KR101005079B1 - Biodegradable Nanofiber sheet for Anti-adhesion Membrane and Process for Preparing the Same - Google Patents

Abstract

The present invention relates to an anti-adhesion membrane in the form of a biodegradable nanofiber sheet capable of preventing adhesion of abnormal tissues, and in particular, a nanofiber formed by electrospinning using a bio-derived polymer called biogammaglutamic acid, a biodegradable polymer, and a hydrophilic polymer. The present invention relates to a sheet anti-adhesion film and a method of manufacturing the same. The nanofiber sheet of the present invention has a high specific surface area and is flexible and porous because of the nanoscale diameter of the fiber, and can easily adhere to the wound, rapid decomposition rate, and rapid release of the contained drug. Therefore, adhesion of tissues can be effectively prevented.

Tissue adhesion prevention, nanofiber, polygammaglutamic acid (γ-PGA), nonsteroidal anti-inflammatory agent, PLGA, PEO, biodegradable polymer, ibuprofen, electrospinning

Description

Biodegradable Nanofiber Sheet for Anti-Adhesion Membrane and its Manufacturing Method {Biodegradable Nanofiber sheet for Anti-adhesion Membrane and Process for Preparing the Same}

The present invention relates to an anti-adhesion film that can prevent abnormal adhesion of tissue, and more particularly, to a biodegradable anti-adhesion film in the form of a nanofiber sheet using an electrospinning method and a method of manufacturing the same.

Tissue adhesion refers to the combination of abnormal fibrous connective tissue with other tissues that may occur during the natural healing of wounds formed in the abdominal cavity after surgical open surgery. Tissue adhesion is one of the complications that have not yet been resolved in many modern medical procedures. Internal abdominal tissue and long term adhesion frequently occur after open surgery. Some of the adhesions spontaneously decompose, but in most cases, adhesion remains after wound healing, causing pain in patients with various sequelae. The causes of intestinal adhesions after surgery are known to be foreign substances introduced into the abdominal cavity, inflammatory reactions due to infection, tissue ischemia, blood coagulation, excessive tissue traction, tearing of the intestinal membrane, and coarse surgery. The perfect way to do this is currently unknown. According to the statistical data, such adhesion occurs in more than 93% of patients after laparotomy, according to the degree of adhesion, causing chronic pain in the patient, female infertility due to uterine and pelvic adhesions, and organ or tissue dysfunction. Re-surgery is needed to remove the skin, and sometimes it can be life-threatening.

Known anti-adhesion methods include, firstly, micro-surgical techniques to minimize wounds during laparotomy, or second, chemical methods such as anti-inflammatory agents, inhibitors of fibrin formation, anticoagulants, and protein hydrolysates. (Eg, t-PA), but some of the drugs have the disadvantage of causing side effects that delay the healing rate of the wound compared to the anti-adhesion effect. Third, apart from this, recently, a method of using a physical barrier to encapsulate or cover the wound after surgery is used to isolate it from surrounding tissues, and a lot of results have been reported that this method is very effective.

In situ cross-linkable hyaluronic acid (HA), a group that studied the possibility of adhesion prevention using a temperature-responsive polymer (PNIPAM-grafted hyaluronan / gelatin) as an example of using a physical barrier. hydrogel) and groups with autocrosslinked hyaluronan derivative gels, groups with UV cross-linked gelatin films, groups with polygalacturonic acid (PGA), collagen Group studying film / gel, SH / CMC and fibrin glue, sodium alginate (Alg), SCMC, polyethylene glycol-polypropylene glycol, PEG- PPG, Poloxamer) group, N, O-carboxymethyl chitosan group, PLLA (poly (L-lactic acid))-PEG diblock copolymer film (diblock copolyme) r film), chitosan-poloxamer gel complex, hyaluronic acid-carboxymethylcellulose film (Seprafilm®), dextran 40, fibrinogen ™ (Beriplast ™), etc. There have been many reports, including one group and the group using SCMC-heparin. In the previous studies on the prevention of adhesion using a physical barrier, many studies have shown that SCMC (sodium carboxymethyl cellulose) and hyaluronic acid as the main ingredients are effective in preventing adhesion, but the mechanism of prevention of adhesion is not known yet. Although celluloses and dextrans are natural polymers, they are known to cause foreign body reactions in vivo because they are not constituents of living organisms, and they are decomposed through oxidation and hydrolysis because they do not have degrading enzymes for these materials. It is known that it should be made. On the other hand, hyaluronic acid (USP 4,141,973) has a high degradation rate in vivo, so the shape barrier required for a certain period of time as a physical barrier is not satisfactory. Some of these anti-adhesion agents have been commercialized and attempts have been made to inhibit the formation of adhesions between organs and tissues after surgery, and currently oxidized regenerated cellulose (Interceed TC-7; Johnson and Johnson Medical Inc.), non-absorbable polytetra Fluoroethylene (polytetrafluoroethylene, PTFE, Gore-Tex; WL Gore Co.), sodium hyaluronate / carboxymethyl cellulose, Seprafilm, Genzyme Co., etc. are used. Neuro-tex® MANC NT (Textile Hi-Tech Co.) consisting of urethane is used as an anti-adhesion agent. However, products composed of synthetic polymers such as PTFE, polyester, and polyurethane are not decomposed in vivo, so they are not good for the human body in the long term. Recently, SprayGel ™ (SprayGel ™; Confluent Surgical Inc.) is attracting attention as an anti-adhesion film that is slowly decomposed and absorbed after the treatment is completed with PEG hydrogel. However, polyethylene glycol, which is a synthetic polymer, can be used only with a material having a small molecular weight. In this case, it is absorbed and discharged out of the body through metabolic pathways. However, it is difficult to control the duration as a barrier for preventing adhesion due to fast absorption.

On the other hand, conventional techniques for manufacturing nanofibers are known as complex spinning, melt blow spinning, flash spinning, electrospinning, etc., but considering the variety of applied polymers, simplicity of the manufacturing process, commercialization possibilities, and application to various technologies It is recognized as the most promising microfiber manufacturing technology. Recently, research on nano-technology (NT) has been conducted competitively around the world, especially in the United States. In particular, electrospinning method applies a high voltage to the polymer solution, and the polymer jet is ejected by evaporating the solvent, resulting in nanoscale As a spinning method to obtain a fiber having a diameter, it has a high specific surface area, porosity, high aspect ratio and flexibility, and it is easy to control the fiber diameter by controlling the spinning conditions. Nanofibers manufactured by electrospinning method can be applied to various fields such as reinforcing agent, membrane material for high efficiency filter, functional fiber, military supplies using antifouling function, wound dressing, drug delivery system (DDS), scaffold for tissue engineering It is recently attracting attention as a processing method for medical materials having high added value.

In general, the electrospinning system can be roughly divided into a solution supply part, a high voltage supply part, a collector part in which nanofibers are formed. In addition, the radiation environment (humidity, temperature) should be able to be maintained at optimum constant conditions. The solution supply part is composed of a syringe pump and a syringe (or nozzle) part for precisely discharging the solution at a constant speed, and can control the characteristics of the fiber according to the shape, diameter, and material of the syringe needle. The high voltage supply part controls the voltage and current with an insulated cable composed of a positive electrode which charges the polymer solution portion having a high dielectric constant and a negative electrode where the charged solution is collected in the form of nanofiber filaments. The collector portion in which the nanofibers are collected can adjust the arrangement of the nanofiber strands according to the design of its shape, movement, and speed, and also manufacture various materials according to the purpose. The type of material used for electrospinning is generally in a well-dissolved solution state and has a great influence on fiber formation depending on the solution characteristics of the polymer used for electrospinning. Such solution characteristics include concentration, viscosity, surface tension, Conductivity, dielectric properties, volatility, and the like. The concentration of the polymer solution is closely related to the viscosity. Since the viscosity is a measure of the entanglement and fluidity of the polymer chain, it is known as an important factor that affects the shape, diameter, and spraying speed of the fiber produced during electrospinning. have. Although there are differences depending on the polymer properties, it is reported that fibrosis can be achieved by having a viscosity of about 0.5-50 poise. Fibrosis does not occur when the viscosity is too high or too low. Electrospinning is a technique for producing fibers of several nm to several micrometers by radiating a large potential difference between charged polymer and grounded current collector plate by applying electrostatic force to the polymer solution or melt. It is a spinning technology that can be spun with a high spinning speed and small amount, obtains the form of nonwovens at the same time as spinning, and is easy to add additives.

Techniques for using nanofibers, especially nanofibers obtained by electrospinning polymer solutions, as physical barriers to prevent adhesion of tissues have been proposed. Benjamin Chu of the United States tried to make biodegradable nanofibers containing antibiotics based on PLGA, a commonly used material for tissue engineering, and to use it as a tissue adhesion prevention film. However, this technique suffers from severe shrinkage in aqueous solution when the main material PLGA is made of nanofiber sheet with hydrophobic polymer (Hongliang Jiang, Benjamin Chu, "Preparation and characterization of ibuprofen-loaded poly (lactide- co -glycolide). ) / poly (ethylene glycol) -g -chitosan electrospun membranes ", J. Biomater. Sci. Polymer Edn , Vol. 15. No. 3, 279-296 2004). In Korean Patent No. 10-0785378, a multi-layered structure consisting of a base layer of nanofiber structure formed by electrospinning a hydrophobic biodegradable and biocompatible polymer and a polymer layer formed by coating a hydrophilic bio-derived polymer on the surface of the base layer The anti-adhesion agent is described.

As described above, many studies have been made and new technologies have been proposed. However, the proposed technologies have their problems and limitations, and the anti-adhesion effect remains at 50-80%. In the United States alone, the cost of medical care for peritoneal and pelvic adhesions is estimated at $ 12 billion annually. In addition, currently used anti-adhesion coatings are a factor of increasing medical costs at a considerable cost. In Korea, research on anti-adhesion agents has not been actively carried out, so the total amount is dependent on imports, so the burden of medical expenses is greater.

Therefore, there is a need for the development of a new high performance anti-adhesion agent that can effectively prevent abnormal tissue adhesion. The present inventors prepared nanofiber sheets by electrospinning with polygamma glutamic acid (γ-PGA) as a main component and PLGA and ibuprofen in order to apply them as anti-adhesion films in the previous studies (Korea Polymer Society, 2007 spring). The method of spinning with PLGA mixed with poly gamma glutamic acid solves the problem that poly gamma glutamic acid is easily decomposed to moisture, maintains the shape of the fabric sheet and adjusts the decomposition time. In addition, PLGA (poly (lactic-co-glycolic acid) is a biocompatible, biodegradable polymer, but hydrophobic, and shrinks severely in culture.By blending with polygamma glutamic acid, PLGA solves the shrinkage problem. Since it is hydrophobic compared to polygamma glutamic acid, the nanofiber sheet blended with polygamma glutamic acid and PLGA has a surface suitable for cell proliferation, and thus it is not very effective in improving its function as an anti-adhesion membrane. In order to solve the problem of the study is to include PEO to increase the hydrophilicity.

The present invention is to solve the problems of the conventional anti-adhesion film as described above, the present invention to provide a nanofiber sheet that can be used as a new high-performance anti-adhesion film that can effectively prevent abnormal tissue adhesion. do.

Ideal conditions for the nanofiber sheet as a physical barrier to prevent tissue adhesion are as follows. First, there should be a surface property inherent to minimize adhesion, and second, the physical properties that cover the wound while physically maintaining the shape during the wound healing period, and then decomposes and absorbs properties. Third, as a medical material to be inserted into the living body, it must be biocompatible and nontoxic, and the degradation product must be safe because it is harmless to the human body. Fourth, it should be effective to reduce the wound healing time by reducing the inflammatory response of the wound. Fifth, lastly, the convenience of being flexible and well-adhesive is required so that it can be easily used in the surgical process. It is an object of the present invention to provide an ideal anti-adhesion film that satisfies the above conditions.

In particular, in the present invention, crosslinking problems of the nanofiber sheets using polygammaglutamic acid, hydrophobic problems of the nanofibers using PLGA, and even when the two are used together, surface properties are still undesirable as an anti-adhesion film. Its high hydrophilicity makes it easy for cell proliferation towards the anti-adhesion membrane and easily adheres to the wound area, and provides an ideal anti-adhesion membrane for rapid decomposition and rapid release of the drug. It aims to do it.

In addition, an object of the present invention is to provide a nanofiber sheet that can maintain the form as a physical barrier to completely block the wound area until the treatment of the wound is completed, and can be quickly decomposed thereafter.

It is also an object of the present invention to provide a nanofiber sheet having a desirable drug release behavior that can rapidly release the drug contained in the initial application and then maintain a constant concentration with continuous release.

In addition, an object of the present invention is to provide a method for producing a nanofiber sheet having the above characteristics by using a simple electrospinning process.

To this end, in the present invention, a nanofiber sheet suitable as an anti-adhesion film is formed by using an electrospinning method using polygamma glutamic acid, a biodegradable polymer, a biodegradable polymer, and a hydrophilic polymer as main components. The nanofiber sheet molded according to the present invention is composed of a material having safety and biodegradability to the human body and has a specific surface area, flexibility and porosity.

Specifically, in the present invention, 10 to 100 parts by weight of polygamma glutamic acid; Provided is a biodegradable nanofiber sheet obtained by electrospinning a mixed polymer solution including 10 to 100 parts by weight of a biodegradable polymer and 1 to 50 parts by weight of a hydrophilic polymer. The nanofiber sheet of the present invention has particularly the use of an anti-adhesion film. As used herein, the term "anti-adhesion membrane" means a membrane that functions as a physical barrier to prevent tissue adhesion.

In the present invention,

(a) 10 to 100 parts by weight of polygamma glutamic acid; 10 to 100 parts by weight of the biodegradable polymer; And dissolving 1-50 parts by weight of the hydrophilic polymer in a solvent to form a mixed polymer solution,

(b) The electrospinning conditions of the mixed polymer solution at a solution concentration of 0.1 to 50% by weight, a voltage of 5 to 100 kV, a discharge rate of the solution to 0.1 to 10 ml / h, a spinning distance of 3 to 50 cm, and a humidity of 1 to 30%. There is provided a method for producing a biodegradable nanofiber sheet comprising the step of electrospinning to obtain a nanofiber sheet.

In the present invention, by forming a nanofiber sheet consisting of three main components of γ-PGA / biodegradable polymer (PLGA) / hydrophilic polymer (PEO), it is necessary to use nanofibers prepared using polygamma glutamic acid alone as an anti-adhesion film. It can reduce the crosslinking process required, solve the hydrophobic problem of PLGA, and further increase the hydrophilicity can have the ideal conditions of the anti-adhesion film. In addition, by modifying the ratio of γ-PGA, PLGA, PEO it can effectively control the surface modification and decomposition rate of nanofibers.

The nanofiber sheet of the present invention has a very high specific surface area because the diameter of the fiber is nanoscale, it becomes a flexible, three-dimensional porous non-woven fabric structure can be easily adhered to the wound, quick decomposition rate, Release of the drug contained can also occur quickly.

Therefore, when the nanofiber sheet of the present invention is applied as an anti-adhesion film, it is biodegradable biocompatible polymer material such as polygamma glutamic acid, which is safe for the human body, and effectively prevents adhesion of wounds, It is a flexible, large surface area porous material that is easy to handle and controls biodegradation rate when applied after surgery, and the release behavior of drug is good, and non-steroidal anti-inflammatory agent is introduced into biodegradable nanofibers and then released to the wound area locally. It can also suppress the inflammatory response. Nanofiber sheet of the present invention applied as an anti-adhesion film can maximize the anti-adhesion effect of the tissue by the synergy of these functions.

Biodegradable nanofiber sheet of the present invention 10 to 100 parts by weight of bio-derived polymer; It contains 10-100 weight part of biocompatible polymers, and 1-50 weight part of hydrophilic polymers as a main component.

Bio-derived polymer constituting the biodegradable nanofiber sheet of the present invention should be safe for human body because there is little foreign body reaction in the human body and there is no toxicity of decomposition products during biodegradation. In the present invention, polygamma glutamic acid is used as the bio-derived polymer. Poly (gamma) glutamic acid (Poly (γ-glutamic acid), γ-PGA) is a viscous substance produced by the enzyme produced by Bacillus subtilis ( Bacillus subtilis ) during the fermentation process of Cheonggukjang. Polygamma glutamic acid is an amino acid polymer material in which the amino acid glutamic acid is linked to the γ-position (γ-peptide bond) and is non-toxic, completely biodegradable, hydrophilic and moisturizing anionic biopolymer. . The structural formula of the polygamma glutamic acid is represented by the following Chemical Formula 1. Polygamma glutamic acid is also an advanced bio-new material that is expected to be used in food, cosmetics, medicine, etc. as it is reported that it efficiently transports anti-cancer substances in the body and itself has anti-cancer activity (Makoto Ashiuchi, Kazuya Shimanouchi, Hisaaki). Nakamura, Tohru Kamei, Kenji Soda, Chung Park, Moon-Hee Sung and Haruo Misono, “Isolation of Bacillus subtilis (chungkookjang) , a poly-γ-glutamate producer with high genetic competence”, Appl.Microbiol Biotechnol. , Vol. 57 , 764-769, 2001) (Moon-Hee Sung, Chung Park, Chul-Joong Kim, Haryoung Poo, Kenji Soda, Makoto Ashiuchi, "Natural and Edible Biopolymer Poly-γ-glutamic Acid: Synthesis, Production, and Applications" , The Chemical Record , Vol. 5, 352-366, 2005).

In order to apply the anti-adhesion film, it is necessary to cover the wound completely, so hydrophobic surface property that can cause shrinkage is not desirable, and the hydrophilic surface property such as polygamma glutamic acid adheres well to the wound and covers the wound sufficiently. It is preferable because it can be. However, polygamma glutamic acid is very weak to moisture and is easily decomposed, so a crosslinking process is required. And since the decomposition rate can be adjusted according to the degree of crosslinking, there is an advantage that it can be applied to various fields depending on the use, but there is a problem that the selection of the crosslinking agent and the crosslinking method are difficult and the degree of crosslinking is not easy to control. Therefore, in the present invention, the form was maintained in a method of spinning with PLGA mixed well with polygamma glutamic acid, and the decomposition time was controlled.

As the biodegradable polymer constituting the biodegradable nanofiber sheet of the present invention, a polymer having excellent physical properties and biocompatible materials is used. In the anti-adhesion film of the present invention, the biodegradable polymer plays a role of improving the radioactivity, mechanical strength and stability of the polygamma glutamic acid, and plays a role of controlling the hydrophilicity of the prepared nanofiber nonwoven fabric surface. Such polymers include, for example, PH (poly (β-hydroxy butyrate)], PHBV (3-hydroxy butyrate-co-3-hydroxy valerate), PGA [poly (glycolic acid)], PLA [poly (lactic acid) ], PLGA (polylactic-co-glycolic acid), PCL [poly (ε-caprolactone)], polydioxanone, polyorthoester, polyanhydride, chitosan, Gelatin, silk, collagen, cellulose, alginic acid, hyaluronic acid, and the like. In the present invention, as the biodegradable polymer, PLGA (poly (lactic-co-glycolic acid)) or PCL (poly (ε-caprolactone)) may be preferably used, and more preferably PLGA.

PLGA is a FDA-approved biocompatible, biodegradable polymer commonly used in medical devices and biomaterials. The structural formula of PLGA is represented by the following formula (2). However, PLGA is basically a hydrophobic polymer, which is characterized by severe shrinkage in the culture medium, which is undesirable as an anti-adhesion film that must completely cover the wound. In the present invention, this shrinkage problem is solved by blending polygamma glutamic acid and PLGA together. In the present invention, the nanofiber sheet obtained by blending polygamma glutamic acid and PLGA together was effective in the form of an anti-adhesion film because hardly shrinkage occurred and no structural deformation of the support. However, since PLGA is more hydrophobic than polygamma glutamic acid, the nanofiber sheet blended with polygamma glutamic acid and PLGA has a problem of having a surface suitable for cell proliferation. Therefore, the present invention solves this problem by introducing PEO (polyethylene oxide), which is excellent in electroradioactivity and biocompatible and hydrophilic in addition to polygamma glutamic acid and PLGA.

The hydrophilic polymer constituting the biodegradable nanofiber sheet of the present invention is PEO (poly ethylene oxide), PVA (poly vinyl alcohol), chitosan (chitosan), gelatin (gelatin), silk (collagen), cellulose (cellulose), alginic acid and hyaluronic acid may be used alone or in combination. As the hydrophilic polymer, preferably, polyethylene oxide (PEO) or PVA may be used alone or in combination, and more preferably, PEO may be used.

PEO not only facilitates the blending of polygammaglutamic acid with PLGA, but also improves the radioactivity of the mixed solution, and above all, the hydrophilicity of PEO hydrophilizes the surface of the nanofiber sheet obtained by electrospinning while the wound heals. It inhibits cell proliferation towards the anti-adhesion membrane while maintaining the shape of the sheet and effectively allowing degradation to occur.

In the present invention, by forming a nanofiber sheet consisting of three main components of γ-PGA / biodegradable polymer (PLGA) / hydrophilic polymer (PEO), it is necessary to use nanofibers prepared using polygamma glutamic acid alone as an anti-adhesion film. It can reduce the crosslinking process required, solve the hydrophobic problem of PLGA, and further increase the hydrophilicity can have the ideal conditions of the anti-adhesion film. In addition, by modifying the ratio of γ-PGA, PLGA, PEO to effectively control the surface modification and degradation rate of nanofibers, it is expected that it can also act to reduce the hyperproliferation of fibrous connective tissue cells.

The anti-adhesion membrane of the present invention may further include drugs such as nonsteroidal anti-inflammatory agents, antibiotics, and anticancer agents.

Non-steroidal anti-inflammatory agents may preferably include non-steroidal anti-inflammatory drugs. Nonsteroidal anti-inflammatory agents include aspirin (acetyl salicylic acid); Ibuprofen; Naproxen; Sulindac; Diclofenac; Pyroxycam; Ketofurofen; Diflunisal; Nabumetone; Etodolak; Oxapurozin; Indomethacin; Tolmetin and the like may be used, and particularly preferably ibuprofen may be used. These nonsteroidal anti-inflammatory drugs can reduce the inflammatory response that can occur inside the abdominal cavity, thereby more effectively preventing adhesion formation.

Antibiotics include, preferably, penicillin; Streptomycin; Tetratracycline; Kanamycin; Chloramphenicol; Actinomysin; Ampicillin; Bacitracin; Gramicidin; Nalidixic acid; Neomycin; Nonactin; Norfloxacin; Patulin; Terramysin and the like can be used.

As an anticancer agent, Preferably, Nitrogen Mustard; Chlorambucil; Melphalan; Cyclophosphamide; Procarbazine; Mesotrexate (MTX); 6-mercaptopurine (6-MP); 6-Thioguanine; 5-fluorouracil; Cytarabine; Adriamycin; Daunorubicin; Bleomycin; Mitomycin-C; Actinomycin-D; Vincristine; Vinblastine; VP-16-213; VM-26; Cisplatin; o, p-DDD and the like may be used.

In the present invention, a nonsteroidal anti-inflammatory agent is contained in a nanofiber made of polygamma glutamic acid-PLGA-PEO using electrospinning. In this way, the drug contained in the nanofibers can be quickly and smoothly released in a small amount by using the large specific surface area, flexibility and porosity of the nanofibers. The content of nonsteroidal anti-inflammatory agents can be used within the dosage range of known drugs. In the case of ibuprofen, it can be preferably used in the range of 0.5 to 5% by weight of the solids content in the polygammaglutamic acid-PLGA-PEO mixed solution.

In the present invention, the electrospinning method was used as a film formation method. Conventional electrospinning systems and theories suggest that the electrospinning process should be performed under high voltage, and the air condition inside the chamber is also very important due to the nature of electrostatic spinning. As such, when nanofibers are manufactured by a general process, due to the electrostatic process characteristics sensitive to the environment (temperature, humidity) of the spinning chamber, microfibers of the nanofibers are changed and it is difficult to produce reproducible materials. In addition, because the process proceeds under high voltage, it causes electrical malfunction of the main pump, which wastes a lot of spinning process time and may cause an electric shock in close proximity. In addition, when volatile solvent accumulates in the chamber during spinning, it has a problem that may be harmful to humans and an explosion may occur. In particular, the bio-derived polymer is characterized in that the molecular weight is not as constant as the synthetic polymer, so the process parameters should be stabilized as much as possible when manufacturing nanofibers. Therefore, in the present invention, in order to maximize the reproducibility in the production of nanofibers, it is possible to stabilize the air conditions during electrospinning and to control the spinning conditions from the outside, and to prevent malfunction of the machine and damage to the human body. Use a radiation system. The configuration of the preferred electrospinning system used in the present invention is shown in FIG.

) mm, stainless steel)의 집전판 (collector)(4); 금속드럼의 회전속도 제어장치 (drum speed controller unit, 0∼176 rpm)(도시되지 않음); 고분자용액을 일정한 유량 (volume) 및 유체속도 (flow rate)로 제어하는 주사기펌프 (syringe pump, KDS220, KD Scientific Inc.)(5); 주사기 (Hamilton81620 gastight syringe, 10.0 ㎖, USA)(2), 금속 주사기바늘 (Hamilton91022 metal hub needle, 22 Guage [length: 50.8 mm, inner diameter: 0.41 mm], USA), 디지털 온/습도계 (JB913R, Oregon scientific Inc., USA) 등을 포함한다. 이렇게 설계된 본 발명의 전기방사시스템 은 주사기펌프와 용액 토출 장치가 긴 피스톤(1)으로 연결되어 챔버 외부에서 밀어주는 방식이므로, 고전압 하에서 발생하는 기계의 오작동 및 인체에 대한 위험을 줄여줄 수 있다. 또, 주사기 고정대(3)가 있어 용액토출장치(주사기)를 고정할 수 있고, 높이(상하) 및 거리조절(좌우)이 가능하다. 이밖에도 본 발명의 전기방사시스템은 챔버내의 환경을 전기방사에 최적조건으로 유지하기 위해 습도조절용 에어컨(6), 용매 휘발 및 섬유화 촉진용 전열기(8), 휘발성 용매를 제거하기 위한 배기시스템(7) 등을 포함하여 재현성있고 안정적인 전기방사가 가능하게 한다. The electrospinning system shown in FIG. 1 includes a DC high voltage generator capable of supplying a voltage of 0 to 40 kV (DC High Voltage Generator [40 kV / 3 mA], Chungpa EMT Co.) (not shown); Plate type support jack, 200 x 200 mm, stainless steel (not shown) or rotating drum (metal drum, 400 (w) x 216 (

) mm, stainless steel collector (4); Drum speed controller unit (0 to 176 rpm) (not shown); A syringe pump (KDS220, KD Scientific Inc.) 5, which controls the polymer solution at a constant volume and flow rate; Hamilton81620 gastight syringe, 10.0 ml, USA (2), Hamilton91022 metal hub needle, 22 Guage [length: 50.8 mm, inner diameter: 0.41 mm], USA, digital temperature / hygrometer (JB913R, Oregon scientific Inc., USA). The electrospinning system of the present invention designed in this way is connected to the syringe pump and the solution discharging device by a long piston (1) to push the outside of the chamber, thereby reducing the risk of malfunction and human body of the machine occurring under high voltage. Moreover, there is a syringe holder 3 to fix the solution dispensing apparatus (syringe), and height (up and down) and distance adjustment (left and right) are possible. In addition, the electrospinning system of the present invention is a humidity control air conditioner (6), a solvent volatilization and fibrosis promoting heater (8), exhaust system (7) for removing volatile solvent in order to maintain the environment in the chamber to the best conditions for electrospinning It enables reproducible and stable electrospinning.

Hereinafter, the production method of the anti-adhesion film of the present invention will be described. The anti-adhesion film of the present invention comprises the steps of (a) dissolving polygammaglutamic acid, biodegradable polymers and hydrophilic polymers in a solvent to form a mixed polymer solution, and (b) electrospinning the mixed polymer solution to obtain a nanofiber sheet. It is molded into a non-woven thin film made of a fiber having a nanoscale diameter. Preferably, the method may further include adding a nonsteroidal anti-inflammatory drug to the mixed polymer solution prior to electrospinning.

For electrospinning, the polymers must be uniformly dissolved in a solvent. As a solvent for dissolving the polymer, ie, polygammaglutamic acid, biodegradable polymer and hydrophilic polymer, respectively or together, alkaline water, trifluoro acetic acid (TFA), dimethyl formamide, dimethyl sulfoxide sulfoxide, TFE (trifluoro ethylene), acetone (acetone), hexafluorofluoro isopropanol (HFIP), methylene chloride (MC), tetrahydrofuran (THF), acetic acid, and formic acid Or a mixture of two or more may be used. More preferably, TFA having high spinnability is used as the solvent. The dissolving method is to prepare a polygamma glutamic acid solution by first dissolving polygamma glutamic acid in a solvent, and then adding a biodegradable polymer and a hydrophilic polymer, or polygamma glutamic acid, a biodegradable polymer, and a hydrophilic polymer, respectively. The method of mixing after melt | dissolving in a solvent can be used. In this case, in order to make a uniform solution state, the solution is stirred for 1 to 24 hours in a constant temperature bath at 20 ° C. to 90 ° C. to be completely dissolved to avoid impurities, and stirred at room temperature for about 24 hours, and then used for electrospinning.

The electrospinning preferably uses a flat plate collector plate or a rotating drum collector plate fixed using the electrospinning device shown in FIG. In the present invention, after fabricating each nanofiber sheet according to the concentration of the solution, applied voltage, spinning distance, fluid velocity, the shape of the current collector plate, humidity, etc., which have an important effect on the fiber form of various process factors after analyzing the structure and shape Electrospinning conditions with the best reproducibility were obtained and applied. In the present invention, electrospinning is preferably performed at a concentration of 0.1-50% by weight of the mixed solution, a voltage of 5-100 kV, a discharge rate of 0.1-10 ml / h of the solution, a spinning distance of 3-50 cm and a humidity of 1-30%. Carry out under electrospinning conditions.

The nanofiber sheet of the present invention, obtained by electrospinning a mixed solution of polygammaglutamic acid / PLGA / PEO, has a very high specific surface area and has a flexible, three-dimensional porous nonwoven fabric structure because the diameter of the fiber is nanoscale. do. Since the nanofiber sheet (anti-adhesion film) of the present invention is such a structure, it can be easily adhered to the wound site, the decomposition rate is fast, and the release of the contained drug can also be made quickly. The average diameter of the nanofibers produced in the present invention is preferably 10 to 2000 nm.

The nanofiber sheet of the present invention may be used as a wound treatment coating material and tissue engineering scaffold in addition to being used as an anti-adhesion film.

In the present invention, in vitro biodegradation behavior experiment was conducted to confirm the availability and effect of the prepared nanofiber sheet as an anti-adhesion film. Some of the conventional anti-adhesion films have a disadvantage in that the decomposition rate is too fast to be absorbed before treatment is completed or the decomposition rate is too long to cause a foreign body reaction. In general, the anti-adhesion film is most preferably blocked completely before the treatment is completed, and then decomposed and absorbed into the living body. Usually, since the wound healing period takes about 7 days after surgery, it can be said that from this point of view, the anti-adhesion film is most preferably decomposed about 7 days. As confirmed by the following experimental example, the nanofiber sheet (anti-adhesion film) of the present invention was decomposed about 7 days and was found to be the most preferable among the materials under test.

In addition, in the present invention, the in vitro drug release behavior analysis experiment was carried out to confirm the release rate and duration of the drug of the drug contained in the nanofiber sheet. Usually, the time required for tissue adhesion mechanism after surgery is less than 3 days, and the duration of treatment is known to be about 7 days. The mechanism reveals the release of plasma fibrin (serofibrinous exudate) around the wound or inflamed area, fibrin deposits, and adhesion to other surrounding tissues within three hours to form a fibrin matrix. Normally, the fibrin matrix thus formed disappears within a few days by being decomposed and absorbed by proteolytic enzymes in vivo, but most of the fibrin matrix is excessively generated and accumulated beyond the tissue's self-degrading ability, and is accumulated around wounds and adheres to surrounding tissues. It causes adhesion in the body. Adhesion occurs due to the balance of a series of fibronogenesis and fibronosis. That is, in order to effectively prevent adhesion, most of the drug introduced before 3 days should be released to the wound area, and the drug must be released quickly to suppress the inflammatory response at an early stage. From this point of view, the nanofiber sheet containing the drug of the present invention exhibited the most desirable drug release behavior among the tested materials.

[Example]

Hereinafter, the present invention will be described in more detail with reference to specific examples and experimental examples. However, these Examples and Experimental Examples are only for illustrating the present invention more specifically, and the scope of the present invention is not limited by these Examples and Experimental Examples.

Example 1

Preparation of Polygamma Glutamic Acid Nanofiber Sheet

In order to prepare a nanofiber sheet containing poly gamma glutamic acid as a main component, a uniform γ-PGA-TFA 10 wt% solution was prepared and electrospun. Other process factors were fixed at a voltage of 16 kV, a spinning distance of 18 cm, a fluid velocity of 1 ml / h, spinning for 10 hours at a drum collector (20 rpm = 13.56 m / min), and maintaining humidity at 30% or less. It was. Thereafter, in order to prevent hydrolysis of γ-PGA nanofibers by moisture present in the air, the recovered nanofiber sheets were cut to about 7 x 7 cm in size and immediately immersed in a crosslinking solution and sealed for 10 hours to crosslink. The cross-linking solution used was a mixture of hexamethylene diisocyanate (HMDI, Fluka) and isopropanol (HPLC grade, Sigma) at a ratio of 1:99 v / v%. At this time, if the crosslinking degree of the nanofibers is too high, it will become loose, so in order to prevent this, it is preferable to use a crosslinking solution having a mixing ratio of 1:99 v / v% of hexamethylene diisocyanate and isopropanol. When the crosslinking of the nanofiber sheet having suitable flexibility and physical properties as the anti-adhesion film was completed, the resultant was dried in a vacuum oven at 35 ° C. for 5 hours in order to remove the remaining solvent and the crosslinking solution. The nanofiber sheet removed from the aluminum foil was finally dehumidified after sterilization for about 1 hour in a UV-sterilizer (VS-950M, Vision scientific Co. Ltd.). The result of observing the prepared nanofiber nonwoven fabric by using an electron microscope is shown in FIG. 2.

Example 2

Preparation of Polygamma Glutamic Acid / PLGA Nanofiber Sheet

Nanofibers were prepared in which PLGA was mixed with polygammaglutamic acid. First, a uniform γ-PGA / PLGA (1: 1) -TFA 10 wt% solution was prepared, sufficiently stirred, and electrospun. The process factors were fixed at a voltage of 16 kV, a spinning distance of 20 cm, a fluid velocity of 1 ml / h, and spun at a drum collector (20 rpm) for 10 hours, and kept at a humidity of 30% or less. Thereafter, in order to remove the residual solvent contained in the sheet, it was sufficiently dried in a vacuum oven at 35 ° C. for 3 hours. The pure nanofiber sheet removed from the aluminum foil was sealed and dehumidified. The result of observing the prepared nanofiber nonwoven fabric by magnifying through an electron microscope is shown in FIG. 2.

Example 3

Preparation of Polygamma Glutamic Acid / PLGA / PEO Nanofiber Sheets

A solution of PLGA and PEO in polygamma glutamic acid was prepared as nanofibers through electrospinning. First, a uniform γ-PGA / PLGA / PEO (4.5: 4.5: 1) -TFA 12 wt% solution was prepared, sufficiently stirred and then electrospun. The process factors were fixed at a voltage of 17 kV, a spinning distance of 17 cm, a fluid velocity of 1 ml / h, and spun at a drum collector (20 rpm) for 10 hours, and kept at a humidity of 30% or less. Thereafter, in order to remove the residual solvent contained in the sheet, it was sufficiently dried in a vacuum oven at 35 ° C. for 3 hours. The pure nanofiber sheet removed from the aluminum foil was sealed and dehumidified. As a result of observing the nanofiber nonwoven fabric prepared above through an electron microscope, it was confirmed that the nanofiber aggregate is porous and has a diameter of about 400 to 600 nm (FIG. 2).

Comparative Example 1

Preparation of PLGA Nanofiber Sheets

In order to manufacture nanofiber sheets using PLGA, which is widely known as a biodegradable / biocompatible copolymer and has been approved by the Food and Drug Administration (FDA) for medical use, a uniform PLGA-HFIP 6 wt% solution is first prepared and then reproducible conditions are used. Electrospinning at The process factors were fixed at a voltage of 15 kV, a spinning distance of 19 cm, a fluid velocity of 1 ml / h, and spun onto a plate collector for 5 hours. Thereafter, in order to remove the residual solvent contained in the sheet, it was sufficiently dried in a vacuum oven at 35 ° C. for 3 hours. The pure nanofiber sheet removed from the aluminum foil was sealed and dehumidified. The result of observing the prepared nanofiber nonwoven fabric by magnifying through an electron microscope is shown in FIG. 2.

Example 4

Preparation of Nanofiber Sheets Incorporating Ibuprofen

In order to prepare a tissue adhesion preventing film in which ibuprofen was introduced into biodegradable nanofibers containing polygammaglutamic acid, a solution was prepared in the same manner as in the above-described solutions of Examples 1, 2, 3 and Comparative Example 1 Ibuprofen (2 wt% of solid content) was added, mixed uniformly and electrospun. There was no adjustment of the electrospinning conditions due to the mixing of ibuprofen, and subsequent production processes were carried out in the same manner as in Examples 1 to 3. The prepared nanofiber nonwoven fabric was observed in an enlarged view through an electron microscope in FIG. 2.

Electron micrographs of the various nanofiber sheets made in Examples 1 to 4 and Comparative Example 1 are as shown in FIG. 2. Adhesion prevention films, sponges, hydrogels, etc., which are proposed as conventional physical barriers, are difficult to control decomposition and drug release rates, but the nanofiber sheets of the present invention prepared in Examples 3 and 4 have a very high diameter because the diameter of the fibers is nanoscale. It has a specific surface area, and is a flexible, three-dimensional porous nonwoven fabric, so that the decomposition rate and drug release are quick and easily adhered to the wound.

Experimental Example 1

Water contact angle measurement of various nanofiber sheets

Water contact angle was measured to analyze the surface properties of the prepared nanofiber sheet. Water contact angle measurements are used as an important measure to assess the wettability or degree of hydrophilicity / hydrophobicity of solid surfaces. As shown in FIG. 3, the ibuprofen-introduced group was relatively hydrophilic. The polygamma glutamic acid nanofiber sheet in which ibuprofen was introduced initially showed hydrophobic surface properties but showed hydrophilic surface properties with time. This is considered to contain ibuprofen which improves hydrophilicity. γ-PGA and PLGA showed relatively hydrophobic surface properties, and despite the introduction of ibuprofen, PLGA- ibuprofen nanofiber sheets showed relatively hydrophobic surface properties even after elapse of time.

Experimental Example 2

Analysis of Ibuprofen in Polygammaglutamic Acid Nanofibers

Very small amount of ibuprofen contained in the nanofiber sheet was analyzed using FTIR (FT / IR-460 plus, JASCO, Japan). As a result, it was confirmed that the polygamma glutamic acid nanofibers introduced with ibuprofen as shown in Figure 4 has all the characteristic peaks observed in ibuprofen and polygammaglutamic acid, so that it is included.

Experimental Example 3

In vitro  Biodegradation Behavior Experiment

In order to analyze the biodegradation behavior of the various biodegradable nanofibers prepared in the above Examples and Comparative Examples, the prepared nanofiber sheet was prepared in a size of 1 x 1 cm, and then fixed on the bottom of a 24well tissue culture plate, followed by 1 mL phosphate buffered saline. (phosphate buffered saline, PBS; pH 7.4) and incubator (MCO-15AC (164L), 37 ° C, 5% CO ₂ , SANYO, Japan) time-lapse (3h, 9h, 1d, 3d, 5d, 7d, 9d) , 11d, 14d, 17d, 21d, 28d, 35d) , the morphological changes, shrinkage and biodegradation behavior of the fibers were observed. The results are shown in FIG. Polygammaglutamic acid / PLGA / PEO nanofibers containing ibuprofen together with polygammaglutamic acid nanofibers showed a high degradation rate around 7 days, while other nanofibers had a relatively low degradation rate, especially PLGA nanofibers (Comparative Example 1). In the case of, significant contraction occurred even after 1 day.

Some of the conventional anti-adhesion films have a disadvantage in that the decomposition rate is too fast to be absorbed before treatment is completed or the decomposition rate is too long to cause a foreign body reaction. In general, the anti-adhesion film is most preferably blocked completely before the treatment is completed, and then decomposed and absorbed into the living body. Since wound healing usually takes about 7 days after surgical operation, it is most efficient to decompose around 7 days, such as polygammaglutamic acid / PLGA / PEO nanofiber sheet containing ibuprofen of the present invention. have.

Experimental Example 4

In vitro  Drug Release Behavior Analysis

In order to investigate the release behavior of the nonsteroidal anti-inflammatory agent (Ibuprofen) contained in the surface and inside of the nanofibers prepared in Examples and Comparative Examples, put the prepared specimen (2 x 2 cm) in a vial and 10 mL PBS solution After the injection, the drug release behavior was analyzed over time in a thermostat (37 ℃). The results are shown in FIG.

It was confirmed that γ-PGA / PLGA / PEO-Ibuprofen nanofibers of the present invention were released about 80% of ibuprofen after one day and released more than 85% around one week. On the other hand, γ-PGA / PLGA-Ibuprofen and PLGA-Ibuprofen nanofibers had a slight release of drug until the first 7 days, and since the release was slightly increased, less than 30% of the drug was released even after 35 days. It was confirmed. This is thought to be a slow release rate of the drug, as seen in the biodegradation behavior of PLGA, after one month, the erosion of nanofibers occurs visually. Usually, the time required for tissue adhesion mechanism after surgery is less than 3 days, and the treatment period is known to be about 7 days. The mechanism reveals the release of plasma fibrin (serofibrinous exudate) around the wound or inflamed area, fibrin deposits, and adhesion to other surrounding tissues within three hours to form a fibrin matrix. Normally, the fibrin matrix thus formed disappears within a few days by being decomposed and absorbed by proteolytic enzymes in vivo, but most of the fibrin matrix is excessively generated and accumulated beyond the tissue's self-degrading ability, and is accumulated around wounds and adheres to surrounding tissues. It causes adhesion in the body. Adhesion occurs due to the balance of a series of fibronogenesis and fibronosis. Therefore, in order to effectively prevent adhesion, most of the drug introduced before 3 days should be released to the wound area, and the drug should be controlled to release the drug so as to suppress the inflammatory response at an early stage. From this point of view, the γ-PGA / PLGA / PEO-Ibuprofen nanofiber sheet of the present invention showed the most effective drug release behavior to be applied as a tissue adhesion prevention film.

Experimental Example 5

Comparison of Cell Proliferation on the Surface of Nanofiber Sheets

Investigation of cell adhesion and proliferation behavior in various nanofiber sheets prepared in Examples and Comparative Examples was carried out by culturing fibroblasts to examine their potential as anti-tissue adhesion membranes before applying them to animal experiments. Analyzed. The results are shown in FIG. When cell culture was performed using the γ-PGA / PLGA / PEO and γ-PGA / PLGA / PEO-ibuprofen nanofibers of the present invention as a support, cell proliferation was significantly lower than that of other supports. This is because the hydrophilic γ-PGA and PEO absorb water during cultivation to change into a soft membrane like hydrogel to provide a form as a support, but also to prevent cells from growing into the support. On the other hand, when γ-PGA / PLGA and γ-PGA / PLGA-ibuprofen nanofibers were used as a support, cell proliferation was active. The γ-PGA / PLGA sheet showed the best growth of the cells by providing biocompatibility and sufficient cell proliferation space because shrinkage did not occur and structural support of the support did not occur as observed in the biodegradation experiment. In the PLGA and PLGA-ibuprofen nanofibers, the cell proliferation rate was relatively low because the PLGA is basically a hydrophobic polymer and severely contracts in the culture medium, which may be due to the reduced space required for the cell proliferation. .

These results suggest that PLGA sheets may not be able to completely cover the peritoneal wound due to severe contraction or to be peeled off to one side, making them unsuitable as a tissue adhesion barrier. On the other hand, when the γ-PGA / PLGA / PEO-Ibuprofen nanofiber sheet of the present invention is used as a tissue adhesion prevention film, not only the crosslinking process necessary for using the sole polygamma glutamic acid nanofibers as adhesion prevention film can be reduced. By varying the ratios of γ-PGA, PLGA, and PEO, it was expected to effectively control the surface modification and degradation rate of nanofibers, thereby reducing the overproliferation of fibrous connective tissue cells.

Experimental Example 6

Investigation of efficiency of tissue adhesion prevention through animal experiment

In order to evaluate the anti-adhesion effect of the biodegradable nanofiber sheet containing polygamma glutamic acid in the above Examples and Comparative Examples, outbred male Sprague Dawley rats were used as the test subjects. Adapted in the laboratory for 3 days prior to surgery, Rett applied 30 animals of 8 weeks of age (weight: 230-280 g) to animal experiments in healthy condition. Animal experiments were carried out by Reven Kennedy, Darren J. Costain, Vivian C. MeAlister and Timothy DG Lee, "Prevention of experimental postoperative peritoneal adhesions by N, O-carboxymethyl chitosan", Surgery , Vol. 120, No. 5, 866-870, 1996), scraping the inner peritoneum of the rat with a knife to injure it, and rubbing the vein of the adjacent appendix with sandpaper to peel it off, inducing bleeding and artificially creating conditions that can easily cause adhesion. (Fig. 8). As a control group, mice in which the anti-adhesion membrane was not inserted and the experimental groups in which the anti-adhesion membrane was inserted were examined after 4 weeks in the state of adhesion, depth and anti-adhesion effect. As a control of the experiment, rats that did not insert the anti-adhesion membrane and the experimental groups were inserted into the abdomen and the peritoneum after 4 weeks after the operation were completed. Investigation of depth and anti-adhesion effect and experimental method of Vlahos (Angie Vlahos, Pingyang Yu, Charles E. Lucas, Anna M. Ledgerwood, "Effect of a composite membrane of chitosan and poloxamer gel on postoperative adhesive interations", The American Surgeon , The degree of adhesion was assessed according to Vol. 67, 15-21, 2001). The measured values in each experiment were expressed as mean ± SD, and the comparison of each group was tested by one-way analysis of variance test and p <0.05 was considered significant. The results are shown in Table 1.

In the control group, the degree of adhesion was mostly 4 or 5, and the average degree of adhesion was 2.33. On the other hand, the degree of adhesion of the experimental group incorporating γ-PGA / PLGA / PEO and γ-PGA / PLGA / PEO-Ibuprofen nanofiber sheets showed 1.32 and 0.87. This results from the improvement of the wound healing effect by the biocompatibility and hydrophilicity of the polygamma glutamic acid having the ideal properties derived from the bio-derived, which indicates that the nanofiber sheet of the present invention effectively serves as a physical barrier during the treatment of wounds. It is working. In addition, it was found that the degree of adhesion is somewhat reduced by introducing ibuprofen. On the other hand, the degree of adhesion of the experimental group in which the γ-PGA / PLGA and γ-PGA / PLGA-Ibuprofen nanofiber sheets were introduced was about 2.13 and 2. Although the degree of adhesion was lower than that of the control group, it showed the highest value among the experimental groups. When γ-PGA alone was used to produce nanofibers by blending PLGA with nanoparticles, the physical properties of nanofiber sheets were improved by supplementing the decomposition by moisture, but they were much more effective in improving the function as anti-adhesion agent. It did not work. The degree of adhesion of the experimental group with PLGA and PLGA-Ibuprofen nanofiber sheets was 1.38 and 1.13, respectively. In this case, due to the shrinkage of the nanofiber sheet due to PLGA's inherent hydrophobicity, it is thought that coalescence was formed because the contact surface with the wound could not be completely covered and the adhesion preventing film did not function properly. As shown in FIG. 10, the rats of the control group were heavily adherent to the cecum and abdominal wall, whereas the polygammaglutamic acid / PLGA / PEO group introduced with ibuprofen showed a cleanly treated abdominal wall.

From the above results, it could be confirmed through animal experiments that γ-PGA / PLGA / PEO-ibuprofen nanofiber sheet had the most anti-adhesion effect. In addition, in order to utilize as an anti-adhesion film, it was confirmed that the nanofiber sheet having a biocompatibility and hydrophilicity should be rapidly decomposed after improving the wound healing effect between the cecum and abdominal wall.

In the previous test results, the polygamma glutamic acid nanofiber sheet containing ibuprofen was the most excellent anti-adhesion effect, but the polygamma glutamic acid nanofiber sheet without crosslinking process was weak in moisture and was finally evaluated as inappropriate for use as an anti-adhesion film. In addition, the nanofiber sheet hybridized with polygamma glutamic acid and PLGA has improved physical properties, but due to the influence of PLGA, which is hydrophobic compared to polygamma glutamic acid, the nanofiber sheet is modified to a surface where cell proliferation can occur smoothly and functions as an anti-adhesion film. It did not have much effect on further improving.

The specific parts of the present invention have been described in detail, and for those skilled in the art to which the present invention pertains, these specific descriptions are merely preferred embodiments, and the scope of the present invention is not limited thereto. Will be obvious. Therefore, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Nanofiber sheet of the present invention is excellent in the anti-adhesion effect compared to the conventional anti-adhesion film can be usefully used in the art as a new high-performance anti-adhesion agent, as well as a coating material for wound treatment and scaffolds for tissue engineering, etc. It can be used for various medical or non-medical purposes that require such physical properties.

1 is a block diagram of an electrospinning system designed in the present invention.

Figure 2 is an electron micrograph showing the surface shape and the average diameter of the various nanofiber sheets prepared in Examples and Comparative Examples.

Figure 3 shows the results of measuring the water contact angle of the various nanofiber sheets prepared in Examples and Comparative Examples.

4 is an FTIR graph of a polygamma glutamic acid sheet containing ibuprofen.

Figure 5 is a photograph showing the results of biodegradation behavior of the nanofiber sheets prepared in Examples and Comparative Examples.

Figure 6 is a graph showing the drug release behavior over time of the nanofiber sheet prepared in Examples and Comparative Examples.

7 is a graph showing the results of MTT analysis in each nanofiber sheet.

FIG. 8 is an animal test procedure of abdominal wall injuries and the subepilateral friction model.

9 is a photograph of the abdominal wall after the formation of adhesion and treatment.

  <Description of the symbols for the main parts of the drawings>

    1: Piston of non-conductive material 2: Electrospinning syringe

    3: syringe holder 4: current collector plate of rotating drum type

    5: syringe pump 6: air conditioner (dehumidification function)

    7: Ventilation hole 8: Heater (solvent volatilization promotion)

Claims (11)

10 to 100 parts by weight of poly gamma glutamic acid; Biodegradable nanofiber sheet obtained by electrospinning a mixed polymer solution containing 10 to 100 parts by weight of biodegradable polymer and 1 to 50 parts by weight of hydrophilic polymer. The method of claim 1, wherein the biodegradable polymer is PHB [poly (β-hydroxy butyrate)]; 3-hydroxy butyrate-co-3-hydroxy valerate (PHBV); Poly (glycolic acid) [PGA]; PLA [poly (lactic acid)]; Polylactic-co-glycolic acid (PLGA); PCL [poly (ε-caprolactone)]; Polydioxanone; Polyorthoesters; Polyanhydrides; Chitosan; Gelatin; Silk; Collagen; Cellulose; A biodegradable nanofiber sheet selected from the group consisting of alginic acid and hyaluronic acid. The method of claim 1, wherein the hydrophilic polymer is PEO (polyethylene oxide); Polyvinyl alcohol (PVA); chitosan; Gelatin; Silk; Collagen; Cellulose; A biodegradable nanofiber sheet selected from the group consisting of alginic acid and hyaluronic acid. The biodegradable nanofiber sheet of any one of claims 1 to 3, wherein the mixed polymer solution further comprises a drug. According to claim 4, wherein the drug is aspirin (acetyl salicylic acid); Ibuprofen; Naproxen; Sulindac; Diclofenac; Pyroxycam; Ketofurofen; Diflunisal; Nabumetone; Etodolak; Oxapurozin; A biodegradable nanofiber sheet which is a nonsteroidal anti-inflammatory agent selected from the group consisting of indometh-acin and tolmetin. The method of claim 4, wherein the drug comprises penicillin; Streptomycin; Tetratracycline; Kanamycin; Chloramphenicol; Actinomysin; Ampicillin; Bacitracin; Gramicidin; Nalidixic acid; Neomycin; Nonactin; Norfloxacin; A biodegradable nanofiber sheet, which is an antibiotic selected from the group consisting of patulin and teramycin. The method of claim 4, wherein the drug comprises: nitrogen mustard; Chlorambucil; Melphalan; Cyclophosphamide; Procarbazine; Mesotrexate (MTX); 6-mercaptopurine (6-MP); 6-Thioguanine; 5-fluorouracil; Cytarabine; Adriamycin; Daunorubicin; Bleomycin; Mitomycin-C; Actinomycin-D; Vincristine; Vinblastine; VP-16-213; VM-26; A biodegradable nanofiber sheet which is an anticancer agent selected from the group consisting of cisplatin and o, p-DDD. The biodegradable nanofiber sheet according to claim 1, wherein an average diameter of the fiber cross section is 10 to 2000 nm. The biodegradable nanofiber sheet according to claim 1, wherein the biodegradable nanofiber sheet has any one of an anti-adhesion film, a wound treatment coating material, and a tissue engineering scaffold. (a) 10 to 100 parts by weight of polygamma glutamic acid; 10 to 100 parts by weight of the biodegradable polymer; And dissolving 1-50 parts by weight of the hydrophilic polymer in a solvent to form a mixed polymer solution, (b) The electrospinning conditions of the mixed polymer solution at a solution concentration of 0.1 to 50% by weight, a voltage of 5 to 100 kV, a discharge rate of the solution to 0.1 to 10 ml / h, a spinning distance of 3 to 50 cm, and a humidity of 1 to 30%. Method of producing a biodegradable nanofiber sheet comprising the step of electrospinning to obtain a nanofiber sheet. The method of claim 10, wherein the solvent is alkaline water; Trifluoro acetic acid (TFA); Dimethyl formamide; Dimethyl sulfoxide; Trifluoro ethylene (TFE); Acetone; Hexa fluoro isopropanol (HFIP); Methylene chloride (MC); Tetra hydro furan (THF); Method for producing a biodegradable nanofiber sheet is one or two or more mixed solvents selected from the group consisting of acetic acid and formic acid.

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