Composition for preventing or treating mental diseases or behavioral disorders in animals

Abstract

According to one embodiment disclosed herein, a composition for preventing or treating mental diseases or behavioral disorders in animals may include a selective serotonin reuptake inhibitor (SSRI) and a serotonin antagonist-reuptake inhibitor (SARI). The representative figure may be figure 3. The representative figure may be figure 3.

Description

Composition for preventing or treating mental illness or behavioral disorders in animals

[0001] The present disclosure relates to a composition for preventing or treating mental illness or behavioral disorder in animals, and more particularly, to a composition for preventing or treating mental illness or behavioral disorder in animals by co-administering two or more serotonin agonists.

[0002] Serotonin is a crucial neurotransmitter. Serotonin is involved in appetite, sleep, and cognitive regulation, as well as directly influencing mood, anxiety, and well-being. Imbalances in serotonin levels can lead to a variety of mental health conditions. For example, low serotonin levels have been linked to depressive symptoms. Conditions such as generalized anxiety disorder (GAD), panic disorder, and social anxiety disorder are also linked to serotonin dysregulation. Furthermore, individuals with obsessive-compulsive disorder or post-traumatic stress disorder (PTSD) often exhibit serotonin imbalances.

[0003] However, because serotonin used in the brain must be produced within the body and cannot cross the blood-brain barrier (BBB), direct regulation of brain serotonin levels is difficult. Instead, indirect approaches, such as inhibiting serotonin reuptake, are used to treat serotonin-related mental disorders. However, mental illness or behavioral disorders are difficult to determine solely based on brain serotonin levels. They are determined by the type of mental illness or behavioral disorder and by biological and social factors specific to the animal species, making it difficult to select appropriate serotonin-modulating medications.

[0004] Separation anxiety, on the other hand, is caused by the fear of being separated from a person, such as a parent or caregiver. It can often manifest as distress, crying, or clinging behavior when faced with the possibility of separation from a parent or caregiver. While this condition is frequently observed in human babies and children, it can also be common in companion animals like dogs.

[0005] Separation anxiety in pets can cause significant discomfort to their owners, making treatment and alleviation essential. Veterinary approaches to managing separation anxiety in pets can include a combination of behavior modification, environmental changes, and potential medications, but the effectiveness of these medications is limited.

[0006] To solve the above problem, the present disclosure aims to prevent or treat mental illness or behavioral disorder by co-administering a serotonin reuptake inhibitor (SRI).

[0007] The technical problems of the present disclosure are not limited to the technical problems mentioned above, and other technical problems not mentioned will be clearly understood by those skilled in the art from the description below.

[0008] According to one embodiment of the present disclosure, a pharmaceutical composition for preventing or treating a mental illness or behavioral disorder in an animal is provided, comprising a selective serotonin reuptake inhibitor (SSRI) and a serotonin antagonist-reuptake inhibitor (SARI) as active ingredients.

[0009] In one embodiment of the present disclosure, the selective serotonin reuptake inhibitor (SSRI) may be a pharmaceutical composition comprising at least one of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone, or vortioxetine.

[0010] In one embodiment of the present disclosure, the serotonin reuptake inhibitor (SARI) may be a pharmaceutical composition comprising at least one of trazodone or nefazodone.

[0011] In one embodiment of the present disclosure, the selective serotonin reuptake inhibitor (SSRI) is Escitalopram, and the Escitalopram may be a pharmaceutical composition formulated to be administered to a subject at a dose of 0.5 mg / kg.

[0012] In one embodiment of the present disclosure, the serotonin reuptake inhibitor (SARI) is trazodone, and the trazodone may be a pharmaceutical composition formulated to be administered to a subject at a dose of 2 mg / kg.

[0013] In one embodiment of the present disclosure, the selective serotonin reuptake inhibitor (SSRI) may be formulated to be administered to a subject at a dose of 0.5 mg / kg, and the serotonin antagonist-reuptake inhibitor (SARI) may be formulated to be administered to a subject at a dose of 2 mg / kg.

[0014] In one embodiment of the present disclosure, the mental illness or behavioral disorder in the animal may include anxiety disorder toward companion animals, and the companion animals may be dogs or cats.

[0015] According to one embodiment of the present disclosure, the pharmaceutical composition may be characterized by further comprising a pharmaceutically acceptable carrier.

[0016] According to one embodiment of the present disclosure, a method for preventing or treating a mental illness or behavioral disorder in an animal other than a human is provided. The method may comprise administering a selective serotonin reuptake inhibitor (SSRI) or a serotonin antagonist-reuptake inhibitor (SARI).

[0017] In one embodiment of the present disclosure, the selective serotonin reuptake inhibitor (SSRI) may include at least one of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone, or vortioxetine.

[0018] In one embodiment of the present disclosure, the serotonin reuptake inhibitor (SARI) may comprise at least one of trazodone or nefazodone.

[0019] In one embodiment of the present disclosure, the serotonin reuptake inhibitor (SARI) is escitalopram, and the escitalopram can be administered to the subject at a dose of 0.5 mg / kg.

[0020] In one embodiment of the present disclosure, the serotonin reuptake inhibitor (SARI) is trazodone, and the trazodone can be administered to the subject at a dose of 2 mg / kg.

[0021] In one embodiment of the present disclosure, the selective serotonin reuptake inhibitor (SSRI) may be formulated to be administered to a subject at a dose of 0.5 mg / kg, and the serotonin antagonist-reuptake inhibitor (SARI) may be formulated to be administered to a subject at a dose of 2 mg / kg.

[0022] In one embodiment of the present disclosure, the selective serotonin reuptake inhibitor (SSRI) and the serotonin antagonist-reuptake inhibitor (SARI) may be co-administered to a subject.

[0023] In one embodiment of the present disclosure, the mental illness or behavioral disorder in the animal may include anxiety disorder toward companion animals, and the companion animals may be dogs or cats.

[0024] Through the drug of the present disclosure, mental illness or behavioral disorder appearing in companion animals can be effectively prevented or treated.

[0025] Meanwhile, the effects that can be obtained from the present disclosure are not limited to the effects mentioned above, and other effects that are not mentioned can be clearly understood by a person having ordinary skill in the technical field to which the present disclosure belongs from the description below.

[0026] Figures 1a to 1d are LC-MS / MS chromatograms of beagle experimental dog blood plasma, escitalopram lower limit of quantitation (LLOQ), upper limit of quantitation (ULOQ), and 30 minutes after administration on the first day, respectively.

[0027] Figures 2a to 2d are LC-MS / MS chromatograms of the beagle experimental dog blood plasma, trazodone lower limit of quantification (LLOQ), upper limit of quantification (ULOQ), and 30 minutes after the first day of administration, respectively.

[0028] Figure 3 shows the pharmacokinetic results of oral administration of 0.5 mg / kg of escitalopram oxalate, showing the plasma concentration of escitalopram according to the experimental period.

[0029] Figure 4 shows the pharmacokinetic results of oral administration of 2 mg / kg of trazodone HCL, showing the plasma concentration of trazodone according to the experimental period.

[0030] Various embodiments are described. In this specification, various descriptions are provided to facilitate understanding of the present disclosure. However, it will be apparent that these embodiments may be practiced without these specific details.

[0031] Furthermore, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or." That is, unless otherwise specified or clear from context, "X employs A or B" is intended to mean either of the natural inclusive permutations. That is, if X employs A; X employs B; or X employs both A and B, "X employs A or B" can apply to any of these cases. Furthermore, the term "and / or" as used herein should be understood to refer to and include all possible combinations of one or more of the associated items listed.

[0032] Additionally, the terms "comprises" and / or "comprising" should be understood to imply the presence of the features and / or components in question. However, it should be understood that the terms "comprises" and / or "comprising" do not exclude the presence or addition of one or more other features, components, and / or groups thereof. Furthermore, unless otherwise specified or clear from the context to refer to the singular form, the singular in the specification and claims should generally be construed to mean "one or more."

[0033] And, the term "at least one of A or B" should be interpreted to mean "if it includes only A", "if it includes only B", or "if it is combined in the composition of A and B".

[0034] According to one embodiment of the present disclosure, a composition for preventing, treating, improving or alleviating mental illness or behavioral disorder, comprising a serotonin reuptake inhibitor (SRI) as an active ingredient, can be provided.

[0035] Serotonin reuptake inhibitors (SRIs) may be co-administered. For example, a composition according to one embodiment of the present disclosure may include at least one of a selective serotonin reuptake inhibitor (SSRI); and a serotonin antagonist and reuptake inhibitor (SARI).

[0036] Selective serotonin reuptake inhibitors (SSRIs) can relieve symptoms of depression and selectively prevent serotonin from being reabsorbed into neurons. The SSRIs may include at least one of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone, or vortioxetine.

[0037] Fluoxetine (Prozac or Oxactin) is the most well-known SSRI frequently used to treat major depressive disorder, obsessive-compulsive disorder (OCD), and panic disorder. Sertraline (Lustral) is often prescribed for depression, OCD, panic disorder, and social anxiety disorder. Paroxetine (Seroxat) is used to treat depression, anxiety disorders, and menopausal symptoms. It can improve mood, sleep, appetite, and energy levels, and help restore interest in daily life. Citalopram (Celexa) is another SSRI used to treat depression and may increase happiness and energy levels. Escitalopram (Cipralex) is an SSRI used to treat depression and generalized anxiety disorder and may help reduce irritability and improve energy levels. Fluvoxamine (Faverin) is primarily used to treat obsessive-compulsive disorder (OCD) and may help reduce persistent, unwanted thoughts (obsessions) and urges to perform repetitive tasks (compulsions). Vilazodone (Viibryd) and vortioxetine (Brintellix) can be used to treat depression.

[0038] Serotonin antagonist-reuptake inhibitors (SARIs) block the reuptake of serotonin and can antagonize specific serotonin receptors. They are used to treat major depressive disorder and, due to their sedative effects, may also be used for insomnia. SARIs may include at least one of trazodone or nefazodone.

[0039] Trazodone is primarily used to treat major depressive disorder by blocking serotonin reuptake. Its sedative effects are also known, making it a preferred treatment for insomnia and anxiety disorders. Nefazodone is a phenylpiperazine compound that may exhibit similar effects to trazodone.

[0040] Additionally, a composition according to one embodiment of the present disclosure may further comprise a tricyclic antidepressant (TCA) capable of increasing serotonin and norepinephrine levels in the brain. The tricyclic antidepressant (TCA) may comprise at least one of amitriptyline and nortriptyline.

[0041] A composition according to one embodiment of the present disclosure may be for a mental illness or behavioral disorder in a human or animal.

[0042] The above mental illness or behavioral disorder may be an anxiety disorder, and may occur in either animals or humans. In particular, the mental illness or behavioral disorder in companion animals may include separation anxiety. While separation anxiety can occur in other companion animal species, it is a common problem in dogs.

[0043] In both dogs and humans, anxiety can generally occur in response to threatening or stressful situations. However, in dogs, it differs from various human anxiety disorders in that it can occur when they are left alone and separated from their attached human. This separation anxiety can cause excessive distress in dogs and can lead to a variety of behaviors that may be considered abnormal or indicative of mental illness. For example, separation anxiety in dogs can lead to destructive behaviors, excessive barking, or howling.

[0044] Furthermore, this separation anxiety can occur not only in dogs but also in other animals. Animals may experience at least one of the following emotions along with separation anxiety: fear, dread, or depression, and may additionally exhibit at least one of the following symptoms: obsessive-compulsive behavior, depression, cognitive dysfunction, or aggression.

[0045] Animals with phobias and fears may develop intense fear or phobia of certain things, such as thunderstorms, fireworks, or certain people or animals, and this fear may cause the animal to exhibit behaviors such as hiding, trembling, or attempting to escape.

[0046] Animals experiencing compulsive behaviors may exhibit repetitive behaviors that seem to be purposeless, such as excessive grooming, tail chasing, or pacing, which may be signs of obsessive-compulsive disorder. While characteristics of obsessive-compulsive disorder (OCD) in animals may be similar to those of obsessive-compulsive disorder (OCD) in humans, they are not identical.

[0047] Some animals may experience symptoms of depression, such as decreased activity, loss of interest in activities they used to enjoy, decreased food intake or changes in sleep patterns, may develop cognitive dysfunction syndrome (CDS), or may become aggressive.

[0048] When the composition of the present disclosure is administered, the serotonin level in the brain can be appropriately controlled, thereby effectively preventing, treating, improving or alleviating the separation anxiety.

[0049] The composition in the present disclosure may be a pharmaceutical composition.

[0050] In the present disclosure, the pharmaceutical composition is not limited thereto, but may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods. The pharmaceutical composition of the present disclosure may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, fragrances, etc. for oral administration, and buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc. for injections, and bases, excipients, lubricants, preservatives, etc. for topical administration. The formulation of the pharmaceutical composition of the present disclosure may be prepared in various ways by mixing with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it can be manufactured in the form of unit dose ampoules or multiple doses. In addition, it can be formulated in the form of solutions, suspensions, tablets, capsules, sustained-release preparations, etc.

[0051] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may be additionally included.

[0052] As used herein, the term "pharmaceutically effective amount" refers to a sufficient amount of an agent to produce a desired biological result. This result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic purposes is the amount of a compound disclosed herein required to produce a clinically significant reduction in a disease. The appropriate "effective" amount in any individual case can be determined by one skilled in the art using routine experimentation. Accordingly, the expression "effective amount" generally refers to an amount of an active substance that produces a therapeutic effect.

[0053] The expression "administration" as used herein refers to the process of introducing the active ingredient of the present disclosure into a subject by any suitable method, and the pharmaceutical composition of the present disclosure may be administered in the form of a "combination drug," or individual drugs may be administered in the form of "combined administration." The combination drug and the combination administration are concepts related to pharmacology and drug administration, but may refer to different things. The combination drug is a product consisting of any combination of a pharmaceutical and a medical device, or a biological agent and a medical device, and is essentially a single product in which two or more active ingredients are combined together.

[0054] Conversely, combination therapy can involve administering two or more individual drugs simultaneously or sequentially to a subject. Combination therapy does not involve physically combining multiple drugs into a single product, but rather administering them together for a combined therapeutic effect. In both cases, drug interactions can be an important consideration, as some drugs may affect the metabolism, efficacy, or side effects of others.

[0055] Meanwhile, the formulation of the compound administered as described above in the present disclosure is not particularly limited, and may be administered as a solid formulation, a liquid formulation, or an aerosol formulation for inhalation, and may be administered as a solid formulation intended to be converted into a liquid formulation for oral or parenteral administration immediately before use, and may be formulated and administered in the form of, for example, oral formulations such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and sterile injectable solutions, but is not limited thereto.

[0056] The routes of administration of the pharmaceutical compositions disclosed herein include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal.

[0057] Oral administration of the present disclosure refers to taking a drug in tablet form. The subject receives the drug in pill form and swallows the pill by placing it in the mouth. This can sometimes be accomplished with the aid of water, another beverage, or a dosing device to aid swallowing, but is not always necessary. The swallowed pill travels up the esophagus and enters the stomach, where it dissolves, releasing the active ingredient contained therein. The active ingredient is absorbed into the bloodstream through the intestinal wall and the blood-brain barrier (BBB), and can travel to various parts of the body to exert its therapeutic effect.

[0058] Oral administration in animals operates very similarly to the human process, involving substances ingested through the mouth and then processed in the digestive system. Oral administration in animals is commonly used due to its non-invasive nature. Each of these forms can be tailored to the specific needs of the drug and the animal's preferences.

[0059] Meanwhile, parenteral administration of the present disclosure includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present disclosure may also be administered in the form of a suppository for rectal administration.

[0060] The pharmaceutical composition of the present disclosure may vary depending on several factors including the activity of the specific compound used, age, body weight, general health, sex, dosage, time of administration, route of administration, excretion rate, drug combination, and severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, route of administration, and period of time, but may be appropriately selected by a person skilled in the art.

[0061] The compositions of the present disclosure may be used alone or in combination with methods using additional behavioral therapies, hormone therapy, chemotherapy, and biological response modifiers.

[0062] Hereinafter, the present disclosure will be described in detail with reference to the following examples. However, the following examples are merely illustrative of the present disclosure, and the contents of the present disclosure are not limited by the following examples.

[0063] Example: Analysis of co-administration of trazodone and escitalopram in a beagle dog model

[0064] Trazodone HCl belongs to the SARI (Serotonin anatagonist and reuptake inhibitor) class of drugs and is primarily used to induce sedation in companion animals. However, increased dosages raise concerns about adverse effects. Therefore, in one example of the present disclosure, the lowest dose level used was set at 2 mg / kg, and the pharmacokinetics of trazodone HCl were studied in oral co-administration with escitalopram.

[0065] Escitalopram oxalate has not been clinically used in pets, but is known to exhibit a binding occupancy of 75% on the serotonin transporter at a dose of 1 mg / kg. Therefore, in one embodiment of the present disclosure, a dose of 0.5 mg / kg was determined to reduce concerns about adverse effects, and the pharmacokinetics of escitalopram oxalate were studied in oral co-administration with trazodone HCL.

[0066] In the examples below, peak areas were calculated as integers, peak area ratios were calculated as four decimal places, and concentration, retention time (RT), accuracy, and pharmacokinetic parameters were calculated as two decimal places.

[0067] Animal testing methods

[0068] According to one embodiment of the present disclosure, an experiment was conducted to determine the effect of co-administration on separation anxiety in dogs. In one embodiment, the experiment may involve repeated oral administration of a test substance to a male beagle dog. In another embodiment, the experiment may involve collecting blood from the beagle dog on a schedule to conduct a comparative evaluation of the in vivo kinetics of the drug. For example, beagles are widely used in pharmacodynamics-related testing and have accumulated a wealth of basic test data, making interpretation and evaluation of test results easy, making them suitable candidates for use as experimental dogs.

[0069] According to one embodiment of the present disclosure, three non-naive male beagle dogs for testing produced by an external institution were raised in a breeding room with environmental conditions of temperature 23±3℃, relative humidity 50±20%, ventilation frequency 10 to 15 times / hour, lighting for 12 hours, and illumination intensity 150 Lux. According to one embodiment of the present disclosure, food and water were fed freely, and the drinking bottles were replaced three times a week.

[0070] According to one embodiment of the present disclosure, the test substances were prepared by dissolving escitalopram oxalate and trazodone HCL in distilled water at doses of 0.5 mg / kg and 2 mg / kg, respectively. According to one embodiment, the administration volume was administered at a volume of 5 mL / kg. For example, for administration to a test animal weighing 7 kg, 3.5 mg of escitalopram oxalate and 14 mg of trazodone HCL may be dissolved in 35 mL of distilled water and administered. According to one embodiment, the test group was administered orally using a feeding tube at a predetermined dose and volume in a non-fasting state. According to one embodiment, the administration was performed a total of 4 times over 4 days.

[0071] According to one embodiment of the present disclosure, blood samples were collected at set times for each administration day. According to one embodiment of the present disclosure, blood samples were collected 30 minutes before, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after administration on the first day. According to one embodiment of the present disclosure, blood samples were collected before administration on the second day (24 hours after administration on the first day), before administration on the third day (48 hours after administration on the first day), and before administration on the fourth day (72 hours after administration on the first day), and after administration on the fourth day, blood samples were collected 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours, respectively.

[0072] According to one embodiment of the present disclosure, 1 mL of blood was collected at a time, placed in a tube treated with Na-heparin, an anticoagulant, and mixed well. According to one embodiment, after collection, the blood was centrifuged at 4°C and 5,000 rpm for 10 minutes to separate the plasma, and then approximately 30 μL + 30 μL + pooled into tubes labeled with the animal number and blood collection time and stored in an ultra-low temperature freezer (approximately -80°C).

[0073] Observe general symptoms

[0074] In one embodiment, general symptoms, such as body weight and clinical symptoms, were observed during the post-administration test period. According to one embodiment of the present disclosure, no statistically significant weight loss or clinical symptoms were observed throughout the test period, and no adverse effects were observed following administration of the test substance.

[0075] chromatography-mass spectrometry (LC-MS / MS)

[0076] According to one embodiment of the present disclosure, 51 samples in total, 17 samples per blood collection time for 3 animals, were analyzed using liquid chromatography-mass spectrometry (LC-MS / MS).

[0077] According to one embodiment of the present disclosure, standard plasma was prepared for LC-MS / MS analysis. According to one embodiment of the present disclosure, the test substance standard solution (Working solution) was diluted with blank plasma that had been frozen and stored at -80°C, and the standard plasma was prepared so that the concentration of each test substance in the plasma was 0, 1, 2, 5, 10, 20, 50, 100, 200, 500, and 1000 ng / mL, respectively.

[0078] In one embodiment, an internal standard may be used to improve the accuracy of LC-MS / MS. For example, an internal standard is a substance of known concentration with similar physical and chemical properties to the test substance. It operates alongside the test substance in the analysis sample and can be used to correct for errors caused by various variables during the analysis process, such as differences in sample size, injection volume, and variations in analytical equipment. According to one embodiment of the present disclosure, chlorpromazine may be used as an internal standard.

[0079] According to one embodiment of the present disclosure, 10 μL of each standard plasma was placed in a test tube, and 100 μL of a 500 ng / mL acetonitrile solution of chlorpromazine selected as an internal standard was added thereto, followed by an additional 400 μL of acetonitrile. According to one embodiment of the present disclosure, the mixture was vortexed for 10 seconds and centrifuged at 13,000 rpm for 5 minutes. According to one embodiment, 5 μL of the centrifugation supernatant was injected into an Agilent1200LC + 4000 Qtrap to perform LC-MS / MS.

[0080] quantitative limit

[0081] In analysis by LC-MS / MS, a quantitatively reliable concentration interval can be defined according to one embodiment.

[0082] In a method according to one embodiment of the present disclosure, the limit of quantitation is set as a concentration that satisfies the conditions of a signal-to-noise ratio (S / N ratio) of 10 or more on a chromatogram, a precision of 20% or less, and an accuracy of 80 to 120%, and when detected at a concentration below the lower limit of quantitation (ULOQ), it is indicated as a Below Quantitation Limit (BQL).

[0083] Calibration curve

[0084] In one embodiment, a calibration curve was generated using peak areas obtained from LC-MS / MS analysis. In one embodiment, the peak area may be proportional to the concentration of the substance. In one embodiment, the peak area of ​​the test substance may be compared with the peak area of ​​an internal standard of known concentration to obtain a peak area ratio.

[0085] Tables 1 and 2 show the results of preparing calibration curves for escitalopram and trazodone using standard plasma, respectively, according to one embodiment of the present disclosure.

[0086] Escitalopram calibration curve measurement nominal concentration peak area peak area ratio measured concentration accuracy (%) ng / mL test substance internal standard ng / mL 0 N / A3 2 2 5 1 6 1 N / AN / AN / A1 1 2 5 3 3 8 9 2 9 5 0.000 4 1.1 1 1 1 1 3 2 1 9 2 9 3 3 7 8 9 3 0.000 6 1.9 ... .004618.9994.94504483637656900.011949.6399.251007444233043560.022594.2994.2920014750632988840.0447187.5893.7950040650933358630.1219511.98102.40100078229932646910.23961007.18100.72

[0087] Calibration curve of trazodone Nominal concentration Peak area Peak area ratio Measurement concentration Accuracy (%) ng / mL Test substance Internal standard ng / mL 0 N / A3225161 N / AN / AN / A154633892950.00021.01100.562125733378930.00042.14106.795313033605000.00095.05100.9810627432441880.001910.31103.14201108532303210 .003418.1890.88503485037656900.009348.7597.501006356633043560.0192101.16101.1620011961032988840.0363190.5395.2750033421633358630.1002526.21105.24100061214532646910.1875984.6698.47

[0088] In one embodiment, the nominal concentration may be various concentrations of a standard material prepared for preparing a calibration curve. In one embodiment of the present disclosure, the nominal concentration may include 0, 1, 2, 5, 10, 20, 50, 100, 200, 500, and 1000 ng / mL. In one embodiment, the accuracy of the analysis may be calculated through the difference between the measured concentration calculated using the peak area and the nominal concentration. In the results corresponding to Tables 1 and 2 according to one embodiment of the present disclosure, the accuracy was found to meet the acceptance criterion of within ±15% (±20% for the lower limit of quantitation) of the nominal concentration.

[0089] In one embodiment according to the present disclosure, data can be plotted by setting the X-axis as the nominal concentration of the standard substance and the Y-axis as the peak area ratio for each concentration. In one embodiment according to the present disclosure, a straight line equation reflecting each pair of nominal concentration and peak area ratio can be obtained through linear regression analysis. In one embodiment, the straight line equation is

[0090]

[0091] y: peak area ratio

[0092] a : slope

[0093] x: concentration of test substance

[0094] b: y-intercept

[0095] It can be written in the form of. For example, through the results of Table 1 above, the linear equation according to the linear regression analysis of the escitalopram standard plasma can be defined as the following values.

[0096] Correlation coefficient (R) 0.99959 y = ax + ba 0.000237811 b 0.000105059 Weighting factor 1 / x

[0097] For example, through the results of Table 2 above, the linear equation according to linear regression analysis of trazodone standard plasma can be defined as the following values.

[0098] Correlation coefficient (R) 0.99938 y = ax + ba 0.000190456 b - 0.0000303108 Weighting factor 1 / x

[0099] For example, the correlation coefficient (R) can be a numerical measure of the degree of correlation between two variables, expressing the statistical relationship between them. For example, a correlation coefficient closer to 1 indicates a stronger correlation, and the calibration curve can be assessed as having higher linearity.

[0100] For example, a weight may be a value applied to each data value in linear regression analysis. According to one embodiment of the present disclosure, the weight may be 1 / x. For example, by setting the weight to 1 / x, data values ​​in a low-concentration range are given more weight, thereby reducing errors in the low-concentration range. For example, when the concentration range is wide, setting the weight to 1 / x reduces the weight of high-concentration data points, thereby not excessively affecting the overall regression analysis, and thus may be suitable for balancing the entire data.

[0101] Results Analysis

[0102] According to one embodiment of the present disclosure, 17 samples each for each blood collection time, a total of 51 samples, were analyzed using liquid chromatography-mass spectrometry (LC-MS / MS) for 3 test dogs. According to one embodiment, 10 μL of each sample plasma was placed in a test tube, and 100 μL of a 500 ng / mL acetonitrile solution of chlorpromazine selected as an internal standard was added, and 400 μL of an acetonitrile solution was additionally added. According to one embodiment, the mixture was vortexed for 10 seconds and centrifuged at 13,000 rpm for 5 minutes. According to one embodiment, 5 μL of the centrifugation supernatant was injected into an Agilent1200LC + 4000 Qtrap to perform LC-MS / MS.

[0103] According to one embodiment of the present disclosure, the peak areas of the test substance and the internal standard in each sample were obtained from the resulting chromatogram.

[0104] Figures 1a to 1d are LC-MS / MS chromatograms of the beagle experimental dog blood plasma, escitalopram oxalate lower limit of quantification (LLOQ), upper limit of quantification (ULOQ), and 30 minutes after administration on the first day, respectively.

[0105] Figures 2a to 2d are LC-MS / MS chromatograms of the beagle experimental dog blood plasma, trazodone HCL lower limit of quantification (LLOQ), upper limit of quantification (ULOQ), and 30 minutes after administration on the first day, respectively.

[0106] In one embodiment, the peak area ratio for the internal standard was calculated from the peak area of ​​each sample. In one embodiment of the present disclosure, the peak area ratio was input into the calibration curve obtained using the standard plasma to calculate the test substance concentration of each sample. In one embodiment, the average of three values ​​for each experimental subject can be calculated for each test substance and administration time. Table 5 shows the results of calculating the average concentration of each sample according to one embodiment of the present disclosure.

[0107] Time (h) Escitalopram (0.5 mg / kg) Trazodone (2 mg / kg) 1 day 4 days 1 day 4 days 0.0ND1.14ND34.100.251.381.901037.63625.280.506.654.33838.76795.84115.0310.32781.42628.48215.6615.04668.43778.64410.6714.26434.62436.3483.635.89155.34174.40240.51BQL26.44BQL481.02-33.45-

[0108] According to one embodiment of the present disclosure, the unit of the measured plasma concentration is ng / mL, and FIGS. 3 and 4 are graphs plotting such concentration over time.

[0109] According to one embodiment of the present disclosure, various pharmacokinetic parameters were calculated using the concentration values ​​calculated according to Table 5, Figures 3 and 4. For example, AUC last can be the area under the curve up to the last measurement time. For example, the area under the curve (AUC) is the value that integrates the blood concentration of the test substance over time and can reflect the exposure time of the drug in the body. For example, AUC inf is the value of the area under the curve that is integrated by extrapolating the x-axis to infinity, and may be a value that reflects the exposure in the body until the test substance is completely excreted. For example, C max may be the peak blood concentration. For example, it may be the blood concentration that reaches the highest level after the test substance is absorbed into the body. For example, T max may be the time to reach peak blood concentration. For example, T max C is the highest blood concentration of the test substance. maxIt can be the time to reach the bioavailability. For example, Vz / F can be the ratio of the volume of distribution to the bioavailability. For example, Vz can represent the volume in which the drug is distributed in the body. For example, F can be the bioavailability. For example, F can reflect the physiological effect exhibited by a certain amount of the drug. For example, Vz / F can represent the volume of distribution in the body when administered orally. For example, Cl / F can be the ratio of the clearance to the bioavailability. For example, Cl is the clearance and can represent the rate at which the test substance is eliminated from the body. For example, t 1 / 2 may be the elimination half-life. For example, the elimination half-life may refer to the time it takes for the blood concentration of a test substance to decrease by half. For example, the elimination half-life may indicate how long a test substance persists in the body.

[0110] According to one embodiment of the present disclosure, the pharmacokinetic parameters of escitalopram and trazodone were obtained as shown in Table 6.

[0111] Pharmacokinetic parameters Units Citalopram Trazodone 1 day 4 days 1 day 4 days Dose mg / kg 0.50 0.50 2.00 2.00 AUC last h*ng / mL97.54112.144922.334912.64AUC inf h*ng / mL102.65113.465169.095114.54C max ng / mL15.8617.001037.63921.73T max h1.672.670.250.92Vz / FL / kg33.1220.032.822.87Cl / FL / h / kg7.394.900.390.40T 1 / 2 h4.083.114.995.01

[0112] According to one embodiment of the present disclosure, the time to peak blood concentration (T) on the first day after co-administration of escitalopram and trazodone max) were 1.67 hours and 0.25 hours, respectively, and the times to reach the maximum blood concentration on the 4th day after a total of 4 administrations were 2.67 hours and 0.92 hours, respectively, effectively reaching the maximum concentration in a short period of time.

[0113] According to one embodiment of the present disclosure, the accumulation ratio according to oral co-administration of escitalopram and trazodone was calculated as shown in Table 7. For example, the accumulation ratio is C max and AUC can be calculated respectively.

[0114] Test substance dose (mg / kg)AR Cmax AR AUC Escitalopram 0.51.071.15 Trazodone 20.891.00

[0115] For example, AR Cmax The highest blood concentration on the first day (C max ) may be the ratio of the highest blood concentration on the fourth day.

[0116] For example, the AUC on the first day last AUC on the 4th day last It can be a ratio of .

[0117] As shown in Table 7, the method according to one embodiment of the present disclosure has an AR of 1.07 for escitalopram. Cmax and AR of 1.15 AUC , and AR of 0.89 for trazodone. Cmax and AR of 1.00 AUC , no accumulation pattern in the body was observed for both escitalopram and trazodone.

[0118] In humans, a daily dose of 10 mg escitalopram resulted in a C of approximately 21 ng / mL. maxWhen referring to what is expected (https: / go.drugbank.com / drugs / DB01175), oral administration of escitalopram according to one embodiment of the present disclosure exhibited a peak blood concentration similar to that of administration of 5 mg to 10 mg in humans. In addition, oral administration of escitalopram according to one embodiment of the present disclosure exhibited elimination half-lives of 4.08 hours and 3.11 hours (Table 6), and no accumulation in the body was observed (Table 7).

[0119] In one embodiment of the present disclosure, trazodone HCl reached peak blood concentrations within a short period of time, approximately 30 minutes after administration. Furthermore, in one embodiment of the present disclosure, blood concentrations were sustained for 8 hours between blood concentrations of 130 ng / ml and 2 ug / ml, which is known to be a therapeutic dose range in humans (Figure 4). Furthermore, in one embodiment of the present disclosure, trazodone HCl exhibited an elimination half-life of 5 hours (Table 6), and did not exhibit a pattern of accumulation in the body, similar to that observed with oral administration of escitalopram (Table 7).

[0120] The description of the disclosed embodiments is provided for illustrative purposes only and is intended to enable any person skilled in the art to make or use the present disclosure. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments without departing from the scope of the present disclosure. Therefore, the present disclosure is not intended to be limited to the embodiments disclosed herein but is to be construed in the broadest scope consistent with the principles and novel features disclosed herein.

[0121] As described above, the relevant contents have been described in the best form for carrying out the invention.

[0122] It can be used to prevent or treat mental illness or behavioral disorders in animals.

Claims

1. Containing selective serotonin reuptake inhibitors (SSRIs) and serotonin antagonist-reuptake inhibitors (SARIs) as active ingredients, A pharmaceutical composition for preventing or treating mental illness or behavioral disorders in animals.

2. In paragraph 1, The above selective serotonin reuptake inhibitors (SSRIs) are Containing at least one of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone or vortioxetine; Pharmaceutical composition.

3. In paragraph 1, The above serotonin reuptake inhibitors (SARIs) are, Containing at least one of Trazodone or Nefazodone, Pharmaceutical composition.

4. In paragraph 1, the selective serotonin reuptake inhibitor (SSRI) is Escitalopram, The above escitalopram is formulated to be administered to a subject at a dose of 0.5 mg / kg. Pharmaceutical composition.

5. In paragraph 1, the serotonin reuptake inhibitor (SARI) is trazodone, The above trazodone is formulated to be administered to a subject at a dose of 2 mg / kg. Pharmaceutical composition.

6. In paragraph 1, The above selective serotonin reuptake inhibitor (SSRI) is formulated to be administered to a subject at a dose of 0.5 mg / kg, and The above serotonin reuptake inhibitor (SARI) is formulated to be administered to a subject at a dose of 2 mg / kg. Pharmaceutical composition.

7. In paragraph 1, Mental illness or behavioral disorder in the above animals, Including separation anxiety in dogs or cats, Pharmaceutical composition.

8. In paragraph 1, The pharmaceutical composition is characterized in that it further comprises a pharmaceutically acceptable carrier. Pharmaceutical composition.

9. A method for preventing or treating mental illness or behavioral disorders in animals other than humans, The method comprises administering a selective serotonin reuptake inhibitor (SSRI) and a serotonin antagonist-reuptake inhibitor (SARI). method.

10. In paragraph 9, The above selective serotonin reuptake inhibitors (SSRIs) are Containing at least one of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone or vortioxetine; method.

11. In paragraph 9, The above serotonin reuptake inhibitors (SARIs) are, Containing at least one of Trazodone or Nefazodone, method.

12. In paragraph 9, The above serotonin reuptake inhibitor (SARI) is escitalopram, The above escitalopram is administered to the subject at a dose of 0.5 mg / kg. method.

13. In paragraph 9, The above serotonin antagonist-reuptake inhibitor (SARI) is trazodone, The above trazodone is administered to the subject at a dose of 2 mg / kg. method.

14. In paragraph 9, The above selective serotonin reuptake inhibitor (SSRI) is formulated to be administered to a subject at a dose of 0.5 mg / kg, and The above serotonin reuptake inhibitor (SARI) is formulated to be administered to a subject at a dose of 2 mg / kg. method.

15. In paragraph 9, The above selective serotonin reuptake inhibitor (SSRI) and the above serotonin antagonist-reuptake inhibitor (SARI) are administered together to the subject. method.

16. In paragraph 9, Mental illness or behavioral disorder in the above animals, Including separation anxiety in dogs or cats, method.

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