KR101349200B1 - Pharmaceutical composition for preventing or treating post-operative adhesion comprising hexosamine compounds or pharmaceutically acceptable salts thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prophylaxis or treatment of post-operative adhesion, comprising a hexosamine compound of Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient, the composition of the present invention The hexosamine compound or a pharmaceutically acceptable salt thereof contained in the rat shows excellent bowel adhesion inhibitory activity in a rat model that induced fibrotic bowel adhesions in the abdominal cavity, so it is one of the side effects caused by various surgical procedures. It can be usefully used to prevent or treat phosphorus fibrotic intestinal adhesions.

Description

PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING POST-OPERATIVE ADHESION COMPRISING HEXOSAMINE COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF}

1 is a picture taken inside the abdominal cavity after stimulating with a toothbrush around the cecum of the laparotomy rats,

2 is a graph showing the effect of inhibiting adhesion after surgery according to glucosamine salt administration,

Figure 3 is a photograph of gross lesion findings of postoperative adhesions centering on the cecum at necropsy (a: no treatment; b: benign); c: carrier; d: glucosamine salt 10 mg / kg; e: glucosamine salt 20 mg / kg and f: melatonin 10 mg / kg).

The present invention relates to a pharmaceutical composition for the prevention or treatment of post-operative adhesion, comprising a hexosamin compound or a pharmaceutically acceptable salt thereof.

Post-operative adhesion is a type of scar that occurs during abnormal wound healing through a complex chain reaction involving inflammatory cells, fibroblasts, and several cytokines. (Thompson JN et al., Br J Surg . 82: 3-5, 1995) and Holmdahl L et al. , Eur J Surg. 165: 1012-1019, 1999). Postoperative adhesions occur at a significant frequency (more than two thirds of all abdominal patients) and cause clinically serious problems, such as intestinal obstruction, chronic pelvic pain, urethra In case of Ureteral obstruction and female reproductive organs (ovaries, fallopian tubes), it causes infertility, etc. (Ellis H, Eur J Surg Suppl. 577: 5-9, 1997), and Menzies D, Ann R Coll. Surg Engl. 75: 147-153, 1993]. In addition, when the lesion is reopened to the patient's abdominal cavity for surgery, there is a problem in ensuring adequate time for surgical operation by delaying the opening time (Van Der Krabben AA et al. , Br J Surg. 87: 467). -471, 2000). In addition, postoperative adhesions can last for weeks, months or years, resulting in long-term, high-cost and often advanced to chronic inflammatory diseases.

Currently, drugs to treat postoperative adhesions are very limited clinically, for example, drugs such as steroidal or nonsteroidal anti-inflammatory drugs are often used for treatment, but they can cause problems with long-term use. Specifically, in the case of steroidal agents can cause Cushing's disease, and in the case of nonsteroidal agents can cause side effects of gastric ulcers.

On the other hand, hydroflotation or barrier technology is also used for the treatment, which includes various synthetic barrier membranes (gels) containing hyaluronic acid and carboxymethylcellulose before the abdominal cavity is closed. Or in the form of a film) between the intraperitoneal internal tissue surfaces damaged by incisions or resections has been reported to relieve postoperative adhesions (Burns JW et al. Eur J Surg Suppl. 577: 40-48, 1997), and Brunelli G et al., J Orthop Res. 23: 1377-1382, 2005). However, when the treatment is performed in animal or clinical trials, their anti-adhesion effect is shown to be insignificant. For example, Johnson &Johnson's Interceed TC7 containing cellulose contains a large amount of blood. The barrier was not able to function in the environment (Alponat A et al., J Sur Research. 68: 126-132, 1997), and hyaluronic acid-containing gels exhibit very low anti-adhesion effects due to their ability to degrade too easily in vivo (Johns DB et al. , Fertil Steril. 68: 37-42, 1997).

Other efforts have been made to reduce postoperative adhesions using L-arginin, pentoxifylline, methylene blue, and vitamin E. (Kaleli B et al., Acta Obstet Gynecol Scand. 77: 377-380, 1998), and Kluger Y et al. , Eur J Surg. 166: 568-571, 2000).

Therefore, there is a need for the development of a postoperative adhesion therapy agent having an improved therapeutic effect while having fewer side effects.

On the other hand, Glucosamine (Glucosamine; 2-amino-2-deoxy-D-glucose) of Formula 2 is an essential component of mucopolysaccharide and chitin, and N-acetylglucosamine (from glucose in the body) N-acetylglucosamine) (Barclay TS et al . , Ann Pharmacother. 32: 574-579, 1998) and Anderson JW et al., Food Chem Toxicol . 43: 187-201, 2005).

Glucosamine is known to be present in cartilage at high concentrations and to relieve osteoarthritis symptoms (D'Ambrosio E et al. , Pharmatherapeutica. 2: 504-508, 1981). More specifically, glucosamine stimulates chondrocytes. It is known to prevent the progression of arthritis by promoting the synthesis and secretion of glycosaminoglycan and proteoglycan. In addition, the pain inhibitory effect of arthritis using the glucosamine-based preparations has been demonstrated in human and animal clinical trials (Houpt JB et al . , J Rheumatol. 26: 2423-2430, 1999), and protein degradation causing arthritis. It has also been reported to exhibit anti-inflammatory action by inhibiting enzymes (Hungerford DS et al . , J Arthroplasty. 18: 5-9, 2003).

Chondroitin sulfate, a typical component of glycosaminoglycans with glucosamine, is linked to glucuronic acid (D-glucuronic acid) and N-acetylgalactosamine (β-1,3). It is structured. Chondroitin sulfate, like glucosamine, is a component of cartilage and is used for the prevention of degenerative articular disease (Bali JP et al., Semin Arthritis Rheum. 31: 58-68, 2001).

In addition, galactosamine hydrochloride (D-(+)-Galactosamine Hydrochloride) of Formula 3 has a structurally similar form to glucosamine hydrochloride (D-(+)-Glucosamine Hydrochloride), and also has a similar physiological function in the body. have.

Accordingly, the present inventors have completed the present invention while finding out that they prevent post-operative adhesion while studying the efficacy of the hexosamine compound.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of post-operative adhesion.

In order to achieve the above object, the present invention comprises a hexosamine compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for preventing or treating post-operative adhesion Provides:

≪ Formula 1 >

"Adhesion" in the present invention is most often formed after surgery, and in most cases refers to aberrant attachment between tissues or between organs or between tissues and implants (artificial organs), which causes significant pain and discomfort. When adhesions affect normal tissue function, adhesions are thought to be a complication of surgery. Such tissue binding often occurs between the two surfaces of the tissue during postoperative recovery or during the initial phase of the treatment process. Adhesion is a fibrous structure that connects tissues or organs that are not normally bound. Postoperative adhesions of the present invention include, for example, intraperitoneal organ adhesion and pelvic adhesion. Adhesions are also used in connection with all types of surgery including skeletal muscle surgery, abdominal surgery, gynecology surgery, ophthalmology, orthopedic surgery, central nervous system, cardiovascular. In the present invention, the adhesion is, for example, post-operative intra-abdominal fibrinous adhesion.

The hexosamine compound of Chemical Formula 1 according to the present invention is a main component of glycosaminoglycan and is mainly used as a therapeutic agent for arthritis, and specific examples include glucosamine and galactosamine.

The hexosamine compound of the present invention may be reacted with a pharmaceutically acceptable inorganic acid, organic acid or base to form an addition salt. For example, sodium, potassium, magnesium, calcium, etc., which are alkali and alkaline earth metal salts, and hydrochloric acid, sulfuric acid, etc., as inorganic acids, acetic acid, maleic acid, etc. can be used as organic acids. In the composition of the present invention, hydrochloride of hexamine is preferably used, and most preferably glucosamine hydrochloride or galactosamine hydrochloride.

The hexosamine compound of Formula 1 and pharmaceutically acceptable salts thereof according to the present invention effectively inhibit the production of post-operative adhesion, and thus may be usefully used for the prevention or treatment of postoperative adhesion. .

The composition of the present invention can be prepared into a pharmaceutical formulation according to a conventional method. In the preparation of the formulations, it is preferred that the active ingredient is mixed with or diluted with the carrier, or enclosed in a carrier in the form of a container. When the carrier is used as a diluent, it may be a solid, semisolid or liquid substance which acts as a carrier, excipient or medium for the active ingredient. Thus, the formulations may be in the form of tablets, pills, powders, assays, elixirs, suspensions, emulsions, solutions, syrups, aerosols, soft or hard gelatin capsules, sterile injectables, sterile powders and the like.

Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, Propylhydroxybenzoate, talc, magnesium stearate and mineral oils. The formulations may additionally include fillers, anti-coagulants, lubricants, wetting agents, perfumes, emulsifiers, preservatives, and the like. Compositions of the present invention may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. The dosage of the active ingredient, such as the hexosamine derivative or pharmaceutically acceptable salt thereof, of the present invention depends on the subject being treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. As an active ingredient, the compounds of the present invention can be used orally once a day or in divided doses in an amount of 750 to 3000 mg / kg body weight, preferably 1000 to 1500 mg / kg body weight, for mammals including humans. Or by parenteral routes. In some cases, smaller dosages may be more suitable than the above-mentioned ranges, larger amounts may be used without causing harmful side effects, and higher dosages may be dispensed in several smaller portions throughout the day. do.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only intended to help the understanding of the structure and operation of the present invention and the scope of the present invention is not limited to these examples.

Reference Example: Statistical Analysis

The results of this example are all expressed as the average value including the standard deviation. The significance of the results was verified using Student's t-test. Only when the P value calculated by testing the control group and the experimental group was less than 0.05, the difference between the control group and the experimental group was evaluated as significant. Also, when the P value calculated by performing the test was also less than 0.05 between each experimental group, the difference between each experimental group was evaluated as significant.

Example: Effect of Glucosamine in Cecal Sidewall Adhesion Animal Models

(Step 1) Induce Wounds for Fabrication of Adhesion Models of Caecal Sidewalls in Rats

A caecum sidewall adhesion model was constructed using female SD rats as follows.

A total of 30 female SD (Sprague Dawley) rats (weight: 200-250 g, 7-8 weeks old) (Orient, Seoul, South Korea) were divided into 6 groups, 5 per each group. Minimized. 25 rats, except the first group, were anesthetized with 0.4 ml of pentobarbital sodium, prepared by diluting with physiological saline at a concentration of 45 mg / kg. After shaving the anesthetized rat's abdomen, the surgical site was sterilized in turn with 70% alcohol and Povidone iodine. The skin was dissected about 3 cm in the middle of the abdomen using a scarl. After skin incisions, abdominal wall incisions were made in the same manner and direction. After the catheter was taken out of the abdominal cavity through the incision, the wound was caused by rubbing the small intestine and the large intestine 20 times around the caecum and the cecum using a toothbrush dipped in alcohol and sterile saline. At this time, moderate erosion and hemorrahage were observed in the rubbed caecum, small intestine (part of the ileum and ileum), and large intestine (upper colon) (FIG. 1). After the intestine was put back into the abdominal cavity, the suture wall was closed with the sutures.

(Step 2) Glucosamine adhesion inhibitory effect

As mentioned in step 1, the first group performed only the treatment of opening the abdominal cavity and closing it again, and did nothing. The second group did not administer any substance after the above-mentioned intestinal adhesion-induced surgery, and the third group, after the above-mentioned intestinal adhesion-induced surgery, 2 ml of sterile saline solution containing 5% alcohol as a carrier intraperitoneally. Administered. In the fourth group, 2 ml of a solution of glucosamine hydrochloride (Sigma Aldrich) diluted with sterile physiological saline containing 5% alcohol was administered intraperitoneally to the dose of 10 mg / kg. The fifth group was administered intraperitoneally with 2 ml of the diluent prepared in the same manner as the fourth group so that the dose of glucosamine salt was 20 mg / kg. The sixth group was intraperitoneally administered 2 ml of a solution of melatonin (Sigma Aldrich) diluted with sterile saline solution containing 5% alcohol to a dose of 10 mg / kg after the intestinal adhesion-induced surgical procedure.

The melatonin was used as a positive control material of the present experiment, the adhesion was significantly inhibited when intraperitoneal injection of melatonin at a dose of 10 mg / kg 30 minutes before and after the wound induction in the model that caused the adhesion to the uterine angle of the rat Already known (Ozcelik B et al . , Hum Reprod. 18: 1703-1706, 2003).

After 7 days of surgery, the degree of adhesion between the organs that caused the wound and the open organ and other organs that were wounded after euthanasia was evaluated visually by the criteria of Table 1 below according to the degree of separation, which is a graph in FIG. Represented by. Observation of adhesion was graded in principle by two pathologists, and the value was expressed as an average to exclude the intervention of observer's subjectivity.

As a result of adhesion evaluation, as shown in FIG. 2, adhesion was not significantly inhibited when sterile physiological saline added with 5% alcohol as a carrier was administered alone. In contrast, adhesion was significantly inhibited in the group administered with glucosamine hydrochloride at 10 mg / kg and 20 mg / kg, and adhesion was more effectively suppressed at the administration of 20 mg / kg (Student's t in the experimental and control groups). As a result of the assay, the p value was determined to be significantly suppressed because it was less than 0.02). This was a similar degree of inhibitory effect with no significant difference from the positive control melatonin.

Figure 3 is a photograph showing the state of intestinal adhesions around the abdominal organs, especially the cecum during necropsy. A was an untreated group which did not cause adhesion and could not observe the adhesion phenomenon. B and C, respectively, caused intestinal adhesions and were not administered any substance or administered sterile saline solution added with 5% alcohol as a carrier alone. Could. On the other hand, D and E in the group administered with the glucosamine hydrochloride concentration, intestinal adhesion occurred, but it can be confirmed that the extent and intensity of the adhesion is lower than the positive induction group.

As described above, the hexosamine derivative according to the present invention shows an excellent intestinal adhesion inhibitory activity in a rat model that induced fibrotic intestinal adhesion in the abdominal cavity, which is one of the side effects induced after various surgical procedures. It can be usefully used to prevent or treat fibrotic organ adhesions.

Claims (4)

A pharmaceutical composition for the prophylaxis or treatment of post-operative intra-abdominal fibrinous adhesion, comprising a hexosamine compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: ≪ Formula 1 >

The method of claim 1, Pharmaceutical composition, characterized in that the active ingredient is selected from the group consisting of glucosamine, galactosamine, glucosamine hydrochloride (D-(+)-glucosamine hydrochloride), and galactosamine hydrochloride (D-(+)-galactosamine hydrochloride). The method of claim 2, Pharmaceutical composition, characterized in that the active ingredient is glucosamine hydrochloride. delete

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