KR20050045113A - Anti-adhesion agent with gas bubble - Google Patents

Abstract

The present invention relates to an anti-adhesion agent comprising a bubble, and more particularly, a structure comprising a bubble derived from a bio-derived polymer and / or a non-living-derived biocompatible polymer and / or a derivative thereof as a main component and swelling in water. It relates to a porous material for preventing adhesion. The anti-adhesion porous material according to the present invention minimizes the foreign body reaction using bio-derived or non-bio-derived biocompatible materials, improves the physical barrier role by manufacturing a bubble-containing structure, and stays in the body for a certain time. It is completely decomposed and absorbed, and does not prevent the wound from being healed after surgery, and has an effect of providing maximum convenience when applied to the surgical site.

Description

Anti-adhesion agent containing air bubbles {Anti-adhesion agent with gas bubble}

The present invention relates to an anti-adhesion agent comprising a bubble, and more particularly, a structure comprising a bubble derived from a bio-derived polymer and / or a non-living-derived biocompatible polymer and / or a derivative thereof as a main component and swelling in water. It relates to a porous material for preventing adhesion.

Adhesion refers to tissue damage caused by inflammation, cuts, friction, or wounds caused by surgery, which causes different tissues or tissues to be separated from each other by excessive fibrous tissue or blood leakage and coagulation. Sticking can actually occur after all surgery and can lead to serious clinical sequelae.

Adhesion usually occurs at a rate of 67% to 93% after open surgery, according to US statistics, it is 49% to 74% of small intestine occlusion, 15% to 20% infertility, It is known that chronic pelvic pain is 20% to 50% and bowel perforation is 19% in subsequent surgery.

Adhesion is initiated by fibrin, which occurs during the coagulation of blood in exudate after surgery. In the next few days, several cellular factors are included in the fibroblasts, which are then replaced by angioblasts, including macrophages, fibroblasts, and giant cells. Four days after surgery, most of the fibrin is lost and more fibroblasts and collagen are formed. Fibroblasts were cultured in adhesions for 5 to 10 days and after two weeks there were mainly fibroblasts. After a month or two, collagen fibers are organized into discrete bundles.

The mechanism of the development of intraperitoneal adhesions is published by Granger (Granger DA, Incidence and causes of pelvic adhesions, Infert. Reprod. Med. Clin. North Am., 1994; 5 (3): 391-404 The peritoneum consists of two layers, the outer mesothelial layer and the lower matrix, and when the peritoneum is injured, the lower substrate is exposed to the vascular activators kinins and histamine by macrophages. (histamine) is released immediately. These substances locally increase the permeability of capillaries and lead to the formation of serous blood mothers, including inflammatory cells. These cells can produce cytokines and growth factors, and their role is not well understood, but according to the rat caecum friction model, the degree of adhesion of Interleukin-1 (IL-1) , And this increase is not dose or time dependent, suggesting that IL-1 acts as an early medium of adhesion formation. Moreover, inflammatory exudates are rich in fiber and form blood clots on the wound surface. As the fiber breaks down (3 days) and the mesothelial regenerates (5 days), the wound heals normally. Fibrin breakdown relies on the conversion of plasminogen to plasmin, a fibrinolytic enzyme, which is a tissue plasminogen activator (tPA) coexisting in the mesothelial and underlying substrate. Is facilitated by However, if the breakdown of fibrin does not occur, the inflammatory cells and fibroblasts penetrate into the fibroblasts and the adhesions are organized.

Common methods for reducing these adhesions have been to minimize wounds during surgery, to use anti-inflammatory agents, to enhance fibrin degradation, and to exfoliate the surface where the adhesions have been formed. Methods of using barriers have been developed and used.

When used as an effective barrier to prevent adhesion, it should not act as a physical barrier while the wound of a tissue or organ is healing and should not affect the healing of the wound and prevent the formation of adhesion between adjacent tissues. In addition, after a certain period of wound healing, it should be disassembled or absorbed and removed, and the barrier material itself or its degradation products should be harmless to the human body.

The anti-adhesion agents used for these barriers can be classified into two types. First, solution barriers including gels, and second, membrane barriers including films, nonwovens, and sponges.

Solution type anti-adhesion materials include lactate Ringer's solution, dextran-70 solution, heparin solution, carboxymethylcellulose sodium solution (hereafter CMC solution), hyaluronic acid solution, chondroitin sulfate solution, polyethylene glycol solution, and poloxamer solution Etc.

Dextran-70 has a high molecular weight, is used as a 32% solution of dextrose, and appears to be the main mechanism to float the tissues to float together. CMC solutions are water soluble polymers that can form a viscous barrier between adjacent membrane surfaces.

Hyaluronic acid solutions have the ability to coat and smooth the intestinal surface and potentially prevent them from forming postoperative adhesions. Animal studies with hyaluronic acid solutions have proven to reduce intraperitoneal adhesion formation (SIHOLZMAN, MD. 1994). However, these biopolymer solutions are absorbed too quickly in vivo and do not produce the desired anti-adhesion effect.

On the other hand, since polyethylene glycol, which is a synthetic polymer, is not decomposed in vivo, only a material having a small molecular weight can be used, and in this case, it is known to be absorbed and discharged through metabolic pathways. On the other hand, since only a small molecular weight should be used, absorption occurs quickly, and thus, there is a disadvantage in that the barrier role for preventing adhesion cannot be maintained for a long time.

Anti-adhesion agents in the form of membranes include Oxidized-regenerated cellulose (ORC), expanded PTFE (expanded polytetrafluoroethylene) (ePTFE), hyaluronic acid and carboxymethylcellulose sodium (CMC). have. Oxidatively regenerated cellulose was originally introduced as a hemostatic agent and has been shown to reduce adhesion formation after cecal trauma of rats, but was ineffective without complete hemostasis.

Arora et al. Have reported that oxidatively regenerated cellulose causes an immune response involving macrophage, eosinophils, foreign body giant cells, etc. (Arora et al. 1994; Haney & Doty 1992).

ePTFE is in the form of a chemically inactive sheet and prevents cell penetration. It is specifically designed as a pericardial substitute in cardiovascular surgery (Minale et al. 1988; Revuelta et al. 1985). However, this membrane is safe for tissue but not bioabsorbable and requires surgery to remove it again as needed. In addition, there is a disadvantage that must be firmly fixed to the wound.

US Patent No. 5,017,229; 5,527,893; No. 5,760,200 and the like describe a water-insoluble film composed of hyaluronic acid (HA), a polysaccharide, and a carboxymethyl cellulose (CMC) and a chemical crosslinking agent. However, these films require a strong cleaning process to remove a large amount of crosslinking agent, and they are brittle because they are too hard in a dry state and are greatly deformed when contacted with moisture, which makes them difficult to handle while wearing wet gloves during surgery. Caution must be taken when using the product.

Therefore, it is hard to say that successful anti-adhesion agents have been developed to date.

The first object of the present invention is to minimize or prevent adhesions occurring after surgery, to prevent the formation of adhesions after primary surgery, to prevent the remodeling of adhesions after secondary surgery intended to remove the adhesions, It is to provide anti-adhesion agents, including bubbles, when swelled in water that can be disintegrated and / or absorbed and completely discharged out of the body.

Still another object of the present invention is to provide an anti-adhesion agent that can prevent adhesion formation while the wound is healed by controlling a certain time of disintegration and absorption in the body without affecting the process of wound healing after surgery.

The above and other objects of the present invention can be achieved by the present invention described below.

The present invention to achieve the above object

Provided is an anti-adhesion agent comprising a bio-derived polymer and / or a non-biologically-derived biocompatible polymer and / or a derivative thereof as a main component and having a structure containing bubbles when swollen in water.

The bio-derived polymer may include chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, hyaluronic acid, and proteoglycan including glycosaminoglycans; Collagen and its degradation products gelatin; Elastin, laminin, fibronectin, vitronectin, thrombospontin, tininicin, entaxin; Heparin, hirudin, fibrin; Phospholipids; Keratin; may be one or more selected from the group consisting of.

The non-biodegradable biocompatible polymers include polylactic acid (PLA), polyglycolic acid (PGA) and copolymers thereof (PLGA), poly-ε-caprolactone, poly-N-isopropylacrylamide (PNIPAM) and its Cellulose derivatives such as copolymers, polypeptides, regenerated cellulose, carboxyethyl cellulose (CEC) and carboxymethyl cellulose (CMC), chitosan, chitin and derivatives thereof, glucan, sodium alginate, PEG, PEG-PPG- It may be at least one member selected from the group consisting of poloxamer, polyanhydride, polyacetal, polyketal, poly-ortho-ester, polyylphosphazene, and the like made of a PEG block copolymer.

The bubble may be a bubble trapping a gas harmless to the human body, the bubble may be one or more selected from the group consisting of nitrogen, oxygen, carbon dioxide, helium, argon.

The anti-adhesion agent is 0.1 to 10% by weight of the bio-derived polymer; 0.1-10% by weight of non-biologically derived biocompatible polymers; And the reaction initiator is further included in an amount of 0.01 to 0.5% by weight, the balance may be prepared by containing water, the reaction initiator is carbodiimides (carbodiimides), glycidyl ether series (glycidyl ethers), vinyl It may be one or more selected from the group consisting of sulfyl series (vinyl sulphones), epoxides (epoxides), and aldehydes (aldehydes).

The pore size of the anti-adhesion agent may be 1 μm to 1000 μm.

The density of the anti-adhesion agent may be 0.01 g / ml to 0.7 g / ml.

The porosity of the anti-adhesion agent may be 10% to 500%.

Swelling degree (sponge weight after hydration / sponge weight before hydration) of the anti-adhesion agent may be 10 to 300.

The anti-adhesion agent may be 1% to 60% weight loss after enzymatic degradation for 24 hours.

The anti-adhesion agent is composed of a structure including a bubble, it may be better to form a triple structure having a dense structure of both surfaces. In addition, it may be a structure made of a structure of the dense layer / bubble layer / dense layer so that the bubbles are easily maintained.

Hereinafter, the present invention will be described in detail.

The anti-adhesion agent according to the present invention minimizes foreign body reaction by using a bio-derived material, is manufactured in a structure containing bubbles and stays in the body for a certain time to be completely decomposed and absorbed, and does not prevent wound healing after surgery. In addition, it can be conveniently applied to the surgical site.

The anti-adhesion agent according to the present invention is prepared in a structure containing bubbles by mixing or chemically combining a bio-derived polymer of a suitable composition and a non-bio-derived biocompatible polymer. The sponge acts as a barrier to prevent adhesion during the healing of the wound. Finally, when the wound tissue is healed, the sponge breaks down and is absorbed and completely disappears from the body.

The bio-derived polymer may include chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate and hyaluronic acid, which are a kind of glycosaminoglycans, and proteo glycans including the same; Collagen and its degradation products gelatin; Elastin, laminin, fibronectin, vitronectin, thrombospondin, tininicin, entaxin; Heparin, hirudin, fibrin; Phospholipids; Keratin; may be one or more selected from the group consisting of.

The non-biodegradable biocompatible polymers include polylactic acid (PLA), polyglycolic acid (PGA) and copolymers thereof (PLGA), poly-ε-caprolactone, poly-N-isopropylacrylamide (PNIPAM), and Cellulose derivatives such as copolymers thereof, polypeptides, oxidized regenerated cellulose, carboxyethyl cellulose (CEC) and carboxymethyl cellulose (CMC), chitosan and chitin and derivatives thereof, glucan, sodium alginate, PEG, PEG-PPG One or more selected from the group consisting of poloxamers, polyanhydrides, polyacetals, polyketals, poly-ortho-esters, polyylphosphazenes, etc., consisting of -PEG block copolymers are possible.

The structure of the anti-adhesion sponge including the bubble made in the present invention is as shown in FIG.

In the case of the anti-adhesion sponge or film proposed as a conventional physical barrier, it is attached to the wound site, and the blood leaked from the wound during use, or the cells or fibers, seep into the swollen sponge or film, and serve as a perfect barrier with other tissues. Although there was a disadvantage that can not be performed, since the bubbles contained in the sponge prepared in the present invention is in a closed state, it is possible to maintain the bubble layer when swollen in water. Therefore, the bubble contained in the sponge may serve as a barrier made of gas.

The anti-adhesion sponge that contains bubbles is less likely to penetrate blood, cells, and fibres leaked from the wound, and as a result, a more effective anti-adhesion effect can be obtained as a barrier.

In addition, by adjusting the porosity of the bubbles contained in the sponge prepared in the present invention can slow down the decomposition rate of the sponge by the enzyme activity in vivo, the side reaction of the chemical bond used for the abuse of the crosslinking agent for chemical crosslinking and the control of the decomposition rate Foreign body reaction in the human body can also be prevented.

Sponge including the bubble of the present invention can be produced by collecting a variety of gas entering the bubble in the manufacturing step. The bubble may be at least one selected from the group consisting of nitrogen, oxygen, carbon dioxide, helium, and argon.

These bubbles are replaced by body fluids after application of the anti-adhesion agent in vivo and remain filled with gas to serve as a gas barrier. As a method for preparing an anti-adhesion agent having such a bubble structure, one or more methods selected from among methods such as lyophilization, salt dissolution, emulsification, good solvent / non-solvent mixing, and addition of a blowing agent are used. The structure of the bubble may be a structure in which two or more bubbles are connected to each other so that the closed bubble is most ideal but is not replaced by liquid or body fluid.

In addition, the anti-adhesion agent of the present invention may be chemically crosslinked to control the degradation rate in vivo. The reactants used for chemical crosslinking are selected from radical initiators, cationic initiators, anion initiators and the like. Among these reaction initiators, carbodiimides, glycidyl ethers, vinyl sulphones, epoxides, aldehydes, and the like are recommended. Examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC), 1,4-butanediol diglycidyl ether, divinylsulphone and the like.

In addition, as the crosslinking method, one or more methods selected from stirring, heating, UV, ultrasonic waves, plasma, gamma rays, and the like are used.

The properties of the anti-adhesion agent according to the present invention may vary depending on the porosity (%), the pore size, the density and the degree of swelling.

It is preferable that the density of the anti-adhesion agent according to the present invention is 0.01 g / ml to 0.7 g / ml, and if the density is less than 0.01 g / ml, the porous structure is too rich to form an open structure without forming a closed bubble layer. There is a problem that can not form a barrier to prevent adhesion due to seeps exudates formed after surgery, if the excess exceeds 0.7g / ml sponge structure is too dense to form a structure containing porous bubbles Problems may arise.

In addition, the pore size of the anti-adhesion agent according to the present invention is preferably 1 μm to 1000 μm, and the porosity is preferably 10 to 500%. If the porosity exceeds 500%, there is a problem in that the decomposition rate of the sponge containing bubbles is delayed by the enzyme activity in vivo, so that it cannot be decomposed and absorbed for a predetermined time. If the porosity is less than 10%, it is caused by the enzyme activity in vivo. Due to the rapid decomposition, there is a problem in that it does not act as an anti-adhesion barrier for a certain time and is absorbed.

In addition, the swelling degree (sponge weight after hydration / sponge weight before hydration) of the anti-adhesion agent according to the present invention is preferably 10 to 300, if less than 10, the sponge does not absorb the moisture does not decompose in vivo If there is more than 300, there is a problem that the sponge is not dissolved in water when the sponge is swelled can not be a structure containing the bubble.

The anti-adhesion agent of the present invention is composed of a bubble-containing structure, and more preferably, may have a triple structure having a dense structure on both surfaces thereof. That is, it may be a structure made of a structure of the dense layer / bubble layer / dense layer so that bubbles are easily maintained.

The method for making a sponge structure including the closed bubble is a sponge hot pressing, sponge surface coating, hot pressing after sponge surface coating, transfer the film made of the same material on both sides of the sponge structure and then hot pressing or both sides of the sponge structure After thin melting, crosslinking methods may be used alone or in combination.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to Examples.

Example 1

Preparation of Sponge for Preventing Adhesion by Heat Pressing Method

1% hyaluronic acid solution and 1% CMC solution are mixed at a ratio of 1: 1. 0.25% 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC) acetone and water (9: 1) by weight of the sponge after lyophilization After cross-linking for at least 12 hours after addition to the mixed solution. After washing with ethanol three more times and dried. The dried sponge is heated and compressed to a thickness of 120 ° C. and 2 mm. The sponge thus made swells without dissolving in water as shown in FIGS. 2 and 3 and includes numerous bubbles upon swelling.

Example 2

Preparation of Sponge for Preventing Adhesion by Surface Coating Method

Sponge manufacturing method up to the lyophilization process is the same as in Example 1. 0.25% of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide by weight after coating the mixed solution of hyaluronic acid and carboxymethylcellulose on the surface of the sponge; EDAC) is added to the mixed solution of acetone and water (9: 1) and crosslinked for at least 12 hours. After washing with ethanol three more times and dried.

Example 3

Preparation of Sponge for Preventing Adhesion by Pressing Method after Surface Coating

In Example 2, the same procedure as for washing after drying three times or more with ethanol. The dried sponge is heated and compressed to a thickness of 120 ° C. and 2 mm.

Example 4

Heat compression after the production of sponge for preventing adhesion by salt elution method

1% hyaluronic acid solution and 1% CMC solution are mixed at a ratio of 1: 1. After lyophilization, ethanol and distilled water were immersed in the mixed solution at a ratio of 9: 1, and then the pH was adjusted to 2.5 using 1N HCl. After acid treatment for 6 hours, the ratio of ethanol and distilled water is washed with 5: 5, 4: 6, 3: 7 and 2: 8, respectively. After several washings until the pH is 6.8 to 7.2, the final washing with ethanol and heat-squeezed to a thickness of 2mm, 120 ℃ dried sponge.

[Comparative Example]

Preparation of anti-adhesion film containing no bubbles

1% hyaluronic acid solution and 1% CMC solution are mixed at a ratio of 1: 1. 12 hours after adding 0.25% of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC) to the mixed solution After the crosslinking reaction, it is dried.

Experimental Example 1

Comparison of Enzymatic Degradation of Sponges with Bubbles and Films without Bubbles

Sponges containing bubbles prepared in Examples 1 to 4 and 10 units of enzyme solution (Hyaluronidase) per 1 mg of hyaluronic acid were prepared from the film containing no bubbles prepared in Comparative Example. Was immersed in the enzyme solution and then subjected to enzymatic reaction in a 37 ° C. carbon dioxide incubator for 24 hours. In vitro degradation was divided into before and after enzymatic degradation and the physical properties were compared, and the results are shown in Tables 1 and 2, respectively.

As shown in Tables 1 and 2, the physical properties of the sponges prepared in Examples 1 to 4 and the enzymatic decomposition of the films containing no bubbles of Comparative Example were compared. Although the difference was not large, Table 2 showed more weight loss in physical properties after enzymatic digestion in comparison with the examples in weight change in the comparative example. It can be seen that the film which does not contain the bubble layer is rapidly decomposed by the enzymatic activity.

Properties before enzymatic decomposition Sponge film Example 1 Example 2 Example 3 Example 4 Comparative example Density (g / ml) 0.13 0.15 0.17 0.08 0.34 Swelling degree (Ws / Wd) 198.87 169.58 154.46 135.40 177.73 Porosity (%) 159.26 123.27 107.17 130.12

Properties after enzymatic degradation Sponge film Example 1 Example 2 Example 3 Example 4 Comparative example Weight loss rate (%) 35.63 23.63 40.41 41.93 54.40 Density (g / ml) 0.14 0.21 0.20 0.22 0.24 Swelling degree (Ws / Wd) 171.95 177.71 146.64 165.08 121.02 Porosity (%) 135.10 56.00 62.33 84.32

Experimental Example 2

Measurement of Adhesion, Adhesion Strength, and Adhesion Area of Sponge with Bubble and Film without Bubble

Forced adhesion to the cecum and peritoneum of rats was observed by using an anti-adhesion sponge including the bubble layer of Example 1 and a film not containing the air bubbles of Comparative Example. The degree of adhesion and adhesion strength were evaluated according to the following criteria.

The results of the experimental example are shown in Figures 12 to 14.

<Adhesion level>

0: when no adhesion occurs

1: Partial focal adhesion occurs

2: when there are many sticky adhesions

3: In case of surface adhesion

4: deep adhesion on the surface

5: when blood vessels are formed with cohesion

Adhesion Century

0: when no adhesion occurs

1: Adhesion that is film-like and drops with very weak force

2: Adhesion requiring moderate force

3: Adhesion that can be released with considerable pressure

4: The coalescence is very strong and difficult to peel off or requires very high pressure

As can be seen in Figures 12 to 14, in the case of the film containing the foam of the sponge of Example 1 according to the present invention and the bubble of the comparative example, the degree of adhesion, the degree of adhesion compared to the control group not treated at all And it can be seen that the adhesion area is very low, and in the case of the sponge containing the foam of Example 1 it was found that the degree of adhesion and adhesion strength is relatively lower than the film of the comparative example. That is, it was found that the sponge containing the bubble is more effective in preventing adhesion.

As described above, the anti-adhesion agent according to the present invention minimizes the foreign body reaction by using a bio-derived material, is manufactured in a structure containing air bubbles and stays in the body for a certain time, completely decomposed and absorbed, and wound after surgery It is a useful invention that has the effect of providing maximum convenience when applied to the surgical site without disturbing the healing.

While the invention has been described in detail above with reference to the described embodiments, it will be apparent to those skilled in the art that various modifications and variations are possible within the scope and spirit of the invention, and such modifications and variations fall within the scope of the appended claims. It is also natural.

1 is a cross-sectional view showing a sponge structure for preventing adhesion of the present invention including bubbles.

Figure 2 is a photograph showing the swelling state of the anti-adhesion sponge of the present invention before the enzyme decomposition.

Figure 3 is a micrograph showing the swelling state of the anti-adhesion sponge of the present invention before enzyme digestion.

Figure 4 is a photograph showing the state of the anti-adhesion sponge of the present invention after the enzyme decomposition.

Figure 5 is a micrograph showing the state of the anti-adhesion sponge of the present invention after the enzyme digestion.

Figure 6 is a photograph showing the state of the anti-adhesion film containing no bubbles after enzyme digestion.

Figure 7 is a micrograph showing the state of the anti-adhesion film after enzyme digestion.

8 is an electron micrograph showing the state of the anti-adhesion sponge of the present invention before the enzyme decomposition.

Figure 9 is an electron micrograph showing the state of the anti-adhesion sponge of the present invention after the enzyme decomposition.

10 is an electron micrograph showing the state of the anti-adhesion film before enzyme decomposition.

Figure 11 is an electron micrograph showing the state of the anti-adhesion film after enzyme digestion.

12 is a graph showing the degree of adhesion according to the animal experiment of the sponge according to the present invention compared to the film.

13 is a graph showing the adhesion strength according to the animal experiment of the sponge according to the present invention compared to the film.

14 is a graph showing the adhesion area according to the animal experiment of the sponge according to the present invention in comparison with the film.

Claims (17)

An anti-adhesion agent comprising a bio-derived polymer and / or a non-bio-derived biocompatible polymer and / or a derivative thereof as a main component and having a structure containing bubbles when swollen in water. The method of claim 1, 0.1 to 10% by weight of the bio-derived polymer; 0.1 to 10% by weight of the non-biologically derived biocompatible polymer; And The reaction initiator is further included in an amount of 0.01 to 0.5% by weight, and the anti-adhesion agent, characterized in that the remaining water is produced. The method of claim 1, The bio-derived polymer is chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, hyaluronic acid, which is a kind of glycosaminoglycan, and proteoglycan including the same; Collagen and its degradation products gelatin; Elastin, laminin, fibronectin, vitronectin, thrombospontin, tininicin, entaxin; Heparin, hirudin, fibrin; Phospholipids; And Keratin; anti-adhesion agent, characterized in that at least one member selected from the group consisting of. The method of claim 1, The non-biologically derived biocompatible polymers include polylactic acid (PLA), polyglycolic acid (PGA) and copolymers thereof (PLGA); Poly-ε-caprolactone, poly-N-isopropylacrylamide (PNIPAM) and copolymers thereof; Cellulose derivatives such as polypeptides, regenerated cellulose, carboxyethyl cellulose (CEC) and carboxymethyl cellulose (CMC); Chitosan, chitin and derivatives thereof; Glucan, sodium alginate; Poloxamers consisting of PEG, PEG-PPG-PEG block copolymers; And Anti-adhesion agent, characterized in that at least one selected from the group consisting of polyanhydrides, polyacetals, polyketals, poly-ortho-esters, poly phosphazenes. The method of claim 2, The reaction initiator is selected from the group consisting of carbodiimides, glycidyl ethers (glycidyl ethers), vinyl sulfones (vinyl sulphones), epoxides, and aldehydes (aldehydes) Adhesion inhibitors, characterized in that the species or more. The method of claim 1, The bubble is an anti-adhesion agent, characterized in that the bubble trapped gas harmless to the human body. The method of claim 1, The bubble is an anti-adhesion agent, characterized in that at least one selected from the group consisting of nitrogen, oxygen, carbon dioxide, helium, argon. The method of claim 1, Adhesion inhibitors, characterized in that the pore size of the anti-adhesion agent is 1㎛ to 1000㎛. The method of claim 1, Adhesion inhibitors, characterized in that the density of the adhesion inhibitor is 0.01g / ml to 0.7g / ml. The method of claim 1, The anti-adhesion agent, characterized in that the porosity of the anti-adhesion agent is 10% to 500%. The method of claim 1, Adhesion inhibitors, characterized in that the swelling degree of the anti-adhesion agent is 10 to 300. The method of claim 1, After the enzymatic decomposition of the anti-adhesion agent for 24 hours, the anti-adhesion agent, characterized in that the weight loss rate is 1 to 60%. The method of claim 1, The anti-adhesion agent is a structure containing a bubble, characterized in that the anti-adhesion agent is produced by applying heat and pressure during manufacturing. The method of claim 1, The anti-adhesion agent is a structure comprising a bubble, characterized in that the anti-adhesion agent is prepared by coating the surface during manufacture. The method of claim 1, The anti-adhesion agent is a structure comprising a bubble, the production of the anti-adhesion agent characterized in that it is produced by applying heat and pressure after transferring the film made of the same material on both sides of the sponge structure during manufacture. The method of claim 1, The anti-adhesion agent is a structure comprising a bubble, the anti-adhesion agent characterized in that it is produced by the method of cross-linking and then thinly dissolving both sides of the sponge structure during manufacture. The anti-adhesion agent according to any one of claims 1 to 16, wherein the anti-adhesion agent is in the form of a sponge.