KR102233566B1 - Composition comprising stilbene derivative for preventing or treating of chronic pulmonary disease - Google Patents

Abstract

The present invention is expected to be used for the prevention or treatment of various chronic obstructive pulmonary diseases because the composition for preventing or treating chronic lung diseases containing a stilbene derivative can effectively inhibit damage and inflammatory reactions to lung tissue. do.

Description

Composition comprising stilbene derivative for preventing or treating of chronic pulmonary disease

The present invention relates to a composition for preventing and/or treating chronic lung diseases, etc. comprising a stilbene derivative as an active ingredient.

Chronic pulmonary disease is a general term for pulmonary disease in which inflammation of the bronchi or lungs occurs due to various causes, resulting in coughing or phlegm, and in severe cases, difficulty breathing. Also known as chronic obstructive pulmonary disease (COPD). These chronic obstructive pulmonary diseases include emphysema and chronic bronchitis. This chronic obstructive pulmonary disease is a trend of increasing incidence and mortality due to an increase in smoking rate and prolongation of life expectancy, and is one of the top 10 causes of death in Korea. In addition, the World Health Organization predicts that in 2020, chronic obstructive pulmonary disease will be the third leading cause of death in the world. Emphysema, one of the chronic obstructive pulmonary diseases, causes damage to the alveoli in the peripheral airways and the interalveolar space wall of the distal bronchi, which loses elasticity and is destroyed, resulting in abnormally permanent expansion, reducing the oxygen-carbon dioxide exchange capacity of the lungs, causing breathing difficulties. It is a disease. The main cause of emphysema is known to be smoking, but it can also be caused by exposure to air pollution or harmful working environments, and it is known that the speed of progression is accelerated when accompanied by respiratory infections. The main symptom of emphysema, alveolar dilatation due to tissue destruction, is the expression of proteolytic enzymes such as matrix metalloproteinase (MMP) and neutrophil elastase, while the expression of proteolytic enzymes is activated. It is known that this is because the expression of the inhibitory α1-antitrypsin is decreased. In addition, by inducing the secretion of various cytokines and chemokines from macrophages and epithelium in the alveoli by smoking, the inflammatory response is activated, and cytokines/chemokines (TNF-α, IL- 1βIL-8, MCP-1, IFN-γ, etc.), reactive oxygen species (ROS), etc.) are increased, which is known to accelerate tissue damage due to increased expression and activation of proteases. have. These emphysema is a disease in which the lung structure is irreversibly damaged and cannot be treated. Currently, the treatments used are symptomatic treatment according to symptoms such as steroids to alleviate inflammatory reactions, bronchodilators to alleviate respiratory distress, and expectorants. Only the method is being used.

Therefore, in order to effectively treat such chronic obstructive pulmonary disease, the development of a therapeutic agent capable of reducing the rate of damage to the lung structure or suppressing lung tissue damage is urgently needed.

Domestic registered patent 10-1647029

The present invention was conceived to solve the problems of the prior art as described above, and an object thereof is to provide a composition for preventing or treating chronic lung diseases, including a stilbene derivative as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned will be clearly understood by those of ordinary skill in the art from the following description.

The present invention provides a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease, comprising a stilbene derivative as an active ingredient.

In addition, the present invention provides a food composition for preventing or improving chronic obstructive pulmonary disease, comprising a stilbene derivative as an active ingredient.

In one embodiment of the present invention, the stilbene derivative may preferably be gaylussacin or the like, but if it is a stilbene derivative isolated from a plant, a stilbene derivative capable of preventing or treating chronic obstructive pulmonary disease It is not limited thereto.

In another embodiment of the present invention, the chronic obstructive pulmonary disease (COPD) may be preferably emphysema, chronic bronchitis, and the like, more preferably emphysema or lung tissue. If it is a chronic obstructive pulmonary disease caused by damage, an increase in inflammatory reaction, etc.

In another embodiment of the present invention, the composition is characterized in that it maintains or restores lung function by inhibiting damage and inflammatory reactions of lung tissue.

In addition, the present invention provides a method for treating chronic obstructive pulmonary disease, comprising administering to an individual a composition comprising a stilbene derivative as an active ingredient.

In addition, the present invention provides a use of a composition comprising a stilbene derivative as an active ingredient to prevent or treat chronic obstructive pulmonary disease.

The composition comprising the stilbene derivative of the present invention as an active ingredient effectively inhibits damage and inflammatory reactions to lung tissue, so that it can be widely used in the treatment of not only chronic obstructive pulmonary disease, but also various lung diseases caused by lung tissue damage and increased inflammatory response. It is expected.

1 is a diagram showing an experimental method according to an embodiment of the present invention.
2 is a view showing the result of confirming the recovery of lung function by geilusacin according to an embodiment of the present invention.
3 is a view showing a result of confirming the effect of inhibiting lung tissue damage by geilusacin according to an embodiment of the present invention.
4 is a view showing the results of confirming the effect of inhibiting the activation of matrix metalloproteinases by geilusacin according to an embodiment of the present invention.
5 is a view showing a result of confirming the effect of inhibiting apoptosis of lung tissue by geilosacin according to an embodiment of the present invention.

In a situation where there are almost no effective therapeutic agents and treatment methods for chronic obstructive pulmonary disease, the geilusacin derived from the present invention is expected to be effectively used for the treatment or prevention of chronic obstructive pulmonary disease.

In the present specification, the term "chronic obstructive pulmonary disease (COPD)" causes inflammation in the bronchi or lungs due to various causes, resulting in coughing or phlegm, and in severe cases, breathing difficulties. As a collective term for lung diseases, preferably emphysema, chronic bronchitis, etc. may be, more preferably emphysema or lung diseases caused by inflammation of the lungs and damage to the tissues of the lungs It is not limited thereto.

In the present specification, “stilbene derivative” refers to a similar compound obtained by chemically changing a part of stilbene. Preferably, it may be gaylussacin or the like, but it is not limited thereto as long as it is a stilbene derivative capable of reducing lung inflammation and tissue damage.

In the present specification, "prevention" refers to any action that suppresses or delays the onset of diseases such as chronic obstructive pulmonary disease by administration of the composition according to the present invention.

In the present specification, "treatment" refers to any action in which symptoms such as chronic obstructive pulmonary disease are improved or beneficially changed by administration of the composition according to the present invention.

In the present specification, “individual” refers to a subject to which the composition of the present invention can be administered, and the subject is not limited.

In the present specification, the term "pharmaceutical composition" may be characterized in that it is in the form of capsules, tablets, granules, injections, ointments, powders, or beverages, and the pharmaceutical composition is intended for humans. I can. The pharmaceutical compositions are not limited thereto, but may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterile injectable solutions according to a conventional method. . The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be used as binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colors, fragrances, etc. for oral administration, and buffers, preservatives, and painlessness in the case of injections. Agents, solubilizers, isotonic agents, stabilizers, etc. can be mixed and used, and in the case of topical administration, base agents, excipients, lubricants, preservatives, etc. can be used. The formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixir, suspension, syrup, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained-release preparation, and the like.

On the other hand, examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, and the like may additionally be included.

The route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, local , Sublingual or rectal. Oral or parenteral administration is preferred. The term “parenteral” as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of suppositories for rectal administration.

The pharmaceutical composition of the present invention depends on a number of factors, including the activity of the specific compound used, age, weight, general health, sex, formulation, time of administration, route of administration, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. It may vary in various ways, and the dosage of the pharmaceutical composition varies depending on the patient's condition, weight, degree of disease, drug type, administration route and duration, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg per day /kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be divided several times. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.

In the present invention, the food composition can be used in various foods, for example, beverages, gums, teas, vitamin complexes, health supplements, etc., and can be used in the form of pills, powders, granules, needles, tablets, capsules or beverages. I can. At this time, the amount of the stilbene derivative in the food or beverage may be generally added in an amount of 0.01 to 15% by weight of the total food weight in the case of the food composition of the present invention, and 0.02 to 10 g based on 100 mL in the case of a health drink composition , Preferably it can be added in a ratio of 0.3 to 1 g.

The food composition of the present invention may include food additives conventional in the art, such as flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like. The food composition according to the present invention is an essential ingredient, and there is no particular limitation on the ingredients to be added in addition to the stilbene derivative, and may contain various flavoring agents or natural carbohydrates as additional ingredients, as in ordinary foods. Examples of the natural carbohydrate include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; Polysaccharides such as dextrin, cyclodextrin; And sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 mL of the composition of the present invention.

In addition to the above, the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid, and It may contain salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. These components may be used independently or in combination. The proportion of these additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, the following examples are presented to aid the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

Example

Example One: Geilusa Confirmation of effects on chronic obstructive pulmonary disease

1.1. Lung function Confirmation experiment

To determine the effect of gaylussacin on the decline in lung function caused by chronic obstructive pulmonary disease (COPD) in live animals, FVB mice were given geilusacin 40 mg/kg for 6 times a week. After oral administration, 0.25 U of elastase was administered once into the airway. And again, geilusacin was administered 6 times a week for 5 weeks. The overall experimental method is shown in FIG. 1. Afterwards, in order to confirm lung function, the lung compliance and elasticity (elasticity, ability to breathe through the muscle contraction of the diaphragm) of the mouse were measured using the FlexiVent RM, and the results are shown in FIG. 2.

As shown in Fig. 2, when elastase is treated, the pulmonary purity is increased and elasticity is reduced, so that the function of the lung is significantly reduced, but in the experimental group to which geilosacin is administered, the pulmonary purity is reduced again, It was confirmed that the elasticity was increased again and the lung function was restored. Through the above results, it was confirmed that geilusacin has a preventive and therapeutic effect on chronic obstructive pulmonary disease.

1.2. H&E dyeing

In order to confirm the effect of geilosacin administration on lung tissue damage, the lungs of the mice treated in the same manner as in Example 1.1 were isolated, and the isolated lungs were fixed for 24 hours using 10% formalin. After that, a paraffin block was manufactured using paraffin. Then, the prepared paraffin block was cut to a thickness of 4 μm, attached to a silane coating slide, and dried. The dried slides were put in a 65°C dry oven to deparaffin for 16 hours, and washed by immersing them in a xylene solution for 2 times for 5 minutes each. Then, the fixed lung tissue sections were deparaffinized and hydrated with 100%, 95%, and 70% alcohol, washed with distilled water, and stained with Harris hematoxylin solution for 1 minute and 30 seconds, followed by 1% HCl alcohol. After immersion and washing with a solution and ammonia, it was stained for 30 seconds using an eosin solution. Then, after sequentially dehydrating using 95% ethanol and 100% ethanol again, final washing with xylene solution, sealing was carried out, and observed under a microscope, and photographs were obtained. The results are shown in FIG. 3.

As shown in FIG. 3, the lung tissue of the control group to which only elastase was administered was collapsed, but it was confirmed that the damage to the lung tissue was reduced in the case of the experimental group to which geilusacin was administered together with elastase.

1.3. MMP Activity measurement

In order to confirm the activity of matrix metalloproteinase (MMP), which is known as a major factor inducing chronic obstructive pulmonary disease, bronchoalveolar lavage (BAL) of mice treated in the same manner as in Example 1.1 was obtained. After drying and fixing on a slide, a reaction buffer (Thermofisher) containing DQ gelatin bound with FITC (fluorescein isothiocyanate) was added in an appropriate amount, and then reacted in a dark room at 37° C. for 12 hours. Activated matrix metalloproteinase decomposes DQ gelatin, resulting in fluorescence by FITC. The reacted slide was observed using a fluorescence microscope and photographs were obtained. The results are shown in FIG. 4.

As shown in FIG. 4, it was confirmed that the activated MMP was increased in the control group to which elastase was administered and fluorescence by FITC was observed, but the MMP activity was not increased in the experimental group to which geilusacin was administered. Through the above results, it was confirmed that geilusacin inhibited an increase in the inflammatory response caused by elastase.

1.4. Apoptosis Checking the inhibitory effect

In order to confirm the effect of geilosacin on the apoptosis of lung tissue cells, one of the indicators of lung tissue damage, TUNEL analysis and DAPI staining were performed. For TUNEL analysis, lung tissues of mice treated in the same manner as in Example 1.1 were extracted and then fixed with sections on slides. In addition, DNA fragments caused by apoptosis were observed with red fluorescence using a TUNEL assay kit (Abcam). Then, the nuclei were stained using DAPI solution (Thermofisher). The results are shown in FIG. 5.

As shown in FIG. 5, it was confirmed that DNA fragmentation due to apoptosis was increased in the control group to which elastase was administered, but almost no apoptosis was observed in the experimental group to which geilusacin was administered.

Through the above results, the composition containing geilosacin as an active ingredient of the present invention inhibits damage and destruction of lungs in an animal model of chronic obstructive pulmonary disease administered with elastase, and effectively reduces the inflammatory response of the lungs. It was confirmed that the function was maintained and/or restored, and through this, it was confirmed that geilosacin can be used as a composition for preventing or treating chronic obstructive pulmonary disease.

The above-described description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains can understand that it is possible to easily transform it into other specific forms without changing the technical spirit or essential features of the present invention. There will be. Therefore, it should be understood that the embodiments described above are illustrative and non-limiting in all respects.

Claims (8)

A pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease, comprising gaylussacin as an active ingredient. delete The method of claim 1,
The chronic obstructive pulmonary disease is characterized in that the emphysema (emphysema) or chronic bronchitis (chronic bronchitis), pharmaceutical composition. The method of claim 1,
The pharmaceutical composition is characterized in that to maintain or restore lung function by inhibiting the damage and inflammatory reaction of the lung tissue, pharmaceutical composition. Food composition for preventing or improving chronic obstructive pulmonary disease, comprising gaylussacin as an active ingredient. delete The method of claim 5,
The chronic obstructive pulmonary disease is emphysema or chronic bronchitis, characterized in that, food composition. The method of claim 5,
The food composition is characterized in that to maintain or restore lung function by inhibiting the damage and inflammatory reaction of the lung tissue, food composition.

Images