CN1370539A - Preparation method of separant for preventing postoperative adhesion of abdominal cavity - Google Patents

Abstract

A method for preparing a release agent for preventing postoperative adhesions in the abdominal cavity. The release agent is composed of two parts. The first component is an aqueous solution of polymer sodium carboxymethyl cellulose capable of forming a gel, and carboxymethyl cellulose of carboxymethyl cellulose. The substitution degree of the group is 0.5-1.2; when preparing the aqueous solution, gradually add solid sodium carboxymethyl cellulose under stirring, and heat to a slight boiling after the addition, with a mass concentration of 0.5-5%; the second component is FeCl ₃ , Fe ₂ ( SO ₄ ) ₃ , Al(NO ₃ ) ₃ and Al ₂ (SO ₄ ) ₃ and other polyvalent metal cation salt aqueous solutions, the mass concentration is 1-40%; the molar ratio of trivalent ions and carboxylate is 10%- Add the trivalent ion salt solution to the sodium carboxymethyl cellulose solution at a ratio of 0.1%, and stir evenly. The release agent of the present invention gradually gels after being applied to the site to be isolated, so as to prevent adhesion and is finally absorbed by the body.

Description

Preparation method of release agent for preventing postoperative adhesion in abdominal cavity

Technical field: the present invention relates to a kind of preparation method that is used for reducing and preventing the release agent of abdominal postoperative adhesion.

Technical background: Adhesion between tissues and organs after surgery is a clinically frequent disease. The reason for this is an increase in the release of fibrinogen and a decrease in the amount of fibrinolytic enzymes at the relevant sites after surgery. The destruction of the balance between the two leads to the deposition, coagulation, and organization of fibrin, forming permanent fibrous adhesions. Studies have shown that adhesion between tissues and organs is related to mechanical injury, tissue ischemia, implantation of foreign substances, and local inflammation. Therefore, in order to reduce and prevent postoperative adhesions, corresponding measures should be taken, such as reducing tissue damage, preventing tissue ischemia, reducing tissue inflammation, using appropriate drugs to increase the activity of plasminogen activator (Plasminogen Activator Activity, PAA), and promoting Digestion and dissolution of fibrin, inhibition of fibroblast proliferation, etc. Another method is to use a physical barrier, that is, to place a film or fabric between two tissues or organs that may be adhered to block the possible fibrous connection between them. For example, Chinese Patent (Application No.) 97114981: "Bio-dissolvable oxidized cellulose composite material to prevent postoperative adhesion" is to coat a layer of oxidized cellulose on the surface of cellulose fabric to form a composite film, and use this film as a physical barrier layer to prevent adhesions between tissues or organs near the wound after surgery. This method has a certain effect on cases where the shape of the interface between tissues or organs is relatively simple in clinical practice. But for the interface with complex shape, it is very difficult to isolate the surgical operation. The materials used cannot be completely absorbed or degraded by the body after the wound has healed. If they remain in the human body or are removed by a second operation, they will cause pain to the patient and bring new adhesion risks.

Among various postoperative adhesions, abdominal postoperative adhesions, especially intestinal adhesions, are very common. This is because the abdominal cavity is full of various organs such as the small intestine and large intestine, and the contact area between the peritoneum and the intestinal wall, and between the intestinal wall and the intestinal wall is very large. high. During abdominal surgery, it is inevitable to destroy or injure the peritoneum and intestinal wall, and the fluid and bacteria in the intestine are likely to enter the abdominal cavity through the trauma site or through the intestinal wall, causing inflammation. Intestinal adhesions caused by these factors can cause intestinal obstruction in severe cases, requiring secondary operations, and even endangering the patient's life.

The methods proposed above to reduce and prevent postoperative adhesions are basically not applicable to abdominal or intestinal adhesions. The reason is that the shape of the intestinal tube is slender, the contact surface between the intestines, between the intestinal wall and the peritoneum is very large, and the small intestine is in constant peristalsis. During the movement of the contents in the intestine, the outer diameter and shape of the intestinal tube are constantly changing. When using a solid barrier membrane, it is very difficult to coat the outer surface of a long section or several sections of bowel with a membrane. Since it is impossible to suture and fix between the isolation membrane and the intestinal tube, and the intestinal tube is in constant peristalsis, the isolation membrane is prone to slipping, so that the part that needs to be isolated cannot be isolated, or new trauma is caused in the original healthy part. . Therefore, for intestinal adhesions and abdominal adhesions, measures to adapt to the characteristics of the abdominal cavity and intestine must be taken.

Summary of the invention: One of the objectives of the present invention is to provide a release agent for preventing postoperative adhesions in the abdominal cavity. The release agent adapts to the characteristics of large contact area between the peritoneum and the intestine, and between the intestine and the intestine, and the contact position and degree of contact are uncertain. , in the form of solution and gel, it is easy to reach the part that needs to be isolated, and it is easy to cover the outer surface of the intestine.

As a material used in the abdominal cavity, it should meet the requirements of non-toxicity, harmlessness, biocompatibility, and no foreign body reaction. The time for the formation of intestinal adhesions is about one week, so the residence time of the isolation material to prevent adhesions in the designated parts should also be equivalent to it. If it is too short, it will not have the effect of preventing adhesion; if it is too long, although intestinal adhesion will not occur, it will remain in the abdominal cavity as a foreign body, which will always cause various troubles. Therefore, the second purpose of the present invention is to adjust the residence time of the spacer in the abdominal cavity so that it can not only prevent intestinal adhesion, but also be gradually digested and absorbed by the human body and excreted after the intestinal function returns to normal.

Physical barrier materials for anti-adhesion, which can be in the form of solutions, gels, films, fabrics, etc. The advantage of the solid isolation layer is that its composition and shape can be effectively controlled, but the disadvantage is that it may not be able to meet the requirements of surgery or treatment. As mentioned above, the shape and area of films, fabrics, etc. are limited, it is difficult to access the parts that should be isolated, and it is difficult to cover all the surfaces that are expected to be covered. In contrast, the solution is easy to do this, but the solution is easy to flow in the abdominal cavity, and it is difficult to ensure that it stays in the part that needs to be isolated. Viscose is between the two and is more suitable for intraperitoneal use. However, generally the viscosity is relatively high, the fluidity is limited, and the effect is not necessarily very good. Therefore, the third object of the present invention is to take the advantages of the solution being easy to flow, easy to reach and fill the wound site, and the gel is not easy to lose and ensure the isolation effect, and adopt the method of on-site preparation before the operation. When the spacer fluid is injected into the peritoneal cavity, it is in the nature of a general solution and is easy to operate. After reaching the designated site, the spacer solution gels, increases in viscosity, is difficult to flow, and basically remains at the designated site.

In order to achieve the above three purposes, the present invention uses an aqueous solution of sodium carboxymethyl cellulose as a component, and the carboxymethyl substitution degree of carboxymethyl cellulose is 0.5 to 1.2, preferably 0.8 to 1.0. It should be above food grade, preferably medical grade. The aqueous solution is prepared with distilled water, and the mass concentration is 0.5-5%, preferably 1-3%. According to the dissolving characteristics of carboxymethyl cellulose, the method of gradually adding under stirring is adopted to prevent the polymer from agglomerating and insoluble. In order to ensure the dissolution, after adding the solid sodium carboxymethylcellulose, it can be properly heated until it boils slightly. After the solution is cooled, it is filtered, bottled, sterilized by high-pressure steam, and set aside.

The second component of the spacer used in the present invention is an aqueous solution of polyvalent metal ion compounds that can cross-link and gel the sodium carboxymethyl cellulose. The polyvalent metal ion compound should have no toxic and side effects in the human body, and has a good gelling effect on sodium carboxymethyl cellulose, and FeCl ₃ , Fe ₂ (SO ₄ ) ₃ , Al(NO ₃ ) ₃ and Al ₂ can be selected. (SO ₄ ) ₃ etc. They are formulated into aqueous solutions with a mass concentration of 1-40%, preferably 5-15%, by conventional methods. After the aqueous solution is bottled, it is sterilized by high-pressure steam and ready for use.

The mixing of the two components used in the present invention is carried out before the operation. Add specified volume of sodium carboxymethylcellulose solution into a sterilized beaker, then add trivalent ion salt solution, stir evenly, and let it stand for use. The volume ratio of the two solutions is determined according to their respective concentrations, so that the mol ratio of the trivalent ion and the carboxyl group in the carboxymethyl cellulose is 1: 10～0.1%, preferably 1: 5～0.5%, most preferably 1 : 3-1%. This ratio is determined according to the surgical site and specific conditions. Generally speaking, when a large area is isolated, the amount of cross-linking agent can be less, so that the viscosity of the mixed solution will not be too high, causing inconvenience in operation. For small area local isolation, the amount of cross-linking agent can be larger to reduce flow. But not so much that the mixture settles before it is placed. The way of injection can be directly injected into the wound site, or the solution can be dipped in sterile gauze and coated. Local aggregation of large pieces should be avoided. If local stasis is found, it can be appropriately diverted to the required place, or withdrawn with a syringe.

The preparation and application methods of the above barrier agent for preventing intestinal adhesion will be further illustrated in the following examples. But the present invention is not limited to these examples, and those who are familiar with biomedical materials can make appropriate improvements and developments in the variety, preparation and use of materials according to the principle of the present invention.

Detailed ways:

Embodiment 1: Sodium carboxymethyl cellulose/ferric chloride anti-adhesion release agent.

Take 2.0 g of powdered pharmaceutical grade sodium carboxymethyl cellulose (hereinafter abbreviated as CMC, the degree of carboxymethyl substitution is 0.92), and gradually add it to 100 ml of distilled water under stirring, and it takes about 10 minutes to complete the addition. Continue to stir for 0.5h after the addition, slowly raise the temperature to a slight boil, then cool down to room temperature naturally, filter through a _G2 glass sand funnel, put it into a glass bottle, steam sterilize at 121°C, and set aside.

Weigh 5.0g of blocky ferric chloride (FeCl ₃ 6H ₂ O) with crystalline water, put it in a beaker, add 50ml of distilled water, stir until it is completely dissolved, filter it through a _G2 glass sand funnel, and put it into a glass bottle , 121 ℃ steam sterilization, spare.

Take 100ml of the above CMC solution and 10ml of _FeCl3 solution, mix them in a beaker, stir evenly, and let stand for later use.

Take 15 Wistar rats, male or female, weighing 200±20g. Under anesthesia, a 3 cm long midline laparotomy was made, and the ileal serosa was peeled off with a blade, starting at 5 cm from the ileocecal and about 15 cm long. Put 3ml of the above mixed solution into the wound, and then close the abdomen. Rats were killed 7 days after the operation and observed by laparotomy. Results 15 rats had mild adhesion in 4 and no adhesion in 11 rats.

Embodiment 2: Sodium carboxymethyl cellulose/iron sulfate anti-adhesion release agent.

Weigh 5.0 g of powdered iron sulfate (Fe ₂ (SO ₄ ) ₃ ), put it in a beaker, add 50 ml of distilled water, and stir until completely dissolved. Filter with a _G2 glass funnel, put it into a glass bottle, steam sterilize at 121°C, and set aside.

Get 100ml of the CMC solution in Example 1, add 15ml of the above-mentioned ferric sulfate solution, mix in a beaker, stir evenly, and let it stand for later use.

Take 15 Wistar rats, male or female, weighing 200±20g. Under anesthesia, a 3 cm long midline laparotomy was made, and the ileal serosa was peeled off with a blade, starting at 5 cm from the ileocecal and about 15 cm long. Put 3ml of the above mixed solution into the wound, and then close the abdomen. Rats were killed 7 days after the operation and observed by laparotomy. Results Of the 15 rats, 5 had mild adhesion and 10 had no adhesion.

Embodiment 3: Sodium carboxymethyl cellulose/aluminum nitrate anti-adhesion release agent.

Weigh 5.0 g of powdered aluminum nitrate (Al(NO ₃ ) ₃ ·9H ₂ O), put it in a beaker, add 50 ml of distilled water, and stir until completely dissolved. Filter with a _G2 glass funnel, put it into a glass bottle, steam sterilize at 121°C, and set aside.

Get 50ml of the CMC solution in Example 1, add 20ml of the above-mentioned ferric nitrate solution, mix in a beaker, stir evenly, and let it stand for later use.

Take 15 Wistar rats, male or female, weighing 200±20g. Under anesthesia, a 4 cm long median laparotomy was made, and the ileum serosa was peeled off with a blade at a place 5 cm away from the ileocecal, with a length of about 15 cm. Put 3ml of the above mixed solution into the wound, and then close the abdomen. Rats were killed 7 days after the operation and observed by laparotomy. Results Of the 15 rats, 6 had mild adhesion and 9 had no adhesion. Control Example 1: Animal test of blank control group.

Take 15 Wistar rats, male or female, weighing 200±20g. Under anesthesia, a 3 cm long midline laparotomy was made, and the ileal serosa was peeled off with a blade, starting at 5 cm from the ileocecal and about 15 cm long. The wound was closed without any other treatment. Rats were killed 7 days after the operation and observed by laparotomy. Results All 15 rats had obvious adhesions.

Control Example 2: Animal test of non-crosslinked control group.

Take 15 Wistar rats, male or female, weighing 200±20g. Under anesthesia, a 3 cm long midline laparotomy was made, and the ileal serosa was peeled off with a blade, starting at 5 cm from the ileocecal and about 15 cm long. 3ml of 3% sodium carboxymethylcellulose was placed in the wound, and then the abdomen was closed. Rats were killed 7 days after the operation and observed by laparotomy. Results Of the 15 rats, 2 had obvious adhesions, 7 had mild adhesions, and 6 had no adhesions.

Claims (8)

1. A preparation method of a release agent for preventing abdominal postoperative adhesions. The release agent is composed of two parts. The first component is an aqueous solution of high molecular weight sodium carboxymethyl cellulose capable of forming a gel. The carboxymethyl substitution degree is 0.5-1.2; when preparing the aqueous solution, gradually add solid sodium carboxymethyl cellulose under stirring, and heat to a slight boiling after adding, with a mass concentration of 0.5-5%; The second component is an aqueous solution of polyvalent metal cation salt, with a mass concentration of 1-40%; The trivalent ion salt solution is added to the sodium carboxymethyl cellulose solution according to the molar ratio of the trivalent ion and the carboxylate radical being 10% to 0.1%, and the mixture is evenly stirred. 2. The preparation method according to claim 1, characterized in that the sodium carboxymethyl cellulose is pharmaceutical grade carboxymethyl cellulose, and the degree of carboxymethyl substitution is 0.8-1.0. 3. The preparation method according to claim 1 or 2, characterized in that the mass concentration of the sodium carboxymethylcellulose aqueous solution is 1-3%. 4. The preparation method according to claim 1, characterized in that the mass concentration of the aqueous solution of the polyvalent metal cation salt of the second component is 5-15%. 5. The preparation method according to claim 1 or 4, characterized in that the second component polyvalent metal cation salt is ferric chloride or ferric sulfate ferric salt. 6. The preparation method according to claim 1 or 4, characterized in that the second component polyvalent metal cation salt is aluminum nitrate, aluminum sulfate or trivalent aluminum salt of aluminum trichloride. 7. The preparation method according to claim 1, characterized in that the molar ratio of the trivalent ions to carboxylate is 5-0.5%. 8. The preparation method according to claim 1 or 7, characterized in that the molar ratio of the trivalent ions to carboxylate is 3-1%.