KR20230087245A - Pharmacological Composition for Treating or Preventing the ischemia Stroke Disease Containing active ingredient for alkaloid of sessiline extract Acanthopanaxs sessiliflours - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating ischemic stroke containing a Butanol extract from Acanthopanaxs sessiliflorus fruit or the alkaloid of sessiline isolated from the extract as an active ingredient. The butanol extract or fractions thereof or alkaloids such as sessiline exhibit a brain protective effect against ischemic brain tissue damage caused by middle cerebral aorta occlusion/reperfusion, and can be useful in the pharmaceutical and food fields for preventing, alleviating or treating stroke by reducing infarction in the internal capsule. Accordingly, the present invention includes butanol compounds from the fruit of Acanthopanaxs sessiliflorus or a pharmaceutically acceptable salt thereof as an active ingredient, and alkaloids such as sessiline exhibit a brain-protective effect against ischemic brain tissue damage caused by middle cerebral aorta occlusion/reperfusion and reduce infarction in the internal capsule. Thus, the present invention can be usefully used in the pharmaceutical and food fields to prevent, alleviate, or treat stroke. Alkaloids such as sessiline exhibit a brain-protective effect against ischemic brain tissue damage caused by middle cerebral aorta occlusion/reperfusion and reduce infarction in the internal capsule.

Description

Pharmaceutical composition for treating or preventing ischemia stroke disease containing an alkaloid of cecilin isolated from an extract of butanol of quinoa fruit or an extract thereof as an active ingredient }

The present invention relates to a composition for preventing and treating stroke, and more specifically, to a pharmaceutical composition for preventing or treating stroke, comprising as an active ingredient an alkaloid of sessilin isolated from a butanol extract of a rhododendron fruit or an extract thereof, It relates to a health functional food composition for prevention or improvement and a method for preventing or treating stroke.

The butanol extract or a fraction thereof or an alkaloid such as sessiline of the present invention exhibits a brain protective effect against ischemic brain tissue damage caused by middle cerebral aorta occlusion/reperfusion and prevents infarction in the internal capsule. Contains as an active ingredient the butanol extract of Acanthopanaxs sessiliflorus fruit, which can be usefully used in the pharmaceutical and food fields for the prevention, improvement or treatment of stroke, or the alkaloid of sessiline isolated from the extract. It relates to a pharmaceutical composition for preventing or treating ischemic stroke.

Stroke (or cerebrovascular disease) is a neurological symptom in which a blood vessel supplying blood to the brain is blocked or burst, resulting in the death of brain cells in the damaged area, resulting in physical disorders such as loss of consciousness, speech impairment, and hemiplegia.

Stroke is largely divided into ischemic stroke (cerebral infarction) in which blood vessels in the brain are blocked and hemorrhagic stroke (cerebral hemorrhage) in which blood vessels in the brain burst. In the case of ischemic stroke, thrombosis or embolism in the cerebral artery due to atherosclerosis of the blood vessels and cardiogenic embolism due to heart disease are the main causes. am.

Cerebral infarction caused by blockage of cerebral blood vessels is further divided into cerebral thrombosis and cerebral embolism. In cerebral thrombosis, arteriosclerosis is caused by hypertension, diabetes, hyperlipidemia, etc., and the walls of the arteries become thick or hard, resulting in narrowing of the blood vessels and damage to the blood vessels. The inner wall is easily damaged and not smooth, so the blood is clotted and eventually blocked, and the blood supply is significantly reduced or stopped, resulting in a lack of oxygen and nutrient supply to the brain cells, resulting in impaired brain function. Or, due to diseases such as atrial fibrillation, an abnormality in the blood flow in the heart occurs, and a part of the blood partially stagnates and coagulates in the heart, resulting in a blood clot, which falls off and blocks the cerebral blood vessel, resulting in a cerebral infarction.

In the case of cerebral hemorrhage, primary cerebral hemorrhage in which the wall of a small blood vessel bursts because the pressure in the cerebral blood vessel increases due to high blood pressure, and cerebral aneurysm, a state in which a part of the wall of the blood vessel is weak and the wall of the weak part stretches and bulges out in the shape of an auricle, at any moment Subarachnoid hemorrhage caused by rupture and cerebral arteriovenous malformation are congenitally present, and high arterial pressure is directly transmitted to the vein.

Currently, drug therapy using antithrombotic agents, anticoagulants, antiplatelet agents, and thrombolytic agents is used as a treatment method, but antithrombotic agents (tPA), which are currently the only licensed drug, are effective only within 4 to 5 hours after cerebral infarction. However, tPA further aggravates the disease in the case of hemorrhagic stroke and causes side effects such as allergy. In other words, stroke is not easy to diagnose, difficult to detect early, and there is no fundamental treatment yet.

The inventors of the present invention completed the present invention by confirming that sessiline has a cranial nerve cell protective effect and can be used for the prevention, improvement, and treatment of stroke by reducing the size of an infarct while researching a method for treating stroke.

1. Pharmaceutical composition for blood vessel disease prevention or treatment comprising substance extracted from the fruits of acanthopanax sessiliflorus and method for manufacturing thereof (patent registration No. 10-1816601) 2. Novel compounds isolated from extract of Acanthopanax sp. fruit and pharmaceutical composition for preventing and treating hypertension including thereof (Patent Registration No. 10) -2158484) 3. Composition comprising extract of Acanthopanaxs senticosus for anti-angiogenesis (Patent Registration No. 10-1721780)

The present invention has been made to solve the above problems, and an object thereof is that a butanol extract or a fraction thereof or an alkaloid such as sessilin has a brain protective effect against ischemic brain tissue damage caused by middle cerebral aorta occlusion/reperfusion. Butanol extract of Acanthopanas sessiliflorus fruit or an extract thereof, which can be usefully used in the pharmaceutical and food fields for preventing, improving or treating stroke by reducing infarction in the internal capsule. It is to provide a pharmaceutical composition for preventing or treating ischemic stroke comprising an alkaloid of sessiline isolated from as an active ingredient.

According to a feature of the present invention for achieving the above object, a pharmaceutical composition for preventing or treating stroke comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient is provided.

[Formula 1]

In addition, the present invention provides a health functional food composition for preventing or improving stroke containing the compound represented by Formula 1 as an active ingredient.

In addition, the present invention provides a method for preventing or treating stroke, comprising administering the compound represented by Formula 1 to a non-human subject.

At this time, the compound represented by Chemical Formula 1 of the present invention is characterized in that it consists of sessilene.

The pharmaceutical composition for preventing or treating ischemic stroke, comprising the butanol extract of Acanthopanaxs sessiliflorus fruit or the alkaloid of sessiline isolated from the extract according to the present invention as an active ingredient, provides a neuronal cell protective action.

In addition, the pharmaceutical composition for preventing or treating ischemic stroke comprising the butanol extract of the fruit of Acanthopanaxs sessiliflorus or the alkaloid of sessiline isolated from the extract of the present invention as an active ingredient exhibits a protective effect on brain cells. In addition, since it shows excellent efficacy in suppressing cerebral infarction, which is a brain disease, by reducing the infarct size, it can be usefully used in the pharmaceutical and food fields for the prevention, improvement, and treatment of various types of cerebrovascular diseases and stroke.

In addition, the pharmaceutical composition for preventing or treating ischemic stroke comprising the butanol extract of the fruit of Acanthopanaxs sessiliflorus or the alkaloid of sessiline isolated from the extract of the present invention as an active ingredient is a butanol extract or a fraction thereof or secillin Alkaloids such as (sessiline) exhibit brain protective effects against ischemic brain tissue damage caused by middle cerebral aorta occlusion/reperfusion and reduce infarction in the internal capsule to prevent, improve or treat stroke. It can be applied as a medical product for the purpose.

In addition, the pharmaceutical composition for preventing or treating ischemic stroke comprising the butanol extract of the fruit of Acanthopanaxs sessiliflorus or the alkaloid of sessiline isolated from the extract of the present invention as an active ingredient has a protective effect on brain nerve cells. And, by reducing the infarct size, it can be usefully used in the pharmaceutical and food fields for the prevention, improvement, and treatment of stroke.

1 is a TTC (2,3,5-triphenyl-tetrazolium chloride)-stained state image of sections of mice of four groups of experimental examples.
Figure 2 is a graph showing the results of the volume of the infarct area after drug treatment of the brain slices of mice of each group according to Figure 1

Hereinafter, embodiments according to the present invention will be described in detail with reference to the accompanying drawings.

The inventors of the present invention completed the present invention by confirming that sessilin reduces the size of infarction in the internal capsule in a rodent cerebral ischemia model while studying a substance effective for stroke. .

Accordingly, the present invention provides a pharmaceutical composition for preventing or treating stroke comprising a compound represented by Formula 1 below as an active ingredient.

[Formula 1]

“Sessiline” represented by Chemical Formula 1 is one of plant alkaloids, and it has not been clarified whether the specific pharmacological activity of the compound has direct preventive and therapeutic effects on stroke.

Accordingly, the present applicant confirmed that the compound represented by Formula 1 reduced the size of infarction in the internal capsule of ischemia-induced mice.

Each description and embodiment disclosed in the present invention can also be applied to each other description and embodiment. In particular, the present invention is not particularly limited to a method for obtaining sessilene, and is chemically prepared by a method known in the art. Synthetic or commercially available materials may be used.

In addition, sessiline of the present invention may exist in unsolvated form as well as solvated form, and sessiline may exist in crystalline or amorphous form, all of these physical forms. is included in the scope of the present invention.

The pharmaceutical composition of the present invention may include not only the compound represented by Formula 1 but also a pharmaceutically acceptable salt thereof. In the present invention, "pharmaceutically acceptable salt" is in the form of a salt in which the compound is combined with another substance, and means a substance that can exhibit similar activity pharmacologically.

Types of the pharmaceutically acceptable salt include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate or sulfate, and organic acid salts such as carboxylic acid salts or sulfonic acid salts.

In addition, types of carboxylate include, but are not limited to, acetate, maleate, fumarate, malate, citrate, tartrate, lactate or benzoate. In addition, types of sulfonic acid salts include, but are not limited to, methanesulfonic acid salts, ethanesulfonic acid salts, benzenesulfonic acid salts, toluenesulfonic acid salts, or naphthalenedisulfonic acid salts.

In the present invention, 'stroke' means a symptom of a local neurological deficit suddenly induced due to an abnormal cerebral blood flow. Such a stroke may include cerebral infarction in which death of brain cells is induced due to blockage of cerebral blood vessels by blood clots or the like. Specific symptoms of a stroke include sudden headache and vomiting, paralysis of a part of the body, paralysis of a part of the body, numbness and loss of sensation in a part of the body, language disorder (aphasia or speech disorder), facial nerve disorder, and ataxia. can appear Stroke in the present invention may mean a stroke.

The pharmaceutical composition of the present invention may promote recovery of motor function damaged due to stroke or reduce the size of an infarct.

In a specific embodiment of the present invention, as a result of treating a stroke animal model with the compound of Formula 1 of the present invention, it was confirmed that brain nerve cells were protected and the infarct size in the entrapment was reduced compared to a stroke drug-free group.

Through the above results, it was confirmed that the composition containing the compound of Formula 1 of the present invention has an excellent effect for preventing or treating stroke.

In the present invention, the term "prevention" refers to any action that inhibits or delays the onset of stroke by administering a composition containing the compound of Formula 1 of the present invention, and the term "treatment" in the present invention includes the compound of Formula 1 It refers to all activities that improve or beneficially change the symptoms of the disease by administering the composition.

Therefore, the pharmaceutical dosage form of the composition for preventing or treating stroke of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, and may also be used alone or in combination with other pharmaceutically active compounds as well as in a suitable set. there is.

In addition, the composition for preventing or treating stroke of the present invention may additionally include a pharmaceutically acceptable carrier.

The composition for preventing or treating stroke of the present invention may be prepared into a pharmaceutical formulation using a method well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. In preparation of a dosage form, it is preferable to mix or dilute the active ingredient with a carrier or to encapsulate it in a carrier in the form of a container.

Therefore, the composition for preventing or treating stroke of the present invention is formulated according to conventional methods in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions. It can be formulated and used, and may further include suitable carriers, excipients and diluents commonly used in the preparation of compositions.

For example, carriers that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

In addition, solid preparations for oral administration in the present invention include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient, for example, starch, calcium carbonate ), sucrose or lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

Liquid preparations for oral use include suspensions, solutions for oral use, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, preservatives, etc. may be included in addition to water and liquid paraffin, which are commonly used simple diluents. there is.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.

The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And it can be single or multiple administrations. It is important to administer the amount that can obtain the maximum effect with the minimum amount without causing side effects in consideration of all of the above factors, and can be easily determined by those skilled in the art.

As used herein, the term "administration" refers to introducing the pharmaceutical composition of the present invention to a patient by any suitable method, and the administration route of the composition of the present invention can be oral or parenteral as long as it can reach the target tissue. It can be administered via any route.

Therefore, the administration method of the pharmaceutical composition according to the present invention is not particularly limited, and may follow a method commonly used in the art. As a non-limiting example of the administration method, the composition may be administered by oral administration or parenteral administration. The pharmaceutical composition according to the present invention may be prepared in various formulations depending on the desired administration method.

The frequency of administration of the composition of the present invention is not particularly limited thereto, but may be administered once a day or administered several times by dividing the dose.

A typical daily dose of the composition containing the compound of Formula 1 of the present invention as an active ingredient may be administered at 1 to 1,000 mg/kg, specifically 11 to 450 mg/kg, once or several times. Can be administered in divided doses.

In addition, the present invention provides a health functional food composition for preventing or improving stroke, comprising a compound represented by Formula 1 below as an active ingredient.

[Formula 1]

The compound represented by Formula 1 reduces the size of an infarction in an internal capsule in a rodent cerebral ischemia model.

The food composition for preventing or ameliorating stroke of the present invention includes pills, powders, granules, precipitates, tablets, capsules or liquids, and the food to which the composition of the present invention can be added includes, for example, various foods. , For example, there are beverages, chewing gum, tea, vitamin complexes, and health functional foods.

There are no particular restrictions on other ingredients except for containing the composition, its active ingredient, or its physiologically acceptable salt as an essential ingredient that can be included in the food composition for preventing or improving stroke of the present invention, and as in conventional foods, various Eggplant herb extract, food supplement additives, or natural carbohydrates may be included as additional ingredients.

As mentioned above, supplementary food additives may be additionally added, and supplementary food additives include conventional food additives in the art, for example, flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like.

Examples of the natural carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. In addition to the above, natural flavors (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can advantageously be used as flavoring agents.

In addition to the above, the food composition for preventing or improving stroke of the present invention contains various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like. In addition, it may contain fruit flesh for the manufacture of natural fruit juice and fruit juice beverages and vegetable beverages. These components may be used independently or in combination.

The health functional food (functional food) is the same term as food for special health use (FoSHU), and means a food with high medical and medical effects processed to efficiently display bioregulatory functions in addition to nutritional supply. do. Here, "function" means obtaining useful effects for health purposes such as regulating nutrients for the structure and function of the human body or physiological functions. The food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and ingredients commonly added in the art during the preparation.

In addition, the formulation of the food may also be prepared without limitation as long as the formulation is recognized as a food. The composition for food of the present invention can be prepared in various types of formulations, and unlike general drugs, it has the advantage of not having side effects that can occur when taking drugs for a long time by using food as a raw material, and has excellent portability. Of the foods can be consumed as supplements to enhance the effect of preventing or ameliorating stroke.

In addition, the present invention provides a method for preventing or treating stroke, comprising administering a compound represented by Formula 1 below to a non-human subject.

[Formula 1]

The prevention or treatment method may further include a rehabilitation training step.

As used herein, the term "subject" may refer to all animals, including humans, who have suffered or are likely to have a stroke. The animal may be not only humans but also mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, and cats that require treatment for similar symptoms, but are not limited thereto.

Specifically, the preventive or therapeutic method of the present invention may include administering the composition in a pharmaceutically effective amount to a subject having or at risk of having a stroke.

Example. Experiment method

Experimental Example 1. Administration drug preparation

Preparation of sessiline

Sessiline used in this experiment was isolated from the butanol layer or synthesized and used in the experiment.

Experimental Example 2. Production of rodent cerebral ischemia model

C57/BL6 mice aged 55 days were used in the experiments. The mice were divided into 4 groups of 5 each: Sham (surgical control group), Stoke (stroke surgery group), stroke+BuOH, and stroke+SSL. A middle cerebral artery occlusion and reperfusion operation (MCAO/R) was performed to induce focal cerebral ischemia. Behavioral function tests were performed 24 hours after MCAO/R (n = 5, each). The mice were subjected to inhalational anesthesia, reperfusion with a buffer solution, and the brains were immediately removed and TTC (2,3,5-triphenyl-tetrazolium chloride) staining was performed. If necessary, tissues were used for molecular biological experiments.

Experimental Example 3. Volume measurement of cerebral infarct area

Figure 1 shows TTC-stained brain slices of 4 groups of mice. Brain slices were cut at 2 mm intervals from the frontal pole of the brain, and stained for about 20 minutes.

As a result of measuring the volume of cerebral infarction, the white area represents the infarct area and the red area represents the undamaged area. ), it was significantly confirmed that the red area was not damaged. That is, it can be confirmed that the oral administration of SSL (cecillin)-containing was not significantly damaged in red without a significant cerebral infarct area compared to the other group.

The quantitative graph of FIG. 2 compared the volume of the ipsilateral infarct area of each brain slice. The cerebral infarct volume due to focal cerebral ischemia was significantly reduced by administration of sessiline. (*** p<0.001)

Hereinafter, formulation examples of the composition containing the powder of the present invention will be described, but the present invention is not intended to limit them, but only to be specifically described.

Formulation Example 1. Preparation of powder

sessilene 500mg

lactose 100mg

talc 10 mg

A powder is prepared by mixing the above ingredients and filling them in an airtight bag.

Formulation Example 2. Preparation of tablets

sessilene 300mg

corn starch 100mg

lactose 100mg

magnesium stearate 2mg

After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet manufacturing method.

Formulation Example 3. Preparation of capsule formulation

sessilene 200mg

crystalline cellulose 3 mg

lactose 14.8mg

magnesium stearate 0.2mg

Capsules are prepared by mixing the above ingredients and filling them into gelatin capsules according to a conventional capsule preparation method.

Formulation Example 4. Preparation of Injections

sessilene 600mg

mannitol 180mg

Sterile Distilled Water for Injection 2974mg

Na2HPO4,12H ₂ O 26mg

It is prepared with the above component content per 1 ampoule according to the conventional method for preparing injections.

Formulation Example 5. Preparation of liquid formulation

sessilene 4g

Lee Seonghwadang 10g

mannitol 5g

Purified water Appropriate amount

According to the conventional liquid formulation manufacturing method, each component is dissolved in purified water, lemon flavor is added in an appropriate amount, the above components are mixed, and then purified water is added to adjust the total amount to 100g, and then filled into a brown bottle to be sterilized. to prepare a liquid.

Formulation Example 6. Preparation of granules

sessilene 1,000 mg

vitamin mixture Appropriate amount

Vitamin A Acetate 70 μg

vitamin E 1.0mg

vitamin B1 0.13mg

vitamin B2 0.15mg

vitamin B6 0.5mg

vitamin B12 0.2 μg

vitamin C 10 mg

biotin 10 μg

nicotinic acid amide 1.7mg

folic acid 50 μg

Calcium Pantothenate 0.5mg

mineral mixture Appropriate amount

ferrous sulfate 1.75mg

zinc oxide 0.82mg

magnesium carbonate 25.3mg

Potassium Phosphate Monobasic 15mg

Dibasic calcium phosphate 55mg

potassium citrate 90 mg

calcium carbonate 100mg

magnesium chloride 24.8mg

Although the composition ratio of the above vitamin and mineral mixture was prepared by mixing ingredients suitable for granules in a preferred embodiment, the mixing ratio may be arbitrarily modified, and after mixing the above ingredients according to a conventional granule manufacturing method, It can be prepared and used for preparing a health functional food composition according to a conventional method.

Formulation Example 7. Manufacturing of functional beverages

sessilene 1,000 mg

citric acid 1,000 mg

oligosaccharide 100g

plum concentrate 2g

taurine 1g

by adding purified water Total 900mL

After mixing the above ingredients according to the usual functional beverage manufacturing method, stirring and heating at 85 ° C. for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2L container, sealed and sterilized, and then refrigerated according to the present invention. It is used for the preparation of functional beverage compositions.

Although the composition ratio is a mixture of ingredients suitable for a relatively favorite beverage in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as class of demand, country of demand, and purpose of use.

Although the above has been described in detail through specific embodiments of the present invention, the terms specifically used here are only used for the purpose of describing the present invention, but to limit the meaning or scope of the present invention described in the claims. It is not used for Therefore, those skilled in the art can make various modifications and variations to other equivalent embodiments.

Claims (6)

A pharmaceutical composition for preventing or treating stroke, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Formula 1]

According to claim 1,
The stroke is an ischemic stroke (ischemic stroke), a pharmaceutical composition for preventing or treating stroke, characterized in that.
According to claim 1,
A pharmaceutical composition for preventing or treating stroke, characterized in that the compound represented by Formula 1 reduces the size of an infarction in an internal capsule. A food composition for preventing or improving stroke, comprising a compound represented by Formula 1 as an active ingredient.
[Formula 1]

According to claim 4,
The stroke is a functional food composition for preventing or improving stroke, characterized in that ischemic stroke (ischemic stroke).
According to claim 4,
The compound represented by Formula 1 is a functional food composition for preventing or improving stroke, characterized in that it reduces the size of an infarction in an internal capsule.

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