KR101668349B1 - Adhesion barrier agent - Google Patents
Adhesion barrier agent Download PDFInfo
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- KR101668349B1 KR101668349B1 KR1020150047013A KR20150047013A KR101668349B1 KR 101668349 B1 KR101668349 B1 KR 101668349B1 KR 1020150047013 A KR1020150047013 A KR 1020150047013A KR 20150047013 A KR20150047013 A KR 20150047013A KR 101668349 B1 KR101668349 B1 KR 101668349B1
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- adhesion
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- aqueous solution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
- A61L31/046—Fibrin; Fibrinogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/041—Mixtures of macromolecular compounds
Abstract
The present invention relates to an adhesion preventive agent, which comprises 1 to 50 parts by weight of an aqueous solution of silk fibroin; And 20 to 50 parts by weight of a thermosensitive polymer aqueous solution.
Such a biodegradable natural polymer, silk fibroin, not only can prevent local bleeding, but also acts as a physical barrier during the healing period to maximize the anti-adhesion function, and thereafter biodegrades in the body The aqueous solution of the thermosensitive polymer having excellent biocompatibility is liquid in the room temperature and has a characteristic of being transferred into a gel form at body temperature (35 to 38 ° C), so that it flows in the body It is easy to apply to the wound site without lowering it, so that the efficiency of prevention of adhesion can be improved.
Description
The present invention relates to an adhesion inhibitor.
Generally, adhesion refers to the fact that the skin or membranes that are separated from each other are attached to each other due to inflammation, and the adhesion of organs and tissues after surgery is a natural phenomenon that can occur during the proliferation and regeneration of damaged tissue cells.
Here, excessive adhesion or unintentional adherence to other organs and tissues may result in dysfunction of the organs, and in some cases, reattachment of the adhesions may be necessary and may be life-threatening.
Clinically, the most serious problem is caused by peritoneal adhesions after abdominal surgery, repetitive surgery due to intestinal adhesions, coarse surgery, excessive bleeding, tissue reaction of suture materials, foreign substances during surgery, and postoperative inflammation .
Such a method for preventing adhesion can be roughly classified into three types.
First, it is a method that minimizes tissue damage and foreign matter adhesion due to delicate attention and unnecessary procedures during surgery.
Second, the pathophysiological processes required for inflammatory reactions and adhesion formation are mediated by drug therapy based on adhesion mechanisms.
Third, it is a method to physically block the contact with the surrounding tissue by wrapping or covering the wound area using an adhesion preventive membrane after surgery.
Here, the formulations of the adhesion preventive membrane are solid (endogenous and extrinsic), liquid and gel-like, and prevention of post-operative adhesion is a very important factor for reducing complications. Therefore, an adhesion preventive agent is widely used.
In relation to such an adhesion inhibitor, in the Korean Patent Registration No. 10-0552954 filed on Apr. 26, 2002 (hereinafter referred to as "the prior art"), a thermosensitive adhesion- Films, sponges and powders were presented.
Specifically, the prior art uses a natural polymer (hyaluronic acid) and a polyethylene glycol-polypropylene glycol-polyethylene glycol copolymer as a thermosensitive polymer, so that there is little foreign body reaction and the body is completely discharged through decomposition and absorption in the body , It is possible to locally deliver the drug to the surgical site for a certain period of time by using various functional drugs and to prevent adhesion which can reduce or prevent adhesion formation between tissues by a simple application method at the time of surgery or after surgery Films, sponges, solutions, powders, thermosensitive compositions and methods of application thereof.
However, since such conventional techniques are easily washed away in the body, the problem of low adhesion prevention efficiency remains.
The present invention has been made in order to solve the above problems, and it is an object of the present invention to provide a biocompatibility excellent hemostatic function, and a sol-gel gel transition according to temperature, And an anti-adhesion agent that is easy to apply to a wound site.
In order to attain the above object, the present invention provides an anti-adhesion agent comprising 100 parts by weight of distilled water; 1 to 50 parts by weight of silk fibroin; And 20 to 50 parts by weight of the thermosensitive polymer.
The thermosensible polymer is prepared by dissolving a thermosensitive polymer in distilled water. The thermosensitive polymer is selected from the group consisting of poly (N-isopropylacrylamide), PNiPAAM copolymer, polyethylene glycol (PEG) -Polypropylene glycol (PPG) -polyethylene glycol (PEG) copolymer and polyethylene glycol (PEG) -poly lactide glycolide (PLGA) -polyethylene glycol (PEG) copolymer .
In addition, the anti-adhesion agent is characterized in that the formulation is liquid at room temperature and transitioned to a gel form at a temperature of 35 to 38 [deg.] C by the thermosensitive polymer in an aqueous solution state.
The anticancer agent may further comprise an antibiotic, wherein the antibiotic is selected from the group consisting of penicillin, streptomycin, tetracycline, kanamycin, chliramphenicol, actinomysin, The compounds of the present invention may be used in combination with other therapeutic agents such as ampicillin, bacitracin, gramicidin, naildixic acid, neomtcin, nonactin, norfloxacin, ) And terramysin, or a mixture of at least two thereof.
The adhesion preventive agent may further comprise an additive, wherein the additive is selected from the group consisting of cabopol, hydropropylcellulose, polyethylene glycol, polyvinylpyrollidone, alginate, And sodium chloride, or a mixture of at least two of them.
The present invention has the following effects.
First, silk fibroin, a biodegradable natural polymer, not only can prevent local bleeding, but also acts as a physical barrier during the healing period to maximize the anti-adhesion function, and then biodegrades and absorbs Whereby effective adhesion prevention can be achieved.
Second, a thermosensitive polymer aqueous solution having excellent biocompatibility is liquid at room temperature and has a characteristic of being transferred into a gel form at body temperature (35 to 38 ° C), so that it can be easily applied to the wound area without flowing down from the body The efficiency of the adhesion prevention can be increased.
FIG. 1 is a photograph showing the sol-gel transition behavior according to the temperature change of the mixed solution prepared in the example of the present invention.
2 is a photograph showing the sol-gel transition behavior according to the temperature change of the mixed solution prepared in the comparative example of the present invention.
3 is a photograph showing an experimental procedure of animal model of abdominal wall disruption and cecal membrane friction model according to Experimental Example 2 of the present invention.
FIG. 4 is a photograph showing the adhesion site of a control group to which the anti-adhesion agent of the present invention is not injected.
5 and 6 are photographs showing adhesion sites of an experimental group injected with an anti-adhesion agent of the present invention.
Before describing the configuration of the present invention in detail, the terms used in the present specification and claims should not be construed in a dictionary meaning, and the inventor must understand the concept of a term The present invention should be construed as meaning and concept consistent with the technical idea of the present invention.
Therefore, the embodiments described herein are merely preferred embodiments of the present invention, and not all of the technical ideas of the present invention are expressed, so that various equivalents and modifications are possible at the time of filing of the present application It should be understood.
The preferred embodiments of the present invention will be described in more detail with reference to the accompanying drawings.
≪ Explanation of Antiadhesive Agent >
The present invention relates to an anti-adhesion agent having excellent biocompatibility capable of preventing adhesion of abnormal tissues together with a hemostatic action at a wound site, and is composed of distilled water, silk fibroin and thermosensitive polymer.
Here, silk is a fibrous protein obtained from cocoon and is a natural polymer chemically belonging to natural protein.
Specifically, silk is composed of fibroin which exists in two strands in the central part and sericin which surrounds it. Among them, proteins having hydrophilicity and adhesiveness are removed through refining process and proteins Only Fibroin is used.
Such silk fibroin has been used as a material for the finest garments since it has excellent strength, gloss and feel, and has been used as a medical material because of its excellent biocompatibility and biodegradability. Recently, silk fibroin has been dissolved, But may be manufactured in various forms such as films, sponges, nanofibers, fine particles, and the like.
The water-soluble silk fibroin powder may be dissolved in distilled water to provide an aqueous solution, and it is preferable that 100 parts by weight of distilled water contains 1 to 50 parts by weight of silk fibroin powder. This is because if the amount of the silk fibroin powder is less than 1 part by weight, it is unsuitable for use as an anti-adhesion agent, and if it exceeds 50 parts by weight,
In general, the temperature sensitive polymer aqueous solution is in the form of a sol, which is an aqueous solution at room temperature. When the temperature rises and reaches the cloud point or the low temperature critical solution temperature (LCST), the aqueous solution is transformed into a semi-solid gel.
In other words, the temperature sensation is that the aqueous solution of the polymer is dissolved in water and hydrogen bond at a temperature below the LCST, and as the temperature increases, the hydrogen bond is dissociated and the polymer is entangled to form a precipitate.
The temperature-sensitive polymer may be dissolved in distilled water to prepare an aqueous solution. The sol-gel transition temperature varies depending on the concentration. In the present invention, 20 to 50 parts by weight of the thermosensible polymer is contained in 100 parts by weight of distilled water . This is because if the thermosensitive polymer is less than 20 parts by weight, it is not only used at room temperature but also in liquid form (35 to 38 ° C), it is unsuitable for use as an adhesion inhibitor. If it exceeds 50 parts by weight, It is because it occurs.
The anti-adhesion agent prepared by mixing the silk fibroin and the thermosensitive polymer in the distilled water in the form of an aqueous solution is in the form of a liquid at room temperature and is injected into the body (35 to 38 ° C) by the thermosensitive polymer in an aqueous solution state. Because it has a characteristic of being transferred into the form of gel, it can be injected not only in a complex structure of organs and tissues, but also in preventing local bleeding which may occur during surgery, thereby maximizing the function of preventing adhesion.
Herein, the thermosensitive polymer may be a poly (N-isopropylacrylamide) copolymer, a poly (ethylene glycol) (PEG) -polypropylene glycol (PPG) -polyethylene glycol And a polyethylene glycol (PEG)-polylactide glycolide (PLGA) -polyethylene glycol (PEG) copolymer, or a mixture of at least two thereof.
In addition, polyethylene glycol (PEG) -polypropylene glycol (PPG) -polyethylene glycol (PEG) copolymer is widely used as a nonionic surfactant and is also called Poloxamer.
Meanwhile, the anti-adhesion agent of the present invention may further include an antibiotic for preventing infection and an additive for increasing strength or viscosity.
Wherein the antibiotic is selected from the group consisting of penicillin, streptomycin, tetracycline, kanamycin, chliramphenicol, actinomysin, ampicillin, bacitracin, One or at least two of gramicidin, naildixic acid, neomtcin, nonactin, norfloxacin, patulin and terramysin, But the present invention is not limited thereto.
The additive may be selected from the group consisting of cabopol, hydroxy propylcellulose, polyethylene glycol, polyvinyl pyrollidone, alginate, and sodium chloride, But it is not limited thereto.
As described above, the anti-adhesion agent according to the present invention is preferably provided as an injectable material by sterilizing a mixed solution prepared by mixing distilled water, silk fibroin, thermosensitive polymer, antibiotic and additives, and injecting it into a syringe.
< Example >
Hereinafter, preferred embodiments of the present invention will be described. However, the following embodiments are only examples of the present invention showing the structure and effects of the present invention, and the present invention is not limited to the following embodiments.
An anti-adhesion agent was prepared using the composition shown in Table 1 below, and divided into Examples and Comparative Examples according to the weight parts of silk fibroin and poloxamer 407 dissolved in distilled water to prepare an aqueous solution.
≪ Example 1 >
10 parts by weight of water-soluble silk fibroin powder and 40 parts by weight of poloxamer 407 as a thermosensitive polymer were dissolved in 100 parts by weight of distilled water.
The aqueous solution of silk fibroin and Poloxamer 407 was stirred at a temperature of 0 to 5 ° C to prepare a mixed solution.
≪ Example 2 >
30 parts by weight of water-soluble silk fibroin powder and 40 parts by weight of poloxamer 407 as a thermosensitive polymer were dissolved in 100 parts by weight of distilled water.
The aqueous solution of silk fibroin and Poloxamer 407 was stirred at a temperature of 0 to 5 ° C to prepare a mixed solution.
≪ Comparative Example 1 &
10 parts by weight of water-soluble silk fibroin powder and 10 parts by weight of poloxamer 407 as a thermosensitive polymer were dissolved in 100 parts by weight of distilled water.
The aqueous solution of silk fibroin and Poloxamer 407 was stirred at a temperature of 0 to 5 ° C to prepare a mixed solution.
≪ Comparative Example 2 &
30 parts by weight of water-soluble silk fibroin powder and 10 parts by weight of poloxamer 407 as a thermosensitive polymer were dissolved in 100 parts by weight of distilled water.
The aqueous solution of silk fibroin and Poloxamer 407 was stirred at a temperature of 0 to 5 ° C to prepare a mixed solution.
< Experimental Example 1 >: Observation of sol-gel transition behavior with temperature
3 g each of the mixed solution prepared in Example 1, Example 2, Comparative Example 1 and Comparative Example 2 was placed in a vial of 10 ml, and the sol-gel transfer behavior at a human body temperature of 37 ° C was visually observed The results are shown in Figs. 1 and 2. Fig.
As shown in Fig. 1, the mixed solution prepared in Example 1 and Example 2 is liquid at 20 ° C and gelated at 37 ° C.
As described above, the mixed solution of Example 1 and Example 2, which are provided in the form of a gel, is highly viscous at 37 ° C and is not applied to the inside of the body.
On the other hand, as shown in FIG. 2, the mixed solution prepared in Comparative Example 1 and Comparative Example 2 had a poloxamer 407 content of less than 20 parts by weight, It can be seen that it maintains.
In other words, since the mixed solution of Comparative Example 1 and Comparative Example 2, which keeps the liquid form at 37 ° C, flows down in the body, it is difficult to precisely coat the wound area, thus preventing the function of preventing adhesion.
< Experimental Example 2 >: Evaluation of effectiveness of anti-adhesion agent by animal experiment
Animal experiments were conducted to evaluate the effectiveness of the anti-adhesion agent of the present invention.
Outbred male Sprague Dawley rats were used as the experimental animals, and they were adapted in the laboratory for 3 days before the experiment. Rats were divided into six groups according to the weight of the animals (weight: 230-280 g) Respectively.
The model is damaged abdominal wall and cecum film friction model used in animal experiments (Renee Kennedy, Darren J. Costain, Vivian C. MeAlister and Timothy DG Lee, "Prevention of experimental postoperative peritoneal adhesions by N, O-carboxymethyl chitosan", Surgery, Vol. 120, No. 5, 866-870, 1996).
As shown in Fig. 3, the peritoneal membrane in the abdominal portion of the rat was scratched with a knife to wounds, and the curtain of the adjacent cecum was rubbed with sandpaper to induce hemorrhage, thereby artificially creating a condition in which adhesion could easily occur.
(
After the operation was completed for the rats in which the anti-adhesion agent was not inserted as a control group and the anti-adhesion agent as an experimental group, and the regeneration of tissue inside the cecum and peritoneum was completed after 4 weeks, the abdomen of the rat was opened again. and adhesion prevention examine the validity of the experimental method Vlahos (Angie Vlahos, Pingyang Yu, Charles E. Lucas, Anna M. Ledgerwood, "Effect of a composite membrane of chitosan and poloxamer gel on postoperative adhesive interations", the American Surgeon, Vol 67, 15-21, 2001), and the results are shown in Table 2 below.
Table 3 below shows the degree of adhesion and the degree of adhesion according to Vlaho's experimental method.
As shown in Tables 2 and 3, in the control group, the values of adhesion grade of 2 rats were 3 and 4, respectively, and the average value was 3.5, indicating a strong degree of adhesion, and the results are shown in Fig.
On the other hand, as shown in Tables 2 and 3, the degree of adhesion was 0.0 in
Specifically, as shown in Fig. 4, it can be seen that the cecum and the abdominal wall are severely adhered to each other in the rats of the control group. On the other hand, as shown in Figs. 5 and 6, The rats of the
As described above, the anti-adhesion agent of the present invention not only can prevent local bleeding, but also acts as a physical barrier during the healing period to maximize the anti-adhesion function, and thereafter biodegrades in the body to absorb Whereby effective adhesion prevention can be achieved.
The embodiments disclosed in the present invention are not intended to limit the scope of the present invention but to limit the scope of the technical idea of the present invention. The scope of protection is to be construed in accordance with the following claims, and all technical ideas within the scope of equivalents thereof should be construed as being included in the scope of the present invention.
Claims (5)
10 to 30 parts by weight of silk fibroin; And
40 parts by weight of Flocumer 407,
Characterized in that the formulation is a liquid form at room temperature and the formulation is transferred into a gel form at a temperature of 35 to 38 ° C by means of the above-mentioned flow-throughmodule 407 which is a temperature sensitive polymer in an aqueous solution dissolved in the distilled water
Adhesion inhibitor.
The anti-
Further comprising an antibiotic,
The antibiotic may be selected from the group consisting of penicillin, streptomycin, tetracycline, kanamycin, chliramphenicol, actinomysin, ampicillin, bacitracin, One or at least two of gramicidin, naildixic acid, neomtcin, nonactin, norfloxacin, patulin and terramysin, Or more,
Adhesion inhibitor.
The anti-
Further comprising an additive,
The additive may be selected from the group consisting of at least one of cabopol, hydroxypropylcellulose, polyethylene glycol, polyvinyl pyrollidone, alginate, and sodium chloride, or at least one of Characterized in that it is provided in a mixture of two or more
Adhesion inhibitor.
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| KR1020150047013A KR101668349B1 (en) | 2015-04-02 | 2015-04-02 | Adhesion barrier agent |
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| KR1020150047013A KR101668349B1 (en) | 2015-04-02 | 2015-04-02 | Adhesion barrier agent |
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| KR20160118624A KR20160118624A (en) | 2016-10-12 |
| KR101668349B1 true KR101668349B1 (en) | 2016-10-21 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20220071357A (en) | 2020-11-24 | 2022-05-31 | 한국과학기술연구원 | Composition for intraperitoneal administration for the prevention or treatment of ovarian cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111790002A (en) * | 2019-10-11 | 2020-10-20 | 杨鑫 | Preparation method of medical biogel hemostatic dressing |
| CN111968335A (en) * | 2020-08-28 | 2020-11-20 | 上海科技大学 | Application of ion conductor material, fire sensing device, alarm method, equipment and system |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100565881B1 (en) | 2003-07-24 | 2006-03-29 | 이진호 | Tissue adhesion barrier gel using biocompatible polymers |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR100552954B1 (en) * | 2002-09-04 | 2006-02-20 | 주식회사 바이오레인 | Temperature Sensitive Adhesion Prevention Composition, Solution, Film, Sponge and Powder |
| KR100588614B1 (en) * | 2003-11-10 | 2006-06-13 | 주식회사 바이오레인 | Anti-adhesion agent with gas bubble |
| KR20140140212A (en) * | 2013-05-28 | 2014-12-09 | 금오공과대학교 산학협력단 | Multilayered nanofibrous anti-adhesion membranes containing hydrophilic natural polymer and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR100565881B1 (en) | 2003-07-24 | 2006-03-29 | 이진호 | Tissue adhesion barrier gel using biocompatible polymers |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220071357A (en) | 2020-11-24 | 2022-05-31 | 한국과학기술연구원 | Composition for intraperitoneal administration for the prevention or treatment of ovarian cancer |
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