KR20190063261A - Composition for increasing salivary secretion or prevention or treatment of xerostomia comprising phytosterols - Google Patents

Abstract

The present invention relates to a composition for increasing salivation or preventing or treating a mouth dryness, containing phytosterols as an active ingredient, and more particularly, to a composition for increasing salivation or preventing or treating a mouth dryness, containing at least one of β-sitosterol, stigmasterol, campesterol, and fucosterol as an active ingredient. The phytosterols of the present invention increase the concentration of calcium ions in a cell, which is a main factor of a salivation mechanism, and thus has an excellent effect of increasing salivation or preventing, alleviating, or treating a mouth dryness. Therefore, the composition which is a natural substance to be safely used without side effects, and exhibits an excellent effect in increasing salivation or preventing, alleviating, or treating a mouth dryness, can be provided.

Description

TECHNICAL FIELD The present invention relates to a composition for preventing or treating dry mouth or for enhancing saliva secretion containing phytosterols as an active ingredient. The present invention relates to a composition for preventing or treating xerostomia,

The present invention relates to a composition for preventing or treating saliva secretion enhancement or dry mouth disease comprising phytosterols as an active ingredient, and more particularly, to a composition for preventing or treating saliva secretion enhancement or dry mouth syndrome comprising phytosterols as an active ingredient, Or a composition for preventing or treating dry mouth.

Saliva is the secretion secreted from the salivary gland into the oral cavity. In normal people, the average daily saliva is 1 to 1.5 liters. Approximately 99.5% of saliva is water and the remaining 0.5% is composed of electrolyte, mucus, glycoprotein, enzyme, and antimicrobial substance. Saliva lubricates the oral mucosa, protects the oral tissues, and engages in digestion, taste, and remineralization of teeth. In particular, many proteins present in saliva have a profound effect on oral microbiota due to antibacterial, antiviral and antifungal effects (Journal of Dentistry 33: 223-233, 2005).

The secretion mechanism of saliva can be divided into protein secretion and secretion of liquid and electrolyte. Heterotrimeric G-protein and adenylyl cyclase are activated by the binding of the sympathetic neurotransmitter, norepinephrine, to the β-adrenergic receptor present in the cell membrane at the bottom of the secretory endothelial cells. When protein kinase A is activated by the formation of cyclic adenosine monophosphate, the secreted granules in the cell membrane secrete the protein into the lumen by extracellular leaching. On the other hand, secretion of fluid and electrolytes is mainly caused by the binding of acetylcholine, a parasympathetic neurotransmitter, to muscarinic cholinergic receptors. When the muscarinic receptor agonist binds to this receptor, heterotrimeric G-protein and phospholipase C are activated in turn, ultimately promoting the formation of inositol triphosphate (IP3). Inositol triphosphate (IP3) releases Ca ²⁺ stored in the cell, and the increased concentration of Ca ² opens the Cl ^- channel present in the lumenal side and the K ⁺ channel present in the bottom side. Na ⁺ / K ⁺ / 2Cl ^- co-transporter is activated. In addition, the aquaporin 5 (AQP5) protein in the follicles migrates to the lining membrane. The increased Cl ^- in the lumen side equilibrates along Na ⁺ , which moves through the closed synapse to the lumen, resulting in an osmotic gradient. The osmotic gradient moves water from the cell to the lumen through aquaporin 5 (AQP5) and closure synapses (Annual Review of Physiology 67: 445-469, 2005).

On the other hand, aquaporin is a water channel protein and is found in the cornea, kidney, liver and skin. Aquaporin has a variety of subfamilies ranging from AQP0 to AQP12, and aquaporin 5 is a major biomarker for saliva secretion. In particular, AQP5 knockout mice have been shown to reduce salivary secretion by more than 60% (The Journal of Biological Chemistry, 274: 20071-20074, 1999).

Salivary glands are affected by various diseases. Viruses such as Cytomegalovirus, Epstein-Barr virus and Human herpes virus infect salivary gland cells. Diabetes mellitus reduces salivary secretion by reducing salivary function and increases salivary glucose, which can have an adverse effect on plaque metabolism. Sjogren's syndrome and rheumatoid arthritis also destroy salivary gland tissue, and adrenal disease changes the composition of the electrolyte in saliva. In addition, pathological changes are observed in the salivary glands of patients with acquired immune deficiency syndrome, lymphoepithelial cyst, lymphadenopathy, and cystic fibrosis (Ten Cate'Oral Biology, 8 ^th ed, St Louis, MO: Mosby (2013)

Xerostomia is the most common clinical symptom associated with salivary glands. If the amount of saliva secreted during non-stimulation is less than 0.1 mL per minute, dry mouth is diagnosed. The cause of dry mouth is mainly a side effect of various drugs such as antidepressant, antidiabetic and antiallergic. Oral dryness due to natural aging is caused by a decrease in the parenchymal tissue of the salivary gland, a substitution of adipose tissue, or a decrease in the volume of the acini. In addition, autoimmune diseases such as Sjögren's syndrome or radiotherapy may result in destruction of salivary glands or blockage of salivary blood flow. When the amount of saliva in the oral cavity is reduced, it is possible that the oral cavity, acid candidiasis, dysgeusia, dysphagia, oral dysesthesia, intraoral halitosis, (The Journal of the American Dental Association, 138: S15-S20, 2007).

The most commonly used drugs for the treatment of oral dryness include parasympathomimetic pilocarpine, cevimeline, and bethanechol. However, these therapies have the disadvantage of causing side effects such as sweating, vomiting, vasodilation, diarrhea, and bronchospasm. Therefore, it is very important to prevent and treat dry mouth based on natural products with characteristics of low side effects and high safety.

Phytosterols are phytochemicals of the steroidal alcohol system that can be obtained naturally in plants, typically β-sitosterol, stigmasterol, campesterol, and fucosterol. β-Sitosterol has been reported to be effective in the prevention and treatment of various diseases including antimicrobial (Natural Product Research, 22: 1085-1093, 2008), anti-inflammation (Journal of Ethnopharmacology, 116: 263-269, 2008), Acta Pharmacologica Sinica (29: 341-348, 2008) , Journal of Diabetes, 3 (1): 29-37, 2011), and atherosclerosis (226 (1): 110-117, 2013) have been reported. Fucosterol is abundant in marine algae and is an antioxidant (Pharmacognosy Magazine, 8 (29): 60-64, 2012), antidiabetic (Archives of Pharmacal Research, 27 (11): 1120-1122, 2004) Bioorganic & Medicinal Chemistry, 17 (5): 1963-1973, 2009), and improvement of blood lipid composition (Biochemical and Biophysical Research Communications, 369 (2): 363-368, 2008).

Stigmasterol and campesterol have been shown to be effective in the treatment of osteoarthritis and osteoarthritis (18 (1): 106-116, 2010), thyroid suppression and antioxidant (Fitoterapia, 80 (2) (4): 218-221, 2009).

However, prior to the present invention, the prevention, improvement, or therapeutic effect of phytosterols on oral dryness has not been reported in detail.

Accordingly, the present inventors have conducted studies to search for natural products that can be safely applied without adverse effect on saliva secretion enhancement, and as a result, phytosterols increase the expression amount of aquaporin, a salivary secretion marker, The present invention has been completed.

It is therefore an object of the present invention

The present invention provides a pharmaceutical composition for enhancing saliva secretion comprising plant sterol (pnytosterols) as an active ingredient.

Another object of the present invention is

The present invention provides a food composition for enhancing saliva secretion comprising plant sterol (pnytosterols) as an active ingredient.

Another object of the present invention is to provide

The present invention also provides a pharmaceutical composition for preventing or treating dry mouth, which comprises plant sterol (pnytosterols) as an active ingredient.

Another object of the present invention is to provide

And to provide a food composition for preventing or ameliorating dry mouth, which comprises plant sterol (pnytosterols) as an active ingredient.

Another object of the present invention is to provide

For enhancing saliva secretion containing plant sterol as an active ingredient; Or for preventing or improving dry mouth; Quasi-drug compositions and quasi-drugs.

In order to achieve the above object,

There is provided a pharmaceutical composition for enhancing saliva secretion comprising plant sterol (pnytosterols) as an active ingredient.

According to another aspect of the present invention,

There is provided a food composition for enhancing saliva secretion comprising plant sterol (pnytosterols) as an active ingredient.

In order to accomplish still another object of the present invention,

The present invention provides a pharmaceutical composition for preventing or treating dry mouth, which comprises plant sterol (pnytosterols) as an active ingredient.

In order to accomplish still another object of the present invention,

The present invention provides a food composition for preventing or ameliorating dry mouth, which comprises plant sterol (pnytosterols) as an active ingredient.

In order to accomplish still another object of the present invention,

For enhancing saliva secretion containing plant sterol as an active ingredient; Or for preventing or improving dry mouth; Quasi-drug compositions and quasi-drugs.

Hereinafter, the present invention will be described in detail.

The present invention provides a composition for enhancing saliva secretion comprising plant sterol (pnytosterols) as an active ingredient.

The term " phytosterol "of the present invention is a generic term for sterol substances derived from all kinds of plants, and is mainly made by separating and purifying vegetable oil from distillation components generated during final deodorization under high-temperature vacuum.

The plant sterol of the present invention is not limited in its kind, but may be preferably beta-sitosterol, fucosterol, stigmasterol or camptosterol.

The beta-sitosterol is represented by the following formula (1). The β-sitosterol may be one isolated from an extract such as brown rice, soybean, peanut, radish or Chinese cabbage. Preferably, the β-sitosterol is ethanol extract, hot water extract, hexane extract, ethyl Acetate extract, and ultra-high pressure extract.

[Chemical Formula 1]

The stigmasterol is represented by the following formula (2). The stigmasterol may be one isolated from an extract such as soybean, kidney bean, pea, or red bean. Preferably, the stigmasterol is selected from the group consisting of ethanol extract, hot water extract, hexane extract, ethyl acetate extract and ultra high pressure extract using soybean, kidney bean, pea, Separated, or purified.

(2)

The camesterol is represented by the following formula (3). The campesterol may be one isolated from an extract such as soybean, citronella, grapefruit, and red pepper. Preferably, the campesterol may be an ethanol extract using a soybean plant seed, a citronella, a grapefruit, , Hexane extract, ethyl acetate extract, ultra high pressure extract.

(3)

The fucosterol is represented by the following formula (4). The fucosterol may be one selected from the group consisting of mushroom, red pepper, mushroom, and mushypie. Preferably, the fucosterol is ethanol extract, hot water extract, hexane extract, ethyl acetate extract, have.

[Chemical Formula 4]

The extraction solvent may be at least one selected from the group consisting of water, an organic solvent, a subcritical fluid and a supercritical fluid. The organic solvent may be a polar solvent, a nonpolar solvent, a polar and nonpolar mixed solvent or water. Specific examples of the solvent include alcohols having 1 to 6 carbon atoms, acetone, ether, benzene, chloroform, ethyl acetate, methylene chloride, hexane ), Cyclohexane, petroleum ether, and water.

The plant sterol may be isolated and purified from plant extracts, chemically synthesized, or commercially available compounds. The chemical synthesis of the plant sterol may be performed by a general method known in the art.

In this specification, "saliva" is also referred to as saliva, which means a colorless viscous digestive juice secreted from the salivary glands of the mouth (salivary gland). In general, the amount of saliva secreted for 24 hours in a normal person is about 1000 to 1500 ml. Generally, when not stimulated by autonomic nerve, it produces 0.001 ~ 0.2ml per minute, and when stimulated, the flow rate increases to 0.18 ~ 1.7ml per minute. The average secretion per minute is about 1mL. About 99% of it is water, and it contains various minerals.

In the present invention, the composition may be a composition for enhancing saliva secretion in that the saliva secretion ratio can be improved to less than normal.

The present invention also provides a composition for preventing, treating or ameliorating dry mouth, which comprises plant sterol (pnytosterols) as an active ingredient.

The term 'oral dry' or 'dry mouth' according to the present invention means a symptom in which saliva is reduced or the mouth is dry due to various other causes. Specifically, if the amount of saliva secreted for 24 hours is less than 1000 to 1500 ml, the user may feel that the mouth is dry and dry, or that the oral cavity is dry due to evaporation of moisture in the mouth while breathing through the mouth.

The term 'oral dry' is used to refer to the treatment of Sjogren's syndrome, chronic inflammatory disease, radiation therapy or salivary insults caused thereby, severe diarrhea, systemic water loss, diabetes, nutrient deficiency, aging, neurological disease, side effects of anti- A side effect of an allergic drug, or a side effect of an allergic drug.

As used herein, " prevention " refers to any action that inhibits or delays the onset of a disease or condition. In the present invention, it means activation of salivary secretion action of salivary glands to delay or delay the onset of symptom of salivary gland malfunction, hypofunction of salivary glands, atrophy or other causes of decreased salivation.

In the present invention, 'improvement' refers to all actions that alleviate or alleviate a disease or pathological condition. In the present invention, the salivary gland secretion action is activated to cause a salivary gland malfunction, a malfunctioning of the salivary gland, This means that the saliva secretion is reduced and the symptoms of mouth dryness and mouth dryness are improved.

In the present invention, the term " treatment " means any action that delays, stops or reverses the progress of disease or pathology. In the present invention, the salivary gland secretion action is activated in the present invention to cause salivary gland malfunction, Means to stop, alleviate, relieve, relieve, or reverse the symptoms of dry mouth and mouth dryness caused by decreased saliva secretion by cause.

The composition according to the present invention may be in the form of a food composition such as a form of a pharmaceutical composition such as an oral administration agent, a transdermal administration agent and an inhalation administration agent, a functional food, a nutritional supplement, a health food and a food additive, . Such compositions can also be applied to oral health products such as toothpaste, mouthwash, and animal feed products such as dogs and cats.

The pharmaceutical compositions of the present invention may include pharmaceutically acceptable salts of plant sterols. As used herein, the term " pharmaceutically acceptable " refers to those that are physiologically acceptable and do not normally cause an allergic reaction or similar reaction when administered to humans, wherein the salt includes a pharmaceutically acceptable free acid acid is preferred.

The pharmacologically acceptable salt of the plant sterol may be an acid addition salt formed using an organic acid or an inorganic acid. Examples of the organic acid include formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, There may be mentioned acetic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, , p-toluenesulfonic acid or methanesulfonic acid. The inorganic acid includes, for example, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid or boric acid. The acid addition salt may preferably be in the form of a hydrochloride or an acetate, more preferably in the form of a hydrochloride.

The above-mentioned acid addition salts may be prepared by directly a) mixing the plant sterol and the acid, b) dissolving and mixing one of them in a solvent or a water solvent, or c) placing the plant sterol in a solvent or an acid in an anhydrous solvent And mixing them.

Separately, additionally saltable forms include, but are not limited to, the salts of gabapentin, gabapentin, pregabalin, nicotinate, adipate, hemimarate, cysteine, acetylcysteine, methionine, arginine, lysine, Aspartate and the like.

In addition, the composition for preventing or treating dry mouth or saliva secretion enhancement of the present invention may further comprise a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. The carrier for parenteral administration may also contain water, suitable oils, saline, aqueous glucose and glycols and the like. In addition, stabilizers and preservatives may be further included. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).

The pharmaceutical composition of the present invention can be administered to mammals including humans by any method. For example, it can be administered orally or parenterally, and parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, , Intranasal, enteral, topical, sublingual or rectal administration.

The pharmaceutical composition of the present invention may be formulated into oral or parenteral dosage forms according to the route of administration as described above. When formulated, one or more buffers (e.g., saline or PBS), antioxidants, bacteriostats, chelating agents (e.g., EDTA or glutathione), fillers, extenders, binders, adjuvants Side), suspending agents, thickening agents, disintegrating agents or surfactants, diluents or excipients.

Solid preparations for oral administration include tablets, pills, powders, granules, solutions, gels, syrups, slurries, suspensions or capsules, etc. These solid preparations can be prepared by incorporating into the pharmaceutical composition of the present invention at least one excipient, , Starch (including corn starch, wheat starch, rice starch and potato starch), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose , Methyl cellulose, sodium carboxymethyl cellulose and hydroxypropylmethyl-cellulose or gelatin. For example, tablets or tablets may be obtained by combining the active ingredient with a solid excipient, then milling it, adding suitable auxiliaries, and processing the mixture into granules.

In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions or syrups. In addition to water or liquid paraffin, which is a simple diluent commonly used, various excipients such as wetting agents, sweeteners, fragrances or preservatives may be included .

In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may optionally be added as a disintegrant, and may further include an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent .

For parenteral administration, the pharmaceutical compositions of the present invention may be formulated in accordance with methods known in the art in the form of injectable, transdermal and nasal inhalers, together with suitable non-oral carriers. In the case of such injections, they must be sterilized and protected against contamination of microorganisms such as bacteria and fungi. Examples of suitable carriers for injectables include, but are not limited to, solvents or dispersion media containing water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and / or vegetable oils . More preferably, as a suitable carrier, PBS containing Hanks solution, Ringer's solution and triethanolamine can be used, such as sterile water for injection, isotonic solution such as 10% ethanol, 40% propylene glycol and 5% dextrose, etc. . In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like may be further included. In addition, the injections may in most cases additionally include isotonic agents, such as sugars or sodium chloride.

Examples of transdermal dosage forms include ointments, creams, lotions, gels, solutions for external use, pastes, liniments, and air lozenges. In the above, 'transdermal administration' means that the pharmaceutical composition is locally administered to the skin, whereby an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin.

In the case of an inhalation dosage form, the compounds used according to the invention can be formulated into a pressurized pack or a pressurized pack using a suitable propellant, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. It can be conveniently delivered in the form of an aerosol spray from a nebulizer. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated to contain a compound, and a powder mixture of a suitable powder base such as lactose or starch. Formulations for parenteral administration are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, commonly known in all pharmaceutical chemistries.

The pharmaceutical composition of the present invention can provide a desirable saliva-boosting effect when the plant sterol is contained in an effective amount. As used herein, the term " effective amount " refers to an amount exhibiting a further reaction than that of a negative control, and preferably refers to an amount sufficient to enhance salivation. The pharmaceutical composition of the present invention may contain 0.01 to 99.99% of phytosterol, and the remaining amount may be occupied by a pharmaceutically acceptable carrier. The effective amount of the plant sterol contained in the pharmaceutical composition of the present invention will vary depending on the form and the like of the composition.

The total effective amount of the pharmaceutical composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol administered over a prolonged period of time in multiple doses. The pharmaceutical composition of the present invention may vary in the content of the active ingredient depending on the degree of the disease. In the case of parenteral administration, it is preferably administered in an amount of 0.01 to 50 mg, more preferably 0.1 to 30 mg per kg of body weight per day on the basis of the plant sterol, and when administered orally, β-sitosterol, stigmasterol, campesterol And fucosterol, preferably in an amount of 0.01 to 100 mg, more preferably 0.01 to 10 mg per kg of body weight per day. However, the dosage of the plant sterol may be determined depending on various factors such as the route of administration and the number of treatments of the pharmaceutical composition, as well as the patient's age, weight, health, sex, severity of disease, diet and excretion rate In view of this point, one of ordinary skill in the art will be able to determine the appropriate effective dose according to the specific use for enhancing salivation of the plant sterol. The pharmaceutical composition according to the present invention is not particularly limited to the formulation, administration route and administration method as long as the effect of the present invention is exhibited.

The pharmaceutical compositions of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy or biological response modifiers.

The pharmaceutical composition for preventing or treating saliva secretion enhancement or oral dryness or saliva secretion of the present invention may also be provided as a formulation of a topical preparation containing plant sterol as an active ingredient. In this respect, the composition of the present invention may be a quasi-drug composition for enhancing salivation, or for preventing or improving dry mouth, and a quasi-drug comprising the composition.

The external agent may be applied directly to the skin or oral cavity. When the composition of the present invention is used as a external preparation, it may further contain at least one selected from the group consisting of fatty substances, organic solvents, solubilizers, thickening and gelling agents, softening agents, antioxidants, suspending agents, stabilizing agents, foaming agents, Such as an ionic emulsifier, a nonionic emulsifier, a filler, a chelating agent, a chelating agent, a preservative, a vitamin, a barrier agent, a humectant, essential oil, a dye, a pigment, a hydrophilic activator, a lipophilic active agent, And any other ingredients used in the skin sciences. In addition, the components can be introduced in amounts commonly used in the dermatology field.

When the composition of the present invention is provided as a external preparation, it may be a formulation such as, but not limited to, a liquid, an ointment, a patch, a gel, a cream or a spray. According to one embodiment of the present invention, the quasi-drug of the present invention may include an oral care product including toothpaste, a mouthwash and a mouse spray, an ointment, a mask, a poultice, a patch, and a percutaneous absorbent.

In the embodiment of the present invention, when the plant sterol is treated, salivary secretion action of the salivary gland is increased. When the active ingredient is applied to oral care products, salivary secretion action of the salivary gland is increased, The symptom of dry mouth and the symptoms caused thereby can be improved. Therefore, the quasi-drug composition may be a composition for oral administration for preventing or improving saliva secretion enhancement, oral dryness, or saliva secretion.

When the composition of the present invention is used as a quasi-drug composition, the plant sterol may be added as it is or may be suitably used according to a conventional method together with other quasi-drug components. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment).

The food composition of the present invention includes all forms of functional foods, nutritional supplements, health foods, food additives and feeds, It is targeted for eating. Food compositions of this type may be prepared in a variety of forms according to conventional methods known in the art.

Food compositions of this type may be prepared in a variety of forms according to conventional methods known in the art. Common foods include but are not limited to beverages (including alcoholic beverages), fruits and processed foods (eg, canned fruits, jam, maamalade, etc.), fish, meat and processed foods (Eg butter, chewing), edible vegetable oil, margarine (such as corn oil, etc.), breads and noodles (eg udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), juice, various drinks, cookies, , Vegetable protein, retort food, frozen food, various kinds of seasoning (for example, soybean paste, soy sauce, sauce, etc.). The nutritional supplement may be prepared by adding the above plant sterols to capsules, tablets, rings and the like. The health functional foods include, but are not limited to, for example, vegetable sterols themselves can be prepared in the form of tea, juice, and drink to be liquefied, granulated, encapsulated, and powdered for drinking have. In addition, in order to use the plant sterol in the form of a food additive, it may be prepared in the form of powder or concentrate. In addition, the plant sterol may be prepared in the form of a composition by mixing the plant sterol with a known active ingredient known to have a saliva secretion enhancing effect or an effect of preventing or treating dry mouth.

When the food composition of the present invention is used as a health beverage composition, the health beverage composition may contain various flavors or natural carbohydrates as additional components such as ordinary beverages. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose; Polysaccharides such as dextrin, cyclodextrin; Xylitol, sorbitol, erythritol, and the like. Sweeteners include natural sweeteners such as tau Martin and stevia extract; Synthetic sweetening agents such as saccharin and aspartame, and the like can be used. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.

The plant sterol may be contained as an active ingredient of the food composition, and the amount thereof is not particularly limited to an amount effective to achieve saliva secretion enhancement or prevention / treatment of dry mouth, but is preferably 0.01 to 100 wt% . The food composition of the present invention may be prepared by mixing together with other active ingredients known to be effective in saliva enhancing compositions with plant sterols.

In addition to the above, the health food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acid, protective colloid thickener, pH adjusting agent, Glycerin, an alcohol or a carbonating agent, and the like. In addition, the health food of the present invention may contain natural fruit juice, fruit juice drink, or pulp for the production of vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

.

In one embodiment of the present invention, in order to confirm the saliva secretion enhancing effect of beta-sitosterol, stigmasterol, camptosterol, and fucosterol, human sterile saline cells were treated with the plant sterols, And Ca2 +, which is a major factor of.

In another embodiment of the present invention, in order to confirm the effect of enhancing the saliva secretion of beta-sitosterol, stigmasterol, camptosterol, and fucosterol, human sterile saline cells were treated with the plant sterols, As a result, it was confirmed that the plant sterols of the present invention had an enhanced salivary secretion enhancing effect.

The plant sterol of the present invention increases the concentration of intracellular calcium ions, which is a major factor in the salivary secretion, and thus has an excellent effect in preventing salivation, improving or treating dry mouth. Therefore, the present invention can be used safely without side effects because it is a natural product, and it is possible to provide a composition showing an excellent effect on saliva secretion enhancement or prevention, improvement or treatment of dry mouth.

FIG. 1 is a graph showing intracellular Ca ²⁺ measurement by β-sitosterol treatment in human salivary gland (HSG).
FIG. 2 is a graph showing intracellular Ca ²⁺ measurement by stigmasterol treatment in human salivary gland cells (HSG). FIG.
FIG. 3 is a graph showing the intracellular Ca ²⁺ concentration measured by treatment with campesterol in human salivary gland cells (HSG).
FIG. 4 is a graph showing intracellular Ca ²⁺ measurement by fucosterol treatment in human salivary gland cells (HSG).
FIG. 5 shows the results of RT-PCR of mRNA expression of AQP5 in human salivary gland cells (HSG) following treatment with plant sterols (1.beta.-Sitosterol, 2. Campesterol, 3. Fucosterol, 4. Stigmasterol).

Hereinafter, the present invention will be described in detail.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

<Materials>

(CAS Number: 83-46-7, Empirical Formula: C ₂₉ H ₅₀ O, Molecular Weight :: 414.72 g / mol), stigmasterol (CAS Number: 83-48-7, Empirical Formula: C ₂₉ H ₄₈ O, Molecular Weight: 412.70 g / mol), campesterol (CAS Number: 474-62-4, Empirical Formula: C 28 H 48 O, Molecular Weight: 400.69 g / mol) and fucosterol (CAS Number: 17605-67-3 , Empirical Formula: C ₂₉ H ₄₈ O, Molecular Weight: 412.69 g / mol) were purchased from Sigma-Aldrich (St. Louis, Mo., USA).

&Lt; Example 1 >

Verification of enhancing efficacy of β-Sitosterol on salivary secretion

The effect of β-sitosterol on salivary secretion enhancement by intracellular Ca ²⁺ assay was examined. Human HSCs were cultured in Dulbecco's Modified Eagle's Medium (DMEM, Hyclone) medium containing 10% fetal bovine serum (FBS, Hyclone, Logan, UT, USA) in two 100 mm dishes. When the cell density reached 95% in a 100 mm dish, the cells were collected and placed in a cuvette. 5 μL of sulfinpyrazone (Thermo Fisher Scientific) was added to Fura-2AM (Thermo Fisher Scientific Inc., Waltham, Mass., USA) as a Ca ²⁺ indicator. The color change was confirmed and then placed in a cuvette containing the cells. A cuvette was placed on a Spectrofluorophotometer RF-5301 (Shimadzu, Kyoto, Japan), and the stirrer was operated for 1 hour. After 1 hour, the cells in the cuvette were transferred to a 1.5 mL tube and washed with DMEM (Hyclone) to remove Ca ²⁺ from the extracellular media. 100 μL of the cells suspended in 900 μL of Locke's solution and 100 μL of DMEM (Hyclone) were placed in a cuvette and waited for 100 seconds, and β-sitosterol was treated at a concentration of 50 μM. The absorbance of the two materials was measured with a Spectrofluorophotometer RF-5301 (Shimadzu) at a wavelength of 380 nm, which is a self absorption wavelength band of Fura-2AM (Thermo Fisher Scientific), and 340 nm, which is an absorption wavelength band of fura-2AM (Thermo Fisher Scientific) combined with Ca ²⁺ As a result, the increase rate of intracellular Ca ²⁺ was expressed by F340 nm / F380 nm. The increase of Ca ²⁺ was calculated after the pretreatment before the treatment of?-Sitosterol according to the following formula (1).

As a result, as shown in FIG. 1, the lowest value of F340 / F380 ratio before treatment with β-sitosterol was 2.273, and the highest value of F340 / F380 ratio after treatment with β-sitosterol was 3.474. 3.474 / 2.273 × 100 = 152.8%, indicating that intracellular Ca ²⁺ level was increased by about 53% by β-sitosterol. This means that the β-sitosterol of the present invention increases the salivary secretion enhancing effect by increasing Ca 2+, which is a major factor of salivation.

&Lt; Example 2 >

Stigmasterol was proved to enhance salivary secretion

The effect of stigmasterol on salivary secretion enhancement through intracellular Ca ²⁺ assay was examined. After incubation with human salivary gland cells (HSG) in the same manner as in Example 1, the growth rate of intracellular Ca ²⁺ was expressed as F340 nm / F380 nm by treating stigmasterol at a concentration of 50 μM. The Ca ²⁺ growth rate was calculated after the pretreatment before stigmasterol treatment according to Equation (1) above.

As a result, as shown in FIG. 2, the lowest value of F340 / F380 ratio before stigmasterol treatment was 2.065, and the highest value of F340 / F380 ratio after stigmasterol treatment was 3.129. 3.129 / 2.065 × 100 = 151.5%, indicating that the intracellular Ca ²⁺ level was increased by about 52% by stigmasterol. This means that the stigmasterol of the present invention increases the salivary secretion enhancing effect by increasing Ca ²⁺ , which is a major factor in salivary secretion.

&Lt; Example 3 >

The efficacy of Campesterol to enhance salivation

The intracellular Ca ²⁺ assay was performed to examine the effect of campesterol on saliva secretion enhancement. After incubation with human salivary gland cells (HSG) in the same manner as in Example 1, the growth rate of intracellular Ca ²⁺ was expressed as F340 nm / F380 nm by treating campesterol with a concentration of 50 μM. The Ca ²⁺ growth rate was calculated after the pretreatment before the treatment of campesterol according to Equation (1) above.

As a result, as shown in FIG. 3, the lowest value of F340 / F380 ratio before treatment with campesterol was 2.337, and the highest value of F340 / F380 ratio after campesterol treatment was 3.328. 3.328 / 2.337 × 100 = 142.4%, indicating that the intracellular Ca ²⁺ level was increased about 42% by campesterol. This means that the campesterol of the present invention increases the salivary secretion enhancing effect by increasing Ca ²⁺ , which is a major factor in salivary secretion.

<Example 4>

The efficacy of fucosterol to enhance salivation

The effect of fucosterol on salivary secretion enhancement through intracellular Ca ²⁺ assay was examined. After incubation with human salivary gland cells (HSG) in the same manner as in Example 1, fucosterol was treated at a concentration of 20 μM, and the increase rate of intracellular Ca ²⁺ was expressed by F340 nm / F380 nm. The Ca ²⁺ growth rate was calculated after the pretreatment before fucosterol treatment according to Equation (1) above.

As a result, as shown in FIG. 4, the lowest value of F340 / F380 ratio before treatment with fucosterol was 2.22, and the highest value of F340 / F380 ratio after treatment with fucosterol was 3.837. 3.837 / 2.22 × 100 = 172.8%, indicating that the intracellular Ca ²⁺ level was increased by about 73% by fucosterol. This means that fucosterol of the present invention increases the salivary secretion enhancing effect by increasing Ca ²⁺ , which is a main factor of salivary secretion.

&Lt; Example 5 >

The effect of β-sitosterol, stigmasterol, campesterol, and fucosterol on RT-PCR

Human HSCs were grown in Dulbecco's Modified Eagle's Medium (DMEM, Hyclone) containing 10% fetal bovine serum (FBS, Hyclone, Logan, UT, USA) in a 6-well microtiter plate Lt; / RTI &gt; cells / well. After 24 hours, the medium in the wells was removed and DMEM (Hyclone) containing 10% FBS (Hyclone) was treated with 50 μM β-sitosterol, campesterol, stigmasterol and 20 μM fucosterol for 20 minutes. RT-PCR was performed to determine the mRNA expression level of AQP5, a major protein expressed in saliva secretion. Total RNA was isolated from the cells using TRIzol reagent (Takara, Tokyo, Japan). The isolated total RNA was quantified using NanoDrop 1000 (Thermo Fisher Scientific, Waltham, Mass., USA). Quantified 16 μL of RNA was incubated at 42 ° C for 55 min at 70 ° C using a Reverse Transcriptase Premix (ELPIS-Biotech, Daejeon, Korea) and a PCR machine (Gene Amp PCR System 2700, Applied Biosystems, Waltham, 15 minutes. (Bioneer, Daejeon, Korea) and HiPi PCR Premix (ELPIS-Biotech) for 30 seconds at 95 ° C, 1 minute at 53 ° C, 72 ° C PCR was performed by repeating 1 min 23 times.

AQP5:

Forward primer: 5'-AAGACCATGGAGCTGACCAC-3 '(SEQ ID NO: 1)

Reverse primer: 5'-CCCTCTCTAACTGTGCAGCC-3 '(SEQ ID NO: 2)

GAPDH:

Forward primer: 5'-CTCCTGTTCGACAGTCAGCC-3 '(SEQ ID NO: 3)

Reverse primer: 5'-TCGCCCCACTTGATTTTGGA-3 '(SEQ ID NO: 4)

As a result, as shown in FIG. 5, it was confirmed that the amount of AQP5 mRNA expression was increased in human salivary gland cells by treatment with β-sitosterol, campesterol, stigmasterol, and fucosterol. This means that the plant sterol of the present invention is excellent in enhancing the saliva secretion enhancing effect.

Hereinafter, production examples of pharmaceuticals and foods containing the plant sterols of Examples 1 to 5 according to the present invention as an active ingredient will be described, but the present invention is not intended to be limited thereto but is specifically described. The pharmaceutical compositions and food compositions of Preparation Examples 1 to 2 were prepared according to the conventional methods according to the following composition components and composition ratios with the phytosterols having excellent saliva secretion enhancement or dry mouth symptom prevention, improvement or treatment effect.

[Production Example 1]

<1-1> Powder

After mixing 50 mg of β-sitosterol, stigmasterol, campesterol and / or fucosterol and 2 g of crystalline cellulose in Examples 1 to 5, the powder was filled in an airtight container according to a conventional powder preparation method to prepare powders.

<1-2> Purification

The tablets were prepared by mixing 50 mg of β-sitosterol, stigmasterol, campesterol and / or fucosterol, 400 mg of crystalline cellulose, and 5 mg of magnesium stearate in Examples 1 to 5, followed by tableting according to a conventional tablet preparation method.

&Lt; 1-3 >

After mixing 30 mg of β-sitosterol, stigmasterol, campesterol and / or fucosterol, 100 mg of whey protein, 400 mg of crystalline cellulose and 6 mg of magnesium stearate in Examples 1 to 5, the mixture was added to gelatin capsules To prepare a capsules.

<1-4> Injection

The active ingredient was dissolved in distilled water for injection and the pH was adjusted to about 7.5. Then, 100 mg of β-sitosterol, stigmasterol, campesterol and / or fucosterol in the above Examples 1 to 5, distilled water for injection, pH Control agents were mixed and filled into ampoules of 2 ml volume and sterilized to prepare injections.

[Production Example 2]

<2-1> Production of health food

Vitamin E acetate, vitamin E 1.0 mg, vitamin B1 0.13 mg, vitamin B2 0.15 mg, vitamin B6 0.5 mg, and vitamin B12 0.2 mg of fucosterol, 1000 mg of fucosterol, 70 g of vitamin A acetate, ug, vitamin C 10 mg, biotin 10 mg, nicotinamide 1.7 mg, folic acid 50 mg, calcium pantothenate 0.5 mg, ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, potassium monophosphate 15 mg The mixture ratio may be arbitrarily changed, and it may be prepared by mixing 55 mg of calcium diphosphate, 90 mg of potassium citrate, 100 mg of calcium carbonate and 24.8 mg of magnesium chloride, , Granules are prepared and used in the manufacture of a health food composition according to a conventional method.

<2-2> Manufacture of health drinks

Citric acid, 100 g of oligosaccharide, 2 g of plum concentrate, and 1 g of taurine were added to the whole 900 ml normal healthy beverage preparation method of the above Examples 1 to 5 by adding [beta] -sitosterol, stigmasterol, campesterol and / or fucosterol 1000 mg, citric acid 1000 mg, oligosaccharide 100 g, , And the mixture is heated for about 1 hour at 85 ° C., and the resulting solution is filtered to obtain a sterilized 2 L container. The resulting solution is sterilized by sealing, and then stored in a refrigerator for use in the manufacture of a health beverage composition .

<2-3> Chewing gum

Stauramesterol, campesterol and / or fucosterol in an amount of 20% by weight of a gum base, 76.9% by weight of sugar, 1% by weight of a flavor and 2% by weight of water and the above-mentioned examples 1 to 5, .

<2-4> Candy

Stigmasterol, campesterol and / or fucosterol 0.1% by weight of the above-mentioned Examples 1 to 5 were mixed with 60% by weight of sugar, 39.8% by weight of starch syrup and 0.1% by weight of fragrance, and candies were prepared by a conventional method.

<2-5> Biscuit

A mixture of 0.75% by weight of sodium chloride, 0.78% by weight of glucose, 11.78% by weight of palm shortening, 1.54% by weight of ammonium, 0.17% by weight of sodium bicarbonate and 0.16% by weight of sodium bisulfite, 25.59% by weight of Grade I, 22.22% 1.45 wt% of rice flour, 0.0001 wt% of vitamin B, 0.04 wt% of milk fractions, 20.6998 wt% of water, 1.16 wt% of whole milk powder, 0.29 wt% of replacement milk powder, 0.03 wt% of calcium phosphate, 0.29 wt% 7.27% by weight of milk and the β-sitosterol, stigmasterol, campesterol and / or fucosterol% by weight of the above Examples 1 to 5 were mixed to prepare biscuits in a conventional manner.

As described above, the plant sterol of the present invention increases the concentration of intracellular calcium ions, which is a major factor in salivary secretion, and thus has an excellent effect in preventing saliva secretion enhancement or preventing, improving or treating dry mouth. Therefore, the present invention can be used safely without side effects, and it is possible to provide a composition exhibiting an excellent effect for enhancing saliva secretion or preventing, ameliorating or treating dry mouth.

&Lt; 110 > AAT Costech Co., Ltd. <120> Composition for increasing salivary secretion; or prevention or          treatment of xerostomia comprising phytosterols <130> NP17-0121 <160> 4 <170> KoPatentin 3.0 <210> 1 <211> 20 <212> RNA <213> Artificial Sequence <220> <223> Aquasporin 5 primer Forward <400> 1 aagaccatgg agctgaccac 20 <210> 2 <211> 20 <212> RNA <213> Artificial Sequence <220> <223> Aquasporin 5 primer Reverse <400> 2 ccctctctaa ctgtgcagcc 20 <210> 3 <211> 20 <212> RNA <213> Artificial Sequence <220> <223> GAPDH primer Forward <400> 3 ctcctgttcg acagtcagcc 20 <210> 4 <211> 20 <212> RNA <213> Artificial Sequence <220> <223> GAPDH primer Reverse <400> 4 tcgccccact tgattttgga 20

Claims (10)

A pharmaceutical composition for enhancing salivation comprising plant sterol (pnytosterols) as an active ingredient.
2. The composition of claim 1, wherein the plant sterol is selected from at least one of?-Sitosterol, stigmasterol, campesterol, and fucosterol.
A food composition for enhancing saliva secretion comprising plant sterol (pnytosterols) as an active ingredient.
A pharmaceutical composition for preventing or treating dry mouth, which comprises plant sterol (pnytosterols) as an active ingredient.
5. The composition according to claim 4, wherein the plant sterol is at least one selected from the group consisting of?-Sitosterol, stigmasterol, campesterol, and fucosterol. A pharmaceutical composition for preventing or ameliorating dry mouth disease comprising plant sterol (pnytosterols) as an active ingredient.
For enhancing saliva secretion containing plant sterol as an active ingredient; Or for preventing or improving dry mouth; Quasi-drug composition.
For enhancing saliva secretion containing plant sterol as an active ingredient; Or for preventing or improving dry mouth; Quasi-drugs.
The quasi-drug composition according to claim 7, wherein the plant sterol is at least one selected from the group consisting of?-Sitosterol, stigmasterol, campesterol, and fucosterol.
8. The oral care product of claim 7, wherein the quasi-drug comprises an oral care product comprising toothpaste, a mouthwash and a mouse spray; Ointment; Mask; Wetting agents; Patches; And transdermal absorbers. &Lt; RTI ID = 0.0 &gt; 18. &lt; / RTI &gt;

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