KR102251534B1 - A pharmaceutical composition for preventing or treating dry mouth comprising peony and licorice mixed extract - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating dry mouth, comprising a mixed extract of peony and licorice.

Description

{A pharmaceutical composition for preventing or treating dry mouth comprising peony and licorice mixed extract}

The present invention relates to a pharmaceutical composition for preventing or treating dry mouth, comprising a mixed extract of peony and licorice.

Dry mouth (xerostomia) is a disease in which the oral mucosa becomes dry due to a decrease in the secretion of saliva due to various causes. It mainly complains of abnormal mastication and speech functions, and severe bad breath and tooth decay occur, depending on the degree of oral mucosa. A burning sensation or ulcers in the oral mucosa may cause severe pain.

Saliva plays an important role in the maintenance of the oral environment and oral function. That is, saliva has two functions: food intake and oral environment maintenance. In the food intake function of saliva, saliva maintains taste through digestion, such as formation of food lumps and digestive enzymes, or solubilization of taste-stimulating substances or secretion of gastine (which is a carbonate dehydrogenase). Shows action. In the oral environment maintenance function, saliva exhibits a self-cleaning effect of teeth and mucous membranes, a remineralization effect of teeth, an antibacterial effect, an immune function, an effect of promoting tissue repair by growth factors, and an anti-inflammatory effect.

Recently, the number of patients complaining of a decrease in salivation caused by various factors is increasing. Therefore, the social demand for his treatment is increasing. Decreased salivation is accompanied by abnormalities in the salivary glands themselves caused by radiation therapy or mumps, and metabolic diseases (e.g., Basedow's disease, diabetes, etc.), or other diseases such as collagen disease, and the decrease in salivation is also caused by stress. It is also caused by factors or side effects of various drugs. With the aging of the recent population, the function of the salivary glands is degraded by aging, and the number of patients complaining of a decrease in salivation as a result of various drug therapies for various complex diseases that occur in the elderly is expected to increase in the future. Has become.

The decreased salivation, as a result of dry mouth, causes the tongue to turn red and sometimes crack, so that patients with reduced salivation complain of pain during feeding and difficulty in chewing or swallowing. In addition, salivation is known to cause discomfort in the oral cavity or impaired taste and pronunciation, and cause denture instability, tooth decay, onset of periodontitis, stomatitis, pneumonia, and digestive insufficiency.

The topical application of artificial saliva is used as a treatment for salivation reduction, but its effect is temporary and limited. As salivation promoters, anethol trithione, known as a muscarinic receptor agonist, and sebimeline hydrochloride are used, and these are unstable and have problems with the possibility of side effects of the digestive system such as nausea, vomiting, loss of appetite, and abdominal discomfort. There are several drawbacks. In this situation, the development of a new therapeutic agent for the treatment of hyposalivation is desired.

For the prevention and treatment of dry mouth accompanied by severe pain as described above, it is urgently needed to develop a composition for promoting the secretion of a natural substance without side effects other than the compound known to have an effect of promoting salivation. For example, Korean Laid-Open Patent No. 10-2016-0028423 discloses a composition for the prevention and treatment of dry mouth containing a compound (ID-56D2) isolated from an extract of Sukiyaki as an active ingredient. No. 10-2011-0049015 discloses a composition for enhancing saliva secretion containing a rhubarb extract.

Peony is a double-leaf plant, and it is widely used for horticulture because of its beautiful flowers. It is distributed in Korea, Mongolia, and Siberia, and grows in mountainous areas. The root is used as a medicine for pain relief, abdominal pain, menstrual pain, amenorrhea, hemoemia, anemia, and bruises. Licorice has excellent pharmacological action from ancient times, has been used in various herbal medicines, and has been particularly effective in hepatitis, urticaria, dermatitis, and eczema.

As a result of conducting research for the treatment of dry mouth, the present inventors confirmed that the mixed extract of peony and licorice was effective in treating dry mouth, and completed the present invention.

The present inventors conceived to solve the above problem, confirmed that the mixed extract of peony and licorice has a therapeutic effect on dry mouth, and completed the present invention.

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating dry mouth comprising a mixed extract of peony and licorice.

Another object of the present invention is to provide a health functional food composition for preventing or improving dry mouth comprising a mixed extract of peony and licorice.

Another object of the present invention is to provide an oral composition for improving dry mouth comprising a mixed extract of peony and licorice.

The present invention can provide a pharmaceutical composition for preventing or treating dry mouth comprising a mixed extract of peony and licorice.

The mixed extract of peony and licorice may be a hot water extract.

The peony and licorice may be mixed in a weight ratio of 10:1 to 1:1.

The dry mouth may be caused by any one or more selected from the group consisting of Sjogren's syndrome, diabetes, anemia, malnutrition, and aging.

The concentration of the mixed extract of peony and licorice may be 50 to 500mg/kg.

The present invention can provide a health functional food composition for preventing or improving dry mouth comprising a mixed extract of peony and licorice.

The present invention can provide a composition for oral dryness improvement comprising a mixed extract of peony (Paeonia lactiflora Pallas) and licorice (Glychrrhiza uralensis Fischer).

The oral composition may be a liquid toothpaste, a mouthwash, an oral spray, or an oral ointment.

As a result of treating the mixed extract of peony and licorice of the present invention on salivary gland cells, there is an effect of increasing the amount of expression of amylase and water pump Aquaporin-5, which directly promotes the secretion of saliva and inhibits ROS production, in a concentration-dependent manner. In addition, as a result of administering the mixed extract of peony and licorice to diabetic rats, there was an effect of increasing the amount of salivation in a concentration-dependent manner compared to the untreated rats. Therefore, when treated with mixed extract of peony and licorice, there is an effect of preventing or treating dry mouth.

Figure 1 is a measurement of the amount of ROS when a mixture of peony and licorice extract is treated in human salivary gland cells (Human submandibular duct cell).A is a measure of the amount of ROS in the cytoplasm using DCFH dye, and B is a MitoSox dye. It is a measure of the amount of ROS produced in mitochondria.
Figure 2 is a result of confirming the expression levels of amylase and water pump Aquaporin-5 when treated with a mixed extract of peony and licorice in human salivary gland cells (Human submandibular duct cells), A is the result of Western blot, B and C is the result of A It is a graph that quantifies.
3 is a result of measuring the amount of saliva secretion when a mixed extract of peony and licorice is administered to diabetic mice.

Hereinafter, the present invention will be described in detail.

Dry mouth (xerostomia) is a disease in which the oral mucosa becomes dry due to a decrease in the secretion of saliva due to various causes. It mainly complains of abnormal mastication and speech functions, and severe bad breath and tooth decay occur, depending on the degree of oral mucosa. It is a disease that causes severe pain due to a burning sensation or an ulcer of the oral mucosa. Accordingly, the present inventors confirmed that the mixed extract of peony and licorice has a therapeutic effect and completed the present invention.

The present invention can provide a pharmaceutical composition for preventing or treating dry mouth comprising a mixed extract of peony and licorice.

The mixed extract of peony and licorice reduced the amount of ROS generated in the cytoplasm and mitochondria (FIG. 1), and increased the expression levels of amylase and ater pump Aquaporin-5 related to salivation in a concentration-dependent manner (FIG. 2). Furthermore, as a result of administering the mixed extract of peony and licorice in diabetic mice, it was confirmed that saliva secretion was increased in a concentration-dependent manner compared to non-administered diabetic mice (FIG. 3).

The peony may be, for example, a peony of the scientific name Paeonia lactiflora Pallas, and the licorice may be, for example, a licorice of the scientific name Glychrrhiza uralensis Fischer, but is not limited thereto.

The extraction site of each medicinal material is not particularly limited, and all sites may be used, but preferably roots may be used.

The extraction solvent is not particularly limited, for example, water or an organic solvent can be used, and the organic solvent is methanol, ethanol, propanol, isopropanol, butanol, etc. Alcohol having 1 to 4 carbon atoms, acetone, ether, benzene, chloroform, ethyl acetate, methylene chloride, hexane, and cyclo Various solvents such as hexane (cyclohexane) may be used alone or in combination, but the present invention is not limited thereto. Preferably, water can be used.

As the extraction method, any one of methods such as hot water extraction, cold precipitation extraction, reflux cooling extraction, solvent extraction, steam distillation, ultrasonic extraction, elution, compression, and the like may be selected and used, and preferably hot water extraction may be used. In addition, the desired extract may be further subjected to a conventional fractionation process, or may be purified using a conventional purification method. There is no limitation on the method for preparing the extract according to the present invention, and any known method may be used.

As a specific example of hot water extraction, for example, 3 to 20 times the weight of the medicine, specifically 5 to 15 times of water is added, and the temperature is 80 to 100°C, specifically 85 to 95°C for 1 hour to 24 hours. , Specifically, it may be extracted for 5 to 12 hours, but is not limited thereto.

The extract according to the invention may be subjected to processes such as filtration, concentration, drying, etc., as necessary after the extraction. The method and conditions are not limited, and may be performed by a method known in the art, or under commonly performed conditions.

The content ratio of the peony and licorice is not particularly limited, but the peony and licorice are preferably mixed in a weight ratio of 10:1 to 1:1, and mixed in a weight ratio of 10:1, 8:1 and 4:1 It is more preferable to do, and it is most preferable to mix in a weight ratio of 2:1.

The dry mouth may be caused by any one or more selected from the group consisting of Sjogren's syndrome, diabetes, anemia, malnutrition, and aging, and may preferably be diabetes, but is not limited thereto.

The concentration of the mixed extract of peony and licorice is not particularly limited, preferably 50 to 500 mg/kg, and more preferably 100 to 250 mg/kg.

The pharmaceutical composition comprising the extract according to the present invention is in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injectable solutions according to a conventional method. It can be formulated and used.

Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, and preservatives may be included. . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

The amount of the extract according to the present invention may vary depending on the age, sex, and weight of the patient, but may be administered in a range of 01 to 100 mg/kg, preferably 01 to 10 mg/kg once to several times a day. In addition, the dosage may be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any way.

The present invention can provide a health functional food composition for preventing or improving dry mouth, including peony and licorice extract.

The mixed extract of peony and licorice may be within the above-described range.

The health functional food of the present invention may be formulated as one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, and liquid formulations, further including at least one of carriers, diluents, excipients and additives. Foods to which the extract of the present invention can be added include various foods, powders, granules, tablets, capsules, syrups, beverages, gums, teas, vitamin complexes, and health functional foods.

As additives that may be further included in the present invention, natural carbohydrates, flavoring agents, nutrients, vitamins, minerals (electrolytes), flavoring agents (synthetic flavoring agents, natural flavoring agents, etc.), coloring agents, fillers (cheese, chocolate, etc.), Pactic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, antioxidants, glycerin, alcohols, carbonation agents and one or more components selected from the group consisting of pulp can be used. .

Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the flavoring agent, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.

In addition to the above, the health functional food of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid. And salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, the composition according to the present invention may contain pulp for the production of natural fruit juice and vegetable beverages. These components may be used independently or in combination.

Specific examples of the carrier, excipient, diluent, and additive are, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium phosphate, calcium Silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate And it is preferable that at least one selected from the group consisting of mineral oil is used.

When formulating the health functional food of the present invention, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. that are usually used.

The content of the extract according to the present invention as an active ingredient in the above-described formulation can be appropriately adjusted according to the form and purpose of use, the condition of the patient, the type and severity of symptoms, etc., based on the weight of the solid content, 0.001 to 99.9% by weight, preferably May be 0.01 to 50% by weight, but is not limited thereto.

The dosage of the health functional food of the present invention may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease degree, and according to the judgment of a doctor or pharmacist, once a day or several times a day. It can also be administered in divided doses. For example, the daily dosage may be 0.5 to 500 mg/kg, preferably 1 to 300 mg/kg based on the active ingredient content. The above dosage is an example of an average case, and the dosage may be high or low depending on individual differences. If the daily dosage of the health functional food of the present invention is less than the above dosage, a significant effect may not be obtained, and if it exceeds that, it is not only uneconomical, but also outside the range of the normal dosage, undesirable side effects may occur. have.

The present invention can provide a composition for oral dryness improvement comprising a mixed extract of peony (Paeonia lactiflora Pallas) and licorice (Glychrrhiza uralensis Fischer).

The oral composition may be a liquid toothpaste, a mouthwash, an oral spray, or an oral ointment.

Hereinafter, examples will be described in detail in order to describe the present invention in detail.

Example 1. Preparation of peony and licorice extract

To prepare mixed extracts of Peony Root and Licorice, peony was purchased from CK Herb (Boeun, Chungcheongbuk-do, Korea), and Licorice was purchased from Licorice Farming Association (Jecheon, Chungcheongbuk-do, Korea). 100 parts by weight of peony (Paeonia lactiflora Pallas) and 50 parts by weight of licorice (Glychrrhiza uralensis Fischer) were put in a container, and 1500 parts by weight of water were added. Thereafter, hot water extraction was performed at 90° C.±5° C. for 8 hours to obtain an extract, which was filtered through a 50 μm filter to obtain a filtrate. The filtrate was mixed with maltodextrin and solid content at a ratio of 3:7, and concentrated to a solid content of 35%±5% at 50°C±5°C. The concentrate was spray-dried at 170°C±30°C to obtain an extract with a moisture content of 5% or less (with a yield of 40±5% excipient).

Example 2. Functional test of salivary secretion in in vitro salivary gland cells

2-1. Efficacy in inhibiting the production of active oxygen (ROS)

In order to confirm the damage to salivary gland cells caused by ROS, which is one of the main causes of dry mouth, the production of ROS was induced under high blood sugar conditions (30 mM high glucose) and the activity of EGHB010 was verified. Human submandibular duct cells, A253 cells (American Type Culture Collection, Manassas, VA, USA) are cultured using Complete Growth Medium (American Type Culture Collection, Manassas, VA, USA). ^{After growing 2*10 5} /well cells in a 96 well plate, EGHB010 was diluted to various concentrations and treated for 1 hour, followed by treatment for 24 hours in 30 mM high glucose condition to induce the production of ROS. Thereafter, they were stained with DCF-DA (Invitrogen Corp., CA, USA) and MitoSOX (Invitrogen Corp.), respectively, and then incubated for 1 hour. Thereafter, fluorescence was measured in a fluorescence microplate reader to measure the amount of ROS produced in the cytoplasm and in the mitochondria. As a result of confirming the amount of ROS generated in the cytoplasm using DCFH dye as shown in FIG. 1, the production of ROS increased by 1.5 times or more under high glucose conditions, and as a result of treatment with EGHB010 at a concentration of 10 to 100 ug/ml, concentration-dependently The efficacy of inhibiting the production of ROS was confirmed. In addition, in the result of confirming the amount of ROS produced in mitochondria using MitoSox dye, it was confirmed that the amount of ROS produced in high glucose increased in a concentration-dependent manner by EGHB010 treatment, similar to the previous result.

2-2. Analysis of expression levels of salivary digestive enzyme amylase and water pump Aquaporin-5

In order to verify the efficacy of EGHB010 in promoting the secretion of saliva in salivary gland cells, the expression levels of the salivary digestive enzyme amylase and water pump Aquaporin-5 were analyzed. After growing A253 cells in a 96 well plate at 2*10 ⁵ /well, EGHB010 was diluted to various concentrations and treated for 1 hour, followed by treatment under 30 mM high glucose condition for 24 hours. Subsequently, the protein was extracted and western blot was performed. After measuring the protein concentration using a BCA kit (Sigma-Alderich Co. LLC), the same amount of the protein was electrophoresed on an SDS-PAGE gel, and a Hybond-ECL nitrocellulose membrane (Amersham Pharmacia Biotech, Inc., Piscataway, Inc., Piscataway, etc.) NJ, USA). After that, the membrane was blocked with 0.1% skim milk for 1 hour, then reacted with the primary antibody for 1 hour, and then reacted with HRP-conjugated secondary antibody (Thermo Fisher Scientific Inc.) for 1 hour, and SuperSignal West Pico ECL The protein was detected with a solution (Thermo Fisher Scientific Inc.) and the protein was detected with a Fuji LAS-3000 system (Fujifilm, Tokyo, Japan). The primary antibodies used in this experiment were mouse anti-amylase antibody (Santa Cruz Biotechnology, CA, USA), rabbit anti-AQP5 antibody (Santa Cruz Biotechnology), and β-actun (Sigma-Alderich Co. LLC). As shown in FIG. 2, when high glucose is treated, the expression level of the digestive enzyme amylase in salivary gland cells decreases, and the expression level of aquaporin-5 (AQP5), an important pump secreting saliva in salivary cells, is significantly reduced. However, it was confirmed that when EGHB010 was treated at a concentration of 10 to 100 ug/ml, the amount of expression of these proteins was increased in a concentration-dependent manner.

Example 3. Evaluation of the efficacy of promoting salivation in diabetic mice in vivo

Six-week-old male SD rats (Samtaco, Korea) were used after being acclimated for one week. Feed and drinking water were fed freely. After inducing diabetes with STZ (60 mg/kg, ip), only subjects with blood glucose of 350 mg/dL or more were selected and used in the experiment after a week. The test drug was administered by separating the groups as follows. (1) Normal group, (2) diabetes induction group, (3) EGHB010 100 mg/kg administration group, (4) EGHB010 250 mg/kg administration group. The test drug was administered orally and once a day for 4 weeks. Autopsy was performed 4 weeks after drug administration for each group. In order to measure the amount of salivation, the rat was intraperitoneally injected with pilocarpine9 (0.6 mg/kg) to induce salivation. Thereafter, a cotton ball, weighed in advance, was inserted into the oral cavity and left for 1 minute to allow the secreted saliva to be absorbed. After 1 minute, saliva is absorbed and the wet cotton ball is recovered, the weight is measured, and the saliva is collected by centrifugation at 10,000 rpm to quantify the amount of saliva. The salivary secretion was measured for 4 times once a week for 4 weeks. As shown in FIG. 3, in the diabetic-induced rat, the amount of salivation was reduced by about half after one week, and the amount of salivary secretion gradually decreased during the next 4 weeks, reaching a state in which almost no saliva was secreted after 4 weeks. However, in the mice administered EGHB010, the amount of saliva secretion decreased compared to that of the normal mice, but no further reduction in the amount of saliva was observed. Although the amount was small in the 250 mg/kg group, the amount of salivation after 4 weeks administration This small increase was observed.

Claims (8)

Peony (Paeonia lactiflora Pallas) and licorice (Glychrrhiza uralensis Fischer) comprising a mixed extract containing only, the peony and licorice is a weight ratio of 2: 1, a pharmaceutical composition for preventing or treating dry mouth due to diabetes or aging.
The pharmaceutical composition of claim 1, wherein the mixed extract of peony and licorice is a hot water extract, preventing or treating dry mouth due to diabetes or aging.
delete delete The pharmaceutical composition according to claim 1, wherein the concentration of the mixed extract of peony and licorice is 50 to 500mg/kg, preventing or treating dry mouth due to diabetes or aging.
Contains a mixed extract containing only peony (Paeonia lactiflora Pallas) and licorice (Glychrrhiza uralensis Fischer), wherein the peony and licorice is a weight ratio of 2: 1, health functional food composition for preventing or improving dry mouth due to diabetes or aging.
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