KR0174763B1 - Remedy for wound or hemorrhoid - Google Patents

Abstract

The present invention relates to a wound or hemorrhoidal therapeutic agent, in particular an external wound or hemorrhoidal therapeutic agent, comprising as an active ingredient prostaglandin I ₂ , prostaglandin E ₁ and one or more derivatives thereof, particularly veraprost or a salt thereof, which is a derivative of prostaglandin I ₂ , and A method of treating wound or hemorrhoids, characterized by administering one active ingredient.

Description

[Name of invention]

Wound or hemorrhoids

Detailed description of the invention

[Technical Field]

The present invention relates to a therapeutic agent for wounds or hemorrhoids.

[Background]

It is known that prostaglandin I ₂ (PGI ₂ ) and prostaglandin E ₂ (PGE ₁ ) have a wide range of pharmacological effects such as potent platelet aggregation inhibition and peripheral vasodilation. It was expected, but PGI ₂ and PGE ₁ itself is chemically unstable, so it is difficult to be commercialized due to difficulty in sustaining pharmacological effects.

However, since veraprost, a derivative of PGI ₂ , is chemically stable, it was first developed as an oral preparation for the treatment of peripheral blood flow disorders, and is currently commercially available as a therapeutic agent for ischemic diseases caused by chronic arterial obstruction.

By the way, it is known that most wounds, such as intractable skin ulcers including pressure sores, develop due to peripheral blood circulation failure. Since the possibility of topical administration of the therapeutic agent has fewer side effects than systemic administration, the development of its external preparation is desired, but the external preparation for wound treatment containing PGI _2, PGE ₁ and one or more of their derivatives as an active ingredient is still known. It is not.

On the other hand, hemorrhoids are generally classified into hemorrhoids, anal dentition, perianalitis, anal abscess, dental floss, and the like, and their therapeutic agents are roughly divided into steroid-containing or non-local topical hemorrhoids and local or systemic varicose veins.

The mechanism of action of the hemorrhoid therapeutic agent may include peripheral blood circulation improvement, thrombogenesis inhibitory action, anti-inflammatory action, and tissue repair action. PGI _2, PGE ₁ and their derivatives have all of the above pharmacological actions, and thus are useful as therapeutic agents for hemorrhoids. This suggests, but its application is not yet known.

An object of the present invention is a wound or hemorrhoidal therapeutic agent containing PGI _2, PGE ₁ and one or more derivatives thereof as an active ingredient, in particular an external wound or hemorrhoidal therapeutic agent, and wound or hemorrhoids characterized by administering the active ingredient. To provide treatment.

[Initiation of invention]

The present inventors have found that a composition prepared by containing PGI _2, PGE ₁ and one or more derivatives thereof as an active ingredient and blending it into a pharmaceutically acceptable carrier has a wound or hemorrhoid therapeutic effect.

The inventors of the present invention can formulate it as an external preparation suitable for the symptoms of hemorrhoids, since veraprost or a salt thereof, which is a derivative of PGI ₂ , is a chemically stable powder, which is soluble in water. It has been found to exhibit potent wound healing promoting action by hypergranulation and epidermal formation.

In addition, the inventors have also found that the administration of veraprost or salts thereof exhibits a particularly potent hemorrhoidal therapeutic effect.

Therefore, the present invention is a wound or hemorrhoidal therapeutic agent containing at least _one of PGI _2, PGE ₁ and derivatives thereof, particularly veraprost or salt thereof, and a pharmaceutically acceptable carrier as an active ingredient (hereinafter referred to as the therapeutic agent Abbreviated).

The therapeutic agent of the present invention contains at least _one of PGI _2, PGE ₁ and derivatives thereof as an active ingredient. Derivatives of PGI ₂ include Veraprost, Carbacyclin, Iloprost, Ciprosten, Nileprost, Cicaprost, CG 4203, FCE 22509, OP-41483, OP-2507, and their salts are mentioned. Salts of PGI ₂ itself are also included in the derivatives of PGI ₂ .

Salts of PGI ₂ and their derivatives include, for example, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, ammonium salts, primary, secondary or tertiary amine salts and basic amino acid salts. And salts that can be tolerated.

Particularly preferred as derivatives of the PGI ₂ are beraprost and salts thereof (particularly alkali metal salts such as sodium salts).

Here the term beraprost is (±)-(1R ^* , 2R ^* , 3aS ^* , 8bS ^* )-2, 3, 3a, 8b-tetrahydro-2-hydroxy-1-[(E)-(3S ^* ) -3-hydroxy-4-methyl-1-octene-6-inyl]-1H-cyclopenta [b] benzofuran-5-butyric acid is a common name, d- form and 1- Type racemates.

Verafrost can be manufactured by the method described, for example in Unexamined-Japanese-Patent No. 58-124778.

Examples of derivatives of PGI ₂ include misoprostol, ornoprostil, limaprost, and salts thereof. Salts of PGI ₂ itself are also included in the derivatives of PGI ₂ .

Examples of the salts include pharmacologically acceptable salts such as alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts and basic amino acid salts as described above.

The therapeutic agent of the present invention is produced by combining the active ingredient described above with a pharmaceutically acceptable carrier.

Examples of the carrier include water, ethanol, isopropanol, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, carboxymethylcellulose sodium, sodium polyacrylate, sodium alginate, water soluble dextran, sodium carboxymethyl starch, pectin, Methyl cellulose, ethyl cellulose, propyl cellulose, ethyl methyl cellulose, hydroxypropyl cellulose, xanthan rubber, gum arabic, tragagant rubber, casein, albumin, gelatin, agar, chitin, sorbitol, multitol, dextrin, lactose, white sugar And glucose, glycerin, diglycerin, triglycerine, triglycerine, propylene glycol, 1,3-butylene diol, polyethylene glycol, waschelin, paraffin, stearyl alcohol, glycerin monostearate and stearic acid. It is preferable to use these carriers in combination as needed.

The carrier is appropriately selected depending on the formulation of the therapeutic agent of the present invention.

Examples of the dosage form of the therapeutic agent of the present invention include oral and parenteral administration. The dosage of the therapeutic agent of the present invention depends on the patient's age, weight, symptoms, route of administration, and frequency of administration, but a dose of 0.1 µg to 100 mg, preferably 1 µg to 1 mg is administered 1 to 4 times a day. It is desirable to.

In the case of oral administration, it is used in the form of general orally available pharmaceutical preparations such as tablets, capsules, powders, granules, liquids and the like. In the case of parenteral administration, it can also be used as an injection, suppository, or external preparation, for example.

When the therapeutic agent of the present invention is used in the form of an external preparation, it is used in the form of general pharmaceutical preparations such as ointments, gels, creams, emulsions, solutions, patches, sprays, tapes, patches, and suppositories.

When using the therapeutic agent of this invention as an external preparation, as content of the active ingredient in a formulation, it is 0.0001-10 weight%, Preferably it is 0.001-1 weight%.

The biblical term treatment should be understood in its broadest sense and includes prevention in addition to the original treatment. The therapeutic agent of the present invention exerts its effects not only for the treatment of wounds or hemorrhoids but also for the prevention of such diseases.

Best Mode for Carrying Out the Invention

Hereinafter, the present invention will be further described with reference to Examples.

[Example 1]

Liquid

Macrogol 400 was mixed in purified water, Veraprost sodium salt was dissolved, and ethanol was added to make the total amount 100 ml to obtain a liquid formulation.

[Example 2]

Ointment

After macrogols 400 and 4000 are dissolved at 80 ° C., the mixture is cooled and solidified while kneading well under vacuum. After returning the produced solid to atmospheric pressure, the solution obtained by dissolving veraprost sodium salt in purified water is added and knead well under vacuum again to obtain an ointment.

[Example 3]

Crime

After dissolving the oil phase components (white waschelin, liquid paraffin, stearyl alcohol, and glycerin monostearate) at 80 ° C. and the aqueous phase components (polyoxyl 40 stearate, macrogol 400 and purified water 45.9 g) at 80 ° C. Add it.

The mixture was stirred while cooling under reduced pressure to emulsify and solidify. After the reaction mixture was returned to normal pressure, a solution obtained by dissolving veraprost sodium salt in 5 g of purified water was added and kneaded well under reduced pressure to obtain a creaming agent.

[Example 4]

refine

Prepared according to the conventional method by the above formulation, a tablet containing 20 µg of veraprost sodium is obtained.

[Example 5]

Suppository

After dissolving U.tesol H-15 at 40 ° C, veraprost sodium is added, uniformly dispersed by stirring and sonication, and the dispersion is dispensed into 2 g of a suppository container and cooled to obtain a suppository.

The effects of the present invention will be described with reference to the following test examples.

[Test Example 1]

Influence of Verafrost on Wound Healing in Diabetic Mouse Skin Excision Model

1. Test Method

Hair on the back of hereditary diabetic mice (C57BL / KsJ-dbm male (db + / db +) male, 11-12 weeks old, 6 per group) is removed on the day before the test. After wiping the skin of the dorsal area with ethanol under ether anesthesia, a circular non-cutaneous excisional resection (2cm2) is made in the median of the dorsal area using surgical curved scissors.

Veraprost (sodium salt) as a test agent is prepared in the form of a physiological saline solution containing 20% ethanol and administered dropwise in an amount of 5 μg / 10 μl / cm 2 x 14 times (1 day 14 days). . As a control, only the solution (carrier) containing no medicament is administered in the same way.

In order to evaluate the effect by the to-be-tested agent, the wound surface is placed in a plastic sheet at intervals of two to three days, and then the wound area is measured by a planimeter. The ratio of the wound area to the area immediately after skin excision was calculated, and the number of days required until the skin defect wound visually completed (cures) the epidermis was taken as an index.

In addition, the degree of angiogenesis and granulation formation of the wound surface was visually recorded, and changes and side effects with the passage of days were observed.

Nine days after skin excision, the exudates were collected and the white blood cell counts in the mixed solution of the exudates and the solutions in which the wounds were washed with physiological saline were measured under a microscope.

On the 31st day of excision, the mouse was anesthetized with ether to remove the wound skin and fixed with 10% neutral buffered formalin solution, followed by paraffin sections, hematoxyrin-Eosin and Masson trichrome (Masson). trichrome) stained specimens were prepared and observed through a microscope.

2. Test result

The effect of the test agent on the rate of change and the cure of the wound area is shown in Table 1 compared to the carrier administration control.

As shown in Table 1, the wound surface of the veraprost-administered group showed a clear reduction after 6 days compared to the carrier-administered group, and was reduced to 24.4% and 0.1% on average after 10 and 21 days, respectively.

Cures were observed after 21 days, and all rats were cured after at least 24 days. The average cure days are 22 days, which shows a clear shortening compared to the carrier administration group.

Angiogenesis and granulation of the wound surface were observed over the course of days, and the veraprost group clearly showed angiogenesis and granulation earlier than the carrier group.

The effect of veraprost administration on the amount of exudates and infiltrating leukocyte count on the wound surface (9 days after administration) is shown in Table 2. As shown in Table 2, the veraprost group showed a clear increase in the amount of exudates and infiltrating leukocytes compared to the carrier group.

In the wound healing process, the rate of epidermal growth in the wet wound surface is increased compared to the dried wound surface.

Therefore, an increase in the amount of exudates observed in the early stages after veraprost administration contributes to the promotion of wound healing.

Increasing the number of infiltrating leukocytes also promotes the healing process of inflammation. In addition, since no body weight difference was observed between the veraprost-administered group and the carrier-administered group, no systemic side effects caused by veraprost administration were observed.

The histopathological deata of the wound site after 31 days of skin excision is shown in Table 3.

As shown in Table 3, the skin resection site of the carrier-administered group was prominent in fibrotic proliferation (granulation) and exudates of the dermis, and histologically, the wound surface was not completely covered with the regenerated epidermis.

On the other hand, in the Verafrost-treated group, the entire area of the skin resection site was covered with the regenerated epidermis, and the dermal exudate was lost. In addition, fibroblast proliferation was a histological transition to pre-emulsification, and did not show abnormal tissue formation or hyperplasia scars and showed normal wound healing.

[Test Example 2]

Hemorrhoids Prevention and Therapeutic Effects of Veraprost in Experimental Hemorrhoids Model of Rats

1.test material

1) Preparation of croton oil-containing base salt

A mixture of 1 volume of distilled water, 4 volumes of pyridine, 5 volumes of ethyl ether, and 10 volumes of 3% croton oil ethylether solution is used. Distilled water and a small amount of ethyl ether were added to the pyridine, followed by 3% croton oil ethyl ether solution, and the remaining ethyl ether was added vigorously to prepare a croton oil-containing base salt. This solution was prepared just before the test, and ice-cooled during the test.

2) Preparation and dose of test solution

Veraprost (sodium salt) was dissolved in distilled water for oral administration, and dissolved in physiological saline for rectal administration.

The dose is 0.1, 0.3 or 1.0 mg / kg for oral administration and 0.01, 0.03, 0.1, 0.3 or 1.0 mg / kg for oral administration in the hemorrhoidal preventive effect test. In the hemorrhoids treatment trial, 0.1 mg / kg for oral administration and 0.03 mg / kg for rectal administration. The dosage is 10 ml / kg for oral administration and 100 μl / kg for rectal administration.

3) used for animals

7-8 weeks SLC: Wistar male rats (SL Japan Co., Ltd.) were fasted overnight, and weighed 167-200 g, and 7-8 animals were used for each group.

2. Test method

In the hemorrhoidal preventive effect test, veraprost was administered orally or rectally, and after 30 minutes of administration, 100 µl of croton oil-containing base salt was stained with the cotton ball of cotton swab (# 103 Surgical Yamamoto Bandage Material Co., Ltd.) Insertion into rat anus for 10 seconds under intoxication caused inflammation.

After 3 hours of erosion, Ethe was bled under anesthesia, and the weight of the rectum-anus was extracted to the exact length of 20 mm from the edge of the hair with the annulus of the anal epithelium.

For the rectal administration group, the extracted rectal-anal region was fixed with 10% neutral buffered formalin solution, and then paraffin fragments, hematoxylin-eosin and phosphotungstic acid hematoxyline according to the conventional method. acid hematoxyin) stained specimens were prepared, and observed and photographed with an optical microscope (Microphot FXA, Nikon) to examine the operational data of rectal administration of veraprost.

In the hemorrhoid treatment effect test, inflammation was caused by croton oil-containing base salt in the same manner as the prevention effect test. The weight of the rectal-anal region was measured 4 days twice a day from the first day after tidal effusion and after 5 days, the same as the preventive effect test.

In the control group, distilled water for oral administration and physiological saline (carrier) for rectal administration were administered. For comparison, the same test was performed on the untreated group which was not treated with croton oil-containing base salts and drugs and was not administered distilled water or physiological saline.

3. Statistical Processing

Verafrost's effect on rectal-anus weight was measured using the t test of Student, and histological data using the H test of kruskal-wallis. Was tested. Moreover, the inhibition rate was computed by the following formula from the average weight of the rectum-anus part of each group.

% Inhibition = [1-[(Drug-treated group) / (Control-untreated group)]] x 100

4. Test result

Table 4 shows the results of the hemorrhoidal prophylactic effect test by oral administration of veraprost.

The mean value of rectal-anus weight of the untreated group was 165.1 mg, which was 353.2 mg in the control group treated with the GI after administration of the carrier only, and all of them were significantly increased (P 0.01) compared to the untreated group. Admitted.

Under these conditions, the veraprost 0.1-1.0 mg / kg administration group showed a clear swelling inhibitory effect correlated with the veraprost dose.

Table 5 shows the results of the hemorrhoidal prophylactic effect test by rectal administration of veraprost.

Regarding the increase in rectal-anal region weight by inflammatory drugs, any of the groups treated with veraprost 0.01-1.0mg / kg (P 0.05-0.01) showed a significant inhibitory effect, and the effect was maximum in the group treated with veraprost 0.03mg / kg. It was.

Table 6 shows the results of testing the effects on histological data by rectal administration of veraprost.

In the control group administered with saline solution only, the rectum showed widespread bleeding, necrosis, and detachment of the mucosal layer caused by the basement agent (the average length from the anal transition region was 8.0 ± 9.51 mm), and edema of the submucosal tissue and inflammatory cell infiltration. Was remarkable. In addition, in the mucosa and submucosal tissues, a number of congestion-enlarging capillaries (mean 22.4 ± 2.54) with red thrombus formation (the total number observed in blood vessels with a diameter of 500 μm or more present in the entire field of vision) were observed.

On the other hand, in the 0.03 mg / kg rectal administration group of veraprost, the range of bleeding, necrosis and detachment (mean 5.4 ± 0.19mm) of the mucosal layer was significantly suppressed (P 0.01). The degree of edema and inflammatory cell infiltration was reduced, and the nuclei of mucosal epithelial cells were stained darker than those of normal sites, and cells which were considered to be in an activated state were remarkably observed. In addition, the degree of congestion was suppressed, and the number of red blood clot-forming blood vessels (mean 6.8 ± 2.35) also decreased significantly (P 0.01).

In the above results, in the hemorrhoidal preventive effect test, veraprost apparently inhibits the swelling of the rectal-anal region caused by croton oil-containing bases in either the oral and rectal administration route, and on pathological histological data. Even a remarkable effect was shown.

The results of the hemorrhoidal treatment effect test by oral and rectal administration of veraprost are shown in Table 7.

As a result, 0.1 mg / kg oral administration and 0.03 mg / kg rectal administration of veraprost showed significant (P 0.05) swelling inhibitory effect.

[Effects of the Invention]

According to the present invention, there is provided a useful wound or hemorrhoidal therapeutic agent, particularly an external wound or hemorrhoidal therapeutic agent, and a wound or hemorrhoidal treatment method that exhibit potent wound healing promoting action and hemorrhoidal therapeutic effect.

Claims (4)

A wound treatment comprising veraprost or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier. The wound treatment according to claim 1, which is used as an external preparation. A therapeutic agent for hemorrhoids containing veraprost or a salt thereof and a pharmaceutically acceptable carrier as an active ingredient. The hemorrhoidal therapeutic agent according to claim 3, which is used as an external preparation.