KR20200117506A - Pharmaceutical composition for the prevention or treatment of depressive or anxiety symptoms through nasal administration of GABA-B receptor antagonists or agonists - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating depression or anxiety symptoms through nasal administration of a GABA-B receptor antagonist or an agonist. More specifically, the present invention is to provide a pharmaceutical composition which can reduce anxiety by nasal administration of the antagonist, and also can relieve depression symptoms by nasal administration of the agonist. According to the present invention, it is possible to distinguish between a depressive disorder patient and an anxiety disorder patient to access treatment, and it is expected that a lesser amount of neurotransmitters can be used to effectively prevent or treat depressive and/or anxiety symptoms.

Description

Pharmaceutical composition for the prevention or treatment of depressive or anxiety symptoms through nasal administration of GABA-B receptor antagonists or agonists}

The present invention is a pharmaceutical composition for the treatment of depression or anxiety symptoms through nasal administration of a GABA-B receptor antagonist or an agonist, and more specifically, the nasal administration of the antagonist can reduce anxiety, which is an anxiety symptom, and of the agonist It is to provide a pharmaceutical composition that can relieve anxiety disorders and other depression symptoms by nasal administration.

Anxiety disorders and depressive disorders are very common mental disorders. According to epidemiological surveys, the prevalence is high enough to occupy the first and second place among mental disorders, respectively. Anxiety disorders and depressive disorders are classified into separate diagnostic categories, but they tend to be similar or common in clinical manifestations and diagnostic criteria. In the case of depressive episodes, anxiety, fatigue from generalized anxiety disorder, insomnia, difficulty concentrating, and loss of interest in post-traumatic stress disorder are examples. Moreover, these two diseases have a high coexistence rate, which is diagnosed by one person at the same time. However, anxiety disorder and depressive disorder are qualitatively different diseases, and their risk factors, natural course, and psychopathological characteristics are also different. The dominant view is that the coexistence of anxiety and depression is primarily due to the onset of anxiety disorder and that the depressive image appears as a result of a dose-response relationship. Accordingly, there is a need to develop a method that can independently control anxiety and depression.

The treatment of depression is accompanied by a psychotherapeutic approach and drug treatment, but the drug used for drug treatment has not been developed with a breakthrough mechanism since the monoamine reuptake inhibitory drug developed in the 1950s. Recently, a variety of drugs such as SSRI, NDRI, and SNRI have been developed according to the neurotransmitter system, but they are still in the clinical trial stage. In addition, antidepressants generally show efficacy over several days to several weeks, so the effect of the drug can be confirmed after at least 4 to 6 weeks after taking it, and in some cases, it will take a long time to improve due to an increase in the drug dose or drug replacement. It might take. Accordingly, it is necessary to develop a drug that exhibits more immediate effects and has less side effects.

On the other hand, the brain is floating in about 150ml of cerebrospinal fluid (CSF), and the cerebrospinal fluid slowly circulates between the four ventricles and the space under the arachnoid, and exits into the cerebral vein through the arachnoid vili. Since there is no lymphatic system in the brain, cerebrospinal fluid partially replaces it. Since the brain and cerebrospinal fluid are separated by an oil membrane that has some degree of permeability, the blood-cerebrospinal fluid barrier and the blood-brain barrier (BBB) prevent the production of undesirable blood substances. Block. The blood-brainstem barrier creates a chemical environment that protects the brain, where certain molecules can perform functions independent of what they do elsewhere in the body.

Thus, in order to develop a drug effective against disorders of the central nervous system (CNS), nasal delivery has been studied. Nasal delivery of drugs has many advantages. Direct access to the brain is possible, absorption is fast due to the abundant capillaries in the nose, the initiation of action is quick, and the first-pass metabolism of the liver can be avoided. It is effective in chronic drug treatment, and can be easily administered. It is also known that, in contrast to large molecules and/or ionized molecules, lipophilic pharmaceutical compounds with sufficiently small molecular weight are generally readily absorbed by the mucous membrane of the nose.

Gammaaminobutyric acid (GABA) is a representative inhibitory neurotransmitter acting on the central nervous system, and is known to show aggressiveness when the inhibitory regulation of the limbic system by GABA is lost. In addition, GABA-A receptor agonists such as benzodiazepine are mainly prescribed to reduce anxiety symptoms and muscle spasm. In addition, GABA-B receptor is a ligand receptor, and GABA-B receptor agonists such as baclofen have been mainly prescribed for the treatment of muscle spasms such as spinal injury or multiple sclerosis, and such as SCH-50911. GABA-B receptor antagonists have been prescribed as anticonvulsants. Recently, GABA-B receptors have been reported to have an effect on mental disorders such as drug addiction, depression, and anxiety disorders. However, studies on specific mechanisms of action have been insufficient, so the appropriate administration method and dosage of substances capable of regulating its function have been investigated. Research is needed.

Accordingly, the present inventors targeted the GABA-B receptor and administered the antagonist or agonist of the receptor to the nasal cavity or intraperitoneally to confirm the effect on the symptoms of anxiety disorder and depressive disorder, and completed the present invention.

US 2005/0215521

The technical task of the present invention is to provide an optimal administration method and dosage of a pharmaceutical composition containing a GABA-B receptor-specific agonist or antagonist for the prevention or treatment of depressive disorder or anxiety disorder.

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

In order to solve the above problems, the present invention provides a pharmaceutical composition for nasal administration comprising an agonist specific to GABA-B receptor as an active ingredient and having an antidepressant effect.

In one embodiment of the present invention, the composition is administered once a day, but 1 to 4 mg, preferably 1.4 to 1.8 mg, more preferably 1.6 mg of an agonist specific to the GABA-B receptor per unit kg An agonist specific for the GABA-B receptor may be included for administration.

As another embodiment of the present invention, the antidepressant effect may be due to alleviation of hopelessness.

In another embodiment of the present invention, the GABA-B receptor-specific agonist is Phenibut, Isovaline, Lesogaberan, SKF-97541, CGP-44532, Picamilon, Progabide, SL-75102, Tolgabide, baclofen, and Arbaclofen Placarbil. It may be one or more selected from the group, preferably baclofen.

In addition, the present invention can provide a pharmaceutical composition for nasal administration containing an antagonist specific for GABA-B receptor as an active ingredient and having an anti-anxiety effect.

As an embodiment of the present invention, the composition may relieve anxiety symptoms but not affect depression symptoms.

In another embodiment of the present invention, the composition may be administered once a day, but may include an antagonist specific to the GABA-B receptor such that 2 to 4 mg of an antagonist specific to the GABA-B receptor per kg is administered.

In another embodiment of the present invention, the GABA-B receptor specific antagonist may be CGP36216, CGP46381, CGP52432, CGP54626, CGP55845, 2-Hydroxysaclofen, CGP-35348, Homotaurine, Phaclofen, Saclofen, and SCH50911, but preferred For example, it may be SCH50911.

In addition, the present invention provides a method for preventing or treating depressive disorder comprising administering an agonist specific for GABA-B receptor to the nasal cavity of an individual.

In addition, the present invention provides a method for preventing or treating anxiety disorders comprising administering an antagonist specific to the GABA-B receptor to the nasal cavity of an individual.

As an embodiment of the present invention, the GABA-B receptor-specific agonist administered to the nasal cavity of the individual may be 1 to 4 mg per kg of the individual, and may be administered once a day.

In another embodiment of the present invention, the GABA-B receptor specific antagonist administered to the nasal cavity of the subject may be 2 to 4 mg per kg of the subject, and may be administered once a day.

In addition, the present invention provides the use of an agonist specific to the GABA-B receptor for the manufacture of a drug for nasal administration having an effect of preventing or treating depressive disorder.

In addition, the present invention provides the use of a GABA-B receptor specific antagonist for the manufacture of a drug for nasal administration having an anxiety disorder prevention or treatment effect.

The present invention confirmed that the effect of reducing hopelessness can be obtained through nasal administration of a GABA-B receptor agonist, unlike intraperitoneal administration, and through nasal administration of a GABA-B receptor antagonist, compared to intraperitoneal administration. Excellent anxiety symptom reduction effect was confirmed, and by the provision of the present invention, there is an advantage that it is possible to effectively prevent or treat depression and/or anxiety disorders using a smaller amount of drugs. In addition, since the drug is directly delivered to the brain through nasal administration, there is no problem with the liver, and there is no or little side effects.

1 is a diagram illustrating a nasal administration method and an action of a nasal drug.
FIG. 2 is a graph of the results of a behavioral experiment of mice administered with baclofen nasally. Specifically, it was confirmed that the mice to which baclofen was administered nasally in the tail suspension method and forced swimming experiment decreased immobility (A and B).
FIG. 3 is a graph of the results of a behavioral experiment of a mouse administered SCH50911 nasally. Specifically, in a high zero maze test, a mouse nasal administration of SCH50911 increased both the time to stay in the open space (A) and the number of visits to the open space (B). Are checking.
4 is a graph of the results of behavioral experiments of mice administered intraperitoneally with SCH50911, and mice administered with SCH50911 intraperitoneally show statistical differences in behavioral changes according to drug administration in all of the high-level zero maze test, tail suspension, and forced swimming experiments. It is confirming that it is not.
FIG. 5 is a view confirming the efficacy according to the amount of SCH50911 administered to the nasal cavity. Specifically, it is a view confirming that the effect on relieving anxiety symptoms is insignificant when a drug of less than 2 mg per unit weight (1 kg) of the subject to be administered is administered. .

As a result of intensive research on effective treatment methods for depression and anxiety disorders, the present inventors showed neuro anxiety symptoms and depression symptoms with only a small amount of drugs by administering an antagonist or agonist of the receptor targeting the GABA-B receptor through the nasal cavity. It was confirmed that it effectively alleviates the present invention.

GABA-B receptor, an inhibitory or active target of the present invention, is a receptor for gamma-Aminobutyric acid (GABA), a representative inhibitory neurotransmitter acting on the central nervous system. Although it has been found to affect mental disorders such as disability, a method for controlling the appropriate activity of the receptor has not yet been developed.

The GABA-B receptor agonist of the present invention activates the activity of the receptor, and non-limiting examples thereof include Phenibut, Isovaline, Lesogaberan, SKF-97541, CGP-44532, Picamilon, Progabide, SL-75102 , Tolgabide, baclofen, and Arbaclofen Placarbil, etc., but in a specific embodiment of the present invention, it was confirmed that baclofen is used to relieve depression when the agonist is administered through the nasal cavity (see Example 3-1). .

On the other hand, baclofen, a GABA-B receptor agonist used in a specific example of the present invention, is beta-(4-chlorophenyl)-gamma-aminobutric acid (βγacid) having the following structure. Baclofen has been used as a drug for the treatment of muscle spasm such as spinal injuries or multiple sclerosis, and has been used only by oral administration or administration through spinal canal injection, and the effects of baclofen's nasal administration have not been revealed.

[Structural Formula 1]

In addition, the GABA-B receptor antagonist of the present invention directly and/or indirectly inhibits the activity of the receptor, and non-limiting examples thereof include CGP36216, CGP46381, CGP52432, CGP54626, CGP55845, 2-Hydroxysaclofen, CGP -35348, Homotaurine, Phaclofen, Saclofen, and SCH-50911, etc., but in a specific embodiment of the present invention, the antagonist using SCH-50911, unlike the case of intraperitoneal administration, when administered through the nasal cavity, the symptoms of depression It was confirmed that there is an effect of alleviating anxiety symptoms without affecting (see Examples 3-2 and 3-3).

In the present invention, that the GABA-B receptor antagonist is intranasally administered and does not affect depression symptoms means that the antagonist does not cause a significant change in the state and/or the degree of depression before and after administration.

On the other hand, SCH-50911, a GABA-B receptor antagonist used in specific examples of the present invention, has the following structure: 2-[(2 S )-5,5-dimethylmorpholin-2-yl]acetic acid (2 -[(2 S )-5,5-dimethylmorpholin-2-yl]acetic acid). Although SCH-50911 has been used as an anticonvulsant, it has yet to be known about its effect in relation to depression or anxiety disorder.

[Structural Formula 2]

Anxiety disorder and depressive disorder, which the composition of the present invention is the target of prevention or treatment, are very common mental disorders, and tend to be similar or common in clinical manifestations and diagnostic criteria. Depressive disorders are divided into separate diagnostic categories.

Depressive disorder, commonly referred to as depression, refers to a disease that causes a variety of cognitive and psychosomatic symptoms, resulting in a decrease in function, with decreased motivation and depression as the main symptoms, and anxiety disorder is caused by various types of abnormal, pathological anxiety and fear. As a result, it is a collective term for mental disorders that cause disorders in daily life, which means that anxiety and fear exceed the normal range, causing mental pain and physical symptoms.

The present invention presents more detailed experimental results to allow access to treatment by distinguishing between anxiety disorders and depressive disorders, and specifically, as an experimental technique for confirming the degree of depression, the tail suspension test (TST) and forced A forced swim test (FST) was performed, and an elevated zero maze test (EZM) was performed to confirm the degree of anxiety.

In addition, the present invention has confirmed that when an agonist of the GABA-B receptor is administered through the nasal cavity, it has been confirmed that anxiety symptoms are aggravated and depressive symptoms are alleviated. Changes in symptoms appearing after nasal administration of the agonist It can be used for differential diagnosis of depressive disorder by observing. Likewise, when an antagonist of GABA-B receptor is administered through the nasal passages, it is irrelevant to the symptoms of depression and has the effect of alleviating the symptoms of anxiety.The degree of remission of symptoms after nasal administration of the antagonist to the individual is observed to differentiate anxiety disorders. It can also be used for doing.

On the other hand, the present inventors believe that the antagonist or agonist of the GABA-B receptor exhibits its effect through the nasal cavity, so the optimal dose is based on the unit weight (1 kg) of the administered individual, 2 to 4 mg for the antagonist, and 2 to 4 mg for the agonist. It was confirmed that it was 1 to 4 mg. If the dose is less than the above dose, it is difficult to expect the effect of the drug, and if the dose is administered in a larger amount than the above dose, there is a problem that non-specific side effects or decrease in therapeutic efficacy due to overdose of the drug appear.

In addition, in the present invention, "individual" means a mammal showing symptoms of a depressive disorder or an anxiety disorder, and preferably means a human or livestock.

In addition, the term "prevention" in the present invention means that anxiety, fear, and depression do not deviate from the normal range by administration of the composition according to the present invention, or any interest and interest in life are maintained to delay the occurrence of depression or depressive disorder. It means an action, and "treatment" means any action in which symptoms of anxiety disorder or depressive disorder are improved or advantageously changed by the administration of the composition according to the present invention, and "improvement" means depression by administration of the composition according to the present invention. Any action that reduces the severity of a disability or an anxiety disorder-related parameter, e.g. symptoms.

In the present invention, the pharmaceutical composition (pharmaceutical composition) may further include a suitable carrier, excipient, and diluent commonly used in the preparation of the pharmaceutical composition.

In the present invention, the term "carrier" is also called a vehicle, and refers to a compound that facilitates the addition of proteins or peptides into cells or tissues. For example, dimethyl sulfoxide (DMSO) is It is a commonly used carrier that facilitates the introduction of a large number of organic substances into cells or tissues.

In the present invention, "diluent" is defined as a compound diluted in water that not only stabilizes the biologically active form of the protein or peptide of interest, but also dissolves the protein or peptide. Salts dissolved in buffer solutions are used as diluents in the art. The commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely alter the biological activity of a compound. The compounds containing azelaic acid as used herein can be administered to a human patient as such, or as a pharmaceutical composition mixed with other ingredients, such as in combination therapy, or with a suitable carrier or excipient.

In the present invention, various transformations can be applied and various embodiments can be applied, and specific embodiments are illustrated in the drawings and described in detail in the detailed description below. However, this is not intended to limit the present invention to a specific embodiment, it is to be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, when it is determined that a detailed description of a related known technology may obscure the subject matter of the present invention, a detailed description thereof will be omitted.

[Example]

Example 1. Preparation of experimental animals

All experimental procedures using animals were approved by the Animal Care and Use Committee of Korea University and were performed in accordance with the guidelines of Korea University. Experimental animals were C57BL/6 male mice (Japan SLC, Inc., Japan), and after taming the experimental animals for one week before the experiment, they were randomly divided into a test group (administered with Baclofen or SCH50911) and a control group (injected with PBS).

Example 2. Drug administration to experimental animals

Respiratory anesthesia was performed with 4% isoflurane in order to administer the drug to the experimental mice nasally. As shown in FIG. 1, the anesthetized mice were gripped with their heads facing downwards so that the nasal cavity was sufficiently secured, and then 2.5 μl of each drop was added to each drop using a micropipette, so that about 10 μl of the anesthetized mice finally entered the nasal cavity. Anesthesia time was chosen to induce an unconscious state for a minimum time sufficient to complete dosing. The dosage of Baclofen and SCH50911 was determined to be 1.6 mg/kg and 4 mg/kg per mouse, respectively, taking into account the amount used in the intraperitoneal injection method. Mice returned to consciousness within 1-2 minutes after intranasal administration of the drug, and 30 minutes was sufficient for complete recovery. Animal behavior tests were performed with sufficiently recovered mice.

In order to intraperitoneally administer SCH50911, a GABA-B receptor-specific antagonist, to experimental mice, an injectable SCH50911 solution was prepared by diluting in PBS (Phosphate-buffered saline) and administered 4 mg/kg per mouse.

Example 3. Animal behavior experiment

3-1. Elevated zero maze test (EZM)

Place the mouse in the closed area of the altitude zero maze, which is an open arm with two round and facing quadrants with walls, and the other two quadrants and explore the maze for 5 minutes. Allowed. Animal movements during the entire test period were recorded for video analysis, and behavioral measurements consisted of the percentage of time spent in the open area and frequency of entering the open area. When all four paws were in the open area, the mice were analyzed as being in the open area. Since the open area is open, it causes anxiety in the mice, so if the time spent in the open area or the number of visits increases, it can be seen that anxiety decreases.

3-2. Tail suspension test (TST)

The tail suspension device has four compartments divided into opaque partitions, and the entire device is made of matte acrylic. Each mouse was suspended in the air for 6 minutes so that the tail was fixed with a tape so that it could not grab the surrounding surface or escape. Immobility was defined as a state in which the limb had no movement. During the 6 minute test period, immobility was recorded for the last 4 minutes. The longer the mouse is in the immobile position, the greater the feeling of despair.

3-3. Forced swim test (FST)

In the case of the forced swimming experiment, the mouse was placed in a clean cylinder (diameter 12 cm, height 24 cm) partially filled with tap water at 24 to 25 degrees Celsius. For the measurement of active (swimming or climbing) or passive (floating) behavior, the depth of water was set so that the hind legs or tail did not touch the bottom of the cylinder. Actions were recorded using an infrared camera for 6 minutes. Immobility was defined as a state in which there was no movement except for the minimum movement required to float the head above the water. The duration of motionless behavior was recorded during the last 4 minutes of the 6-minute test period. The longer the mouse is in the immobile position, the greater the feeling of despair.

3-4. Results of nasal administration of GABA-B receptor agonists

In the tail suspension performed after nasal delivery of baclofen, a GABA-B receptor-specific agonist, mice treated with baclofen showed a lower immobility compared to control mice administered with PBS, reducing hopelessness, a key symptom of depression. It could be confirmed that (see Fig. 2). In other words, it was found that the effect of reducing hopelessness can be obtained through nasal administration of baclofen. This result is completely contrary to the result that baclofen through intraperitoneal injection relieves anxiety symptoms and increases hopelessness.

3-4. Results of nasal administration of GABA-B receptor antagonist

In the high zero maze test conducted after nasal drug delivery of SCH50911, a GABA-B receptor-specific antagonist, mice administered with SCH50911 were statistically statistically significant in terms of time to stay in the open area and the number of movements to the open area compared to control mice administered with PBS. It was confirmed that anxiety decreased from the result of increasing by (see FIG. 3). There was no difference between the tail suspension method and the forced swimming experiment, so it was judged that the parameters related to the feeling of hopelessness were not affected. These results are consistent with the results of the conventional intraperitoneal injection of SCH50911 to reduce anxiety symptoms, but are different from the results of antidepressant efficacy by reducing immobility in the forced swimming test.

3-4. Results of intraperitoneal administration of GABA-B receptor antagonists

In the animal behavior evaluation conducted after drug delivery of the GABA-B receptor-specific antagonist SCH50911 through the intraperitoneal cavity, there was no statistical difference in all of the high zero maze test, tail suspension method, and forced swimming experiment (see FIG. 4). Therefore, it is judged that nasal drug administration is more effective in depression-related behavioral changes than drug administration through abdominal cavity.

As described above, a specific part of the present invention has been described in detail, and for those of ordinary skill in the art, it is obvious that this specific technology is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Therefore, it will be said that the practical scope of the present invention is defined by the appended claims and their equivalents.

Claims (8)

As a pharmaceutical composition containing a GABA-B receptor-specific agonist as an active ingredient and having an antidepressant effect,
The composition is characterized in that for nasal administration, pharmaceutical composition.
The method of claim 1,
The composition is administered once a day, characterized in that it comprises a GABA-B receptor-specific agonist to administer 1 to 4 mg of an agonist specific to the GABA-B receptor per kg.
The method of claim 1,
The antidepressant effect is characterized in that by relieving the feeling of hopelessness, pharmaceutical composition.
The method of claim 1,
The GABA-B receptor-specific agonist is at least one selected from the group consisting of Phenibut, Isovaline, Lesogaberan, SKF-97541, CGP-44532, Picamilon, Progabide, SL-75102, Tolgabide, baclofen and Arbaclofen Placarbil. To, pharmaceutical composition.
As a pharmaceutical composition containing an antagonist specific to GABA-B receptor as an active ingredient and having an anti-anxiety effect,
The composition is characterized in that for nasal administration, pharmaceutical composition.
The method of claim 5,
The composition is characterized in that it has an effect of reducing anxiety symptoms without affecting the symptoms of depression, pharmaceutical composition.
The method of claim 5,
The composition is administered once a day, but comprises a GABA-B receptor specific antagonist to administer 2 to 4 mg of an antagonist specific to the GABA-B receptor per kg.
The method of claim 5,
The GABA-B receptor specific antagonist is at least one selected from the group consisting of CGP36216, CGP46381, CGP52432, CGP54626, CGP55845, 2-Hydroxysaclofen, CGP-35348, Homotaurine, Phaclofen, Saclofen, and SCH-50911. , Pharmaceutical composition.

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