KR20210020969A - Multilayered nanofibers for storage and delivery of drugs - Google Patents

Abstract

To improve the properties of nanofibers that store and deliver drugs, the present invention provides multilayered nanofibers which comprise: one or more inner layers including nanofibers for storing one or more drugs; and one or more outer layers including polymer nanofibers on one or both sides of the inner layer. According to the multilayered nanofibers, a drug delivery rate can be controlled by using appropriate polymer nanofibers as outer layers. In addition, a polymer having high physical strength can be introduced into the outer layers, thereby making it possible to prepare nanofibers with excellent physical rigidity. Furthermore, it is possible to improve the properties of nanofibers by introducing a polymer having desired properties, such as adhesiveness, adhesion, biocompatibility or the like to the outer layers.

Description

Multilayered nanofibers for storage and delivery of drugs

The present invention relates to a multi-layer nanofiber for storage and delivery of a drug, wherein the multi-layer including the nanofiber controls the inner layer storing the drug and the delivery rate of the drug, and improves or adds physical properties, etc. It includes an outer layer for

Nanofibers have a higher surface area than general fibers, so they are easy to introduce functional groups to the surface and have dense pores, so they can be used as high-performance gas or liquid filters. In addition, since the shape of the spun nanofibers can mimic the extra cellular matrix (ECM) of the human body (Sisson, K. et al. Biomicromolecules 2009 , 10 , 1675-1680), it is widely used in medical and biological fields. It is applied in the form.

As an example, interest in nanofibers that can store and deliver various drugs including nitric oxide (NO) is increasing recently, and related technologies have been developed (N- diazeniumdiolate nanofiber, S- nitrosothiol nanofiber, etc. ). However, nanofibers for storage and delivery of these drugs have limitations by themselves. That is, for effective drug storage and delivery, it is required to control the delivery rate (or release rate), biocompatibility, and physical stiffness of the drug, but the physical properties of a single nanofiber cannot sufficiently satisfy such demand.

Therefore, efforts have been made to supplement the properties of nanofibers for storage and delivery of these drugs. Examples of this include a method of manufacturing a fiber by mixing it with another polymer solution as a method for manufacturing a multifunctional fiber, and a method of manufacturing a fiber having a core-shell structure.

The method of manufacturing fibers by mixing several polymers is simple, but there is a disadvantage in that the fibers containing drugs cannot be protected because they are exposed to the external environment. In addition, the core-shell structure has limitations in the manufacturing method that it is not easy to control the spinning conditions for forming the core-shell structure of the polymer used as the core and the polymer used as the shell, and the two polymers should not mix well with each other.

Therefore, the present invention was reached while trying to provide nanofibers for storage and delivery of drugs that can control the release characteristics of drugs by a relatively simple method, and can easily impart various functions according to the intended use.

The present invention is to provide a method capable of controlling the delivery rate and physical properties of a drug in nanofibers for storage and delivery of drugs.

Specifically, it is intended to manufacture multifunctional nanofibers that can be applied to various fields by freely controlling drug release characteristics and improving physical rigidity lacking in nanofibers, and by giving properties suitable for use purposes.

The present invention provides a multi-layered nanofiber manufactured by sequentially spinning a polymer having properties to be imparted to a drug-storing nanofiber.

Specifically, the present invention provides storage and delivery of drugs including one or more inner layers containing nanofibers for storing one or more drugs and one or more outer layers containing polymeric nanofibers on one or both sides of the inner layer. It provides multi-layer nanofibers for

Preferably, the nanofibers included in the inner layer store one or more drugs.

Preferably, each layer of the inner layer includes nanofibers storing one or more drugs.

Preferably, the inner layer comprises nanofibers storing nitric oxide (NO).

Preferably, the inner layer includes at least one selected from the group consisting of N- diazeniumdiolate nanofibers, S- nitrosothiol nanofibers, organic nitrates nanofibers, and sodium nitrite nanofibers.

Preferably, the outer layer is poly(benzylmethacrylate) (Poly(benzylmethacrylate)), poly(tetra-fluoroethylene) (Poly(tetra-fluoroethylene)), poly(acrylonitrile-co-methylacrylate) Manufactured from one or more polymers selected from the group consisting of (Poly(acrylonitrile-co-methylacrylate)) and poly(vinylidene-fluoride-co-hexafluoropropylene) (Poly(vinylidene-fluoride-co-hexafluoropropylene)) Contains the nanofibers.

Preferably, the outer layer comprises nanofibers made from polyurethane (Polyurethane (PU)) or polycaprolactone (PCL).

Preferably, the outer layer is polyacrylic acid (PAA), poly-L-lactide (PLLA)), poly(glycolic acid) (PGA)), Poly(lactic-co-glycolic acid) (PLGA)), cellulose (Cellulose), collagen (Collagen), gelatin (Gelatin) and 1 selected from the group consisting of chitosan (Chitosan) It includes nanofibers made from polymers of more than one species.

Preferably, the outer layer is polyacrylonitrile (PAN), polyethylene oxide (PEO)), polyethylene terephtalate (PET)), polymethacrylate (PMA)), Polystyrene (PS)), poly(vinylidene fluoride) (Poly(vinylidene fluoride) (PVDF)), polyurethane (Polyurethane (PU)) and polyvinylphenol (PVP)) It includes nanofibers made from one or more polymers.

Preferably, on one side of the inner layer, poly(benzylmethacrylate) (Poly(benzylmethacrylate)), poly(tetra-fluoroethylene) (Poly(tetra-fluoroethylene)), poly(acrylonitrile-co-methylacrylic) At least one polymer selected from the group consisting of (Poly(acrylonitrile-co-methylacrylate)) and poly(vinylidene-fluoride-co-hexafluoropropylene) (Poly(vinylidene-fluoride-co-hexafluoropropylene)) An outer layer comprising nanofibers electrospun from the is positioned, and an outer layer comprising nanofibers made from polyurethane (Polyurethane (PU)) or polycaprolactone (PCL) is positioned on the other side.

Preferably, the outer layer comprises nanofibers made from two or more polymers.

Preferably, the outer layers positioned on both sides of the inner layer include nanofibers made from the same polymer.

Preferably, the outer layers positioned on both sides of the inner layer include nanofibers made from different polymers.

Preferably, the nanofibers are electrospun.

According to the present invention, it is possible to deliver (or release) the drug at a controlled rate from the inner layer by using a nanofiber of an appropriate polymer according to the environment on one side or both sides of the inner layer of the nanofiber storing the drug as the outer layer. There is an advantage to do.

In addition, it is possible to improve the properties of nanofibers by introducing polymers having desired properties such as adhesion, adhesiveness or biocompatibility to the outer layer. In particular, according to the present invention, nanofibers having excellent physical rigidity can be manufactured by introducing a polymer having high physical strength into the outer layer. Therefore, according to the present invention, there is an advantage in that it is multifunctional and facilitates handling of nanofibers that store and deliver drugs.

1A to 1E illustrate various types of multilayer nanofibers of the present invention.
Figures 2a and 2b show the manufacturing process of the nanofibers storing nitrogen monoxide (NO) in an embodiment of the present invention.
Figures 3a and 3b shows an electrospinning device that can be used to manufacture the nanofibers of the present invention.
FIG. 4 shows the results of measuring contact angles of the inner layer and the multilayer nanofibers prepared in Examples 1 to 4. FIG.
Figure 5 shows the NO emission characteristics of the inner layer and multi-layer nanofibers prepared in Examples 1 to 4.
6 shows the results of measuring the tensile strength of the inner layer and multi-layer nanofibers prepared in Examples 1 to 4.

The present invention has the advantage of being able to simply store and deliver under specific conditions when using nanofibers applicable to biological applications as a means of storage and delivery of various drugs including nitric oxide (NO) due to various advantages. On the other hand, it provides a method of introducing nanofibers made from polymers having characteristics to be imparted to compensate for the disadvantages such as lack of physical rigidity.

The present invention includes one or more inner layers containing nanofibers for storing drugs and one or more outer layers containing polymeric nanofibers on one or both sides of the inner layer, as shown in FIGS. 1A to 1E. It provides multi-layer nanofibers for storage and delivery of drugs. The structures shown in FIGS. 1A to 1E will be described in detail later.

The multi-layer nanofibers are largely located on one and both sides of the inner layer including nanofibers for storing drugs and the inner layer to store drugs such as drug delivery properties, physical stiffness and adhesion, adhesion, and biocompatibility of the inner layer. It includes an outer layer that functions to add or improve several properties to the nanofiber for delivery.

The inner layer is a nanofiber made from a material capable of storing and delivering a drug under specific conditions, for example, a nanofiber for storage and delivery of nitrogen monoxide (NO). Specific examples of such nanofibers include N- diazeniumdiolate nanofibers, S- nitrosothiol nanofibers, organic nitrates nanofibers, or sodium nitrite nanofibers, among which FIGS. 2A and 2B are N- diazeniumdiolate nanofibers (FIG. 2A) and It shows the manufacturing process of S-nitrosothiol nanofibers (Figure 2b). However, the nanofibers that may be included in the inner layer of the present invention are not limited to those for storage and delivery of NO, for example, and may be included without limitation, whatever is used for drug release.

The inner layer may consist of one or more layers. That is, as shown in Figure 1e, in order to perform the function of storing and delivering two or more different drugs at the same time, the inner layer may be made of multiple layers, and each layer includes nanofibers storing each drug. Can be.

In addition, each layer of the inner layer may be made of nanofibers that store one type of drug, or may be made of nanofibers that store two or more drugs at the same time, and in some cases, each of different types of drugs is stored. It is provided in a form that can be applied as many times as required, such as may be made of fractions of nanofibers.

Next, the present invention provides an outer layer comprising nanofibers made from a polymer having properties to be added or improved on one or both sides of the inner layer in order to impart physical properties that cannot be achieved with the nanofibers included in the inner layer alone. Introduce layers.

Therefore, the polymer included in the outer layer may be selected to suit the characteristics to be added or improved according to the user's request. For example, in the case of controlling the drug delivery rate, that is, the release characteristics of the nanofibers, since most drugs are released in the presence of water, poly(benzylmethacrylate), a hydrophobic polymer, Poly(tetra-fluoroethylene)), poly(acrylonitrile-co-methylacrylate) (Poly(acrylonitrile-co-methylacrylate)) or poly(vinylidene-fluoride-co- Using hexafluoropropylene (Poly(vinylidene-fluoride-co-hexafluoropropylene)) can delay the release rate. That is, if the outer layer containing the hydrophobic polymer nanofibers as illustrated above is placed on one or both sides of the inner layer storing the drug, the amount of the drug released from the inner layer is reduced and the drug is slowly released over a long time. To be able to.

As another example, the use of nanofibers made from polymers with excellent physical rigidity such as polyurethane (PU) or polycaprolactone (PCL) as an outer layer improves the physical rigidity of multi-layered nanofibers. It can bring about the effect of making handling easier. These advantages are to overcome the disadvantages that are difficult to be applied in various fields because nanofibers having the function of storing drugs in normal cases lack physical rigidity, expanding the scope of application of nanofibers for drug storage and delivery. It is to let.

As another example, the outer layer is polyacrylic acid (PAA), poly-L-lactide in order to impart various properties according to the user's needs, such as adhesiveness, adhesion, or biocompatibility. (PLLA)), poly(glycolic acid) (Poly(glycolic acid) (PGA)), poly(lactic-co-glycolic acid) (Poly(lactic-co-glycolic acid) (PLGA)), cellulose (Cellulose), It may include nanofibers made from polymers such as collagen, gelatin, or chitosan.

In addition to the above-described polymers, the polymer included in the outer layer of the present invention can be used without limitation as long as it can be generally made of nanofibers, and examples thereof include polyacrylonitrile (PAN)), polyethylene oxide ( Polyethylene oxide (PEO)), polyethylene terephtalate (PET)), polymethacrylate (PMA)), polystyrene (PS)), poly(vinylidene fluoride) (Poly(vinylidene fluoride)) (PVDF)), polyurethane (Polyurethane (PU)), and polyvinylphenol (PVP)), and the like. In each of these cases, it is selected according to the properties required according to the environment and the nanofibers of the inner layer storing the drug.

In the end, the outer layer is located on one or both sides of the inner layer, providing and improving properties such as drug delivery properties, physical stiffness, adhesion, adhesion, and biocompatibility, as well as protecting the inner layer. The polymeric material of may be selected according to each characteristic, and it should be understood that it is included in the present invention without limitation, as long as it can be made of nanofibers.

The outer layer consists of one or more layers. That is, even if it is located on one surface of the inner layer, there may be one or more layers, and in this case, the polymer included in each layer may be one type, or in some cases, two or more types. In addition, in the case of a multilayered outer layer, two or more functions may be given or improved, including nanofibers made from different types of polymers performing different functions.

1A to 1E show embodiments of a multilayer nanofiber including an outer layer positioned in various forms around the inner layer. Referring to this, first, a simple structure in which only one outer layer exists (Fig. 1A) is mainly It can be used to impart a single characteristic. Next, an outer layer including nanofibers made from the same polymer may be located on both sides of the inner layer (FIG. 1B). In addition, it has a structure in which an outer layer containing nanofibers of different polymers is located in two layers on both sides of the inner layer (Fig. 1c).For example, an outer layer and other functions for controlling the drug release rate are provided. It can also form a multi-functional multi-layer structure where the external layers are located.

As another example, this time, it is a sandwich structure in which an outer layer containing nanofibers made from two types of different polymers is located on both sides of the inner layer (Fig. 1D), which improves physical rigidity at the same time as drug release properties. It can provide multifunctionality. Meanwhile, even in the case of the inner layer, it may be composed of two layers including nanofibers each storing two kinds of drugs (FIG. 1E).

Among these various possible embodiments, the present invention is a preferred embodiment of a multilayer nanofiber, in particular, in which the inner layer is made of nanofibers that store nitrogen monoxide, and a hydrophobic polymer on one side thereof to control drug properties. It is proposed to form a sandwiched structure by placing an outer layer including nanofibers manufactured from and on the other side, an outer layer including nanofibers manufactured from a polymer that improves physical rigidity. Such multi-layer nanofibers, for example, when storing organs harvested for organ transplantation, have an outer layer of a polymer for controlling drug properties on the side of the nitrogen monoxide-releasing nanofibers in contact with the organs, and the side in contact with the external environment. When sealed with multi-layer nanofibers with an outer layer of a polymer that improves physical rigidity, nitrogen monoxide is gradually supplied to the organ over a long period of time to delay organ necrosis, protect the organ from the outside, and facilitate handling. It can lead to loss.

Nanofibers included in the inner layer and the outer layer may be prepared from an electrospinning device as shown in FIGS. 3A and 3B. Electrospinning can be applied to most polymers that can be dissolved in a solvent. Therefore, in particular, the selection range of nanofibers that can be used as the outer layer of the present invention can be broadened.

The present invention will be described in more detail through the following examples. However, the scope of the present invention should not be construed as being limited thereto, and the scope of the invention is determined by the claims.

Example One

(1) Preparation of the inner layer

MMA (methylmethacrylate) 30 mmol (60 mol%), HMA (hexylmethacrylate) 10 mmol (20 mol%) and SiMA ((trimethoxysilylpropyl) methacrylate) 10 mmol (20 mol%) were added to 30 mL of toluene and synthesized As an initiator, azobisisobutyronitile (AIBN) was dissolved in methanol and added for 30 minutes, followed by reaction at 80° C. for 12 hours to synthesize a polymer. Next, 5 mmol of methylaminopropyltrimethoxysilane (MAP3) and 5 mmol of NaOMe were added to pure methanol from which water was removed, and the total volume was adjusted to 5 mL, and then NO was added to 10 atm for 3 days with stirring in a reactor capable of withstanding up to 40 atm. It was charged and maintained to prepare NO-bound MAP3. A polymer solution was prepared so that the weight of the prepared polymer was 30 wt%, and the weight of the mixed solution of acetone and DMF (75% acetone, 25% DMF) was 70 wt%, and 1 g After extraction and mixing so that 85 mol% of the polymer, 12 mol% of MTMOS (methyltrimethoxysilane), and 3 mol% of NO conjugated MAP3 were mixed, 19 mg of aluminum acetylacetonate as a catalyst was mixed with acetone and DMF. (75% of acetone, 25% of DMF) was dissolved in 400 μL and 30 μL of deionized water, and then added to the solution to perform a sol-gel reaction. At this time, the reaction temperature was 4°C, the pH was 7, and the reaction time was 1 hour. The reaction proceeded with stirring.

5 mL of the solution was put into a syringe and nanofibers having a diameter of a nano level were prepared using an inner layer electrospinning equipment (NTSee (Gwangju), NT-ESS-300) as shown in FIG. 3A. . The conditions for electrospinning are as follows. The size of the needle was 25 G (0.25 mm in diameter), the distance between the needle and the aluminum plate was 15 cm, the voltage was 17.5 kV, and the discharge rate was 10 μL/min.

MMA, HMA, SiMA, MAP3, and MTMOS used in the above are all manufactured by Sigma-Aldrich (St. Louis, MO, USA).

(2) Preparation of the outer layer

TPU (Tecoflex polyurethane) (Fluka (Buchs, Switzerland), SG-80A) 10 wt% and a mixed solution of THF and DMF (THF 75%, DMF 25%) 90 wt% in a 20 mL vial, and shaker It was sufficiently dissolved for 12 hours to prepare a TPU polymer solution.

By putting the TPU polymer solution on the prepared inner layer in a 5 mL syringe and using the outer layer electrospinning equipment of the multi-nozzle as shown in FIG. 3B, nanofibers having a diameter of a nano level were prepared. Layer nanofibers were prepared. The conditions for electrospinning are as follows. The size of the needle was 25 G (0.25 mm in diameter), the distance between the needle and the aluminum plate was 15 cm, the voltage was 17.5 kV, and the discharge rate was 50 μL/min.

Example 2

In the manufacturing process of the outer layer, HPU (Tecophilic polyurethane) (Fluka (Buchs, Switzerland), SP-93A-100) 15 wt% and a mixed solution of THF and DMF (THF 75%, DMF 25%) 85 wt% A multi-layer nanofiber was prepared in the same manner as in Example 1, except that the mixture was mixed to prepare an HPU polymer solution.

Example 3

In the process of manufacturing the outer layer, PCL (Polycaprolactone) (Sigma-Aldrich (St. Louis, MO, USA)) 8 wt%, a mixed solution of chloroform and methanol (chloroform 75%, methanol 25%) 92 wt% A multilayer nanofiber was prepared in the same manner as in Example 1, except that the mixture was mixed to prepare a PCL polymer solution.

Example 4

In the manufacturing process of the outer layer, PVDF (poly(vinylidene fluoride) (Sigma-Aldrich (St. Louis, MO, USA)) 20 wt%, DMF and acetone mixed solution (DMF 66.66%, acetone 33.33%) 80 wt% A multilayer nanofiber was prepared in the same manner as in Example 1, except that the mixture was mixed to prepare a PVDF polymer solution.

<Characteristic evaluation of multi-layer nanofibers>

Contact angle Measure

In order to measure the contact angles of the inner layer and the multilayer nanofibers prepared in Examples 1 to 4, distilled water was dropped at any five points on the fiber surface, and a static contact angle was measured using a contact angle meter, and the measurement results were averaged. The results are shown in FIG. 4.

Looking at the results, the contact angle of the inner layer itself was 100°, and in Examples 1 and 3, when TPU and PCL were used as outer layers, they were 107° and 119°. On the other hand, in the case of the PVDF of Example 4, which is a hydrophobic polymer, the contact angle was significantly increased to 131 °. On the other hand, in the case of the HPU of Example 2, which is a hydrophilic polymer, the moment the distilled water is placed on the fiber surface, the water droplets permeate into the fiber, and the contact angle cannot be measured.

NO emission characteristics measurement

A flask containing PBS connected to a chemiluminescent NO analyzer (Sievers NOA 280i) of GE (Boulder, CO, USA) using the inner layer and multi-layer nanofibers prepared in Examples 1 to 4 to measure the emission characteristics of nitrogen monoxide And the generated NO is moved to NOA by argon, a carrier gas, so that the instantaneous maximum emission ([NO] _m ), total emission (t[NO]), half-life (t _1/2 ), maximum The time to reach release (t _m ) and the total release time (t _d ) were measured. The results are shown in Table 1 below. In addition, the change in the amount of release during the initial 1 hour and the amount of accumulated release over the total release time are shown in FIG.

division t[NO]
(μmolㆍ4 cm ^-2 ) t _1/2 (min) [NO] _m
(ppbㆍ4 cm ^-2 ) t _m (min) t _d (h) Inner layer 0.45 5 10700 2.5 30 Example 1 0.41 17 3600 5 44 Example 2 0.43 5.5 8800 2.8 26 Example 3 0.43 87 4500 2.7 38 Example 4 0.40 70 2500 4.5 62

Looking at the results, the total NO emission amount of the inner layer itself and the multilayer nanofibers of Examples 1 to 4 are similar. In the case of the multilayer nanofiber using the HPU polymer of Example 2, the half-life and total emission time did not show a significant difference from the inner layer. On the other hand, in the case of the multi-layer nanofibers using the TPU and PCL of Examples 1 and 3, it was confirmed that the half-life and total release time were delayed. In addition, in the case of the multi-layer nanofiber of Example 4 using the hydrophobic polymer PVDF, the half-life was 70 minutes and the total release time was 62 hours, compared with the case of the inner layer, the half-life was 14 times and the total release time was doubled. It showed over results. This is because due to the high hydrophobicity of PVDF, the outer layer protects the inner layer in which NO is stored from water, so that a small amount of NO could be slowly released over a long period of time. This can be confirmed by looking at the change in the amount of release during the initial 1 hour and the amount of accumulated release over the entire release time in FIG. 5. That is, in the case of Example 4, the instantaneous maximum emission amount ([NO] _m ) is the least, and it can be seen that NO is gradually released over the total emission time.

Therefore, the multi-layered nanofiber of the present invention can control the drug release characteristics according to the selection of the outer layer.

Measurement of tensile strength

The inner layer and multilayer nanofibers prepared in Examples 1 to 4 were mounted between clamps of a tensile strength analyzer (MTS (Minesota, USA), MTS 858), and were measured and averaged at a speed of 1 mm/sec. The results are shown in Table 2 and FIG. 6 below.

division Yield load (N) Elongation (%) Inner layer 0.7 One Example 1 4.6 192 Example 2 1.6 50 Example 3 > 7 > 230 Example 4 0.7 18

As a result, when compared to the inner layer itself, when HPU and PVDF of Examples 2 and 4 were used as outer layers, there was no significant difference in yield load. However, when the TPU and PCL were used as outer layers in Examples 1 and 3, the yield load increased, and in particular, the PCL of Example 3 showed significantly improved results in yield load and elongation. That is, according to the multi-layer nanofiber of the present invention, physical rigidity can be improved according to the selection of the outer layer.

Claims (9)

Multi-layer nano for storage and delivery of drugs including one or more inner layers containing nanofibers for storing one or more drugs and one or more outer layers containing polymeric nanofibers on one or both sides of the inner layer As a fiber,
At least one layer of the inner layer includes N- diazeniumdiolate nanofibers or S- nitrosothiol nanofibers,
At least one layer of the outer layer is poly(benzylmethacrylate), poly(tetra-fluoroethylene) (Poly(tetra-fluoroethylene)), poly(acrylonitrile-co-methylacrylate) ) (Poly(acrylonitrile-co-methylacrylate)), poly(vinylidene fluoride) (Poly(vinylidene fluoride) (PVDF)) and poly(vinylidene-fluoride-co-hexafluoropropylene) (Poly(vinylidene- Fluoride-co-hexafluoropropylene)) multi-layered nanofibers, characterized in that it comprises nanofibers made from one or more polymers selected from the group consisting of. In claim 1,
Each layer of the inner layer is a multi-layer nanofiber, characterized in that the nanofibers that store one or more kinds of drugs. In claim 1,
At least one layer of the outer layer is a multi-layer nanofiber comprising a nanofiber made from polyurethane (Polyurethane (PU)) or polycaprolactone (PCL). In claim 1,
At least one layer of the outer layer is polyacrylic acid (PAA), poly-L-lactide (PLLA)), poly(glycolic acid) (PGA)) , Poly(lactic-co-glycolic acid) (PLGA)), cellulose (Cellulose), collagen (Collagen), gelatin (Gelatin) and chitosan (Chitosan) selected from the group consisting of Multi-layer nanofiber, characterized in that it comprises nanofibers made from one or more polymers. In claim 1,
At least one layer of the outer layer is polyacrylonitrile (PAN), polyethylene oxide (PEO), polyethylene terephtalate (PET)), polymethacrylate (PMA)). , Polystyrene (PS) and polyvinylphenol (Polyvinylphenol (PVP)), characterized in that it comprises a nanofiber made from one or more polymers selected from the group consisting of. In claim 1,
The outer layer is located on both sides of the inner layer, and on one side of the inner layer, poly(benzylmethacrylate), poly(tetra-fluoroethylene) (Poly(tetra-fluoroethylene)), poly (Acrylonitrile-co-methylacrylate) (Poly(acrylonitrile-co-methylacrylate)), poly(vinylidene fluoride) (Poly(vinylidene fluoride) (PVDF)) and poly(vinylidene-fluoride-co- An outer layer containing nanofibers made from one or more polymers selected from the group consisting of hexafluoropropylene) (Poly(vinylidene-fluoride-co-hexafluoropropylene)) is located, and on the other side is polyurethane (Polyurethane (PU)). ) Or polycaprolactone (Polycaprolactone (PCL)) is a multi-layer nanofiber, characterized in that the outer layer comprising the nanofibers are located. In claim 1,
Wherein the outer layer is located on both sides of the inner layer, and the outer layer on both sides includes nanofibers made from the same polymer. In claim 1,
Wherein the outer layer is located on both sides of the inner layer, and the outer layer on both sides includes nanofibers made from different polymers. In any one of claims 1 to 8,
The nanofibers are multi-layered nanofibers, characterized in that electrospun.

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