WO2018192562A1 - Hemostatic material and preparation method therefor - Google Patents

Abstract

A hemostatic material and a preparation method therefor. The hemostatic material comprises the following raw materials in terms of parts by weight: carboxymethyl chitosan 0.1-1.5, polyvinyl alcohol 0.5-2, a compound toughener (a plasticizing system) 0.2-5, and an ionic crosslinking agent 0.5-1.5, and also may comprise a broad-spectrum hemostatic antibacterial agent 0.5-3. The hemostatic material has great mechanical elasticity, quickly stops bleeding, is completely degradable and nontoxic, has strong antibacterial properties, and is applicable in the hemostasis of a wound, particularly hemostasis of the naval cavity.

Description

Hemostatic material and preparation method thereof Technical field

The invention belongs to the field of medical hemostatic materials, and in particular relates to a hemostatic material and a preparation method thereof.

Background technique

Chitosan is a high molecular polysaccharide formed by the removal of some or all of the acetate groups by hydrolysis of chitin under alkaline conditions. Its chemical name is poly(1,4)-2-amino-2-deoxy- β-D-glucose, the structural formula is as follows:

The chitosan molecule itself is very complex in structure and has many ionic primary amine groups. It can easily carry out chemical reactions and react with acids to form salts. Therefore, it can carry out a series of amino reactions. At the same time, chitosan and other polysaccharides. Similarly, there are also available reactive hydroxyl groups in their structure, so they can also be derivatized. Various derivatives of chitosan have different physical and chemical properties and functions due to different molecular weights and functional groups. Chemical derivatization reactions such as carboxylation, acylation, and alkylation are common methods for preparing chitosan derivatives. Carboxymethyl chitosan is a type of chitosan derivative which is widely used due to its good water solubility.

Chitosan is a pure natural biomaterial that can completely degrade in the human body and has good biocompatibility. A large number of experimental studies have shown that chitosan can promote the non-specific immunity and specific immunity of animals, and it is a good immune promoter; chitosan structure contains high activity functional groups, performance The characteristics of antibiotics can inhibit the growth and activity of various bacteria; chitosan can play a role in maintaining the balance of cholesterol concentration in human body.

At present, there are many companies in China that produce chitosan foam materials, such as Shanghai Meibao Life Technology Co., Ltd. and Qingdao Bolt Technology Co., Ltd.

Among them, the chitosan hemostatic sponge prepared by Shanghai Meibao Life Science Co., Ltd. has the water swelling property, and its patent number is ZL 200510024503.3. The preparation process is carboxymethyl chitosan. A small amount of chitosan powder or chitin powder is added to the aqueous chitosan solution, and a certain amount of glycerin is used as a plasticizer. After stirring and foaming, an environmentally-friendly ionic crosslinking agent is added to fully crosslink and freeze-dry. The sponge produced by this process uses water-soluble substances as raw materials, avoids the use of acidic solvents, and thus has environmental significance; the use of non-aldehyde-based ionic crosslinking agents avoids residual toxicity of aldehyde groups. However, the chitosan sponge material provided by this patent has poor performance in toughness, hemostasis effect and degradation time. In practical surgical applications, there are problems of easy degradation and poor toughness.

The chitosan hemostatic sponge produced by Qingdao Boyite Biomaterial Co., Ltd. has similar problems. It is only modified by chitosan. Although it has good hemostatic effect in a small range, it does not have good mechanical properties such as flexibility. And elasticity, poor adhesion, too fast degradation, and poor compression of blood vessels.

Worldwide, Polyganics BV of the Netherlands is able to produce a degradable high-expansion hemostatic foam material, namely Nasopore, which is based on polyurethane. Due to its high expansion, the mechanical compression ability of blood vessels is strong, and the unique advantage of controllable degradation time makes it quickly occupy the international hemostatic material market within a few years.

The product first synthesizes a polyester prepolymer of high molecular weight ε-caprolactone and L-lactide random copolymer; the post-synthesis structure is a block copolymer of BDI/BDO/BDI; finally, the polyester is pre-polymerized. The body reacts with the block copolymer and is subjected to chain extension to obtain a polyurethane material.

However, it also has defects: 1 the main component is polyurethane, and its final degradation product is humic acid, commonly known as "corpse venom". The product can only be stored in a small amount and needs to be discharged out of the body for a short time, so it can only be applied to the human body pipe system in a short time, such as body cavity, reproductive tract and the like. 2 Polyurethane component does not have hemostatic properties, can only rely on mechanical elastic compression, so the hemostatic effect is general; 3 the material itself has no antibacterial properties.

The Merocel series of body cavity packing materials produced by Medtronic in the United States is another widely used body cavity filled degradable material. The main components of the material are polyvinyl alcohol (PVA) and glycerol, and the volume of the material can be rapidly expanded after absorbing the body fluid to act to stop bleeding in the bleeding area. The material has many advantages, such as PVA itself has good biological affinity, is non-toxic to the human body, the product is light in damage to the nasal mucosa, and the patient has mild headache symptoms.

However, it also has defects: 1 the pressure caused by the volume expansion of the product after absorption of body fluid is limited, there is the possibility of failure of stuffing and hemostasis, and the filling success rate is not as good as the traditional stuffing material such as Vaseline packing strip; 2 its raw material polyvinyl alcohol (PVA) ) itself has no hemostatic and anti-inflammatory effects, so the performance of the material in anti-inflammatory sterilization needs to be improved; 3 in clinical operation, if a plurality of such materials are filled into the body cavity, it is not easy to take out a part of the filled materials, The other part remains in the body cavity and the filling pressure cannot be selected depending on the actual condition of the patient.

The sorbalgon calcium alginate dressing produced by Hartmann in Germany is another biomaterial widely used for body cavity filling. The dressing is made of soft seaweed and calcium acid fiber. When it comes into contact with the sodium salt in blood and wound secretions, the contact surface can be transformed into a gelatinous substance to achieve hemostasis. The product has good ventilation, can fully adapt to the wound position, the wound tissue is well accepted and adaptable, and the patient is well tolerated; the patient does not need to fill the entire body cavity, and the patient has less tolerance pain; the material has a hemostatic effect, so two The possibility of secondary infection is small.

However, it also has defects: 1 has certain requirements for wound wounds, suitable for narrow and deep wounds. If the wound is too large, it can not form an effective hemostatic interface; 2 the filling pressure is very limited, and the effective filling must be matched with Vaseline gauze or Use for expansion sponges.

At present, hemostatic materials with excellent performance, especially body cavity filling materials, are mainly expensive foreign products, and the performance of domestic related products is generally poor. Therefore, the development of new surgical hemostatic materials with independent intellectual property rights, good mechanical elasticity, rapid hemostasis, complete degradation, non-toxicity and strong antibacterial properties is imminent.

Summary of the invention

The technical problem to be solved by the present invention is to provide a hemostatic material and a preparation method thereof. In order to achieve the above object, the present invention adopts the following technical solutions:

The material of the hemostatic material comprises: carboxymethyl chitosan, polyvinyl alcohol, compound toughening material, ionic crosslinking agent; preferably, the hemostatic material is used for wound hemostasis, preferably for use The body cavity is hemostasis; more preferably, the body cavity is a lumen; further preferably, the body cavity is a nasal cavity.

In a preferred embodiment, the hemostatic material comprises the following raw materials by weight ratio: carboxymethyl chitosan 0.1-1.5, polyvinyl alcohol 0.5-2, compound toughener 0.2-5, ionic cross-linking The agent is 0.5 to 1.5.

In a preferred embodiment, the polyvinyl alcohol is one or more of EG-05, EG-25, EG-30, and EG-40.

In a preferred embodiment, the compound toughening material comprises: polyethylene glycol and glycerin in a weight ratio of 1: (1 to 0.2); preferably, the polyethylene glycol is PEG-3350, PEG -1430, one or more of PEG-2000, PEG-400.

In a preferred embodiment, the ionic crosslinking agent is one or more of an iron salt, a calcium salt, a sodium salt or an aluminum salt.

In a preferred embodiment, the raw material of the hemostatic material further comprises a broad-spectrum hemostatic antibacterial agent; preferably, the broad-spectrum hemostatic antibacterial agent is used in an amount of 0.5 to 3 parts by weight; preferably, the broad-spectrum hemostatic antibacterial agent It is one or more of polyhexamethylene sulfonium, notoginseng powder, vitamin K1, vitamin K3, and vitamin K4.

The preparation method of the hemostatic material sequentially includes the following steps:

a dissolving step: dissolving the carboxymethyl chitosan and polyvinyl alcohol in water to obtain an aqueous solution of a main raw material; and crosslinking step: adding the compound toughening material to the aqueous solution of the main raw material to carry out a crosslinking reaction, Obtaining a cross-linked product; lyophilizing step: lyophilizing the cross-linked product to obtain the hemostatic material; in the cross-linking step, stirring a mixed system including the main raw material aqueous solution and the compound toughened material After treatment for 15-40 min, the ionic cross-linking agent is added thereto, and then pre-frozen at -10 to -25 ° C, and then thawed at room temperature, and repeated 3 to 8 times.

Another method of preparing the hemostatic material in turn includes the following steps:

Dissolving step: dissolving the carboxymethyl chitosan and polyvinyl alcohol in water to obtain an aqueous solution of a main raw material; crosslinking step: adding the compound toughening material and the broad-spectrum hemostatic antibacterial agent to the aqueous solution of the main raw material The crosslinking reaction is carried out to obtain a crosslinked product; a freeze-drying step: the crosslinked product is subjected to freeze-drying treatment to obtain the hemostatic material.

Another method of preparing the hemostatic material in turn includes the following steps:

Dissolving step: dissolving the carboxymethyl chitosan and polyvinyl alcohol in water respectively, respectively obtaining at least two portions of an aqueous solution of carboxymethyl chitosan and at least two portions of an aqueous solution of polyvinyl alcohol; and a crosslinking step: respectively Each of the carboxymethyl chitosan aqueous solution and the polyvinyl alcohol aqueous solution is added to the compound toughening material, and respectively subjected to a crosslinking reaction to obtain an ion crosslinking product and a physical crosslinking product, respectively; The ion-crosslinked product and the physically cross-linked product are interleaved to obtain a layer-layer assembly structure; and the layer-layer assembly structure is pre-frozen at -10 to -25 ° C to obtain a cross-linked product having an interpenetrating network structure;

a freeze-drying step: lyophilizing the crosslinked product having an interpenetrating network structure to obtain the hemostatic material; preferably, in the crosslinking step, the carboxymethyl chitosan aqueous solution and the compounding increase The cross-linking reaction is carried out by an ionic cross-linking agent method; the aqueous polyvinyl alcohol solution and the compound toughening material are subjected to the cross-linking reaction by a physical cyclic crosslinking method; further preferably, the ion-crossing is carried out The method of the mixture is to stir the mixed system comprising the aqueous solution of the carboxymethyl chitosan and the compound toughening agent for 15-40 min, and then add the ionic crosslinking agent thereto, and then store at 0 ° C; further preferably The physical circulation crosslinking method is to pre-freeze a mixed system comprising the aqueous polyvinyl alcohol solution and the compound toughening material at -10 to -25 ° C, and then thaw at room temperature for 3 to 8 times.

Another method of preparing the hemostatic material in turn includes the following steps:

Dissolving step: dissolving the carboxymethyl chitosan and polyvinyl alcohol in water respectively, respectively obtaining at least two portions of an aqueous solution of carboxymethyl chitosan and at least two portions of an aqueous solution of polyvinyl alcohol; and a crosslinking step: respectively Each of the carboxymethyl chitosan aqueous solution and the polyvinyl alcohol aqueous solution is added to the compound toughening material and the broad-spectrum hemostatic antibacterial agent, respectively, to carry out a crosslinking reaction to obtain an ion-crosslinked product and a physical cross-linked product, respectively. Then, each of the ion crosslinked products and the physically crosslinked product are interleaved to obtain a layer-layer assembly structure; and the layer-layer assembly structure is pre-frozen at -10 to -25 ° C to obtain an interpenetrating network structure. Cross-linked product; freeze-drying step: freeze-drying the cross-linked product of the interpenetrating network structure to obtain the hemostatic material; preferably, in the cross-linking step, the carboxymethyl shell The aqueous solution of sugar and the compound toughening material are subjected to the crosslinking reaction by an ionic crosslinking agent method; the aqueous solution of polyvinyl alcohol and the compound toughening material are subjected to the crosslinking reaction by a physical cyclic crosslinking method; further preferably Ground The cross-linking method is to agitate the mixed system comprising the aqueous solution of the carboxymethyl chitosan, the complex toughening substance and the broad-spectrum hemostatic antibacterial agent for 15-40 min, and then add the ionic cross-linking agent thereto, and then add the ionic cross-linking agent thereto. Preserving at 0 ° C; further preferably, the physical cyclic crosslinking method is to pre-freeze the mixed system comprising the aqueous solution of polyvinyl alcohol, the complex toughening substance, and the broad-spectrum hemostatic antibacterial agent at -10 to -25 ° C Then thaw at room temperature and repeat 3 to 8 times.

The hemostatic material provided by the present invention has the following advantages:

(1) The raw materials used in the present invention are all biodegradable materials, which are capable of being degraded in the human body, and the degradation products are not toxic to the human body. At the same time, the cross-linking of the two materials of carboxymethyl chitosan and polyvinyl alcohol to form an interpenetrating cross-linking structure, adjusting the degradation rate of the material, so that the material does not degrade too quickly to cause body cavity packing failure.

(2) The good hydrophilicity of the hemostatic material of the present invention makes it capable of rapidly absorbing body fluid, and has a high expansion ratio which cannot be compared with other similar materials while promoting hemostasis, and has a good effect of suppressing hemostasis.

(3) In the present invention, PVA itself can exert a certain plasticizing effect on carboxymethyl chitosan, and at the same time, the compounding plasticizing system is superior in effect to the single glycerin plasticizing effect in other inventions. The material toughness is much better than other chitosan foam products, which is greatly improved compared to other brittle chitosan materials.

(4) All the raw materials and additives in the present invention are water-soluble, and there is no human toxicity and environmental toxicity caused by the solvent; moreover, the crosslinking method of the present invention employs a non-toxic ion crosslinking method and a physical crosslinking method.

(5) The hemostatic material provided by the present invention has good solubility and biodegradability; at the same time, the hemostatic material has good permeability and causes less headache and the like. Therefore, the pain of the patient during the treatment can be greatly reduced.

(6) The invention uses carboxymethyl chitosan and medical polyvinyl alcohol (PVA) as main raw materials, both of which have good water solubility and biocompatibility, can avoid solvent toxicity and human immune system rejection. At the same time, since both of the raw materials have good hydrophilicity, the body fluid can be quickly absorbed to achieve a high expansion rate, thereby squeezing and stopping bleeding.

(7) The invention has the double hemostasis effect of direct coagulation and compression hemostasis, and the degradation time is controllable, and the application range is wide, and can be used in vivo and in vitro, and can be used for hemostasis, traumatic wound healing, or as a human cavity. The hemostatic material can be especially used as a hemostatic material in the lumen of the human body, especially in the nasal cavity.

detailed description

In a first aspect, the present invention provides a hemostatic material comprising the following parts by weight:

Carboxymethyl chitosan 0.1 to 1.5, polyvinyl alcohol (PVA) 0.5 to 2, compound toughening material (hereinafter also referred to as: plasticizing system) 0.2 to 5, and ionic crosslinking agent 0.5 to 1.5.

The hemostatic material may further comprise 0.5 to 3 parts by weight of a broad spectrum hemostatic antibacterial agent.

The polyvinyl alcohol is a pharmaceutical grade EG series: one or more of EG-05, EG-25, EG-30 and EG-40; the compound toughening material comprises: a weight ratio of 1: ( 1-0.2) (for example: polyethylene glycol (PEG) and glycerin which may be any value of 1:1, 1:0.8, 1:0.5, 1:0.2 or a range between any values), the polyethylene The diol is a pharmaceutical grade PEG series: one or several of PEG-3350, PEG-1430, PEG-2000, PEG-400; the ionic crosslinking agent is in an iron salt, a calcium salt, a sodium salt or an aluminum salt. One or more; the broad-spectrum hemostatic antibacterial agent is one or more of polyhexamethylene sulfonium, panax notoginseng powder, vitamin K1, vitamin K3, and vitamin K4.

Illustratively, the above carboxymethyl chitosan may be between any value of 0.1 parts by weight, 0.3 parts by weight, 0.5 parts by weight, 0.75 parts by weight, 1 part by weight, 1.25 parts by weight, 1.5 parts by weight or between any values. The range, the polyvinyl alcohol may be in any range of 0.5 parts by weight, 0.75 parts by weight, 1 part by weight, 1.25 parts by weight, 1.5 parts by weight, 1.75 parts by weight, 2 parts by weight or any value, and the compound is toughened. The amount may be in any range of 0.2 parts by weight, 0.5 parts by weight, 1 part by weight, 2 parts by weight, 3 parts by weight, 4 parts by weight, or 5 parts by weight, or the range of any value, and the ionic crosslinking agent may be 0.5 weight. Any of a range of 0.75 parts by weight, 1 part by weight, 1.25 parts by weight, and 1.5 parts by weight, or a range between any values, the broad-spectrum hemostatic antibacterial agent may be 0.5 parts by weight, 1 part by weight, 2 parts by weight, 2.5 parts by weight. Any value in parts, 3 parts by weight, or a range between any values.

In a second aspect, the present invention provides a method of preparing a hemostatic material; the method of preparation can be achieved by the following two different operations.

The first preparation method in turn includes the following steps:

(1) Dissolution: The carboxymethyl chitosan and polyvinyl alcohol are dissolved in water according to the above ratio to obtain a main raw material aqueous solution (the mass percentage concentration is 0.5-5%, which may be 0.5%, 1%, 2%, 3) %, 4%, 5%)

(2) Crosslinking: A compound toughening material obtained by mixing polyethylene glycol and glycerin and an antibacterial agent are added to the main raw material aqueous solution in accordance with the above ratio, and a crosslinking reaction is carried out to obtain a crosslinked product.

Wherein, the mixed system consisting of the main raw material aqueous solution, the compound toughening material, and the antibacterial agent is stirred for 15-40 min (preferably 30 min); and an ionic cross-linking agent is added thereto (here, specifically an aqueous solution containing an ionic cross-linking agent) , the mass percentage concentration is 5-15%, can be 5%, 8%, 10, 12.5%, 15%), and then pre-freeze at -10 ~ -25 ° C (preferably -20 ° C), each pre-freezing The time is 6-10 hours (preferably 8 hours), and then thawed at room temperature, and repeated 3 to 8 times (preferably 5 times).

(3) Freeze-drying: The cross-linked product is subjected to freeze-drying treatment for 18 to 36 hours (preferably 24 hours), and after the completion of the freeze-drying, the cross-linked product is completed in a foaming process to obtain a hemostatic material.

Illustratively, in the first preparation method, the stirring time may be any value of 15 min, 20 min, 25 min, 30 min, 40 min or a range between any values, and the pre-freezing temperature may be -10 ° C, -15 ° C. , any value in -17.5 ° C, -20 ° C, -22.5 ° C, -25 ° C or a range between any value, the pre-freezing time may be any value of 6h, 7h, 8h, 9h, 10h or any value The range between the freeze drying time may be any value of 18h, 20h, 25h, 30h, 35h, 36h or a range between any values.

Specifically, examples are as follows:

For example, a mixed aqueous solution of 100mLPVA and carboxymethyl chitosan is prepared, and the total amount of PVA and carboxymethyl chitosan per 100 mL of the aqueous solution is 1 to 10 g, and the polyethylene glycol (PEG)/glycerin is compounded. Plasticizing system 0.2 ~ 5g, containing hemostatic drugs 0.5 ~ 3g; adding ionic cross-linking agent for cross-linking chitosan, and physical cross-linking method for cross-linking PVA; then pre-freezing the whole system at -20 ° C 5 Next, wherein the product is thawed after about 6-10 hours (preferably 8 hours) of freezing, and freeze-dried for about 24 hours to obtain a product; cutting, encapsulation.

The second preparation method sequentially includes the following steps:

(1) Dissolution: carboxymethyl chitosan and polyvinyl alcohol are separately dissolved in water according to the above ratio, respectively, to obtain at least two portions of aqueous solution of carboxymethyl chitosan (the concentration per part is 0.1-7.5% by mass) , which may be 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 7%, 7.5%) and at least two parts of aqueous polyvinyl alcohol solution (the concentration per part is 0.5-15) % can be 0.5%, 1%, 5%, 7.5%, 10%, 12.5%, 15%).

Preferably, the concentration of each aqueous solution of carboxymethyl chitosan is the same, and the concentration of each aqueous solution of polyvinyl alcohol is also the same.

(2) Cross-linking:

1 According to the above ratio, each part of the carboxymethyl chitosan aqueous solution is added with a part of the compound toughening substance and the broad-spectrum hemostatic antibacterial agent, and then the ionic crosslinking agent is added (here specifically, the ionic crosslinking agent is added) An aqueous solution having a mass percentage concentration of 5-30%, which may be 5%, 10%, 15%, 20%, 25%, 30%), is cross-linked by an ion crosslinking method to obtain an ion-crosslinked product;

The above ion crosslinking method comprises the steps of: stirring a mixture system comprising a carboxymethyl chitosan aqueous solution, a complex toughening substance, and a broad-spectrum hemostatic antibacterial agent for 15-40 minutes (preferably 30 minutes), the stirring treatment is finished, and then An ionic crosslinking agent is added thereto to obtain an ion-crosslinked product; the ion-crosslinked product can be used immediately or after storage at 0 ° C for the next step of pre-freezing. 2 according to the above ratio, each of the polyvinyl alcohol aqueous solution is added to the remaining part of the compound toughening material and the broad-spectrum hemostatic antibacterial agent, and the cross-linking reaction is carried out by physical circulation crosslinking method to obtain a physically cross-linked product;

The above physical crosslinking method comprises the steps of: pre-freezing a mixed system comprising an aqueous solution of polyvinyl alcohol, a complex toughening substance, and a broad-spectrum hemostatic antibacterial agent at -10 to -25 ° C (preferably -20 ° C), each time pre-freezing The freezing time is 6-10 hours (preferably 8 hours), and then thawed at room temperature, and repeated 3 to 8 times (preferably 5 times) to obtain a physically crosslinked product.

Preferably, the amount of the compound toughening agent added to each aqueous solution of carboxymethyl chitosan is the same, and the amount of the broad-spectrum hemostatic antibacterial agent added to each aqueous solution of carboxymethyl chitosan is the same, and each aqueous solution of polyvinyl alcohol is added. The compounding toughening substance is used in the same amount, and the broad-spectrum hemostatic antibacterial agent added in each part of the polyvinyl alcohol aqueous solution is used in the same amount; the above compound toughening substance is mixed by polyethylene glycol and glycerin.

3 The above-mentioned ion-crosslinked product and the physically cross-linked product are alternately assembled to form a layer-layer assembly structure.

The above staggered assembly method is specifically: placing n parts of physical cross-linked products in turn on m parts of ion-crosslinked products, and then placing m parts of ion-crosslinked products, and then placing n parts of physical cross-linked products (m and n are equal to or greater than 1). The natural number, preferably m and n are equal to 1).

4 The above layer-layer assembly structure is further pre-frozen at -10 to -25 ° C (preferably -20 ° C) for 6 to 10 hours (preferably 8 hours) to obtain a crosslinked product having an interpenetrating network structure.

Among the cross-linked products of the interpenetrating network structure, the interpenetrating network structure is a general concept in the field of polymer chemistry, and refers to: two different linear polymer blends, two different polymers a three-dimensional network structure formed by physical crosslinking or chemical crosslinking between a molecule and a polymer molecule; the molecular level is blended compared to a polymer obtained by separately crosslinking two polymer molecules alone. The method of cross-linking after blending can significantly absorb the advantages of the two polymers in different properties; for example, the addition of the above PEG and PVA can significantly improve the toughness, and the addition of chitosan can improve the foamability of the system.

(4) Freeze-drying: The above-mentioned crosslinked product is subjected to freeze-drying treatment for 18 to 36 hours (preferably 24 hours), and after the completion of the freeze-drying, the cross-linked product is completed in a foaming process to obtain a hemostatic material.

Illustratively, in the second preparation method, the stirring time may be any value of 15 min, 20 min, 25 min, 30 min, 40 min or a range between any values, and the pre-freezing temperature may be -10 ° C, -15 ° C. , any value in -17.5 ° C, -20 ° C, -22.5 ° C, -25 ° C or a range between any value, the pre-freezing time may be any value of 6h, 7h, 8h, 9h, 10h or any value The range between the freeze drying time may be any value of 18h, 20h, 25h, 30h, 35h, 36h or a range between any values.

Specifically, examples are as follows:

Prepare multiple parts of PVA solution and multiple parts of carboxymethyl chitosan solution. Take the total volume of all solutions as 100mL. The total amount of PVA and chitosan per 100mL solution is 1~10g, including compound plasticization. 0.2～5g of the system, containing 0.5～3g of hemostatic drug, wherein the content of each component in the single solution can be adjusted; then, the ionic crosslinking agent is added to each chitosan solution to crosslink chitosan, and each Part of the PVA solution cross-links PVA by physical crosslinking; then, the PVA solution obtained after cross-linking and the multi-part chitosan solution are interlaced to form a layer-layer assembly structure; and the whole system after assembly is -15 After pre-freezing for 8 hours at ° C, freeze-drying for 24 hours to obtain the product; cutting, encapsulation.

In the present invention, the hemostatic material is prepared by using a hydrophilic raw material of carboxymethyl chitosan and polyvinyl alcohol (PVA) as a main component, dissolved, foamed, crosslinked, and freeze-dried according to a certain ratio; The system of ethylene glycol (PEG) and glycerin is used as a plasticizer; the cross-linked chitosan is cured by an ionic crosslinking agent, and the PVA is cross-linked by physical crosslinking, and the cross-linking curing process of the two is rationally controlled. A hemostatic material having an interpenetrating cross-linking structure; in addition, a hemostatic antibacterial agent is selectively added during the preparation to enhance the hemostatic and anti-inflammatory effects of the hemostatic material.

The present invention will be described in detail below with reference to the embodiments.

Example 1

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 1.4,

PVA (EG-40) 0.6,

Compounded toughener 1.5 (where PEG-2000 1, glycerol 0.5),

Polyhexamethylene hydrazine 0.5,

Ferric chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 1.4 g of carboxymethyl chitosan and 0.6 g of PVA (EG-40), 1.5 g of a compound toughening substance and 0.5 g of polyhexamethylene hydrazine were added, and the mixture was uniformly mixed at room temperature. After stirring for 30 minutes, 10 mL of a 10% by weight ferric chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 2

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 1.2,

PVA (EG-40) 0.8,

Compounded toughener 1.5 (where PEG-2000 1, glycerol 0.5)

Polyhexamethylene hydrazine 0.5,

Ferric chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 1.2 g of carboxymethyl chitosan and 0.8 g of PVA (EG-40), 1.5 g of a compound toughening substance and 0.5 g of polyhexamethylene hydrazine were added, and the mixture was uniformly mixed at room temperature. After stirring for 30 minutes, 10 mL of a 10% by weight ferric chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 3

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 1,

PVA(EG-40) 1,

Compound toughening 1 (where PEG-2000 0.5, glycerol 0.5)

Polyhexamethylene hydrazine 1,

Ferric chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 1.0 g of carboxymethyl chitosan and 1.0 g of PVA (EG-40), 1.0 g of a compound toughening substance and 1.0 g of polyhexamethylene hydrazine were added, and uniformly mixed at room temperature. After stirring for 30 minutes, 10 mL of a 10% by weight ferric chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and pre-frozen for 8 hours each, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 4

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.8,

PVA (EG-40) 1.2,

Compounded toughener 0.5 (where PEG-2000 0.25, glycerol 0.25)

Polyhexamethylene hydrazine 1.5,

Calcium chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 0.8 g of carboxymethyl chitosan and 1.2 g of PVA (EG-40), 0.5 g of a compound toughening substance and 1.5 g of polyhexamethylene hydrazine were added, and the mixture was uniformly mixed at room temperature. After stirring for 30 minutes, 10 mL of a 10% by mass calcium chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 5

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.6,

PVA (EG-40) 1.4,

Compounded toughener 0.5, (where PEG-2000 0.25, glycerol 0.25)

Polyhexamethylene hydrazine 1.5,

Calcium chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 0.6 g of carboxymethyl chitosan and 1.4 g of PVA (EG-40), 0.5 g of a compound toughening substance and 1.5 g of polyhexamethylene hydrazine were added, and uniformly mixed at room temperature. After stirring for 30 minutes, 10 mL of a 10% by mass calcium chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 6

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.4,

PVA (EG-40) 1.6,

Compounded toughener 0.5 (where PEG-2000 0.25, glycerol 0.25)

Polyhexamethylene hydrazine 1.5,

Calcium chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 0.4 g of carboxymethyl chitosan and 1.6 g of PVA (EG-40), 0.5 g of a compound toughening substance and 1.5 g of polyhexamethylene hydrazine were added, and the mixture was uniformly mixed at room temperature. After stirring for 30 minutes, 10 mL of a 10% by mass calcium chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 7

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 1.2,

PVA (EG-40) 0.8,

Compounded toughener 1.5 (where PEG-2000 1, glycerol 0.5)

Polyhexamethylene hydrazine 0.5,

Ferric chloride 1.76.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 1.2 g of carboxymethyl chitosan and 0.8 g of PVA (EG-40), 1.5 g of a compound toughening substance and 0.5 g of polyhexamethylene hydrazine were added, and the mixture was uniformly mixed at room temperature. After stirring for 30 minutes, 10 mL of a 15% by weight ferric chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 8

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.6,

PVA (EG-40) 1.4,

Compounded toughener 1.5 (where PEG-2000 1, glycerol 0.5),

Polyhexamethylene hydrazine 0.5,

Ferric chloride 1.76.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 0.6 g of carboxymethyl chitosan and 1.4 g of PVA (EG-40), 1.5 g of a compound toughening substance and 0.5 g of polyhexamethylene hydrazine were added, and the mixture was uniformly mixed at room temperature. After stirring for 30 minutes, 10 mL of a 15% by weight ferric chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 9

The hemostatic material of the present embodiment is prepared by a second method, the hemostatic material comprising the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 1.2,

PVA (EG-40) 0.8,

Compounded toughener 1.5 (where PEG-2000 1, glycerol 0.5)

Polyhexamethylene hydrazine 0.5

Calcium chloride 1.65.

The preparation method of this embodiment sequentially includes the following steps:

Preparing three parts of a 20 mL aqueous solution containing 0.4 g of carboxymethyl chitosan, containing 20 g of an aqueous solution of 0.4 g of PVA (EG-40) in two portions, and adding a plasticizing system and polyhexamethylene oxime according to the corresponding ratio; The amount of the plasticizing system of each aqueous solution of carboxymethyl chitosan is the same, the amount of polyhexamethylene hydrazine added to each aqueous solution of carboxymethyl chitosan is the same, and the amount of plasticizing system added to each PVA is the same, and each portion is added. The amount of polyhexamethylene hydrazine in PVA is the same; each carboxymethyl chitosan system is stirred and foamed for 30 min and stored at 0 ° C, and 5 mL of 10% calcium chloride solution is added in a mass percentage; each PVA system is at -20 ° C Pre-freeze and thaw at room temperature and repeat 5 times. The above 5 parts of the solution were assembled in the same mold and pre-frozen at -20 ° C, and after the completion of the pre-freezing, the mold was released and immediately freeze-dried for 24 hours. The resulting sponge material is cut and packaged.

Example 10

The hemostatic material of the present embodiment is prepared by a second method, the hemostatic material comprising the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.8,

PVA (EG-40) 1.2,

Compounded toughener 1.5 (where PEG-2000 1, glycerol 0.5)

Polyhexamethylene hydrazine 0.5,

Calcium chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

Preparing two portions of a 20 mL aqueous solution containing 0.4 g of carboxymethyl chitosan, containing 20 g of an aqueous solution of 0.4 g of PVA (EG-40) in three portions, and adding a plasticizing system and polyhexamethylene oxime according to the corresponding ratio; The amount of the plasticizing system of each aqueous solution of carboxymethyl chitosan is the same, the amount of polyhexamethylene hydrazine added to each aqueous solution of carboxymethyl chitosan is the same, and the amount of plasticizing system added to each PVA is the same, and each portion is added. The amount of polyhexamethylene hydrazine in PVA is the same; each carboxymethyl chitosan system is stirred and foamed for 30 min and stored at 0 ° C, and 5 mL of 10% calcium chloride solution is added in a mass percentage; each PVA system is at -20 ° C Pre-freeze and thaw at room temperature and repeat 5 times. The above 5 parts of the solution were assembled in the same mold and pre-frozen at -20 ° C, and after the completion of the pre-freezing, the mold was released and immediately freeze-dried for 24 hours. The resulting sponge material is cut and packaged.

Example 11

The hemostatic material of this embodiment is prepared by a second method comprising the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 1,

PVA(EG-40) 1,

Compound toughening 1 (where PEG-2000 0.5, glycerol 0.5)

Polyhexamethylene hydrazine 1,

Calcium chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

Preparing two portions of a 20 mL aqueous solution containing 0.5 g of carboxymethyl chitosan, containing 20 g of an aqueous solution of 0.5 g of PVA (EG-40) in two portions, and adding a plasticizing system and polyhexamethylene oxime according to the corresponding ratio; The amount of the plasticizing system of each aqueous solution of carboxymethyl chitosan is the same, the amount of polyhexamethylene hydrazine added to each aqueous solution of carboxymethyl chitosan is the same, and the amount of plasticizing system added to each PVA is the same, and each portion is added. PVA polyhexamethylene hydrazine is used in the same amount; each part is stirred and foamed for 30 min in carboxymethyl chitosan system and stored at 0 ° C, adding 5 mL of mass percentage concentration of 10% calcium chloride solution; for PVA system at -20 ° C Pre-freeze and thaw at room temperature and repeat 5 times. The above-mentioned 4 systems were assembled in the same mold and pre-frozen at -20 ° C, and after the completion of the pre-freezing, the mold was released and immediately freeze-dried for 24 hours. The resulting sponge material is cut and packaged.

Example 12

The hemostatic material of the present embodiment is prepared by a second method, the hemostatic material comprising the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 1.4,

PVA (EG-40) 0.6,

Compounded toughening 1 (where PEG-2000 0.5, glycerol 0.5),

Polyhexamethylene hydrazine 1.5,

Ferric chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

Preparing two portions of a 20 mL aqueous solution containing 0.7 g of carboxymethyl chitosan, containing 20 g of an aqueous solution of 0.3 g of PVA (EG-40) in two portions, and adding a plasticizing system and polyhexamethylene oxime according to the corresponding ratio; The amount of the plasticizing system of each aqueous solution of carboxymethyl chitosan is the same, the amount of polyhexamethylene hydrazine added to each aqueous solution of carboxymethyl chitosan is the same, and the amount of plasticizing system added to each PVA is the same, and each portion is added. The amount of polyhexamethylene hydrazine in PVA is the same; each part is stirred and foamed for 30 min in carboxymethyl chitosan system and stored at 0 ° C, and 5 mL of 10% ferric chloride solution is added; the PVA system is at -20 ° C. Pre-freeze and thaw at room temperature and repeat 5 times. The above-mentioned 4 systems were assembled in the same mold and pre-frozen at -20 ° C, and after the completion of the pre-freezing, the mold was released and immediately freeze-dried for 24 hours. The resulting sponge material is cut and packaged.

Example 13

The hemostatic material of the present embodiment is prepared by a second method, the hemostatic material comprising the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.6,

PVA (EG-40) 1.4,

Compounded toughener 0.5 (where PEG-2000 0.25, glycerol 0.25),

Polyhexamethylene hydrazine 1.5,

Ferric chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

Preparing two portions of a 20 mL aqueous solution containing 0.3 g of carboxymethyl chitosan, containing 20 g of an aqueous solution of 0.7 g of PVA (EG-40) in two portions, and adding a plasticizing system and polyhexamethylene oxime according to the corresponding ratio; The amount of the plasticizing system of each aqueous solution of carboxymethyl chitosan is the same, the amount of polyhexamethylene hydrazine added to each aqueous solution of carboxymethyl chitosan is the same, and the amount of plasticizing system added to each PVA is the same, and each portion is added. The amount of polyhexamethylene hydrazine in PVA is the same; each part is stirred and foamed for 30 min in carboxymethyl chitosan system and stored at 0 ° C, and 5 mL of 10% ferric chloride solution is added; the PVA system is at -20 ° C. Pre-freeze and thaw at room temperature and repeat 5 times. The above-mentioned 4 systems were assembled in the same mold and pre-frozen at -20 ° C, and after the completion of the pre-freezing, the mold was released and immediately freeze-dried for 24 hours. The resulting sponge material is cut and packaged.

Example 14

The hemostatic material of the present embodiment is prepared by a second method, the hemostatic material comprising the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.4,

PVA (EG-40) 1.6,

Compounded toughener 0.5 (where PEG-2000 0.25, glycerol 0.25),

Polyhexamethylene hydrazine 1.5

Ferric chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

Prepare two portions of 20 mL aqueous solution containing 0.2 g of carboxymethyl chitosan, and add 20 mL of an aqueous solution containing 0.8 g of PVA (EG-40) in two portions, and add a plasticizing system and polyhexamethylene oxime according to the corresponding ratio; The amount of the plasticizing system of each aqueous solution of carboxymethyl chitosan is the same, the amount of polyhexamethylene hydrazine added to each aqueous solution of carboxymethyl chitosan is the same, and the amount of plasticizing system added to each PVA is the same, and each portion is added. The amount of polyhexamethylene hydrazine in PVA is the same; each part is stirred and foamed for 30 min in carboxymethyl chitosan system and stored at 0 ° C, and 5 mL of 10% ferric chloride solution is added; the PVA system is at -20 ° C. Pre-freeze and thaw at room temperature and repeat 5 times. The above-mentioned 4 systems were assembled in the same mold and pre-frozen at -20 ° C, and after the completion of the pre-freezing, the mold was released and immediately freeze-dried for 24 hours. The resulting sponge material is cut and packaged.

Example 15

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.6,

PVA (EG-05) 0.6,

Compounded toughener 1.5 (where PEG-3350 1, glycerol 0.5),

Sanqi powder 0.5,

Aluminum chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 0.6 g of carboxymethyl chitosan and 0.6 g of PVA (EG-05), 1.5 g of compound toughening material and 0.5 g of notoginseng powder were added, and uniformly mixed at room temperature, and stirred and foamed. After 30 minutes, 10 mL of a 10% by mass aluminum chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 16

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 1.2,

PVA (EG-25) 0.8,

Compounded toughener 1.5 (where PEG-2000 1, glycerol 0.5),

Vitamin K1 0.5,

Aluminum chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 1.2 g of carboxymethyl chitosan and 0.8 g of PVA (EG-25), 1.5 g of a compound toughening substance and 0.5 g of vitamin K1 were added, and uniformly mixed at room temperature, and the foaming was stirred 30 After a minute, 10 mL of a 10% by mass aluminum chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 17

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 1,

PVA(EG-30) 1,

Compounded toughened material 1 (where PEG-1430 0.5, glycerol 0.5),

Vitamin K3 1,

Calcium chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 1 g of carboxymethyl chitosan and 1 g of PVA (EG-30), 1 g of the compound toughened material and 1 g of vitamin K3 were added, and the mixture was uniformly mixed at room temperature, stirred for 30 minutes, and then added. A 10% calcium chloride solution containing 10% by mass was placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material was cut and packaged.

Example 18

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.8,

PVA (EG-25) 1.2,

Compounded toughener 0.5 (where PEG-400 0.25, glycerol 0.25),

Vitamin K4 1.5,

Ferric chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 0.8 g of carboxymethyl chitosan and 1.2 g of PVA (EG-25), 0.5 g of a compound toughening substance and 1.5 g of vitamin K4 were added, and uniformly mixed at room temperature, and the foaming was stirred 30 After a minute, 10 mL of a 10% by weight ferric chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 19

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.6,

PVA (EG-30) 1.4,

Compounded toughener 0.5 (where PEG-2000 0.25, glycerol 0.25),

Sanqi powder 1.5,

Aluminum chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 0.6 g of carboxymethyl chitosan and 1.4 g of PVA (EG-30), 0.5 g of a compound toughening substance and 1.5 g of notoginseng powder were added, and uniformly mixed at room temperature, and stirred and foamed. After 30 minutes, 10 mL of a 10% by mass aluminum chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Example 20

The hemostatic material of the present embodiment is prepared by the first method, and the hemostatic material comprises the following parts by weight ratio of raw materials:

Carboxymethyl chitosan 0.6,

PVA (EG-30) 1.4,

Compounded toughener 0.5 (where PEG-2000 0.25, glycerol 0.25),

Sanqi powder 1.5,

Sodium chloride 1.1.

The preparation method of this embodiment sequentially includes the following steps:

To 100 mL of an aqueous solution containing 0.6 g of carboxymethyl chitosan and 1.4 g of PVA (EG-30), 0.5 g of a compound toughening substance and 1.5 g of notoginseng powder were added, and uniformly mixed at room temperature, and stirred and foamed. After 30 minutes, 10 mL of a 10% by mass sodium chloride solution was added, and then placed in a mold, pre-frozen at -20 ° C and thawed at room temperature, and repeated 5 times. The material at -20 ° C was demolded and immediately freeze dried for 24 hours. The resulting sponge material is cut and packaged.

Test case:

After testing, the basic performance indexes of the sponge materials prepared in the above examples are shown in Table 1, which proves that the technical index data of the composite hemostatic material is stable.

project index Material density 0.01-0.20g/cm ³ Void ratio 85%-99% Water absorption ratio ≥6g/g Modulus ≥32MPa Tensile Strength ≥8.0MPa Elongation at break ≥300%

Table 1 Summary of basic performance indicators of hemostatic materials

The specific test methods for the basic properties of the sponge material in the above embodiments are as follows:

Among them: (1) The method for measuring the density of the sponge material adopts the glycerin discharge volume method. The prepared dry hemostatic sponge material is taken into a certain volume and placed in a measuring cylinder of the original volume. The volume of the glycerin in the measuring cylinder is V0, the volume after the sponge is placed into V1, and the mass of the sea sponge material weighed by the balance is m. The density of the sponge material is ρ = (V1 - V0) / m.

(2) The porosity measurement method of the sponge material is tested by the mass-volume direct calculation method, and the calculation formula is:

为孔隙率，ρf为止血海绵试样的表观密度(试样质量与试样表观体积之比)，ρs为对应止血海绵实心材料的密度。 In the formula:

The porosity, the apparent density of the blood sponge sample (the ratio of the sample mass to the apparent volume of the sample), ρs is the density of the solid material corresponding to the hemostatic sponge.

(3) The determination of the water absorption multiple of the material is carried out according to the Pharmacopoeia of the People's Republic of China. The specific method is: weighing the weighing bottle that has been completely dried, recorded as W0, accurately weighing about 2g has been completely soaked in deionized water for one day. For the sponge material to be tested, the total weight is W1. The sponge material and the weighing bottle are placed in a vacuum drying oven, set to a temperature of 80 ° C, vacuum dried for 24 hours, taken out and transferred to a desiccator for 30 minutes. Accurately measure, after repeating the operation several times, the difference between the weights to be weighed is less than 5mg, and note that the weight weighed last time is W2, then the water absorption multiple W of the material is (W1-W2)/(W1-W0) .

The electronic balance used in the experiment was an AL-104 electronic balance (METTLER TOLEDO Instrument Co., Ltd.), and the vacuum oven used was a 101-3AB vacuum oven (Tianjin Taisite Instrument Co., Ltd.).

(4) Tensile strength and elongation at break are tested according to national standard GB/T10802-2006.

(5) The compressive stress strain and stress relaxation curves are tested according to YY/T-0471 standard, and the modulus of the material is obtained by computer processing. The test equipment adopts TM7105 electronic universal testing machine (Zhuhai Sansi Testing Equipment Co., Ltd.), the sample is The dumbbell type spline has a pattern size of 65 mm x 12 mm x 0.6 to 0.8 mm, a loading speed of 0.5 mm/min, and a relaxation test compression amount of 45%. Put the corresponding spline into the universal material testing machine and input the corresponding parameters to obtain the corresponding curve, tensile strength, elongation at break and material modulus. The modulus obtained here is the compressive modulus.

Taking Example 1 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 85%, the water absorption ratio was 6 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 1 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 85%, the water absorption ratio was 6 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 2 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 90%, the water absorption ratio was 8 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 3 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 85%, the water absorption ratio was 7 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 4 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 90%, the water absorption ratio was 7.5 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break is 300%.

Taking Example 5 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 85%, the water absorption ratio was 9 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 6 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 80%, the water absorption ratio was 7 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 7 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 90%, the water absorption ratio was 6 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 8 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 85%, the water absorption ratio was 7 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 9 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 95%, the water absorption ratio was 10 g/g, the modulus was 36 MPa, and the tensile strength was 12 MPa. The elongation at break was 400%.

Taking Example 10 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 95%, the water absorption ratio was 12 g/g, the modulus was 35 MPa, and the tensile strength was 13 MPa. The elongation at break was 400%.

Taking Example 11 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 95%, the water absorption ratio was 15 g/g, the modulus was 40 MPa, and the tensile strength was 12 MPa. The elongation at break was 400%.

Taking Example 12 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 95%, the water absorption ratio was 12 g/g, the modulus was 35 MPa, and the tensile strength was 12 MPa. The elongation at break was 400%.

Taking Example 13 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 95%, the water absorption ratio was 10 g/g, the modulus was 36 MPa, and the tensile strength was 12 MPa. The elongation at break was 400%.

Taking Example 14 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 95%, the water absorption ratio was 12 g/g, the modulus was 38 MPa, and the tensile strength was 13 MPa. The elongation at break was 400%.

Taking Example 15 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 85%, the water absorption ratio was 6 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 16 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 80%, the water absorption ratio was 8 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 17 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 85%, the water absorption ratio was 7 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 18 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm3, the porosity of the material was 80%, the water absorption ratio was 6 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation is 300%.

Taking Example 19 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 85%, the water absorption ratio was 8 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

Taking Example 20 as an example, according to the above method, the density of the material was measured to be 0.2 g/cm ³ , the porosity of the material was 85%, the water absorption ratio was 7 g/g, the modulus was 32 MPa, and the tensile strength was 8 MPa. The elongation at break was 300%.

The following table 2 is a comprehensive comparison of the performance of the body cavity filled hemostatic material provided by the present invention and the conventional hemostatic material. Specifically, the performance of the present hemostatic material of Examples 1-20 and Vaseline gauze, PVA material, and collagen are compared.

Table 2 Performance comparison between body cavity filled hemostatic materials and traditional hemostatic materials

It can be seen from the above comparison that the body cavity filled hemostatic material provided by the present invention has advantages in terms of expansibility, hemostatic effect, degradability, safety, patient quality of life, residual cavity and price compared with the conventional hemostatic material. The hemostatic material has a dual hemostatic effect of direct coagulation and compression to stop bleeding, and its degradation time is controllable. This product has no toxicity, no allergic and rejection reaction; comfortable and painless, complete degradation, no need to take out; degradation of the final product is CO ₂ and H ₂ O, promote wound tissue healing; cheap. The body cavity filled hemostatic material is particularly suitable for use in a lumen, particularly a nasal cavity to stop bleeding.

The body cavity filled hemostatic material provided by the invention can be used for medical products in surgical and emergency departments, and can also be designed as daily medical articles for ordinary consumers. The hemostatic material can be used for surgical hemostasis, traumatic wound healing, especially in the body cavity hemostasis, and can be used as a filling material for the lumen, especially the nasal cavity.

The hemostatic material provided by the present invention and a preparation method thereof are described in detail above. Any obvious changes made to the present invention without departing from the spirit of the invention will constitute an infringement of the patent right of the present invention and will bear corresponding legal liabilities.

Claims (10)

A hemostatic material, characterized in that: the raw material of the hemostatic material comprises: carboxymethyl chitosan, polyvinyl alcohol, compound toughening substance, ionic crosslinking agent; Preferably, the hemostatic material is used for wound hemostasis, preferably for body cavity hemostasis; more preferably, the body cavity is a lumen; further preferably, the body cavity is a nasal cavity. The hemostatic material according to claim 1, wherein said hemostatic material comprises a raw material in the following parts by weight ratio: The carboxymethyl chitosan is 0.1 to 1.5, the polyvinyl alcohol is 0.5 to 2, the toughened material is 0.2 to 5, and the ionic crosslinking agent is 0.5 to 1.5. The hemostatic material according to claim 1 or 2, wherein the polyvinyl alcohol is one or more of EG-05, EG-25, EG-30 and EG-40. A hemostatic material according to claim 1 or 2, characterized in that: The compound toughening material comprises: polyethylene glycol and glycerin in a weight ratio of 1: (1 to 0.2); Preferably, the polyethylene glycol is one or more of PEG-3350, PEG-1430, PEG-2000, PEG-400. The hemostatic material according to claim 1 or 2, wherein the ionic crosslinking agent is one or more of an iron salt, a calcium salt, a sodium salt or an aluminum salt. The hemostatic material according to claim 1 or 2, wherein the raw material of the hemostatic material further comprises a broad-spectrum hemostatic antibacterial agent; Preferably, the broad-spectrum hemostatic antibacterial agent is used in an amount of 0.5 to 3 parts by weight; Preferably, the broad-spectrum hemostatic antibacterial agent is one or more of polyhexamethylene sulfonium, notoginseng powder, vitamin K1, vitamin K3, and vitamin K4. A method of producing a hemostatic material according to any one of claims 1 to 5, wherein the method comprises the following steps in sequence: Dissolving step: dissolving the carboxymethyl chitosan and polyvinyl alcohol in water to obtain an aqueous solution of a main raw material; a crosslinking step: adding the compound toughening material to the aqueous solution of the main raw material to carry out a crosslinking reaction to obtain a crosslinked product; a freeze-drying step: freeze-drying the cross-linked product to obtain the hemostatic material; Preferably, in the crosslinking step, the mixed system comprising the aqueous solution of the main raw material and the compound toughening material is stirred for 15-40 minutes, and the ionic crosslinking agent is added thereto, and then at -10 to -25 Pre-freeze at °C, then thaw at room temperature, repeat 3 to 8 times. The method for preparing a hemostatic material according to any one of claims 1 to 6, wherein the method comprises the following steps in sequence: Dissolving step: dissolving the carboxymethyl chitosan and polyvinyl alcohol in water to obtain an aqueous solution of a main raw material; Cross-linking step: adding the compound toughening substance and the broad-spectrum hemostatic antibacterial agent to the aqueous solution of the main raw material to carry out a crosslinking reaction to obtain a cross-linked product; Freeze-drying step: The cross-linked product is subjected to freeze-drying treatment to obtain the hemostatic material. A method of preparing a hemostatic material according to any one of claims 1 to 5, wherein: The method in turn includes the following steps: Dissolving step: dissolving the carboxymethyl chitosan and polyvinyl alcohol in water respectively to obtain at least two portions of an aqueous solution of carboxymethyl chitosan and at least two portions of an aqueous solution of polyvinyl alcohol; Cross-linking step: adding the compound toughening materials to each of the aqueous solution of carboxymethyl chitosan and polyvinyl alcohol solution, respectively, and performing cross-linking reaction to obtain ion-crosslinked products and physical cross-linked products, respectively Then, each of the ion crosslinked products and the physically crosslinked product are interleaved to obtain a layer-layer assembly structure; and the layer-layer assembly structure is pre-frozen at -10 to -25 ° C to obtain an interpenetrating network structure. Cross-linked product; a freeze-drying step: freeze-drying the cross-linked product having an interpenetrating network structure to obtain the hemostatic material; Preferably, in the crosslinking step, the carboxymethyl chitosan aqueous solution and the compound toughening material are subjected to the crosslinking reaction by an ionic crosslinking agent method; the polyvinyl alcohol aqueous solution and the compound toughening The crosslinking reaction is carried out by a physical cyclic crosslinking method; Further preferably, the ionic cross-linking agent method comprises stirring a mixed system comprising the aqueous solution of the carboxymethyl chitosan and the compound toughening agent for 15-40 minutes, and then adding the ionic crosslinking agent thereto. Store at 0 ° C again; Further preferably, the physical cyclic crosslinking method is to pre-freeze the mixed system comprising the aqueous solution of polyvinyl alcohol and the compound toughening material at -10 to -25 ° C, and then thaw at room temperature, repeating 3 to 8 times. . A method of preparing a hemostatic material according to any one of claims 1 to 6, wherein: The method in turn includes the following steps: Dissolving step: dissolving the carboxymethyl chitosan and polyvinyl alcohol in water respectively to obtain at least two portions of an aqueous solution of carboxymethyl chitosan and at least two portions of an aqueous solution of polyvinyl alcohol; Cross-linking step: adding the compound toughening substance and the broad-spectrum hemostatic antibacterial agent to each of the carboxymethyl chitosan aqueous solution and the polyvinyl alcohol aqueous solution, respectively, and performing cross-linking reaction to obtain ion crosslinking a product and a physically cross-linked product; each of the ion-crosslinked product and the physically cross-linked product are interleaved to obtain a layer-layer assembly structure; and the layer-layer assembly structure is pre-frozen at -10 to -25 ° C Obtaining a crosslinked product having an interpenetrating network structure; a freeze-drying step: freeze-drying the cross-linked product having an interpenetrating network structure to obtain the hemostatic material; Preferably, in the crosslinking step, the carboxymethyl chitosan aqueous solution and the compound toughening material are subjected to the crosslinking reaction by an ionic crosslinking agent method; the polyvinyl alcohol aqueous solution and the compound toughening The crosslinking reaction is carried out by a physical cyclic crosslinking method; Further preferably, the ionic cross-linking agent method comprises stirring a mixed system comprising the aqueous solution of the carboxymethyl chitosan, the complex toughening substance, and the broad-spectrum hemostatic antibacterial agent for 15-40 minutes, and then adding the solution thereto. Said ionic crosslinker, and then stored at 0 ° C; Further preferably, the physical circulation crosslinking method is to pre-freeze a mixed system comprising the aqueous solution of polyvinyl alcohol, a complex toughening substance, and a broad-spectrum hemostatic antibacterial agent at -10 to -25 ° C, and then thaw at room temperature. , repeat 3 to 8 times.