KR102030123B1 - Composition for preventing or treating hearing loss - Google Patents

Abstract

The present invention relates to a composition for preventing or treating hearing loss containing an extract of Shuteria involucrata as an active component. Since the composition containing the extract of Shuteria involucrata can effectively inhibit improvement of hearing due to hearing loss and damage to hair cells caused by the use of antibiotics, the composition is useful for preventing, treating or alleviating hearing loss, in particular, ototoxic deafness, thereby being able to be usefully used as a pharmaceutical composition or health functional food.

Description

Composition for preventing or treating hearing loss

The present invention is Shuteria Involukratta Involucrata ) relates to a composition for the prevention or treatment of hearing loss comprising the extract as an active ingredient.

To date, the research and development of diseases related to the ear has been largely related to diseases caused by inflammation such as bacterial otitis, malignant otitis, fungal otitis, binary fungus, otitis media, or otitis media, and mainly focused on the development of related therapeutic agents. have.

Looking specifically at a disease associated with the ear, first, otitis externa (external ear infection) is caused by inflammation occurring in the outer ear and the ear canal, and is a common cause of ear pain in humans. The inflammation may be caused by a fungal, viral or bacterial organism. The external auditory meatus is often swollen, painful, and painful if touched. In another embodiment, otitis media (middle ear infection) occurs at the site between the eardrum and the inner ear, including the eustachian tube. It is very common in children, on average infants experience two to three times per year, usually accompanied by viral upper respiratory tract infection (URI) and most common colds. Otitis media can cause swelling and hyperemia of rhinoviruses and adenoviruses, which are the most common causes of cold symptoms, and can also be caused by a variety of bacteria and other viruses.

Since most of the ear-related diseases are accompanied by inflammation, the treatments are those using antibiotics, anti-inflammatory agents, etc., and to date, most treatments are based on antibiotics or anti-inflammatory agents.

However, due to the increase in noise exposure and the aging of the population, problems related to hearing loss due to cellular or nerve damage are emerging, rather than the above-described inflammatory-based ear-related diseases. Moreover, to the extent that the general population can distinguish between ear-related diseases caused by inflammation such as bacterial otitis, malignant otitis, fungal otitis, binary fungus, otitis media, or otitis, and hearing loss caused by cellular or nerve damage, Hearing loss is one of the most prevalent and widely known diseases in modern society. Hearing loss caused by damage to cells and nerves may include noise, aging, and other toxic drugs, neurotoxic chemicals, viruses, and genetics.

For the treatment of hearing loss, a number of specialists and workers in the pharmaceutical industry are still aiming to treat the disease with a therapeutic agent based on existing antibiotics or anti-inflammatory agents, but it cannot be used as a suitable treatment for hearing loss. On the other hand, the use of antibiotics or anti-inflammatory based therapeutics for the treatment of hearing loss is because, firstly, there are no known treatments related to hearing loss, and secondly, a number of specialists and workers in the pharmaceutical industry are concerned about the treatment of hearing loss. Because they are not clearly aware. Due to these problems, the problem of inadequately performing the treatment of hearing loss continues to arise.

In particular, the use of antibiotics presents a major problem due to its toxicity. For example, aminoglycoside antibiotics have the side effects of toxic and nephrotoxicity that cause hearing and equilibrium dysfunction in the inner ear, which can occur not only in overdose but also in long-term doses as therapeutic doses, and in some cases even in short-term titration doses. This may occur. Aminoglycoside antibiotic toxicity is seen in both ears, with vestibular dysfunction in about 15% of users and hearing loss in 10-30%, mainly in the form of acute high hearing loss at high frequencies above 4000Hz.

Accordingly, preclinical studies on various drugs have been reported as studies to find an effective substance for the prevention and treatment of hearing loss, but it has been confirmed that there is a limit to proceeding to clinical trials. In addition, there are no approved drugs to date for the prevention and treatment of hearing loss. Moreover, there are few drugs developed for the treatment of hearing loss using natural materials or natural materials which can be used without toxicity or danger to the human body. In other words, unlike ear-related diseases caused by inflammation, no suitable treatment for hearing loss has been developed.

Accordingly, the present inventors have made intensive research efforts to find a material having a preventive or therapeutic effect on hearing loss from natural plant materials, such as food or pharmaceutical materials, which have secured safety, and have been studied as a result. Shuteria involucrata ) extract, such as methanol extract thereof, was found to have an effect of protecting hair cells from damage by antibiotics, and the present invention was completed.

1. Korea Patent Registration No. 10-1367479 2. Korea Patent Registration No. 10-1777157

One object of the present invention is Shuteria It is to provide a pharmaceutical composition for preventing or treating hearing loss ( involucrata ) extract as an active ingredient.

Another object of the present invention is to provide a method for preventing or treating hearing loss, comprising administering the pharmaceutical composition to a subject in need thereof.

It is another object of the present invention to provide a food composition for preventing or improving hearing loss, which comprises an extract of Steria involukratata as an active ingredient.

As one embodiment for achieving the above object, the present invention provides a pharmaceutical composition for preventing or treating hearing loss ( shuteria involucrata ) extract containing as an active ingredient (hearing loss).

The present invention finds that a non-toxic alien plant native to China and used as a medicament, Steria involukrata, such as its methanol extract, can inhibit damage to hair cells by external stimuli such as drugs. Based on what you did.

Terminology of the present invention, " Steria Involukrata ( Shuteria) involucrata ) "is Shuteria involucrata (Wallich) Wight & Arnott or Glycine involucrata Wallich, a plant in Chinese character 宿 苞 豆. Herbs 1 to 3 m in size, the stems are thin and entangled, densely pubescent or glabrous without hair. The leaves are pinnately divided into three small leaves (3-foliolate). The stipules persist in ovate-lanceolate. Leaf tip 2.5-7.5 cm, small stipels linear, leaflets broadly ovate, egg-shaped or nearly rounded (1.5-6.5 cm) x (1.1-5.5 cm) (suborbicular), can form a thin papery film (membranous to thinly papery). The base is round, the apex is round, somewhat concave and has a small mucro. Inhabits China, Bhutan, Cambodia, India, Indonesia, Malaysia, Myanmar, Nepan, Philippines, Thailand, Sri Lanka and Vietnam, and grows in mountains, roadsides and forest margins. Blooms from September to March and bears fruit from November to March. It is also known to be used as a medicine, but the effect of preventing or treating hearing loss is not known.

As used herein, the term "hearing loss" may mean any condition in which hearing is deteriorated or lost. The hearing loss may include conductive hearing loss and sensorineural hearing loss. The pre-negative hearing loss is a hearing loss caused by the ear disease, a hearing loss caused by problems such as the eardrum and iso bone, which are organs that transmit sound, and sensory neuron deafness that transmits sound through the cochlea and electrical energy. Hearing loss caused by problems in the auditory nerve and the brain responsible for the overall role of sound discrimination and understanding. The cause of the dual sensorineural hearing loss may be noise, drugs, aging, trauma, etc., a typical example is the toxic hearing loss caused by the administration of optotoxic drugs. Drugs that can cause the toxic hearing loss are gentamycin (gentamycin), streptomycin (streptomycin), kanamycin (kanamycin), neomycin (neomycin), amikacin (amikacin), tobramycin (tobramycin), netylmycin ( antibiotics such as netilmycin, dibekacin, sisomicin, or ribodomycin; And anticancer agents such as cisplatin, carboplatin, or oxaliplatin.

Diseases that can be prevented or treated by the pharmaceutical composition of the present invention may include noise-induced hearing loss, senile hearing loss, sudden hearing loss, neuropathy caused by diabetes, toxic hearing loss, traumatic hearing loss, viral hearing loss, and the like. If it is a reduced or lost condition, it is not limited to the above-exemplified diseases and may be included in the scope of the present invention.

As used herein, the term "extract" refers to an extract obtained by extracting the Steria involut krata, a diluent or concentrate of the extract, a dried product obtained by drying the extract, a crude or purified product of the extract, or a mixture thereof. And the like, including extracts themselves and all formulations of preparations that can be made using the extracts.

The extract of the present invention can be obtained by extracting the starch, stem, leaves, flowers, berries, roots or mixtures thereof of Steria involukrat, and can be extracted from its natural, hybrid or variant plants, Extraction from tissue culture is also possible.

The method of extracting the steric involucrata 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 performed alone or in combination of two or more methods.

In addition, the kind of extraction solvent used for extracting the steric involukratta is not particularly limited, and any solvent known in the art may be used. Non-limiting examples of the extraction solvent include water or C _1-4 lower alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, etc.), and these may be used alone or in combination of one or more. . Specifically, methanol or ethanol aqueous solution may be used, the methanol or ethanol aqueous solution is 70 to 90% (v / v), more specifically 75 to 85% (v / v), most specifically 80% (v / v ) Methanol or ethanol, but is not limited thereto.

Further, the extraction temperature may be adopted by those skilled in the art in various temperature ranges suitable for the extraction method, for example, may be carried out at 20 ℃ to 100 ℃, etc., but is not limited thereto. In addition, the extraction time is different depending on the extraction method, a person skilled in the art can adopt an appropriate extraction time, but is not limited to this, can be performed in a single or multiple times in the range of about 1 hour to 10 days. Extract obtained by performing the extraction with the primary extraction solvent is obtained in a liquid form by removing impurities by filtration in accordance with a conventional method, or the extract of the liquid form obtained in a powder form by concentrating under reduced pressure and / or drying in accordance with a conventional method You can get it.

In addition, the extraction process may further comprise the step of obtaining a fraction having a high content of the active ingredient, if necessary. That is, after dispersing the extract obtained by the extraction with the primary extraction solvent in water, and performing the step of extracting with an appropriate secondary extraction solvent, for example, saturated C _1-4 lower alcohol can increase the content of the active ingredient. have.

In a specific embodiment of the present invention, extracting the aqueous solution of sterile involukratta methanol was extracted by extracting the steric involut krata of Chinese origin. Specifically, the outpost of Steria involukratta was prepared by dipping in 80% (v / v) methanol for 1 hour at 80 ℃.

The composition of the present invention may contain, but is not limited to, the Steria involukrata extract in an amount of 0.1 to 95% based on the total weight of the composition.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier, and oral formulations, external preparations, suppositories, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to conventional methods. And sterile injectable solutions.

Such pharmaceutically acceptable carriers are those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. In addition, the pharmaceutical compositions of the present invention include diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and other pharmaceutically acceptable additives.

When the pharmaceutical composition of the present invention is formulated as an oral solid preparation, it includes tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, Sucrose or lactose, gelatin, and the like, and include, but are not limited to, lubricants such as magnesium stearate, talc, and the like.

When the pharmaceutical composition of the present invention is formulated for oral liquid preparation, it includes a suspending agent, a liquid solution, an emulsion, a syrup, and the like, and includes, but is not limited to, diluents such as water and liquid paraffin, wetting agents, sweeteners, fragrances, preservatives and the like.

When the pharmaceutical composition of the present invention is formulated for parenteral use, it includes sterilized aqueous solution, non-aqueous solvent, suspending agent, emulsion, lyophilized preparation, suppository, and non-aqueous solvent, suspending agent is propylene glycol, polyethylene glycol, olive Vegetable oils such as oils, injectable esters such as ethyloleate, and the like. Bases of suppositories may include, but are not limited to, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.

In another aspect, the present invention provides a method for preventing or treating hearing loss, comprising administering the pharmaceutical composition to a subject in need thereof.

In the present invention, terms such as "steria involukratata extract" and "hard of hearing loss" are the same as described above.

The term "individual" of the present invention refers to all animals including humans that may or may not have hearing loss, typically, by treatment with a pharmaceutical composition comprising the Steria involukratta extract of the present invention as an active ingredient It may be a mammal, which may have a beneficial effect, for example, a primate, such as a human, but includes, without limitation, any subject that has or is likely to have symptoms of hearing loss. As described above, by administering the pharmaceutical composition of the present invention to an individual, the hearing loss can be effectively prevented or treated. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent, or in combination with an existing hearing loss treatment agent, and may be administered sequentially or simultaneously with the conventional treatment agent.

The term "administration" of the present invention means introducing a predetermined substance into a patient in an appropriate manner and the route of administration of the composition can be administered via any general route as long as it can reach the target tissue. In addition, the pharmaceutical compositions of the present invention may be administered by any device in which the active substance may be transferred to the target tissue. For example, oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, pulmonary administration, rectal administration, but is not limited thereto. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, suppositories.

The composition may be administered in single or multiple amounts in a pharmaceutically effective amount. As used herein, the term “pharmaceutically effective amount” means an amount sufficient to prevent or treat a disease at a reasonable benefit / risk ratio applicable to medical prophylaxis or treatment, and an effective dose level refers to the severity of the disease, the activity of the drug, Including the age, body weight, health, sex of the patient, sensitivity to the drug of the patient, time of administration of the composition of the invention used, route of administration and rate of release, duration of treatment, drugs used in combination or concurrently with the composition of the invention used Factors, and factors well known in the medical arts. For example, the steria involukratta extract may be administered at a dose of 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg, and the administration may be administered once or several times a day. have.

As another aspect, the present invention provides a food composition for preventing or improving hearing loss, which comprises an extract of Steria involukratta as an active ingredient.

The food composition of the present invention can be used as a dietary supplement. The term "health functional food" means a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body according to the law on health functional foods, and "functionality" refers to the structure and function of the human body. It means the ingestion for the purpose of obtaining a useful effect for health use such as nutrient control or physiological action.

The food composition of the present invention may include a conventional food additive, and the suitability as the "food additive" is applicable according to the General Regulations and General Test Law of the Food Additives approved by the Ministry of Food and Drug Safety unless otherwise specified. Judge according to the standards and standards for the item.

Examples of the items listed in the "Food Additive Revolution" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamon acid, natural additives such as color pigments, licorice extracts, crystalline cellulose, high color pigments, guar gum, Mixed preparations, such as a sodium L- glutamate preparation, an addition of an alkali, a preservative preparation, and a tar pigment preparation, are mentioned.

The food composition of the present invention may comprise from 0.01 to 95% by weight, preferably 1 to 80% by weight of the Steria involukratta extract relative to the total weight of the composition. In addition, the Steria involukrata extract contained in the food composition of the present invention may be obtained by the same or similar method as the extraction method mentioned in the preparation of the pharmaceutical composition, but is not limited thereto.

In addition, the food composition of the present invention may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills and the like for the purpose of preventing and / or improving hearing loss.

For example, the health functional food in the form of tablets may be granulated in a conventional manner by mixing a mixture with a steria involutcrata extract, an excipient, a binder, a disintegrant, and other additives, and then compression molding with a lubricant or the like. The mixture may be directly compression molded. In addition, the health functional food in the form of tablets may contain a mating agent and the like, if necessary, may be coated with a suitable coating agent.

Hard capsules of the health functional food in the form of capsules can be prepared by filling a conventional hard capsules with a mixture of additives such as Steria involut krata extract, and excipients or granules or peeled granules thereof. The preparation may be prepared by filling a capsule base such as gelatin with a mixture of an additive such as a steria involukrat extract and an excipient. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, as necessary.

The dietary supplement in cyclic form may be prepared by molding a mixture of Steria involukrat extract, excipient, binder, disintegrant, etc. in a suitable manner, and may be coated with sucrose or other suitable coating agent, or starch, talc, if necessary. Or they may be greeted with a suitable substance.

The health functional food in the form of granules may be prepared by granulating a mixture of a steria involut krata extract, an excipient, a binder, a disintegrating agent and the like in an appropriate manner, and may contain a flavoring agent, a copper, and the like as necessary. As for the health functional food in the form of granules, using No. 12 (1680 μm), No. 14 (1410 μm) and No. 45 (350 μm) sieves, the total size of No. 12 remaining in No. 14 body when the next particle size test is performed It may be 5.0% or less of the total amount, and passing through No. 45 may be 15.0% or less of the total amount.

The definitions of the excipients, binders, disintegrants, lubricants, copulation agents, flavoring agents and the like are described in literature known in the art and may include those having the same or similar functions. , Korean College of Pharmacy, 5th Edition, p33-48, 1989).

There is no particular limitation on the type of food, and examples of foods to which the extract of the present invention may be added include beverages, gums, vitamin complexes, drinks, and the like, and include all health functional foods in a conventional sense.

Shuteria Involukratta of the present invention The composition comprising the involucrata ) extract can effectively suppress the damage of the hair cells caused by the use of antibiotics as well as the hearing increase due to hearing loss, and thus is useful for the prevention, treatment or improvement of hearing loss, in particular, toxic hearing loss. Or it can be usefully used as a dietary supplement.

1 is Shuteria Involukratta Involucrata ) is a diagram showing the inhibitory effect on hair cell damage by neomycin treatment. NOR represents a non-neomycin-treated normal control group, NM represents a comparison group treated with neomycin only, and SIE represents an experimental group treated with Steria involukratta extract at a concentration of 1 μg / mL.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.

Production Example  One: Steria Involukrata  Preparation of Extract

Steria involluta of Chinese origin (Shuteria involucrata) 80% (v / v) methanol extract was distributed from the Korea Institute of Bioscience and Biotechnology's Overseas Biomaterials Center.

The Steria involukratta methanol extract was extracted at 80 ° C for 1 hour by immersing the Steria involukratta outpost in 80% (v / v) methanol. The above procedure was repeated once to prepare an extract, concentrated at 55 ° C. under a reduced pressure concentrator, and freeze-dried to finally obtain the Steria involukratta methanol extract.

Production Example  2: Toxicity  Deafness Zebrafish  Manufacturing of models

After six days of fertilization, zebrafish larvae were placed in 24 wells, and neomycin was treated at 2 μM concentration to expose for 1 hour to prepare a toxic hearing loss model. Along with the neomycin-treated untreated normal control was prepared.

Example  One: Toxicity  Deafness Zebrafish  About the model Steria Involukrata  Effect of Extract

The toxic deafness zebrafish model prepared according to Preparation Example 2 was treated with a concentration of 1 μg / mL of the Steria involukratta methanol extract prepared according to Preparation Example 1 and exposed for 6 hours. As a comparison group, 0.03% sea salt solution was used. In the normal control group prepared according to Preparation Example 2 and the toxic deafness model of Preparation Example 2, an experimental group and a comparative group of zebrafish fry treated with Steria involukratta methanol extract and sea salt solution were anesthetized with 0.02% tricaine, Hair cells were stained with 0.1% YO-PRO for 30 minutes and observed by naked eye using a fluorescence microscope (Olympus 1 × 70, Olympus, Japan). Specifically, the number of hair cells observed with the naked eye was counted and graphed, and the fluorescence image was photographed and shown in FIG. 1.

As shown in FIG. 1, the number of hair cells in the comparison group that was not treated with Steria involukratata methanol extract in the toxic deafness-induced zebrafish model was significantly reduced compared to the normal control group, whereas the toxic deafness-induced zebrafish In the experimental group treated with Esterria involukratta methanol extract, the number of hair cells was significantly increased again. This reduces the hair cell damage caused by toxic hearing loss by treatment with Steria involukratta methanol extract, indicating that it is effective in the prevention and treatment of hearing loss.

Formulation example  1: preparation of tablets

Steria Involukrata Extract 1000 mg

Lactose 100 mg

Starch 100 mg

Magnesium stearate proper amount

Tablets were prepared by mixing and tableting each component with the above composition according to a conventional tablet manufacturing method.

Formulation example  2: Liquid  Produce

Steria Involukrata Extract 1000 mg

20 g of CMC-Na

20 g of isomerized sugar

Lemon flavor

Up to 1000 mL of purified water

According to the conventional liquid preparation method, each component was mixed with the above composition, and then filled into a brown bottle and sterilized to prepare a liquid preparation.

Formulation example  3: Preparation of Capsule

Steria Involukrata Extract 1000 mg

3 mg of crystalline cellulose

Lactose 14.8 mg

Magnesium Stearate 0.2 mg

According to the conventional capsule preparation method, each component was mixed with the above composition and filled into gelatin capsules to prepare a capsule.

Formulation example  4: Preparation of Injection

Steria Involukrata Extract 1000 mg

Mannitol 180 mg

Sterile distilled water for injection 2974 mg

_{Na 2 HPO 4 · 12H 2 O} 26 mg

Injectables were prepared to contain each component in the above composition per 2 mL dose of ampoule according to a conventional injectable preparation method.

Formulation example  5: Preparation of Health Functional Drink

Steria Involukrata Extract 1000 mg

Citric acid 1000 mg

100 g oligosaccharides

Plum concentrate 2 g

Up to 900 mL of purified water

According to the conventional health functional beverage production method, the health functional beverage was prepared by mixing each component with the above composition.

Claims (10)

Shuteria Involucrata ) A pharmaceutical composition for preventing or treating hearing loss, comprising the extract as an active ingredient.
The method of claim 1,
The hearing loss is a pharmaceutical composition that is conductive hearing loss or sensorineural hearing loss.
The method of claim 1,
The hearing loss is any one selected from the group consisting of noise-induced hearing loss, senile hearing loss, sudden hearing loss, neuropathy caused by diabetes, toxic hearing loss, traumatic hearing loss and viral hearing loss.
The method of claim 1,
The steric involukratta extract is a pharmaceutical composition of the water, C _1-4 lower alcohol or a mixed solvent extract of the steric involutcrata.
The method of claim 4, wherein
The Steria involukrata extract is a pharmaceutical composition of 80% (v / v) methanol extract of the Steria involucrata.
Food composition for the prevention or improvement of hearing loss comprising a steria involukratata extract as an active ingredient.
The method of claim 6,
The hearing loss is food composition that is deafness or sensorineural hearing loss.
The method of claim 6,
The hearing loss is any one selected from the group consisting of noise-induced hearing loss, senile hearing loss, sudden hearing loss, neuropathy caused by diabetes, toxic hearing loss, traumatic hearing loss and viral hearing loss.
The method of claim 6,
The Steria involukratta extract is a food composition of the water, C _1-4 lower alcohol or a mixed solvent extract of the Steria involutcrata.
The method of claim 9,
The Steria involukrata extract is a food composition of 80% (v / v) methanol extract of Steria involucrata.

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