WO2018117572A1 - Composition comprising sea cucumber extract as effective ingredient for preventing and treating bruch's membrane dysfunction-related disease - Google Patents

Abstract

The present invention relates to a composition comprising a sea cucumber extract as an effective ingredient for preventing and treating Bruch's membrane dysfunction-related disease and, more particularly, to a composition for preventing and treating Bruch's membrane dysfunction-related disease, the composition comprising a sea cucumber extract, which has the effect of regenerating the Bruch's membrane of eyes and improving the transport function of Bruch's membrane. A composition according to the present invention shows the effect of delaying or reversing the senescence of the eye by regenerating the Bruch's membrane of the eye and improving the transport function of Bruch's membrane and thus is very useful for preventing and treating diseases attributed to senescence-associated Bruch's membrane dysfunction, such as age-related macular degeneration (AMD), Sorsby's fundus dystrophy, Malattia Levintanese (ML), Stargardt disease, Best's vitelliform retinal dystrophy or Doyne's honeycomb retinal dystrophy (DHRD).

Description

A composition for preventing and treating diseases related to the deterioration of the function of Bruk's membrane using sea cucumber extract

The present invention relates to a composition for preventing and treating diseases related to Bruch's membrane deterioration, which comprises sea cucumber extract as an active ingredient, and more specifically, includes a sea cucumber extract having an effect of regenerating the eye's Bruch's membrane and improving transportation function. It relates to a composition for the prevention and treatment of diseases associated with decreased Bruk's membrane function.

Sea cucumber is a general name of sea cucumbers belonging to the equatorial animal sea cucumber river, and it is the best health food product called sea ginseng because it contains large amounts of medicinal ingredients such as saponin. Sea cucumber is a medicine that has been used for a long time in China and the East. It has excellent effects on diabetes, asthma, etc., and it is a medicine that can regain energy when you lose energy and collapse due to sweating due to temperature increase in summer. Known. In addition, sea cucumbers have a remarkable resilience effect that when the part of the body is cut, the cut site returns to its original state in three months, and new intestines are formed in one month even if the intestines are removed. It is known to enhance phagocytosis by enhancing phagocytic activity, thereby boosting immune function and treating wounds.

Sea cucumber is used as food for children's development, tonic food for the elderly, food for recovery from disease, food for preventing anemia of pregnant women, food for promotion of bowel movement, and it is also gaining attention as a diet food because it contains less fat and sugar. There is no research on improving eye function.

Eye cells are light-sensitive cells in the retina that transmit information to the brain during visual processes, allowing objects to be recognized. Eye cells are the most active part of our body's metabolism, and effective nutrient delivery and waste removal are essential. Due to the nature of an environment rich in essential fatty acids, light and high levels of oxygen, much of the damage is caused by free radicals. In this case, retinal pigment epithelium (RPE) can be used to continuously regenerate the outer segments of damaged cells.

Eye cells and RPE are supplied with nutrients through the choroid blood circulation. If nutrients from the blood are secreted from the capillaries of the choroid, they must first pass through the extracellular matrix Bruch's membrane before reaching the RPE and the cell. Nutrients such as small glucose, oxygen, and amino acids pass through the Bruch's membrane with simple passive diffusion, and vitamins, trace metals, and lipids bind to the carrier protein and then pass through the Bruch's membrane to the RPE. Are separated. In contrast, waste products from the cells and RPE pass through the Bruch's membrane and are removed from the choroid. Most waste products are toxic and can potentially damage the Brueck's membrane and trigger inflammatory reactions. Therefore, the efficient mass transport ability of the Bruch's membrane can be seen as a prerequisite for maintaining normal visual acuity and survival of visual cells (FIG. 1).

Aging increases the thickness of the Brueck membrane by two to three times, reducing the diffusion gradients in which nutrients and waste are exchanged, making it difficult to spread the material in the Brueck membrane. This results in deposition of lipids and proteo-lipid complexes and waste products discarded in RPE on membranes, increased cross-linking of collagen and increased amounts of denatured collagen. In addition, glycosylation increases protein and lipid glycosides (AGE; advanced protein glycation end-products, ALE; advanced lipid glycation end-products) (Handa et al. 1999), and damaged or polymerized proteins. The deposition of complexes also increases, eventually disrupting the transport capacity of the membrane (Holz et al. 1994), adversely affecting nutrient delivery and waste removal (Figure 2).

These changes due to aging are much more severe in the case of age-related macular degeneration (AMD), in which aging is a major cause of disease, and as a result, the transport capacity of the Brueck membrane is reduced. RPE and blind cells are blinded by death (Figure 3).

Clinically, the aging of the Bruk's membrane in the elderly population has been reported to reduce scotopic thresholds due to insufficient vitamin A regeneration (Steinmetz et al. 1993; Owsley et al. 2001), currently in some countries Is prescribed by adding metal and antioxidants to vitamin A. There are two problems with this method. The first is that only certain nutrients are added, so that other essential nutrients are still in scarce condition. The second is that when metal is added to the Brueck's membrane, which has reduced transport, It continues to be deposited on the membrane, and the damage is inevitably even greater. In addition, the age-related eye disease study (ARDS), a US-related macular degeneration study that has been conducted for more than 10 years, has not yet demonstrated the effectiveness of a composition consisting of vitamin and mineral additives (Kassof et al. 2001).

The ideal solution would be to facilitate the transport of the Brueck membrane, so that all the necessary nutrients in the plasma are supplied.

The inventors of the present application have made diligent efforts to develop a therapeutic method that can solve the root cause of eye deterioration due to aging, including age-related macular degeneration. The present invention was completed by confirming that the composition can be used as a composition for the prevention and treatment of diseases caused by a decrease in the function of Bruk's membrane.

Reference Literature

[1] Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkendal-Hansen B, DeCarlo A, Engler JA. (1993) Matrix metalloproteinases: a review. Crit. Rev. Oral Biol. Med. 4: 197-250.

[2] Handa JT, Verzijl N, Matsunaga H, Aotaki-Keen A, Lutty GA, te Koppele JM, Miyata T and Hjelmeland LM. Increase in the advanced glycation end-product pentosidine in Bruch's membrane with age. Invest. Ophthalmol. Vis. Sci. 1999; 40: 775-779.

[3] Holz FG, Sheraidah GS, Pauleikhoff D and Bird AC. Analysis of lipid deposits extracted from human macular and peripheral Bruch's membrane. Arch. Ophthalmol. 1994; 112: 402-406.

[4] Hussain AA, Lee Y, Zhang JJ, Marshall J. (2011) Disturbed matrix metalloproteinase activity of Bruch's membrane in age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 52: 4459-66.

[5] Hussain AA, Starita C, Hodgetts A, Marshall J. (2010) Macromolecular characteristics of ageing human Bruch's membrane: implications for age-related macular degeneration (AMD). Exp. Eye Res. 90: 703-710.

[6] Hussain AA, Lee Y, Marshall J. (2010) High molecular weight gelatinase species of human Bruch's membrane: compositional analyses and age-related changes. Invest. Ophthalmol. Vis. Sci. 51: 2363-71.

[7] Hussain AA, Starita C, and Marshall J. (2004) Chapter IV. Transport characteristics of ageing human Bruch's membrane: Implications for AMD. In: Focus on Macular Degeneration Research, (Editor O. R. Ioseliani). Pages 59-113. Nova Science Publishers, Inc. New York.

[8] Hussain AA, Rowe L, Marshall J. (2002) Age-related alterations in the diffusional transport of amino acids across the human Bruch's-choroid complex. Journal of the Optical Society of America, A, Optics, Image Science, & Vision. 19 (1): 166-72.

[9] Karwatowski WSS, Jefferies TE, Duance VC, Albon J, Bailey AJ & Easty DL. Preparation of Bruch's membrane and analysis of the age related changes in the structural collagens. (1995) Brit. J. Ophthalmol. 79: 944-952.

[10] Kassof A, Kassoff J, Buehler J, et al., A randomized, placebo-controlled, clinical trial of high dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report No. 8. Arch Ophthalmol. 2001; 119: 1417-36.

[11] Kumar A, El-Osta A, Hussain AA, Marshall J. (2010) Increased sequestration of matrix metalloproteinases in ageing human Bruch's membrane: implications for ECM turnover. Invest. Ophthalmol. Vis. Sci. 51: 2664-70.

[12] Moore DJ and Clover GM. The effect of age on the macromolecular permeability of human Bruch's membrane. Invest. Ophthalmol. Vis. Sci. 2001; 42: 2970-2975.

[13] Moore DJ, Hussain AA, Marshall J. (1995). Age-related variation in the hydraulic conductivity of Bruch's membrane. Invest. Ophthalmol. Vis. Sci. 36 (7): 1290-7.

[14] Owsley C, Jackson GR, White M, Feist R and Edwards D. Delays in rod mediated dark adaptation in early age-related maculopathy. Ophthalmol. 2001; 108: 1196-1202.

[15] Owsley C, McGwin G, Jackson GR, Heinburger DC, Piyathilake CJ, Klein R, White MF, Kallies K. Effect of short term, high-dose retinol on dark adaptation in age and age-related maculopathy. Invest. Ophthalmol. Vis. Sci. 2006. 47 (4): 1310-8.

[16] Ramratten RS, van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PGH and de Jong PTVM. Morphometric analysis of Bruch's membrane, the choriocapillaris and the choroid in ageing. Invest. Ophthalmol. Vis. Sci. 1994; 35: 2857-2864.

[17] Starita C, Hussain AA, Pagliarini S, Marshall J. (1996) Hydrodynamics of ageing Bruch's membrane: implications for macular disease. Exp. Eye Res. 62 (5): 565-72.

[18] Steinmetz RL, Haimovici R, Jubb C, Fitzke FW, Bird A. Symptomatic abnormalities of dark adaptation in patients with age-related Bruch's membrane change. Br. J. Ophthalmol. 1993; 77: 549-554.

[19] Hussain AA, Lee Y (2016) unpublished data

[20] Lee Y, Hussain AA, Seok J, Kim S, Marshall J. (2015). Modulating the Transport Characteristics of Bruch's Membrane With Steroidal Glycosides and its Relevance to Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 56 (13): 8403-18.

It is an object of the present invention to provide a pharmaceutical composition for preventing, delaying and treating a disease related to Bruch's membrane, which comprises sea cucumber extract or fraction as an active ingredient.

Still another object of the present invention is to provide a nutraceutical composition for the prevention, delay and treatment of Bruch's membrane function-related diseases, including sea cucumber extract or fraction as an active ingredient.

Still another object of the present invention is a pharmaceutical composition for preventing, delaying, and treating a disease related to Bruch's membrane deterioration, including Frondoside A, an isomer thereof, a hydrate thereof, or a salt thereof as an active ingredient. To provide.

Still another object of the present invention is to provide a functional food for preventing, delaying, and improving diseases related to Bruch's membrane deterioration, including Frondoside A, an isomer thereof, a hydrate thereof, or a salt thereof as an active ingredient. It is to provide a composition.

The present invention is to solve the above problems, and provides a pharmaceutical composition for the prevention, delay and treatment of Bruch's membrane function-related diseases, including sea cucumber extract or fraction as an active ingredient.

The term "sea cucumber" used in the present invention refers to marine invertebrates belonging to Phylum Echinodermata Class Holothuroidea, scale sea cucumber, Hwamun sea cucumber, multifoot ring sea cucumber, Orthodox sea cucumbers, Monakari sea cucumbers, Snake-eye black sea cucumbers, Sea cucumbers, etc. belonging to the Order Aspidochirotida, etc. ) May include, but is not limited to, white sea cucumbers, ginseng sea cucumbers, and the like. The sea cucumber is recommended as a health food for high blood pressure, arteriosclerosis, diabetic and obese patients, but it is recommended for the use of rejuvenation and tonics, pregnant women and women with weak physical condition. There is no bar.

The term "extract" as used in the present invention is an extract obtained by the extraction process of sea cucumber, dried product obtained by drying the sea cucumber, diluent or concentrate of the extract, dried product obtained by drying the extract, a crude agent or purified product of the extract, Or extracts of all formulations that can be formed using the extract itself and the extract, such as mixtures thereof. The extract or fraction of the present invention may preferably be used in liquid form after extraction.

In the sea cucumber extract of the present invention, the method of extracting the sea cucumber is not particularly limited, and may be extracted according to a method commonly used in the art. Non-limiting examples of the extraction method, hot water extraction method, ultrasonic extraction method, filtration method, reflux extraction method and the like, these may be carried out alone or in combination of two or more methods.

The type of extraction solvent used to extract the sea cucumber in the present invention is not particularly limited, and any solvent known in the art may be used. Non-limiting examples of the extraction solvent include water, alcohols or mixed solvents thereof, and when using alcohol as the solvent, preferably C1 to C4 alcohol, more preferably C1 to C2 lower alcohol More preferably, 80% ethanol aqueous solution may be used, but is not limited thereto. The sea cucumber extract of the present invention may preferably be water or ethanol extract.

When extracting the sea cucumber in the hot water extraction method in the present invention, it is preferable to extract once to five times, more preferably three times to extract repeatedly, but is not limited thereto. The extraction solvent may be added 0.1 to 100 times the weight of the dried sea cucumber, preferably 0.3 to 5 times. Extraction temperature is preferably 20 ℃ to 130 ℃ but is not limited thereto. In addition, the extraction time is preferably 30 minutes to 48 hours, but is not limited thereto.

In the method for preparing the sea cucumber extract of the present invention, the reduced pressure concentration is preferably a vacuum reduced pressure concentrator or a vacuum rotary evaporator, but is not limited thereto. In addition, drying is preferably, but not limited to, drying under reduced pressure, vacuum drying, boiling drying, spray drying, or freeze drying.

The method for preparing the sea cucumber dried product of the present invention may be natural drying, hot air drying, freeze drying method, etc., but is not limited to any method known in the art in order to remove the water of the sea cucumber.

In the sea cucumber extraction or drying method of the present invention, the skin and gut of the sea cucumber can be extracted or dried as a whole, and the skin and gut of the sea cucumber can be separated or dried separately, respectively, and the skin and gut extract or dried It may be used or may be mixed.

According to a specific embodiment of the present invention, the dried sea cucumber is pulverized to prepare a sea cucumber powder, 70% ethanol is added thereto as an extraction solvent, and then extracted for about 3 to 6 hours, and ethanol is removed under vacuum to extract the extract. Obtained.

The term "fraction" as used in the present invention means the result obtained by performing fractionation to separate a specific component or a specific component group from a mixture comprising various various components.

In the present invention, the fractionation method for obtaining the fraction 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 the extract obtained by extracting sea cucumber with a predetermined solvent.

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; Nonpolar solvents, such as hexane, ethyl acetate, chloroform, dichloromethane, etc. are mentioned. These may be used alone or in combination of two or more thereof. In the case of using alcohol in the fractionation solvent, alcohols of C1 to C4 may be preferably used.

The active ingredient of the present invention has an effect of preventing the onset of the disease, delaying the progress of the disease, or treating the disease related to the decrease of the Bruk's membrane function by improving the transport function of the Bruk's membrane.

The active ingredient of the present invention is transported by improving the hydraulic conductivity of the Brueck membrane, improving the diffusion function of the Brueck membrane, or by removing proteins or lipids bound or trapped in the Brueck membrane. You can improve the function.

The active ingredient of the present invention can prevent the onset of the disease, delay the progression of the disease, or treat the disease by which the Bruch membrane is reduced by improving the Brux membrane function.

The active ingredient of the present invention can regenerate the Brueck membrane and improve the Brueck membrane function by removing the high molecular weight complex (HMW) or lipid component bound or deposited on the Brueck membrane.

In addition, the active ingredient of the present invention can regenerate the Brooke membrane and improve the Brooke membrane function by secreting pro-MMP2, pro-MMP9, active MMP2 and active MMP9 from the matrix of the Brooke membrane.

In addition, the active ingredient of the present invention can regenerate the Bruch's membrane by activating the active MMP secretion from retinal epithelial cells (RPE), and improve the Bruch's membrane function.

As described above, the sea cucumber extract composition of the present invention is polymerized on the Brueck membrane to degrade the Brueck membrane and decomposes its functions, and secretes nutrients and wastes such as proteins or lipids trapped or bound in the matrix of the Brueck membrane. It helps to nourish the eyes and release waste products. It is also involved in regenerating the function of the Bruch's membrane by releasing the MMP of the Bruch's membrane and restoring the function of the enzyme. Regeneration is effective in preventing, delaying and treating the loss of retinal function due to aging.

As used herein, the term "prevention" or "delay" refers to any action that inhibits or delays the onset of a disease resulting from a decreased function of the Bruch's membrane by administering the composition of the invention to a subject.

As used herein, the term "treatment" refers to any action by which the composition of the present invention is administered to a subject so that the symptoms of a disease resulting from a decreased function of the Bruch's membrane improve or benefit.

As used herein, the term " improvement " means any action that at least reduces the parameters associated with the condition being treated, such as the extent of symptoms.

In the pharmaceutical composition of the present invention, the sea cucumber extract or fractions thereof may be contained in an amount of preferably 0.1 wt% to 99.99 wt%, more preferably 10 wt%, based on the total weight of the pharmaceutical composition. It may be contained in% to 99.99% by weight, more preferably from 50% to 99.99% by weight. Within this range, the effect of improving the transport function of the Brux membrane according to the sea cucumber extract or fractions thereof, the recovery of the Brux membrane, and the Brux membrane function is sufficiently exerted, which has the advantage of being more suitable for achieving the object of the present invention.

The pharmaceutical composition of the present invention, in addition to containing the sea cucumber extract or a fraction thereof as an active ingredient, may further comprise a pharmaceutically acceptable carrier.

In the present invention, the "pharmaceutically acceptable" means that it is commonly used in the pharmaceutical field that does not impede the biological activity and properties of the compound to be administered without stimulating the organism upon administration thereof.

The pharmaceutical composition of the present invention may be formulated with the carrier, and may be utilized as food, medicine, feed additives, drinking water additives, and the like. In the present invention, the type of the carrier is not particularly limited and any carrier can be used as long as it is commonly used in the art. Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, maltodextrin, glycerol, ethanol, and the like. Can be. These may be used alone or in combination of two or more thereof.

In addition, the pharmaceutical composition of the present invention may be used by adding other pharmaceutically acceptable additives, such as excipients, diluents, antioxidants, buffers or bacteriostatic agents, if necessary, fillers, extenders, wetting agents, disintegrants, dispersants, interfaces Active agents, binders, lubricants, and the like may be additionally added and used.

The pharmaceutical compositions of the present invention can be formulated and used in a variety of formulations suitable for oral or parenteral administration. Non-limiting examples of the formulation for oral administration include troches, lozenges, tablets, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, and the like. Can be mentioned.

In order to formulate the pharmaceutical composition for oral administration, a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose (Cellulose) or gelatin (Gelatin) and the like; Excipients such as Dicalcium phosphate and the like; Disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax can be used, and sweeteners, fragrances, and syrups can also be used. Can be.

Furthermore, in the case of a capsule, a liquid carrier such as fatty oil may be additionally used in addition to the above-mentioned materials.

Non-limiting examples of the parenteral preparations include injection liquids, suppositories, respiratory inhalation powders, spray aerosols, ointments, application powders, oils, creams, and the like.

In order to formulate the pharmaceutical composition for parenteral administration, a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a freeze-dried preparation, an external preparation, and the like may be used. The non-aqueous solvent and the suspension may be propylene glycol, Polyethyleneglycol, vegetable oils such as olive oil, injectable esters such as ethyloleate and the like can be used.

Further, more specifically, when the pharmaceutical composition of the present invention is formulated into an injection solution, the composition of the present invention is mixed with water with a stabilizer or buffer to prepare a solution or suspension, which is then used as an ampoule or vial. It can be formulated for unit administration of. In addition, when the pharmaceutical composition of the present invention is formulated with an aerosol, a propellant or the like may be combined with the additive to disperse the dispersed concentrate or the wet powder.

In addition, when the pharmaceutical composition of the present invention is formulated into an ointment, a cream, etc., animal oil, vegetable oil, wax, paraffin, starch, trakant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, oxidation It can be formulated using zinc etc. as a carrier.

A pharmaceutically effective amount, effective dosage of the pharmaceutical composition of the present invention may vary depending on the method of formulation, the mode of administration, the time of administration and / or route of administration, and the like, to achieve by administering the pharmaceutical composition. The type and extent of the response, type of subject, age, weight, general state of health, condition or extent of the disease, sex, diet, excretion, drug used concurrently or simultaneously with the individual And various similar factors well known in the medical arts, and those skilled in the art can readily determine and prescribe a dosage effective for the desired treatment.

The dosage for the more preferred effect of the pharmaceutical composition of the present invention may be preferably 0.01 mg / kg to 1,000 mg / kg, more preferably 1 mg / kg to 500 mg / kg per day. Administration of the pharmaceutical composition of the present invention may be administered once a day, may be divided into several times. Therefore, the above dosage does not limit the scope of the present invention in any aspect.

The route of administration and mode of administration of the pharmaceutical composition of the present invention may be independent of each other, and are not particularly limited in the way, and any route of administration and administration as long as the pharmaceutical composition can reach the desired site of interest. You can follow the way. The pharmaceutical composition may be administered by oral or parenteral administration.

As the parenteral administration method, for example, intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration or subcutaneous administration may be used, and the method of applying, spraying or inhaling the composition to a diseased site may also be used. May be, but is not limited to these.

The pharmaceutical composition of the present invention may preferably be administered orally or by injection.

The composition of the present invention may further comprise a frontoside A (Frondoside A) to increase the effect of preventing, delaying and treating the Bruch's membrane function-related diseases.

In the present invention, "Frondoside A" or "Frondoside A" is a saponin compound represented by the following [Formula], and is known to be included in the sea cucumber of the present invention. The CAS number is 127367-76-4 (anhydrous) and the formula is C ₆₀ H ₉₆ O ₂₉ SNa. In the present invention, it was confirmed that the frontoside A is involved in the improvement of the transport function of the Brueck membrane through the improvement of the hydraulic conductivity, the MMP secretion and the lipid secretion of the Brueck membrane, the regeneration and the function of the Brueck membrane, through which New uses have been identified for the prevention, delay, treatment and amelioration of diabetic lowering related diseases.

[Formula]

The composition of the present invention further comprises at least one composition selected from the group consisting of amino acids, antioxidants, minerals, metals, lutein, astaxanthin and zeaxanthin in order to enhance the prevention, delay and treatment effect of Bruch's membrane-related diseases can do.

In the present invention, the Bruch's membrane deterioration-related diseases include age-related macular degeneration (AMD), Sorsby's fundus dystrophy, ML (Malattia Levintanese), Stargardt disease (Stargardt disease), Best yolk-shaped macular dystrophy (Best's) vitelliform retinal dystrophy) or Doyne's honeycomb retinal dystrophy (DHRD), but is not limited thereto.

In addition, the present invention also provides a health functional food composition for the prevention, delay and treatment of Bruch's membrane function-related diseases including the sea cucumber extract as an active ingredient.

In the health functional food composition of the present invention, the sea cucumber extract or fractions thereof, and the efficacy thereof are the same as described above in connection with the pharmaceutical composition of the present invention.

When the health functional food composition of the present invention is used as a food additive, the composition may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.

The kind of the food is not particularly limited, and includes all foods in a general sense. Non-limiting examples of foods that can be added to the material include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, dairy products, including other noodles, gums, ice cream, various soups, drinks, tea , A drink, an alcoholic beverage, and a vitamin complex.

When the health functional food composition of the present invention is a beverage composition, it may contain various flavors or natural carbohydrates and the like as an additional ingredient, as in a conventional beverage. Non-limiting examples of the natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; Natural sweeteners such as dextrin, cyclodextrin; Synthetic sweeteners such as saccharin and aspartame; and the like. The proportion of the additional components added above may be appropriately determined by the choice of those skilled in the art.

In addition to the above, the nutraceutical composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin , Alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the health functional food composition of the present invention may contain a flesh for preparing natural fruit juice, fruit drink or vegetable drink. These components can be used independently or can be used in combination of 2 or more. The proportion of such additives may also be appropriately selected by those skilled in the art.

In addition, the present invention is a pharmaceutical composition for the prevention, delay and treatment / improvement of the Bruch's membrane function-related diseases, including Frontoside A, isomers, hydrates thereof, or salts thereof as an active ingredient. To provide.

In addition, the present invention provides a health functional food composition for preventing, delaying and improving diseases related to Bruch's membrane deterioration, including Frondoside A, an isomer thereof, a hydrate thereof, or a salt thereof as an active ingredient. to provide.

The composition according to the present invention has an effect of slowing or reversing the aging process of the eye by improving the transport function of the Bruch's membrane and promoting the regeneration of the Brux's membrane, thereby causing age-related macular degeneration caused by the functional degradation of the Bruch's membrane with aging. Dystrophy such as denaturation (AMD), Sorsby's fundus dystrophy, Malattia Levintanese, ML, Stargardt disease, Best's vitelliform retinal dystrophy or DHRD (Doyne's honeycomb retinal) Excellent prevention and treatment of diseases

1 is a diagram illustrating the cross-sectional image of the human retina and the components of phototransduction.

Figure 2 is a graph showing the structural changes of the Bruk's membrane due to aging, (A) the thickness of the Bruk's membrane increases by two to three times with age, (B) the accumulation of damaged or denatured collagen, and (C ) Major lipid substances, such as cholesterol esters, increase exponentially, and (D) free thiol groups decrease, causing aggregation of proteins.

3 is a diagram showing the change of Bruch's membrane due to aging and the rapid change in macular degeneration patients.

Figure 4 shows the mechanism of MMP action that plays a role in aging and regeneration of the Bruch's membrane and abnormal MMP action mechanism in macular degeneration patients.

5 is a result showing the change in hydraulic conductivity of the Bruch's membrane of the human due to aging of the general public and macular degeneration patients.

Figure 6 shows the change in the degree of diffusion of the Bruk's membrane in humans due to aging of the general population and macular degeneration patients.

7 is a result showing the effect of improving the transport function of the Bruch membrane of the sea cucumber extract of the present invention.

8 is a dose response curve showing the lipid secretion effect from the Bruch membrane of the sea cucumber extract of the present invention.

9 shows the result of removing free MMP enzyme from a human Bruch's membrane.

10 is a result showing the removal effect of the MMP enzyme bound to the Bruk membrane of a human using the sea cucumber extract of the present invention.

11 is a result showing the removal effect of HMW2 bound to the human Bruch membrane using the sea cucumber extract of the present invention.

12 is a result of confirming the saponin of the fraction obtained by separating the sea cucumber concentrate through a silica gel column by TLC.

FIG. 13 is a result of TLCs classified into five groups of fractions of similar components among the fractions of FIG. 12 (Std, whole sea cucumber powder; F1 to F5, fraction of sea cucumber powder).

14 is a result showing the effect of improving the hydraulic conductivity of the five fractions of FIG.

Figure 15 is a result of comparing the type of saponin contained in each fraction. (A) is the result of confirming the types of saponins present in each of the sea cucumber fractions, (B) is a result of comparing the saponins present in Frondoside A and whole sea cucumber extract (SC, whole sea cucumber; FA, Frondoside A; F1 ~ F5 , Sea cucumber fraction).

Figure 16 shows the results of culturing human Bruch's membrane with sea cucumber fractions (F1 ~ F5) and confirming the secretion of MMP enzyme from the Bruch's membrane (FCS, fetal calf serum; C, control; F1 ~ F5, incubated with each fraction) One Bruch film; n = 3 each)

17 is a result of analyzing the change of lipid secreted after cultivation of sea cucumber fraction (ChE, cholesterol ester; TG, triglyceride; Ch, cholesterol; PC, phosphatidylcholine).

18 is a result of confirming the effect of improving the hydraulic conductivity of the frontoside A.

19 shows the results of confirming the effect of removing the MMP in the Brueck membrane of the frontoside A.

20 shows the results of confirming the lipid removal effect of the Frodoside A in the Bruch's membrane.

Referring to the present invention in more detail as follows.

Degenerative changes in the Bruch's membrane transport function due to aging cause vision problems in the elderly and, in severe cases, cause age-related macular degeneration (AMD) leading to blindness.

Numerous studies have shown that aging has a serious adverse effect on the material transport capacity and the waste removal process of the Brueck membrane (Hussain et al., 2002; 2004; 2010; Starita et al. 1996; Moore et al. 1995; Moore and Clover, 2001), it is known that waste accumulated in the Brueck's membrane due to aging is composed of lipids and denatured proteins. In addition, the root cause of waste accumulation in the Bruch's membrane was found to be due to the inability of proteolytic enzymes called matrix metalloproteinases (MMPs) to perform the role of the Bruch's membrane. .

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are secreted in the form of pro-forms that are inactive from the RPE to the Bruch's membrane. The small peptides are removed from these precursors, resulting in activated MMP2 and active MMP9. Activated MMP2 and MMP9 enzymes can degrade most of the substances that make up the extracellular matrix through the activation process, removing the damaged components and replacing them with new ones. The mechanism of regeneration of the membrane plays a role in maintaining the structure and function of the Brooke membrane in a healthy state. However, it was found that the amount of activated forms of MMP2 and MMP9 was reduced by the aging of the Bruch's membrane, and the amount of activated MMP2 and MMP9 was reduced by about 60% in the Bruch's membrane in patients with macular degeneration (Hussain). et al., 2011).

Specifically, the mechanism of action of MMP according to aging is shown in FIG. 4. The precursor forms pro-MMP2 and pro-MMP9 form high molecular weight complexes (HMW) called HMW1 and HMW2 in the Brueck membrane. These materials also combine with other pro-MMP2 and pro-MMP9 molecules to form larger polymers, called large macromolecular complexes (LMMCs) (Kumar et al., Hussain et al. 2010). As the synthesis of the polymer material increases due to aging, the polymer compound is trapped or bound in the matrix, and pro-MMP and active MMP are also trapped in the membrane and cannot be used. Therefore, since the amount of free MMP required for the Brueck membrane regeneration is reduced, the membrane is not degraded and regenerated normally. As a result, a considerable amount of waste accumulates, leading to a decrease in the transport capacity of the membrane.

The macular and peripheral areas of central vision were examined in the eyes of 56 healthy subjects in the range of 1 to 96 years and the eyes of 11 patients with macular degeneration. ) And their effects were evaluated.

First, the hydraulic conductivity of the Brueck membrane separated from the donated eye was measured to confirm the transport capacity of the waste. The separated Bruch membrane was placed in an open Ussing chamber to measure the quantitative change of the fluid under hydrostatic pressure, and the change in hydraulic conductivity was calculated (FIGS. 5B and C). As a result, the fluid transport capacity of the macular section decreased exponentially as aging progressed, and the transport capacity decreased by half every 16 years (FIG. 5D). The data in FIG. 5D is shown by converting the exponential decay linearly using a semi-log plot on the Y axis. In order to maintain the function of the cell, the Bruch's membrane requires a minimum hydraulic conductivity function, which is indicated by a failure line. If the transport function falls below this, fluid accumulates below the RPE, causing RPE exfoliation, leading to the death of the cell at the top. This symptom occurs in about 12 to 20% of patients with macular degeneration. Normally in normal people this line does not fall below the failure threshold for life, but in the general elderly population there is a crossing of this failure threshold, which can cause serious problems such as abnormal night vision. appear. In macular degeneration, it is impossible to measure the macular area independently because the macular area is significantly damaged by the nature of the disease. The hydraulic conduction of the periphery was also similar to that of the macula, decreasing exponentially with a half-life of about 22 years (Fig. 5E). It can be seen that the hydraulic conductivity measured in the periphery of 11 patients with macular degeneration is all below the mean regression line (see black circle and red line in FIG. 5E), which is a serious condition of material transport loss in the periphery rather than the macular area. It is showing progress.

Next, protein diffusion experiments were performed to confirm the nutrient transport capacity of the Brueck membrane. Specifically, the diffusion degree through which the FITC-dextran (MW 23 kDa) passes through the Bruch membrane was tested using a general Ussing chamber (FIGS. 6B and C). Dextran was chosen to be similar in size to most carrier proteins that play a role in transporting substances such as vitamin A, trace metals and lipids. Due to the aging of the Bruch's membrane, it was confirmed that the diffusion rate of the protein-sized material passing through the macula was sharply reduced (FIG. 6D). Because of this, despite the presence of normal vitamins and antioxidants in the plasma, the absence of these substances is observed in the macula. In the peripheral part, the degree of diffusion decreases slowly compared to the macula part (FIG. 6E), but in the case of macular degeneration, it was confirmed to decrease very rapidly (see black circle and red line of FIG. 6E). Thus, if the function of the macular part of the macular degeneration patient can be measured as compared with the degree of reduction of the peripheral part, it can be confirmed that the degree is much more rapid and rapid than the peripheral part. This reduction in diffusion transport interferes with nutrient supply and removal of hazardous wastes, which in turn increases the risk of damage and death of RPE and visual cells and causes blindness.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.

Example  1. Preparation of Sea Cucumber Extract

Dried sea cucumber was used to prepare sea cucumber powder using a grinder, and 70% ethanol was added thereto, followed by extraction for about 3 to 6 hours. Removing ethanol in a vacuum to prepare a sea cucumber extract used in the embodiment of the present invention.

Example  2. Using sea cucumber extract Brooke  Repair conductivity improvement effect

In order to confirm the effect on the brink's membrane hydraulic conductivity of the sea cucumber extract prepared in Example 1 was tested using eyes of 14 eye donors (ages 52 to 84). Specifically, the Bruch membrane isolated from donated human eyes was incubated with 2.5% sea cucumber extract for 24 hours, and Tris-HCl was used as a control.

The results are shown in Figure 7, it can be seen that the sea cucumber extract 2.3 times increased the hydraulic conductivity of the Brueck membrane (Fig. 7A, p <0.001). The improvement in the hydraulic conductivity of sea cucumber extract is the same as the effect that makes the Bruch's membrane youthful for about 20 to 25 years. This improvement in hydraulic conductivity prevents the failure from reaching a failure threshold, thereby reducing the likelihood of developing macular degeneration.

In addition, the Bruch's membrane isolated from four eyes ranging from 69 to 84 years was measured in order to determine the effect of improving the transport function of the Bruch's membrane according to the dose of sea cucumber extract. Specifically, the Bruch membrane is placed in an open-type Ussing chamber and passed through Tris-HCl buffer under hydrostatic pressure through a tube, and after a certain period of time, the solution passed through the fluid transport (fluid transport) Was measured. Tris-HCl was used as a control group, and the experimental group was treated with sea cucumber extract at concentrations of 0 to 10%, and the fluid transport was measured again after incubation for 24 hours ([13] Moore DJ, Hussain AA, Marshall J. ( Age-related variation in the hydraulic conductivity of Bruchmembrane.Invest.Ophthalmol.Vis.Sci. 36 (7): 1290-7. [17] Starita C, Hussain AA, Pagliarini S, Marshall J. (1996) Hydrodynamics of ageing Bruchmembrane: implications for macular disease.Exp. Eye Res. 62 (5): 565-72.)

As a result, according to the dose response curve of the sea cucumber extract shown in Figure 7, the hydraulic conductivity for the membrane was improved as the capacity of the sea cucumber extract was increased, and the hydraulic conductivity was 3.2 times higher than when the sea cucumber extract was not added when saturated. It can be seen (Fig. 7B), which is equivalent to improving the hydraulic conductivity function of the reduction curve due to aging about 33 years (Fig. 7C).

Therefore, it was confirmed that the sea cucumber extract can have a significant effect on improving the transport function of the Bruch's membrane at various ages as aging progresses.

Example  3. Using sea cucumber extract Brooke  Lipid Waste Removal Effect

The main components of the lipid waste of the Bruk's membrane are cholesterol esters, cholesterol, triglycerides and phospholipids. Dose-response experiments were conducted to determine whether sea cucumber extracts were effective in removing lipid extracts accumulated on Bruch's membrane. Specifically, the Bruch membrane (50-82 years old) isolated from four human eyes was mixed and homogenized in Tris-HCl buffer. Homogenate was separated by centrifugation into pellets containing supernatant and lipid waste. The pellet was re-mixed with Tris-HCl buffer and incubated with sea cucumber extract at 0-2.5% concentration in a 37 ° C incubator for 24 hours. After the incubation, the sample was centrifuged and the amount of lipid secreted from the pellet into the supernatant was quantified by Thin Layer Chromatography (TLC).

The result is secretion data and kinetics of various types of lipids. As shown in Figure 8, the secretion of cholesterol esters, cholesterol and triglycerides showed hyperbolic kinetics, the secretion of phosphatidyl choline showed the form of sigmoid kinetics, with sea cucumber extract When cultured, it was confirmed that the lipid waste deposited on the Brueck membrane was released from the membrane.

Example  4. Using sea cucumber extract Brooke MMP  Enzyme secretion effect

The MMP enzyme of the Bruch's membrane exists in free form or bound to the membrane. In order to confirm that the sea cucumber extract can remove the MMP enzyme from the Bruch's membrane, MMP bound to the membrane was first identified in the separated Bruch's membrane.

 When the separated Bruch membrane was placed in the Ussing chamber and flowed through the Tris-HCl buffer, free MMPs were secreted slowly from the membrane for about 6 to 12 hours depending on the hydraulic conductivity of the Bruch membrane (FIG. 9A). Once the free MMP was released from the membrane, the Bruch membrane was separated from the chamber and the remaining MMP was extracted using the SDS buffer. Soluble or freely present MMP material was secreted mostly slowly between 5-12 hours of perfusion (FIG. 9B). However, it can be seen that most of the MMPs present in the Bruch's membrane remain bound or trapped in the membrane and are not removed after 5-12 hours of perfusion.

To see if these MMPs, bound or confined to the membrane, could be removed by sea cucumber extract, the Bruch membrane isolated from the eyes of donors 73 and 79 years old was freed through perfusion with Tris-HCl for 12 hours. The state MMP enzyme was secreted and removed first. Subsequently, as a result of perfusion with 2.5% sea cucumber extract, it was confirmed that MMPs bound to the membrane were secreted as shown in FIG. 10.

The removal of HMW1 and HMW2, which were blocking the Brueck membrane, can help the transport capacity of the Brueck membrane, and the secretion of activated MMPs can also break down abnormal proteins. It is expected to have a positive impact on the return.

Example  5. Human Eyes Using Sea Cucumber Extract Brooke On pellet  Present MMP  Secretion effect of enzyme

In order to confirm the secretion effect of MMP enzyme from the Bruch's membrane of sea cucumber extract, the Bruch's membrane of human eyes separated from two eyes of a 75-year-old donor was used. In the pellet of the Brueck membrane used as a sample, MMP enzymes were trapped or bound in the membrane. A certain volume of pellets were incubated with Tris-HCl buffer as a control and incubated with 2.5% sea cucumber extract as an experimental group. After incubation at 37 ° C. for 24 hours, centrifugation was performed to determine the amount of MMP secreted into the supernatant and the MMPs present in the bound state of the pellets.

As a result, the HMW2 compound was hardly secreted in the control group, and most of the compound remained in the pellet, but the Bruch membrane cultured with the sea cucumber extract showed that most of the HMW2 bound to the membrane was secreted into the supernatant (FIG. 11). ). This means that the flow of the membrane can be improved by removing the HMW2 that is blocking the membrane, thereby improving the transport capacity of the Brueck membrane. In addition, it was confirmed that the culture of sea cucumber extract can positively affect the transport function by removing activated wastes from the membrane by releasing HMW1 and pro-MMP2 and pro-MMP9 in the precursor state from the membrane.

Example  6. of sea cucumber powder Fractions  Used Brooke Mak  Repair conductivity improvement effect

Sea cucumber powder was prepared by crushing dried sea cucumber, and 1.5 g of sea cucumber powder was dissolved in 15 ml of methanol, and then the solvent was evaporated. Then, 3 ml of CMW (chloroform: methanol: H ₂ O = 50: 30: 6) A solvent was added to prepare a sea cucumber concentrate. 0.8 ml of the prepared sea cucumber concentrate was separated through a silica gel column. The column used the same CMW solvent as above, and a total of 34 fractions were taken once every 20 minutes (about 2 ml). Each fraction was dissolved in 200 μl of methanol after evaporation of the solvent, and 5 μl of each solution was taken to quantify the amount of saponin by TLC (thin layer chromatography) (FIG. 12). As a result, as shown in FIG. 12 and Table 1, fractions consisting of similar components were divided into five groups (F1 to F5), and TLC was performed for each fraction group (FIG. 13). In order to equalize the amount of saponin contained in the five fractions, dilution with CMW solvent normalized the saponins per fraction to a concentration of 250 μg / ml.

Fraction  Kinds	Fraction  No.	Amount of saponin (mg)
F1	11, 12, 13	6.1
F2	14, 15, 16, 17	11.4
F3	18,19, 20	7.7
F4	21, 22, 23, 24, 25	19.7
F5	26, 27, 28	17.5
Total saponin amount		62.4

In order to confirm the effect of improving the hydraulic conductivity of the Brueck membrane for each fraction of the sea cucumber powder, the Brueck membrane separated from the eyes of the donor (78 years old, 82 years old) was measured in the same manner as in the Experimental Experiment of Hydraulic Conductivity described in Example 2. It was.

As a result, as shown in Table 2 and Figure 14, the fraction of F3 was statistically significantly improved ( p <0.001), F2, F4, F5 also showed a tendency to increase the hydraulic conductivity with respect to the control group .

Fraction	Hydraulic conductivity improved degree (fold change after, culture fraction before comparison) Mean ± SD (n)	Significance
Control (Tris Buffer)	1.1 ± 0.08 (5)
F1	1.03 ± 0.01 (3)	NS
F2	1.16 ± 0.06 (3)	NS
F3	1.39 ± 0.11 (3)	P <0.001
F4	1.15 ± 0.05 (3)	NS
F5	1.19 ± 0.05 (3)	NS

Example  7. of sea cucumber powder In fractions  Identify active substances present

In Example 6, in order to identify a substance specific to the F3 fraction which showed the best effect on improving the hydraulic conductivity of the Brueck membrane, saponin types present in each fraction were analyzed.

In FIG. 15, saponins present in F3 but not in F1 and F2 are indicated by arrows (→), and the substance was also present in trace amounts in F4 and F5. This substance was also identified at the same position of the separation result (SC) of the whole sea cucumber sample, and it was found that it is called Frondoside A (FA), which is known as saponin of sea cucumber.

Example  8. Sea cucumber Fraction MMP  Secretory effect

To confirm the effect of the sea cucumber fractions secreting MMP from the Bruch's membrane, the Bruch's membrane was isolated from donated eyes from patients between 65 and 76 years. Specifically, 36 round 8 mm diameter Brooke membranes were prepared, and two circular tissues (Trephine) were put in a total of 18 test tubes, and three test tubes were divided into a total of 6 groups (control). , F1, F2, F3, F4, F5). Sea cucumber fraction was adjusted in the same amount of saponin to 250 μg / ml as described above, and after 24 hours incubation was carried out by zymography with 50 μl of the culture, to confirm the MMP secretion. The control group was incubated with Tris buffer instead of sea cucumber fraction. The remaining culture solution was added to the CM solution (chloroform: methanol = 2: 1, v / v) was used to analyze the amount of lipid secreted in Example 9 below.

As a result, as shown in FIG. 16, in the control group and the fraction F1 cultured with Tris buffer, HMW2 and Pro-MMP9 and trace amounts of HMW1 were secreted, but pro-MMP2 was not observed. Fraction F3 was additionally secreted from Pro-MMP2 compared to the control group, and fractions F4 and F5 secreted HMW2, HMW1, and Pro-MMP2 in the membrane, as well as Pro-MMP9. From this, fraction F3 increases the amount of Pro-MMP2 secretion, and fractions F4 and F5 secrete most of the MMP enzymes bound to the Bruch's membrane.

Example  9. Sea cucumber Fraction  Lipid change effect

After incubating the Bruch membrane with each sea cucumber fraction for 24 hours as in Example 8, 0.95 ml of the culture was extracted using a CM solution (chloroform: methanol = 2: 1, v / v). After evaporating the solvent, 50 μl of CM solution was added, and 30 μl of each sample was added to the TLC plate to analyze the type of lipid present.

As a result, as shown in FIG. 17, in the case of the control group and the fraction F1, phosphatidylcholine (PC) was not secreted, cholesterol ester (Cholesterol ester, ChE) and triglyceride (TG) were secreted, and a small amount of cholesterol (Cholesterol). , Ch) was secreted. Fraction F3 was effective in the release of cholesterol esters, triglycerides and cholesterol, and also in the removal of other types of UL-1 and UL-3 lipids. Fractions F4 and F5 showed little effect on lipid removal compared to the control.

Example  10. Frontoside  A ( Frondoside  Of A) On the brink  Improvement of repair conductivity for

Using a single saponin frontoside A confirmed in Example 7 it was confirmed whether there is an effect of improving the substance transport capacity in the Bruk membrane of humans. Specifically, the change in hydraulic conductivity of 167 μg / ml of the Frontoside A solution was measured in the same manner as in the above example, using the Bruk film of 68 and 79 year old patients. Tris buffer was used as a control. As a result, as shown in Table 3 and Figure 18, it was found that the effect of improving the hydraulic conductivity of the frontoside A is 1.6 times more than the control.

	Fold-change Mean ± SD (n)
Control (Tris buffer only)	0.97 ± 0.16 (4)
Frondoside A (167 μg / ml)	1.65 ± 0.2 (3) ***

Example  11. Frontoside  A ( Frondoside  A) MMP  Secretory effect

In Example 10, zymography was performed using a solution incubated for 30 hours when measuring hydraulic conductivity. Specifically, the Tris buffer solution and the Frontoside A solution (167 μg / ml) were incubated with the Bruch membrane for 30 hours, 50 μl of the solution and 50 μl of the SDS sample buffer were mixed, and 30 μl of the The gel was loaded and measured for the secretion of MMP enzymes from human Bruch's membrane.

As a result, as shown in FIG. 19, MMP was hardly secreted when incubated with Tris buffer as a control, whereas when cultured with Frondoside A, a large amount of Pro-MMP9 bound to the membrane was secreted. there was. From this, it was found that Frontoside A can selectively bind to Pro-MMP9 and remove it from Bruk's membrane among several kinds of MMPs.

Example  12. Frontoside  A ( Frondoside  A) lipid removal effect

In order to confirm the lipid removal effect of the frontoside A, after measuring the hydraulic conductivity in Example 10, the Bruch membrane having a diameter of 6 mm was cut out, lipid was extracted with CM solution (chloroform: methanol = 2: 1), and the solvent was extracted. Was evaporated. Again, 50 μl of CM solution was added and 40 μl of this was added to a silica gel TLC plate to analyze the type and amount of lipids.

As a result, as shown in Figure 20, when cultured with the frontoside A did not affect the removal of cholesterol esters, triglycerides, cholesterol, it was confirmed that there is an effect of removing the phosphatidyl choline of the Bruch membrane.

Claims (32)

1. A pharmaceutical composition for preventing, delaying, and treating a disease related to decreased Bruch's membrane, including sea cucumber extract or fraction as an active ingredient.
2. The method of claim 1,

   The active ingredient is a pharmaceutical composition for preventing, delaying and treating a disease related to Brueck's membrane function, characterized in that to improve the transport function of the Bruk's membrane.
3. The method of claim 2,

   A pharmaceutical composition for preventing, delaying, and treating diseases related to Brueck's membrane deterioration, characterized by improving transport function by improving hydraulic conductivity of the Bruch's membrane.
4. The method of claim 2,

   A pharmaceutical composition for preventing, delaying, and treating a disease related to Brueck's membrane deterioration, characterized by improving transport function by improving a substance diffusion function of the Bruk's membrane.
5. The method of claim 2,

   A pharmaceutical composition for preventing, delaying, and treating a disease related to Brueck's membrane deterioration, characterized by improving transport function by removing proteins or lipids bound or trapped in the Bruk's membrane.
6. The method of claim 1,

   The active ingredient is a pharmaceutical composition for the prevention, delay and treatment of Bruch's membrane function-related diseases, characterized in that to regenerate the Bruch's membrane, improve the function of the Bruch's membrane.
7. The method of claim 6,

   The active ingredient regenerates the brux membrane by removing high molecular weight complexes 1 (HMW1), high molecular weight complexes 2 (HMW2) or lipid components bound or deposited on the bruc membrane, and improves the bruc membrane function. Pharmaceutical composition for the prevention, delay and treatment of diseases related to Brueck's membrane function.
8. The method of claim 6,

   The active ingredient is pro-MMP2 (pro-matrix metalloproteinases 2), pro-MMP9 (pro-matrix metalloproteinases 9), active matrix metalloproteinases 2 (active MMP2) and active matrix metalloproteinases (MMP9) active matrix A pharmaceutical composition for preventing, delaying, and treating a disease related to Brueck's membrane deterioration, characterized by regenerating the Bruch's membrane by secreting the same, and improving the Bruch's membrane function.
9. The method of claim 6,

   The active ingredient prevents, delays, and treats Bruch's membrane deterioration-related diseases by regenerating the Bruch's membrane by activating active MMP secretion from retinal pigment epithelium (RPE) and improving the Bruk's membrane function. Pharmaceutical composition for.
10. The method of claim 1,

    The active ingredient is a pharmaceutical composition for the prevention, delay and treatment of Bruch's membrane function-related diseases, characterized in that it comprises a Frontoside A (Frondoside A).
11. The method of claim 1,

    The composition is a pharmaceutical composition for preventing, delaying, and treating diseases related to Bruch's membrane function, further comprising Frontoside A.
12. The method of claim 1,

    The composition for the prevention, delay and treatment of Bruch's membrane deterioration-related diseases further comprises at least one composition selected from the group consisting of amino acids, antioxidants, minerals, metals, lutein, astaxanthin and zeaxanthin Pharmaceutical compositions.
13. The method according to any one of claims 1 to 12,

    The Bruch's dysfunction-related diseases include age-related macular degeneration (AMD), Sorsby's fundus dystrophy, ML (Malattia Levintanese), Stargardt disease, Best yolk-shaped macular dystrophy (Best's vitelliform retinal dystrophy) ) And DHRD (Doyne's honeycomb retinal dystrophy) is selected from the group consisting of pharmaceutical composition for the prevention, delay and treatment of diseases related to Brueck's membrane function.
14. Health functional food composition for the prevention, delay and improvement of Bruch's membrane function-related diseases including sea cucumber extract or fraction as an active ingredient.
15. The method of claim 14,

    The active ingredient prevents, delays and improves the health functional food composition of Bruch's membrane function-related diseases, characterized in that to improve the transport function of the Bruk's membrane.
16. The method of claim 15,

    Health functional food composition for the prevention, delay and improvement of the Bruch's membrane function-related diseases, characterized in that to improve the transport function by improving the hydraulic conductivity of the Bruch's membrane (hydraulic conductivity).
17. The method of claim 15,

    Health functional food composition for the prevention, delay and improvement of the Bruch's membrane function-related diseases, characterized in that to improve the transport function by improving the substance diffusion (diffusion) function of the Bruk's membrane.
18. The method of claim 15,

    A health functional food composition for preventing, delaying, and improving diseases related to Bruch's membrane deterioration, characterized in that the transport function is improved by removing lipids bound or trapped in the Bruch's membrane.
19. The method of claim 14,

    The active ingredient is a health functional food composition for preventing, delaying and improving the Bruch's membrane function-related diseases, characterized in that to regenerate the Bruk's membrane, improve the function of the Bruk's membrane.
20. The method of claim 19,

    The active ingredient prevents, delays, and improves the health of Bruch's membrane deterioration-related diseases, which is characterized by regenerating the Bruch's membrane by removing HMW1, HMW2, or lipid components bound or deposited on the Bruch's membrane, and improving Bruk's membrane function. Nutraceutical composition.
21. The method of claim 19,

    The active ingredient regenerates the brux membrane by secreting pro-MMP2, pro-MMP9, active MMP2, and active MMP9 from the matrix of Bruch's membrane, and improves Bruch's membrane function. Health functional food composition for prevention, delay and improvement.
22. The method of claim 19,

    The active ingredient is a health functional food composition for preventing, delaying and improving the Bruch's membrane function-related diseases, characterized in that by reactivating the active MMP secretion from the RPE to improve the Bruch's membrane function.
23. The method of claim 14,

    The active ingredient prevents, delays and improves the health functional food composition of Bruch's membrane function-related diseases, characterized in that it comprises a frontoside A.
24. The method of claim 14,

    The composition is a health functional food composition for the prevention, delay and improvement of the Bruch's membrane function-related diseases further comprising a Frontoside A.
25. The method of claim 14,

    The composition for the prevention, delay and improvement of the Bruch's membrane function-related diseases further comprises one or more compositions selected from the group consisting of amino acids, antioxidants, minerals, metals, lutein, astaxanthin and zeaxanthin Health food composition.
26. The method according to any one of claims 14 to 25,

    The Bruch's dysfunction-related diseases include age-related macular degeneration (AMD), Sorsby's fundus dystrophy, ML (Malattia Levintanese), Stargardt disease, Best yolk-shaped macular dystrophy (Best's vitelliform retinal dystrophy) ) And DHRD (Doyne's honeycomb retinal dystrophy) is selected from the group consisting of health functional food composition for the prevention, delay and improvement of Bruch's membrane function-related diseases.
27. A pharmaceutical composition for preventing, delaying, and treating a disease related to Brueck's membrane function, including a Frontoside A, an isomer thereof, a hydrate thereof, or a salt thereof as an active ingredient.
28. The method of claim 27,

    The active ingredient is a pharmaceutical composition for the prevention, delay and treatment of Bruch's membrane function-related diseases, characterized in that derived from sea cucumber.
29. The method of claim 27,

    The active ingredient is a pharmaceutical composition for preventing, delaying and treating a disease related to Brueck's membrane deterioration, characterized in that it improves the transport function of the Bruk's membrane by removing Pro-MMP9 or phosphatidylcholine that is bound or trapped in the Bruk's membrane.
30. Health functional food composition for the prevention, delay and improvement of the Bruch's membrane function-related diseases comprising a frontoside A (Frondoside A), an isomer thereof, a hydrate thereof, or a salt thereof as an active ingredient.
31. The method of claim 30,

    The frontoside A is a functional food composition for the prevention, delay and improvement of Bruch's membrane function-related diseases, characterized in that derived from sea cucumber.
32. The method of claim 30,

    The active ingredient is a health functional food composition for preventing, delaying and improving the Bruch's membrane function-related diseases, characterized in that to improve the transport function of the Bruk's membrane by removing Pro-MMP9 or phosphatidylcholine bound or trapped in the Bruk's membrane.

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