KR101828581B1 - Pharmaceutical Composition for Preventing or Treating Dopamine Induced Dyskinesia comprising Metformin as Active Ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating dopamine induced dyskinesia comprising metformin or pharmaceutically allowable salts thereof as active ingredients. The present invention further relates to a food composition or a feed composition for preventing or alleviating dopamine induced dyskinesia comprising metformin or pharmaceutically allowable salts thereof as active ingredients.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for preventing or treating dopaminergic dyskinesia including metformin as an active ingredient,

The present invention relates to a pharmaceutical composition for preventing or treating dopamine induced dyskinesia comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to a food composition or feed composition for preventing or ameliorating dopamine induced dyskinesia comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient.

Parkinson's disease is a neurodegenerative brain disorder that exhibits chronic and progressive loss of voluntary movement. It is known to occur in one out of every 100 people in the elderly over 60 years of age and is characterized by selective cell death of dopaminergic cells in the midbrain substantia nigra. Also, the tremor of the hands, arms, legs, jaws, and face; Rigidity or stiffness of the limbs and trunk; Bradykinesia or slowness of movement; Dyskinesia; And postural instability or impaired balance and coordination. The disease is also associated with dementia, sleep disturbances, and cognitive confusion.

The reported treatment strategies for Parkinson's disease focus on symptom control through one or more medications, surgery, and physical therapy. The administration of the dopamine precursor levodopa as a dopamine replacement agent is known to be the most effective and most commonly used for the treatment of Parkinson's disease. This is because it better treats motor deficits associated with Parkinson's disease compared to dopamine agonists (Goodman & Gillman ' s Pharmacolgical Basis of Therapeutics, 11th edition, L. Brunton editor, The McGraw Hill Company, 2006). However, in a large number of patients, a significant adverse effect of long-term dopamine drug therapy is caused by abnormal motility (involuntary movement) (Fabbrini et al., Movement Disorders, 2007, 22 (10), 1379-1389; Konitsiotis, Expert Opin Investig Drugs, 2005, 14 (4), 377-392; Brown et al., IDrugs, 2002, 5 (5), 454-468). Thus, effective therapies for inhibiting or treating aberrant motility, which can be performed without adversely affecting anti-Parkinson's disease treatment, are needed.

Metformin is an FDA-approved drug that is widely prescribed for type 2 diabetes and is known to inhibit cancer development in people with diabetes. (Martin-Montalvo, Mercken et al., 2013) has been reported to improve cognitive function in metabolic disorders (Pintana Apaijai et al., 2012) .

Under these circumstances, the inventors of the present invention have conducted intensive research to prevent and treat adverse effects of dopamine-related drugs in Parkinson's disease patients. As a result, it has been shown that metformin in combination with L-DOPA in Parkinson's disease- DOPA induced dyskinesia was significantly reduced without affecting the efficacy, and the present invention was completed.

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating dopamine induced dyskinesia comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a food composition for preventing or ameliorating dopamine induced dyskinesia comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient.

It is still another object of the present invention to provide a feed composition for preventing or ameliorating dopamine induced dyskinesia comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient.

It is still another object of the present invention to provide a method for preventing or treating dopaminergic dyskinesia comprising administering the above pharmaceutical composition to a subject.

In order to achieve the above object, one aspect of the present invention provides a pharmaceutical composition for preventing or treating dopamine induced dyskinesia comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient.

The term "metformin" in the present invention is a drug known as a biguanides oral diabetes remedy. (AMPK), which inhibits glucose synthesis, stimulates the uptake of glucose into cells, inhibits the metabolic syndrome, and inhibits cardiovascular disease. . The metformin is a substance having a molecular formula of C4H11N5, and its specific structure is shown in the following formula (1). Metformin also has the IUPAC name of N, N-dimethylimidodicarbonimidic diamide.

[Chemical Formula 1]

Such a compound may be commercially available through a known synthesis method.

The term "pharmaceutically acceptable salt " as used herein means a formulation that does not impair the biological activity and properties of the metformin administered. The pharmaceutically acceptable salts include those acids which form a non-toxic acid addition salt containing a pharmaceutically acceptable anion such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like, Organic carboxylic acids such as formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- Sulfonic acid such as sulfonic acid, sulfonic acid, sulfonic acid, and the like. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium and the like, amino acid salts such as lysine, arginine and guanidine, dicyclohexylamine, N Organic salts such as methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like.

"Dopamine induced dyskinesia" in the present invention refers to dyskinetic symptoms caused by drugs that increase the stimulation of dopamine receptors. Such anomalous motility often appears to be a side effect of the dopaminergic agonist of Parkinson's disease, but it is not the only cause. Characteristics of these abnormalities include movement disorders, such as the appearance of slow and uncooperative involuntary movements, tremors, stiffness and gait disturbances.

The term "dopamine agonist" means any agonist that increases dopamine receptor stimulation. Specifically, the dopamine agonist may be levodopa, levodopa decarboxylase, monoamine oxidase B, bromocriptine, pergolide, pramipexole, lopinilol, carbogolin, apomorphine or lysuride, It is not limited.

In the present invention, dopamine induced dyskinesia may be, but is not limited to, dyskinetic dystrophy due to long-term administration of levodopa to Parkinson's disease.

The term "prophylactic" in the present invention means all the actions of inhibiting or delaying the onset of dopaminergic dyskinesia by administration of the pharmaceutical composition according to the present invention, and "treatment" Suspicion of dyskinesia and all the behaviors that alleviate symptoms of the onset individuals.

A specific embodiment of the present invention may be, but is not limited to, those used in combination therapy with levodopa (L-DOPA) or an acceptable salt thereof with a pharmaceutically acceptable salt thereof.

The term " levodopa " of the present invention is collectively referred to as catecholamine as a precursor of neurotransmitters dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline). Levodopa is also known as L-DOPA, or the like. Further, in the present invention, the levodopa can be mixed with L-DOPA. In addition, levodopa itself is known to mediate neurotrophic factor release by the brain and CNS. L-DOPA is also used as a drug in the treatment of Parkinson's disease. The levodopa has the IUPAC name of L-3,4-dihydroxyphenylalanine [L-3,4-dihydroxyphenylalanine].

(2)

Specifically, patients with Parkinson's disease treated with levodopa often have symptoms of decreased Parkinson's disease, but they experience increasingly difficulty standing or even keeping sitting. After the use of sustained levodopa, most of the patients develop such aberrations. Anomalous motility may occur at any time during the levodopa therapy cycle.

Metformin or a pharmaceutically acceptable salt thereof may be used in combination with levodopa or a pharmaceutically acceptable salt thereof to prevent or treat more effective dopamine induced dyskinesia, more specifically, to prevent or treat Parkinson's disease caused by long-term administration of levodopa It can bring about prevention or treatment of the disease.

According to one embodiment of the present invention, it was confirmed that the therapeutic efficacy of L-DOPA in a Parkinson's disease-induced mouse animal model was affected by the combined administration of metformin. As a result, The number of times was reduced by 6-OHDA administration and increased by administration to L-DOPA, thereby confirming the therapeutic effect of L-DOPA on Parkinsonism dyskinesia (Fig. 2).

This indicates that metformin did not affect the therapeutic efficacy of L-DOPA.

According to one embodiment of the present invention, in order to confirm the treatment of dyskinesia caused by long-term administration of levodopa to Parkinson's disease using metformin, the animal model of Parkinson's disease was treated with L-DOPA and the drug in combination, As the days of administration of metformin prolonged, it was confirmed that the abnormal involuntary movement was reduced (FIG. 4).

These results indicate that metformin is effective for the prevention and treatment of dopamine induced dyskinesia by confirming that abnormal immobility movement occurs during long-term administration of L-DOPA but the abnormal immobility movement is significantly reduced due to metformin administration.

According to one embodiment of the present invention, long-term administration of amantadine and metformin to an animal model of Parkinson's disease showed that the metformin administration group had lower total AIM and ALO AIM levels than amantadine administration group (Fig. 9).

This suggests that metformin is more effective at reducing L-DOPA induced dyskinesia than long-term drug administration compared to amantadine.

The pharmaceutical compositions of the present invention may further comprise suitable carriers, excipients or diluents conventionally used in the manufacture of pharmaceutical compositions. Specifically, the pharmaceutical composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method . In the present invention, the carrier, excipient and diluent which may be contained in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, Sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use may include various excipients such as wetting agents, sweetening agents, fragrances, preservatives, etc. in addition to water and liquid paraffin, which are simple diluents commonly used in suspension, liquid solutions, emulsions and syrups have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The amount of metformin or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention is not limited as long as the pharmaceutical composition has a preventive or therapeutic effect on dopamine induced dyskinesia, 99.9% by weight, more particularly 0.01 to 80% by weight.

The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention means an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention And the effective dose level is determined according to the severity of the disease, the activity of the drug, the age, body weight, health, sex, sensitivity of the patient to the drug, administration time of the composition of the present invention, , Factors including drugs used in combination with or co-used with the compositions of the present invention used, and other factors well known in the medical arts.

 The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered singly or multiply. It is important to take into account all of the above factors and administer an amount that will achieve the maximum effect in the least amount without side effects.

The dosage of the pharmaceutical composition of the present invention can be, for example, but not limited to, 0.1 to 500 mg / kg of body weight per day for an animal, including humans, containing the pharmaceutical composition of the present invention. The frequency of administration of the composition of the present invention is not particularly limited, but it may be administered once a day or divided into several doses. The dose is not intended to limit the scope of the invention in any way.

The term "individual" of the present invention means a mammal which is capable of infecting or having developed a disease, such as a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, It means all animals including. The kind of an individual is not limited as long as the disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the individual.

The term "administering" of the present invention means providing a predetermined substance to a subject in any suitable manner, and the administration route of the composition of the present invention may be administered through any conventional route so long as it can reach the target tissue have. But are not limited to, intravenous, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, rectal. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. Specific administration methods and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and drop injection.

The dose of the compound according to the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity. Day to 0.01 mg to 5000 mg, and may be administered once or several times a day at a predetermined time interval according to the judgment of a physician or a pharmacist, but is not limited thereto.

Another aspect of the present invention provides a food composition for preventing or ameliorating dopamine induced dyskinesia comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient.

Metformin, pharmaceutically acceptable salts, dopamine induced dyskinesia, prevention are as described above.

Since the food composition of the present invention can be ingested routinely, the effect of preventing or ameliorating dopamine induced dyskinesia can be expected, which is very useful.

The term "improvement" of the present invention means any action that at least reduces the degree of symptomatology associated with the condition being treated by administration of a composition comprising the metformin of the invention or a pharmaceutically acceptable salt thereof, do.

The food composition of the present invention includes forms such as pill, powder, granule, infusion, tablet, capsule or liquid, and the food to which the composition of the present invention can be added includes, for example, various foods, Beverages, gum, tea, vitamin complex, and health supplement foods.

The other ingredients other than those containing metformin as an essential ingredient that can be contained in the food composition of the present invention are not particularly limited and may include various herbal medicine extracts, food supplementary additives, natural carbohydrates, . In addition, the food-aid additive includes food-aid additives customary in the art, for example, flavoring agents, flavoring agents, coloring agents, fillers, stabilizers and the like.

Examples of such natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. In addition to the above, natural flavoring agents (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used as flavoring agents.

In addition to the above, the food composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and fillers (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, it may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components may be used independently or in combination.

In the present invention, the health supplement food includes health functional food, health food and the like.

The term "functional food" as used herein means the same term as "food for special health use" (FoSHU). In addition to nutrition, It means food. Here, the term "function (surname)" means that the structure and function of the human body have a beneficial effect for health use such as controlling nutrients or physiological action. 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 which are conventionally added in the art. In addition, the formulations of the food can also be produced without restrictions as long as they are formulations recognized as food. The food composition of the present invention can be manufactured in various formulations, and unlike general pharmaceuticals, it has an advantage of being free from side effects that may occur when a food is used as a raw material for a long period of time, and is excellent in portability. Food can be taken as an adjuvant to enhance the effect of preventing or ameliorating dopamine induced dyskinesias.

Another aspect of the present invention provides a feed composition for preventing or ameliorating dopamine induced dyskinesia comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient.

Metformin, pharmaceutically acceptable salts, dopamine induced dyskinesia, prevention are as described above.

The feed composition may include a feed additive. The feed additive of the present invention corresponds to an auxiliary feed in the feed control method.

As used herein, the term "feed" means any natural or artificial diet, single meal, or the like component for feeding, ingesting, digesting or suitable for the animal.

The kind of the feed is not particularly limited, and feeds conventionally used in the art can be used. Non-limiting examples of such feeds include vegetable feeds such as cereals, muscle roots, food processing busines logistics, algae, fibers, pharmaceuticals, buses, oils, pastes, pulses or cereals; Animal feeds such as proteins, inorganic substances, fats, oils, fats, oils, monocellular proteins, animal plankton or foods. These may be used alone or in combination of two or more.

The composition comprising metformin of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient has an effect of improving dyskinesia caused by long-term administration of levodopa to Parkinson's disease, , Pharmaceuticals for improvement or treatment, foods and feed compositions, and the like.

FIG. 1 shows d-amphetamine induced asymmetric rotational movement by dopaminergic neuronal cell death to determine the establishment of animal models in a 6-OHDA-induced Parkinson's disease mouse model. The mice were treated with 100 mg / kg, 200 mg / kg metformin It is a graph divided into groups.
FIG. 2 is a graph showing the ability of the right frontal leg, which is the opposite side of the left left brain, to be used to examine whether the metformin combination treatment affects the improvement of the movement disorder represented by L-dopa in the Parkinson's disease by the cylinder test.
FIG. 3 is a graph showing the results of the drug administration to determine the prophylactic and therapeutic effect of metformin of L-dopa induced dyskinesia by administering vehicle and metformin 100 mg / kg and 200 mg / kg 30 minutes before the administration of benzurazide and L-dopa AIM is a graph showing the total AIM value at the first AIM test.
FIG. 4 is a graph showing the effect of a drug administered to 100 mg / kg and 200 mg / kg of vehicle and metformin 30 minutes before the administration of benzalkonium AIM is a graph showing the total AIM value at the first AIM test.
FIG. 5 is a graph showing the results of a prospective, randomized, double-blind, placebo-controlled trial in which 100 mg / kg and 200 mg / kg of vehicle and metformin were administered 30 minutes before the administration of benzalkonium and L- A graph showing the ALO AIM values after the first AIM test.
FIG. 6 is a graph showing the effect of drug administration to determine the prophylactic and therapeutic effect of metformin on L-dopa induced dyskinesia by administering vehicle and metformin 100 mg / kg and 200 mg / kg 30 minutes before the administration of benzurazide and L-dopa A graph showing LCO AIM values at the first AIM test.
FIG. 7 shows the effect of metformin on the prophylactic and therapeutic effects of L-dopa induced dyskinesia by administration of vehicle, amantadine 40 mg / kg, and metformin 200 mg / kg 1 hour and 30 minutes before the administration of benzalkonium and L- FIG. 7 is a graph showing ALO AIM values by AIM test on the 10th day after drug administration for comparison. FIG.
FIG. 8 shows the effect of metformin on the prophylactic and therapeutic effect of L-dopa induced dyskinesia by administering vehicle, amantadine 40 mg / kg, and metformin 200 mg / kg 1 hour and 30 minutes before the administration of benzalkonium and L- A comparison of total AIM values by AIM test on the 10th day after drug administration for comparison.
Figure 9 shows the effect of L-dopa induced dyskinesia on the prophylactic and therapeutic effect of amphotericin B and amantadine 40 mg / kg and metformin 200 mg / kg, respectively, 1 and 30 minutes before the administration of benzalkonium and L-dopa, A comparison of total AIM values by AIM test at day 20 of drug administration for comparison.
FIG. 10 shows the effect of metformin on the prophylactic and therapeutic effect of L-dopa induced dyskinesia by administration of vehicle, amantadine 40 mg / kg, and metformin 200 mg / kg 1 hour and 30 minutes before and after administration of benzalkonium and L- A comparison of ALO AIM values with AIM testing at day 20 of drug administration for comparison.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the present invention.

Example 1: 6 - OHDA (6- hydroxyldopamine ) Mouse model of Parkinson's disease

Male C57BL / 6J mice at 9 weeks of age were used as experimental animals. The mice were allowed to freely consume sterilized feed and water in a specific pathogen free (SPF) environment maintained at a temperature of 22 to 24 ° C, and were maintained in a 12-hour day / night cycle.

The mice were treated with a mixture of ketamine and rumpun, and 6-OHDA was injected into the substantia nigra (brain) to produce dopaminergic cell loss in the middle cerebral hemisphere ) Were used. Twenty-five mg / kg of desipramine was intraperitoneally administered 30 minutes before 6-OHDA to prevent noradrenergic neurons from destroying, and a total of 15 μg of 6-OHDA was injected into the left nasopharynx (substania nigra pas compacta) (Brain microinjection coordinates: front-back -3.0, left-right -1.3, depth-4.7). As described above, 6-OHDA was directly administered to the brain, and the surgical site was closed and disinfected. Thereafter, the body temperature of the mice was maintained at 37 ° C in a warmer.

It is known that the more the dopaminergic cell death by 6-OHDA is, the more brain lesions become severe and the number of rotations is increased in the experimental animal model. Two weeks after the administration of 6-OHDA, 5 mg / kg dextroamphetamine (d-amphetamine) was intraperitoneally injected into mice to evaluate the degree of abnormality of exercise control ability by dopaminergic cell death, Behavior was observed. Specifically, after administration of the dextroamphetamine drug, the mice were placed in a cylinder having a diameter of 20 cm, and the number of rotations in the counterclockwise direction for 30 minutes was measured to evaluate the rotational behavior. This is a method of evaluating the degree of lesion induced by dopaminergic neuronal cell death through the asymmetric behavior of the mouse. It was used as a mouse classification standard for levodopa administration in cases where dopaminergic cell death was similar in the control and experimental groups. At this time, the vehicle was divided into control group and metformin 100 mg / kg and 200 mg / kg administration groups so that the average of the counterclockwise rotation number was the same, and the graph shown is a behavior analysis graph before the control group and metformin administration (FIG.

Example  2: In a mouse model of Parkinson's disease, L- DOPA's  For treatment efficacy Mat Influence of formin

To determine whether the therapeutic efficacy of L-DOPA in motor disorders was affected by the combination of metformin with 6-OHDA-induced Parkinson's disease mice, the number of paws was measured using a transparent cylinder for mice. (6-OHDA), 4 weeks after induction of 6-OHDA lesion, + 6 days after L-DOPA administration, and 6 minutes after L-DOPA administration (6-OHDA) L-DOPA), respectively. Specifically, the number of times the cylinder wall was stuck with the left front foot and the right front foot for 5 minutes in the cylinder was measured, and then the percentage of each foot was calculated from the total number of front paws.

As a result, it was confirmed that the number of times of right-leg stiffness opposite to that of the left brain with 6-OHDA lesion was decreased by 6-OHDA administration and increased by administration to L-DOPA, Respectively.

At this time, it was confirmed that administration of metformin 100 mg / kg and 200 mg / kg together with L-DOPA does not affect the therapeutic effect of L-DOPA on Parkinson's disease to exercise disorders (Fig. 2).

Example  3: In animal models of Parkinson's disease mice Metformin  The L- DOPA  Treatment of Induced Abnormalities

To investigate whether treatment of L-DOPA induced dyskinesia with metformin in a 6-OHDA induced Parkinson's disease mouse model, the following experiment was conducted.

L-DOPA (20 mg / kg) and benzurazide (12 mg / kg) were administered daily to the abdominal cavity of the mice four weeks after the 6-OHDA lesion and the vehicle control group treated with L-DOPA alone, 100 mg / kg and 200 mg / kg of metformin were orally administered 30 minutes before the administration of L-DOPA. Metformin and L-DOPA were measured for the appearance of abnormal involuntary movement (AIM) on the 5th and 10th day of the mice. The measurement method was a known method (Journal of Neuroscience 25 April 2012, 32 (17) 5900-5910).

Specifically, immediately after administration of L-DOPA, the mice were placed in separate cages and abnormal movements were evaluated for 120 minutes every 1 minute (monitoring period) every 20 minutes. Anomalous involuntary movements (AIM), distinct from natural fixed behavior, are classified into four subtypes: locomotive, axially anomalous tension of the neck and upper body, , Limb (trembling of the lateral femoral limb) and orofacial (vacuum jaw movement and tongue projection). In addition, each subtype was scored on a severity scale of 0 to 4 (0, no; 1, sometimes; 2, often; 3, contiguous; 4, continuous and not disturbed by external stimuli). The total AIM score corresponds to the sum of the individual scores of each AIM subtype. Composite scores were obtained by adding scores to axes, limbs, and nonuniform AIM (ALO score).

As a result, abnormal amorphous motility (AIM) on day 5 when administered with L-DOPA / benglarazide resulted in a statistically significant decrease in total AIM levels in the group administered with 200 mg / kg metformin compared to the vehicle-administered group (Fig. 3). In addition, at day 10 of drug administration, the total AIM level increased in the vehicle-administered control group significantly decreased in the 100 mg / kg group of metformin and significantly decreased in the group administered 200 mg / kg of metformin (FIG. 4). At this time, the LOC (locomotive) AIM value (FIG. 5), the ALO [axial (posture of the neck and upper body abnormal tension), the limb (the quadriceps of the lateral side of the lesion and the orofacial: AIM (Fig. 6) was significantly lower in the groups receiving metformin 100 mg / kg and 200 mg / kg than the vehicle-administered control group (Fig. 5 and Fig. 6).

The results showed that when metformin was administered with L-DOPA, abnormal immobility was observed by long-term administration of L-DOPA. However, when metformin was administered, metformin significantly decreased the abnormal involuntary movement compared to the vehicle-administered group. DOPA induced dyskinesia was found to be effective for prevention and treatment.

Example  4: In animal models of Parkinson's disease mice Metformin and  Comparison of Amantadine-induced L-DOPA induced dyskinesia

In order to compare amantadine, which is known to be effective for L-DOPA induced dyskinesia, to the metformin-administered group, the 6-OHDA-induced Parkinson's disease mouse model was established and after 4 weeks, vehicle-treated control and amantadine 40 mg / kg of metformin and 200 mg / kg of metformin were administered orally. After 1 and 30 minutes of drug administration, L-DOPA / benzzlazide was administered repeatedly every day for 10 days and 20 days after the administration. Respectively. At this time, the dose of amantadine was selected to be 40 mg / kg, which is a good therapeutic effect in L-DOPA induced dyskinesia in mice.

As a result, at the 10th day of drug administration, amantadine 40 mg / kg and metformin 200 mg / kg administration group were lower in ALO AIM and total AIM levels than the vehicle control control group (FIGS. 7 and 8). In addition, as a result of the administration on the 20th day, the total AIM value was lower in the amantadine and metformin administration groups than in the control group, and in particular, the ALO AIM level was lower than that in the amantadine administration group 10).

Thus, the administration of metformin 200 mg / kg was found to be more effective in reducing L-DOPA induced dyskinesia than longer administration of amantadine 40 mg / kg.

From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.

Claims (9)

Pharmaceuticals for the prophylaxis or treatment of abnormal motility due to long-term administration of levodopa (L-DOPA) to Parkinson's disease, comprising metformin and levodopa (L-DOPA) or a pharmaceutically acceptable salt thereof as an active ingredient Gt;
The method according to claim 1,
Wherein the pharmaceutical composition reduces adverse effects due to Levodopa (L-DOPA) administration compared to a control treated with only levodopa (L-DOPA).
delete The method according to claim 1,
The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient or diluent.
The method according to claim 1,
Wherein the pharmaceutical composition is in the form of a liquid preparation, a powder, an aerosol, an injection, a sap, a capsule, a pill, a tablet, or a suppository.
(L-DOPA) for Parkinson's disease, which comprises metformin and levodopa (L-DOPA) or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or ameliorating dyskinesia caused by long-term administration of levodopa Composition.
(L-DOPA) for Parkinson's disease, comprising metformin and levodopa (L-DOPA) or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or amelioration of dyskinesia caused by long-term administration of levodopa Composition.
A method for the prophylaxis or treatment of abnormal motor manifestations due to long-term administration of levodopa (L-DOPA) to Parkinson's disease, comprising administering the pharmaceutical composition of claim 1 to a subject other than a human. delete

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