KR20020031351A - Antiadhesion barrier containing water-soluble alginate and carboxymethyl cellulose as major components and preparation method thereof - Google Patents

Abstract

PURPOSE: Provided are an antiadhesion barrier preventive of the formation of adhesions attributable to surgical operation, infection, trauma, etc. and a method for preparing such an antiadhesion barrier. CONSTITUTION: The antiadhesion barrier is composed mainly of water-soluble and carboxymethyl cellulose with the alginate crosslinked by calcium ions. The barrier has a semi-interpenetrating network structure as a result of the crosslinking of the alginate with the calcium ions. In addition, to be superb in reattachment and bioreadhesiveness, the antiadhesion barrier shows high structural integrity maintenance and retains a certain degree or higher of strength even in a wet state. Also, it lacks blood anticoagulant effects, so that it can be applied for the surgical operations in which the surgical sites are relatively large or bleeding flows profusely. It can effectively prevent the formation of adhesion during injury healing. Further, the antiadhesion barrier is easy to handle and useful in surgical operations and secondary operative procedures.

Description

Anti-adhesion agent based on water-soluble alginate and carboxymethyl cellulose, and a method for preparing the same {Antiadhesion barrier containing water-soluble alginate and carboxymethyl cellulose as major components and preparation method

Excessive fibrous tissue in the course of natural wound healing during surgical injury or tissue damage caused by inflammation or the like causes abnormal junctions with surrounding tissues. adhesion). In general, adhesions occur at a frequency of 67 to 93% after open surgery, and some of them spontaneously decompose, but in most cases, adhesions exist even after wound healing, causing various sequelae. The sequelae caused by this adhesion include intestinal dysfunction, intestinal obstruction, and chronic pain in the case of abdominal surgery. In particular, the adhesion after obstetric surgery is known to cause infertility ( Eur. J. Surg . 1997 , Suppl 577). , 32-39).

Unlike skin, when wounds occur in vivo, a general healing process is the release of plasma fibrin (serofibrinous exudate) around the wound or inflamed area, fibrin deposits, and adhesion to other tissues within 3 hours. It will form a fibrin matrix. Normally, the fibrin matrix thus formed disappears within a few days by being decomposed and absorbed by proteolytic enzymes in vivo, but most of the fibrin matrix is excessively generated and accumulated beyond the tissue's own degrading capacity and accumulates around the wound and adheres to surrounding tissues. Causes adhesion in the body. Adhesion occurs by this series of fibrinogenesis and fibrinolysis, but the relationship between them is not simple ( Eur. J. Surg. 1997 , Suppl 577 , 10-16; Eur. J. Surg. 1997 , Suppl 577 , 24-31) closely related to the healing process of wounds. In general, when a wound occurs in the body due to any cause, it is known that it takes about a week for the wound to return to its original state through normal healing process ( Surgery 1995 , 117 , 663-). 669). Therefore, in order to use adjuvant for the purpose of preventing adhesion, it is necessary to isolate the surgical site or wound from other tissues around the area for at least one week, or to administer the drug to block the intermediate stage of adhesion.

Drugs mainly used for the prevention of adhesions include non-steroidal anti-inflammatory drugs, anticoagulants, and protein hydrolysates (eg, t-PA). Most of these drugs except tissue plasminogen activator (t-PA) are drugs that inhibit the deposition of fibrin that occurs naturally during wound healing, and thus have side effects that slow the healing of wounds compared to the anti-adhesion effect to be achieved. There is a problem that causes it. Therefore, great care is needed in using these drugs as anti-adhesion agents ( Eur. J. Surg . 1997 , Suppl 577 , 32-39; Fertil. Steril., 1994 , 61 , 219).

Apart from the use of these drugs, recent studies on antiadhesion barriers that can block contact with surrounding tissues by covering or covering postoperative wounds have been actively conducted. Methods of using biopolymers having carboxy end groups have been studied. They are hydrated in vivo to isolate the wound from surrounding tissues during wound healing, preventing adhesions from occurring, and once healed, they are naturally removed and do not affect normal tissue.

An example of such a biopolymer is hyaluronic acid (HA) used in USP 4,141,973. However, since HA decomposes and absorbs in a relatively fast time in vivo, there is a limitation in performance as an anti-adhesion agent.

In addition, methyl cellulose and its derivatives are also known to prevent adhesion, and there is an example using sodium carboxymethyl cellulose (SCMC) as a representative material (Fertil. Steril., 1984 Jun, 41: 6, 926-928). Fertil. Steril., 1984 Jun, 41: 6, 929-932; Am J. Obstet.Gynecol., 1986, 155: 3, 667-670). However, solutions of such polymers are also absorbed too quickly and cannot exhibit the desired anti-adhesion effect. Therefore, a method of forming intramolecular crosslinks has been proposed as a method of reducing the water solubility of such biopolymers and preventing their degradation and absorption.

EP 507,604 discloses a method of using polysaccharides having carboxy end groups as ionic bonds by reducing the solubility by ionic bonding with polyvalent metal ions. This is a good way to extend the residence time in the abdominal cavity, but simply because of the long residence time in the abdominal cavity does not prevent the adhesion. In other words, metal ions excessively used to make metal ions may act as a cause of adhesion in the abdominal cavity ( Eur. J. Surg . 1997 , Suppl 577 , 32-39). In addition, polysaccharides form a rigid hydrogel or film by metal ions, but the film thus produced has a disadvantage of being easily broken.

On the other hand, USP 5,266,326 discloses a method of producing alginate hydrogels crosslinked with metal ions on the wound in vivo by simultaneously injecting sodium alginate (SA) solution and metal ion solution using a specially designed syringe. Presented. This so-called in situ gelation method, in which the formulation is administered at the same time as the solution, has the advantage that the two fluid solutions have a rigid hydrogel in the body, but does not consider the tissue adhesion of the formulation. to be. That is, when a solution formulation is administered with a crosslinking agent, the crosslinked solution from the surface loses adhesion to the tissues and thus does not effectively prevent adhesion, and the adhesion phenomenon caused by the overdosed metal ion solution is different from the abdominal cavity. It can happen anywhere. In addition, there is a disadvantage that the device for the procedure is complicated.

USP 5,318,780 also discloses an anti-adhesion method using an in situ gelation method, which is a membrane-forming polymer (eg, hydroxypropyl methyl cellulose (HPMC)) and an ion. It is a technique to mix the polysaccharide and add the metal ions to it at the same time to produce a film to prevent adhesion in the body. The method has the advantage that a film is formed in the body at the same time as the biological administration, but the ionic polysaccharide-metal ion compound used does not have any adhesion to the biological tissue, and the film-forming polymer also adheres to the biological tissue. It cannot be used as an anti-adhesion film for the required period at the desired wound site. In addition, once the gel formulation is applied to the wound site by using the in-situ gellation method, there is a drawback that there is no re-adhesiveness of the formulation.

USP 5,017,229; USP 5,527,893; USP 5,760,200 et al. Described a method for preventing adhesion by using HA (hyaluronic acid) and CMC (carboxymethyl cellulose). When HA and CMC are the main components and EDC [1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride] is reacted, a part of them reacts with the carboxy terminal group and becomes positively charged, which is negatively charged carboxy terminal group. Spontaneously form a polyelectrolyte complex. It is a compound in which positive and negative charges coexist in a polymer, and this type of compound has a hydrogel structure that is not easily decomposed or dissolved by ionic bonds in the polymer itself. Drying the hydrogel creates a barrier that has great absorbency and is not easily degraded in vivo. However, since the EDC used at this time has a biotoxicity, it must be dialyzed for a long time to remove it during the manufacturing process, and since HA, a raw material, is a very expensive material, there is a problem in that the cost of the film to be manufactured is high. In addition, the film produced by the patent is very fragile due to its weak flexibility and strength during drying and gelation at a rapid rate as the hydration proceeds. Is difficult to handle and carry out such procedures that cannot be removed and re-treated (Surg. Clin. Nor. Am., 1997, 77: 3, 671-688).

US Pat. No. 5,906,997 shows a method for preparing an anti-adhesion agent having low water solubility by appropriately adjusting pH using carboxypolysaccharide (CPS) and polyether (PE) as main components. It is known that film formulations prepared by the techniques of this patent may also have relatively high moisture content and hence adhesion to tissues. However, since the driving force of the tissue adhesion of the film is hydration, it cannot exhibit adhesion with tissue after being saturated with water. Therefore, there is a need for a method that can maintain adhesion with tissue even after the film is saturated with moisture.

Bioadhesion refers to a phenomenon in which a polymer, a biopolymer, or a biological tissue is bonded to another biological tissue. Such bioadhesion is commonly observed in nature ( J. Controlled Release 1985 , 2 , 257), and in dentistry and orthopedics, bioadhesion is commonly used to adhere adjuvant to living organisms. Adhesion in Biological Systems Academic Press NY, 1970 ). The adhesion between the polymer and the biological tissue is largely divided into chemical bonds, van der Waals or similar forces, and the polymer and the surface structure of the tissue. Many hypotheses have been proposed to explain this adhesion phenomenon ( Bioadhesive Drug Delivery Systems, CRC Press, 1990 ). However, in the adhesion between the thin film and the biological tissue, the first step of the thin film and the tissue may be hydration or hydrogen bonding. It is known that carboxy end groups penetrate each other's tissues and form adhesion when adhesion occurs and the adhesion reaches equilibrium ( Macromolecules, 1980 , 13 , 880). At this time, the property affecting the adhesion by the initial hydration action (tackiness), after the completion of the hydration (hydration) is the property that affects the adhesion when bonded by direct intermolecular bonding (adherence) do. In addition, the adhesion of biopolymers or synthetic polymers to biological tissues also consists of two stages: adhesion by hydration and adhesion between polymers and tissues due to intermolecular bonding of polymers themselves ( J. Pharm Sci. 1982 , 71). , 975; J. Pharm. Pharmacol. 1982 , 34 , 70).

There are several factors that determine the adhesion of the polymer itself to the biological tissues after the adhesion is completed. However, as described above, the carboxy terminal groups present on the surface of the polymer adhered to each other. Diffusion theory of diffusion, entanglement and adhesion is the most commonly accepted ( J. Controlled Release 1985 , 2 , 257).

The adhesion phenomenon of the general hydrophilic biopolymers to the biological tissues has the greatest effect on the initial adhesion regardless of the composition and structure of the hydrophilic biopolymers. A polymer having a carboxy end group capable of binding itself to a biological tissue should be used. In the case of gel formulation, the polymer itself is more important because it is already saturated with water.

On the other hand, the formulation of the anti-adhesion agent may be divided into a solution formulation, gel formulation and film formulation.

Since severe damage to skin or tissues can cause adhesions between tissues, recent surgical techniques have tended to change the direction of reducing skin and tissue scars and minimizing tissue damage. Further, this was so even be obtained because of the side effects such as changes in surgical technique to prevent adhesion (Hepato-Gastroenterol, 1991, 38 , 283). Recent developments in anti-adhesions have led to the development of solutions or gel formulations in response to changes in surgical techniques ( The Adhesion Prevention Opportunity , Report from MDI, 1998 ). The solution form is a method of administering a large amount of solution formulation after surgery in the abdominal cavity or pelvic cavity, which is a kind of anti-adhesion method that has been tried in various ways from the early days when the intraperitoneal adhesion phenomenon is known. However, although it is excreted within two to three days by the body's excretion, it is not widely used due to the psychological burden of overdosing foreign bodies ( Eur. J. Surg . 1997 , Suppl 577 , 32-). 39). On the other hand, gel formulation is a method recently attracted attention in that it can effectively prevent adhesion by using only a small amount on the wound site. To date, gel formulations have been developed that can be used in a limited manner such as lumbar and dry surgery (USP 5,605,938). The technique is characterized by a composition consisting of dextran sulfate as an active substance and the addition of a protein adhesive to the dextran sulfate to prevent access to the glia cells involved in the production of fibrous tissue. It was focused on the fact that it is a characteristic compound. However, the technique has a disadvantage in that dextran sulfate cannot be used for a relatively large surgical site or a bleeding surgery because of the property of inhibiting coagulation of blood. Therefore, the formulation can be used only for micro-surgery such as tendon surgery or lumbar surgery, but gel formulation has many advantages such as ease of use and prevention of unintentional adhesion.

In addition, in the case of a film-type anti-adhesion agent, the necessity of detaching and reattaching soon after the procedure often occurs. Therefore, when formulated in the form of a film, it is desirable to have excellent initial adhesion as well as readhesiveness of the anti-adhesion agent.

As described above, while trying to solve the problems of the conventional anti-adhesion agent and develop an anti-adhesion agent having desirable tissue adhesion, morphological performance in vivo and a function as a barrier, the present inventors are soluble alginate and carboxymethyl The present invention has been completed by revealing that the anti-adhesion agent of semi-IPN structure, which selectively crosslinks only water-soluble alginate with calcium ions in an appropriate concentration with cellulose as its main component, can be used as an effective anti-adhesion agent by showing high adhesion and form retention performance. It was.

Summary of the Invention

It is an object of the present invention to provide new compositions and methods of anti-adhesion agents that can reduce the occurrence of adhesions during and after surgery as well as prevent the occurrence of new adhesions. The anti-adhesion agent of the present invention can be used to prevent the recurrence of adhesion during reoperation performed to remove the adhesion developed in the first surgery.

It is another object of the present invention to provide an inexpensive anti-adhesion agent which can maintain its shape at an early stage which is very important in wound healing process.

It is also an object of the present invention to provide an anti-adhesion agent that is not only easy to handle and use, but also suitable for tissue morphology, flexible, and of such strength that it is not easily broken.

In addition, it is an object of the present invention to provide an anti-adhesion agent that enables re-separation after attachment to tissues by maintaining strength at a certain degree or more even when wet.

In addition, it is an object of the present invention to provide an anti-adhesion agent that is absorbed and excreted when wound healing is completed while maintaining a certain form in vivo until the self-healing reaction of the living body is completed.

Finally, it is an object of the present invention to provide an anti-adhesion agent capable of releasing drugs locally during wound healing by additionally introducing a suitable drug.

The present invention relates to an anti-adhesion agent for preventing adhesions caused by surgical operations, infections and traumas, and more particularly, based on water-soluble alginate and carboxymethyl cellulose. The present invention relates to an anti-adhesion agent and a method for producing the same, wherein the anti-adhesion agent has a semi-interpenetrating network structure by selectively crosslinking.

1 is a graph showing that a semi-IPN structured composition exhibits a similar adhesion tendency to carboxymethyl cellulose (CMC) rather than alginate.

Hereinafter, the present invention will be described in detail with reference to Examples.

However, the following examples are intended to illustrate the present invention, but the content of the present invention is not limited thereto.

In order to achieve the above object, the present invention provides an anti-adhesion agent, wherein the water-soluble alginate and carboxymethyl cellulose are the main components and the water-soluble alginate is selectively crosslinked by calcium ions.

The anti-adhesion agent is characterized in that the alginate has a semi-interpenetrating network (IPN) structure by selectively crosslinking with calcium ions.

In addition, the present invention provides a suitable calcium ion concentration so that the anti-adhesion agent can exhibit desirable adhesion, form retention performance and re-adhesion.

When the concentration of calcium ions in the anti-adhesion agent of the present invention is too high, not only alginate but also carboxymethyl cellulose may form crosslinks with calcium ions, and thus, may not form a semi-IPN structure, which is a structure of the present invention. As described above, the formulations in which both polymers participate in crosslinking show adhesiveness to tissues due to absorption of moisture at the beginning of the procedure, but after the saturation of moisture, they cannot exhibit adhesiveness to biological tissues. In addition, there is a possibility of new coalescence caused by excess metal ions. On the other hand, when the concentration of calcium ions is too low, crosslinking is insufficient to maintain the membrane between tissues for the time required for wound healing, to decompose and absorb, and thus to function as an anti-adhesion agent. Based on this fact, in the anti-adhesion agent of the present invention, the calcium ion that can be used preferably has a weight ratio of alginate to 1: 0.05-1: 0.2. When the amount of calcium ions is included in the above range, the carboxymethyl cellulose can crosslink only alginate without participating in the crosslinking to obtain a semi-IPN structure exhibiting effective anti-adhesion performance.

The present invention also provides a preferred ratio of alginate and carboxymethyl cellulose in order to maximize the performance of the anti-adhesion agent.

When the concentration of alginate in the anti-adhesion agent of the present invention is too high, the form of the formulation may be maintained for a longer period of time, but the adhesion with tissue cannot be guaranteed. On the other hand, when the concentration of carboxymethyl cellulose in the anti-adhesion agent is too low, absorption to the biological tissue is performed before the wound healing is completed, and thus it may not exhibit proper anti-adhesion performance. In consideration of this, in the anti-adhesion agent of the present invention, the preferred weight ratio of alginate is 90 to 10%, more preferably 50 to 10%. In addition, the weight ratio of carboxymethyl cellulose is 90 to 10%, and it is more preferable that it is 90 to 50%.

The anti-adhesion agent of the present invention can be prepared in gel formulation or film form.

In addition, the present invention adds an appropriate amount of calcium ion solution capable of crosslinking only alginate while slowly stirring the solution of alginate and carboxymethyl cellulose mixed powder in distilled water, or each alginate solution and carboxymethyl cellulose solution This method provides a method for preparing an anti-adhesion agent of a gel formulation by adding an appropriate amount of calcium ion solution capable of crosslinking only alginate by slowly mixing the mixture.

The present invention also provides an anti-adhesion agent in which the drug is released locally during the wound healing period by introducing an appropriate drug. Drugs that may be introduced therein include nonsteroidal anti-inflammatory agents, anticoagulants, proteolytic agents, growth hormones and the like.

Hereinafter, the present invention will be described in detail.

First, the definitions of terms used in the specification of the present invention are as follows.

"Water-soluble alginate" refers to water soluble in the metal salt of alginic acid copolymerized with mannuronic acid and guluronic acid. "Sodium alginate (SA)" means that the kind of metal ion in the water-soluble alginate is sodium. "Alginate" refers to a polymer in which the water-soluble alginate is dissolved in water and metal ions are dissociated.

"Sodium carboxymethyl cellulose (SCMC)" is a cellobiose unit is connected by a 1,4-glycosidic linkage, a part of the hydroxyl group of this cellobiose unit is carboxy The sodium salt of the polymer substituted by a methyl group. "Carboxymethyl cellulose (CMC)" refers to a polymer in which the SCMC is dissolved in water to dissociate sodium ions.

"Hydrogel" refers to a three-dimensional structure composed of hydrophilic polymers and containing a large amount of water. In addition, a "semi-interpenetrating network" refers to a structure in which only one of the two polymer components is selectively crosslinked without affecting one component. On the other hand, "IPN" refers to a structure in which two components of polymer are crosslinked without affecting other components.

The present invention is a composition of selectively crosslinking only the alginate component with calcium ion solution after mixing the water-soluble alginate solution and the SCMC solution, to prevent adhesion by applying to wounds in the biological tissues for reasons such as surgical operation. The purpose. The anti-adhesion agent of the present invention prepared as described above is easy to handle, excellent in tissue adhesion and re-adhesion, and can maximize the ability to maintain a shape in the abdominal cavity.

Formulations having excellent tissue adhesion and re-adhesion and morphology maintenance in vivo, which are the properties to be achieved in the present invention, can be obtained by controlling the amount of calcium solution added and the mixing ratio of SCMC and water-soluble alginate.

In the present invention, alginate is selectively ionically crosslinked with calcium ions to maximize its performance as a barrier, and the other uncrosslinked component, CMC, maximizes adhesion to biological tissues. According to such a configuration, the anti-adhesion agent of the present invention has a composition for maximally maintaining tissue adhesion, morphology retention performance in vivo, and function as a barrier. In particular, the anti-adhesion agent proposed in the present invention can be prepared both in the form of a gel form and a film form, the film formulation is to prevent the existing polysaccharide adhesion by improving the brittle properties that are characteristic of the general polysaccharide film Compared with the product, it is not easily broken and can be re-adhesive.

Sodium alginate (SA) is not only inexpensive, but also known to form a very hard hydrogel when crosslinked by divalent metal ions (particularly calcium ions). Also known as the "egg-box" model, this type of gel refers to the formation of calcium ions as eggs between the carboxy terminal groups of alginates and the carboxy terminal groups of alginates across it ( Biodegradable Hydrogels). for Drug Delivery , 1993 , p. 116). The binding strength between calcium ions and alginates is very strong, and the structure of calcium-alginate gels does not break well unless a chelating agent or a high concentration of magnesium ions or sodium ions are generally present. It is known. Alginate crosslinked by the metal ion in this way can increase the shape retention rate in the living body can exhibit a function as a protective film.

The present inventors have prepared the aqueous solution by mixing the two polymers of water-soluble alginate and SCMC in the preparation of the anti-adhesion agent and then selectively crosslinking only the alginate with calcium ions to maintain the morphology in the abdominal cavity for the period necessary for wound healing. While focusing on the adhesiveness by the CMC can maintain the adhesion with the tissue. In particular, the cross-linking conditions at this time is not physically crosslinked by ionic bonds with metal ions, not chemical bonds, so there is no need to worry about specific side effects in vivo.

SA, one of the biopolymers used in the present invention, is crosslinked in the presence of calcium ions to form a rigid hydrogel having the above-described egg-box structure. The range of values similar to SCMC, semi-IPN, IPN film and the like, but the re-adhesion and wet adhesion is very low (see Table 3 ). This result is due to the hydration of the film to some extent the initial adhesive force, but when the hydration reaction reaches an equilibrium, as described above, the carboxy terminal group of the alginate can participate in crosslinking and thus cannot exhibit adhesion to biological tissues. It can be said.

To address this reduction in adhesion, we introduced SCMC. SCMC is a kind of cellulose derivative and is a biopolymer having a certain amount of carboxyl end groups introduced into the cellulose unit, which is inexpensive and easy to obtain. In addition, when forming a thin film by forming an aqueous solution it can be easily produced as a stable film structure and has an excellent water absorption rate, as well as showing the adhesiveness by hydration as described above, by the diffusion of the carboxy terminal group of CMC It has excellent properties of adhesion with biological tissues.

In contrast to alginate, which combines with calcium ions to form a very robust hydrogel structure, CMC is not easily crosslinked by calcium, and SCMC solutions require high concentrations of calcium ions to make calcium ions and strong hydrogels. It is known to be necessary ( Biodegradable Hydrogels for Drug Delivery , 1993 , p. 119). This means that if the concentration of calcium ions is properly adjusted, CMC can be prepared in a formulation in which only alginate forms a rigid structure with calcium without forming crosslinks. As such, a structure in which only one polymer is selectively crosslinked without affecting one of the two polymer components is called a semi- interpenetrating network ( IPN ) structure. On the other hand, a structure in which two polymers are crosslinked without affecting other components is called an interpenetrating network (IPN) structure.

Thus, when SA and SCMC are the main ingredients and an appropriate amount of calcium ions is added thereto, alginate forms a solid hydrogel with calcium ions, and CMC does not participate in crosslinking and the network structure of alginate-calcium ions By being present in between, an effective semi-IPN structure can be formed.

A very important factor in determining this structure is the concentration of calcium ions added. In the case of film formulations with a very high concentration of calcium ions, as mentioned above, CMC is also crosslinked by calcium ions to form an IPN structure. After this saturation, the adhesiveness with the biological tissues cannot be exhibited, thereby deviating from the procedure site. In addition, since it has a very solid structure, the absorption and excretion of the formulation may not be possible even after a period required for wound healing, and an excessive amount of metal ions may be present in addition to the calcium ions participating in the crosslinking to cause new adhesion. On the other hand, formulations with too low amounts of calcium ions do not sufficiently crosslink and do not remain in vivo during wound healing due to overly rapid biodegradability and absorption of polysaccharides and thus cannot function as anti-adhesion agents.

Therefore, by appropriately adjusting the amount of calcium ions added, it is possible to prepare an anti-adhesion agent that can be easily handled, has excellent tissue adhesion and re-adhesion, and exhibits morphological retention in the abdominal cavity. Therefore, in the anti-adhesion agent composed of SA, SCMC, and calcium ions having a semi-IPN structure of the present invention, it is preferable that a suitable calcium ion has a weight ratio of alginate to 1: 0.05 to 1: 0.2. When the amount of calcium ions is included in the above range, the carboxymethyl cellulose can crosslink only alginate without participating in crosslinking, thereby obtaining a semi-IPN structure exhibiting effective anti-adhesion performance.

The ratio of SCMC and SA as well as the amount of calcium solution added is very important for preparing a formulation having excellent tissue adhesion and readhesiveness and morphological maintenance performance in vivo, which are the properties to be achieved in the present invention.

When the ratio of SCMC is too small, the prepared formulation is well maintained in vivo, but the tissue adhesion is insufficient. On the contrary, when the ratio of SA is too small, the ratio of bioavailability is lowered and is rapidly degraded and absorbed. The weight ratio of SCMC of the formulation having excellent tissue adhesion and in vivo shape retention performance obtained in the present invention is 90 to 10% and more preferably 90 to 50%, the weight ratio of SA is 90 to 10% and 50 to 10% desirable.

On the other hand, in order to test the adhesion between the anti-adhesion agent in the form of gel and film obtained in the present invention and the biological tissues, the following in vitro (in vitro) Adhesion test method and in vitro (ex vivoTwo methods of adhesion test were introduced. Where in vitro (in vitro)The adhesion test method refers to a method of testing adhesion using a solution that mimics a living tissue without directly using the living tissue.ex vivo)Adhesion test method is a method of using a part of the living tissue, but because the nature of the adhesion test can not be directly tested in vivo because the part of the living body is removed and used (Bioadhesive Drug Delivery SystemsCRC Press1990).

The adhesiveness of the gel formulation obtained in the present invention was measured using an in vitro adhesion test method. As a result, the semi-IPN structure composition showed a median degree of maximum adhesive strength of the gel of SA and CMC alone. And very low values for alginate-Ca ²⁺ or IPN formulations crosslinked with calcium ions (see Table 1 ).

In the case of gel formulations, there is no influence of adhesion by initial hydration, so the adhesion of the material itself has a major influence on in vitro adhesion. Since alginate and CMC are each bioadhesive and have no special interactions, the bioadhesiveness of a simple mixture of the two polymers represents the arithmetic mean of the bioadhesive properties of the two polymers. In this case, the alginate-Ca ²⁺ formulation crosslinked with the alginate component with calcium ions cannot exhibit adhesion to tissues, even in the case of the IPN formulation in which the two polymers are crosslinked, respectively.

In the case of a formulation in which the water-soluble alginate and SCMC mentioned in the present invention are the main components and crosslinking only the alginate with calcium ions, the alginate component is crosslinked with calcium ions to lose adhesiveness and the CMC exhibits bioadhesiveness of the formulation. do. The adhesion tendency of SA and SCMC shows different aspects. The adhesion tendency of gel formulations having the composition of the present invention exhibits the same appearance as SCMC, so that the gel formulation of the present invention selectively participates in crosslinking with only the alginate component. Indirectly proved that the presence (see Fig. 1 ).

Gel formulation having a semi-IPN structure of the present invention has the advantage that it can be used even in the case of a relatively large wound surgery because there is no anticoagulant effect such as dextran sulfate (as described above), The formulation itself has adhesion to biological tissues and thus has an effective anti-adhesion ability.

In practice, film-type anti-adhesions often need to be removed and reattached soon after the procedure ( The market for anti-adhesion products , Pieter Halter, Medical Data International, Mar, 2, 1996 ). In order to measure this, the re-adhesion test was performed along with the adhesion test in the dry state using an ex vivo adhesion test method (see Table 3 ). As already mentioned, in the case of the film formulation, the adhesion in the dried state is mainly caused by the hydration reaction, but in the saturated state of the water, the adhesion of the substance itself to the biological tissue is affected. That is, even though the adhesion in the dry state is similar, the adhesion in the hydrated state is different from each other.

According to Table 3 , the initial adhesion of the semi-IPN-structured film in dry state is similar to that of an alginate-Ca ²⁺ film or a film composed of SCMC alone, and slightly lower than that of the IPN-structured film. see. As already mentioned above, the adhesion of the film formulation in the dry state is affected by the hydration reaction and thus does not show a big difference in the case of polysaccharide films exhibiting a hydration rate above a certain level. However, in the case of re-adhesiveness, the film of semi-IPN structure shows a much higher value than other formulations, which means that the carboxy-terminated group of SCMC retains its physical strength by the alginate-Ca ²⁺ structure. It is because it shows adhesive force. This excellent re-adhesiveness makes it convenient for the procedure and re-treatment.

The hydration patterns of some of the formulations mentioned in the present invention are shown in Table 2 . According to Table 2 , it can be seen that after about 2 minutes or more, the hydration reaction of each formulation is completed. Based on this, after hydration for about 2 minutes, the adhesion in the wet state was measured. As shown in Table 3 , the adhesion in the wet state of the film formulation of the semi-IPN structure according to the present invention is similar to the SCMC and SA-SCMC mixed formulations, etc., but significantly higher than the alginate-Ca ²⁺ or IPN structure. It is proved that even after sufficient hydration reaction has occurred, the adhesion to biological tissues is shown.

Taken together, the results of the two adhesion test methods showed that the semi-IPN-structured composition exhibited an initial adhesiveness suitable for the procedure, exhibited excellent re-adhesiveness, and was excellent in biological tissue even after the complete hydration reaction. It can be seen that the adhesion.

Typical physical properties of the film include strength and elongation, where strength indicates strength of the film and elongation indicates flexibility. In the present invention, the easiness of use when the anti-adhesion agent is used for the first time by measuring the elongation in the dry state was used as a measure indicating the ease of reoperation mentioned above by measuring the elongation in the wet state.

Adhesion inhibitors using polysaccharide films that are already in use are not easily broken or can not be removed after a single procedure, so many films need to be used in a stack. However, in the case of a film obtained by crosslinking alginate with calcium ions, flexibility and strength are superior to other polysaccharide films.

As shown in the results of Table 4 , the difference between the strength of the semi-IPN structure film and the simple mixed formulation is not so great in the dry state, but in the wet state, the film formulation of the semi-IPN structure is much higher than the other formulations except the IPN structure. It can be seen that the intensity. This is because, unlike other formulations that are easily dissolved by water, crosslinking with calcium ions is formed, so that the solubility in water is reduced. The high strength in the wet state of the formulations obtained in the present invention makes it possible to drastically eliminate the inconvenience of use, which is a disadvantage of the existing polysaccharide film formulations.

In summary, the gel and film formulations obtained by forming a semi-IPN structure by selectively crosslinking only the alginate component with water-soluble alginate and SCMC prepared by the present invention and SCMC as the main component have excellent tissue adhesion. It is an anti-adhesion agent having sex and re-adhesion property and having a shape retention rate for a period necessary for wound healing in vivo.

On the other hand, the anti-adhesion agent prepared according to the present invention can be released locally during the wound healing period by introducing an appropriate drug. Specific drug introduction methods can be applied by applying what is mentioned in USP 5,578,305. The introduction of the drug may be made in the middle of the preparation of the formulation, and the drug used may be an antithrombotic drug such as heparin or t-PA or an anti-inflammatory agent such as aspirin or ibuprofen. drugs), hormones, analgesics or anesthetics can be used with any of the formulations of the present invention.

In addition, in the present invention, in order to demonstrate the anti-adhesion effect of the composition prepared by the above method, various types of formulations were tested for anti-adhesion efficacy. Adhesion-forming animal models were referred to the rat adhesion model ( Surgery, 1995 , 117 , 663-669). Comparing and testing the formulation of the semi-IPN structure prepared by the method proposed in the present invention based on the animal model and the formulation having various compositions, the formulation of the semi-IPN structure of the present invention shows a very good anti-adhesion effect. It was confirmed.

Example 1 Preparation of Gel and Film Formulations with Semi-IPN Structure

<1-1> Gel Formation of Semi-IPN Structure Using CMC and Alginate Powder

8 g of carboxymethyl cellulose (CMC) and 2 g of alginate were mixed in powder form. The mixed powder was added for about 5 minutes while stirring distilled water at about 400 rpm using a mechanical stirrer. As dissolution proceeded and the viscosity increased, the stirring speed was reduced to about 120 to 150 rpm, and stirring was continued for about 4 hours to obtain a completely homogeneous solution. The homogenized solution was added at an amount of 0.1 times the weight of SA while stirring at 300 to 350 rpm. At this time, the calcium ion solution was slowly added for 10 to 15 hours to form a uniform semi-IPN structure.

<1-2> Gel Formation of Semi-IPN Structure Using SCMC and SA Solution

A solution of 2.0 wt% SA dissolved in distilled water and 2.0 wt% SCMC dissolved in distilled water were mixed and stirred at 120 to 150 rpm using a mechanical stirrer to obtain a uniform solution. While stirring the SA-SCMC mixed solution at 300 to 350 rpm, calcium ions were added in an amount of 0.1 times the SA weight, but calcium ion solution was slowly added for 10 to 15 hours to form a uniform semi-IPN structure. .

<1-3> Preparation of Film with Semi-IPN Structure

After thin film molding the gel solution prepared in the <1-1> and <1-2> it was completely dried at 35 ~ 40 ℃, atmospheric pressure to complete the film formulation.

Comparative Example 1 Preparation of Film Using SA Single Solution

SA powder was added to distilled water, and stirred at 350 to 400 rpm using a mechanical stirrer to form a solution, which was then thin-film molded and dried under the same conditions as in Example <1-3> to prepare a film of SA alone formulation.

Comparative Example 2 Preparation of Film Using SCMC Single Solution

Except for using the SCMC powder, a film of the SCMC alone formulation was prepared in the same manner as in Comparative Example 1.

Comparative Example 3 SA-Ca ²⁺ Preparation of Film Using Solution

After thin film molding the SA solution prepared in Comparative Example 1 and immersed in 0.2 ~ 5.0% calcium ion solution for 1 to 30 minutes to form a SA-Ca ²⁺ structure and dried it in the same manner as in Example <3-1> It was made into a film.

Comparative Example 4 SCMC-Al ³⁺ Preparation of Film Using Solution

After SCMC solution prepared in Comparative Example 2 thin-film molding and immersed in 0.2 ~ 5.0% aluminum ion solution for 1 to 30 minutes to create a SCMC-Al ^{3 +} structure and dried in the same manner as in Example <1-3> film Was prepared.

Comparative Example 5 Film Preparation of SA-SCMC Mixed Solution

The SA-SCMC simple mixed solution prepared in Example <1-2> was thin-film molded and dried in the same manner as in Example <1-3> to prepare a film of SA-SCMC mixed formulation.

Comparative Example 6 Film Preparation of IPN Structure

Thin film molding of the SA-SCMC simple mixed solution of Comparative Example 5 and immersed in 5 to 15% calcium ion solution for 2 to 12 hours to form an IPN structure that completely crosslinks not only alginate but also CMC, Example It dried under the same conditions as <1-3>, and manufactured the film of an IPN structure.

Example 2 Preparation of Film with Semi-IPN Structure

In order to investigate the effect of calcium ion concentration on the performance of the anti-adhesion agent, various formulations having different calcium ion concentrations were prepared as follows. Gel formulation was prepared in the same manner as in Example 1, but the amount of calcium ions added was 0.2 times the SA weight. The gel formulation thus obtained was completed in the same manner as in Example <1-3>.

Example 3 Preparation of Film with Semi-IPN Structure

A film formulation was prepared in the same manner as in Example 2, but the amount of calcium ions added was 0.05 times the SA weight.

Example 4 Preparation of Film with Semi-IPN Structure

On the other hand, in order to investigate the effect of the composition ratio of SA-SCMC on the performance of the anti-adhesion agent, a film formulation having a semi-IPN structure having a different composition ratio of SA and SCMC was prepared as follows. First, a solution was prepared by using 9 g of CMC and 1 g of alginate in the semi-IPN film manufacturing process of Example 1, and then adding a calcium ion solution of 0.1 times the weight of SA to give a semi- A formulation with an IPN structure was obtained. After forming the thin film, the film was completely dried at 35 to 40 ° C. and atmospheric pressure to complete film formation.

Example 5 Preparation of Film with Semi-IPN Structure

A film formulation was prepared in the same manner as in Example 4, but the amount of CMC added was 5 g, and the amount of alginate was 5 g.

Example 6 Preparation of Film with Semi-IPN Structure

A film formulation was prepared in the same manner as in Example 4, but the amount of CMC added was 2 g, and the alginate was 8 g.

Experimental Example 1 Shape Retention Rate Test

In order to test the retention rate in vitro , the film prepared under various conditions was cut into a certain shape and shaken at 37 ° C, pH 7.4 phosphate buffered saline (PBS) at 60 times per minute. The time the shape of the thin film was maintained was observed. The degree of decomposition of the film was visually measured to determine the degree of degradation in the PBS solution. In the case of gel formulation, the degree of degradation was tested under the same conditions.

On the other hand, in order to test the morphology retention in vivo state, healthy rat rats of about 200-250 g were tested by applying anti-adhesion agents of various formulations in the same manner as in animal model experiments. Each animal group used a total of 27 animals and randomly extracted three animals on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 11th and 14th days after the procedure. Visually confirmed

As a result of measuring the shape retention rate of the film of the semi-IPN formulation prepared according to Example 1, the thin film was able to maintain its shape for 12 to 17 days in an in vitro test and was about 16 to 17 days. It started to lose form and was dissolved until more than 20 days.

In addition, in the test in vivo conditions, the film of the semi-IPN formulation was maintained in the applied site until the 7th day after the procedure, it was confirmed that the trace is not completely absorbed even after 14 days.

On the other hand, the film prepared in Example 2 as a result of measuring the in vitro morphology retention rate of the semi-IPN formulation film having a different calcium concentration prepared by Examples 2 and 3 by the above method The shape was maintained for a longer time compared to the film formulation having the composition of Example 1, and gradually began to lose form after 28 to 29 days, and after about 40 days, the form became invisible. On the other hand, the film formulation according to Example 3 remained in shape for about 7 to 8 days and gradually began to lose shape, and after 13 days or more, the body could not be observed.

In addition, the film having the composition of Example 2 in the test in the in vivo condition was maintained at the site applied to the 7th day after the procedure, and after 14 days, the morphology remained relatively large, so that the decomposition rate was Example 1 It was confirmed that the slower than the case of. In addition, the film formulation prepared by the method of Example 3 was disintegrated faster and gradually began to lose form from the third day after the procedure, and almost no form was recognized after 7 days.

Experimental Example 2 In Vitro of Gel Formulation in vitro ) Adhesive test

The gel of the semi-IPN formulation of Example 1 above and the gel of the formulations mentioned in Comparative Examples 1 to 6 were prepared, the cover glass was soaked in this gel and coated on the surface and then taken out and dried in air. The cover glass was immersed in a 5 wt% mucin suspension at a depth of 10 mm, and then the force obtained when the cover glass was pulled at a speed of 0.1 to 2.0 mm / min was measured to compare and measure adhesion. The instrument used for the adhesion test was an INSTRON 4465 model, and a load cell (250 g) was used. Table 1 shows the results of the in vitro adhesion test.

Maximum adhesion of gel formulation Experimental composition Max Load (mg) Comparative Example 1 401 ± 53 Comparative Example 2 754 ± 45 Comparative Example 3 42 ± 5 Comparative Example 5 634 ± 55 Comparative Example 6 29 ± 3 Example 1 611 ± 29 Example 2 540 ± 51 Example 3 619 ± 29 Example 4 627 ± 36 Example 5 548 ± 27 Example 6 505 ± 34

In the case of gel formulation, the adhesion by the initial hydration (hydration) can not be represented, the in vitro adhesion is determined by the adhesion of the material itself. Therefore, SA, SCMC, and SA-SCMC simple mixed formulations having bioadhesive properties show more than adequate levels of adhesion, and SA-Ca ²⁺ and IPN gels having carboxy end groups of the polymer participating in crosslinking have very low adhesion. On the other hand, the semi-IPN composition of the present invention shows a similar level of adhesion as the SA-SCMC simple mixed formulation.

On the other hand, exhibited a mucin suspension (mucin suspension) and gels of the coating composition to the cover glass and semi--IPN SCMC gel, SA gels adhesion tendency of appearing while pulling the cover glass in FIG. At this time, the SCMC gel shows a curve in which the load is continuously increased while the cover glass is pulled, and the SA gel shows an adhesion curve in the form that this value is continuously maintained after the load is initially increased. The semi-IPN formulations prepared by the present invention exhibit an adhesion curve with a similar tendency to SCMC gels, since the alginate component crosslinks with calcium, loses adhesion and CMC shows adhesion of the formulation. Therefore, the semi-IPN composition prepared by the method proposed in the present invention is a composition in which the alginate component forms a crosslink with calcium ions and maintains adhesion by the carboxy end groups possessed by the CMC while having excellent shape retention. It can be seen that.

On the other hand, in order to investigate the effect according to the calcium ion concentration, in vitro adhesion was measured and compared to the gel of the semi-IPN formulations having the composition of Example 2 and Example 3 using the above method.

The results are shown in Table 1 , wherein the in vitro adhesion of the gel of Example 2 was somewhat lower than that of the gel having the composition of Example 1. This is because, when the concentration of calcium ions is high, in addition to the alginate that participates in the crosslinking, some of the CMC is combined with the calcium ions, thereby lowering the concentration of the carboxy terminal group indicating adhesion to biological tissues. On the other hand, in the case of the formulation having the composition of Example 3, CMC, which has a major influence on adhesion, does not form crosslinks with calcium ions, and a part of alginate also exhibits a similar tendency to the value of Example 1 above.

In addition, in order to investigate the effect of the composition ratio of SA and SCMC, in vitro adhesion according to the method described above for the gel of the semi-IPN formulation having the composition of Examples 4, 5 and 6 Were measured and compared.

As a result, as shown in Table 1 , the lower the ratio of SCMC in the composition of the formulation showed a tendency to decrease the adhesion. In the case of gel formulations, the greatest influence on adhesion is the adhesion of the polymer itself to the biological tissue. Therefore, it can be seen that the higher the ratio of SCMC capable of exhibiting bioadhesiveness, the better the bioadhesiveness, and the higher the ratio of the SAs forming crosslinking with calcium ions, the lower the bioadhesiveness.

Experimental Example 3 Measurement of Hydration Degree of Film Preparation

The film of each composition prepared was cut into the fixed size, and the mass was measured. 50 ml vial was filled with distilled water, and the film pieces were soaked. After a predetermined time, the film pieces in the vials were taken out and weighed to measure the degree of moisture absorption by the degree of swelling (% S). .

The degree of swelling (% S) was calculated by the following equation.

The hydration rates of the formulations mentioned in the present invention are shown in Table 2 .

Hydration rate of film forming Hydration time (seconds) Hydration Rate (% S) Example 1 Comparative Example 5 Comparative Example 6 0 0 0 0 5 417.0 801.6 99.21 10 535.6 813.1 149.1 20 715.9 1051 154.9 30 740.2 1825 154.8 60 1176 2080 231.8 90 1659 3082 300.7 120 3046 ^-a 304.1 150 3054 ^{-a -b} a: Formulation starts to melt and cannot be weighed b: Hydration equilibrium reached

The SA-SCMC simple mixed formulations began to dissolve immediately after the start of the measurement, making it virtually impossible to measure water absorption. In addition, the formulation with the SA-SCMC mixed solution of Comparative Example 5 or the IPN formulation of Comparative Example 6 reached a hydration equilibrium state after about 1 minute or longer, so that further measurement of the hydration rate became meaningless. In contrast, the semi-IPN formulation absorbed moisture at a relatively slow rate and reached a hydration equilibrium after about 2 minutes. At this time, the hydration rate was about 3000%.

Experimental Example 4 In Vitro of Film Preparation ex vivo ) Adhesive test

200-250 g of SD-Rat females were anesthetized with diethyl ether, opened, abdominal wall was removed, and washed with 4 ° C saline solution to remove impurities on abdominal wall. It was soaked in physiological saline at 4 ° C. and kept fresh until just before being used in the experiment. The extracted tissues were used within 1 hour after extraction, and all tissues which had passed time were destroyed.

Films of various formulations are cut to size and fixed on a 100 mm ² (10 x 10 mm), 10.0 g stainless steel weight, placed on top of the extracted tissue and held for 2 min. Pulling at a speed of mm / min was measured the force that appears when the base of the weight falls from the abdominal wall tissue.

The adhesion test was carried out in the same manner as above, with the film formulation used again on the abdominal wall tissue to determine readhesiveness. Re-adhesiveness indicates how much the adhesive strength of the film in the dried state is maintained in the wet state, and expressed by the re-adhesion rate obtained from the following equation.

The following tests were carried out to determine the adhesion when the film or gel formulation was fully hydrated. Film formulations of each composition were hydrated with physiological saline for 2 minutes, cut to size and fixed under a stainless steel weight of 100 mm ² (10 × 10 mm) with a base area of 10.0 g. Put the weight on the tissue and hold it for 2 minutes, then 0.1 ~ 2.0 mm / min. Pulling at a speed of, the maximum value of the force when the base of the weight falls from the abdominal wall tissue was measured. The instrument used for the adhesion test was an INSTRON 4465 model, and a load cell (250 g) was used.

The adhesion and re-adhesion of the dry state to the film of each formulation by the method as described above, the adhesion in the wet state was measured and shown in Table 3 below.

Maximum adhesive force of film forming Experimental composition Dry adhesion (g) Reattachment rate (%) Wetting Adhesion (g) Comparative Example 1 21.8 ± 1.5 55.2 ± 3.8 15.1 ± 0.3 Comparative Example 2 25.2 ± 2.1 56.7 ± 3.6 17.4 ± 0.6 Comparative Example 3 25.6 ± 1.6 36.3 ± 2.5 8.7 ± 1.2 Comparative Example 5 23.4 ± 1.2 58.1 ± 4.0 16.9 ± 0.7 Comparative Example 6 29.4 ± 2.0 42.9 ± 2.7 11.2 ± 0.4 Example 1 26.8 ± 1.5 89.1 ± 4.5 19.0 ± 0.5 Example 2 27.7 ± 2.3 81.2 ± 3.1 17.5 ± 0.9 Example 3 24.9 ± 1.7 88.4 ± 3.9 17.9 ± 0.8 Example 4 24.8 ± 2.1 79.4 ± 4.7 18.2 ± 1.1 Example 5 25.3 ± 1.4 81.6 ± 3.2 16.7 ± 0.9 Example 6 25.7 ± 1.7 74.4 ± 2.9 14.8 ± 0.6

The semi-IPN film formulations prepared by the method presented in the present invention exhibited similar initial adhesion values as the film formulations composed of SA-Ca ²⁺ and SCMC alone in the dry state and slightly lower than the films of the IPN formulations. As already mentioned, there is no significant difference in the film formulations made of polysaccharides having a certain level of hydration because the most important factor of the initial adhesion requirement is hydration. However, in the case of re-adhesiveness, the semi-IPN film formulation shows an extremely high value, since the hydration reaction affecting the initial adhesion is performed to some extent, and thus the adhesion of the formulation itself to the biological tissue is important. In other words, since crosslinking of alginate and calcium ions is formed, adhesion to biological tissues occurs due to diffusion of carboxy terminal groups of CMC that do not participate in crosslinking while maintaining physical strength, thereby showing excellent re-adhesiveness. This excellent re-adhesion greatly contributes to the convenience of the procedure and re-treatment.

The adhesion of such polymers to biological tissues can be expected in film formulations consisting of SA and SCMC, or simple mixing of two polymers, but these formulations do not exhibit physical strength because they dissolve simultaneously with contact with moisture. Re-adhesion is not good.

The greatest influence on the adhesion in the wet state is the adhesion of the polymer itself to the living tissue. Therefore, SA, SCMC, SA-SCMC simple mixture formulations, which may exhibit adhesion due to biotissue and diffusion, have relatively high values, and films of SA-Ca ²⁺ and IPN formulations in which all constituent polymers participate in crosslinking. They cannot exhibit adhesion with biological tissues and thus exhibit adhesion in a very low wet state.

The semi-IPN formulations also show relatively high values compared to other formulations even in the adhesion state in the wet state, which means that the CMC can be adhered to the biological tissues while the alginate-calcium ion crosslinked structure maintains physical strength. Because it represents.

On the other hand, in order to determine the effect of the calcium ion concentration, the ex vivo adhesion test was performed on the film formulations prepared in Examples 2 and 3 by the above method. The dry adhesion, re-adhesion, and wet adhesion to the films of each formulation are shown in Table 3 above.

As mentioned above, the initial adhesion in the dry state is affected by the hydration reaction. When the amount of calcium ion is added, the initial hydration does not show a big difference in the adhesion. However, the re-adhesiveness and adhesion in the wet state is dependent on the adhesion to the biological tissues of the CMC, so the lower the ratio of CMC was lower.

In addition, in order to investigate the effect according to the composition ratio of SA and SCMC, an ex vivo adhesion test was performed on the film formulations prepared in Examples 4, 5 and 6 by the above method.

As a result, since the hydration reaction has a great effect on the initial adhesion of the dry state, even if the ratio of CMC and alginate is changed, there is no big difference. However, as the ratio of CMC decreased, the concentration of carboxy end groups, which had a major influence on the adhesion of the formulation itself to the biological tissues, was lowered, indicating low re-adhesiveness and low adhesion in the wet state.

Experimental Example 5 Elongation Measurement of Film Preparation

The thin films prepared with the respective compositions were cut to a size of 100 x 120 mm to prepare specimens, and then the elongation of the film was measured under a condition of a sample gauge of 50 mm and a measuring speed of 30 to 70 mm / min. In addition, in order to measure the physical properties of the wet film, the specimen was placed in a filter paper soaked in water, hydrated for 2 minutes, and elongation was measured in the same manner.

The elongation in dry and wet conditions was measured by the above-mentioned method for the films prepared in Example 1 and Comparative Examples. The instrument used to measure the elongation is INSTRON 4465, 100 kg load cell (dry cell) for the measurement of elongation in the dry state, 250 g load cell (load cell) was used for measuring the properties of the wet film. The experimental results are shown in Table 4 .

Elongation of Film Forming Experimental composition Dry Hydration status Strength (g) Elongation (%) Strength (g) Elongation (%) Comparative Example 1 (SA) 4681 ± 377 10.7 ± 2.15 0.49 ± 0.09 10.4 ± 2.41 Comparative Example 2 (SCMC) 3854 ± 153 5.64 ± 1.78 8.25 ± 1.64 60.4 ± 4.78 Comparative Example 5 (SA-SCMC) 6214 ± 256 12.2 ± 1.96 6.81 ± 1.85 47.3 ± 4.56 Comparative Example 6 (IPN) 695 ± 94 13.2 ± 2.77 198 ± 10.3 84.5 ± 6.68 Example 1 (semi-IPN) 7039 ± 231 16.9 ± 1.24 72.4 ± 5.37 68.8 ± 5.63

As noted above, the strength of the film is a measure of the robustness of the film and elongation is a measure of flexibility. In the present invention, the ease of use when the anti-adhesion agent is used for the first time by measuring the elongation in the dry state was used as a measure indicating the ease of re-operation mentioned above by measuring the elongation in the wet state.

As shown in the results of Table 4 , the difference between the strength of the semi-IPN structure film and the simple mixed formulation is not much different in the dry state, but in the wet state, the film formulation of the semi-IPN structure is superior to other formulations except the IPN structure. It can be seen that the high strength. This is because, unlike other formulations that are easily dissolved by water, crosslinking with calcium ions is formed, so that the solubility in water is reduced. In addition, IPN formulations had good elongation in the wet state but too low in the dry state. Therefore, it can be seen that the IPN formulation is difficult to achieve an effective procedure and thus does not achieve the convenience of the procedure intended in the present invention.

As such, the high strength in the wet state of the formulations obtained in the present invention makes it possible to significantly solve the inconvenience of use, which is a disadvantage of the existing polysaccharide film formulations.

Experimental Example 6 Animal Effectiveness Experiments According to Formulation and Composition Ratio

<6-1> Adhesion Formation Animal Model Experiment (Control)

Sprague-Dawley rats weighing 200-250 g were anesthetized with diethyl ether and then opened in the abdomen with clean surgical instruments. After the cecum was exposed, the surface was rubbed with sandpaper until bleeding spots appeared. The epithelium in the left abdominal wall area was removed to create a 1 cm × 1 cm wound. After the caecum was relocated into the abdominal cavity to adjoin the wound, the abdominal wall was closed with 4-0 silk suture, and the skin layer was closed with 3-0 silk suture. After 7 days, the mice were euthanized and opened to investigate the degree of adhesion formation (development and depth of adhesion). The criterion for adhesion was the adhesion of the cecum to the abdominal wall.

The following rating system was used to assess the depth of adhesion.

0 grade: no adhesion at all

Grade 1: Intraperitoneal fat is attached to the wound slightly.

Grade 2: Mesentery and wounds are in contact with each other.

Grade 3: Vascular tissue is developed, and the cecum and abdominal wall are heavily adhered.

According to the method mentioned in the animal model, 36 rats of SD rats were tested for adhesion formation and the following results were obtained.

Rating Marisu 0 ratings One 1 rating 4 2 ratings 6 3 ratings 25 system 36 A.S. = 2.53, S.E.M. = 0.14

A.S. (average adhesion score) and S.E.M. (standard error of mean) were calculated using the following equation.

A.S. means the degree of adhesion of the animal group. The closer to 3, the more severe the adhesion. The closer to 0, the less the adhesion. In addition, S.E.M. indicates the difference between experimental animal populations, and the smaller the value, the smaller the individual difference.

<6-2> Animal efficacy test for each formulation according to the type of formulation

Each formulation was applied to 36 SD rats to test the animal efficacy according to the formulation of the gel and film formulations of the formulations prepared in Example 1 and Comparative Examples 1 to 6 on the basis of the above criteria. After the wound was generated according to the method of <6-1>, the film was cut into 4 × 5 cm ² and 1.5 × 2 cm ² sizes and applied to the cecum and abdominal wall, respectively, and 2 ml of gel was applied. One week later, the euthanasia was observed and the depth of the adhesion was observed. The results are shown in Table 5 below.

Anti-adhesion Effect by Composition Experimental composition A.S. S.E.M. Comparative Example 1 (SA) Gel 2.58 0.21 film 2.82 0.21 Comparative Example 2 (SMC) Gel 1.67 0.31 film 1.88 0.21 Comparative Example 3 (SA-Ca ²⁺ ) film 2.59 0.32 Comparative Example 4 (SCMC-Ca ²⁺ ) film 2.88 0.26 Comparative Example 5 (SA-SCMC) Gel 1.79 0.12 film 2.69 0.16 Comparative Example 6 (IPN) film 2.66 0.32 Example 1 (semi-IPN) Gel 0.31 0.12 film 0.28 0.09

As can be seen from the results of Table 5, the anti-adhesion agent of the semi-IPN structure of the present invention has excellent anti-adhesion in animal models compared to the anti-adhesion agent of the SAN or SCMC alone or mixed formulation or the anti-adhesion agent of the IPN structure in both the film and the gel formulation. The effect was shown.

<6-3> Animal efficacy test according to the composition ratio of SA and SCMC

In order to determine the anti-adhesion effect of the semi-IPN composition by component ratio, the composition ratio of SA and SCMC was changed to prepare a film formulation according to the method of Example 1, and then test the anti-adhesion performance according to the method of Experimental Example <6-1>. The results are shown in Table 6 .

Adhesion Prevention Effect by Component Ratio ratio SA (%) 10 20 40 50 60 80 90 SCMC (%) 90 80 60 50 40 20 10 Rating 0 26 28 22 17 13 11 10 One 8 6 10 15 13 10 7 2 One 2 3 2 6 8 7 3 One 0 One 2 4 7 12 Total 36 36 36 36 36 36 36 A.S. 0.361 0.278 0.528 0.694 1.028 1.306 1.583 S.E.M. 0.114 0.094 0.129 0.137 0.167 0.186 0.205

As a result, the anti-adhesion agents of the semi-IPN structure of the present invention are all excellent in the anti-adhesion effect compared to the adhesion formation model in the composition ratio of the full range, in particular 10 to 50% by weight of SA, 90 to 50% by weight of SCMC The anti-adhesion agent of the semi-IPN structure having a composition ratio of showed an excellent anti-adhesion effect.

Therefore, the anti-adhesion agent of the present invention is composed of water-soluble alginate and carboxymethyl cellulose as main components, and calcium ions selectively ion-bond to alginate to form a semi-IPN structure, thereby providing excellent tissue adhesion and re-adhesion as well as in vivo. It exhibits high form retention at and maintains a certain degree of strength even when wet, effectively preventing adhesion during the healing period of the wound, and is convenient to use and can be easily applied to the procedure and re-treatment.

Claims (9)

In order to prevent adhesions between biological tissues during and after surgery, which are mainly composed of water-soluble alginate and carboxymethyl cellulose and the water-soluble alginate is selectively crosslinked with calcium ions to have a semi-interpenetrating network (IPN) structure. Adhesion inhibitors used. The anti-adhesion agent according to claim 1, wherein the weight ratio of the alginate to the calcium ion to be added is 1: 0.05-1: 0.2. The anti-adhesion agent according to claim 1, wherein the weight ratio of alginate is 90 to 10%, and the weight ratio of carboxymethyl cellulose is 90 to 10%. 4. The anti-adhesion agent according to claim 3, wherein the weight ratio of alginate is 50 to 10%, and the weight ratio of carboxymethyl cellulose is 90 to 50%. The anti-adhesion agent according to claim 1, wherein the anti-adhesion agent is in a film form. To prepare a gel solution by adding a calcium ion solution to a solution of alginate and carboxymethyl cellulose mixed powder in distilled water, and to form the gel solution in the form of a film to dry, the calcium ion weight ratio of the calcium ion solution is the alginic acid A method for preparing the anti-adhesion agent according to claim 1, wherein the salt is 1: 0.05 to 1: 0.2. The gel solution is prepared by adding calcium ion solution to the mixed solution obtained by mixing the alginate solution and the carboxymethyl cellulose solution, and forming the gel solution in a film form to dry the gel solution. The calcium ion weight ratio of the calcium ion solution is A method for preparing the anti-adhesion agent according to claim 1, wherein the alginate salt is 1: 0.05 to 1: 0.2. The anti-adhesion agent according to claim 1, wherein the anti-adhesion agent additionally contains a drug. The anti-adhesion agent according to claim 8, wherein the drug is a drug selected from the group consisting of nonsteroidal anti-inflammatory agents, anticoagulants, proteolytic agents and growth hormones.