KR20150046770A - Flexible hyaluronic acid coating and its production method. - Google Patents

Abstract

Disclosure of Invention Technical Problem [10] Accordingly, the present invention has been made to solve the problems occurring in adhesion preventive membranes that are utilized to prevent adhesion, and it has been found that when a flat membrane- There is a problem in that a displacement of the treated film may occur, and it is difficult to fix the film to a certain position at a certain position. Also, when the film is not adhered to the curved adhesion site, adhesion inducing components may flow out to the side face of the film, . Accordingly, the present invention relates to the production of various types of adhesion preventive films in order to increase the efficiency of the adhesion preventive film, suppress the positional fluctuation of the adhesion preventive film, and suppress the diffusion of the adhesion promoting substance.

Description

Flexible hyaluronic acid coating and its production method.

The present invention relates to a method for changing the shape of an adhesion preventive film to improve the efficiency of the adhesion preventive film.

More particularly, the present invention relates to a method for restricting the movement of the adhesion preventive membrane to restrict the adhesion of the adhesion inducing substance to the periphery, And a method for producing the same.

If tissue damage occurs after surgical operation or due to inflammation, foreign body, bleeding, infection, wound, friction, etc., blood will flow out and coagulate in the process of proliferation and regeneration of damaged organs and tissues, Adhesion occurs. When the cells penetrate into these adhesion sites, stronger adhesion occurs. Adherence to excessive tissue, or unintentional adhesion to other tissues or organs, can result in dysfunction of organs or tissues and, in some cases, may require life-threatening rehabilitation.

These adhesions can occur in almost all parts of the human body such as muscles, sclera, conjunctiva, Tenon's capsule, and fascia. Clinically, the biggest problem is peritoneal adhesion or intestinal adhesions that occur after abdominal surgery, It is known to be caused by surgery, excessive bleeding, tissue reaction of the suture material, foreign substances during surgery, and inflammation after surgery. In general, the incidence of adhesions after laparoscopic surgery is reported to be quite high, ranging from 60 to 95%. Tissue adhesions are the main cause of intestinal obstruction (80% to 90%), and long-term sequelae and pelvic pain after gynecologic procedures , The uterine tissue adhesion during pelvic surgery may cause infertility.

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 order to improve the efficiency of the adhesion preventing film, it is necessary to add an additional function to the adhesion preventing film so as not to move at the origin of adhesion such as the surgical site.

The problem to be solved by the present invention is to improve the inefficient adhesion prevention function of the adhesion preventive film.

A basic object of the present invention is to provide a wave-type adhesion preventive film capable of suppressing the displacement of the adhesion preventive film, which is a problem of the adhesion preventive film, and preventing the diffusion of the adhesion inducing substance to effectively utilize the function of the adhesion preventive film.

The wave-form adhesion preventive membrane of the present invention is generally designed to inhibit positional fluctuation between peripheral tissues applied for 7 days or more, which is a period necessary for healing wounds, have appropriate flexibility to synchronize with changes in surrounding tissues, As shown in FIG.

And minimizes or eliminates the adhesion phenomenon occurring in the body due to various causes such as a surgical operation. As a means for this, adhesion preventive membranes are utilized, but they may cause expansion of the membrane displacement and adhesion sites.

The present invention is a means for solving the problem of the adhesion preventive film, and the present invention has been accomplished by introducing a bending form into the adhesion preventive film to suppress the displacement which is pushed to the surrounding tissue.

In the present invention, in order to minimize the natural movement of tissues or organs as well as the displacement of the adhesion preventing film caused by movement of the inside of the human body when the patient is active, appropriate forms and materials of the adhesion preventing film are considered.

Considerations in the development of a new adhesion barrier include: 1) Keep the form in the application process. 2) Have the form and physical properties that will not be pushed out by the unique movement of the tissue or organ or the movement of the individual's activity. 3) Maintain appropriate flexibility to cope with the movement of the application site. 4) The product should be sterilized. 5) Persist in the body for about 7 days. 6) Biocompatible and biodegradable.

A condition that can closely meet the above considerations is to alternately pour the crosslinked hyaluronic acid solution with the appropriate strength into the wave mold mold. And then washed to remove remaining unreacted materials.

Hyaluronic acid was used as a base material. Hyaluronic acid is a linear polymeric polysaccharide in which disaccharides composed of? -D-N-acetylglucosamine and? -D-glucuronic acid are repeatedly bonded. Have no species and organ specificity, and have excellent biocompatibility and very high viscoelasticity even when they are transplanted or injected into living bodies. When hyaluronic acid is used alone as the adhesion preventive film, the residence time in the living body is relatively short due to biodegradability due to excellent biocompatibility of hyaluronic acid, so that the effect of preventing adhesion is weak, and since water solubility is high, There is a problem of flowing down.

Thus, in the present invention, not only the shape of the hyaluronic acid but also the degree of crosslinking is formed so that two layers are alternately formed.

A layer of hyaluronic acid having a degree of crosslinking of 1% or less and another layer having a degree of crosslinking of 1% or more and 10% or less were alternately connected to each other to prepare a wave-like hyaluronic acid coating film. By doing so, proper viscosity, adhesion and application properties were maintained with shape maintenance.

The present invention has completed a wave form adhesion preventive film in which a gel layer based on hyaluronic acid having an appropriate viscosity and a solid type film layer are alternately mixed. However, the scope of right of the present invention is not limited to the wave form mentioned here, and it is also possible to include various types of membranes, and the manufacture of the membrane is not limited to the alternation of two layers having different degrees of crosslinking. Several layers with different properties can be constructed alternately.

By providing the wave-type adhesion preventive film of the present invention, it is possible to improve the problems of the adhesion preventive film which is superior in adhesion prevention effect to the liquid or gel type adhesion preventive agent, but its use is limited due to deterioration of adhesion prevention effect due to positional change after insertion into the adhesion site , And it is expected that the frequency of various adherence situations occurring during medical treatment can be greatly reduced.

Fig. 1 shows a wave-form adhesion preventive film produced by putting into a wave mold (casting mold).

A variety of barrier layers have been developed for the purpose of inhibiting adhesion, but no satisfactory products have yet emerged in terms of efficiency. Therefore, in order to provide a more effective adhesion preventive film, the adhesion preventive film is completed in the present invention in consideration of spatial problems so as not to be pushed or peeled by the movement of the wound. First, hyaluronic acid, which is widely used as an adhesion inhibitor, was used as a material for material properties considering the spatial morphology problem and the interaction between the adhesion preventive film and the wound area.

In the present invention, the form of the adhesion preventive film is not limited to the wave form. The side surface of the film may be selected from the group consisting of a wave form, a triangular wave form, a square wave form, a round curved wave form, a square sawtooth form, and combinations of these forms, but is not limited thereto.

In the present invention, hyaluronic acid cross-linked layers having various strengths can be prepared through cross-linking reaction using various concentrations of hyaluronic acid. The coupling reaction can be carried out using a conventional coupling agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). The binding reaction of hyaluronic acid can be carried out using an ordinary binder in an acidic condition of pH 4 to 5.

For example, in the case of producing a adhesion preventive membrane composed of two strengths, two different concentrations of hyaluronic acid are mixed with a certain amount of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) And then alternately poured to prepare an anti-adhesion film.

<Production example> Production of wave hyaluronic acid film

In the present invention, a wave-like hyaluronic acid membrane to be used for adhesion prevention was produced by the following production method. 0.5 g and 1.5 g of sodium hyaluronate (10 ⁶ Da; Shiseido Co., Ltd. Japan) were dissolved in 15 ml of a sodium hydroxide solution at a concentration of 0.05 mol / l at room temperature to prepare an aqueous solution. When sodium hyaluronate was completely dissolved, 1.0 ml of sodium hydroxide solution at a concentration of 10 mol / l was added to the aqueous solution of hyaluronic acid to increase the alkalinity.

In a separate vessel, the selected crosslinking agent, 1,4-butanediol diglycidyl ether (BDDE) is diluted in 1% sodium hydroxide solution.

Next, the BDDE solution prepared is added to the sodium hyaluronate solution having a different dissolved concentration and homogenized. For a substantially homogeneous, alkaline hyaluronic acid gel, the mixture is mixed for 2 hours at about 20 ° C. The mixture is then placed in warm water for 2 to 3 hours at 50 ° C., soaked for 15 minutes and then further homogenized.

The resulting crosslinked hyaluronic acid polymer is then poured alternately into a wave mold (casting mold). After holding at room temperature for 3 hours, the pH is stabilized by soaking in phosphate buffer (PB). The total of three phosphate buffers are replaced to remove unreacted crosslinking agent and hyaluronic acid.

Finally, a wave type hyaluronic acid membrane according to the present invention is provided.

Test Example 1 Comparative Test of Displacement of Hyaluronic Acid Film

A test was conducted to compare the degree of displacement of the currently commercially available flat anti-adhesion film and the wave-type anti-adhesion film produced in the present invention. As a basis of comparison, the distance traveled relative to the first added position is expressed in cm. In one subject, the comparison points were taken at three points, and these points were held so that the angles of each vertex were the same as possible.

Experimental rats (Sprague Dawley, male, 10 weeks old, body weight: 230 ~ 270g) were assigned to control group and experimental group (wave adhesion preventive membrane), respectively. And a 1 cm diameter circular adhesion preventive membrane was placed on the abdominal cavity and photographed at each position. The incision site was sutured and maintained normal life.

On the 7th day and the 14th day after the application of the anti-adhesion film, each was lapped and photographed to evaluate the degree of displacement. The degree of dissolution of the adhesion preventive film was evaluated by measuring the residual weight.

Claims (7)

Various types of crosslinked adhesion preventive film for preventing displacement of the adhesion preventing film and improving the efficiency of adhesion prevention. The high purity raw material according to claim 1, wherein one of the raw materials has a weight average molecular weight of at least about 2.0 MDa as a hyaluronic acid (HA) component. The method according to claim 1, wherein the various forms of the adhesion preventive film (when viewed from the side) are selected from the group consisting of a wave form, a triangular wave form, a square wave form, a round curved wave form, a square sawtooth form, But not limited to, [3] The method according to claim 2, wherein one of the raw materials is a hyaluronic acid component but is not limited thereto, and various polymers such as chitosan, alginic acid, chondroitin, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, Yes. The method of claim 1, wherein the crosslinking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis (2,3-epoxypropoxy) butane, 1,4- (2,3-epoxypropoxy) ethylene and 1- (2,3-epoxypropyl) -2,3-epoxycyclohexane, and 1,4-butanediol diglycidyl Ether. The adhesion preventive film is not composed of a single concentration, but is composed of two or more concentrations and is composed of alternating or continuous concentrations. The composition of the concentration is not limited thereto. 7. The method of claim 6, wherein the material composition of the adhesion preventive film is not limited to concentration but may include, but is not limited to, alternate or concordant continuity of microparticles, additives, materials, Not available.

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