Medical nanofiber membrane with antibacterial and hemostatic functions and hemostatic agent comprising same

Abstract

This disclosure provides medical nanofiber membranes produced by electrospinning a polymer solution comprising: polyethylene oxide; at least one selected from hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginate, carrageenan, poloxamer, and cellulose; and at least one selected from chitosan, thrombin, and collagen.

Description

Technical Field

[0001] This disclosure relates to medical nanofiber membranes with antibacterial and hemostatic functions, and hemostatic agents containing the same. Background Technology

[0002] Hemostasis refers to the activation of the blood clotting mechanism by the body's natural defenses, including vasoconstriction and platelet aggregation, when bleeding occurs due to trauma or surgery. However, for patients with blood clotting disorders caused by platelet abnormalities (such as hemophilia and diabetes) and critically ill patients (such as those undergoing open abdominal or thoracotomy), hemostatic agents are essential for life support.

[0003] Bleeding during or after surgery is a very serious problem that can lead to higher-than-expected mortality, and hemostatic agents are essential during surgery. In routine surgeries ranging from minor procedures to open abdominal surgeries, and especially in critical situations such as open abdominal or open thoracotomy, hemostatic agents are crucial to prevent unforeseen complications such as massive hemorrhage, and various types of hemostatic agents are required.

[0004] Types of hemostatic agents include liquid gels that harden upon application to a wound, patch-like structures that compress the injured area, and mixed types in which hemostatic agent components are applied to the patch. Among these, mixed hemostatic agents offer high practicality because they are in a form where the hemostatic agent components are activated upon contact with blood in the wound area, exhibit rapid activity in vivo, are flexible, and move with tissue.

[0005] While various forms of hemostatic agents are used depending on the type of surgery, they need to prevent external infection, adhere well to the hemostatic site, and remain in place. In cases of hernia repair and rectocolectomy, which are representative laparoscopic surgeries, electrocautery is sufficient for hemostasis even if bleeding is present, as the bleeding is minimal. However, in patients with blood clotting disorders (such as cirrhosis or liver disease), patch-type hemostatic agents are essential to ensure hemostasis. However, unlike liquid hemostatic agents, patch-type hemostatic agents are difficult to apply to areas of large bleeding or tortuous areas, have poor adhesive strength, and require gauze or secondary hemostasis. Summary of the Invention

[0006] Technical issues

[0007] One object of this disclosure is to provide a medical nanofiber membrane and hemostatic components comprising the membrane that can stop bleeding caused by trauma or surgery and can be applied to large areas.

[0008] Technical solution

[0009] In one general aspect, a medical nanofiber membrane is provided, produced by electrospinning a polymer solution comprising: polyethylene oxide; selected from any one or more of hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginate, carrageenan, poloxamer, and cellulose; and selected from any one or more of chitosan, thrombin, and collagen.

[0010] Medical nanofiber membranes can be produced by mixing 1 to 10 parts by weight of any one or more of hyaluronic acid, polyvinyl alcohol, polyvinylpyrrolidone, alginate, carrageenan, poloxamer and cellulose relative to 100 parts by weight of polyethylene oxide.

[0011] Medical nanofiber membranes can be produced by mixing 1 to 20 parts by weight of chitosan, thrombin, and collagen relative to 100 parts by weight of polyethylene oxide.

[0012] The polymer solution may contain chitosan, thrombin, and collagen.

[0013] The polymer solution may contain 3 to 10 parts by weight of collagen and 1 to 10 parts by weight of chitosan, relative to 1 part by weight of thrombin.

[0014] The polymer solution may contain a mixture of water and ethanol as solvents.

[0015] The polymer solution may contain polyethylene oxide, water, and ethanol in a weight ratio of 10:10 to 30:40 to 70.

[0016] The number-average molecular weight of polyethylene oxide can range from 10,000 g / mol to 2,000,000 g / mol.

[0017] The average diameter of medical nanofiber membranes can range from 10 nm to 1000 nm.

[0018] In another general aspect, the hemostatic component comprises a medical nanofiber membrane according to one embodiment of the present disclosure.

[0019] Beneficial effects

[0020] The biodegradable medical nanofiber membrane disclosed herein has the following effects: excellent skin adhesion and absorbency, reduced heat sensation from wounds, and prevention of bacterial infection.

[0021] Because the biodegradable medical nanofiber membrane of this disclosure has antibacterial properties, it can effectively protect the wound area from external infectious agents when applied to an open wound.

[0022] The hemostatic component disclosed herein can be attached to a tissue area and quickly and easily stop bleeding in the bleeding area. Attached Figure Description

[0023] Figure 1 This is a conceptual diagram of the method for producing medical nanofiber membranes using electrospinning, as disclosed in this publication.

[0024] Figure 2 A medical nanofiber membrane according to one embodiment of the present disclosure is shown (Example 3).

[0025] Figure 3 A medical nanofiber membrane according to one embodiment of the present disclosure is shown (Example 4). Detailed Implementation

[0026] The present disclosure will be described in detail below. Unless otherwise defined, the terminology used in this specification should be interpreted as having the meaning commonly understood by those skilled in the art. The accompanying drawings and embodiments are provided to enable those skilled in the art to readily understand and implement the present disclosure. Descriptions in the drawings and embodiments that may obscure the main points of the disclosure may be omitted, and the present disclosure is not limited to the drawings and embodiments.

[0027] Unless otherwise stated in the context, the singular form used in this specification may be intended to include the plural form as well.

[0028] Furthermore, the numerical ranges used in this disclosure include all values ​​within a range that includes both the lower and upper limits, increments derived logically from the form and span of the defined range, all values ​​with double constraints, and all possible combinations of the upper and lower limits within a numerical range defined in different forms. Unless otherwise defined in the description of this disclosure, values ​​that may be outside the defined numerical range due to experimental error or rounding are also included within the defined numerical range.

[0029] In this specification, terms such as “including / comprises,” “having,” and “equipped with” mean that the features or components described in the specification are present, and the possibility of adding one or more other features or components is not excluded unless otherwise specified.

[0030] Routinely, various forms of hemostatic agents are used depending on the type of surgery, and hemostatic agents that prevent external infection, adhere well to the hemostatic site, and remain in place are essential. In particular, patch hemostatic agents are essential for ensuring hemostasis in patients with blood clotting disorders (such as cirrhosis or liver disease), but it is difficult to apply patch hemostatic agents to areas of large bleeding or curved areas.

[0031] This disclosure aims to provide a medical nanofiber membrane that can be applied to large areas with bleeding caused by trauma or surgery, and achieves regeneration, hemostasis and antibacterial effects in the wound area with excellent adhesive strength and absorbency.

[0032] This disclosure provides medical nanofiber membranes produced by electrospinning a polymer solution comprising: polyethylene oxide; any or more of hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginate, carrageenan, poloxamer, and cellulose; and any or more of chitosan, thrombin, and collagen.

[0033] Since this disclosure is produced by electrospinning a polymer solution containing materials having the above-described configuration, it can provide a medical nanofiber membrane that achieves excellent hemostatic and antibacterial effects.

[0034] According to one embodiment, relative to 100 parts by weight of polyethylene oxide, the polymer solution may contain 1 to 10 parts by weight of any one or more of hyaluronic acid, polyvinyl alcohol, polyvinylpyrrolidone, alginate, carrageenan, poloxamer and cellulose, and specifically, the lower limit may be 1 part by weight, 2 parts by weight, 3 parts by weight or 4 parts by weight, and the upper limit may be 10 parts by weight, 9 parts by weight, 8 parts by weight, 7 parts by weight or 6 parts by weight.

[0035] Specifically, the polymer solution may contain at least one of hyaluronic acid, polyvinyl alcohol, polyvinylpyrrolidone, and alginate, and may contain at least one of polyvinyl alcohol and polyvinylpyrrolidone, and more specifically, may contain polyvinyl alcohol.

[0036] The viscosity-average molecular weight (Mv) of hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginate, carrageenan, poloxamer and cellulose can be from 100,000 g / mol to 1,000,000 g / mol, but is not limited thereto.

[0037] Hyaluronic acid can be extracted from *Streptococcus zooepidemicus* and can have a weight-average molecular weight selected from 100,000 Da to 1,600,000 Da, specifically 156,000 Da to 1,590,000 Da, and can have Na-substituted end groups to increase solubility. In this study, when the weight-average molecular weight of hyaluronic acid is less than 100,000 Da, hydrolysis is too rapid, and the resulting sheet has poor stability; while when the weight-average molecular weight is greater than 1,600,000 Da, the nanofiber yield is poor, which is undesirable.

[0038] According to one embodiment, relative to 100 parts by weight of polyethylene oxide, the polymer solution may contain at least one of chitosan, thrombin, and collagen, and specifically, the lower limit may be 1 part by weight, 2 parts by weight, 3 parts by weight, 4 parts by weight, 5 parts by weight, or 5 parts by weight, and the upper limit may be 20 parts by weight, 19 parts by weight, 18 parts by weight, 17 parts by weight, 16 parts by weight, 15 parts by weight, 14 parts by weight, 13 parts by weight, 12 parts by weight, 11 parts by weight, or 10 parts by weight.

[0039] According to one embodiment, the polymer solution may contain chitosan, thrombin, and collagen.

[0040] According to one embodiment, relative to 1 part by weight of thrombin, the polymer solution may contain 3 to 10 parts by weight of collagen and 1 to 15 parts by weight of chitosan, specifically 3 to 7 parts by weight of collagen and 3 to 15 parts by weight of chitosan, and more specifically 4 to 6 parts by weight of collagen and 5 to 12 parts by weight of chitosan.

[0041] According to one embodiment, the polymer solution may contain a mixed solvent of water and ethanol.

[0042] According to one embodiment, the polymer solution may contain polyethylene oxide, water, and ethanol in a weight ratio of 10:10 to 30:40 to 70, specifically 10:10 to 25:50 to 60, and specifically 10:15 to 20:50 to 60.

[0043] According to one embodiment, the number average molecular weight of the polyethylene oxide can be from 10,000 g / mol to 2,000,000 g / mol, wherein the lower limit can be 10,000 g / mol, 20,000 g / mol, 30,000 g / mol, 40,000 g / mol, 50,000 g / mol, 60,000 g / mol, 70,000 g / mol, 80,000 g / mol, 90,000 or 100,000 g / mol, and the upper limit can be 2,000,000 g / mol, 1,800,000 g / mol, 1,600,000 g / mol, 1,400,000 g / mol, 1,200,000 g / mol or 1,000,000 g / mol.

[0044] The polymer solution can be reacted at 40°C to 80°C for 0.5 to 5 hours, with the lower limit being 45°C, 50°C or 55°C, and the upper limit being 75°C, 70°C or 65°C.

[0045] Electrospinning can be performed at voltages from 10 V to 200 V and spinning distances from 5 cm to 50 cm, specifically at voltages from 10 V to 100 V. Furthermore, the average voltage used for electrospinning can be from 5 V to 50 V, 10 V to 40 V, or 15 V to 30 V.

[0046] The polymer solution may contain a variety of materials containing flavoring agents and / or additives; and, for example, suitable flavoring agents may include menthol, eugenol, spearmint, peppermint, cocoa, vanilla, cinnamon, licorice, citrus, or other fruit flavorings, and combinations thereof, and examples of non-flavoring additives may include coolants, diluents, aerosol forming agents, etc.

[0047] According to one embodiment, the average diameter of the medical nanofiber membrane can be from 10 nm to 1000 nm, and specifically, the lower limit can be 10 nm, 50 nm, 100 nm or 150 nm, and the upper limit can be 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm or 400 nm.

[0048] According to one implementation scheme, the density of the medical nanofiber membrane can be 1.00 mg / cm³. 3 Up to 2.00 mg / cm 3 Specifically, the lower limit can be 1.00 mg / cm³. 3 1.10 mg / cm 3 1.20 mg / cm 3 1.30 mg / cm 3 1.40 mg / cm 3 1.50 mg / cm 3 Or 1.60 mg / cm 3 And the upper limit can be 2.00 mg / cm³ 3 1.80 mg / cm 3 Or 1.70 mg / cm 3 .

[0049] This disclosure provides a hemostatic component comprising a medical nanofiber membrane. The hemostatic component can be manufactured in the form of a hemostatic patch, and specifically, a hemostatic foam patch. The hemostatic component can be directly applied to the affected area to perform hemostasis. As described above, the hemostatic component, through the medical nanofiber membrane comprising this disclosure, can achieve wound area regeneration and antibacterial effects with effective hemostasis.

[0050] In the following, medical nanofiber membranes according to this disclosure will be described in more detail by way of specific embodiments. However, the following embodiments are merely references for describing this disclosure in detail, and this disclosure is not limited thereto and can be implemented in various forms. Furthermore, the terminology used herein is only for effectively describing certain embodiments and is not intended to limit the scope of this disclosure.

[0051] [Example 1]

[0052] 1. Weigh 10 mg of polyethylene oxide (PEO) on a precision balance.

[0053] 2. Place the Falcon tube on a precision balance, set the balance to zero, and add 18.75 mg of water.

[0054] 3. Slowly add the powder from step 1 to the solution in step 2 and mix.

[0055] 4. Add 5 mg of hyaluronic acid, 0.11 mg of chitosan, 0.53 mg of collagen and 0.11 mg of thrombin to the solution in step 3.

[0056] 5. Stir the solution from step 4 in a stirrer for 1 hour to ensure complete dissolution, so that it dissolves well at 60°C.

[0057] 6. While stirring the solution in a stirrer, slowly add 56.25 mg of alcohol (ethanol) (density: 0.79 g / mL) to the solution in step 5.

[0058] 7. Stir the solution from step 6 in a stirrer at 60°C for 1 hour.

[0059] 8. Fill the syringe with solution 7 in increments of 1 cc to produce a polymer solution.

[0060] 9. The prepared polymer solution is electrospun to produce a nanofiber membrane. In this case, the portable triboelectric device described in Korean Patent Registration No. 10-2353832 can be used for electrospinning.

[0061] [Examples 1 to 8 and Comparative Examples 1 and 2]

[0062] The process was carried out in the same manner as in Example 1, except that the same amounts as those in Tables 1 and 2 below were used.

[0063] The diameters and densities of the nanofiber membranes produced in Examples 1 to 8 and Comparative Examples 1 and 2 are shown in Tables 1 and 2 below.

[0064] Furthermore, the results of observing the appearance of the nanofiber membranes produced in Examples 3 and 4 using scanning electron microscopy (SEM) are shown below. Figure 2 andFigure 3 middle.

[0065] [Assessment Example 1] Hemostasis Assessment and Antimicrobial Assessment

[0066] Hemostasis assessment

[0067] The rabbit's abdominal aorta was exposed and injured using a 22G needle. Bleeding was examined, and nanofiber samples produced in Examples 1 to 8, as well as Comparative Examples 1 and 2, were applied to the bleeding area. The time required for hemostasis was measured by visually monitoring the pattern and duration of blood clotting at 5-second intervals using a timer. The results are shown in Tables 1 and 2 below.

[0068] Antibacterial assessment

[0069] The antimicrobial test was performed according to KSM 0146. 1.0 mL of *E. coli* was collected each time and inoculated into a sterile 250 mL Erlenmeyer flask, and incubated at 37°C for 24 hours. Dilutes were then performed to achieve a bacterial count of 1 × 10⁻⁶, as measured by an absorption spectrophotometer. 5 CFU / mL, and 1.0 mL of bacteria were inoculated and mixed each time. Nanofiber samples produced in Examples 1 to 8 and Comparative Examples 1 and 2 were added and shaken for 24 hours. The absorbance of the culture medium was measured to calculate the bacterial count, and the results of the bacterial count reduction rate (antibacterial activity) compared with the initial bacterial count are shown in Tables 1 and 2 below.

[0070] [Table 1]

[0071]

[0072] [Table 2]

[0073]

[0074] According to Tables 1 and 2, it was determined that when chitosan, collagen, and thrombin were not present in Comparative Example 1, it took a long time to stop bleeding. When 8 or more parts by weight of chitosan, collagen, and thrombin were added to 100 parts by weight of a mixed solution of polyethylene oxide and water, as in Comparative Example 2, no nanofibers were formed.

[0075] It will be apparent to those skilled in the art that the present disclosure is not limited to the exemplary embodiments and drawings described above, and that various substitutions, modifications and alterations can be made without departing from the scope and spirit of the present disclosure.

Claims

1. A medical nanofiber membrane produced by electrospinning a polymer solution, said polymer solution comprising: Polyethylene oxide; Selected from any one or more of hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginate, carrageenan, poloxamer, and cellulose; and It is selected from chitosan, thrombin, and collagen, or one or more of them.

2. The medical nanofiber membrane according to claim 1, wherein, relative to 100 parts by weight of the polyethylene oxide, it is mixed with 1 to 10 parts by weight of any one or more of hyaluronic acid, polyvinyl alcohol, polyvinylpyrrolidone, alginate, carrageenan, poloxamer and cellulose.

3. The medical nanofiber membrane according to claim 1, wherein, relative to 100 parts by weight of the polyethylene oxide, at least any one of chitosan, thrombin, and collagen is mixed in.

4. The medical nanofiber membrane according to claim 1, wherein the polymer solution comprises chitosan, thrombin, and collagen.

5. The medical nanofiber membrane according to claim 4, wherein, relative to 1 part by weight of the thrombin, the polymer solution comprises 3 to 10 parts by weight of the collagen and 1 to 10 parts by weight of the chitosan.

6. The medical nanofiber membrane according to claim 1, wherein the polymer solution comprises a mixed solvent of water and ethanol.

7. The medical nanofiber membrane according to claim 6, wherein the polymer solution comprises the polyethylene oxide, water and ethanol in a weight ratio of 10:10 to 30:40 to 70.

8. The medical nanofiber membrane according to claim 1, wherein the number-average molecular weight of the polyethylene oxide is from 10,000 g / mol to 2,000,000 g / mol.

9. The medical nanofiber membrane according to claim 1, wherein the average diameter of the medical nanofibers is from 10 nm to 1000 nm.

10. A hemostatic component comprising a medical nanofiber membrane according to any one of claims 1 to 9.

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