Drug-loaded hemostatic cotton, and preparation method therefor and drug sustained-release system

Abstract

Provided in the present invention are drug-loaded hemostatic cotton, and a preparation method therefor and a drug sustained-release system. The drug-loaded hemostatic cotton comprises a porous sponge and a drug loading layer, wherein the porous sponge has a compression strength of greater than 3 Kpa and a resilience rate of greater than 80%, and the porous sponge has a hemostatic effect by means of compressing capillaries. In addition, the porous sponge can also absorb and store exuded blood, thereby allowing for platelet aggregation in blood. Therefore, a drug-loaded hemostatic cotton having a good hemostatic effect, a short degradation time, good mechanical properties, a good safety and low costs is obtained.

Description

Drug-loaded hemostatic cotton, preparation method of drug-loaded hemostatic cotton and drug sustained-release system Technical Field

[0001] 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 applications thereof. Background Art

[0002] Bleeding during surgery is a common clinical symptom, and otolaryngology surgery is one of the most common medical surgical procedures. Taking otolaryngology surgery as an example, these bleeding sites are deep, confined, and surrounded by a large number of capillaries, making them difficult to suture after surgery. Clinically, compression hemostasis using gauze and expandable sponges can effectively reduce bleeding and accelerate wound healing. However, the extraction process causes secondary damage, leading to secondary infection and, more importantly, causing unbearable pain for the patient, even leading to collapse and shock. Therefore, how to effectively and quickly stop bleeding after surgery has become a research hotspot for many scholars.

[0003] Hemostatic cotton is currently a relatively effective method for rapid hemostasis. However, due to problems such as low compression strength and poor rebound rate, drug-loaded hemostatic cotton cannot perform conformal compression and hemostasis in narrow cavities, nor can it simultaneously meet the problem of blood storage and prevention of blood leakage. At the same time, the degradation rate is difficult to control, and it is not possible to achieve both compression and hemostasis and effective degradation. In addition, there are no drug-loaded hemostatic cotton on the market, and it is not possible to achieve drug delivery while performing compression and hemostasis. These problems urgently require technical personnel to develop new products to solve existing problems.

[0004] Currently, the preparation method for hemostatic cotton involves first preparing a polyurethane polymer, dissolving the resulting polyurethane polymer in dioxane and chitosan aqueous solution, and then freeze-drying the mixture. Another method also involves pre-preparing a polyurethane polymer, mixing a polyurethane solution with a foaming agent, and then freeze-drying and sterilizing the resulting hemostatic sponge. However, the hemostatic cotton produced by these methods has the following problems: 1) Side effects are common and chemical residues are high, thus affecting the clinical safety of the cotton. 2) The hemostatic cotton produced by these methods degrades slowly and over an uncontrollable timeframe, typically exceeding three days. Once the cotton is placed at the target site, it fails to degrade promptly, resulting in a prolonged retention period at the hemostatic site. This process completely blocks the narrow lumen at the site, prolonging the patient's suffering. Although some degradation occurs, the slow degradation also hinders lumen cleaning. While hemostasis is typically complete within 48 hours, prolonged retention of the cotton in the body can hinder wound healing. 3) The hemostatic cotton produced by these methods has weak mechanical properties, resulting in poor compression and hemostasis effectiveness and poor adhesion prevention. 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.

[0005] Therefore, it is an urgent problem to develop a hemostatic cotton that has good hemostatic effect, high clinical safety, short degradation time, good mechanical properties, can achieve drug sustained release, and low cost.

[0006] Summary of the Invention

[0007] 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 hemostatic cotton such as poor hemostatic effect, poor clinical safety, long degradation time, poor mechanical properties, inability to slowly release drugs and high cost.

[0008] In order to solve the above technical problems, the present invention provides a drug-loaded hemostatic cotton, which is used in the ear, nose, and throat cavities. 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 capillaries. At the same time, the porous sponge can also absorb and store exuded blood, causing platelets in the blood to aggregate; the drug-loaded layer is arranged in at least one of the outer layer, middle layer or inner layer of the porous sponge, and the drug-loaded layer contains drugs.

[0009] Optionally, the water absorption rate of the drug-loaded hemostatic cotton is greater than 500%; the content of PEG chains 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.

[0010] Optionally, 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.

[0011] Optionally, the porous sponge is made of at least one of polyurethane, gelatin, chitosan, sodium hyaluronate, and collagen.

[0012] Optionally, the drug includes at least one of anti-inflammatory drugs, antibacterial drugs, analgesics, hemostatic drugs or anti-allergic 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 anti-allergic drugs preferably include ebastine, loratadine, and acrivastine.

[0013] Optionally, when the drug-loaded hemostatic cotton is used in the nasal cavity, the drug loading amount of each piece of drug-loaded hemostatic cotton is 100ug~1000ug / g; preferably, it can be 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1000ug / g.

[0014] 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 the drug-loaded hemostatic cotton comprises:

[0015] 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, wherein the polyethylene glycol has an average molecular weight of 800-1500;

[0016] S2: mixing a diisocyanate compound and a polyol compound, reacting them at a certain temperature, and then separating and purifying them to prepare an isocyanate-terminated triblock compound, wherein the molar ratio of the polyol compound to the diisocyanate compound is 1:4 to 1:10;

[0017] S3: dissolving the isocyanate-terminated triblock compound prepared in S2 in an organic solvent and reacting with the polyester prepolymer prepared in S1 at a certain feed ratio, and using a poor solvent for precipitation. After precipitation, the polyurethane polymer is dried to a constant weight without water precipitation or alcohol soaking treatment;

[0018] Wherein, step S4 is S4-1: dissolving the polyurethane prepared in S3 and the drug in an organic solvent and placing them in a mold, and obtaining the drug-loaded hemostatic cotton after freezing, drying, and sterilization;

[0019] Alternatively, step S4 is S4-2: the polyurethane polymer prepared in S3 is dissolved in dioxane and placed in a mold, and freeze-dried to obtain a blank sponge without the drug; the drug is dispersed in a poor solvent to form a suspension, the blank sponge is placed in the suspension under stirring, and after stirring, the blank sponge is removed and dried, so that the drug is adsorbed in the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton;

[0020] Alternatively, step S4 is S4-3: the polyurethane polymer prepared in S3 is dissolved in dioxane and placed in a mold, and freeze-dried to obtain a blank sponge without medicine; the 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 blank 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.

[0021] Optionally, when S4 is S4-1, the S4 step includes:

[0022] S41: dissolving the polyurethane polymer and the drug prepared in S3 with dioxane and placing them in a mold, followed by freezing to obtain a first drug-loaded layer, wherein the thickness of the first drug-loaded layer is less than the height inside the mold;

[0023] S42: dissolving the polyurethane polymer prepared in S3 in dioxane and placing the solution in the mold, followed by freezing to obtain a polyurethane layer, wherein the polyurethane layer is superimposed on the first drug-loaded layer, and the sum of the thickness of the first drug-loaded layer and the polyurethane layer is less than the height inside the mold;

[0024] S43: dissolving the polyurethane polymer and the drug prepared in S3 with dioxane and placing the mixture in a mold, freezing the mixture to obtain a second drug-loaded layer, superimposing the second drug-loaded layer on the polyurethane layer, and drying the mixture to obtain a drug-loaded hemostatic cotton, such that the drug-loaded hemostatic cotton sequentially includes the first drug-loaded layer, the polyurethane layer, and the second drug-loaded layer;

[0025] Wherein, in the step S41 or the step S43, the polyurethane polymer, drug and porogen prepared in S3 are dissolved and placed in a mold; or, in the step S42, the polyurethane polymer and porogen prepared in S3 are dissolved and placed in a mold.

[0026] Optionally, the porogen is an inorganic salt; or, the porogen includes one or more of ammonium phosphate, ammonium hydrogen phosphate, and ammonium bicarbonate;

[0027] Alternatively, the preparation method further comprises step S5: adding a moisture-inducing agent to the hemostatic cotton;

[0028] Alternatively, in step S1, the mass ratio of polyethylene glycol to cyclic ester monomer is 1:1-1:2;

[0029] Alternatively, in step S2, the diisocyanate compound is hexamethylene diisocyanate, and the molar ratio of 1,4-butanediol to hexamethylene diisocyanate is 1:4 to 1:10;

[0030] Alternatively, in 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;

[0031] Alternatively, in step S3, 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;

[0032] Alternatively, in step S1, the average molecular weight of the polyethylene glycol is 900 to 1100;

[0033] Alternatively, the step S4 further comprises dissolving the polyurethane polymer, drug, porogen and degradation enzyme prepared in S3 together and placing them in a mold; or dipping the drug-loaded hemostatic cotton obtained in S4 in a liquid containing the degradation enzyme and then implanting it into the target location.

[0034] The present invention also provides a drug sustained-release system, which comprises the drug-loaded hemostatic cotton as described above.

[0035] The present invention provides a drug-loaded hemostatic cotton, a method for preparing the drug-loaded hemostatic cotton, and a drug sustained-release system. The drug-loaded hemostatic cotton comprises a porous sponge and a drug-loading layer. The porous sponge has a porosity greater than 80%, a viscosity greater than 0.4 dL / g, and a glass transition temperature between -50°C and -20°C, such that the porous sponge has a compressive strength greater than 3 kPa and a rebound rate greater than 80%. The porous sponge acts by compressing capillaries to stop bleeding. Furthermore, the porous sponge can absorb and store exuded blood, causing platelets in the blood to aggregate. Thus, a drug-loaded hemostatic cotton with excellent hemostatic effect, short degradation time, excellent mechanical properties, good safety, and low cost is obtained. The preparation method of the drug-loaded hemostatic cotton, through the selection of specific reagents, specific reagent amounts, and specific step design, yields a drug-loaded hemostatic cotton with a short degradation time, excellent mechanical properties, good safety, low cost, high product stability, high yield, simple operation, universal applicability, and ease of large-scale production. At the same time, through different drug adding methods, drug-loaded hemostatic cotton with different drug loading mechanisms, different release rates and different properties is formed. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] 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.

[0037] FIG1 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.

[0038] 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 degradation time.

[0039] FIG3 shows the initial morphology of the sample of Example 1 in phosphate buffered saline solution (PBS solution).

[0040] FIG4 shows the morphology of the sample of Example 1 after degradation in phosphate buffered saline solution (PBS solution) for 24 hours.

[0041] FIG5 shows the cumulative release rate of the drug in the samples of Examples 1-16 and Comparative Examples 1-2 at different time periods. DETAILED DESCRIPTION

[0042] To make the objects, advantages and features of the present invention more clear, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments. It should be noted that the drawings are all in a very simplified form and not drawn to scale, and are only used to facilitate and clearly illustrate the purpose of the embodiments of the present invention.

[0043] 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 meaning as commonly understood by those of ordinary skill in the art to which this application belongs.

[0044] The term "degradable" means that under certain conditions, the material can be degraded into low molecular weight substances and lose its original properties.

[0045] The term "target site" refers to a lumen at which hemostasis is desired.

[0046] The term "degradation" refers to "degradation behavior," which includes degradation rate, product formation during degradation, and changes in morphology and mechanical properties. To facilitate description of the degree of degradation, the endpoint of degradation is defined herein as stress fracture, compressive stress less than 50% of the original value, and molecular weight less than 30% of the original value.

[0047] The present invention provides a drug-loaded hemostatic cotton, a preparation method for 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 exuded blood, causing platelets in the blood to aggregate. 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.

[0048] In an embodiment of the present invention, a method for preparing drug-loaded hemostatic cotton includes the following steps: S1: In an anhydrous and oxygen-free environment, using polyethylene glycol as an initiator, a cyclic ester monomer undergoes a ring-opening reaction in the presence of a catalyst to synthesize a polyester prepolymer, wherein the polyethylene glycol has an average molecular weight of 800-1500. S2: Mixing a diisocyanate compound with a polyol compound, reacting them at a predetermined temperature, and then separating and purifying them to prepare an isocyanate-terminated triblock compound, wherein the molar ratio of the diisocyanate compound to the polyol compound is 1:4-6. S3: Dissolving the isocyanate-terminated triblock compound prepared in S2 in an organic solvent and reacting them with the polyester prepolymer prepared in S1 at a predetermined feed ratio, followed by precipitation using a poor solvent. After precipitation, the polyurethane polymer is purified and dried without water precipitation or alcohol soaking. S4: Dissolving the polyurethane polymer prepared in S3 and the drug in dioxane, placing the mixture in a mold, freezing, drying, and sterilizing the mixture to obtain the drug-loaded hemostatic cotton. Alternatively, step S4 may also be: dissolving the polyurethane polymer and drug prepared in S3 with dioxane and placing them in a mold, freezing, drying, and sterilizing to obtain a polyurethane sponge; or preparing a suspension of the drug in a poor solvent, placing the blank sponge without the drug into the suspension while stirring, removing it from the suspension after stirring, and drying it, so that the drug is adsorbed into the pores of the polyurethane sponge to form a hemostatic cotton. Alternatively, 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 into the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton. Thus, through the selection of specific reagents, specific reagent amounts, and specific process design, a drug-loaded hemostatic cotton with a short degradation time, excellent mechanical properties, superior safety, low cost, high product stability, high yield, simple operation, universal applicability, and easy large-scale production was obtained. Furthermore, through different drug addition methods, drug-loaded hemostatic cotton with different drug loading mechanisms, different release rates, and different performance properties was developed.

[0049] An embodiment of the present invention provides a drug-loaded hemostatic cotton, which is used in ear, nose, and throat cavities. The drug-loaded hemostatic cotton includes a porous sponge and a drug-loaded layer.

[0050] 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 compressive 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 exuded blood, causing platelets in the blood to aggregate. In this way, it can be ensured that the drug-loaded hemostatic cotton can perform conformal compression hemostasis in narrow cavities, and when the drug-loaded hemostatic cotton has a certain pressure and rebound performance, the drug-loaded hemostatic cotton has support performance and can also have a certain space for absorbing blood and preventing blood leakage. Preferably, 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, or -20°C. Preferably, 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, or 18 kPa, preferably greater than 10 kPa. Preferably, the rebound rate can be 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 kPa, preferably greater than 95%. It has excellent mechanical properties and good conformability.

[0051] The drug-loaded layer is arranged in at least one of the outer layer, middle layer or inner layer of the porous sponge. It should be understood that the outer layer means that the drug-loaded layer is coated on the outside of the porous sponge. The middle layer means that the drug-loaded 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-loaded layer is in the middle part of the porous outside. When the drug-loaded layer is located in the middle layer or the outer layer, when the porous sponge degrades or hydrolyzes, the drug in the drug-loaded layer can penetrate into the cavity. When the drug-loaded layer is arranged in the outer layer, middle layer or inner layer of the porous sponge, the drug-loaded layer is evenly distributed in the entire porous sponge. In this way, the drug-loaded hemostatic cotton can achieve directional drug delivery while compressing and stopping bleeding.

[0052] Preferably, the drug particles in the drug-loading layer are embedded in the porous sponge; alternatively, the drug particles in the drug-loading layer are contained in the pores of the porous sponge. "Embedded" means that the drug is present within the framework of the porous sponge, while "contained" means that the drug is present in pores outside the framework.

[0053] The water absorption rate of the drug-loaded hemostatic cotton is greater than 500%, for example, 600%, 700%, 800%, 900%, preferably greater than 1000%, and more preferably greater than 1500%. This allows the drug-loaded hemostatic cotton to better absorb liquid (such as blood, body fluids, etc.) or store liquid.

[0054] The content of PEG (polyethylene glycol) 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 PEG chain is hydrophilic, which makes the drug-loaded hemostatic cotton have good hydrophilic properties and a short water absorption time. Preferably, the water absorption time of the drug-loaded hemostatic cotton is less than 5 minutes. The porosity of the drug-loaded hemostatic cotton is high and the water absorption rate is high, thereby providing favorable conditions for degradation. Among them, the water absorption time refers to the time required for the drug-loaded hemostatic cotton to be placed on the water surface at 37°C ± 1°C (simulating human body temperature) until the drug-loaded hemostatic cotton is completely immersed in water. The water absorption rate refers to the ratio of the increased mass after complete immersion to the initial mass.

[0055] 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℃±1℃); 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. Preferably, 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℃±1℃.

[0056] The porous sponge is made of at least one of polyurethane, gelatin, chitosan, sodium hyaluronate, and collagen. Preferably, the porous sponge is polyurethane.

[0057] The drug-carrying layer contains a drug, including at least one of an anti-inflammatory drug, an antibacterial drug, an analgesic drug, a hemostatic drug, or an anti-allergic drug. The anti-inflammatory drug includes a glucocorticoid drug; the glucocorticoid drug includes mometasone furoate, budesonide, or fluticasone propionate; and the anti-allergic drug includes ebastine, loratadine, or acrivastine. It should be understood that in this embodiment, the drug can be any drug that can be disposed on the drug-carrying hemostatic cotton, and is not limited to the drugs described in this embodiment.

[0058] When the drug-loaded hemostatic cotton is used in the nasal cavity, the drug loading amount of each drug-loaded hemostatic cotton is 100 μg to 1000 μg / g, for example, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 μg / g. In this way, the drug can be safely released every day.

[0059] Preferably, each piece of the drug-loaded hemostatic cotton has a size of length * width * thickness = 80 mm * 20 mm * 15 mm. The drug-loaded hemostatic cotton can be cut to a size of length * width * thickness = 10 cm * 1 cm * 3 cm for use. Preferably, the drug-loaded layer comprises 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.

[0060] The embodiment of the present invention further provides a method for preparing drug-loaded hemostatic cotton, which is used to realize the above-mentioned drug-loaded hemostatic cotton and achieve various parameter indicators of the above-mentioned drug-loaded hemostatic cotton.

[0061] S1. Preparation of prepolymer: In an anhydrous and oxygen-free environment, cyclic ester monomers undergo a ring-opening reaction in the presence of a catalyst using polyethylene glycol (PEG) as an initiator to synthesize a polyester prepolymer, wherein the polyethylene glycol (PEG) has an average molecular weight of 800-1500. Preferably, 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. The prepolymer is directly used in step S3 without post-processing, thereby simplifying the steps of the preparation method and reducing production costs. The average molecular weight of the polyethylene glycol (PEG) is a specific choice. When the average molecular weight is 800-1500, for example, 900-1100, the prepared drug-loaded hemostatic cotton begins to degrade approximately 10 times earlier than the degradation time of drug-loaded hemostatic cotton in the prior art, thereby improving the degradation rate. The degradation rate is greatly increased, and the drug-loaded hemostatic cotton can quickly achieve lumen recanalization after hemostasis is completed at the target location. Based on this, because the polyethylene glycol (PFG) in this embodiment degrades very quickly, the water precipitation and alcohol soaking steps cannot be used in the step of synthesizing polyurethane in S3, so these two steps can be omitted. At the same time, the drug-loaded hemostatic cotton prepared using the polyester prepolymer synthesized with polyethylene glycol (PEG) can control the degradation time to within 36 hours, with the fastest degradation rate within 6-12 hours. Compared with the uncontrollable degradation time of the existing technology, it can ensure degradation within a controllable 36 hours.

[0062] Preferably, in step S1, the cyclic ester monomer is one or more of DL-lactide, L-lactide, glycolide, caprolactone, trimethylene carbonate, and p-dioxanone. Furthermore, the cyclic ester monomer is glycolide, lactide, and caprolactone. Preferably, in step S1, 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 the drug-loaded hemostatic cotton, and improving the degradation rate. For details, please refer to Example 3 and other examples below, as well as the analysis of degradation performance below. Preferably, in step S1, 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. Preferably, the reaction temperature in step S1 is 120°C to 140°C; the reaction time is 12 to 36 hours.

[0063] S2. Preparation of chain extender: A diisocyanate compound is mixed with a polyol compound, reacted at a certain temperature, and then separated and purified to prepare an 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 an isocyanate-terminated triblock compound (HBH). 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). Compared with tetramethylene diisocyanate used in currently available products, hexamethylene diisocyanate (HDI) is low in price and easy to obtain, thereby reducing the cost of drug-loaded hemostatic cotton. At the same time, the drug-loaded hemostatic cotton prepared by HBH obtained by HDI does not affect its degradation rate, mechanical properties, etc. The polyol compound is preferably 1,4-butanediol (BDO). 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.

[0064] Preferably, in step S2, the molar ratio of 1,4-butanediol to hexamethylene diisocyanate is 1:4 to 1:6. Preferably, in step S2, the reaction temperature is 70°C to 90°C; and the reaction time is 4 to 6 hours. Preferably, in step S2, the separation and purification process is as follows: 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.

[0065] S3, Preparation of Polyurethane: The isocyanate-terminated triblock compound (HBH) prepared in S2 is dissolved in an organic solvent and reacted with the polyester prepolymer prepared in S1 at a certain feed ratio. After sedimentation using a poor solvent, no water precipitation or alcohol soaking treatment is performed, and the polyurethane polymer is purified and dried. Preferably, in the SS step, 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, diethyl ether, n-pentane, petroleum ether, and cyclohexane.

[0066] In one embodiment, step S3 includes dissolving the isocyanate-terminated triblock compound prepared in S2 in dimethyl sulfoxide (DMSO), reacting the mixture with the polyester prepolymer prepared in S1 at a certain feed ratio, and using a poor solvent, such as diethyl ether, for precipitation. In another embodiment, step S3 includes reacting the polyester prepolymer prepared in S1 with a dimethylformamide solution of the isocyanate-terminated triblock compound prepared in S2, and using diethyl ether for precipitation after the polymerization is completed. The dimethylformamide (DMF) may be N,N-dimethylformamide, which is a solvent for the isocyanate-terminated triblock compound (HBH). Diethyl ether is used for precipitation because it has good volatility and low residue. It should be understood that the polyurethane polymer prepared in S3 has a fast degradation rate due to the specific selection of polyethylene glycol. Specifically, in the S3 step, the aqueous solution is not used for sedimentation and alcohol soaking, 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. At the same time, the steps of aqueous solution sedimentation and alcohol soaking are also reduced, reducing the production steps and thus reducing the production cost. Those skilled in the art understand that in the production steps, 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 soaking. In addition, in the S1-S2 steps, the polyester prepolymer and the isocyanate-terminated triblock compound (HBH) are pre-synthesized, and the reaction process is controllable, avoiding monomer residues of by-products. An effective post-treatment process for the obtained product can remove small molecule monomers and heavy metal residues in the synthesis process, effectively improving the safety of the drug-loaded hemostatic cotton.

[0067] Preferably, in step S3, the mass concentration of the HBH DMF solution is 0.2 to 0.5 g / g. Preferably, in 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. Preferably, in step S3, the reaction temperature of the polyurethane polymer is 75-90°C, and the reaction time is 3 to 6 hours. Preferably, in step S3, the purification process includes diluting the reaction mixture to 10%-25% with dioxane, slowly pouring it into 5 to 8 times the volume of icy ether while 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.

[0068] 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. The drug-loaded hemostatic cotton is then frozen, dried, and sterilized to produce the drug-loaded hemostatic cotton. The freezing and drying process is a sublimation process for the solution. Sublimation of the solution forms uniform pores, forming a microporous solid. The organic solvent is preferably dioxane, which has a high melting point, a low boiling point, and good solubility. This organic solvent can dissolve both the polyurethane polymer and the drug. By co-dissolving the polyurethane polymer and the drug, followed by freezing and drying to produce the drug-loaded hemostatic cotton, the drug is embedded in the polyurethane, allowing for sustained release during the degradation of the drug-loaded hemostatic cotton. This embedding is understood to be physical. Compared to existing techniques, some clinicians use drug-free, drug-loaded hemostatic cotton dipped in a solution and then placed in the target area. However, the concentration and release of the solution cannot be controlled, and the solution is administered all at once, preventing quantitative sustained-release administration. The drug-loaded hemostatic cotton of this embodiment can achieve sustained drug release, and the drug release is stable and effective. The doctor does not need to temporarily prepare medicine and dip the medicine 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, which avoids new safety issues arising from cumbersome steps or the process of dipping in liquid medicine. It also saves the doctor-patient operation time and improves 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, and can achieve compression hemostasis in a short time. It does not require secondary surgery to remove, and can flow out after being degraded by the body's metabolism, and the degradation product is non-toxic. The drug-loaded hemostatic cotton can also achieve sustained drug release, and the production cost of the drug-loaded hemostatic cotton is low, making it safer and more convenient. The degradation time of the drug-loaded hemostatic cotton obtained by the preparation method of the drug-loaded hemostatic cotton in the embodiment of the present invention can be shortened to within 3 days. After the drug-loaded hemostatic cotton is placed in the target position, hemostasis is completed within 48 hours. After that, the degraded drug-loaded hemostatic cotton fragments at the target position can be flushed out of the cavity by cleaning, thereby facilitating the healing of the wound tissue at the target position.

[0069] Preferably, in step S4, 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. Preferably, in step S4, the mass concentration of the polyurethane polymer solution is 3% to 5%. Preferably, in step S4, 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. Preferably, in step S4, the sterilization method used is irradiation sterilization and ethylene oxide sterilization.

[0070] Preferably, 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. 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.

[0071] S42: The polyurethane polymer prepared in S3 is dissolved in dioxane and placed in the mold, and then frozen to obtain a polyurethane layer. 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 inside the mold, thereby facilitating the mold to accommodate the second drug-carrying layer described below.

[0072] S43: The polyurethane polymer and drug prepared in S3 are dissolved in dioxane and placed in a mold. The mixture is frozen to obtain a second drug-loaded layer. The second drug-loaded layer is superimposed on the polyurethane layer and dried to obtain a drug-loaded hemostatic cotton, such that the drug-loaded hemostatic cotton comprises, in order, the first drug-loaded layer, the polyurethane layer, and the second drug-loaded layer. This arrangement allows the drug to be present on both surface layers of the drug-loaded hemostatic cotton. Compared to drug-loaded hemostatic cotton containing the drug throughout, this facilitates drug release at the same drug content. Furthermore, because the drug-loaded hemostatic cotton does not contain the drug internally, explosive drug release upon complete degradation of the drug-loaded hemostatic cotton is avoided. Furthermore, it should be understood that the drug-loaded hemostatic cotton, as an implantable device, must be loaded within a specified drug dosage range. Therefore, within this specified drug dosage range, the polyurethane layer of the drug-loaded hemostatic cotton contains no drug, while the first and second drug-loaded layers contain the drug. This increases the drug concentration, increases the amount of drug released during sustained release, and improves drug efficacy. Of course, 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.

[0073] Preferably, the ratio of the thickness of the first or second drug-carrying layer to the thickness of the drug-loaded hemostatic cotton is less than 1 / 3. This increases the drug concentration per layer at a given drug dosage and prevents explosive drug release from the drug-loaded hemostatic cotton during degradation. Preferably, the thickness ratio of the first to second drug-carrying layers can be 1:1, with the thickness of the first and second drug-carrying layers preferably being 1 mm, though thicknesses of 2 mm, 3 mm, or the like are also possible.

[0074] It should be understood that the medication includes at least one of anti-inflammatory drugs, antibacterial drugs, analgesics, hemostatic drugs, or antiallergic drugs. Preferably, the anti-inflammatory drug includes a glucocorticoid. The antibacterial drugs include penicillins, cephalosporins, ofloxacin, ciprofloxacin, clotrimazole, chloramphenicol, and the like. The analgesics include ibuprofen, and the like. Preferably, the glucocorticoids include mometasone furoate or budesonide. The antiallergic drugs can be administered nasally, such as levocabastine hydrochloride, ketotifen fumarate, beclomethasone dipropionate, mometasone furoate, budesonide, and fluticasone propionate. The medication can also include a ciliary stimulant or mucus-promoting drug, such as myrtle oil. The medication can also be a nasal mucosa protective drug, such as compound peppermint oil or chlorhexidine cod liver oil nasal drops. This solves the problem of inflammation caused by postoperative bacterial infection, accelerates wound healing, and prevents problems such as adhesions at the wound site. Preferably, mometasone furoate is used in this embodiment for verification and explanation.

[0075] The drug content of the anti-inflammatory drug, antibacterial drug, analgesic drug, hemostatic drug or anti-allergic 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.

[0076] Preferably, in step S41 or S43, the polyurethane polymer prepared in S3, the drug, and the porogen are dissolved together and placed in a mold. The porogen is an inorganic salt; the inorganic salt can further be ammonium phosphate, ammonium hydrogen phosphate, or ammonium bicarbonate. Since inorganic salts decompose into non-toxic and harmless gases when heated and do not leave any residue, for example, ammonium bicarbonate disappears after being heated to ammonia and carbon dioxide. This, on the one hand, prevents the drug-loaded hemostatic cotton from producing harmful substances during use due to the presence of the porogen, and also prevents the generation and precipitation of harmful substances, thereby improving product safety. It is well known in the art that the primary requirement for implantable medical devices is the safety of the product after implantation, and the choice of reagents determines whether the product can be marketed. This embodiment uses inorganic salts to solve the safety problem and has excellent safety performance. On the other hand, the addition of the porogen increases the porosity of the drug-loaded hemostatic cotton, thereby improving the rebound rate and drug sustained release performance of the drug-loaded hemostatic cotton. It should be understood that the drug-loaded hemostatic cotton of this embodiment also needs to be able to be packed into narrow cavities. Taking the nasal cavity as an example, these narrow cavities contain numerous capillaries and are irregular in shape. Adding a porogen to the drug-loaded hemostatic cotton improves its resilience (the degree to which it recovers after the external force is removed), allowing it to rebound effectively when inserted into the nasal cavity, compressing the capillaries and achieving a good hemostatic effect. Furthermore, the porogen content is 3-5% of the polyurethane polymer.

[0077] Preferably, the preparation method further includes 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.

[0078] This embodiment also provides a method for preparing drug-loaded hemostatic cotton, comprising:

[0079] 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, wherein the polyethylene glycol has an average molecular weight of 800-1500;

[0080] S2: mixing a diisocyanate compound and a polyol compound, reacting them at a certain temperature, and then separating and purifying them to prepare an isocyanate-terminated triblock compound, wherein the molar ratio of the polyol compound to the diisocyanate compound is 1:4 to 1:10;

[0081] S3: reacting the polyester prepolymer prepared in S1 with the N,N-dimethylformamide solution of the isocyanate-terminated triblock compound prepared in S2, and using ether for precipitation. After precipitation, the polyurethane polymer is obtained by purification and drying without water precipitation or alcohol soaking treatment.

[0082] S4: The polyurethane polymer prepared in S3 is dissolved in dioxane and placed in a mold. The polyurethane sponge is then frozen, dried, and sterilized to obtain a polyurethane sponge. The drug is suspended in a poor solvent, and the polyurethane sponge is placed in the suspension while stirring. After stirring, the sponge is removed and dried, so that the drug is adsorbed into the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton. This ensures the presence of the drug in the drug-loaded hemostatic cotton and facilitates drug release. The poor solvent can carry drug particles into the pores of the polyurethane sponge through the flow of the poor solvent.

[0083] Preferably, this embodiment also provides another method for preparing drug-loaded hemostatic cotton. S1, S2, and S3 are described above and are not further described. S4 may also be: the polyurethane polymer prepared in S3 is dissolved in dioxane and placed in a mold, and then frozen, dried, and sterilized to obtain a polyurethane sponge. 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. 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 the drug-loaded hemostatic cotton.

[0084] 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 and acetone.

[0085] Preferably, the poor solvent is one or more of water, n-hexane, and cyclohexane. The poor solvent is preferably cyclohexane.

[0086] Preferably, 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 increasing until it dissolves and destroys the sponge.

[0087] Preferably, the concentration of the drug in the benign solvent is 0.5 mg / ml-10 mg / ml.

[0088] Preferably, in the mixed solution, 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 damaged, and if it is too low, the drug will precipitate in the solution.

[0089] Preferably, the concentration of the drug mixture solution is 0.01 mg / ml-2 mg / ml. The concentration of the drug is preferably much lower than its saturated solubility in the benign solvent, otherwise it will precipitate after being added to the poor solvent.

[0090] Specifically, the drug solution is prepared in ethyl acetate to a certain concentration and then diluted with cyclohexane to a certain ratio to obtain a drug solution. The drug can then be applied by spraying, dripping, or immersion. The key is the formulation of the drug solution, which ensures a balance between drug precipitation and non-precipitation without damaging the polyurethane sponge.

[0091] The technical solutions of the embodiments of the present invention are described in detail below through Examples 1 to 16 and Control Groups 1 to 2.

[0092] [Example 1]

[0093] Preparation of polyurethane:

[0094] In step S1, 25.0 g of polyethylene glycol (average molecular weight of 1000, Mn=1000) was accurately weighed and added to a 250 mL vacuum reaction bottle. The bottle was continuously vacuumed for 2 h at 100° C. using a vacuum oil pump to remove water. After the water removal was completed, the bottle was cooled to below 70° C., 12.5 g of D,L-lactide, 12.5 g of ε-caprolactone, and 0.005 g of stannous isooctanoate were added in sequence, and the bottle was vacuumed for 3 minutes. The temperature was then raised to 130° C., and the bottle was reacted for 24 h and can be directly used in the next reaction without post-treatment.

[0095] In step S2, a three-necked flask was placed in an 80°C oil bath for preheating, 50.4 g of hexamethylene diisocyanate was added, and 4.5 g of 1,4-butanediol was added dropwise under mechanical stirring. The mixture was sealed and reacted for 4.5 hours to obtain a milky white paste. The mixture was then stirred and washed with 400 mL of n-hexane, filtered, and dried on a rotary evaporator at 40°C for 3 hours to obtain a pure white solid powder (HBH).

[0096] In step S3, 50 g of the polyester prepolymer obtained in step S1 was added to a three-necked flask, and then 13.84 g of HBH obtained in step S2 was dissolved in 30.00 g of DMF solution and added dropwise to the three-necked flask under stirring. The mixture was sealed and reacted at 80° C. for 3 hours to obtain a transparent viscous liquid. Dioxane was added to dilute the liquid to 20%, and the liquid was slowly poured into icy ether while hot. The liquid was soaked in n-hexane for 3 hours and then dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid, which is a polyurethane polymer.

[0097] Preparation of drug-loaded hemostatic cotton:

[0098] In step S4, two solutions, A and B, are prepared separately. Solution A is a 3.5% polyurethane polymer solution containing mometasone furoate in dioxane, wherein the mometasone furoate content is 0.25‰ of the polyurethane polymer, and 3% ammonium bicarbonate and 1% PEG (Mn=10,000) are added. Solution B is a 3.5% polyurethane polymer solution in dioxane, to which 3% ammonium bicarbonate and 1% PEG (Mn=10,000) are added. A layer of solution A is first poured into a mold, frozen at 0°C, and then solution B is poured in. After freezing again, a layer of solution A is covered. After freezing at -20°C, the mold is transferred to a freeze dryer for freeze drying. After irradiation sterilization, the freeze-dried cotton wool is obtained, which is layered and freeze-dried, and is recorded as M1.

[0099] [Example 2]

[0100] According to the method in Example 1, S1, S2 and S3 were implemented to obtain the corresponding polymer.

[0101] In step S4, the polymer is dissolved in a dioxane solution to obtain a 3.5% solution. Ammonium bicarbonate (3% by weight of the polymer) and PEG (Mn = 10,000) are added to obtain a lyophilized solution. A layer of the lyophilized solution is first poured into a mold, frozen at 0°C, and then covered with another layer of the lyophilized solution. After freezing at -20°C, the solution is transferred to a freeze dryer for freeze drying to obtain a drug-free blank sponge. Mometasone furoate is ultrasonically dispersed in a cyclohexane solution to prepare a drug solution with a concentration of 16 μg / ml. The blank sponge is immersed in the stirring drug solution for 30 seconds, removed, and dried in a vacuum drying oven to constant weight. After irradiation sterilization, a suspension nanoabsorbent drug-loaded cotton is obtained. This is designated M2.

[0102] [Example 3]

[0103] The corresponding blank sponge was obtained according to the method in Example 2.

[0104] Dissolve mometasone furoate in ethyl acetate to create an initial concentration of 1.5 mg / ml. Dilute the solution to 125 μg / ml with cyclohexane. Use a pipette to drop 1 ml onto each of the upper and lower surfaces of the sponge. Dry in a vacuum oven to constant weight and sterilize by irradiation to obtain a solvent-precipitated drug-loaded cotton ball, designated M3.

[0105] [Example 4]

[0106] Preparation of polyurethane:

[0107] In the step S1, 20.0 g of polyethylene glycol (Mn=800) was accurately weighed and added to a 250 mL vacuum reaction bottle. The bottle was continuously vacuumed for 2.5 h using a vacuum oil pump at 95° C. to remove water. After the water removal was completed, the bottle was cooled to below 70° C., 10 g of glycolide, 10 g of ε-caprolactone, and 0.004 g of stannous isooctanoate were added in sequence, and the bottle was vacuumed for 30 seconds. The bottle was then heated to 135° C. and reacted for 30 h before being used directly in the next reaction without post-treatment.

[0108] The preparation method of the chain extender HBH is the same as that in Example 1 and will not be described again here.

[0109] In step S3, 40 g of the polyester prepolymer obtained in step S1 was added to a three-necked flask, and then 14.00 g of HBH obtained in step S2 was dissolved in 30.00 g of DMF solution and added dropwise to the three-necked flask under stirring. The mixture was sealed and reacted at 80° C. for 3.5 hours to obtain a transparent viscous liquid, which was diluted to 15% by adding dioxane. The liquid was slowly poured into icy ether while hot, soaked in n-hexane for 3 hours, and then dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.

[0110] Preparation of drug-loaded hemostatic cotton:

[0111] In step S4, two solutions, A and B, are prepared separately. Solution A is a 4.0% polyurethane polymer solution containing mometasone furoate in dioxane, wherein the mometasone furoate content is 0.30‰ of the polyurethane polymer, and 3.5% ammonium bicarbonate and 1% PEG (Mn=15000) are added. Solution B is a 4.0% polyurethane polymer solution in dioxane, to which 3.5% ammonium bicarbonate and 1% PEG (Mn=15000) are added. A layer of solution A is first poured into the mold, frozen at 0°C, and then solution B is poured in. After freezing again, a layer of solution A is covered. After freezing at -20°C, the mold is transferred to a freeze dryer for freeze drying. After irradiation sterilization, the freeze-dried cotton wool is obtained, which is layered and freeze-dried, and is recorded as M4.

[0112] [Example 5]

[0113] According to the method in Example 4, S1, S2 and S3 were implemented to obtain the corresponding polymer.

[0114] In step S4, the polymer is dissolved in a dioxane solution to obtain a 4.0% solution. Ammonium bicarbonate (3.5% by weight of the polymer) and PEG (Mn = 15,000) (1% by weight) are added to obtain a lyophilized solution. A layer of the lyophilized solution is first poured into a mold, then frozen at 0°C and covered with another layer of the lyophilized solution. After freezing at -20°C, the solution is transferred to a freeze dryer for freeze drying to obtain a drug-free blank sponge. Mometasone furoate is ultrasonically dispersed in a cyclohexane solution to prepare a drug solution with a concentration of 20 μg / ml. The blank sponge is immersed in the stirring drug solution for 45 seconds, removed, and dried in a vacuum drying oven to constant weight. After irradiation sterilization, a suspension nanoabsorbent drug-loaded cotton is obtained. This is designated M5.

[0115] [Example 6]

[0116] The corresponding blank sponge was obtained according to the method in Example 5.

[0117] Dissolve mometasone furoate in ethyl acetate to create an initial concentration of 2.0 mg / ml, then dilute to 150 μg / ml with cyclohexane. Use a pipette to drop 1 ml onto each of the upper and lower surfaces of the sponge. Dry in a vacuum oven to constant weight and sterilize by irradiation to obtain a solvent-deposited drug-loaded cotton ball, designated M6.

[0118] [Example 7]

[0119] Preparation of polyurethane:

[0120] In step S1, 15.0 g of polyethylene glycol (Mn=1000) was accurately weighed and added to a 250 mL vacuum reaction bottle. The bottle was continuously vacuumed for 2.0 h using a vacuum oil pump at 95° C. to remove water. After the water removal was completed, the bottle was cooled to below 70° C., 15 g of L-lactide, 15 g of ε-caprolactone, and 0.004 g of stannous isooctanoate were added in sequence, and the bottle was vacuumed for 30 seconds. The bottle was then heated to 130° C. and reacted for 30 h before being used directly in the next reaction without post-treatment.

[0121] The preparation method of the chain extender HBH is the same as that in Example 1 and will not be described again here.

[0122] In step S3, 40 g of the polyester prepolymer obtained in step S1 was added to a three-necked flask, and then 14.00 g of HBH obtained in step S2 was dissolved in 30.00 g of DMF solution and added dropwise to the three-necked flask under stirring. The mixture was sealed and reacted at 80° C. for 3.5 hours to obtain a transparent viscous liquid, which was diluted to 15% by adding dioxane. The liquid was slowly poured into icy ether while hot, soaked in n-hexane for 3 hours, and then dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.

[0123] Preparation of drug-loaded hemostatic cotton:

[0124] In step S4, two solutions, A and B, are prepared separately. Solution A is a 4.5% polyurethane polymer solution containing mometasone furoate in dioxane, wherein the mometasone furoate content is 0.30‰ of the polyurethane polymer, and 4.0% ammonium bicarbonate and 1.5% PEG (Mn=20,000) are added. Solution B is a 4.5% polyurethane polymer solution in dioxane, and 4.0% ammonium bicarbonate is added. A layer of solution A and 1.5% PEG (Mn=20,000) is first poured into a mold, frozen at 0°C, then solution B is poured in, and then frozen again and covered with a layer of solution A. After freezing at -25°C, the mold is transferred to a freeze dryer for freeze drying. After irradiation sterilization, the freeze-dried sample is obtained to obtain a degradable drug-loaded hemostatic sponge, denoted as M3.

[0125] [Example 8]

[0126] S1, S2 and S3 were carried out according to the method in Example 7 to obtain the corresponding polymer.

[0127] In step S4, the polymer is dissolved in a dioxane solution to obtain a 4.5% solution. Ammonium bicarbonate (4.0% by weight of the polymer) and PEG (Mn = 15,000) (1%) are added to obtain a lyophilized solution. A layer of the lyophilized solution is poured into a mold, frozen at 0°C, and then covered with another layer of the lyophilized solution. After freezing at -20°C, the solution is transferred to a freeze dryer for freeze drying to obtain a drug-free blank sponge. Mometasone furoate is ultrasonically dispersed in n-hexane to prepare a drug solution with a concentration of 20 μg / ml. The blank sponge is immersed in the stirred drug solution for 45 seconds, removed, and dried in a vacuum drying oven to constant weight. After irradiation sterilization, a suspension nanoabsorbent drug-loaded cotton is obtained. This is designated M8.

[0128] [Example 9]

[0129] The corresponding blank sponge was obtained according to the method in Example 8.

[0130] Dissolve mometasone furoate in ethyl acetate to create an initial concentration of 1.0 mg / ml, then dilute to 100 μg / ml with cyclohexane. Use a pipette to drip 1.5 ml onto each of the upper and lower surfaces of the sponge. Dry in a vacuum oven to constant weight and sterilize by irradiation to obtain a solvent-deposited drug-loaded cotton ball, designated M9.

[0131] [Example 10]

[0132] Preparation of polyurethane:

[0133] In step S1, 25.0 g of polyethylene glycol (Mn=1500) was accurately weighed and added to a 250 mL vacuum reaction bottle. The bottle was continuously vacuumed for 2.0 h using a vacuum oil pump at 95° C. to remove water. After the water removal was completed, the bottle was cooled to below 70° C., 12.5 g of L-lactide, 12.5 g of ε-caprolactone, and 0.004 g of stannous isooctanoate were added in sequence, and the bottle was vacuumed for 30 seconds. The bottle was then heated to 130° C. and reacted for 24 h before being used directly in the next reaction without post-treatment.

[0134] The preparation method of the chain extender HBH is the same as that in Example 1 and will not be described again here.

[0135] In step S3, 50 g of the polyester prepolymer obtained in step S1 was added to a three-necked flask, and then 13.00 g of HBH obtained in step S2 was dissolved in 26.00 g of DMF solution and added dropwise to the three-necked flask under stirring. The mixture was sealed and reacted at 85° C. for 2.5 hours to obtain a transparent viscous liquid, which was diluted to 15% by adding dioxane. The liquid was slowly poured into icy ether while hot, soaked in n-hexane for 3 hours, and then dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.

[0136] Preparation of drug-loaded hemostatic cotton:

[0137] In step S4, two liquids, A and B, are prepared separately. Liquid A is a 3.5% polyurethane polymer solution containing mometasone furoate in dioxane, where the mometasone furoate content is 0.30‰ of the polyurethane polymer. Liquid B is a 3.5% polyurethane polymer solution in dioxane. A layer of Liquid A is first poured into a mold, frozen at 0°C, then Liquid B is poured in, and then frozen again and covered with a layer of Liquid A. After freezing at -20°C, the mold is transferred to a freeze dryer for freeze drying. The freeze-dried sample is sterilized by irradiation to obtain a biodegradable drug-loaded hemostatic sponge, designated M10.

[0138] [Example 11]

[0139] S1, S2 and S3 were carried out according to the method in Example 10 to obtain the corresponding polymer.

[0140] In step S4, a polymer is dissolved in a dioxane solution to obtain a 3.5% solution. A layer of the solution is poured into a mold, then frozen at 0°C and covered with another layer of the solution. After freezing at -20°C, the solution is transferred to a freeze dryer for freeze drying to obtain a drug-free blank sponge. Mometasone furoate is ultrasonically dispersed in n-hexane to prepare a drug solution with a concentration of 20 μg / ml. The blank sponge is immersed in the stirring drug solution for 45 seconds, removed, and dried in a vacuum drying oven to constant weight. After irradiation sterilization, a suspension nanoabsorbent drug-loaded cotton is obtained. This is designated M11.

[0141] [Example 12]

[0142] The corresponding blank sponge was obtained according to the method in Example 11.

[0143] Dissolve mometasone furoate in ethyl acetate to create an initial concentration of 2.0 mg / ml, then dilute to 100 μg / ml with cyclohexane. Use a pipette to drip 1.5 ml onto each of the upper and lower surfaces of the sponge. Dry in a vacuum oven to constant weight and sterilize by irradiation to obtain a solvent-precipitated drug-loaded cotton ball, designated M12.

[0144] [Example 13]

[0145] The prepolymer and chain extender described in S1 and S2 were prepared according to the method in Example 4.

[0146] In 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 mixture was sealed and reacted at 75° C. for 3.5 h until the NCO peak of infrared detection completely disappeared (2300 cm -1 The mixture was vacuumed overnight to remove DMSO, and then dioxane was added to dilute the mixture to 20%. The mixture was precipitated with n-hexane and then dried in an oven to a constant weight to obtain a light yellow solid, which was a polyurethane polymer.

[0147] The drug-loaded hemostatic cotton was prepared according to the method described in step S4 of Example 1 and recorded as M13.

[0148] [Example 14]

[0149] The prepolymer and chain extender described in S1 and S2 were prepared according to the method in Example 1.

[0150] In 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 mixture was sealed and reacted at 75° C. for 3.5 h until the NCO peak of infrared detection completely disappeared (2300 cm -1 The mixture was vacuumed overnight to remove DMSO, and then dioxane was added to dilute the mixture to 20%. The supernatant was collected after centrifugation and precipitated with n-hexane. The mixture was dried in an oven to a constant weight to obtain a light yellow solid, which was a polyurethane polymer.

[0151] The drug-loaded hemostatic cotton was prepared according to the method described in Example 12 and was recorded as M14.

[0152] [Example 15]

[0153] The prepolymer and chain extender described in S1 and S2 were prepared according to the method in Example 1.

[0154] In 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 mixture was sealed and reacted at 75° C. for 3 h until the NCO peak of infrared detection completely disappeared (2300 cm -1 Dioxane was added again to dilute the mixture to 20%, and the mixture was precipitated with petroleum ether and then dried in an oven to constant weight to obtain a light yellow solid which was a polyurethane polymer.

[0155] The drug-loaded hemostatic cotton was prepared according to the method described in Example 12 and was recorded as M15.

[0156] [Example 16]

[0157] The prepolymer and chain extender described in S1 and S2 were prepared according to the method in Example 4.

[0158] In 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 mixture was sealed and reacted at 70° C. for 3 h until the NCO peak of infrared detection completely disappeared (2300 cm -1 Dioxane was added again to dilute the mixture to 25%, and the mixture was precipitated with cyclohexane and then dried in an oven to a constant weight to obtain a light yellow solid which was a polyurethane polymer.

[0159] The drug-loaded hemostatic cotton was prepared according to the method described in Example 12 and was recorded as M16.

[0160]

Comparative Example 1

[0161] In step S1, 15.0 g of polyethylene glycol (Mn=600) was accurately weighed and added to a 250 mL vacuum reaction bottle. The bottle was continuously vacuumed for 2.0 h using a vacuum oil pump at 95° C. to remove water. After the water removal was completed, the bottle was cooled to below 70° C., 12.5 g of L-lactide, 12.5 g of ε-caprolactone, and 0.004 g of stannous isooctanoate were added in sequence, and the bottle was vacuumed for 30 seconds. The bottle was then heated to 130° C. and reacted for 24 h. The bottle was directly used in the next reaction without post-treatment.

[0162] The preparation method of the chain extender HBH is the same as that in Example 1 and will not be described again here.

[0163] In the step S3, 40 g of the polyester prepolymer obtained in step S1 was added to a three-necked flask, and then 10.4 g of HBH obtained in step S2 was dissolved in 26.00 g of DMSO solution and added dropwise to the three-necked flask under stirring. After the reaction was sealed at 85° C. for 2.5 hours, a transparent viscous liquid was obtained. Dioxane was added to dilute the solution to 15%, and the solution was slowly poured into purified water while hot to precipitate a white strip-like solid. After being fished out, the water was squeezed out and the solution was soaked in ice ethanol to further remove water. The solution was again dissolved in dioxane to 15%, and the solution was precipitated into ice ether to form a filamentous solid, which was dried to constant weight.

[0164] Preparation of drug-loaded hemostatic cotton:

[0165] In 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 solution, and the lyophilized solution is freeze-dried in a mold to prepare drug-loaded hemostatic cotton, which is denoted as DBM.

[0166] [Control Example 2]: This control example provides a commercially available product as a reference sample, denoted as NXM.

[0167] Performance Testing

[0168] Porosity: Pre-weighed drug-impregnated hemostatic cotton was immersed in a known volume of water (V1) and degassed using a vacuum pump for 5 minutes. The total volume of water and the water-impregnated sponge was recorded as (V2). After removing the water-impregnated sponge, the residual volume of water was recorded as (V3). The porosity (a) of the sponge was calculated as follows:

[0169] (a)%=(V1-V3) / (V2-V3)×100%.

[0170] Water absorption indirectly reflects the effectiveness of the drug-loaded hemostatic cotton in stopping bleeding. The specific test method for water absorption is as follows: A freeze-dried drug-loaded hemostatic cotton sample prepared in the example is weighed (recorded as dry weight) and gently placed on the surface of purified water. Water can spread upward through the pores of the sample until the top is completely submerged. The water absorption time is recorded. The surface free water is wiped off and the sample is weighed, recorded as the wet weight. The water absorption rate of the sample is calculated based on the wet / dry weight ratio. Each sample is repeated three times. Specific test results are shown in Table 1.

[0171] Table 1

[0172] According to Table 1, the porosity of the samples increases with the use of porogen. This is because the porogen ammonium bicarbonate occupies a certain amount of space in the solvent. During the cooling process, the porogen is separated from it. During the drying process, it decomposes into carbon dioxide and ammonia and is discharged from the drug-loaded hemostatic cotton, forming a large number of pores and increasing the porosity. In addition, the water absorption rate and water absorption rate of the sponge are directly proportional to the proportion of polyethylene glycol in the entire molecular chain segment and the amount used as a dehumidifying agent. 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.

[0173] Compression performance: The drug-loaded hemostatic cotton sample prepared in the embodiment was placed statically between two upper and lower compression plates. The sample was slowly compressed to 50% of its original height. After maintaining the pressure for 5 minutes, the pressure was removed. The height of the sample after recovery was tested, and the rebound rate was calculated based on the change in height before and after compression.

[0174] Table 2

[0175] According to Table 2, it can be found that except for the comparative example DBM, the compressive 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 samples in 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. In the comparative example DBM, the compressive strength is significantly lower than that of other samples because water precipitation and alcohol immersion are 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 and alcohol immersion are used to obtain drug-loaded hemostatic cotton with good mechanical properties.

[0176] Degradation performance: The drug-loaded hemostatic cotton 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 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 were preliminarily degraded within 3 hours. At 3 hours, their weight average molecular weight and compressive strength decreased to below 60%, and as the degradation time prolonged, their values ​​gradually decreased, and eventually tended to be stable due to the influence of water surface tension.

[0177] Among them, in Examples 7-9, the ratio of PEG / cyclic ester monomers is the smallest, that is, the proportion of PEG is small, so the content of PEG segments is low, its hydrophilicity deteriorates, inhibiting the contact of water molecules with ester bonds, resulting in a relatively slow degradation rate. This shows that the ratio of PEG to polyester in the polyurethane polymer structure directly affects the degradation rate of the drug-loaded hemostatic cotton. As can be seen from Figure 1, the number average molecular weight of the M7-M9 samples is higher than that of the other samples. It can be seen that due to their poor hydrophilicity, their degradation rate is low. As can be seen from Figure 2, the compressive strength of the M7-M9 samples is higher than that of the other samples, which further verifies that the M7-M9 samples have a low degree of degradation and a low degree of crushing. Therefore, the proportion of PEG segments also affects the degree of degradation of the drug-loaded hemostatic cotton. Preferably, the ratio of PEG segments to polyester segments is 1:1-1:1.25.

[0178] As shown in Figure 3, 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. As shown in Figure 4, Figure 4 is the morphology of the M1 sample after 24 hours of degradation. It can be seen from the figure 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.

[0179] Drug Release: Immerse the drug-loaded hemostatic cotton in 500 ml of 1.0% SDS solution, seal the container, and place it in a 37°C constant-temperature shaker. For example, 1 ml of SDS solution was removed at regular intervals and replenished with 1 ml. The drug concentration was measured by liquid chromatography, and the drug release was calculated. The test results are shown in Figure 5.

[0180] Judging from the release results, different dosing methods have a more obvious effect on the drug release results. For example, the drug release of the upper and lower layered dosing method (M1, M4, M7, and M10 samples) showed a linear trend in the first two days, and then the release was slow and tended to be stable. Compared with layered dosing, the direct freeze-drying dosing method allows the sponge to contain drugs inside and outside. In the early stage of release, only part of the drug in the outermost layer is released by solvent diffusion. Then, after degradation, the release amount increases rapidly, and a burst release occurs, which can easily cause local tissue poisoning reactions in clinical applications. The use of external dosing methods on blank sponges (suspension nanoabsorption and solvent precipitation) can enable the drug to be released quickly in the early stage, which is conducive to eliminating inflammatory reactions and accelerating the recovery of the injured area. Through layered freeze-drying, the drug is slowly released when the outer layer degrades, further improving the safety of the drug-loaded hemostatic cotton; and the use of external dosing methods can quickly administer drugs to the injured area in the early stage, reduce inflammatory reactions and accelerate wound healing.

[0181] The above description is only a description of the preferred embodiments of the present invention and does not limit the scope of the present invention. Any changes and modifications made by ordinary technicians 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 drug-loaded hemostatic cotton, It is characterized in that The drug-loaded hemostatic cotton is used in the ear, nose and throat cavities, and 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. At the same time, the porous sponge can also absorb and store exuded blood to aggregate platelets in the blood; The drug-carrying layer is arranged on at least one of the outer layer, the middle layer or the inner layer of the porous sponge, and the drug-carrying layer contains drugs.

2. The drug-loaded hemostatic cotton according to claim 1, It is characterized in that 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.

3. The drug-loaded hemostatic cotton according to claim 2 is degradable, and the degradation time of the drug-loaded hemostatic cotton is 3h to 24h; 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.

4. The drug-loaded hemostatic cotton according to claim 1, It is characterized in that The porous sponge is made of at least one of polyurethane, gelatin, chitosan, sodium hyaluronate and collagen.

5. The drug-loaded hemostatic cotton according to claim 1, It is 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; 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.

6. The drug-loaded hemostatic cotton according to claim 5, It is characterized in that When the drug-loaded hemostatic cotton is used in the nasal cavity, the drug loading amount of each piece of drug-loaded hemostatic cotton is 100 ug to 1000 ug / g.

7. A method for preparing drug-loaded hemostatic cotton. It is characterized in that Used for preparing the drug-loaded hemostatic cotton according to any one of claims 1 to 6, the preparation method of the drug-loaded hemostatic cotton 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, wherein the average molecular weight of the polyethylene glycol is 800-1500; S2: a diisocyanate compound is mixed with a polyol compound, reacted at a certain temperature, and then separated and purified to prepare an isocyanate-terminated triblock compound, wherein the molar ratio of the polyol compound to the diisocyanate compound is 1:4 to 1: 10； S3: dissolving the isocyanate-terminated triblock compound prepared in S2 in an organic solvent and reacting with the polyester prepolymer prepared in S1 at a certain feed ratio, using a poor solvent for precipitation, and after precipitation, drying to a constant weight without water precipitation or alcohol soaking treatment to obtain a polyurethane polymer; Wherein, step S4 is S4-1: the polyurethane prepared in S3 and the drug are dissolved in an organic solvent and placed in a mold, and after freezing, drying and sterilization, the drug-loaded hemostatic cotton is obtained; Alternatively, 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; Alternatively, step S4 is S4-3: the polyurethane polymer prepared in S3 is dissolved in dioxane and placed in a mold, and freeze-dried to obtain a blank sponge without medicine; the 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 blank 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.

8. The method for preparing the drug-loaded hemostatic cotton according to claim 7, It is characterized in that When the S4 is S4-1, 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 less than the height in the mold; S42: dissolving the polyurethane polymer prepared in S3 with dioxane and placing it in the mold, freezing it to obtain a polyurethane layer, wherein the polyurethane layer is superimposed on the first drug-carrying layer, and the sum of the thickness of the first drug-carrying layer and the polyurethane layer is less than the height in the mold; S43: dissolving the polyurethane polymer and the drug prepared in S3 with dioxane and placing them in a mold, freezing them to obtain a second drug-carrying layer, superimposing the second drug-carrying layer on the polyurethane layer, and drying them to obtain drug-carrying hemostatic cotton, so that the drug-carrying hemostatic cotton includes the first drug-carrying layer, the polyurethane layer, and the second drug-carrying layer in sequence; Wherein, in the step S41 or the step S43, 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.

9. The method for preparing the drug-loaded hemostatic cotton according to claim 8, It is characterized in that The porogen is an inorganic salt; or, the porogen includes one or more of ammonium phosphate, ammonium hydrogen phosphate, and ammonium hydrogen carbonate; Alternatively, the preparation method further comprises step S5: adding a moisture-inducing agent to the hemostatic cotton; Alternatively, in step S1, the mass ratio of polyethylene glycol to cyclic ester monomer is 1:1-1:2; or, in step S2, the diisocyanate compound is hexamethylene diisocyanate, and the molar ratio of 1,4-butanediol to hexamethylene diisocyanate is 1:4-1:10; Alternatively, in 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; or, in step S3, 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; Alternatively, in the step S1, the average molecular weight of the polyethylene glycol is 900 to 1100; Alternatively, the step S4 further comprises dissolving the polyurethane polymer, drug, porogen and degradation enzyme prepared in S3 together and placing them in a mold; or dipping the drug-loaded hemostatic cotton obtained in S4 in a liquid containing the degradation enzyme and implanting it into the target position.

10. A drug sustained release system, It is characterized in that The drug sustained-release system comprises the drug-loaded hemostatic cotton according to claim 1.

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