TW201313261A - Adhesion-preventing agent and method for preventing adhesion using the same - Google Patents

Abstract

The present invention relates to an adhesion-preventing agent comprising hyaluronic acid, carboxymethyl cellulose, and alginate, and a method for preventing adhesion at the surface of local organs using the same. The adhesion-preventing agent comprising hyaluronic acid, carboxymethyl cellulose and alginate according to the present invention shows excellent biocompatibility, in vivo durability, and tissue adhesiveness, and ultimately exhibits excellent adhesion preventing effects.

Description

Anti-adhesion agent and method for preventing adhesion by using the anti-adhesion agent

The present invention relates to an anti-adhesion agent comprising hyaluronic acid, carboxymethyl cellulose, and alginate, and a method of preventing adhesion on a surface of a local organ using the anti-adhesion agent.

Postoperative adhesion of organs and tissues is a physiological phenomenon that occurs during cell proliferation and regeneration in wound tissue. However, the tissue is excessively or undesirably stuck to other tissues and organs, causing damage to the function of the organ or tissue. Therefore, a second operation for adhesion stripping is required, and some cases are even life-threatening.

In general, the frequency of adhesion after abdominal surgery is 60% to 95%, which causes pain, intestinal obstruction, or infertility. In particular, tissue adhesion is the main cause of intestinal obstruction (80% to 90%) and causes long-term complications and pelvic pain after gynecological surgery. Postoperative tissue adhesion may occur in all parts of the body. According to 2006 statistics, about 69,000 cases of tissue adhesion after spinal surgery (146 cases per 100,000 cases) and about 51,000 cases after hysterectomy (220 cases per 100,000 cases) ). Due to the gradual increase in the incidence, the prevention of adhesion has received much attention.

The method of preventing sticking is to reduce the size of the wound during surgery, use an anti-inflammatory agent, increase tPA activity, and use physical shielding. Physical shielding materials suitable for use as anti-adhesives should only be used as a shield during wound healing in the body. After a certain period of time, the materials should be removed by decomposition, and the materials used for the adhesive shielding should be non-toxic, and their decomposition by-products should be It is harmless.

Natural polymers used as anti-adhesive agents include bio-oriented natural polymers and non-bio-oriented natural polymers. Specifically, oxidized cellulose (OC), methyl cellulose, ethyl cellulose, dextran sulfate, hyaluronic acid (HA), collagen, fibrin, and gelatin are known to be useful. These materials are used alone or in combination.

Currently, British Teixido (Interceed ^TM) a biodegradable oxidized regenerated cellulose (ORC) made of (Johnson & Johnson Pharmaceuticals (Johnson & Johnson Medical, Inc. ), Arlington, Texas), was hyaluronic acid and carboxymethyl cellulose (CMC) by crosslinking of the film-type seats Pa membrane (Seprafilm ^TM) (Genzyme Corporation (Genzyme Corp.), Cambridgeshire Massachusetts), and was a simple mixture of HA and CMC of the gel type GuardixTM ⁽ developed by Biorane, manufactured by Hanmi Pharmaceutical Co.) has been commercially available and widely used as an anti-adhesive.

British Teixido ^TM a non-biological material comprises oxidized regenerated cellulose (ORC) as a main component, and thus has poor bio-compatibility. Moreover, because Intex is a fabric type with a large pore size, it has been reported in many animal experiments that cells and blood proteins easily penetrate the shield, so its efficacy as an anti-adhesive shield is low (Surgical Research Journal 1997, 68:126-132).

XI Pa ^TM film including urea N- acyl side chain group, the system group using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (PEI) (EDC) As a crosslinking activator, it is formed by reacting HA and CMC in a ratio of 2:1 (U.S. Patent Nos. 5,017,229, 5,527,893 and 5,760,200). The preparation method of the derivative disclosed in the aforementioned patent includes a procedure for preparing a film by drying a crosslinking activator EDC together with a mixture of HA and CMC, and then removing unreacted substances and impurities therefrom to prepare a derivative.

XI Pa film ^TM (Seprafilm ^TM) derived homogeneous thin-film, and the HA derivative (about 66% decomposition) was based preliminary decomposition, and CMC derivatives (33%) is maintained unnecessarily long in vivo. In addition, fine pores are formed during the process of removing impurities from the film, and thus may be fragile and difficult to handle when dried. The film also tends to roll up when exposed to water, depending on where it is applied, resulting in different results. Therefore, the effect has not been clearly verified.

Best Jordi ^{TM (Guardix TM)} issues prepared by mixing the HA and CMC in that when directly used, it is very rapidly absorbed hyaluronic acid, thus preventing the adhesion-reducing effect.

As described above, bio-oriented polymers and non-bio-oriented polymers have been used to prevent sticking, but it is difficult to obtain a satisfactory preventive sticking effect. Non-biologically oriented polymers exhibit significantly lower biocompatibility compared to bio-oriented polymers and remain in the body for extended periods of time due to the lack of enzymes in the body, which may cause side effects such as undesired tissue reactions. The bio-oriented polymer exhibits excellent biocompatibility, but it is difficult to anticipate the effect of sticking due to its short absorption time. In order to overcome such problems, attempts have been made to improve biocompatibility and in vivo durability by mixing non-biooriented polymers with natural polymers in an appropriate ratio. However, there is such a problem that the adhesion prevention effect is not satisfactory.

The present inventors have devoted themselves to developing an anti-adhesive agent which is excellent in display. Different biocompatibility, in vivo durability and tissue adhesion, and ultimately have excellent anti-sticking effect. As a result, the inventors have found that an anti-adherent agent comprising hyaluronic acid, carboxymethylcellulose, and alginate exhibits excellent biocompatibility, in vivo durability, and tissue adhesion, and finally has excellent anti-sticking properties. The sticking effect, thus completing the present invention.

It is an object of the present invention to provide an anti-adherent agent comprising hyaluronic acid, carboxymethyl cellulose, and alginate.

Another object of the present invention is to provide a method of preventing sticking comprising the step of contacting an anti-adhesive agent onto the surface of a local organ of an animal.

The anti-adhesion agent containing hyaluronic acid, carboxymethyl cellulose, and alginate according to the present invention exhibits excellent biocompatibility, in vivo durability, and tissue adhesion, and finally has excellent anti-sticking effect. .

Further, the anti-adhesion agent of the present invention can prevent intraperitoneal bleeding, and thus can be used as a post-operative anti-adhesion agent or a hemostatic agent.

[Best mode]

In one aspect, in order to achieve the foregoing objects, the present invention provides an anti-adhesion agent comprising hyaluronic acid, carboxymethylcellulose, and alginate.

As used herein, the term "sticking" refers to the adhesion of skin or film that should substantially separate from each other. Viscosity due to tissue injury (such as surgery, inflammation, foreign body, bleeding, infection, cuts, abrasions, and chemotherapy) after wound healing and repair process exudation and blood coagulation and surrounding tissue Caused by abnormal adhesion. Stickiness often occurs after surgery. When it is sticky in the pelvic cavity, it may cause chronic pain, sexual dysfunction, and the like. After the thyroid is removed, the adhesion caused by the formation of scar tissue causes side effects such as chest pain and reduced swallowing ability. The adhesion caused by spinal surgery causes sharp pain due to nerve compression; while the adhesion of the endometrium can cause infertility, menstrual disorders, habitual abortion, and the like.

Hyaluronic acid (HA) is a linear polymer composed of D-glucuronic acid and D-N-ethionylglucosamine linked by β-1,4 and β-1,3 glycosidic bonds. The hyaluronic acid found in the body has a molecular weight of about 5,000 to 20,000,000 Daltons (Da), has no organ or species specificity, and has excellent biocompatibility and extremely high viscosity and elasticity.

The anti-adhesion agent of the present invention may comprise a hyaluronic acid polymer having an average molecular weight of 500,000 Daltons or more, and preferably 1,000,000 Daltons or more, and more preferably 500,000 to 10,000,000 Daltons, and even more preferably The hyaluronic acid polymer of 1,000,000 to 10,000,000 Daltons, and preferably an average molecular weight of 2,000,000 to 6,000,000 Daltons, is not limited thereto.

The anti-adherent of the present invention can be included in the optimal concentration of hyaluronic acid so that even after sterilization, the hyaluronic acid does not adhere to the tissue surface and adheres to the surface of the tissue.

Preferably, the hyaluronic acid is contained in an amount of from 0.1% by weight to 10% by weight, more preferably from 0.5% by weight to 3% by weight, and still more preferably 1% by weight, based on the total mass of the anti-sticking composition. If the content of hyaluronic acid is less than 0.1% by weight, the adhesion of the tissue is lowered when it contacts a local part. If hyaluronic acid content If it is more than 10% by weight, it is difficult to process and manufacture an anti-adhesive agent, and since the viscosity is high, the adhesion of the tissue is also lowered.

The hyaluronic acid may include hyaluronic acid and salts thereof, which may include, but are not limited to, sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate or tetrabutylammonium hyaluronate.

Hyaluronic acid can be obtained by cockerel extraction or by microbial fermentation, but is not limited thereto.

Carboxymethylcellulose (CMC) is a semi-synthetic hydrophilic cellulose derivative having a high viscosity and a molecular weight of 21,000 to 500,000 Daltons, which is prepared by introducing a glycolate group into a cellulose molecular unit. CMC is a white, yellow or gray granulated powder or fibrous powder which is hygroscopic, odorless and tasteless.

The carboxymethyl cellulose may be in the form of a sodium salt, a calcium salt, or a zinc salt, but is not limited thereto.

Carboxymethylcellulose is a hydrophilic derivative whose viscosity varies with the degree of substitution of the glycolate. The preferred degree of substitution of carboxymethylcellulose may range from 0.7 to 1.2, more preferably from 0.8 to 1.2, and still more preferably from 1.0 to 1.2.

The preferred viscosity of the carboxymethylcellulose may range from 25 to 4,500 centipoise (cP), more preferably from 1,000 to 4,000 centipoise, and still more preferably from 1,500 to 3,500 centipoise.

The anti-adhesive agent of the present invention can be finally prepared through a sterilization process to prevent microbial infection during surgery, and the preferred viscosity of the carboxymethylcellulose after sterilization can be 10 to 100 centipoise.

The anti-adhesive agent of the present invention may comprise carboxymethyl fiber having an appropriate viscosity Vitamins, to control tissue adhesion and in vivo durability, or for use in clinical trials using a spray gun to apply anti-adhesion to tissue. Preferably, when an carboxymethylcellulose having a viscosity falling within the foregoing range is used, the anti-adhesion agent has excellent tissue adhesion, and more specifically, the anti-adhesion agent has an excellent preventive effect. At the same time, carboxymethyl cellulose does not stay in the body for a long time.

Preferably, the content of carboxymethylcellulose may be from 0.1% by weight to 8% by weight, more preferably from 0.2% by weight to 5% by weight, and still more preferably 0.5, based on the total weight of the anti-stick composition. weight%.

Alginate may have alginic acid as a main component, which is composed of a chain of β-D-mannuronic acid and a chain of α-L-guluronic acid.

Alginates include, but are not limited to, for example, sodium alginate, calcium alginate, potassium alginate, and the like.

Alginate has a wide range of viscosities, and the anti-adherent of the present invention may include low or high viscosity alginate. The anti-adherent of the present invention may include alginate having an optimum viscosity to control tissue adhesion, or for application of an anti-adhesion agent to tissue using a spray gun in clinical trials. Preferably, the alginate may have a viscosity of from 10 to 900 centipoise, more preferably from 10 to 600 centipoise, and still more preferably from 20 to 200 centipoise. When an alginate having a viscosity falling within the foregoing range is used, the anti-adhesive agent has excellent tissue adhesion, thereby effectively preventing adhesion to the surface of a local organ.

Preferably, the alginate content may be from 0.01% by weight to 5% by weight, and more preferably 0.1% by weight, based on the total weight of the anti-stick composition. If the content of alginate is less than 0.01% by weight, the effect is reduced due to low concentration. low. If the content of alginate is more than 5% by weight, biocompatibility is reduced.

The content of hyaluronic acid, carboxymethyl cellulose, and alginate can be appropriately controlled in consideration of the decomposing nature of the body, the formulation properties of the anti-adhesive agent, and the nature of the site to be treated (tissue, organ, region, etc.).

Preferably, the anti-adhesive agent of the present invention may comprise a content of 0.1% by weight to 10% by weight, 0.1% by weight to 8% by weight, and 0.01% by weight to 5% by weight, respectively, based on the total weight of the composition. Hyaluronic acid, carboxymethylcellulose, and alginate, and other residual materials (such as buffers, isotonic agents, excipients, preservatives, etc.) required for the preparation of anti-adhesion agents. More preferably, the anti-adherent agent may include 0.5% by weight to 3% by weight of hyaluronic acid, 0.2% by weight to 5% by weight of carboxymethylcellulose, 0.01% by weight to 5% by weight of alginate, and anti-sticking agent. Other remaining materials required for the preparation of the adhesive.

The anti-adhesive of the present invention may have an optimum viscosity and thus will not adhere to the surface of the tissue as it flows down the tissue, and preferably has a viscosity of from 400 to 1000 centipoise.

The anti-adherent of the present invention may be a formulation selected from the group consisting of powders, granules, gels, sols, solutions, and films, but is not limited thereto. The formulation may vary depending on the scope of clinical application. For example, a solution type anti-adhesion agent can be prepared as follows. The alginate is dissolved in a buffer, microorganisms are removed therefrom, and carboxymethylcellulose is added thereto, followed by stirring. Subsequently, hyaluronic acid is added to the mixture, followed by stirring and sterilization. At this time, the viscosity of the anti-adhesion agent can be controlled by changing the sterilization time.

For example, a film type anti-adhesive can also be prepared as follows. Uric acid, carboxymethylcellulose, and alginate are dissolved in a buffer, followed by stirring and drying.

Preferably, the anti-adhesive agent of the present invention has a synergistic effect of preventing adhesion and hemostasis by synergistic synergistic effects between the respective components. In a specific embodiment of the present invention, the anti-adhesion agent of the present invention is tested for the prevention of intraperitoneal bleeding compared to a mixture of hyaluronic acid and carboxymethylcellulose, and the results show that the intraperitoneal bleeding can be significantly reduced (Fig. 3). . Therefore, the anti-adhesive agent of the present invention exhibits a hemostatic effect as well as an excellent preventive adhesion effect, and thus can be used for preventing bleeding of a tissue and bleeding at a surgical site during surgery.

At the same time, there have been many attempts to prevent post-adhesion by preparing anti-adhesion agents by a combination of various bio-oriented polymers and non-bio-oriented polymers. However, when an anti-adhesion agent is prepared by mixing a polymer known to have a tack-preventing effect, the anti-adhesive agent exhibits excellent biocompatibility, but has tissue adhesion, in vivo durability, and prevention of adhesion. In contrast, the anti-adhesive agent does not exhibit satisfactory effects; or the anti-adhesive agent exhibits a slight preventive effect, but causes side effects due to low biocompatibility. Therefore, by selecting appropriate bio-orientation polymers and non-bio-oriented polymers, it is excellent in anti-sticking in terms of biocompatibility, tissue adhesion, in vivo durability, and especially in preventing adhesion. There are many difficulties on the adhesive. Under such circumstances, the inventors have endeavored to find a combination of substances exhibiting excellent biocompatibility, tissue adhesion, and in vivo durability, and excellent prevention of adhesion. As a result, the inventors have developed an anti-adherent agent including hyaluronic acid, carboxymethyl cellulose, and alginate. The anti-adhesive agent of the invention comprises a large number of bio-oriented polymers and non-biological The hyaluronic acid, carboxymethylcellulose, and alginate selected from the tropic polymer have an excellent biocompatibility, tissue adhesion, and in vivo durability, and have a hemostatic effect. Ultimately, it has an excellent anti-sticking effect.

More specifically, in one embodiment of the present invention, the anti-adherent effect of the anti-adhesive agent comprising the mixture of hyaluronic acid, carboxymethyl cellulose, and alginate is combined with hyaluronic acid and carboxymethyl The anti-adhesive agent (control group) of the mixture of the base cellulose was compared. The results of gross anatomy of the experimental animals and histological observations showed that the control group (Fig. 1 and Fig. 2) was resistant to sticking in terms of sticking grade, sticking strength and sticking area. The agent showed excellent anti-adhesive effects, and in clinical studies, postoperative endometrial adhesions were significantly reduced in different patient groups (Tables 5 to 8). In particular, the anti-adherent of the present invention is useful for patients suffering from uterine fibroids or patients without endometrial adhesion, which can significantly prevent endometrial adhesion. Therefore, the anti-adhesive agent of the present invention can be used for preventing post-operative adhesion, and can also be used for preventing postoperative bleeding and sticking.

The anti-adherent of the present invention may further comprise a buffer solution. The buffer solution is used to maintain the pH of the solution by resisting sudden changes in pH. Preferred examples of the buffer solution may include phosphate buffer, histidine buffer, citrate buffer, tris buffer, and the like.

The anti-adherent of the present invention may further comprise an isotonic agent. When administered to a body as a solution, the isotonic agent is used to maintain osmotic pressure, and preferred examples of the isotonic agent may include amino acids, polyhydric alcohols, sodium chloride, and the like.

The anti-adhesive agent of the present invention may further comprise a pharmaceutically acceptable Shape agent. The excipient may include sugars and polyols, surfactants, polymers, and the like. Examples of the saccharides and polyhydric alcohols may include sucrose, trehalose, lactose, maltose, galactose, mannitol, sorbitol, glycerin, and the like. Examples of the surfactant may include a nonionic surfactant such as Polysorbate 20, Polysorbate 80, and

Isopropyl acrylamide (poloxamer). Examples of the polymer may include dextran, polyethylene glycol, polypropylene glycol, cyclodextrin, and the like.

Further, the anti-adherent of the present invention may further comprise a preservative. Examples of the preservative may include benzyl alcohol, cresol, alkyl p-hydroxybenzoate, phenol, and the like.

The foregoing additional substances may be used singly or in combination of two or more kinds thereof, and may be easily selected by a skilled person based on the formulation, use, and target site of the anti-adhesion agent.

In another aspect, the invention provides a method of preventing adhesion comprising the step of contacting an anti-adhesion agent of the invention with a surface of a local organ of an animal.

The term "contact" as used herein refers to the application, application, or attachment of an anti-adhesive to the surface of a local organ for the purpose of preventing surface adhesion (and hemostasis) of a local organ.

As used herein, the term "surface of a local organ" means that it is intended to prevent all or part of the surface of an organ or tissue from sticking due to surgery, such as surgery or certain diseases. The site or species of the organ is preferably, but not limited to, an organ other than the body (skin) surface of a mammal, including humans and laboratory animals such as mice, rats, hamsters, and rabbits. The organ includes, for example, Organized organs such as the stomach, small intestine and large intestine, reproductive organs such as the uterus and ovaries, respiratory organs such as the heart and lungs, moving organs such as muscles, bones and ligaments, and sensory organs such as the eyes. Preferably, it may be a reproductive organ such as the uterus and ovaries. The surface of a local organ is not limited to a specific state.

There are no special restrictions on the type of organ surgery. The surface of the local organ may be a direct target of the procedure, or a damaged portion that is not directly targeted by the procedure but is damaged by the surgical outcome.

In the process of contacting the anti-adhesive with the surface of the local organ, the form of the anti-adhesion agent or the percentage of the active ingredient may be appropriately determined depending on the type of the organ and tissue, and the state and area of the wound portion. The anti-adhesion dose to the surface of the local organ can be set such that the surface is properly covered.

[Invention Mode]

Hereinafter, the present invention will be described in further detail with reference to the embodiments. However, these examples are for illustrative purposes only and the invention is not limited thereto.

Comparative Example 1: Preparation of Phosphate Buffered Saline Solution (PBS)

A phosphate buffered saline solution to be used in this experiment was prepared.

Comparative Example 2: Preparation of a mixed solution of hyaluronic acid and carboxymethyl cellulose

To evaluate the prevention of adhesion, carboxymethylcellulose was dissolved in PBS buffer, hyaluronic acid was added to the mixture, followed by stirring until dissolved. According to the preparation method, the mixed solution of Comparative Example 2 shown in the following Table 1 was prepared.

Examples 1 and 2: Preparation of a mixed solution of hyaluronic acid, carboxymethyl cellulose, and alginate

To evaluate the prevention of adhesion, the alginate was dissolved in PBS buffer and sterilized. Then, carboxymethylcellulose was added thereto and stirred. Subsequently, hyaluronic acid was added to the mixture and stirred, and autoclaved to prepare a mixed solution of hyaluronic acid, carboxymethylcellulose, and alginate. At this time, a mixed solution having a high viscosity (Example 1) and a low viscosity (Example 2) was prepared by changing the sterilization time.

According to the preparation method, the mixed solutions of Examples 1 and 2 shown in Table 2 below were prepared.

Experimental Example 1: Test for anti-adhesion agent for preventing adhesion in animals - gross anatomical results

In order to evaluate the prevention of adhesion through gross anatomical results, the following experiment was performed. After anesthesia, the abdominal surface was cleaned using a povidone solution and after shaving the hair, the rat abdomen was cut with a 4 to 5 cm (cm) midline. The ileum is then removed and a bone drill with a size of approximately 1 x 2 cm is used to scratch and the opposite peritoneum is also injured by the same size. In order to connect the two injured surfaces, three scratches were made at intervals of 1 cm from the scratch wound to induce tissue sticking. Various experimental substances were injected therein. Survive until the end of the experiment The animals were sacrificed by using euthanasia using carbon dioxide gas, and pathological examinations were performed after gross dissection to record the adhesion grade, adhesion strength and adhesion area of each animal. The adherent site was fixed in 10% neutral fumarin for histological examination.

By means of gross anatomical results, Vlahos A, Yu P, Lucas CE, Ledgerwood AM, chitin and polyoxyalkylene copolymer gel composite membranes were used for postoperative adhesion interaction according to the method of Vlahos et al. Effect, a composite membrane of chitosan and Poloxamer gel on post operative adhesive interactions The American Surgeon, 2001, 67: 15-21. In detail, measure and evaluate the adhesion level of the sticky part (0 -5, Table 3), the adhesion strength (1-4, Table 4) based on the hand-separated adhesive parts, and the area of the adhesive part, the results are shown in Fig. 1.

As shown in Fig. 1, the anti-adhesion agent of the present invention prepared by mixing hyaluronic acid, carboxymethyl cellulose and alginate in terms of sticking grade, adhesive strength, and sticking area (Example 1 and 2), compared with PBS (Comparative Example 1) or an anti-adherent prepared by mixing hyaluronic acid and carboxymethylcellulose (Comparative Example 2), the anti-adhesive agent of the present invention shows superior anti-adhesion. Sticky effect.

Experimental Example 2: Anti-adherent test for the prevention of adhesion in animals - histological observation

The prevention of adhesion was evaluated by histological observation based on fibrosis of the adherent site, granulation tissue formation, giant cell infiltration, and macrophage infiltration. Four-week-old Sprague-Dawley rats (CrjBgi: CD ^® (SD) IGS) were supplied by Orient Co. and served as experimental animals. After 14 days of isolation/accitation, healthy animals showing no change in body weight and without any general symptoms were shaved, and animals showing good skin condition were selected for the experiment. The initial body weight of the rat ranged from 92 grams to 125 grams.

The cecal/abdominal wall of the ileum was removed from all rats and fixed in 10% neutral formalin solution, followed by general tissue fixation and H&E staining. color. In histological observation, the fibrosis was scored on a scale of 0 to 3. Data from gross pathology and histology observations were scored and evaluated by a Bartlett test at a = 0.05. When the single factor ANOVA obtained significant results, the Kruskal-Wallis test was performed at α = 0.05. When the results of the one-way ANOVA were significant, the significant results were compared between the control group and the experimental group by the Bonferroni multiple comparison test. When the results of the Ku-Wah test were significant, the significant results were compared between the control and experimental groups by the Dunn test.

As shown in Figure 2, the tissue was collected from the adherent site and stained for observation. The results show that the tissue treated with the anti-adherent agent of the present invention containing hyaluronic acid, carboxymethylcellulose and alginate (Example 1), when compared with the tissue treated with PBS (Comparative Example 1), the present invention Anti-adhesives showed a significantly slow rate of fibrosis progression (Figure 2).

Experimental Example 3: Test for prevention of intraperitoneal bleeding by anti-adhesion agent

In order to evaluate the efficacy of anti-adhesion agents for preventing intraperitoneal bleeding, the following experiment was conducted. Rats (350 g) were anesthetized with urethane, and then the abdominal cavity was opened by a midline incision and a 0.5 cm incision at the end of the spleen. A phosphate buffered saline solution (PBS), a commercially available anti-adhesive product (Jialdi, Hammi Pharmaceutical Co., Ltd.), or 1 ml of each of the anti-adherent agents of the present invention was applied to the incision site of the spleen. The abdomen incision site is then sutured using sutures. Four hours later, the abdomen was cut, the abdominal cavity was wiped with gauze, and the gauze was weighed. The yarn was placed in 30 ml of distilled water. Then, using the bank Kuang Kang (QuantiChrom ^TM) assay kit heme group (biological assay systems Catalog number DIHB-250) to determine the quantitative concentration of hemoglobin intraperitoneal hemorrhage. The results are shown in Figure 3.

As shown in Fig. 3, the anti-adhesive agent containing hyaluronic acid, carboxymethyl cellulose, and alginate of the present invention was found to be compatible with commercially available anti-adhesive products (Jialdi, hyaluronic acid and carboxymethyl cellulose). The anti-adherent of the present invention significantly reduces intra-peritoneal bleeding when compared to the mixed composition (Fig. 3).

Experimental Example 4: Anti-adherent for clinical studies in patients with uterine fibroids

In order to evaluate the composition and the hyaluronic effect and safety of the composition of Example 1 and hyaluronic acid and carboxymethylcellulose of Jiaerdi-Sol (Hammi Pharmaceutical Co., Ltd.) after intrauterine surgery, multicenter single blindness was performed. Randomized controlled trials.

The clinical trials were conducted in a multicenter, and patients scheduled for intrauterine surgery were enrolled in a 1:1 ratio for use in experimental medical devices or control medical devices. After random assignment, the patient undergoes intrauterine surgery, and the medical device for clinical research is applied to the surgical site. At this time, the application volume is not more than 10 ml. After the operation, the patient is observed for a predetermined period of time to see if an abdominal reaction has occurred. Then, an observation visit is made. A colposcopy was performed at the last visit to assess the presence of endometrial adhesion, adherence area, and adherence. Photographs were taken and used to assess endometrial adhesion. This clinical study is a single-blind test. However, after the first and second efficacy tests, all 12 centers were evaluated by an intermediate assessor in a blinded condition to maintain the evaluator's blindness.

As shown in Table 5, after treatment with Guardian for patients with uterine fibroids, 5 of 53 patients developed endometrial adhesion (incidence rate: 9.43%). Conversely, after treatment of patients with uterine fibroids using the anti-adhesion agent of Example 1, one of 54 patients developed endometrial adhesion (incidence rate: 1.85%), which was noted in clinical studies. Excellent anti-adhesion effect (Table 5).

As shown in Table 6, after treatment with Guardian-free uterine fibroids, 10 of 31 patients developed endometrial adhesion (incidence rate: 32.26%). Conversely, after treatment of patients without uterine fibroids using the anti-adhesion agent of Example 1, 7 of 34 patients developed endometrial adhesion (incidence rate: 20.59%), which was noted in clinical studies. The preventive adhesion effect (Table 6).

As shown in Table 7, after treatment with a patient with endometrial adhesion with Jaldi, 7 of 14 patients developed endometrial adhesion (incidence rate: 50%). Conversely, after treatment of patients with endometrial adhesion using the anti-adhesion agent of Example 1, 7 of 15 patients developed endometrial adhesion (incidence rate: 46.67%) in clinical studies. Indicates excellent preventive adhesion effects (Table 7).

As shown in Table 8, after treatment with a patient without endometrial adhesions, 8 of 70 patients developed endometrial adhesion (incidence rate: 11.43%). Conversely, after treatment with the anti-adhesion agent of Example 1 for endometrial adhesion, one of 73 patients developed endometrial adhesion (incidence rate: 1.37%) in clinical studies. Point out the excellent preventive adhesion effect (Table 8).

In summary, the results of Tables 5 to 8 show that when it is commercially resistant to sticking In comparison with the drug product Gardi, the anti-adhesive agent containing hyaluronic acid, carboxymethylcellulose and alginate of the present invention showed excellent anti-adhesion effect in each group of patients.

Fig. 1 is a view showing the preventive adhesion effect of the anti-adherent agents (Examples 1 and 2) and the control group (Comparative Examples 1 and 2) of the present invention, as seen from the general anatomy of the experimental animals; An image showing the preventive adhesion effect of the anti-adherent agent of the present invention (Example 1, B) and the control group (Comparative Example 1, A) by histopathological observation of the experimental animal, wherein the arrow indicates the indication The length of the formed granulation tissue; and Fig. 3 is a diagram showing the prevention of intraperitoneal bleeding by the anti-adhesion agent (HA/CMC/alginate) of the present invention and a mixed composition of hyaluronic acid and carboxymethylcellulose (commercially available) The effect.

The representative figure has no component symbols and the meaning of its representation.

Claims (14)

An anti-sticking agent, including hyaluronic acid, carboxymethyl cellulose and alginate. The anti-adhesion agent of claim 1, wherein the hyaluronic acid has a molecular weight of from 500,000 Daltons (Da) to 10,000,000 Daltons. The anti-adhesion agent of claim 2, wherein the hyaluronic acid has a molecular weight of from 1,000,000 Daltons to 10,000,000 Daltons. The anti-adhesion agent of claim 1, wherein the anti-adherent agent comprises 0.1% by weight to 10% by weight of the hyaluronic acid based on the total weight of the anti-adhesive agent. The anti-adhesion agent of claim 4, wherein the anti-adhesion agent comprises 0.5% by weight to 3% by weight of the hyaluronic acid based on the total weight of the anti-adhesive agent. The anti-adhesion agent of claim 1, wherein the anti-adhesive agent comprises 0.1% by weight to 8% by weight of the carboxymethyl cellulose based on the total weight of the anti-adhesive agent. . The anti-adhesion agent of claim 6, wherein the anti-adhesive agent comprises 0.2% by weight to 5% by weight of the carboxymethyl cellulose based on the total weight of the anti-adhesive agent. . The anti-adhesion agent of claim 1, wherein the anti-adherent agent comprises 0.01% by weight to 5% by weight of the alginate based on the total weight of the anti-adhesive agent. For example, the anti-adhesive agent described in claim 1 of the patent scope, wherein Based on the total weight of the adhesive, the anti-adhesive agent comprises 0.1% by weight to 10% by weight of the hyaluronic acid, 0.1% by weight to 8% by weight of the carboxymethylcellulose, and 0.01% by weight to 5% by weight. The alginate. The anti-adhesion agent of claim 1, wherein the viscosity is from 400 centipoise (cp) to 1000 centipoise. The anti-adherent agent of claim 1, wherein the anti-adherent agent is a formulation selected from the group consisting of powder, granule, gel, sol, solution and film formulation. The anti-adhesive agent described in claim 1 is for preventing adhesion of the endometrium. The anti-adhesion agent of claim 1, wherein the anti-adhesive agent further has a hemostatic effect. A method of preventing adhesion comprising the step of contacting the surface of a part of an individual's organ with an anti-adhesive agent as described in any one of claims 1 to 13.