KR20110080690A - Tissue adhesion barrier and method for preparing of the same - Google Patents

Abstract

PURPOSE: A tissue adhesion barrier and a method for manufacturing the same are provided to effectively prevent tissue adhesion caused during surgery and to lower medical expense. CONSTITUTION: A method for preparing a tissue adhesion barrier comprises: a step of mixing 0.01-5 weight% of hydrophilic natural polymers, 0.01-4 weight% of polyvalent cation, and 0.01-2 weight% of crosslinking agent into an aqueous solvent for crosslinking polymers; and a step of physically blocking hydrophilic polymers from crosslinked polymer chains. The crosslinking agent is selected from compounds, chitosan, and poly-ene-lysine.

Description

Tissue adhesion barrier and method for preparing the same {Tissue adhesion barrier and method for preparing of the same}

The present invention relates to a tissue adhesion inhibitor and a method for producing the same, which are stably present on the wound surface during healing of the wound and have excellent anti-adhesion efficacy.

In surgery today, laparotomy is one of the routine operations. Adhesion of organs and tissues that occurs frequently after surgery is one of the natural phenomena that occurs when cells of damaged tissues proliferate and regenerate, but they cause continuous discomfort or dysfunction and require reoperation for adhesion detachment. It can also be a life-threatening factor.

Particularly in women, pelvic surgery may cause infertility due to tissue adhesion of the uterus [DB John et al., "Reduction of adhesion formation by postoperative administeration of ionically cross-linked hyaluronic acid", Fertil . Steril ., 68, 37-42 (1997). This complication is deeply related to the body's biological defense mechanisms, and the process is complicated, and there are many difficulties in preventing it in the clinic.

Therefore, despite many research efforts since abdominal surgery, it remains one of the most important surgical problems that have not yet been completely solved.

The incidence of adhesion after laparotomy is reported to be high, 55-93% [D. Menzies, "Postoperative adhesions: their treatment and relevance in clinical practice", Ann . Royal Coll. Surg . Engl ., 75, 147-153 (1993). It is not an exaggeration to say that such adhesion occurs in almost all parts of the human body such as muscles, sclera, conjunctiva, tenon cyst, and mesentery, but the biggest clinical problem is repetitive peritoneal or intestinal adhesion after abdominal surgery. It is known to be caused by surgery, rough surgery, excessive bleeding, tissue response of sutures, foreign objects during surgery, postoperative inflammation, etc. [L. Holmdahl et al., "Experimental models for quantitative studies on adhesion formation in rats and rabbits", Eur . Surg . Res . , 26, 248-256 (1994).

In addition, since adhesion is also a part of the wound healing process by the surgery itself, complete prevention is difficult, and the extent of minimization can be minimized by accurate tissue detachment, bleeding prevention, aseptic surgery, shortening of operation time and appropriate selection of suture. . Therefore, in order to solve the problem of tissue adhesion after surgery, attempts have been made to suppress adhesion between tissues after surgery using various adhesion agents of various materials and forms.

Among them, research using various hydrophilic natural polymers known to be excellent in tissue adhesion suppression performance and biocompatibility is mainly performed, but as shown in FIG. Despite their excellent anti-adhesion efficacy, they are known to have limited adhesion to anti-adhesion agents when applied to actual wounds. Protection should prevent tissue adhesion).

In the present invention, in using the conventional hydrophilic natural polymer as a tissue adhesion inhibitor, despite the excellent adhesion inhibition properties of their own, the problem that does not properly exert the ability to inhibit tissue adhesion by being washed faster than the time the wound is healed in the introduced wound site Will be solved.

Therefore, the present invention sought a method that can maintain a stable hydrophilic natural polymer having excellent tissue adhesion inhibitory properties, but easily washed away in the body during the wound healing period. In the process, when the hydrophilic natural polymer is mixed with the weakly crosslinked polymer, as shown in FIG. 2, the hydrophilic natural polymer is physically blocked, that is, trapped in the polymer chain that is weakly crosslinked to enable injection. It is now possible to develop a novel anti-adhesion agent having excellent tissue adhesion inhibitory ability, which is endowed with stability in the body (protecting the wound stably without being washed off the wound surface for a sufficient time for the wound to heal).

Accordingly, it is an object of the present invention to provide an anti-tissue adhesion agent that can effectively inhibit tissue adhesion during the wound healing period.

In addition, another object of the present invention is to provide a method for preparing a tissue adhesion inhibitor that can effectively inhibit tissue adhesion during the wound healing period.

The anti-tissue adhesion agent according to the present invention is stably present at the wound site while the wound is healed by using a cross-linked polymer formed by a polyvalent cation that is weakly crosslinked with a hydrophilic natural polymer having a tissue adhesion inhibiting property and capable of injection injection. By effectively preventing the adhesion of the tissue frequently generated after the operation, it has the effect of significantly reducing the patient's medical expenses due to pain reduction, reoperation.

In addition, the anti-tissue adhesion agent according to the present invention has a variety of forms that can be used in the tissue in the body, such as gel, film, powder, sponge, has the advantage that can be used in a variety of applications for the prevention of adhesion.

1 is a diagram illustrating a problem when a tissue adhesion inhibitor containing only conventional hydrophilic natural polymer is applied to the body,
2 is a diagram illustrating a structure in which a hydrophilic natural polymer is blocked in a weakly crosslinked polymer in one embodiment according to the present invention.
Figure 3 shows a tissue adhesion inhibitor in the gel state according to an embodiment of the present invention,
4 and 5 are the results of stability experiments in the aqueous phase of Example 4 and Comparative Examples 1 and 2,
6 is a result of measuring the degree of tissue adhesion through the animal experiment of Example 4 and Comparative Examples 1 and 2,
7 is a result of measuring the percentage of inflammatory cells through the animal experiment of Example 4 and Comparative Examples 1 and 2,
8 is a result of measuring the granulation tissue formation degree through the animal experiment of Example 4 and Comparative Examples 1 and 2,
9 is a result of measuring the degree of tissue adhesion through the animal experiment of Example 10 and Comparative Examples 3 to 4,
10 is a result of measuring the degree of tissue adhesion through the animal experiment of Example 16 and Comparative Examples 5-6.

Tissue adhesion inhibitor according to the present invention for achieving the above object 0.01 to 5% by weight of hydrophilic natural polymer of the weight average molecular weight 5,000 ~ 10,000,000 g / mol; 0.01 to 4% by weight of a polymer forming crosslinks by a polyvalent cation; And it is characterized in that it comprises 0.01 to 2% by weight of a crosslinking agent for crosslinking of the polymer forming a crosslink by the polyvalent cation.

In addition, a method for preparing a tissue adhesion inhibitor for achieving the object according to the present invention is 0.01-5% by weight of a hydrophilic natural polymer, 0.01-4% by weight of a polyvalent cation to form a crosslinking polymer, and 0.01 ~ And mixing 2% by weight of a crosslinking agent to crosslink the polymer forming the crosslink by the polyvalent cation, and to physically block the hydrophilic natural polymer in the crosslinked polymer chain.

In addition, the method for producing a tissue adhesion inhibitor for achieving the object according to the present invention is mixed by adding a polymer forming a crosslink by 0.01 to 5% by weight of hydrophilic natural polymer and 0.01 to 4% by weight of a polyvalent cation in an aqueous solvent. Preparing an aqueous solution; And adding 0.01 to 2% by weight of a crosslinking agent aqueous solution to the mixed aqueous solution to crosslink the polymer forming crosslink by the polyvalent cation, and to physically block the hydrophilic natural polymer in the crosslinked polymer chain. It is characterized by including.

Hereinafter, the tissue adhesion inhibitor according to the present invention and a detailed manufacturing method thereof will be described in detail.

Tissue adhesion inhibitor according to the present invention is a hydrophilic natural polymer; It includes a polymer that forms a crosslink by a polyvalent cation for imparting stability to the hydrophilic natural polymer, the polymer forming a crosslink by the polyvalent cation so that the hydrophilic natural polymer can stably withstand a certain period in the body In order to do this, the crosslinking is preferably weakly crosslinked to enable injection.

The hydrophilic natural polymer according to the present invention preferably has excellent anti-adhesion performance, wound healing performance, high viscosity, and no inflammatory reaction. Specifically, the weight average molecular weight is 5,000 to 10,000,000 g / mol, preferably It is 100,000-5,000,000 g / mol, and it is 1 or more types chosen from the group which consists of hyaluronic acid, dextran, hydroxypropyl methylcellulose, and carboxymethyl cellulose, and hyaluronic acid is the most preferable among these.

The hydrophilic natural polymer is preferably contained in 0.01 ~ 5% by weight in the tissue adhesion inhibitor, less than 0.01% by weight is not preferable due to the insufficient adhesion inhibitory performance, when the content exceeds 5% by weight is too difficult to handle there is a problem.

The polymers are very useful as anti-adhesion properties, wound healing performance, high viscosity, and no inflammatory reactions as a tissue adhesion inhibitor, but because they are hydrophilic, when the polymer is introduced to prevent adhesion to the wound site, There is a problem that is easily washed away from within.

Therefore, in the present invention, the hydrophilic natural polymer is prevented from being easily decomposed or washed away in the body, thereby stably protecting the wound while the wound is healed, thereby forming a crosslink by a polyvalent cation for improving the stability in the body. It contains a polymer.

The polymer forming the crosslink by the polyvalent cation is preferably at least one selected from the group consisting of alginate, carrageenan, pectin, gellan gum, xanthan gum and derivatives thereof, of which alginate is most preferred.

Since the hydrophilic natural polymer included in the tissue adhesion inhibitor of the present invention and the polymer which forms a crosslink by the polyvalent cation have similar characteristics, it is true that the same use has been used in various fields. However, in the present invention, rather than including them as one component, the hydrophilic natural polymers for the purpose of tissue adhesion properties and wound healing properties, the polymer that forms a crosslink by the polyvalent cation is weakly crosslinked in the body of the hydrophilic natural polymers Each component must be included to indicate stability implications.

If only the hydrophilic natural polymer is included, there is a problem that the wound is not tolerated for a period of healing, and is easily washed down, and also includes only a polymer that forms a crosslink by the polyvalent cation. This is not desirable because it falls short of expectations.

The polymer which forms a crosslink by the polyvalent cation of the present invention is preferably crosslinked with a crosslinking agent in view of improving the stability of the hydrophilic natural polymer and introducing into various wounds.

The crosslinking agent is at least one selected from a compound containing a polyvalent cation, chitosan, and poly-L-lysine.

Approaching from the compound containing the multivalent cation cations ^{Mg 2 +, Ca 2 +,} Sr 2 +, Ba 2 +, Be 2 +, Cr 2 +, Co 2 +, Cu 2+, Fe 2 +, Mn 2 + ^{, Sn 2 +, Ni 2 +} , Zn 2 +, Al 3 +, Cr 3 +, Co 3 +, Cu 3 +, Ga 3 +, Au 3 +, Fe 3 +, Mn 3 +, Ni 3 +, Mn ^{+ 4,} Sn ^{+ 4,} Cr ^{+ 6,} and preferably at least one selected from Mn ^{+ 7.}

The crosslinking agent is preferably contained in an aqueous solvent of 0.01 to 2% by weight in terms of weakly crosslinking the polymer forming the crosslink by the polyvalent cation.

This weakly crosslinked polymer serves to impart viscosity to the final adhesion inhibitor to maintain a viscosity of about 1,000 ~ 9,000cps. In addition, the weakly crosslinked polymer has a structure in which the hydrophilic natural polymer is trapped in the chain of the crosslinked polymer when mixed with the hydrophilic natural polymer. In this case, even though the hydrophilic natural polymer trapped inside is used as a tissue adhesion inhibitor, it is not easily washed away but is trapped in the crosslinked polymer chain so that it can be stably present on the wound surface during wound healing to maintain sufficient tissue adhesion prevention performance. do.

On the other hand, the tissue adhesion inhibitor according to an embodiment of the present invention may be a gel state in which the hydrophilic natural polymer, a polymer forming a crosslink by a polyvalent cation, and a crosslinking agent dissolved in water in the concentration range. As shown in FIG. 3, the "gel state" of the present invention is preferably in the form of a gel that is capable of injection injection, rather than a hard (non-injectable) gel form.

In addition, the tissue adhesion inhibitor according to an embodiment of the present invention is a hydrophilic natural polymer, a polymer forming a crosslink by a polyvalent cation, and a crosslinking agent is applied to a predetermined thickness of an aqueous solution in which the crosslinking agent is dissolved in water in the concentration range, and then the solvent It may also be in the form of a film prepared by evaporation. The film adhesion preventing agent in the form of a film is flexible enough to be introduced into the wound surface of the complex shape, the adhesiveness enough to be introduced without sealing on the wound surface [muco-adhesiveness, in the case of the existing film form does not have the adhesive properties to seal the It is desirable to have strength enough to detach and attach to the wound surface when it is attached to tissues other than the wound surface.

In addition, the tissue adhesion inhibitor according to an embodiment of the present invention is a powder state obtained by evaporating the solvent from the aqueous solution in which the hydrophilic natural polymer, the polymer forming a crosslink by the polyvalent cation, and the crosslinking agent dissolved in water in the above concentration range It may be The method of preparing the powder is not particularly limited, and the aqueous solution may be prepared in powder form using a freezer / mill after freeze-drying the aqueous solution.

In the case of spraying the tissue adhesion inhibitor in the form of powder, it is preferable that the spraying is possible, for example, having a particle size of less than 200 μm, and in the case of simple application without spraying, less than 1,000 μm It is preferred to have a particle size of.

In addition, the tissue adhesion inhibitor according to an embodiment of the present invention is a hydrophilic polymer, a polymer forming a crosslink by a polyvalent cation, and a crosslinking agent is applied to a predetermined thickness of an aqueous solution dissolved in water in the concentration range, and then freeze The solvent may be prepared in the form of a sponge after evaporation of the solvent.

The sponge-type tissue adhesion inhibitors, like the film-type tissue adhesion inhibitors, are flexible enough to be introduced into complex wound surfaces, and adhesive enough to be introduced into the wound surfaces without suture [muco-adhesiveness, conventional film]. In the case of the form, it has no adhesiveness, so it is used to suture (suture causes the formation of new adhesion)], and when it is attached to a tissue other than the wound surface, it is strong enough to be detached and attached to the wound surface It is preferable.

Referring to the specific manufacturing method of the tissue adhesion inhibitor according to the invention consisting of the above configuration as follows.

In the first method, 0.01 to 5% by weight of a hydrophilic natural polymer, 0.01 to 4% by weight of a polyvalent cation to form a crosslinking agent, and 0.01 to 2% by weight of a crosslinking agent by mixing the crosslinking by the polyvalent cation At the same time as the cross-linked polymer to be formed, it is prepared through the step of physically blocking the hydrophilic natural polymer in the cross-linked polymer chain. That is, all the components included in the tissue adhesion inhibitor of the present invention are added at the same time, and then a weak crosslinking is formed between the crosslinking agent and the polymer forming the crosslink by the polyvalent cation, and the hydrophilic natural polymer in the chain of the crosslinked polymer To be trapped.

The second method is to prepare a mixed aqueous solution by adding 0.01-5% by weight of a hydrophilic polymer and a polymer forming a crosslink by 0.01-4% by weight of a polyvalent cation in an aqueous solvent; And adding 0.01 to 2% by weight of a crosslinking agent aqueous solution to the mixed aqueous solution to crosslink the polymer forming crosslink by the polyvalent cation, and to physically block the hydrophilic natural polymer in the crosslinked polymer chain. Manufacture through.

That is, the second method is characterized by first mixing a hydrophilic natural polymer and a polymer which forms a crosslink by a polyvalent cation, and then separately adding a crosslinking agent aqueous solution. At this time, the crosslinking agent aqueous solution added separately may include the hydrophilic natural polymer.

In addition, the method of adding the crosslinking agent aqueous solution may be spray-injected or added in a droplet state, and may be appropriately selected.

Hereinafter, the present invention will be described in detail with reference to Examples. However, the present invention is not limited thereto, but the present invention has been described only as an example of specific materials, even when these materials and equivalents are used. Equally similar effects are apparent in the art.

Example  One

1% by weight of hyaluronic acid (weight average molecular weight to 4,800,000 g / mol), 0.6% by weight of alginate (Medium viscosity, Sigma) having a weight average molecular weight of 80,000 to 120,000, and 0.065% by weight of crosslinking agent CaCl ₂ Mix as much as possible. The mixed solution was stirred at 24,000 rpm for 1 minute to crosslink the alginate to the extent that injection can be injected, and at the same time, the hyaluronic acid was blocked into the chain of the weakly crosslinked alginate, with a viscosity of about 2,300 cps. A tissue adhesion inhibitor was prepared.

Example  2

Except that the hyaluronic acid concentration is 2% by weight, a tissue adhesion inhibitor in a gel state having a viscosity of about 6,000 cps was prepared using the same method as in Example 1.

Example  3

Except that the crosslinking agent is aluminum chloride (AlCl ₃ ), using the same method as in Example 1 to prepare a tissue adhesion inhibitor in the gel state.

Example  4

Aqueous solution of 1% by weight of hyaluronic acid and 1.2% by weight of alginate; An aqueous solution of 1% by weight of hyaluronic acid and 0.13% of CaCl ₂ was prepared. Each aqueous solution was mixed at a ratio of 1: 1 (v / v) and stirred at 24,000 rpm for 1 minute to allow the alginate to be weakly crosslinked and to block the hyaluronic acid into the chain of the weakly crosslinked alginate, and had a viscosity of about 2300 cps. A tissue adhesion inhibitor in the gel state was prepared.

Example  5

Except that the hyaluronic acid concentration is 2% by weight, a tissue adhesion inhibitor in a gel state was prepared in the same manner as in Example 4.

Example  6

Except that the crosslinking agent is aluminum chloride (AlCl ₃ ), a tissue adhesion inhibitor in a gel state was prepared in the same manner as in Example 4.

Example  7-12

The tissue adhesion agent in the gel state prepared in Examples 1 to 6 was applied to a mold of a predetermined size to a thickness of about 2,000 μm, and then stored at 37 ° C. for 2 days to evaporate the solvent, followed by a film adhesion inhibitor in the form of a film. Got.

Example  13-18

After freeze-drying the tissue adhesion inhibitor in the gel state prepared in Examples 1 to 6 to obtain a tissue adhesion inhibitor in the form of a powder using a freezer / mill.

Example  19-24

The gel tissue adhesion inhibitor prepared in Examples 1 to 6 was applied to a mold having a predetermined size to a thickness of about 2,000 μm, and then freeze-dryed to evaporate the solvent to obtain a sponge-type tissue adhesion inhibitor.

Comparative example  One

A 1% by weight aqueous solution of hyaluronic acid was used as a tissue adhesion inhibitor.

Comparative example  2

Alginate 1.2 wt% aqueous solution and CaCl ₂ 0.13 wt% aqueous solution was prepared, and then the alginate aqueous solution and CaCl ₂ The aqueous solution was mixed at 1: 1 (v / v) to obtain a weakly crosslinked gel adhesion agent.

Comparative example  3

A 1% by weight aqueous solution of hyaluronic acid was applied to a mold of a constant size to a thickness of about 3,000 μm, and then stored at 37 ° C. for 2 days to evaporate the solvent, thereby obtaining a tissue adhesion inhibitor in the form of a film.

Comparative example  4

Alginate 1.2 wt% aqueous solution and CaCl ₂ 0.13 wt% aqueous solution was prepared, and then the alginate aqueous solution and the CaCl ₂ aqueous solution were mixed at a ratio of 1: 1 (v / v) to apply a weakly cross-linked gel to a mold having a predetermined size of about 4,000 μm, and then 37 Stored at 2 ℃ for 2 days to evaporate the solvent to obtain a tissue adhesion inhibitor in the form of a film

Comparative example  5

After freeze-drying an aqueous solution of 1% by weight of hyaluronic acid, a tissue adhesion inhibitor in powder form was obtained using a freezer / mill.

Comparative example  6

Alginate 1.2 wt% aqueous solution and CaCl ₂ After preparing 0.13% by weight aqueous solution, the alginate aqueous solution and CaCl ₂ aqueous solution were mixed at 1: 1 (v / v) to freeze-dry the weakly cross-linked gel state, and then adhered in the form of powder using freezer / mill. An inhibitor was obtained.

Comparative example  7

A 1% by weight aqueous solution of hyaluronic acid was applied to a mold of a constant size to a thickness of about 2,000 μm, followed by freeze-drying to evaporate the solvent to obtain a sponge-type tissue adhesion inhibitor.

Comparative example  8

Alginate 1.2 wt% aqueous solution and CaCl ₂ 0.13 wt% aqueous solution was prepared, and then the alginate aqueous solution and the CaCl ₂ aqueous solution were mixed at a ratio of 1: 1 (v / v) to apply a weakly cross-linked gel to a mold of a predetermined size to a thickness of about 2,000 μm, followed by freeze The solvent was evaporated to dry to obtain a tissue adhesion inhibitor in the form of a sponge.

Experimental Example  1: stability evaluation (gel form)

1 ml of each tissue adhesion inhibitor prepared in Example 4 and Comparative Examples 1 and 2 was placed in a vial, and 1 ml of PBS (phosphate buffer solution) was added thereto, and then stored in a 37 ° C. incubator and floated over time. Only PBS was removed and the residual thickness of the tissue adhesion inhibitor was observed. The results are shown in FIGS. 4 and 5 below.

As can be seen in Figures 4 and 5, in the case of Comparative Example 1, the tissue adhesion inhibitor was dissolved in the phosphate buffer solution in about 4 days, in Comparative Example 2 was present for about 8 days, but they fell off the wall of the vial It was confirmed to exist.

However, it can be confirmed that Example 4, which is a tissue adhesion inhibitor in a gel state according to the present invention, remains for about 10 days to 11 days.

Therefore, in the case of using only hyaluronic acid, which has been used mainly as a tissue adhesion inhibitor in the past, all of them are dissolved in the body before the wound is healed and cannot play a role as a tissue adhesion inhibitor. If only weakly crosslinked alginic acid is used, it exists on the wound surface. Easily move elsewhere, but in accordance with the present invention can perform the performance as a tissue adhesion inhibitor for a sufficient time.

Experimental Example  2: stability evaluation (film type)

150 mg of each tissue adhesion inhibitor film prepared in Example 10 and Comparative Examples 3 and 4 was placed in a vial containing 40 mL of PBS (phosphate buffer solution), and then stored in an incubator at 37 ° C., after a predetermined time through a filter. The PBS was removed and their weight was measured to evaluate the stability in the aqueous solution of the sample, and the results were similar to those of Experimental Example 1.

Experimental Example  3: stability evaluation (powder form)

150 mg of each tissue adhesion inhibitor powder prepared in Example 16 and Comparative Examples 5 and 6 was placed in a vial containing 40 mL of PBS (phosphate buffer solution), and then stored in an incubator at 37 ° C., after a predetermined time through a filter. The PBS was removed and their weight was measured to evaluate the stability in the aqueous solution of the sample, and the results were similar to those of Experimental Example 1.

Experimental Example  4: stability evaluation (sponge type)

150 mg of each tissue anti-adhesion sponge prepared in Example 22 and Comparative Example 7,8 was placed in a vial containing 40 mL of PBS (phosphate buffer solution), and then stored in an incubator at 37 ° C., and after a predetermined time, the filter was PBS was removed and their weight was measured to evaluate the stability in the aqueous solution of the sample, and the results were observed to be similar to Experimental Example 1.

Experimental Example  5: animal experiment (gel form)

Animal models (SD rats) were used to evaluate tissue adhesion prevention performance using Example 4, Comparative Examples 1 and 2, and a control group without suture of any material between wounds and wounds. First, ketamine hydrochloride (10 mg / kg) and 2% nitric acid hydrochloride (2 mg / kg) were mixed, and anesthesia was performed by injection into the lower abdomen of rats. The abdomen of the anesthetized rat is incised, a 1 x 1 cm 2 wound is formed on the epidermal part of the peritoneum with a surgical knife, and a wound about the epidermis peeling slightly from the cecum in contact with the wound is removed. It was formed using sandpaper. Tissue adhesion was confirmed by dividing the control group sutured without inserting any material between the wound and the experimental group applied to the wound site by applying 1 mL of the material of Example 4, Comparative Examples 1 and 2 in 2 x 2 cm 2. Since wounds in the body are known to heal within 7 days, the extent of tissue adhesion was checked 7 days after surgery. According to the degree of tissue adhesion, the results were summed and averaged using a grading system of four stages (0, 1, 2, 3, the larger the number, the more severe the adhesion) [AA Luciano, et al., " Evaluation of commonly used adjuvants in the prevention of postoperative adhesions ", AM . J. Obstet . Gynecol ., 146, 88-92 (1983).

The degree of tissue adhesion by the animal experiment is shown in FIG. 6, the degree of inflammatory response (percentage of inflammatory cells present in the wound) of surrounding tissues by the material is shown in FIG. 7, and the degree of granulation tissue formation in FIG. 8. Indicated.

As shown in Figure 6, Example 4 was able to observe that the tissue adhesion is significantly reduced compared to the control and Comparative Examples 1, 2, from which the tissue adhesion inhibitory effect of the tissue adhesion inhibitor according to the invention is more excellent. I could confirm.

As shown in the results of FIGS. 7 and 8, no unusual inflammatory reaction or adverse reaction according to Example 4 according to the present invention was observed as compared to the control group, and thus, the tissue adhesion inhibitor according to the present invention has biocompatibility. It was confirmed.

Experimental Example  6: animal experiment (film form)

Example 10, Comparative Examples 3 to 4, and the extent of tissue adhesion was observed in the same process as Experimental Example 5, except that the control group was closed without inserting any material between the wound and the wound. 9 is shown.

As shown in Figure 9, Example 10 was able to observe that the tissue adhesion is significantly reduced compared to the control and Comparative Examples 3, 4, from which the tissue adhesion inhibitory performance of the tissue adhesion inhibitors according to the present invention is more excellent. I could confirm.

In addition, as in Experiment 5, no unusual inflammatory reaction or adverse reaction according to Example 10 was observed, and it was confirmed that the tissue adhesion inhibitor according to the present invention had biocompatibility.

Experimental Example  7: animal experiment (powder form)

Example 16, Comparative Examples 5-6, and the degree of tissue adhesion was observed in the same process as in Experiment 5, except that the control group was closed without inserting any material between the wound and the wound. 10 is shown. As shown in FIG. 10, it could be observed that Example 16 significantly reduced tissue adhesion compared to the control and Comparative Examples 5 and 6, from which the tissue adhesion inhibitory effect of the tissue adhesion inhibitor according to the present invention was better. I could confirm.

In addition, as in Experimental Example 2, no unusual inflammatory reactions or adverse reactions according to Example 10 were observed, confirming that the anti-tissue adhesion agent according to the present invention had biocompatibility.

Experimental Example  8: animal experiment (sponge form)

Example 22, Comparative Examples 7 to 8, and the degree of tissue adhesion, inflammation of the surrounding tissue by the material in the same procedure as in Experiment 5, except that the control group was used without suturing any material between the wound and the wound The degree of response (the percentage of inflammatory cells present in the wound) and the granulation tissue formation were observed.

It was confirmed that the degree of tissue adhesion by the animal experiment, the degree of inflammatory reaction of the surrounding tissues by the material and the degree of granulation tissue formation had excellent tissue adhesion inhibitory performance and excellent biocompatibility of Example 22 as in Experimental Example 5.

From the above experimental results, the tissue adhesion inhibitor including alginate weakly crosslinked with hyaluronic acid according to the present invention is excellent in tissue adhesion prevention performance even if applied in any of various forms such as gel, film, powder, sponge, It was confirmed that it was excellent without adverse reaction.

Claims (14)

0.01 to 5% by weight of hydrophilic natural polymer having a weight average molecular weight of 5,000 to 10,000,000 g / mol;
0.01 to 4% by weight of a polymer forming crosslinks by a polyvalent cation; And
A tissue adhesion inhibitor comprising 0.01 to 2% by weight of a crosslinking agent for crosslinking a polymer forming crosslinks by the polyvalent cation.
2. The tissue adhesion inhibitor according to claim 1, wherein the hydrophilic natural polymer is at least one selected from the group consisting of hyaluronic acid, dextran, hydroxypropylmethylcellulose, and carboxymethylcellulose.
2. The tissue adhesion inhibitor according to claim 1, wherein the polymer which forms a crosslink by the polyvalent cation is at least one selected from the group consisting of alginate, carrageenan, pectin, gellan gum, xanthan gum and derivatives thereof.
The anti-tissue adhesion agent according to claim 1, wherein the crosslinking agent is at least one selected from a compound containing a polyvalent cation, chitosan, and poly-L-lysine.
The method according to claim 4, wherein the polyvalent cation is Mg ²⁺ , Ca ²⁺ , Sr ²⁺ , Ba ²⁺ , Be ²⁺ , Cr ²⁺ , Co ²⁺ , Cu ²⁺ , Fe ²⁺ , Mn ²⁺ , Sn ²⁺ , Ni ²⁺ , Zn ²⁺ , Al ³⁺ , Cr ³⁺ , Co ³⁺ , Cu ³⁺ , Ga ³⁺ , Au ³⁺ , Fe ³⁺ , Mn ³⁺ , Ni ³⁺ , Mn ⁴ A tissue adhesion inhibitor, characterized in that at least one member selected from the group consisting of ⁺ , Sn ⁴⁺ , Cr ⁶⁺ and Mn ⁷⁺ .
2. The tissue adhesion inhibitor of claim 1, wherein the viscosity is 1,000 to 9,000 cps.
The tissue adhesion inhibitor of claim 1, wherein the tissue adhesion inhibitor is in a gel state.
2. The tissue adhesion inhibitor according to claim 1, wherein the tissue adhesion inhibitor is in a film state.
2. The tissue adhesion inhibitor of claim 1, wherein the tissue adhesion inhibitor is in a powder state.
2. The tissue adhesion inhibitor of claim 1, wherein the tissue adhesion inhibitor is in a sponge state.
A polymer which forms a crosslink by the polyvalent cation by mixing 0.01-5% by weight of a hydrophilic natural polymer, a polymer which forms a crosslink by 0.01-4% by weight of a polyvalent cation, and a 0.01-2% by weight crosslinking agent in an aqueous solvent. At the same time cross-linking, the method of producing a tissue adhesion inhibitor comprising the step of physically blocking the hydrophilic polymer in the cross-linked polymer chain.
Preparing a mixed aqueous solution by adding a polymer forming a crosslink by 0.01-5% by weight of a hydrophilic natural polymer and 0.01-4% by weight of a polyvalent cation to an aqueous solvent; And
Adding an aqueous solution of a crosslinking agent in an amount of 0.01 to 2% by weight to the mixed aqueous solution to crosslink the polymer forming the crosslink by the polyvalent cation, and to physically block the hydrophilic polymer in the crosslinked polymer chain. Method for preparing a tissue adhesion inhibitor.
The method of claim 12, wherein the aqueous solution of the crosslinker further comprises a hydrophilic natural polymer.
The method of claim 12, wherein the aqueous solution of the crosslinker is spray sprayed or dropped into a droplet state.

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