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

Abstract

The invention provides drug-loaded hemostatic cotton, a preparation method of the drug-loaded hemostatic cotton and a drug sustained release system. The drug-loaded hemostatic cotton comprises porous sponge and a drug-loaded layer, the compression strength of the porous sponge is larger than 3 Kpa, the rebound rate is larger than 80%, the porous sponge plays a role in stopping bleeding by pressing blood capillaries, meanwhile, the porous sponge can absorb and store exuded blood, and blood platelets in the blood are gathered. Therefore, the drug-loaded hemostatic cotton which is good in hemostatic effect, short in degradation time, good in mechanical property, good in safety and low in cost is obtained.

Description

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 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 otorhinolaryngology surgery as an example, these bleeding sites are deep, the space is narrow, and there are a large number of capillaries around them, which are difficult to suture after surgery. In clinical practice, compression hemostasis through gauze and expanded sponges can effectively reduce the amount of bleeding and accelerate wound healing. However, secondary injuries are caused during the extraction process, causing secondary infections. More importantly, it will make patients feel unbearable pain, and even lead to collapse, shock, etc. Therefore, how to effectively and quickly stop bleeding after surgery has become a research hotspot for many scholars.

[0003] Hemostatic cotton is currently a relatively effective way to stop bleeding quickly. However, due to problems such as low compression strength and poor rebound rate, drug-loaded hemostatic cotton cannot perform conformal compression and hemostasis on narrow cavities, nor can it simultaneously store blood and prevent 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 cottons on the market, and it is not possible to achieve drug administration while performing compression and hemostasis. These problems urgently require technicians to develop new products to solve existing problems.

[0004] At present, the preparation method of hemostatic cotton is to first prepare a polyurethane polymer, and then dissolve the obtained polyurethane polymer in dioxane and chitosan aqueous solution and freeze-dry it to obtain it. Another method is to prepare a polyurethane polymer in advance, and then freeze-dry and sterilize it to obtain a hemostatic sponge by mixing a polyurethane solution with a foaming agent. However, the hemostatic cotton formed by these methods has the following problems: 1) It is easy to have side reactions and high chemical residues, which affects the clinical safety of hemostatic cotton. 2) The hemostatic cotton obtained by these methods degrades slowly and the degradation time is uncontrollable. The degradation time is greater than 3 days. When the hemostatic cotton is placed in the target position, it cannot be degraded in time, so that the hemostatic cotton stays in the hemostatic site for a long time. In this process, the narrow cavity at the hemostatic site is completely blocked, prolonging the patient's pain time. Although partial degradation occurs, it is not conducive to the cleaning of the cavity because of the slow degradation. Under normal circumstances, the hemostatic process can be completed within 48 hours. If the hemostatic cotton stays in the body for a long time, it is not conducive to the healing of the wound. 3) The hemostatic cotton obtained by this method has weak mechanical properties, poor compression hemostasis effect, and poor anti-adhesion effect. 4) The hemostatic cotton does not have antibacterial and anti-inflammatory effects, thereby slowing down wound healing. 5) The cost of this method is high.

[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. Summary of the invention

[0006] The purpose of the present invention is to provide a preparation method of drug-loaded hemostatic cotton, drug-loaded hemostatic cotton and a drug sustained-release system to solve the technical problems of poor hemostatic effect, poor clinical safety, long degradation time, poor mechanical properties, inability to slowly release drugs and high cost of hemostatic cotton.

[0007] 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, and 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 capillaries, and at the same time, the porous sponge can also absorb and store exuded blood to aggregate platelets in the blood; the drug-loaded layer is arranged in at least one of the outer layer, middle layer or inner layer of the porous sponge, and the drug-loaded layer contains drugs.

[0008] Optionally, 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.

[0009] 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.

[0010] Optionally, the porous sponge is made of at least one of polyurethane, gelatin, chitosan, sodium hyaluronate, and collagen.

[0011] Optionally, the drug includes at least one of anti-inflammatory drugs, antibacterial drugs, analgesics, hemostatic drugs or antiallergic drugs; the anti-inflammatory drugs preferably include glucocorticoid drugs; the glucocorticoid drugs preferably include at least one of mometasone furoate, budesonide or fluticasone propionate; the antiallergic drugs preferably include ebastine, loratadine, and acrivastine.

[0012] 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 to 1000ug / g; preferably, it can be 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1000ug / g.

[0013] The present invention also provides a method for preparing drug-loaded hemostatic cotton, which is used to prepare the drug-loaded hemostatic cotton as described above. The method for preparing drug-loaded hemostatic cotton comprises:

[0014] 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;

[0015] 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;

[0016] 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;

[0017] 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;

[0018] 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;

[0019] 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.

[0020] Optionally, when S4 is S4-1, the S4 step includes:

[0021] 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;

[0022] 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;

[0023] 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;

[0024] 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.

[0025] Optionally, the porogen is an inorganic salt; or, the porogen includes one or more of ammonium phosphate, ammonium hydrogen phosphate, and ammonium bicarbonate;

[0026] Alternatively, the preparation method further comprises step S5: adding a moisture-inducing agent to the hemostatic cotton;

[0027] Alternatively, in step S1, the mass ratio of polyethylene glycol to cyclic ester monomer is 1:1-1:2;

[0028] 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;

[0029] 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;

[0030] 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;

[0031] Alternatively, in the step S1, the average molecular weight of the polyethylene glycol is 900 to 1100;

[0032] 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.

[0033] The present invention also provides a drug sustained-release system, which comprises the drug-loaded hemostatic cotton as described above.

[0034] The present invention provides a drug-loaded hemostatic cotton, a preparation method of drug-loaded hemostatic cotton, and a drug sustained release system. The drug-loaded hemostatic cotton includes: a porous sponge and a drug-loaded layer; the porosity of the porous sponge is greater than 80%, the viscosity of the porous sponge is greater than 0.4dL / g, and the glass transition temperature of the porous sponge is -50 to -20°C, so that the compression strength of the porous sponge is greater than 3Kpa and the rebound rate is greater than 80%. The porous sponge plays a hemostatic role by compressing the capillaries. At the same time, the porous sponge can also absorb and store the exuded blood to aggregate the platelets in the blood. In this way, a drug-loaded hemostatic cotton with good hemostatic effect, short degradation time, good mechanical properties, good safety, and low cost is obtained. The preparation method of the drug-loaded hemostatic cotton, through the methods of specific reagent selection, specific reagent amount selection, specific step design, etc., obtains a drug-loaded hemostatic cotton with short degradation time, good mechanical properties, good safety, low cost, high product stability, high yield, simple operation, universality, and easy 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 are formed. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] 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.

[0036] Figure 1 This 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.

[0037] Figure 2 This is a graph showing the relationship between the compression strength of the samples in Examples 1-16 and Comparative Examples 1-2 when compressed to 50% and the degradation time.

[0038] Figure 3 This is the initial morphology of the sample of Example 1 in phosphate buffered saline solution (PBS solution).

[0039] Figure 4 This is the morphology of the sample in Example 1 after being degraded in a phosphate buffered saline solution (PBS solution) for 24 hours.

[0040] Figure 5It is 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

[0041] 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.

[0042] 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.

[0043] The term "degradable" means that under certain conditions, the material can be degraded into low molecular weight substances and lose its original properties.

[0044] The term "target site" refers to a lumen at which hemostasis is desired.

[0045] 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.

[0046] The present invention provides a drug-loaded hemostatic cotton, a preparation method of the drug-loaded hemostatic cotton, and a drug sustained-release system. The drug-loaded hemostatic cotton comprises: a porous sponge and a drug-loaded layer; the porosity of the porous sponge is greater than 80%, the viscosity of the porous sponge is greater than 0.4dL / g, and the glass transition temperature of the porous sponge is -50 to -20°C, so that the compression strength of the porous sponge is greater than 3Kpa and the rebound rate is greater than 80%. The porous sponge plays a hemostatic role by compressing the capillaries. At the same time, the porous sponge can also absorb and store the exuded blood to aggregate the platelets in the blood. In this way, a drug-loaded hemostatic cotton with good hemostatic effect, short degradation time, good mechanical properties, good safety, and low cost is obtained.

[0047] In a preparation method of a drug-loaded hemostatic cotton provided in an embodiment of the present invention, the method comprises: S1: in an anhydrous and oxygen-free environment, using polyethylene glycol as an initiator, a cyclic ester monomer undergoes a ring-opening reaction under the action of a catalyst to synthesize a polyester prepolymer, wherein the average molecular weight of the polyethylene glycol is 800-1500. 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 diisocyanate compound to the polyol compound is 1:4-6. S3: the isocyanate-terminated triblock compound prepared by S2 is dissolved in an organic solvent and reacted with the polyester prepolymer prepared by S1 according to a certain feed ratio, and a poor solvent is used for precipitation. After precipitation, no water precipitation or alcohol soaking treatment is performed, and then the polyurethane polymer is obtained by purification and drying. S4: the polyurethane polymer prepared by S3 and the drug dioxane are dissolved and placed in a mold, and the drug-loaded hemostatic cotton is obtained after freezing, drying, and sterilization. Alternatively, step S4 may also be: dissolving the polyurethane polymer and the drug prepared in S3 with dioxane and placing them in a mold, freezing, drying, and sterilizing to obtain a polyurethane sponge; or preparing the drug into a suspension in a poor solvent, placing the blank sponge without the drug into the suspension under stirring, removing it after stirring and drying it, so that the drug is adsorbed in the pores of the polyurethane sponge to form a hemostatic cotton. 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 in the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton. Thus, by selecting specific reagents, selecting specific reagent amounts, designing specific steps, etc., drug-loaded hemostatic cotton with short degradation time, good mechanical properties, good safety, low cost, high product stability, high yield, simple operation, universal applicability, and easy large-scale production is obtained. At the same time, by different drug addition methods, drug-loaded hemostatic cotton with different drug loading mechanisms, different release rates, and different performances is formed.

[0048] The embodiment of the present invention provides a drug-loaded hemostatic cotton, which is used in the ear, nose, and throat cavities. The drug-loaded hemostatic cotton comprises: a porous sponge and a drug-loaded layer.

[0049] The porosity of the porous sponge is greater than 80%, the viscosity of the porous sponge is greater than 0.4dL / g, and the glass transition temperature of the porous sponge is -50 to -20°C, so that the compression strength of the porous sponge is greater than 3Kpa and the rebound rate is greater than 80%. The porous sponge plays a hemostatic role by compressing the capillaries. At the same time, the porous sponge can also absorb and store the exuded blood to aggregate the platelets in the blood. In this way, it can be ensured that the drug-loaded hemostatic cotton can perform conformal compression hemostasis in a narrow cavity, and when the drug-loaded hemostatic cotton has a certain pressure and rebound performance, the drug-loaded hemostatic cotton has a supporting 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, -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, 18 kPa, preferably greater than 10 kPa. Preferably, the rebound rate can be 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 kPa, preferably greater than 95%, and it has excellent mechanical properties and good conformability.

[0050] 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 is degraded or hydrolyzed, 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.

[0051] Preferably, the drug particles in the drug-carrying layer are embedded in the porous sponge; or, the drug particles in the drug-carrying layer are contained in the pores of the porous sponge. The embedding means that the drug exists in the skeleton of the porous sponge, and the containing means that the drug exists in the pores outside the skeleton.

[0052] The water absorption rate of the drug-loaded hemostatic cotton is greater than 500%, such as 600%, 700%, 800%, 900%, preferably greater than 1000%, and more preferably greater than 1500%, so that the drug-loaded hemostatic cotton has a better function of absorbing liquid (such as blood, body fluid, etc.) or storing liquid.

[0053] The content of PEG (polyethylene glycol) chain in the molecular chain of the porous sponge is 30% to 70%, so that the water absorption time of the drug-loaded hemostatic cotton is less than 10 minutes. The PEG chain is hydrophilic, which makes the drug-loaded hemostatic cotton have good hydrophilicity and short water absorption time. Preferably, the water absorption time of the drug-loaded hemostatic cotton is less than 5 minutes. The drug-loaded hemostatic cotton has high porosity and high water absorption rate, which provides favorable conditions for degradation. Among them, the water absorption time indicates the time required for the drug-loaded hemostatic cotton to be placed on the water surface of 37℃±1℃ (simulating human body temperature) until the drug-loaded hemostatic cotton is completely immersed in the water. The water absorption rate indicates the ratio of the increased mass after complete immersion to the initial mass.

[0054] The drug-loaded hemostatic cotton is degradable, and the degradation time of the drug-loaded hemostatic cotton is 3h to 24h (in rabbit blood, simulating human body temperature, 37°C ± 1°C); in its release behavior, the drug release rate in the first three days is greater than 60%; the drug release rate in the first two days is greater than 40%, and the release rate is 20% to 40% per day. 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. Among them, the test environment is in rabbit blood, simulating human body temperature, 37°C ± 1°C.

[0055] The porous sponge is made of at least one of polyurethane, gelatin, chitosan, sodium hyaluronate and collagen. Preferably, the porous sponge is polyurethane.

[0056] The drug-carrying layer contains drugs, and the drugs include at least one of anti-inflammatory drugs, antibacterial drugs, analgesic drugs, hemostatic drugs or anti-allergic drugs. The anti-inflammatory drugs include glucocorticoid drugs; the glucocorticoid drugs include mometasone furoate, budesonide or fluticasone propionate; the anti-allergic drugs include ebastine, loratadine, and acrivastine. It should be understood that in this embodiment, the drug can be any drug that can be set on the drug-carrying hemostatic cotton, and is not limited to the drugs in this embodiment.

[0057] When the drug-loaded hemostatic cotton is used in the nasal cavity, the drug loading amount of each drug-loaded hemostatic cotton is 100 ug to 1000 ug / g, such as 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 ug / g. In this way, the drug can be safely released every day.

[0058] Preferably, the size of each piece of the drug-loaded hemostatic cotton is length*width*thickness=80mm*20mm*15mm, and the size of the drug-loaded hemostatic cotton can be cut to length*width*thickness=10cm*1cm*3cm for use. Preferably, the drug-loaded layer includes a first drug-loaded layer and a second drug-loaded layer. The porous sponge is a polyurethane sponge. The first drug-loaded layer, the polyurethane layer, and the second drug-loaded layer are sequentially arranged along the thickness direction thereof.

[0059] The embodiment of the present invention further provides a method for preparing drug-loaded hemostatic cotton, and the preparation method is used to realize the above-mentioned drug-loaded hemostatic cotton and achieve various parameter indicators of the above-mentioned drug-loaded hemostatic cotton.

[0060] S1. Preparation of prepolymer: In an anhydrous and oxygen-free environment, with polyethylene glycol (PEG) as an initiator, cyclic ester monomers undergo a ring-opening reaction under the action of a catalyst to synthesize a polyester prepolymer, wherein the average molecular weight of the polyethylene glycol (PEG) is 800-1500. 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. It is directly used in step S3 without post-treatment, thus simplifying the steps of the preparation method and reducing production costs. The selection of the average molecular weight of the polyethylene glycol (PEG) is a specific selection. When its average molecular weight is 800-1500, for example, when 900-1100 is selected, the time when the prepared drug-loaded hemostatic cotton begins to degrade is about 10 times earlier than the degradation time of the drug-loaded hemostatic cotton in the prior art, and the degradation rate is thereby improved, and the degradation rate is greatly increased. After the drug-loaded hemostatic cotton completes hemostasis at the target position, the cavity can be quickly recanalized. Based on this, because the degradation rate of polyethylene glycol (PFG) in this embodiment is very rapid, in the step of synthesizing polyurethane in S3, the steps of water precipitation and alcohol immersion cannot be used, so these two steps can be omitted. At the same time, the drug-loaded hemostatic cotton prepared by the polyester prepolymer synthesized by polyethylene glycol (PEG) can control the degradation time within 36 hours, and the degradation rate is fastest within 6-12 hours. Compared with the uncontrollable degradation time of the prior art, it can ensure degradation within a controllable 36 hours.

[0061] Preferably, in the step S1, the cyclic ester monomer is one or more of DL-lactide, L-lactide, glycolide, caprolactone, trimethylene carbonate, and p-dioxanone. Further, the cyclic ester monomer is glycolide, lactide, and caprolactone. Preferably, in the 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 drug-loaded hemostatic cotton, and improving the degradation rate. For details, please refer to Example 3 and other embodiments below, as well as the analysis of degradation performance below. Preferably, in the 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 the step S1 is 120°C to 140°C; the reaction time is 12 to 36 hours.

[0062] S2. Preparation of chain extender: diisocyanate compound and polyol compound are mixed, reacted at a certain temperature, and separated and purified to prepare isocyanate-terminated triblock compound (HBH), wherein the molar ratio of the diisocyanate compound to the polyol compound is 1:4 to 1:10, so that the polyol compound and the diisocyanate compound can fully react to form isocyanate-terminated triblock compound (HBH). The diisocyanate compound can be one or more of hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), and methylcyclohexyl diisocyanate. Preferably, the diisocyanate compound is preferably hexamethylene diisocyanate (HDI). Compared with tetramethylene diisocyanate used in current commercial 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.

[0063] Preferably, in the step S2, the molar ratio of 1,4-butanediol to hexamethylene diisocyanate is 1:4 to 1:6. 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 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.

[0064] S3, preparation of polyurethane: dissolving the isocyanate-terminated triblock compound (HBH) 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 sedimentation, and then purifying and drying to obtain a polyurethane polymer without water precipitation or alcohol soaking. Preferably, in the SS step, 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.

[0065] One embodiment may be that step S3 includes dissolving the isocyanate-terminated triblock compound prepared by S2 in dimethyl sulfoxide (DMSO), reacting with the polyester prepolymer prepared by S1 at a certain feed ratio, and using a poor solvent, such as ether, for precipitation. Another embodiment may also be that step S3 includes: reacting the polyester prepolymer prepared by S1 with a dimethylformamide solution of the isocyanate-terminated triblock compound prepared by S2, and using ether for precipitation after the polymerization is completed. Wherein dimethylformamide (DMF) may be N,N-dimethylformamide, which is a solvent for the isocyanate-terminated triblock compound (HBH). Ether is used for precipitation because ether has good volatility and less residue. 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 immersion, which avoids the influence of water on the polyurethane polymer, maintains the stability of the degradation of the drug-loaded hemostatic cotton, and improves the yield. At the same time, the steps of aqueous solution sedimentation and alcohol immersion are also reduced, the production steps are reduced, and the production cost is reduced. 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 immersion. 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 the monomer residue of the by-product. The obtained product is effectively post-processed to remove the small molecule monomers and heavy metal residues in the synthesis process, effectively improving the safety of the drug-loaded hemostatic cotton.

[0066] Preferably, in the step S3, the mass concentration of the DMF solution of HBH is 0.2-0.5 g / g. Preferably, in the step S3, the molar ratio of the polyester prepolymer obtained in S1 to the HBH obtained in S2 is 1:1.0-1:1.5. Preferably, in the step S3, the reaction temperature of the polyurethane polymer is 75-90°C, and the reaction time is 3-6 hours. Preferably, in the step S3, the purification process includes diluting the reaction mixture to 10%-25% with dioxane, slowly pouring it into 5-8 times of ice ether under stirring, and then transferring the precipitated white filamentous solid to n-hexane, soaking it for more than 3 hours, and then drying it in an oven at 40°C for 10 hours.

[0067] S4: Preparation of drug-loaded hemostatic cotton: The polyurethane polymer prepared in S3 and the drug are dissolved in an organic solvent and placed in a mold, and then frozen, dried, and sterilized to obtain drug-loaded hemostatic cotton. The freezing and drying process is a process of solution sublimation. After the solution sublimates, uniform pores can be formed to form a microporous solid. The organic solvent is preferably dioxane, which has a high melting point, a low boiling point, and good solubility. The organic solvent can dissolve the polyurethane polymer and the drug at the same time. By dissolving the polyurethane polymer and the drug together, and obtaining the drug-loaded hemostatic cotton through freezing, drying and other steps, the drug can be embedded in the polyurethane, and the drug can be sustained-released during the degradation process of the drug-loaded hemostatic cotton. It can be understood that the embedding is physical embedding. Compared with the prior art, in clinical practice, some doctors use drug-free drug-loaded hemostatic cotton to dip in medicine and then place it in the target position, but the concentration and release of the dipped medicine are uncontrollable, and the medicine is administered once, and quantitative sustained-release administration cannot be achieved. The drug-loaded hemostatic cotton of 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 in medicine during surgery. The drug-loaded hemostatic cotton can be directly implanted into the target position without the step of dipping in medicine, which avoids new safety issues derived from cumbersome steps or dipping in medicine. It also saves the operation time of doctors and patients 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, can achieve compression hemostasis in a short time, does not need secondary surgery to remove, can flow out after degradation with body metabolism, and the degradation product is non-toxic. The drug-loaded hemostatic cotton can also achieve 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.

[0068] 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.

[0069] 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, wherein the thickness of the first drug-carrying layer is smaller than the height in the mold, so that the mold can accommodate the polyurethane layer and the second drug-carrying layer described below.

[0070] S42: The polyurethane polymer prepared in S3 is dissolved in dioxane and placed in the mold, and a polyurethane layer is obtained by freezing. The polyurethane layer is superimposed on the first drug-carrying layer. The sum of the thickness of the first drug-carrying layer and the polyurethane layer is less than the height in the mold, so that the mold can accommodate the second drug-carrying layer described below.

[0071] S43: The polyurethane polymer and the drug prepared in S3 are dissolved in dioxane and placed in a mold, and the second drug-carrying layer is obtained by freezing. The second drug-carrying layer is superimposed on the polyurethane layer, and the drug-carrying hemostatic cotton is obtained by drying, so that the drug-carrying hemostatic cotton includes the first drug-carrying layer, the polyurethane layer, and the second drug-carrying layer in sequence. Such a configuration can make the two surface layers of the drug-carrying hemostatic cotton have drugs, which is more convenient for drug release when the drug content is the same compared to the drug-carrying hemostatic cotton that is completely added with drugs. At the same time, because the drug-carrying hemostatic cotton does not contain drugs inside, the explosive release of drugs when the drug-carrying hemostatic cotton is completely degraded is avoided. In addition, it should be understood that the drug-carrying hemostatic cotton, as an implantable device, needs to have a drug loading within a specified drug loading range. Therefore, within the specified drug loading range, the polyurethane layer of the drug-carrying hemostatic cotton does not contain drugs, and the first drug loading layer and the second drug loading layer contain drugs, and the drug loading concentration increases, and the amount of drugs released during drug sustained release increases, thereby improving the drug efficacy. 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.

[0072] Preferably, the ratio of the thickness of the first drug-carrying layer or the second drug-carrying layer to the thickness of the drug-carrying hemostatic cotton is less than 1 / 3, which increases the concentration of the single-layer drug under the condition of a certain drug dosage. It also avoids the situation where the drug-carrying hemostatic cotton releases the drug explosively when it degrades. Preferably, the thickness ratio of the first drug-carrying layer to the second drug-carrying layer can be 1:1, and the thickness of the first drug-carrying layer to the second drug-carrying layer is preferably 1 mm, and of course, it can also be 2 mm or 3 mm, etc.

[0073] It should be understood that 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. Preferably, the glucocorticoid drugs include mometasone furoate or budesonide. The antiallergic drugs can be used for nasal medication, such as levocabastine hydrochloride, ketotifen fumarate, beclomethasone propionate, mometasone furoate, budesonide, fluticasone propionate. The drugs can also be ciliary agonists and mucus-promoting drugs, such as myrtle oil. The drugs can also be nasal mucosa protective drugs, such as compound peppermint oil, chlorhexidine cod liver oil nasal drops, etc. In this way, the inflammation problem caused by postoperative bacterial infection is solved, the healing of the wound is accelerated, and the problems such as adhesion at the wound site can be avoided. Preferably, mometasone furoate is used in this embodiment as an example for verification and explanation.

[0074] The drug content of the anti-inflammatory drug, antibacterial drug, analgesic drug, hemostatic drug or antiallergic drug is 0.25-0.30‰ (mass ratio) of the polyurethane polymer, thereby ensuring a safe drug loading ratio while ensuring drug loading and achieving a sustained release effect.

[0075] Preferably, in the step S41 or S43, the polyurethane polymer, the drug and the porogen prepared in S3 are dissolved together and placed in a mold, and the porogen is an inorganic salt; the inorganic salt can further be ammonium phosphate, ammonium hydrogen phosphate, and ammonium bicarbonate. Since the inorganic salt is decomposed into non-toxic and harmless gas by heat, and no residue remains, for example, ammonium bicarbonate disappears after being heated to ammonia and carbon dioxide. On the one hand, the drug-loaded hemostatic cotton will not produce harmful substances due to the presence of the porogen during use, and no harmful substances will be produced and precipitated, thereby improving the safety of the product. It is well known in the art that the primary requirement for implantable medical devices is the safety of the product after implantation. The choice of reagents determines the key to whether the product can be listed. This embodiment uses inorganic salts to solve the problem of safety, and has excellent safety performance. On the other hand, the addition of the porogen increases the porosity of the drug-loaded hemostatic cotton, thereby increasing 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 filled into a narrow cavity. Taking the nasal cavity as an example, there are many capillaries in these narrow cavities of the nasal cavity, and the cavities are irregular. The rebound rate (the degree of deformation recovery after the external force is removed) of the drug-loaded hemostatic cotton with the addition of porogen is improved, and the deformation recovery is good. It can rebound well when inserted into the nasal cavity, compressing the capillaries and achieving a good hemostatic effect. Furthermore, the content of the porogen is 3-5% of the polyurethane polymer.

[0076] Preferably, the preparation method further comprises step S5: adding a wetting agent (PEG) to the drug-loaded hemostatic cotton to increase the hydrophilicity and compressive stress of the drug-loaded hemostatic cotton, thereby increasing the degradation rate and the supporting strength of the drug-loaded hemostatic cotton.

[0077] This embodiment also provides a method for preparing drug-loaded hemostatic cotton, comprising:

[0078] 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;

[0079] 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;

[0080] S3: reacting the polyester prepolymer prepared in S1 with the N,N-dimethylformamide solution of the isocyanate-terminated triblock compound prepared in S2, using ether for precipitation, and after precipitation, not performing water precipitation or alcohol soaking treatment, and then purifying and drying to obtain a polyurethane polymer;

[0081] S4: dissolving the polyurethane polymer prepared in S3 with dioxane and placing it in a mold, freezing, drying, and sterilizing to obtain a polyurethane sponge; preparing a suspension of the drug in a poor solvent, placing the polyurethane sponge in the suspension under stirring, removing the suspension after stirring, and drying the suspension, so that the drug is adsorbed in the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton, thereby ensuring the presence of the drug in the drug-loaded hemostatic cotton and facilitating the release of the drug. The poor solvent can bring the drug particles into the pores of the polyurethane sponge through the flow of the poor solvent.

[0082] Preferably, this embodiment also provides another method for preparing drug-loaded hemostatic cotton, wherein S1, S2, and S3 are described above and are not repeated here, and S4 may also be: the polyurethane polymer prepared in S3 is dissolved in dioxane and placed in a mold, and a polyurethane sponge is obtained after freezing, drying, and sterilization. The drug is dissolved in a good solvent to form a drug solution, and the drug solution is diluted with a poor solvent to obtain a drug mixture, and the drug mixture is added to the polyurethane sponge by spraying, dripping, injection, or dipping, and then dried to allow the drug to precipitate and be fixed in the pores of the polyurethane sponge to form a drug-loaded hemostatic cotton.

[0083] 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.

[0084] Preferably, the poor solvent is one or more of water, n-hexane, and cyclohexane. The poor solvent is preferably cyclohexane.

[0085] 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 becoming higher and higher until it dissolves and destroys the sponge.

[0086] Preferably, the concentration of the drug in the benign solvent is 0.5 mg / ml-10 mg / ml.

[0087] 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 destroyed, and if it is too low, the drug will precipitate in the solution.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] [Example 1]

[0092] Preparation of polyurethane:

[0093] In the step S1, 25.0 g of polyethylene glycol (average molecular weight of 1000, Mn=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 is removed, it is cooled to below 70 ° C, and 12.5 g of D, L-lactide, 12.5 g of ε-caprolactone, and 0.005 g of stannous isooctanoate are added in sequence, and vacuumed for 3 minutes, and then the temperature is raised to 130 ° C. After reacting for 24 hours, it can be directly used for the next reaction without post-treatment.

[0094] In step S2, the three-necked flask was fixed in an oil bath pot at 80°C for preheating, 50.4g of hexamethylene diisocyanate was added, 4.5g of 1,4-butanediol was added dropwise under mechanical stirring, and the mixture was sealed and reacted for 4.5h to obtain a milky white paste. The mixture was fully stirred and washed with 400mL of n-hexane, and filtered by suction. After repeating 3 times, the mixture was dried at 40°C for 3h using a rotary evaporator to obtain a pure white solid powder (HBH).

[0095] In the step S3, 50 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 30.00 g of DMF solution is used to dissolve 13.84 g of HBH obtained in step S2 and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 80° C. for 3 hours, a transparent viscous liquid is obtained, dioxane is added to dilute it to 20%, and the liquid is slowly poured into ice ether while hot. After being soaked in n-hexane for 3 hours, the liquid is dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.

[0096] Preparation of drug-loaded hemostatic cotton:

[0097] In step S4, 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 0.25‰ of the polyurethane polymer, and 3% ammonium bicarbonate and 1% PEG (Mn=10000) are added. Liquid B is a 3.5% polyurethane polymer dioxane solution, and 3% ammonium bicarbonate and 1% PEG (Mn=10000) are added. A layer of liquid A is first poured into the mold, and liquid B is poured after freezing at 0°C, and then covered with a layer of liquid A after freezing. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying. After irradiation sterilization of the freeze-dried sample, a layered freeze-dried drug-loaded cotton is obtained, which is recorded as M1.

[0098] [Example 2]

[0099] According to the method in Example 1, S1, S2 and S3 are implemented to obtain the corresponding polymer.

[0100] In the step S4, the polymer is dissolved in a dioxane solution to obtain a 3.5% solution, and 3% of the polymer mass of ammonium bicarbonate and 1% of PEG (Mn=10000) are added to obtain a lyophilized solution. A layer of lyophilized solution is first poured into the mold, and then covered with a layer of lyophilized solution after freezing at 0°C. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying to obtain a blank sponge without medicine. Mometasone furoate is ultrasonically dispersed in a cyclohexane solution to prepare a drug solution with a concentration of 16ug / ml, and the blank sponge is immersed in the drug solution under continuous stirring for 30 seconds, and then taken out and dried in a vacuum drying oven to constant weight, and then sterilized by irradiation to obtain a suspended nanoabsorption drug-loaded cotton. It is recorded as M2.

[0101] [Example 3]

[0102] The corresponding blank sponge was obtained according to the method in Example 2.

[0103] Mometasone furoate was dissolved in ethyl acetate to prepare an initial solution with a concentration of 1.5 mg / ml, and then diluted to 125 ug / ml with cyclohexane. 1 ml was added to the upper and lower surfaces of the sponge using a pipette, and dried to constant weight in a vacuum drying oven. After irradiation sterilization, a solvent-precipitated drug-loaded cotton was obtained, which was recorded as M3.

[0104] [Example 4]

[0105] Preparation of polyurethane:

[0106] In the step S1, 20.0 g of polyethylene glycol (Mn=800) is accurately weighed and added to a 250 mL vacuum reaction bottle, and vacuumed continuously for 2.5 h with a vacuum oil pump at 95° C. to remove water. After the water removal is completed, the bottle is cooled to below 70° C., 10 g of glycolide, 10 g of ε-caprolactone, and 0.004 g of stannous isooctanoate are added in sequence, and vacuumed for 30 seconds. The bottle is then heated to 135° C., reacted for 30 h, and used directly in the next step without post-treatment.

[0107] The preparation method of chain extender HBH is the same as that in Example 1 and will not be described again here.

[0108] In the step S3, 40 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 30.00 g of DMF solution is used to dissolve 14.00 g of HBH obtained in step S2 and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 80° C. for 3.5 hours, a transparent viscous liquid is obtained, dioxane is added to dilute it to 15%, and the liquid is slowly poured into ice ether while hot. After being soaked in n-hexane for 3 hours, it is dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.

[0109] Preparation of drug-loaded hemostatic cotton:

[0110] In step S4, 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 0.30‰ of the polyurethane polymer, and 3.5% ammonium bicarbonate and 1% PEG (Mn=15000) are added. Liquid B is a 4.0% polyurethane polymer dioxane solution, and 3.5% ammonium bicarbonate and 1% PEG (Mn=15000) are added. A layer of liquid A is first poured into the mold, and liquid B is poured after freezing at 0°C, and then covered with a layer of liquid A after freezing. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying. After irradiation sterilization of the freeze-dried sample, a layered freeze-dried drug-loaded cotton is obtained, which is recorded as M4.

[0111] [Example 5]

[0112] According to the method in Example 4, S1, S2 and S3 were implemented to obtain the corresponding polymer.

[0113] In the step S4, the polymer is dissolved in a dioxane solution to obtain a 4.0% solution, 3.5% of the polymer mass of ammonium bicarbonate and 1% of PEG (Mn=15000) are added to obtain a lyophilized solution, a layer of lyophilized solution is first poured into the mold, and then covered with a layer of lyophilized solution after freezing at 0°C. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying to obtain a blank sponge without medicine. Mometasone furoate is ultrasonically dispersed in a cyclohexane solution to prepare a drug solution with a concentration of 20ug / ml, and the blank sponge is immersed in the drug solution under continuous stirring for 45 seconds, and then taken out and dried in a vacuum drying oven to constant weight, and then sterilized by irradiation to obtain a suspended nanoabsorption drug-loaded cotton. It is recorded as M5.

[0114] [Example 6]

[0115] The corresponding blank sponge was obtained according to the method in Example 5.

[0116] Mometasone furoate was dissolved in ethyl acetate to prepare an initial solution with a concentration of 2.0 mg / ml, and then diluted to 150 ug / ml with cyclohexane. 1 ml was added to the upper and lower surfaces of the sponge using a pipette, and dried to constant weight in a vacuum drying oven. After irradiation sterilization, a solvent-precipitated drug-loaded cotton was obtained, which was recorded as M6.

[0117] [Example 7]

[0118] Preparation of polyurethane:

[0119] In the step S1, 15.0 g of polyethylene glycol (Mn=1000) is accurately weighed and added to a 250 mL vacuum reaction bottle, and vacuumed continuously for 2.0 h at 95° C. using a vacuum oil pump to remove water. After the water removal is completed, the bottle is cooled to below 70° C., 15 g of L-lactide, 15 g of ε-caprolactone, and 0.004 g of stannous isooctanoate are added in sequence, and vacuumed for 30 seconds. The bottle is then heated to 130° C., reacted for 30 h, and used directly in the next step without post-treatment.

[0120] The preparation method of chain extender HBH is the same as that in Example 1 and will not be described again here.

[0121] In the step S3, 40 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 30.00 g of DMF solution is used to dissolve 14.00 g of HBH obtained in step S2 and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 80° C. for 3.5 hours, a transparent viscous liquid is obtained, dioxane is added to dilute it to 15%, and the liquid is slowly poured into ice ether while hot. After being soaked in n-hexane for 3 hours, it is dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.

[0122] Preparation of drug-loaded hemostatic cotton:

[0123] In step S4, two liquids A and B are respectively prepared, wherein liquid A is a 4.5% polyurethane polymer dioxane solution containing mometasone furoate, wherein the content of mometasone furoate is 0.30‰ of the polyurethane polymer, and 4.0% ammonium bicarbonate and 1.5% PEG (Mn=20000) are added. Liquid B is a 4.5% polyurethane polymer dioxane solution, and 4.0% ammonium bicarbonate is added. A layer of liquid A and 1.5% PEG (Mn=20000) is first poured into the mold, and liquid B is poured after freezing at 0°C, and then covered with a layer of liquid A after freezing. After freezing at -25°C, it is transferred to a freeze dryer for freeze drying. After irradiation sterilization of the freeze-dried sample, a degradable drug-loaded hemostatic sponge is obtained, which is recorded as M3.

[0124] [Example 8]

[0125] According to the method in Example 7, S1, S2 and S3 were implemented to obtain the corresponding polymer.

[0126] In the step S4, the polymer is dissolved in a dioxane solution to obtain a 4.5% solution, 4.0% of the polymer mass of ammonium bicarbonate and 1% of PEG (Mn=15000) are added to obtain a lyophilized solution, a layer of lyophilized solution is first poured into the mold, and then covered with a layer of lyophilized solution after freezing at 0°C. After freezing at -20°C, it is transferred to a lyophilizer for lyophilization to obtain a blank sponge without medicine. Mometasone furoate is ultrasonically dispersed in a n-hexane solution to prepare a drug solution with a concentration of 20ug / ml, and the blank sponge is immersed in the drug solution under continuous stirring for 45 seconds, taken out and dried in a vacuum drying oven to constant weight, and sterilized by irradiation to obtain a suspended nanoabsorption drug-loaded cotton. It is recorded as M8.

[0127] [Example 9]

[0128] The corresponding blank sponge was obtained according to the method in Example 8.

[0129] Mometasone furoate was dissolved in ethyl acetate to prepare an initial solution with a concentration of 1.0 mg / ml, and then diluted to 100 ug / ml with cyclohexane. 1.5 ml was dripped onto the upper and lower surfaces of the sponge using a pipette, and dried to constant weight in a vacuum drying oven. After irradiation sterilization, a solvent-precipitated drug-loaded cotton was obtained, which was recorded as M9.

[0130] [Example 10]

[0131] Preparation of polyurethane:

[0132] In the step S1, 25.0 g of polyethylene glycol (Mn=1500) is accurately weighed and added to a 250 mL vacuum reaction bottle, and vacuumed continuously for 2.0 h at 95° C. using a vacuum oil pump to remove water. After the water removal is completed, the bottle is cooled to below 70° C., 12.5 g of L-lactide, 12.5 g of ε-caprolactone, and 0.004 g of stannous isooctanoate are added in sequence, and vacuumed for 30 seconds. The bottle is then heated to 130° C., reacted for 24 h, and used directly in the next step without post-treatment.

[0133] The preparation method of chain extender HBH is the same as that in Example 1 and will not be described again here.

[0134] In the step S3, 50 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 13.00 g of the HBH obtained in step S2 is dissolved in 26.00 g of DMF solution and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 85° C. for 2.5 hours, a transparent viscous liquid is obtained, dioxane is added to dilute it to 15%, and the liquid is slowly poured into ice ether while hot. After being soaked in n-hexane for 3 hours, it is dried in an oven at 40° C. for 10 hours to obtain a transparent filamentous solid as a polyurethane polymer.

[0135] Preparation of drug-loaded hemostatic cotton:

[0136] In the step S4, 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 0.30‰ of the polyurethane polymer. Liquid B is a 3.5% polyurethane polymer dioxane solution. A layer of liquid A is first poured into the mold, and liquid B is poured after freezing at 0°C, and then covered with a layer of liquid A after freezing again. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying. After irradiation sterilization of the freeze-dried sample, a degradable drug-loaded hemostatic sponge is obtained, which is recorded as M10.

[0137] [Example 11]

[0138] According to the method in Example 10, S1, S2 and S3 were implemented to obtain the corresponding polymer.

[0139] In the step S4, the polymer is dissolved in a dioxane solution to obtain a 3.5% solution, a layer of the solution is first poured into the mold, and then covered with another layer of the solution after freezing at 0°C. After freezing at -20°C, it is transferred to a freeze dryer for freeze drying to obtain a blank sponge without medicine. Mometasone furoate is ultrasonically dispersed in a n-hexane solution to prepare a drug solution with a concentration of 20ug / ml, and the blank sponge is immersed in the drug solution under continuous stirring for 45 seconds, and then taken out and dried in a vacuum drying oven to constant weight, and then sterilized by irradiation to obtain a suspended nanoabsorption drug-loaded cotton. It is recorded as M11.

[0140] [Example 12]

[0141] The corresponding blank sponge was obtained according to the method in Example 11.

[0142] Mometasone furoate was dissolved in ethyl acetate to prepare an initial solution with a concentration of 2.0 mg / ml, and then diluted to 100 ug / ml with cyclohexane. 1.5 ml was dripped onto the upper and lower surfaces of the sponge using a pipette, and dried to constant weight in a vacuum drying oven. After irradiation sterilization, a solvent-precipitated drug-loaded cotton was obtained, which was recorded as M12.

[0143] [Example 13]

[0144] The prepolymer and chain extender described in S1 and S2 were prepared according to the method in Example 4.

[0145] 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 detected by infrared detection completely disappeared (2300 cm -1 ). Continue to vacuum overnight to remove DMSO, then add dioxane to dilute to 20%, precipitate with n-hexane and dry in an oven to constant weight to obtain a light yellow solid which is a polyurethane polymer.

[0146] The drug-loaded hemostatic cotton was prepared according to the method described in step S4 of Example 1 and was recorded as M13.

[0147] [Example 14]

[0148] The prepolymer and chain extender described in S1 and S2 were prepared according to the method in Example 1.

[0149] 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 detected by infrared detection completely disappeared (2300 cm -1 ). Continue to vacuum overnight to remove DMSO, then add dioxane to dilute to 20%, collect the supernatant after centrifugation and precipitate with n-hexane, and dry in an oven to constant weight to obtain a light yellow solid as a polyurethane polymer.

[0150] The drug-loaded hemostatic cotton was prepared according to the method described in Example 12 and was recorded as M14.

[0151] [Example 15]

[0152] The prepolymer and chain extender described in S1 and S2 were prepared according to the method in Example 1.

[0153] 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 detected by infrared detection completely disappeared (2300 cm -1 ). Dioxane was added again to dilute to 20%, and petroleum ether was used for precipitation and then dried in an oven to constant weight to obtain a light yellow solid which was a polyurethane polymer.

[0154] The drug-loaded hemostatic cotton was prepared according to the method described in Example 12 and was recorded as M15.

[0155] [Example 16]

[0156] The prepolymer and chain extender described in S1 and S2 were prepared according to the method in Example 4.

[0157] 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 detected by infrared detection completely disappeared (2300 cm -1 ). Dioxane was added again to dilute to 25%, cyclohexane was used for precipitation, and then dried in an oven to constant weight to obtain a light yellow solid which was a polyurethane polymer.

[0158] The drug-loaded hemostatic cotton was prepared according to the method described in Example 12 and was recorded as M16.

[0159]

Comparative Example 1

[0160] In the step S1, 15.0 g of polyethylene glycol (Mn=600) is accurately weighed and added to a 250 mL vacuum reaction bottle, and vacuumed continuously for 2.0 h at 95° C. using a vacuum oil pump to remove water. After the water removal is completed, the bottle is cooled to below 70° C., 12.5 g of L-lactide, 12.5 g of ε-caprolactone, and 0.004 g of stannous isooctanoate are added in sequence, and vacuumed for 30 seconds. The bottle is then heated to 130° C., reacted for 24 h, and used directly in the next step without post-treatment.

[0161] The preparation method of chain extender HBH is the same as that in Example 1 and will not be described again here.

[0162] In the step S3, 40 g of the polyester prepolymer obtained in step S1 is added to a three-necked flask, and then 10.4 g of the HBH obtained in step S2 is dissolved in 26.00 g of DMSO solution and added dropwise to the three-necked flask under stirring. After the reaction is sealed at 85° C. for 2.5 hours, a transparent viscous liquid is obtained, dioxane is added to dilute it to 15%, and the liquid is slowly poured into purified water while hot to precipitate a white strip-like solid. After being fished out, the water is wrung out and the liquid is soaked in ice ethanol to further remove the water, and the liquid is dissolved again with dioxane to 15%, and the liquid is precipitated into a filamentous solid in ice ether, and dried to constant weight.

[0163] Preparation of drug-loaded hemostatic cotton:

[0164] In the step S4, the polymer is dissolved in dioxane to prepare 3.5%, 0.3‰ of the mass of the polymer is added to obtain a lyophilized liquid, and the drug-loaded hemostatic cotton is prepared after freeze-drying in a mold, which is recorded as DBM.

[0165] [Comparative Example 2]: This comparative example provides a commercially available product as a reference sample, denoted as NXM.

[0166] Performance Testing

[0167] Porosity: Pre-weighed drug-loaded hemostatic cotton was immersed in a known volume of water (V1) and degassed with a vacuum pump for 5 minutes. The total volume of water and the water-impregnated sponge was recorded as (V2), and the water-impregnated sponge was removed and the residual volume of water was recorded as (V3); the porosity (a) of the sponge was calculated as follows:

[0168] (a)%=(V1-V3) / (V2-V3)×100%.

[0169] The water absorption performance indirectly reflects the effect of the drug-loaded hemostatic cotton on hemostasis. The specific test method of the water absorption performance is: weigh the freeze-dried drug-loaded hemostatic cotton sample prepared in the embodiment (record as dry weight) and gently place it on the surface of purified water. The water can extend upward along the pores of the sample until the top is completely immersed, and the water absorption time is recorded; wipe off the surface flowing water and weigh it, record it as wet weight, and calculate the water absorption rate of the sample according to the ratio of wet / dry weight. Each sample is repeated three times. The specific test results are shown in Table 1.

[0170] Table 1

[0171]

[0172]

[0173] According to Table 1, the porosity of the sample increases with the increase of the use of the porogen. This is because the porogen ammonium bicarbonate occupies a certain space in the solvent. During the cooling process, the porogen is separated from it, and decomposed into carbon dioxide and ammonia during the drying process to be discharged from the drug-loaded hemostatic cotton, forming a large number of pores and improving the porosity. In addition, the water absorption rate and water absorption rate of the sponge are proportional to the proportion of polyethylene glycol in the entire molecular chain segment and the amount used as a humectant. The water absorption time can reach less than three minutes, which is comparable to the commercially available product NXM and better than the comparative example DBM. This shows that the lower the molecular weight of PEG, the lower the proportion of hydrophilic chains in the entire polymer chain segment, which reduces the hydrophilicity.

[0174] Compression performance: The drug-loaded hemostatic cotton sample prepared in the embodiment is placed statically between two upper and lower compression plates, and the sample is slowly compressed to 50% of its original height. After maintaining the pressure for 5 minutes, the pressure is removed and the height of the sample after recovery is tested. The rebound rate is calculated based on the change in height before and after compression.

[0175] Table 2

[0176]

[0177]

[0178] According to Table 2, it can be found that except for the comparative example DBM, the compression strength of the drug-loaded hemostatic cotton is above 10kPa, the rebound rate is greater than 95%, and the conformability of the drug-loaded hemostatic cotton is good. The performance of the sample of the embodiment is comparable to that of the comparative example NXM, and as the porosity increases, more radial support forces in different directions are generated, the rebound rate is improved, and the degree of recovery after the drug-loaded hemostatic cotton is squeezed and unloaded is facilitated. In the comparative example DBM, the compression strength is significantly lower than that of other samples because the alcohol bubble after water precipitation is used, which causes a certain degree of hydrolysis and alcoholysis in the subsequent dissolution process of dioxane, resulting in a decrease in molecular weight and performance degradation. It can be seen from this that the specific polyethylene glycol used in this embodiment and the process of non-water precipitation alcohol bubble have obtained drug-loaded hemostatic cotton with good mechanical properties.

[0179] Degradation performance: The drug-loaded hemostatic cotton samples prepared in the example 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) and stress value when compressed to 50% of the sample were tested and recorded every 1 hour. The results are as follows: Figure 1 , Figure 2 The drug-loaded hemostatic cotton M1-M12 prepared in the examples began to degrade within 1 hour and could be preliminarily degraded within 3 hours. At 3 hours, the weight average molecular weight and compressive strength decreased to less than 60%, and as the degradation time increased, the values ​​gradually decreased and eventually became stable due to the influence of water surface tension.

[0180] 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 becomes poor, inhibiting the contact between water molecules and 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. Figure 1 It can be seen that the number average molecular weight of M7-M9 samples is higher than that of the other samples, which shows that their degradation rate is low due to their poor hydrophilicity. Figure 2It can be seen that the compression 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 the PEG segment will also affect the degradation degree of the drug-loaded hemostatic cotton. Preferably, the ratio of the PEG segment to the polyester segment is 1:1-1:1.25.

[0181] like Figure 3 , Figure 3 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 Figure 4 The morphology of Figure 4 , Figure 4 This is the morphology of the M1 sample after 24 hours of degradation. As can be seen from the figure, the drug-loaded hemostatic cotton has been degraded and broken, indicating that the sample of this example 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 example 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.

[0182] Drug release: Immerse the drug-loaded hemostatic cotton in 500 ml of SDS solution (1.0%), seal it, and place it in a 37°C constant temperature shaker. For example, take 1 ml of SDS solution at regular intervals and add 1 ml. Determine the drug concentration by liquid chromatography, and then calculate the drug release amount. Test results are as follows: Figure 5 shown.

[0183] From the release results, different dosing methods have a more obvious change on the drug release results. For example, the drug release of the upper and lower layered dosing method (M1, M4, M7, M10 samples) showed a linear trend in the first two days, and then the release was slow and stable. Compared with layered dosing, the direct freeze-drying dosing method makes the sponge contain drugs inside and outside. In the early stage of release, only part of the outermost layer of drugs is released by solvent diffusion, and then after degradation, the release amount increases rapidly, and burst release occurs, which is easy to cause local tissue poisoning reactions in clinical applications. The use of external dosing methods on blank sponges (suspension nanoabsorption and solvent precipitation) can make the drug released quickly in the early stage, which is conducive to eliminating inflammatory reactions and accelerating the recovery of injured parts. Through layered freeze-drying, the drug is slowly released when the outer layer degrades, further improving the safety of the use of drug-loaded hemostatic cotton; and the use of external dosing methods can quickly administer drugs to the injured part in the early stage, reduce inflammatory reactions and accelerate wound healing.

[0184] 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 drug-loaded hemostatic cotton, 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, 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, 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, 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, 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, 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: 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; 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, 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 drug-loaded hemostatic cotton according to claim 8, 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, characterized in that: The drug sustained-release system comprises the drug-loaded hemostatic cotton according to claim 1.

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