An injectable branched polyester hemostatic powder and its preparation method and application

Abstract

The application belongs to the field of biomedical materials, and discloses an injectable branched polyester hemostatic powder based on a branched polyethylene glycolized polysebacic acid fatty triol ester derivative, and a preparation method and application thereof. A new branched polyester derivative is provided, and an injectable hemostatic powder is prepared based on the branched polyester derivative, and the hemostatic powder has the characteristics of injectability, high water absorption and adhesion, can quickly seal and hemostasis, and can be used in scenes such as high-pressure bleeding in a wet environment, so as to achieve the function of effective wound sealing and hemostasis. Based on the above characteristics, the injectable hemostatic powder can be used as a relatively universal medical instrument basic material for hemostasis in different tissues, organs and environments.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials, and mainly relates to an injectable branched polyester hemostatic powder, its preparation method and application. Background Technology

[0002] In both military and civilian settings, uncontrollable bleeding from severe trauma remains a leading cause of preventable death globally, claiming more than two million lives annually. While the body's inherent coagulation cascade often fails to prevent massive hemorrhage, rapid and effective on-site hemostasis using hemostatic materials, especially in wartime trauma environments, is essential for saving lives and preventing bleeding complications.

[0003] Traditional acute wound management primarily relies on gauze and bandages for hemostasis and dressing. However, gauze-assisted physical compression is rarely effective for deep, non-compressible bleeding, let alone preventing infection and reducing inflammation. Furthermore, gauze-covered wounds are prone to secondary damage, delayed healing, and cause pain and inconvenience to patients. Despite significant advancements in hemostatic materials, rapidly and completely closing narrow, irregularly shaped, non-compressible, and life-threatening wounds remains challenging for most hemostatic agents. Moreover, hemostatic materials suitable for emergency treatment need to meet a range of important requirements, including biocompatibility, availability, ease of application to various types of tissue injury, biodegradability or portability, low cost, and stable storage. These unmet requirements have spurred the development of new hemostatic material technologies. Summary of the Invention

[0004] Based on the above needs and challenges, this invention constructs an injectable, portable, high-density, high-adhesion hemostatic powder suitable for severe traumatic bleeding and even field combat wound environments. This product is suitable for closing narrow, irregularly shaped, and non-compressible wounds. After injection and appropriate pressure, it can effectively seal the bleeding site, buying valuable time for pre-hospital emergency care. Compared to existing hemostatic materials, this product has good biocompatibility, excellent tissue adhesion, and highly efficient hemostatic properties. Its hemostatic performance does not depend on the body's coagulation cascade reaction, and it has achieved good results in animal bleeding models.

[0005] The purpose of this invention is to provide a novel injectable branched polyester hemostatic powder, its preparation method, and its application. It can effectively seal arterial high-pressure bleeding in wet environments, and the adhesion time can be precisely controlled to the second. After application to the wound, it can effectively adhere and stop bleeding immediately.

[0006] To achieve the above-mentioned objectives, the following technical solution is adopted:

[0007] In a first aspect, this application provides a branched polyethylene glycol-modified polysaccharide triol ester, wherein the branched polyethylene glycol-modified polysaccharide triol ester is named a precursor polymer, and the precursor polymer is a novel branched polyether diol polysaccharide triol ester with a number-average molecular weight of 5000~10000 Da; the molecular weight distribution coefficient of the precursor polymer is 1.0~2.0; and the precursor polymer has the general structural formula shown in the following formula (I):

[0008] Equation (I); Where z is 8 and n is 40-50.

[0009] The method for preparing the precursor polymer includes the following steps: Under nitrogen protection, glycerol, polyethylene glycol, and sebacic acid were dissolved in anhydrous N,N-dimethylformamide in a molar ratio of 1:1:1. Then, 1.2 eq of dicyclohexylcarbodiimide and 0.12 eq of 4-dimethylaminopyridine were added, and the mixture was stirred at 25-70°C (preferably 50-60°C) for 3-12 h (preferably 4-6 h) to obtain product 1. Product 1 was purified by dialysis to obtain the desired precursor polymer: branched polyethylene glycol-modified polysaccharide triol ester.

[0010] Secondly, this application provides a branched polyethylene glycol-modified polysaccharide triol ester derivative, the derivative being named a first polymer, which is prepared based on a precursor polymer.

[0011] The first polymer is a branched polyethylene glycol-modified polysaccharide triol ester with functional groups on the side groups; a more preferred embodiment is that the first polymer is obtained by modifying the branched polyethylene glycol-modified polysaccharide triol ester with acryloyl chloride; an even more preferred embodiment is that the grafting rate of the branched polyethylene glycol-modified polysaccharide triol ester derivative with functional groups on the side groups is 20-100%, more preferably 50-100%, and even more preferably 75-100%.

[0012] The first polymer has the general structural formula shown in the following formula (II):

[0013] Formula (II); Where z is 8 and n is 40-50.

[0014] The method for preparing the first polymer includes the following steps: Under a nitrogen atmosphere, the precursor polymer and triethylamine were dissolved in anhydrous N,N-dimethylformamide at a molar ratio of 1:100 to 1:150. Acryloyl chloride (precursor polymer:acryloyl chloride = 1:100 to 1:150) was added dropwise at 0°C. After the reaction was complete, the mixture was filtered, precipitated with methyl tert-butyl ether, purified by dialysis, and then lyophilized to obtain a white waxy solid, which was the first polymer.

[0015] Thirdly, this application provides an injectable branched polyester hemostatic powder, comprising: branched polyester hemostatic powder and a hydrophobic agent; The branched polyester hemostatic powder comprises a first polymer, a monomer, and a photoinitiator. The mass ratio of the first polymer to the monomer is 1:10 to 1:5, preferably 1:9 to 1:6, and more preferably 1:8. The photoinitiator accounts for 0.3 to 2% of the monomer mass, preferably 0.6 to 1%.

[0016] The monomer is one or a combination of the following compounds: acrylic acid, N-isopropylacrylamide, dimethylaminoethyl methacrylate, and N-succinimide acrylate.

[0017] The photoinitiator is one or a combination of the following compounds: lithium phenyl-2,4,6-trimethylbenzoyl phosphite, 2,4,6-(trimethylbenzoyl)diphenylphosphine oxide, ethyl 2,4,6-trimethylbenzoyldiphenylphosphine oxide, and 2-hydroxy-2-methyl-1-phenyl-1-propanone.

[0018] Furthermore, the hydrophobic agent is selected from one or more of silicone oil, mineral oil, vegetable oil derivatives, and perfluorocarbon liquid.

[0019] The concentration of the hydrophobic agent is 5-30% (w / w), preferably 20-30% (w / w).

[0020] The hydrophobic agent has the functions of preventing agglomeration, improving surface adhesion, and lubricating pipe walls.

[0021] The preparation method of the injectable polyester hemostatic powder includes the following steps: Step S1: The branched polyethylene glycol-modified polysaccharide triol derivative, monomer and photoinitiator are mixed to obtain a hydrogel precursor solution, which is then subjected to ultraviolet light-initiated polymerization and curing to obtain a hydrogel; the wavelength of the ultraviolet light-initiated polymerization and curing is 300-700nm, preferably 350-450nm, and more preferably 405nm. Step S2: Place the hydrogel from step S1 into a freeze dryer and freeze dry for 24-96 hours to obtain a freeze-dried solid. Step S3: The freeze-dried solid from step S2 is pulverized to obtain the branched polyester hemostatic powder. Step S4: Add a hydrophobic agent to the branched polyester hemostatic powder from step S3 above, and stir until homogeneous to obtain the injectable branched polyester hemostatic powder.

[0022] Fifthly, this application provides the use of the injectable branched polyester hemostatic powder in the preparation of in vivo and in vitro hemostatic products.

[0023] The uses include the preparation of hemostatic instruments, consumables, or drugs for different tissues, organs, and environments.

[0024] The injectable branched polyester hemostatic powder has high water absorption capacity of 3-5 g / g and is injectable, achieving rapid hemostasis with a hemostasis time of 5-60 seconds.

[0025] In summary, this application has the following beneficial effects: The hemostatic powder of this invention exhibits high biosafety, is unlikely to cause inflammation or foreign body reactions, and its synthesis and phase transition processes are conducted under mild reaction conditions, preventing deformation of bioactive substances. The hemostatic powder provided by this invention is suitable for applications involving high-pressure bleeding in moist environments, effectively achieving wound sealing and hemostasis. Based on these characteristics, the hemostatic powder disclosed in this invention can serve as a relatively universal basic material for medical devices, applicable to hemostasis in various tissues, organs, and environments. Attached Figure Description

[0026] Figure 1 : 1H NMR spectrum of branched polyethylene glycol-modified polysaccharide triol ester derivative; Figure 2 Fourier transform infrared spectra of branched polyethylene glycol-modified polysaccharide triol derivatives; Figure 3 Scanning electron microscope image of injectable hemostatic powder; Figure 4 : Hemostatic effect diagram of injectable hemostatic powder. Detailed Implementation

[0027] The technical solutions and effects of this application will be further described in detail below with reference to the embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention.

[0028] Example 1 Preparation of branched polyethylene glycol-modified polysaccharide triol ester (precursor polymer) Under nitrogen protection, 0.46 g of glycerol, 5.00 g of polyethylene glycol, and 1.01 g of sebacic acid were dissolved in 10 mL of anhydrous N,N-dimethylformamide. Then, 1.24 g of N,N-dicyclohexylcarbodiimide and 0.07 g of 4-dimethylaminopyridine were added, and the mixture was stirred at 60°C for 4 h to obtain product 1, the precursor polymer. The product was purified by dialysis and was a white waxy solid with a yield of 87.7%.

[0029] Example 2 Preparation of branched polyethylene glycol-modified polysaccharide triol ester derivatives (first polymer) Under a nitrogen atmosphere, 0.36 g of the precursor polymer (0.00006 mol) and 0.73 g of triethylamine (0.0072 mol) were dissolved in 10 mL of anhydrous N,N-dimethylformamide. 0.65 g of acryloyl chloride (0.0072 mol) was added dropwise at 0°C, and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the mixture was filtered, precipitated with methyl tert-butyl ether, purified by dialyzing, and lyophilized to give product 2, the first polymer, with a yield of 72%.

[0030] The proton NMR spectrum of product 2 was measured using deuterated dimethyl sulfoxide as a deuteration reagent, as shown below. Figure 1 As shown in the figure, the peak at 7-6 ppm represents hydrogen atoms on the acryloyl functional group, confirming the successful preparation of crosslinking agent-branched polyethylene glycol-modified polysaccharide triol ester derivatives.

[0031] The molecular structure of the product was characterized by Fourier transform infrared spectroscopy in the range of 1765–1720 cm⁻¹. -1 The characteristic peak of C=O stretching vibration appears at 1280~1000 cm⁻¹. -1 The presence of a COC stretching vibration characteristic peak at the point indicates the successful preparation of a branched polyethylene glycol-modified polysaccharide triol derivative.

[0032] Example 3 Preparation of injectable branched polyester hemostatic powder Step 1: Dissolve 5 w / w% of the first polymer, 42 w / w% of acrylic acid, 3 w / w% of N-succinimide acrylate and 0.1 w / w% of phenyl-2,4,6-trimethylbenzoyl lithium phosphite in ultrapure water and mix thoroughly to obtain a homogeneous precursor solution. Then, inject the precursor solution into a mold and solidify it under 365 nm wavelength irradiation to obtain a hydrogel.

[0033] Step 2: Place the hydrogel obtained in Step 1 into a freeze dryer, and remove it after 48 hours to obtain a freeze-dried solid. Step 3: The freeze-dried solids from the above two steps are pulverized to obtain the branched polyester hemostatic powder.

[0034] Step S4: Add hydrophobic silicone oil to the branched polyester hemostatic powder from step S3 above, wherein the mass ratio of branched polyester hemostatic powder to silicone oil is 3:1, and stir evenly to obtain the injectable branched polyester hemostatic powder.

[0035] Example 4 Water absorption performance test of injectable polyester hemostatic powder.

[0036] Take 0.1g of branched polyester hemostatic powder, soak it in 20mL of physiological saline, and weigh it after 24 hours. Calculate the water absorption per gram of material based on the difference in total weight before and after soaking. Simultaneously, compare it with commercially available chitosan hemostatic powder (Registration Certificate No.: Lu Medical Device Registration 20152140682, Manufacturer: Qingdao Boyite Biomaterials Co., Ltd.). The results are shown in the table below.

[0037] Note: The photoinitiator for all groups above is lithium phenyl-2,4,6-trimethylbenzoyl phosphite; the hydrophobic agent is silicone oil.

[0038] Example 5 The microstructure of the injectable polyester hemostatic powder was characterized using scanning electron microscopy, such as... Figure 3 As shown in the figures, Figure A shows branched polyester hemostatic powder without a hydrophobic agent, Figure B shows injectable branched polyester hemostatic powder with a hydrophobic agent, and Figure C compares it to commercially available chitosan hemostatic powder. The figures reveal that the branched polyester hemostatic powder without a hydrophobic agent is in the form of dispersed granules; after adding a hydrophobic agent, it forms a branched polyester hemostatic powder with a film-like surface. In contrast, the commercially available chitosan hemostatic powder is in the form of flake-like granules.

[0039] Example 6 The hemostatic effect of injectable polyester hemostatic powder.

[0040] After anesthetizing the pig, the femoral artery is transversely severed with a scalpel. A large amount of blood will gush out. Hemostatic powder is quickly injected into the bleeding wound, and pressure is applied for 10-60 seconds, releasing every 10 seconds to observe. If bleeding does not stop, pressure is continued. The effect is as follows: Figure 4 As shown. By injecting the hemostatic powder in situ into the bleeding site, rapid hemostasis can be achieved within 30 seconds.

[0041] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A branched polyethylene glycol-modified polysaccharide triol ester, characterized in that, The branched polyethylene glycol-modified polysaccharide triol ester has a number-average molecular weight of 5000~10000 Da and a molecular weight distribution coefficient of 1.0~2.0, and has the general structural formula shown in the following formula (Ⅰ): Equation (I); Where z is 8 and n is 40~50.

2. The method for preparing branched polyethylene glycol-modified polysaccharide triol ester according to claim 1, characterized in that, The process includes the following steps: under nitrogen protection, glycerol, polyethylene glycol, and sebacic acid are dissolved in anhydrous N,N-dimethylformamide, then dicyclohexylcarbodiimide and 4-dimethylaminopyridine are added, and the reaction is stirred to obtain product 1. Product 1 is purified by dialysis to obtain branched polyethylene glycolated polysaccharide triol ester.

3. A branched polyethylene glycol-modified polysaccharide triol ester derivative, characterized in that, The derivative is prepared based on the branched polyethylene glycol-modified polysaccharide triol ester according to claim 1, and has the general structural formula shown in formula (II) below: Formula (II); Where z is 8 and n is 40~50.

4. The derivative according to claim 3, characterized in that, The grafting rate of the derivative is 20-100%, more preferably 50-100%, and even more preferably 75-100%.

5. The method for preparing the branched polyethylene glycol-modified polysaccharide triol ester derivative according to claim 3, characterized in that, Includes the following steps: Under a nitrogen atmosphere, the branched polyethylene glycol-modified polysaccharide triol ester and triethylamine described in claim 1 were dissolved in anhydrous N,N-dimethylformamide. Acryloyl chloride was then added, and the mixture was stirred to react. After the reaction was completed, the mixture was filtered, precipitated with methyl tert-butyl ether, purified by dialyzing, and then lyophilized to obtain product 2, which is the branched polyethylene glycol-modified polysaccharide triol ester derivative.

6. An injectable branched polyester hemostatic powder, characterized in that, include: Branched polyester hemostatic powder and hydrophobic agent; The branched polyester hemostatic powder includes the branched polyethylene glycol-modified polysaccharide triol ester derivative, monomer, and photoinitiator as described in claim 3 or 4.

7. The injectable branched polyester hemostatic powder according to claim 6, characterized in that, The monomer is selected from one or more of acrylic acid, N-isopropylacrylamide, dimethylaminoethyl methacrylate, and N-succinimide acrylate.

8. The injectable branched polyester hemostatic powder according to claim 6, characterized in that, The photoinitiator is one or a combination of the following compounds: lithium phenyl-2,4,6-trimethylbenzoyl phosphite, 2,4,6-(trimethylbenzoyl)diphenylphosphine oxide, ethyl 2,4,6-trimethylbenzoyldiphenylphosphine oxide, and 2-hydroxy-2-methyl-1-phenyl-1-propanone.

9. The injectable branched polyester hemostatic powder according to claim 6, characterized in that, The mass ratio of the derivative to the monomer is 1:10 to 1:5, preferably 1:9 to 1:6, and more preferably 1:8; the concentration of the photoinitiator is 0.3 to 2% (w / w), preferably 0.6 to 1% (w / w).

10. The injectable branched polyester hemostatic powder according to claim 6, characterized in that, The hydrophobic agent is selected from one or more of silicone oil, mineral oil, vegetable oil derivatives, and perfluorinated carbon liquid.

11. The injectable branched polyester hemostatic powder according to claim 6, characterized in that, The concentration of the hydrophobic agent is 5-30% (w / w), preferably 20-30% (w / w).

12. The method for preparing the injectable polyester hemostatic powder according to any one of claims 6-11, characterized in that, Includes the following steps: Step S1: The branched polyethylene glycol-modified polysaccharide triol derivative, monomer and photoinitiator are mixed to obtain a hydrogel precursor solution, which is then polymerized and cured by ultraviolet light to obtain a hydrogel. Step S2: Place the hydrogel from step S1 into a freeze dryer and freeze dry for 24-96 hours to obtain a freeze-dried solid. Step S3: The freeze-dried solid from step S2 is pulverized to obtain the branched polyester hemostatic powder. Step S4: Add a hydrophobic agent to the branched polyester hemostatic powder from step S3 above, and stir until homogeneous to obtain the injectable branched polyester hemostatic powder.

13. Use of the injectable branched polyester hemostatic powder according to any one of claims 6-11 in the preparation of in vivo and in vitro hemostatic products.

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