KR101799534B1 - Composition for preventing tissue adhesion and method for preparing the same - Google Patents

Abstract

The present invention relates to a composition for preventing tissue adhesion, which can be applied to minimally invasive surgery or laparoscopic surgery, which can be easily applied to raw materials and cost of raw materials, And a method for producing the same.

Description

TECHNICAL FIELD The present invention relates to a composition for preventing tissue adhesion and a method for preparing the same,

TECHNICAL FIELD The present invention relates to a composition for preventing tissue adhesion which is excellent in biocompatibility and excellent in adhesion prevention, comprising carboxymethyl cellulose, alginate, polyethylene oxide-polypropylene oxide copolymer and calcium chloride as active ingredients, and a method for producing the same.

Organ organs, which are common after surgery, are a result of biochemical reactions in the process of repairing damaged cells, leading to many medical problems. Adhesion refers to the entanglement of fibrils that are entangled with each other or are deposited in large quantities when forming parenchyma or scarring, and normally separated biomolecules are abnormally connected to adjacent biomolecules through surgery. Coarse and repetitive surgery, postoperative tissue damage, infection, excessive bleeding, inflammation of the suture material and foreign body, ischemia, and exposure to circulating fluid cause adhesion. Most of these tissue adhesions occur in surgical operations and cause dysfunction of the organs. Therefore, if the treatment is not performed with non - surgical treatment, reattachment surgery is necessary and it is a life - threatening factor.

It also causes the patient to feel a constant discomfort and may cause many complications. Adhesion can be categorized as the first occurring at the site where surgery has not been performed or the site where surgery has not been performed, and the case of reattachment, where adhesions have recurred after the removal of adhesions. Adhesion occurs in almost all parts of the body, but the most common problem is peritoneal adhesion or intestinal adhesions with a high frequency of about 60 to 95% after abdominal surgery. In addition, adherence is a major burden on rehabilitation due to complications, which is a significant burden on social costs. US statistical data suggest that the cost of treatment for complications following abdominal surgery is approximately $ 1.3 billion .

Complications due to adhesions include bowel obstruction, intestinal perforation, small bowel obstruction, sexual dysfunction, infertility, and chronic pain. In order to solve the problem of tissue adhesion, various types of adhesion that can prevent tissue adhesion by precise tissue detachment, appropriate surgical method to minimize damage during surgery, various drug treatments that can inhibit tissue adhesion, and physical barriers The use of inhibitors has been proposed. However, surgical methods can reduce the formation of adhesions, but they can not be completely prevented. In the case of various drug treatments, they are easily absorbed into the body and often do not perform effectively. In contrast, the anti-adhesion agent is known to have superior efficacy compared to other methods because it acts as a physical barrier to prevent adhesion between the injured tissue and the surrounding tissues to prevent adhesion between the surgical site and normal tissues.

Adhesion inhibitors are less toxic, easier to apply and cost effective. Typical types of adhesion inhibitors include films, solutions and gels. Non-degradable polymers and degradable polymers have been used, for example, in the form of films, such as membranes, made from a variety of biocompatible polymers. Polymers such as polyethylene glycol-polypropylene glycol (PEG-PPG), polyethylene glycol (PEG), Gore-Tex, carboxymethyl cellulose and polylactic acid are widely used. The non-degradable polymer is excellent in the separation technique and is excellent in the prevention of adhesion, but it is present as a foreign substance in the body, causing irritation or obstructing the regeneration of the tissue, thus requiring reoperation for removal.

On the other hand, the degradable polymer is decomposed in the body, so it is not necessary to remove it separately, but it is reported that the performance is lower than that of the non-degradable polymer. In the case of such a film-type adhesion inhibitor, it is relatively difficult to adhere to living tissue and tends to have low flexibility. In addition, it is used for spinal surgery and obstetrics and gynecology. It is difficult to introduce into the fine wound area and is recognized as a foreign substance in the tissue, so that it is hardened to prevent long-term adhesion.

In addition, in order to prevent migration of the adhesion preventive membrane, there is a problem that new tissue adhesion frequently occurs at the suture site of the surrounding tissue in the process of suturing with the surrounding tissue. In case of solution, there is a advantage of quick absorption, but it is flowable, it flows from the body and it is difficult to apply accurately to the wound, so it spreads out from the surgical site and spreads in the abdominal cavity as a whole. The gel form is easy to be localized and has an advantage of being injectable. On the other hand, since the gel is easily decomposed or absorbed in the body before the wound is healed, the gel does not sufficiently stay in the body for a long time, .

In order to overcome such problems, studies on hydrogel-based adhesion inhibitors have been actively conducted. Hydrogels are also known as hydration gels and can have both hydrophilic and hydrophobic properties and can maintain a three-dimensional shape without dissolving in water. Various preventive measures such as careful surgical methods and anti-adhesion agents have been used to prevent adhesion, which is a very important factor for reducing postoperative complications. However, until now there is no material showing the effect of preventing complete adhesion. Therefore, it is necessary to develop a new material that can be decomposed or absorbed in the body after the inhibition of tissue adhesion, stably attached to the applied site, and to exhibit its function.

The present invention relates to a biodegradable resin composition comprising carboxymethyl cellulose, alginate, polyethylene oxide-polypropylene oxide copolymer and calcium chloride as effective ingredients and having excellent biocompatibility and excellent anti-adhesion property and capable of preventing adhesion phenomenon caused by surgical operation, infection and trauma And a method for producing the same.

The composition for preventing tissue adhesion is converted into a gel from a sol by a temperature in the body, so that it is possible to apply only the precise part of the wound to prevent it from flowing to another part seen in a conventional solution type product.

The present invention provides a composition for preventing tissue adhesion, which comprises low-viscosity carboxymethyl cellulose, high viscosity carboxymethyl cellulose, alginate, a polyethylene oxide-polypropylene oxide copolymer and calcium chloride (CaCl ₂ ) as an active ingredient.

The viscosity of the low viscosity carboxymethyl cellulose is 50 to 200 cps and the viscosity of the high viscosity carboxymethyl cellulose is 1,500 to 3,000 cps. The content of the high viscosity carboxymethyl cellulose is 0.1 to 0.5% by weight, preferably 0.1 to 0.3% by weight, and the content of the low viscosity carboxymethyl cellulose is 0.5 to 1.5% by weight, preferably 0.8 to 1.2% by weight .

The present invention also provides a composition for preventing tissue adhesion, wherein the composition has an alginate viscosity of 4 to 12 cps. The content is 0.2 to 1.0 wt%, preferably 0.3 to 0.6 wt%.

The present invention also provides a composition for preventing tissue adhesion, wherein said polyethylene oxide-polypropylene oxide copolymer is contained in an amount of 17 to 19% by weight.

In another embodiment, the present invention provides a composition for preventing tissue adhesion, wherein the calcium chloride (CaCl ₂ ) is contained in an amount of 0.8 to 1.2 wt% in a 0.05 mol concentration solution.

(A) mixing high viscosity carboxymethylcellulose in an amount of 87.5% of the total amount of the sterilized distilled water and stirring at a stirring speed of 80-100 rpm; (b) adding a polyethylene oxide-polypropylene oxide copolymer; (c) adding an amount of 12.5% of the total amount of sterilized distilled water and adding and stirring low-viscosity carboxymethyl cellulose; (d) adding alginate at 18 to 23 DEG C and removing air bubbles; And (e) membrane filter with a CaCl ₂ And a step of adding a solution to the composition.

In the present invention, sterilized distilled water may be sterilized by autoclaving tertiary distilled water, and preferably has a pH of 6 to 7. In step (b), it is preferable to mix and stir at room temperature, wherein the normal temperature is about 18 to 25 ° C, and most preferably about 20 ° C.

In the step (a), the viscosity of the highly viscous carboxymethyl cellulose is preferably 1,500 to 3,000 cps and 0.1 to 0.3% by weight. In the step (c), the viscosity of the low-viscosity carboxymethyl cellulose is preferably 50 to 200 cps and the content is preferably 0.8 to 1.2% by weight. In step (d), the alginate preferably has a viscosity of 4 to 12 cps, and the content of the alginate is 0.2 to 1.0 wt%, preferably 0.3 to 0.6 wt%.

The present invention also provides a method of adding 17 to 19% by weight of the polyethylene oxide-polypropylene oxide copolymer in the step (b). In another embodiment, the present invention provides a method for producing a composition for preventing tissue adhesion, wherein the calcium chloride (CaCl ₂ ) is contained in an amount of 0.8 to 1.2% by weight as a 0.05 mol concentration solution.

The anti-adhesion composition provided by the present invention has an effect of facilitating entry into the market because it is easy to supply and receive raw materials and the price of raw materials is relatively low. In addition, it is converted from sol to gel by body temperature, and it can be applied accurately to the wound, preventing the flow of the solution to other parts like the conventional solution type to prevent the adhesion prevention function from being made improper. In addition, it can be applied to minimally invasive surgery or laparoscopic surgery.

Fig. 1 shows viscosity change of the composition for preventing tissue adhesion according to temperature.
FIG. 2 is a graph showing the relationship between the adhesion of the anti-tissue coagulant and the concentration of the anti-tissue coagulant in the case where no adhesion occurs, one thin film cohesion occurs, two or more film cohesion occurs, The results of animal experiments are shown.
Fig. 3 shows a method of applying an anti-adhesion composition to an organ tissue of an animal.
Fig. 4 shows a state after application of a composition for preventing adhesion to organ tissues. Fig.

Hereinafter, preferred embodiments of the present invention will be described in detail. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. It will be obvious to those who have knowledge of. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

In the present invention, the term "prevention of tissue adhesion" refers to a phenomenon in which a fibrous tissue is excessively formed during the healing process of a wound caused by tissue damage due to inflammation, wound, friction, Which is a phenomenon in which the surrounding organs or tissues that are supposed to be adhered to each other are adhered to each other. In other words, vascular endothelial cells, fibroblasts, and muscle fiber cells are grown by various hormones and cytokines contained in the blood due to damage to blood vessels around the tissues, resulting in entanglement for restoration of tissue around collagen It is said to inhibit something.

In the present invention, the polyethylene oxide-polypropylene oxide copolymer has solubility at room temperature and ease of use that changes from a body temperature to a gel form. In the present invention, it has been used as an element that induces a change in viscosity according to temperature, and Pluronic F127 (EO99PO65EO99, Mw 12,500; BASF, USA) can be used as a commercially available product.

Carboxymethyl cellulose (CMC) is a semisynthetic hydrophilic cellulose derivative having a viscosity and a molecular weight of ~ 90,000 daltons, which is a granular or fibrous powder, which is obtained by introducing a glycolic acid ether group into a unit of cellulose molecule, It is grayish and has some damp, odorless and tasteless characteristics. This is characterized by superior in vivo resistance. In general, it is used alone or as a stabilizer or a viscous agent in combination with an emulsifier, and is applied to lotion, cosmetic emulsion, eye ointment base, eyedrops, injection, syrup and the like. In the present invention, carboxymethyl cellulose having a low viscosity and a high viscosity was used as a main component for preventing adhesion. In the present invention, a high viscosity CMC means a viscosity of 1,500 to 3,000 cps in an aqueous 1% solution, and a low viscosity CMC means a viscosity of 4% aqueous solution has a viscosity of 50 to 200 cps. In the present invention, when the high viscosity carboxymethyl cellulose and the low viscosity carboxymethyl cellulose are mixed and used, the physical properties are changed according to the order of mixing. The carboxymethylcellulose may be in the form of a sodium salt, a calcium salt or a zinc salt, but is not limited thereto.

Alginate has a low viscosity of 4-12 cps and is composed of β-D-mannuronic acid and α-D-mannuronic acid chains. Nick acid may be the main component. It has a molecular weight of 10,000 to 600,000 daltons (Da) and is in the form of white, yellowish powder. It is known that it mainly exhibits a hemostatic effect. In the present invention, the composition is added as a component for hemostatic effect. The alginate may include salts such as sodium alginate, calcium alginate, and potassium alginate.

In the present invention, CaCl ₂ (Cacium chloride) is a salt having a white crystal structure composed of calcium and chlorine, and has a property of absorbing moisture and having a molecular weight of 110 daltons (Da). It was added as a component to increase the viscosity and the viscosity of the whole composition could be changed according to the amount of calcium chloride added.

The production method of the present invention is characterized in that low-viscosity carboxymethyl cellulose and high-viscosity carboxymethyl cellulose are mixed and used, and that they are prepared by different mixing order, concentration and content. In the case of mixing in the order mentioned above, it was possible to optimize the proper viscosity and the required physical properties such as LCST and degree of hemorrhage of polyethylene oxide-polypropylene oxide copolymer, which are major components, in vivo application.

Hereinafter, the present invention will be described in detail with reference to specific examples.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

≪ Example 1 > Preparation of composition

After adding 68.95% water 7/8 (689.5 g) to the round bottom flask and stirring at 80-100 rpm, 0.2% high viscosity sodium carboxymethylcellulose (SCMC-high viscosity) (2.0 g) was added and stirred at 80-100 rpm Lt; / RTI > At this time, care should be taken not to form a hydrogel, and the process proceeds to the next step without inflating. 18.5% polyethylene oxide-polypropylene oxide copolymer (185.0 g) was added and stirred at 80-100 rpm. Below 15%, the gel is not formed. The lower the temperature (below 20 ℃), the better the melt. Below 20 ℃, the other raw materials do not dissolve. Proceed to the next step in the unexpanded state. Add 9.85% water 1/8 (98.5 g) and stir at 80-100 rpm. At this time, water can be added up to + 0.5%. Add 1% SCMC (low viscosity) (10.0 g) and stir at 80-100 rpm. The total SCMC ratio is 1.0-1.2% and the next step is performed without inflation. Add 0.5% sodium alginate (5.0 g) and stir at 80-100 rpm. If the temperature is low, it does not dissolve well and maintains 20 ℃. When the solution changes from a white opaque state to a light yellow transparent state, the viscosity increases. When the solution becomes transparent, proceed to the next step. After removing the bubbles, 1.0% CaCl ₂ (10.0 g, 0.05 mol) is added slowly while stirring rapidly. After the crosslinking reaction, the membrane is filtered after the reaction is completed.

<Example 2-6>

The preparation method was the same as that of the above example, and the contents were varied. However, in Example 2, the addition of polyethylene oxide-polypropylene oxide copolymer was performed by first mixing low-viscosity carboxymethylcellulose and high-viscosity carboxymethylcellulose and then changing the order. The content of each component in each example is shown in the following table.

High viscosity CMC PEO-PPO copolymer Low viscosity CMC Sodium alginate 0.05 mol calcium chloride Sterile distilled water weight% Example 1 0.2 18.5 1.0 0.5 1.0 78.8 Example 2 0.2 18.5 1.0 0.5 1.0 78.8 Example 3 0.3 18 1.2 0.6 1.0 78.9 Example 4 0.1 19 1.2 0.4 0.9 78.4 Example 5 0.4 20 1.5 0.6 - 77.5 Example 6 1.3 18.5 - 0.7 1.2 78.3

Example 2 Measurement of Optimum Mixing Ratio of Polyethylene Oxide-Polypropylene Oxide Copolymer

In general, a temperature-responsive polymer is a polymer whose properties are changed according to an external temperature, and a reversible sol-gel phase transition or volume phase transition occurs at a specific temperature. The sol-gel phase transition system is known to exhibit a reversible phase transition phenomenon as a system that physically forms hydrogels due to temperature. The temperature at which this phase transition appears is called the critical solution temperature and the lowest phase transition temperature in the concentration-temperature diagram for the phase transition is called the lower critical solution temperature (LCST) and the higher phase transition temperature is the critical dissolution temperature Temperature (upper critical solution temperature, UCST). Since UCST is a relatively high temperature, there is a limitation that can affect the properties of drugs or biomolecules, and LCST systems have received much attention in most drug delivery. As a result of observing the change of LCST according to the concentration of the polyethylene oxide-polypropylene oxide copolymer (pluronic F-127), the concentration of F-127 is preferably 17 to 19% by weight with LCST at ordinary room temperature, Of 18% to 18.5% by weight was the most ideal. (See Table 2 below)

density 16% 17% 18% 19% 20% 21% 22% 23% 24% 25% 17 degrees - 585 - 671 806 836 748 993 1268 - 20 degrees 535 605 562 719 877 967 985 1278 1772 1760 23 degrees 548 686 706 931 962 1225 1132 1849 3751 2551 26 degrees 667 829 1011 1373 1139 1966 1564 3836 - 7680 29 degrees 906 1127 1955 2757 1782 3787 3072 - - - 32 degrees 1468 2200 - - 3827 - - - - - Density
(g / cm ³⁾ 1.0982 1.0668 1.0580 1.0495 1.0618 1.0961 1.0800 1.0698 1.0483 1.1099 PH 6.62 6.62 7.05 6.85 7.07 6.93 7.04 6.92 6.99 7.12 LCST 29 26 25 23 22 21 20 19 18 17

&Lt; Example 3 > Animal experiment

Sprague-Dawely rats were male 5-week-old males. After one week of adaptation to the surrounding environment, it was used in the experiment. During the experimental period, water and feed were freely supplied, and the temperature and temperature were maintained at 23 ± 2 ℃ and 55 ± 5%, respectively. Zoletil (5 mg per 100 g body weight) and Ronpun (5 mg per 100 g body weight) were injected into the thigh muscles for anesthesia in laboratory animals. After anesthesia, the abdomen was disinfected with povidone and alcohol, followed by 3 to 4 cm laparotomy along the median line. Then, the cecum was removed and the suture was used with a size of 1 × 1 ㎠ to damage the serous membrane enough to cause bleeding, and the saphene was damaged by the same size in the opposed peritoneum. In the case of the control group, each of the adhesion-preventing hydrogels was injected in the experimental group without any action, and the peritoneal membrane was closed by the continuous suturing method, and the skin was similarly sewn. Finally, 0.5 ml of penicillin was injected. The animals were sacrificed for 1 week with enough water and food to evaluate the degree of adhesion. The degree of adhesion was assessed by assessing the extent of adhesion and the strength of adhesion in each group according to the criteria in the following table and assessing the overall adhesion size.

<Decomposition of strength when separation of adhesion surface>

Rating Justice Vascularity 0 No adhesion occurs No One One thin film-type adhesion occurs and very weak force No bleeding 2 More than one film adhesion occurs, requiring moderate force Petechial bleeding 3 A concentrated centralized thick adhesion occurs and significant pressure can separate it Bleeding that required suture

Strength of adhesion Adhesion area (㎠) % Reduction of adhesion area Example 1 0.19 ± 1.81 * 0.07 0.06 * 80.5 Example 2 0.95 + - 1.81 * 0.20 0.06 * 75.7 Example 3 0.70 ± 1.81 * 0.15 + 0.15 * 80.0 Example 4 0.89 1.81 * 0.15 + 0.15 * 80.0 Example 5 2.80 ± 1.81 * 0.60 ± 0.16 * 45.5 Example 6 2.50 1.81 * 0.79 ± 0.18 * 55.4 Control ** 1.17 ± 2.99 * 0.81 0.07 * 0

* p <0.05 Versus None

** Control group was treated with sterilized water

As shown in Table 4, it was confirmed that the tissue adhesion of Example 1 was reduced compared to the control group, and that the compositions of the compositions were the same in content ratio, and that the mixing order of the low viscosity carboxymethyl cellulose and the high viscosity carboxymethyl cellulose was different 2, the adhesion area according to Example 1 produced by the manufacturing method of the present invention is relatively small and the adhesion strength is also very low, so that adhesion hardly occurs. Also, in Examples 2 to 4, the values of adhesion strength and area were relatively higher than those of Example 1, but they were combined in an optimum composition ratio range, so that they had an effect suitable for use as an adhesion inhibitor have. In the case of Example 5 and Example 6, the difference in the effect of using alginate with two kinds of carboxymethylcellulose (Example 1-4) was found.

Also, the degree of adhesion was measured as shown in FIG. 2, and it was found that the composition of the present invention prepared in Example 1 had no adhesion at all, as shown in FIG.

The foregoing description is merely illustrative of the present invention, and various modifications may be made without departing from the essential characteristics of the present invention. Accordingly, the embodiments disclosed herein are for the purpose of limiting the present invention and are not to be construed as limiting the spirit and scope of the present invention. The scope of protection of the present invention should be construed according to the claims, and all the techniques within the scope of the same should be construed as being included in the scope of the present invention.

Claims (12)

delete delete delete delete delete delete delete delete delete (a) mixing high viscosity carboxymethylcellulose having a viscosity of 1,500 to 3,000 cps in an amount of 87.5% of the total amount of sterilized distilled water and stirring at a stirring speed of 80-100 rpm;
(b) adding a polyethylene oxide-polypropylene oxide copolymer;
(c) adding and stirring low-viscosity carboxymethyl cellulose with an added amount of 12.5% of the total amount of sterilized distilled water and having a viscosity of 50 to 200 cps;
(d) adding alginate at 18 to 23 DEG C and removing air bubbles;
And (e) adding a CaCl ₂ solution, which is a membrane filter, to the composition,
11. The method of claim 10,
Wherein 0.1 to 0.3% by weight of the high viscosity carboxymethyl cellulose and 0.8 to 1.2% by weight of the low viscosity carboxymethyl cellulose are added.
11. The method of claim 10,
Characterized in that the polyethylene oxide-polypropylene oxide copolymer is contained in an amount of 17 to 19% by weight

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