Modified sodium alginate / quaternized chitosan self-expanding composite hemostatic powder and preparation method thereof

Abstract

The invention discloses modified sodium alginate / quaternized chitosan self-expanding composite hemostatic powder and a preparation method thereof. The preparation method comprises the following steps: S1, preparing sodium alginate grafted dopamine through amidation reaction, dialyzing, freeze-drying and grinding into powder; s2, mixing the modified sodium alginate and the quaternized chitosan powder according to different mass ratios; s3, adding citric acid and sodium bicarbonate powder with different masses into the mixed powder, and uniformly mixing to obtain the modified sodium alginate / quaternized chitosan self-expansion composite hemostatic powder. The hemostatic powder obtained by the method has the excellent characteristics of blood-triggered expansion, fast gelation, shape self-adaption, coagulation promotion and the like, and has excellent hemostatic performance in deep irregular wounds. Compared with commercial styptic powder, the styptic powder prepared by the method is simple in preparation process, low in cost and relatively high in safety. The modified sodium alginate / quaternized chitosan self-expansion composite hemostatic powder has a great application prospect in the field of incompressible bleeding control materials.

Description

Technical Field

[0001] The present invention belongs to the field of medical polymer materials, and specifically relates to a modified sodium alginate / quaternized chitosan self-expanding composite hemostatic powder and a preparation method thereof. The hemostatic powder has a wide range of raw materials, has excellent properties such as rapid blood-triggered expansion, rapid gelation, high shape adaptability, and blood coagulation promotion, and exhibits excellent hemostatic performance for deep, irregular, and non-pressable wounds. Background Art

[0002] In the field of modern medicine, bleeding control has always been a crucial part of surgical operations and trauma treatment. With the advancement of medical technology and the aging of the population, wound types and bleeding conditions have become increasingly complex. Among them, the problem of hemostasis of non-pressable and irregular wounds is particularly prominent, which not only brings great challenges to medical personnel, but also poses a serious threat to the life safety of patients. Non-pressable wounds mainly refer to those wounds located deep in the body, near internal organs or important blood vessels. Since it is difficult to directly apply sufficient pressure to these parts with hands or materials, traditional direct compression hemostasis methods are often difficult to work. This type of wound usually bleeds a lot and quickly. If effective measures are not taken in time, the patient may go into shock or even die due to excessive blood loss. The edges of irregular wounds are complex and difficult to fit tightly with standard dressing materials, which easily causes blood to seep out from the edges, increasing the difficulty of hemostasis. In addition, irregular wounds often involve multiple tissues and blood vessels, making the hemostasis process more complicated.

[0003] At present, the hemostatic techniques for non-pressible and irregular wounds mainly include packing, tourniquets and injectable hemostatic agents. However, these methods have certain limitations in practical applications. The packing method may cause local tissue ischemia, hypoxia and necrosis, improper use of tourniquets may cause nerve and muscle damage, and injectable hemostatic agents may be ineffective because they are difficult to reach the bleeding point. In order to overcome the limitations of traditional hemostatic techniques, it is of great significance to prepare a hemostatic material with better biocompatibility and hemostatic effect, which can control bleeding more quickly and effectively, for efficient hemostasis of non-pressible and irregular wounds.

[0004] Sodium alginate is a natural polysaccharide compound. It has excellent water solubility, biocompatibility and degradability and has been widely used in many fields. Its adhesion has great potential in medical applications such as trauma hemostasis. Dopamine is one of the simplest catecholamines, and its catechol group has excellent adhesion. Quaternized chitosan has excellent antibacterial properties, good solubility in neutral or even weak alkaline aqueous solutions, and good biocompatibility and biodegradability. The above three substances are used for hemostasis. The traditional method is usually to compound one or more of them into a gel or powder and then apply it to the bleeding wound. These methods cannot quickly adapt to non-pressable and irregular wounds, and the hemostatic materials cannot reach the source of bleeding but can only stay in the shallow layer or surface of the wound, so they cannot achieve fully effective hemostasis. Different from the traditional method, the present invention creatively adds citric acid and sodium bicarbonate to the composite powder of modified sodium alginate and quaternary ammonium chitosan, and uses the blood-triggered reaction to produce carbon dioxide to push the hemostatic material - the composite powder of modified sodium alginate and quaternary ammonium chitosan, to reach the source of bleeding for timely and effective hemostasis. So far, the preparation method of this sodium alginate / quaternary ammonium chitosan composite hemostatic powder that can gel quickly and self-propelled has not been reported. Summary of the invention

[0005] In order to overcome the technical problems that the above-mentioned hemostatic materials cannot quickly adapt to non-pressable and irregular wounds and the hemostatic materials cannot reach the bleeding area to achieve sufficient and effective hemostasis, and to prepare an efficient hemostatic powder that can quickly gel, self-propelled and can quickly adapt to the shape of the wound, the purpose of the present invention is to provide a modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder propelled by carbon dioxide and a preparation method thereof. The present invention ingeniously adds citric acid and sodium bicarbonate to the composite powder of modified sodium alginate and quaternary ammonium chitosan, and uses the blood-triggered reaction to generate carbon dioxide to push the composite hemostatic powder of modified sodium alginate and quaternary ammonium chitosan to reach the source of bleeding for timely and effective hemostasis. Dopamine with catechol groups is grafted onto sodium alginate to improve the adhesion of sodium alginate. Quaternary ammonium chitosan is added to the modified sodium alginate to further improve the structural stability and hemostatic properties of the composite powder, and give the powder certain antibacterial properties. Finally, by adding citric acid and sodium bicarbonate, the blood-triggered reaction produces carbon dioxide to push the modified sodium alginate and quaternary ammonium chitosan composite powder deep into the bleeding source to form a gel for physical blocking and hemostasis.

[0006] The present invention is achieved through the following technical solutions:

[0007] A modified sodium alginate / quaternized chitosan self-swelling composite hemostatic powder and a preparation method thereof, comprising the following steps:

[0008] S1. Using sodium alginate and dopamine hydrochloride as raw materials, grafting dopamine on sodium alginate by amidation reaction to obtain a solution;

[0009] S2, dialyzing the solution obtained in step S1 in an acidic solution, freeze-drying and grinding into powder to obtain modified sodium alginate powder;

[0010] S3, mixing the modified sodium alginate powder obtained in step S2 with the quaternized chitosan powder in different mass ratios to obtain a modified sodium alginate / quaternized chitosan mixed powder;

[0011] S4. Add different masses of citric acid powder and sodium bicarbonate powder to the modified sodium alginate / quaternary ammonium chitosan mixed powder obtained in step S3 and mix them evenly to obtain modified sodium alginate / quaternary ammonium chitosan self-swelling composite hemostatic powder with rapid gelation performance.

[0012] As a preferred embodiment, the sodium alginate in step S1 is an anionic polyelectrolyte having a negatively charged carboxyl group, the dopamine hydrochloride is a catechol compound having a primary amine group and a catechol group, and the sodium alginate and dopamine hydrochloride are added in a mass ratio of 2:1.

[0013] As a preferred solution, the sodium alginate in step S1 is dissolved in a 2-morpholineethanesulfonic acid solution with a pH of 5.5, with a concentration of 0.1 wt%.

[0014] As a preferred embodiment, the coupling agents used in the amidation reaction in step S1 are 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and nitrogen-hydroxysuccinimide, the mass ratio of the two coupling agents is 2:1, the mass ratio of sodium alginate to the coupling agent is 2:1, the amidation reaction temperature is 20-30°C, and the reaction time is 4-6h.

[0015] As a preferred embodiment, the acidic solution in step S2 is a sodium chloride aqueous solution with a pH value of 4.

[0016] As a preferred solution, the dialysis molecular weight limit in step S2 is 7000 and the dialysis time is 5 days.

[0017] As a preferred embodiment, the modified sodium alginate powder in step S2 is a sodium alginate / dopamine compound.

[0018] As a preferred embodiment, the quaternized chitosan described in step S3 is a cationic polyelectrolyte having a positively charged quaternary ammonium group, and the mass ratio of the modified sodium alginate powder to the quaternized chitosan powder is 1:9 to 9:1.

[0019] As a preferred embodiment, the molar ratio of citric acid to sodium bicarbonate in step S4 is 1:1, the mixing method is mechanical mixing, and the total mass of citric acid and sodium bicarbonate added in step S4 is 0.01 to 50 mg.

[0020] The modified sodium alginate / quaternized chitosan self-expanding composite hemostatic powder obtained by the preparation method of the present invention.

[0021] The present invention adopts the above technical scheme, and the modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder can use the carbon dioxide generated by the reaction of citric acid and sodium bicarbonate triggered by blood to promote the modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder to quickly fill non-pressable and irregular wounds, and form a gel network structure with a certain viscosity at the source of bleeding, completing timely physical blocking. On this basis, the modified sodium alginate and quaternary ammonium chitosan further promote the occurrence of coagulation cascade reaction, thereby achieving a rapid and effective hemostatic effect.

[0022] Compared with the prior art, the method of the present invention has the following beneficial effects:

[0023] 1. The raw materials of the hemostatic powder of the present invention are widely available, do not contain any harmful substances, are safe and harmless to the human body, and have no antigenicity.

[0024] 2. The hemostatic powder described in the present invention is a modified sodium alginate / quaternized chitosan complex.

[0025] 3. The hemostatic powder of the present invention has the ability to expand rapidly when triggered by blood, and can quickly physically block the wound. While having the physical hemostatic effect, it also has the ability to resist bacterial infection of the wound. The modified sodium alginate and quaternized chitosan further promote the occurrence of coagulation cascade reaction and promote hemostasis.

[0026] 4. The method for preparing hemostatic powder of the present invention is simple, has mild reaction, low energy consumption, is environmentally friendly, and has low raw material cost and is easy to obtain.

[0027] 5. The hemostatic powder of the present invention can be stored in bags or compressed into tablets, and can be directly used on deep irregular bleeding wounds and bleeding wounds in areas that cannot be pressed during surgery. It is simple and convenient to use, can be injected, and is easy to store, transport and carry. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The modified sodium alginate S prepared by the present invention and the quaternized chitosan Q are mixed in different mass ratios, and then an equal amount of deionized water is added. It can be seen that the modified sodium alginate and the quaternized chitosan prepared in the present invention can form a stable gel state after being mixed in a mass ratio of 4:6;

[0029] Figure 2This is a state diagram of volume change over time after the modified sodium alginate / quaternized chitosan composite hemostatic powder prepared in Example 2 of the present invention is mixed with water or anticoagulated blood;

[0030] Figure 3 The hemolysis rate of the modified sodium alginate / quaternized chitosan composite hemostatic powder prepared in Example 2 of the present invention;

[0031] Figure 4 The modified sodium alginate / quaternized chitosan composite powder prepared in Comparative Example 1 of the present invention, the modified sodium alginate / quaternized chitosan composite hemostatic powder prepared in Example 2, Celox TM and scanning electron microscopy images of gelatin sponge adhesion to erythrocytes;

[0032] Figure 5 The modified sodium alginate / quaternized chitosan composite powder prepared in Comparative Example 1 of the present invention, the modified sodium alginate / quaternized chitosan composite hemostatic powder prepared in Example 2, Celox TM and gelatin sponge in the rat liver puncture wound hemostasis and bleeding volume.

[0033] Figure 6 This is an overview diagram of the preparation and application effects of the modified sodium alginate / quaternized chitosan composite hemostatic powder prepared by the present invention. DETAILED DESCRIPTION

[0034] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several variations and improvements may be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0035] Example 1

[0036] This embodiment relates to a method for preparing a modified sodium alginate / quaternized chitosan composite hemostatic powder, comprising the following steps:

[0037] 1. Dissolve 1 g of sodium alginate in 100 mL of 2-morpholineethanesulfonic acid solution with a pH of 5.5 to a concentration of 0.1 wt %, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and nitrogen-hydroxysuccinimide in a mass ratio of 2:1, then add 0.5 g of dopamine hydrochloride and react for 4 h to obtain modified sodium alginate;

[0038] 2. The modified sodium alginate obtained in step 1 is dialyzed in a sodium chloride aqueous solution at pH = 4 for 5 days with a dialysis molecular weight limit of 7000, and then freeze-dried and ground into powder to obtain modified sodium alginate powder;

[0039] 3. The modified sodium alginate powder obtained in step 2 is uniformly mixed with the quaternized chitosan powder at a mass ratio of 4:6 to obtain a modified sodium alginate / quaternized chitosan composite powder;

[0040] 4. Add 20 mg of a mixed powder of citric acid and sodium bicarbonate in a molar ratio of 1:1 (20 mg is the total mass of citric acid and sodium bicarbonate) to the modified sodium alginate / quaternary ammonium chitosan composite powder of step 3, and then mechanically mix to obtain a modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder.

[0041] The modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder prepared in Example 1 was recorded as modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder-1.

[0042] Example 2

[0043] This embodiment relates to a method for preparing a modified sodium alginate / quaternized chitosan composite hemostatic powder, comprising the following steps:

[0044] 1. Dissolve 1 g of sodium alginate in 100 mL of 2-morpholineethanesulfonic acid solution with a pH of 5.5 to a concentration of 0.1 wt %, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and nitrogen-hydroxysuccinimide in a mass ratio of 2:1, then add 0.5 g of dopamine hydrochloride and react for 4 h to obtain modified sodium alginate;

[0045] 2. The modified sodium alginate obtained in step 1 is dialyzed in a sodium chloride aqueous solution at pH = 4 for 5 days with a dialysis molecular weight limit of 7000, and then freeze-dried and ground into powder to obtain modified sodium alginate powder;

[0046] 3. The modified sodium alginate powder obtained in step 2 is uniformly mixed with the quaternized chitosan powder at a mass ratio of 4:6 to obtain a modified sodium alginate / quaternized chitosan composite powder;

[0047] 4. Add 40 mg of a mixed powder of citric acid and sodium bicarbonate in a molar ratio of 1:1 to the modified sodium alginate / quaternary ammonium chitosan composite powder of step 3, and then mechanically mix to obtain a modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder.

[0048] The modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder prepared in Example 2 was recorded as modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder-2.

[0049] Effect of the mass ratio of modified sodium alginate and quaternized chitosan on the structure Figure 1 As shown in Figure 2, when the mass ratio of modified sodium alginate to quaternized chitosan is 4:6, a stable gel structure can be maintained. Figure 2As shown, the gel can maintain a stable structure for 1 hour after being triggered by blood, and citric acid / sodium bicarbonate plays a role in promoting the powder to form a gel.

[0050] Example 3

[0051] This embodiment relates to a method for preparing a modified sodium alginate / quaternized chitosan composite hemostatic powder, comprising the following steps:

[0052] 1. Dissolve 1 g of sodium alginate in 100 mL of 2-morpholineethanesulfonic acid solution with a pH of 5.5 to a concentration of 0.1 wt %, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and nitrogen-hydroxysuccinimide in a mass ratio of 2:1, then add 0.5 g of dopamine hydrochloride and react for 4 h to obtain modified sodium alginate;

[0053] 2. The modified sodium alginate obtained in step 1 is dialyzed for 5 days with a sodium chloride aqueous solution having a pH value of 4, with a dialysis molecular weight limit of 7000, and is freeze-dried and ground into powder to obtain modified sodium alginate powder;

[0054] 3. The modified sodium alginate powder obtained in step 2 is uniformly mixed with the quaternized chitosan powder at a mass ratio of 6:4 to obtain a modified sodium alginate / quaternized chitosan composite powder;

[0055] 4. Add 20 mg of a mixed powder of citric acid and sodium bicarbonate in a molar ratio of 1:1 to the modified sodium alginate / quaternary ammonium chitosan composite powder of step 3, and then mechanically mix them evenly to obtain a modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder.

[0056] The modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder prepared in Example 3 was recorded as modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder-3.

[0057] Example 4

[0058] This embodiment relates to a method for preparing a modified sodium alginate / quaternized chitosan composite hemostatic powder, comprising the following steps:

[0059] 1. Dissolve 1 g of sodium alginate in 100 mL of 2-morpholineethanesulfonic acid solution with a pH of 5.5 to a concentration of 0.1 wt %, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and nitrogen-hydroxysuccinimide in a mass ratio of 2:1, then add 0.5 g of dopamine hydrochloride and react for 4 h to obtain modified sodium alginate;

[0060] 2. The modified sodium alginate obtained in step 1 is dialyzed in a sodium chloride aqueous solution at pH = 4 for 5 days with a dialysis molecular weight limit of 7000, and then freeze-dried and ground into powder to obtain modified sodium alginate powder;

[0061] 3. The modified sodium alginate powder obtained in step 2 is uniformly mixed with the quaternized chitosan powder at a mass ratio of 6:4 to obtain a modified sodium alginate / quaternized chitosan composite powder;

[0062] 4. Add 40 mg of a mixed powder of citric acid and sodium bicarbonate in a molar ratio of 1:1 to the modified sodium alginate / quaternary ammonium chitosan composite powder of step 3, and then mechanically mix to obtain a modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder.

[0063] The modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder prepared in Example 4 was recorded as modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder-4.

[0064] Comparative Example 1

[0065] 1g of sodium alginate was dissolved in 100mL of 2-morpholineethanesulfonic acid solution with a pH of 5.5, with a concentration of 0.1wt%, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and nitrogen-hydroxysuccinimide were added in a mass ratio of 2:1, followed by adding 0.5g of dopamine hydrochloride for 4h. The obtained modified sodium alginate was dialyzed in a sodium chloride aqueous solution with a pH of 4 for 5 days, with a dialysis molecular weight limit of 7000, and freeze-dried and ground into powder, and mixed with quaternized chitosan at a mass ratio of 4:6 to obtain a modified sodium alginate / quaternized chitosan composite powder without the addition of citric acid and sodium bicarbonate, which was recorded as modified sodium alginate / quaternized chitosan composite powder.

[0066] Example 5

[0067] This embodiment relates to a hemostatic effect test of a modified sodium alginate / quaternized chitosan composite hemostatic powder, comprising the following steps:

[0068] 1. Inject 0.9 mL of 10% chloral hydrate into the rat's peritoneum to anesthetize it;

[0069] 2. Make a 0.4 cm × 0.4 cm × 0.4 cm puncture wound on the liver;

[0070] 3. Immediately add a known mass of modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder (modified sodium alginate / quaternary ammonium chitosan composite powder, modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder), commercial hemostatic powder Celox TM Use a syringe to push the gelatin sponge into the wound. Also, use gauze to apply pressure to the wound for a short time to stop bleeding.

[0071] 4. After 120 seconds, collect the blood sample, weigh it, and calculate the amount of bleeding;

[0072] 5. Control group Celox TM, gelatin sponge, the amount of bleeding of the modified sodium alginate / quaternary ammonium chitosan composite powder used in Comparative Example 1 and the modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder used in Example 2 is as follows: Figure 5 As shown. With Celox TM Compared with the modified sodium alginate / quaternary ammonium chitosan composite powder used in comparative example 1 and the modified sodium alginate / quaternary ammonium chitosan composite hemostatic powder used in example 2, the hemostatic effect is greatly improved. This is because the modified sodium alginate / quaternary ammonium chitosan forms a gel network structure with a certain viscosity at the bleeding site, completing timely physical blocking. On this basis, the two further promote the occurrence of coagulation cascade reaction, thereby achieving a rapid and effective hemostatic effect. The addition of citric acid and sodium bicarbonate gives the composite powder the ability to expand rapidly, which can further penetrate deep into the wound to stop bleeding at the source of the trauma, accelerate the hemostatic efficiency, and the blood loss is Celox TM The hemostatic rate was 41.8% for PE and 41.2% for gelatin sponge, demonstrating its excellent hemostatic ability on non-compressible wounds.

[0073] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for preparing a modified sodium alginate / quaternized chitosan composite hemostatic powder, comprising the following steps: S1. Using sodium alginate and dopamine hydrochloride as raw materials, grafting dopamine on sodium alginate by amidation reaction to obtain a solution; S2, dialyzing the solution obtained in step S1 in an acidic solution, freeze-drying and grinding into powder to obtain modified sodium alginate powder; S3, mixing the modified sodium alginate powder obtained in step S2 with the quaternized chitosan powder in different mass ratios to obtain a modified sodium alginate / quaternized chitosan mixed powder; S4. Add different masses of citric acid powder and sodium bicarbonate powder to the modified sodium alginate / quaternary ammonium chitosan mixed powder obtained in step S3 and mix them evenly to obtain modified sodium alginate / quaternary ammonium chitosan self-swelling composite hemostatic powder with rapid gelation performance.

2. The preparation method according to claim 1, characterized in that: The sodium alginate in step S1 is an anionic polyelectrolyte having a negatively charged carboxyl group. The dopamine hydrochloride is a catechol compound having a primary amine group and a catechol group. The sodium alginate and dopamine hydrochloride are added in a mass ratio of 2:

1.

3. The preparation method according to claim 1, characterized in that: The sodium alginate in step S1 is dissolved in a 2-morpholineethanesulfonic acid solution with a pH of 5.5, with a concentration of 0.1 wt%.

4. The preparation method according to claim 1, characterized in that: The coupling agents used in the amidation reaction in step S1 are 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and nitrogen-hydroxysuccinimide, the mass ratio of the two coupling agents is 2: 1, the mass ratio of sodium alginate to the coupling agent is 2: 1, the amidation reaction temperature is 20-30 ° C, and the reaction time is 4-6 h.

5. The preparation method according to claim 1, characterized in that: The acidic solution described in step S2 is a sodium chloride aqueous solution with a pH value of 4.

6. The preparation method according to claim 1, characterized in that: The dialysis molecular weight limit described in step S2 is 7000, and the dialysis time is 5 days.

7. The preparation method according to claim 1, characterized in that: The modified sodium alginate powder in step S2 is a sodium alginate / dopamine compound.

8. The preparation method according to claim 1, characterized in that: The quaternized chitosan described in step S3 is a cationic polyelectrolyte having a positively charged quaternary ammonium group, and the mass ratio of the modified sodium alginate powder to the quaternized chitosan powder is 1:9 to 9:

1.

9. The preparation method according to claim 1, characterized in that: The molar ratio of citric acid to sodium bicarbonate in step S4 is 1:1, the mixing method is mechanical mixing, and the total mass of citric acid and sodium bicarbonate added in step S4 is 0.01-50 mg.

10. Modified sodium alginate / quaternized chitosan self-swelling composite hemostatic powder obtained by the preparation method according to any one of claims 1 to 9.

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