A composition for preventing or treating post-traumatic stress disorder, comprising a phosphodiesterase type 5 inhibitor as an active ingredient

Abstract

The present invention relates to a composition for preventing or treating post-traumatic stress disorder, which comprises a phosphodiesterase type 5 (PDE5) inhibitor as an active ingredient, and more particularly to a pharmaceutical composition or health functional food composition for preventing, ameliorating, or treating post-traumatic stress disorder, which comprises a PDE5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for preventing or treating post-traumatic stress disorder, which comprises administering the pharmaceutical composition to an individual.

Description

[Technical Field]

[0001] The present invention relates to a composition for preventing or treating post-traumatic stress disorder, which comprises a phosphodiesterase type 5 (PDE5) inhibitor as an active ingredient. Specifically, the present invention relates to a pharmaceutical composition or health functional food for preventing, ameliorating, or treating post-traumatic stress disorder, which comprises a PDE5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for preventing or treating post-traumatic stress disorder, which comprises administering the pharmaceutical composition to an individual. [Background technology]

[0002] Post-traumatic stress disorder (PTSD), now classified as a trauma- and stress-related disorder, is an anxiety disorder that can occur in response to life-threatening situations. It primarily occurs after experiences that are outside of everyday life, such as natural disasters, fires, war, physical assault, torture, sexual assault, hostage situations, abuse, and other major accidents. Symptoms may begin soon after the trauma or may take days, weeks, months, or even years to appear.

[0003] Symptoms of PTSD include hyperalertness, re-experiencing or intrusion of the shock, and emotional avoidance or numbness. Symptoms of PTSD can also include headaches, indigestion, vomiting, stomach pain, tremors, and allergies due to hormonal changes. They can also manifest in a variety of ways, including decreased cognitive ability, memory loss, separation anxiety, fear of school, and fear of outsiders. Unrealistic emotions can lead to dependence on alcohol or drugs, leading to abuse and addiction, and autonomic nervous system disorders, hallucinations, dissociative disorders, and panic attacks.

[0004] PTSD is treated using cognitive therapy, behavioral therapy, hypnotherapy, group therapy, drug therapy, and neuroleptic therapy, among other methods. Drug therapy primarily involves antidepressants such as selective serotonin reuptake inhibitors (SSRIs). Fluoxetine, known by the trade name Prozac, is a representative example of SSRIs. It has been reported that fluoxetine can be used to treat PTSD (Journal of Traumatic Stress, 1991 July, 4(3):419-423; Neurosciences (Riyadh), 2011 July, 16(3):257-62). While various new drugs for treating PTSD exist, fluoxetine is known as the most widely prescribed drug in many countries. However, the SSRIs exhibit efficacy-limiting side effects, including cognitive impairment, weight gain, sexual dysfunction, sedation, addiction, and withdrawal symptoms, leading to efforts to use safer drugs for long-term treatment.

[0005] Meanwhile, phosphodiesterase (PDE) is an enzyme that catalyzes the hydrolysis of cyclic AMP and / or cyclic GMP into 5-AMP and 5-GMP, respectively, in cells, and thus plays an important role in the cellular regulation of cAMP or cGMP levels. A total of 11 PDEs have been identified (Nature, 674-682 (2002)). Among the PDEs, PDE5 is an enzyme that degrades cGMP to produce 5'-GMP. It has been reported that its inhibition maintains the cGMP concentration and prolongs erection (Boolel, M. et al., Br. J. of Urology, 78, 257-261 (1996)). Therefore, PDE5 inhibitors are used as therapeutic agents for erectile dysfunction.

[0006] Many PDE5 inhibitors are known. Viagra™ (generic name: sildenafil; WO94 / 28902) was the first drug approved by the U.S. FDA for the treatment of male erectile dysfunction, followed by Cialis™ (generic name: tadalafil; WO95 / 19978) and Levitra™ (generic name: vardenafil; Bioorganic & Medicinal Chemistry Letters). MVIX™ (generic name: mirodenafil; KR0358083) is also known as a PDE5 inhibitor. This drug is known to exhibit excellent therapeutic efficacy and improve sexual function in approximately 70% of patients. Other medicinal uses of PDE5 inhibitors include their therapeutic effects on portal hypertension, hepato-renal syndrome, and hepato-pulmonary syndrome (Korean Patent Publication No. 10-2012-0024807), and their reported effect on improving reproductive capacity in mammals (Korean Patent Publication No. 10-2002-0031062). However, research into PDE5 inhibitors as agents for treating or ameliorating psychiatric symptoms such as PTSD has been limited. Summary of the Invention [Problem to be solved by the invention]

[0007] The present inventors have made extensive efforts to develop drugs for preventing or treating post-traumatic stress disorder (PTSD), and have confirmed that phosphodiesterase type 5 inhibitors, such as mirodenafil, sildetafil, and tadalafil, can selectively block contextual fear memory in mouse models exposed to trauma or stress (see Passive Avoidance Test), while preserving novel object recognition ability (see Novel Object Recognition Test) and spatial recognition ability (see Y-maze Test). This led to the completion of the present invention.

[0008] An object of the present invention is to provide a pharmaceutical composition for preventing or treating post-traumatic stress disorder, which comprises a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] Another object of the present invention is to provide a method for preventing or treating post-traumatic stress disorder, which comprises administering to an individual a pharmaceutically effective amount of a composition comprising a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof.

[0010] Another object of the present invention is to provide a health functional food for preventing or ameliorating post-traumatic stress disorder, which contains a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011] However, the problems to be solved by this specification are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description. [Means for solving the problem]

[0012] The present invention provides a pharmaceutical composition or health functional food for preventing, ameliorating, or treating post-traumatic stress disorder, which comprises a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for preventing or treating post-traumatic stress disorder, which comprises administering the pharmaceutical composition to an individual.

[0013] According to the first embodiment, Disclosed is a pharmaceutical composition for preventing or treating post-traumatic stress disorder, comprising a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] In the present invention, the phosphodiesterase type 5 inhibitor may be selected from mirodenafil, sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, and pharmaceutically acceptable salts thereof.

[0015] In the present invention, the administration of the phosphodiesterase type 5 inhibitor may include oral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intravaginal administration, intrapulmonary administration, intrarectal administration, or a combination thereof.

[0016] In the present invention, the dosage of the phosphodiesterase type 5 inhibitor may be 0.01 mg / kg to 10 mg / kg.

[0017] In the present invention, the pharmaceutical composition may further comprise a second agent for preventing or treating post-traumatic stress disorder, which may comprise an antidepressant, an anxiolytic, an alpha-1 blocker, or a combination thereof.

[0018] In the present invention, the second active agent is selected from the group consisting of sertraline, paroxetine, fluoxetine, citalopram, escitalopram, fluvoxamine, venlafaxine, duloxetine, desvenlafaxine, amitriptyline, nortriptyline, phenelzine, and the like. The active ingredient may include benzodiazepine, benzocaine, ...

[0019] In the present invention, the pharmaceutical composition may be used in conjunction with additional therapies including Eye Movement Desensitization & Reprocessing (EMDR), Cognitive Behavioral Therapy (CBT), exposure therapy, group therapy, or a combination thereof.

[0020] According to the second embodiment, A method for preventing or treating post-traumatic stress disorder is disclosed, which comprises administering to an individual a pharmaceutical composition containing, as an active ingredient, the phosphodiesterase type 5 inhibitor according to the present invention or a pharmaceutically acceptable salt thereof.

[0021] According to the third embodiment, Disclosed is a health functional food for preventing or ameliorating post-traumatic stress disorder, which contains a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0022] In the present invention, the phosphodiesterase type 5 inhibitor may be selected from mirodenafil, sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, and pharmaceutically acceptable salts thereof. [Effects of the Invention]

[0023] The phosphodiesterase type 5 inhibitor according to the present invention can selectively block situation-specific fear memories while maintaining novel object recognition and spatial recognition abilities. Therefore, the phosphodiesterase type 5 inhibitor according to the present invention exhibits excellent therapeutic effects on post-traumatic stress disorder (PTSD), and is expected to be included as an active ingredient in pharmaceutical compositions or health functional foods and to be used in the development of therapeutic or ameliorating agents for PTSD. [Brief explanation of the drawings]

[0024] [Figure 1] 1 shows the effect of administration of phosphodiesterase type 5 on the results of a passive avoidance experiment in mice. [Figure 2] 1 shows the effect of administration of phosphodiesterase type 5 on the results of a novel object recognition test in mice. [Figure 3] 1 shows the effect of administration of phosphodiesterase type 5 on the results of the Y-maze test in mice. DETAILED DESCRIPTION OF THE INVENTION

[0025] Hereinafter, a composition for preventing or treating post-traumatic stress disorder, comprising a phosphodiesterase type 5 inhibitor as an active ingredient, according to a specific embodiment of the present invention, will be described in detail. However, this is presented as an example of the invention, and the scope of the invention is not limited thereto. It will be obvious to those skilled in the art that various modifications to the embodiment are possible within the scope of the invention. Unless otherwise specified throughout this specification, the words "comprise" or "contain" refer to the inclusion of a certain component (or components) without any particular limitation, and are not to be construed as excluding the addition of other components (or components).

[0026] As used herein, the term "phosphodiesterase type 5 inhibitor" or "PDE5 inhibitor" refers to a substance that can selectively or non-selectively inhibit or reduce the catalytic activity of PDE5. The PDE5 inhibitor may include a compound, a peptide, a small molecule, an antibody or a fragment thereof, and a natural extract. In an exemplary embodiment, the PDE5 inhibitor may be a compound.

[0027] The term "pharmaceutically acceptable salt" as used herein means a salt in a form that can be used pharmaceutically, among salts that are substances in which a cation and an anion are bound by electrostatic attraction, and typically may be a metal salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like. For example, metal salts include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, barium salt, etc.), aluminum salts, etc.; salts with organic bases may be salts with triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.; salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; salts with basic amino acids may be salts with arginine, lysine, ornithine, etc.; and salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0028] As used herein, the term "active ingredient" means an ingredient that exhibits a desired activity alone or that can exhibit an activity together with a carrier that is inactive by itself.

[0029] As used herein, the term "post-traumatic stress disorder (PTSD)" refers to a condition characterized by persistent abnormal psychosomatic symptoms following a traumatic event. A diagnosis of post-traumatic stress disorder is made when the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) of the American Psychiatric Association are met. The onset of the condition varies from individual to individual, and can begin immediately after the trauma or may take days, weeks, months, or even years to appear. Key symptoms include dissociative phenomena, panic attacks, perceptual abnormalities such as auditory hallucinations, aggressive tendencies, impulse control disorders, depression, substance abuse, and cognitive problems such as impaired concentration and memory.

[0030] As used herein, the term "prevention" refers to any action that inhibits or delays the onset of PTSD by administering a PDE5 inhibitor according to the present invention.

[0031] As used herein, the term "treatment" refers to any action that results in an improvement or beneficial alteration of symptoms in individuals suspected of and affected with PTSD through the administration of said PDE5 inhibitors.

[0032] The term "amelioration" according to the present invention means any action that at least reduces the parameters associated with the condition treated by administration of said PDE5 inhibitor, eg the severity of the symptoms.

[0033] 1. Composition for preventing or treating post-traumatic stress disorder An object of the present invention is to provide a composition for preventing or treating post-traumatic stress disorder, which comprises a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0034] In the composition for preventing or treating post-traumatic stress disorder according to the present invention, the phosphodiesterase type 5 inhibitor may be selected from mirodenafil, sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, and pharmaceutically acceptable salts thereof. According to an exemplary embodiment, the PDE5 inhibitor may be mirodenafil, sildenafil, tadalafil, or a pharmaceutically acceptable salt thereof.

[0035] In the composition for preventing or treating post-traumatic stress disorder according to the present invention, the composition may be a pharmaceutical composition, a food composition, or a feed composition.

[0036] (1) Pharmaceutical compositions According to an example embodiment, the present invention provides a pharmaceutical composition for preventing or treating post-traumatic stress disorder, comprising a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0037] The pharmaceutical composition of the present invention can be administered orally or parenterally. Parenteral administration can be by intravenous, subcutaneous, intramuscular, intraperitoneal, intradermal, topical, intranasal, intravaginal, pulmonary, or rectal administration. For oral administration, the pharmaceutical composition can be formulated as an uncoated tablet, or the active agent can be coated or otherwise protected from digestion in the stomach. The composition can also be administered by any device capable of delivering the active agent to target cells. The route of administration can vary depending on the general condition and age of the subject, the nature of the condition being treated, and the active ingredient selected.

[0038] The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, the patient's age, weight, sex, pathological condition, diet, administration time, administration route, excretion rate, and reaction sensitivity. A skilled physician can generally easily determine and prescribe an effective dosage for the desired treatment or prevention. For example, the pharmaceutical composition can be administered in a single or multiple doses, and can be administered in divided doses once to four times daily. For example, the pharmaceutical composition may contain 0.01 mg / kg to 10 mg / kg, preferably 0.02 mg / kg to 9 mg / kg, and more preferably 0.03 mg / kg to 8 mg / kg per adult.

[0039] The pharmaceutical composition of the present invention may further comprise a second agent for preventing or treating post-traumatic stress disorder, such as an antidepressant, an anxiolytic, or another alpha-1 blocker. For example, the antidepressant may be a selective serotonin reuptake inhibitor (SSRI) such as sertraline, paroxetine, fluoxetine, citalopram, escitalopram, or fluvoxamine; a serotonin-norepinephrine reuptake inhibitor (SNRI) such as venlafaxine, duloxetine, or desvenlafaxine; or a tricyclic antidepressant (TCA) such as amitriptyline or nortriptyline. Antidepressants may include, but are not limited to: monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine; or atypical antidepressants such as mirtazapine, trazodone, and bupropion.The anti-anxiety agents may include, but are not limited to, benzodiazepines such as diazepam, lorazepam, alprazolam, and clonazepam; thienodiazepines such as etizolam and metizolam; or non-benzodiazepine anxiolytics such as buspirone. The alpha-1 adrenergic blockers may include, but are not limited to, prazosin or doxazosin.

[0040] In the pharmaceutical composition of the present invention, the pharmaceutical composition may be used in conjunction with an additional therapy, for example, Eye Movement Desensitization & Reprocessing (EMDR), Cognitive Behavioral Therapy (CBT), exposure therapy, group therapy, or a combination thereof, but is not limited thereto.

[0041] The pharmaceutical compositions of the present invention may be formulated with pharmaceutically acceptable carriers and / or excipients in a unit dose form or in a multi-dose container by a method readily understood by those skilled in the art. The dosage form may be a solution, suspension, or emulsion in an oily or aqueous medium, or may be in the form of a tablet, powder, granules, tablet, or capsule, and may further contain a dispersant or stabilizer. The pharmaceutical compositions may also be administered in the form of a suppository, spray, ointment, cream, gel, inhalant, or skin patch. Furthermore, the pharmaceutical compositions may be formulated for mammalian administration, more preferably for human administration.

[0042] In the pharmaceutical composition of the present invention, the pharmaceutically acceptable carrier may be solid or liquid and may be one or more selected from the group consisting of excipients, antioxidants, buffers, bacteriostats, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, lubricants, release-modifying agents, wetting agents, stabilizers, suspending agents, and lubricants. Furthermore, the pharmaceutically acceptable carrier may be selected from the group consisting of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures thereof.

[0043] In one embodiment, suitable fillers include, but are not limited to, sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), starch hydrolysates (e.g., dextrins and maltodextrins), cellulose or cellulose derivatives (e.g., microcrystalline cellulose), or mixtures thereof.

[0044] In one embodiment, suitable binders include, but are not limited to, povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gums, sucrose, starch, or mixtures thereof.

[0045] In one embodiment, suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA, or mixtures thereof.

[0046] In one embodiment, suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starch, microcrystalline cellulose, or mixtures thereof.

[0047] In one embodiment, suitable sweeteners include, but are not limited to, sucralose, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose, sucrose, maltose, or mixtures thereof.

[0048] In one embodiment, suitable glidants may be used, including but not limited to silica, colloidal silicon dioxide, talc, and the like.

[0049] In one embodiment, suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glyceride waxes, or mixtures thereof.

[0050] (2) Food composition According to an example embodiment, the present invention provides a food composition for preventing or ameliorating post-traumatic stress disorder, comprising a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0051] In the food composition of the present invention, the food may be any food generally defined as meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, drinking water, tea, health supplements, alcoholic beverages, vitamin complexes, and functional health foods, as long as it contains the PDE5 inhibitor of the present invention. As used herein, "functional health foods" refers to foods manufactured and processed using raw materials or ingredients that have functional properties beneficial to the human body in accordance with Korean Act No. 6727 on Functional Health Foods, and "functionality" refers to the provision of beneficial health effects, such as regulating nutrients for the structure and function of the human body or providing physiological effects. Meanwhile, health foods refer to foods that have more active health maintenance or promotion effects than general foods, and health supplements refer to foods intended for health supplementation, although the terms "functional health foods," "health foods," and "health supplements" may be used interchangeably in some cases.

[0052] In the food composition of the present invention, the PDE5 inhibitor may be added as is or may be used together with other foods or food ingredients, and may be used appropriately according to conventional methods.

[0053] The food composition according to the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and ingredients commonly used in the art. Specifically, the food composition may further contain a physiologically acceptable carrier, but the type of carrier is not particularly limited, and any carrier commonly used in the art can be used. The food composition may also contain food additives such as preservatives, bactericides, antioxidants, colorants, color formers, bleaching agents, seasonings, sweeteners, flavorings, leavening agents, strengthening agents, emulsifiers, thickeners, coating agents, gum bases, foam inhibitors, solvents, and improvers. The additives can be selected according to the type of food and used in appropriate amounts.

[0054] The food composition of the present invention may be prepared in any dosage form as long as it is approved as a food. The food composition of the present invention can be prepared in various dosage forms, and unlike general medicines, it has the advantage of being made from food ingredients, so there are no side effects that can occur with long-term drug use. Furthermore, because it is highly portable, the food of the present invention can be taken as an adjuvant to enhance the effects of preventing or improving PTSD.

[0055] (3) Feed composition According to an example embodiment, the present invention provides a feed composition for preventing or ameliorating post-traumatic stress disorder, comprising a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0056] As used herein, the term "feed" means any natural or artificial diet, meal, etc., or component of said meal, intended for or suitable for eating, ingesting, and digestion by an animal.

[0057] The type of feed in the feed composition of the present invention is not particularly limited, and feeds commonly used in the art can be used. Non-limiting examples of the feed include plant-based feeds such as grains, roots and fruits, food processing by-products, algae, fibers, pharmaceutical by-products, oils and fats, starches, gourds, and grain by-products; and animal-based feeds such as proteins, minerals, oils and fats, minerals, single-cell proteins, zooplankton, and food and beverages. These may be used alone or in combination of two or more.

[0058] 2. How to prevent or treat post-traumatic stress disorder An object of the present invention is to provide a method for preventing or treating post-traumatic stress disorder, which comprises administering to an individual a pharmaceutical composition containing, as an active ingredient, a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof.

[0059] The term "administering" as used herein means introducing the composition into an individual by any suitable method.

[0060] As used herein, the term "individual" refers to any animal, including humans, that has or may develop post-traumatic stress disorder, such as mice, rats, livestock, etc., and specific examples may include, but are not limited to, mammals, including humans.

[0061] As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention. The effective dose level can be determined based on factors including the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, and sensitivity to the drug, the administration time, route of administration, and excretion rate of the composition of the present invention used, the duration of treatment, drugs used in combination with or concomitantly with the composition of the present invention, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered alone or in combination with known therapeutic agents. Taking all of the above factors into consideration, it is important to administer an amount that will achieve maximum effect at the minimum dose without side effects.

[0062] The preventive or therapeutic method according to the present invention may further comprise administering a second agent to an individual before, simultaneously with, or after administering to the individual a pharmaceutical composition comprising a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient. The second agent may comprise an antidepressant, an anxiolytic, or another alpha-1 blocker. For example, the antidepressant may be a selective serotonin reuptake inhibitor (SSRI) such as sertraline, paroxetine, fluoxetine, citalopram, escitalopram, or fluvoxamine; a serotonin-norepinephrine reuptake inhibitor (SNRI) such as venlafaxine, duloxetine, or desvenlafaxine; or a tricyclic antidepressant (TCA) such as amitriptyline or nortriptyline. Antidepressants may include, but are not limited to: monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine; or atypical antidepressants such as mirtazapine, trazodone, and bupropion.The anti-anxiety agents may include, but are not limited to, benzodiazepines such as diazepam, lorazepam, alprazolam, and clonazepam; thienodiazepines such as etizolam and metizolam; or non-benzodiazepine anxiolytics such as buspirone. The alpha-1 adrenergic blockers may include, but are not limited to, prazosin or doxazosin.

[0063] In the preventive or therapeutic method according to the present invention, the administration may include various routes such as oral, intravenous, subcutaneous, intradermal, intranasal, intraperitoneal, intramuscular, and transdermal.

[0064] In the preventive or therapeutic methods of the present invention, the dosage of the composition can be determined by one skilled in the art, taking into consideration the purpose of use, the severity of the disease, the patient's age, weight, sex, medical history, and the type of substance used as the active ingredient. For example, the composition of the present invention can be administered at a dose of 0.01 mg / kg to 10 mg / kg, preferably 0.02 mg / kg to 9 mg / kg, and more preferably 0.03 mg / kg to 8 mg / kg per adult. The administration frequency of the composition of the present invention is not particularly limited, and the composition may be administered once a day or in divided doses administered several times. The dosages described above do not limit the scope of the present invention in any way.

[0065] The preventive or therapeutic method according to the present invention may include a combination treatment with an additional therapy after administration of the composition, for example, Eye Movement Desensitization & Reprocessing (EMDR), Cognitive Behavioral Therapy (CBT), exposure therapy, group therapy, or a combination thereof, but is not limited thereto. [Example]

[0066] Various examples are presented below to help understand the invention. The following examples are provided to make the invention easier to understand, and the scope of protection of the invention is not limited to the following examples.

[0067] <Experimental preparation and methods> 1. Experimental Animals The experimental animals used were 28 ICR mice (male, 5 weeks old) weighing approximately 27-30g. They were kept in a constant temperature and humidity environment (temperature: 26.8±0.5°C, relative humidity: 48.4±1.7%), and lighting: 07:00-19:00. They were fed a general diet (AIN-93G diet) and allowed free access to drinking water for 7 days after adaptation and acclimation.

[0068] 2. Preparation of Experimental Materials Mirodenafil (12 mg) was dissolved in 10 ml of distilled water and prepared at 12 MPK. Sildenafil and Tadalafil were also prepared at 12 MPK.

[0069] 3. Group composition 1) Control group (n=7): po (Distilled water) 2) Experimental group 1 (n = 7): po (Mirodenafil 12 MPK) 3) Experimental group 2 (n = 7): po (Sildenafil 12 MPK) 4) Experimental group 3 (n = 7): po (Tadalafil 12 MPK)

[0070] 4. Experimental Method 4-1. Drug administration After 7 days of adaptation and acclimation, the control group received oral administration of DW once a day for 15 days, and the experimental group received oral administration of each drug once a day for 15 days.

[0071] 4-2. Passive avoidance test (1) Passive avoidance (Accommodation) Passive avoidance step-through set: A light (50%) was shone in the bright box, and the mouse was placed in it. After that, it was allowed to move freely between the dark and bright boxes for 5 minutes. After 5 minutes, accommodation ended, and the mouse was allowed to rest in its cage.

[0072] (2) Passive avoidance (Training) Passive avoidance step-through set: A light (Lightness: 50%) was shone in the bright box, and mice that had completed accommodation were placed in the same location as during accommodation. When the mouse moved into the dark box and all four paws touched the floor of the dark box, it received an electric shock (0.4 mA, 2 seconds, repeated twice for 2 seconds) (Latency maximum time limit: 65 seconds, 1 shock). After the shocked mouse was allowed to stabilize in the bright box for 10 seconds, training ended, and the mice that had completed training were allowed to rest in their cages.

[0073] (3) Passive avoidance (Test) Passive avoidance step-through set: A light (Lightness: 50%) was shone in the bright box, and mice that had completed training were placed in the same location as during accommodation and training. The time it took for the mouse to move into the dark box and for all four paws to reach the floor of the dark box was measured, and the test was then completed (Latency maximum time limit: 300 seconds, No shock). After completing the test, the mice were allowed to rest in their cages.

[0074] 4-3. Novel object recognition test After placing the mouse in the center of the rat cage, it was allowed to move freely for 5 minutes, after which accommodation was terminated. After completing accommodation, the mouse was allowed to rest in its cage.

[0075] (1)Novel object recognition(Training1) Mice that had completed accommodation for novel object recognition were prepared. Objects A and B, identical in color, shape, and size, were placed at regular intervals in the rat cage. The prepared mice were placed in the center of the cage and allowed to explore each object for 5 minutes. After completing Training 1, the mice were allowed to rest in their home cage.

[0076] (2)Novel object recognition(Training2) Mice were prepared 24 hours after completing training 1 for novel object recognition. Objects A and B, identical in color, shape, and size, were placed at regular intervals in the rat cage. The prepared mice were placed in the center of the cage, and the time spent exploring each object was measured for 5 minutes. After completing training 2, the mice were allowed to rest in their cages.

[0077] (3) Novel object recognition (Test) After completing the training of Novel object recognition, mice that had elapsed 24 hours were prepared. Object A and C with different colors, shapes, and sizes were placed at regular intervals in the rat cage. After placing the prepared mice in the center of the rat cage, the exploration time of each mouse for each object was measured for 5 minutes. The mice that had finished the test were allowed to rest in the breeding cage. The time measured for 5 minutes was substituted into the following formula to calculate the percentage of the exploration time for both objects.

[0078]

Number

[0079] 4-4. Y-maze experiment (Y-maze Test) After placing the mice in the center of the Y-maze, when all four feet entered each Arm entry for 8 minutes, the case entry and exit were recorded. Each time the experiment for each individual was completed, the Y-maze was wiped with 70% alcohol and then proceeded. The recorded number of entries and exits was processed by the Yamada statistical processing method. The number of crossovers was counted as one when the mouse passed through three passages continuously. The amount of spontaneous crossover behavior was calculated as the percentage of the number of crossovers and the total number of passages passed.

[0080]

Number

[0081] 5.Analysis All experimental analysis results were shown as Mean ± Standard Error of the Mean (Mean ± SEM). After verification by T-Test, statistical significance was based on **P < 0.01 or *0.01 < P < 0.05. The measured data were labeled using a statistical program (Prism8).

[0082] <Results> 1. Passive avoidance test results After 15 electrical stimulation sessions and drug administration, the PAT experiment was performed. The results showed that latency time in the drug-treated groups was reduced by 73.5% for Mirodenafil, 55.5% for Sildenafil, and 63.2% for Tadalafil compared to the control group. This confirms that PDE5 inhibitors can block contextual fear memory (Figure 1). To demonstrate that these results are not related to cognitive function, we compared them with the results of NOR and Y maze.

[0083] 2. Novel object recognition test results The NOR test results 8 days after drug administration showed that the degree of exploration of the novel object was 49.0% in the control group, and 53.7%, 57.9%, and 57.0% in the mirodenafil, sildenafil, and tadalafil groups, respectively, indicating a prolonged exploration time for the novel object (Figure 2). Therefore, it was confirmed that although contextual fear memory was blocked by PDE5 inhibitors in PTSD-induced mice, object recognition ability and memory ability were maintained.

[0084] 3. Y-maze Test Results Ten days after drug administration, the Y-maze test results showed that cross-sectional activity was 61.8% for the control, 58.4% for mirodenafil, 60.7% for sildenafil, and 59.6% for tadalafil, showing a similar trend to the control (Figure 3). Therefore, it was confirmed that spatial cognition and memory abilities were maintained in PTSD-induced mice despite the blocking of contextual fear memory by PDE5 inhibitors.

[0085] Although specific aspects of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the true scope of the present invention is defined by the appended claims and their equivalents. [Industrial Applicability]

[0086] The phosphodiesterase type 5 inhibitor according to the present invention can selectively block situation-specific fear memories while maintaining novel object recognition and spatial recognition abilities. Therefore, the phosphodiesterase type 5 inhibitor according to the present invention exhibits excellent therapeutic effects on post-traumatic stress disorder (PTSD), and is expected to be included as an active ingredient in pharmaceutical compositions or health functional foods and to be used in the development of therapeutic or ameliorating agents for PTSD.

Claims

1. A pharmaceutical composition for preventing or treating post-traumatic stress disorder, comprising a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

2. 2. The pharmaceutical composition for the prevention or treatment of post-traumatic stress disorder according to claim 1, wherein the phosphodiesterase type 5 inhibitor is selected from the group consisting of mirodenafil, sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, and pharmaceutically acceptable salts thereof.

3. 2. The pharmaceutical composition for the prevention or treatment of post-traumatic stress disorder according to claim 1, wherein the administration of the phosphodiesterase type 5 inhibitor includes oral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intravaginal administration, intrapulmonary administration, intrarectal administration, or a combination thereof.

4. 2. The pharmaceutical composition for preventing or treating post-traumatic stress disorder according to claim 1, wherein the dosage of the phosphodiesterase type 5 inhibitor is 0.01 mg / kg to 10 mg / kg.

5. The pharmaceutical composition for preventing or treating post-traumatic stress disorder according to claim 1, further comprising a second agent for preventing or treating post-traumatic stress disorder.

6. The pharmaceutical composition for preventing or treating post-traumatic stress disorder according to claim 5, wherein the second agent comprises an antidepressant, an anxiolytic, an alpha-1 blocker, or a combination thereof.

7. The second agent may be selected from the group consisting of sertraline, paroxetine, fluoxetine, citalopram, escitalopram, fluvoxamine, venlafaxine, duloxetine, desvenlafaxine, amitriptyline, nortriptyline, phenelzine, and tranylcypromine.

6. The pharmaceutical composition for preventing or treating post-traumatic stress disorder according to claim 5, comprising at least one of benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzoylcypromine, mirtazapine, trazodone, bupropion, diazepam, lorazepam, alprazolam, clonazepam, etizolam, metizolam, buspirone, prazosin, doxazosin, or a combination thereof.

8. 10. The pharmaceutical composition for the prevention or treatment of post-traumatic stress disorder according to claim 1, wherein the pharmaceutical composition is used in conjunction with additional therapies including Eye Movement Desensitization & Reprocessing (EMDR), Cognitive Behavioral Therapy (CBT), exposure therapy, group therapy, or a combination thereof.

9. A method for preventing or treating post-traumatic stress disorder, comprising administering to an individual a pharmaceutical composition comprising, as an active ingredient, the phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8.

10. A health functional food for preventing or ameliorating post-traumatic stress disorder, comprising a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

11. 11. The health functional food for preventing or ameliorating post-traumatic stress disorder according to claim 10, wherein the phosphodiesterase type 5 inhibitor is selected from the group consisting of mirodenafil, sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, and pharmaceutically acceptable salts thereof.

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