Polyglutamic acid-based composite degradable dressing as well as preparation method and application thereof

Abstract

The invention discloses a polyglutamic acid-based composite degradable dressing as well as a preparation method and application thereof. The blending dressing is prepared from polyglutamic acid and hyaluronic acid or polyvinyl alcohol through an electrostatic spinning technology, the combination of hyaluronic acid and polyglutamic acid can increase the local anti-inflammatory performance of the blending dressing, and the combination of polyvinyl alcohol and polyglutamic acid can enhance the degradability and film-forming property of the blending dressing; the polyglutamic acid-based composite degradable dressing prepared by adopting an electrostatic spinning method is actually non-woven fiber membrane cloth formed by superfine fibers, the fibers have high surface area and porosity, the composition and the structure of the fibers can be adjusted according to different application requirements, and multifunctional integration is realized; fiber membrane dressings with different shapes and sizes can be prepared, the requirements of different skin parts are met, and traditional gauze can be replaced; the degradable dressing prepared by the preparation method disclosed by the invention has good degradability and skin-friendly property, good ductility, good biological safety and small irritation, and has a good application prospect.

Description

Technical Field

[0001] The invention relates to a polyglutamic acid-based composite degradable dressing and a preparation method and application thereof, belonging to the technical field of biomedical materials. Background Art

[0002] With the rapid development of the medical and health field, the demand for efficient, safe and convenient drug delivery systems is growing. As a new drug delivery platform, multifunctional dressings have attracted widespread attention due to their advantages such as sustainable drug release, reduced side effects, and improved patient compliance. Multifunctional dressings have good biocompatibility, can provide a moist environment, promote wound healing, and also have multiple functions such as antibacterial and hemostatic. In addition, dressings can also be used as surgical aids as hemostatic agents or suture aids to help control bleeding and promote wound closure; they can also be used for drug delivery and for postoperative pain management or infection prevention, reducing systemic drug side effects through local administration.

[0003] Polyglutamic acid (γ-PGA) is a bio-based polymer, which is polymerized from L-glutamic acid monomers through amide bonds. Due to its water solubility, moisture retention, non-toxicity, and biodegradability, polyglutamic acid can be used to make medical supplies such as dressings, artificial skin, trauma dressings, and hemostatic agents. Polyglutamic acid has a wide range of applications, and polyglutamic acid of different molecular weights is used in different fields and scenarios. For example, in the agricultural field, low molecular weight (<100,000 units) polyglutamic acid is used, which has the functions of absorbing water and moisturizing and regulating plant growth; in the cosmetics and food fields, medium molecular weight (100,000 to 700,000 units) polyglutamic acid is used, which has certain moisturizing, water locking and antioxidant effects; pharmaceutical grade uses high molecular weight (700,000 to 1.5 million units) polyglutamic acid, which has the function of improving stability. Different molecular weights have an impact on degradability. Generally, the lower the molecular weight, the easier it is to degrade. Therefore, by adjusting its molecular weight and formula, customized multifunctional dressings can be achieved. For example, some anti-inflammatory components such as hyaluronic acid (HA) are added to polyglutamic acid to reduce local inflammation. In addition, polyvinyl alcohol has excellent biodegradability. It is a polymer containing a large number of hydroxyl groups, a large number of hydrogen bonds in the molecule, high crystallinity, and difficult to thermoform. The water absorption rate mainly depends on the degree of hydrolysis and the molecular weight. The biodegradable material prepared with it as a raw material is not only highly hydrophilic, but also has poor mechanical properties. Therefore, improving the mechanical properties and improving its water resistance have become the main problems to be solved urgently.

[0004] At present, there are some patent technology reports on biomedical materials based on polyglutamic acid. For example, the authorized patent CN 113975197 B discloses a multi-component liquid compound composition containing sodium polyglutamate, which is attached to a folded film cloth for repairing skin after medical cosmetic surgery, microneedle trauma, severe acne, etc. The patent only uses sodium polyglutamate as a compounding component in a liquid composition. The liquid composition cannot be directly applied as a dressing and needs to be additionally loaded on a substrate such as a film cloth for application. For another example, the authorized patent CN 112341640B discloses a hydrogel obtained by mixing and molding a cysteine-modified γ-polyglutamic acid and an aldehyde-modified hyaluronic acid polymer in water or a buffer solution, which is expected to be used in medical dressings, 3D printing, tissue engineering and other fields. However, the patent involves the use of chemical modification methods to chemically modify polyglutamic acid and hyaluronic acid respectively to form special chemical bonds, and then obtain a hydrogel through chemical cross-linking reaction. The disadvantage is that the chemical reaction steps are relatively large, and dialysis separation and purification of the modified products are required. The operation is complicated and time-consuming, and it will produce three wastes, which is not suitable for large-scale production. Summary of the invention

[0005] The purpose of the present invention is: to address the deficiencies in the prior art, the present invention provides a polyglutamic acid-based composite degradable dressing, a preparation method and application thereof. The present invention adopts electrostatic spinning technology to prepare the polyglutamic acid-based composite degradable dressing, and compounding polyglutamic acid with other components to jointly adjust the absorption time and performance of the degradable dressing. The dressing has unique application scenarios and practical application value, especially in hemostasis or drug administration during skin and organ surgery, and has unique degradable absorption, hemostasis, drug sustained release, adhesion prevention and other effects.

[0006] In order to achieve the above object, the present invention provides a method for preparing a polyglutamic acid-based composite degradable dressing, comprising the following steps:

[0007] Step 1: dissolving polyglutamic acid in an organic solvent to obtain a polyglutamic acid solution;

[0008] Step 2: Mixing the polyglutamic acid solution with the hyaluronic acid aqueous solution and / or the polyvinyl alcohol aqueous solution to obtain an electrospinning solution;

[0009] Step 3: The electrospinning solution obtained in step 2 is subjected to electrospinning to prepare a fiber membrane cloth, which is a polyglutamic acid-based composite degradable dressing.

[0010] Furthermore, the molecular weight of the polyglutamic acid in the preparation method of the present invention can be selected from any one or any combination of low molecular weight (<100,000 units, molecular weight refers to relative molecular mass, the same below), medium molecular weight (100,000 to 700,000 units) and high molecular weight (700,000 to 1.5 million units) polyglutamic acid;

[0011] Furthermore, the hyaluronic acid used in the hyaluronic acid aqueous solution in step 2 can be selected from any one of oligomeric hyaluronic acid (molecular weight <10,000) and low molecular weight (100,000 to 1,000,000) hyaluronic acid or a combination of both;

[0012] Furthermore, the polyvinyl alcohol used in the polyvinyl alcohol aqueous solution in step 2 can be any one of low-polymerization degree (molecular weight <35,000) polyvinyl alcohol and medium-polymerization degree polyvinyl alcohol (molecular weight 120,000-150,000) or a combination of both.

[0013] The molecular weights and raw material ratios of the three raw materials in the preparation method of the present invention can be selected and matched accordingly according to actual performance requirements. The molecular weight affects the degradability and absorbability. The lower the molecular weight, the more conducive to degradation and absorption.

[0014] Furthermore, the organic solvent in step 1 is an organic solvent miscible with water.

[0015] Furthermore, the water-miscible organic solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, hexafluoroisopropanol and tetrahydrofuran.

[0016] Most preferably, the water-miscible organic solvent is ethanol.

[0017] Most preferably, the water-miscible organic solvent is tetrahydrofuran.

[0018] Furthermore, the concentration of the polyglutamic acid solution in step 1 is 5 to 20%;

[0019] And / or, the concentration of the hyaluronic acid aqueous solution in step 2 is 5-20%;

[0020] And / or, the concentration of the polyvinyl alcohol aqueous solution in step 2 is 5-20%.

[0021] Furthermore, the mass ratio of polyglutamic acid to hyaluronic acid in the electrospinning solution in step 2 is 0.3 to 3:1.

[0022] Furthermore, the mass ratio of polyglutamic acid to polyvinyl alcohol in the electrospinning solution of step 2 is 0.3 to 3:1.

[0023] Furthermore, the step 3 specifically includes: transferring the electrospinning solution to the injection pump of the electrospinning device, connecting the fine nozzle at the pump head to the positive electrode of the high-voltage power supply, and after starting the high-voltage power supply, the nozzle sprays the solution to form nanofibers, and these nanofibers are deposited on the collector to form a fiber membrane cloth, which is a polyglutamic acid-based composite degradable dressing.

[0024] Furthermore, the electrospinning process conditions are as follows: micro nozzle model 10G-30G, electrospinning flow rate 0.5-5mL / h, spinning voltage 10-30kV, spinning environment temperature 20-30°C, and spinning environment relative humidity 50-70%.

[0025] The present invention also provides application of the degradable dressing prepared by the above preparation method in preparing medical skin dressing.

[0026] Preferably, skin drugs can be added to the degradable dressing to prepare a medical skin dressing, such as drugs that promote skin wound repair (skin growth factors, etc.), or drugs that prevent skin wound infection (anti-infection drugs), or drugs used to stop bleeding from skin wounds, etc.

[0027] The present invention adopts electrospinning technology to prepare polyglutamic acid-based composite degradable dressing, which is to compound polyglutamic acid and other components to jointly adjust the absorption time and performance of the degradable dressing. It has unique application scenarios and practical application value, especially in hemostasis or drug administration during skin and organ surgery, and has unique degradable absorption, hemostasis, drug sustained release, and adhesion prevention effects.

[0028] The polyglutamic acid-based composite biodegradable dressing prepared by the electrospinning method of the present invention is actually a non-woven fiber membrane cloth formed by ultrafine fibers. These fibers have a high surface area and porosity, and the fiber composition and structure can be adjusted according to different application requirements to achieve multifunctional integration. In addition, the electrospinning technology can prepare fiber membrane dressings of different shapes and sizes, and the fiber membrane dressing exhibits good mechanical properties, which can meet the needs of different skin parts and can replace traditional gauze.

[0029] The present invention regulates the degradable formula and optimizes the preparation process to obtain a dressing with adjustable degradation time, good bio-tissue compatibility and high biosafety; the dressing prepared by electrospinning in the present invention has the characteristics of simple operation, controllable cost, good skin-friendly feel and high air permeability. In particular, as a dressing for application, it has a wide range of application scenarios and good adaptability, complementing traditional dressings.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. The present invention uses polyglutamic acid and hyaluronic acid or polyglutamic acid and polyvinyl alcohol to prepare a blended dressing through electrospinning technology, wherein the combination of hyaluronic acid and polyglutamic acid can increase its local anti-inflammatory properties, and the combination of polyvinyl alcohol and polyglutamic acid can enhance its degradability and film-forming properties; the degradable dressing provided by the present invention can be used as a drug carrier and applied in the field of skin medical health, thereby preparing a series of multifunctional medical skin dressings with a wide range of application scenarios;

[0032] 2. The degradable dressing prepared by the electrospinning method of the present invention has good degradability and skin-friendliness, good ductility, good biosafety and low irritation; it has good application prospects in skin-related application scenarios. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 A scanning electron microscope image of the polyglutamic acid / hyaluronic acid blended dressing provided by the present invention.

[0034] Figure 2 A scanning electron microscope image of the polyglutamic acid / polyvinyl alcohol blended dressing provided by the present invention.

[0035] Figure 3 Photographs of the polyglutamic acid / hyaluronic acid blended dressing (a) and the polyglutamic acid / polyvinyl alcohol blended dressing (b) provided by the present invention.

[0036] Figure 4 The degradation and release curves of the polyglutamic acid / hyaluronic acid blended dressing, polyglutamic acid / polyvinyl alcohol blended dressings with different ratios and polystyrene dressings provided by the present invention within 30 days.

[0037] Figure 5 Stress-strain curves of the polyglutamic acid / hyaluronic acid blended dressing, the polyglutamic acid / polyvinyl alcohol blended dressing and the polystyrene dressing provided by the present invention.

[0038] Figure 6 The water contact angles of the polyglutamic acid / hyaluronic acid blended dressing, polyglutamic acid / polyvinyl alcohol blended dressing and polystyrene dressing provided by the present invention at ten seconds: (a) polyglutamic acid / hyaluronic acid blended dressing; (b) polyglutamic acid / polyvinyl alcohol blended dressing; (c) polystyrene dressing. DETAILED DESCRIPTION

[0039] In order to make the present invention more clearly understood, preferred embodiments are described in detail below with reference to the accompanying drawings.

[0040] In the following examples, the materials, reagents, etc. used are conventional commercially available products unless otherwise specified.

[0041] Example 1: Synthesis and characterization of polyglutamic acid / hyaluronic acid composite dressing

[0042] (1) Synthesis of electrospinning solution: Take 5 parts of tetrahydrofuran, anhydrous ethanol, acetone, N-methylpyrrolidone and N,N-dimethylformamide as solvents, take 0.5 parts of polyglutamic acid (molecular weight ≥ 700,000) to prepare a polyglutamic acid solution with a concentration of 10% (g / mL), and stir it in a 55°C water bath for 2 hours. Take 5 parts of deionized water as solvent, take 0.5 parts of hyaluronic acid (molecular weight 100,000-200,000) to prepare a hyaluronic acid solution with a concentration of 10% (g / mL), and stir it in a 55°C water bath for 2 hours. After mixing the above polyglutamic acid solution and hyaluronic acid solution in a volume ratio of 1:1, magnetically stir at room temperature for 8 hours to obtain a polyglutamic acid / hyaluronic acid mixed spinning solution. The performance comparison results of the mixed spinning solution are shown in Table 1:

[0043] Table 1 Comparison results of mixed spinning solution properties

[0044] Solvents Effect Tetrahydrofuran The solution is uniform and has good viscosity Anhydrous ethanol The solution is uniform and has poor viscosity. acetone The solution is uneven and has good viscosity N-Methylpyrrolidone The solution is uniform and has poor viscosity. N,N-Dimethylformamide The solution is uneven and has poor viscosity.

[0045] According to the experimental results in Table 1, tetrahydrofuran was selected as the good solvent.

[0046] (2) Preparation of polyglutamic acid / hyaluronic acid composite dressing: The polyglutamic acid / hyaluronic acid mixed spinning solution is transferred to the injection pump of the electrospinning device. A G22 model micro-nozzle is used at the pump head and connected to the positive electrode of the high-voltage power supply. Other electrospinning parameters are flow rate of 2 mL / h, receiving distance of 20 cm, drum speed of 500 rad / min, ambient temperature of 25 °C, humidity of 85%, and collector is double-sided silicone oil paper. The voltage is set to 19 kV. After starting the high-voltage power supply, the nozzle sprays the solution to form nanofibers, which are deposited on the collector to form a fiber membrane dressing;

[0047] (3) Characterization of polyglutamic acid / hyaluronic acid blend dressing: The scanning electron microscopy image of polyglutamic acid / hyaluronic acid blend dressing is shown in Figure 1 , see the actual photos Figure 3 (a).

[0048] Example 2: Synthesis and characterization of polyglutamic acid / polyvinyl alcohol composite dressing:

[0049] (1) Synthesis of electrospinning solution: Take 5 parts of tetrahydrofuran, anhydrous ethanol, acetone, N-methylpyrrolidone and N,N-dimethylformamide as solvents, take 0.5 parts of polyglutamic acid (molecular weight <100,000) to prepare a polyglutamic acid solution with a concentration of 10% (g / mL), and stir it in a 30°C water bath for 2 hours. Take 5 parts of deionized water as solvent, take 0.5 parts of polyvinyl alcohol (molecular weight 100,000-200,000) to prepare a polyvinyl alcohol solution with a concentration of 10% (g / mL), and stir it in a 30°C water bath for 2 hours. After mixing the above polyglutamic acid solution and polyvinyl alcohol solution in a volume ratio of 1:1, stir at room temperature for 1 hour to obtain a polyglutamic acid / polyvinyl alcohol mixed spinning solution. The performance comparison results of the mixed spinning solution are shown in Table 2:

[0050] Table 2 Comparison results of mixed spinning solution properties

[0051] Solvents Effect Tetrahydrofuran The solution is uniform and has poor viscosity. Anhydrous ethanol The solution is uniform and has good viscosity acetone The solution is uneven and has good viscosity N-Methylpyrrolidone The solution is uniform and has poor viscosity. N,N-Dimethylformamide The solution is uneven and has poor viscosity.

[0052] According to the experimental results in Table 2, anhydrous ethanol was selected as the good solvent.

[0053] (2) Preparation of polyglutamic acid / polyvinyl alcohol composite dressing: The polyglutamic acid / polyvinyl alcohol mixed spinning solution is transferred to the injection pump of the electrospinning device. A G24 model micro-nozzle is used at the pump head and connected to the positive electrode of the high-voltage power supply. Other electrospinning parameters are flow rate of 1 mL / h, receiving distance of 13 cm, drum speed of 300 rad / min, ambient temperature of 25 °C, humidity of 60%, and collector is double-sided silicone oil paper. The voltage is set to 21 kV. After starting the high-voltage power supply, the nozzle sprays the solution to form nanofibers, which are deposited on the collector to form a fiber membrane dressing;

[0054] (3) Characterization of polyglutamic acid / polyvinyl alcohol composite dressing: The scanning electron microscopy image of polyglutamic acid / polyvinyl alcohol composite dressing is shown in Figure 2 , see the actual photos Figure 3 (b).

[0055] Example 3: Synthesis of polyglutamic acid / polyvinyl alcohol composite dressings with different ratios

[0056] (1) Synthesis of electrospinning solution: (2.5 or 7.5) parts of anhydrous ethanol were used as solvent, and (0.25 or 0.75) parts of polyglutamic acid (molecular weight <100,000) were taken to prepare a polyglutamic acid solution with a concentration of 10% (g / mL), and stirred in a 30°C water bath for 2 hours. (7.5 or 2.5) parts of deionized water were used as solvent, and (0.75 or 0.25) parts of polyvinyl alcohol (molecular weight 100,000-200,000) were taken to prepare a polyvinyl alcohol solution with a concentration of 10% (g / mL), and stirred in a 30°C water bath for 2 hours. The above polyglutamic acid solution and polyvinyl alcohol solution (the volume ratio of the two was 1:3 or 3:1) were mixed, and stirred at room temperature for 1 hour to obtain polyglutamic acid / polyvinyl alcohol mixed spinning solutions with different ratios.

[0057] (2) Preparation of polyglutamic acid / polyvinyl alcohol composite dressing: The polyglutamic acid / polyvinyl alcohol mixed spinning solution with different ratios was transferred to the injection pump of the electrospinning device. A G24 type micro-nozzle was used at the pump head and connected to the positive electrode of the high-voltage power supply. Other electrospinning parameters were flow rate of 1.5 mL / h, receiving distance of 13 cm, drum speed of 500 rad / min, ambient temperature of 25 °C, humidity of 60%, and double-sided silicone oil paper as the collector. The voltage was set to 21 kV. After starting the high-voltage power supply, the nozzle sprayed the solution to form nanofibers, which were deposited on the collector to form a fiber membrane dressing.

[0058] Performance Test:

[0059] The performance tests of Examples 1 to 3 and polystyrene dressings are as follows

[0060] (1) Take the dressings prepared in Examples 1 to 3 respectively, add a certain amount of rhodamine B dye during preparation, cut into cubes of length × width = 2 × 2 cm, simulate drug release with rhodamine B, and test the degradability of polyglutamic acid / hyaluronic acid composite dressings, polyglutamic acid / polyvinyl alcohol composite dressings with different ratios, and polystyrene dressings. Figure 4 It can be seen that the dressings prepared in Examples 1 and 2 have better degradation performance than polystyrene dressings and are almost completely degraded after 30 days. The degradation test results of polyglutamic acid / polyvinyl alcohol blended dressings with different ratios prepared in Examples 2 and 3 also verify that different ratios can adjust the performance of their degradable time.

[0061] (2) The stress-strain method was used to test the mechanical properties of polyglutamic acid / hyaluronic acid blended dressings, polyglutamic acid / polyvinyl alcohol blended dressings, and polystyrene dressings. Figure 5 The maximum load of the dressings prepared in Examples 1 to 2 is greater than that of the polystyrene dressing, indicating that the dressings prepared in Examples 1 to 2 have better mechanical properties.

[0062] (3) The contact angle test was used to characterize the hydrophilicity and hydrophobicity of polyglutamic acid / hyaluronic acid blended dressings, polyglutamic acid / polyvinyl alcohol blended dressings, and polystyrene dressings. Figure 6 It can be seen that the contact angles of the dressings prepared in Examples 1 and 2 when in contact with water for 10 seconds are smaller than that of the polystyrene dressing, which proves that the hydrophilic properties of the dressings in Examples 1 and 2 are better than those of the polystyrene dressing.

[0063] The above description is only a preferred embodiment of the present invention and is not any formal or substantial limitation of the present invention. It should be pointed out that a person skilled in the art may make several improvements and supplements without departing from the present invention, and these improvements and supplements should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing a polyglutamic acid-based composite degradable dressing, characterized in that: The following steps are involved: Step 1: dissolving polyglutamic acid in an organic solvent to obtain a polyglutamic acid solution; Step 2: Mixing the polyglutamic acid solution with the hyaluronic acid aqueous solution and / or the polyvinyl alcohol aqueous solution to obtain an electrospinning solution; Step 3: The electrospinning solution obtained in step 2 is subjected to electrospinning to prepare a fiber membrane cloth, which is a polyglutamic acid-based composite degradable dressing.

2. The preparation method according to claim 1, characterized in that The organic solvent in step 1 is an organic solvent miscible with water.

3. The preparation method according to claim 2, characterized in that: The water-miscible organic solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, hexafluoroisopropanol and tetrahydrofuran.

4. The preparation method according to claim 3, characterized in that: The organic solvent miscible with water is ethanol.

5. The preparation method according to claim 3, characterized in that: The organic solvent miscible with water is tetrahydrofuran.

6. The preparation method according to claim 1, characterized in that: The concentration of the polyglutamic acid solution in step 1 is 5-20%; And / or, the concentration of the hyaluronic acid aqueous solution in step 2 is 5-20%; And / or, the concentration of the polyvinyl alcohol aqueous solution in step 2 is 5-20%.

7. The preparation method according to claim 1, characterized in that: The mass ratio of polyglutamic acid to hyaluronic acid in the electrospinning solution of step 2 is 0.3 to 3:1; And / or, the mass ratio of polyglutamic acid to hyaluronic acid in the electrospinning solution is 0.3 to 3:

1.

8. The preparation method according to claim 1, characterized in that: The step 3 specifically includes: transferring the electrospinning solution to the injection pump of the electrospinning device, connecting the micro-nozzle at the pump head to the positive electrode of the high-voltage power supply, and after starting the high-voltage power supply, the nozzle sprays the solution to form nanofibers, and these nanofibers are deposited on the collector to form a fiber membrane cloth, which is a polyglutamic acid-based composite degradable dressing.

9. The preparation method according to claim 1, characterized in that: The electrospinning process conditions are as follows: fine nozzle model 10G-30G, electrospinning flow rate 0.5-5mL / h, spinning voltage 10-30kV, spinning environment temperature 20-30°C, and spinning environment relative humidity 50-70%.

10. Use of the degradable dressing prepared by the preparation method according to any one of claims 1 to 9 in the preparation of medical skin dressings.

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