TW201536287A - Use of rebamipide as a topical hemostatic agent - Google Patents

Abstract

The invention provides a topical hemostatic agent for reducing bleeding from physically-damaged mucosa, comprising as an active ingredient rebamipide or a pharmaceutically acceptable salt thereof.

Description

Rebate's local hemostasis use

The present invention relates to a partial hemostatic agent for bleeding caused by physical mucosal damage using a carbostyril compound or a salt thereof as an active ingredient, and more particularly, to a compound represented by the following formula (1) a local hemostatic agent for bleeding caused by physical mucosal damage as an active ingredient:

The quinolinone compound represented by the above formula (1), which is known as rebamipide [chemical name: (2RS)-2-(4-chlorobenzhydrylamino)-3-( 2-oxo-oxy-1,2-dihydroquinolin-4-yl)propionic acid], the production method of which is described in Patent Document 1, and it is described that these can be used as an antiulcer agent. Further, Patent Document 2 discloses that rebamipide can be used as a therapeutic agent for gastritis, and Patent Documents 3 to 5 can also be used for the treatment of various diseases. In the above In one document, rebamipide is mainly administered systemically by means of oral administration, and even in the case of the above-mentioned treatment of gastritis, it is not treated by locally spreading the drug to the affected part of the stomach. Patent Document 6 discloses that rebamipide can be used as a therapeutic agent for eye diseases, and eye drops are administered topically, but the efficacy is to improve dry eye, etc., rather than to stop bleeding.

In recent years, the use of laparoscopy and endoscopy has been gradually developed due to the advancement of medical technology. Compared with open surgery, these methods are less invasive to patients and become the treatment of choice for more patients.

In the case of laparoscopic and endoscopic operation, there are biopsy, removal, resection, and exfoliation. No matter which method is used, temporary bleeding will occur during surgery.

Intraoperative hemostasis is necessary for the purpose of temporarily healing the injured area, and is necessary to ensure the visual field of the operating area. Moreover, in order to prevent postoperative bleeding, there is a need for adequate hemostasis treatment of the exfoliated face after resection.

Hemostasis methods include: mechanical hemostasis using hemostatic forceps, high-temperature coagulation, argon plasma coagulation and other thermal coagulation methods, local injection of ethanol, hypertonic Na-adrenalin, etc., and dissemination of thrombin, alginic acid A method such as sodium or the like.

The above mechanical hemostasis method is a measure of massive bleeding, so it is not suitable for a small amount of bleeding. Moreover, medical devices used in mechanical hemostasis, thermocoagulation, and the like have a problem of high price.

For the temporary small amount of bleeding that is handled by an endoscope or the like, the simplest means is to spread the agent such as thrombin or sodium alginate. law. However, the optimum pH of thrombin is around 7, so when used in the stomach, it is necessary to properly neutralize gastric acid. Moreover, the raw material of thrombin is blood of cattle or humans, and thus there is a risk of infection. In addition, it is considered that sodium alginate is effective in the physical mechanism of hemostasis covering the affected part, and although Allid G internal liquid 5% (Common Pharmaceutical Co., Ltd.) is commercially available as an active ingredient, the color is green, so There are so-called problems that are difficult to see clearly in the operating area, and there are also side effects of so-called squatting and constipation. In spite of the above problems, the method widely used for temporary bleeding of a digestive tube such as an endoscope is still only a method of dispersing thrombin and sodium alginate.

In the medical front, it is strongly desired to increase the type of the drug, and to appropriately select the agent depending on the condition of the patient and the site of the bleeding, especially the agent which is strongly expected to increase the mechanism of different hemostasis.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Publication No. Sho 63-35623

[Patent Document 2] Japanese Patent Laid-Open No. 3-74329

[Patent Document 3] Japanese Patent Laid-Open No. Hei 6-211662

[Patent Document 4] Japanese Patent Laid-Open No. Hei 7-101862

[Patent Document 5] Japanese Patent Laid-Open No. Hei 8-12578

[Patent Document 6] Japanese Patent Laid-Open Publication No. Hei 9-301866

The object of the present invention is to provide a physical mucosal damage A local hemostatic agent for bleeding caused by injury, especially a local hemostatic agent caused by mechanical physical mucosal damage of the digestive tract (oral, throat, esophagus, stomach, small intestine, large intestine and anus).

In order to solve the above problems, the present inventors have intensively reviewed and found that rebamipide which is a quinolinone compound represented by the above formula (1) is an accidental mechanical physical mucosal damage to an endoscope or the like. The resulting bleeding has the effect of stopping bleeding, and the present invention has been completed.

That is, the present invention is as described below.

Item 1 A topical hemostatic agent comprising, as an active ingredient, rebamipide or a pharmaceutically acceptable salt thereof.

Item 2 The topical hemostatic agent according to Item 1, which is a liquid preparation.

The topical hemostatic agent according to Item 2, wherein the active ingredient is contained in an amount of from 0.05% by weight to 50% by weight.

Item 4. The topical hemostatic agent according to Item 1, which is dissolved and diluted in an aqueous solution.

The topical hemostatic agent according to any one of the items 1 to 4, which is directly dispersed in the bleeding site.

The topical hemostatic agent according to any one of the items 1 to 5, wherein the hemostasis inhibits bleeding caused by mechanical physical mucosal damage.

Item 7. The topical hemostatic agent according to Item 6, wherein the mechanical physical mucosal damage is a physical mucosal damage of the digestive tract.

Item 8 Use of a salt permissible by rebamipide or its medicinal use for the manufacture of a topical hemostatic agent.

Item 9 A salt that is tolerated by rebamipide or its medicinal use for inhibiting local bleeding.

Item 10 A method for inhibiting bleeding by locally administering a therapeutically effective amount of rebamipide or a pharmaceutically acceptable salt thereof to a patient having local bleeding.

The partial hemostatic agent of the present invention can be used as a local hemostatic agent for physical mucosal damage, for example, as a local hemostatic agent for bleeding caused by mechanical physical mucosal damage in an operation treatment such as an endoscope.

In particular, the topical hemostatic agent of the present invention can be used as a bleeding originating from small blood vessels, capillaries, and parenchymal organs caused by physical mucosal damage (for example, bleeding after extraction, source during surgery) A local hemostatic agent from the gastrointestinal tube (bleeding of the mouth, throat, esophagus, stomach, small intestine, large intestine, anus, etc.).

Moreover, the local hemostatic agent of the present invention can provide a local hemostasis effect of bleeding caused by physical mucosal damage, and can provide other effects of rebamipide which is an active ingredient thereof (anti-ulcer agent, gastritis treatment effect, intestine) Mucosal damage protection effect, urease (urease) inhibition effect and interleukin-8 inhibition effect, etc.).

The topical hemostatic agent of the present invention comprises, as an active ingredient, rebamipide or a pharmaceutically acceptable salt thereof, and can be prepared into a liquid by a usual method together with an appropriate carrier of one or more kinds of pharmaceutically acceptable carriers. The form of the agent. In the form of the liquid agent, the solution, the suspension, the emulsion, or the like may be directly dispersed in the affected part of the bleeding, or may be administered to the operation by local injection or the like by an endoscope or the like after local injection or the like ( The liquidity of the site of the mucosa resection and/or its surroundings may be preferably a solution or a suspension.

Further, the topical hemostatic agent of the present invention also includes a liquid agent which is used after being diluted with an aqueous solution before use. In addition, the aqueous solution may, for example, be purified water, physiological saline, a buffer solution or the like, and may be diluted and used therein.

Further, the topical hemostatic agent of the present invention is also included in a solid composition which can be dissolved and diluted in an aqueous solution before use, and can be dissolved in an aqueous solution (refined water, physiological saline, buffer, etc.). Use, dilution, suspension, opacity, etc.

The administration of the local hemostatic agent of the present invention may be exemplified by a method of spraying, spraying or perfusing a part (especially a mucous membrane or the like) subjected to mechanical physical damage in an operation treatment using an endoscope or the like, or by An endoscope or the like is administered by local injection to a portion of the operation treatment (mucosal resection) and/or its surroundings before or after the operation.

Furthermore, an aspect of the present invention may be a solid composition which can be directly dispersed in an affected part, and for example, a method of dispersing a local hemostatic agent of the present invention in a form of a powder or the like on a bleeding site.

Moreover, as another aspect of the local administration of the digestive tract, the local part of the invention can also be administered by oral administration or transanal administration. The hemostatic agent is in contact with the bleeding mucosa. Examples of the preparation form of the topical hemostatic agent of the present invention to be administered orally can be exemplified by liquid preparations, elixirs, capsules, powders, granules, pills, suspensions, emulsions, powders, lozenges. Oral administration of a syrup agent, a troche, or the like. As an example of the form of the preparation for transanal administration, for example, a suppository can be mentioned as an anal administration preparation which is generally used. Further, for the bleeding in the oral cavity and the throat, in addition to the above-mentioned oral administration preparation, a preparation such as a peony-containing medicine is also effective. The manufacture of such preparations can be carried out, for example, in accordance with the methods described in the prior art documents of the present specification.

The salts permitted by the above-mentioned drugs of rebamipide may be various salts which are physiologically or pharmaceutically acceptable. For example, a salt formed together with the general bases listed below: sodium hydroxide, potassium hydroxide, trometamol (paragon [hydroxymethyl] aminomethane), monoethanolamine, diethanolamine, triethanolamine, Diisopropanolamine, meglumine, and the like.

The carrier/additive contained in the liquid preparation of the present invention is not particularly limited as long as it is pharmaceutically acceptable for general use, and for example, a solvent (for example, water, ethanol, propylene glycol, macrogol, and propylene) can be used. Alcohol, etc.; dissolution aids (eg propylene glycol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, tromethamine (g [hydroxymethyl] aminomethane), meglumine, etc.) Suspending agent (eg carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate, triblock polymerization) Pluronic, polysorbate 80, etc.); Isotonic agents (eg, glucose, glycerol, D-mannitol, D-sorbitol, sodium chloride, sucrose, potassium chloride, etc.); buffers (eg, trisodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate) , potassium dihydrogen phosphate, boric acid, citric acid, sodium citrate, tartaric acid, acetic acid, sodium acetate, ε-aminocaproic acid, sodium glutamate, etc.; pH adjusting agent (such as sodium hydrogen phosphate, sodium acetate, sodium carbonate) , sodium citrate, sodium hydroxide, hydrochloric acid, etc.); a dissolving agent (such as meglumine).

Moreover, the liquid preparation of the present invention may further comprise: a preservative (for example, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, chlorobutanol, benzalkonium chloride, Benzethonium chloride, thimerosal, phenylethyl alcohol; antioxidants (such as sodium sulfite, sodium metabisulfite, sodium bisulfite, ascorbic acid, etc.); colorants (eg food coloring, beta-carotene, etc.) Additives such as sweeteners (such as sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia).

The liquid preparation of the invention of the present invention is desirably a sterilized treatment.

The pH of the liquid formulation is preferably from about 3 to about 11, more preferably from about 4.5 to about 9.5, most preferably from about 5.5 to about 8.5.

The amount of the rebamipide or the pharmaceutically acceptable salt thereof contained in the topical hemostatic agent of the present invention can be selected in a wide range without particular limitation, but is generally about 0.05% by weight to about the composition of the preparation. 70 weight%. When it is a liquid, it is preferably from about 0.05% by weight to about 50% by weight, more preferably from about 0.1% by weight to about 20% by weight, still more preferably from about 0.2% by weight to about 10% by weight. In the case of a solid composition which can be dissolved and diluted in an aqueous solution before use, the liquid obtained by dissolving and diluting is also the concentration.

The dosage of the medicament of the present invention can be appropriately selected depending on the administration method, the age of the patient, other conditions of the sex, and the degree of the disease. Generally, the amount of the salt allowed in the rebamipide or its medicinal agent per The concentration of 0.01 to 50 mg, preferably 3 to 5 mg per 1 kg of body weight on the 1st, should be considered in consideration of the concentration of the salt and the amount of local dispersion allowed in rebamipide or its medicinal preparation in the preparation.

When the administration unit is a defined preparation, the amount of the salt which is contained in the composition contained in the rebamipide or its medicinal substance is preferably from 0.1 to 3,000 mg, preferably from 0.5 to 300 mg per unit.

The topical hemostatic agent of the present invention can be administered in 1 or 2 to several administrations.

The "bleeding caused by physical mucosal damage" of the present invention means mucosal bleeding other than bleeding caused by mucosal lesions, and examples thereof include, for example, open surgery and operation using a laparoscope or an endoscope. Or hemorrhage caused by sporadic bleeding or mechanical physical damage associated with hemorrhage of the extraction operation.

The "suppression of bleeding" of the present invention means stopping bleeding and reducing the amount of bleeding. Moreover, the "suppression of bleeding" of the present invention also includes prevention of rebleeding from physical mucosal damage and hemostasis which aids in general ligation.

The "therapeutically effective amount" of the present invention means sufficient to provide The amount of the desired hemostatic effect. The amount required may vary depending on the age and health of the patient, the form of administration of the agent, and the like, depending on each patient.

[Example 1]

The present invention is illustrated by the following formulation examples and pharmacological experiments, but the present invention is not limited to the examples.

Formulation Example 1

Each of the above components is dissolved or suspended in water for injection.

Formulation Example 2

Each of the above components is dissolved or suspended in water for injection.

Formulation Example 3

Subtotal 100.0mL

Each of the above components is dissolved or suspended in water for injection.

Formulation Example 4

Each of the above components is dissolved or suspended in water for injection.

Pharmacological test

In order to investigate the hemostasis effect of rebamipide, rebamipide was administered to a Lucite chamber containing a stomach for hemoglobin measurement to assess the location of gastric bleeding.

Pharmacological test 1 (modulation of the test compound liquid)

Hydroxypropyl methylcellulose (HPMC, Sigma-Aldrich Japan) was prepared into a concentration of 1 w/v% (1% HPMC) with water for injection (Otsuka Pharmaceutical Co., Ltd.).

A proper amount of rebamipide (Otsuka Pharmaceutical Co., Ltd.) was placed in an agate mortar and ground to a concentration of 2, 4 and 10 w/v% using 1% HPMC.

(mucosa take and sample taken)

Male Crl:CD (SD) rats fasted from the day before the test were intraperitoneally administered with 4% pentobarbital 1 mL/kg, anesthetized and laparotomy, and the junction of the duodenum and the pylorus of the stomach was ligated. Cut along the big curve of the stomach, wash the contents, and put it in the Resert box. The mucosa of the corpus corpus was taken by an endoscope using a biopsy forceps (manufactured by Boston Scientific, 2.8 mm) to cause bleeding. Immediately after the bleeding, 0.5 mL of the rebamipide solution or suspension and 0.5 mL of artificial gastric juice (0.1 N HCl, Wako Pure Chemical Industries Co., Ltd.) were administered and left for 10 minutes. For the normal group and the control group, 0.5 mL of 1% HPMC and 0.5 mL of artificial gastric juice (0.1 N HCl, Wako Pure Chemical Industries, Ltd.) were administered and left for 10 minutes.

After that, the addition liquid was collected, and the washing solution was further recovered in a 1 mL washing tank of physiological saline (Otsuka Pharmaceutical Co., Ltd.). The recovered liquid was used as a sample, and hemoglobin (5 in each group) was measured.

(Measurement of heme)

Sodium dodecyl sulfate (SDS, Wako Pure Chemical Industries, Ltd.) was prepared at a concentration of 1 w/v% (hereinafter referred to as 1% SDS) with water for injection (Otsuka Pharmaceutical Co., Ltd.).

After adding 1 mL of the recovered liquid sample to 1 mL of 1% SDS, the mixture was heated at about 100 ° C for 5 minutes to extract heme. Thereafter, the mixture was centrifuged (5417R, Eppendorf) (12,000 rpm, room temperature, 10 minutes), and the supernatant was collected, and the absorbance at 410 nm was measured using a spectrophotometer (U-3010, Hitachi High-Technologies).

The test results are shown in Table 1.

Pharmacological test 2 (modulation of the test compound liquid)

Water for injection was added to a phosphate buffer powder (1/15 mol/L, pH 7.0, Wako Pure Chemical Industries, Ltd.) to prepare 1/15 mol/L, pH 7.0 (1/15 M phosphate buffer).

An appropriate amount of rebamipide (Otsuka Pharmaceutical Co., Ltd.) was weighed and added to a 1/15 M phosphate buffer to obtain a 1.0 w/v% concentration for ultrasonic treatment. Thereafter, serial dilution was carried out using 1/15 M phosphate buffer in a manner of 0.4% and 0.2%.

(mucosa take and sample taken)

The stomach of the rat was placed in the Resert box in the same manner as in the pharmacological test 1. Inside, make it bleeding. Immediately after the bleeding, 1 mL of the rebamipide solution or suspension was administered and allowed to stand for 10 minutes. 1 mL of 1/15 M phosphate buffer was administered to the normal group and the control group, and left for 10 minutes.

After that, the addition liquid was collected, and the washing solution was further recovered in a 1 mL washing tank of physiological saline (Otsuka Pharmaceutical Co., Ltd.). The recovered liquid was used as a sample to measure hemoglobin. (5 in each group)

(Measurement of heme)

It was measured in the same manner as in the pharmacological test 1.

The test results are shown in Table 2.

Claims (10)

A topical hemostatic agent comprising, as an active ingredient, rebamipide or a pharmaceutically acceptable salt thereof. The topical hemostatic agent according to claim 1, wherein the liquid hemostatic agent is used. The topical hemostatic agent according to claim 2, wherein the active ingredient is contained in an amount of 0.05% by weight to 50% by weight. The topical hemostatic agent according to claim 1, which is dissolved and diluted in an aqueous solution. The topical hemostatic agent according to any one of claims 1 to 4, which is directly dispersed in the bleeding site. The topical hemostatic agent according to any one of claims 1 to 5, wherein the hemostasis inhibits bleeding caused by mechanical physical mucosal damage. The topical hemostatic agent according to claim 6, wherein the mechanical physical mucosal damage is a physical mucosal damage of the digestive tract. A use of a salt approved by rebamipide or a medicinal herb thereof for the manufacture of a topical hemostatic agent. A salt that is approved by rebamipide or its medicinal use to inhibit local bleeding. A method of inhibiting bleeding by topical administration of a therapeutically effective amount of rebamipide or a pharmaceutically acceptable salt thereof to a patient having local bleeding.