WO2020186715A1 - 一种载药纳米纤维膜及其制备方法和应用 - Google Patents

一种载药纳米纤维膜及其制备方法和应用 Download PDF

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WO2020186715A1
WO2020186715A1 PCT/CN2019/106837 CN2019106837W WO2020186715A1 WO 2020186715 A1 WO2020186715 A1 WO 2020186715A1 CN 2019106837 W CN2019106837 W CN 2019106837W WO 2020186715 A1 WO2020186715 A1 WO 2020186715A1
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drug
nanofiber membrane
loaded
loaded nanofiber
glycolic acid
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PCT/CN2019/106837
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English (en)
French (fr)
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韩志超
许杉杉
伍家恩
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深圳市光远生物材料有限责任公司
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Publication of WO2020186715A1 publication Critical patent/WO2020186715A1/zh
Priority to US17/467,427 priority Critical patent/US20210393568A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
    • D01D5/0038—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion the fibre formed by solvent evaporation, i.e. dry electro-spinning
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0061—Electro-spinning characterised by the electro-spinning apparatus
    • D01D5/0069—Electro-spinning characterised by the electro-spinning apparatus characterised by the spinning section, e.g. capillary tube, protrusion or pin
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F1/00—General methods for the manufacture of artificial filaments or the like
    • D01F1/02—Addition of substances to the spinning solution or to the melt
    • D01F1/10—Other agents for modifying properties
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
    • D01F6/58—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products
    • D01F6/62—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from polyesters
    • D01F6/625—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from polyesters derived from hydroxy-carboxylic acids, e.g. lactones
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
    • D01F6/78—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from copolycondensation products
    • D01F6/84—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from copolycondensation products from copolyesters
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/40—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties
    • D04H1/42—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties characterised by the use of certain kinds of fibres insofar as this use has no preponderant influence on the consolidation of the fleece
    • D04H1/4326—Condensation or reaction polymers
    • D04H1/435—Polyesters
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/40—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties
    • D04H1/42—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties characterised by the use of certain kinds of fibres insofar as this use has no preponderant influence on the consolidation of the fleece
    • D04H1/4382—Stretched reticular film fibres; Composite fibres; Mixed fibres; Ultrafine fibres; Fibres for artificial leather
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/70—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres
    • D04H1/72—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged
    • D04H1/728—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged by electro-spinning
    • D—TEXTILES; PAPER
    • D10—INDEXING SCHEME ASSOCIATED WITH SUBLASSES OF SECTION D, RELATING TO TEXTILES
    • D10B—INDEXING SCHEME ASSOCIATED WITH SUBLASSES OF SECTION D, RELATING TO TEXTILES
    • D10B2509/00—Medical; Hygiene
    • D10B2509/02—Bandages, dressings or absorbent pads
    • D10B2509/022—Wound dressings

Definitions

  • the application belongs to the technical field of fiber membranes, and specifically relates to a drug-loaded nanofiber membrane and a preparation method and application thereof.
  • oral and intravenous injections After surgery, drugs are usually combined with oral and intravenous injections. Whether it is antibiotics to prevent infection or chemotherapy drugs to prevent tumor spread and recurrence, oral or intravenous injections have disadvantages such as low utilization and large toxic side effects, especially for For the protection of surgical wounds or lesions, the local drug concentration is difficult to reach the actual effective concentration required, which leads to poor treatment effects.
  • absorbable drug-loaded membranes can effectively solve this problem.
  • the drug can be absorbed by the tissue in situ to prevent local wound infection or tumor metastasis. After the release of the drug, the carrier will be further absorbed by the body, thereby effectively achieving the effect of physical targeting.
  • the fiber prepared by high-voltage electrospinning has a small diameter, high surface area to volume ratio, high porosity and pore connectivity, has structural characteristics similar to extracellular matrix, has excellent biocompatibility, and can efficiently exchange nutrients for cells Substances, gases and metabolic waste, and can imitate the surface of various shapes to form a film. Electrospinning is widely used in tissue engineering, drug delivery and wound dressings.
  • the drug-loaded fiber membrane system obtained by high-voltage electrospinning in the prior art is roughly divided into the following forms: (1) the surface of the fiber membrane is loaded with drugs; (2) the drug is directly blended with the polymer; (3) the use of coaxial Electrospinning prepares a core-shell structure fiber membrane. Regardless of the above, the drug will be released exponentially, and it cannot be released linearly.
  • Polylactic acid-glycolic acid copolymer is a widely used carrier. Although its spinning is simple and drug loading is relatively simple, it is also difficult to achieve linear drug release.
  • CN106512013A discloses a drug-carrying composite nanofiber membrane for sustained drug release and a preparation method thereof.
  • the technical proposal is that polyamide and chitosan are mixed and dissolved in formic acid to obtain a mixed solution, and then the drug is added to the mixed solution. The dissolution is accelerated by stirring to obtain a uniform and transparent spinning dope, and the drug-loaded chitosan/polyamide composite nanofiber membrane is prepared by using the electrostatic spinning technology.
  • the invention regulates the release of drugs through the swelling and degradation of chitosan, and fully exerts the good mechanical properties and chemical stability of polyamide. It has good drug slow-release effect and high cumulative drug release rate, but it cannot achieve linear drug release.
  • CN107447366A discloses a pH-sensitive drug-carrying slow-release nanofiber membrane and its preparation method and application.
  • the composition of the nanofiber membrane includes ethyl cellulose, polyacrylic acid resin and drugs.
  • the preparation method includes mixing and dissolving polyacrylic resin and ethyl cellulose, adding the drug and stirring until the dispersion is uniform to obtain a spinning solution, electrostatic spinning the spinning solution to obtain a fiber membrane, and then drying.
  • the pH-sensitive drug-loaded sustained-release nanofiber membrane can be used in a pH-sensitive drug sustained-release system, has alkaline response function and slow release function, and cannot achieve linear drug release.
  • CN107157960A discloses a method for preparing a drug-loaded nanofiber membrane, which includes the steps of: (1) dissolving a hydrophobic biodegradable polymer in an organic solvent to obtain a shell spinning solution; (2) combining a drug carrier with a drug Dissolve in water to obtain the core layer spinning solution; (3) Spin the shell layer prepared in step (1) and step (2) at a temperature of 22-28°C and a humidity of 45-55% The liquid and the core layer spinning solution are coaxially electrospun to obtain the drug-loaded nanofiber membrane.
  • the drug-loaded nanofiber membrane prepared by the method has the characteristics of simple structure and excellent drug slow-release performance, but the drug in the fiber membrane has an exponential release phenomenon and cannot achieve linear release.
  • the purpose of this application is to provide a drug-loaded nanofiber membrane and its preparation method and application.
  • the present application provides a drug-loaded nanofiber membrane.
  • the composition of the drug-loaded nanofiber membrane includes polylactic acid-glycolic acid copolymer fiber, polydioxanone fiber and a drug; wherein the drug is dispersed In the polylactic acid-glycolic acid copolymer fiber.
  • the polylactic acid-glycolic acid copolymer and poly(p-dioxanone) are separately formed into fibers, and the drug is dispersed in the polylactic acid-glycolic acid copolymer fiber; wherein the polylactic acid-hydroxyl
  • the swelling performance of acetic acid copolymer fiber is good, it will swell in the internal environment, and the fibers will stick together to block the drug release channel from the fiber; and the swelling performance of polydioxanone fiber in the fiber membrane Poor, it is difficult for the fibers to bond together. It plays a certain supporting role in the polylactic acid-glycolic acid copolymer fiber, so that part of the drug release channel can be retained, thereby achieving linear controlled drug release.
  • the polylactic acid-glycolic acid copolymer is a mixture of a high molecular weight polylactic acid-glycolic acid copolymer and a low molecular weight polylactic acid-glycolic acid copolymer
  • the high molecular weight refers to a viscosity average molecular weight of 100,000 to 150,000 Da, for example 100,000 Da, 110,000 Da, 120,000 Da, 130,000 Da, 140,000 Da, or 150,000 Da, etc.
  • the low molecular weight refers to a viscosity average molecular weight of 40,000 to 80,000 Da, such as 40,000 Da, 50,000 Da, 60,000 Da, 70,000 Da, or 80,000 Da.
  • This application adopts the method of adding a small amount of high molecular weight polylactic acid-glycolic acid copolymer to the low molecular weight polylactic acid-glycolic acid copolymer to prepare fibers, increasing the diameter of the fiber, so as to better exert the swelling behavior.
  • High-molecular-weight polylactic acid-glycolic acid copolymer only needs to add a small amount to significantly increase the fiber diameter. Too much addition will make the viscosity too large and affect the final swelling behavior.
  • the mass ratio of the high molecular weight polylactic acid-glycolic acid copolymer and the low molecular weight polylactic acid-glycolic acid copolymer is 25:75-3:97, such as 25:75, 20:80, 15:85, 12 :88, 10:90, 8:92, 7:93, 6:96, 5:95 or 3:97 etc.
  • the controllability of the fiber swelling behavior can be achieved by adjusting the high and low molecular weight and its ratio; the molecular weight of the high molecular weight polylactic acid-glycolic acid copolymer is controlled in the range of 100,000-150,000 Da, and the molecular weight of the low molecular weight polylactic acid-glycolic acid copolymer is controlled. In the range of 40,000 to 80,000 Da, and the mass ratio of the two is 25:75-3:97, the polylactic acid-glycolic acid copolymer fibers can be swollen and completely bonded together.
  • the total mass of the polydioxanone fiber is 1%-25% of the total mass of the polylactic acid-glycolic acid copolymer fiber, such as 1%, 5%, 8%, 10%, 15%, 18 %, 20% or 25%, etc., preferably 1%-15%.
  • the different poly-dioxanone fiber content in the drug-loaded nanofiber membrane will affect the release curve of the drug.
  • the higher the poly-dioxanone fiber content the faster the release of the drug, which can be adjusted by adjusting the poly-dioxanone fiber content.
  • the content of dioxanone fiber is used to control the release period of the drug; when the total mass of poly-dioxanone fiber is 1%-25% of the total mass of polylactic acid-glycolic acid copolymer fiber, the drug release period can be accurate Control it from 1 day to 26 days.
  • the molar ratio of the lactic acid structural unit to the glycolic acid structural unit in the polylactic acid-glycolic acid copolymer is (1-9):1, for example, 1:1, 2:1, 3:1, 3.5:1, 4:1, 5:1, 5.5:1, 6:1, 7:1, 8:1 or 9:1, etc.
  • the molecular weight of the polydioxanone is 60000-250,000 Da, for example, 60000 Da, 80,000 Da, 100,000 Da, 120,000 Da, 150,000 Da, 180,000 Da, 200,000 Da, or 250,000 Da.
  • the drug includes any one or a combination of at least two of antibiotic drugs, anti-tumor drugs and anti-inflammatory drugs, such as a combination of antibiotic drugs and anti-tumor drugs.
  • the drug includes ciprofloxacin, ciprofloxacin hydrochloride, moxifloxacin, levofloxacin, cefradine, tinidazole, 5-fluorouracil, adriamycin, cisplatin, paclitaxel, gemcitabine, capecitabine, Any one or a combination of at least two of aspirin and indomethacin, such as a combination of ciprofloxacin and ciprofloxacin hydrochloride, a combination of moxifloxacin and levofloxacin, 5-fluorouracil And the combination of adriamycin, etc.
  • the drug loaded in the drug-loaded nanofiber membrane of the present application is not limited to the above-listed drug types, and all drug types acceptable in the pharmaceutical field can be loaded in the drug-loaded nanofiber film of the present application.
  • the total mass of the drug is 1%-35% of the total mass of the fiber, such as 1%, 2%, 5%, 8%, 10%, 15%, 20%, 25%, 30% or 35%, etc. .
  • the total mass of the drug should be controlled within the range of 1%-35% of the total mass of the fiber. If it exceeds this range, the drug dose will cause a sudden drug release, which will cause the local drug concentration to be too high and cause toxicity; less than this range, small doses cannot be achieved Effective onset concentration.
  • the present application provides a method for preparing the drug-loaded nanofiber membrane as described above, and the preparation method includes the following steps:
  • step (2) Separately sample the two mixed solutions of step (1), and use multi-jet electrospinning equipment to perform electrostatic spinning to obtain the drug-loaded nanofiber membrane.
  • the drug-loaded nanofiber membrane described in this application is prepared by electrospinning using a degradable polymer, which is stable in nature and has high porosity, similar to extracellular matrix, applied to the postoperative stump, without the need for secondary surgery to remove it. Can be degraded in vivo.
  • the preparation method adopts a multi-jet electrospinning equipment for electrostatic spinning, the loading method of the two mixed solutions adopts the method of point-to-point spacing, and the mixed solution of the drug, polylactic acid-glycolic acid copolymer and the solvent is installed in the more Many syringes. If there are 7 nozzles, the first nozzles 1, 2, 3, 5, 6, and 7 can be filled with a mixture of medicine, polylactic acid-glycolic acid copolymer and solvent, and the fourth nozzle can be filled with polydioxanone and solvent.
  • It can also be a mixture of the first 1, 3, 5, and 7 nozzles containing drugs, polylactic acid-glycolic acid copolymer and solvent, and the second, 4, and 6 nozzles are equipped with polydioxanone and solvent Mixture. In this way, the two fibers in the system can be mixed more evenly.
  • the solvent in step (1) includes any one or a combination of at least two of N,N-dimethylformamide, acetone and hexafluoroisopropanol, the combination of at least two such as N, The combination of N-dimethylformamide and acetone, the combination of acetone and hexafluoroisopropanol, the combination of N,N-dimethylformamide and hexafluoroisopropanol, etc.
  • the mixing method in step (1) is heating and stirring at 40-50°C (for example, 40°C, 42°C, 44°C, 45°C, 46°C, 48°C or 50°C, etc.).
  • the inner diameter of the spinneret during electrospinning is 0.4 mm.
  • the voltage during electrospinning is 10-25kV, such as 10kV, 12kV, 13kV, 14kV, 15kV, 16kV, 18kV, 20kV, 22kV, 24kV or 25kV, etc., preferably 20-25kV.
  • the spinning distance during electrospinning is 5-15 cm, such as 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 12 cm, 14 cm or 15 cm, etc., preferably 8-15 cm.
  • the temperature during electrospinning is 20-30°C, such as 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C or 30°C. °C etc.
  • the solution advancing speed during electrospinning is 4-10mL/L, for example, 4mL/L, 5mL/L, 6mL/L, 7mL/L, 8mL/L, 9mL/L or 10mL/L, etc., It is preferably 6-10 mL/L.
  • the receiving device for electrospinning is a metal drum with a diameter of 5-15cm (for example, 5cm, 6cm, 8cm, 10cm, 12cm, 14cm or 15cm, etc.), and the rotating speed is 600-900rpm (for example, 600rpm, 650rpm, 700rpm, 750rpm, 800rpm, 850rpm or 900rpm, etc.), preferably 800rpm.
  • the step (2) after obtaining the drug-loaded nanofiber membrane further includes post-processing, and the post-processing operation is: placing the drug-loaded nanofiber membrane at (for example, 20°C, 21°C, 22°C, Vacuum drying at 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C or 30°C etc.) for 24-72h (24h, 30h, 35h, 50h, 60h or 72h etc.).
  • the post-processing operation is: placing the drug-loaded nanofiber membrane at (for example, 20°C, 21°C, 22°C, Vacuum drying at 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C or 30°C etc.) for 24-72h (24h, 30h, 35h, 50h, 60h or 72h etc.).
  • the preparation method includes the following steps:
  • step (1) The two mixed solutions of step (1) are separately loaded into a 22G flat-head dispensing syringe, and electrospinning is performed at 20-30°C using a multi-jet electrospinning equipment.
  • the inner diameter of the spinneret is 0.4mm, and the solution
  • the advancing speed is 4-10mL/L
  • the spinning voltage is 10-25kV
  • the spinning distance is 5-15cm
  • the receiving device is a metal drum with a diameter of 5-15cm
  • the rotation speed is 600-900rpm to obtain the drug-loaded nano Fibrous membrane
  • step (3) Dry the drug-loaded nanofiber membrane obtained in step (2) under vacuum at 20-30°C for 24-72h.
  • the present application provides an application of the drug-loaded nanofiber membrane described above in the preparation of a drug controlled release system.
  • the polylactic acid-glycolic acid copolymer and polydioxanone are separately formed into fibers, and the drug is dispersed in the polylactic acid-glycolic acid copolymer fiber; wherein Polylactic acid-glycolic acid copolymer fiber swells in the body environment, blocking the drug release channel from the fiber; while the polydioxanone in the fiber membrane plays a role in the polylactic acid-glycolic acid copolymer fiber.
  • a certain supporting effect retaining part of the drug release channel, thereby achieving controlled drug release, and achieving linear drug release.
  • the drug-loaded nanofiber membrane involved in this application is prepared by electrospinning using a degradable polymer, has stable properties and high porosity, similar to extracellular matrix, and is applied to the postoperative stump without the need for two It can be degraded in the body after the second operation.
  • Figure 1 is a drug release curve diagram of the drug-loaded nanofiber membrane prepared in Example 1;
  • Fig. 2 is a drug release curve diagram of the drug-loaded nanofiber membrane prepared in Example 2;
  • Figure 3 is a drug release curve diagram of the drug-loaded nanofiber membrane prepared in Example 3.
  • Figure 4 is a drug release curve diagram of the drug-loaded nanofiber membrane prepared in Example 4.
  • Figure 5 is a drug release curve diagram of the drug-loaded nanofiber membrane prepared in Example 5;
  • Figure 6 is a drug release curve diagram of the drug-loaded nanofiber membrane prepared in Example 6;
  • Figure 7 is an electron micrograph of a cross section of the drug-loaded nanofiber membrane prepared in Example 1;
  • Example 8 is an electron micrograph of a cross-section of the drug-loaded nanofiber membrane prepared in Example 2;
  • Example 9 is an electron micrograph of a cross-section of the drug-loaded nanofiber membrane prepared in Example 3.
  • Example 10 is an electron micrograph of a cross-section of the drug-loaded nanofiber membrane prepared in Example 4.
  • Figure 11 is an electron micrograph of a cross-section of the drug-loaded nanofiber membrane prepared in Example 5.
  • This embodiment provides a drug-loaded nanofiber membrane.
  • the mass ratio of the two is 25:75; the total mass of the polydioxanone fiber is 10% of the total mass of the polylactic acid-glycolic acid copolymer fiber; the total mass of paclitaxel is 10% of the total mass of the fiber.
  • the preparation method is:
  • step (1) The two mixed solutions of step (1) were separately loaded into a 22G flat-head dispensing syringe, and electrospinning was carried out at 25°C using a multi-jet electrospinning equipment.
  • the inner diameter of the spinneret was 0.4mm, and the solution advancing speed It is 5mL/L, the spinning voltage is 15kV, the spinning distance is 5cm, the receiving device is a metal drum with a diameter of 5cm, and the rotation speed is 600rpm to obtain the drug-loaded nanofiber membrane;
  • step (3) Dry the drug-loaded nanofiber membrane obtained in step (2) under vacuum at 25° C. for 24 hours.
  • the specific method is: cut the dried drug-loaded nanofiber membranes into 10mg samples, and put the samples into 10mL fresh PBS. The solution in the centrifuge tube. Then they were put into an air bath constant temperature shaker, the temperature was set to 37°C, and the speed of the shaker was 100 rpm. At designated time intervals, 1 mL of release solution was taken out, and an equal amount of fresh PBS solution was added. Then, the standard curve of the drug is measured with an ultraviolet-visible spectrophotometer, and the amount of drug released by the drug-loaded electrospun membrane is determined according to the standard curve.
  • the specific experimental method is as follows: first, take the drug-loaded nanofiber membrane samples soaked in PBS for 7 days from the centrifuge tube, rinse with deionized water several times, and then put Dry for 48 hours at room temperature in a vacuum drying oven. The sample used for cross-sectional morphology observation must first be immersed in liquid nitrogen to break. Before observing by SEM, the samples used for cross-sectional morphology observation are respectively attached to the sample stage, and a layer of conductive platinum is coated by a vacuum sputtering apparatus. The experimental results are shown in Figure 7.
  • the mass ratio of the two is 15:85; the total mass of the polydioxanone fiber is 15% of the total mass of the polylactic acid-glycolic acid copolymer fiber; the total mass of 5-fluorouracil is the total mass of the fiber 20%.
  • the preparation method is:
  • step (1) The two mixed solutions of step (1) were separately loaded into a 22G flat-head dispensing syringe, and electrospinning was carried out at 25°C using a multi-jet electrospinning equipment.
  • the inner diameter of the spinneret was 0.4mm, and the solution advancing speed It is 10mL/L, the spinning voltage is 25kV, the spinning distance is 10cm, the receiving device is a metal drum with a diameter of 5cm, and the rotation speed is 800rpm to obtain the drug-loaded nanofiber membrane;
  • step (3) Dry the drug-loaded nanofiber membrane obtained in step (2) under vacuum at 25° C. for 48 hours.
  • the drug release experiment was performed on the obtained drug-loaded nanofiber membrane, and the drug release curve was drawn.
  • the specific method was the same as that in Example 1.
  • the experimental results are shown in Figure 2. It can be seen from Figure 2 that the drug release system basically has no sudden release phenomenon. , The entire drug release cycle is maintained at 7 days. At 18h, the drug release curve will have a turning point where the release rate increases, and the drug release rate greatly increases, and most of the drug has been released at 5 days.
  • the preparation method is:
  • step (1) The two mixed solutions of step (1) were separately loaded into a 22G flat-head dispensing syringe, and electrospinning was carried out at 25°C using a multi-jet electrospinning equipment.
  • the inner diameter of the spinneret was 0.4mm, and the solution advancing speed
  • the spinning voltage is 8mL/L
  • the spinning voltage is 10kV
  • the spinning distance is 15cm
  • the receiving device is a metal drum with a diameter of 5cm
  • the rotation speed is 900rpm to obtain the drug-loaded nanofiber membrane
  • step (3) Dry the drug-loaded nanofiber membrane obtained in step (2) in vacuum at 25° C. for 72 hours.
  • the drug release experiment was performed on the obtained drug-loaded nanofiber membrane, and the drug release curve was drawn.
  • the specific method was consistent with the examples; the experimental results are shown in FIG. 3, and it can be seen from FIG. 3 that the drug release system basically has no burst release.
  • the entire drug release cycle was maintained at nearly 26 days.
  • the PDO content is 1%, and the drug release curve gradually tends to contain only the drug release characteristics of the PLGA electrospun membrane. The turning point that the release rate increased did not appear until the 7th day, after which the system maintained a high drug release rate until all the drugs were released.
  • the composition of the drug-loaded nanofiber membrane includes polylactic acid-glycolic acid copolymer fiber, polydiox
  • the preparation method is:
  • step (1) The two mixed solutions of step (1) were separately loaded into a 22G flat-head dispensing syringe, and electrospinning was carried out at 25°C using a multi-jet electrospinning equipment.
  • the inner diameter of the spinneret was 0.4mm, and the solution advancing speed
  • the spinning voltage is 6mL/L
  • the spinning voltage is 15kV
  • the spinning distance is 15cm
  • the receiving device is a metal drum with a diameter of 5cm
  • the rotation speed is 600rpm to obtain the drug-loaded nanofiber membrane
  • step (3) Dry the drug-loaded nanofiber membrane obtained in step (2) in vacuum at 25° C. for 72 hours.
  • the drug release experiment was performed on the obtained drug-loaded nanofiber membrane, and the drug release curve was drawn.
  • the specific method was consistent with the examples; the experimental results are shown in FIG. 4, and it can be seen from FIG. 4 that the drug release system basically has no burst release.
  • the entire release cycle was maintained at nearly 25 days.
  • the drug-loaded electrospun membrane with a PDO content of 5% showed a turning point in the drug release curve on the 5th day. Thereafter, the drug release rate greatly increased until the drug was released completely.
  • This embodiment provides a drug-loaded nanofiber membrane.
  • the mass ratio of the two is 10:90; the total mass of the polydioxanone fiber is 7% of the total mass of the polylactic acid-glycolic acid copolymer fiber; the total mass of cefradine is 10% of the total fiber mass.
  • the preparation method is:
  • step (1) The two mixed solutions of step (1) were separately loaded into a 22G flat-head dispensing syringe, and electrospinning was carried out at 25°C using a multi-jet electrospinning equipment.
  • the inner diameter of the spinneret was 0.4mm, and the solution advancing speed
  • the spinning voltage is 6mL/L
  • the spinning voltage is 15kV
  • the spinning distance is 15cm
  • the receiving device is a metal drum with a diameter of 5cm
  • the rotation speed is 600rpm to obtain the drug-loaded nanofiber membrane
  • step (3) Dry the drug-loaded nanofiber membrane obtained in step (2) under vacuum at 25° C. for 24 hours.
  • the drug release experiment was performed on the obtained drug-loaded nanofiber membrane, and the drug release curve was drawn.
  • the specific method was consistent with the examples; the experimental results are shown in FIG. 5, and it can be seen from FIG. 5 that the drug release system basically has no burst release.
  • the entire drug release cycle was maintained at nearly 15 days.
  • the drug-loaded nanofiber membrane with a PDO content of 7% showed a turning point in the drug release curve of the drug release rate on the 4th day. Thereafter, the drug release rate greatly increased until the drug was released completely.
  • This embodiment provides a drug-loaded nanofiber membrane.
  • the mass ratio of the two is 10:90; the total mass of the polydioxanone fiber is 25% of the total mass of the polylactic acid-glycolic acid copolymer fiber; the total mass of levofloxacin is 10% of the total fiber mass.
  • the preparation method is:
  • step (1) The two mixed solutions of step (1) were separately loaded into a 22G flat-head dispensing syringe, and electrospinning was carried out at 25°C using a multi-jet electrospinning equipment.
  • the inner diameter of the spinneret was 0.4mm, and the solution advancing speed
  • the spinning voltage is 6mL/L
  • the spinning voltage is 15kV
  • the spinning distance is 15cm
  • the receiving device is a metal drum with a diameter of 5cm
  • the rotation speed is 600rpm to obtain the drug-loaded nanofiber membrane
  • step (3) Dry the drug-loaded nanofiber membrane obtained in step (2) under vacuum at 25° C. for 24 hours.
  • the drug release experiment was performed on the obtained drug-loaded nanofiber membrane, and the drug release curve was drawn.
  • the specific method was consistent with the examples; the experimental results are shown in FIG. 6, and it can be seen from FIG. 6 that the drug release system basically has no burst release. The entire release cycle is maintained at 1 day.

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Abstract

一种载药纳米纤维膜及其制备方法和应用，所述载药纳米纤维膜的成分包括聚乳酸-羟基乙酸共聚物纤维、聚对二氧环己酮纤维和药物；其中，所述药物分散于所述聚乳酸-羟基乙酸共聚物纤维中；其制备方法为：(1)将药物、聚乳酸-羟基乙酸共聚物与溶剂混合，再将聚对二氧环己酮与溶剂混合，得到两种混合溶液；(2)将两种混合溶液独立装样，采用多喷头电纺设备进行静电纺丝，得到所述载药纳米纤维膜。所制得的载药纳米纤维膜通过静电纺丝方式制得，性质稳定且具有高孔隙率，类似于细胞外基质，敷于术后残端，无需二次手术取出，可体内降解，并且可以实现药物的线性释放。

Description

一种载药纳米纤维膜及其制备方法和应用 技术领域
本申请属于纤维膜技术领域，具体涉及一种载药纳米纤维膜及其制备方法和应用。
背景技术
外科手术后一般会合并用药，利用口服、静脉注射等方式，无论是防止感染的抗生素还是防止肿瘤扩散复发的化疗药物，经口服或静脉注射都有利用率低，毒副作用大等缺点，尤其针对手术创面或病灶部分的防护，局部药物浓度很难达到实际需要的起效浓度，从而导致治疗效果不佳。利用可吸收的载药膜能够有效地解决这一问题，药物能在原位被组织吸收，防止局部创面感染或肿瘤转移。药物释放结束后，载体会进一步被人体吸收，从而有效实现物理靶向的作用。
利用高压静电纺丝制备的纤维直径较小，具有高表面积体积比、高孔隙率和孔连通性，具有类似于细胞外基质的结构特点，具有优良的生物相容性，能够为细胞高效交换营养物质、气体和代谢废物，并可仿造多种形状物体的表面形成覆膜，静电纺丝被广泛用于组织工程、药物传输和伤口敷料等。
现有技术中通过高压静电纺丝获得的载药纤维膜体系大体分为以下几种形式：(1)纤维膜表面装载药物；(2)药物与聚合物直接共混；(3)利用同轴电纺制备核壳结构的纤维膜。以上无论哪种形式，药物都会出现指数型释放现象，不能做到线性释放。聚乳酸-羟基乙酸共聚物是一种应用广泛的载体，虽然其纺丝简单，负载药物也相对简单，但起也难以实现对药物的线性释放。
CN106512013A公开了一种用于药物缓释的载药复合纳米纤维膜及其制备 方法，其技术方案是：将聚酰胺、壳聚糖混合后溶于甲酸得到混合溶液，然后将药物加入混合溶液后通过搅拌加速溶解，得到均匀透明的纺丝原液，采用静电纺丝技术制得载药壳聚糖/聚酰胺复合纳米纤维膜。本发明通过壳聚糖的溶胀与降解进行药物释放的调控，充分发挥出了聚酰胺良好的力学性能、化学稳定性。其具有较好的药物缓释效果、药物累积释放率高，但不能做到对药物的线性释放。
CN107447366A公开了一种pH敏感载药缓释纳米纤维膜及其制备方法和应用，所述纳米纤维膜的成分包括乙基纤维素、聚丙烯酸树脂和药物。制备方法包括将聚丙烯酸树脂和乙基纤维素混合溶解，并加入药物搅拌至分散均匀得到纺丝液，将纺丝液进行静电纺丝得到纤维膜，再进行干燥。该pH敏感载药缓释纳米纤维膜可用于pH敏感药物缓释体系，具有碱性响应功能和缓慢释放功能，也不能做到药物的线性释放。
CN107157960A公开了一种载药纳米纤维膜的制备方法，包括步骤：(1)将疏水性的生物可降解聚合物溶于有机溶剂中，得到壳层纺丝液；(2)将药物载体与药物溶于水中，得到核层纺丝液；(3)在温度为22-28℃、湿度为45-55％条件下，将步骤(1)中和步骤(2)中制得的壳层纺丝液与核层纺丝液进行同轴静电纺丝，得到所述载药纳米纤维膜。该方法制得的载药纳米纤维膜具有结构简单、药物缓释性能优异的特点，但该纤维膜中的药物会出现指数型释放现象，不能做到线性释放。
综上，若能开发出一种能够实现药物线性释放的载药纳米纤维膜是非常有意义的。
发明内容
针对现有技术的不足，本申请的目的在于提供一种载药纳米纤维膜及其制 备方法和应用。
为达到此申请目的，本申请采用以下技术方案：
一方面，本申请提供一种载药纳米纤维膜，所述载药纳米纤维膜的成分包括聚乳酸-羟基乙酸共聚物纤维、聚对二氧环己酮纤维和药物；其中，所述药物分散于所述聚乳酸-羟基乙酸共聚物纤维中。
本申请所述的载药纳米纤维膜中聚乳酸-羟基乙酸共聚物和聚对二氧环己酮分别独立成纤维，且药物分散于聚乳酸-羟基乙酸共聚物纤维中；其中聚乳酸-羟基乙酸共聚物纤维的溶胀性能好，在体内环境下发生溶胀，纤维会粘合在一起，阻断药物从纤维中释放出来的通道；而在纤维膜中的聚对二氧环己酮纤维溶胀性能差，纤维间很难粘合在一起，其在聚乳酸-羟基乙酸共聚物纤维中起一定的支撑作用，从而能够保留部分的药物释放通道，由此实现药物线性控制释放。
优选地，所述聚乳酸-羟基乙酸共聚物为高分子量聚乳酸-羟基乙酸共聚物和低分子量聚乳酸-羟基乙酸共聚物的混合物，所述高分子量是指粘均分子量为100000-150000Da，例如100000Da、110000Da、120000Da、130000Da、140000Da或150000Da等，所述低分子量是指粘均分子量为40000-80000Da，例如40000Da、50000Da、60000Da、70000Da或80000Da等。
本申请采用在低分子量聚乳酸-羟基乙酸共聚物中添加少量高分子量聚乳酸-羟基乙酸共聚物的方式来制备纤维，增加纤维的直径，以此更好地发挥溶胀行为。高分子量聚乳酸-羟基乙酸共聚物只需添加少量即可显著增大纤维直径，添加量过多会使粘度过大反而影响最终的溶胀行为。
优选地，所述高分子量聚乳酸-羟基乙酸共聚物和低分子量聚乳酸-羟基乙酸共聚物的质量比为25:75-3:97，例如25:75、20:80、15:85、12:88、10:90、8:92、 7:93、6:96、5:95或3:97等。
通过调节高低分子量及其配比能够实现纤维溶胀行为的可控性；将高分子量聚乳酸-羟基乙酸共聚物的分子量控制在100000-150000Da范围内，低分子量聚乳酸-羟基乙酸共聚物的分子量控制在40000-80000Da范围内，且两者的质量比为25:75-3:97时，即可使聚乳酸-羟基乙酸共聚物纤维溶胀后完全粘合在一起。
优选地，所述聚对二氧环己酮纤维总质量为聚乳酸-羟基乙酸共聚物纤维总质量的1％-25％，例如1％、5％、8％、10％、15％、18％、20％或25％等，优选1％-15％。
所述载药纳米纤维膜中不同的聚对二氧环己酮纤维含量会影响药物的释放曲线，聚对二氧环己酮纤维含量越高，药物的释放越快，即能通过调节聚对二氧环己酮纤维含量来控制药物的释放周期；当聚对二氧环己酮纤维总质量为聚乳酸-羟基乙酸共聚物纤维总质量的1％-25％时，能够将释药周期精确控制在1天到26天。
优选地，所述聚乳酸-羟基乙酸共聚物中乳酸结构单元与羟基乙酸结构单元的摩尔比为(1-9):1，例如1:1、2:1、3:1、3.5:1、4:1、5:1、5.5:1、6:1、7:1、8:1或9:1等。
优选地，所述聚对二氧环己酮的分子量为60000-250000Da，例如60000Da、80000Da、100000Da、120000Da、150000Da、180000Da、200000Da或250000Da等。
优选地，所述药物包括抗生素类药物、抗肿瘤药物和抗炎类药物中的任意一种或至少两种的组合，所述至少两种的组合例如抗生素类药物和抗肿瘤药物的组合。
优选地，所述药物包括环丙沙星、盐酸环丙沙星、莫西沙星、左氧氟沙星、 头孢拉定、替硝唑、5-氟尿嘧啶、阿霉素、顺铂、紫杉醇、吉西他滨、卡培他滨、阿司匹林和吲哚美辛中的任意一种或至少两种的组合，所述至少两种的组合例如环丙沙星和盐酸环丙沙星的组合、莫西沙星和左氧氟沙星的组合、5-氟尿嘧啶和阿霉素的组合等。
本申请所述载药纳米纤维膜中负载的药物不仅限于上述列举的药物类型，药学领域可接受的所有药物类型均可以实现在本申请所述载药纳米纤维膜中的负载。
优选地，所述药物总质量为纤维总质量的1％-35％，例如1％、2％、5％、8％、10％、15％、20％、25％、30％或35％等。
药物总质量需控制在为纤维总质量的1％-35％范围内，若超过此范围，药物剂量大会造成药物突释，使得局部药物浓度过高而产生毒性；小于此范围，小剂量无法达到有效的起效浓度。
另一方面，本申请提供一种如上所述的载药纳米纤维膜的制备方法，所述制备方法包括如下步骤：
(1)将药物、聚乳酸-羟基乙酸共聚物与溶剂混合，再将聚对二氧环己酮与溶剂混合，得到两种混合溶液；和
(2)将步骤(1)的两种混合溶液独立装样，采用多喷头电纺设备进行静电纺丝，得到所述载药纳米纤维膜。
本申请所述载药纳米纤维膜使用可降解的聚合物通过静电纺丝方式制得，性质稳定且具有高孔隙率，类似于细胞外基质，敷于术后残端，无需二次手术取出，可体内降解。
所述制备方法采用多喷头电纺设备进行静电纺丝，两种混合溶液的装样方式采用点位间隔的方法装样，且药物、聚乳酸-羟基乙酸共聚物与溶剂的混合液 装于更多的注射器里。如有7个喷头，可为第1、2、3、5、6、7喷头装药物、聚乳酸-羟基乙酸共聚物与溶剂的混合液，第4喷头装聚对二氧环己酮与溶剂的混合液；也可为第1、3、5、7喷头装药物、聚乳酸-羟基乙酸共聚物与溶剂的混合液，第2、4、6喷头装聚对二氧环己酮与溶剂的混合液。这样能使体系中的两种纤维混合更加均匀。
优选地，步骤(1)所述溶剂包括N,N-二甲基甲酰胺、丙酮和六氟异丙醇中的任意一种或至少两种的组合，所述至少两种的组合例如N,N-二甲基甲酰胺和丙酮的组合、丙酮和六氟异丙醇的组合、N,N-二甲基甲酰胺和六氟异丙醇的组合等。
优选地，步骤(1)所述混合的方式为在40-50℃(例如40℃、42℃、44℃、45℃、46℃、48℃或50℃等)下加热搅拌混合。
优选地，所述进行静电纺丝时的喷丝头内径为0.4mm。
优选地，所述进行静电纺丝时的电压为10-25kV，例如10kV、12kV、13kV、14kV、15kV、16kV、18kV、20kV、22kV、24kV或25kV等，优选20-25kV。
优选地，所述进行静电纺丝时的纺丝距离为5-15cm，例如5cm、6cm、7cm、8cm、9cm、10cm、12cm、14cm或15cm等，优选8-15cm。
优选地，所述进行静电纺丝时的温度为20-30℃，例如20℃、21℃、22℃、23℃、24℃、25℃、26℃、27℃、28℃、29℃或30℃等。
优选地，所述进行静电纺丝时溶液推进速度为4-10mL/L，例如4mL/L、5mL/L、6mL/L、7mL/L、8mL/L、9mL/L或10mL/L等，优选6-10mL/L。
优选地，所述进行静电纺丝时的接受装置为直径为5-15cm(例如5cm、6cm、8cm、10cm、12cm、14cm或15cm等)的金属转筒，转速为600-900rpm(例如600rpm、650rpm、700rpm、750rpm、800rpm、850rpm或900rpm等)， 优选800rpm。
优选地，步骤(2)所述得到载药纳米纤维膜后还包括对其后处理，所述后处理操作为：将所述载药纳米纤维膜在(例如20℃、21℃、22℃、23℃、24℃、25℃、26℃、27℃、28℃、29℃或30℃等)下真空干燥24-72h(24h、30h、35h、50h、60h或72h等)。
作为本申请的优选技术方案，所述制备方法包括如下步骤：
(1)将药物、聚乳酸-羟基乙酸共聚物与溶剂混合，再将聚对二氧环己酮与溶剂混合，得到两种混合溶液；
(2)将步骤(1)的两种混合溶液独立装样于22G平头点胶注射器中，采用多喷头电纺设备在20-30℃下进行静电纺丝，喷丝头内径为0.4mm，溶液推进速度为4-10mL/L，喷丝电压为10-25kV，纺丝距离为5-15cm，接受装置为直径为5-15cm的金属转筒，转速为600-900rpm，得到所述载药纳米纤维膜；和
(3)将步骤(2)得到的载药纳米纤维膜在20-30℃下真空干燥24-72h。
再一方面，本申请提供一种如上所述的载药纳米纤维膜在制备药物控释系统中的应用。
相对于现有技术，本申请具有以下有益效果：
(1)本申请所涉及的载药纳米纤维膜中使聚乳酸-羟基乙酸共聚物和聚对二氧环己酮分别独立成纤维，且药物分散于聚乳酸-羟基乙酸共聚物纤维中；其中聚乳酸-羟基乙酸共聚物纤维在体内环境下发生溶胀，阻断药物从纤维中释放出来的通道；而在纤维膜中的聚对二氧环己酮在聚乳酸-羟基乙酸共聚物纤维中起一定的支撑作用，保留部分的药物释放通道，由此实现药物控制释放，更可实现药物的线性释放。
(2)本申请所涉及的载药纳米纤维膜使用可降解的聚合物通过静电纺丝方 式制得，性质稳定且具有高孔隙率，类似于细胞外基质，敷于术后残端，无需二次手术取出，可体内降解。
附图说明
图1是实施例1制得的载药纳米纤维膜的释药曲线图；
图2是实施例2制得的载药纳米纤维膜的释药曲线图；
图3是实施例3制得的载药纳米纤维膜的释药曲线图；
图4是实施例4制得的载药纳米纤维膜的释药曲线图；
图5是实施例5制得的载药纳米纤维膜的释药曲线图；
图6是实施例6制得的载药纳米纤维膜的释药曲线图；
图7是实施例1制得的载药纳米纤维膜横截面的电镜图；
图8是实施例2制得的载药纳米纤维膜横截面的电镜图；
图9是实施例3制得的载药纳米纤维膜横截面的电镜图；
图10是实施例4制得的载药纳米纤维膜横截面的电镜图；
图11是实施例5制得的载药纳米纤维膜横截面的电镜图；
图12是实施例6制得的载药纳米纤维膜横截面的电镜图。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
实施例1
本实施例提供一种载药纳米纤维膜，所述载药纳米纤维膜的成分包括聚乳酸-羟基乙酸共聚物纤维、聚对二氧环己酮纤维和紫杉醇；所述紫杉醇分散于聚乳酸-羟基乙酸共聚物纤维中；所述聚乳酸-羟基乙酸共聚物为高分子量聚乳酸-羟基乙酸共聚物(MW＝150000)和低分子量聚乳酸-羟基乙酸共聚物 (MW＝80000)的混合物，两者的质量比为25:75；所述聚对二氧环己酮纤维总质量为聚乳酸-羟基乙酸共聚物纤维总质量的10％；紫杉醇总质量为纤维总质量的10％。
其制备方法为：
(1)将紫杉醇、聚乳酸-羟基乙酸共聚物与丙酮混合，再将聚对二氧环己酮与六氟异丙醇混合，得到两种混合溶液；
(2)将步骤(1)的两种混合溶液独立装样于22G平头点胶注射器中，采用多喷头电纺设备在25℃下进行静电纺丝，喷丝头内径为0.4mm，溶液推进速度为5mL/L，喷丝电压为15kV，纺丝距离为5cm，接受装置为直径为5cm的金属转筒，转速为600rpm，得到所述载药纳米纤维膜；
(3)将步骤(2)得到的载药纳米纤维膜在25℃下真空干燥24h。
对得到的载药纳米纤维膜进行药物释放实验，并绘制释药曲线，具体方法为：将已干燥的载药纳米纤维膜切割成10mg的试样，将试样分别放入装有10mL新鲜PBS溶液的离心管中。然后将它们放入空气浴恒温摇床中，温度设为37℃，摇床的速度为100rpm。在指定的时间间隔，分别取出1mL释放溶液，并补充等量的新鲜PBS溶液。然后用紫外可见分光光度计测定药物的标准曲线，并根据标准曲线测定载药静电纺丝膜释放的药量。所有实验组均为一式五份，测得的药物释放量表示为平均值±标准偏差。实验结果如图1所示，由图1可知：该释药体系药物释放周期维持在11天左右，24h后药物释放曲线会出现释放速率增大的转折点，药物开始高速释放直至完全释放。
对得到的载药纳米纤维膜进行扫描电镜实验，具体实验方法为首先，将在PBS中浸泡7天的载药纳米纤维膜试样从离心管中取出，用去离子水冲洗数次， 然后放入真空干燥箱内室温干燥48小时。用于横截面形貌观察的试样首先要浸泡在液氮中掰断。用SEM进行观察前，先将用于横截面形貌观察的试样分别贴在样品台上，并通过真空溅射仪包覆一层导电铂金。实验结果如图7所示，由图可知：当载药静电纺丝纤维在PBS中浸泡7天以后，PDO含量为10％的载药纳米纤维膜发生进一步溶胀，纤维间空隙逐渐缩小，小部分纤维已经开始融合在一起。
实施例2
本实施例提供一种载药纳米纤维膜，所述载药纳米纤维膜的成分包括聚乳酸-羟基乙酸共聚物纤维、聚对二氧环己酮纤维和5-氟尿嘧啶；所述5-氟尿嘧啶分散于聚乳酸-羟基乙酸共聚物纤维中；所述聚乳酸-羟基乙酸共聚物为高分子量聚乳酸-羟基乙酸共聚物(MW＝100000)和低分子量聚乳酸-羟基乙酸共聚物(MW＝40000)的混合物，两者的质量比为15:85；所述聚对二氧环己酮纤维总质量为聚乳酸-羟基乙酸共聚物纤维总质量的15％；5-氟尿嘧啶总质量为纤维总质量的20％。
其制备方法为：
(1)将5-氟尿嘧啶、聚乳酸-羟基乙酸共聚物与丙酮混合，再将聚对二氧环己酮与六氟异丙醇混合，得到两种混合溶液；
(2)将步骤(1)的两种混合溶液独立装样于22G平头点胶注射器中，采用多喷头电纺设备在25℃下进行静电纺丝，喷丝头内径为0.4mm，溶液推进速度为10mL/L，喷丝电压为25kV，纺丝距离为10cm，接受装置为直径为5cm的金属转筒，转速为800rpm，得到所述载药纳米纤维膜；
(3)将步骤(2)得到的载药纳米纤维膜在25℃下真空干燥48h。
对得到的载药纳米纤维膜进行药物释放实验，并绘制释药曲线，具体方法为与实施例1一致；实验结果如图2所示，由图2可知：该释药体系基本没有突释现象，整个药物释放周期维持在7天。18h时，药物释放曲线会出现释放速率增大的转折点，药物释放速度大大增加，5天时已释放了大部分的药物。
对得到的载药纳米纤维膜进行扫描电镜实验，实验具体方法与实施例1一致，实验结果如图8所示，由图可知：当载药纳米纤维膜在PBS中浸泡7天以后，PDO含量为15％的载药纳米纤维膜发生溶胀，部分纤维已经部分融合在一起。
实施例3
本实施例提供一种载药纳米纤维膜，所述载药纳米纤维膜的成分包括聚乳酸-羟基乙酸共聚物纤维、聚对二氧环己酮纤维和卡培他滨；所述卡培他滨分散于聚乳酸-羟基乙酸共聚物纤维中；所述聚乳酸-羟基乙酸共聚物为高分子量聚乳酸-羟基乙酸共聚物(MW＝120000)和低分子量聚乳酸-羟基乙酸共聚物(MW＝60000)的混合物，两者的质量比为5:95；所述聚对二氧环己酮纤维总质量为聚乳酸-羟基乙酸共聚物纤维总质量的1％；卡培他滨总质量为纤维总质量的15％。
其制备方法为：
(1)将卡培他滨、聚乳酸-羟基乙酸共聚物与丙酮混合，再将聚对二氧环己酮与六氟异丙醇混合，得到两种混合溶液；
(2)将步骤(1)的两种混合溶液独立装样于22G平头点胶注射器中，采用多喷头电纺设备在25℃下进行静电纺丝，喷丝头内径为0.4mm，溶液推进速度为8mL/L，喷丝电压为10kV，纺丝距离为15cm，接受装置为直径为5cm 的金属转筒，转速为900rpm，得到所述载药纳米纤维膜；
(3)将步骤(2)得到的载药纳米纤维膜在25℃下真空干燥72h。
对得到的载药纳米纤维膜进行药物释放实验，并绘制释药曲线，具体方法为与实施例一致；实验结果如图3所示，由图3可知：该释药体系基本无突释。整个释药周期维持在近26天。PDO含量为1％，药物释放曲线逐渐趋向于仅含PLGA静电纺丝膜的药物释放特点。第7天才出现释放速率增大的转折点，此后体系维持较高的药物释放速率直至全部药物释放完毕。
对得到的载药纳米纤维膜进行扫描电镜实验，实验具体方法与实施例1一致，实验结果如图9所示，由图可知：当载药纳米纤维膜在PBS中浸泡7天以后，PDO含量为1％的载药纳米纤维膜发生了很大的溶胀，纤维间空隙进一步缩小，大部分纤维已经融合在一起。
实施例4
本实施例提供一种载药纳米纤维膜，所述载药纳米纤维膜的成分包括聚乳酸-羟基乙酸共聚物纤维、聚对二氧环己酮纤维和环丙沙星；所述环丙沙星分散于聚乳酸-羟基乙酸共聚物纤维中；所述聚乳酸-羟基乙酸共聚物为高分子量聚乳酸-羟基乙酸共聚物(MW＝150000)和低分子量聚乳酸-羟基乙酸共聚物(MW＝60000)的混合物，两者的质量比为3:97；所述聚对二氧环己酮纤维总质量为聚乳酸-羟基乙酸共聚物纤维总质量的5％；环丙沙星总质量为纤维总质量的10％。
其制备方法为：
(1)将环丙沙星、聚乳酸-羟基乙酸共聚物与丙酮混合，再将聚对二氧环己酮与六氟异丙醇混合，得到两种混合溶液；
(2)将步骤(1)的两种混合溶液独立装样于22G平头点胶注射器中，采用多喷头电纺设备在25℃下进行静电纺丝，喷丝头内径为0.4mm，溶液推进速度为6mL/L，喷丝电压为15kV，纺丝距离为15cm，接受装置为直径为5cm的金属转筒，转速为600rpm，得到所述载药纳米纤维膜；
(3)将步骤(2)得到的载药纳米纤维膜在25℃下真空干燥72h。
对得到的载药纳米纤维膜进行药物释放实验，并绘制释药曲线，具体方法为与实施例一致；实验结果如图4所示，由图4可知：该释药体系基本无突释。整个释药周期维持在近25天。PDO含量为5％的载药静电纺丝膜在第5天的时候药物释放曲线出现了释放速率增大的转折点。此后药物释放速率大大增加直至药物全部释放完毕。
对得到的载药纳米纤维膜进行扫描电镜实验，实验具体方法与实施例1一致，实验结果如图10所示，由图可知：当载药纳米纤维膜在PBS中浸泡7天以后，PDO含量为5％的载药纳米纤维膜发生了较大的溶胀，纤维间空隙进一步缩小，大部分纤维已经融合在一起。
实施例5
本实施例提供一种载药纳米纤维膜，所述载药纳米纤维膜的成分包括聚乳酸-羟基乙酸共聚物纤维、聚对二氧环己酮纤维和头孢拉定；所述头孢拉定分散于聚乳酸-羟基乙酸共聚物纤维中；所述聚乳酸-羟基乙酸共聚物为高分子量聚乳酸-羟基乙酸共聚物(MW＝150000)和低分子量聚乳酸-羟基乙酸共聚物(MW＝60000)的混合物，两者的质量比为10:90；所述聚对二氧环己酮纤维总质量为聚乳酸-羟基乙酸共聚物纤维总质量的7％；头孢拉定总质量为纤维总质量的10％。
其制备方法为：
(1)将头孢拉定、聚乳酸-羟基乙酸共聚物与丙酮混合，再将聚对二氧环己酮与六氟异丙醇混合，得到两种混合溶液；
(2)将步骤(1)的两种混合溶液独立装样于22G平头点胶注射器中，采用多喷头电纺设备在25℃下进行静电纺丝，喷丝头内径为0.4mm，溶液推进速度为6mL/L，喷丝电压为15kV，纺丝距离为15cm，接受装置为直径为5cm的金属转筒，转速为600rpm，得到所述载药纳米纤维膜；
(3)将步骤(2)得到的载药纳米纤维膜在25℃下真空干燥24h。
对得到的载药纳米纤维膜进行药物释放实验，并绘制释药曲线，具体方法为与实施例一致；实验结果如图5所示，由图5可知：释药体系基本无突释。整个释药周期维持在近15天。PDO含量为7％的载药纳米纤维膜在第4天的时候药物释放曲线出现了释放速率增大的转折点。此后药物释放速率大大增加直至药物全部释放完毕。
对得到的载药纳米纤维膜进行扫描电镜实验，实验具体方法与实施例1一致，实验结果如图11所示，由图可知：当载药纳米纤维膜在PBS中浸泡7天以后，PDO含量为7％的载药纳米纤维膜发生了较大的溶胀，纤维间空隙进一步缩小，部分纤维已经开始融合在一起。
实施例6
本实施例提供一种载药纳米纤维膜，所述载药纳米纤维膜的成分包括聚乳酸-羟基乙酸共聚物纤维、聚对二氧环己酮纤维和左氧氟沙星；所述左氧氟沙星分散于聚乳酸-羟基乙酸共聚物纤维中；所述聚乳酸-羟基乙酸共聚物为高分子量聚乳酸-羟基乙酸共聚物(MW＝150000)和低分子量聚乳酸-羟基乙酸共聚物 (MW＝60000)的混合物，两者的质量比为10:90；所述聚对二氧环己酮纤维总质量为聚乳酸-羟基乙酸共聚物纤维总质量的25％；左氧氟沙星总质量为纤维总质量的10％。
其制备方法为：
(1)将左氧氟沙星、聚乳酸-羟基乙酸共聚物与丙酮混合，再将聚对二氧环己酮与六氟异丙醇混合，得到两种混合溶液；
(2)将步骤(1)的两种混合溶液独立装样于22G平头点胶注射器中，采用多喷头电纺设备在25℃下进行静电纺丝，喷丝头内径为0.4mm，溶液推进速度为6mL/L，喷丝电压为15kV，纺丝距离为15cm，接受装置为直径为5cm的金属转筒，转速为600rpm，得到所述载药纳米纤维膜；
(3)将步骤(2)得到的载药纳米纤维膜在25℃下真空干燥24h。
对得到的载药纳米纤维膜进行药物释放实验，并绘制释药曲线，具体方法为与实施例一致；实验结果如图6所示，由图6可知：该释药体系基本无突释。整个释药周期维持在1天。
对得到的载药纳米纤维膜进行扫描电镜实验，实验具体方法与实施例1一致，实验结果如图12所示，由图可知：当载药纳米纤维膜在PBS中浸泡7天以后，PDO含量为25％的载药纳米纤维膜纤维间空隙比较大，只有很少部分纤维融合在一起。
申请人声明，本申请通过上述实施例来说明本申请的载药纳米纤维膜及其制备方法和应用，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等， 均落在本申请的保护范围和公开范围之内。
以上详细描述了本申请的优选实施方式，但是，本申请并不限于上述实施方式中的具体细节，在本申请的技术构思范围内，可以对本申请的技术方案进行多种简单变型，这些简单变型均属于本申请的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本申请对各种可能的组合方式不再另行说明。

Claims (15)

  1. 一种载药纳米纤维膜，其包括聚乳酸-羟基乙酸共聚物纤维、聚对二氧环己酮纤维和药物；其中，所述药物分散于所述聚乳酸-羟基乙酸共聚物纤维中。
  2. 如权利要求1所述的载药纳米纤维膜，其中，所述聚乳酸-羟基乙酸共聚物为高分子量聚乳酸-羟基乙酸共聚物和低分子量聚乳酸-羟基乙酸共聚物的混合物，其中，所述高分子量是指粘均分子量为100000-150000Da，所述低分子量是指粘均分子量为40000-80000Da。
  3. 如权利要求2所述的载药纳米纤维膜，其中，所述高分子量聚乳酸-羟基乙酸共聚物和低分子量聚乳酸-羟基乙酸共聚物的质量比为25:75-3:97。
  4. 如权利要求1-3中任一项所述的载药纳米纤维膜，其中，所述聚对二氧环己酮纤维总质量为聚乳酸-羟基乙酸共聚物纤维总质量的1％-25％，优选1％-15％。
  5. 如权利要求1-4中任一项所述的载药纳米纤维膜，其中，所述聚乳酸-羟基乙酸共聚物中乳酸结构单元与羟基乙酸结构单元的摩尔比为(1-9):1。
  6. 如权利要求1所述的载药纳米纤维膜，其中，所述聚对二氧环己酮的分子量为60000-250000Da。
  7. 如权利要求1-6中任一项所述的载药纳米纤维膜，其中，所述药物包括抗生素类药物、抗肿瘤药物和抗炎类药物中的任意一种或至少两种的组合。
  8. 如权利要求7所述的载药纳米纤维膜，其中，所述药物包括环丙沙星、盐酸环丙沙星、莫西沙星、左氧氟沙星、头孢拉定、替硝唑、5-氟尿嘧啶、阿霉素、顺铂、紫杉醇、吉西他滨、卡培他滨、阿司匹林和吲哚美辛中的任意一种或至少两种的组合。
  9. 如权利要求1所述的载药纳米纤维膜，其中，所述药物总质量为纤维总质量的1％-35％。
  10. 如权利要求1-9中任一项所述的载药纳米纤维膜的制备方法，其包括如下步骤：
    (1)将药物、聚乳酸-羟基乙酸共聚物与溶剂混合，再将聚对二氧环己酮与溶剂混合，得到两种混合溶液；和
    (2)将步骤(1)的两种混合溶液独立装样，采用多喷头电纺设备进行静电纺丝，得到所述载药纳米纤维膜。
  11. 如权利要求10所述的载药纳米纤维膜的制备方法，其中，步骤(1)所述溶剂包括N,N-二甲基甲酰胺、丙酮和六氟异丙醇中的任意一种或至少两种的组合。
  12. 如权利要求10所述的载药纳米纤维膜的制备方法，其中，步骤(1)所述混合的方式为在40-50℃下加热搅拌混合。
  13. 如权利要求10-12中任一项所述的载药纳米纤维膜的制备方法，其中，所述进行静电纺丝时的喷丝头内径为0.4mm；
    所述进行静电纺丝时的电压为10-25kV，优选20-25kV；
    所述进行静电纺丝时的纺丝距离为5-15cm，优选8-15cm；
    所述进行静电纺丝时的温度为20-30℃；
    所述进行静电纺丝时溶液推进速度为4-10mL/L，优选6-10mL/L；
    所述进行静电纺丝时的接受装置为直径为5-15cm的金属转筒，转速为600-900rpm，优选800rpm；
    步骤(2)所述得到载药纳米纤维膜后还包括对其后处理，所述后处理操作为：将所述载药纳米纤维膜在20-30℃下真空干燥24-72h。
  14. 如权利要求10-13中任一项所述的载药纳米纤维膜的制备方法，其中，所述制备方法包括如下步骤：
    (1)将药物、聚乳酸-羟基乙酸共聚物与溶剂混合，再将聚对二氧环己酮与溶剂混合，得到两种混合溶液；
    (2)将步骤(1)的两种混合溶液独立装样于22G平头点胶注射器中，采用多喷头电纺设备在20-30℃下进行静电纺丝，喷丝头内径为0.4mm，溶液推进速度为4-10mL/L，喷丝电压为10-25kV，纺丝距离为5-15cm，接受装置为直径为5-15cm的金属转筒，转速为600-900rpm，得到所述载药纳米纤维膜；和
    (3)将步骤(2)得到的载药纳米纤维膜在20-30℃下真空干燥24-72h。
  15. 如权利要求1-9中任一项所述的载药纳米纤维膜在制备药物控释系统中的应用。
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CN112760812A (zh) * 2020-12-30 2021-05-07 中国热带农业科学院南亚热带作物研究所 复合纳米纤维膜及其制备方法和应用

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