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WO2025018810A1 - Composition pour la prévention ou le traitement de maladies mentales ou de troubles comportementaux chez les animaux - Google Patents

Composition pour la prévention ou le traitement de maladies mentales ou de troubles comportementaux chez les animaux Download PDF

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Publication number
WO2025018810A1
WO2025018810A1 PCT/KR2024/010360 KR2024010360W WO2025018810A1 WO 2025018810 A1 WO2025018810 A1 WO 2025018810A1 KR 2024010360 W KR2024010360 W KR 2024010360W WO 2025018810 A1 WO2025018810 A1 WO 2025018810A1
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present disclosure
reuptake inhibitor
administered
escitalopram
serotonin
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English (en)
Korean (ko)
Inventor
안국준
강현희
홍정원
김규혜
지길용
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Geovista Inc
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Geovista Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present disclosure relates to a composition for preventing or treating mental illness or behavioral disorders in animals, and more particularly, to a composition for preventing or treating mental illness or behavioral disorders in animals by co-administering two or more serotonin agonists.
  • Serotonin is one of the most important neurotransmitters. Serotonin is involved in appetite, sleep, and cognitive regulation, as well as having the most direct effect on mood, anxiety, and well-being. Imbalances in serotonin levels can lead to a number of mental health conditions, including: For example, low levels of serotonin have been linked to depressive symptoms. In addition, conditions such as generalized anxiety disorder (GAD), panic disorder, and social anxiety disorder have also been linked to serotonin dysregulation. Additionally, people with obsessive-compulsive disorder or post-traumatic stress disorder (PTSD) often have imbalances in serotonin levels.
  • GAD generalized anxiety disorder
  • PTSD post-traumatic stress disorder
  • serotonin used in the brain must be produced within it and cannot pass through the blood-brain barrier (BBB), it is difficult to directly control the serotonin concentration in the brain. Instead, indirect methods such as inhibiting the reuptake of serotonin are used to treat serotonin-related mental disorders.
  • mental disorders or behavioral disorders are difficult to determine simply by the level of serotonin in the brain alone, and are determined by the type of mental disorder or behavioral disorder and biological/social factors according to the animal species, so it may be difficult to select an appropriate serotonin-regulating drug.
  • Separation anxiety is caused by the fear of being separated from a person, such as a parent or caregiver. It can often be expressed as distress, crying, or clinging behavior when faced with the possibility of being separated from the parent or caregiver. This condition is often seen in human babies and children, but can also be common in companion animals such as dogs.
  • Separation anxiety in companion animals can be very distressing to their owners, and treatment or relief is essential.
  • Veterinary approaches to managing separation anxiety in companion animals may include a combination of behavior modification, environmental changes, and potential medications, but the effectiveness of medications is limited.
  • the present disclosure seeks to prevent or treat mental illness or behavioral disorders by co-administering a serotonin reuptake inhibitor (SRI).
  • SRI serotonin reuptake inhibitor
  • a pharmaceutical composition for preventing or treating a mental illness or behavioral disorder in an animal comprising a selective serotonin reuptake inhibitor (SSRI) and a serotonin antagonist-reuptake inhibitor (SARI) as active ingredients.
  • SSRI selective serotonin reuptake inhibitor
  • SARI serotonin antagonist-reuptake inhibitor
  • the selective serotonin reuptake inhibitor may be a pharmaceutical composition comprising at least one of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone, or vortioxetine.
  • the serotonin reuptake inhibitor may be a pharmaceutical composition comprising at least one of Trazodone or Nefazodone.
  • the selective serotonin reuptake inhibitor is Escitalopram
  • the Escitalopram may be a pharmaceutical composition formulated to be administered to a subject at a dosage of 0.5 mg/kg.
  • the serotonin reuptake inhibitor is trazodone
  • the trazodone may be a pharmaceutical composition formulated to be administered to a subject at a dosage of 2 mg/kg.
  • the selective serotonin reuptake inhibitor may be formulated to be administered to a subject at a dose of 0.5 mg/kg
  • the serotonin antagonist-reuptake inhibitor may be a pharmaceutical composition formulated to be administered to a subject at a dose of 2 mg/kg.
  • 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.
  • the pharmaceutical composition may be characterized by further comprising a pharmaceutically acceptable carrier.
  • a method of preventing or treating a mental illness or behavioral disorder in an animal other than a human may comprise administering a selective serotonin reuptake inhibitor (SSRI) and a serotonin antagonist-reuptake inhibitor (SARI).
  • SSRI selective serotonin reuptake inhibitor
  • SARI serotonin antagonist-reuptake inhibitor
  • the selective serotonin reuptake inhibitor may include at least one of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone, or vortioxetine.
  • the serotonin reuptake inhibitor is escitalopram, and the escitalopram can be administered to the subject at a dose of 0.5 mg/kg.
  • the serotonin reuptake inhibitor is trazodone, and the trazodone can be administered to the subject at a dose of 2 mg/kg.
  • the selective serotonin reuptake inhibitor can be formulated to be administered to the subject at a dose of 0.5 mg/kg
  • the serotonin antagonist-reuptake inhibitor can be formulated to be administered to the subject at a dose of 2 mg/kg.
  • the selective serotonin reuptake inhibitor (SSRI) and the serotonin antagonist-reuptake inhibitor (SARI) can be co-administered to a subject.
  • 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.
  • Figures 1a to 1d are LC-MS/MS chromatograms of the beagle dog plasma, escitalopram lower limit of quantification (LLOQ), upper limit of quantification (ULOQ), and 30 minutes after administration on day 1, respectively.
  • Figures 2a to 2d are LC-MS/MS chromatograms of the beagle dog plasma, trazodone lower limit of quantification (LLOQ), upper limit of quantification (ULOQ), and 30 minutes after administration on the first day, respectively.
  • Figure 3 shows the pharmacokinetic results of oral administration of 0.5 mg/kg of escitalopram oxalate, showing the plasma concentration of escitalopram over the experimental period.
  • 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.
  • a composition for preventing, treating, improving or alleviating mental illness or behavioral disorder comprising a serotonin reuptake inhibitor (SRI) as an active ingredient.
  • SRI serotonin reuptake inhibitor
  • Serotonin reuptake inhibitors may be intended for co-administration.
  • 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).
  • SSRI selective serotonin reuptake inhibitor
  • SARI Serotonin Antagonist and Reuptake Inhibitor
  • Selective serotonin reuptake inhibitors can relieve symptoms of depression and selectively prevent serotonin from being reabsorbed into neurons.
  • the selective serotonin reuptake inhibitors can include at least one of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone, or vortioxetine.
  • Fluoxetine Prozac or Oxactin is the most well-known SSRI, often used to treat major depressive disorder, obsessive-compulsive disorder (OCD), and panic disorder.
  • Sertraline Lustral
  • Paroxetine is used to treat depression, anxiety disorders, and menopausal symptoms. It may help improve mood, sleep, appetite, and energy levels, and restore interest in daily life.
  • Citalopram is another SSRI used to treat depression, and may increase feelings of well-being and energy levels.
  • Escitalopram is an SSRI used to treat depression and generalized anxiety disorder, and may help reduce irritability and improve energy levels.
  • Fluvoxamine 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
  • vortioxetine Bostioxetine
  • Serotonin antagonist-reuptake inhibitors block the reuptake of serotonin and can act as antagonists at specific serotonin receptors. They are used to treat major depressive disorder and may also be used for insomnia due to their sedative effects. SARIs may include at least one of trazodone or nefazodone.
  • Trazodone is mainly used to treat major depressive disorder by blocking the reuptake of serotonin, and is known to have a sedative effect, so it can be prescribed for insomnia and anxiety disorders.
  • Nefazodone is a phenylpiperazine compound that can have a similar effect to the above trazodone.
  • 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.
  • TCA tricyclic antidepressant
  • the tricyclic antidepressant (TCA) may comprise at least one of amitriptyline or nortriptyline.
  • a composition according to one embodiment of the present disclosure may be for a mental illness or behavioral disorder in a human or animal.
  • the above mental illness or behavioral disorder may be an anxiety disorder and may occur in animals or humans.
  • the mental illness or behavioral disorder for the companion animal may include separation anxiety. Separation anxiety can occur in other companion animal species, but is a common problem in canines.
  • anxiety can occur in response to threatening or stressful situations, but it differs from various human anxiety disorders in that it can occur in dogs when they are left alone and separated from the person with whom they have formed an attachment relationship.
  • this separation anxiety the dog can suffer excessive distress and exhibit a variety of behaviors that may be considered abnormal or indicative of mental illness.
  • separation anxiety in dogs can cause destructive behavior, excessive barking, or howling.
  • this separation anxiety can occur not only in dogs but also in other animals. Animals can feel at least one emotion of fear, fear, or depression along with separation anxiety, and can additionally show at least one symptom of obsessive behavior, depression, cognitive dysfunction, or aggression.
  • Animals that suffer from phobias or fears may develop intense fears or phobias of certain things, such as thunderstorms, fireworks, or certain people or animals, and this fear may cause the animal to display behaviors such as hiding, trembling, or trying to escape.
  • OCD obsessive-compulsive disorder
  • 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.
  • CDS cognitive dysfunction syndrome
  • the formulation of the pharmaceutical composition of the present disclosure may be variously prepared by mixing with the pharmaceutically acceptable carriers described above.
  • for oral administration it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.
  • for injections it can be manufactured in the form of unit dose ampoules or multiple doses.
  • it can be formulated in the form of solutions, suspensions, tablets, capsules, sustained-release preparations, etc.
  • examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.
  • a "pharmaceutically effective amount” refers to a sufficient amount of an agent to provide a desired biological result. That result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration in a biological system.
  • an “effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in a disease.
  • An appropriate “effective” amount in any individual case can be determined by one of skill in the art using routine experimentation. Accordingly, the expression “effective amount” generally refers to an amount of an active agent that has a therapeutic effect.
  • 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.
  • oral formulations such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and sterile injectable solutions, but is not limited thereto.
  • the routes of administration of the pharmaceutical compositions of the present disclosure include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal.
  • Oral administration in animals works very similarly to the human process, involving the animal ingesting a substance through the mouth and then processing it in the digestive system. Oral administration in animals is commonly used because of its non-invasive nature. Each of these forms can be tailored to the specific needs of the drug and the preferences of the animal.
  • 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 those skilled in the art.
  • compositions of the present disclosure may be used alone or in combination with methods using additional behavioral therapies, hormonal treatments, chemotherapy, and biological response modifiers.
  • Trazodone HCl is a drug of the SARI (Serotonin anatagonist and reuptake inhibitor) series and is mainly used to induce sedation in companion animals.
  • SARI Serotonin anatagonist and reuptake inhibitor
  • Trazodone HCl is a drug of the SARI (Serotonin anatagonist and reuptake inhibitor) series and is mainly used to induce sedation in companion animals.
  • SARI Strerotonin anatagonist and reuptake inhibitor
  • peak areas were calculated as integers
  • peak area ratios were calculated as four decimal places
  • concentration, retention time (RT), accuracy, and pharmacokinetic parameters were calculated as two decimal places.
  • an experiment was conducted to confirm the effect of combined administration on separation anxiety in dogs.
  • the experiment may be to repeatedly administer a test substance orally using a male beagle dog.
  • the experiment may be to collect blood from the beagle dog according to a schedule to perform a comparative evaluation of the body dynamics of the drug.
  • beagles are widely used in pharmacodynamic-related tests, and abundant test basic data have been accumulated, making it easy to interpret and evaluate test results, so they may be suitable for adoption as test dogs.
  • 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°C, relative humidity 50 ⁇ 20%, ventilation frequency 10 to 15 times/hour, lighting 12 hours, and illumination intensity 150 Lux.
  • food and water were fed freely, and the drinking water bottle was replaced three times a week.
  • 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.
  • the administration volume was administered at a volume of 5 mL/kg.
  • Escitalopram oxalate and Trazodone HCL can be dissolved in 35 mL of distilled water and administered.
  • the test group was administered orally using a feeding tube at a determined dose and volume in a non-fasting state.
  • the administration was performed a total of 4 times over 4 days.
  • blood collection was performed at set times for each administration day.
  • blood collection was performed 30 minutes before administration on the first day, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after administration on the first day, respectively.
  • blood collection was performed 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 collection was performed 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours, respectively.
  • 1 mL of blood was collected at a time, placed in a tube treated with Na-heparin, an anticoagulant, and mixed well.
  • the blood was centrifuged at 4°C and 5,000 rpm for 10 minutes to separate the plasma, and about 30 ⁇ L +30 ⁇ L + of the separated plasma was pooled into tubes labeled with the animal number and the blood collection time and stored in an ultra-low temperature freezer (about -80°C).
  • general symptoms such as body weight and clinical symptoms were observed during the test period after administration.
  • no statistically significant weight loss and clinical symptoms were found during the test period, and no adverse effects were observed due to administration of the test substance.
  • LC-MS/MS liquid chromatography-mass spectrometry
  • a standard plasma was prepared for LC-MS/MS analysis.
  • a test substance standard solution (Working solution) was diluted with blood plasma that had been frozen and stored at -80° C., to prepare a standard plasma such that the concentrations of each test substance in the plasma were 0, 1, 2, 5, 10, 20, 50, 100, 200, 500, and 1000 ng/mL, respectively.
  • an internal standard may be used to improve the accuracy of LC-MS/MS.
  • an internal standard is a substance of known concentration that has similar physical and chemical properties to a test substance, operates together with the test substance in the analysis sample, and may be used to correct errors caused by various variables such as differences in samples, differences in injection amounts, and variations in analysis equipment during the analysis process.
  • chlorpromazine may be used as an internal standard.
  • 10 ⁇ L of each standard plasma was placed in a test tube, and 100 ⁇ L of a 500 ng/mL acetonitrile solution of chlorpromazine selected as an internal standard was added thereto, and additionally 400 ⁇ L of acetonitrile was added thereto.
  • vortex mixing was performed for 10 seconds, and then centrifugation was performed at 13,000 rpm for 5 minutes.
  • 5 ⁇ L of the centrifugation supernatant was injected into Agilent1200LC + 4000 Qtrap to perform LC-MS/MS.
  • a quantitatively reliable concentration interval can be defined according to one embodiment.
  • the limit of quantitation is set as a concentration satisfying 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 expressed as BQL (Below Quantitation Limit).
  • S/N ratio signal-to-noise ratio
  • UEOQ lower limit of quantitation
  • a calibration curve is created using peak areas obtained from LC-MS/MS performance.
  • the peak area may be proportional to the concentration of the substance.
  • the peak area of the test substance may be compared with the peak area of an internal standard substance of known concentration to obtain a peak area ratio.
  • Tables 1 and 2 show the results of creating calibration curves for escitalopram and trazodone using standard plasma, respectively, according to one embodiment of the present disclosure.
  • the nominal concentration can be a variety of concentrations of a standard material made for creating a calibration curve.
  • the nominal concentration can include 0, 1, 2, 5, 10, 20, 50, 100, 200, 500, and 1000 ng/mL.
  • the accuracy of the analysis can 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 satisfy the acceptance criterion of within ⁇ 15% ( ⁇ 20% in case of the lower limit of quantitation) of the nominal concentration.
  • 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.
  • a straight line equation reflecting each pair of nominal concentration and peak area ratio can be obtained through linear regression analysis.
  • the straight line equation is
  • the correlation coefficient (R) can be a coefficient that numerically represents the degree of a specific correlation to express the statistical relationship between two variables. For example, the closer the absolute value of the correlation coefficient is to 1, the stronger the correlation can be, and the higher the linearity of the calibration curve can be evaluated.
  • the weight may be a value applied to each data value in linear regression analysis.
  • the weight may be 1/x.
  • weights are applied to data values in a low-concentration section, thereby reducing errors in the low-concentration section.
  • concentration range is wide
  • the weights of high-concentration data points are reduced, so that they do not have an excessive influence on the overall regression analysis, and thus may be suitable for balancing the overall data.
  • 10 ⁇ L of each sample plasma was placed in a test tube, 100 ⁇ L of a 500 ng/mL acetonitrile solution of chlorpromazine selected as an internal standard was added, and 400 ⁇ L of an acetonitrile solution was additionally added.
  • vortex mixing was performed for 10 seconds and then centrifugation was performed at 13,000 rpm for 5 minutes.
  • 5 ⁇ L of the centrifugation supernatant was injected into an Agilent1200LC + 4000 Qtrap to perform LC-MS/MS.
  • the peak areas of the test substance and the internal standard in each sample were obtained from the resulting chromatogram.
  • Figures 1a to 1d are LC-MS/MS chromatograms of the beagle dog plasma, escitalopram oxalate lower limit of quantification (LLOQ), upper limit of quantification (ULOQ), and 30 minutes after administration on day 1, respectively.
  • Figures 2a to 2d are LC-MS/MS chromatograms of the beagle dog plasma, trazodone HCL lower limit of quantification (LLOQ), upper limit of quantification (ULOQ), and 30 minutes after administration on the first day, respectively.
  • the peak area ratio for the internal standard was obtained from the peak area of each sample. In one embodiment of the method of the present disclosure, the peak area ratio was substituted 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 obtained 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.
  • the unit of the measured plasma concentration is ng/mL
  • FIGS. 3 and 4 are graphs plotting this concentration over time.
  • AUC last may be the area under the curve until the last measurement time.
  • the area under the curve (AUC) is a value obtained by integrating the blood concentration of the test substance over time, and may reflect the exposure time of the drug in the body.
  • AUC inf may be a value of the area under the curve obtained by extrapolating the x-axis to infinity and integrating it, and may reflect the exposure in the body until the test substance is completely excreted.
  • C max may be the maximum blood concentration. For example, this may be the blood concentration at which the test substance is absorbed into the body and then reaches the maximum.
  • T max may be the time to reach the maximum blood concentration.
  • T max may be the time for the concentration of the test substance to reach the maximum blood concentration, C max .
  • Vz/F can be the ratio of volume of distribution to bioavailability.
  • Vz can represent the volume through which a drug is distributed in the body.
  • F can be bioavailability.
  • F can reflect the physiological effect exhibited by a certain amount of the drug.
  • Vz/F can represent the volume of distribution in the body when administered orally.
  • Cl/F can be the ratio of clearance to bioavailability.
  • Cl is clearance and can represent the rate at which a test substance is eliminated from the body.
  • t 1/2 can be the elimination half-life.
  • the elimination half-life can mean the time it takes for the blood concentration of the test substance to decrease by half.
  • the elimination half-life can represent how long a test substance is maintained in the body.
  • the pharmacokinetic parameters of escitalopram and trazodone were obtained as shown in Table 6.
  • the times to reach the maximum blood concentration (T max ) on the first day after co-administration of escitalopram and trazodone were 1.67 hours and 0.25 hours, respectively, and the times to reach the maximum blood concentration on the fourth day after a total of four administrations were 2.67 hours and 0.92 hours, respectively, effectively reaching the maximum concentration within a short period of time.
  • the accumulation ratio according to oral co-administration of escitalopram and trazodone was calculated as shown in Table 7.
  • the accumulation ratio can be calculated for C max and AUC, respectively.
  • AR Cmax may be the ratio of the peak blood concentration on day 4 to the peak blood concentration (C max ) on day 1.
  • it could be the ratio of AUC last on day 4 to AUC last on day 1.
  • the method according to one embodiment of the present disclosure exhibited an AR Cmax of 1.07 and an AR AUC of 1.15 for escitalopram, and an AR Cmax of 0.89 and an AR AUC of 1.00 for trazodone, indicating that there was no accumulation pattern in the body for both escitalopram and trazodone.
  • oral administration of escitalopram according to one embodiment of the present disclosure exhibited a peak blood concentration similar to administration of 5 mg to 10 mg in humans.
  • 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 pattern in the body was observed (Table 7).
  • trazodone HCl reached peak blood concentration within a short period of time, approximately 30 minutes after administration.
  • blood concentrations were sustained for 8 hours between blood concentrations of 130 ng/ml and 2 ug/ml, which are known to be a therapeutic dose range in humans ( Figure 4).
  • it exhibited an elimination half-life of 5 hours (Table 6) and did not exhibit an accumulation pattern in the body, similar to oral administration of escitalopram (Table 7).
  • It can be used to prevent or treat mental illness or behavioral disorders in animals.

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Abstract

Selon un mode de réalisation divulgué ici, une composition de prévention ou de traitement de maladies mentales ou de troubles comportementaux chez les animaux peut comprendre un inhibiteur sélectif de la recapture de la sérotonine (ISRS) et un inhibiteur de recapture de l'antagoniste de la sérotonine (SARI). Le dessin représentatif peut être la figure 3. Le dessin représentatif peut être la figure 3.
PCT/KR2024/010360 2023-07-18 2024-07-18 Composition pour la prévention ou le traitement de maladies mentales ou de troubles comportementaux chez les animaux Pending WO2025018810A1 (fr)

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KR20230093052 2023-07-18
KR10-2023-0093052 2023-07-18
KR10-2024-0090295 2024-07-09
KR1020240090295A KR20250013110A (ko) 2023-07-18 2024-07-09 동물에 대한 정신질환 또는 행동장애의 예방 또는 치료용 조성물

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KR20070118103A (ko) * 2005-04-04 2007-12-13 다케다 야쿠힌 고교 가부시키가이샤 우울증 또는 불안신경증의 예방 또는 치료제
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