KR20190006461A - Composition for prevention or treatment of inflammatory eye disease comprising (7S,8R)-dihydrodehydrodiconiferylalcohol-9-β-D-glucopyranoside - Google Patents

Abstract

The present invention relates to: a pharmaceutical composition for prevention or treatment of inflammatory eye disease containing (7S,8R)-dihydrodehydrodiconiferyl alcohol-9-β-D-glucopyranoside; a quasi drug composition; a method of treating inflammatory eye disease comprising a step of applying the pharmaceutical composition to eyes of an entity; a food composition; and an eye makeup additive composition.

Description

(7S, 8R) -dihydrodihydrodiconiperyl alcohol-9- [beta] -D-glucopyranoside, and a composition for preventing or treating inflammatory eye diseases, , 8R) -dihydrodehydrodiconiferylalcohol-9- [beta] -D-glucopyranoside}

The present invention relates to a pharmaceutical composition for the prophylaxis or treatment of inflammatory eye diseases comprising (7S, 8R) -dihydro dihydrodiciconyl peroxide-9-? -D-glucopyranoside; Quasi-drug composition; A method of treating an inflammatory eye disease comprising administering the pharmaceutical composition to the eye of an individual; Food compositions and eye cosmetic additive compositions.

Inflammatory diseases are collectively referred to as inflammation-predominant diseases, and are known to be involved in many human diseases. In fact, the specific diseases of inflammatory diseases are listed as follows: acne, asthma, autoimmune diseases, periodic fever syndrome, colitis, pelvic inflammation, rheumatoid arthritis, .

Inflammatory ocular disease refers to diseases that occur in the eye due to inflammation of the eye or its surrounding tissue among many kinds of inflammatory diseases. It focuses on the immune response that occurs through activation.

Inflammatory ocular diseases include dry eye syndrome, conjunctivitis, red blood cell, keratitis, and the like. These diseases are diseases that occur directly in the eye due to inflammation in the eyes or surrounding tissues.

Dry eye syndrome is a common disease that occurs in 5.5 to 15% of adults worldwide. It is caused by inflammation of the tear and ocular surface (cornea and conjunctiva), not merely a shortage of tears, It is known to cause instability and damage the surface of the eye. Features of this disease include ocular pain, irregular corneal surface, corneal ulcer, and decreased vision. Corneal permeability changes in chronic eye dryness and dry keratitis are well known to cause inflammation, which is known to be induced by increased inflammation mediated cytokines.

Conjunctivitis is the inflammatory state of conjunctiva caused by microorganisms such as bacteria, viruses, fungi, and environmental factors such as pollen and chemical stimuli. It is the most common eye disease because the conjunctiva is exposed to the outside. Usually it is well cured, but in some cases it is fatal and can lead to blindness due to tissue damage. Conjunctivitis is classified as infectious conjunctivitis and noninfective conjunctivitis, depending on the cause.

Hyperemia is a symptom in which the blood vessels of the conjunctiva are enlarged and the whites of the eyes are visible. Eye irritation such as all types of conjunctivitis, achalitis and iridocyclitis can cause congestion, dryness can lead to congestion if the eyes can not adequately protect the eye, and even if the contact lens is worn for a long period of time Many blood vessels are formed around the cornea and become congested.

Keratitis accounts for more than 90% of the corneal diseases, resulting in loss of corneal epithelium, which is the outermost part of the eye, and decreased opacity caused by inflammation in the corneal parenchyma. In the United States, more than 50,000 cases of keratitis develop annually, and keratitis is the most important disease that can cause blindness in the United States. Keratitis is a symptom of congestion, foreign body sensation, pain, sensitivity to light, symptoms of tears or blurred vision. Keratitis is also classified as infectious keratitis and non-infectious keratitis depending on the cause.

Patients suffering from inflammatory eye diseases account for more than half of the patients suffering from ocular disease, and thus drugs with ocular anti-inflammatory properties play an important role in the medical field. Specific examples include steroidal drugs and non-steroidal drugs, and recently, steroidal drugs such as unpreserved fluorometholone (FML) and non-steroidal drugs such as cyclosporin A cyclosporine A, CsA) have been widely used.

However, it is known that the above steroidal drugs for the treatment of inflammatory eye diseases have a side effect such as increased intraocular pressure or occurrence of cataract or glaucoma when used over a long period of time. Even if nonsteroidal drugs are used continuously, It is known that leukocyte reduction leads to weakened self-immunity. In addition, inflammatory eye diseases are rapidly increasing as the use of computers and smart phones is rapidly increasing. Therefore, there is a demand for development of inflammatory eye disease drugs that can be used safely and at various age groups.

On the other hand, (7S, 8R) -dihydrodihydrodiconiperyl alcohol-9-? -D-glucopyranoside ((7S, 8R) -dihydrodehydrodiconiferyl alcohol- Levl.) Has been reported to have DPPH scavenging activity as a lignan compound isolated from the extract (Pharmacology, Ph.D., 2011, Ph.D.), but little is known about the efficacy other than the efficacy.

Under these circumstances, the present inventors have continuously studied a compound having excellent effects for the prevention or treatment of inflammatory eye disease, specifically, dry eye syndrome, conjunctivitis, conjunctivitis or keratitis. As a result, it has been found that (7S, 8R) -dihydrodihydrodi 9-β-D-glucopyranoside as an active ingredient has a therapeutic effect on human conjunctival epithelial cells and human corneal epithelial cells, thereby providing a pharmaceutical composition, quasi-drug composition, Food composition and eye cosmetic additive composition.

The main object of the present invention is to provide a pharmaceutical composition containing (7S, 8R) -dihydrodihydrodiconiferyl alcohol-9- [beta] -D-glucopyranoside represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient And to provide a pharmaceutical composition for preventing or treating inflammatory ocular diseases.

Another object of the present invention is to provide a pharmaceutical composition containing (7S, 8R) -dihydrodihydrodiconiferyl alcohol-9- [beta] -D-glucopyranoside represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient And to provide a quasi-drug composition for the prophylaxis or treatment of inflammatory eye diseases.

Another object of the present invention is to provide a pharmaceutical composition containing (7S, 8R) -dihydrodihydrodiconiferyl alcohol-9- [beta] -D-glucopyranoside represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient A method for preventing or treating an inflammatory eye disease, comprising administering to the eye of a subject a composition for preventing or treating an inflammatory eye disease.

It is still another object of the present invention to provide a method for producing (7S, 8R) -dihydrodihydrodiconiferyl alcohol-9- [beta] -D-glucopyranoside represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient And to provide a food composition for improving inflammatory ocular diseases.

Another object of the present invention is to provide a pharmaceutical composition containing (7S, 8R) -dihydrodihydrodiconiferyl alcohol-9- [beta] -D-glucopyranoside represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient And to provide an eye cosmetic additive composition for preventing or improving inflammatory eye disease.

In one aspect of the present invention, there is provided a process for producing (7S, 8R) -dihydrodihydrodiciconyl alcohol-9- [beta] -D-glucopyranoside represented by the following formula A pharmaceutical composition for the prevention or treatment of inflammatory eye disease.

[Chemical Formula 1]

In the present invention, "(7S, 8R) -dihydrodihydrodiconiperyl alcohol-9-? -D-glucopyranoside ((7S, 8R) -dihydrodehydrodiconiferylalcohol-9-? -D-glucopyranoside" Represented by the above formula (1), has the molecular formula C ₂₆ H ₃₄ 0 ₁₁ and molecular weight of 522.21.

The present invention is not particularly limited to the method for obtaining the above compound, and natural or chemically synthesized products can be used by methods known in the art, and commercially available substances can be used. For example, it can be obtained from natural phenol and polyphenol extracts extracted by known methods from Ilex integra Thunb. By separation and purification according to a known method.

The compounds represented by Formula 1 of the present invention may exist in a solvated form as well as a non-solvated form. In addition, the compounds of the present invention may exist in crystalline or amorphous form, and all such physical forms are included within the scope of the present invention.

Pharmaceutically acceptable salts are acid addition salts formed by the pharmaceutically acceptable free acids of the above compounds. As the free acid, organic acid and inorganic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid.

The addition salt according to the present invention can be obtained by a conventional method, that is, by dissolving the above compound in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile or the like, adding an equivalent amount or excess amount of an organic acid, Precipitation or crystallization, or by evaporating a solvent or excess acid, followed by drying or precipitation of the precipitated salt by suction filtration. The present invention encompasses all possible solvates, hydrates and stereoisomers thereof, as well as the above compounds or their pharmaceutically acceptable salts, which may be prepared therefrom.

The term " inflammatory eye disease " in the present invention may have various types of ocular diseases accompanied by various pain, depending on the location of inflammation, and may include itching, flare, edema, ulcer and the like. More than half of the patients with ocular disease account for inflammatory ocular diseases, and drugs with ocular anti-inflammatory properties play an important role in the medical field. Specific examples of the inflammatory eye disease according to the present invention may include dry eye syndrome, conjunctivitis, congestion and keratitis.

In one specific example of the present invention, CsA and FML, which are therapeutic agents for inflammatory eye diseases, were tested as a positive control group to confirm the therapeutic efficacy against the inflammatory eye diseases of the compound represented by the formula 1, The results of this study are as follows.

In the present invention, the term " dry eye syndrome " refers to diseases caused by irritation of the lacrimal gland and ocular hardening of the cornea, tear secretion is suppressed or abnormal tear evaporation occurs due to dysfunction of the eyebrows or eyebrows And may be a corneal epithelium disorder in which the tears are over-dried by the dry eye syndrome and appear as wounds of the cornea. For example, it may be useful for the treatment of diseases such as loss of lacrimal gland, occlusion of the canaliculus, reduction of tear secretion due to drugs that can damage the tear production, myalgia dysfunction, eyelid openness, low eye blinking, vitamin A deficiency, And may include increased tear evaporation due to ocular surface conditions such as preservatives, contact lens wear, allergies, and each conjunctival epithelium disorder.

The term " conjunctiva " refers to a tissue that forms the surface of the eye together with the cornea, which protects the eye from external substances, and is involved in the mucosal layer formation and immune function of the tear. The term " conjunctivitis " in the present invention refers to an inflammatory disease caused by a conjunctiva, which is a tissue surrounding the eye from the outside, and a typical symptom is epidemic conjunctivitis.

As an example, the conjunctivitis may be non-infectious conjunctivitis. The non-infective conjunctivitis is caused by an allergic reaction to an external substance.

In another example, the conjunctivitis may be infectious conjunctivitis. The infectious conjunctivitis may be caused by infection of various pathogens such as bacteria, viruses, and fungi, and may be, for example, epidemic conjunctivitis, acute hemorrhagic conjunctivitis (apolloidal conjunctivitis), and bacterial conjunctivitis.

In the present invention, the term " congestion " means a symptom in which the blood vessels of the conjunctiva are enlarged and the whiteness of the eyes is visible. Congestion due to conjunctivitis is most severe on the far side of the eye, and congestion due to irritation of the cornea or iris is most severe in the conjunctiva of the eye. Eye irritation, such as conjunctivitis and keratitis, can cause congestion. Dry eye syndrome can lead to congestion if tears do not protect the eyes sufficiently.

The term " cornea " is a transparent film of the surface of the eyeball in the middle of the eye, meaning a structure that protects the eye from the outside and allows light to pass through and refract. In the present invention, the term " keratitis " refers to a disease caused by inflammation of the cornea, resulting in pain, decreased visual acuity, and corneal opacity. Typical symptoms include eye irritation.

For example, the keratitis may be non-infectious keratitis. For example, it can mean exposed keratitis caused by continuous exposure to the outside air, toxic keratitis due to drugs, neurotrophic keratitis due to corneal damage, contact lens damage, trauma, or allergic keratitis. Noninfectious keratitis is difficult to treat as a treatment for common infectious keratitis.

In another example, the keratitis may be infectious keratitis caused by bacteria, viruses, fungi (fungi), and the like.

The term " prophylactic " in the present invention refers to a composition comprising (7S, 8R) -dihydrodihydrodiciconyl peryl alcohol-9-? -D-glucopyranoside or a pharmaceutically acceptable salt thereof according to the present invention Refers to any act that inhibits or delays the symptoms of inflammatory eye diseases, in particular, dry eye syndrome, conjunctivitis, hyperemia or keratitis.

In the present invention, the term " treatment " refers to a composition comprising (7S, 8R) -dihydro dihydrodiciconyl peryl alcohol-9 -? - D-glucopyranoside or a pharmaceutically acceptable salt thereof according to the present invention May be used to mean all the actions of improving or alleviating the symptoms of the inflammatory eye disease.

As used herein, the term " improvement " may mean any action that at least reduces the degree of symptom associated with the condition being treated.

In the present invention, the composition may inhibit inflammation-induced cytokines. Inflammatory ocular diseases include inflammation-inducing cytokines such as TNF-a, IL-1 [beta] and IL-6, and the composition of the present invention may suppress the expression amount thereof.

In one embodiment of the present invention, the cell viability of the human conjunctival epithelial cells and the human corneal epithelial cells of the compound represented by the formula (1) was observed to show a significant cell survival rate at a concentration of 25 μM or less And Fig. 4).

In another embodiment of the present invention, the effect of inhibiting the expression level of the inflammatory cytokine protein of the compound on human conjunctival epithelial cells and human corneal epithelial cells was confirmed. As a result, in the dry eye syndrome induced by osmotic stress, the compound improves the inflammation by decreasing the expression amount of TNF-α, IL-1β and IL-6, and thus is useful for the amelioration or treatment of dry eye syndrome, conjunctivitis, (Fig. 2 and Fig. 5).

The pharmaceutical composition of the present invention may contain 0.000001 to 80% by weight of the above compound, specifically 0.00001% to 40% by weight, based on the weight of the total composition, but is not limited thereto.

In the present invention, the term " pharmaceutical composition " means a preparation intended for the prevention or treatment of disease, and may be formulated into various forms according to ordinary methods. For example, it can be formulated into oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions and syrups, and can be formulated in the form of external preparations and sterilized injection solutions. For example, the pharmaceutical composition may be an external preparation for eyeball, and may be specifically formulated into any one selected from the group consisting of ophthalmic solution, eye drops, and spray, but the formulation used for ocular administration in the art .

In the present invention, a composition comprising (7S, 8R) -dihydro dihydrodiciconyl peryl alcohol-9- [beta] -D-glucopyranoside may further comprise a pharmaceutically acceptable carrier, excipient or diluent .

The term " pharmaceutically acceptable carrier " may mean a carrier or diluent that does not disturb the biological activity and properties of the compound being injected, without irritating the organism. The type of the carrier that can be used in the present invention is not particularly limited, and any carrier conventionally used in the art and pharmaceutically acceptable may be used. Non-limiting examples of the carrier include saline, sterilized water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and the like. These may be used alone or in combination of two or more. The carrier may comprise a non-naturally occuring carrier. In addition, if necessary, other conventional additives such as an antioxidant, a buffer and / or a bacteriostatic agent can be added and used. A diluent, a dispersant, a surfactant, a binder, a lubricant, Pills, capsules, granules or tablets, and the like.

In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate ( calcium carbonate, sucrose or lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use may include various excipients such as wetting agents, sweetening agents, fragrances, preservatives, etc. in addition to water and liquid paraffin, which are simple diluents commonly used in suspension, liquid solutions, emulsions and syrups have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

In addition, the pharmaceutical composition of the present invention comprises a pharmaceutically effective amount of (7S, 8R) -dihydrodihydrodiciconyl peryl-9- [beta] -D-glucopyranoside or a pharmaceutically acceptable salt thereof . The term, " pharmaceutically effective amount " means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and is generally in the range of 0.001 to 1000 mg / kg, mg / kg, more specifically 0.1 to 100 mg / kg, may be administered once a day to several times a day. For purposes of the present invention, however, the specific therapeutically effective amount for a particular patient will depend upon the nature and extent of the reaction to be achieved, the particular composition, including whether or not other agents are used, the age, weight, Sex and diet of the patient, the time of administration, the route of administration and the rate of administration of the composition, the duration of the treatment, the drugs used or concurrently used with the specific composition, and similar factors well known in the medical arts.

The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with conventional therapeutic agents. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer an amount that can achieve the maximum effect in a minimal amount without causing side effects, and can be readily determined by those skilled in the art.

As used herein, the term " administering " means introducing the pharmaceutical composition of the present invention to a patient by any suitable method, and the (7S, 8R) -dihydro dihydrodiciconyl peryl alcohol- Since the composition comprising β-D-glucopyranoside or a pharmaceutically acceptable salt thereof is effective for preventing or treating dry eye syndrome, conjunctivitis, red blood cell or keratitis, the administration route of the composition can be administered through the eye have.

Another aspect of the present invention is a pharmaceutical composition comprising (7S, 8R) -dihydrodihydrodiconiferyl alcohol-9- [beta] -D-glucopyranoside represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Which comprises administering to a mammal in need thereof an effective amount of the composition.

The term " (7S, 8R) -dihydrodihydrodiconiperyl alcohol-9- [beta] -D-glucopyranoside ", " inflammatory eye disease ", " prevention & same.

The term " quasi-drug product " in the present invention means products which are less active than drugs, for example, for the purpose of diagnosing, treating, improving, alleviating, treating or preventing a disease in a human or an animal. For example, Quasi-drugs are products that are not used for medicines, such as fibers and rubber products used for the treatment and prevention of diseases of humans and animals, and are not acting directly or indirectly on the human body, These include sterilization and insecticides to prevent infectious diseases. The kind or formulation of the quasi-drug composition of the present invention is not particularly limited, but it may be an eye-cleansing agent or an eye drop.

Another aspect of the present invention is a pharmaceutical composition comprising (7S, 8R) -dihydrodihydrodiconiperyl alcohol-9- [beta] -D-glucopyranoside represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient Comprising administering to the individual's eye an effective amount of the composition.

The term " (7S, 8R) -dihydrodihydrodiconiperyl alcohol-9- [beta] -D-glucopyranoside ", " inflammatory eye disease ", " prevention & same.

The term " individual " as used herein may refer to any animal including, but not limited to, a human suffering from, or susceptible to, inflammatory eye disease, in particular dry eye syndrome, conjunctivitis, congestion or keratitis. The animal may be, but is not limited to, a mammal such as a cow, a horse, a sheep, a pig, a goat, a camel, a nutrient, a dog, a cat,

The composition may be administered in single or multiple doses in a pharmaceutically effective amount.

The route of administration of the pharmaceutical composition for preventing or treating inflammatory eye disease of the present invention can be administered through any ordinary route so long as it can reach the target tissue. The pharmaceutical composition of the present invention may be administered orally, intraperitoneally, intramuscularly, subcutaneously, intradermally, transdermal patch, oral, intranasal, intrapulmonary, Intramuscular administration, rectal administration, etc., and can be administered through the route of topical administration, specifically.

Another aspect of the present invention is a method for producing (7S, 8R) -dihydrodihydrodiconiferyl alcohol-9- [beta] -D-glucopyranoside represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient And a food composition for preventing or ameliorating an inflammatory eye disease.

At this time, the "(7S, 8R) -dihydro dihydrodiconiperyl alcohol-9-? -D-glucopyranoside", "inflammatory eye disease" and "improvement" are the same as described above.

Foods include dairy products including meats, sausages, breads, chocolates, candies, snacks, confectionery, pizza, ramen noodles, other noodles, gums and ice cream, soups, beverages, tea, drinks, alcoholic beverages, And health food, all of which include foods in a conventional sense.

Since the food composition of the present invention can be routinely ingested, it can be expected to be highly effective for improving dry eye syndrome, conjunctivitis, congestion and keratitis, and thus can be very useful for health promotion purposes.

The above-mentioned functional foods are the same terms as food for special health use (FoSHU). In addition to the nutritional supply, functional food is a medicine which is processed so that the biological control function appears efficiently, . Here, 'function (surname)' refers to the structure and function of the human body to obtain a beneficial effect for health use such as controlling nutrients or physiological action. The food of the present invention can be prepared by a method commonly used in the art and can be prepared by adding raw materials and ingredients which are conventionally added in the art. In addition, the above-mentioned food formulations can be manufactured without limitations as long as they are formulations recognized as food. The composition for food of the present invention can be manufactured in various formulations, and unlike ordinary drugs, it has advantages of being free from side effects that may occur when a natural product is used as a raw material for a long period of time, and is excellent in portability. The food of the invention can be ingested as an adjuvant to improve the dry eye syndrome.

The health food refers to a food having an active health promotion or promotion effect compared with a general food, and a health supplement food refers to a food for health assistance. In some cases, the terms health functional foods, health foods, and health supplements are used.

Specifically, the food composition is a food prepared by adding the compound of the present invention to a food material such as a beverage, a tea, a spice, a gum, a confectionery, or the like, or encapsulating, pulverizing or suspending it. However, unlike general medicine, there is an advantage that there is no side effect that may occur when a food is used as a raw material for a long period of taking the medicine.

The food composition may further comprise a pharmaceutically acceptable carrier. The carrier is not particularly limited and any carrier conventionally used in the art may be used.

In addition, the health functional food may contain additional components which are commonly used in food compositions and can improve odor, taste, visual appearance and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid and the like. Minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu) and chromium (Cr); And amino acids such as lysine, tryptophan, cysteine, valine, and the like.

In addition, the food composition may contain at least one kind selected from the group consisting of preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate), disinfectants (such as bleaching powder and highly bleached white powder, sodium hypochlorite), antioxidants (butylhydroxyanisole (BHA) (Sodium nitrite), bleach (sodium sulfite), seasoning (sodium MSG glutamate, etc.), sweeteners (dicin, cyclamate, saccharin, etc.), coloring agents , Sodium, etc.), perfume (vanillin, lactones, etc.), swelling agents (alum, potassium hydrogen D-tartrate), emulsifiers, thickeners (foams), encapsulating agents, gum bases, foam inhibitors, solvents, And may include food additives. The additives may be selected and used in appropriate amounts depending on the type of food.

As an example of the food composition of the present invention, it can be used as a health beverage composition. In this case, various flavors or natural carbohydrates can be added as an additional ingredient like ordinary beverages. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose; Polysaccharides such as dextrin, cyclodextrin; Xylitol, sorbitol, erythritol, and the like. Sweeteners include natural sweeteners such as tau Martin and stevia extract; Synthetic sweetening agents such as saccharin and aspartame, and the like can be used. The ratio of the natural carbohydrate may be generally about 0.0001 to 0.4 g, specifically about 0.0002 to 0.3 g per 100 mL of the health beverage composition of the present invention.

In addition to the above, the health beverage composition may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acid, protective colloid thickener, pH adjuster, stabilizer, Alcohols or carbonating agents, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks, or vegetable drinks. These components may be used independently or in combination. Although the ratio of these additives is not critical, it is generally selected in the range of 0.0001 to 0.10 parts by weight per 100 parts by weight of the health beverage composition of the present invention.

Another aspect of the present invention is a pharmaceutical composition comprising (7S, 8R) -dihydrodihydrodiconiferyl alcohol-9- [beta] -D-glucopyranoside represented by the above formula (1) or a cosmetically acceptable salt thereof as an active ingredient The present invention provides an eye cosmetic additive composition for prevention or amelioration of an inflammatory eye disease. The additive may be included in eye make-up products and may be effective in preventing or improving the disease.

The term " (7S, 8R) -dihydrodihydrodiconiperyl alcohol-9- [beta] -D-glucopyranoside ", " inflammatory eye disease ", " prevention ", and " improvement " same.

The cosmetically acceptable carrier may further contain at least one kind of cosmetically acceptable carrier. Examples of the cosmetically acceptable carrier include ordinary ingredients such as oil, water, a surfactant, a moisturizer, a lower alcohol, a thickener, a chelating agent, , Fragrance and the like can be appropriately mixed, but the present invention is not limited thereto.

The cosmetically acceptable carrier included in the eye cosmetic additive composition of the present invention varies depending on the formulations.

When the formulation of the present invention is an ointment, a paste, a cream or a gel, the carrier component may be an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide Mixtures of these may be used.

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder or a mixture thereof may be used as the carrier component, Propellants such as fluorohydrocarbons, propane / butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, 1,3-butyl glycol oil may be used, in particular fatty acid esters of cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol aliphatic esters, polyethylene glycols or sorbitan may be used have.

When the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Crystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is a soap, an alkali metal salt of a fatty acid, a fatty acid hemiester salt, a fatty acid protein hydrolizate, isethionate, a lanolin derivative, an aliphatic alcohol, a vegetable oil, glycerol, .

In the present invention, the composition may include eye make-up products, and the eye make-up cosmetic product may be one selected from the group consisting of an eye pencil, an eyeliner, eye shadow, a mascara, and an eye makeup remover have.

The pharmaceutical composition comprising the (7S, 8R) -dihydro dihydrodicodiphenyl alcohol-9- [beta] -D-glucopyranoside of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is useful as an anti- Specifically, it is effective for preventing, ameliorating or treating dry eye syndrome, conjunctivitis, congestion or keratitis.

1 is a graph showing the cell survival rate of human conjunctival epithelial cells according to the concentration of (7S, 8R) -dihydro dihydrodiciconyl peroxide-9- [beta] -D-glucopyranoside according to an embodiment of the present invention (** p <0.01, *** p <0.001 vs. control).
2 is a graph showing the inhibitory effect of (7S, 8R) -dihydro dihydrodiciconyl peroxide-9- [beta] -D-glucopyranoside on the expression of inflammatory cytokines in conjunctival epithelial cells according to an embodiment of the present invention (P <0.01, *** p <0.001 vs. control, p <0.05, p <0.01, p <0.001 vs p <0.01) HOS).
FIG. 3 is a graph showing the relationship between TNF-.alpha. Proteins (a) and (TNF-.alpha.) In the conjunctival epithelial cells of (7S, 8R) -dihydrodihydrodiconiperyl alcohol-9-.beta.-D-glucopyranoside according to an embodiment of the present invention. As an image showing the inhibitory effect of IL-1? Protein (b) and IL-6 protein (c) expression, the expression pattern of the protein was confirmed using fluorescent pigments DAPI and FITC.
4 is a graph showing the cell survival rate of corneal epithelial cells according to the concentration of (7S, 8R) -dihydro dihydrodiciconyl peroxide-9-? -D-glucopyranoside according to an embodiment of the present invention (** p < 0.01, *** p < 0.001 vs. control).
FIG. 5 is a graph showing the inhibitory effect of (7S, 8R) -dihydrodihydrodiconiferyl alcohol-9-? -D-glucopyranoside on the expression of inflammatory cytokines in corneal epithelial cells according to an embodiment of the present invention (HOS: osmotic stress, CsA and FML: positive control; *** p <0.001 vs. control, ## p <0.01, ### p <0.001 vs. HOS).
FIG. 6 is a graph showing the expression of TNF-.alpha. Protein (a) in corneal epithelial cells of (7S, 8R) -dihydrodihydrodiconiperyl alcohol-9-? -D-glucopyranoside according to an embodiment of the present invention, As an image showing the inhibitory effect of IL-1? Protein (b) and IL-6 protein (c) expression, the expression pattern of the protein was confirmed using fluorescent pigments DAPI and FITC.

Hereinafter, the constitution and effects of the present invention will be described in more detail through production examples and examples. These production examples and examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Reference Example  One: ( 7S, 8R ) - Dihydrodi &lt; / RTI &gt; di-coniferyl Alcohol -9- [beta] -D- Glucopyranoside  Material Information

[Chemical Formula 1]

Material name: (7S, 8R) -dihydrodehydrodiconiferylalcohol-9-β-D-glucopyranoside

Molecular formula: C ₂₆ H ₃₄ O ₁₁

Molecular weight: 522.21

Example  One: ( 7S, 8R ) - Dihydrodi &lt; / RTI &gt; di-coniferyl Alcohol -9- [beta] -D- Glucopyranoside  Cytotoxicity Assessment

In order to evaluate the toxicity of (7S, 8R) -dihydro dihydrodiconiperyl alcohol-9- [beta] -D-glucopyranoside to cells, the compounds were treated with human conjunctival epithelial cells and corneal epithelial cells, respectively , And the viability of the cells was observed.

First, the cells were stabilized by growing them in a growth medium, and then the cells were treated with 0.5, 1, 5, 10 and 25 μM of the compound for 24 hours. Then, 100 μl of MTT (3- (4,5-Dimethylthiazol-2-yl) -2,5-Diphenyltetrazolol M Bromide) at a concentration of 5 mg / ml was added and cultured for 2 hours. After removing the supernatant, DMSO dimethyl sulfoxide) to dissolve the precipitate, and the viability of the cells was measured at an absorbance of 570 nm.

As a result, as shown in FIG. 1 and FIG. 4, the compound represented by Chemical Formula 1 of the present invention did not show cytotoxicity below the concentration of 25 μM for conjunctival epithelial cells and corneal epithelial cells, respectively.

Example  2: ( 7S, 8R ) - Dihydrodi &lt; / RTI &gt; di-coniferyl Alcohol -9- [beta] -D- Glucopyranoside  Effect of inhibiting the expression of inflammatory cytokines

Example  2-1: Human In conjunctival epithelial cells  Confirming the efficacy of inhibiting the expression of inflammatory cytokines

Inflammatory ocular disease induces overexpression of inflammatory cytokines. Therefore, in order to confirm the inflammation-inhibitory effect of the compound of the present invention on human conjunctival epithelial cells in the same environment as osmotic stress-induced dry eye syndrome, representative inflammatory cytokines such as TNF-a, IL-1 beta and IL-6 Protein expression levels were analyzed.

Specifically, human conjunctival epithelial cells were stabilized by growing them in a growth medium, and DMEM / F-12 medium of 450 mOsM was added to the cells to add hyperosmolar stress (HOS) to the same environment as ocular-dryness induced by osmotic stress Human conjunctival epithelial cells were exposed. At this time, considering the cytotoxicity of the compound to the cells, the cells were treated at a concentration of 0.5, 1 and 5 μM for 24 hours, and the supernatant of the cell culture was recovered. Human IL-1β ELISA kit II (eBioscience catalog No. 88-7346), Human IL-1β ELISA kit II (eBioscience catalog No. 88-7261) and Human IL-6 ELISA kit II (eBioscience catalog No. 88-7066) Were used to measure the expression levels of TNF- ?, IL-1? And IL-6 contained in the cell culture solution.

As a result, as shown in FIG. 2, it was confirmed that when 0.5, 1 and 5 μM of the compound was treated, the expression level of TNF-α was remarkably decreased compared with the positive control CsA and FML (FIG. 2 (a) ), The expression level of IL-1β was decreased at the above concentrations similarly to the positive control CsA and FML (FIG. 2 (b)), and the expression level of IL-6 was also significantly decreased at all concentrations 2 (c)).

Example 2-2: Determination of protein expression level in conjunctival epithelial cells by immunostaining

Immunostaining was performed using TNF-α, IL-1β, and IL-6 specific antibodies to confirm the expression pattern of TNF-α, IL-1β and IL-6, which are inflammatory cytokines.

Specifically, the conjunctival epithelial cells were treated with HOS and the compounds were treated at a concentration of 1, 5, 25 uM and cultured for 24 hours. Thereafter, the cells were reacted with TNF-α, IL-1β and IL-6 specific antibodies (green), and the expression of TNF-α, IL-1β and IL-6 in the cells was confirmed by fluorescence microscopy .

As a result, as shown in FIGS. 3A to 3C, when the compounds were treated, the expression levels of TNF-α, IL-1β and IL-6 increased by HOS were decreased in a concentration-dependent manner. The effect of these compounds is similar or superior to the known anti-inflammatory agents cyclosporine A (CsA) and unpreserved fluorometholone (FML), as well as a similar level to that of the control without HOS treatment The amount of the protein expressed was reduced.

Example  2-3: Effect of inhibiting the expression of inflammatory cytokines in human corneal epithelial cells

In order to confirm the anti-inflammatory effect of the compound on human corneal epithelial cells in the same environment as dry eye syndrome induced by osmotic stress in the same manner as in Example 2-1, the compound was treated at a concentration of 1 and 5 μM TNF-α, IL-1β and IL-6.

As a result, as shown in Fig. 5, the expression levels of TNF-a and IL-6 decreased in a concentration-dependent manner (Figs. 5A and 5C), and the expression level of IL- (Fig. 5 (b)).

Example 2-4: Determination of Protein Expression Levels in Corneal Epithelial Cells by Immunostaining

In order to examine the expression pattern of TNF-α, IL-1β, and IL-6, which are inflammatory cytokines, in the same environment as ocular dryness induced by osmotic stress in the same manner as in Example 2-3, TNF- α, IL-1β and IL-6 specific antibodies were used for immunostaining.

As a result, as shown in FIGS. 6A to 6C, when the compound was treated, the expression levels of TNF-α, IL-1β and IL-6 increased by HOS were decreased in a concentration-dependent manner. The effect of these compounds is similar or superior to the known anti-inflammatory agents cyclosporine A (CsA) and unpreserved fluorometholone (FML), as well as a similar level to that of the control without HOS treatment The amount of the protein expressed was reduced.

The results of Example 2 demonstrate that the (7S, 8R) -dihydrodihydrodiconiperyl alcohol-9- [beta] -D-glucopyranoside of the present invention is a human conjunctival epithelial cell And IL-6 protein expression in corneal epithelial cells, thereby improving the inflammation, and thus it can be used effectively in the improvement and treatment of dry eye syndrome, conjunctivitis, red blood cell, or keratitis.

From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.

Claims (13)

1. A pharmaceutical composition for the prophylaxis or treatment of inflammatory ocular diseases comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]

The pharmaceutical composition according to claim 1, wherein the inflammatory eye disease is dry eye syndrome, conjunctivitis, red blood cell or keratitis.
The pharmaceutical composition according to claim 1, wherein the composition inhibits the expression of an inflammation-inducing cytokine in human conjunctival epithelial cells and human corneal epithelial cells.
3. The pharmaceutical composition according to claim 2, wherein the conjunctivitis and keratitis are infectious or non-infectious.
2. The pharmaceutical composition according to claim 1, wherein the composition is an ocular external preparation.
The pharmaceutical composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent.
A quasi-drug composition for the prophylaxis or treatment of inflammatory eye disease, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

7. A method for the prophylaxis or treatment of inflammatory eye disease, comprising administering the composition of any one of claims 1 to 6 to the eye of a subject other than a human.
A food composition for preventing or ameliorating an inflammatory eye disease, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]

10. The food composition according to claim 9, wherein the inflammatory eye disease is dry eye syndrome, conjunctivitis, red blood cell or keratitis.
Claims 1. An eye cosmetic additive composition for preventing or ameliorating an inflammatory eye disease, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]

12. The composition according to claim 11, wherein the inflammatory eye disease is dry eye syndrome, conjunctivitis, red blood cell or keratitis.
13. The eye-care cosmetic additive composition according to claim 11 or 12, wherein the composition has a formulation of an eye cosmetic product selected from the group consisting of an eye pencil, an eyeliner, an eye shadow, a mascara, and an eye make-up remover.

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