KR20190127461A - Composition comprising stilbene derivative for preventing or treating of chronic pulmonary disease - Google Patents

Abstract

The present invention is expected to be used for preventing or treating various chronic obstructive pulmonary diseases since a composition for preventing or treating chronic pulmonary diseases, containing stilbene derivatives can effectively inhibit the damage or inflammatory response of lung tissues. A purpose of the present invention is to provide the composition for preventing or treating chronic pulmonary diseases containing stilbene derivatives as active components.

Description

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

The present invention relates to a composition for the prevention and / or treatment of chronic lung disease comprising a stilbene derivative as an active ingredient.

Chronic pulmonary disease generally refers to a pulmonary disease that causes inflammation of the bronchus or lung due to various causes, cough or sputum, and in severe cases, respiratory distress. Also called chronic obstructive pulmonary disease (COPD). These chronic obstructive pulmonary diseases include emphysema, chronic bronchitis, bronchial asthma and the like. The chronic obstructive pulmonary disease is a trend of increasing the incidence and mortality due to the increase in smoking rate and life expectancy, which is one of the 10 leading causes of death in Korea. In addition, the World Health Organization predicts that 2020 chronic obstructive pulmonary disease will be the third largest cause of death worldwide. Emphysema, one of chronic obstructive pulmonary diseases, is caused by damage to the peripheral airway alveoli and the loss of elasticity and destruction of the alveolar space walls of the terminal three bronchus, resulting in abnormal permanent expansion, resulting in decreased lung-to-oxygen-carbon exchange capacity. It is a disease. Although the main cause of emphysema is known as smoking, it can also be caused by air pollution or exposure to hazardous work environments, and is known to accelerate progression with respiratory infections. Alveolar dilatation, a major symptom of emphysema, is the expression of proteolytic enzymes, such as matrix metalloproteinase (MMP) and neutrophil elastase, while activating proteolytic enzymes. It is known that the expression of inhibitory α1-antitrypsin is reduced. In addition, smoking induces the release of various cytokines and chemokines from alveolar macrophages and epithelium, thereby activating the inflammatory response, resulting in cytokine / chemokine (TNF-α, IL-) caused by inflammation-related cells. 1βIL-8, MCP-1, IFN-γ, etc.), reactive oxygen species (ROS), etc. are increased, thereby increasing tissue expression due to increased expression and activation of proteases. have. These emphysema are irreversible damage to the lung structure, and the underlying treatment is impossible, and currently used therapeutic agents are symptomatic treatments according to symptoms such as steroid preparations for inflammatory reactions, bronchodilators for reducing respiratory distress, and expectorants. Only the method is used.

Therefore, in order to effectively treat such chronic obstructive pulmonary disease, it is urgently needed to develop a therapeutic agent that can reduce the damage rate of lung structure or suppress lung tissue damage.

Domestic Patent 10-1647029

The present invention has been made to solve the above problems in the prior art, and an object thereof is to provide a composition for the prevention or treatment of chronic lung disease, including a stilbene derivative as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled 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 another aspect, the present invention provides a food composition for the prevention or improvement of chronic obstructive pulmonary disease, comprising a stilbene derivative (stilbene derivative) as an active ingredient.

In one embodiment of the present invention, the stilbene derivative may preferably be gaylussacin, combretastatin, lunurular acid, and the like, and more preferably, , And stilbene derivatives isolated from plants, and stilbene derivatives capable of preventing or treating chronic obstructive pulmonary disease are not limited thereto.

In another embodiment of the invention, the chronic obstructive pulmonary disease (COPD) is preferably emphysema, chronic bronchitis, bronchial asthma, etc., more preferably emphysema In addition, chronic obstructive pulmonary disease caused by damage to lung tissue, increased inflammatory response is not limited thereto.

In another embodiment of the present invention, the composition is characterized in that to maintain or restore lung function by inhibiting damage and inflammatory response of lung tissue.

The present invention also provides a method for treating chronic obstructive pulmonary disease, comprising administering to a subject a composition comprising a stilbene derivative as an active ingredient.

The present invention also provides a preventive or therapeutic use of chronic obstructive pulmonary disease of a composition comprising a stilbene derivative as an active ingredient.

The composition comprising the stilbene derivative of the present invention as an active ingredient effectively inhibits the damage and inflammatory response of lung tissue, so that it can be widely used for the treatment of various lung diseases due to lung tissue damage and inflammatory response as well as chronic obstructive pulmonary disease It is expected to be.

1 is a view showing an experimental method according to an embodiment of the present invention.
2 is a view showing the results of confirming the recovery of lung function by geilusacin according to an embodiment of the present invention.
3 is a view showing the results confirming the effect of inhibiting lung tissue damage by geilusacin according to an embodiment of the present invention.
Figure 4 is a view showing the results confirming the inhibitory effect on the substrate metalloproteinase activation by geylusacin according to an embodiment of the present invention.
5 is a view showing the results of confirming the effect of inhibiting apoptosis of lung tissue by geilusacin according to an embodiment of the present invention.

In the situation where there are almost no therapeutic agents and methods for the treatment of chronic lung diseases, the composition comprising the stilbene derivative of the present invention as an active ingredient can effectively inhibit the damage to the lungs, thereby preventing and / or treating various chronic lung diseases. It is expected to be used effectively.

In the present specification, “chronic obstructive pulmonary disease (COPD)” refers to inflammation of the bronchus or lung due to various causes, resulting in coughing or sputum, and severe respiratory distress. Lung disease is referred to collectively, preferably emphysema, chronic bronchitis, bronchial asthma, etc., more preferably due to emphysema, inflammation of the lungs and damage to tissues of the lungs Lung disease is not limited to this.

As used herein, “stilbene derivative” refers to a similar compound obtained by chemically changing a portion of stilbene. Preferably, it may be gaylussacin, combretastatin, lunurular acid, and the like, and more preferably, gailusacin or stilbene may reduce lung inflammation and tissue damage. The derivative is not limited thereto.

As used herein, "prevention" means any action that inhibits or delays the onset of a disease such as chronic obstructive pulmonary disease by administration of a composition according to the present invention.

In the present specification, "treatment" means any action that improves or advantageously changes symptoms of chronic obstructive pulmonary disease 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 "pharmaceutical composition" may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, wherein the pharmaceutical composition may be characterized as targeting humans. Can be. The pharmaceutical composition is not limited to these, but can be used in the form of oral dosage forms, such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. . The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be used as oral administration binders, suspending agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc. In the case of injections, buffers, preservatives, analgesic Topical agents, solubilizers, isotonic agents, stabilizers and the like can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives and the like can be used. The formulation of the pharmaceutical composition of the present invention may be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in the case of injections, in unit dosage ampoules or multiple dosage forms. have. And others, solutions, suspensions, tablets, capsules, sustained release preparations and the like.

Examples of suitable carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.

Routes of administration of the pharmaceutical compositions according to the invention are not limited to these, but are oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , Sublingual or rectal. Oral or parenteral release is preferred. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intramuscular, intrasternal, intradural, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.

The pharmaceutical composition of the present invention is dependent on a number of factors, including the activity, age, weight, general health, sex, formulation, time of administration, route of administration, rate of release, drug combination and severity of the particular disease to be prevented or treated, of the specific compound employed. The dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, extent of disease, drug form, route of administration and duration, and may be appropriately selected by those skilled in the art and may be 0.0001 to 50 mg per day. / kg or 0.001-50 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.

In the present invention, the food composition may be used in various foods, for example, beverages, gums, teas, vitamin complexes, health supplements, and the like, and may be used in the form of pills, powders, granules, acupuncture tablets, capsules, or beverages. Can be. In this case, the amount of the stilbene derivative in the food or beverage can generally be added as 0.01 to 15% by weight of the total food weight in the case of the food composition of the present invention, 0.02 to 10 g based on 100 mL for the health beverage composition Preferably, it can be added in the ratio of 0.3-1 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 added in addition to the stilbene derivative, and may contain various flavors or natural carbohydrates as additional ingredients, as in general foods. Examples of the natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as dextrin, cyclodextrin; Conventional sugars such as and the like and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have. The proportion of said natural carbohydrates is generally about 1-20 g, preferably about 5-12 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), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. These components can be used independently or in combination. The proportion of such 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 help understand the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

Example

Example  One: Geilusacin  Identify the effects on chronic obstructive pulmonary disease

1.1. Lung function  Confirmation experiment

To determine the effect of gaylussacin on pulmonary dysfunction caused by chronic obstructive pulmonary disease (COPD) in live vegetables, FGB mice were given a dose of 40 mg / kg of geilusacin for 6 times a week. After oral administration, 0.25 U of elastase was administered to the airways once. Again geilusacin was administered 6 times a week for 5 weeks. The overall experimental method is shown in FIG. 1. Then, in order to confirm the lung function, the lung purity (elasticity) and elasticity (elasticity, the ability to breathe by the contractile muscle contraction of the diaphragm) of the mouse was measured using FlexiVent RM, and the results are shown in FIG. 2.

As shown in Figure 2, the treatment of elastase increases the purity of the lungs, the elasticity is reduced to significantly reduce the function of the lungs, in the experimental group administered geilusacin lung purity decreases again, The elasticity was increased again to confirm that the lung function was restored. Through the above results, it was confirmed that geilusacin is effective in preventing and treating chronic obstructive pulmonary disease.

1.2. H & E Dyeing

In order to confirm the effect of geilusacin administration on the damage of lung tissue, the lungs of 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 the paraffin was prepared using a paraffin block. The prepared paraffin block was cut to a thickness of 4 μm, and then attached to a silane coated slide and dried. The dried slide was deparaffinized in a dry oven at 65 ° C. for 16 hours, and immersed in xylene solution twice for 5 minutes and washed. The fixed lung tissue sections were deparaffinized and hydrated with 100%, 95%, and 70% alcohol, washed with distilled water, and then stained with Harris hematoxylin solution for 1 minute and 30 seconds, followed by 1% HCl alcohol. The solution was washed with immersion with ammonia and then stained for 30 seconds using an eosin solution. And again dehydrated sequentially using 95% ethanol and 100% ethanol, and finally washed with a xylene solution and then sealed and observed under a microscope to obtain a photograph. The results are shown in FIG.

As shown in FIG. 3, the lung tissue of the control group administered with elastase was collapsed, but in the experimental group administered with gaelusacin with elastase, damage of the lung tissue was confirmed to be reduced.

1.3. MMP  Active measurement

In order to confirm the activity of matrix metalloproteinase (MMP), which is known as a major factor causing chronic obstructive pulmonary disease, bronchoalveolar lavage (BAL) of mice treated in the same manner as in Example 1.1 was obtained. After drying on a slide and fixing, a suitable amount of a reaction buffer (thermofisher) containing DQ gelatin combined with fluorescein isothiocyanate (FITC) was added thereto, followed by reaction for 12 hours in a dark room at 37 ° C. Activated matrix metalloproteinases break down DQ gelatin and are fluoresced by FITC. The reacted slides were observed using a fluorescence microscope and photographs were obtained. The results are shown in FIG.

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

1.4. Apoptosis  Confirm inhibitory effect

In order to confirm the effect of geilusacin on apoptosis, 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 sectioned onto slides. And DNA fragments caused by apoptosis were observed in red fluorescence using a TUNEL assay kit (Abcam). The nuclei were stained using DAPI solution (Thermofisher). The results are shown in FIG.

As shown in FIG. 5, DNA fragmentation by apoptosis was increased in the control group administered with elastase, but apoptosis was hardly observed in the experimental group administered with geillusacin.

Based on the above results, the composition comprising the geilusacin of the present invention as an active ingredient inhibits lung damage and destruction in an animal model of chronic obstructive pulmonary disease administered with elastase, and effectively reduces the inflammatory response. It was confirmed that the function is maintained and / or restored, thereby confirming that geilusacin can be used as a composition for preventing or treating chronic obstructive pulmonary disease.

The description of the present invention set forth above is for illustrative purposes, and it will be understood by those skilled in the art that the present invention may be easily modified 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 exemplary in all respects and not restrictive.

Claims (8)

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

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