KR20170076107A - A Pharmaceutical composition comprising extract of Santalum album L. for enhancing the therapy of the Alzheimer's disease - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for enhancing the therapeutic effect of Alzheimer including a sandalwood extract. The present invention is expected to be useful for the effective treatment of Alzheimer's disease by confirming the improvement of the therapeutic effect of Alzheimer and the reduction of the side effects caused by Memantine through the combination of the extract of sandalwood extract and a representative Alzheimer's treatment agent, Memantine.

Description

Technical Field [0001] The present invention relates to a pharmaceutical composition for enhancing the therapeutic effect of Alzheimer's disease,

The present invention relates to a pharmaceutical composition for enhancing the therapeutic effect of Alzheimer. More specifically, the present invention relates to a composition comprising a Santalum album L. extract for enhancing the Alzheimer's therapeutic effect of Memantine, a therapeutic agent for Alzheimer's disease.

Dementia has been shown to significantly reduce cognitive functions such as memory, language ability, vision, perception, time and space configuration ability, and management function compared to the age and education level, It refers to complex clinical syndrome that causes discomfort. Alzheimer's dementia, vascular dementia, brain damage dementia, and dementia caused by Parkinson's disease are classified into dementia. With the population aging, the number of dementia patients in Korea is estimated to reach 610,000 in 2014 and 2.7 million in 2050. In particular, Alzheimer's disease, which accounts for about 65% of elderly dementia, is the most common type of dementia, characterized by granulovacuolar degeneration of neurons in the cortex or hippocampus, ), and noinban atrophy (senile plaque) and characterized by tissue anatomical findings such as nerve fibers (neurofibrillary tangles) and amyloid beta (β -amyloid, Aβ) is a major cause of Alzheimer's disease occurs as a major component of noinban , And it is known that reactive oxygen species (ROS) are generated to cause necrosis and cell death of brain cells due to oxidative stress.

The clinically used Alzheimer's remedy, known to date, is a cholinesterase-based remedy that inhibits the degradation of acetylcholine, a neurotransmitter in the brain, and an NMDA inhibitor that inhibits the excess secretion of glutamate, (N-methyl-D-aspartate) receptor antagonists. Among them, the cholinesterase inhibitor-based drugs include Donepezil, Tacrine, Revastigmine, Galantamine and the like. Examples of NMDA receptor antagonist drugs include memantine Memantine).

Among these Alzheimer's drugs, Memantine was originally developed by Merz Pharmaceuticals in Germany in the 1980s as a treatment for Parkinson's disease and exercise disorders, and has been marketed as a treatment for dementia in Germany. In 1999, it was approved as a treatment for Alzheimer's disease in Europe in 2002. It was approved by the US FDA in October 2003 for the treatment of moderate to severe Alzheimer's disease. It has recently been sold in Korea by Lundbeck as EBIXA®. The commercially available product, which contains mannitine hydrochloride in tablets or liquid form, is administered within a range that does not exceed the maximum required dose of 20 mg per day, taking into consideration both efficacy and tolerability.

The mechanism of action of memantine is to block glutamate, an excitatory neurotransmitter. Glutamate over-stimulates the brain's nerves, leading to excessive calcium influx into the brain cells, causing damage and death of the brain. Memantine is known to prevent this. Alzheimer's patients are known to be over-secreted by glutamate and the calcium ion channel of the NMDA receptor is always open in the stable phase, leading to excessive calcium intake into the cells, which is associated with the death of the brain. Memantine acts as an antagonist with low affinity in the calcium channel located at the center of the NMDA receptor and blocks the intracellular influx of calcium to prevent the destruction of neuronal cells, and calcium is excessively introduced into cells, When excitability is needed and when physiological action such as memory or learning is needed, it escapes the calcium channel and causes depolarization to occur normally, stabilizing the physiological nerve signal and normalizing the function of the nerve cell.

However, side effects caused by memantine have been reported as anorexia, diarrhea, weight loss, dry mouth, dizziness, sleep disturbance, and fatigue. It has also been reported to rarely cause dizziness, headache, constipation, drowsiness and hypertension. Such side effects can be partially solved by methods of reducing the minimum and / or sustained dose or reducing the number of doses.

Therefore, the main object of the present invention is to increase the therapeutic effect of memantine on the Alzheimer's effect and decrease side effects through the combination or mixing of drugs, and related studies have been made (Korean Patent Registration No. 10-0852834).

Disclosure of the Invention The present invention has been conceived to solve the problems as described above. The present inventors have found that the combination of Memantine and Santalum album L. extract with Alzheimer's treatment improves Alzheimer's therapeutic effect and reduces side effects Thus, the present invention has been completed on the basis of these findings.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for enhancing the therapeutic effect of Alzheimer's, comprising a sandalwood extract, which is used in combination with Memantine, a therapeutic agent for Alzheimer's disease.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

In order to accomplish the object of the present invention as described above, the present invention provides a pharmaceutical composition for enhancing the therapeutic effect of Alzheimer's, comprising a sandalwood extract, which is used in combination with Memantine, a therapeutic agent for Alzheimer's disease.

In one embodiment of the present invention, the composition is administered simultaneously, separately or sequentially with the Alzheimer's agent Memantine.

In another embodiment of the present invention, the composition is characterized by preventing or reducing the side effects of memantine simultaneously with increasing the therapeutic effect of Alzheimer's.

In another embodiment of the present invention, the composition is characterized by enhancing the neuronal protective effect.

In another embodiment of the present invention, the sandalwood extract is characterized by being extracted with at least one solvent selected from the group consisting of water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof.

The present invention provides a method for enhancing the therapeutic effect of Alzheimer's disease comprising administering the above pharmaceutical composition to an individual.

The present invention provides a use of a composition comprising a sandalwood extract to enhance the therapeutic effect of Alzheimer's.

The composition according to the present invention comprises a sandalwood extract as an active ingredient, and the combination of the sandalwood extract and Memantine, which is an Alzheimer's therapeutic agent, can be used for the treatment of Alzheimer's disease such as Behavioral and Psychological Symptoms of Dementia (BPSD) , Depression, sleep disorder, and reduction of side effects. As a result, it is expected to be useful as a pharmaceutical composition for enhancing the therapeutic effect of Alzheimer's.

Fig. 1 shows the results of the treatment of SH-SY5Y cells treated with a mixture of control (normal group), 50 쨉 g / ml of sandalwood extract and Memantine 1 袖 M, 5 袖 M, 10 袖 M, β -amyloid 25 袖 M alone, / ㎖, and Memantine, respectively. The cell viability of the group treated with 1 μM, 5 μM, 10 μM and 25 μM of β- amyloid was confirmed.

In the present invention, the cell viability associated with the effect of enhancing Alzheimer's treatment by combination of Memantine and Santalum album L. extract was confirmed, and the present invention was completed based on this finding.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for enhancing an Alzheimer's therapeutic effect comprising a sandalwood extract, which is used in combination with Memantine, a therapeutic agent for Alzheimer's disease.

As used herein, the term "treatment" refers to any action in which the symptoms of Alzheimer's are delayed and / or improved or beneficially altered by the administration of the pharmaceutical composition according to the present invention.

"Alzheimer's disease", a disease to be prevented and treated by the composition of the present invention, is the most common degenerative brain disease causing dementia. It is a disease in which progressive deterioration of cognitive function including memory is gradually progressed. A small protein called amyloid ( β- amyloid) is over-formed and deposited in the brain, causing harmful effects on the brain cells. It is known as the key mechanism of the onset. In the process of disease, not only the cognitive decline but also personality change, , Behavioral and Psychological Symptoms of Dementia (BPSD) are often accompanied by delusions, hallucinations, increased aggression, and sleeping disorders. Neurological disorders such as stiffness and gait abnormality at the end of life or incontinence, Of the disease.

The therapeutic agent for Alzheimer's used in combination with the composition of the present invention may be Donepezil, Tacrine, Revastigmine, Galantamine and the like, preferably Memantine, , But is not limited thereto.

For example, "Memantine ", which is an Alzheimer's therapeutic agent used in the present invention, is a drug belonging to the NMDA receptor antagonist family and has adverse effects such as anorexia, diarrhea, weight loss, dry mouth, dizziness, It is necessary to pay special attention to this.

Accordingly, the composition according to the present invention is characterized in that it is administered simultaneously, separately or sequentially with the Alzheimer's therapeutic agent in order to enhance the therapeutic effect of Alzheimer's treatment by the administration of the therapeutic agent for Alzheimer's and reduce the side effects.

In addition, the composition according to the present invention is characterized by enhancing the therapeutic effect of Alzheimer and simultaneously preventing or reducing side effects of memantine.

In addition, the composition according to the present invention is characterized by enhancing the nerve cell protection effect.

In the present invention, the sandalwood extract can be extracted by a conventional method known in the art for extracting an extract from a natural product, that is, using a conventional solvent under the conditions of ordinary temperature and pressure. For example, in the present invention, the sandalwood extract may be extracted using at least one solvent selected from the group consisting of water, an alcohol having 1 to 4 carbon atoms, and a mixed solvent thereof. In addition, the method for extracting the extract from the sandalwood can be extracted by various methods such as hot water extraction, cold extraction, reflux extraction, and ultrasonic extraction, but is not limited thereto.

The extract thus prepared may be filtered, concentrated or dried to remove the solvent, and may be subjected to both filtration, concentration and drying. For example, the filtration can be performed using a filter paper or a vacuum filter, the concentration can be carried out using a vacuum concentrator, and the lyophilization can be carried out, but the present invention is not limited thereto.

Further, the extract extracted with the solvent may be further fractionated with a solvent selected from the group consisting of hexane, methylene chloride, acetone, ethyl acetate, ethyl ether, chloroform, water, and mixtures thereof. The fractionation temperature may be 4 캜 to 120 캜, but is not limited thereto.

In one embodiment of the present invention, a sandalwood extract and Memantine and ? -Amyloid were cultured in SH-SY5Y cells. Through the cell survival rate of the cultured cells, improvement of the effect of Alzheimer's treatment and decrease of side effects caused by Memantine were confirmed (See Example 1).

The pharmaceutical composition according to the present invention may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier. Herein, pharmaceutically acceptable carriers are those conventionally used at the time of formulation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, absorbency, inactivation rate and excretion rate of the active ingredient in the body, type of disease, 0.001 to 150 mg, preferably 0.01 to 100 mg, per 1 kg of body weight may be administered daily or every other day, or one to three divided doses per day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.

In another aspect of the present invention, the present invention provides a method for treating Alzheimer, comprising administering the above pharmaceutical composition to a subject. The term " individual "as used herein refers to a subject in need of treatment for a disease, and more specifically refers to a mammal such as human or non-human primate, mouse, mouse, dog, cat, horse and cattle.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

Example 1: Protective effect analysis (MTT assay) against neurotoxicity of sandalwood extract and memantine

To observe neuronal cytotoxicity, MTT assay was performed as follows. SH-SY5Y cells (5 × 10 ³ cells / well) were cultured in a 12-well plate for 12 hours and then stabilized in a medium without FBS (Fetal bovine serum) for 16 hours. / Ml and Memantine were mixed with 1 μM, 5 μM and 10 μM of each, β- amyloid 25 μM alone, 50 μg / ml of sandalwood extract and 1 μM, 5 μM and 10 μM of Memantine were mixed with 25 μM of β- amyloid Treated group, total 8 groups. Then, each treatment group was cultured for 24 hours and then 2 mg / ml of 3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyl-tetra-zolium bromide (MTT, Sigma) After incubation for 4 hours, the cells were dissolved with dimethylsulfoxide (DMSO, Sigma) and the absorbance was measured with a microplate reader (Molecular devices, USA) at a wavelength of 580 nm to confirm cell viability. All data were expressed as mean ± standard deviation.

As a result, as shown in FIG. 1, it was confirmed that when the extract of sandalwood extract and Memantine was treated, the cytotoxicity was not induced regardless of the concentration and the survival rate was significantly higher than that of the control group.

On the other hand, after a single treatment than the β -amyloid, handle sandalwood extract 50㎍ / ㎖ and Memantine at a concentration of 5 ㎎ / ㎖, the β -amyloid 25μM , The cell viability was significantly increased in the case of treatment.

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (5)

A pharmaceutical composition for enhancing the therapeutic effect of Alzheimer's in combination with a therapeutic agent for Alzheimer's disease,
Wherein the composition comprises a Santalum album L. extract and the Alzheimer remedy is Memantine. The method according to claim 1,
Wherein said composition is administered simultaneously, separately or sequentially with said Alzheimer's therapeutic agent. The method according to claim 1,
Wherein the composition is characterized by preventing or reducing the side effects of memantine while simultaneously enhancing the therapeutic effect of Alzheimer's. The method according to claim 1,
Wherein said composition enhances a neuronal protective effect. The method according to claim 1,
Wherein the extract of the sandalwood extract is extracted with at least one solvent selected from the group consisting of water, an alcohol having 1 to 4 carbon atoms or a mixed solvent thereof.

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