KR102070850B1 - Composition for treatment and prevention of dry eye syndrome comprising mixed extract or fraction thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating dry eye syndrome comprising a mixed extract or a fraction thereof of peony and licorice as an active ingredient, and a health functional food for preventing or improving dry eye syndrome comprising a mixed extract or a fraction thereof as an active ingredient. . The mixed extract of peony and licorice and fractions thereof of the present invention can significantly inhibit the decrease of tear secretion and the change of corneal morphology due to dry eye syndrome, and thus the pharmaceutical composition, health functional food and treatment for the prevention or treatment of dry eye syndrome. It may be provided as an active ingredient of the method.

Description

Composition for treatment and prevention of dry eye syndrome comprising mixed extract or fraction

The present invention relates to a pharmaceutical composition for preventing or treating dry eye syndrome comprising a mixed extract or a fraction thereof of peony and licorice as an active ingredient, and a health functional food for preventing or improving dry eye syndrome comprising a mixed extract or a fraction thereof as an active ingredient. .

Dry eye syndrome is not simply a lack of tears, but also causes eye discomfort, eye strain, decreased vision, and tear instability due to tears and inflammation of the ocular surface (cornea and conjunctiva). Risk of developing pain, irregular corneal surfaces, blurred vision and increased corneal ulcers. However, the pathogenesis has not yet been fully understood, but studies have shown that inflammation plays an important role, such as invasion of inflammatory cells, increased immune activating molecules and adhesion molecules, Th1 and Th17 responses, abnormal changes in apoptosis markers and chemokines, and so on. have.

In general, it is recommended to eat foods rich in potassium and anthocyanin for the treatment of dry eye. In addition, it is strongly recommended to eat fruits such as kale, kiwi, and apples. Some modalities may be used.

According to the Global Data Report, the global dry eye market is expected to grow at an average annual rate of 12.8% from US $ 1.6 billion in 2012 to US $ 5.5 billion in 2011. According to the Korea Health Insurance Review & Assessment Service, the total medical expenses used to treat dry eye syndrome increased by 8.6% per year, up to KRW 51.5 billion in 2009 and KRW 72.7 billion in 2013, more than KRW 20 billion in five years (EToday, 2016. 06.27) .

However, dry eye syndrome is a common disease that occurs in about 20% of Korean adults. In particular, dry eye syndrome continues to increase due to rising temperatures due to global climate change, especially Elino, and environmental pollution such as fine dust. There is no therapeutic or functional food.

Currently, a large amount of functional foods related to dry eye and eye fatigue are imported from abroad. The development of excellent functional foods in Korea prevents eye fatigue and dry eye syndrome, which can prevent not only the health of the people but also the enormous national financial loss.

Peeonia lactiflora) and is native to Siberia and part of South Korea and one in China with a herbaceous perennial belonging to the peony (Paeoniaceae), Chinese medicine Alimentarius has the Paeonia Paeonia japonica and jeokjakyak lactiflora It is defined as the root of a Pallas or other cognate plant. The pharmacological activity of peony has been reported to inhibit platelet aggregation, circulatory system, anti-tumor effect and immune enhancing effect (Dong, Dong-Ju, Korean Journal of Food and Nutrition, 2002, 31, 511; 4, 445).

Licorice ( Glycyrrhiza uralensis ) is a perennial herbaceous plant belonging to the legume and can be used as a medicine for drying roots. The pharmacologic activity of licorice has been shown to improve chronic hepatitis, antidiabetic (Mae, Tatsumasa, et al., The Journal of nutrition 133.11 (2003): 3369-3377.), Anti-ulcer effect (Hong, Jae Seung, et al. ., Korean Journal of Plant Resources 27.5 (2014): 401-414.), Inhibitory Effect of Ulcerative Colitis (Lee, Keyong-Ho, and Ki-Hyeong Rhee., The Korean Journal of Food and Nutrition 23.4 (2010): 435 -439.), Antioxidant effects (Woo, Koan-Sik, et al., Journal of the Korean Society of Food Science and Nutrition 36.6 (2007): 689-695.).

The present inventors have confirmed that the mixed extract of peony and licorice or fractions thereof can cure dry eye syndrome by increasing tear secretion and suppressing corneal morphology, thereby completing the present invention.

One object of the present invention is to provide a pharmaceutical composition for preventing or treating dry eye syndrome comprising a mixed extract of peony and licorice or fractions thereof as an active ingredient.

Another object of the present invention is to provide a health functional food for preventing or improving dry eye syndrome comprising a mixed extract of peony and licorice or fractions thereof as an active ingredient.

Still another object of the present invention is to provide a method for preventing or treating dry eye syndrome, comprising administering a mixed extract of peony and licorice or a fraction thereof to an individual except a human.

The inventors of the present invention, while developing various therapeutic agents that can effectively treat dry eye syndrome, found that a mixed extract of peony and licorice or a fraction thereof exhibited the effect of treating dry eye syndrome. The mixed extract or fraction of the peony and licorice not only significantly suppresses the decrease in tear secretion and corneal morphology caused by dry eye, but also shows similar effects to commercially available drugs used for the treatment of dry eye. there was. Techniques for treating dry eye syndrome using the above mixed extracts or fractions are not known at all, and were first developed by the present inventors.

As one embodiment for achieving the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of dry eye syndrome comprising a mixed extract of peony and licorice or fractions thereof as an active ingredient.

The mixed extract of peony and licorice having prophylactic and therapeutic activity for dry eye can be extracted from various organs of natural, hybrid, and mutant plants, for example roots, stems, leaves, flowers, trunks of fruits, bark of fruit. As well as extractable from plant tissue culture.

The terms used in the present invention "Peony (Paeonia lactiflora ) is a perennial herb belonging to the Paeoniaceae family, which is native to parts of China, Siberia and Korea. Chinese Medicine Standards Paeonia Peony It is defined as the root of lactiflora or other homologous plants. Peeled and dried are called peony, and dried together with the peel are called peony. The pharmacological activity of peony is reported to inhibit platelet aggregation, action on the circulatory system, antitumor action, and immune enhancing action.

The term “ Glycyrrhiza ” used in the present invention uralensis ) ”is a perennial herbaceous plant belonging to the legume, which can be dried and used as a medicine or sweetener. The pharmacological activity of licorice has been reported to improve chronic hepatitis, antidiabetic, antiulcer effect, ulcerative colitis inhibitory effect, and antioxidant effect by detoxification.

In the present invention, the mixed extract may be extracted from the root, stem, leaf, flower, or fruit of the peony and licorice, but is not particularly limited thereto.

In the present invention, the mixed extract of the peony and licorice include, but not limited to, extracted with a solvent selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms, and mixed solvents thereof. In the present invention, the extract may include an extract obtained by an extraction treatment, a diluent or concentrate of the extract, a dried product obtained by drying the extract, or any one of these modifiers or purified products.

The alcohol may be butyl alcohol, ethyl alcohol, methyl alcohol or a water soluble alcohol thereof. Specifically, the water-soluble alcohol may be one that contains alcohol in the range of 0.1 to 100% by weight.

As used herein, the term "fraction" refers to the result obtained by performing fractionation to separate a specific component or a specific group of components from a mixture comprising several different components.

The fractionation method of obtaining the fraction in the present invention is not particularly limited, and may be performed according to a method commonly used in the art. Non-limiting examples of the fractionation method is a method of obtaining a fraction from the extract by treating a predetermined solvent with an extract obtained by extracting a mixed extract of peony and licorice.

In the present invention, the fraction may be a hexane fraction, ethyl acetate fraction, butanol fraction or water fraction of the mixed extract of peony and licorice. The fractions may each comprise 0.01 to 100% by weight, more specifically 1 to 80% by weight relative to the total weight of the pharmaceutical composition.

The kind of the fractionation solvent used to obtain the fraction in the present invention is not particularly limited, and any solvent known in the art may be used. Non-limiting examples of the fractionation solvents include polar solvents such as water and alcohols; And nonpolar solvents such as hexane, ethyl acetate, chloroform, dichloromethane, and the like. These may be used alone or in combination of two or more thereof. In the case of using alcohol in the fractionation solvent, specifically, alcohols of C1 to C4 may be used.

As used herein, the term " dry eye syndrome " refers to a condition in which dry eye syndrome is inhibited by inflammation of the tear glands and denervation of the cornea, or meibomian gland dysfunction or eyelid dysfunction. It may be a disease caused by abnormal tear evaporation, etc., and may be a corneal conjunctival epithelial disorder represented by scarring of the cornea due to excessive drying of the tear due to dry eye.

As used herein, the term "prevention" refers to any action that inhibits or delays the symptoms of dry eye with the administration of a composition comprising a mixed extract of peony and licorice or fractions thereof according to the present invention.

As used herein, the term "treatment" refers to any action in which the symptoms of dry eye symptoms are improved or beneficially modified by administration of a composition comprising a mixed extract of peony and licorice according to the present invention or a fraction thereof.

In the present invention, the composition may be to increase the amount of tear secretion or to suppress the morphological changes of the cornea. The change in the shape of the cornea is due to the over-drying of the tear, the surface of the cornea is uneven, showing a rounded curved and crushed form, the composition of the present invention may be to improve it smoothly and flat.

In one embodiment of the present invention by administering the mixed extract of peony and licorice, it was confirmed that the tear secretion significantly increased in all concentration groups, the effect was increased depending on the concentration (Fig. 1 and 2). ).

In another embodiment of the present invention by administering a mixed extract of peony and licorice, it was confirmed that the high concentration (100mg / kg and 250mg / kg) significantly inhibits the changes in the corneal morphology in the dry eye disease group ( 3 and 4).

Therefore, it can be seen from the above results that the mixed extract of peony and licorice have a therapeutic effect on dry eye.

As used herein, the term "pharmaceutical composition" means that is prepared for the purpose of preventing or treating a disease, and can be used by formulating in various forms according to each conventional method. For example, it may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, and the like, and may be used in the form of external preparations, suppositories, and sterile injectable solutions. In particular, it may be used in a form suitable for topical administration, for example, eye drops, creams, ointments, gels or lotions.

The composition of the present invention may be prepared in the form of a pharmaceutical composition for preventing or treating dry eye syndrome further comprising a suitable carrier, excipient or diluent commonly used in the manufacture of a pharmaceutical composition, the carrier is an unnatural carrier (non-naturally occuring carrier).

In the present invention, carriers, excipients and diluents that can be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations include at least one excipient such as starch, calcium carbonate, and the like in the above extracts and fractions thereof. , Sucrose or lactose, gelatin and the like are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used. Liquid preparations for oral use may include various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used to include suspensions, solvents, emulsions, and syrups. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

The dosage of the pharmaceutical composition of the present invention can be determined by those skilled in the art in consideration of the purpose of use, the degree of addiction of the disease, the age, weight, sex, history, or type of substance used as an active ingredient of the patient. For example, the pharmaceutical composition of the present invention may be administered at about 0.1 ng to about 1,000 mg / kg, specifically, 1 ng to about 1,000 mg / kg per adult, and the frequency of administration of the composition of the present invention is particularly limited thereto. However, it may be administered once a day or several times in divided doses. The dosage does not limit the scope of the invention in any aspect.

In another aspect, the present invention provides a method for treating dry eye syndrome comprising administering the pharmaceutical composition in a pharmaceutically effective amount to a subject other than a human suffering from dry eye syndrome.

As used herein, the term "individual" may include, without limitation, mammals, including rats, livestock, and the like having dry eye.

More specifically, the "individual" may include a companion animal. The companion animal refers to an animal that lives together with a human, and includes, but is not limited to, mammals such as dogs, cats, hamsters, guinea pigs, birds such as parrots, canaries, and the like.

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 dry eye syndrome of the present invention may be administered through any general route as long as the target tissue can be reached.

The pharmaceutical composition of the present invention is not particularly limited, but as desired, instillation, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, transdermal patch administration, oral administration, intranasal administration, intrapulmonary administration, It may be administered through a route such as rectal administration, and specifically, may be administered through a route of oral administration.

As another aspect, the present invention provides a health functional food for preventing or improving dry eye syndrome comprising a mixed extract of peony and licorice or fractions thereof as an active ingredient.

Peony, licorice, fractions, dry eye in the health functional food of the present invention is as defined above.

As used herein, the term "improvement" refers to all the actions that improve or beneficially dry dry eye by oral administration of the composition.

As used herein, the term "functional" means to obtain a useful effect on health use, such as nutrient regulation or physiological action on the structure and function of the human body.

The health functional food of the present invention can be prepared by a method commonly used in the art, and the preparation can be prepared by adding raw materials and ingredients commonly added in the art. In addition, the formulation of the health functional food can also be prepared without limitation as long as the formulation is recognized as a health functional food. The health functional food of the present invention can be prepared in various forms of dosage forms, unlike the general medicine has the advantage of having no side effects, etc. that can occur when taking a long-term use of the drug as a raw material and excellent portability, the present invention Dietary supplements can be taken as a supplement to enhance the effect of preventing or improving dry eye syndrome.

Specifically, the health functional food is a food prepared by adding the mixed extract or fraction of the present invention to food materials, such as beverages, teas, spices, gums, confections, or the like, encapsulated, powdered, suspensions, etc. Means bringing a specific effect on health, but unlike general medicine has the advantage that there is no side effect that can occur when taking long-term use of the drug as a raw material.

Therefore, the results of the above extracts and extracts of peony and licorice or fractions thereof, it can be seen that it can be usefully used as a health functional food for preventing or improving dry eye or eye fatigue.

The mixed extract of the peony and licorice of the present invention and its fractions can significantly inhibit the decrease in tear secretion and corneal morphology due to dry eye syndrome, and thus can be widely used in the development of pharmaceutical compositions for the prevention or treatment of dry eye syndrome. Could be.

1 is a photograph confirming the tear secretion change according to the administration of the mixed extract through the tear test paper.
Figure 2 is a graph quantitatively showing the change in tear secretion according to administration of the mixed extract (*: p <0.05 vs. Normal; #: p <0.05 vs. dry eye).
Figure 3 is a photograph showing the corneal morphology changes of rats following administration of the mixed extract.
Figure 4 is a graph showing the corneal smoothness (corneal smoothness score) score of rats following administration of the mixed extract. The corneal smoothness score was evaluated by measuring the corneal morphology by scoring the degree of distortion in a round circle from 0 to 5 (0 points: no distortion, 1 point: crushed at 1/4 site, 2 points: 2/4 site) Distortion at, 3 points: Distortion at 3/4 area, 4 points: Distortion at all sites, 5 points: Severe distortion, round shape not recognizable; #: p <0.05 vs. dry eye).
Figure 5 is a graph quantitatively showing the change in tear secretion according to the licorice extract administration (*: p <0.05 vs. Normal).
Figure 6 is a photograph showing the corneal morphology of rats following the administration of licorice extract.
Figure 7 is a graph showing the corneal smoothness (corneal smoothness score) score of rats according to administration of the mixed extract (*: p <0.05 vs. Normal).

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Example  1. Preparation of Mixed Extract of Peony and Licorice

Peony and licorice were weighed in a ratio of 2: 1, and purified water was added thereto, and the extract obtained by reflux extraction at about 90 ° C. for 8 hours was filtered, concentrated under reduced pressure at about 50 ° C., and dried to prepare a mixed extract.

Example  2. Drug test using experimental animals

Example  2.1: Construction of Dry Eye Experiment Animals

Six-week-old female SD rats (Oriental Bio, Korea) were purchased and purified one week, followed by anesthesia with pentobarbital sodium (30 mg / kg body weight, Hallym Pharmaceutical, Korea) to remove tear glands. The hair at the center of the eye between the eye and the ear is depilated, the surgical site is disinfected, the skin is incised about 1 cm, the extraorbital lacrimal gland is removed from the incision, and the skin is sutured. Thirty seconds after contacting the phenol-red thread tear test paper (FCI Opthalmics Zone Quick, Japan) with the eye surface at the outer end of the eyelid, the color of the test paper was measured by tears. Drug testing was conducted using only these reduced agents.

Example  2.2: tear secretion

In order to confirm the effect of the mixed extract on dry eye, the change of tear secretion according to the administration of the mixed extract using the experimental animal of Example 2.1 was confirmed.

Five subjects were randomly assigned to each experimental group, and the experimental group consisted of the following groups: a non-surgical normal group (NOR) without any abnormalities, a disease causing dry eye syndrome by removing the extraocular tear gland by the method of Example 2.1. Group (DED), drug administration group (JGT-50) administered 50 mg / kg of the mixed extract (JGT) of the present invention, drug administration group (JGT-) administered 100 mg / kg of the mixed extract (JGT) of the present invention (JGT- 100), the drug administration group (JGT-250) administered 250 mg / kg of the mixed extract (JGT) of the present invention. The drug containing the mixed extract of the present invention was prepared by dissolving the dose in sterile saline containing 0.5% DMSO, and further administered for 3 days to induce dry eye at day 5 after oral administration for 4 days. The animals were anesthetized on the 7th day of total administration, and the phenol-red thread tear test paper (FCI Opthalmics Zone Quick, Japan) was contacted with the eye surface at the outer end of the eyelid, and then 30 seconds after tearing, the color of the test paper was measured. Drug efficacy evaluation was performed.

As a result, as shown in Fig. 1 and Fig. 2, it was confirmed that the dry eye disease group was short in length, whereas the normal group had a very long changed color. Compared with the dry eye disease group, the drug-administered group was significantly increased in all experimental concentrations, and the concentration-dependently increased.

Thus, through the above results, it was confirmed that the tear secretion is improved by administering a mixed extract of peony and licorice, it was found that the mixed extract has a dry eye treatment effect.

Example  2.3: measuring changes in the shape of the cornea

In order to confirm the effect of the mixed extract on dry eye, the morphological changes of the cornea according to the administration of the mixed extract using the experimental animal of Example 2.1 was confirmed.

The composition of the experimental group and the administration of drugs were performed in the same manner as in Example 2.2.

The cornea was anesthetized and photographed using a stereoscopic microsope (Olympus, Japan) with a circular fiber optic illuminator (fiberoptic ring illuminator). The morphological changes of the cornea were evaluated by scoring the distortion from 0 to 5 for the round circle shape of the circular illumination reflected by the corneal epithelial cells. 0 points: no distortion, 1 point: dent at 1/4 area, 2 points: dent at 2/4 area, 3 points: dent at 3/4 area, 4 points: dent at all parts, 5 points: severe dent Unable to recognize the shape of a round circle.

As a result of evaluating the morphological changes of the cornea, in the normal group, tears secreted from the tear glands form a tear film to maintain a smooth and flat surface state, so that the circular shape is reflected as it is, as shown in FIG. It was. However, in the dry eye disease group, corneal epithelial cell degeneration and smooth corneal surface become rugged due to abnormalities in the tear film covering the cornea, and the rounded rounded and distorted form was observed. In (JGT-100 and JGT-250) it was confirmed that significantly inhibit the corneal morphology, such as disease group (Figs. 3 and 4).

Therefore, through the above results, it was confirmed that administration of the mixed extract of peony and licorice inhibits the morphological changes of the cornea caused by dry eye syndrome, and thus the mixed extract has a dry eye treatment effect.

Comparative example 1. Licorice  Pharmacological test of extract

Comparative example  1.1 Measurement of tear secretion in licorice extract group

In order to confirm the dry eye treatment effect of licorice extract extracted using the method of Example 1 alone licorice, tear secretion amount was measured using the method of Example 2.2. The dose of licorice extract was administered 84 mg / kg, a dose of licorice based on JGT-250 (250 mg / kg administration).

As a result, as shown in Figure 5, compared with the dry eye disease group did not show a significant difference in the tear secretion of the licorice extract administration group was confirmed that the licorice extract does not increase the tear secretion.

Comparative example  1.2 Measurement of Corneal Morphology in the Licorice Extract Group

In order to confirm the dry eye treatment effect of licorice extract, corneal morphology was confirmed using the method of Example 2.3. The dose of licorice extract was administered 84 mg / kg, a dose of licorice based on JGT-250 (250 mg / kg administration).

As a result, as shown in Figure 6, it can be confirmed that the corneal morphology of the licorice extract administration group is not clear compared to the normal group, even when evaluated by the score, corneal morphology change of the licorice extract administration group compared to the dry eye disease group As the score did not show a significant decrease, it was confirmed that the licorice extract did not inhibit corneal morphological changes.

Therefore, the licorice extract alone did not affect the tear secretion through the comparative example, it did not have a corneal morphological inhibitory effect was confirmed that it is inappropriate as a composition for treating dry eye syndrome.

In the present specification, those skilled in the art of the present invention can fully recognize and infer the details that have been omitted, and in addition to the specific examples described herein, the technical spirit or essential configuration of the present invention is changed. Many more variations are possible without departing from the scope of the invention. Therefore, the present invention can be implemented in a manner different from that specifically described and illustrated herein, which can be understood by those skilled in the art.

Claims (9)

A pharmaceutical composition for preventing or treating dry eye syndrome comprising a mixture of peony and licorice as an active ingredient.
The method of claim 1,
The extract is a pharmaceutical composition that is extracted with a solvent selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms and mixed solvents thereof.
delete The method of claim 1,
The extract is a pharmaceutical composition for the prevention and treatment of dry eye syndrome, characterized in that extracted by high temperature extraction, hot water extraction, reflux extraction, hot water extraction, room temperature extraction, ultrasonic extraction or steam extraction method.
The method of claim 1,
The composition is to increase the amount of tear secretion or inhibit corneal morphological changes, or improve eye fatigue.
The method of claim 1,
The composition is a pharmaceutical composition, characterized in that to mix peony and licorice in a weight ratio of 10: 1 to 1:10.
Health functional food for preventing or improving dry eye syndrome comprising a mixture of peony and licorice as an active ingredient.
Health functional food for improving the amount of tear secretion comprising a mixed extract of peony and licorice as an active ingredient.
A method of preventing or treating dry eye syndrome comprising administering a mixture of peony and licorice to a subject other than humans.

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