carrier, the preparation method is simple, the safety is higher, the biocompatibility is higher, and a better microenvironment can be provided for adhesion, proliferation and physiological functions of cells, so that the problem to be solved is urgently needed.
Disclosure of Invention
Aiming at the defects and actual requirements of the prior art, the invention provides the drug-loaded nanofiber scaffold particle and the preparation method and application thereof, wherein the drug-loaded nanofiber scaffold particle has sustained-release drug property and targeting property, can realize accurate release of drugs, improves the utilization rate of the drugs, reduces toxic and side effects, and has good dispersibility, stability and biocompatibility, and a wide application range.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a drug-loaded nanofiber scaffold particle, which is a three-dimensional network structure particle formed by drug-loaded nanofibers;
the raw materials of the drug-loaded nanofiber comprise high polymer materials;
and the drug-loaded nanofiber scaffold particles are prepared by crushing drug-loaded nanofiber scaffold membranes.
According to the invention, the nanofiber increases the specific surface area by forming a three-dimensional network structure, so that a small-size effect and a surface interface effect are generated, a large number of contact sites are provided for cells, a medicament can conveniently exert corresponding effects, and the proliferation and tissue repair of the cells can be promoted; by mutually matching the high polymer material and the biological high polymer material, the defects of poor hydrophilicity, poor biocompatibility and poor tissue adhesion capability of a single high polymer material are overcome, the release time of the medicament can be controlled by adjusting the proportion of the high polymer material and the biological high polymer material, the medicament is released stably for a long time, and enzyme degradation in a body is avoided; by adding the active material, the drug-loaded nanofiber scaffold particle has a targeting function, can realize accurate release of the drug, improves the utilization rate of the drug and can reduce the toxic and side effects of the drug; in addition, the micro-particles can be administered in the form of injection, so that the pain of a patient caused by surgical implantation is avoided.
Preferably, the diameter of the nanofibers in the drug-loaded nanofiber scaffold particle is 0.5-60000 nm, such as 0.5nm, 1nm, 10nm, 50nm, 100nm, 500nm, 1000nm, 5000nm, 10000nm, 15000nm, 20000nm, 25000nm, 30000nm, 35000nm, 40000nm, 45000nm, 50000nm, 55000nm or 60000nm, preferably 10-1000 nm.
Preferably, the polymer material includes an organic synthetic polymer material and/or a biopolymer material.
Preferably, the monomer of the organic synthetic polymer material includes any one or a combination of at least two of glycolide, lactide, caprolactone, vinyl alcohol, methyl methacrylate, cyclohexanone-p-oxide, trimethylene carbonate, ethylene, propylene, tetrafluoroethylene, urethane, ethylene glycol, or vinylpyrrolidone, and may be, for example, glycolide or a combination of lactide and caprolactone.
In the present invention, the polymer material may be a single-substance polymer, or a copolymer and/or a block copolymer of a plurality of substances. For example, the polymer material may be any one or a combination of at least two of Polylactide (PLA), Polyglycolide (PGA), Polycaprolactone (PCL), polylactide-glycolide copolymer (PLGA), polyvinyl alcohol, polylactide-polyethylene glycol copolymer, polylactide polyethylene glycol block copolymer, or polymethyl methacrylate (PMMA).
Preferably, the biopolymer material includes any one of polylysine, polyglutamic acid, collagen, gelatin, soy protein, elastin, hyaluronic acid, chitosan, carboxymethyl dextran, carboxymethyl glucose, heparin, alginic acid, chondroitin sulfate, carboxymethyl starch, or carboxymethyl cellulose, or a combination of at least two thereof, and may be, for example, polyglutamic acid or a combination of collagen and silk fibroin.
Preferably, the raw materials for preparing the nanofiber scaffold membrane also comprise an active material.
Preferably, the active material comprises a functional factor and/or a functional polypeptide.
Preferably, the functional factor includes any one of fibronectin, laminin, vascular endothelial growth factor, fibrinogen, nerve growth factor, epidermal growth factor, fibroblast growth factor, transforming growth factor, bone morphogenetic protein, insulin-like growth factor, platelet-derived growth factor, hydroxyapatite, strontium chloride or thrombin or a combination of at least two thereof, for example, fibronectin or a combination of laminin and vascular endothelial growth factor.
Preferably, the functional polypeptide includes any one of or a combination of at least two of-arginine-glycine-aspartic acid-containing polypeptide, valine-glycine-valine-alanine-proline-glycine-containing polypeptide, or isoleucine-lysine-valine-alanine-valine-containing polypeptide, such as a combination of-valine-glycine-valine-alanine-proline-glycine-containing polypeptide or isoleucine-lysine-valine-alanine-valine-containing polypeptide and-arginine-glycine-aspartic acid-containing polypeptide.
Preferably, the drug includes any one or a combination of at least two of antipyretic analgesics, efferent nervous system drugs, narcotics, sedative hypnotics, antipsychotics, central nervous system drugs, antihypertensives, hematologic drugs, endocrine system drugs, antimicrobial drugs, antiparasitic drugs, antitumor drugs, immunomodulator drugs, vitamins, proteinic drugs, polysaccharide drugs, nucleic acid drugs, vaccine biologies or gene therapy drugs, and for example, the drug may be antipyretic analgesics or a combination of analgesics and efferent nervous system drugs.
Preferably, the protein drug comprises a protein drug and/or a polypeptide drug.
Preferably, the nucleic acid drug includes any one of antisense nucleic acid, small interfering RNA or mRNA or a combination of at least two of them, for example, the combination of antisense nucleic acid or small interfering RNA and mRNA.
Preferably, the vaccine-like biological product includes any one of a protein vaccine, a DNA vaccine or an mRNA vaccine or a combination of at least two of them, and for example, may be a protein vaccine or a combination of a DNA vaccine and an mRNA vaccine.
Preferably, the mass fraction of the polymer material in the raw material of the drug-loaded nanofiber is 45% to 99.95%, and may be, for example, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99.95%.
Preferably, the mass fraction of the drug in the constituent raw materials of the drug-loaded nanofibers is 0.01% to 50%, and may be, for example, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.
Preferably, the mass fraction of the active material in the raw material of the drug-loaded nanofiber is 0.01% to 50%, and may be, for example, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.
Preferably, the raw materials of the drug-loaded nanofiber comprise, by mass, 45% -99.95% of a high polymer material, 0.01% -50% of a drug and 0.01% -50% of an active material.
Preferably, the mass ratio of the medicine to the raw materials of the nano-fibers is 1 (1-10000), and the raw materials can be 1:1, 1:10, 1:50, 1:100, 1:500, 1:1000, 1:2000, 1:3000, 1:4000, 1:5000, 1:6000, 1:7000, 1:8000, 1:9000 or 1: 10000.
Preferably, the drug-loaded nanofiber scaffold particle is administered by any one of oral administration, topical administration, aerosol inhalation, surgical implantation, minimally invasive intervention, subcutaneous implantation, intravenous injection, subcutaneous injection or intramuscular injection.
In a second aspect, the present invention provides a method for preparing a drug-loaded nanofiber scaffold microparticle according to the first aspect, the method comprising:
preparing a drug-loaded nanofiber scaffold membrane from a high polymer material and a drug, and crushing to obtain the drug-loaded nanofiber scaffold particles.
In the invention, the drug is loaded in the nanofiber scaffold membrane, so that the drug can be prevented from being degraded in the transportation process; the nano fiber support membrane is prepared and then crushed, so that the specific surface area of particles can be increased, and the biocompatibility is improved; the preparation method is simple, reasonable, scientific, efficient and high in success rate, can realize industrial production, and promotes popularization and use of products.
Preferably, the thickness of the drug-loaded nanofiber scaffold membrane is 0.01 to 1000 μm, and may be, for example, 0.01 μm, 0.05 μm, 0.1 μm, 0.5 μm, 1 μm, 5 μm, 10 μm, 50 μm, 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm or 1000 μm, and is preferably 0.1 to 200 μm.
Preferably, the drug-loaded nanofiber scaffold membrane is prepared by the preparation method I and/or the preparation method II;
wherein the preparation method I comprises the following steps: the polymer material and the drug are combined by an additive manufacturing method to obtain the drug-loaded nanofiber scaffold membrane;
the preparation method II comprises the following steps: the polymer material is made into a nanofiber scaffold membrane through additive manufacturing, and then a drug is combined on the nanofiber scaffold membrane through a surface modification method to obtain the drug-loaded nanofiber scaffold membrane.
Preferably, the preparation method I further comprises a step of adding the drug to the organic synthetic polymer material and/or biopolymer material.
Preferably, the preparation method I further comprises a step of adding the active material to the organic synthetic polymer material and/or biopolymer material.
Preferably, the additive manufacturing process in preparation process I and preparation process II is the same or different.
Preferably, the additive manufacturing comprises electrospinning and/or 3D printing.
Preferably, the electrospinning comprises any one of melt electrospinning, solution electrospinning, coaxial electrospinning, conjugate electrospinning or side-by-side electrospinning.
Preferably, the surface modification in the preparation method II includes any one of electrostatic self-assembly, cross-linking, or spraying.
Preferably, the preparation method further comprises the step of adding an active material.
Preferably, the step of sterilizing is further included after the pulverization.
As a preferred technical scheme, the preparation method of the drug-loaded nanofiber scaffold particle comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 0.01-1000 mu m;
the drug-loaded nanofiber scaffold membrane is prepared by a preparation method I and/or a preparation method II:
the preparation method I comprises the following steps: combining the organic synthetic polymer material and/or biological polymer material, active material and drug through electrostatic spinning and/or 3D printing to obtain the drug-loaded nanofiber scaffold membrane; the drug is firstly added into the organic synthetic polymer material and/or the biological polymer material and then subjected to additive manufacturing, and the active material is firstly added into the organic synthetic polymer material and/or the biological polymer material and then subjected to additive manufacturing;
the preparation method II comprises the following steps: preparing the organic synthetic polymer material and/or the biological polymer material into a nanofiber scaffold membrane through electrostatic spinning and/or 3D printing, and then modifying the surface of the nanofiber scaffold membrane by using a medicament and/or an active material, wherein the surface modification comprises any one of electrostatic self-assembly, crosslinking or spraying to form a surface modification layer, so as to obtain the medicament-loaded nanofiber scaffold membrane;
(2) crushing the drug-loaded nanofiber scaffold membrane;
(3) sterilizing to obtain the drug-loaded nano-fiber scaffold particle.
In a third aspect, the invention provides an application of the drug-loaded nanofiber scaffold particle as described in the first aspect in preparation of a drug carrier.
In the invention, the drug-loaded nanofiber scaffold particles have good stability, dispersibility and biocompatibility, and provide a better microenvironment for physiological activities of cells; by controlling the proportion of the substances, the release time of the internal medicine can be regulated and controlled while the stability of the nano-fiber scaffold particles is ensured, so that the long-acting release of the medicine is realized; the drug-loaded nanofiber scaffold particle also has targeting property, can realize accurate release, reduces toxic and side effects, is used for related preparation of drug carriers, and has extremely high application value.
Compared with the prior art, the invention has the following beneficial effects:
(1) the drug-loaded nanofiber scaffold particle prepared by mutually matching the high polymer material, the biological high polymer material and the active material has good hydrophilicity, dispersibility, biocompatibility and targeting property, is in a three-dimensional grid structure under a scanning electron microscope, is good in stability and strong in cell adhesion, helps to accurately position drugs, improves drug effect and reduces toxic and side effects; the drug-loaded nanofiber scaffold particle can be loaded with various drugs, the release rate and the release period of the drugs can be controlled by adjusting the proportion of the raw materials, a sustained-release or controlled-release drug carrier can be prepared according to the characteristics of the drugs, the treatment effect of the drugs is further improved, when the raw material proportion and the preparation method are under better conditions, the drug release rate is uniform, the total drug release amount in 30 days after use is more than 80%, and the sustained-release effect is good; the drug-loaded nanofiber scaffold particle also has the characteristics of an engineering scaffold, and can promote cell proliferation so as to improve the repair speed of the tissues of the focus;
(2) the invention changes the mode of drug-loaded membrane implantation drug delivery through the traditional surgical operation mode, can deliver drug through various modes such as injection, oral administration, atomization, minimally invasive intervention and the like, reduces the pain of patients, improves the use experience and has good clinical application prospect;
(3) the preparation method of the drug-loaded nanofiber scaffold particle is efficient, energy-saving, simple and feasible, mature in technology, low in requirement on production environment and has the potential of mass production; the cost is low, and conditions are created for the related preparation and research of the drug carrier.
Drawings
Fig. 1 is a scanning electron microscope photograph (scale bar 100 μm) of drug-loaded nanofiber scaffold microparticles prepared in example 1 of the present invention;
fig. 2 is a scanning electron microscope picture (scale bar is 1 μm) of drug-loaded nanofiber scaffold microparticles prepared in example 1 of the present invention;
FIG. 3 is a picture showing the results of drug release performance testing of drug-loaded nanofiber scaffold particles prepared in example 1 of the present invention;
FIG. 4 is a picture showing the results of drug release performance testing of drug-loaded nanofiber scaffold particles prepared in example 2 of the present invention;
FIG. 5 is a picture showing the results of drug release performance tests of drug-loaded nanofiber scaffold particles prepared in example 3 of the present invention;
FIG. 6 is a picture showing the results of drug release performance testing of drug-loaded nanofiber scaffold particles prepared in example 4 of the present invention;
FIG. 7 is a picture showing the results of drug release performance testing of drug-loaded nanofiber scaffold particles prepared in example 5 of the present invention;
FIG. 8 is a picture showing the results of drug release performance testing of drug-loaded nanofiber scaffold particles prepared in example 6 of the present invention;
FIG. 9 is a graph showing the results of drug release performance testing of drug-loaded nanofiber scaffold particles prepared in example 7 of the present invention;
FIG. 10 is a graph showing the results of drug release performance tests of drug-loaded nanofiber scaffold particles prepared in examples 1 and 8 to 10 respectively;
fig. 11 is a picture of the result of the detection of the drug release performance of the drug-loaded nanofiber scaffold particles prepared in example 1 and comparative examples 1 to 3 respectively.
Detailed Description
To further illustrate the technical means adopted by the present invention and the effects thereof, the present invention is further described below with reference to the embodiments and the accompanying drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or apparatus used are conventional products commercially available from normal sources, not indicated by the manufacturer.
Raw materials:
polylactic acid was purchased from dendri handleanifer bioengineering, ltd;
collagen was purchased from Tianjin Xeroning bioengineering technologies, Inc.;
epidermal growth factor, chitosan, RGD polypeptide, fluorouracil, polypropylene, carboxymethyl dextran, fibronectin, minocycline, polyurethane, and laminin were purchased from alatin reagent;
paclitaxel was purchased from shanghai gold and biopharmaceutical limited;
sulfamethoxazole, polyethylene glycol and trimethoprim were purchased from national drug agents.
Example 1
The embodiment provides a diameter is 200 nm's medicine carrying nanofiber scaffold particle, the three-dimensional network structure particle that medicine carrying nanofiber scaffold particle constitutes for the nanofiber that loads the medicine, and, medicine carrying nanofiber scaffold particle is smashed the back by the nanofiber scaffold membrane that loads the medicine and is made.
The raw materials of the drug-loaded nanofiber are shown in table 1.
TABLE 1
Figure BDA0002991386880000101
Figure BDA0002991386880000111
The preparation method of the drug-loaded nanofiber scaffold particle comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 100 microns;
the organic synthetic polymer material, the biological polymer material, the active material and the medicine are combined through electrostatic spinning, the medicine and the active material are firstly added into the organic synthetic polymer material and then electrostatic spinning is carried out, the specific steps of the electrostatic spinning are that the organic synthetic polymer material, the biological polymer material, the active material and the medicine are dissolved into hexafluoroisopropanol, an electrostatic spinning solution is prepared and added into an injector of an electrostatic spinning device, the injection rate of a micro injection pump is adjusted to be 0.1mm/min, the positive voltage is adjusted to be 15KV and the negative voltage is adjusted to be 2KV, the receiving distance of a receiving device is adjusted to be 15cm, and the fiber is received into a film structure, so that the nanofiber scaffold film loaded with the medicine is obtained;
(2) putting the drug-loaded nanofiber scaffold membrane into a liquid nitrogen cryomill for grinding and crushing, screening and collecting, and performing vacuum drying;
(3) and (5) performing irradiation sterilization to obtain the drug-loaded nanofiber scaffold particles.
Observation by scanning electron microscope
The drug-loaded nanofiber scaffold particles prepared in this example were placed on a sample stage, placed in a vacuum deposition apparatus, and plated with a conductive layer, and observed by using a field emission scanning electron microscope, and the results are shown in fig. 1 and 2. As can be seen from the figure, the prepared drug-loaded nano-fiber scaffold particles are of irregular granular structures on the surface, have a three-dimensional network structure inside, have a large specific surface area, can provide contact sites for cells, are convenient to exert drug effects, and are more favorable for repairing and proliferating damaged tissues.
Drug release performance detection
The prepared drug-loaded nanofiber scaffold microparticles were put in 100mL of phosphate buffer (pH 7.4), sealed, and shaken at 60rpm in a shaker at 37 ℃. 10mL of the delivery medium was removed and supplemented with 10mL of phosphate buffer (pH 7.4). And (3) rotationally evaporating the taken buffer solution to remove dry water, adding 2mL of acetonitrile, carrying out ultrasonic treatment for 5min to redissolve, filtering by using a 0.45-micron microporous filter membrane to obtain a solution to be detected, and detecting by using a liquid chromatography instrument.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; methanol-water-acetonitrile (volume ratio of 23:41:36) is used as a mobile phase, and the detection wavelength is 227 nm.
After drug release detection, the drug release curve of the drug-loaded nanofiber scaffold particle prepared in example 1 is shown in fig. 3.
Example 2
The embodiment provides a medicine carrying nano fiber scaffold particle with the diameter of 700nm, the medicine carrying nano fiber scaffold particle is a three-dimensional network structure particle formed by nano fibers for loading medicines, and the medicine carrying nano fiber scaffold particle is prepared after being smashed by a nano fiber scaffold film for loading the medicines.
The raw materials of the drug-loaded nanofiber are shown in table 2.
TABLE 2
Figure BDA0002991386880000121
The preparation method of the drug-loaded nanofiber scaffold particle comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 1000 mu m;
combining the organic synthetic polymer material, the biological polymer material, the active material and the medicine through electrostatic spinning, wherein the active material is firstly added into the organic synthetic polymer material, the medicine is firstly added into the biological polymer material, and then the electrostatic spinning is carried out, the electrostatic spinning comprises the specific steps of dissolving the organic synthetic polymer material, the biological polymer material, the active material and the medicine in N, N dimethyl formamide, preparing electrostatic spinning solution, adding the electrostatic spinning solution into an injector of an electrostatic spinning device, adjusting the injection rate of a micro injection pump to be 0.5mm/min, adjusting the positive voltage to be 10KV and the negative voltage to be 1KV, adjusting the receiving distance of a receiving device to be 10cm, receiving the fiber into a film-shaped structure, and obtaining the nano fiber stent film loaded with the medicine;
(2) putting the drug-loaded nanofiber scaffold membrane into a liquid nitrogen cryomill for grinding and crushing, screening and collecting, and performing vacuum drying;
(3) and sterilizing by using ethylene oxide to obtain the drug-loaded nanofiber scaffold particles.
Drug release performance detection
The prepared drug-loaded nano-fiber scaffold particles are put into 100mL of 0.1mol/L hydrochloric acid solution, sealed and shaken at the speed of 60rpm in a shaking table at the temperature of 37 ℃. Taking out 10mL of drug release medium, adding 10mL0.1mol/L hydrochloric acid solution for supplement, measuring absorbance of the drug release medium at 265nm by ultraviolet-visible spectrophotometry, and calculating drug release amount.
After drug release detection, the drug release curve of the drug-loaded nanofiber scaffold particle prepared in example 2 is shown in fig. 4.
Example 3
The embodiment provides a diameter is 0.5 nm's medicine carrying nanofiber scaffold particle, the three-dimensional network structure particle that medicine carrying nanofiber scaffold particle constitutes for the nanofiber that loads the medicine, and, medicine carrying nanofiber scaffold particle is smashed the back by the nanofiber scaffold membrane that loads the medicine and is made.
The raw materials of the drug-loaded nanofibers are shown in table 3.
TABLE 3
Figure BDA0002991386880000141
The preparation method of the drug-loaded nanofiber scaffold particle comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 0.01 mu m;
the preparation method comprises the following steps of preparing a nanofiber scaffold membrane from an organic synthetic polymer material and a biological polymer material through electrostatic spinning, dissolving the organic synthetic polymer material and the biological polymer material in N, N-dimethylformamide, preparing an electrostatic spinning solution, adding the electrostatic spinning solution into an injector of an electrostatic spinning device, adjusting the injection rate of a micro-injection pump to be 0.5mm/min, adjusting the positive voltage to be 20KV and the negative voltage to be 1KV, adjusting the receiving distance of a receiving device to be 10cm, receiving fibers into a membrane-shaped structure, and preparing the nanofiber scaffold membrane; adding fibronectin into water for dissolving, adjusting the pH value to be 6, preparing an electrostatic assembly solution, carrying out surface modification on the prepared nanofiber scaffold membrane through electrostatic self-assembly to form a surface modification layer, and adding sulfamethoxazole into the surface modification layer to obtain the drug-loaded nanofiber scaffold membrane;
(2) shearing, crushing, screening and collecting the drug-loaded nanofiber scaffold membrane, and drying in vacuum;
(3) and sterilizing by using ethylene oxide to obtain the drug-loaded nanofiber scaffold particles.
Drug release performance detection
After the sample to be detected is pretreated by the detection method in the embodiment 1, a liquid chromatography instrument is used for detection, and the chromatographic conditions are as follows:
octadecylsilane chemically bonded silica is used as a filling agent; water-acetonitrile-triethylamine (volume ratio of 800:198:2) is used as a mobile phase, and the detection wavelength is 240 nm.
After drug release detection, the drug release curve of the drug-loaded nanofiber scaffold particle prepared in example 3 is shown in fig. 5.
Example 4
The embodiment provides a medicine carrying nano fiber scaffold particle with the diameter of 60000nm, and the medicine carrying nano fiber scaffold particle is a three-dimensional network structure particle formed by nano fibers for loading medicines, and is prepared after the medicine carrying nano fiber scaffold particle is smashed by a nano fiber scaffold membrane for loading medicines.
The raw materials of the drug-loaded nanofibers are shown in table 4.
TABLE 4
Figure BDA0002991386880000151
The preparation method of the drug-loaded nanofiber scaffold particle comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 150 microns;
combining the organic synthetic polymer material, the biological polymer material, the active material and the medicine through 3D printing, adding the medicine and the active material into the biological polymer material, and then performing 3D printing, wherein the 3D printing specifically comprises the steps of dissolving the organic synthetic polymer material, the biological polymer material, the active material and the medicine into acetone, preparing a 3D printing solution, adding the 3D printing solution into a 3D printing device, introducing 3D printing related data into a computer, and performing 3D printing to obtain a three-dimensional nanofiber scaffold membrane, wherein the printing speed is 0.15mm/min, and the printing temperature is 8 ℃, so that the nanofiber scaffold membrane loaded with the medicine is obtained;
(2) freezing, shearing and crushing the drug-loaded nanofiber scaffold membrane, screening and collecting, and performing vacuum drying;
(3) and (5) performing irradiation sterilization to obtain the drug-loaded nanofiber scaffold particles.
Detection of drug Release Properties
The prepared drug-loaded nanofiber scaffold particles were placed in 100mL of purified water, sealed, and shaken at 60rpm in a shaker at 37 ℃. Taking out 10mL of drug release medium, adding 10mL of purified water for supplement to obtain a solution to be detected, and detecting by a liquid chromatography instrument.
Chromatographic conditions are as follows: using octyl silane bonded silica gel as a filling agent; taking 0.2mol/L ammonium acetate-dimethylformamide-tetrahydrofuran (volume ratio is 600:398:2, and contains 0.01mol/L disodium ethylene diamine tetraacetate) as a mobile phase; the detection wavelength was 280 nm.
After drug release detection, the drug release curve of the drug-loaded nanofiber scaffold particle prepared in example 4 is shown in fig. 6.
Example 5
The embodiment provides a medicine carrying nano fiber scaffold particle with the diameter of 900nm, the medicine carrying nano fiber scaffold particle is a three-dimensional network structure particle formed by nano fibers for loading medicines, and the medicine carrying nano fiber scaffold particle is prepared after being smashed by a nano fiber scaffold film for loading the medicines.
The raw materials of the drug-loaded nanofibers are shown in table 5.
TABLE 5
Figure BDA0002991386880000161
Figure BDA0002991386880000171
The preparation method of the drug-loaded nanofiber scaffold particle comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 200 mu m;
the organic synthetic polymer material and the biological polymer material are made into a nanofiber scaffold membrane through 3D printing, the specific steps of the 3D printing are that the organic synthetic polymer material and the biological polymer material are dissolved in acetone to prepare a 3D printing solution, the 3D printing solution is added into a 3D printing device, 3D printing related data are imported into a computer, and 3D printing is conducted to obtain a three-dimensional nanofiber scaffold membrane, the printing speed is 0.1mm/min, and the printing temperature is 10 ℃; preparing a nanofiber scaffold membrane; adding laminin, trimethoprim and sulfamethoxazole into water for dissolving, adjusting the pH value to 6, preparing an electrostatic spraying solution, and carrying out surface modification on the prepared nanofiber scaffold membrane by spraying to form a surface modification layer so as to obtain the drug-loaded nanofiber scaffold membrane;
(2) putting the drug-loaded nanofiber scaffold membrane into a freezing ball mill for crushing, screening and collecting, and performing vacuum drying;
(3) sterilizing with ethylene oxide to obtain the drug-loaded nano-fiber scaffold particle.
Drug release performance detection
After the sample to be detected is pretreated by the detection method in the embodiment 1, a liquid chromatography instrument is used for detection, and the chromatographic conditions are as follows:
octadecylsilane chemically bonded silica is used as a filling agent; water-acetonitrile-triethylamine (80:20:0.02) is used as a mobile phase, and the detection wavelength is 240 nm.
After drug release detection, the drug release curve of the drug-loaded nanofiber scaffold particle prepared in example 5 is shown in fig. 7.
Example 6
The embodiment provides a diameter is 100 nm's medicine carrying nanofiber scaffold particle, the three-dimensional network structure particle that medicine carrying nanofiber scaffold particle constitutes for the nanofiber that loads the medicine, and, medicine carrying nanofiber scaffold particle is smashed the back by the nanofiber scaffold membrane that loads the medicine and is made.
The raw materials of the drug-loaded nanofibers are shown in table 6.
TABLE 6
Figure BDA0002991386880000181
The preparation method of the drug-loaded nanofiber scaffold particle comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 100 mu m;
the organic synthetic polymer material, the biological polymer material, the active material and the medicine are combined through electrostatic spinning, the medicine and the active material are firstly added into the organic synthetic polymer material and then electrostatic spinning is carried out, the specific steps of the electrostatic spinning are that the organic synthetic polymer material, the biological polymer material, the active material and the medicine are dissolved into hexafluoroisopropanol, an electrostatic spinning solution is prepared and added into an injector of an electrostatic spinning device, the injection rate of a micro injection pump is adjusted to be 0.1mm/min, the positive voltage is adjusted to be 15KV and the negative voltage is adjusted to be 2KV, the receiving distance of a receiving device is adjusted to be 15cm, and the fiber is received into a film structure, so that the nanofiber scaffold film loaded with the medicine is obtained;
(2) putting the drug-loaded nanofiber scaffold membrane into a liquid nitrogen cryomill for grinding and crushing, screening and collecting, and performing vacuum drying;
(3) sterilizing to obtain the drug-loaded nano-fiber scaffold particle.
Drug release performance detection
After the sample to be detected is pretreated by the detection method in the embodiment 4, a liquid chromatography instrument is used for detection, and the chromatographic conditions are as follows:
taking chromatographic gel with molecular mass of 5-60 kD protein as a filler; taking 0.1mol/L phosphate-0.1 mol/L sodium chloride buffer solution (pH 7.0) as a mobile phase; the loading amount was 20. mu.g, and the detection wavelength was 280 nm.
After drug release detection, the drug release curve of the drug-loaded nanofiber scaffold particle prepared in example 6 is shown in fig. 8.
Example 7
The embodiment provides a medicine carrying nano fiber scaffold particle with the diameter of 200nm, the medicine carrying nano fiber scaffold particle is a three-dimensional network structure particle formed by nano fibers for loading medicines, and the medicine carrying nano fiber scaffold particle is prepared after being smashed by a nano fiber scaffold film for loading the medicines.
The raw materials of the drug-loaded nanofibers are shown in table 7.
TABLE 7
Figure BDA0002991386880000191
The preparation method of the drug-loaded nanofiber scaffold particle comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 100 microns;
combining the organic synthetic polymer material, the biological polymer material, the active material and the medicament through electrostatic spinning, adding the medicament and the active material into the organic synthetic polymer material firstly, and then carrying out electrostatic spinning, wherein the electrostatic spinning comprises the specific steps of dissolving the organic synthetic polymer material, the biological polymer material, the active material and the medicament into hexafluoroisopropanol, preparing an electrostatic spinning solution, adding the electrostatic spinning solution into an injector of an electrostatic spinning device, adjusting the injection rate of a micro-injection pump to be 0.1mm/min, adjusting the positive voltage to be 12KV and the negative voltage to be 1.5KV, adjusting the receiving distance of a receiving device to be 18cm, receiving fibers into a film structure, and obtaining the medicament-loaded nanofiber scaffold film;
(2) putting the drug-loaded nanofiber scaffold membrane into a liquid nitrogen cryomill for grinding and crushing, screening and collecting, and performing vacuum drying;
(3) sterilizing to obtain the drug-loaded nano-fiber scaffold particle.
Drug release performance detection
The prepared drug-loaded nanofiber scaffold particles were placed in 100mL of purified water, sealed, and shaken at 60rpm in a shaker at 37 ℃. Taking out 10mL of drug release medium, adding 10mL of purified water for supplement, measuring absorbance of the drug release medium at a wavelength of 260nm by using an ultraviolet-visible spectrophotometry, and calculating the drug release amount.
After drug release detection, the drug release curve of the drug-loaded nanofiber scaffold particle prepared in example 7 is shown in fig. 9.
Example 8
The difference from example 1 is that in this example, collagen was not added, the missing mass fraction was made up by polylactic acid, and the remaining raw materials and preparation method were the same as example 1.
The method for detecting the drug release performance of the present example is the same as that of example 1.
Example 9
The only difference from example 1 is that polylactic acid is not added in this example, the missing mass fraction is made up of collagen, and the rest of the raw materials and the preparation method are the same as example 1.
The method for detecting the drug release performance of the present example is the same as that of example 1.
Example 10
The difference from example 1 is that in this example, no epidermal growth factor is added, the missing mass fraction is supplemented with polylactic acid 6.2% and collagen 1.8%, and the rest of the raw materials and the preparation method are the same as example 1.
The method for detecting the drug release performance of the embodiment is the same as that of the embodiment 1.
The drug release curves of the drug-loaded nanofiber scaffold microparticles prepared in examples 1 and 8-9 are shown in fig. 10.
Comparative example 1
The difference from example 1 is only that the drug-loaded nanofiber scaffold particles in the comparative example are directly subjected to vacuum drying and sterilization without the pulverization process in step (2) in the preparation process, so as to obtain the drug-loaded nanofiber scaffold membrane.
The method for detecting the drug release performance of the comparative example is the same as that of example 1.
Comparative example 2
The only difference from example 1 is that in this comparative example, polylactic acid, collagen, epidermal growth factor and paclitaxel were physically mixed without electrospinning.
The method for detecting the drug release performance of the comparative example is the same as that of example 1.
Comparative example 3
The comparative example provides a drug-loaded microsphere, and the raw materials of the drug-loaded microsphere are the same as those in example 1.
The preparation method of the drug-loaded nanofiber scaffold particle comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 100 microns;
the organic synthetic polymer material, the biological polymer material, the active material and the medicine are combined through electrostatic spinning, the medicine and the active material are firstly added into the organic synthetic polymer material and then electrostatic spinning is carried out, the specific steps of the electrostatic spinning are that the organic synthetic polymer material, the biological polymer material, the active material and the medicine are dissolved into hexafluoroisopropanol to prepare an electrostatic spinning solution, the electrostatic spinning solution is added into an injector of an electrostatic spinning device, a special needle and a receiver for microspheres are used, the injection rate of a micro-injection pump is adjusted to be 0.1mm/min, the positive voltage is adjusted to be 10KV, the negative voltage is adjusted to be 2KV, the receiving distance of the receiving device is adjusted to be 15cm, and the microspheres are received onto a specified receiver;
(2) vacuum drying;
(3) and (5) performing irradiation sterilization to obtain the drug-loaded microspheres.
The method for detecting the drug release performance of the comparative example is the same as that of example 1.
The drug release curves of the drug-loaded nanofiber scaffold particles prepared in example 1 and comparative examples 1-3 are shown in fig. 11.
Comparing the drug release curves of fig. 3-11, it can be seen that the drug release curves of examples 1-7 and 10 are smoother, and the total drug release amount is on the trend of increasing at a constant speed, which indicates that the prepared drug-loaded nanofiber scaffold particle has uniform drug release rate and better drug release control effect, and the total drug release amount is not lower than 80% after 30 days, which is beneficial to improving the treatment effect of the drug;
compared with examples 1-7 and 10, the drug-loaded nanofiber scaffold particle prepared in example 9 has the advantages that the drug release amount reaches about 90% in 5 days after use, the speed is high, the absorption and utilization of drugs are not facilitated, and the treatment effect is poor; on the 30 th day of use, the total drug release amount of the drug-loaded nanofiber scaffold particle prepared in example 8 is only about 36%, more than half of the drug is not released, and the waste of the drug is caused; in example 9, no organic synthetic polymer material is added, and in example 8, no biopolymer material is added, so that the drug release performance of the prepared product is slightly poor, which indicates that the drug release period and the drug release speed of the drug can be regulated and controlled by combining the organic synthetic polymer material and the biopolymer material, and the treatment effect of the drug is improved;
comparing the drug release curves of the example 1 and the comparative examples 1-3, the nanofiber scaffold membrane is not crushed in the comparative example 1, the volume of the product is large, the specific surface area is small, and the release efficiency of the drug is poor; in comparative example 2, only the raw materials were physically mixed, and the ability to control drug release was not provided; the drug-loaded microspheres prepared in the comparative example 3 have the same problems of small specific surface area and incapability of releasing all drugs;
in conclusion, the drug-carrying medium with the structure of the nano-fiber scaffold particles is prepared, and the biopolymer material and the organic synthetic polymer material are added into the raw materials at the same time, so that the good slow-release and controlled-release effects can be produced.
In conclusion, compared with a drug-loaded stent membrane and drug-loaded microspheres, the drug-loaded nanofiber stent particles provided by the invention have higher specific surface area, so that the drug-loaded nanofiber stent particles have better dispersibility and biocompatibility; the release rate and the release period of the medicament are controlled by adjusting the proportion of the raw materials, and the medicament is accurately released by matching with an active material, so that the treatment effect is good and the toxic and side effects are small; the preparation method is simple and efficient, can adopt various administration modes, and has wide application prospect.
The applicant states that the present invention is illustrated in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e. it is not meant that the present invention must rely on the above detailed methods for its implementation. It should be understood by those skilled in the art that any modifications of the present invention, equivalent substitutions of the raw materials of the product of the present invention, and the addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims (10)

1. The drug-loaded nanofiber scaffold particle is characterized in that the drug-loaded nanofiber scaffold particle is a three-dimensional network structure particle formed by drug-loaded nanofibers;
the raw materials of the drug-loaded nanofiber comprise high polymer materials;
and the drug-loaded nanofiber scaffold particles are prepared by crushing drug-loaded nanofiber scaffold membranes.
2. The drug-loaded nanofiber scaffold particle according to claim 1, wherein the diameter of the nanofiber in the drug-loaded nanofiber scaffold particle is 0.5-60000 nm, preferably 10-1000 nm;
preferably, the polymer material comprises an organic synthetic polymer material and/or a biopolymer material;
preferably, the monomer of the organic synthetic polymer material includes any one or a combination of at least two of glycolide, lactide, caprolactone, vinyl alcohol, methyl methacrylate, cyclohexanone-p-oxide, trimethylene carbonate, ethylene, propylene, tetrafluoroethylene, urethane, ethylene glycol, or vinylpyrrolidone;
preferably, the biopolymer material comprises any one of or a combination of at least two of polylysine, polyglutamic acid, collagen, gelatin, silk fibroin, soy protein, elastin, hyaluronic acid, chitosan, carboxymethyl dextran, carboxymethyl glucose, heparin, alginic acid, chondroitin sulfate, carboxymethyl starch, or carboxymethyl cellulose.
3. The drug-loaded nanofiber scaffold microparticle according to claim 2, wherein the raw material for preparing the nanofiber scaffold membrane further comprises an active material;
preferably, the active material comprises a functional factor and/or a functional polypeptide;
preferably, the functional factor comprises any one of fibronectin, laminin, vascular endothelial growth factor, fibrinogen, nerve growth factor, epidermal growth factor, fibroblast growth factor, transforming growth factor, bone morphogenetic protein, insulin-like growth factor, platelet-derived growth factor, hydroxyapatite, strontium chloride or thrombin or a combination of at least two thereof;
preferably, the functional polypeptide comprises any one of or a combination of at least two of-arginine-glycine-aspartic acid-containing polypeptides, valine-glycine-valine-alanine-proline-glycine-containing polypeptides, or isoleucine-lysine-valine-alanine-valine-containing polypeptides.
4. The drug-loaded nanofiber scaffold microparticle according to any one of claims 1 to 3, wherein the drug includes any one or a combination of at least two of an antipyretic analgesic, an efferent nervous system drug, an anesthetic, a sedative hypnotic, an antipsychotic, a central nervous system drug, an antihypertensive, a blood system drug, an endocrine system drug, an antimicrobial, an antiparasitic drug, an antitumor drug, an immunomodulatory drug, a vitamin drug, a protein drug, a polysaccharide drug, a nucleic acid drug, a vaccine-based biologic or a gene therapy drug;
preferably, the protein drug comprises a protein drug and/or a polypeptide drug;
preferably, the nucleic acid drug includes any one or a combination of at least two of antisense nucleic acid, small interfering RNA or mRNA;
preferably, the vaccine-based biological product comprises any one of a protein vaccine, a DNA vaccine or an mRNA vaccine or a combination of at least two of the two.
5. The drug-loaded nanofiber scaffold particle according to any one of claims 1 to 4, wherein the mass fraction of the polymer material in the raw materials of the drug-loaded nanofiber is 45-99.95%;
preferably, the mass fraction of the medicine in the raw materials for forming the nanometer fiber loaded with the medicine is 0.01-50%;
preferably, the mass fraction of the active material in the raw material for forming the drug-loaded nanofiber is 0.01-50%;
preferably, the raw materials of the drug-loaded nanofiber comprise, by mass, 45% -99.95% of a high polymer material, 0.01% -50% of a drug, and 0.01% -50% of an active material.
6. The drug-loaded nanofiber scaffold particle according to any one of claims 1 to 5, wherein the drug-loaded nanofiber scaffold particle is administered by any one of oral administration, body surface administration, aerosol inhalation, surgical implantation, minimally invasive intervention, subcutaneous implantation, intravenous injection, subcutaneous injection or intramuscular injection.
7. The preparation method of the drug-loaded nanofiber scaffold microparticle according to any one of claims 1 to 6, wherein the preparation method comprises the following steps:
preparing a drug-loaded nanofiber scaffold membrane from a high polymer material and a drug, and crushing to obtain the drug-loaded nanofiber scaffold particles.
8. The method for preparing the drug-loaded nanofiber scaffold particle according to claim 7, wherein the thickness of the drug-loaded nanofiber scaffold membrane is 0.01-1000 μm, preferably 0.1-200 μm;
preferably, the drug-loaded nanofiber scaffold membrane is prepared by the preparation method I and/or the preparation method II;
wherein the preparation method I comprises the following steps: the polymer material and the drug are combined by an additive manufacturing method to obtain the drug-loaded nanofiber scaffold membrane;
the preparation method II comprises the following steps: the polymer material is made into a nanofiber scaffold membrane through additive manufacturing, and then a drug is combined on the nanofiber scaffold membrane through a surface modification method to obtain the drug-loaded nanofiber scaffold membrane;
preferably, the additive manufacturing process in preparation process I and preparation process II is the same or different;
preferably, the additive manufacturing comprises electrospinning and/or 3D printing;
preferably, the electrostatic spinning comprises any one of melt electrostatic spinning, solution electrostatic spinning, coaxial electrostatic spinning, conjugate electrostatic spinning or parallel electrostatic spinning;
preferably, the surface modification in the preparation method II includes any one of electrostatic self-assembly, crosslinking, or spraying;
preferably, the preparation method further comprises the step of adding an active material;
preferably, the step of sterilizing is further included after the pulverization.
9. The method for preparing a drug-loaded nanofiber scaffold particle according to claim 7 or 8, wherein the method comprises the following steps:
(1) preparing a drug-loaded nanofiber scaffold membrane with the thickness of 0.01-1000 mu m;
the drug-loaded nanofiber scaffold membrane is prepared by a preparation method I and/or a preparation method II:
the preparation method I comprises the following steps: combining the organic synthetic polymer material and/or biological polymer material, active material and drug through electrostatic spinning and/or 3D printing to obtain the drug-loaded nanofiber scaffold membrane; the drug is firstly added into the organic synthetic polymer material and/or the biological polymer material and then subjected to additive manufacturing, and the active material is firstly added into the organic synthetic polymer material and/or the biological polymer material and then subjected to additive manufacturing;
the preparation method II comprises the following steps: preparing the organic synthetic polymer material and/or the biological polymer material into a nanofiber scaffold membrane through electrostatic spinning and/or 3D printing, and then modifying the surface of the nanofiber scaffold membrane by using a medicament and/or an active material, wherein the surface modification comprises any one of electrostatic self-assembly, crosslinking or spraying to form a surface modification layer, so as to obtain the medicament-loaded nanofiber scaffold membrane;
(2) crushing the drug-loaded nanofiber scaffold membrane;
(3) sterilizing to obtain the drug-loaded nano-fiber scaffold particle.
10. The use of a drug-loaded nanofiber scaffold particle as defined in any one of claims 1 to 6 for the preparation of a drug carrier.
CN202110315674.0A 2021-03-24 2021-03-24 Drug-loaded nanofiber scaffold particle and preparation method and application thereof Pending CN115120562A (en)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
CN102266282A (en) * 2011-07-28 2011-12-07 上海交通大学 Micro/nanometer fiber slow release preparation for treating cicatrices and preparation method thereof
CN109381737A (en) * 2018-09-29 2019-02-26 华中科技大学鄂州工业技术研究院 Load the medicament slow release suppository and its preparation method and application of Finasteride
CN109575349A (en) * 2018-11-27 2019-04-05 上海交通大学 Enhance the method for plant source protein three-dimensional bracket mechanical property
CN110064074A (en) * 2018-01-23 2019-07-30 苏州博创同康生物工程有限公司 A kind of compound support frame material and its preparation method and application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102266282A (en) * 2011-07-28 2011-12-07 上海交通大学 Micro/nanometer fiber slow release preparation for treating cicatrices and preparation method thereof
CN110064074A (en) * 2018-01-23 2019-07-30 苏州博创同康生物工程有限公司 A kind of compound support frame material and its preparation method and application
CN109381737A (en) * 2018-09-29 2019-02-26 华中科技大学鄂州工业技术研究院 Load the medicament slow release suppository and its preparation method and application of Finasteride
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