High-imbibition polyvinyl formal hemostatic sponge and preparation method thereof

Abstract

The invention belongs to the field of medical materials, and particularly relates to a high-imbibition polyvinyl formal hemostatic sponge and a preparation method thereof. The preparation method comprises the following steps: preparing a polyvinyl alcohol solution, adding starch to prepare a premixed solution, then adding a cross-linking agent, a foaming agent, a catalyst and a surfactant, fully mixing, then putting into a drying oven for curing, then cleaning the materials, freeze-drying, and carrying out irradiation sterilization to obtain the high-imbibition polyvinyl formal hemostatic sponge. The sponge prepared by the invention has high expansibility and high water absorbability, and achieves the purpose of reducing the cost by reducing the material and reaction time while ensuring excellent physical and chemical properties and biological properties. The prepared polyvinyl formal sponge is mainly applied to surgical operations, wound first aid, cavity hemostasis and the like.

Description

Technical Field

[0001] The invention belongs to the field of medical materials, and in particular relates to a high-swelling polyvinyl formal hemostatic sponge and a preparation method thereof. Background Art

[0002] Commonly used hemostatic materials in clinical practice include vaseline gauze strips, gelatin sponges, etc. Although these materials have a certain hemostatic effect, they have many shortcomings. For example, after the vaseline gauze strips are packed, the patient's local nasal cavity and head discomfort are obvious, and it is easy to cause tissue adhesion; gelatin sponges have problems such as poor absorption and easy residue. Polyvinyl alcohol hemostatic sponge is made by cross-linking, micro-foaming, and curing. It has the advantages of soft texture, strong toughness, high water absorption rate, and good hemostatic effect. Compared with traditional hemostatic materials, polyvinyl alcohol hemostatic sponge can absorb body fluids more effectively, expand rapidly and compress the wound to achieve the purpose of hemostasis. At the same time, its good biocompatibility reduces the risk of tissue reaction and adhesion.

[0003] In the currently disclosed preparation methods of polyvinyl alcohol formal sponge, many types of materials are added when preparing the sponge (7 to 9 kinds), and the curing time is long (5 to 24 hours). For example, CN115746375A discloses a polyvinyl alcohol formal sponge with high water absorption rate and its preparation method, which uses 8 kinds of materials such as polyvinyl alcohol, formaldehyde, hydrochloric acid, etc., and the curing time is 5 to 10 hours.

[0004] Therefore, based on this, the technical solution of the present invention is proposed. Summary of the invention

[0005] In order to solve the problems existing in the prior art, the present invention provides a high swelling polyvinyl alcohol formal hemostatic sponge and a preparation method thereof. The sponge prepared by the method has excellent physical and chemical properties and hemostatic properties, and can save production costs by reducing materials and curing time. The operation is simple, the reaction conditions are mild, the reaction time is short, the product performance is stable, and it is suitable for large-scale production.

[0006] The present invention provides a method for preparing a high-swelling polyvinyl formal hemostatic sponge, the preparation method comprising the following steps:

[0007] (1) mixing polyvinyl alcohol and ultrapure water and heating to dissolve them to obtain a polyvinyl alcohol solution;

[0008] (2) adding starch to the polyvinyl alcohol solution and stirring evenly to obtain a premixed solution;

[0009] (3) adding formaldehyde aqueous solution, a catalyst, a foaming agent, and a surfactant to the premixed liquid and stirring the mixture to obtain a mixed liquid;

[0010] (4) solidifying the mixed solution, and then washing, drying and sterilizing in sequence to obtain a high swelling polyvinyl formal hemostatic sponge.

[0011] Preferably, in step (1), the average degree of polymerization of the polyvinyl alcohol is 1600 to 2400, and the degree of alcoholysis is 88 to 99.9%.

[0012] Preferably, in step (1), the mass ratio of the polyvinyl alcohol to water is 1:5-7, the heating temperature is 80-90° C., and the dissolution time is 50-70 min.

[0013] Preferably, in step (2), the starch is one of corn starch, sweet potato starch, wheat starch, potato starch, and pea starch;

[0014] And / or, in step (3), the concentration of the formaldehyde aqueous solution is 37-40%;

[0015] And / or, in step (3), the catalyst is one of sulfuric acid and hydrochloric acid;

[0016] And / or, in step (3), the foaming agent is one of n-pentane, n-hexane, sodium carbonate, and sodium bicarbonate;

[0017] And / or, in step (3), the surfactant is one of sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, Tween-80, and polyoxyethylene fatty acid ester.

[0018] Preferably, in step (2) and step (3), the usage ratio of the polyvinyl alcohol solution, starch, formaldehyde aqueous solution, catalyst, foaming agent and surfactant is 20-40 (g): 4-6 (g): 4-7 (mL): 4-7 (mL): 1-3 (mL): 0-300 (mg).

[0019] Preferably, in step (2) and step (3), the stirring speed is 200 to 300 r / min, and the stirring time is 3 to 5 min.

[0020] Preferably, in step (4), the curing temperature is 40 to 80° C., and the curing time is 2 to 3 hours.

[0021] Based on the same technical concept, another embodiment of the present invention is to provide a high swelling polyvinyl formal hemostatic sponge obtained by the above preparation method.

[0022] The beneficial effects of the present invention are:

[0023] 1. The high swelling polyvinyl formal hemostatic sponge of the present invention has uniform pore size, high swelling and high water absorption characteristics, and the sponge is soft and elastic after absorbing water.

[0024] 2. The high swelling polyvinyl formal hemostatic sponge of the present invention has stable performance, simple preparation and operation, and is suitable for large-scale production. Moreover, the reaction conditions are mild, less materials are used, the curing time is shorter, and the production cycle and production cost can be reduced.

[0025] 3. The high swelling polyvinyl formal hemostatic sponge described in the present invention has good biocompatibility.

[0026] 4. The high swelling polyvinyl formal hemostatic sponge of the present invention has good hemostatic performance and can be better applied to the fields of surgical trauma, cavity hemostasis, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0028] Figure 1 This is the infrared spectrum of the product obtained in Example 5.

[0029] Figure 2 This is the infrared spectrum of the product obtained in Example 1.

[0030] Figure 3 This is the SEM image of the product obtained in Example 5.

[0031] Figure 4 This is the SEM picture of the product obtained in Comparative Example 1.

[0032] Figure 5 It is a graph showing the BCI value detection results of Example 5 and Comparative Example 1.

[0033] Figure 6 This is a data graph of the cytotoxicity results of the product obtained in Example 5.

[0034] Figure 7 This is a graph showing the bleeding volume in the rat liver injury model.

[0035] Figure 8 This is a graph showing the hemostasis time results of the rat liver injury model. DETAILED DESCRIPTION

[0036] To make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0037] Example 1

[0038] This embodiment provides a method for preparing a high-swelling polyvinyl formal hemostatic sponge, the preparation method comprising the following steps:

[0039] (1) weighing polyvinyl alcohol and water in a mass ratio of 1:7, then heating in a water bath at 80° C., mixing and stirring to dissolve, to obtain a polyvinyl alcohol solution;

[0040] (2) After cooling, weigh 30 g of the polyvinyl alcohol solution, add 5 g of corn starch and stir (speed 200 r / min, stirring for 3 min) to obtain a premixed solution;

[0041] (3) adding 6 mL of formaldehyde (concentration of 37%), 2 mL of n-pentane, and 6 mL of sulfuric acid (mass ratio of water to sulfuric acid = 2:1) to the premixed solution in sequence, and continuing to stir at a speed of 200 r / min for 5 min to obtain a premixed solution;

[0042] (4) The premixed liquid is placed in an oven at 80° C. for curing for 2 h, and then the material is washed and freeze-dried to obtain a high swelling polyvinyl formal hemostatic sponge.

[0043] Example 2

[0044] This embodiment provides a method for preparing a high-swelling polyvinyl formal hemostatic sponge, the preparation method comprising the following steps:

[0045] (1) weighing polyvinyl alcohol and water in a mass ratio of 1:7, then heating in a water bath at 80° C., mixing and stirring to dissolve, to obtain a polyvinyl alcohol solution;

[0046] (2) After cooling, weigh 30 g of the polyvinyl alcohol solution, add 4.5 g of corn starch and stir (speed 200 r / min, stirring for 3 min) to obtain a premixed solution;

[0047] (3) adding 5 mL of formaldehyde (concentration of 37%), 2 mL of n-pentane, and 5 mL of sulfuric acid (mass ratio of water to sulfuric acid = 2:1) to the premixed solution in sequence, and continuing to stir at a speed of 200 r / min for 5 min to obtain a premixed solution;

[0048] (4) The premixed liquid is placed in an oven at 80° C. for curing for 2 h, and then the material is washed and freeze-dried to obtain a high swelling polyvinyl formal hemostatic sponge.

[0049] Example 3

[0050] This embodiment provides a method for preparing a high-swelling polyvinyl formal hemostatic sponge, the preparation method comprising the following steps:

[0051] (1) weighing polyvinyl alcohol and water in a mass ratio of 1:5, then heating in a water bath at 85° C., mixing and stirring to dissolve, to obtain a polyvinyl alcohol solution;

[0052] (2) After cooling, weigh 30 g of the polyvinyl alcohol solution, add 5 g of corn starch and stir (speed 200 r / min, stirring for 3 min) to obtain a premixed solution;

[0053] (3) Add 5 mL of formaldehyde (concentration of 37%), 2.5 mL of n-pentane, 5 mL of sulfuric acid (mass ratio of water to sulfuric acid = 2:1), and 15 mg of sodium dodecyl sulfate to the premixed solution in sequence, and continue stirring at a speed of 200 r / min for 5 min to obtain a premixed solution;

[0054] (4) The premixed solution was placed in a 40° C. oven for curing for 30 min, and then the temperature was raised to 80° C. and the reaction was continued for 1.5 h. The material was then washed and freeze-dried to obtain a high swelling polyvinyl formal hemostatic sponge.

[0055] Example 4

[0056] This embodiment provides a method for preparing a high-swelling polyvinyl formal hemostatic sponge, the preparation method comprising the following steps:

[0057] (1) weighing polyvinyl alcohol and water in a mass ratio of 1:5, then heating in a water bath at 90° C., mixing and stirring to dissolve, to obtain a polyvinyl alcohol solution;

[0058] (2) After cooling, weigh 30 g of the polyvinyl alcohol solution, add 4.5 g of corn starch and stir (speed 200 r / min, stirring for 3 min) to obtain a premixed solution;

[0059] (3) adding 5 mL of formaldehyde (concentration of 37%), 2.5 mL of n-pentane, and 5 mL of sulfuric acid (mass ratio of water to sulfuric acid = 2:1) to the premixed solution in sequence, and continuing to stir at a speed of 200 r / min for 5 min to obtain a premixed solution;

[0060] (4) The premixed liquid is placed in an oven at 80° C. for curing for 2 h, and then the material is washed and freeze-dried to obtain a high swelling polyvinyl formal hemostatic sponge.

[0061] Example 5

[0062] This embodiment provides a method for preparing a high-swelling polyvinyl formal hemostatic sponge, the preparation method comprising the following steps:

[0063] (1) weighing polyvinyl alcohol and water in a mass ratio of 1:5, then heating in a water bath at 90° C., mixing and stirring to dissolve, to obtain a polyvinyl alcohol solution;

[0064] (2) After cooling, weigh 30 g of the polyvinyl alcohol solution, add 4.5 g of corn starch and stir (speed 200 r / min, stirring for 3 min) to obtain a premixed solution;

[0065] (3) 5 mL of formaldehyde (concentration of 37%), 2.6 mL of n-pentane, 5 mL of sulfuric acid (mass ratio of water to sulfuric acid = 2:1), and 10 mg of sodium dodecyl sulfate were added to the premixed solution in sequence, and the mixture was stirred at a speed of 200 r / min for 5 min to obtain a premixed solution;

[0066] (4) The premixed solution was placed in a 40° C. oven for curing for 30 min, the temperature was raised to 80° C., and the reaction was continued for 2 h. The material was then washed and freeze-dried to obtain a high swelling polyvinyl formal hemostatic sponge.

[0067] Example 6

[0068] This embodiment provides a method for preparing a high-swelling polyvinyl formal hemostatic sponge, the preparation method comprising the following steps:

[0069] (1) weighing polyvinyl alcohol and water in a mass ratio of 1:5, then heating in a water bath at 90° C., mixing and stirring to dissolve, to obtain a polyvinyl alcohol solution;

[0070] (2) After cooling, weigh 30 g of the polyvinyl alcohol solution, add 4.5 g of corn starch and stir (speed 200 r / min, stirring for 3 min) to obtain a premixed solution;

[0071] (3) 6 mL of formaldehyde (concentration of 37%), 2.5 mL of n-pentane, 5 mL of sulfuric acid (mass ratio of water to sulfuric acid = 2:1), and 200 mg of sodium dodecyl sulfate were added to the premixed solution in sequence, and the mixture was stirred at a speed of 200 r / min for 5 min to obtain a premixed solution;

[0072] (4) The premixed solution was sequentially placed in an oven at 40° C. for curing for 30 min, an oven at 65° C. for curing for 30 min, and an oven at 80° C. for curing for 1 h, and then the material was washed and freeze-dried to obtain a high swelling polyvinyl formal hemostatic sponge.

[0073] Comparative Example 1

[0074] A commercially available polyvinyl formal hemostatic sponge was used as a comparative example (trade name: MEROCEL hemostatic sponge; product number: 400402; manufacturer: Medtronic Corporation, USA).

[0075] Test Example 1: Water absorption test

[0076] The water absorption performance of the samples of Examples 1 to 6 and Comparative Example 1 was tested with reference to the water absorption multiple determination method of the industry standard "YY / T 1803-2019 Polyvinyl Alcohol Hemostatic Sponge". The specific method is to take a sample with a mass of (1.0±0.1) g and weigh it as m1. At room temperature, add (37±1)℃ water to a beaker with a diameter of not less than 11 cm to a height of (11±1) cm. Gently rub the sample with your fingers until it is completely soaked and all the air is removed. Be careful not to damage it. After absorbing enough water, gently clamp a corner of the sample with tweezers to remove it from the water, and let the sample hang in the air for (30±1)s to control the water, and weigh it again, recorded as m2. Calculate the water absorption multiple A according to formula (1). Report the results as the average of 3 measurements. The test results are shown in Table 1.

[0077] A=(m2-m1) / m1…………(1)

[0078] Where:

[0079] A: Water absorption multiple of the sample, keep 1 decimal place;

[0080] m1: mass of the sample before wetting, in grams (g);

[0081] m2: The mass of the sample after being soaked, in grams (g).

[0082] Table 1

[0083] Group Water absorption multiple Example 1 17.8 Example 2 17.6 Example 3 19.1 Example 4 18.7 Example 5 20.5 Example 6 18.8 Comparative Example 1 17.1 Industry Standards ≥5.0

[0084] The samples of Example 5 with the highest water absorption multiple were prepared in batches, and other performance tests were performed after the samples were cut, compressed, packaged and sterilized.

[0085] Test Example 2: Water absorption time and expansion multiple detection

[0086] With reference to the industry standard "YY / T 1803-2019 Polyvinyl Alcohol Hemostatic Sponge" expansion multiple and water absorption time detection method, the samples of Example 5 and Comparative Example 1 were tested. The specific method is to place the sample in water and start timing with a stopwatch. When the sample is completely wetted and there is no obvious change in appearance, stop timing. Report the results as the average of 3 measurements in seconds (s). Gently clamp a corner of the sample with tweezers to remove it from the water, and let the sample hang in the air for (30±1)s to control the water. Use a general or special measuring tool to measure the size of the hemostatic sponge after liquid absorption and expansion, calculate the expansion multiple of the sample in all directions (size after liquid absorption / size before liquid absorption), and report the maximum expansion multiple. The results are shown in Table 2.

[0087] Table 2

[0088] Example 5 Comparative Example 1 Industry Standards Average water absorption time 7.96s 7.15s ≤15s Maximum expansion multiple 10.6 5.7 ≤2.0

[0089] Test Example 3: Infrared Identification

[0090] Take samples and test them according to the infrared spectrophotometry method 0402 of the Pharmacopoeia of the People's Republic of China (Part IV of the 2020 edition). According to the industry standard "YY / T 1803-2019 Polyvinyl Alcohol Hemostatic Sponge", when the sponge is tested by infrared spectroscopy, it should be (2940±10)cm -1 and (2920±10)cm -1 There is a characteristic absorption peak at the wave number. The results are as follows Figure 1 , Figure 2 As shown. Comparative Example 1 and Example 5 samples at (2940±10)cm -1 and (2920±10)cm -1 There are characteristic absorption peaks at all wavelengths.

[0091] Test example 4: SEM inspection

[0092] The expanded freeze-dried sponges of Example 5 and Comparative Example 1 were observed by scanning electron microscopy. Figure 3 , Figure 4 shown.

[0093] Depend on Figure 3 , Figure 4 It can be seen that the pore size of Example 5 is between 0 and 100 μm, and the pore size of Comparative Example 1 is between 50 and 500 μm.

[0094] Test Example 5: Formaldehyde Residue Test

[0095] Preparation of the test solution: Accurately weigh the mass of the hemostatic sponge in the single package, recorded as m1, cut into pieces, mix evenly, take about 0.1g, accurately weigh, recorded as m2, add 20mL of water, soak at (37±1)℃ for 2h, and shake from time to time to obtain the test solution. Take two more packages of samples and repeat the above steps. Test according to the formaldehyde residue detection method in Appendix A of YY / T1803-2021 Polyvinyl Alcohol Hemostatic Sponge. The results are shown in Table 3. The formaldehyde residue of the sample in Example 5 is less than the industry standard.

[0096] Table 3

[0097] project Sample 1 Sample 2 Sample 3 Industry Standards Formaldehyde residue (μg / g) 166.16 151.84 179.41 ≤400

[0098] Test Example 6: In vitro coagulation test

[0099] BCI Blood Clotting Index is an indicator used to evaluate the in vitro coagulation effect of a material. Specifically, it measures the ability of a material to stimulate blood coagulation after contact with blood. The lower the BCI value, the more effectively the material can stimulate blood coagulation, that is, the better the coagulation effect. The samples of Example 5 and Comparative Example 1 were tested for the BCI index. The specific operating steps are as follows: take 20 mg of sponge sample in a beaker, preheat in a 37°C water bath for 5 minutes, add 100 μL of anticoagulated blood drop by drop to the surface of the sponge (make sure that all the blood is dripped on the sponge), draw 20 μL, 0.2M CaCl2 drop by drop to the surface of the sponge, and incubate at 37°C for 5 minutes. Add 25 mL of deionized water, shake gently at 37°C for 5 minutes, take the supernatant, and measure ABS1 at 540 nm. Measure 3 parallel samples for each sample. Blank control: 100 μL of anticoagulated blood + 25 mL of deionized water, take the supernatant, and measure ABS0 at 450 nm. BCI = ABS1 / ABS0 × 100%. The results are as follows Figure 5 The BCI value of the sample sponge of Example 5 is less than that of Comparative Example 1, that is, the sponge prepared in Example 5 is more conducive to blood coagulation.

[0100] Test Example 7: Cytotoxicity

[0101] Cytotoxicity analysis was performed on the samples of Example 5. The sponge was dispersed in the culture medium to prepare a 0.2 g / mL suspension, and then immersed in a sterile environment at 37°C for 72 hours and filtered using a 0.22 μm sterile filter. 100 μL of the cell density was 5×10 4The cell suspension was added to a 96-well plate. After culturing for 24 hours, the original culture medium in the 96-well plate was aspirated, and 100 μL of sample solution of appropriate concentration was added to each well. After culturing for 24 hours and 72 hours, the 96-well plate was taken out, and 10 μL of CCK-8 solution was added to each well. The culture plate was incubated in the incubator for another hour, and the absorbance at 450 nm was measured with an enzyme marker. According to the formula, cell viability = [OD (experimental) - OD (blank)] / [OD (control) - OD (blank)] × 100%, the cytotoxicity of the material was evaluated. The results are shown in Figure 6 As shown, the cytotoxicity experiment shows that the polyvinyl formal sponge in Example 5 has no toxic side effects on L929 cells.

[0102] Test Example 8: Hemostasis Test

[0103] The hemostatic performance of Example 5 and Comparative Example 1 was evaluated by using a SD rat liver injury model. The specific method is as follows: After the rat is anesthetized, excess hair on the abdomen is removed, the abdomen is opened to expose the liver. The weighed filter paper is placed under the liver, and a wound about 1 cm long and 0.2 cm deep is cut on the liver with a scalpel. Then the material is immediately attached to the bleeding, and the timer is started to calculate the amount of bleeding and the time of hemostasis. The results are shown in FIG. Figure 7 , Figure 8 Compared with the blank group, the hemostatic sponge in Example 5 can effectively reduce the amount of bleeding and the hemostatic time. And the hemostatic ability of the hemostatic sponge in Example 5 is better than that in Comparative Example 1.

[0104] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A method for preparing a high swelling polyvinyl formal hemostatic sponge, characterized in that: The preparation method comprises the following steps: (1) mixing polyvinyl alcohol and ultrapure water and heating to dissolve them to obtain a polyvinyl alcohol solution; (2) adding starch to the polyvinyl alcohol solution and stirring evenly to obtain a premixed solution; (3) adding formaldehyde aqueous solution, a catalyst, a foaming agent, and a surfactant to the premixed liquid and stirring the mixture to obtain a mixed liquid; (4) solidifying the mixed solution, and then washing, drying and sterilizing in sequence to obtain a high swelling polyvinyl formal hemostatic sponge.

2. The method for preparing the high swelling polyvinyl formal hemostatic sponge according to claim 1, characterized in that: In step (1), the average polymerization degree of the polyvinyl alcohol is 1600-2400, and the alcoholysis degree is 88-99.9%.

3. The method for preparing the high swelling polyvinyl formal hemostatic sponge according to claim 1, characterized in that: In step (1), the mass ratio of polyvinyl alcohol to water is 1:5-7, the heating temperature is 80-90° C., and the dissolution time is 50-70 min.

4. The method for preparing the high swelling polyvinyl formal hemostatic sponge according to claim 1, characterized in that: In step (2), the starch is one of corn starch, sweet potato starch, wheat starch, potato starch, and pea starch; And / or, in step (3), the concentration of the formaldehyde aqueous solution is 37-40%; And / or, in step (3), the catalyst is one of sulfuric acid and hydrochloric acid; And / or, in step (3), the foaming agent is one of n-pentane, n-hexane, sodium carbonate, and sodium bicarbonate; And / or, in step (3), the surfactant is one of sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, Tween-80, and polyoxyethylene fatty acid ester.

5. The method for preparing the high swelling polyvinyl formal hemostatic sponge according to claim 1, characterized in that: In step (2) and step (3), the usage ratio of the polyvinyl alcohol solution, starch, formaldehyde aqueous solution, catalyst, foaming agent and surfactant is 20-40 (g): 4-6 (g): 4-7 (mL): 4-7 (mL): 1-3 (mL): 0-300 (mg).

6. The method for preparing the high swelling polyvinyl formal hemostatic sponge according to claim 1, characterized in that: In step (2) and step (3), the stirring speed is 200 to 300 r / min, and the stirring time is 3 to 5 min.

7. The method for preparing the high swelling polyvinyl formal hemostatic sponge according to claim 1, characterized in that: In step (4), the curing temperature is 40 to 80° C. and the curing time is 2 to 3 hours.

8. The high swelling polyvinyl formal hemostatic sponge obtained by the preparation method according to any one of claims 1 to 7.

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