KR101016365B1 - Fine powder-type tissue adhesion barrier - Google Patents

Abstract

The present invention relates to a micropowder-type tissue adhesion inhibitor having an inhibitory effect on tissue adhesion frequently occurring after surgery using biocompatible natural polymers, and more particularly, a wound site in a fine powder form in vitro. The present invention relates to an anti-adhesion agent capable of uniformly spraying and spreading on the body and presenting adhesiveness at the application site of the body to stably exist on the wound surface during the wound healing period, thereby separating the wound surface from surrounding tissues and organs.

Tissue adhesion inhibitor, fine powder, natural polymer, biocompatibility

Description

Fine powder-type tissue adhesion barrier

The present invention relates to a micropowder-type tissue adhesion inhibitor having an inhibitory effect on tissue adhesion frequently occurring after surgery using biocompatible natural polymers, and more particularly, a wound site in a fine powder form in vitro. The present invention relates to an anti-adhesion agent capable of uniformly spraying and spreading on the body and presenting adhesiveness at the application site of the body to stably exist on the wound surface during the wound healing period, thereby separating the wound surface from surrounding tissues and organs.

(W. L. Gore)와 분해성 고분자인 셀룰로우스를 산 화시켜 제조한 Interceed

(Johnson & Johnson Medical), 히알루론산 (hyaluronic acid)과 카르복시메틸셀룰로우스(carboxymethyl cellulose)를 가교시켜 제조한 Seprafilm

(Genzyme), 고분자량의 폴리에틸렌옥사이드 (polyethylene oxide)와 카르복시메틸셀룰로우스를 가교시켜 제조한 Oxiplex

(FzioMed) 등이 사용되고 있다. 그러나 비분해성 고분자의 경우는 상처와 상처를 원천적으로 분리하므로 유착 방지 성능은 양호하나 시술 후 이물질로 체 내에 계속 존재하므로 주변조직에 염증반응을 일으키거나 조직 재생에 장애요인이 되어, 경우에 따라서는 일정기간 후 제거를 위해 재수술이 필요하기도 하다. 생분해성 고분자의 경우는 체내에서 일정기간 후 분해되어 소멸되므로 이물질로 남지 않는다는 장점은 있으나 아직까지는 비분해성 고분자에 비해 유착 방지 성능이 다소 낮은 편이다. 필름형태의 유착 방지막을 이용할 경우 가장 큰 단점은 적용 부위에서 유착 방지막의 이동을 막기 위해 봉합사를 이용해 주변조직과 봉합을 해 주어야 하는데 봉합부위에서 조직 유착이 빈번하게 일어난다는 점과 적용 부위가 복잡하거나 미세한 부분, 도관 형태의 부분에는 도입이 어렵다는 점이다. 이를 극복하기 위해 겔 형태의 카르복시메틸셀룰로우스, 덱스트란 70 (dextran 70), 폴리에틸렌옥사이드-폴리프로필렌옥사이드 공중합체 (polyethylene oxide-polypropylene oxide 공중합체; Pluronic F127)로 제조한 Flowgel

(Mediventures), 폴리락틱산을 기본으로 한 Adcon

-L (Gliatech), 히알루론산을 기본으로 한 Intergel

(Lifecore Biomedical), 천연고분자를 원료로 한 AdbA

(Amitie)와 스프레이 형태의 폴리에틸렌옥사이드를 기본으 로 한 Spraygel

(Confluent Surgical) 등이 연구되거나 일부 시판되고 있지만, 겔 형태의 유착 방지제의 경우에는 일반적으로 수술 부위의 상처 치유가 7일 정도 걸리는 것으로 알려져 있는데 상처가 치유되기 전에 체내 (수용액상)에서 쉽게 분해·흡수되어 유착 방지제로서의 효능이 낮은 문제점을 가지고 있다. 이러한 문제점으로 인해 기존의 유착 방지제를 사용시 유착 방지 효능이 50 ~ 70% 정도에 불과한 것으로 알려져 있다 (J. M. Becker, et al., presented at Clinical Congress of Am. College of Surgeon, New Orleans, October 22 (1995)). 고분자를 이용한 유착 방지제 사용 이외에도 약리적인 방법에 의해 조직 유착을 방지하고자 하는 시도가 되어져 왔는데, 조직 유착의 한 원인으로 알려진 염증반응을 억제하게 위해 수술부위에 소염제를 주입해주는 방법이 그 한 예이다. 그러나 이 방법은 적용 부위에 소염제가 장시간 머물지 못해 유착 방지 성능이 그다지 높지 않은 것으로 나타나고 있다. In surgery today, laparotomy is one of the routine operations. Adhesion of organs and tissues that occurs frequently after surgery is one of the natural phenomena that occurs when cells of damaged tissues proliferate and regenerate, but they cause continuous discomfort or dysfunction and require reoperation for adhesion detachment. It can also be a life threatening factor. Particularly in women, pelvic surgery may cause infertility due to tissue adhesion of the uterus (DB John, et al., "Reduction of adhesion formation by postoperative administeration of ionically cross-linked hyaluronic acid", Fertil. Steril. , 68, 37-42 (1997). This complication is deeply related to the body's biological defense mechanisms, and the process is complicated, and there are many difficulties in preventing it in the clinic. Therefore, despite many research efforts since abdominal surgery, it remains one of the most important surgical problems that have not yet been completely solved. The incidence of adhesion after open surgery has been reported to be quite high (55-93%) (D. Menzies, "Postoperative adhesions: their treatment and relevance in clinical practice", Ann. Royal Coll. Surg. Engl., 75, 147-153 (1993)). It is not an exaggeration to say that such adhesion occurs in almost all parts of the human body such as muscles, sclera, conjunctiva, tenon cyst, and mesentery, but the biggest clinical problem is repetitive peritoneal or intestinal adhesion after abdominal surgery. It is known to be caused by surgery, coarse surgery, excessive bleeding, tissue response of sutures, foreign bodies during surgery, and postoperative inflammation (L. Holmdahl, et al., "Experimental models for quantitative studies on adhesion formation in rats and rabbits ", Eur. Surg. Res., 26, 248-256 (1994)). In addition, since adhesion is also a part of the wound healing process by the surgery itself, complete prevention is difficult, and the extent of minimization can be minimized by accurate tissue detachment, bleeding prevention, aseptic surgery, shortening of operation time and appropriate selection of suture. . Therefore, in order to solve the problem of tissue adhesion after surgery, attempts have been made to suppress the adhesion between tissues after surgery using various types of anti-adhesion agents. Such materials include preforms made of Teflon, a non-degradable polymer, in the form of a film.

Interlaced by oxidizing WL Gore and degradable polymer cellulose

(Johnson & Johnson Medical), Seprafilm made by crosslinking hyaluronic acid and carboxymethyl cellulose

(Genzyme), Oxiplex prepared by crosslinking high molecular weight polyethylene oxide and carboxymethyl cellulose

(FzioMed) and the like are used. However, in the case of non-degradable polymers, the wound and the wound are separated at the source, so the adhesion prevention performance is good, but since it remains in the body as a foreign substance after the procedure, it causes an inflammatory reaction to surrounding tissues or becomes a barrier to tissue regeneration. Reoperation may be necessary to remove after a period of time. Biodegradable polymers are decomposed and extinguished after a certain period of time in the body, so they do not remain as foreign substances. However, the anti-adhesion performance is somewhat lower than non-degradable polymers. When using the film-type anti-adhesion film, the biggest disadvantage is to suture the surrounding tissue with a suture to prevent the movement of the anti-adhesion film at the application site. It is difficult to introduce into the minute part, the conduit-shaped part. In order to overcome this problem, the gel is formed of carboxymethylcellulose, dextran 70, and a flowgel made of polyethylene oxide-polypropylene oxide copolymer (Pluronic F127).

(Mediventures), Adcon based on polylactic acid

-L (Gliatech), Intergel based on hyaluronic acid

(Lifecore Biomedical), AdbA from Natural Polymers

Spraygel based on Amitie and sprayed polyethylene oxide

(Confluent Surgical), etc. have been studied or some commercially available, but gel-type anti-adhesion agents are generally known to take 7 days to heal wounds, which are easily broken down in the body (aqueous solution) before the wound is healed. It is absorbed and has a problem of low efficacy as an anti-adhesion agent. Due to these problems, it is known that the anti-adhesion efficacy is only about 50 to 70% when using the conventional anti-adhesion agent (JM Becker, et al., Presented at Clinical Congress of Am. College of Surgeon, New Orleans, October 22 (1995). )). In addition to the use of anti-adhesion agents using polymers, attempts have been made to prevent tissue adhesion by pharmacological methods. For example, an anti-inflammatory agent is injected into the surgical site to suppress an inflammatory reaction known as a cause of tissue adhesion. However, this method does not appear to have a high anti-adhesion performance because the anti-inflammatory agent does not stay on the site for a long time.

As described above, many researches have been conducted on the prevention of tissue adhesion after surgery, but the conventional materials that do not improve the above problems have not been shown to pay an expensive treatment fee and have no corresponding effect.

Accordingly, the present invention is intended to solve various problems that the conventional film- and gel-type tissue adhesion inhibitors have.

Therefore, in the present invention, natural polymers in the form of fine powders, not in the form of films or gels, can be easily sprayed and applied from the outside into the fine powders themselves. The present invention was completed by stably presenting the wound surface from the surrounding tissues and organs so that the wound surface can be separated from the surrounding tissues and organs.

In the present invention, the natural polymer in the form of fine powder that can be sprayed and applied is stably present on the wound surface due to its inherent mucoadhesiveness, and thus it is easy to spray and apply even to complex wounds, thereby providing excellent tissue adhesion prevention performance. It can be very useful as a new type of tissue adhesion inhibitor.

The present invention is characterized by a micropowder-type tissue adhesion inhibitor of a biocompatible natural polymer having a molecular weight in the range of 1,000 to 1,500,000.
The present invention is described in more detail as follows.

The present invention relates to a micropowder-type tissue adhesion inhibitor which exhibits ease of treatment while having an inhibitory effect on tissue adhesion frequently occurring after surgery using a biocompatible natural polymer having a molecular weight in the range of 1,000 to 1,500,000. It can be sprayed and applied evenly to the wound area in the form of fine powder outside the body, and stably exists on the wound surface during the wound healing period by adhesiveness at the applied part of the body to separate the wound surface from the surrounding tissues and organs at the source. The present invention relates to a tissue adhesion inhibitor.

As the biocompatible natural polymer, one or more polymers selected from the group consisting of alginic acid, pectin, carrageenan, gellan gum, hyaluronic acid, carboxymethylcellulose, and dextran may be used. At this time, the diameter of the fine powder particles is in the range of 0.1 ~ 1,000 ㎛, preferably 1 ~ 300 ㎛. The fine powder of natural polymer can be prepared using a mill or freezer mill generally used in the art. If the diameter of the fine powder exceeds 1,000 ㎛, it is difficult to spray through the spray nozzle and there is a problem to apply evenly to the wound surface, and the particle size of less than 0.1 ㎛ is a common method using a mill or freezer mill, etc. Hard to manufacture

Although this invention is demonstrated in detail based on an Example, this invention is not limited to an Example.

Example 1

To prepare a fine powder that can be sprayed, alginic acid (Medium viscosity, Sigma) is pulverized using a freeze mill (SPEX 6750, USA), and then fine particles of 200 μm or less using a micro sieve. Got.

Animal model (SD rat) was used to evaluate the anti-tissue adhesion of alginic acid micropowder. First, tiltamine / zolazepam (10 mg / kg) and 2% nitrazine hydrochloride (2 mg / kg) were mixed, followed by anesthesia by injection into the lower abdomen of rats. An incision is made in the anesthetized rat's abdomen, a 1 x 1 cm ² wound is formed on the epidermis of the peritoneum using a surgical knife, and the wound is slightly peeled off from the cecum in contact with the wound. Was formed using sandpaper. The sprayed control group and alginic acid micropowder sealed without any material between the wound and the wound were sprayed and applied evenly to the wound site (epidermal area) 2 x 2 cm ² using a sprayer (Fig. 3). The degree of tissue adhesion was confirmed by dividing into one experimental group. Since the wound in the body is known to heal within 7 days, the degree of tissue adhesion was checked 7 days after surgery. According to the degree of tissue adhesion, the grades were summed and averaged using a grading system of four levels (0, 1, 2, 3, the larger the number, the more severe the adhesion) (AA Luciano, et al., “ Evaluation of commonly used adjuvants in the prevention of postoperative adhesions ", Am. J. Obstet. Gynecol., 146, 88-92 (1983)).

Comparative Example 1

An aqueous 2% by weight aqueous alginate solution was prepared using ultrapure water, and was tested in the same animal model as Example 1, except that 1 mL of the aqueous alginic acid solution was applied to the wound 2 × 2 cm ² .

Comparative Example 2

The aqueous solution prepared in Comparative Example 1 was cast in a constant mold (5 cm x 5 cm x 2 cm, width x height x height), which was crosslinked for 1 hour in an aqueous solution of calcium chloride dissolved in 2% by weight of calcium chloride in ultrapure water. After crosslinking, the resultant was sufficiently washed in ultrapure water to remove residual calcium chloride, and then completely dried in a dryer at 37 ° C. to prepare a crosslinked alginic acid film. Experiment with the same animal model as in Example 1, but the cross-linked alginic acid film (2 x 2cm x 50μm, horizontal x vertical x height) was introduced to the wound surface.

Comparative Example 4

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(Johnson & Johnson Medical)를 실시예 1과 동일한 동물모델로 실험하되, Interceed

(2 x 2cm, 가로 x 세로)를 상처면에 도입하였다.Interceed manufactured by oxidizing cellulose, a degradable polymer, among commercialized anti-adhesion agents

(Johnson & Johnson Medical) was tested in the same animal model as Example 1, but Interceed

(2 x 2 cm, width x length) was introduced into the wound surface.

The degree of tissue adhesion by animal testing of the alginic acid fine powder prepared in Example 1 and the material [other types of alginic acid (aqueous solution, crosslinked film, uncrosslinked film) or commercialized anti-adhesion agent] prepared in Comparative Examples 1 to 4 1 is shown in Figure 1, the degree of inflammatory response (lymphocyte ratio of the total cells present in the tissue of the wound) of the surrounding tissue by the material is shown in Figure 2.

As shown in FIG. 1, it was observed that tissue adhesion was significantly reduced compared to the control and Comparative Examples 1, 2, and 4.

In Comparative Examples 1, 2 and 4, since the anti-adhesion effect appeared similar to the control group, it was confirmed that there is almost no anti-adhesion effect.

However, as shown in Figure 2, compared with the control group was not observed a specific inflammatory response by the material of the comparative example, it was confirmed that the applied materials have a biocompatibility.

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1 is a graph showing the degree of tissue adhesion by animal testing.

Figure 2 is a graph showing the inflammatory response of the surrounding tissues by the material, that is, the ratio of lymphocytes to the total cells present in the tissue of the wound site.

Figure 3 is a photograph showing the alginate fine powder uniformly sprayed and applied to the cecum of the model animal.

≪ Description of reference numerals &

(A): Alginate fine powder sprayed and applied to wound area

Claims (5)

In the form of fine powder particles composed of biocompatible natural polymers having a molecular weight in the range of 1,000 to 1,500,000 so as to have a stickiness, The fine powder particles have a particle size in the range of 0.1 ~ 1000㎛ to enable uniform spraying and coating on the wound site outside the body, The fine powdery tissue adhesion inhibitor is a fine powdery tissue adhesion agent, characterized in that it is stably present at the application site in the body by the adhesion. [Claim 2] The tissue adhesion inhibitor of claim 1, wherein the natural polymer is one or more polymers selected from the group consisting of alginic acid, pectin, carrageenan, gellan gum, hyaluronic acid, carboxymethylcellulose and dextran. . delete delete delete

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