WO2024255874A1 - 载药止血棉、载药止血棉的制备方法及药物缓释系统 - Google Patents

载药止血棉、载药止血棉的制备方法及药物缓释系统 Download PDF

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WO2024255874A1
WO2024255874A1 PCT/CN2024/099345 CN2024099345W WO2024255874A1 WO 2024255874 A1 WO2024255874 A1 WO 2024255874A1 CN 2024099345 W CN2024099345 W CN 2024099345W WO 2024255874 A1 WO2024255874 A1 WO 2024255874A1
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Prior art keywords
drug
hemostatic cotton
loaded
sponge
layer
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English (en)
French (fr)
Inventor
滕金伟
栾瀚森
常舰
谢建
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PUYI (SHANGHAI) BIOTECHNOLOGY CO Ltd
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PUYI (SHANGHAI) BIOTECHNOLOGY CO Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/62—Compostable, hydrosoluble or hydrodegradable materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0036—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/32—Polyhydroxy compounds; Polyamines; Hydroxyamines
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/73—Polyisocyanates or polyisothiocyanates acyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the present invention relates to the technical field of medical devices, and in particular to a drug-loaded hemostatic cotton, a preparation method of the drug-loaded hemostatic cotton and an application thereof.
  • Otolaryngology surgery is one of the most common medical surgical procedures. Taking otorhinolaryngology surgery as an example, these bleeding sites are deep, the space is narrow, and there are a large number of capillaries around them, which are difficult to suture after surgery.
  • compression hemostasis through gauze and expanded sponges can effectively reduce the amount of bleeding and accelerate wound healing.
  • secondary injuries are caused during the extraction process, causing secondary infections. More importantly, it will make patients feel unbearable pain, and even lead to collapse, shock, etc. Therefore, how to effectively and quickly stop bleeding after surgery has become a research hotspot for many scholars.
  • Hemostatic cotton is currently a relatively effective way to stop bleeding quickly.
  • drug-loaded hemostatic cotton cannot perform conformal compression and hemostasis on narrow cavities, nor can it simultaneously store blood and prevent blood leakage.
  • the degradation rate is difficult to control, and it is not possible to achieve both compression and hemostasis and effective degradation.
  • drug-loaded hemostatic cottons on the market, and it is not possible to achieve drug administration while performing compression and hemostasis.
  • the preparation method of hemostatic cotton is to first prepare a polyurethane polymer, and then dissolve the obtained polyurethane polymer in dioxane and chitosan aqueous solution and freeze-dry it to obtain it.
  • Another method is to prepare a polyurethane polymer in advance, and then freeze-dry and sterilize it to obtain a hemostatic sponge by mixing a polyurethane solution with a foaming agent.
  • the hemostatic cotton formed by these methods has the following problems: 1) It is easy to have side reactions and high chemical residues, which affects the clinical safety of hemostatic cotton. 2) The hemostatic cotton obtained by these methods degrades slowly and the degradation time is uncontrollable. The degradation time is greater than 3 days.
  • the hemostatic cotton When the hemostatic cotton is placed in the target position, it cannot be degraded in time, so that the hemostatic cotton stays in the hemostatic site for a long time. In this process, the narrow cavity at the hemostatic site is completely blocked, prolonging the patient's pain time. Although partial degradation occurs, it is not conducive to the cleaning of the cavity because of the slow degradation. Under normal circumstances, the hemostatic process can be completed within 48 hours. If the hemostatic cotton stays in the body for a long time, it is not conducive to the healing of the wound. 3) The hemostatic cotton obtained by this method has weak mechanical properties, poor compression hemostasis effect, and poor anti-adhesion effect. 4) The hemostatic cotton does not have antibacterial and anti-inflammatory effects, thereby slowing down wound healing. 5) The cost of this method is high.
  • the purpose of the present invention is to provide a preparation method of drug-loaded hemostatic cotton, drug-loaded hemostatic cotton and a drug sustained-release system to solve the technical problems of poor hemostatic effect, poor clinical safety, long degradation time, poor mechanical properties, inability to slowly release drugs and high cost of hemostatic cotton.
  • the present invention provides a drug-loaded hemostatic cotton, which is used for the ear, nose and throat cavities.
  • the drug-loaded hemostatic cotton comprises: a porous sponge and a drug-loaded layer; the porosity of the porous sponge is greater than 80%, the viscosity of the porous sponge is greater than 0.4 dL/g, and the glass transition temperature of the porous sponge is -50 to -20°C, so that the compression strength of the porous sponge is greater than 3Kpa and the rebound rate is greater than 80%, the porous sponge plays a hemostatic role by compressing capillaries, and at the same time, the porous sponge can also absorb and store exuded blood to aggregate platelets in the blood; the drug-loaded layer is arranged on at least one of the outer layer, middle layer or inner layer of the porous sponge, and the drug-loaded layer contains drugs.
  • the water absorption rate of the drug-loaded hemostatic cotton is greater than 500%; the content of PEG chain in the molecular chain of the porous sponge is 30% to 70%, thereby making the water absorption time of the drug-loaded hemostatic cotton less than 10 minutes.
  • the degradation time of the drug-loaded hemostatic cotton is 3 hours to 24 hours; the drug release rate in the first three days is greater than 60%; the drug release rate in the first two days is greater than 40%, and the release rate is 20% to 40% per day.
  • the porous sponge is made of at least one of polyurethane, gelatin, chitosan, sodium hyaluronate, and collagen.
  • the drug includes at least one of anti-inflammatory drugs, antibacterial drugs, analgesics, hemostatic drugs or antiallergic drugs;
  • the anti-inflammatory drugs preferably include glucocorticoid drugs;
  • the glucocorticoid drugs preferably include at least one of mometasone furoate, budesonide or fluticasone propionate;
  • the antiallergic drugs preferably include ebastine, loratadine, and acrivastine.
  • the drug loading amount of each piece of drug-loaded hemostatic cotton is 100ug to 1000ug/g; preferably, it can be 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1000ug/g.
  • the present invention also provides a method for preparing drug-loaded hemostatic cotton, which is used to prepare the drug-loaded hemostatic cotton as described above.
  • the method for preparing drug-loaded hemostatic cotton comprises:
  • step S4 is S4-2: the polyurethane polymer prepared in S3 is dissolved in dioxane and placed in a mold, and a blank sponge containing no drug is obtained after freeze-drying; the drug is dispersed in a poor solvent to prepare a suspension, and the blank sponge is placed in the suspension under stirring, and after stirring, the blank sponge is taken out and dried, so that the drug is adsorbed in the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton;
  • step S4 is S4-3: dissolving the polyurethane polymer prepared in S3 with dioxane and placing it in a mold, and freeze-drying to obtain a blank sponge without drug; dissolving the drug in a good solvent to form a drug solution, and diluting the drug with a poor solvent.
  • the drug mixture is added to the blank sponge by spraying, dripping, injecting or dipping, and then dried to allow the drug to precipitate and be fixed in the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton.
  • the S4 step includes:
  • the polyurethane polymer, the drug and the porogen prepared in S3 are dissolved and placed in a mold; or, in the step S42, the polyurethane polymer and the porogen prepared in S3 are dissolved and placed in a mold.
  • the preparation method further comprises step S5: adding a moisture-inducing agent to the hemostatic cotton;
  • step S1 the mass ratio of polyethylene glycol to cyclic ester monomer is 1:1-1:2;
  • step S3 the molar ratio of the polyester prepolymer obtained in S1 to the HBH obtained in S2 is 1:1.0 to 1:1.5;
  • the organic solvent includes at least one of dimethyl sulfoxide, dimethylformamide, dioxane, and chloroform;
  • the poor solvent includes at least one of n-hexane, ether, n-pentane, petroleum ether, and cyclohexane;
  • the average molecular weight of the polyethylene glycol is 900 to 1100;
  • the present invention also provides a drug sustained-release system, which comprises the drug-loaded hemostatic cotton as described above.
  • the present invention provides a drug-loaded hemostatic cotton, a preparation method of drug-loaded hemostatic cotton, and a drug sustained-release system.
  • the drug-loaded hemostatic cotton includes: a porous sponge and a drug-loaded layer; the porosity of the porous sponge is greater than 80%, the viscosity of the porous sponge is greater than 0.4dL/g, and the glass transition temperature of the porous sponge is -50 to -20°C, so that the compression strength of the porous sponge is greater than 3Kpa, and the rebound rate is greater than 80%.
  • the porous sponge plays a hemostatic role by compressing the capillaries. At the same time, the porous sponge can also absorb and store the exuded blood to aggregate the platelets in the blood.
  • a drug-loaded hemostatic cotton with good hemostatic effect, short degradation time, good mechanical properties, good safety, and low cost is obtained.
  • the preparation method of the drug-loaded hemostatic cotton through the methods of specific reagent selection, specific reagent amount selection, specific step design, etc., obtains a short degradation time, good mechanical properties, good safety, low cost, high product stability, high yield, simple operation, universality, and easy large-scale production.
  • drug-loaded hemostatic cotton with different drug loading mechanisms, different release rates and different properties is formed.
  • FIG. 1 is a graph showing the relationship between the number average molecular weight of the samples in Examples 1-16 and Comparative Examples 1-2 and the degradation time.
  • FIG2 is a graph showing the relationship between the compression strength of the samples in Examples 1-16 and Comparative Examples 1-2 at 50% compression and the degradation time.
  • FIG3 shows the initial morphology of the sample of Example 1 in a phosphate buffered saline solution (PBS solution).
  • PBS solution phosphate buffered saline solution
  • FIG. 4 shows the morphology of the sample of Example 1 after degradation in a phosphate buffered saline solution (PBS solution) for 24 hours.
  • PBS solution phosphate buffered saline solution
  • FIG5 is a graph showing the cumulative release rates of the drugs in the samples of Examples 1-16 and Comparative Examples 1-2 at different time periods.
  • degradable means that under certain conditions, the material can be degraded into low molecular weight substances and lose its original properties.
  • target site refers to a lumen at which hemostasis is desired.
  • degradation means “degradation behavior”, which includes degradation rate, generation of products during degradation, changes in morphology and mechanical properties, etc.
  • end point of the degradation is defined as force breakage, compression stress less than 50% of the original, and molecular weight less than 30% of the original.
  • the present invention provides a drug-loaded hemostatic cotton, a preparation method of the drug-loaded hemostatic cotton, and a drug sustained-release system.
  • the drug-loaded hemostatic cotton comprises: a porous sponge and a drug-loaded layer; the porosity of the porous sponge is greater than 80%, the viscosity of the porous sponge is greater than 0.4dL/g, and the glass transition temperature of the porous sponge is -50 to -20°C, so that the compression strength of the porous sponge is greater than 3Kpa and the rebound rate is greater than 80%.
  • the porous sponge plays a hemostatic role by compressing the capillaries. At the same time, the porous sponge can also absorb and store the exuded blood to aggregate the platelets in the blood. In this way, a drug-loaded hemostatic cotton with good hemostatic effect, short degradation time, good mechanical properties, good safety, and low cost is obtained.
  • the method comprises: S1: in an anhydrous and oxygen-free environment, using polyethylene glycol as an initiator, a cyclic ester monomer undergoes a ring-opening reaction under the action of a catalyst to synthesize a polyester prepolymer, wherein the average molecular weight of the polyethylene glycol is 800-1500.
  • S3 the isocyanate-terminated triblock compound prepared by S2 is dissolved in an organic solvent and reacted with the polyester prepolymer prepared by S1 according to a certain feed ratio, and a poor solvent is used for precipitation. After precipitation, no water precipitation or alcohol soaking treatment is performed, and then the polyurethane polymer is obtained by purification and drying.
  • S4 the polyurethane polymer prepared by S3 and the drug dioxane are dissolved and placed in a mold, and the drug-loaded hemostatic cotton is obtained after freezing, drying, and sterilization.
  • step S4 may also be: dissolving the polyurethane polymer and the drug prepared in S3 with dioxane and placing them in a mold, freezing, drying, and sterilizing to obtain a polyurethane sponge; or preparing the drug into a suspension in a poor solvent, placing the blank sponge without the drug into the suspension under stirring, removing it after stirring and drying it, so that the drug is adsorbed in the pores of the polyurethane sponge to form a hemostatic cotton.
  • step S4 may also be: dissolving the polyurethane polymer prepared in S3 with dioxane and placing it in a mold, freezing, drying, and sterilizing to obtain a polyurethane sponge; dissolving the drug in a good solvent to form a drug solution, diluting the drug solution with a poor solvent to obtain a drug mixture, adding the drug mixture to the polyurethane sponge by spraying, dripping, injecting, or dipping, and then drying it so that the drug is adsorbed in the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton.
  • the embodiment of the present invention provides a drug-loaded hemostatic cotton, which is used in the ear, nose, and throat cavities.
  • the drug-loaded hemostatic cotton comprises: a porous sponge and a drug-loaded layer.
  • the porosity of the porous sponge is greater than 80%, the viscosity of the porous sponge is greater than 0.4dL/g, and the glass transition temperature of the porous sponge is -50 to -20°C, so that the compression strength of the porous sponge is greater than 3Kpa and the rebound rate is greater than 80%.
  • the porous sponge plays a hemostatic role by compressing the capillaries. At the same time, the porous sponge can also absorb and store the exuded blood to aggregate the platelets in the blood.
  • the porosity of the porous sponge is greater than 90%, for example, 90%, 95%, 99%, etc.
  • the viscosity of the porous sponge is greater than 0.6dL/g, and more preferably greater than 0.7dL/g, for example, 0.7, 0.8, 0.9dL/g.
  • the glass transition temperature of the porous sponge is -50 to -20°C, for example, -50, -40, -35, -25, -20°C.
  • the compressive strength of the drug-loaded hemostatic cotton can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 kPa, preferably greater than 10 kPa.
  • the rebound rate can be 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 kPa, preferably greater than 95%, and it has excellent mechanical properties and good conformability.
  • the drug-carrying layer is disposed in at least one of the outer layer, middle layer or inner layer of the porous sponge.
  • the outer layer means that the drug-carrying layer is coated on the outside of the porous sponge.
  • the middle layer means that the drug-carrying layer is neither on the outside of the porous sponge nor in the innermost part of the porous sponge.
  • the inner layer means that the drug-carrying layer is in the middle part of the porous sponge.
  • the drug particles in the drug-carrying layer are embedded in the porous sponge; or, the drug particles in the drug-carrying layer are contained in the pores of the porous sponge.
  • the embedding means that the drug exists in the skeleton of the porous sponge, and the containing means that the drug exists in the pores outside the skeleton.
  • the water absorption rate of the drug-loaded hemostatic cotton is greater than 500%, such as 600%, 700%, 800%, 900%, preferably greater than 1000%, and more preferably greater than 1500%, so that the drug-loaded hemostatic cotton has a better function of absorbing liquid (such as blood, body fluid, etc.) or storing liquid.
  • the content of PEG (polyethylene glycol) chain in the molecular chain of the porous sponge is 30% to 70%, so that the water absorption time of the drug-loaded hemostatic cotton is less than 10 minutes.
  • the PEG chain is hydrophilic, which makes the drug-loaded hemostatic cotton have good hydrophilicity and short water absorption time.
  • the water absorption time of the drug-loaded hemostatic cotton is less than 5 minutes.
  • the drug-loaded hemostatic cotton has high porosity and high water absorption rate, which provides favorable conditions for degradation.
  • the water absorption time indicates the time required for the drug-loaded hemostatic cotton to be placed on the water surface of 37°C ⁇ 1°C (simulating human body temperature) until the drug-loaded hemostatic cotton is completely immersed in the water.
  • the water absorption rate indicates the ratio of the increased mass after complete immersion to the initial mass.
  • the drug-loaded hemostatic cotton is degradable, and the degradation time of the drug-loaded hemostatic cotton is 3h to 24h (in rabbit blood, simulating human body temperature, 37°C ⁇ 1°C); in its release behavior, the drug release rate in the first three days is greater than 60%; the drug release rate in the first two days is greater than 40%, and the release rate is 20% to 40% per day.
  • the drug release rate in the first three days is greater than 80%; the drug release rate in the first two days is greater than 70%, and the release rate is 35% to 40% per day. In this way, the drug can be sustained-released within the degradation time, and the release rate is moderate and the dosage is moderate.
  • the test environment is in rabbit blood, simulating human body temperature, 37°C ⁇ 1°C.
  • the porous sponge is made of at least one of polyurethane, gelatin, chitosan, sodium hyaluronate and collagen.
  • the porous sponge is polyurethane.
  • the drug-carrying layer contains drugs, and the drugs include at least one of anti-inflammatory drugs, antibacterial drugs, analgesic drugs, hemostatic drugs or anti-allergic drugs.
  • the anti-inflammatory drugs include glucocorticoid drugs; the glucocorticoid drugs include mometasone furoate, budesonide or fluticasone propionate; the anti-allergic drugs include ebastine, loratadine, and acrivastine.
  • the drug can be any drug that can be set on the drug-carrying hemostatic cotton, and is not limited to the drugs in this embodiment.
  • the drug loading amount of each drug-loaded hemostatic cotton is 100 ug to 1000 ug/g, such as 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 ug/g. In this way, the drug can be safely released every day.
  • the drug-loaded layer includes a first drug-loaded layer and a second drug-loaded layer.
  • the porous sponge is a polyurethane sponge. The first drug-loaded layer, the polyurethane layer, and the second drug-loaded layer are sequentially arranged along the thickness direction thereof.
  • the present invention also provides a method for preparing drug-loaded hemostatic cotton, which is used to achieve the above-mentioned drug-loaded Hemostatic cotton achieves all the parameter indicators of the above-mentioned drug-loaded hemostatic cotton.
  • Preparation of prepolymer In an anhydrous and oxygen-free environment, with polyethylene glycol (PEG) as an initiator, cyclic ester monomers undergo a ring-opening reaction under the action of a catalyst to synthesize a polyester prepolymer, wherein the average molecular weight of the polyethylene glycol (PEG) is 800-1500.
  • the average molecular weight of the polyethylene glycol (PEG) is 900-1100. More preferably, the average molecular weight of the polyethylene glycol (PEG) is 950-1050. It is directly used in step S3 without post-treatment, thus simplifying the steps of the preparation method and reducing production costs.
  • the selection of the average molecular weight of the polyethylene glycol (PEG) is a specific selection.
  • its average molecular weight is 800-1500, for example, when 900-1100 is selected, the time when the prepared drug-loaded hemostatic cotton begins to degrade is about 10 times earlier than the degradation time of the drug-loaded hemostatic cotton in the prior art, and the degradation rate is thereby improved, and the degradation rate is greatly increased. After the drug-loaded hemostatic cotton completes hemostasis at the target position, the cavity can be quickly recanalized.
  • the degradation rate of polyethylene glycol (PFG) in this embodiment is very rapid, in the step of synthesizing polyurethane in S3, the steps of water precipitation and alcohol immersion cannot be used, so these two steps can be omitted.
  • the drug-loaded hemostatic cotton prepared by the polyester prepolymer synthesized by polyethylene glycol (PEG) can control the degradation time within 36 hours, and the degradation rate is fastest within 6-12 hours. Compared with the uncontrollable degradation time of the prior art, it can ensure degradation within a controllable 36 hours.
  • the cyclic ester monomer is one or more of DL-lactide, L-lactide, glycolide, caprolactone, trimethylene carbonate, and p-dioxanone.
  • the cyclic ester monomer is glycolide, lactide, and caprolactone.
  • the mass ratio of polyethylene glycol to cyclic ester monomer is 1:1-1:1.05, thereby ensuring the proportion of polyethylene glycol, avoiding the problem of poor hydrophilicity of drug-loaded hemostatic cotton, and improving the degradation rate.
  • Example 3 and other embodiments below as well as the analysis of degradation performance below.
  • the catalyst is a tin catalyst, and the mass of the catalyst is 0.01% to 0.05% of the total mass of the reactants.
  • the reaction temperature in the step S1 is 120°C to 140°C; the reaction time is 12 to 36 hours.
  • diisocyanate compound and polyol compound are mixed, reacted at a certain temperature, and separated and purified to prepare isocyanate-terminated triblock compound (HBH), wherein the molar ratio of the diisocyanate compound to the polyol compound is 1:4 to 1:10, so that the polyol compound and the diisocyanate compound can fully react to form isocyanate-terminated triblock compound (HBH).
  • the diisocyanate compound can be one or more of hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), and methylcyclohexyl diisocyanate.
  • the diisocyanate compound is preferably hexamethylene diisocyanate (HDI).
  • HDI hexamethylene diisocyanate
  • the polyol compound is preferably 1,4-butanediol (BDO).
  • BDO 1,4-butanediol
  • the isocyanate-terminated triblock compound (HBH) provides more urethane bonds, which have dense hydrogen bonds and enhance the mechanical properties of the drug-loaded hemostatic cotton.
  • the molar ratio of 1,4-butanediol to hexamethylene diisocyanate is 1:4 to 1:6.
  • the reaction temperature is 70°C to 90°C; the reaction time is 4 to 6 hours.
  • the separation and purification process is: washing the crude product obtained after the reaction with a large amount of n-hexane, stirring continuously during the washing process until the product is completely dispersed into a solid powder, filtering, washing again with n-hexane, repeating 3 to 6 times, and rotary evaporating at 40°C to 50°C for 2 to 5 hours to obtain a pure white solid powder, which is the chain extender.
  • the organic solvent includes at least one of dimethyl sulfoxide, dimethylformamide, dioxane, and chloroform; and the poor solvent includes at least one of n-hexane, ether, n-pentane, petroleum ether, and cyclohexane.
  • step S3 includes dissolving the isocyanate-terminated triblock compound prepared by S2 in dimethyl sulfoxide (DMSO), reacting with the polyester prepolymer prepared by S1 at a certain feed ratio, and using a poor solvent, such as ether, for precipitation.
  • step S3 includes: reacting the polyester prepolymer prepared by S1 with a dimethylformamide solution of the isocyanate-terminated triblock compound prepared by S2, and using ether for precipitation after the polymerization is completed.
  • dimethylformamide (DMF) may be N,N-dimethylformamide, which is a solvent for the isocyanate-terminated triblock compound (HBH).
  • Ether is used for precipitation because ether has good volatility and less residue.
  • the polyurethane polymer prepared in S3 has a fast degradation rate due to the specific selection of polyethylene glycol.
  • the aqueous solution is not used for sedimentation and alcohol immersion, which avoids the influence of water on the polyurethane polymer, maintains the stability of the degradation of the drug-loaded hemostatic cotton, and improves the yield.
  • the steps of aqueous solution sedimentation and alcohol immersion are also reduced, the production steps are reduced, and the production cost is reduced.
  • the selection and omission of any step are crucial.
  • the dimethyl sulfoxide and N, N-dimethylformamide (DMF) solvents can be specifically selected, which can be directly dissolved by ether, thereby providing conditions for omitting the steps of water precipitation and alcohol immersion.
  • the polyester prepolymer and the isocyanate-terminated triblock compound (HBH) are pre-synthesized, and the reaction process is controllable, avoiding the monomer residue of the by-product.
  • the obtained product is effectively post-processed to remove the small molecule monomers and heavy metal residues in the synthesis process, effectively improving the safety of the drug-loaded hemostatic cotton.
  • the mass concentration of the DMF solution of HBH is 0.2-0.5 g/g.
  • the molar ratio of the polyester prepolymer obtained in S1 to the HBH obtained in S2 is 1:1.0-1:1.5.
  • the reaction temperature of the polyurethane polymer is 75-90°C, and the reaction time is 3-6 hours.
  • the purification process includes diluting the reaction mixture to 10%-25% with dioxane, slowly pouring it into 5-8 times of ice ether under stirring, and then transferring the precipitated white filamentous solid to n-hexane, soaking it for more than 3 hours, and then drying it in an oven at 40°C for 10 hours.
  • S4 Preparation of drug-loaded hemostatic cotton: The polyurethane polymer prepared in S3 and the drug are dissolved in an organic solvent and placed in a mold, and then frozen, dried, and sterilized to obtain drug-loaded hemostatic cotton.
  • the freezing and drying process is a process of solution sublimation. After the solution sublimates, uniform pores can be formed to form a microporous solid.
  • the organic solvent is preferably dioxane, which has a high melting point, a low boiling point, and good solubility. The organic solvent can dissolve the polyurethane polymer and the drug at the same time.
  • the drug By dissolving the polyurethane polymer and the drug together, and obtaining the drug-loaded hemostatic cotton through freezing, drying and other steps, the drug can be embedded in the polyurethane, and the drug can be sustained-released during the degradation process of the drug-loaded hemostatic cotton.
  • the embedding is physical embedding.
  • some doctors use drug-free drug-loaded hemostatic cotton to dip in medicine and then place it in the target position, but the concentration and release of the dipped medicine are uncontrollable, and the medicine is administered once, and quantitative sustained-release administration cannot be achieved.
  • the drug-loaded hemostatic cotton of the present embodiment can achieve sustained-release of drugs, and the drug release is stable and effective.
  • the doctor does not need to temporarily prepare drugs and dip the drugs in liquid medicine during surgery.
  • the drug-loaded hemostatic cotton can be directly implanted into the target position without the step of dipping in liquid medicine, thus avoiding new safety issues caused by complicated steps or the process of dipping in liquid medicine, saving the operation time of doctors and patients and improving the operation efficiency.
  • the preparation method of the drug-loaded hemostatic cotton of the embodiment of the present invention through the selection of specific raw materials, solvents and specific steps, has a short degradation time, good mechanical properties, can achieve compression hemostasis in a short time, does not require secondary surgery to remove, can flow out after degradation with body metabolism, and the degradation product is non-toxic.
  • the drug-loaded hemostatic cotton can also achieve drug sustained release, and the production cost of the drug-loaded hemostatic cotton is low, making it safer and more convenient.
  • the drug-loaded hemostatic cotton obtained by the preparation method of the drug-loaded hemostatic cotton of the embodiment of the present invention can shorten its degradation time to within 3 days. After the drug-loaded hemostatic cotton is placed in the target position, hemostasis is completed within 48 hours, and then the degraded drug-loaded hemostatic cotton fragments at the target position can be washed out of the cavity by a cleaning method, thereby facilitating the healing of the wound tissue at the target position.
  • the number average molecular weight of the polyethylene glycol used is 4000 to 20000, and the mass fraction is 0.5% to 3%. More preferably, the number average molecular weight of the polyethylene glycol is 10000 to 15000, which further improves the stress.
  • the mass concentration of the polyurethane polymer solution is 3% to 5%.
  • the freeze-drying process can be divided into three steps: pre-freezing, freezing, and drying, with a total duration of 30 to 90 hours and a temperature of -25°C to 20°C.
  • the sterilization method used is irradiation sterilization and ethylene oxide sterilization.
  • the S4 step includes: S41: dissolving the polyurethane polymer and the drug prepared in S3 with dioxane and placing them in a mold, and freezing them to obtain a first drug-carrying layer, wherein the thickness of the first drug-carrying layer is smaller than the height in the mold, so that the mold can accommodate the polyurethane layer and the second drug-carrying layer described below.
  • S42 The polyurethane polymer prepared in S3 is dissolved in dioxane and placed in the mold, and a polyurethane layer is obtained by freezing. The polyurethane layer is superimposed on the first drug-carrying layer. The sum of the thickness of the first drug-carrying layer and the polyurethane layer is less than the height in the mold, so that the mold can accommodate the second drug-carrying layer described below.
  • the drug-carrying hemostatic cotton does not contain drugs inside, the explosive release of drugs when the drug-carrying hemostatic cotton is completely degraded is avoided.
  • the drug-carrying hemostatic cotton as an implantable device, needs to have a drug loading within a specified drug loading range. Therefore, within the specified drug loading range, the polyurethane layer of the drug-carrying hemostatic cotton does not contain drugs, and the first drug loading layer and the second drug loading layer contain drugs, and the drug loading concentration increases, and the amount of drugs released during drug sustained release increases, thereby improving the drug efficacy.
  • those skilled in the art can also configure the drug-loaded hemostatic cotton with a single-sided drug layer according to actual usage, which is also within the protection scope of the present invention.
  • the ratio of the thickness of the first drug-carrying layer or the second drug-carrying layer to the thickness of the drug-carrying hemostatic cotton is less than 1/3, which increases the concentration of the single-layer drug under the condition of a certain drug dosage. It also avoids the situation where the drug-carrying hemostatic cotton releases the drug explosively when it degrades.
  • the thickness ratio of the first drug-carrying layer to the second drug-carrying layer can be 1:1, and the thickness of the first drug-carrying layer to the second drug-carrying layer is preferably 1 mm, and of course, it can also be 2 mm or 3 mm, etc.
  • the drug includes at least one of anti-inflammatory drugs, antibacterial drugs, analgesics, hemostatic drugs or antiallergic drugs.
  • the anti-inflammatory drugs include glucocorticoid drugs.
  • the antibacterial drugs include penicillins, cephalosporins, ofloxacin, ciprofloxacin, clotrimazole, chloramphenicol and other drugs.
  • the analgesics include ibuprofen and the like.
  • the glucocorticoid drugs include mometasone furoate or budesonide.
  • the antiallergic drugs can be used nasally, such as levocabastine hydrochloride, ketotifen fumarate, beclomethasone propionate, mometasone furoate, budesonide, Fluticasone propionate.
  • the drug can also be a ciliary agonist and a mucus promoting drug, such as myrtle oil.
  • the drug can also be a nasal mucosa protective drug, such as compound peppermint oil, chlorhexidine cod liver oil nasal drops, etc. In this way, the inflammation problem caused by postoperative bacterial infection is solved, the healing of the wound is accelerated, and the adhesion problem of the wound site can be avoided.
  • mometasone furoate used in this embodiment is used as an example for verification and explanation.
  • the drug content of the anti-inflammatory drug, antibacterial drug, analgesic drug, hemostatic drug or antiallergic drug is 0.25-0.30 ⁇ (mass ratio) of the polyurethane polymer, thereby ensuring a safe drug loading ratio while ensuring drug loading and achieving a sustained release effect.
  • the polyurethane polymer, the drug and the porogen prepared in S3 are dissolved together and placed in a mold, and the porogen is an inorganic salt;
  • the inorganic salt can further be ammonium phosphate, ammonium hydrogen phosphate, and ammonium bicarbonate. Since the inorganic salt is decomposed into non-toxic and harmless gas by heat, and no residue remains, for example, ammonium bicarbonate disappears after being heated to ammonia and carbon dioxide.
  • the drug-loaded hemostatic cotton will not produce harmful substances due to the presence of the porogen during use, and no harmful substances will be produced and precipitated, thereby improving the safety of the product.
  • the rebound rate (the degree of deformation recovery after the external force is removed) of the drug-loaded hemostatic cotton with the addition of porogen is improved, and the deformation recovery is good. It can rebound well when inserted into the nasal cavity, compressing the capillaries and achieving a good hemostatic effect. Furthermore, the content of the porogen is 3-5% of the polyurethane polymer.
  • the preparation method further comprises step S5: adding a wetting agent (PEG) to the drug-loaded hemostatic cotton to increase the hydrophilicity and compressive stress of the drug-loaded hemostatic cotton, thereby increasing the degradation rate and the supporting strength of the drug-loaded hemostatic cotton.
  • PEG wetting agent
  • This embodiment also provides a method for preparing drug-loaded hemostatic cotton, comprising:
  • S4 dissolving the polyurethane polymer prepared in S3 with dioxane and placing it in a mold, freezing, drying, and sterilizing to obtain a polyurethane sponge; preparing a suspension of the drug in a poor solvent, placing the polyurethane sponge in the suspension under stirring, removing the suspension after stirring, and drying the suspension, so that the drug is adsorbed in the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton, thereby ensuring the presence of the drug in the drug-loaded hemostatic cotton and facilitating the release of the drug.
  • the poor solvent can bring the drug particles into the pores of the polyurethane sponge through the flow of the poor solvent.
  • this embodiment also provides another method for preparing drug-loaded hemostatic cotton, wherein S1, S2, and S3 are described above and are not repeated here, and S4 may also be: the polyurethane polymer prepared in S3 is dissolved in dioxane and placed in a mold, and a polyurethane sponge is obtained after freezing, drying, and sterilization.
  • the drug is dissolved in a good solvent to form a drug solution, and the drug solution is diluted with a poor solvent to obtain a drug mixture, and the drug mixture is added to the polyurethane sponge by spraying, dripping, injection, or dipping, and then dried to allow the drug to precipitate and be fixed in the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton.
  • the good solvent is one or more of acetonitrile, methanol, dioxane, dichloromethane, ethyl acetate, acetone, dimethyl sulfoxide, and dimethylformamide.
  • the good solvent is preferably ethyl acetate and acetone.
  • the poor solvent is one or more of water, n-hexane, and cyclohexane.
  • the poor solvent is preferably cyclohexane.
  • the benign solvent is miscible with the poor solvent, and the boiling point of the benign solvent is lower than that of the poor solvent. If the benign solvent and the poor solvent are not miscible, a uniform solution cannot be formed, and the benign solvent should evaporate first to avoid the concentration of the benign solvent becoming higher and higher until it dissolves and destroys the sponge.
  • the concentration of the drug in the benign solvent is 0.5 mg/ml-10 mg/ml.
  • the ratio of good solvent to poor solvent (volume ratio, mass ratio or molar ratio) is 1:4-1:49, and the dilution factor is 5-50 times. If the ratio of good solvent to poor solvent is too high, the sponge will be destroyed, and if it is too low, the drug will precipitate in the solution.
  • the concentration of the drug mixed solution is 0.01 mg/ml-2 mg/ml.
  • the concentration of the drug is preferably much lower than its saturated solubility in a good solvent, otherwise it will precipitate out and form a precipitate just after adding a poor solvent.
  • the drug solution is prepared into a certain concentration in ethyl acetate and then diluted into a certain proportion with cyclohexane to obtain a drug solution. Then the drug can be added by spraying, dripping or soaking.
  • the key is the preparation of the drug solution, which makes the drug in a balanced state between precipitation and non-precipitation without destroying the polyurethane sponge.
  • step S2 the three-necked flask was fixed in an 80°C oil bath for preheating, 50.4g of hexamethylene diisocyanate was added, 4.5g of 1,4-butanediol was added dropwise under mechanical stirring, and the mixture was sealed for reaction for 4.5h to obtain a milky white paste.
  • the mixture was fully stirred and washed with 400mL of n-hexane, and filtered by suction. After repeating 3 times, the mixture was dried at 40°C for 3h using a rotary evaporator to obtain a pure white solid powder (HBH).
  • step S3 50 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 13.84 g of the HBH obtained in step S2 is dissolved in 30.00 g of DMF solution and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 80° C. for 3 h, a transparent viscous liquid is obtained, dioxane is added to dilute it to 20%, and the liquid is slowly poured into ice ether while hot, and soaked in n-hexane for 3 h. The product was then dried in an oven at 40°C for 10 h to obtain a transparent filamentous solid, which is a polyurethane polymer.
  • a layer of liquid A is first poured into the mold, and liquid B is poured after freezing at 0°C, and then covered with a layer of liquid A after freezing. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying. After irradiation sterilization of the freeze-dried sample, a layered freeze-dried drug-loaded cotton is obtained, which is recorded as M1.
  • a layer of lyophilized solution is first poured into the mold, and then covered with a layer of lyophilized solution after freezing at 0°C. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying to obtain a blank sponge without medicine.
  • Mometasone furoate is ultrasonically dispersed in a cyclohexane solution to prepare a drug solution with a concentration of 16ug/ml, and the blank sponge is immersed in the drug solution under continuous stirring for 30 seconds, and then taken out and dried in a vacuum drying oven to constant weight, and then sterilized by irradiation to obtain a suspended nanoabsorption drug-loaded cotton. It is recorded as M2.
  • Mometasone furoate was dissolved in ethyl acetate to prepare an initial solution with a concentration of 1.5 mg/ml, and then diluted to 125 ug/ml with cyclohexane. 1 ml was added to the upper and lower surfaces of the sponge using a pipette, and dried to constant weight in a vacuum drying oven. After irradiation sterilization, a solvent-precipitated drug-loaded cotton was obtained, which was recorded as M3.
  • chain extender HBH The preparation method of chain extender HBH is the same as that in Example 1 and will not be described again here.
  • step S3 40 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 30.00 g of DMF solution is used to dissolve 14.00 g of HBH obtained in step S2 and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 80° C. for 3.5 hours, a transparent viscous liquid is obtained, dioxane is added to dilute it to 15%, and the liquid is slowly poured into ice ether while hot. After being soaked in n-hexane for 3 hours, it is dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.
  • a layer of lyophilized solution is first poured into the mold, and then covered with a layer of lyophilized solution after freezing at 0°C. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying to obtain a blank sponge without medicine.
  • Mometasone furoate is ultrasonically dispersed in a cyclohexane solution to prepare a drug solution with a concentration of 20ug/ml, and the blank sponge is immersed in the drug solution under continuous stirring for 45 seconds, and then taken out and dried in a vacuum drying oven to constant weight, and then sterilized by irradiation to obtain a suspended nanoabsorption drug-loaded cotton. It is recorded as M5.
  • the corresponding blank sponge was obtained according to the method in Example 5.
  • Mometasone furoate was dissolved in ethyl acetate to prepare an initial solution with a concentration of 2.0 mg/ml, and then diluted to 150 ug/ml with cyclohexane. 1 ml was added to the upper and lower surfaces of the sponge using a pipette, and dried to constant weight in a vacuum drying oven. After irradiation sterilization, a solvent-precipitated drug-loaded cotton was obtained, which was recorded as M6.
  • the bottle is continuously vacuumed for 2.0 h at 95°C using a vacuum oil pump to remove water. After the water is removed, the bottle is cooled to below 70°C.
  • 15 g of L-lactide, 15 g of ⁇ -caprolactone, and 0.004 g of stannous isooctanoate are added in sequence.
  • the bottle is vacuumed for 30 seconds, and then the temperature is raised to 130°C. After reacting for 30 h, the bottle is directly used in the next step without post-treatment.
  • chain extender HBH The preparation method of chain extender HBH is the same as that in Example 1 and will not be described again here.
  • step S3 40 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 30.00 g of DMF solution is used to dissolve 14.00 g of HBH obtained in step S2 and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 80° C. for 3.5 hours, a transparent viscous liquid is obtained, dioxane is added to dilute it to 15%, and the liquid is slowly poured into ice ether while hot. After being soaked in n-hexane for 3 hours, it is dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.
  • Liquid B is a 4.5% polyurethane polymer dioxane solution, and 4.0% ammonium bicarbonate is added.
  • Mometasone furoate is ultrasonically dispersed in a n-hexane solution to prepare a drug solution with a concentration of 20ug/ml, and the blank sponge is immersed in the drug solution under continuous stirring for 45 seconds, and then taken out and dried in a vacuum drying oven to constant weight, and then sterilized by irradiation to obtain a suspended nanoabsorption drug-loaded cotton. It is recorded as M8.
  • Mometasone furoate was dissolved in ethyl acetate to prepare an initial solution with a concentration of 1.0 mg/ml, and then diluted to 100 ug/ml with cyclohexane. 1.5 ml was dripped onto the upper and lower surfaces of the sponge using a pipette, and dried to constant weight in a vacuum drying oven. After irradiation sterilization, a solvent-precipitated drug-loaded cotton was obtained, which was recorded as M9.
  • chain extender HBH The preparation method of chain extender HBH is the same as that in Example 1 and will not be described again here.
  • step S3 50 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 13.00 g of the HBH obtained in step S2 is dissolved in 26.00 g of DMF solution and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 85° C. for 2.5 hours, a transparent viscous liquid is obtained, dioxane is added to dilute it to 15%, and the liquid is slowly poured into ice ether while hot. After being soaked in n-hexane for 3 hours, it is dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.
  • liquid A is a 3.5% polyurethane polymer dioxane solution containing mometasone furoate, wherein the content of mometasone furoate is 0.30 ⁇ of the polyurethane polymer.
  • Liquid B is a 3.5% polyurethane polymer dioxane solution.
  • a layer of liquid A is first poured into the mold, and liquid B is poured after freezing at 0°C, and then covered with a layer of liquid A after freezing again. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying. After irradiation sterilization of the freeze-dried sample, a degradable drug-loaded hemostatic sponge is obtained, which is recorded as M10.
  • the polymer is dissolved in a dioxane solution to obtain a 3.5% solution, a layer of the solution is first poured into the mold, and then covered with another layer of the solution after freezing at 0°C. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying to obtain a blank sponge without medicine.
  • Mometasone furoate is ultrasonically dispersed in a n-hexane solution to prepare a drug solution with a concentration of 20ug/ml, and the blank sponge is immersed in the drug solution under continuous stirring for 45 seconds, and then taken out and dried in a vacuum drying oven to constant weight, and then sterilized by irradiation to obtain a suspended nanoabsorption drug-loaded cotton. It is recorded as M11.
  • Mometasone furoate was dissolved in ethyl acetate to prepare an initial solution with a concentration of 2.0 mg/ml, and then diluted to 100 ug/ml with cyclohexane. 1.5 ml was dripped onto the upper and lower surfaces of the sponge using a pipette, and dried to constant weight in a vacuum drying oven. After irradiation sterilization, a solvent-precipitated drug-loaded cotton was obtained, which was recorded as M12.
  • step S3 50.00 g of prepolymer was added to a three-necked flask, 13.84 g of HBH was dissolved in 25.00 g of DMSO and then added dropwise to the reaction flask, and the flask was sealed and reacted at 75° C. for 3.5 hours until the infrared detection NCO peak completely disappeared (2300 cm -1 ). Vacuum was continuously drawn overnight to remove DMSO, and then dioxane was added to dilute to 20%, and then precipitated with n-hexane and dried in an oven to constant weight to obtain a light yellow solid as a polyurethane polymer.
  • the drug-loaded hemostatic cotton was prepared according to the method described in step S4 of Example 1 and was recorded as M13.
  • step S3 50.00 g of prepolymer was added to a three-necked flask, 13.84 g of HBH was dissolved in 25.00 g of DMSO and then added dropwise to the reaction flask, and the flask was sealed and reacted at 75° C. for 3.5 hours until the infrared detection NCO peak completely disappeared (2300 cm -1 ). Vacuum was continuously applied overnight to remove DMSO, and then dioxane was added to dilute to 20%, and the supernatant was collected after centrifugation and precipitated with n-hexane, and dried in an oven to constant weight to obtain a light yellow solid as a polyurethane polymer.
  • the drug-loaded hemostatic cotton was prepared according to the method described in Example 12 and was recorded as M14.
  • step S3 50.00 g of prepolymer was added to a three-necked flask, 13.84 g of HBH was dissolved in 50.00 g of dioxane and then added dropwise to the reaction flask, and the flask was sealed and reacted at 75° C. for 3 hours until the infrared detection NCO peak (2300 cm -1 ) completely disappeared.
  • Dioxane was added again to dilute to 20%, and petroleum ether was used for precipitation and then dried in an oven to constant weight to obtain a light yellow solid as a polyurethane polymer.
  • the drug-loaded hemostatic cotton was prepared according to the method described in Example 12 and was recorded as M15.
  • step S3 50.00 g of prepolymer was added to a three-necked flask, 13.00 g of HBH was dissolved in 50.00 g of toluene and then added dropwise to the reaction flask, and the flask was sealed and reacted at 70° C. for 3 hours until the infrared detection NCO peak (2300 cm -1 ) completely disappeared.
  • Dioxane was added again to dilute to 25%, cyclohexane was used for precipitation, and then dried in an oven to constant weight to obtain a light yellow solid as a polyurethane polymer.
  • the drug-loaded hemostatic cotton was prepared according to the method described in Example 12 and was recorded as M16.
  • chain extender HBH The preparation method of chain extender HBH is the same as that in Example 1 and will not be described again here.
  • step S3 40 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 10.4 g of the HBH obtained in step S2 is dissolved in 26.00 g of DMSO solution and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 85° C. for 2.5 hours, a transparent viscous liquid is obtained, dioxane is added to dilute it to 15%, and the liquid is slowly poured into purified water while hot to precipitate a white strip-like solid.
  • the water After being fished out, the water is wrung out and the liquid is soaked in ice ethanol to further remove the water, and the liquid is dissolved again with dioxane to 15%, and the liquid is precipitated into a filamentous solid in ice ether, and dried to constant weight.
  • step S4 the polymer is dissolved in dioxane to prepare 3.5%, 0.3 ⁇ of the mass of the polymer is added to obtain a lyophilized liquid, and the drug-loaded hemostatic cotton is prepared after freeze-drying in a mold, which is recorded as DBM.
  • Comparative Example 2 This comparative example provides a commercially available product as a reference sample, denoted as NXM.
  • the water absorption performance indirectly reflects the effect of the drug-loaded hemostatic cotton on hemostasis.
  • the specific test method of the water absorption performance is: weigh the freeze-dried drug-loaded hemostatic cotton sample prepared in the embodiment (record as dry weight) and gently place it on the surface of purified water. The water can extend upward along the pores of the sample until the top is completely immersed, and the water absorption time is recorded; wipe off the surface flowing water and weigh it, record it as wet weight, and calculate the water absorption rate of the sample according to the ratio of wet/dry weight. Each sample is repeated three times.
  • Table 1 The specific test results are shown in Table 1.
  • the porosity of the sample increases with the increase of the use of the porogen. This is because the porogen ammonium bicarbonate occupies a certain space in the solvent. During the cooling process, the porogen is separated from it, and decomposed into carbon dioxide and ammonia during the drying process to be discharged from the drug-loaded hemostatic cotton, forming a large number of pores and improving the porosity.
  • the water absorption rate and water absorption rate of the sponge are proportional to the proportion of polyethylene glycol in the entire molecular chain segment and the amount used as a humectant. The water absorption time can reach less than three minutes, which is comparable to the commercially available product NXM and better than the comparative example DBM. This shows that the lower the molecular weight of PEG, the lower the proportion of hydrophilic chains in the entire polymer chain segment, which reduces the hydrophilicity.
  • Compression performance The drug-loaded hemostatic cotton sample prepared in the embodiment is placed statically between two upper and lower compression plates, and the sample is slowly compressed to 50% of its original height. After maintaining the pressure for 5 minutes, the pressure is removed and the height of the sample after recovery is tested. The rebound rate is calculated based on the change in height before and after compression.
  • the compression strength of the drug-loaded hemostatic cotton is above 10kPa, the rebound rate is greater than 95%, and the conformability of the drug-loaded hemostatic cotton is good.
  • the performance of the sample of the embodiment is comparable to that of the comparative example NXM, and as the porosity increases, more radial support forces in different directions are generated, the rebound rate is improved, and the degree of recovery after the drug-loaded hemostatic cotton is squeezed and unloaded is facilitated.
  • the compression strength is significantly lower than that of other samples because the alcohol bubble after water precipitation is used, which causes a certain degree of hydrolysis and alcoholysis in the subsequent dissolution process of dioxane, resulting in a decrease in molecular weight and a decrease in performance. It can be seen from this that the specific polyethylene glycol used in this embodiment and the process of non-water precipitation alcohol bubble have obtained drug-loaded hemostatic cotton with good mechanical properties.
  • the weight average molecular weight (Mw) of the samples and the stress value when compressed to 50% were tested and recorded every 1 hour.
  • the results are shown in Figures 1 and 2, respectively.
  • the drug-loaded hemostatic cotton M1-M12 prepared in the examples began to degrade within 1 hour and initially degraded within 3 hours. At 3 hours, their weight average molecular weight and compressive strength decreased to less than 60%, and as the degradation time increased, their values gradually decreased, and eventually became stable due to the influence of water surface tension.
  • the ratio of PEG/cyclic ester monomer is the smallest, that is, the proportion of PEG is small, so the content of PEG segment is low, its hydrophilicity deteriorates, suppresses the contact of water molecules with ester bonds, and causes the degradation rate to be relatively slow. It is shown that the ratio of PEG to polyester in the polyurethane polymer structure directly affects the degradation rate of drug-loaded hemostatic cotton. As can be seen from Figure 1, the number average molecular weight of M7-M9 samples is higher than the number average molecular weight of the remaining samples, and it can be seen that due to its poor hydrophilicity, it leads to its own low degradation rate.
  • the compressive strength of M7-M9 samples is higher than the compressive strength compared to the remaining samples, which further verifies that due to the low degree of degradation of M7-M9 samples, the degree of crushing is low. Therefore, the proportion of PEG segment content will also affect the degradation degree of drug-loaded hemostatic cotton.
  • the ratio of PEG segment to polyester segment is 1: 1-1: 1.25.
  • Figure 3 is the initial morphology of the drug-loaded hemostatic cotton of the M1 sample. After 24 hours of degradation, the drug-loaded hemostatic cotton was completely broken by slight shaking, and the morphology of Figure 4 was obtained.
  • Figure 4 is the morphology of the M1 sample after 24 hours of degradation. As can be seen from the figure, it means that the drug-loaded hemostatic cotton has been degraded and broken, indicating that the sample of this embodiment shows a degradation effect similar to that of NXM. The degradation results show that the degradation rate of the drug-loaded hemostatic cotton prepared in the embodiment is fast, and it is completely degraded within 3 to 6 hours, which can greatly shorten the patient's discomfort time. It should be understood that the drug-loaded hemostatic cotton in Examples 1-16 is similar to that of M1.
  • Drug release Immerse the drug-loaded hemostatic cotton in 500 ml of SDS solution (1.0%), seal it, and place it in a 37°C constant temperature shaker. For example, take 1 ml of SDS solution at regular intervals and add 1 ml. Determine the drug concentration by liquid chromatography, and then calculate the drug release amount. The test results are shown in Figure 5.
  • the method of external dosing on a blank sponge can make the drug be released quickly in the early stage, which is conducive to eliminating inflammatory response and accelerating the recovery of the injured part.
  • a blank sponge mixed Suspended nanoabsorption and solvent precipitation
  • the drug is slowly released when the outer layer degrades, further improving the safety of drug-loaded hemostatic cotton; and the use of external dosing means can quickly administer the drug to the injured part in the early stage, reduce inflammatory response and accelerate wound healing.

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Abstract

本发明提供了一种载药止血棉、载药止血棉的制备方法以及药物缓释系统，所述载药止血棉包括：多孔海绵以及载药层；所述多孔海绵的压缩强度大于3Kpa、回弹率大于80％，所述多孔海绵通过压迫毛细血管起到止血作用，同时，所述多孔海绵还能够吸纳储存渗出的血液，使血液中的血小板聚集。如此，得到了止血效果佳、降解时间短、力学性能好、安全性佳、成本低的载药止血棉。

Description

载药止血棉、载药止血棉的制备方法及药物缓释系统 技术领域
本发明涉及医疗器械技术领域，特别涉及一种载药止血棉、载药止血棉的制备方法及其应用。
背景技术
外科手术中的出血是常见的临床症状，耳鼻喉科手术是最常见的医疗外科手术之一，以耳鼻喉科手术为例，这些出血部位位置深、空间狭小，且周边遍布有大量的毛细血管，术后难以缝扎。在临床上，通过纱布和膨胀海绵等方式压迫止血能够有效降低出血量，加快伤口愈合。但在抽取过程中造成二次伤害，引起继发性感染，更关键的是会让患者感到痛苦不堪，甚至导致虚脱、休克等情况。因此，针对于术后如何有效快速的止血成为诸多学者的研究热点。
止血棉是目前效果较好的快速止血的方式。然而，载药止血棉因压迫强度低、回弹率不佳等问题，不能很好的对狭窄腔道进行适形性的压迫止血，也不能够同时满足储血防止血液渗漏的问题，同时，降解速率不好控制，不能够即完成压迫止血，又实现有效降解。并且，市面上并没有载药的止血棉，不能够在压迫止血的同时实现给药。这些问题，亟需技术人员开发新的产品以解决现有问题。
目前，止血棉的制备方法是先制备聚氨酯聚合物，并将得到的聚氨酯聚合物溶于二氧六环与壳聚糖水溶液共混后经冷冻干燥得到。另一种方法也是预先制备聚氨酯聚合物，通过配置聚氨酯溶液与发泡剂混合后经冷冻干燥和灭菌处理得到止血海绵。然而，这些方法形成的止血棉存在以下问题：1)容易存在副反应、化学残留高，从而影响止血棉临床的安全性。2)通过这些方法得到的止血棉降解缓慢且降解时间不可控，降解时间均大于3天，当止血棉置入目标位置后不能及时降解，使得止血棉在止血部位滞留的时间长，该过程中堵塞止血部位处的狭窄腔道被完全堵塞，延长患者的痛苦时间。尽管发生了部分降解，但因为降解较慢，也不利于腔道的清洗。在通常情况下，止血的过程在48小时内即可完成，若止血棉长时间停留体内，也不利于创面的愈合。3)该方法得到的止血棉的力学性能弱，压迫止血的效果差，防粘连的效果差。4)该止血棉不具备抗菌消炎作用，进而减缓伤口愈合。5)该方法的成本高。
因此开发一种使得止血棉的止血效果佳、临床安全性高、降解时间短、力学性能好、能够实现药物缓释，且成本低的止血棉，是亟待解决的问题。
发明内容
本发明的目的在于提供一种载药止血棉的制备方法、载药止血棉以及药物缓释系统，以解决止血棉止血效果不佳、临床安全性差、降解时间长、力学性能差、不能缓慢释放药物、成本高的技术问题。
为解决上述技术问题，本发明提供一种载药止血棉，所述载药止血棉用于耳、鼻、喉腔 体中，所述载药止血棉包括：多孔海绵以及载药层；所述多孔海绵的孔隙率大于80％，所述多孔海绵的粘度大于0.4dL/g，所述多孔海绵的玻璃化转变温度-50～-20℃，以使得所述多孔海绵的压缩强度大于3Kpa、回弹率大于80％，所述多孔海绵通过压迫毛细血管起到止血作用，同时，所述多孔海绵还能够吸纳储存渗出的血液，使血液中的血小板聚集；所述载药层设置于所述多孔海绵的外层、中层或者内层中的至少一层，所述载药层包含药物。
可选的，所述载药止血棉的吸水率大于500％；所述多孔海绵的分子链中PEG链的含量为30％～70％，进而使得所述载药止血棉的吸水时间小于10分钟。
可选的，所述载药止血棉的降解时间为3h至24h；前三天的药物释放率大于60％；前两天的药物释放率大于40％，其释放速率为20％～40％每天。
可选的，所述多孔海绵的材质为聚氨酯、明胶、壳聚糖、透明质酸钠、胶原蛋白中的至少一种。
可选的，所述药物包括抗炎类药物、抗菌类药物、止痛类药物、止血类药物或者抗过敏药物中的至少一种；所述抗炎类药物优选包括糖皮质激素类药物；所述糖皮质激素类药物包括优选糠酸莫米松、布地奈德或者丙酸氟替卡松中的至少一种；所述抗过敏药优选包括依巴斯汀、氯雷他定、阿伐斯汀。
可选的，当所述载药止血棉用于鼻腔中时，每片载药止血棉中，所述药物的载药量在100ug～1000ug/g；优选的，可以是200、250、300、350、400、450、500、550、600、650、700、800、900、1000ug/g。
本发明还提供一种载药止血棉的制备方法，用于制备如上所述的载药止血棉，所述载药止血棉的制备方法包括：
S1：在无水无氧环境中，以聚乙二醇为引发剂，环酯类单体在催化剂的作用下发生开环反应合成聚酯类预聚物，所述聚乙二醇的平均分子量为800-1500；
S2：二异氰酸酯化合物与多元醇类化合物混合，在一定温度下反应后经分离提纯制备异氰酸基封端的三嵌段化合物，所述多元醇类化合物与二异氰酸酯化合物的摩尔比为1：4～1：10；
S3：将S2制备的异氰酸基封端的三嵌段化合物溶于有机溶剂与S1制备的聚酯类预聚物按一定投料比反应，采用不良性溶剂进行沉降，沉降后，无需水沉、醇泡处理，干燥至恒重得到聚氨酯聚合物；
其中，步骤S4为S4-1：将S3制备的聚氨酯以及药物用有机溶剂溶解后置于模具中，经冷冻、干燥、灭菌处理后得到载药止血棉；
或者，步骤S4为S4-2：将S3制备的聚氨酯聚合物用二氧六环溶解后置于模具中，经冻干后得到不含药的空白海绵；将药物在分散在不良溶剂中制成悬浮液，在搅拌下将所述空白海绵放入悬浮液中，搅拌后捞出干燥，使得药物被吸附于所述聚氨酯海绵的孔隙中，以形成载药止血棉；
或者，步骤S4为为S4-3：将S3制备的聚氨酯聚合物用二氧六环溶解后置于模具中，经冻干得到不含药的空白海绵；将药物在良溶剂中溶解形成药物溶液，用不良溶剂稀释所述药 物溶液得到药物混合液，将药物混合液通过喷涂、滴加、注射或者蘸取等方式加入至空白海绵中，之后干燥使得药物析出并固定于所述聚氨酯海绵的孔隙中，以形成载药止血棉。
可选的，所述S4为S4-1时，所述S4步骤包括：
S41：将S3制备的聚氨酯聚合物和药物用二氧六环溶解后置于模具中，经冷冻得到第一载药层，所述第一载药层的厚度小于所述模具内的高度；
S42：将S3制备的聚氨酯聚合物用二氧六环溶解后置于所述模具中，经冷冻得到聚氨酯层，所述聚氨酯层叠加于所述第一载药层上，所述第一载药层与所述聚氨酯层的厚度之和小于所述模具内的高度；
S43：将S3制备的聚氨酯聚合物和药物用二氧六环溶解后置于模具中，经冷冻得到第二载药层，所述第二载药层叠加于所述聚氨酯层上，经干燥得到载药止血棉，以使得所述载药止血棉依次包括所述第一载药层、聚氨酯层、第二载药层；
其中，在所述S41或所述S43步骤中，将S3制备的聚氨酯聚合物、药物以及致孔剂溶解后置于模具中；或者，在所述S42步骤中，将S3制备的聚氨酯聚合物、致孔剂溶解后置于模具中。
可选的，所述致孔剂为无机盐；或者，所述致孔剂包括磷酸铵、磷酸氢铵、碳酸氢铵中的一种或多种；
或者，所述制备方法还包括S5步骤：在所述止血棉中加入引湿剂；
或者，在所述S1步骤中，聚乙二醇与环酯类单体的质量比为1:1-1:2；
或者，所述S2步骤中，所述二异氰酸酯化合物为六亚甲基二异氰酸酯，1,4-丁二醇与六亚甲基二异氰酸酯的摩尔比为1:4～1:10；
或者，在S3步骤中，S1得到的聚酯类预聚物与S2得到的HBH的摩尔比为1:1.0～1:1.5；
或者，所述S3步骤中，所述有机溶剂包括二甲亚砜、二甲基甲酰胺、二氧六环、氯仿中的至少一种；所述不良溶剂包括正己烷、乙醚、正戊烷、石油醚、环己烷中的至少一种；
或者，在所述S1步骤中，所述聚乙二醇的平均分子量为900～1100；
或者，在所述步骤S4中，还包括，将S3制备的聚氨酯聚合物、药物、致孔剂以及降解酶一起溶解后置于模具中；或者，将所述S4得到的载药止血棉蘸取降解酶的液体后植入到目标位置。
本发明还提供一种药物缓释系统，所述药物缓释系统包括如上所述的载药止血棉。
在本发明提供的一种载药止血棉、载药止血棉的制备方法以及药物缓释系统。所述载药止血棉包括：多孔海绵以及载药层；所述多孔海绵的孔隙率大于80％，所述多孔海绵的粘度大于0.4dL/g，所述多孔海绵的玻璃化转变温度-50～-20℃，以使得所述多孔海绵的压缩强度大于3Kpa、回弹率大于80％，所述多孔海绵通过压迫毛细血管起到止血作用，同时，所述多孔海绵还能够吸纳储存渗出的血液，使血液中的血小板聚集。如此，得到了止血效果佳、降解时间短、力学性能好、安全性佳、成本低的载药止血棉。所述载药止血棉的制备方法，通过特定试剂选择、特定的试剂量的选择、特定的步骤设计等方法，得到了降解时间短、力学性能好、安全性佳、成本低、产品稳定性高、产率高、操作简单、具有普适性、易于规模化生 产的载药止血棉。同时，通过不同的加药方式，形成了不同载药机理的、不同的释放速率的、不同性能的载药止血棉。
附图说明
本领域的普通技术人员将会理解，提供的附图用于更好地理解本发明，而不对本发明的范围构成任何限定。其中：
图1为本实施例1-16、对比例1-2中样品的数均分子量随降解时间变化关系图。
图2为本实施例1-16、对比例1-2中的样品压缩至50％处压缩强度随降解时间变化关系图。
图3为本实施例1的样品在磷酸缓冲盐溶液(PBS溶液)中初始形貌状态。
图4为本实施例1的样品在磷酸缓冲盐溶液(PBS溶液)中降解24h后的形貌状态。
图5为本实施例1-16、对比例1-2中样品在不同时间段下的药物的累计释放率。
具体实施方式
为使本发明的目的、优点和特征更加清楚，以下结合附图和具体实施例对本发明作进一步详细说明。需说明的是，附图均采用非常简化的形式且未按比例绘制，仅用以方便、明晰地辅助说明本发明实施例的目的。
如在本说明书中所使用的，单数形式“一”、“一个”以及“该”包括复数对象，除非内容另外明确指出外。如在本说明书中所使用的，术语“或”通常是以包括“和/或”的含义而进行使用的，除非内容另外明确指出外。另外，在下文的描述中，给出了大量具体的细节以便提供对本发明更为彻底的理解。然而，对于本领域技术人员而言显而易见的是，本发明可以无需一个或多个这些细节而得以实施。应该指出，以下详细说明都是例示性的，旨在对本申请提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
术语“可降解”表示在一定条件下，材料可以降解为低分子量物质并失去原有性能。
术语“目标位置”是指需要止血的部位的腔道。
术语“降解”即表示“降解行为”，所述降解行为包括降解速率、降解过程中产物的生成、形态以及力学性能的变化等。为了便于描述可降解的降解程度，在本文中，将所述降解的终点定义为受力破碎、压缩应力低于原来的50％、以及分子量低于原来的30％。
在本发明提供的一种载药止血棉、载药止血棉的制备方法以及药物缓释系统。所述载药止血棉包括：多孔海绵以及载药层；所述多孔海绵的孔隙率大于80％，所述多孔海绵的粘度大于0.4dL/g，所述多孔海绵的玻璃化转变温度-50～-20℃，以使得所述多孔海绵的压缩强度大于3Kpa、回弹率大于80％，所述多孔海绵通过压迫毛细血管起到止血作用，同时，所述多孔海绵还能够吸纳储存渗出的血液，使血液中的血小板聚集。如此，得到了止血效果佳、降解时间短、力学性能好、安全性佳、成本低的载药止血棉。
在本发明实施例提供的一种载药止血棉的制备方法中，包括：S1：在无水无氧环境中，以聚乙二醇为引发剂，环酯类单体在催化剂的作用下发生开环反应合成聚酯类预聚物，所述聚乙二醇的平均分子量为800-1500。S2：二异氰酸酯化合物与多元醇类化合物混合，在一定温度下反应后经分离提纯制备异氰酸基封端的三嵌段化合物，所述二异氰酸酯化合物与多元醇类化合物的摩尔比为1：4～6。S3：将S2制备的异氰酸基封端的三嵌段化合物溶于有机溶剂与S1制备的聚酯类预聚物按一定投料比反应，采用不良性溶剂进行沉降，沉降后，不进行水沉、醇泡处理，后经纯化、干燥得到聚氨酯聚合物。S4：将S3制备的聚氨酯聚合物以及药物用二氧六环溶解后置于模具中，冷冻、干燥、灭菌处理后得到载药止血棉。或者，S4步骤还可以是：将S3制备的聚氨酯聚合物和药物用二氧六环溶解后置于模具中，冷冻、干燥、灭菌处理后得到聚氨酯海绵；或将药物在不良溶剂中制成悬浮液，在搅拌下将所述不含药的空白海绵放入悬浮液中，搅拌后捞出干燥，使得药物被吸附于所述聚氨酯海绵的孔隙中，以形成止血棉。或者，S4步骤还可以是：将S3制备的聚氨酯聚合物用二氧六环溶解后置于模具中，冷冻、干燥、灭菌处理后得到聚氨酯海绵；将药物在良溶剂中溶解形成药物溶液，用不良溶剂稀释所述药物溶液得到药物混合液，将药物混合液通过喷涂、滴加、注射或者蘸取等方式加入至聚氨酯海绵中，后干燥使得药物被吸附于所述聚氨酯海绵的孔隙中，以形成载药止血棉。如此，通过特定试剂选择、特定的试剂量的选择、特定的步骤设计等方法，得到了降解时间短、力学性能好、安全性佳、成本低、产品稳定性高、产率高、操作简单、具有普适性、易于规模化生产的载药止血棉。同时，通过不同的加药方式，形成了不同载药机理的、不同的释放速率的、不同性能的载药止血棉。
本发明实施例提供一种载药止血棉，所述载药止血棉用于耳、鼻、喉腔体中，所述载药止血棉包括：多孔海绵以及载药层。
所述多孔海绵的孔隙率大于80％，所述多孔海绵的粘度大于0.4dL/g，所述多孔海绵的玻璃化转变温度-50～-20℃，以使得所述多孔海绵的压缩强度大于3Kpa、回弹率大于80％，所述多孔海绵通过压迫毛细血管起到止血作用，同时，所述多孔海绵还能够吸纳储存渗出的血液，使血液中的血小板聚集。如此，可以保证载药止血棉能够在狭窄的腔道中进行适形性的压迫止血，保证载药止血棉具有一定压强以及回弹性能时，载药止血棉具有支撑性能同时还能够具有一定的空间，用于吸纳血液，防止血液渗漏。优选的，所述多孔海绵的孔隙率大于90％，例如、90％、95％、99％等。所述多孔海绵的粘度大于0.6dL/g，更优的大于0.7dL/g，例如是0.7、0.8、0.9dL/g。所述多孔海绵的玻璃化转变温度-50～-20℃，例如，-50、-40、-35、-25、-20℃。优选的，所述载药止血棉的压缩强度可以是3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18kpa，优选大于10kpa。优选的，回弹率可以是80、85、90、91、92、93、94、95、96、97、98、99kpa，优选大于95％，其力学性能优异，且适形性良好。
所述载药层设置于所述多孔海绵的外层、中层或者内层中的至少一层。需理解，所述外层，即表示载药层包覆于多孔海绵外部。所述中层表示，载药层即不在多孔海绵的外部、也不在多孔海绵的最内部。所述内层表示，载药层在多孔外面的中间部位。当载药层位于中层 或者外层时，多孔海绵降解或者水解时，载药层的药物可以通过渗透进入腔道之中。所述载药层设置于多孔海绵的外层、中层或者内层时，所述载药层均匀分布于整个多孔海绵中。如此，可以使得载药止血棉在压迫止血的同时实现定向给药。
优选的，所述载药层中的药物的颗粒被包埋于多孔海绵中；或者，所述载药层中的药物的颗粒被容纳于多孔海绵的孔隙中。所述包埋，表示药物存在于多孔海绵的骨架之中，所述容纳，表示药物存在骨架之外的孔隙中。
所述载药止血棉的吸水率大于500％，例如是600％，700％，800％，900％，优选大于1000％，更优的大于1500％。如此使得载药止血棉具有更好的吸收液体(例如血液、体液等)或者储存液体的功能。
所述多孔海绵的分子链中PEG(聚乙二醇)链的含量为30％～70％，进而使得所述载药止血棉的吸水时间小于10分钟。PEG链具有亲水性，使得载药止血棉的亲水性能佳，吸水时间少。优选的，所述载药止血棉的吸水时间小于5分钟。所述载药止血棉的孔隙率高，吸水率高，进而为降解提供了有利的条件。其中，所述吸水时间表示，将载药止血棉放置于37℃±1℃(模拟人体温度)水面上，直至载药止血棉完全浸没于水中所需的时间。吸水率表示完全浸没后增加的质量与初始质量之比。
所述载药止血棉可降解，所述载药止血棉的降解时间为3h至24h(在兔血中，模拟人体温度，37℃±1℃)；在其释放行为中，前三天的药物释放率大于60％；前两天的药物释放率大于40％，其释放速率为20％～40％每天。优选的，前三天的药物释放率大于80％；前两天的药物释放率大于70％，其释放速率为35％～40％每天。如此，可以使得药物能够在降解时间内实现缓释，且释放速率适中，给药量适中。其中，测试环境为，在兔血中，模拟人体温度，37℃±1℃。
所述多孔海绵的材质为聚氨酯、明胶、壳聚糖、透明质酸钠、胶原蛋白中的至少一种。优选的，所述多孔海绵为聚氨酯。
所述载药层中包含药物，所述药物包括抗炎类药物、抗菌类药物、止痛类药物、止血类药物或者抗过敏药物中的至少一种。所述抗炎类药物包括糖皮质激素类药物；所述糖皮质激素类药物包括糠酸莫米松、布地奈德或者丙酸氟替卡松；所述抗过敏药包括依巴斯汀、氯雷他定、阿伐斯汀。需理解本实施例中，所述药物可以是任何能够设置于载药止血棉上的药物，不限制为本实施例中的药物。
当所述载药止血棉用于鼻腔中时，每片载药止血棉中，所述药物的载药量在100ug～1000ug/g，例如100、200、300、400、500、600、700、800、900、1000ug/g。如此，可以使得药物能够实现每天安全的释放量。
优选的，每片所述载药止血棉的尺寸为长*宽*厚＝80mm*20mm*15mm，可以将所述载药止血棉的尺寸裁剪为长*宽*厚＝10cm*1cm*3cm进行使用。优选的，载药层具有第一载药层、第二载药层。多孔海绵为聚氨酯海绵。第一载药层、聚氨酯层、第二载药层沿其厚度方向依次设置。
本发明实施例还提供了一种载药止血棉的制备方法，所述制备方法用于实现上述的载药 止血棉，实现上述载药止血棉的各项参数指标。
S1、预聚物的制备：在无水无氧环境中，以聚乙二醇(PEG)为引发剂，环酯类单体在催化剂的作用下发生开环反应合成聚酯类预聚物，其中所述聚乙二醇(PEG)的平均分子量为800～1500。较佳的，所述聚乙二醇(PEG)的平均分子量为900～1100。更佳的，所述聚乙二醇(PEG)的平均分子量为950～1050。无需后处理直接用于步骤S3，如此简化了该制备方法的步骤，降低了生产成本。所述聚乙二醇(PEG)的平均分子量的选择为特定的选择，当其平均分子量为800～1500时，例如选择900～1100时，制备的载药止血棉开始降解的时间比现有技术中载药止血棉的降解时间提前约10倍，降解速率也由此提升，降解速率大大增加，载药止血棉在目标位置完成止血后可快速实现腔道再通。基于此，因为本实施例中的聚乙二醇(PFG)的降解速率十分迅速，在S3合成聚氨酯的步骤中，不能采用水沉、醇泡的步骤，因此能够省去这两个步骤。同时，采用所述聚乙二醇(PEG)合成的聚酯类预聚物制备的载药止血棉，可以将降解时间控制在36个小时内，在6-12个小时时间内降解速率最快，相比现有技术降解时间不可控，其能够保证在可控的36小时内降解。
优选的，所述步骤S1中，所述环酯类单体为DL-丙交酯、L-丙交酯、乙交酯、己内酯、三亚甲基碳酸酯、对二氧环己酮的一种或多种。进一步的，所述环酯类单体为乙交酯、丙交酯和己内酯。优选的，所述步骤S1中，聚乙二醇与环酯类单体的质量比为1:1-1:1.05，进而可以保证聚乙二醇的占比，避免载药止血棉亲水性差的问题，提升了降解速率，具体可参考下文实施例3与其他实施例，以及下文降解性能的分析。优选的，所述步骤S1中，所述的催化剂为锡类催化剂，催化剂的质量为反应物总质量的0.01％～0.05％，优选的，所述步骤S1中的反应温度为120℃～140℃；反应时间为12～36小时。
S2、扩链剂的制备：二异氰酸酯化合物与多元醇类化合物混合，在一定温度下反应后经分离提纯制备异氰酸基封端的三嵌段化合物(HBH)，其中，所述二异氰酸酯化合物与多元醇类化合物的摩尔比为1：4～1：10，进而可以使得多元醇类化合物与二异氰酸酯化合物充分反应形成异氰酸基封端的三嵌段化合物(HBH)。二异氰酸酯化合物可以为六亚甲基二异氰酸酯(HDI)、异佛尔酮二异氰酸酯(IPDI)、甲基环己基二异氰酸酯中的一种或几种。优选的，所述二异氰酸酯化合物优选为六亚甲基二异氰酸酯(HDI)，相对与目前市售产品所使用的四亚甲基二异氰酸酯，六亚甲基二异氰酸酯(HDI)的价格低，获取容易，进而降低了载药止血棉的成本，同时，通过HDI得到的HBH制备的载药止血棉，并没有影响其降解速率、力学性能等。所述多元醇类化合物优选为1,4-丁二醇(BDO)。异氰酸基封端的三嵌段化合物(HBH)提供了更多的氨基甲酸酯键，其具有致密的氢键，增强了载药止血棉的力学性能。
优选的，所述步骤S2中，1,4-丁二醇与六亚甲基二异氰酸酯的摩尔比为1:4～1:6。优选的，所述步骤S2中，所述的反应温度为70℃～90℃；反应时间为4～6小时。优选的，所述步骤S2中，所述的分离提纯过程为：将反应后得到的粗产物用大量正己烷洗涤，洗涤过程中不断搅拌至产物完全分散为固体粉末，抽滤，再次用正己烷洗涤，重复3～6次，在40℃～50℃下旋蒸2～5小时，得到纯白色固体粉末即为扩链剂。
S3、聚氨酯的制备：将S2制备的异氰酸基封端的三嵌段化合物(HBH)溶于有机溶剂 与S1制备的聚酯类预聚物按一定投料比反应，采用不良性溶剂进行沉降沉降后，不进行水沉、醇泡处理，后经纯化、干燥得到聚氨酯聚合物。优选的，所述SS步骤中，所述有机溶剂包括二甲亚砜、二甲基甲酰胺、二氧六环、氯仿中的至少一种；所述不良溶剂包括正己烷、乙醚、正戊烷、石油醚、环己烷中的至少一种。
其中一个实施例可以是，S3步骤包括，将S2制备的异氰酸基封端的三嵌段化合物溶于二甲基亚砜(DMSO)，并与S1制备的聚酯类预聚物按一定投料比反应，并采用不良溶剂，例如乙醚进行沉降。其中另一个实施例还可以是，S3步骤包括：将S1制备的聚酯类预聚物与S2制备的异氰酸基封端的三嵌段化合物的二甲基甲酰胺溶液反应，聚合完成后采用乙醚进行沉降。其中二甲基甲酰胺(DMF)可以是N,N-二甲基甲酰胺，N,N-二甲基甲酰胺为异氰酸基封端的三嵌段化合物(HBH)的溶剂。采用乙醚进行沉降，是因为乙醚挥发性好、残留少。需理解，S3制备的聚氨酯聚合物，由于聚乙二醇的特定选择，使得聚氨酯聚合物降解速率快，特定的，S3步骤中，不采用水溶液进行沉降、醇泡的方式，避免了水对聚氨酯聚合物的影响，维持了载药止血棉降解的稳定性，提高了产率。同时，也减少了水溶液沉降、醇泡的步骤，减少了该生产步骤，进而降低了生产成本。本领域技术人员均理解，在生产步骤中，任何一个步骤的选择、省略都至关重要。所述二甲基亚砜以及N,N-二甲基甲酰胺(DMF)溶剂可以为特定选择，其能够直接被乙醚溶解，进而为省去水沉和醇泡的步骤提供条件。此外，在S1-S2步骤中，其预先合成聚酯类预聚物与异氰酸基封端的三嵌段化合物(HBH)，反应过程可控，避免了副产物的单体残留。对所得到的产物进行有效的后处理过程能够去除合成过程中的小分子单体和重金属残留，有效提高了所述载药止血棉的使用安全性。
优选的，所述步骤S3中，所述HBH的DMF溶液的质量浓度为0.2～0.5g/g。优选的，所述步骤S3中，S1得到的聚酯类预聚物与S2得到的HBH的摩尔比为1:1.0～1:1.5。优选的，所述步骤S3中，聚氨酯聚合物的反应温度为75-90℃，反应时间为3～6h。优选的，所述步骤S3中，纯化过程包括将反应后的混合物用二氧六环稀释至10％-25％，搅拌下缓慢倒入5～8倍的冰乙醚中，然后将析出的白色丝状固体转移至正己烷中浸泡3小时以上后用烘箱40℃干燥10小时。
S4：载药止血棉的制备：将S3制备的聚氨酯聚合物与药物用有机溶剂溶解后置于模具中，冷冻、干燥、灭菌处理后得到载药止血棉。所述冷冻、干燥的过程是溶液升华的过程，溶液升华之后，能够形成均匀的孔隙以形成微孔固体。所述有机溶剂优选为二氧六环，熔点高沸点低且溶解性好，所述有机溶剂可以同时溶解聚氨酯聚合物以及药物。通过将聚氨酯聚合物与药物共同溶解，经过冷冻、干燥等步骤得到载药止血棉，可以使得药物被包埋于聚氨酯中，在载药止血棉降解过程中，实现药物的缓释。可理解的，所述包埋为物理包埋。相比现有技术，临床上，部分医生使用不含药的载药止血棉蘸取药水，再置入目标位置，但是蘸取的药水的浓度和释放是不可控的，且药水是一次给药，不能实现定量缓释给药。本实施例的载药止血棉，能够实现药物缓释，且药物释放稳定，效果好，不需要医生在手术时临时配药和蘸取药液，可以直接将载药止血棉植入到目标位置，没有蘸取药水的步骤，避免因为步骤繁琐或者蘸取药水过程中衍生出新的安全性问题，也节省了医患的手术时间，提高了手术效率。 本发明实施例的载药止血棉的制备方法，通过特定原材料、溶剂以及特定步骤的选择，得到了降解时间短、力学性能好、可以实现短时间内的压迫止血，无需二次手术取出，可随身体代谢降解后流出，降解产物无毒。所述载药止血棉还能够实现药物缓释，且生产成本低的载药止血棉，使得更为安全、方便。本发明实施例的载药止血棉的制备方法得到的载药止血棉，其降解时间可以缩短至3天内，当载药止血棉置入目标位置后，在48h内完成止血，之后即可以采用清洗的方式，将目标位置的降解后的载药止血棉碎块冲洗出腔道，进而便于目标位置处的伤口组织的愈合。
优选的，所述步骤S4中，所用聚乙二醇的数均分子量为4000～20000，质量分数0.5％～3％，更优的，所述聚乙二醇的数均分子量为10000～15000，进一步提高应力。优选的，所述步骤S4中，聚氨酯聚合物的溶液的质量浓度为3％～5％。优选的，所述步骤S4中，冷冻干燥处理的过程可分为预冻、冷冻、干燥三个步骤，总持续时间为30～90小时，温度为-25℃～20℃。优选的，所述步骤S4中，采用的灭菌方式为辐照灭菌和环氧乙烷灭菌。
优选的，所述S4步骤包括：S41：将S3制备的聚氨酯聚合物和药物用二氧六环溶解后置于模具中，经冷冻得到第一载药层，所述第一载药层的厚度小于所述模具内的高度，进而便于模具内能够容纳下文所述的聚氨酯层以及第二载药层。
S42：将S3制备的聚氨酯聚合物用二氧六环溶解后置于所述模具中，经冷冻得到聚氨酯层，所述聚氨酯层叠加于所述第一载药层上，所述第一载药层与所述聚氨酯层的厚度之和小于所述模具内的高度，进而便于模具内能够容纳下文所述的第二载药层。
S43：将S3制备的聚氨酯聚合物和药物用二氧六环溶解后置于模具中，经冷冻得到第二载药层，所述第二载药层叠加于所述聚氨酯层上，经干燥得到载药止血棉，以使得所述载药止血棉依次包括所述第一载药层、聚氨酯层、第二载药层。如此设置，可以使得载药止血棉的两个表层具有药物，相比于全部加有药物的载药止血棉，在药物含量相同的情况下，更加便于药物的释放。同时，因为载药止血棉内部不含有药物，避免载药止血棉在完全降解时的药物的爆释。另外，需理解，所述载药止血棉作为植入器械，其载药量需要在指定的药量区间内，因此，在指定的药量区间内，载药止血棉的聚氨酯层不含药，第一载药层、第二载药层含药，其药量浓度增加，药物缓释时释放的药量增加，提高药效。当然，本领域技术人员还可以根据实际的使用情况，设置为单面药物层的载药止血棉，也在本发明的保护范围内。
优选的，所述第一载药层或者第二载药层的厚度与载药止血棉的厚度之比小于1/3，在药量一定的情况下，进而增加了单层药物的浓度。也避免载药止血棉在降解时药物爆释的情况。优选的，所述第一载药层与第二载药层的厚度比可以是1:1，所述第一载药层与第二载药层的厚度优选为1mm，当然，还可以是2mm或者3mm等。
需理解，所述药物包括抗炎类药物、抗菌类药物、止痛类药物、止血类药物或者抗过敏药中的至少一种。优选的，所述抗炎类药物包括糖皮质激素类药物。所述抗菌类药物包括青霉素类、头孢类、氧氟沙星、环丙沙星、克霉唑、氯霉素等药物。所述止痛类药物包括布洛芬等。优选的，所述糖皮质激素类药物包括糠酸莫米松或者布地奈德。所述抗过敏药物可以鼻部用药，例如盐酸左卡巴斯汀、富马酸酮替芬、丙酸倍氯米宋、糠酸莫米松、布地奈德、 丙酸氟替卡松。所述药物还可以是纤毛激动药与黏液促排药等，例如是桃金娘油。药物还可以是鼻粘膜保护药，例如是复方薄荷油、氯己定鱼肝油滴鼻液等。如此，解决了术后细菌感染引起的发炎问题，加快伤口的愈合，进而可以避免伤口部位发生粘连等问题。作为优选，本实施例采用的糠酸莫米松作为实施例进行验证说明。
所述抗炎类药物、抗菌类药物、止痛类药物、止血类药物或者抗过敏药物的药物含量为聚氨酯聚合物的0.25～0.30‰(质量比)，进而可以在保证载药的情况下，保证安全的载药比，实现缓释的效果。
优选的，在所述S41或所述S43步骤中，将S3制备的聚氨酯聚合物、药物以及致孔剂一起溶解后置于模具中，所述致孔剂为无机盐；所述无机盐进一步可以是磷酸铵、磷酸氢铵、碳酸氢铵。由于无机盐受热分解为无毒无害的气体，且不残留，例如，碳酸氢铵受热后变为氨气和二氧化碳消失如此，一方面使得载药止血棉在使用过程中不会因为致孔剂的存在而产生有害物质，也不会有有害物质产生和析出，提高了产品的安全性。本领域人员都知道，植入类的医疗器械，首要的要求即植入后产品的安全性，试剂的选择决定了该产品能否上市的关键，本实施例采用无机盐，解决了安全性的问题，且安全性能优异。另一方面，致孔剂的加入提高了载药止血棉的孔隙率，进而提高了载药止血棉的回弹率以及药物缓释性能。需理解，本实施例的载药止血棉还需要能够填塞至狭窄的腔道中。以鼻腔为例，鼻腔中的这些狭窄腔道的毛细血管多，且腔道不规格，增加致孔剂的载药止血棉其回弹率(撤销外力后形变恢复的程度)提升，形变恢复好，塞进鼻腔里能够很好的回弹起来，压迫毛细血管，止血效果好。进一步的，所述致孔剂的含量为聚氨酯聚合物的3～5％。
优选的，所述制备方法还包括步骤S5：在所述载药止血棉中加入引湿剂(PEG)，进而增加载药止血棉的亲水性能和压缩应力，这样，可以在提高降解速率的同时能够提高载药止血棉的支撑强度。
本实施例还提供一种载药止血棉的制备方法，包括：
S1：在无水无氧环境中，以聚乙二醇为引发剂，环酯类单体在催化剂的作用下发生开环反应合成聚酯类预聚物，所述聚乙二醇的平均分子量为800-1500；
S2：二异氰酸酯化合物与多元醇类化合物混合，在一定温度下反应后经分离提纯制备异氰酸基封端的三嵌段化合物，所述多元醇类化合物与二异氰酸酯化合物的摩尔比为1：4～1：10；
S3：将S1制备的聚酯类预聚物与S2制备的异氰酸基封端的三嵌段化合物的N,N-二甲基甲酰胺溶液反应，采用乙醚进行沉降，沉降后，不进行水沉、醇泡处理，后经纯化、干燥得到聚氨酯聚合物；
S4：将S3制备的聚氨酯聚合物用二氧六环溶解后置于模具中，冷冻、干燥、灭菌处理后得到聚氨酯海绵；将药物在不良溶剂中制成悬浮液，在搅拌下将所述聚氨酯海绵放入悬浮液中，搅拌后捞出干燥，使得药物被吸附于所述聚氨酯海绵的孔隙中，以形成载药止血棉，进而保证载药止血棉中有药物的存在，且便于药物的释放。不良溶剂能够将药物颗粒通过不良溶剂的流动带入到聚氨酯海绵的孔隙中。
较佳的，本实施例还提供另一种载药止血棉的制备方法，所述S1、S2、S3如上所述不再赘述，所述S4还可以是：将S3制备的聚氨酯聚合物用二氧六环溶解后置于模具中，冷冻、干燥、灭菌处理后得到聚氨酯海绵。将药物在良溶剂中溶解形成药物溶液，用不良溶剂稀释所述药物溶液得到药物混合液，将药物混合液通过喷涂、滴加、注射或者蘸取等方式加入至聚氨酯海绵中，之后干燥使得药物析出并被固定于所述聚氨酯海绵的孔隙中，以形成载药止血棉。
优选的，所述良性溶剂为乙腈、甲醇、二氧六环、二氯甲烷、乙酸乙酯、丙酮、二甲基亚砜、二甲基甲酰胺的一种或多种。所述良溶剂优选为乙酸乙酯和丙酮。
优选的，所述不良溶剂为水、正己烷、环己烷的一种或多种。所述不良溶剂优选是环己烷。
优选的，所述良性溶剂可以与不良溶剂互溶，且良性溶剂的沸点低于不良溶剂。若良性溶剂与不良溶剂不互溶则无法形成均一溶液，并且良性溶剂应先挥发，避免良性溶剂浓度会越来越高直至溶解破坏海绵。
优选的，所述药物在良性溶剂中的浓度为0.5mg/ml-10mg/ml。
优选的，所述混合溶液中，良性溶剂与不良溶剂的比例(体积比或质量比或摩尔比)为1:4-1:49，稀释倍数为5-50倍。良性溶剂与不良溶剂比例若过高会破坏海绵，过低药物会在溶液中析出。
优选的，所述药物的混合溶液的浓度为0.01mg/ml-2mg/ml。药物的浓度优选远低于其在良性溶剂在的饱和溶解度，否则在刚加入不良溶剂后就会析出形成沉淀。
具体的，将乙酸乙酯中配置成一定浓度，再用环己烷稀释成一定比例获得药溶液。然后就可以通过喷涂或滴液或者浸泡等方式加药。这个关键是药液的配置，这种药液的配置在不破坏聚氨酯海绵前提下，使药物介于析出和不析出的一种平衡状态。
以下通过实施例1～16以及对照组1～2对本发明实施例的技术方案进行详细阐述。
【实施例1】
聚氨酯的制备：
所述步骤S1中，准确称取25.0g聚乙二醇(平均分子量为1000，Mn＝1000)加入至250mL真空反应瓶中，在100℃下用真空油泵抽连续抽真空2h除水，除水结束后冷却至70℃以下，依次加入12.5g D,L-丙交酯，12.5gε-己内酯，0.005g异辛酸亚锡，抽3分钟真空，然后升温至130℃，反应24h后无需后处理可直接用于下一步反应。
所述步骤S2中，将三口瓶固定于80℃油浴锅预热，加入50.4g六亚甲基二异氰酸酯，在机械搅拌下逐滴滴加4.5g 1,4-丁二醇，密封反应4.5h，得到乳白色膏状物。用400mL正己烷充分搅拌、洗涤，抽滤，重复3次后用旋转蒸发仪在40℃下干燥3h，得到纯白色固体粉末(HBH)。
所述步骤S3中，将50g步骤S1所得的聚酯类预聚物加入至三口瓶，然后用30.00g的DMF溶液溶解13.84g步骤S2所得的HBH并在搅拌下滴加至三口瓶中，80℃下密封反应3h后得到透明粘稠液体，加入二氧六环稀释至20％，趁热缓慢倒入冰乙醚中，在正己烷中浸泡3h 后用烘箱在40℃干燥10h后得到透明丝状固体为聚氨酯聚合物。
载药止血棉的制备：
所述步骤S4中，分别配置A，B两液，其中A液为含糠酸莫米松的3.5％聚氨酯聚合物的二氧六环溶液，其中糠酸莫米松含量为聚氨酯聚合物的0.25‰，加入3％的碳酸氢铵和1％的PEG(Mn＝10000)。B液为3.5％聚氨酯聚合物的二氧六环溶液，加入3％的碳酸氢铵和1％的PEG(Mn＝10000)。在模具中先倒入一层A液，0℃下冷冻后倒入B液，再冷冻后覆盖一层A液。在-20℃下冷冻后转移至冻干机冻干处理。冻干样品辐照灭菌后得到分层冻干载药棉，记作M1。
【实施例2】
按照实施例1中的方法实现S1、S2、S3，制得相应的聚合物。
在所述步骤S4中，将聚合物溶于二氧六环溶液中的得到3.5％的溶解液，加入聚合物质量3％的碳酸氢铵和1％的PEG(Mn＝10000)获得冻干液，在模具中先倒入一层冻干液，在0℃冷冻后再覆盖一层冻干液。在-20℃下冷冻后转移至冻干机冻干处理得到不含药的空白海绵。将糠酸莫米松超声分散于环己烷溶液配置浓度为16ug/ml的药物溶液，将空白海绵浸入不断搅拌中的药物溶液维持30秒，提出后用真空干燥箱干燥至恒重，经辐照灭菌后得到混悬纳吸式载药棉。记作M2。
【实施例3】
按照实施例2中的方法获得相应的空白海绵。
将糠酸莫米松溶于乙酸乙酯制成1.5mg/ml浓度的初始药液，然后用环己烷将其稀释至125ug/ml。使用移液设备分别在海绵上下表面各滴加1ml，用真空干燥箱干燥至恒重，经辐照灭菌后得到溶剂析出式载药棉，记作M3。
【实施例4】
聚氨酯的制备：
所述步骤S1中，准确称取20.0g聚乙二醇(Mn＝800)加入至250mL真空反应瓶中，在95℃下用真空油泵抽连续抽真空2.5h除水，除水结束后冷却至70℃以下，依次加入10g乙交酯，10gε-己内酯，0.004g异辛酸亚锡，抽30秒真空，然后升温至135℃，反应30h后无需后处理直接用于下一步反应。
扩链剂HBH制备方法与实施例1相同，此处不再陈述。
所述步骤S3中，将40g步骤S1所得的聚酯类预聚物加入至三口瓶，然后用30.00g的DMF溶液溶解14.00g步骤S2所得的HBH并在搅拌下滴加至三口瓶中，80℃下密封反应3.5h后得到透明粘稠液体，加入二氧六环稀释至15％，趁热缓慢倒入冰乙醚中，在正己烷中浸泡3h后用烘箱在40℃干燥10h后得到透明丝状固体为聚氨酯聚合物。
载药止血棉的制备：
所述步骤S4中，分别配置A，B两液，其中A液为含糠酸莫米松的4.0％聚氨酯聚合物的二氧六环溶液，其中糠酸莫米松含量为聚氨酯聚合物的0.30‰，加入3.5％的碳酸氢铵和1％的PEG(Mn＝15000)。B液为4.0％聚氨酯聚合物的二氧六环溶液，加入3.5％的碳酸氢铵和 1％的PEG(Mn＝15000)。在模具中先倒入一层A液，0℃下冷冻后倒入B液，再冷冻后覆盖一层A液。在-20℃下冷冻后转移至冻干机冻干处理。冻干样品辐照灭菌后得到分层冻干载药棉，记作M4。
【实施例5】
按照实施例4中的方法实现S1、S2、S3，制得相应的聚合物。
在所述步骤S4中，将聚合物溶于二氧六环溶液中的得到4.0％的溶解液，加入聚合物质量3.5％的碳酸氢铵和1％的PEG(Mn＝15000)获得冻干液，在模具中先倒入一层冻干液，在0℃冷冻后再覆盖一层冻干液。在-20℃下冷冻后转移至冻干机冻干处理得到不含药的空白海绵。将糠酸莫米松超声分散于环己烷溶液配置浓度为20ug/ml的药物溶液，将空白海绵浸入不断搅拌中的药物溶液维持45秒，提出后用真空干燥箱干燥至恒重，经辐照灭菌后得到混悬纳吸式载药棉。记作M5。
【实施例6】
按照实施例5中的方法获得相应的空白海绵。
将糠酸莫米松溶于乙酸乙酯制成2.0mg/ml浓度的初始药液，然后用环己烷将其稀释至150ug/ml。使用移液设备分别在海绵上下表面各滴加1ml，用真空干燥箱干燥至恒重，经辐照灭菌后得到溶剂析出式载药棉，记作M6。
【实施例7】
聚氨酯的制备：
所述步骤S1中，准确称取15.0g聚乙二醇(Mn＝1000)加入至250mL真空反应瓶中，在95℃下用真空油泵抽连续抽真空2.0h除水，除水结束后冷却至70℃以下，依次加入15g L-丙交酯，15gε-己内酯，0.004g异辛酸亚锡，抽30秒真空，然后升温至130℃，反应30h后无需后处理直接用于下一步反应。
扩链剂HBH制备方法与实施例1相同，此处不再陈述。
所述步骤S3中，将40g步骤S1所得的聚酯类预聚物加入至三口瓶，然后用30.00g的DMF溶液溶解14.00g步骤S2所得的HBH并在搅拌下滴加至三口瓶中，80℃下密封反应3.5h后得到透明粘稠液体，加入二氧六环稀释至15％，趁热缓慢倒入冰乙醚中，在正己烷中浸泡3h后用烘箱在40℃干燥10h后得到透明丝状固体为聚氨酯聚合物。
载药止血棉的制备：
所述步骤S4中，分别配置A，B两液，其中A液为含糠酸莫米松的4.5％聚氨酯聚合物的二氧六环溶液，其中糠酸莫米松含量为聚氨酯聚合物的0.30‰，加入4.0％的碳酸氢铵和1.5％的PEG(Mn＝20000)。B液为4.5％聚氨酯聚合物的二氧六环溶液，加入4.0％的碳酸氢铵。在模具中先倒入一层A液和1.5％的PEG(Mn＝20000)，0℃下冷冻后倒入B液，再冷冻后覆盖一层A液。在-25℃下冷冻后转移至冻干机冻干处理。冻干样品辐照灭菌后得到可降解载药止血海绵，记作M3。
【实施例8】
按照实施例7中的方法实现S1、S2、S3，制得相应的聚合物。
在所述步骤S4中，将聚合物溶于二氧六环溶液中的得到4.5％的溶解液，加入聚合物质量4.0％的碳酸氢铵和1％的PEG(Mn＝15000)获得冻干液，在模具中先倒入一层冻干液，在0℃冷冻后再覆盖一层冻干液。在-20℃下冷冻后转移至冻干机冻干处理得到不含药的空白海绵。将糠酸莫米松超声分散于正己烷溶液配置浓度为20ug/ml的药物溶液，将空白海绵浸入不断搅拌中的药物溶液维持45秒，提出后用真空干燥箱干燥至恒重，经辐照灭菌后得到混悬纳吸式载药棉。记作M8。
【实施例9】
按照实施例8中的方法获得相应的空白海绵。
将糠酸莫米松溶于乙酸乙酯制成1.0mg/ml浓度的初始药液，然后用环己烷将其稀释至100ug/ml。使用移液设备分别在海绵上下表面各滴加1.5ml，用真空干燥箱干燥至恒重，经辐照灭菌后得到溶剂析出式载药棉，记作M9。
【实施例10】
聚氨酯的制备：
所述步骤S1中，准确称取25.0g聚乙二醇(Mn＝1500)加入至250mL真空反应瓶中，在95℃下用真空油泵抽连续抽真空2.0h除水，除水结束后冷却至70℃以下，依次加入12.5gL-丙交酯，12.5gε-己内酯，0.004g异辛酸亚锡，抽30秒真空，然后升温至130℃，反应24h后无需后处理直接用于下一步反应。
扩链剂HBH制备方法与实施例1相同，此处不再陈述。
所述步骤S3中，将50g步骤S1所得的聚酯类预聚物加入至三口瓶，然后用26.00g的DMF溶液溶解13.00g步骤S2所得的HBH并在搅拌下滴加至三口瓶中，85℃下密封反应2.5h后得到透明粘稠液体，加入二氧六环稀释至15％，趁热缓慢倒入冰乙醚中，在正己烷中浸泡3h后用烘箱在40℃干燥10h后得到透明丝状固体为聚氨酯聚合物。
载药止血棉的制备：
所述步骤S4中，分别配置A，B两液，其中A液为含糠酸莫米松的3.5％聚氨酯聚合物的二氧六环溶液，其中糠酸莫米松含量为聚氨酯聚合物的0.30‰。B液为3.5％聚氨酯聚合物的二氧六环溶液。在模具中先倒入一层A液，0℃下冷冻后倒入B液，再冷冻后覆盖一层A液。在-20℃下冷冻后转移至冻干机冻干处理。冻干样品辐照灭菌后得到可降解载药止血海绵，记作M10。
【实施例11】
按照实施例10中的方法实现S1、S2、S3，制得相应的聚合物。
在所述步骤S4中，将聚合物溶于二氧六环溶液中的得到3.5％的溶解液，在模具中先倒入一层溶解液，在0℃冷冻后再覆盖一层溶解液。在-20℃下冷冻后转移至冻干机冻干处理得到不含药的空白海绵。将糠酸莫米松超声分散于正己烷溶液配置浓度为20ug/ml的药物溶液，将空白海绵浸入不断搅拌中的药物溶液维持45秒，提出后用真空干燥箱干燥至恒重，经辐照灭菌后得到混悬纳吸式载药棉。记作M11。
【实施例12】
按照实施例11中的方法获得相应的空白海绵。
将糠酸莫米松溶于乙酸乙酯制成2.0mg/ml浓度的初始药液，然后用环己烷将其稀释至100ug/ml。使用移液设备分别在海绵上下表面各滴加1.5ml，用真空干燥箱干燥至恒重，经辐照灭菌后得到溶剂析出式载药棉，记作M12。
【实施例13】
按照实施例4中的方法实现S1、S2中所述预聚物和扩链剂。
在所述步骤S3中，将50.00g预聚物加入至三口瓶，用25.00gDMSO溶解13.84gHBH后滴加进反应瓶，75℃下密封反应3.5h后至红外检测NCO峰完全消失(2300cm-1)。持续抽真空过夜以除去DMSO，然后加入二氧六环稀释至20％，用正己烷沉降后再烘箱中干燥至恒重得到浅黄色固体为聚氨酯聚合物。
按照实施例1中步骤S4所述方法制备载药止血棉，记做M13。
【实施例14】
按照实施例1中的方法实现S1、S2中所述预聚物和扩链剂。
在所述步骤S3中，将50.00g预聚物加入至三口瓶，用25.00gDMSO溶解13.84gHBH后滴加进反应瓶，75℃下密封反应3.5h后至红外检测NCO峰完全消失(2300cm-1)。持续抽真空过夜以除去DMSO，然后加入二氧六环稀释至20％，离心后收集上清液并用正己烷沉降，在烘箱中干燥至恒重得到浅黄色固体为聚氨酯聚合物。
按照实施例12中所述方法制备载药止血棉，记做M14。
【实施例15】
按照实施例1中的方法实现S1、S2中所述预聚物和扩链剂。
在所述步骤S3中，将50.00g预聚物加入至三口瓶，用50.00g二氧六环溶解13.84gHBH后滴加进反应瓶，75℃下密封反应3h后至红外检测NCO峰完全消失(2300cm-1)。再次加入二氧六环稀释至20％，用石油醚沉降后再烘箱中干燥至恒重得到浅黄色固体为聚氨酯聚合物。
按照实施例12中所述方法制备载药止血棉，记做M15。
【实施例16】
按照实施例4中的方法实现S1、S2中所述预聚物和扩链剂。
在所述步骤S3中，将50.00g预聚物加入至三口瓶，用50.00g甲苯溶解13.00gHBH后滴加进反应瓶，70℃下密封反应3h后至红外检测NCO峰完全消失(2300cm-1)。再次加入二氧六环稀释至25％，用环己烷沉降后再烘箱中干燥至恒重得到浅黄色固体为聚氨酯聚合物。
按照实施例12中所述方法制备载药止血棉，记做M16。
【对照例1】：
所述步骤S1中，准确称取15.0g聚乙二醇(Mn＝600)加入至250mL真空反应瓶中，在95℃下用真空油泵抽连续抽真空2.0h除水，除水结束后冷却至70℃以下，依次加入12.5g L-丙交酯，12.5gε-己内酯，0.004g异辛酸亚锡，抽30秒真空，然后升温至130℃，反应24h后无需后处理直接用于下一步反应。
扩链剂HBH制备方法与实施例1相同，此处不再陈述。
所述步骤S3中，将40g步骤S1所得的聚酯类预聚物加入至三口瓶，然后用26.00g的DMSO溶液溶解10.4g步骤S2所得的HBH并在搅拌下滴加至三口瓶中，85℃下密封反应2.5h后得到透明粘稠液体，加入二氧六环稀释至15％，趁热缓慢倒入纯化水中，析出白色条状固体，捞出后拧干水分在冰乙醇中浸泡以进一步去除水分，再次用二氧六环溶解至15％，在冰乙醚中沉降为丝状固体，干燥至恒重。
载药止血棉的制备：
所述步骤S4中，将聚合物溶于二氧六环制备3.5％的，加入聚合物质量的0.3‰得到冻干液，在模具中经冷冻干燥后制备载药止血棉。记作DBM。
【对照例2】：本对照例提供了市售产品作为参比样品。记作NXM。
性能测试
孔隙率：将预先称重的载药止血棉浸入已知体积(V1)的水中并用真空泵脱气5分钟。水和水浸渍海绵的总体积记录为(V2)，除去浸渍水的海绵，记录水残余体积为(V3)；孔隙率(a)的海绵计算如下:
(a)％＝(V1-V3)/(V2-V3)×100％。
吸水性能间接反映了载药止血棉在用于止血上的效果，吸水性能的具体的测试方法为：将实施例制备的冻干后的载药止血棉样品称重后(记录为干重)轻轻放置于纯化水表面，水能够顺着样品的孔隙向上延展，直至完全浸没顶部，记录下吸水时间；将表面流动水擦除后称重，记录为湿重，根据湿/干重的比值计算样品的吸水率，每个样品平行三次。具体测试结果见表1。
表1

根据表1，样品的孔隙率随着致孔剂的使用增加而提高。这是由于致孔剂碳酸氢铵在溶剂中占据一定空间，在降温过程中，致孔剂从中分离出来，干燥过程中分解为二氧化碳和氨气排出载药止血棉，形成大量的孔道，提高孔隙率。并且海绵的吸水速率和吸水率与聚乙二醇在整个分子链段的占比以及作为引湿剂的用量呈正比，吸水时间可达到三分钟以内，与市售产品NXM相当，优于对比例DBM，说明在PEG的分子量越低，亲水链在整个聚合物链段中的占比就越低，降低了亲水性。
压缩性能：将实施例制备的载药止血棉样品静置于上下两块压缩板中间，缓慢压缩样品至原来高度的50％，维持5分钟后撤销压力，测试样品恢复后的高度，根据压缩前后高度的变化计算回弹率。
表2

根据表2，可以发现除对比例DBM外，该载药止血棉的压缩强度均处于10kPa以上，回弹率均大于95％，载药止血棉适形性良好。实施例的样品与对比例NXM的性能相当，并且随着孔隙率增加，产生更多不同方向的径向支撑力，提高了回弹率，便于载药止血棉挤压卸力后恢复的程度。对比例DBM中，压缩强度明显低于其他样品，是因为采用了水沉后醇泡，在后续二氧六环溶解过程中造成一定程度的水解和醇解，导致分子量降低，性能下降。由此可知，本实施例采用的特定聚乙二醇、以及非水沉醇泡的工艺，得到了力学性能良好的载药止血棉。
降解性能：将实施例制备的载药止血棉样品置入磷酸盐缓冲溶液(PBS，pH＝7.4)，并置于37.3℃恒温摇床中(该试验模拟人体组织液)，每隔1小时测试并记录样品的重均分子量(Mw)和压缩至50％时的应力数值。结果分别如图1、图2所示。实施例所制备的载药止血棉M1-M12在1h内即开始降解，3h内即可初步降解，在3h时，其重均分子量和压缩强度降低至60％以下，并且随着降解时间的延长，其数值逐渐降低，最终受水表面张力的影响而趋于稳定。
其中，在实施例7-9中，PEG/环酯类单体的比例最小，即PEG的占比含量小，因此PEG链段的含量较低，其亲水性变差，抑制了水分子与酯键的接触，导致降解速率相对缓慢。说明聚氨酯聚合物结构中PEG与聚酯的比例直接影响载药止血棉的降解速率。从图1中可以看出，M7-M9样品的数均分子量均高于其余样品的数均分子量，由此可知，由于其亲水性差，进而导致了其自身的降解速率低。从图2中可以看出，M7-M9样品的压缩强度高于相比其余样品的压缩强度，这进一步验证了，由于M7-M9样品发生降解的程度低，发生粉碎的程度低导致。因此，PEG链段的占比含量也会影响载药止血棉的降解程度。较佳的，PEG链段占聚酯链段的比值至为1:1-1:1.25。
如图3，图3为M1样品的载药止血棉初始形貌图。在降解24h后轻微震荡载药止血棉完全破碎，即得到图4的形貌图。如图4，图4为M1样品降解24h后的形貌图。由图可知，表示载药止血棉已经降解且发生碎裂，表明本实施例的样品表现出与NXM相似的降解效果。降解结果表明，实施例制备的载药止血棉的降解速率快，在3～6小时内完全降解，可极大地缩短了患者的不适时间。需理解，实施例1-16中的载药止血棉与M1的类似。
药物释放：将载药止血棉浸入500ml的SDS溶液(1.0％)中，密封，放入37℃恒温摇床中，例如每隔一段时间取1mL的SDS溶液，并补充1ml，通过液相色谱测定药物浓度，进而计算出药物释放量。测试结果如图5所示。
从释放结果来看，不同的加药方式对药物释放结果有较为明显的变化。例如上下分层加药的方式(M1、M4、M7、M10样品)药物释放在前两天呈线性趋势，之后释放缓慢并趋于稳定。与分层加药相比，直接冻干加药的方式使海绵整体内外均含有药物，在释放的前期仅通过溶剂扩散作用将最外层的部分药物释放，而后在经历降解之后，释放量迅速提升，发生爆释，在临床应用中容易造成局部组织发生中毒反应。采用在空白海绵上外置加药的方式(混 悬纳吸式和溶剂析出式)，可以使药物在前期得到快速释放，有利于消除炎症反应，加快受创部位的恢复。通过分层冻干，使得药物在外表层降解时缓慢释放，进一步提高了载药止血棉的使用安全性；而采用外置加药手段，可以在受创部位前期快速给药，降低炎症反应加快伤口愈合。
上述描述仅是对本发明较佳实施例的描述，并非对本发明范围的任何限定，本发明领域的普通技术人员根据上述揭示内容做的任何变更、修饰，均属于权利要求书的保护范围。

Claims (10)

  1. 一种载药止血棉，其特征在于，所述载药止血棉用于耳、鼻、喉腔体中，所述载药止血棉包括：多孔海绵以及载药层；
    所述多孔海绵的孔隙率大于80％，所述多孔海绵的粘度大于0.4dL/g，所述多孔海绵的玻璃化转变温度-50～-20℃，以使得所述多孔海绵的压缩强度大于3Kpa、回弹率大于80％，所述多孔海绵通过压迫毛细血管起到止血作用，同时，所述多孔海绵还能够吸纳储存渗出的血液，使血液中的血小板聚集；
    所述载药层设置于所述多孔海绵的外层、中层或者内层中的至少一层，所述载药层包含药物。
  2. 根据权利要求1所述的载药止血棉，其特征在于，所述载药止血棉的吸水率大于500％；所述多孔海绵的分子链中PEG链的含量为30％～70％，进而使得所述载药止血棉的吸水时间小于10分钟。
  3. 根据权利要求2所述的载药止血棉，所述载药止血棉可降解，所述载药止血棉的降解时间为3h至24h；前三天的药物释放率大于60％；前两天的药物释放率大于40％，其释放速率为20％～40％每天。
  4. 根据权利要求1所述的载药止血棉，其特征在于，所述多孔海绵的材质为聚氨酯、明胶、壳聚糖、透明质酸钠、胶原蛋白中的至少一种。
  5. 根据权利要求1所述的载药止血棉，其特征在于，所述药物包括抗炎类药物、抗菌类药物、止痛类药物、止血类药物或者抗过敏药物中的至少一种；
    所述抗炎类药物优选包括糖皮质激素类药物；所述糖皮质激素类药物优选包括糠酸莫米松、布地奈德或者丙酸氟替卡松中的至少一种；所述抗过敏药优选包括依巴斯汀、氯雷他定、阿伐斯汀。
  6. 根据权利要求5所述的载药止血棉，其特征在于，当所述载药止血棉用于鼻腔中时，每片载药止血棉中，所述药物的载药量在100ug～1000ug/g。
  7. 一种载药止血棉的制备方法，其特征在于，用于制备如权利要求1～6中任一项所述的载药止血棉，所述载药止血棉的制备方法包括：
    S1：在无水无氧环境中，以聚乙二醇为引发剂，环酯类单体在催化剂的作用下发生开环反应合成聚酯类预聚物，所述聚乙二醇的平均分子量为800-1500；
    S2：二异氰酸酯化合物与多元醇类化合物混合，在一定温度下反应后经分离提纯制备异氰酸基封端的三嵌段化合物，所述多元醇类化合物与二异氰酸酯化合物的摩尔比为1：4～1： 10；
    S3：将S2制备的异氰酸基封端的三嵌段化合物溶于有机溶剂与S1制备的聚酯类预聚物按一定投料比反应，采用不良性溶剂进行沉降，沉降后，无需水沉、醇泡处理，干燥至恒重得到聚氨酯聚合物；
    其中，步骤S4为S4-1：将S3制备的聚氨酯以及药物用有机溶剂溶解后置于模具中，经冷冻、干燥、灭菌处理后得到载药止血棉；
    或者，步骤S4为S4-2：将S3制备的聚氨酯聚合物用二氧六环溶解后置于模具中，经冻干后得到不含药的空白海绵；将药物在分散在不良溶剂中制成悬浮液，在搅拌下将所述空白海绵放入悬浮液中，搅拌后捞出干燥，使得药物被吸附于所述聚氨酯海绵的孔隙中，以形成载药止血棉；
    或者，步骤S4为为S4-3：将S3制备的聚氨酯聚合物用二氧六环溶解后置于模具中，经冻干得到不含药的空白海绵；将药物在良溶剂中溶解形成药物溶液，用不良溶剂稀释所述药物溶液得到药物混合液，将药物混合液通过喷涂、滴加、注射或者蘸取等方式加入至空白海绵中，之后干燥使得药物析出并固定于所述聚氨酯海绵的孔隙中，以形成载药止血棉。
  8. 根据权利要求7所述的载药止血棉的制备方法，其特征在于，所述S4为S4-1时，所述S4步骤包括：
    S41：将S3制备的聚氨酯聚合物和药物用二氧六环溶解后置于模具中，经冷冻得到第一载药层，所述第一载药层的厚度小于所述模具内的高度；
    S42：将S3制备的聚氨酯聚合物用二氧六环溶解后置于所述模具中，经冷冻得到聚氨酯层，所述聚氨酯层叠加于所述第一载药层上，所述第一载药层与所述聚氨酯层的厚度之和小于所述模具内的高度；
    S43：将S3制备的聚氨酯聚合物和药物用二氧六环溶解后置于模具中，经冷冻得到第二载药层，所述第二载药层叠加于所述聚氨酯层上，经干燥得到载药止血棉，以使得所述载药止血棉依次包括所述第一载药层、聚氨酯层、第二载药层；
    其中，在所述S41或所述S43步骤中，将S3制备的聚氨酯聚合物、药物以及致孔剂溶解后置于模具中；或者，在所述S42步骤中，将S3制备的聚氨酯聚合物、致孔剂溶解后置于模具中。
  9. 根据权利要求8所述的载药止血棉的制备方法，其特征在于，所述致孔剂为无机盐；或者，所述致孔剂包括磷酸铵、磷酸氢铵、碳酸氢铵中的一种或多种；
    或者，所述制备方法还包括S5步骤：在所述止血棉中加入引湿剂；
    或者，在所述S1步骤中，聚乙二醇与环酯类单体的质量比为1:1-1:2；或者，所述S2步骤中，所述二异氰酸酯化合物为六亚甲基二异氰酸酯，1,4-丁二醇与六亚甲基二异氰酸酯的摩尔比为1:4～1:10；
    或者，在S3步骤中，S1得到的聚酯类预聚物与S2得到的HBH的摩尔比为1:1.0～1:1.5；或者，所述S3步骤中，所述有机溶剂包括二甲亚砜、二甲基甲酰胺、二氧六环、氯仿中的至少一种；所述不良溶剂包括正己烷、乙醚、正戊烷、石油醚、环己烷中的至少一种；
    或者，在所述S1步骤中，所述聚乙二醇的平均分子量为900～1100；
    或者，在所述步骤S4中，还包括，将S3制备的聚氨酯聚合物、药物、致孔剂以及降解酶一起溶解后置于模具中；或者，将所述S4得到的载药止血棉蘸取降解酶的液体后植入到目标位置。
  10. 一种药物缓释系统，其特征在于，所述药物缓释系统包括权利要求1所述的载药止血棉。
PCT/CN2024/099345 2023-06-14 2024-06-14 载药止血棉、载药止血棉的制备方法及药物缓释系统 Ceased WO2024255874A1 (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119684567A (zh) * 2025-02-25 2025-03-25 中国科学院长春应用化学研究所 一种聚氨酯多孔材料及其制备方法和应用
CN119838045A (zh) * 2025-03-24 2025-04-18 合肥启灏医疗科技有限公司 一种壳聚糖聚氨酯复合止血海绵及其制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060008419A1 (en) * 2003-01-09 2006-01-12 Polyganics B.V. Biomedical foams
KR100716658B1 (ko) * 2005-11-11 2007-05-09 주식회사 원바이오젠 폴리우레탄 폼 드레싱재의 제조방법
CN104031287A (zh) * 2014-06-19 2014-09-10 山东赛克赛斯药业科技有限公司 可降解鼻腔用止血海绵的制备方法
CN105001393A (zh) * 2015-06-26 2015-10-28 山东师范大学 一种可生物降解聚醚型聚氨酯海绵的制备方法
US20170224867A1 (en) * 2016-02-08 2017-08-10 Datt Mediproducts Limited Ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable porous sponge matrix and a method of manufacturing thereof
CN111035796A (zh) * 2019-12-26 2020-04-21 杭州维力医疗器械有限公司 一种降解可控的载药止血绵及其制备方法
CN115487343A (zh) * 2022-11-16 2022-12-20 合肥启灏医疗科技有限公司 载药聚氨酯止血绵及其制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060008419A1 (en) * 2003-01-09 2006-01-12 Polyganics B.V. Biomedical foams
KR100716658B1 (ko) * 2005-11-11 2007-05-09 주식회사 원바이오젠 폴리우레탄 폼 드레싱재의 제조방법
CN104031287A (zh) * 2014-06-19 2014-09-10 山东赛克赛斯药业科技有限公司 可降解鼻腔用止血海绵的制备方法
CN105001393A (zh) * 2015-06-26 2015-10-28 山东师范大学 一种可生物降解聚醚型聚氨酯海绵的制备方法
US20170224867A1 (en) * 2016-02-08 2017-08-10 Datt Mediproducts Limited Ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable porous sponge matrix and a method of manufacturing thereof
CN111035796A (zh) * 2019-12-26 2020-04-21 杭州维力医疗器械有限公司 一种降解可控的载药止血绵及其制备方法
CN115487343A (zh) * 2022-11-16 2022-12-20 合肥启灏医疗科技有限公司 载药聚氨酯止血绵及其制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119684567A (zh) * 2025-02-25 2025-03-25 中国科学院长春应用化学研究所 一种聚氨酯多孔材料及其制备方法和应用
CN119838045A (zh) * 2025-03-24 2025-04-18 合肥启灏医疗科技有限公司 一种壳聚糖聚氨酯复合止血海绵及其制备方法

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