Preparation method of polyurethane polymer, hemostatic cotton and drug sustained release system

Abstract

The invention provides a preparation method of a polyurethane polymer, which comprises the following steps: S1, taking polyethylene glycol as an initiator, and carrying out ring-opening reaction on a cyclic ester monomer under the action of a catalyst to synthesize a polyester prepolymer; s2, reacting the dihydroxyl compound with diisocyanate, and purifying and drying to obtain a hydroxyl-terminated triblock compound; s3, carrying out condensation reaction on diisocyanate and polyethylene glycol under the action of a catalyst to prepare an isocyanate group-terminated polyurethane prepolymer; s4, the polyester prepolymer prepared in the step S1 is dropwise added into the polyurethane prepolymer prepared in the step S3, then the dimethylformamide solution of the hydroxyl-terminated triblock compound prepared in the step S2 is dropwise added continuously, purification and drying are performed after continuous reaction, and the polyurethane polymer is obtained and is good in mechanical property, high in clinical safety and low in cost.

Description

Technical Field

[0001] The invention relates to the technical field of medical devices, and in particular to a preparation method of a polyurethane polymer, hemostatic cotton and a drug sustained-release system. Background Art

[0002] Bleeding during surgery is a common clinical symptom. Otolaryngology surgery is one of the most common medical surgical procedures. Taking otolaryngology surgery as an example, the bleeding sites are deep, the space is narrow, and there are a large number of capillaries around them, which makes it difficult to suture after surgery. Medical polyurethane sponge can conform to the shape of different parts after being stressed, and can be used as hemostatic cotton in surgery to achieve rapid hemostasis of bleeding sites.

[0003] However, the polyurethane sponge obtained by the existing polyurethane preparation method has at least the following problems: 1) The mechanical properties of polyurethane are weak and the toughness is poor. During the compression hemostasis process, it is easy to break or collapse, and the hemostasis effect and anti-adhesion effect are poor. 2) It is easy to have side reactions and high chemical residues, which affects clinical safety. 3) The polyurethane sponge used does not have antibacterial effect, thereby slowing down wound healing. 4) The cost is high.

[0004] Therefore, developing a polyurethane and hemostatic cotton with good mechanical properties, capable of achieving sustained drug release and low cost is an urgent problem to be solved. Summary of the invention

[0005] The purpose of the present invention is to provide a preparation method of a polyurethane polymer, hemostatic cotton and a drug sustained-release system to solve the technical problems of poor mechanical properties, poor clinical safety, inability to slowly release drugs and high cost of polyurethane polymers.

[0006] In order to solve the above technical problems, the present invention provides a method for preparing a polyurethane polymer, comprising: S1: in an anhydrous and oxygen-free environment, using polyethylene glycol as an initiator, cyclic ester monomers undergo a ring-opening reaction under the action of a catalyst to synthesize a polyester prepolymer; S2: in an anhydrous and oxygen-free environment, a dihydroxy compound reacts with a diisocyanate, and a hydroxyl-terminated triblock compound is obtained after purification and drying; S3: in an anhydrous and oxygen-free environment, a diisocyanate and polyethylene glycol undergo a condensation reaction under the action of a catalyst to prepare an isocyanate-terminated polyurethane prepolymer; S4: the polyester prepolymer prepared in S1 is dripped into the polyurethane prepolymer prepared in S3, and then a dimethylformamide solution of the hydroxyl-terminated triblock compound prepared in S2 is continuously dripped, and the reaction is continued and then purified and dried to obtain a polyurethane polymer.

[0007] Optionally, the method further includes step S5: obtaining drug-loaded polyurethane by absorbing drugs, i.e. first freezing and drying the polyurethane polymer obtained in S4 into a polyurethane sponge, and adsorbing the drugs into the pores of the polyurethane sponge through the pressure difference between the polyurethane sponge and the drug solvent or drug environment.

[0008] Optionally, the method of absorbing the drug includes: using a suspension to absorb the drug, that is, making the drug into a suspension in a poor solvent, placing the polyurethane sponge into the suspension while stirring, and then taking it out and drying it; or, using a negative pressure adsorption method for the drug, that is, placing the polyurethane sponge into a container, the air pressure in the container is lower than the pressure of the environment in which the drug is located, and the drug is adsorbed into the pores of the polyurethane sponge; or, using a combination of negative pressure adsorption and suspension adsorption, that is, first compressing the polyurethane sponge so that the air in its pores is pressed out, and then placing the compressed polyurethane sponge in a suspension, and then taking it out and drying it.

[0009] Optionally, in the method of absorbing the drug by the suspension, the stirring time is 10 seconds;

[0010] Preferably, the particle size of the drug is 0.5um-3um;

[0011] Preferably, the poor solvent is at least one of n-hexane, cyclohexane and diethyl ether.

[0012] Optionally, the drug includes at least one of an anti-inflammatory drug, an antibacterial drug, an analgesic drug, a hemostatic drug or an antiallergic drug;

[0013] Preferably, the anti-inflammatory drugs include glucocorticoid drugs, or the antibacterial drugs include penicillins, cephalosporins and the like, or the analgesic drugs include ibuprofen;

[0014] Preferably, the glucocorticoid drugs include mometasone furoate or budesonide;

[0015] Preferably, the solution solubility of the drug is 5-30ug / mL;

[0016] Preferably, the drug is slowly released, and the drug release rate is greater than 70% in the first 3 days of degradation; preferably, the drug release rate is greater than 50% in the first 1.5 days of degradation; preferably, the drug release rate is greater than 20% in the first 0.5 days of degradation;

[0017] Preferably, the compression strength of the polyurethane sponge in dry and wet states is greater than 10 kPa, and the rebound rate is greater than 98%; Preferably, the compression strength and rebound rate of the polyurethane sponge in wet state are greater than those in dry state;

[0018] Preferably, the porosity of the polyurethane sponge is greater than 90%;

[0019] Preferably, the water absorption rate of the polyurethane sponge is greater than 1860%;

[0020] Preferably, the water absorption time of the polyurethane sponge is less than 33 seconds;

[0021] Preferably, in step S1, the cyclic ester monomer is one or more of DL-lactide, L-lactide, glycolide, caprolactone, trimethylene carbonate, and p-dioxanone;

[0022] Preferably, in step S1, the cyclic ester monomer is one or more of glycolide, lactide and caprolactone;

[0023] Preferably, in step S1, the molecular weight of the polyethylene glycol (PEG) is 1000-4000;

[0024] Preferably, in step S1, the molecular weight of the polyethylene glycol is 1500-2000;

[0025] Preferably, in step S1, the mass ratio of polyethylene glycol to cyclic ester monomer is 1:1-1:1.5;

[0026] Preferably, in step S1, the catalyst is a tin catalyst, and the mass of the catalyst is 0.05% to 0.1% of the total mass of the reactants;

[0027] Preferably, the reaction temperature in step S1 is 120°C to 140°C; the reaction time is 7 to 14 days;

[0028] Preferably, in step S2, the diisocyanate compound is one or more of hexamethylene diisocyanate, isophorone diisocyanate, and methylcyclohexyl diisocyanate;

[0029] Preferably, in step S2, the diisocyanate compound is hexamethylene diisocyanate, and the dihydroxy compound is preferably 1,4-butanediol;

[0030] Preferably, in step S2, the molar ratio of diisocyanate to dihydroxy compound is 1:6 to 1:8;

[0031] Preferably, in step S2, the reaction temperature is 70°C to 90°C; the reaction time is 4 to 6 hours;

[0032] Preferably, in step S2, the separation and purification process is: washing the crude product obtained after the reaction with a large amount of acetone, stirring continuously during the washing process until the product is completely dispersed into a solid powder, filtering with suction, washing with acetone again, 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;

[0033] Preferably, in step S3, the molecular weight of the polyethylene glycol is 4000 to 20000;

[0034] Preferably, in step S3, the molecular weight of the polyethylene glycol is 8000 to 10000;

[0035] Preferably, in step S3, the molar ratio of the polyethylene glycol to the diisocyanate is 1:1.5 to 1:3.0; more preferably 1:2.0;

[0036] Preferably, in step S3, the reaction endpoint of the polyurethane prepolymer is when the isocyanate (-NCO) in the solution detected by the di-n-butylamine method reaches a theoretical value;

[0037] Preferably, in step S3, the amount of polyester prepolymer added is such that the molar ratio of hydroxyl group to residual isocyanate group is 1:1.5 to 1:2;

[0038] Preferably, after adding the polyester prepolymer in step S3, the reaction temperature is 75°C to 85°C, and the reaction time is 4 to 5 hours;

[0039] Preferably, in step S4, the amount of the hydroxyl-terminated triblock compound added is such that the molar ratio of hydroxyl to residual isocyanate (-NCO) is 1:1.0;

[0040] Preferably, in step S4, the mass solubility of the dimethylformamide solution of the hydroxyl-terminated triblock compound is 0.125 to 0.25 g / mL;

[0041] Preferably, in step S4, the polymerization temperature after adding the hydroxyl-terminated triblock compound in step S4 is 75-90° C., and the reaction time is 1 to 2 hours.

[0042] Optionally, the method further includes steps S51, S52, and S53: obtaining drug-loaded polyurethane by freeze-drying and adding drugs;

[0043] S51: dissolving the polyurethane polymer and the drug prepared in S4 and placing them in a mold, and performing post-treatment to obtain a first drug-carrying layer; the post-treatment at least includes freezing and drying;

[0044] S52: dissolving the polyurethane polymer prepared in S4 and placing it in the mold, and obtaining a polyurethane layer through post-processing, wherein the polyurethane layer is superimposed on the first drug-carrying layer;

[0045] S53: The polyurethane polymer and drug prepared in S4 are dissolved and placed in a mold, and after post-processing, a second drug-carrying layer is obtained. The second drug-carrying layer is superimposed on the polyurethane layer to obtain a polyurethane sponge, so that the polyurethane sponge includes the first drug-carrying layer, the polyurethane layer, and the second drug-carrying layer in sequence.

[0046] Optionally, the freeze-drying process of the polyurethane polymer prepared in S4 is as follows: the polyurethane polymer is dissolved in a solvent to prepare a freeze-dried liquid, a portion of the freeze-dried liquid is poured into a mold and frozen at 0°C, and then the remaining freeze-dried liquid is added, and then the freeze-dried liquid is frozen at sub-zero temperature and transferred to a freeze dryer for freeze drying.

[0047] Optionally, the method further includes step S6: dissolving the polyurethane polymer prepared in S4 with dioxane and placing it in a mold, freezing, drying, and sterilizing to obtain a polyurethane sponge; dissolving a 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 so that the drug is adsorbed in the pores of the polyurethane sponge;

[0048] Preferably, the benign solvent is one or more of acetonitrile, methanol, dioxane, dichloromethane, ethyl acetate, acetone, dimethyl sulfoxide, and dimethylformamide;

[0049] Preferably, the benign solvent is miscible with the poor solvent, and the boiling point of the benign solvent is lower than the boiling point of the poor solvent;

[0050] Preferably, the poor solvent is one or more of water, n-hexane, cyclohexane, and cyclopropanone;

[0051] Preferably, the concentration of the drug in the benign solvent is 0.5 mg / ml-10 mg / ml;

[0052] Preferably, in the mixed solution, the volume ratio, mass ratio or molar ratio of the good solvent to the poor solvent is 1:4-1:49, and the dilution factor is 5-50 times; preferably, the concentration of the mixed solution of the drug is 0.01 mg / ml-2 mg / ml.

[0053] In order to solve the above technical problems, the present invention also provides a hemostatic cotton, which is obtained by the preparation method of the polyurethane polymer as described above.

[0054] Optionally, it is used for filling and stopping bleeding in the nasal sinuses or cavities, ear canals, oral cavity, urethra or tissue cavities of the human or animal body; or, the drug-loaded hemostatic cotton is used for occupying space and compressing bleeding; or, the hemostatic cotton is used in surgical operations; preferably, the hemostatic cotton is used in otolaryngology operations.

[0055] In order to solve the above technical problems, the present invention also provides a drug sustained release system, which includes the drug-loaded hemostatic cotton obtained by absorbing the drug or freeze-drying the hemostatic cotton as described above. In a preparation method of a polyurethane polymer provided by the present invention, S1: in an anhydrous and oxygen-free environment, using polyethylene glycol as an initiator, cyclic ester monomers undergo a ring-opening reaction under the action of a catalyst to synthesize a polyester prepolymer; S2: in an anhydrous and oxygen-free environment, a dihydroxy compound reacts with a diisocyanate, and after purification and drying, a hydroxyl-terminated triblock compound is obtained; S3: in an anhydrous and oxygen-free environment, a diisocyanate and polyethylene glycol undergo a condensation reaction under the action of a catalyst to prepare an isocyanate-terminated polyurethane prepolymer; S4: the polyester prepolymer prepared by S1 is added dropwise to the polyurethane prepolymer prepared by S3, and then the dimethylformamide solution of the hydroxyl-terminated triblock compound prepared by S2 is continuously added dropwise, and the reaction is continued and then purified and dried to obtain a polyurethane polymer. In the steps, HDI-PEG-HDI is first reacted with PLC to obtain a linear NCO~~PEG~~PLC~~PFG~~NCO terminal isocyanate product. A hydroxyl-terminated triblock compound (BHB) is then added to extend the chain again to form a polyurethane polymer (DPU), so that the molecular chain of DPU can be arranged in an orderly manner to ensure the orderliness of the molecular chain. PEG is introduced into the molecular chain by chemical means, so that PFG with a hydrophilic effect is not easy to fall off and is evenly distributed, which can effectively accelerate degradation. At the same time, BHB bidirectionally extends the chain on both sides of HDI-PEG-HDI, which can consume more BHB, and then introduce more carbamate groups into the molecular chain, increase the content of carbamate, and then ensure the content of hydrogen bonds, so that the toughness of DPU is improved and the resilience is good. Through the preparation method of the present invention, the hydrolysis of water on the polymer is avoided, the product stability is maintained and the yield is improved. At the same time, the polyurethane polymer is a degradable material, which not only retains the mechanical properties of traditional polyurethane, but also provides degradability, and does not require secondary surgery to remove, but can be discharged after being degraded by body metabolism, and the degradation products are non-toxic. In addition, the reagent cost applicable to the preparation method of the present invention is low, and the preparation method adopted is simple to operate, low in cost, universal, and easy to mass produce. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Those skilled in the art will appreciate that the accompanying drawings are provided for a better understanding of the present invention and do not constitute any limitation on the scope of the present invention.

[0057] Figure 1 is the structural formula of the polyurethane polymer obtained by the preparation method of this embodiment.

[0058] Figure 2This is a graph showing the relationship between the compression strength of the samples in this embodiment and the comparative example when compressed to 50% and the degradation time.

[0059] Figure 3 It is a schematic diagram of the cumulative release rate of the drug in the samples of this embodiment and the comparative example at different time periods. DETAILED DESCRIPTION

[0060] In order to make the purpose, advantages and features of the present invention more clear, the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. It should be noted that the drawings are all in a very simplified form and are not drawn to scale, and are only used to conveniently and clearly assist in explaining the purpose of the embodiments of the present invention.

[0061] As used in this specification, the singular forms "a", "an", and "the" include plural objects, unless the content clearly indicates otherwise. As used in this specification, the term "or" is generally used in a sense including "and / or", unless the content clearly indicates otherwise. In addition, in the description below, a large number of specific details are given in order to provide a more thorough understanding of the present invention. However, it is obvious to those skilled in the art that the present invention can be implemented without one or more of these details. It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those commonly understood by those of ordinary skill in the art to which the present application belongs.

[0062] The term "degradable" means capable of being broken down into harmless products by the action of organisms.

[0063] The term "target site" refers to a lumen at which hemostasis is desired.

[0064] The term "degradation" means "degradation behavior", which includes degradation rate, generation of products during degradation, changes in morphology and mechanical properties, etc. In order to facilitate the description of the degree of degradation of degradable materials, in this article, the 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.

[0065] The present embodiment provides a method for preparing a polyurethane polymer, including: S1, preparation of a polyester prepolymer; S2, synthesis of a chain extender; S3, preparation of a polyurethane prepolymer; S4, preparation of a polyurethane polymer, adding a polyester prepolymer (PLC) prepared by S1 to the polyurethane prepolymer (HDI-PEG-HDI) prepared by S3, reacting for a period of time, and then continuing to add a dimethylformamide solution of a hydroxyl-terminated triblock compound (BHB) prepared by S2, continuing the reaction, and then purifying and drying to obtain a polyurethane polymer. In the steps, HDI-PEG-HDI is first reacted with PLC to obtain a linear NCO~~PEG~~PLC~~PFG~~NCO terminal isocyanate product. Then, a hydroxyl-terminated triblock compound (BHB) is added to extend the chain again to form a polyurethane polymer (DPU), so that the molecular chains of DPU can be arranged in an orderly manner to ensure the orderliness of the molecular chains. By chemical means, PEG is introduced into the molecular chain, so that PFG with hydrophilic effect is not easy to fall off, and is evenly distributed, which can effectively accelerate degradation. At the same time, BHB can consume more BHB by bidirectional chain extension on both sides of HDI-PEG-HDI, thereby introducing more carbamate groups into the molecular chain, increasing the content of carbamate, thereby ensuring the content of hydrogen bonds, thereby improving the toughness of DPU and having good resilience. Through the preparation method in this embodiment, the hydrolysis of water on the polymer is avoided, the product stability is maintained and the yield is improved. At the same time, the polyurethane polymer is a degradable material, which not only retains the mechanical properties of traditional polyurethane, but also provides degradability, does not require secondary surgery to remove, can flow out after degradation with body metabolism, and the degradation product is non-toxic. In addition, the reagent cost applicable to the preparation method of the present application is low, and the preparation method adopted is simple to operate, low in cost, universal, and easy to scale production.

[0066] In addition, this embodiment also provides at least three drug loading methods for polyurethane polymers. The polyurethane polymers obtained by the methods have anti-inflammatory and antibacterial effects and alleviate postoperative inflammatory reactions.

[0067] The present invention provides a method for preparing a polyurethane polymer:

[0068] S1. Preparation of polyester 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 polyester prepolymers (PLC). Preferably, the cyclic ester monomers are one or more of DL-lactide, L-lactide, glycolide, caprolactone, trimethylene carbonate, and p-dioxanone. More preferably, the cyclic ester monomers are glycolide, lactide, and caprolactone. Preferably, the molecular weight of the polyethylene glycol (PEG) is 1000-4000. Preferably, the molecular weight of the polyethylene glycol is 800-2000. Preferably, in the step S1, the mass ratio of polyethylene glycol to cyclic ester monomers is 1:1-1:1.5, thereby ensuring the proportion of polyethylene glycol, avoiding the problem of poor hydrophilicity of polyurethane polymers, and improving the degradation rate. Preferably, in step S1, the catalyst is a tin catalyst, and the mass of the catalyst is 0.05% to 0.1% of the total mass of the reactants. Preferably, the reaction temperature in step S1 is 120° C. to 140° C.; and the reaction time is 7 to 14 days.

[0069] S2, the synthesis of chain extender: in anhydrous and oxygen-free environment, the dihydroxy compound reacts with diisocyanate, and a hydroxyl-terminated triblock compound (BHB) is obtained after purification and drying. Compared with the terminal isocyanate-terminated compound, the hydroxyl-terminated compound has a long shelf life, is easy to store, and has a low synthesis cost. The diisocyanate compound can be one or more of hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), and methylcyclohexyl diisocyanate. Preferably, the diisocyanate compound is preferably hexamethylene diisocyanate (HDI), and the dihydroxy compound is preferably butanediol. Compared with the raw materials of other chain extenders, hexamethylene diisocyanate (HDI) has the lowest price, which further reduces the cost.

[0070] Preferably, in the step S2, the molar ratio of hexamethylene diisocyanate to 1,4-butanediol is 1:6 to 1:8. Preferably, in the step S2, the reaction temperature is 70°C to 90°C; the reaction time is 4 to 6 hours. Preferably, in the step S2, the separation and purification process is: washing the crude product obtained after the reaction with a large amount of acetone, stirring continuously during the washing process until the product is completely dispersed into a solid powder, filtering, washing with acetone again, 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.

[0071] S3, preparation of polyurethane prepolymer: In anhydrous and oxygen-free environment, diisocyanate and polyethylene glycol (PEG) undergo condensation reaction under the action of a catalyst to prepare an isocyanate-terminated polyurethane prepolymer (HDI-PEG-HDI). In this way, the polyurethane prepolymer can be made into a long-chain linear molecular chain structure. In the step S3, the diisocyanate aliphatic diisocyanate is preferably one of hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), lysine diisocyanate (LDI) or dicyclohexylmethane diisocyanate (HMDI). Preferably, in the step S3, the molecular weight of the polyethylene glycol is 4000-20000, more preferably 8000-10000, and a high molecular weight PEG is used to synthesize the polyurethane prepolymer, which increases the proportion of the hydrophilic segment in the entire molecular structure, makes it easier to introduce water molecules, and makes the water molecules contact with the ester bond, thereby greatly improving the degradation performance of the polyurethane polymer. Preferably, in the step S3, the molar ratio of the polyethylene glycol to the diisocyanate is 1:1.5 to 1:3.0, more preferably 1:2.0. Preferably, in the step S3, the reaction endpoint of the polyurethane prepolymer is when the isocyanate (-NCO) in the di-n-butylamine method detection solution reaches the theoretical value. For example, in the step S3, the reaction ratio of the diisocyanate to the polyethylene glycol is 1:1 reaction, and the excess isocyanate remaining after the reaction is the theoretical value. Preferably, the amount of the polyester prepolymer added in the step S3 is such that the molar ratio of the hydroxyl group to the remaining isocyanate is 1:1.5 to 1:2. Preferably, after the polyester prepolymer is added in the step S3, the reaction temperature is 75°C to 85°C, and the reaction time is 4 to 5h. Moreover, the polyethylene glycol (PEG) introduced in this embodiment can also be used as a hydrophilic agent. Compared with physical addition, the PEG is chemically embedded in the molecular chain, making it difficult for PEG to fall off and evenly distributed, which can effectively accelerate degradation and increase the compressive stress of the hemostatic cotton.

[0072] S4, preparation of polyurethane polymer: The polyester prepolymer (PLC) prepared by S1 is added dropwise to the polyurethane prepolymer (HDI-PEG-HDI) prepared by S3. After a period of reaction, the dimethylformamide (DMF) solution of the hydroxyl-terminated triblock compound (BHB) prepared by S2 is added dropwise, and the reaction is continued and then purified and dried to obtain a polyurethane polymer (DPU). In this embodiment, HDI-PEG-HDI is first reacted with PLC to obtain a linear NCO~PEG~PLC~PFG~NCO terminal isocyanate product. Then a hydroxyl-terminated triblock compound (BHB) is added for chain extension again to form DPU. In this way, the molecular chains of DPU can be arranged in an orderly manner to ensure the orderliness of the molecular chains. By chemical means, PEG is introduced into the molecular chain, so that the hydrophilic PFG is not easy to fall off and is evenly distributed, which can effectively accelerate degradation. At the same time, BHB bidirectionally extends the chain on both sides of HDI-PEG-HDI, which can consume more BHB, thereby introducing more carbamate groups into the molecular chain, increasing the content of carbamate, thereby ensuring the content of hydrogen bonds, thereby improving the toughness of DPU and improving its resilience. Through the preparation method in this embodiment, the hydrolysis of water on the polymer is avoided, the product stability is maintained and the yield is improved.

[0073] Preferably, the amount of BHB added in step S4 is such that the molar ratio of hydroxyl to residual isocyanate (-NCO) is 1:1.0, and the mass solubility of BHB in DMF solution is 0.125-0.25 g / mL. In actual use, it can be carried out according to (nBHB+nPLC)=(nHDI-nPEG), wherein n represents the amount of substance. The polymerization temperature after adding BHB in step S4 is 75-90°C, and the reaction time is 1-2h. Preferably, the purification method described in step S4 is to dilute the crude product to 10%-30% with dioxane, slowly pour it into the stirred ice ether to precipitate into a filamentous transparent solid, and naturally evaporate most of the ether and then vacuum dry to constant weight.

[0074] This embodiment also provides a hemostatic cotton, which is prepared by the above-mentioned preparation method of the polyurethane polymer. In this embodiment, the polyurethane polymer can be used for hemostasis after being treated, so the hemostatic cotton hereinafter can also represent the treated polyurethane polymer. The hemostatic cotton has the beneficial effects of the polyurethane polymer.

[0075] Preferably, the method further comprises S5, preparation of drug-loaded polyurethane: three drug adding methods can be adopted.

[0076] The first is a method of absorbing drugs. The polyurethane polymer obtained in S3 is first frozen and dried into a polyurethane sponge. The drug is adsorbed in the pores of the polyurethane sponge through the pressure difference between the polyurethane sponge and the drug solvent or the drug environment. In this way, the drug can be contained in the pores of the polyurethane sponge. While achieving drug loading, it can also ensure that the drug can be quickly released after being placed in the target position. Compared with the solution of coating a layer of drug on the polyurethane sponge, it can avoid the phenomenon of a large amount of drug falling off during the implantation operation. It is understandable that the drug environment can represent the spatial environment in which the drug is located, such as atmospheric pressure, humidity, etc. Preferably, the method of absorbing drugs can adopt the method of absorbing drugs in a suspension. The drug is made into a suspension in a poor solvent, put into a polyurethane sponge under stirring, and then taken out and dried after continuous stirring. The stirring time is preferably 10 seconds. Preferably, the particle size of the drug is 0.5um-3um. Since solvents that can dissolve drugs can dissolve polyurethane polymers, the selection of suspension solvents is particularly important. The solvent can suspend the drug but cannot dissolve the polyurethane polymer. Therefore, as a specific preference, the poor solvent can be a volatile solvent such as n-hexane, cyclohexane, ether, etc. In other embodiments, the drug can also be adsorbed by negative pressure. The air pressure in the container is less than the pressure of the environment in which the drug is located. For example, the prepared polyurethane sponge is placed in a container, preferably by vacuuming to achieve negative pressure, and then the drug particles can be adsorbed into the pores of the polyurethane sponge under the action of negative pressure. Such an arrangement can avoid the influence of the solvent on the shape of the polyurethane sponge and prevent the deformation of the polyurethane sponge. It should be understood that the polyurethane sponge has a certain rebound rate. If a certain deformation is formed on the polyurethane sponge, the rebound performance of the polyurethane sponge will inevitably be affected. In another embodiment, a combination of negative pressure adsorption and suspension adsorption may be used. For example, the polyurethane sponge is first compressed so that the air in its pores is squeezed out, and then the compressed polyurethane sponge is placed in the suspension. The suspension containing the drug is adsorbed in the pores of the polyurethane sponge and then fished out and dried.

[0077] Preferably, in step S5, the mass concentration of the polyurethane prepolymer solution is 3% to 5%.

[0078] Preferably, in step S5, the sterilization methods adopted are radiation sterilization and ethylene oxide sterilization.

[0079] The second method is to add medicine by layered freeze drying. The step S5 comprises:

[0080] S51: The polyurethane polymer and the drug prepared in S4 are dissolved in 1,4-dioxane and placed in a mold, and the first drug-carrying layer is obtained through post-treatment. The thickness of the first drug-carrying layer is less than the height inside the mold, so that the mold can accommodate the polyurethane layer and the second drug-carrying layer described below. The post-treatment includes at least freezing and drying, and of course, sterilization and other steps. The freezing and drying process is a process of solution sublimation. After the solution is sublimated, uniform pores can be formed to form a microporous solid. Among them, 1,4-dioxane has good solubility and can dissolve polyurethane polymers and drugs at the same time. By dissolving the polyurethane polymer and the drug together, and obtaining the drug-carrying polyurethane through freezing, drying and other steps, the drug can be physically embedded and distributed in the polyurethane polymer, and the sustained release of the drug can be achieved during the degradation process of the drug-carrying polyurethane polymer.

[0081] S52: The polyurethane polymer prepared in S4 is dissolved in dioxane and placed in the mold. A polyurethane layer is obtained after post-processing. 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.

[0082] S53: The polyurethane polymer and the drug prepared in S4 are dissolved in dioxane and placed in a mold, and the second drug-carrying layer is obtained by post-processing. The second drug-carrying layer is superimposed on the polyurethane layer to obtain hemostatic cotton, so that the hemostatic cotton includes the first drug-carrying layer, the polyurethane layer, and the second drug-carrying layer in sequence. Such a setting can make the two surface layers of the hemostatic cotton have drugs, which is more convenient for drug release when the drug content is the same compared to the hemostatic cotton with all drugs added. At the same time, because the hemostatic cotton does not contain drugs inside, the explosive release of drugs when the hemostatic cotton is completely degraded is avoided. In addition, it should be understood that the 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 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. Of course, those skilled in the art can also set the hemostatic cotton with a single-sided drug layer according to actual usage, which is also within the protection scope of the present invention. Preferably, in step S5, 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 -35°C to 30°C.

[0083] Preferably, the freeze-drying process is layered freeze-drying, and the thickness ratio of the drug-carrying layer to the polyurethane layer is 1:2-1:5. Preferably, the ratio of the thickness of the first drug-carrying layer or the second drug-carrying layer to the thickness of the 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 is released explosively when the hemostatic cotton is degraded. Preferably, the thickness ratio of the first drug-carrying layer to the second drug-carrying layer is preferably 1:1. The thickness of the first drug-carrying layer or the second drug-carrying layer is preferably 1-3mm. Of course, the thickness can be set according to the actual situation, such as 4mm, 5mm, etc.

[0084] The third method is to add the drug to the solution after the drug is dissolved, and the step S6 is:

[0085] The polyurethane polymer prepared in S4 is dissolved in dioxane and placed in a mold, and then frozen, dried, and sterilized to obtain a polyurethane sponge; a drug is dissolved in a good solvent to form a drug solution, 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 so that the drug is adsorbed in the pores of the polyurethane sponge;

[0086] Preferably, 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.

[0087] Preferably, the poor solvent is one or more of water, n-hexane, cyclohexane, and cyclopropanone. The poor solvent is preferably cyclohexane.

[0088] Preferably, the benign solvent should be miscible with the poor solvent, and the boiling point of the benign solvent is lower than that of the poor solvent. Since the benign solvent and the poor solvent are immiscible and cannot form a uniform solution, the benign solvent should evaporate first, and the proportion of the benign solvent in the formed azeotrope should be greater than that of the poor solvent to avoid the concentration of the benign solvent becoming higher and higher until it dissolves and destroys the sponge.

[0089] Preferably, the concentration of the drug in the benign solvent is 0.5 mg / ml-10 mg / ml.

[0090] Preferably, in the mixed solution, the ratio (volume ratio, mass ratio or molar ratio) of good solvent to poor solvent 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.

[0091] Preferably, 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.

[0092] Specifically, 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.

[0093] Preferably, the drug includes at least one of anti-inflammatory drugs, antibacterial drugs, analgesics, hemostatic drugs or antiallergic drugs. Preferably, 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 antiallergic drugs can be used for nasal administration, such as levocabastine hydrochloride, ketotifen fumarate, beclomethasone propionate, mometasone furoate, budesonide, fluticasone propionate. The drug can also be a cilia 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. Preferably, the glucocorticoid drugs include mometasone furoate or budesonide, etc., and the solubility of the drug solution is 5-30ug / mL. In this way, the inflammation problem caused by postoperative bacterial infection is solved, the healing of wounds is accelerated, and the adhesion problem of the wound site can be avoided. Preferably, 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‰ of the polyurethane polymer, and a safe drug loading ratio is ensured under the condition of ensuring drug loading, so as to achieve a sustained release effect.

[0094] Preferably, Figure 3 As shown, the drug is slowly released, and the drug release rate is greater than 70% in the first 3 days of degradation; preferably, the drug release rate is greater than 50% in the first 1.5 days of degradation; preferably, the drug release rate is greater than 20% in the first 0.5 days of degradation. It can be seen that the drug sustained release rate of the drug-loaded polyurethane polymer of this embodiment is large. After being placed in the target position, it can realize the release of the drug before the polyurethane polymer degrades, which is convenient for drug administration, improves the drug efficacy, and then facilitates wound healing and prevents the occurrence of adhesion.

[0095] Preferably, the compression strength of the polyurethane sponge in dry and wet states is greater than 10 kPa, and the rebound rate is greater than 98%; preferably, the compression strength and rebound rate of the polyurethane sponge in wet state are greater than those in dry state. It can be seen that the polyurethane polymer of this embodiment connects PEG to the molecular chain in a block manner, and avoids the shedding of PEG, thereby ensuring the integrity of the skeleton of the polyurethane polymer formed by the molecular chain.

[0096] Preferably, the porosity of the polyurethane sponge is greater than 90%. Preferably, the water absorption rate of the polyurethane sponge is greater than 1860%. Preferably, the water absorption time of the polyurethane sponge is less than 33 seconds. The polyurethane polymer of this embodiment can improve hydrophilicity, thereby increasing the degradation rate of polyurethane.

[0097] Preferably, the size of the hemostatic cotton is length*width*thickness=80mm*20mm*15mm, and the size of the hemostatic cotton can be cut to a suitable size for use. The first drug-carrying layer, the polyurethane layer, and the second drug-carrying layer are arranged in sequence along the thickness direction. Preferably, the material of the mold includes but is not limited to aluminum, polytetrafluoroethylene, polyoxymethylene, etc., and the shape is 80mm*20mm*15mm, with semicircular grooves with a diameter of 1 cm at both ends.

[0098] Preferably, the freeze-drying process of the polyurethane polymer obtained by S4 is as follows: the polyurethane polymer is dissolved in a solvent to form a freeze-dried liquid, a portion of the freeze-dried liquid is poured into a mold and frozen at 0°C, and then the remaining freeze-dried liquid is added, and then frozen at a temperature below zero and transferred to a freeze dryer for freeze drying. This design is because after part of the freeze-dried liquid is introduced into the mold, there will be a collapse during the freezing process, resulting in an uneven surface of the prepared polyurethane sponge, and even burrs. In order to avoid such a situation, pre-freezing is performed in advance, and after pre-freezing, the remaining freeze-dried liquid is poured in, and the remaining freeze-dried liquid covers the uneven surface, thereby ensuring that the surface of the polyurethane sponge is flat. Preferably, in the freeze-dried liquid, the first portion of the freeze-dried liquid poured is 3 / 4 of the original freeze-dried liquid, and the remaining freeze-dried liquid level is 1 / 4 of the original freeze-dried liquid, thereby ensuring that the remaining freeze-dried liquid can cover the uneven surface of the pre-frozen product.

[0099] This embodiment uses three different drug adding methods to form drug-loaded hemostatic cotton with different drug loading mechanisms, different release rates, and different properties.

[0100] This embodiment provides an application of hemostatic cotton, which is used for filling and stopping bleeding in the nasal sinus or cavity, ear canal, oral cavity, urethra or tissue cavity of human or animal body. Alternatively, the drug-loaded hemostatic cotton is used for space-occupying and compression hemostasis. Alternatively, the hemostatic cotton is used in surgical operations. Preferably, the hemostatic cotton is used in otolaryngology operations. The beneficial effects of the application of the hemostatic cotton can refer to the beneficial effects of the above-mentioned polyurethane polymer, polyurethane sponge, and drug-loaded polyurethane, which will not be described here.

[0101] This embodiment also provides a drug sustained release system, which includes the drug-loaded hemostatic cotton. The characteristics and description of the drug sustained release system can refer to the technical explanations commonly used by those skilled in the art, and will not be described in detail herein. The beneficial effects of the drug sustained release system can refer to the beneficial effects of the drug-loaded hemostatic cotton, which will not be described herein.

[0102] The technical solution of the embodiment of the present invention is described in detail below through Examples 1 to 3 and a comparative example.

[0103] [Example 1]

[0104] Preparation of polyurethane:

[0105] In the step S1, 25.0 g of polyethylene glycol 1000 is accurately weighed and added to a 250 mL vacuum reaction bottle, and vacuumed continuously for 2 h at 100 ° C with a vacuum oil pump to remove water. After the water removal is completed, it is cooled to below 70 ° C, and 12.5 g of D, L-lactide, 12.5 g of ε-caprolactone, and 0.025 g of stannous isooctanoate are added in sequence, and vacuumed for 3 minutes, and then heated to 130 ° C. After reacting for 14 days, it is directly used for subsequent reactions without post-treatment.

[0106] In step S2, the three-necked flask was fixed in an 80°C oil bath for preheating, 19.5 g of 1,4-butanediol (BDO) was added, 6 g of hexamethylene diisocyanate was added dropwise under mechanical stirring, and the mixture was sealed for reaction for 3 hours, and a white precipitate was gradually generated. After cooling to room temperature, the mixture was fully washed and stirred with 400 mL of anhydrous acetone, filtered, and repeated 3 times, and then dried at 45°C for 3 hours using a rotary evaporator to obtain a pure white solid powder (BHB).

[0107] In the steps S3 and S4, 5.05 g (30 mmol) of hexamethylene diisocyanate was added to a three-necked flask, 80 g (20 mmol) of polyethylene glycol (Mn=4000) after vacuum dehydration was added dropwise, 0.05 g of stannous octoate was added, and the reaction was continued at 80°C for 3.5 hours, and the NCO was measured by the di-n-butylamine method to reach the theoretical value. 10 g (5 mmol) of the prepolymer prepared in step S1 was added dropwise, and the reaction was continued at 80°C. During the reaction, the mixture gradually became viscous. After 2 hours, 11.6 mL of a DMF solution of BHB (0.15 g / mL) was added dropwise, and the reaction was continued at 80°C for 2 hours, and then the infrared was measured to the NCO characteristic peak (2300 cm -1 ) disappears, stop the reaction and cool to room temperature, add dioxane to dilute to 20%, slowly pour into the stirring icy ether in a thin stream while hot, and precipitate a filamentous tough and transparent solid. After evaporation, dry it in an oven at 40°C for 10 hours to obtain a transparent filamentous solid, which is a polyurethane polymer.

[0108] Preparation of drug-loaded hemostatic cotton:

[0109] In the step S5, the polymer is dissolved in dioxane to prepare a lyophilized liquid with a concentration of 3.0%, 20 ml is first poured into a polypropylene mold, then 5 ml of the lyophilized liquid is added after freezing at 0°C, and then frozen at -20°C and transferred to a lyophilizer for lyophilization to obtain a blank sponge. 5 mg of mometasone furoate is added to 500 mL of n-hexane, ultrasonically dispersed to a suspension with a particle size of 1-3 um, the lyophilized sponge sample is added to the suspension, rotated for 30 seconds, fished out and dried to constant weight to obtain a degradable drug-loaded hemostatic sponge recorded as M1.

[0110] [Example 2]

[0111] Obtain the corresponding blank sponge according to the method in Example 1.

[0112] Preparation of drug-loaded hemostatic cotton:

[0113] Dissolve budesonide in acetone to prepare a 1.5 mg / ml drug solution, then dilute it with n-hexane to 0.15 mg / ml, use a pipette to drop 1 ml on the upper and lower surfaces of the blank sponge, transfer it to a vacuum drying oven and dry it to constant weight to obtain degradable drug-loaded cotton, recorded as M2.

[0114] [Example 3]

[0115] The corresponding polymer was obtained according to the method in Example 1.

[0116] Preparation of drug-loaded hemostatic cotton:

[0117] In step S5, two liquids A and B are respectively prepared, wherein liquid A is a 3.0% polyurethane polymer dioxane solution containing mometasone furoate, wherein the content of mometasone furoate is 0.30‰ of the polyurethane polymer. Liquid B is a 3.0% polyurethane polymer dioxane solution. A layer of liquid A is first poured into the mold, and then 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 to obtain a degradable drug-loaded hemostatic sponge, which is recorded as M3.

[0118] [Example 4]

[0119] Preparation of polyurethane:

[0120] In the step S1, 25.0 g of polyethylene glycol 2000 is accurately weighed and added to a 250 mL vacuum reaction bottle, and vacuumed continuously for 2 h at 100 ° C with a vacuum oil pump to remove water. After the water is removed, it is cooled to below 60 ° C, 15 g of L-lactide, 20.0 g of ε-caprolactone, and 0.03 g of stannous isooctanoate are added in sequence, and vacuumed for 3 minutes, and then the temperature is raised to 135 ° C. After reacting for 10 days, it is directly used for subsequent reactions without post-treatment.

[0121] In step S2, the three-necked flask was fixed in a 75°C oil bath for preheating, 20 g of 1,4-butanediol (BDO) was added, 6 g of hexamethylene diisocyanate was added dropwise under mechanical stirring, and the mixture was sealed for reaction for 3.5 hours, and a white precipitate was gradually generated. After cooling to room temperature, the mixture was fully washed with 500 mL of anhydrous acetone, stirred, and filtered, and the mixture was repeated 3 times and then dried at 40°C for 3 hours using a rotary evaporator to obtain a pure white solid powder (BHB).

[0122] In the steps S3 and S4, 5.55 g (25 mmol) of isophorone diisocyanate was added to a three-necked flask, 60 g (10 mmol) of polyethylene glycol (Mn=6000) after vacuum dehydration was added dropwise, 0.05 g of stannous octoate was added, and the reaction was continued at 85° C. for 3 h until the NCO reached the theoretical value by using the di-n-butylamine method, 36 g (7.5 mmol) of the prepolymer prepared in step S1 was added dropwise, and the reaction was continued at 80° C. The mixture gradually became viscous during the reaction, and 13.05 mL of a DMF solution of BHB (0.2 g / mL) was added dropwise after 2.5 h, and the reaction was continued at 80° C. for 2.5 h, and then the infrared was measured to the NCO characteristic peak (2300 cm -1 ) disappears, stop the reaction and cool to room temperature, add dioxane to dilute to 25%, slowly pour in a thin stream into the stirring icy ether while hot, precipitate a tough and transparent thread-like solid, take it out and evaporate naturally, then dry it in an oven at 40°C for 10 hours to obtain a transparent thread-like solid which is a polyurethane polymer.

[0123] Preparation of drug-loaded hemostatic cotton:

[0124] In the step S5, the polymer is dissolved in dioxane to prepare a lyophilized liquid with a concentration of 3.5%, 17 ml of the lyophilized liquid is first poured into a polypropylene mold, then 8 ml of the lyophilized liquid is added after freezing at 0°C, and then the lyophilized liquid is transferred to a lyophilizer for lyophilization after freezing at -20°C. 5 mg of mometasone furoate is added to 400 mL of n-hexane, ultrasonically dispersed into a suspension with a particle size of 1-2 um, the lyophilized sponge sample is added, rotated for 60 seconds, and then removed and dried to constant weight to obtain a degradable drug-loaded hemostatic sponge, recorded as M4.

[0125] [Example 5]

[0126] Obtain the corresponding blank sponge according to the method in Example 4.

[0127] Preparation of drug-loaded hemostatic cotton:

[0128] Budesonide was dissolved in ethyl acetate to prepare a 2.0 mg / ml drug solution, then diluted with cyclohexane to 0.1 mg / ml, 1.5 ml was added to the upper and lower surfaces of the blank sponge respectively using a pipette, and the solution was transferred to a vacuum drying oven and dried to constant weight to obtain a degradable drug-loaded cotton, recorded as M5.

[0129] [Example 6]

[0130] The corresponding polymer was obtained according to the method in Example 4.

[0131] Preparation of drug-loaded hemostatic cotton:

[0132] In step S5, two liquids A and B are respectively prepared, wherein liquid A is a 3.5% polyurethane polymer dioxane solution containing mometasone furoate, wherein the content of mometasone furoate is 0.50‰ 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 to obtain a degradable drug-loaded hemostatic sponge, which is recorded as M6.

[0133] [Example 7]

[0134] Preparation of polyurethane:

[0135] In the step S1, 30.0 g of polyethylene glycol 3000 is accurately weighed and added to a 250 mL vacuum reaction bottle, and vacuumed continuously for 2 h at 100 ° C with a vacuum oil pump to remove water. After the water is removed, it is cooled to below 60 ° C, and 25 g of L-lactide, 20.0 g of ε-caprolactone, and 0.03 g of stannous isooctanoate are added in sequence, and vacuumed for 3 minutes, and then heated to 135 ° C. After reacting for 10 days, it is directly used for subsequent reactions without post-treatment.

[0136] In step S2, the three-necked flask was fixed in a 75°C oil bath for preheating, 20 g of 1,4-butanediol (BDO) was added, 6 g of hexamethylene diisocyanate was added dropwise under mechanical stirring, and the mixture was sealed for reaction for 3.5 hours, and a white precipitate was gradually generated. After cooling to room temperature, the mixture was fully washed with 500 mL of anhydrous acetone, stirred, and filtered, and the mixture was repeated 3 times and then dried at 40°C for 3 hours using a rotary evaporator to obtain a pure white solid powder (BHB).

[0137] In the steps S3 and S4, 5.55 g (25 mmol) of isophorone diisocyanate was added to a three-necked flask, 60 g (10 mmol) of polyethylene glycol (Mn=6000) after vacuum dehydration was added dropwise, 0.05 g of stannous octoate was added, and the reaction was continued at 85° C. for 3 h until the NCO reached the theoretical value by using the di-n-butylamine method, 37.5 g (5 mmol) of the prepolymer prepared in step S1 was added dropwise, and the reaction was continued at 80° C. The mixture gradually became viscous during the reaction, and 17.4 mL of a DMF solution of BHB (0.2 g / mL) was added dropwise after 2.5 h, and the reaction was continued at 80° C. for 2.5 h, and then the infrared was measured to the NCO characteristic peak (2300 cm -1) disappeared, stop the reaction and cool to room temperature, add dioxane to dilute to 25%, slowly pour in a thin stream into the stirring icy ether while hot, and precipitate a tough and transparent filamentous solid. After natural evaporation, dry it in an oven at 40°C for 10 hours to obtain a transparent filamentous solid, which is a polyurethane polymer, recorded as DPU-3.

[0138] Preparation of drug-loaded hemostatic cotton:

[0139] In the step S5, the polymer is dissolved in dioxane to prepare a lyophilized liquid with a concentration of 4.0%, 22 ml is first poured into a polypropylene mold, then 3 ml of the lyophilized liquid is added after freezing at 0°C, and then frozen at -25°C and transferred to a lyophilizer for lyophilization. 10 mg of mometasone furoate is added to 400 mL of n-hexane, ultrasonically dispersed into a suspension with a particle size of 2-3 um, the lyophilized sponge sample is added, rotated for 60 seconds, and then fished out and dried to constant weight to obtain a degradable drug-loaded hemostatic sponge, recorded as M7.

[0140] [Example 8]

[0141] Obtain the corresponding blank sponge according to the method in Example 7.

[0142] Preparation of drug-loaded hemostatic cotton:

[0143] Budesonide was dissolved in ethyl acetate to prepare a 2.0 mg / ml drug solution, then diluted with n-hexane to 0.1 mg / ml, 1.5 ml was added to the upper and lower surfaces of the blank sponge respectively using a pipette, and the solution was transferred to a vacuum drying oven and dried to constant weight to obtain a degradable drug-loaded cotton, recorded as M8.

[0144] [Example 9]

[0145] The corresponding polymer was obtained according to the method in Example 7.

[0146] Preparation of drug-loaded hemostatic cotton:

[0147] In step S5, two liquids A and B are respectively prepared, wherein liquid A is a 4.0% polyurethane polymer dioxane solution containing mometasone furoate, wherein the content of mometasone furoate is 1.0‰ of the polyurethane polymer. Liquid B is a 4.0% 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 to obtain a degradable drug-loaded hemostatic sponge, which is recorded as M9.

[0148]

Comparison example

[0149] 1.68g hexamethylene diisocyanate was added dropwise to 20.0g polycaprolactone diol (Mn=2000), 0.01g stannous octoate was added dropwise, reacted at 80°C for 2.5h, then dioxane was added to dilute to 20%, slowly poured into ice ether to settle to a filamentous solid and dried to constant weight to obtain polyurethane (TPU). TPU was dissolved in 200mL dioxane to prepare a 3.5% TPU solution, 1.6mg mometasone furoate and 1.4g polyethylene glycol (Mn=6000) were added, and a lyophilized solution was obtained after stirring and dissolving. 25mL of lyophilized solution was added to a polytetrafluoroethylene mold, frozen at -25°C, and then transferred to a lyophilizer for treatment to obtain a control hemostatic sponge DBM.

[0150] Performance Testing

[0151] Porosity: Pre-weighed hemostatic cotton is immersed in a known volume (V1) of water and degassed with a vacuum pump for 5 minutes. The total volume of water and the water-soaked sponge is recorded as (V2), and the water-soaked sponge is removed and the residual volume of water is recorded as (V3); the porosity (a) of the sponge is calculated as follows:

[0152] (a)%=(V1-V3) / (V2-V3)×100%.

[0153] The water absorption performance indirectly reflects the effect of the hemostatic cotton on hemostasis. The specific test method of the water absorption performance is: weigh the freeze-dried 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 parallel three times. The specific test results are shown in Table 1.

[0154] Table 1

[0155]

[0156] As can be seen from Table 1, the porosity of the samples in the embodiment can be maintained above 90%, and they have good air permeability and higher resilience when used. In addition, as the concentration of polymer in the freeze-dried liquid increases, the porosity decreases slightly, indicating that the porosity of the sample is mainly affected by the concentration of the freeze-dried liquid; the higher the concentration, the higher the content of polymer under the same volume, occupying more space, resulting in a decrease in porosity. The porosity of TDM is comparable to that of TDM, but the water absorption rate and water absorption rate are significantly reduced, which shows that the effect of introducing hydrophilic segments by chemical means is better than that of physical blending.

[0157] Compression performance: The sample prepared in the embodiment is placed between the upper and lower compression plates, and the sample is slowly compressed to 50% of the original height. After 1 minute, 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. Record the dry state result; after the test is completed, the sample is immersed in purified water to completely soak, and the surface water stains are wiped off and the compression test is performed in the same way, and the wet state result is recorded. The test results are shown in Table 2.

[0158] Table 2

[0159]

[0160] According to Table 2, it can be found that the compression strength of the hemostatic cotton is above 10kPa, the rebound rate is greater than 95%, and as the concentration of the lyophilized liquid increases, the compression strength gradually increases, which can provide better effects for compression hemostasis. However, it is worth noting that the test results in the wet state are slightly improved compared to the dry state, and TDM changes the original framework structure of the sponge because the physically blended PEG dissolves in water, resulting in a significant decrease in the compression strength and rebound rate in the wet state, which is not conducive to clinical application. This shows that the introduction of PEG by chemical means in the embodiment not only increases the hydrophilicity of the material, but also makes PEG become a polyurethane segment as a whole, avoiding the problems of PEG falling off or dissolving, and improving the stability of the product.

[0161] Degradation performance: The samples prepared in the examples were placed in a phosphate buffer solution (PBS, pH=7.4) and placed in a 37.3°C constant temperature shaker (this test simulates human tissue fluid). The stress values ​​when the samples were compressed to 50% were tested and recorded at regular intervals. The results are shown in Table 1. Figure 2 shown.

[0162] The sponge prepared in the example can be initially degraded within 3 hours, and its compression strength is reduced to less than 50%. It breaks after compression, and its value gradually decreases with the extension of degradation time, and finally tends to be stable under the influence of water surface tension, and the sponge is completely broken by slight vibration after 24 hours of degradation. The degradation rate of the comparative example DBM is relatively slow, and it still maintains a certain resilience after being compressed for 24 hours of degradation. This shows that compared with the physical blending method to introduce hydrophilic segments, the chemical method can accelerate degradation. In short, the degradation rate of the degradable medical hemostatic cotton prepared in the example is fast, and it is completely degraded within 3 to 6 hours in vitro. It can be completely removed by a suction device after surgery, which can greatly shorten the patient's discomfort time.

[0163] Drug Release:

[0164] 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 as follows: Figure 3 As shown. From the release results, the drug loading method has a significant effect on the drug release results. The drug-loaded cotton prepared by the mixed selection absorption method or the solvent evaporation method can make the drug distributed on the outer surface of the sponge. In the early stage of drug release, it mainly relies on diffusion, so the release is faster, which is conducive to rapid drug administration after surgery to prevent inflammation and infection; in the layered freeze-drying drug addition method, the drug is embedded in the outer surface and slowly released with degradation, which can be released linearly and evenly; while the mixed freeze-drying drug loading method of the comparative example DBM easily makes the drug physically embedded in the polymer, and can only be gradually released by slow degradation, but there are still a lot of drugs remaining in the sponge. With the occurrence of degradation, it will burst at a certain moment, which is easy to cause poisoning reactions.

[0165] The above description is only a description of the preferred embodiments of the present invention, and is not intended to limit the scope of the present invention. Any changes or modifications made by a person skilled in the art in the field of the present invention based on the above disclosure shall fall within the scope of protection of the claims.

Claims

1. A method for preparing a polyurethane polymer, characterized in that: include: S1: In an anhydrous and oxygen-free environment, with polyethylene glycol as the initiator, cyclic ester monomers undergo a ring-opening reaction under the action of a catalyst to synthesize polyester prepolymers; S2: In an anhydrous and oxygen-free environment, a dihydroxy compound reacts with a diisocyanate to obtain a hydroxyl-terminated triblock compound after purification and drying; S3: In an anhydrous and oxygen-free environment, diisocyanate and polyethylene glycol undergo a condensation reaction under the action of a catalyst to prepare an isocyanate-terminated polyurethane prepolymer; S4: adding the polyester prepolymer prepared in S1 to the polyurethane prepolymer prepared in S3, and then adding the dimethylformamide solution of the hydroxyl-terminated triblock compound prepared in S2, continuing the reaction, purifying and drying to obtain a polyurethane polymer.

2. The method for preparing a polyurethane polymer according to claim 1, characterized in that: The method further comprises step S5: obtaining drug-loaded polyurethane by absorbing drugs, namely, first freezing and drying the polyurethane polymer obtained in S4 into a polyurethane sponge, and adsorbing the drugs into the pores of the polyurethane sponge through the pressure difference between the polyurethane sponge and the drug solvent or drug environment.

3. The method for preparing a polyurethane polymer according to claim 2, characterized in that: Ways to take the drug include: The method of absorbing the drug by suspension is adopted, that is, the drug is made into a suspension in a poor solvent, the polyurethane sponge is put into the suspension under stirring, and after stirring, it is fished out and dried; Alternatively, the drug is adsorbed under negative pressure, that is, the polyurethane sponge is placed in a container, the air pressure in the container is lower than the pressure of the environment in which the drug is located, and the drug is adsorbed into the pores of the polyurethane sponge; Alternatively, a method combining negative pressure adsorption and suspension adsorption is adopted, that is, the polyurethane sponge is firstly compressed to squeeze out the air in its pores, and then the compressed polyurethane sponge is placed in the suspension, and then taken out and dried.

4. The method for preparing a polyurethane polymer according to claim 3, characterized in that: In the method of absorbing the drug by suspension, the stirring time is 10 seconds; Preferably, the particle size of the drug is 0.5um-3um; Preferably, the poor solvent is at least one of n-hexane, cyclohexane and diethyl ether.

5. The method for preparing a polyurethane polymer according to any one of claims 2 to 4, characterized in that: The drug includes at least one of an anti-inflammatory drug, an antibacterial drug, an analgesic drug, a hemostatic drug or an antiallergic drug; Preferably, the anti-inflammatory drugs include glucocorticoid drugs, or the antibacterial drugs include penicillins, cephalosporins and the like, or the analgesic drugs include ibuprofen; Preferably, the glucocorticoid drugs include mometasone furoate or budesonide; Preferably, the solution solubility of the drug is 5-30ug / mL; Preferably, the drug is slowly released, and the drug release rate is greater than 70% in the first 3 days of degradation; preferably, the drug release rate is greater than 50% in the first 1.5 days of degradation; preferably, the drug release rate is greater than 20% in the first 0.5 days of degradation; Preferably, the compression strength of the polyurethane sponge in dry and wet states is greater than 10 kPa, and the rebound rate is greater than 98%; Preferably, the compression strength and rebound rate of the polyurethane sponge in wet state are greater than those in dry state; Preferably, the porosity of the polyurethane sponge is greater than 90%; Preferably, the water absorption rate of the polyurethane sponge is greater than 1860%; Preferably, the water absorption time of the polyurethane sponge is less than 33 seconds; Preferably, in step S1, the cyclic ester monomer is one or more of DL-lactide, L-lactide, glycolide, caprolactone, trimethylene carbonate, and p-dioxanone; Preferably, in step S1, the cyclic ester monomer is one or more of glycolide, lactide and caprolactone; Preferably, in step S1, the molecular weight of the polyethylene glycol (PEG) is 1000-4000; Preferably, in step S1, the molecular weight of the polyethylene glycol is 1500-2000; Preferably, in step S1, the mass ratio of polyethylene glycol to cyclic ester monomer is 1:1-1:1.5; Preferably, in step S1, the catalyst is a tin catalyst, and the mass of the catalyst is 0.05% to 0.1% of the total mass of the reactants; Preferably, the reaction temperature in step S1 is 120°C to 140°C; the reaction time is 7 to 14 days; Preferably, in step S2, the diisocyanate compound is one or more of hexamethylene diisocyanate, isophorone diisocyanate, and methylcyclohexyl diisocyanate; Preferably, in step S2, the diisocyanate compound is hexamethylene diisocyanate, and the dihydroxy compound is preferably 1,4-butanediol; Preferably, in step S2, the molar ratio of diisocyanate to dihydroxy compound is 1:6 to 1:8; Preferably, in step S2, the reaction temperature is 70°C to 90°C; the reaction time is 4 to 6 hours; Preferably, in step S2, the separation and purification process is: washing the crude product obtained after the reaction with a large amount of acetone, stirring continuously during the washing process until the product is completely dispersed into a solid powder, filtering with suction, washing with acetone again, 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; Preferably, in step S3, the molecular weight of the polyethylene glycol is 4000 to 20000; Preferably, in step S3, the molecular weight of the polyethylene glycol is 8000 to 10000; Preferably, in step S3, the molar ratio of the polyethylene glycol to the diisocyanate is 1:1.5 to 1:3.0; more preferably 1:2.0; Preferably, in step S3, the reaction endpoint of the polyurethane prepolymer is when the isocyanate (-NCO) in the solution detected by the di-n-butylamine method reaches a theoretical value; Preferably, in step S3, the amount of polyester prepolymer added is such that the molar ratio of hydroxyl group to residual isocyanate group is 1:1.5 to 1:2; Preferably, after adding the polyester prepolymer in step S3, the reaction temperature is 75°C to 85°C, and the reaction time is 4 to 5 hours; Preferably, in step S4, the amount of the hydroxyl-terminated triblock compound added is such that the molar ratio of hydroxyl to residual isocyanate (-NCO) is 1:1.0; Preferably, in step S4, the mass solubility of the dimethylformamide solution of the hydroxyl-terminated triblock compound is 0.125 to 0.25 g / mL; Preferably, in step S4, the polymerization temperature after adding the hydroxyl-terminated triblock compound in step S4 is 75-90° C., and the reaction time is 1 to 2 hours.

6. The method for preparing a polyurethane polymer according to claim 1, characterized in that: The steps S51, S52 and S53 are also included: obtaining drug-loaded polyurethane by freeze-drying and adding drugs; S51: dissolving the polyurethane polymer and the drug prepared in S4 and placing them in a mold, and performing post-treatment to obtain a first drug-carrying layer; the post-treatment at least includes freezing and drying; S52: dissolving the polyurethane polymer prepared in S4 and placing it in the mold, and obtaining a polyurethane layer through post-processing, wherein the polyurethane layer is superimposed on the first drug-carrying layer; S53: The polyurethane polymer and drug prepared in S4 are dissolved and placed in a mold, and after post-processing, a second drug-carrying layer is obtained. The second drug-carrying layer is superimposed on the polyurethane layer to obtain a polyurethane sponge, so that the polyurethane sponge includes the first drug-carrying layer, the polyurethane layer, and the second drug-carrying layer in sequence.

7. The method for preparing a polyurethane polymer according to claim 6, characterized in that: The freeze-drying process of the polyurethane polymer prepared by S4 is as follows: the polyurethane polymer is dissolved in a solvent to prepare a freeze-dried liquid, a portion of the freeze-dried liquid is poured into a mold and frozen at 0°C, and then the remaining freeze-dried liquid is added, and then the freeze-dried liquid is frozen at sub-zero temperature and transferred to a freeze dryer for freeze drying.

8. The method for preparing a polyurethane polymer according to claim 1, characterized in that: The method further includes step S6: dissolving the polyurethane polymer prepared in S4 with dioxane and placing the mixture in a mold, freezing, drying, and sterilizing the mixture to obtain a polyurethane sponge; dissolving a 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 the mixture so that the drug is adsorbed in the pores of the polyurethane sponge; Preferably, the benign solvent is one or more of acetonitrile, methanol, dioxane, dichloromethane, ethyl acetate, acetone, dimethyl sulfoxide, and dimethylformamide; Preferably, the benign solvent is miscible with the poor solvent, and the boiling point of the benign solvent is lower than the boiling point of the poor solvent; Preferably, the poor solvent is one or more of water, n-hexane, cyclohexane, and cyclopropanone; Preferably, the concentration of the drug in the benign solvent is 0.5 mg / ml-10 mg / ml; Preferably, in the mixed solution, the volume ratio, mass ratio or molar ratio of the good solvent to the poor solvent is 1:4-1:49, and the dilution factor is 5-50 times; preferably, the concentration of the mixed solution of the drug is 0.01 mg / ml-2 mg / ml.

9. A hemostatic cotton, characterized in that: The hemostatic cotton is obtained by the preparation method of the polyurethane polymer according to any one of claims 1 to 8.

10. The hemostatic cotton according to claim 9, characterized in that: It is used for filling and stopping bleeding in the nasal sinus or cavity, ear canal, oral cavity, urethra or tissue cavity of human or animal body; or, the drug-loaded hemostatic cotton is used for occupying space and compressing bleeding; or, the hemostatic cotton is used in surgical operation; preferably, the hemostatic cotton is used in otolaryngology operation.

11. A drug sustained-release system, characterized in that: The drug sustained-release system comprises the drug-loaded hemostatic cotton obtained by absorbing the drug or freeze-drying and adding the drug according to any one of claims 9 to 10.

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