JPS648603B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an agent for preventing intraperitoneal adhesion. Peritoneal adhesions associated with laparotomy have long been discussed as a postoperative complication. In other words, abdominal postoperative disorders are generally referred to as abdominal adhesions, and the symptoms include abdominal traction, discomfort, and other pain accompanied by abdominal distension.
In severe cases, it causes intestinal transit obstruction, ileus (intestinal obstruction), etc. Such abdominal postoperative disorders are caused after the existing root of the disease has been removed by surgery in hopes of achieving a therapeutic effect.
Despite today's remarkable progress in medical development, the number of cases is increasing year by year, and this is a serious problem that cannot be ignored in surgical operations. Conventionally, various surgical methods and drug administration methods have been attempted as measures to prevent the above-mentioned adhesions, but no method has yet been developed that can produce a satisfactory effect. That is, as a method of drug administration, a wide variety of drugs have been tested, including substances that are directly injected into the peritoneal cavity, such as fibrinolytic substances, fibrinolysis inhibitors, and substances that prevent contact with damaged areas of the serosa (membrane substances, oils). I have tried this, but it has very little effectiveness. In fact, substances that inhibit the dissolution or precipitation of fibrin include a pre-shield that attempts to heal the wound surface while destroying the wound surface and intraperitoneal fibrin, and the protection of the wound surface is not taken into account. I don't need it. Furthermore, membrane-like substances attempt to cover the wound surface mechanically, and cannot act on the entire intestinal tract, and it is difficult to predict where the adhesions will occur. It is not suitable for preventing peritoneal adhesions. In addition, steroids, polyvinylpyrrolidone (PVP), chondroitin sulfate, and the like are known to be effective substances at present, but their anti-adhesion effects are still unstable and incomplete. In view of the above-mentioned current situation, the present inventors have conducted various studies with the aim of providing a new anti-adhesion drug that can more stably and completely prevent intra-abdominal adhesions. However, it has been discovered that it can exhibit an extremely excellent adhesion prevention effect that meets the above objectives. The present invention
It was completed based on this knowledge. That is, the present invention relates to an intraperitoneal adhesion prevention agent whose main ingredient is an aqueous solution of sodium alginate. Sodium alginate, which is the active ingredient compound of the drug of the present invention, is a sodium salt of a natural polysaccharide that exists in brown algae such as kelp, Kajime, and Arame, and is composed of D-mannuronic acid and L-guluronic acid. , is usually purified and isolated from the above-mentioned brown algae after extraction with a dilute alkaline solution. Sodium alginate is a polymeric substance with various degrees of polymerization, and among these, those with relatively low molecular weights have traditionally been used as plasma expanders, and those with high molecular weights have been used as physical hemostatic agents (local hemostatic agents). It has been shown to be effective in hemostasis and healing of peptic ulcers when taken orally. Furthermore, it has no antigenicity, low toxicity, and almost no side effects. The present inventors completed the present invention based on the completely new finding that this aqueous solution of sodium alginate can have an extremely excellent adhesion prevention effect when directly injected into the surgical site after open surgery. The intraperitoneal adhesion prevention agent of the present invention is prepared and used in the form of the above-mentioned sodium alginate aqueous solution.
As sodium alginate, any one having various known molecular weights (degrees of polymerization) can be used. Usually, the degree of polymerization is preferably about 50-1500. The concentration of the aqueous solution may vary slightly depending on its degree of polymerization, etc., but it is usually about 2% by weight or more to achieve the desired effect of the present invention. A preferred concentration is about 2-8% by weight. The drug of the present invention is also preferably isotonic with body fluids. This tonicity can be achieved using ordinary tonicity agents, such as substances or solutions used in physiological saline, Ringer's solution, Lock's solution, etc., thereby reducing the risk of hemolytic reactions and increases in ascites. Completely avoidable. Furthermore, the drug of the present invention can also be sterilized and formulated according to conventional methods. When using the drug of the present invention to prevent intra-abdominal adhesions, the drug of the present invention is injected into the abdominal area after laparotomy, so that it is uniformly distributed over the entire area, as is the case with known inhibitors of this type. be done. The amount to be applied may be appropriately determined depending on the location of the abdominal incision and its width (area), and is not limited as long as the drug is distributed throughout the entire abdominal region. For normal open surgery, preferably about 30 to 300 ml, more preferably 50 to 200 ml
It can be in the range of ml. Thus, according to the administration of the drug of the present invention, the occurrence of intraperitoneal adhesions due to stimulation such as drying due to exposure to the atmosphere after surgery and contact with surgical instruments, etc., can be prevented.
This can always be prevented stably and reliably.
Therefore, the drug of the present invention makes it possible to perform surgical operations more safely and is of extremely high value. The present invention will be explained in more detail below with reference to test examples conducted on the intraperitoneal adhesion prevention agent of the present invention. Test Example 1 Test was conducted using Wistar rats (200-250 g) according to the Ryan method. That is, after the test animal's abdomen is opened, the surface of the cecum is locally dried for 5 minutes using compressed air. Next, 2 ml of autologous blood is collected directly from the femoral vein and injected intraperitoneally. Thereafter, a predetermined amount of sodium alginate (Al-Na) adjusted to a predetermined concentration with distilled water is similarly injected into the abdominal cavity, and the open abdomen is sutured to complete the surgery. One week later, the abdomen is opened again and the development of intraperitoneal adhesions is observed. Count the number of animals that have developed adhesions, and calculate the incidence of adhesions (number of animals that have developed/number of animals tested x 100). The results are shown in Table 1 below. Table 1 also shows the control (untreated control group).
For comparison, the results obtained when no drug was used and when a 1 ml solution of steroid, known as one of the best anti-adhesion agents to date, were used are also shown.

【table】

[Table] From Table 1 above, it can be seen that the sodium alginate aqueous solution can exhibit a remarkable adhesion prevention effect at a concentration of 2 to 8% by weight (NO1 to 7). In addition, no hemolysis was observed in these cases, but hemolysis was observed in a 1% by weight aqueous solution of Na alginate. Furthermore, although known steroids exhibit excellent adhesion prevention effects, they are known to cause complications such as peritonitis and ileus. Therefore, for each of the above-mentioned test drugs, the following tests were separately conducted according to the Ellis method. That is, after laparotomy, 20 cm on the oral side of the ileocecal region.
After ligating the mesenteric blood vessels at the site to create a 2.5 cm ischemic intestine, the omentum was wrapped at the same time, 1 ml of the test drug was injected, the abdominal part was sutured, and it was left for one week. One week later, laparotomy was performed, and the incidence of adhesions and the state of wound healing in the abdominal area were observed. As a result, in Nos. 1 to 6 and 9 above, there was no change in the incidence of adhesions, but in No. 9 (comparison), peritoneal inflammation and ileus were observed, whereas in Nos. 1 to 6 It was found that (the present invention) did not cause any complications and did not interfere with wound healing. Furthermore, no abnormalities were observed in the clinical examination two weeks after use of Nos. 1 to 6. Examples of preparation of the drug of the present invention are given below. Formulation Example 1 Dissolve 5 g of sodium alginate in 0.62% saline to prepare a 5% sodium alginate isotonic solution. This is sterilized according to the Japanese Pharmacopoeia General Test Method and Sterilization Method to obtain the intraperitoneal adhesion prevention agent of the present invention. This product showed an adhesion incidence of 0% (no adhesions were observed in 10 test animals) in the same test as Test Example 1 above, and was confirmed to have no side effects or inhibition of wound healing. Formulation Example 2 Add 3 g of sodium alginate to 81 ml of Ringer's solution, dissolve, add distilled water for injection to make a total volume of 100 ml, and sterilize as in Formulation Example 1.
Obtain a % sodium alginate isotonic solution. This product was the result of the same test as Test Example 1 above.
No adhesions were observed, nor were any side effects observed.

Claims (1)

[Claims] 1. An intraperitoneal adhesion prevention agent whose main ingredient is an aqueous solution of sodium alginate. 2. The drug according to claim 1, wherein the sodium alginate content is about 2-8% by weight. 3. The drug according to claim 1, which is used in the form of an isotonic solution.