KR20170029817A - Biocompatible composition containing spacers and method for production thereof - Google Patents

Abstract

The purpose of the present invention is to modify an adhesion inhibiting function by applying advantages of gel-type and membrane-type adhesion preventing agents which are most frequently used types among adhesion preventing agents. In particular, there are major problems of a gel-type adhesion agent. When being coated on a part of a human body, adhesion preventing gel falls from a coated part, and thus it is difficult to ensure a sufficient coating amount. Moreover, gel is pushed away by physical compression of an adjacent organ or tissue after coating, so a coating amount may be removed. Moreover, there are major problems of a membrane-type adhesion agent. When an adhesion preventing membrane is coated in a specific part, penetration and coating are difficult to be performed in fine uneven parts due to the properties as a membrane. Also, the position of a coated adhesion preventing membrane can be changed according to the movement of a human body or the movement of an organ or tissue. Thus, an effective adhesion preventing function is difficult to be shown. To this end, the present invention provides an adhesion preventing agent composition and a method for producing the same, wherein the adhesion preventing agent composition has a more improved effect by mixing a material capable of serving as a membrane with a gel-type adhesion preventing agent.

Description

TECHNICAL FIELD The present invention relates to a biocompatible composition containing spacers and a method for producing the same,

The present invention relates to a method for changing the composition and physical properties of a gel in order to increase efficiency in using a gel-type inhibitor to suppress adhesion.

More particularly, the present invention relates to a method for minimizing a surgical site for adhesion-inhibiting treatment to prevent adhesion between peripheral tissues after surgery, and a gel-type anti-adhesion agent for enhancing adhesion inhibition efficiency, And physical pressure, the adhesion between the adjacent tissues occurred and the adhesion suppression function could be reduced.

Therefore, it is necessary to select components of the gel in order to suppress the flow of the anti-adhesion gel and restrict the phenomenon that the gel is pushed by the physical pressing between the adjacent tissues and adhere to the adjacent tissues, The present invention relates to a composition for inhibiting adhesion and a method for producing the same.

The adhesion of organs and tissues after surgery is a physiological phenomenon that occurs during proliferation and regeneration of injured tissue cells. However, adhesion of excessive tissue, or unintended adhesion to other tissues or organs, And in some cases it may be a life-threatening factor, such as a need for reattachment of the adhesiolysis.

Generally, adhesion occurs at a frequency of 60 ~ 95% after laparotomy, and it may cause pain, intestinal obstruction, and infertility, and reoperation is needed to remove adhesion due to organ or tissue dysfunction. Especially, tissue adhesion is the main cause of intestinal obstruction (80 ~ 90%) and causes long term aftereffects and pelvic pain after gynecological procedures.

If the fibrinolysis is normal, the adhesion will not occur. However, if the fibrinolysis is normal, the fibrinolysis will not occur. When the fibrinolysis reaction is inhibited by the cause, adhesion occurs. If these adhesions become worse, the normal activities of the living organisms are restricted and secondary diseases may be induced.

In order to prevent such adhesion, methods of minimizing wounds during surgery, using an anti-inflammatory agent and using physical barriers have been developed and used. The material used as a physical barrier serves only as a barrier for the duration of the wound healing in the body, and thereafter it has to be disassembled. In addition to the toxicity of the material itself, It should be harmless to human body.

There are three main types of adhesion prevention methods currently in use. First, surgical methods that minimizes tissue damage and foreign matter adhesion due to delicate attention and unnecessary injuries during surgery, second, chemical methods that inhibit drug therapy before the adhesions in the pathophysiologic processes necessary for inflammation reaction and adhesion formation, Third, it is widely used in clinical practice as a physical method to prevent adhesion by blocking contact with surrounding tissues by wrapping or covering the wound area using an anti-adhesion barrier after surgery, and its importance has been emphasized.

The adhesion preventive film may be a liquid type, a gel type, or a film type. In general, it takes about 7 days to heal wounds on the surgical site. The commercially available liquid and gel-type anti-adhesion agents can not be precisely fixed to the wound area due to the characteristics of the product, or they are quickly washed away by body fluids and easily decomposed It is known that the effect as an anti-adhesion agent absorbed is only about 50 to 70%. On the other hand, the membrane type adhesion preventive membrane does not flow and does not wash off, which is advantageous in that it has a greater effect of preventing adhesion than liquid or gel type. However, in order to prevent it from adhering to the living body when applied to internal organs, But it can not be put in place due to the movement of the organ itself.

Therefore, in the present invention, the gel introduction type of the conventional anti-adhesion agents, convenience of application to the required site, and effectiveness of the membrane type adhesion and blocking are reflected. It has been confirmed that a hyaluronic acid and a carboxymethyl cellulose component are mixed with each other for the purpose of improving viscoelasticity and that the effect of preventing adhesion can be greatly improved by introducing a spacer for preventing tissue or prolonged adhesion, Thereby completing the invention.

The problem to be solved by the present invention is to improve the adhesion-inhibiting function by reflecting the advantages of the gel-type and film-type adhesion inhibitor.

Specifically, the main problem that the present invention regards is that, in the case of the anti-adhesion gel, leakage of the gel applied by the physical pressing between the falling and the surrounding tissues in the application process of the human tissue, and, in the case of the anti- And to provide an adhesion inhibiting composition capable of improving such a problem as a problem of deviation of an application site of a applied adhesion preventive film in accordance with a decrease in application function and a movement of a human body.

Generally, the period required for wound healing is about 7 days. Therefore, it is important that the anti-adhesion substance is biodegraded in the body after application of the anti-adhesion substance over the period. In the present invention, the present invention has been completed by using biodegradable materials .

If a wound occurs in a tissue or organ due to surgery, infection, inflammation, etc., the tissue is recovered by hemostasis through a coagulation cascade. However, if the excessive amount of the fiber is leaked because the coagulation process is not properly controlled, And blood vessels are developed, resulting in adhesion processes in which adjacent tissues or organs adhere to each other. Therefore, in order to prevent the adhesion process, a substance that blocks the wound site and the adjacent site for a certain period of time (usually 7 days) is required, and when it disappears in vivo, it is suitable as an anti-adhesion agent. In the present invention, it is intended to provide an anti-adhesion composition containing hyaluronic acid, carboxymethyl cellulose and a spacer in consideration of convenience of use, cost of manufacture, etc., as well as a function of preventing adhesion.

&Quot; spacer " is a substance that can partially or wholly create space when a physical contact occurs between tissues or organs in the body.

&Quot; Integrated gel " means a gel comprising a mixture of three or more components that are homogeneously or substantially uniformly dispersed.

The hyaluronic acid may be contained in an amount of 0.01 to 10% by weight, more preferably 0.1 to 5% by weight, and more preferably 1% by weight based on the total amount of the adhesion preventive composition.

The hyaluronic acid includes hyaluronic acid and a salt thereof, and the salt may be sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, or tetrabutylammonium hyaluronate. It is not.

The carboxymethyl cellulose is a semisynthetic hydrophilic cellulose derivative having a high viscosity and a molecular weight of 21,000 to 500,000 Da obtained by introducing a glycolic acid ether group into a unit of a cellulose molecule. Carboxymethylcellulose may be contained in an amount of 0.05 to 10% by weight, more preferably 0.2 to 5% by weight, and more preferably 2% by weight, based on the total amount of the adhesion inhibitor composition. The preferred viscosity of the carboxymethylcellulose may be 25 to 4,500 cP, more preferably 1,000 to 4,000 cP, and even more preferably 1,500 to 3,500 cP. The carboxymethylcellulose may be carboxymethylcellulose sodium, carboxymethylcellulose calcium or carboxymethylcellulose zinc, but is not limited thereto.

The anti-adhesion agent of the present invention can use carboxymethylcellulose having an appropriate viscosity to control tissue adhesion and persistence in the body. In addition, the addition of the spacer to the gel mixed with hyaluronic acid and carboxymethylcellulose suppresses the flowability of the mixed gel components, thereby further improving adhesion and durability as compared with the mixed gel consisting of hyaluronic acid and carboxymethylcellulose, It is possible to inhibit leaching and to exhibit an excellent anti-adhesion effect. The formulations of the gauze can be made in the form of powders, granules, small film fragments, bands with widths and lengths, or combinations of two or more thereof, and can be made in the form of hyaluronic acid, alginic acid, chitosan, collagen, gelatin, fibrin, But are not limited to, elastin, chondroitin, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, heparin, carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxyethylcellulose, cellulose ether, dextran, (PLA), polyglycolic acid (PGA), poly (lactic-co- (-) - lactide), polyoxyethylene (PEG), polyethylene oxide (PEO), polycaprolactone (PLGA), poly [(3-hydroxybutyrate) -co- (3-hydroxyvalerate) (PHBV), polydioxanone (PDO) (Car (Polyvinyl alcohol)] (PVOH), polyacrylic acid (polyvinyl alcohol) [polyvinyl alcohol]), poly (ester urethane) (PEUU) (PAA), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polystyrene (PS) and polyaniline (PAN).

By providing the highly viscoelastic anti-adhesion composition containing the spacer of the present invention, the advantages of the gel-type anti-adhesion inhibitor and the advantages of the film-type anti-adhesion inhibitor are remarkably improved to dramatically improve the problems of the anti- It is expected that the effect of adhesion will be greatly reduced.

FIG. 1 is a graph showing the results of H & E staining for comparing the degree of prevention of adhesion in a control group (untreated group) and an inventive group treated with an integrated gel containing a mixture of hyaluronic acid and carboxymethyl cellulose mixed gels

Hereinafter, the present invention will be described in more detail. However, the following examples are only illustrative of the present invention, and thus the scope of the present invention is not limited by the following examples.

Preparation Example 1. Preparation of a mixed gel composed of hyaluronic acid and carboxymethylcellulose

In the process of preparing the mixed gel, 2.0% of carboxymethylcellulose component was added to 200 ml of PBS (Phosphate Buffered Saline) buffer, and the mixture was stirred and dissolved at 40 ° C. Thereafter, 1.0% of hyaluronic acid was added to this solution, and the mixture was dissolved by heating at 40 ° C to prepare a mixed gel.

Production Example 2. Preparation of spacer

1 g of sodium hyaluronate (molecular weight 1,000,000) and water were mixed to prepare a solution having a total volume of 100 mL. The prepared solution was dispensed into a tray made of polytetrafluoroethylene (diameter 15 cm) in an amount of 50 g each. The mixed solution was air-dried at 30 ° C. to obtain a 0.5 g membrane. The resulting membrane was placed in a tray and 5 mL of a 1% aqueous solution of CaCl 2 .2H 2 O was added thereto. The resulting solution was uniformly wetted, and then air was blown at 30 ° C to dry the film.

This film was cut into 1.5x1.5 mm uniform size to produce a small square film.

Production Example 3. Preparation of an integrated anti-adhesion gel comprising a mixture of CMC and HA mixed with a small gap film

0.5 g of the small gap membrane made of hyaluronic acid prepared in Preparation Example 2 was added to 100 ml of the mixed gel composed of hyaluronic acid and carboxymethylcellulose prepared in Preparation Example 1, Minute.

Experimental Example 1. Compressive force test in a catheter of an integrated adhesion prevention gel

In order to evaluate the rheological properties of the prepared anti-adhesion gels, a compressive force test was performed on each sample. The push-out test can be used to determine whether the integrated anti-adhesion gel will clog or resist when the gel is extruded into the body using a catheter.

A pressure output test was performed on an Instron instrument using a 5 ml syringe fitted with a 1 mm inner diameter catheter. 5.0 ml of each sample was extruded at a constant rate of 200 mm / min. The force applied when a constant value was reached was quantified by the ease of extrusion. The results in Table 1 show that the pressure output of the integrated anti-adhesion gel produced by the method of the present invention is much higher than that of the mixture of hyaluronic acid and carboxymethylcellulose alone without added spacer. This difference in pressure output is a result of the fact that the gap under the flow suppresses the flow and also functions as a physical obstacle.

The pressure output (N) Production Example 1 7.4 Production Example 3 9.8

Experimental Example 2: Anti-adhesion gel-coated animal experiment

Animal experiments were conducted to investigate the efficacy of anti-adhesion gels as follows. After the anesthesia, the rats are mixed with Zoletil and Rompun in a ratio of 5/2. After the anesthesia is fixed to the operating table, the abdomen is disinfected with povidone-iodine solution and the hair is shaved and wiped with ethanol . The incision was made 4 to 5 cm along the midline of the peritoneal cavity. The peritoneum of the abdomen is scraped off with a knife to give a wound (1 x 1 cm), and the adjacent cecum is exposed to rub the curtain of the cecum using sandpaper to cause hemorrhage. Tissue adhesion was induced by suturing three sites about 1 cm away from the friction damage site so that the two damaged surfaces were in contact with each other. Each test material was injected into the peritoneal cavity and the cecum to prevent adhesion of wounded organs, and the peritoneum was quickly covered. The incised peritoneum was closed with a black silk suture, the epidermis was closed with an absorbable suture, disinfected with povidone iodine solution, and an antibiotic and saline were injected into the dermis. After releasing the thread bound to the rat's limbs and indicating the sample number on the tail, the rats whose temperature was lowered while the anesthesia was released were warmed by an infrared lamp, and their health status was checked at any time and water and feed were supplied. After 2 weeks, rats were euthanized with zoletyl and rhomboferrin injections and the abdomen was re-incised to record the degree of adhesion, adhesion strength, adhesion area and morphology, Respectively.

Adhesion site tissue was fixed to 10% neutral formalin for histological examination.

Experimental Example 3: Visual evaluation of anti-adhesion effect

Evaluation of adhesion by visual observation was performed by Vlahos et al. (Vlahos A, Yu P, Lucas CE, Ledgerwood AM. Effect of a composite membrane of chitosan and Poloxamer gel on post operative adhesive interactions, The American Surgeon 2001, 67: 15-21 ). (1 ~ 4, Table 3), the degree of adhesion and the degree of adherence (2 ~ 3) according to the degree of detachment of the two surfaces when the adhesive surface was separated by hand And the results are shown in Table 4. < tb > < TABLE >

Classification according to degree of adhesion Rating Adhesion degree 0 No adhesion One One thin film-type adhesion 2 Two or more thin film-type adhesives 3 Centralized, thick adhesion of point 4 Flattened centralized thick adhesion 5 Very thick adhesion with blood vessels

Classification by adhesion surface separation intensity Rating The adhesion strength One Separate adhesion with very weak force 2 Intermediate force segregation 3 Segregation with strong force 4 Adhesion that is difficult to separate or separate with very strong force

Degree of adhesion Adhesion strength Control group 4.5 3.6 Excellent commercial product 3.3 2.5 Production Example 1 3.8 2.9 Production Example 3 2.4 1.7

As shown in Table 4, the anti-adhesion agent of Production Example 3 exhibited excellent adhesion (non-treated group, washed only with PBS buffer), excellent commercial product (Gadix) and Production Example 1 (gel containing hyaluronic acid and carboxymethyl cellulose) It can be seen that there is an effect of preventing the above. The degree of adhesion formed is greatly reduced and the adhesion strength is also very effective in preventing adhesion of the internal organs due to the large number of initial states. Particularly, in Production Example 3, the degree of adhesion decreased to 47% and the strength of adhesion decreased to 53% as compared with the control.

Experimental Example 4: Histological evaluation of anti-adhesion effect

 Histopathologic observation was performed to assess the degree of tissue adhesion prevention based on fibrosis of the cross - section of the adnexal site.

All cecum / abdominal wall adhesion sites were excised and fixed in 10% neutral formalin solution, and H & E staining was carried out through general tissue fabrication process. As shown in FIG. 1, tissues were collected from the tissue surface where adhesion occurred, and observed through tissue staining. As a result, in the control group (untreated group) (Preparation Example 3) of the present invention, which was obtained by mixing the above-mentioned anti-fouling agent (Example 1) (FIG. 1).

Claims (9)

i) preparing a mixed gel consisting of hyaluronic acid and carboxymethylcellulose;
ii) preparing spacer through cross-linking or drying; And
iii) mixing a small gap body with a gel prepared by mixing hyaluronic acid and carboxymethyl cellulose to prepare an integrated anti-adhesion gel; , And a method for producing the same. The composition of claim 1, wherein the component of the gel is selected from the group consisting of hyaluronic acid, alginic acid, chitosan, collagen, gelatin, carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxyethylcellulose, cellulose ether, dextran, Poly (lactic acid), poly (glycolic acid), poly (N-iso), poly (lactic acid) (PNIPAAm) hydrogel, pluronics, poly (propylene fumarate) (PPF), or a mixture thereof. The method according to claim 1, wherein the shape of the spacer is selected from the group consisting of a circle, a semi-circle, an ellipse, a triangle, a quadrangle, a pentagon, a hexagon, an octagon, a parallelogram, a polygonal, It is possible to use a combination of two or more of these shapes in the form of elliptical, elliptical, octagonal, elliptical, V-shaped, elliptical, A form that can be selected from one or more groups of constituents. [2] The composition according to claim 1, wherein the formulation of the spacer is selected from the group consisting of powder, granules, an endoplasmic reticulum, a small membrane fraction, a band having a width and a length, or a combination of two or more thereof. The composition according to claim 1, wherein the component of the spacer is selected from the group consisting of hyaluronic acid, alginic acid, chitosan, collagen, gelatin, fibrin, elastin, chondroitin, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, heparin, (PEG), polyethylene oxide (PEO), polycaprolactone (PEO), polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, (PCA), polylactic acid (PLA), polyglycolic acid (PGA), poly (lactic-co- (glycolic acid)) (PLGA), poly [(3-hydroxybutyrate) (PEBU), polydioxanone (PDO), poly (L-lactide) -co- (caprolactone), poly (ester urethane) (PEUU), poly [(L-lactide) -co - (D-lactide)], poly [ethylene-co- (vinyl alcohol)] (PV (PA), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polystyrene (PS) and polyaniline (PAN) Gt; The method of claim 1, wherein the crosslinking agent is selected from the group consisting of glutaraldehyde, 1,4-butanediol diglycidylether (BDDE), 1,4-bis (2,3-epoxypropoxy) Bis (2,3-epoxypropoxy) ethylene, 1- (2,3-epoxypropyl) -2,3-epoxycyclohexane, 1,4- One or more selected from the group consisting of butanediol diglycidyl ethers, ethyldiethylaminopropyl carbodiimide (EDC), genepin, and transglutaminase (TG) ≪ / RTI > The anti-adhesion agent according to claim 1, wherein the weight ratio of the gel component to the spacer is in the range of 0.1: 99.9 to 99.9: 0.1. [2] The method according to claim 1, wherein the method of manufacturing the spacer is not limited to a cross-linking reaction between components in a certain mold or by pouring the component solution to dry the solvent. The anti-adhesion agent according to claim 1, wherein the anti-adhesion agent is a formulation selected from the group consisting of a sol, a gel, a film, or a combination of two or more thereof.

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