JP5808898B2 - Tissue adhesion inhibitor - Google Patents

Description

  The present invention relates to an anti-tissue adhesion agent after surgery. More specifically, the present invention relates to a tissue adhesion preventing agent characterized in that a tissue adhesive containing fibrinogen and thrombin as active ingredients contains catechin or a basic polyamino acid.

  Post-operative tissue adhesion occurs in a wide range of areas such as cardiology, digestive surgery, orthopedics, obstetrics and gynecology, and ophthalmology. For example, adhesion in the abdominal cavity after laparotomy is a physiological biological repair reaction, and it is difficult to eliminate adhesions at all. Therefore, adhesion after the operation causes adhesive ileus at a certain frequency. Adhesive intestinal obstruction is generally common in surgery with a peeled surface such as the lower abdomen rather than the upper abdomen. In addition, the frequency is said to be proportional to the operation time and the amount of bleeding. To prevent and reduce the occurrence of adhesive intestinal obstruction, the surgeon's polite and friendly surgical operation, minimal exfoliation, minimal bleeding, minimal surgical time, prevention of contamination during surgery, minimal foreign body Residual, use of absorbable sutures, proper drainage, infection prevention, early bed removal after surgery, etc. are required, and in emergency contamination surgery, sufficient intraperitoneal washing, postoperative position, postoperative antibiotics Use is required. Although each of them is effective to some extent for preventing adhesive intestinal obstruction, this alone cannot completely prevent the occurrence of intestinal obstruction (Fukushima Tsuneo et al., Surgical treatment, 94 (6): 919-924,2006: Non-patent document 1 ).

  In the obstetrics and gynecology field, oviduct adhesion is one of the important problems because it may lead to a decrease in fertility in the future. Various postoperative adhesion preventions have been attempted to date, but a perfect adhesion prevention method has not been established yet (Fujishita et al., Obstetrics and Gynecology Surgery, 13: 91-98,2002: Non-patent literature 2).

  There is a report that $ 1.3 billion was spent annually in the United States for the treatment of abdominal adhesions (Ray NF. Et al .: J. Am. Coll. Surg., 186: 1-9,1998: Non-Patent Document 3) From a medical and economic viewpoint, it is important to take treatments that reduce adhesion as much as possible. Furthermore, it can be expected to reduce postoperative complications by reducing adhesions, improve patient quality of life (QOL), and reduce medical costs. However, under the present circumstances, since tissue adhesion after surgery cannot be completely prevented, it has become a big problem to bother surgeons.

  As physical barriers to prevent adhesion, materials that are currently approved for clinical use include barriers such as sodium hyaluronate / carboxymethyl cellulose (seprafilm (registered trademark)) and oxidized regenerated cellulose (Interceed (registered trademark)). Or anti-adhesion agents such as polytetrafluoroethylene (e-PTFE) (Gore-Tex Surgical Membrane (registered trademark)). Neither material has limited effectiveness and has not yet satisfied surgeons. Gore-Tex Surgical Membrane® is very limited in its use because it requires suturing when it is fixed to the surgical site and is not bioabsorbable and requires reoperation. G. et al., Cochrane Database Syst. Rev .: CD000475, 2008: Non-Patent Document 4). Since any material is in the form of a sheet, there remains a problem that it is difficult to fix it to the application part, and it is more difficult to insert during laparoscopic surgery. Further, there is a problem that the sheet-like material cannot be used for a bleeding site.

  In the clinical field, there is a demand for a drug with an excellent anti-adhesion effect and high convenience. In the field of gastroenterological surgery and obstetrics and gynecology, where there are many adhesion cases, the transition of laparoscopic surgery to laparoscopic surgery aimed at improving minimally invasive and QOL is progressing. In addition, liver and pancreas surgery, which was considered a sanctuary for laparotomy, has begun to shift to laparoscopic surgery, and it can be said that laparoscopic surgery will expand further in the future.

  Along with such a shift in surgical technique, liquid agents have attracted attention as drug dosage forms, and many reports have been made. Examples of the liquid agent for preventing adhesion include those used for covering the wound surface as perfusate, such as 32% dextran 70 (Masanobu Tanaka et al., Obstetrics and Gynecology, 67: 553-556,2000: Non-Patent Document 5), alginic acid Sodium (Japanese Patent Laid-Open No. 57-167919: Patent Document 1), Sodium Chondroitin Sulfate (Patent Document 2,953702: Patent Document 2), Sodium Hyaluronate (Urman B. et al., Fertil. Steril, 56: 563,1991 : Non-patent document 6) and chitosan (Japanese Patent Laid-Open No. 10-502663: Patent document 3), etc., but the effectiveness is not sufficient. Moreover, since all have high viscosity and poor operability, they have a problem that they cannot be injected into the abdominal cavity. Furthermore, since the solution cannot be fixed to the application site, a large amount of drug must be injected into the abdominal cavity.

  Therefore, the drugs required in the clinical field are (1) drugs that have a high anti-adhesion effect, (2) an injectable dosage form that is easy to use even in laparoscopic surgery, and (3) drugs that can be immobilized on the application site. It can be said that. An example of a drug that is an injectable dosage form and can be fixed to an application part is fibrin glue, which is a biological tissue adhesive. Fibrin glue is a biological tissue adhesive that utilizes the final stage of blood coagulation, and fibrinogen contained in it becomes soluble fibrin by the action of thrombin, and further, physical coagulation factor XIII activated by thrombin in the presence of calcium ions It becomes a urea-insoluble stabilized fibrin with sufficient strength and adheres and closes tissues. Up to now, there have been reports on the application of fibrin glue for the purpose of preventing adhesions (Takamichi Sato et al., Obstetrics and Gynecology, 57 (12): 2398-2404, 1990: Non-Patent Document 7) (Kyoji Okuda et al., The world of obstetrics and gynecology, 45 (9): 759-764, 1993: Non-patent document 8). Since fibrin glue cannot completely prevent tissue adhesion, the big problem that plagues surgeons has not been solved yet.

JP-A-57-167919 Japanese Patent No.2953702 Japanese Patent Laid-Open No. 10-502663

Fukushima Tsuneo et al., Surgical treatment, 94 (6): 919-924,2006 Jun Fujishita et al., Obstetrics and Gynecology Surgery, 13: 91-98, 2002 Ray NF. Et al .: J. Am. Coll. Surg., 186: 1-9,1998 Ahamad G. et al., Cochrane Database Syst. Rev.: CD000475,2008 Tanaka Masanobu et al., Obstetrics and Gynecology, 67: 553-556,2000 Urman B. et al., Fertil. Steril, 56: 563,1991 Takamichi Sato et al., Obstetrics and Gynecology, 57 (12): 2398-2404,1990 Kiyoji Okuda et al., Obstetrics and Gynecology, 45 (9): 759-764,1993

  Under such circumstances, the problems of the present invention are (1) an excellent tissue adhesion suppression effect after surgery, and (2) an injectable dosage form that can be easily applied in laparoscopic surgery, (3) To provide a tissue adhesion preventing agent that can be easily fixed to an application site and exerts a local effect, and (4) can also be used at a bleeding site.

Accordingly, the inventors of the present application have made extensive studies in view of the above-mentioned problems, and as a result, applied catechins or basic polyamino acids to the fibrin glue, which is a biological tissue adhesive, to prevent tissue adhesion superior to the prior art. It has been found that it is effective. Hereinafter, the present invention will be described in detail.
[1] A tissue adhesion preventing agent containing fibrinogen and thrombin, and catechin or a basic polyamino acid or a salt thereof as main components.
[2] A tissue adhesion preventing agent comprising a fibrinogen composition and a thrombin composition, and catechin or a basic polyamino acid or a salt thereof.
[3] The tissue adhesion according to [1] or [2], wherein the catechin is at least one selected from the group consisting of epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate Inhibitor.
[4] The tissue adhesion inhibitor according to [1] or [2], wherein the catechin is epigallocatechin gallate.
[5] The tissue adhesion preventing agent according to any one of [1] to [4], wherein the catechin is in a concentration of 0.005 to 0.05% (w / v).
[6] The tissue adhesion preventing agent according to [1] or [2], wherein the basic polyamino acid is polylysine or a salt thereof.
[7] Tissue adhesion prevention according to [1], [2], or [6], characterized in that polylysine or a salt thereof has a concentration of 0.01 to 0.5% (w / v) Agent.
[8] The tissue adhesion preventing agent according to any one of [1] to [7], further comprising a preparation containing blood coagulation factor XIII.

  According to the present invention, there is provided a tissue adhesion preventing agent in which catechin or a basic polyamino acid is included in a fibrin glue which is a biological tissue adhesive. Tissue adhesion prevention effect superior to that of the prior art can be exhibited. Fibrin glue coagulates and adheres instantly by reacting fibrinogen solution and thrombin solution, so it can be easily injected into the abdominal cavity with a trocar (a tool for inserting a surgical instrument into the abdominal cavity) in laparoscopic surgery. In addition, it is possible to immobilize the drug instantly on the application unit. In addition, the clinically used anti-adhesive agent cannot be used for bleeding sites, but the tissue adhesion preventing agent of the present invention uses fibrin glue, which is a biological tissue adhesive, so it can also be used for bleeding sites. .

  The tissue adhesion inhibitor of the present invention contains fibrinogen and thrombin, and catechin or a basic polyamino acid or a salt thereof. The tissue adhesion preventing agent of the present invention includes a fibrinogen composition and a thrombin composition, and catechin or a basic polyamino acid or a salt thereof.

  A fibrinogen composition is a composition in which fibrinogen is dissolved in a suitable solvent. The fibrinogen concentration in the fibrinogen composition is preferably 3% to 15% (w / v).

  A thrombin composition is a composition in which thrombin is dissolved in a suitable solvent. The thrombin concentration in the thrombin composition is preferably 5 U / mL to 1000 U / mL.

  The catechin is preferably at least one selected from the group consisting of epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate. In particular, epigallocatechin gallate is a suitable example. The catechin is preferably used at a concentration of 0.005 to 0.05% (w / v). The catechin may be provided by adding to the fibrinogen composition or thrombin composition in advance, or may be provided as a separate container from those compositions.

  The basic polyamino acid is preferably polylysine or a salt thereof. The polylysine or a salt thereof is preferably used at a concentration of 0.01 to 0.5% (w / v). Furthermore, it is preferable that the polylysine or a salt thereof is selected from either α-form or ε-form. The polylysine or a salt thereof may be provided by adding to the fibrinogen composition or the thrombin composition in advance, or may be provided as a separate container from the composition.

  The fibrinogen composition may additionally contain blood clotting factor XIII or aprotinin for the purpose of cross-linking and fibrinolysis inhibition within the fibrin gel-matrix. Furthermore, the fibrinogen composition can contain nonionic surfactants such as human serum albumin and polysorbate 80, and various amino acids.

  The thrombin composition can additionally contain aprotinin and human serum albumin.

  The method for producing fibrinogen, thrombin, albumin, aprotinin, and blood coagulation factor XIII used in the present invention is not particularly limited. For example, it is produced by a method of separating from human blood or a method of producing by gene recombination technology. can do.

  The composition of the tissue adhesion preventing agent is (1) when it is composed of three types of containers, that is, when it is composed of a fibrinogen composition-containing container, a thrombin composition-containing container, a catechin or a basic polyamino acid-containing container, (2) 2 When comprising a container of a type, that is, comprising a fibrinogen composition and a catechin or basic polyamino acid-containing container, a thrombin composition-containing container, or a thrombin composition and a catechin or basic polyamino acid-containing container, containing a fibrinogen composition When it consists of a container, (3) The case where it consists of one type of container, that is, the case where it consists of a fibrinogen composition and a thrombin composition, and a catechin or a basic polyamino acid containing container may be included. However, when the tissue adhesion preventing agent is one type of container, the dosage form is set so that thrombin does not activate fibrinogen.

  The dosage form of the tissue adhesion preventing agent may be different or the same for each container constituting the inhibitor, and may be liquid, powdery (dry powder, freeze-dried powder), or frozen. I do not care.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

  Epigallocatechin gallate solution is 0.01% (w / v) (-)-epigallocatechin gallate (manufactured by Wako Pure Chemical Industries, Ltd.) with water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) at pH 7.0-7. .3.

  The fibrinogen solution is about 8.5% (w / v) fibrinogen, about 10 U / mL Factor XIII, 1.0% (w / v) human serum albumin, 1.75% (w / v) sodium chloride, 18% (w / v) trisodium citrate, 0.35% (w / v) isoleucine, 0.43% (w / v) glycine, 1.05% (w / v) arginine hydrochloride, The pH was adjusted to 7.0 to 7.3 containing 8% (w / v) sodium glutamate and 0.02% (w / v) polysorbate 80. The thrombin solution was prepared using thrombin lyophilized powder and thrombin solution (calcium chloride solution) from Bolheel (registered trademark, manufactured by Institute of Chemical and Serum Therapy). Fibrin was prepared by mixing a fibrinogen solution and a thrombin solution at a ratio of 1: 1 using a spray application device.

  The epigallocatechin gallate-added fibrinogen solution was prepared to be the fibrinogen solution containing 0.02% (w / v) (−)-epigallocatechin gallate. The epigallocatechin gallate-added fibrin was prepared by mixing the epigallocatechin gallate-added fibrinogen solution and the thrombin solution at a ratio of 1: 1 using a spray application device.

  Interceed (registered trademark, manufactured by Johnson & Johnson), an adhesion prevention agent currently in clinical use, was used as a comparative control.

  An intraperitoneal tissue adhesion animal model was prepared using 7-9 week old SD male rats. Under anesthesia with medetomidine hydrochloride and ketamine hydrochloride, an incision was made by incising about 3 cm downward from the portion about 2.5 cm below the xiphoid process along the midline. The cecum was exposed, and the inside of a circle having a diameter of 1.5 cm was scraped 50 times with gauze, and the scraping portion was further scraped 50 times with a scalpel blade to cause spot bleeding. Next, the inside of a circle having a diameter of 1.5 cm on the surface of the abdominal wall in contact with the cecum rubbing portion was cauterized with an electric knife having an output of 40 W. Four places were fixed with a 7-0 nylon suture thread so that the cecum rubbing part and the cautery part of the abdominal wall were in contact with each other. The abdominal wall and skin of the open wound were sutured and closed. After normal breeding for 30 days, the abdomen was opened, and the adhesion state between the cecum scratched part and the abdominal wall cauterized part was evaluated. The adhesion was evaluated by scoring on the scale shown in Table 1 according to the degree of peeling between the cecum scraping part and the abdominal wall cauterization part, the amount of bleeding, the adhesion area, and the adhesion type. The adhesion score was defined as the total score of the evaluation items A to D.

  In Example 1, the following treatment groups were evaluated. (1) physiological saline, (2) epigallocatechin gallate solution, (3) fibrin, (4) epigallocatechin gallate-added fibrin, (5) Interceed. In the application methods (1) to (4), 0.3 mL of each was spray-applied to the inside of a circle having a diameter of 1.5 cm on the abdominal wall including the caecum scraped part and the cauterized part. In the application method (5), a 2 cm × 2 cm anti-adhesive agent was applied so as to cover the abdominal wall cauterization. The results of evaluating the adhesion score are shown in Table 2. The adhesion score in the table is the sum of the scores of A to D in Table 1.

As is clear from Table 2, a high adhesion prevention effect was confirmed by adding epigallocatechin gallate to fibrin. In addition, superior anti-adhesion effect was confirmed compared with the existing anti-adhesion agent (Interceed). The effect of the epigallocatechin gallate-added fibrin of the present invention was significantly different from all other groups by the Mann-Whitney U test ( *: p <0.05).

  Example 2 was carried out under the same conditions as in Example 1 except that α-poly-L-lysine was used instead of (−)-epigallocatechin gallate in Example 1. However, the polylysine solution was prepared with water for injection so that 0.1% (w / v) α-poly-L-lysine hydrochloride (manufactured by SIGMA-ALDRICH) had a pH of 7.0 to 7.4. A polylysine-added fibrinogen solution was prepared to be the fibrinogen solution containing 0.2% (w / v) α-poly-L-lysine hydrochloride.

  In Example 2, the following treatment groups were evaluated. (1) physiological saline, (2) polylysine solution, (3) fibrin, (4) polylysine-added fibrin, (5) Interceed. In the application methods (1) to (4), 0.3 mL of each was spray-applied to the inside of a circle having a diameter of 1.5 cm on the abdominal wall including the caecum scraped part and the cauterized part. In the application method (5), a 2 cm × 2 cm anti-adhesive agent was applied so as to cover the abdominal wall cauterization. The results of evaluating the adhesion score are shown in Table 3. The adhesion score in the table is the sum of the scores of A to D in Table 1.

As is apparent from Table 3, a high adhesion preventing effect was confirmed by adding polylysine to fibrin. In addition, superior anti-adhesion effect was confirmed compared with the existing anti-adhesion agent (Interceed). The effect of the polylysine-added fibrin of the present invention was significantly different from all other groups by the Mann-Whitney U test ( *: p <0.05).

  The tissue adhesion preventing agent of the present invention exhibits an effect superior to that of the prior art, can be easily used in laparoscopic surgery, and can immobilize the drug instantly on the application site. The present invention provides a tissue adhesion preventing agent that is highly effective and convenient.

Claims (4)

A tissue adhesion-preventing agent comprising fibrinogen, thrombin, blood coagulation factor XIII , and epigallocatechin gallate or polylysine or a salt thereof as main components. A tissue adhesion preventing agent comprising a fibrinogen composition, a thrombin composition and blood coagulation factor XIII , and epigallocatechin gallate or polylysine or a salt thereof. Epigallocatechin gallate is a 0.005-0.05% (w / v) density | concentration, The tissue adhesion prevention agent of Claim 1 or Claim 2 characterized by the above-mentioned. The tissue adhesion preventing agent according to claim 1 or 2, wherein the polylysine or a salt thereof has a concentration of 0.01 to 0.5% (w / v).