KR20020011955A - A conglutination inhibitor - Google Patents

Abstract

PURPOSE: An anti-adhesion barrier containing sodium carboxymethyl cellulose as a main component and gellan gum is provided, which has various characteristics such as anti-adhesion effects, styptic effects, adhesion and compatibility as well as anti-inflammatory and antibacterial properties. CONSTITUTION: This anti-adhesion agent comprises 0.1 to 35.0% by weight of sodium carboxymethyl cellulose(CMC-Na), 0.1 to 35.0% by weight of gellan gum, 10% by weight of an antibiotic and the residual of water. A mixture of sodium carboxymethyl cellulose and gellan gum is dissolved in water, heated at 120 to 150deg.C for 5 to 20 min and then subjected to quick freezing using liquid nitrogen and maintaining at 55deg.C or less for 48hr.

Description

Adhesion Inhibitor {A conglutination inhibitor}

The present invention relates to an anti-adhesion agent having an excellent effect of preventing bleeding of a surgical site (hemostatic effect) and an effect of preventing adhesion between tissues of the surgical site (adhesion effect).

In general, if there is a slight bleeding after surgery or during surgery, the surgical site or the bleeding site and the existing cell tissue portion are bonded after the closure of the surgical site, many problems occur during reoperation.

Adhesion occurs at a frequency of 70-95% after open surgery (Eur. J. Surg. 1997, Suppl 577, 10-16, 24-31, 32-39), especially in the case of abdominal surgery. Many problems arise due to, for example, adhesion of the intestinal and abdominal walls.

In order to solve this problem, studies have been actively conducted to prevent long-term mutual adhesion between long-term mutual adhesion by using an anti-adhesion agent having very low harmfulness as it is decomposed in the body.

In addition to the ability to prevent adhesion between organs and bleeding, the anti-adhesion agent requires properties such as good adhesion, applicability, affinity with tissues, and antibacterial properties.

Recently, studies on antiadhesion barriers that can block the contact of wounds after surgery have been actively conducted. As a method of using a bioabsorbable polymer having a high molecular weight carboxyl end group, it is hydrated in vivo to heal wounds. It isolates the wound from the surrounding tissues for a period of time to prevent adhesions. After healing, it is naturally absorbed and removed, which does not affect normal tissues.

As an example of a method of using a bioabsorbable polymer, US 4,141,973 uses hyaluronic acid (HA), which has a problem in performance as an anti-adhesion agent because it is decomposed and absorbed within a relatively fast time.

In addition, examples using sodium carboxymethyl cellulose (SCMC) (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) also had the disadvantage that the solutions of these polymers were also absorbed too quickly to achieve the desired anti-adhesion effect.

Due to these problems, a method of forming intramolecular crosslinks has been proposed. For example, in EP 507,604, a polysaccharide having a carboxy end group is ion-bonded with a polyvalent metal ion to reduce solubility, thereby providing a method of using an anti-adhesion agent. , US Pat. No. 5,318,780 also proposes an anti-adhesion method using in situ gelation.

However, these methods have the advantage that the film-forming polymer [hydroxypropyl methyl cellulose (HPMC)] film is formed in the body, but is not suitable as an anti-adhesion agent due to reduced tissue adhesion and complexity of the procedure.

US 5,017,229; US 5,527,893; In US 5,760,200, etc., a method of preventing coalescence using hyaluronic acid (HA) and carboxymethyl cellulose (CMC), which are a kind of polysaccharide, has been proposed. However, this method has a problem in removing biotoxic substances generated during the manufacturing process. As the hydration proceeds, the gelation is performed at a rapid rate, so it cannot be removed again and treated (Surg. Clin. Nor. Am., 1997, 77: 3, 671-688). And there was a difficulty in the procedure.

In general, hydrophilic biopolymers have a hydration effect, but a polymer having a carboxy end group capable of binding to a tissue may be appropriately used. Since it is already saturated with water, the adhesion of the polymer itself becomes more important.

Recent advances in surgical techniques have resulted in a side effect of preventing adhesions (Hepato-Gastroenterol 1991 38 283), and the trend toward developing anti-adhesions is a solution in the form of anti-adhesions that are being described in response to changes in these surgical techniques. Progress is being made in the form of solutions or gels in formulations, gel formulations and film formulations (The Adhesion Prevention Opportunity, Report from MDI, 1998).

The gel form is a method recently attracting attention in that it can effectively prevent adhesion by using only a small amount on the wound area, and in particular, a gel-type formulation has been developed that can be used in a limited way such as spinal surgery or dry surgery (US 5,605,938) , Gel type anti-adhesion agent composed of Phosphated saline, Porcine and Polyglycan ester, currently manufactured and marketed by Gliatech, USA (trade name: ADCON-L) ) Has been widely used.

However, the conventional gel-type anti-adhesion agents have good results in anti-adhesion effect and hemostatic properties, but still have a limited effect on adhesion, affinity, anti-inflammatory and antimicrobial properties, and regeneration of wounds. .

The present invention is based on sodium carboxymethyl cellulose (NaCMC) as a main component by applying gellan gum (Gellan gum) of a suitable concentration, has various properties such as anti-adhesion performance, hemostatic, adhesive, affinity, and anti-inflammatory and antibacterial The present invention has an object of presenting an effective anti-adhesion agent evenly equipped with a regeneration function of the wound site.

1 is a photograph showing the test results using the anti-adhesion agent according to Example 1

Figure 2 is a photograph showing the test results using the anti-adhesion agent according to Example 2

Figure 3 is a photograph showing the test results using the anti-adhesion agent according to Example 3

Figure 4 is a photograph showing the test results using the anti-adhesion agent according to Example 4

5 and 6 are photographs showing the test results using the saline solution

For this purpose, the present invention provides an anti-adhesion agent comprising sodium carboxymethyl cellulose (NaCMC) and gellan gum (Gellan gum).

Anti-adhesion agent according to the present invention is sodium carboxymethyl cellulose (NaCMC) of 0.1 to 35.0% by weight, gellan gum (Gellan gum) is 0.1 to 35.0% by weight, the remainder is a gel form consisting of water and antibiotics, antibiotic is 0.0 It is included in the range of -10.0% by weight.

The anti-adhesion agent is sodium carboxymethyl cellulose (NaCMC) or sodium carboxymethyl cellulose (NaCMC) and gellan gum (Gellan gum) is dissolved in water, sterilized and lyophilized, and water is added again and stirred to gel form. Is manufactured.

Sodium carboxymethyl cellulose (NaCMC), the main component of the present invention, has been used in pharmaceutical materials, and has excellent anti-inflammatory, antimicrobial, wound regeneration, and hemostatic properties, and excellent human fitness and safety.

The molecular weight of the sodium carboxymethyl cellulose (NaCMC) is preferably about 700,000 to 1,000,000 Daltons, the content (concentration) in the anti-adhesion agent is 0.1 to 35.0% by weight, more preferably 5.0 to 15.0% by weight.

However, the molecular weight and content of sodium carboxymethyl cellulose (NaCMC) can be properly adjusted according to the surgical site and purpose of use.

If the molecular weight and content of sodium carboxymethyl cellulose (NaCMC) is too high, it is not preferable because it may interfere with the return of organs after surgery and may inhibit absorption and passage of the main component.

On the other hand, when the molecular weight and content of sodium carboxymethyl cellulose (NaCMC) is too low, problems such as adhesion prevention and hemostatic effects may be lowered.

For example, it is recommended that the molecular weight and content of sodium carboxymethyl cellulose (NaCMC) be relatively high when it is used for a traumatic or bleeding area, and the molecular weight of sodium carboxymethyl cellulose (NaCMC) when used for internal organs. And relatively low content.

It is preferable that the content (concentration) of sodium carboxymethyl cellulose (NaCMC) is 5.0% by weight in the abdominal cavity, and in this case, the antiadhesion agent is lubricated and the homeotropic property is improved, and due to the proper viscosity of the antiadhesion agent, After surgery, adhesion of organs can be effectively prevented.

Gellan gum (Gellan gum) included in the anti-adhesion agent of the present invention is to maintain the gel form and to improve lubricity is added in the range of 5.0 to 15.0% by weight relative to the total weight.

The anti-adhesion agent of the present invention is preferably sterilized at high temperature in the form of a gel. The sterilization temperature should be about 5 to 20 minutes at temperatures ranging from 100 to 150.

The anti-adhesion agent of the present invention is freeze-dried in the form of gel after the first high temperature steam sterilization, and the reason for lyophilization is a method for long-term preservation without changing the shape and physical properties of the gel-forming molecules, and the freezing temperature is rapid Liquid nitrogen is used for freezing, and lyophilization is dried at -50 or lower for at least 48 hours, and after drying, it becomes white powder.

The anti-adhesion agent of the present invention is preferably sterilized with ethylene oxide gas (EtO gas) in the form of white powder.

Meanwhile, the anti-adhesion agent of the present invention may optionally contain 0.0 to 10.0% by weight of antibiotics to enhance antimicrobial, adhesiveness, affinity, etc., in this case, after preparing a solution in which the antibiotic is mixed with water, lyophilized. The mixture is added by stirring into a white powder.

The present invention can be applied as in the embodiment in the form of a powder or gel form after lyophilization.

The present invention is composed of sodium carboxymethyl cellulose (NaCMC) as an active ingredient having excellent anti-inflammatory, antimicrobial properties, sexual regeneration function, hemostatic effect, and excellent body compatibility, and is excellent in preventing adhesion between cells and hemostatic effect.

In addition, since the present invention gellan gum is contained, the lubricity, adhesion, affinity, and the like can also be improved.

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

However, the present invention is not limited only to the following examples.

<Preparation of anti-adhesion agent>

Example 1

5.0 g of sodium carboxymethyl cellulose (NaCMC) and 5.0 g of gellan gum (Gellan gum) are dissolved in 90 g of water, sterilized at 120 ° C for 10 minutes, rapidly frozen with liquid nitrogen, and lyophilized at -55 ° C or lower for at least 48 hours. It is made into a powder form to make a powder form and use it, or after the freeze-dried to prepare a gel form by stirring the solution of 90g of a solution containing 5.0% by weight of antibiotics and 95% by weight of water.

In order to test the anti-adhesion and hemostatic effect of the anti-adhesion agent according to the above embodiment, the back of the mouse (weight: 220 g-450 g, male) between 8 and 24 weeks was opened with a scalpel to slightly open the wound around the spinal muscle with a scalpel. After bleeding out, the anti-adhesion agent in the form of powder or gel prepared in Example 1 was applied thereto and then sealed in place after application.

One month after the operation, the result of the scalpel was shown to prevent adhesion and hemostasis of muscle vessels around the spine. As shown in the photo of FIG. 1, the sutures were not adhered to each other, and the healing effect was excellent without bleeding and inflammation.

Example 2

Sodium Carboxymethyl Cellulose (NaCMC) 10.0g Soluble in 90g of water, sterilized at 120 ℃ for 10 minutes and rapidly frozen with liquid nitrogen, and then freeze-dried at -55 ℃ or less for more than 48 hours to form a powder form, after lyophilization Into the powder was prepared by stirring and stirring a solution of 5.0% by weight of antibiotics and 90g of water with 95% by weight of water to prepare a gel form.

In order to test the anti-adhesion and hemostatic effect of the anti-adhesion agent according to the above embodiment, the back of the mouse (weight: 220 g-450 g, male) between 8 and 24 weeks was opened with a scalpel to slightly open the wound around the spinal muscle with a scalpel. After bleeding out, the anti-adhesion agent in the form of a powder or gel prepared in Example 2 is applied thereto and then placed in the original position and sealed.

One month after the operation, the result of opening the scalpel to examine the anti-adhesion and hemostatic effects of the muscle vessels around the spine was that the sutures did not adhere as shown in the photograph of FIG. 2, and the healing effect of the wound was excellent without bleeding and inflammation.

Example 3

10.0 g of sodium carboxymethyl cellulose (NaCMC) and 10.0 g of gellan gum (Gellan gum) are dissolved in 90 g of water, sterilized at 120 ° C for 10 minutes, rapidly frozen with liquid nitrogen, and lyophilized at -55 ° C or lower for at least 48 hours. After making the powder form, and lyophilized to 80g of a solution of 5.0% by weight of antibiotics and 95% by weight of water to the resulting powder to prepare a gel form.

In order to test the anti-adhesion and hemostatic effect of the anti-adhesion agent according to the above embodiment, the back of the mouse (weight: 220 g-450 g, male) between 8 and 24 weeks was opened with a scalpel to slightly open the wound around the spinal muscle with a scalpel. After bleeding out, the anti-adhesion agent in the form of powder or gel prepared in Example 3 is applied thereto, then placed in place and sutured.

After one month after surgery, the anti-adhesion and hemostatic effects of muscle blood vessels around the spine were revealed.

Example 4

15.0 g of sodium carboxymethyl cellulose (NaCMC) and 5.0 g of gellan gum were dissolved in 90 g of water, and then sterilized at 120 ° C. for 10 minutes, followed by rapid freezing with liquid nitrogen for freeze-drying at -55 ° C. or lower for 48 hours. After making a powder form, 80g of a solution of 5.0% by weight of antibiotics and 95% by weight of water is added to the resulting powder after lyophilization to prepare a gel form.

After culturing smooth muscle cells and skin cells (5X105 cells) on a polystyrene cell culture dish having a diameter of 10 cm, the mature cells were removed by a straight cross of 0.5 cm width using tweezers, and in Example 4 The prepared anti-adhesion agent in powder or gel form is applied.

After that, after culturing the cells for 48 hours, the result of taking a micrograph is as shown in FIG. 4.

Looking at the picture, the cells do not grow through the anti-adhesion agent, it can be seen that the inter-cell adhesion is effectively prevented.

Each of the above examples was prepared by varying the content of the anti-adhesion agent within the desired mixing content range of sodium carboxymethyl cellulose (NaCMC) and gellan gum (Gellan gum), there is no significant difference in the anti-adhesion effect and hemostatic effect It can be seen.

Figures 5 and 6 show the results of using physiological saline without using the anti-adhesion agent according to the present invention by opening the dorsal side of the mouse (weight: 220g-450g, male) between 8 and 24 weeks with a scalpel around the spine. Cut the muscle vessel slightly with a scalpel to bleed it, apply physiological saline to it, place it in its original position and suture it, and open it again with a scalpel one month after surgery to examine the anti-adhesion and hemostatic effects of muscle vessels around the spine. The results are shown.

According to the above results, adhesion is generated in the suture portion, it can be seen that bleeding and inflammation occurs, it can be seen that the therapeutic effect of the wound site is also insignificant.

The present invention by the above configuration is characterized by the anti-adhesion agent containing sodium carboxymethyl cellulose (NaCMC) and gellan gum (Gellan gum), each of the above embodiments to show that the present invention can be implemented in various forms The basic idea of the present invention is not limited by the above embodiments.

The present invention has a very good anti-adhesion effect and hemostatic effect, since the main component is sodium carboxymethyl cellulose (NaCMC), which is excellent in anti-epilepticism, antimicrobial properties, wound regeneration function, hemostatic effect and excellent in body compatibility and safety. The present invention contains gellan gum and an antibiotic which improves lubricity (flow rate) in the form of a gel, and is very excellent in adhesiveness, transparency, flow chart, coating property, affinity, and the like.

Claims (6)

Anti-adhesion agent characterized in that the powder is made to include sodium carboxymethyl cellulose (NaCMC) and gellan gum (Gellan gum) and is made in the form of a gel using the powder The method of claim 1, wherein the sodium carboxymethyl cellulose (NaCMC) is 0.1 to 35.0% by weight, gellan gum (Gellan gum) is 0.1 to 35.0% by weight, the remainder is composed of water and antibiotics, the antibiotic is less than 10% by weight Adhesion inhibitors, characterized in that consisting of. The anti-adhesion agent according to claim 2, wherein the content (concentration) of sodium carboxymethyl cellulose (NaCMC) in the anti-adhesion agent is 5.0 to 15.0% by weight. The anti-adhesion agent according to claim 2, wherein the gellan gum content (concentration) in the anti-adhesion agent is 5.0 to 15.0% by weight. According to claim 1, Sodium carboxymethyl cellulose (NaCMC) and gellan gum (Gellan gum) is dissolved in water, sterilized it and then lyophilized, it is added to the water and stirred to prepare a gel form Adhesion inhibitors. The method of claim 4, wherein sterilization is performed by maintaining sodium carboxymethyl cellulose (NaCMC), gellan gum and water mixture at a temperature of 120-150 ° C. for 5-20 minutes, and lyophilization is performed with liquid nitrogen. After rapid freezing using the anti-adhesion agent, characterized in that consisting of a method for maintaining for at least 48 hours at -55 ℃ or less.