WO2010118555A1

WO2010118555A1 - Use of acrylate resin and grafted polymer thereof in preparation of hemostatic dressing and preparation method thereof

Info

Publication number: WO2010118555A1
Application number: PCT/CN2009/000403
Authority: WO
Inventors: 赵伟; 窦桂芳; 欧阳茂海; 景宜品; 杨乡鹰
Original assignee: 深圳市鸿华药业有限公司
Priority date: 2009-04-16
Filing date: 2009-04-16
Publication date: 2010-10-21
Also published as: CN102395387A

Abstract

The invention provides the use of acrylate resin and grafted polymer thereof in preparation of hemostatic dressing, and the preparation method of the acrylate resin and grafted polymer thereof. The preparation method includes: taking measured polymeric monomer and putting it into a neutralizing kettle, adding alkaline neutralizing solution with stirring, diluting the polymeric monomer to determinate concentration to prepare un-polymeric solution after neutralizing, transferring the un-polymeric solution to polymeric disc which has stirring and good heat dispersion function, adding crosslinking agent and stirring, adding initiating agent to initiate polymerization, preparing semi-finished product, drying the semi-finished product at high temperature, crushing, filtrating, sterilizing and getting finished product finally.

Description

Application and preparation method of acrylic resin and graft thereof as preparation of hemostatic dressing

The present invention relates to the use of acrylic resins and grafts thereof, and more particularly to the use of acrylic resins and grafts thereof for the preparation of hemostatic dressings and methods for their preparation. Background technique

Common traditional topical hemostatic drugs include Yunnan Baiyao, Sanqi Powder and Thrombin, and have been widely used in clinical practice. The first two are non-soluble Chinese herbal medicines, which are limited in the operation and exposure of deep wounds due to the scar formation of wounds. Thrombin is an active protein extracted from pig blood. It is allergic and expensive for others. Therefore, most patients are difficult to accept. In addition, they have poor hemostatic effects on large bleeding wounds caused by moderate and severe trauma.

To this end, Medafor of the United States produced a sponge-like hemostatic material based on potato starch. This sponge-like material can absorb a large amount of water in the blood at the bleeding point, and promote the accelerated coagulation of platelets and blood proteins, thereby achieving the purpose of stopping bleeding. This powder-like hemostatic dressing on the surface of the wound can significantly accelerate the formation of blood clots in the skin wound, forming a large blood clot within a few seconds, preventing blood from escaping. Since its hemostasis mechanism relies on the blood itself to coagulate, it does not inhibit wound healing, but the hemostatic material absorbs a large amount of water in the blood to achieve hemostasis, which causes the temperature at the wound to rise and cause damage.

Therefore, it is hoped that hemostatic agents with fast hemostasis, good effects, small side effects, ease of use, and low cost can be developed to meet the hemostatic requirements of moderate and severe open wound bleeding caused by traumatic trauma and surgery. Summary of the invention

The object of the present invention is to provide a new use of acrylic resin and its graft, and

Confirmation A method for preparing an acrylic resin and a graft thereof suitable as a hemostatic dressing and a hemostatic dressing prepared according to the method.

According to a first aspect of an embodiment of the present invention, an acrylic resin and a graft thereof are provided as an application for preparing a hemostatic dressing.

According to a second aspect of the present invention, there is provided a method of preparing an acrylic resin as a hemostatic dressing and a graft thereof, comprising the steps of weighing a polymerized monomer (acrylic acid or a substance involved in a graft reaction) and Put in the neutralization kettle; gradually add the alkaline neutralizing solution in an amount of stirring, neutralize and then add water to dilute the polymerization monomer to a predetermined concentration to prepare a liquid to be polymerized; transfer the liquid to be polymerized to have a stirring In the polymerization tray with good heat dissipation function, the crosslinking agent is uniformly stirred; the initiator is added to initiate the polymerization reaction, and the semi-finished product is obtained after the reaction is completed; and the prepared semi-finished product is dried under high temperature or microwave, and then pulverized. Screen and sterilize.

According to a third aspect of the present invention, there is provided an acrylic resin as a hemostatic dressing and a graft thereof prepared according to the method of the second aspect of the present invention.

According to a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising the acrylic resin as a hemostatic dressing according to the third aspect of the present invention, and a graft thereof, and a pharmaceutically acceptable carrier.

According to a fifth aspect of the present invention, there is provided a first aid kit comprising an acrylic resin as a hemostatic dressing according to a third aspect of the present invention and a graft thereof or a pharmaceutical composition according to the fourth aspect of the embodiment of the present invention Things.

According to a sixth aspect of the present invention, there is provided a hemostatic patch comprising an acrylic resin as a hemostatic dressing according to a third aspect of the present invention and a graft thereof or a pharmaceutical composition according to the fourth aspect of the embodiment of the present invention Things.

According to a seventh aspect of the present invention, there is provided a hemostatic bandage comprising an acrylic resin as a hemostatic dressing according to the third aspect of the present invention and a graft thereof or a pharmaceutical composition according to the fourth aspect of the present invention. Things.

According to an eighth aspect of the present invention, there is provided a hemostatic gauze comprising an acrylic resin as a hemostatic dressing according to the third aspect of the present invention and a graft thereof or A pharmaceutical composition according to the fourth aspect of the embodiments of the present invention.

According to a ninth aspect of the present invention, there is provided a drug sustained-release material comprising an acrylic resin as a hemostatic dressing according to a third aspect of the present invention and a graft thereof or a fourth aspect according to an embodiment of the present invention Pharmaceutical composition.

According to a tenth aspect of the present invention, there is provided a repair implant material comprising an acrylic resin as a hemostatic dressing according to the third aspect of the present invention and a graft thereof or a fourth aspect according to an embodiment of the present invention Pharmaceutical composition.

The hemostatic dressing according to the present invention enables rapid and complete hemostasis. The effect on the wound is purely physical, non-toxic, side effects, safe and reliable. Moreover, the performance is stable, the operation is convenient, there is no temperature rise during the hemostasis, the damage to the wound tissue cells is overcome, and the debridement is facilitated, and the invention is applicable not only to the skin surface wound but also to the larger and deeper wound, which is beneficial to the patient. Accepted. DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a flow chart showing the preparation of a hemostatic dressing according to an embodiment of the present invention, wherein the solid line area is a 100,000-level pure area, and the dotted line area is a 10,000-level pure area.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an infrared spectrum of an acrylic resin hemostatic dressing prepared in accordance with an embodiment of the present invention.

Figure 3 is a scanning electron micrograph of an acrylic resin hemostatic dressing prepared in accordance with an embodiment of the present invention.

Fig. 4 is an optical micrograph of an acrylic resin hemostatic dressing prepared in accordance with an embodiment of the present invention after water absorption and saturation. detailed description

The acrylic resin and the graft thereof for use as a hemostatic dressing according to the present invention means that an organic substance having a double bond or a triple bond is prepared by crosslinking with a crosslinking agent under the action of an initiator to prepare a lightly crosslinked one. The spatial network structure has a physical cross-linking of chemical cross-linking and intertwined molecular chains. At present, these materials have strong water absorption properties and are widely used. It is widely used in sanitary materials such as feminine napkins and diapers. The invention relates to a new use of the material of the acrylic resin and the graft thereof as a hemostatic dressing, and the material is applied to the field of hemostasis for the first time at home and abroad. The principle of hemostasis is: uniformly spreading the sterile hemostatic dressing to cover the entire wound surface, and gently absorbing the blood in a three-dimensional network with a controllable network aperture after being subjected to a liquid. Small molecules such as water molecules allow platelets and coagulation factors to be trapped instantaneously and aggregate and concentrate on damaged wounds to quickly stop bleeding. The dressing absorbs quickly, highly and uniformly, and the long and smooth body is smooth and soft, forming a waterproof gelatinous shape. The concentrating body is used as a compartment to block and fix the bleeding mouth, effectively preventing secondary bleeding; the gel formed by the high expansion of the dressing uniformly squeezes the damaged blood vessel and the muscle tissue around the blood vessel to cause the damaged blood vessel No more bleeding, so as to achieve rapid, complete hemostasis.

However, from a biological safety point of view, the technical specifications of the acrylic resin and its graft when used as a hemostatic dressing are more stringent and different from those conventionally used as a water absorbing material (for example, as a hemostatic dressing). When the amount of physiological saline is larger than that of the water absorbing material, the conventional water absorbing material cannot be directly used as a hemostatic dressing. For this reason, the present invention has further improved the preparation method of the acrylic resin as a hemostatic dressing and the graft thereof, and the method will be specifically described below by way of examples.

The materials used in the process according to the present invention are all common fine chemicals, which are widely available and inexpensive, and the process of the process is as follows.

1. Main raw materials '

The precondition for the implementation of the present invention is the screening and optimization of raw materials, after repeated tests and analysis and analysis of product properties and effects, it is determined that organic acids or ester organic materials having double or triple bonds are the main polymerization raw materials (of course, Other organic materials meeting the polymerization conditions can also be used in the present invention. The main purpose is to facilitate the polymerization of the raw materials such as addition polymerization, copolymerization or graft polymerization; the other main chemical raw material is the alkalinity necessary for the neutralization reaction. The corresponding alkali solution of the compound, the basic compound is mainly the corresponding alkali metal and alkaline earth metal hydroxide in the periodic table, such as 〖0H, NaOH, Ca(0H) _2, etc.; finally, the initiator and the crosslinking agent. Select, consider the safety and efficiency of the polymerization reaction, the initiator is selected by chemical shield or radiation, wherein the initiator is mainly caused by thermal decomposition system and redox System, radiation mainly involves high-energy ray radiation, ultraviolet radiation, electron ray radiation and the like. The cross-linking agent relates to the product structure, so the cross-linking agent is preferred, and the cross-linking agent of the appropriate chain length is selected to control the moderate cross-linking density and the length of the segment between the cross-linking points without affecting the performance of the product. A network reaction is carried out to prepare a polymer material having a certain three-dimensional network pore size.

2. Preparation principle

The basic principle of product preparation is a chain polymerization reaction characterized in that small molecules become macromolecules by reaction between double bonds. After several steps of elementary reaction, no intermediate small molecule product is formed during the process. Generally, it undergoes processes such as chain initiation, chain growth, chain termination, and chain transfer.

For the radical polymerization, there are four methods of bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization.

The present embodiment is preferably a solution polymerization method because, due to the presence of a large amount of solvent water, the viscosity of the system is low, mixing and heat transfer are relatively easy, the polymerization reaction is stable and relatively easy to control, and localized overheating does not occur. phenomenon. At the same time, other additives such as initiators and crosslinking agents are relatively easy to be uniform: the efficiency of initiation and crosslinking is high, the molecular weight distribution of the product is narrow, the molecular weight is relatively high, and the product quality is high. The method has the characteristics of simple method, pure system and uniform cross-linking structure.

In the following examples, the acrylic resin is mainly prepared by using acrylic acid as a single polymerization monomer or copolymerized with acrylamide, and the graft polymer is grafted with starch or carboxymethyl cellulose (sodium) by acrylic acid as a skeleton. Formed, involved in grafting materials including, but not limited to, starch, sodium carboxymethyl cellulose, and the like.

The following mainly describes the use of acrylic acid as a polymerization monomer and sodium hydroxide as a neutralization solution: In the preparation process, various chemical reactions are involved, the most important of which are neutralization reaction and polymerization crosslinking reaction. The reaction process is as follows.

Partial neutralization reaction:

NaOH

CH ₂ =CH , ' - CH ₂ =CH + 3⁄40

COOH COONa Initiating reaction, polymerization

K*

)

The above two-step reaction can better illustrate the implementation process of this embodiment. From the viewpoint of polymerization of a single monomer acrylic acid, the polymerization reaction is a homopolymerization reaction, but the present invention is not limited to the homopolymerization reaction.

3. Technical parameters

In order to obtain a suitable product, factors involved in the reaction process such as monomer concentration, degree of neutralization, reaction time, reaction temperature, initiator concentration, crosslinking agent concentration, and amount are controlled in the following ranges.

The monomer concentration is controlled between 20 - 75 %;

<2) The degree of neutralization is controlled at 55~90%;

6 reaction time is generally 2 ~ 10 hours;

The reaction temperature is controlled at 35~85 °C;

The initiator concentration is about 0.01 ~ 5 %, and the amount is generally 0.001-5% of the monomer mass.

^The concentration of the cross-linking agent is about 0.01~4%, and the dosage one is 0.001~2 of the mass of the monomer.

%

4. Main process

The flowchart shown in Fig. 1 reflects the main steps of the embodiment, and will now be described based on the flowchart. According to the measurement relationship of technical parameters, the relationship between the amount of each raw material is calculated according to the production capacity. First, a certain amount of polymerized monomer A is weighed and placed in a neutralization kettle; the alkaline neutralizing solution B is gradually added in an amount of agitation; after neutralization, a certain amount of water is added to dilute the polymerization monomer A to a predetermined concentration. , that is, the liquid C to be prepared is prepared; then, the liquid C to be quickly transferred to a plurality of small-sized polymerization trays having a function of stirring and good heat dissipation, and the crosslinking agent is uniformly stirred to initiate polymerization under the action of the initiator. The reaction, after completion of the reaction, produces a semi-finished product. After discharging, it is dried at a high temperature, then pulverized, sieved, and sterilized, and packaged into a warehouse. It should be emphasized that, 'To ensure the safety and effectiveness of the products, the relevant stages are carried out in a clean environment of 10,000 or 100,000.

The polymerization solution is dispersed in a small polymerization tray by using a plurality of small polymerization trays, and the polymerization reaction is not only stable and safe, but also complete in reaction, small residual amount of monomers, and relatively easy to discharge, and polymerization in a small polymerization tray. The product can be taken directly for post-treatment. In addition, the heating method is microwave heating, which makes the heating uniform and avoids the local reaction. Among them, powder particles having a particle size of 0.2 to 1.0 leg or a particle size of less than 140 mesh are preferably pulverized.

The initiator includes: chemical initiation, such as hydrogen peroxide, azobisisobutyronitrile, potassium persulfate (or complex with sodium bisulfite), and radiation initiation, such as high-energy radiation, electron beam irradiation, Ultraviolet radiation, etc.

Regarding the crosslinking agent, crosslinking is carried out by means of a chemical crosslinking agent (crosslinking chemical substance) in the case of acrylic acid, and its amount is reduced. The choice of cross-linking agent mainly considers the safety of the human body, as well as the comprehensive consideration of product performance and hemostatic effect, such as selection of polyols, including but not limited to glycerin, polyethylene glycol (or monoether), etc. A compound which conjugates a multiple double bond, such as n, n-methylenebisacrylamide or the like. As for the chain length, crosslink density and the length and length of the cross-linking point, the main consideration is the spatial network structure of the product. The longer the molecular chain of the cross-linking agent, the larger the polymer network is formed, the higher the water absorption rate, the hemostasis. The better the effect. However, if the chain is too long, the polymer network loses rigidity, the water solubility increases, and the water absorption rate decreases. The higher the crosslink density, the shorter the cross section between the crosslinking points, and the smaller the network pore size, the harder the water molecules in the blood enter. The network is not conducive to stopping bleeding. The chain length of the cross-linking agent is selected according to the physical properties of the cross-linking chemical substance, and the chain length between the two groups participating in the cross-linking reaction; the cross-linking density and the length of the segment are mainly Depending on the amount of crosslinker, the higher the amount, the greater the crosslink density.

In another embodiment, a hemostatic dressing is prepared by an acrylic (salt)-acrylamide copolymerization reaction. The metered citric acid, acrylamide and steamed anger 7j were added to the kettle, stirred to dissolve, neutralized part of the acrylic acid with sodium hydroxide solution to 85%, and the crosslinking agent n, n-methylenebisacrylamide was added. The redox initiator combined with the initiator ammonium persulfate or ammonium performate and ammonium hydrogen sulfite was heated to 60 - 80 ° C and reacted for 5 hours to form a white solid. Then, dry, dry, comminuted and sieved. Finally, sterilize, dispense and other products into products.

In yet another embodiment, a hemostatic dressing is prepared using a grafting reaction of starch or sodium carboxymethylcellulose (but not limited to starch, sodium carboxymethylcellulose). The details are as follows: (1) Starch-acrylic acid (salt) grafting reaction

Starch gelatinization: The metered starch was added to water in a round bottom flask, placed in a condensing device and stirred, and gelatinized at 90 ° C for 1.5 hours, and was used.

The acrylate (salt) prepolymerization: In the polymerization vessel, the metered water, acrylic acid, 30% sodium hydroxide solution, 0. 25mol / l (NH ₄ ) ₂ S ₂ O _s solution and 1.0% epoxy chloride The propane ethanol solution was heated to 70 ° C and stirred for 2 hours.

Mixing and drying: The gelatinized starch aqueous solution and the acrylate prepolymer are uniformly mixed, dried at 120 ° C, and the dried product is divided, sieved, and the like. Final sterilization, packaging and production

(2) Carboxymethylcellulose (sodium) grafted acrylic acid polymerization, the preparation method is as follows: Formulation:

Acrylic acid: Carboxymethyl cellulose (sodium) = 10: 1

υ 按 according to the initiator: raw materials =0. 015: 1

Method:

Preparation of sodium acrylate solution: Acrylic acid was placed in a reaction vessel, stirred, and 25% sodium hydroxide solution was added dropwise to a neutralization degree of acrylic acid of 80% to obtain a sodium acrylate polymerization solution.

Graft copolymerization reaction: Transfer the sodium acrylate solution to the reaction vessel, add the pre-weighed sodium carboxymethyl cellulose and the initiator, stir and stir, and carry out the graft copolymerization reaction. When it is viscous, turn it into the tray.

Polymerization: The tray containing the prepolymer is quickly placed in an oven, polymerized at 100-120 Torr and dried, completely dried, pulverized, and sieved. After sterilization, the finished product is dispensed.

In summary, whether it is homopolymerization, copolymerization or graft polymerization, it is mainly determined by the amount and type of raw materials used. In view of cost, ease of production process, etc., polymerization of acrylic acid is preferably employed.

In addition, since the human blood concentration is close to that of physiological saline, similar to the artificial blood, it is obvious that if the hemostatic dressing absorbs the amount of physiological saline and the artificial blood, the more favorable it is to adsorb the liquid component in the blood, so that the blood is in the blood. Other components (such as platelets, red blood cells and other clotting factors) are concentrated to promote blood coagulation. At the same time, the rate of water absorption is the key to rapid hemostasis. If the liquid component in the blood flowing out of the wound wound can be sucked out in a short time, it is beneficial to other components in the blood (such as blood clotting factors such as platelets and red blood cells). Quickly condense in a short time to achieve rapid hemostasis. In order to improve the performance of the hemostatic dressing prepared according to the present embodiment, the present embodiment can selectively use the following method: using a nonionic monomer such as a polymerization reaction of acrylic acid with acrylamide; introducing a hydrophilic group, for example Graft polymerization with starch, because starch is a polyhydroxy polyglycol natural polymer, has strong water absorption properties; also has the introduction of long chains, such as carboxymethyl cellulose (sodium) grafted acrylic acid (salt) polymerization; Selecting an appropriate cross-linking agent; and forming an interpenetrating network structure, such as using polyvinyl alcohol as a cross-linking agent, by changing different molecular weight polyvinyl alcohols to form an interpenetrating polymer. Among them, acrylic acid is used as a single component to participate in polymerization, and the type and amount of the appropriate crosslinking agent and the degree of neutralization of the monomeric acrylic acid are preferably used. The purpose is as follows: 1) The type of the crosslinking agent can be preferably used to facilitate the smooth reaction and improve the performance of the product. , such as complex initiators, polyhydroxy initiators (including polyols, polyethylene glycols, polyols ammonia), mainly because they cross-link with propionic acid bridges, they are introduced into the polymer molecular chain, improve the product Salt tolerance and aspiration rate. 2) The amount of cross-linking agent determines the size of the spatial network structure of the resin; the length of the cross-linking chain is related to the binding ability of the resin to the molecule and the gel strength of the resin after water absorption. 3) Control of the degree of neutralization, the size of the neutralization directly determines the amount of ionic type 1⁄2 (-C00_) in the resin, so the ion concentration of the liquid component and the acceptability of the hydrophilic group to the electrolyte solution The degree has an impact.

5. Product characteristics and principle of action

1) Features: Fast liquid absorption, strong liquid absorption, high expansion after aspiration.

2) Principle of action: Spread the sterile hemostatic dressing evenly over the entire wound surface, and gently cross-link the three-dimensional network with controllable network aperture to selectively absorb the blood in the blood. The small molecules of the molecule allow the platelets and coagulation factors to be trapped in an instant and accumulate and concentrate on the damaged wound to quickly stop the bleeding; the dressing absorbs quickly, highly and uniformly, and the expanded body is smooth and soft, and becomes a waterproof gelatinous body. Blocking and fixing the bleeding mouth for the compartment to effectively prevent secondary bleeding; the gel formed by the high expansion of the dressing evenly squeezes the damaged blood vessels and the muscle tissue around the blood vessels, so that the damaged blood vessels no longer bleed. And achieve rapid, complete hemostasis. The effect of the product on the wound is purely physical, non-toxic and side effects, safe and reliable.

3) Chemical structure of the product: The functional group contained in the product is determined by Fourier transform infrared light. The test method is based on the general rule of Fourier transform infrared spectroscopy of JYT001-1996. The results are shown in Fig. 2. Seen from the figure, at 3424cm- ¹ is -0H stretching vibration, 2931 cm ^-1 is the stretching vibration of CH ₂ in the asymmetric CH, as in the 1582 cm- ¹ - C00H asymmetric stretching vibration peak at 1408 Cm- ¹ is a -C00H symmetric absorption peak.

2) The ^: structure of the product: It is measured by JY/T 010-1996 analytical scanning electron microscopy method, optical microscope and polarized microscope method. The measured results are shown in Figures 3 and 4, respectively. The three-dimensional network structure of the product strongly demonstrates the hemostatic mechanism of the product, that is, the moment when the dressing encounters the liquid, the first step is to selectively absorb small molecules such as water molecules in the blood, and collect other macromolecules such as platelets and red blood cells. The platelets and blood coagulation factors are instantly trapped and aggregated and concentrated in the damaged wound to quickly stop bleeding.

6. How to use

The hemostatic dressing prepared according to the present embodiment may be included in a pharmaceutical composition for use with other pharmaceutically acceptable carriers, wherein the carrier includes, but is not limited to, gauze, medical nonwoven fabric, polymer film, etc.; Release materials and repair implant materials for use. In addition, it includes but is not limited to the following ways of use: 1) Hemostatic patch (film): The hemostatic dressing is uniformly dispersed on the surface thereof by a sandwich method using a polymer film, cloth, medical nonwoven fabric or the like, and then covered with a base material and rolled into a sheet.

2) Hemostasis package: It is prepared by using a polymer film, a cloth, a medical nonwoven fabric or the like as a base material, and then preparing the bag, and then filling the hemostatic dressing into the bag.

3) Hemostatic gauze: A mesh solid material such as cloth, paper or medical nonwoven fabric is placed in a liquid by an impregnation process to absorb components in the liquid to form a water absorbing film on the surface. The post-treatment of the nonwoven fabric is further carried out to prepare a hemostatic gauze.

4) Hemostatic gauze or bandage: It is prepared by blending or copolymerizing spinning method, and is prepared by using a non-woven fabric production process. Hemostasis comparison experiment

1. Experimental Purpose: The acrylic resin and its graft prepared by the method according to the embodiment of the present invention are compared with other hemostatic materials in terms of hemostasis time, blood loss, and 180 minute mortality to determine a method according to an embodiment of the present invention. The hemostatic effect of the prepared hepatitis B acid resin and its graft hemostatic material.

2. Experimental animals: 35 large white rabbits, about half male and female, each weighing 2. 5-3 kg.

3. Experimental materials:

1) Bandage, sterile gauze

2) Yunnan Baiyao

3) Hemostatic sponge

4) Zeolite hemostatic dressing

5) Quikclot: US z- medic, 4 ratio 0106

6) Acrylic resin prepared according to the method of the present invention and its graft (for the purpose of the test, the graft polymer of the grafted starch of the present invention is exemplified as the acrylic resin graft)

4, the actual ^ method:

40 large white rabbits, about half male and female, randomly divided into blank control group, pressure bandaging group, Pressurized dressing plus Yunnan Baiyao group, hemostatic sponge group, zeolite hemostatic dressing, Quikclot group, acrylic resin group, acrylic resin graft group, 5 groups in each group, weighing each experimental rabbit and the dressing used before and after the experiment .

Each experimental rabbit was anesthetized and fixed on the operating table. The femoral artery was surgically exposed and cut laterally 3/4 to allow it to bleed freely for 10 seconds. Observations included hemostasis time, blood loss, and 180-minute mortality. Among them, the calculation method of blood loss is: blood loss of blank control group = body weight before each animal experiment - body weight after completion of blood loss of each animal. The blood loss of the other groups was the actual weight of each animal before and after the experiment and the weight of the dressing used before and after the experiment.

5. Experimental results (see attached table 1)

Table 1: Comparison of hemostatic time, blood loss and 180-minute mortality between acrylic resin and its grafts and other hemostatic materials

Note: In Schedule 1, the hemostatic dressing of zeolite hemostatic dressing, Quikclot® acrylic resin and its grafts is 10g.

6. The experimental results show that: acrylic resin and its grafts are used for hemostasis, and compared with other hemostatic materials on the time of blood loss, blood loss and 180-minute mortality in the white rabbits, which are better than other hemostatic materials. In particular, hemostasis is rapid and effective. Large white rabbit femoral artery transverse incision 3/4, 30 seconds can effectively stop blood vessel bleeding, and the 180-minute mortality rate is

Sterility test Test basis: Pharmacopoeia of the People's Republic of China, 2005 edition of the second part of the appendix x l. H sterility test method determination.

1. Test materials

1. Acrylic resin (or acrylic resin graft) prepared according to the method of the present invention, 2Q-6Q mesh particles, 20 g per bag.

1. 2 saline

2. Medium

2. 1 need gas bacteria, anaerobic culture medium;

2. 2 mold medium; , 2. 3 nutrient broth medium;

2. 4 Staphylococcus aureus.

3, reagent preparation

3. 1 Weigh the gas-removing bacteria, anaerobic culture medium 3g 00L, add steamed distiller water 80ml, and after completely dissolved, dissolve into 100 ml filter, and pack in 20 ml of each tube.

3. 2 Weigh the mold medium 2. 46 g/100 ml, add 80 ml of distilled water. After completely dissolving, dissolve to 100 ml, filter, and dispense in a test tube, 20 ml per tube.

3. 3 Sterilize the above tube at 121 °C for 20 minutes, place it in a 37 °C incubator, and set aside for 24 hours.

3. 4 Dilute the Staphylococcus aureus solution grown to logarithmic growth phase to 100 / ml. 4, try ^ method

4. 1 Check the medium, clear, transparent and non-polluting.

4. 2 Sample placement: Aseptic operation on a clean bench, open the acrylic (or acrylic graft) particle bag, add the acrylic resin (or acrylic graft) particles to the gas, bacteria In the gas culture medium and the mold medium tube, two tubes were placed in each bag. Gastric bacteria, anaerobic culture medium 4 tubes; another tube without material as a negative control, another tube added Staphylococcus aureus 1 ml (100 / ml); 5 mold tubes.

4. 3 Put the gas-removing bacteria, anaerobic culture medium tube and positive control tube into 35 ° C; mold the culture medium tube and incubate in a 25 ° C incubator for 7 days. 5. Observation: Observe the transparency or turbidity of each tube daily.

6, test results

6. 1 After 18 hours of positive control tube culture, the medium appeared turbid, and the turbidity increased day by day.

6. 2 After the culture of the gas-sterilizing and anaerobic culture tubes, the medium is clear, transparent, and free of bacterial growth.

6. 3 Mycelial culture tube After 7 days, the medium was clear, transparent, and free of bacterial growth.

7. Evaluation of results: The acrylic resin (or acrylic resin graft) prepared according to the method of the present invention was negative for the 20-60 mesh granule sterility test. Cytotoxicity test

Inspection basis: GB/T16886. 5-2003 (filter membrane diffusion method)

1. Test materials

1. Acrylic resin (or acrylic resin graft) prepared according to the method of the present invention, 20 g per bag.

1. 2 Rpml 1640 medium

1. 3 phenol solution

2 medium

2. 1 Application medium: Rpml 1640 medium (produced by G16Co, USA) 2. 2 calf serum (Institute of Bioengineering, Chinese Academy of Medical Sciences)

2. 3 penicillin (100 units / ml)

2. 4 puromycin (100 units / ml)

3 cell line: using L ₉₂₉ cells

4 test ^^ method

4. 1 sample preparation: Acrylic resin (or acrylic resin graft) particles are taken under aseptic conditions, placed in a glass container, and an appropriate amount of physiological saline is added to wet the acrylic resin (or acrylic resin graft) particles. spare.

4. 2 cell culture 4. 2 Cell trypsin preparation: Take 3-5 days of culture, vigorously grow the cells, remove the culture solution, D-Hank 'S solution twice, go to Hank, S solution, add appropriate amount of 0.25% trypsin, 1 minute, trypsin solution, place for 5 minutes, add appropriate growth medium, and gently pipette to make a cell suspension. Count the number of cells, adjust the cell concentration, and make the number of cells (2-2. 5 ) x l05/ml.

4. 4 cell culture

4. 4. 1 Place a fully hydrated (20.45 bacteria microporous membrane, 5 in a 60-leg medium, autoclaved at 121 °C, each cell suspension 8ml ₀ was set to 37 ° C, 5% C0 ₂ incubator for 24 hours, the cells grown on the filter.

4. 4. 2 Preparation of nutrient agar medium: Mix 3% agar solution with fresh 2 X Rpml 1640 medium, etc., and pour into the sterilized (2 60 let the incubator, solidify at room temperature.

4. 4. 3 Remove the filter with monolayer cells, wash twice with D- Hank' S solution, and place the filter on nutrient agar medium with the cells facing down, so that the cells are close to the nutrients Base surface.

4. 4. 4 Sample Placement: Place the above-mentioned wet acrylic resin (or acrylic graft) particles on the surface of the filter while placing a soaked Rpml 1640 medium (25 诵 filter paper as a negative control. i, one Jni has cells, but no sample is placed as a negative control; the other has cells and 4 filter papers soaked with 20% phenol as a positive control; the other is no cells, but the sample is placed, negative and positive The control blanks were placed in a 37 ° C, 5% CO ₂ incubator for 2 hours.

4. 4. 5 Remove the filter and wash the D- Hank' S solution twice. Place the filter into the SDH enzyme stain and stain it in the dark for a certain period of time.

The cells on the filter and filter were visually observed and microscopically observed.

5, test results

5. 1 The two sub-filters of the test sample were dyed blue, and blue markings consistent with the sample size appeared. The cells on the filter were observed to be normal and the cells were stained blue.

5. 2 Negative control filter stained into blue, cell morphology and cell staining on the filter The sample is similar.

5. 3 Under the positive control sample and its cycle appeared - 10 decolorization pressure; Microscopic observation: The cells under and around the sample were not stained, the nucleus was not clear, and most of the cells were dissolved. The blank control filter was not colored.

6. Evaluation of results: The acrylic resin (or acrylic resin graft) prepared according to the method of the present invention was not cytotoxic. Acute systemic toxicity test (abdominal approach)

Test basis: GB/T16886. 11—1997

1, test ^ material

1. An acrylic resin (or a propionate graft) prepared according to the method of the present invention.

1, 2 saline

2. Test animals: 30 healthy Kunming mice were selected, weighing 19g-25g, male and female, randomly divided into groups. The test group consisted of 10 polar solvents and 10 non-polar solvents.

3, test ^: method

3. 1 Preparation of extract

3. 2 polarity shield leaching: Under sterile conditions, acrylic resin (or acrylic resin graft) 0. 2g, placed in a glass container with sterile saline 100ml, another sterile saline 100ml Leach for 1 hour at 121 ° C in the container and set aside.

3. 3 Non-polar medium leaching: Under sterile conditions, take acrylic resin (or acrylic resin graft) 0. 2g, add 100ml of refined sesame oil in a glass container, and take 100ml of refined sesame oil in the container. Dip at 121 °C for 1 hour, set aside.

4. Dosage and route: The polar test group was intraperitoneally injected with 50 ml/kg body weight of acrylic acid extract (or acrylic graft) physiological saline extract; the control group was given intraperitoneal injection of normal saline 50 ml. /kg body weight. Non-polar test group mice were injected intraperitoneally with acrylic resin (or acrylic resin graft) sesame oil extract 50ml/kg body weight; The sesame oil 50 ml/kg body weight was intraperitoneally injected into the group.

5. Observation: The general state and toxicity of each group of animals were observed after administration, and the number of dead animals was recorded. The body weight of each animal was weighed daily for 3 days.

6. Test results: The animals in the two test groups and the control group were in good general condition, no toxic reaction, no death in the animals, and the weight of the mice in both groups gradually increased.

7. Evaluation of results

7. The acrylic resin (or acrylic resin graft) polar extract prepared according to the method of the present invention is intoxicated by intraperitoneal injection.

7. Non-polar acrylic resin (or acrylic resin graft) prepared according to the method of the present invention. The sesame oil extract is non-toxic by intraperitoneal injection. Biocompatibility test

1. Test Purpose: To verify the biocompatibility of acrylic resin (or acrylic resin graft) prepared according to the method of the present invention by using the acute toxicity test, skin irritation test and allergy test, eye irritation test method. Sex.

2. Test animals

1 ) , 40 Kunming mice, half male and half female, weighing 180-220g

2), 40 Wis tar rats, half male and half female, weighing 250-300g

3), big white rabbit, body weight 2 - 3kg, no eye disease.

3. Test materials: Acrylic resin (or acrylic resin graft), 20g per bag.

4. Test methods and results

4. 1 acute toxicity test

The acrylic resin (or acrylic resin graft) was divided into 10,000 mg, 4640 mg, 2150 mg, and 1000 mg 4' doses to prepare the same amount of the extract.

Forty Kunming mice were randomly divided into 10000 mg, 4640 mg, 2150 mg, and 1000 mg doses/body recombinant gavage, 10 rats in each group, once every 6 hours, and observed continuously for 7 days.

As a result, none of the mice tested had no symptoms of poisoning and death, and the maximum tolerated dose was greater than l OOOOmg / kg body weight, according to the acute toxicity classification is the actual non-toxic substances.

4. 2 skin irritation and skin allergy test

40 Wi s tar rats were randomly divided into 4 groups, 10 in each group, half male and half female. The skin hair of about 3 cm 3 cm on both sides of the spine of the rats was shaved 24 hours before the test, and the skin was not damaged. The resin (or acrylic resin graft) was uniformly sprinkled on the shaved skin of the tested rats at 4640, 2150, 1000, 464 mg/kg, respectively, and covered with oil sand and gauze. After that, it was fixed with a bandage. After 24 hours, the residue of the test site of the rats was washed with warm water for 7 days.

As a result, none of the tested rats had skin redness and rash, and according to the acute classification, there was no skin irritation and no skin irritation.

4. 3 eye irritation test

For the preparation of the extract, 0.1 g of the acrylic resin (or acrylic graft) was placed in 100 ml of physiological saline, and immersed in a 37 ° C constant temperature water bath for 72 hours or more, and the extract was taken out.

Take 4 large white rabbits, divided into 2 groups, 2 in each group. One eye of the two groups of rabbits was drenched with 0.2 ml, and the other eye was used as a control. The response of both eyes was observed at 8, 24, 48, and 72 hours, and the eye recovery was observed on days 4 and 7.

As a result, the acute stimulation test score index (the highest number) of the eyes of the rabbits tested was 0, and the average index of eye irritation was 0 after 48 hours, which was non-irritating.

5. Evaluation: The acrylic resin (or acrylic resin graft) prepared according to the method of the present invention is safe, non-toxic, non-irritating to skin and skin allergic, and non-irritating to the eyes. According to the method of the present embodiment, an acrylic resin which can be used as a hemostatic dressing is prepared and a hemostatic effect of an acrylic resin which can be used as a water absorbing material in the market. Comparative test 1. Test purpose: By testing a rabbit femoral artery injury bleeding model, a comparative study according to the present Inventive Example The acrylic hemostatic dressing prepared by the method and the commercially available acrylic resin water absorbing material are used as a hemostatic effect when used as a hemostatic material.

Second, test drugs and equipment 1. Test rabbit: 12 New Zealand white rabbits, weighing 2. 5 ~ 3kg, male and female, etc., market purchase;

2. Medical absorbent cotton gauze piece, produced by Shenzhen Baoke Medical Instrument Co., Ltd., product batch number 070806.

3. Elastic bandage, produced by Shenzhen Baoke Medical Devices Co., Ltd., product batch number

070806.

4. The acrylic resin hemostatic dressing prepared according to the embodiment of the invention is produced by the central laboratory of Shenzhen Honghua Pharmaceutical Co., Ltd., product code 20080301.

5. Acrylic resin absorbent material, market purchase, production batch number 20070821.

6. Sodium thiopental for injection, produced by Shanghai Xinya Pharmaceutical Co., Ltd., the product batch number of national medicine Zhunzi H31021846.

Third, the content of the test

1. Hemostasis effect: Hemostasis effects include hemostasis time, amount of bleeding and death rate within 180 minutes.

(1) Hemostasis time (seconds): Record the time from the femoral artery incision to the time when the dressing stops bleeding, minus the free blood spurting for 10 seconds, that is, the blood time.

(2) Blood loss (g)

Blood loss = body weight of the test animal before the experiment - body weight of the test animal after the test, or blood loss = the weight of the dressing after the experiment - the weight of the dressing before the experiment.

(3) Mortality within 180 minutes (%)

Mortality (% _{) =} death of the test animal 3⁄4 _{xl 00 3⁄4}

^ Cattle Total number of animals tested

2. Test method

Twelve rabbits were tested, male and female, and randomly divided into control group and experimental group. The control group was a acrylic resin absorbent material group, and the experimental group was an acrylic resin hemostatic dressing group of 6 rats in each group. The weight of each scorpion animal and each group of materials used was weighed before and after the actual inspection. Among them, the amount of the dressing used for the corresponding dangerous animals of the acrylic resin absorbent material group and the acrylic resin hemostatic dressing group was weighed separately.

Each rabbit was anesthetized with 3% injection of thiopental 1ml / kg ear vein, fixed On the experimental bench, expose the femoral artery, cut the femoral artery 3/4, and freely squirt for 10 seconds, then perform corresponding treatment. The acrylic resin water absorbing material group is directly sprinkled on the wound mouth with acrylic water absorbing material, covered with gauze, pressing pressure 2kg, pressing time 30-60 seconds; acrylic hemostatic dressing treatment group is directly sprinkled on the wound mouth with acrylic hemostatic dressing, Cover with gauze, pressurizing pressure 2kg, compression time 30-60 seconds, observe. The experimental results and corresponding observation indicators are recorded in Table 2.

Fourth, the test results

Experimental results and records of each observation index

V. Comparative analysis of product characteristic parameters: PH, monomer residue, water absorption, water absorption speed, etc.

Comparative analysis of acrylic resins which can be used as a water absorbing material and commercially available as a hemostatic dressing prepared according to an embodiment of the present invention, as shown in Table 3, is shown in Table 3.

Artificial blood, g/g 74. 3 39. 5

H 5. 68 6. 43

Monomer residual amount, % 0. 2 0. 51

Total amount of heavy metals

8. 2 21. 3

Note: ug/g comparison: The acrylic resin hemostatic dressing prepared according to the method of the present invention has a lower water absorption than the purchased acrylic resin water absorbing material, but it is obvious from the comparison of the physiological saline absorption rate, the water absorption rate and the artificial blood absorption amount. Better than acrylic resin absorbent materials purchased on the market. Because the blood concentration of human body is close to that of normal saline, it is similar to artificial blood Shield. It is obvious that the higher the amount of saline and artificial blood, the better the adsorption of liquid components in the blood, so that other components in the blood such as platelets, red blood cells, etc. Concentration of factors promotes blood coagulation. At the same time, the rate of water absorption is the key to rapid hemostasis. It can be used to absorb dry wounds in a short period of time. The liquid components in the blood flow are beneficial to other components in the blood such as platelets, red blood cells and other coagulation factors. Rapid concentration in a short time to achieve rapid hemostasis.

In addition, the pH should be within the acceptable range of the human body. Since the pH of the human body is close to neutral acidity, the pH can be 5-8. Secondly, since the raw material of the product, ie, acrylic acid, has a strong stimulating effect, the complete reaction of the monomer is important in the process of polymerization. The improvement of the production process not only ensures complete reaction of the reaction monomer, but also reduces costs and raw materials. Waste, and ensure the safety of the human body. For the content of heavy metals, the lower the content, the better the safety of the human body. Generally, the total amount of heavy metals (in terms of lead) is not more than 20 ug/g. In addition, other performance parameters are: water absorption is not less than 300g / g, absorption of saline is not less than 50g / g, water absorption rate is not more than 30 seconds, monomer residual amount is not more than 1%.

Sixth, the conclusion of the test

According to the experimental results, it can be seen that the hemostatic dressing prepared by the method according to the embodiment of the present invention has rapid hemostasis and good effect, and is obviously superior to the hemostatic effect of the commercially available acrylic resin water absorbing material. And by analyzing the hemostatic effect of the femoral artery bleeding in the rabbit, it can be predicted that the bleeding of the hemostatic dressing is hemostasis. The present invention has been described above by way of specific embodiments, and it should be understood by those skilled in the art that various modifications, additions and substitutions may be made to the present invention without departing from the spirit and scope of the invention. Within the scope of protection of the invention.

Claims

Claim

1. Acrylic resin and its graft as an application for preparing a hemostatic dressing.

The use according to claim 1, wherein the acrylic resin and its graft are prepared using a small reaction disk.

The use according to claim 1, wherein the acrylic resin and the graft thereof are prepared using a composite initiator.

The use according to claim 1, wherein the acrylic resin and its graft are prepared using a nonionic monomer.

The use according to claim 1, wherein the acrylic resin and the graft thereof are prepared by using polyvinyl alcohol as a crosslinking agent, and an interpenetrating structure is formed by changing polyvinyl alcohol having a different molecular weight.

The use according to claim 1, wherein the acrylic resin and the graft structure thereof comprise a hydrophilic group.

The use according to claim 1, wherein the acrylic resin and its graft are prepared by microwave heating.

The use according to claim 1, wherein the acrylic resin and the graft thereof absorb the physiological saline in an amount larger than the amount of the acrylic resin conventionally used as the water absorbing material.

The use according to claim 8, wherein the acrylic resin and the graft thereof absorb physiological saline in an amount of not less than 50 _g / g.

The use according to claim 1, wherein the acrylic resin and its graft monomer residual amount is less than 1%.

11. A method of preparing an acrylic resin as a hemostatic dressing and a graft thereof, comprising the steps of:

Weighing the metered polymer monomer and placing it in the neutralization kettle;

The alkaline neutralizing solution is gradually added in an amount of agitation under neutralization, and after neutralizing, the polymerized monomer is diluted with water to a predetermined concentration to obtain a liquid to be polymerized; Transferring the liquid to be polymerized to a polymerization tray having a stirring and good heat dissipation function, and adding a crosslinking agent to stir evenly;

An initiator is added to initiate the polymerization reaction, and a semi-finished product is obtained after the reaction is completed; and the prepared semi-finished product is dried at a high temperature, followed by pulverization, sieving, and sterilization.

The method according to claim 11, wherein the polymerizable monomer comprises an organic acid or ester having a double bond or a triple bond.

The method according to claim 12, wherein the concentration of the polymerized monomer is controlled to be 20 to 75 %.

14. The method of claim 13 wherein the polymerized monomer is a nonionic monomer.

The method according to claim 11, wherein the degree of neutralization is controlled between 55 and 90% during neutralization.

The method according to claim 11, wherein the polymerization reaction time is 2 to 10 hours.

The method according to claim 11, wherein the polymerization temperature is 35 to 85 °C.

18. The method of claim 17, wherein microwave heating is employed to control the temperature of the polymerization reaction.

01. The method of claim 11, wherein the initiator concentration is from 0.01 to 5 %, and the amount of the polymerization monomer is from 0.001 to 5%.

20. The method of claim 19, wherein the initiator is a complex initiator.

The 001 ~ 2 %, the amount of the polymerization monomer is 0. 01 ~ 4%, and the amount of the polymerization monomer is 0. 001 ~ 2%.

The method according to claim 21, wherein said crosslinking agent is polyvinyl alcohol, and the polymer is formed into an interpenetrating structure by changing polyvinyl alcohol having a different molecular weight.

23. The method of claim 11 comprising graft polymerizing the polymerized monomer with starch.

24. The method of claim 11 wherein the reaction tray is a plurality of small reaction trays.

An acrylic resin as a hemostatic dressing and a graft thereof prepared by the method according to any one of claims 11 to 24.

The acrylic resin as a hemostatic dressing according to claim 25, wherein the acrylic resin is prepared by copolymerizing acrylic acid as a single polymerization monomer or copolymerized with acrylamide, and the copolymerization reaction substance includes but not Limited to acrylamide.

The acrylic resin as a hemostatic dressing according to claim 25, wherein the acrylic resin graft polymer is obtained by graft-polymerizing acrylic acid as a skeleton with starch or carboxymethyl cellulose (sodium). Participating in grafted materials includes, but is not limited to, starch, sodium carboxymethylcellulose.

The acrylic resin as a hemostatic dressing according to claim 25, wherein the amount of physiological saline absorbed by the acrylic resin and the graft thereof is larger than that of an acrylic resin conventionally used as a water absorbing material. .

The acrylic resin as a hemostatic dressing according to claim 28, wherein the acrylic resin and the graft thereof absorb physiological saline in an amount of not less than 50 g/g.

The acrylic resin as a hemostatic dressing according to claim 25, wherein the residual amount of the acrylic resin and the graft monomer thereof is less than 1%.

The acrylic resin as a hemostatic dressing according to claim 25 and a graft thereof, wherein the polymerizable monomer forming the polymer comprises an organic acid or ester having a double bond or a triple bond.

A pharmaceutical composition comprising the acrylic resin as a hemostatic dressing according to any one of claims 25 to 312, and a graft thereof, and a pharmaceutically acceptable carrier.

33. The pharmaceutical composition of claim 32, wherein the pharmaceutically acceptable carrier comprises, but is not limited to, gauze, a medical nonwoven, a polymeric film.

A first aid kit comprising the acrylic acid resin as a hemostatic dressing according to any one of claims 25 to 31 and a graft thereof or the pharmaceutical composition according to claim 32.

A hemostatic patch comprising the acrylic resin as a hemostatic dressing according to any one of claims 25 to 31 and a graft thereof or the pharmaceutical composition according to claim 32.

36. A hemostatic bandage comprising the method of any one of claims 25 to 31 A bupropion resin of the hemostatic dressing and a graft thereof or the pharmaceutical composition of claim 32.

37. A hemostatic gauze comprising the acrylic resin as a hemostatic dressing according to any one of claims 25 to 31 and a graft thereof or the pharmaceutical composition according to claim 32.

38. A drug sustained release material comprising the acrylic resin as a hemostatic dressing according to any one of claims 25 to 31 and a graft thereof or the pharmaceutical composition according to claim 32.

39. A repairing implant material comprising the acrylic resin as a hemostatic dressing according to any one of claims 25 to 31 and a graft thereof or the pharmaceutical composition according to claim 32.

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