WO2020159044A1 - Composition for preventing or treating cognitive impairment containing dapsone as active ingredient - Google Patents

Abstract

The present invention relates to a composition which is for preventing or treating Alzheimer's dementia and contains Dapsone as an active ingredient. The present invention treats dementia by viewing dementia as an inflammatory disease rather than a degenerative disease. Dapsone according to the present invention stops the progress of Alzheimer's dementia induced by beta-amyloid, and exhibits the effect of improving cognitive function, and thus can be usefully used as a composition for preventing or treating Alzheimer's dementia, or a composition for improving cognitive function.

Description

[Correction 10.12.2019 under Rule 26] Composition for the prevention or treatment of cognitive dysfunction containing 　 Depson as an active ingredient

It relates to a composition for preventing or treating Alzheimer's dementia containing Depson as an active ingredient.

It is reported that dementia is reached at around 15% in 2015 compared to the aged population over 60 years old in Korea due to domestic and foreign aging population. It is a representative old-age disease that has emerged as a serious social problem in the construction of a health and welfare state that is serious for our economic power due to the rapid aging of the population and a serious social problem, resulting in an increase in medical expenses for additional caregivers and an ankle of the national economy. It is a degenerative disease that exhibits clinical symptoms that cause loss of ability and gradual deterioration of cognitive impairment, behavior and personality. In particular, Alzheimer's disease (AD), which is about 70% of patients with dementia, is the most common type of dementia, and as many studies have been conducted, proteins involved in Alzheimer's have been found, but the cause of the disease is not yet known. to be. However, as a result of analyzing the brain tissues of patients after death, the granules of neurons in the cortex or hippocampus (granulovacuolar degeneration), Hirano body (Hirano body), brain atrophy and senile plaque, And it is characterized by histopathologic findings such as neurofibrillary tangles, and beta amyloid (β-amyloid, Aβ) is a major component of the elderly group, presumed to be an important cause of AD, and reactive oxygen species (reactive It is known that oxygen species (ROS) are generated to induce necrosis and apoptosis of cranial nerve cells due to oxidative stress. Beta amyloid is composed of 36-43 amino acids of the peptide, and accumulation of beta amyloid peptide is an early etiology prior to brain damage and development of nerve fiber mass. Methods for inhibiting or eliminating amyloid production are being studied as treatments for Alzheimer's disease.

The clinically used anti-dementia drugs known to date prevent and restore dementia patients' cognitive function, as well as chorinesterase blockers tacrine and MAO-B, which are drugs that enhance life function. There are blockers such as seregiline, vasodilators, donepezil, revastigmine, galantamine, and brain nutrients, and female hormone supplements vitamins also treat cognitive decline. It is proposed as a drug.

On the other hand, Depson (Dapsone, 4,4'-diaminodiphenylsulfone; hereinafter, Depson or DDS) is a substance synthesized a century ago, is well known as a treatment for Hansen's disease, and is used as an important drug in many other skin diseases. However, several studies have reported that Depson acts as an oxidizing agent and can attack hemoglobin, causing hemolytic anemia when administered and destroying hemoglobin, leaving various by-products in the human body, thus limiting the use of Depson.

In addition, studies on the prevention or treatment effect of Alzheimer's dementia and improvement of cognitive function of these Depsons are insufficient.

As a result, the present inventors have researched on Depson, confirmed the significant effect on Depson's brain cell activation and memory enhancement, carefully judged the structure of Depson and allosteric regulation of molecular units, and determined By considering the reaction, concentration, pH, and the like, the usage and dosage of Depson, which can induce necessary pharmacological functions, were limited and the present invention was completed.

In order to achieve the above problems, the present invention provides a pharmaceutical composition for preventing or treating Alzheimer's dementia.

In addition, the present invention provides a health functional food for preventing or improving Alzheimer's dementia.

In addition, the present invention provides a health functional food for improving cognitive function containing Depson as an active ingredient.

The present invention is to change the perspective of dementia from degenerative diseases to inflammatory diseases, and to perform treatment therefor, Depson according to the present invention stops the progression of Alzheimer's dementia induced by beta amyloid and shows an effect of improving cognitive function, It can be useful as a composition for preventing or treating Alzheimer's dementia and a composition for improving cognitive function.

1A to 1R are diagrams showing medical records of hospital B of patient A diagnosed with mild cognitive impairment.

2 is a diagram showing a record of the administration of Depson A patient purchased from the N pharmacy.

3 is a view showing the findings of hospital K diagnosed with dementia.

FIG. 4 is a diagram showing a D hospital imaging department reading statement for diagnosis of dementia.

5 is a view showing the opinion of S hospital after discontinuing the administration of aricept.

6A to 6E are diagrams showing test results for determining the presence or absence of cognitive impairment performed in S hospital after administration of Depson according to the present invention.

The present invention provides a composition for preventing or treating Alzheimer's dementia containing Depson as an active ingredient.

The composition includes a pharmaceutical composition and a food composition.

Hereinafter, the present invention will be described in detail.

Although the exact pathogenesis and cause of Alzheimer's dementia are not known, it is currently known that the key mechanism of the onset is that a small protein called beta-amyloid is excessively made and deposits in the brain and has a detrimental effect on brain cells. , In addition, it is estimated that overphosphorylation, inflammatory reaction, and oxidative damage of tau protein, which plays an important role in maintaining the skeleton of brain cells, also contribute to brain cell damage and affect onset. Neural plaques (or senile plaques), a typical brain pathology finding, are associated with the deposition of beta amyloid protein, and the nerve fiber bundle is associated with tau protein hyperphosphorylation.

The active ingredient of the present invention, depson (dapsone, 4,4'-diaminodiphenylsulfone) is a sulfonamide mainly used in the treatment of leprosy and herpes dermatitis, the chemical formula is C ₁₂ H ₁₂ N ₂ O ₂ S, the structure is as follows Same as:

The depson can attack hemoglobin, causing hemolytic anemia when administered and destroying hemoglobin, leaving various by-products in the human body, and inducing the necessary pharmacological functions by considering the reaction, concentration, and pH when administered to the human body. The possible dosage regimen and dosage should be limited.

To this end, as a result of studying the optimal administration method through the experiment by the present inventor, the composition of the present invention preferably contains 40 to 60 mg of the depson, more preferably 50 mg, and includes the depson. The composition may be administered 2-3 times a day.

In addition, the composition of the present invention may be administered in combination with donepezil.

Donepezil is a dementia treatment that has an effect on Alzheimer's dementia. It helps to improve cognitive function by preventing acetylcholine, a neurotransmitter that plays an important role in memory and cognitive function in the brain, and helps prevent dementia. There is no, but you can slow down the progress.

The donepezil is typically a product such as Aricept, and the aricept is a drug jointly developed by Ezai Japan and Pfizer Pharmaceuticals, Inc. of the United States, used as a treatment for Alzheimer's dementia symptoms.

In addition, the present invention provides a composition for improving cognitive function containing Depson as an active ingredient, the composition may be a health functional food.

Depson, an active ingredient of the present invention, reduces the inflammatory response of beta amyloid deposited in brain cells causing Alzheimer's disease and the resulting neutrophil, and regulates the production of hypochlorous acid to generate neurons (brain) Cell).

As a result of conducting clinical experiments to confirm the effect of Depson on dementia and cognitive function, the neuronal preservation effect responded to the cognitive function improvement effect, and the effect of improving cognitive function and dementia was confirmed rapidly after administration of 50 mg 2-3 times a day. . As a result of this, it was confirmed that the desponsive protein can accumulate in the brain cells and stop the progression of dementia caused by not being discharged by recognizing and dissipating the protein that has broken out of Depson as a bacteria.

The present invention is to change the perspective of dementia from degenerative diseases to inflammatory diseases, and to perform treatment therefor, Depson according to the present invention stops the progression of Alzheimer's dementia induced by beta amyloid and shows an effect of improving cognitive function, It can be useful as a composition for preventing or treating Alzheimer's dementia and a composition for improving cognitive function.

In addition, as a result of clinical trials, it was confirmed that as an additional effect, Depson can block the inflammatory response caused by gout. In the case of the experimental patient, the uric acid level in the blood was normal, but the toes were inflamed, the feet were swollen as a whole, and severe pain was complained, but it was confirmed that the pain and inflammatory response disappeared due to the administration of Depson.

The composition of the present invention may further contain at least one known active ingredient having an effect of preventing or treating Alzheimer's dementia together with Depson.

The composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. In addition, it can be formulated and used in the form of oral formulations, external preparations, suppositories, and sterile injectable solutions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. according to a conventional method. Suitable formulations known in the art are preferred to use those disclosed in Remington's Pharmaceutical Science, recently Mack Publishing Company, Easton PA. Carriers, excipients and diluents that may be included include 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, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil. When formulating the composition, it is usually prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, It is prepared by mixing gelatin. In addition, lubricants such as magnesium stearate and talc are used in addition to simple excipients. Liquid preparations for oral use include suspensions, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are common diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin may be used.

As used herein, the term "administration" means providing a subject the composition of the present invention to an individual in any suitable way.

The preferred dosage of the pharmaceutical composition of the present invention depends on the condition and weight of the individual, the degree of disease, the drug form, the route and duration of administration, but can be appropriately selected by those skilled in the art. For the desired effect, the depson of the present invention can be administered in an amount of 1 mg/kg to 10000 mg/kg per day, or once a day or several times a day.

The pharmaceutical composition of the present invention can be administered to a subject by various routes. Any mode of administration can be expected, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrathecal dura or cerebral vascular injection.

The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormonal therapy, chemotherapy, and biological response modifiers for the prevention and treatment of Alzheimer's dementia.

In the present invention, "health functional food" refers to a food that has a bio-regulatory function, such as prevention and improvement of disease, bio-defense, immunity, recovery after illness, and suppression of aging, and should be harmless to the human body when taken for a long time.

The composition of the present invention may be added to a health functional food for the purpose of preventing or improving Alzheimer's dementia. When the depson of the present invention is used as a food additive, the depson may be added as it is or used with other foods or food ingredients, and may be suitably used according to a conventional method. The mixing amount of the active ingredient can be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment). In general, in the manufacture of food or beverage, the depson of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less relative to the raw material. However, in the case of long-term intake for health and hygiene purposes or for health control, it may be below the above range, and since there is no problem in terms of safety, the active ingredient may also be used in an amount above the above range.

There are no particular restrictions on the type of food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, teas, drinks, Alcoholic beverages, vitamin complexes, and the like, and include all healthy foods in the ordinary sense.

* The health drink composition of the present invention may include various flavoring agents or natural carbohydrates, etc., as additional components, such as ordinary beverages. The natural carbohydrates described above may include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, synthetic sweeteners such as saccharin and aspartame. The proportion of the natural carbohydrate is generally about 0.01 to 10 g per 100 ml of the composition of the present invention, preferably about 0.01 to 0.1 g.

In addition to the above, the composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, And carbonated agents used in carbonated beverages. In addition, the composition of the present invention may include flesh for the preparation of natural fruit juice, fruit juice beverage and vegetable beverage. These ingredients can be used independently or in combination. The proportion of these additives is not critical, but is generally selected from 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, preferred preparation examples, examples, and formulation examples are provided to help understanding of the present invention. However, the following preparation examples, examples, and formulation examples are provided only for easier understanding of the present invention, and the contents of the present invention are not limited thereby.

Preparation Example 1. Obtaining depson

Taegeuk answering tablets (25mg; 100mg) were obtained from N hospital, and Depson tablets (50mg) manufactured by Riemser Pharma, Germany, were obtained through the Korea Orphan Drug Center.

Example 1. 86 years old (actual age 90 years) A patient treatment progress

1-1. Depson administration to diagnose mild cognitive impairment and prevent dementia

Patient A diagnosed with mild cognitive impairment with MMSE 23 (cognitive impairment less than 24) at hospital B in 2008 had no serious problems in daily life by taking ACE inhibitors with hypertension. It is shown in FIG. 1.

Patient A exhibited extremely normal accident judgment behavior and purchased and administered Depson from N pharmacies to prevent dementia. Depson administration records of patients A purchased from N pharmacies during the period from 2010 to 2015 are shown in FIG. 2.

1-2. Development of dementia and administration of Aricept

In June 2018, the symptoms of mild cognitive impairment developed rapidly into dementia and received outpatient treatment at Hospitals K and D, respectively, as shown in FIGS. 3 and 4, respectively. In the remarks, Alzheimer's type dementia was diagnosed and patient A started to receive aricept.

1-3. Side effects occur

After administering aricept, he fell into drowsiness, was unable to cover the stool well, and repeated abnormal behaviors such as injured with a knife on the toe due to severe pain in the soles of the feet, sudden loss of memory, anger behavior, angina, angina symptoms, and 160/110 essentiality It exhibited various side effects, such as symptoms of hypertension.

After discontinuing the administration of aricept, the patient was transferred to hospital S in November 2018 to receive treatment, and the opinions of hospital S are shown in FIG. 5.

Seroxat (Seroxat; paroxetine hydrochloride, Handok) was dosed in the morning with the S hospital prescription in the morning, and in the evening, aricept 1/2 was administered for 15 days, followed by one tablet. However, after changing the aricept to a single dose, the above-mentioned side effects occurred again, and the blood pressure was elevated and the stool could not be covered.

1-4. Discontinuation of aricept administration and administration of dapsone

The depson (50 mg) obtained in Preparation Example 1 was administered to patient A. On the first day, 3 tablets of Depson were administered, followed by a total of 2 tablets in the morning and evening. After the administration of Depson, patient A became more conscious and able to communicate, and the walking movement was smooth and similar to the pre-dementia state. It was also confirmed that the symptoms of gout on the feet were almost eliminated. 5 days after the administration of Depson, the administration of Seratozat and Aricept of patient A was discontinued and Depson was administered alone, but the stability was maintained.

In order to confirm the change after the administration of Depson, a test was conducted to determine the presence or absence of cognitive impairment at the S hospital in January 2019, and the results are shown in FIG. 6.

As shown in FIG. 6, it was confirmed that it showed an improved aspect compared to the previous test (November 2018).

Hereinafter, a formulation example of the pharmaceutical composition and the food composition of the present invention will be described, but this is not intended to limit the present invention, but only to be specifically described.

Formulation Example 1. Preparation of pharmaceutical preparation

1. Preparation of powder

Depson 50 mg

Lactose 100 mg

Talc 10 mg

The above ingredients are mixed and filled in an airtight fabric to prepare a powder.

2. Preparation of tablets

Depson 50 mg

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

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

3. Preparation of capsules

Depson 50 mg

Crystalline cellulose 3 mg

Lactose 14.8 mg

Magnesium stearate 0.2 mg

According to a conventional capsule preparation method, the above ingredients are mixed and filled into a gelatin capsule to prepare a capsule.

4. Preparation of Injection

Depson 50 mg

Mannitol 180 mg

Injectable sterile distilled water 2974 mg

Na ₂ HPO ₄ 2H ₂ O 26 mg

It is prepared with the above-mentioned ingredient content per ampoule (2 ml) according to the preparation method of a conventional injection.

5. Preparation of liquid

Depson 50 mg

Isomerized sugar 10 g

5 g of mannitol

Purified water

Each component was added to the purified water to dissolve it according to the method of preparing a normal liquid, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed and purified water was added to adjust the total to 100 ml, followed by filling into a brown bottle. Sterilization to prepare a liquid formulation.

[Formulation Example 2. Preparation of food preparation]

1. Manufacture of health food

Depson 50 mg

Vitamin mixture

Vitamin A Acetate 70 g

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

Vitamin B2 0.15 mg

Vitamin B6 0.5 mg

Vitamin B12 0.2 g

Vitamin C 10 mg

Biotin 10 g

Nicotinic acid amide 1.7 mg

50 g folic acid

Calcium Pantothenate 0.5 mg

Suitable amount of mineral mixture

Ferrous sulfate 1.75 mg

Zinc oxide 0.82 mg

Magnesium carbonate 25.3 mg

Potassium phosphate 15 mg

Dibasic calcium phosphate 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg

Although the composition ratio of the vitamin and mineral mixture is a composition suitable for a relatively healthy food in a preferred embodiment, the composition ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for preparing a healthy food. , Granules can be prepared and used in the preparation of healthy food compositions according to conventional methods.

2. Production of health drinks

Depson 50 mg

Vitamin C 15 g

Vitamin E (powder) 100 g

Iron lactate 19.75 g

Zinc oxide 3.5 g

Nicotinic acid amide 3.5 g

Vitamin A 0.2 g

Vitamin B1 0.25 g

Vitamin B2 0.3 g

Water metering

After mixing the above components according to a conventional health drink manufacturing method, stirring and heating at 85° C. for about 1 hour, filtering the resulting solution, obtaining it in a sterilized 2 l container, sterilizing and sealing it, and then refrigerating it. It is used for preparing the health drink composition of the present invention.

Although the above composition ratio is a mixture of components suitable for preference beverages in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, country of use, and usage.

The present invention provides a composition for preventing or treating Alzheimer's dementia containing Depson as an active ingredient.

The composition includes a pharmaceutical composition and a food composition.

Claims (11)

A pharmaceutical composition for the prevention or treatment of cognitive dysfunction caused by inflammation, which contains Depson as an active ingredient. According to claim 1, The composition is characterized in that it comprises 40 to 60mg depson, pharmaceutical composition for the prevention or treatment of cognitive dysfunction. According to claim 2, The composition is characterized in that it is administered 2-3 times a day, a pharmaceutical composition for the prevention or treatment of cognitive dysfunction. According to claim 1, The composition is characterized in that to reduce inflammation and hypochlorous acid (hypochlorous acid) production in brain cells, the pharmaceutical composition for the prevention or treatment of cognitive dysfunction. According to claim 1, The composition is characterized in that it is administered in combination with donepezil (donepezil), a pharmaceutical composition for the prevention or treatment of cognitive dysfunction. Deleted by the judge's decision to reject Deleted by the judge's decision to reject A health functional food for improving cognitive function caused by inflammation, which contains Depson as an active ingredient. The health functional food for improving cognitive function according to claim 8, wherein the health functional food contains 40 to 60 mg of depson. The health functional food for improving cognitive function according to claim 9, wherein the health functional food is administered 2-3 times a day. The health functional food for improving cognitive function according to claim 8, wherein the health functional food conserves neurons by regulating the production of hypochlorous acid.

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