KR101619332B1 - Antiadhesion barrier - Google Patents

Abstract

More particularly, the present invention relates to an adhesion inhibitor on a film having a water contact angle of 50 ° to 110 ° and a surface roughness of 1 nm to 10 nm on one side. The adhesion inhibitor has a tensile strength (Lord cell: 500 N, Crosshead speed: 1mm / min) is maintained from 10 gf to 200 gf, the adhesive force to the wound surface containing moisture is relatively low and the re-adhesion force is excellent, And which is advantageous when used on wound surfaces of narrow and deep portions.

Description

ANTIADHESION BARRIER

The present invention relates to an adhesion inhibitor on a film having different surface roughness on both sides.

After surgery, adhesion occurs between the wound site and the tissue or organ. Tissue adhesion occurs in almost all parts of the human body, and the incidence of adhesions after surgical and obstetric procedures is 60-90%. The cause of this phenomenon is that the exudate from the injured tissue does not dissolve and absorb, resulting in the formation of fibrous tissue and the binding of fibroblasts resulting in collagen deposition. Adhesion to the tissues of the surgical site has a great effect on the recovery of the patient after surgery, and there is a high risk of reoperation due to adhesion, which is also related to the mortality rate.

Various research and development are underway to prevent adhesion which is necessary for prevention. In the United States, biodegradable polymers such as cellulose are being studied to prevent tissue adhesion, and commercialized products include Interceed ™ (Jonhson & Johnson Medical Inc.), Seprafilm ™ (Genezyme Corp.), Integel ™ (LifeCore Biomedical) . However, they are merely adapted to the function of separating the tissue from the surgical site and thus fail to demonstrate efficacy as an anti-adhesion agent. Domestic patients relying on imports have to pay a lot of money to prevent adhesion.

In addition, as a conventional technique, there have been proposed "Methods and compositions based on inhibition of cell invasion and fibrosis by anionic polymers, US Patent 6756362, 2004", "Water Insoluble Derivatives of Hyaluronic Acid, US Patent 5017229, New anti-adhesion film synthesized from polygalacturonic acid with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide crosslinker, Biomaterials, Vol. 26 No. 18, Jun 2005 "," Sawada T et al., Cross-linked hyaluronate hydrogel blocking adhesion formation and reformation in mouse uterine horn model, Human Reproduction, Vol. 16, No. 2, Feb 2001 "," Shunquing T et al., Agarose / collagen composite scaffold as an anti-adhesive sheet, Biomedical Materials, Vol. 2, No. 3, Jul 2007. However, they are focused only on the physical separation of the wound and tissue, and because they have a short residence time in the body, they do not stay in the damaged area for a sufficient time to obtain an anti-adhesion effect.

Expanded polytetrafluoroethylene (ePTFE), chitosan, polyglycolic acid, polyvinlyalcohol (PVA), agarose and collagen have been used as anti-adhesion agents. However, synthetic materials such as ePTFE do not have biodegradability and can cause inflammation between the surgical site and tissue. Even with biodegradable materials, the supply of nutrients can not be provided smoothly due to the physical film on the wound area, so that the recovery of the wound site can be delayed.

Thus, various hydrophilic natural polymers, which are known to have superior tissue adhesion inhibition performance and biocompatibility, have been studied. However, when they are introduced into the wound site, there is a limit to the anti-adhesion agent because it is easily washed away before the wound is healed, that is, its performance is low when it is applied to the actual wound site, despite its excellent anti-

In addition, the anti-adhesion agent on a film using a natural polymer has a very high adhesive strength, so that it can be adhered to a part other than a purpose when applied to a wound surface of a narrow and deep part.

An object of the present invention is to provide an adhesion inhibitor on a film which is excellent in adhesion prevention performance and at the same time has a relatively low adhesive force to a wound surface containing moisture as compared with the prior art, thereby being capable of peeling and re-adhesion.

Another object of the present invention is to provide an anti-adhesion agent which is advantageous when applied to a wound surface of a narrow and deep portion because the user can grind or fold it freely.

In order to attain the above object, the present invention provides a film-like adhesion inhibitor having a water contact angle of 50 ° to 110 ° and a surface roughness of 1 nm to 10 nm on one side, wherein the adhesion inhibitor has a tensile strength (Lord cell: speed: 1 mm / min) is 0.01 Kgf to 0.2 Kgf.

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Preferably, the one surface has a water contact angle of 50 ° to 110 ° and a surface roughness of 1 nm to 10 nm, and the other surface may have a water contact angle of 30 ° to 60 ° and a surface roughness of 1 nm to 10 nm.

The anti-adhesion agent may have a thickness of 0.01 mm to 0.1 mm.

0.01 to 5% by weight of hyaluronic acid having a weight average molecular weight of 5,000 to 10,000,000 g / mol; 0.01 to 1% by weight of a polymer which forms crosslinking by polyvalent cation; And 0.01 to 2% by weight of a cross-linking agent for cross-linking the polymer that forms a cross-link by the polyvalent cation.

The anti-adhesion agent according to the present invention is advantageous in that it has a relatively low adhesive force to a wound surface containing moisture and is excellent in re-adhesion force, thus being convenient to use.

In addition, the anti-adhesion agent according to the present invention has advantages in that it can be worn or folded freely by a user, and is useful when used on a wound surface of a narrow and deep portion.

In addition, the anti-adhesion agent according to the present invention has an advantage that it can be uniformly and stably applied to the wound surface by the hydrophilic natural polymer having the tissue sticking property when introduced into the wound surface.

In addition, the anti-adhesion agent according to the present invention has an advantage that the introduced anti-adhesion agent stably exists on the wound surface during wound healing, thereby exhibiting excellent anti-adhesion effect.

1 is a SEM photograph of one side of the anti-adhesion agent of Example 1 according to the present invention,
2 is a SEM photograph of one surface of Comparative Example 1 and the other surface,
3 is an AFM photograph of the anti-adhesion agent of Example 1 according to the present invention,
4 is an AFM photograph of the anti-adhesion agent of Comparative Example 1,
5 shows the stability evaluation of the anti-adhesion agent of Example 1 and Comparative Example 2 according to the present invention.

The present invention relates to an adhesion inhibitor on a film having different surface roughness on both sides.

Hereinafter, the present invention will be described in detail.

The anti-adhesion agent of the present invention is a film having a different shape on both sides, and adjusts the adhesive force with a wound surface containing moisture by the shape difference.

Specifically, the anti-adhesion agent of the present invention is a film having a water contact angle of 50 ° to 110 ° and a surface roughness of 1 nm to 10 nm.

If the water contact angle of the one surface is less than 40 deg. Or the surface roughness is less than 1 nm, re-adhesion is difficult due to the decrease of the water contact surface.

Preferably, the one surface has a water contact angle of 50 to 110 占 and a surface roughness of 1 nm to 10 nm, and the other surface has a water contact angle of 30 to 60 占 and a surface roughness of 1 nm to 10 nm.

The adhesion preventive agent maintains a tensile strength (Lord cell: 500 N, Crosshead speed: 1 mm / min) of 0.01 Kgf to 0.2 Kgf. If the tensile strength is less than 0.01 Kgf, the physical properties may be weakened, and the re-adhesion property and pitting resistance may deteriorate.

In addition, the anti-adhesion agent maintains the water contact angle and surface roughness, which are different from each other, and the light transmittance is lower than that of the conventional art.

The thickness of the anti-adhesion agent can be controlled in consideration of the degree of scarring, stickiness with the wound surface, the period of use, the shape maintenance and the like, and it is preferable to maintain the thickness of 0.01 mm to 0.1 mm Do.

The anti-adhesion agent according to the present invention comprises a hydrophilic natural polymer; The polymer for crosslinking by polyvalent cations for imparting stability to the hydrophilic natural polymer is characterized in that the hydrophilic natural polymer is crosslinked by the polyvalent cation such that the hydrophilic natural polymer stably stays in the body for a predetermined period of time It is preferable that the cross-linking agent is crosslinked to such an extent that injection is possible.

It is preferable that the hydrophilic natural polymer has excellent adhesion preventing ability, wound healing ability, high viscosity, and no inflammatory reaction. Specifically, it has a weight average molecular weight of from 5,000 to 10,000,000 g / mol, preferably from 100,000 to 5,000,000 g / mol, and is preferably selected from the group consisting of hyaluronic acid, dextran, hydroxypropylmethylcellulose and carboxymethylcellulose Among them, hyaluronic acid is most preferable.

When the amount of the hydrophilic natural polymer is less than 0.01% by weight, adhesion inhibition performance is insufficient. When the amount of the hydrophilic natural polymer is more than 5% by weight, the viscosity of the hydrophilic natural polymer is too high, there is a problem.

The polymers are excellent in anti-adhesion performance, wound healing ability, high viscosity, and are not useful as anti-tissue adhesion agents because they do not have inflammatory reaction. However, since they are hydrophilic, they are used to prevent adhesion at wound sites, There is a problem that it is easily washed out from the inside.

Therefore, in the present invention, the hydrophilic natural polymer is easily decomposed or washed down in the body, thereby preventing the wound site from being stained while the wound is being healed, and forming a crosslink by a polyvalent cation for improving the stability in the body Polymer.

The polymer forming the crosslinking by the polyvalent cation is preferably at least one member selected from the group consisting of alginate, carrageenan, pactin, gellan gum, xanthan gum and derivatives thereof, and among them, alginate is most preferable.

The hydrophilic natural polymer contained in the anti-tissue coagulant of the present invention and the polymer forming the crosslinking by the polyvalent cation have similar characteristics and thus have been used for the same purpose in various fields in the related art. However, in the present invention, the hydrophilic natural polymer does not include them as one component, but the polymer which forms the crosslinking by the polyvalent cation for the tissue adhesion property and the wound-healing property is weakly crosslinked to form the hydrophilic natural polymer It should be included in each component so as to show stability.

If only the hydrophilic natural polymer is included, there is a problem that the wound can not withstand the period of healing the wound and it is easily washed down. In addition, in the case of containing only the polymer forming the crosslinking by the polyvalent cation, This is undesirable because it does not meet this expectation.

The crosslinking polymer of the polyvalent cation of the present invention is preferably crosslinked with a crosslinking agent in view of ease of handling for introduction into various wounds and improving the stability of the hydrophilic natural polymer.

Wherein the cross-linking agent is at least one selected from a compound containing a polyvalent cation, chitosan, and poly-l-lysine.

Approaching from the compound containing the multivalent cation is a cation ^{Mg 2+, Ca 2+, Sr 2+} , Ba 2+, Be 2+, Cr 2+, Co 2+, Cu 2+, Fe 2+, Mn 2+ , Sn ²⁺ , Ni ²⁺ , Zn ²⁺ , Al ³⁺ , Cr ³⁺ , Co ³⁺ , Cu ³⁺ , Ga ³⁺ , Au ³⁺ , Fe ³⁺ , Mn ³⁺ , Ni ³⁺ , Mn ⁴⁺ , Sn ⁴⁺ , Cr ⁶⁺ and Mn ⁷⁺ .

The crosslinking agent is preferably contained in an aqueous solvent in an amount of 0.01 to 2% by weight in view of weakly cross-linking the polymer forming the crosslinking by the polyvalent cation.

The weakly cross-linked polymer serves to impart viscosity to the final adhesion inhibitor, thereby maintaining a viscosity of about 1,000 to 9,000 cps. In addition, when a weakly cross-linked polymer is mixed with the hydrophilic natural polymer, the hydrophilic natural polymer is trapped within the cross-linked polymer chain. In this case, the hydrophilic natural polymer trapped in the inside can not be easily washed off even when used as a tissue adhesion inhibitor, and is trapped in the cross-linked polymer chain. Therefore, the hydrophilic natural polymer stably exists on the wound surface during the wound healing period, do.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention. Such variations and modifications are intended to be within the scope of the appended claims.

Example  One

1% by weight of hyaluronic acid (weight average molecular weight ~ 4,800,000 g / mol), 0.6% by weight of alginate (Medium viscosity, Sigma) having a weight average molecular weight of 80,000 ~ 120,000 and 0.065% by weight of crosslinking agent CaCl2 Lt; / RTI > The mixed solution was agitated at 24,000 rpm for 1 minute to weakly cross-link the alginate to allow injection, and the hyaluronic acid was blocked into the weakly cross-linked alginate chain. At this time, a gel state having a viscosity of about 2,300 cps Was prepared.

The anti-adhesion agent in the gel state was cast in a glass mold having a shape of particle size of 1000 ~ 5000 room size and dried at 37 캜 for about 24 hours to prepare an anti-adhesion agent on the film.

FIG. 1 and FIG. 2 are SEM photographs of one surface and one surface of the anti-adhesion agent prepared in Example 1 and Comparative Example 1, respectively, showing that the shape of one surface is uneven.

FIGS. 3 and 4 are AFM photographs of the anti-adhesion agent prepared in Example 1 and Comparative Example 1, respectively.

Example  2 to 3 and Comparative Example  1 to 3

The same procedure as in Example 1 was carried out except that casting and drying were carried out to maintain physical properties as shown in Table 1 to prepare an anti-adhesion agent on the film.

One. Water contact angle

1 [mu] l of water was dropped onto the surface of the anti-adhesion agent prepared in Examples and Comparative Examples described later using an automatic contact angle measuring apparatus (manufactured by ksv instruments), and the contact angle of water drops after 7 seconds Respectively.

Drop the droplet onto the solid surface and measure the angle between the stationary droplet and the surface (static contact angle). Typically, drops are dropped and tested. The higher the surface tension of the solid surface, the better the wettability to water and the smaller the contact angle. A small contact angle means high hydrophilicity, good wettability and good adhesion (ASTM D 5946).

2. Surface roughness

It is measured using an Atomic Force Microscope (AFM). The AFM is a high-precision surface analysis apparatus that measures the shape of a surface of a sample on an atomic basis by using the interaction force between atoms. The AFM is equipped with a cantilever for measuring the sample, and the end of the cantilever is provided with a sharp probe or tip. The tip of the probe has a size of several nm ) Is very acute. When this probe is approached to the surface of the sample, it attracts (pulls) or pushes (repulsive) force depending on the distance between the probe tip atom and the sample surface atom

3. Tensile strength :

The tensile strength of the film specimens prepared above was measured at a stretching speed of 1 mm / min using a universal testing machine (UTM) manufactured by TIRA under ASTM D 882. The conditions of the tensile test were Load cell 500N, LE position 20mm, and the average of 5 tests in total was expressed as a result.

4. Thickness

The thickness of the anti-adhesion material manufactured using a digital burr caliper (manufactured by Mitutoyo Co., Ltd.) was measured randomly and evaluated.

division Water contact angle
(°) Surface roughness (nm) The tensile strength
(gf) thickness
(mm) One side Another aspect Difference Example 1 86.1839 7.98 5.46 2.52 24.51 0.02 Example 2 87.9384 9.13 0.94 8.19 22.62 0.03 Example 3 81.45427 6.64 3.20 3.44 23.81 0.05 Comparative Example 1 40.51483 0.56 0.84 -0.18 41.05 0.07 Comparative Example 2 51.38228 0.52 0.61 -0.09 47.09 0.07 Comparative Example 3 54.57108 0.44 0.72 -0.28 43.49 0.07 mm

Experimental Example  One : Stability evaluation

150 mg of each of the anti-tissue adhesion preventive films prepared in Example 1 and Comparative Example 2 was placed in a vial containing 40 mL of PBS (phosphate buffer solution) and stored in an incubator at 37 ° C. After a certain period of time, PBS And their weights were measured to evaluate the stability of the sample in an aqueous solution. The results are shown in FIG.

As shown in FIG. 5, it can be confirmed that the safety evaluation of the conventional adhesion preventive and the subsequent adhesion inhibitor according to the shape change has safety similar to that of the existing adhesion preventant even after the shape change.

Experimental Example  2: Animal experiment

An animal model (SD rat) was used to evaluate tissue adhesion prevention performance using Example 1 and Comparative Example 2. First, ketamine hydrochloride (10 mg / kg) and 2% hydrochloric acid gyrazine (2 mg / kg) were mixed and injected into the lower abdomen of the rats. The abdomen of the anesthetized rats was incised, and the cuts on the epidermis of the abdominal wall (peritoneum) were formed using a surgical knife. Example 1 and Comparative Example 2 were applied to wound sites and divided into an experimental group to confirm the degree of tissue adhesion. After 30 days of operation, the degree of tissue adhesion was confirmed. The results were summed and averaged using a grading system of 4 grades (0, 1, 2, 3, large number of adhesions, depending on degree of tissue adhesion). A. Luciano, et al., "Evaluation of commonly used adjuvants in the prevention of postoperative adhesions ", AM. J. Obstet. Gynecol., 146, 88-92 (1983)].

 At this time, the degree of adhesion was measured 15 times in Example 1 and Comparative Example 2, respectively.

Table 2 shows the degree of tissue adhesion by the animal experiment. In Example 1 and Comparative Example 2 of the present invention, anti-adhesion agents having the same composition were used, and their surface shapes were different. As shown in Table 2 below, it was confirmed that the degree of adhesion was different between Example 1 and Comparative Example 2.

It was confirmed that Example 1 having different surface roughness exhibited a similar degree of adhesion as compared with Comparative Example 2,

For reference, it is very difficult to improve the numerical value in the case of using the same composition. This is because, with the use of the embodiment 1 of the present invention, the ease of handling of the user (freely grasping or folding) It can be guessed that it has been received.

division Grade Grade Grade Example 1-1 0 Examples 1-6 0 Example 1-11 One Examples 1-2 0 Examples 1-7 0 Examples 1-12 One Example 1-3 0 Examples 1-8 0 Examples 1-13 0 Examples 1-4 One Examples 1-9 One Examples 1-14 One Examples 1-5 One Example 1-10 0 Examples 1-15 One medium 0.47 Comparative Example 1-1 0 Comparative Example 1-6 One Comparative Example 1-11 0 Comparative Example 1-2 One Comparative Example 1-7 0 Comparative Example 1-12 0 Comparative Example 1-3 0 Comparative Example 1-8 2 Comparative Example 1-13 0 Comparative Example 1-4 One Comparative Example 1-9 One Comparative Example 1-14 One Comparative Example 1-5 One Comparative Example 1-10 0 Comparative Example 1-15 2 medium 0.67

Claims (5)

0.01 to 5% by weight of hyaluronic acid having a weight average molecular weight of 5,000 to 10,000,000 g / mol; 0.01 to 1% by weight of a polymer which forms crosslinking by polyvalent cations; And 0.01 to 2% by weight of a crosslinking agent for crosslinking of a polymer which forms a crosslink by a polyvalent cation,
Wherein the one surface of the film has a water contact angle of 80 to 90 °, a surface roughness of 6 to less than 10 nm, and a water contact angle of 30 to 60 and a surface roughness of 0.5 to less than 6 nm,
Wherein the adhesion preventive agent has a tensile strength (Lord cell: 500 N, Crosshead speed: 1 mm / min) of 10 gf to 200 gf.
delete delete The anti-adhesion agent according to claim 1, wherein the anti-adhesion agent has a thickness of 0.01 mm to 0.1 mm.
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