KR20240043126A - Composition for the treatment of emotional and behavioral disorders comprising aripiprazole and mirtazapine as active ingredients - Google Patents

Abstract

The purpose of the present invention is to provide a composition for preventing or treating emotional behavioral disorders containing Aripiprazole and Mirtazapine as active ingredients. When Aripiprazole and Mirtazapine are administered together, It was confirmed that it was more effective in improving hyperactivity disorder and impulsive and compulsive stereotyped behavior than when administered alone. In addition, it was confirmed that not only is the effect superior even when administered at a lower dose than existing treatments, but also the side effects are lower, so it can be usefully used in related businesses.

Description

Composition for the treatment of emotional and behavioral disorders comprising aripiprazole and mirtazapine as active ingredients}

The purpose of the present invention is to provide a composition for preventing or treating emotional behavioral disorders containing aripiprazole and mirtazapine as active ingredients.

Aripiprazole (brand name: 'Abilify') was developed by Japan's Otsuka Pharmaceutical in 1988 and was approved for sale as a treatment for schizophrenia by the US FDA in November 2002. It is currently sold in 45 countries around the world, including Europe, as a treatment for schizophrenia. It is recording overwhelming sales in the market.

Aripiprazole is a unique dopamine partial agonist among the schizophrenia treatments belonging to the phenylpiperazine class. Unlike dopamine antagonist drugs that block dopamine secretion, it partially acts on the dopamine D2 receptor, and when dopamine is excessively secreted, it reduces the concentration of dopamine. It is an antagonist that lowers the secretion of dopamine, and when the amount of dopamine secretion is insufficient, it acts as a dopamine agonist and maintains the amount of dopamine secretion at a certain level.

In addition to improving positive and negative symptoms of schizophrenia, it is well tolerated with significantly fewer side effects such as weight gain and extrapyramidal system disorder (EPS). It is also effective in treating acute mania in bipolar disorder, and has expanded its therapeutic area by obtaining indications as an adjunct therapy to the treatment of major depressive disorder accompanying schizophrenia (it is the only treatment for schizophrenia). Therefore, high patient compliance can be expected with strong clinical effects on acute and chronic mental illness and mood dysregulation and fewer side effects.

Mirtazapine is a broad-spectrum antidepressant belonging to the NaSSA (noradrenaline-specific serotonin) series released by Organon (now MSD) in the United States in 1996, and is used in the treatment of major depression with a mechanism of action that is significantly different from that of SSRIs and SNRIs. After the substance and use patents expired, in the case of Hyundai Pharmaceuticals, a domestic company, in the case of 'Multapin Tablet', 100% local production from raw material synthesis to finished product was succeeded and released as a generic drug, and Myungin Pharmaceutical's 'Multapin Tablet' was used. ', was launched as a generic drug called 'Mirzentak Tablet' by Hwanin Pharmaceutical.

Autism is a neurodevelopmental disorder that begins in infancy, and its core symptoms include sociability and compulsive stereotyped behavior, and is used as the main diagnostic criterion for the disease. As no cure has been developed to date, it is a disease that causes many social costs as patients experience many difficulties in social life.

Attention Deficit/Hyperactivity Disorder (ADHD) is a disorder that occurs frequently in childhood and refers to a condition in which a person continues to lack attention, leading to distractibility, hyperactivity, and impulsivity. If these symptoms are left untreated, difficulties in daily life persist throughout childhood, and in some cases, symptoms remain even into adolescence and adulthood.

Neurochemical factors, genetic factors, and environmental factors have been reported as causes of attention deficit hyperactivity disorder. In particular, the relationship between the neurotransmitter dopamine and attention-deficit hyperactivity disorder is known (Swanson JM et al., Neuropsychol. Rev. 17:39-59, 2007), but previously conducted studies to search for genes associated with susceptibility to attention-deficit hyperactivity disorder. Dopamine-related genes such as dopamine transporter were not included (Franke B et al. Hum. Genet.126:13-50, 2009). Therefore, it is believed that various genetic predispositions play a role in the cause of this disease.

Accordingly, while researching treatments for neurodevelopmental disorders, the present inventors confirmed that neurodevelopmental disorders were improved when Aripiprazole or Mirtazapine was administered to mouse models of neurodevelopmental disorders. In addition, the synergistic effect of improving hyperactivity and stereotypic behavior was confirmed when aripiprazole and mirtazapine were administered together, thereby completing the present invention.

The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating emotional behavioral disorders containing Aripiprazole and Mirtazapine as active ingredients.

The present invention provides a pharmaceutical composition for preventing or treating emotional behavioral disorders containing Aripiprazole and Mirtazapine as active ingredients.

It was confirmed that the combined administration of Aripiprazole and Mirtazapine was more effective in improving hyperactivity disorder, social communication problems, and impulsive and compulsive stereotyped behavior than when administered alone. In addition, it was confirmed that not only is the effect superior even when administered at a lower dose than existing treatments, but also the side effects are lower, so it can be usefully used in related businesses.

Figure 1 is a diagram showing a neurodevelopmental disorder mouse model observed in a home cage to confirm improvement in repetitive behavior.
(Control Veh: normal mouse, animal model Veh: neurodevelopmental disorder mouse model, A: Aripiprazole, M: Mirtazapine, A to M: Aripiprazole and Mirtazapine)
Figure 2 is a diagram showing the improvement in grooming time when Aripiprazole and Mirtazapine of the present invention are administered together to a neurodevelopmental disorder mouse model.
Figure 3 is a diagram showing a neurodevelopmental disorder mouse model observed in a test box to confirm improvement in hyperactivity.
Figure 4 is a diagram showing improvement in hyperactivity when Aripiprazole and Mirtazapine of the present invention are administered together to a neurodevelopmental disorder mouse model.
Figure 5 is a diagram showing the phosphorylation activity of ERK when C6 glioma cells are treated in combination with Aripiprazole and Mirtazapine of the present invention.
Figure 6 is a diagram showing the phosphorylation activity of Akt when C6 glioma cells are treated in combination with Aripiprazole and Mirtazapine of the present invention.

Hereinafter, the present invention will be described in detail by embodiments of the present invention with reference to the attached drawings. However, the following implementation examples are provided as examples of the present invention, and if it is judged that a detailed description of a technology or configuration well known to those skilled in the art may unnecessarily obscure the gist of the present invention, the detailed description may be omitted. , the present invention is not limited by this, and the present invention is capable of various modifications and applications within the description of the claims described later and the scope of equivalents interpreted therefrom.

In addition, the terminology used in this specification is a term used to appropriately express preferred embodiments of the present invention, and may vary depending on the intention of the user or operator or the customs of the field to which the present invention belongs. Therefore, definitions of these terms should be made based on the content throughout this specification. Specification

In the whole, when a part "includes" a certain component, this means that it may further include other components rather than excluding other components, unless specifically stated to the contrary.

All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by a person skilled in the art in the field related to the present invention. In addition, preferred methods and feeds are described in this specification, but similar or equivalent methods are also included in the scope of the present invention. The contents of all publications incorporated by reference herein are hereby incorporated by reference.

As used in the present invention, the term "prevention" may mean any act of suppressing or delaying the onset of emotional behavior disorder by administering the pharmaceutical composition for preventing or treating emotional behavior disorder according to the present invention to an individual.

As used in the present invention, the term “treatment” may refer to any act of administering the composition of the present invention to a subject suspected of having an emotional behavior disorder to improve or benefit the symptoms of the emotional behavior disorder.

As used herein, the term “improvement” may mean any action that reduces at least the degree of a parameter related to the condition being treated, such as a symptom.

The present invention provides a pharmaceutical composition for preventing or treating emotional behavioral disorders containing Aripiprazole and Mirtazapine as active ingredients.

The pharmaceutical composition of the present invention may further include adjuvants in addition to the active ingredients. Any adjuvant known in the art may be used without limitation, but, for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase immunity.

The pharmaceutical composition according to the present invention can be prepared by incorporating the active ingredient into a pharmaceutically acceptable carrier. Here, pharmaceutically acceptable carriers include carriers, excipients, and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, Examples include calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical composition of the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods. .

When formulated, it can be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations contain the active ingredient plus at least one excipient, such as starch, calcium carbonate, sucrose, lactose, and gelatin. It can be prepared by mixing etc. Additionally, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used diluents such as water and liquid paraffin, they contain various excipients such as wetting agents, sweeteners, fragrances, and preservatives. You can. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.

The pharmaceutical composition according to the present invention can be administered to an individual through various routes. All modes of administration are contemplated, for example, by oral, intravenous, intramuscular, subcutaneous, or intraperitoneal injection.

The pharmaceutical composition may be formulated into various oral or parenteral dosage forms.

Dosage forms for oral administration include, for example, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, granules, etc. These dosage forms contain diluents (e.g. lactose, dextrose, water) in addition to the active ingredient. crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Additionally, the tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases starch, agar, alginic acid. or disintegrants such as sodium salts thereof or effervescent mixtures and/or absorbents, colorants, flavoring and sweetening agents. The formulation can be prepared by conventional mixing, granulating or coating methods.

In addition, representative formulations for parenteral administration are injectable formulations, and solvents for injectable formulations include water, Ringer's solution, isotonic saline solution, or suspension. The sterile fixed oil of the injectable preparation can be used as a solvent or suspending medium, and any non-irritating fixed oil, including mono- and di-glycerides, can be used for this purpose.

Additionally, the injectable preparation may use fatty acids such as oleic acid.

In one embodiment, the mixing ratio of Aripiprazole and Mirtazapine is 1 to 10:100 to 300, but is not limited thereto.

In one embodiment, the composition improves hyperactivity, but is not limited thereto.

In one embodiment, the composition improves impulsive and compulsive stereotyped behavior, but is not limited thereto.

In one embodiment, the emotional behavioral disorder may be a disorder that may appear in relation to the relationship development status of young children.

In one embodiment, the emotional behavior disorder includes attention deficit disorder, hyperactivity disorder, interpersonal relationship disorder, depression disorder, antisocial disorder, anxiety disorder, ADHD (Attention Deficit Hyperactivity Disorder) disorder, conduct disorder, autism, obsessive-compulsive disorder, schizophrenia, One or more may be selected from the group consisting of Tourette syndrome.

In one embodiment, the composition may regulate intracellular signaling pathways by inducing an increase in the phosphorylation level of Akt (protein kinase B) and a decrease in the phosphorylation level of ERK (extracellular signal-regulated kinase).

In addition, Aripiprazole and Mirtazapine of the present invention are described in the prior art [Transl Psychiatry (2017) 7_F Rizzo_doi:10.1038/tp.2017.167 and The American Journal of Drug and Alcohol Abuse_Lin Kang_Pages 541-552 | Published online: 07 Jul 2009], compared to high doses of Aripiprazole and Mirtazapine administered individually, it was confirmed that low-dose co-administration was effective in treating emotional behavioral disorders.

Hereinafter, the present invention will be described in more detail through the following examples. However, the following examples are merely examples to easily explain the content and scope of the technical idea of the present invention, and the technical scope of the present invention is not limited or changed thereby. Additionally, based on these examples, it can be easily determined by those skilled in the art that various modifications and changes are possible within the scope of the technical idea of the present invention.

[Example 1] Method for manufacturing neurodevelopmental disorder mouse model

To prepare a neurodevelopmental disorder mouse model, male mice were subjected to an adaptation period for one week, and after the adaptation period, they were treated with Aripiprazole and Mirtazapine purchased from Selleckchem for one week. And Aripiprazole+Mirtazapine was administered orally . Conventional [Neurotoxicol Teratol. 2013 ; 36: 36-46. doi:10.1016/j.ntt.2012.07.007 Moy, SS] Referring to the literature, a neurodevelopmental disorder mouse model was created by inducing neurodevelopmental disorder by treating the drug MK-801 on the last day of administration. A behavioral experiment was performed in a neurodevelopmental disorder mouse model 30 minutes after MK-801 administration to evaluate the effects of Aripiprazole and Mirtazapine of the present invention on improving neurodevelopmental disorder.

[Example 2] Homology improvement effect

In order to confirm the effect of improving homology by the combined administration of Aripiprazole and Mirtazapine of the present invention, a grooming test was performed.

After placing the neurodevelopmental disorder mouse model produced in Example 1 in a home cage (Figure 1), the duration and frequency of repetitive licking or scratching of the face and body using the mouse's grooming or front paws were measured. did. It is known that the longer the grooming time, the more repetitive (grooming test) and compulsive behavior becomes.

Therefore, Aripiprazole (0.005 mg/kg), Mirtazapine (1 mg/kg), and Aripiprazole (0.005 mg/kg) + Mirtazapine (1 mg/kg) were used in hyperactivity disorder mice, respectively. The effect of improving hyperactivity was confirmed by administering it to the model.

As a result, as shown in Figure 2, the combined administration of Aripiprazole (0.005 mg/kg) + Mirtazapine (1 mg/kg) was more effective in compulsive and repetitive stereotyped behavior than Aripiprazole and Mirtazapine alone. improved.

[Example 3] Effect of improving hyperactivity

In order to confirm the effect of improving hyperactivity by the combined administration of Aripiprazole (0.005 mg/kg) and Mirtazapine (1 mg/kg) of the present invention, hypermotor activity evaluation was confirmed.

Hypermotor activity evaluation is used to observe hyperactivity, depression, anxiety, and depression in motor function in animals. The greater the total distance traveled, the more hyperactivity the animal exhibits. The neurodevelopmental disorder mouse model produced in Example 1 was placed in the center of the test box. and observed its behavior for 20 to 30 minutes (Figure 3).

Excessive motor function and behavior were measured by measuring the distance the neurodevelopmental disorder mouse model walked within the box, and the degree of depression and anxiety was measured by measuring the distance and time traveled in the center and outskirts of the box using the EthoVision system (Noldus IT b.v., Netherlands). did.

As shown in Figure 4, combined administration of Aripiprazole (0.005 mg/kg) + Mirtazapine (1 mg/kg) improved hyperlocomotor activity compared to Aripiprazole and Mirtazapine alone. .

[Example 4] Effect of regulating intracellular signaling pathways

To confirm the effect of controlling intracellular survival signaling pathways by the combined treatment of aripiprazole and mirtazapine of the present invention, the following was performed.

After culturing primary nerve cells, treat them with 1 μM each of aripiprazole (A), mirtazapine (M), and combination treatment (A+M), then collect the cells and check the expression and activity of proteins related to the intracellular survival signal transduction pathway. did.

As a result, as shown in Figure 5, when aripiprazole and mirtazapine were treated in combination, the phosphorylation of ERK was found to be significantly reduced compared to when aripiprazole and mirtazapine were treated alone, as shown in Figure 6 As shown, when aripiprazole and mirtazapine were treated in combination, the phosphorylation of Akt was found to significantly increase compared to when aripiprazole and mirtazapine were treated alone.

Therefore, the combined treatment of aripiprazole and mirtazapine has an effect of protecting cells through regulation of survival signaling pathways within the cells, and in particular, it was confirmed that a synergistic effect appears when combined treatment of aripiprazole and mirtazapine. .

So far, the present invention has been examined focusing on its preferred embodiments. A person skilled in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.

Claims (7)

A pharmaceutical composition for preventing or treating emotional behavioral disorders containing aripiprazole and mirtazapine as active ingredients.
The composition according to claim 1, wherein the mixing ratio (W/W) of Aripiprazole and Mirtazapine is 1 to 10:100 to 300.
The composition of claim 1, wherein the composition improves hyperactivity.
The composition of claim 1, wherein the composition improves impulsive and compulsive stereotyped behavior.
The composition according to claim 1, wherein the emotional behavioral disorder is a disorder that may appear in relation to the relationship development status of young children.
The method of claim 1, wherein the emotional behavior disorder includes attention deficit disorder, hyperactivity disorder, interpersonal relationship disorder, depression disorder, antisocial disorder, anxiety disorder, ADHD (Attention Deficit Hyperactivity Disorder) disorder, conduct disorder, autism, obsessive-compulsive disorder, and schizophrenia. A composition selected from the group consisting of disease and Tourette syndrome.
The composition of claim 1, wherein the composition regulates intracellular signaling pathways by inducing an increase in the phosphorylation level of Akt and a decrease in the phosphorylation level of ERK.