Novel applications for glyclazide

Abstract

The present invention relates to novel uses of gliclazide, more specifically to the use of gliclazide or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the prevention and / or treatment of psychotic symptoms, which are typically associated with schizophrenia and other disorders for which antipsychotic drugs may be used, and include delusions, hallucinations, disorganized thinking (language), agitation, severely disorganized or abnormal motor behavior (including catatonia), and irritability.

Description

[Technical Field]

[0001] (Citation of related applications) This document claims priority to the invention patent application filed in China on 4 May 2023, titled "Novel Uses of Glyclazide," with application number 202310492617.9, the entire contents of which are incorporated herein by reference.

[0002] This invention belongs to the pharmaceutical field and relates to novel uses of glyclazide, and more specifically, to novel uses of glyclazide and its derivatives in the pharmaceutical field. [Background technology]

[0003] It is estimated that at least 30 million people worldwide suffer from psychosis symptoms (a rough estimate based on WHO figures).

[0004] Currently, there are approved medications for the treatment of schizophrenia. Atypical antipsychotics (also known as second-generation antipsychotics) can be used as effective drugs for treating psychotic symptoms, but how to balance their safety and efficacy remains a challenge that deserves further research. In particular, studies of patients taking antipsychotics have shown that extrapyramidal symptoms (including dystonia, akathisia, and Parkinsonian syndrome) occur as side effects in more than 20% of cases, leading to decreased medication adherence and becoming a significant factor hindering treatment completion (A. Kadakia, BL Brady, C. Dembek, et al., The incidence and economic burden of extrapyramidal symptoms in patients with schizophrenia treated with second generation antipsychotics in a Medicaid population [J], J. Med. Econ., 2022, 25 (1). 87-98).

[0005] Gliclazide has CAS registry number 21187-98-4 and molecular formula C 15 H 21 It is an N3O3S oral hypoglycemic agent (for example, the brand name of this drug in Japan is GLIMICRON, and specific information can be found in the Japanese Interview Form. The brand name in Europe is DIAMICRON, and specific information can be found in the European SPC). [ka]

[0006] US2022 / 0403469A1 describes a method for treating schizophrenia that selects therapeutic drugs based on RNA expression patterns in the blood. This patent application also discloses the in silico prediction of known compounds (compounds with potential for drug reuse) that may be effective against hallucinations, based on information about RNA expression patterns in the blood of patients with hallucinations. However, in general, the accuracy of in silico predictions is limited, and it is impossible to determine whether a drug is truly effective without actually administering the drug to animals or humans and conducting drug evaluations. Furthermore, the unilaterality of the in silico prediction results in US2022 / 0403469A1 has been confirmed by related literature. For example, clioquinol, one of the compounds with the highest predictive scores on the list, failed to improve symptoms in animal models exhibiting psychosis (E.-J. Lee, H. Lee, T.-N. Huang, et al., Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation [J], Nat. Commun., 2015, 6: 7168). [Overview of the project] [Problems that the invention aims to solve]

[0007] In view of the problems present in the prior art described above, the present invention provides pharmaceutical uses of gliclazide and its derivatives for the prevention and / or treatment of psychotic symptoms associated with schizophrenia and other diseases for which antipsychotic drugs can be used. [Means for solving the problem]

[0008] <First Phase> The present invention provides the use of gliclazide or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the prevention and / or treatment of psychotic symptoms.

[0009] Furthermore, in the use described above, the psychotic symptoms are associated with schizophrenia and one or more other disorders for which antipsychotic drugs may be used.

[0010] Furthermore, in the use described above, the psychotic symptoms are one or more of the following: delusions, hallucinations, disorganized thoughts (language), agitation, severely disorganized or abnormal motor behavior (including catatonia), and irritability.

[0011] Furthermore, in the above use, the psychotic symptoms are one or more of the following: delusions, hallucinations, and agitation.

[0012] Preferably, in the psychosis symptoms, the delusion includes one or more of the following: persecutory delusions, delusions of reference, somatic delusions, grandiose delusions, loving delusions, nihilistic delusions, and jealous delusions.

[0013] Preferably, in the psychosis symptoms, the hallucinations include one or more of the following: auditory hallucinations, visual hallucinations, gustatory hallucinations, olfactory hallucinations, tactile hallucinations, and somatic hallucinations.

[0014] Preferably, in the psychosis symptoms, the disorganized thoughts (language) include one or more of the following: disorganized thoughts and disorganized conversations.

[0015] Preferably, in the schizophrenia symptoms, the agitation includes any one or more of increased purposeless motor activity, marked restlessness, aggressiveness, and emotional instability.

[0016] Preferably, in the schizophrenia symptoms, the severely disorganized or abnormal motor behavior (including catatonia) includes any one or more of markedly confused or abnormal motor behavior and catatonia.

[0017] More preferably, in the severely disorganized or abnormal motor behavior (including catatonia), the catatonia includes any one or more of refusal, mutism, stupor, and pathologic excitement.

[0018] Preferably, in the schizophrenia symptoms, the irritability includes any one or more of irritation, anxiety, anger, sadness, irritability, excitement, aggressiveness, and fits of anger.

[0019] The present invention also provides the use of a pharmaceutical composition or pharmaceutical preparation containing gliclazide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating schizophrenia symptoms.

[0020] Furthermore, in the above use, in addition to the gliclazide or a pharmaceutically acceptable salt thereof, the pharmaceutical composition or pharmaceutical preparation further optionally contains one or more other pharmaceutical active ingredients and / or optionally one or more pharmaceutically acceptable additives.

[0021] <Second aspect> The present invention provides gliclazide or a pharmaceutically acceptable salt thereof for use in preventing and / or treating schizophrenia symptoms.

[0022] Furthermore, the schizophrenia symptoms are related to any one or more of schizophrenia and other diseases for which antipsychotics can be used.

[0023] Furthermore, the psychotic symptoms include one or more of the following: delusions, hallucinations, disorganized thoughts (language), agitation, severely disorganized or abnormal motor behavior (including catatonia), and irritability.

[0024] Furthermore, the aforementioned psychotic symptoms include one or more of the following: delusions, hallucinations, and agitation.

[0025] Preferably, in the psychosis symptoms, the delusion includes one or more of the following: persecutory delusions, delusions of reference, somatic delusions, grandiose delusions, loving delusions, nihilistic delusions, and jealous delusions.

[0026] Preferably, in the psychosis symptoms, the hallucinations include one or more of the following: auditory hallucinations, visual hallucinations, gustatory hallucinations, olfactory hallucinations, tactile hallucinations, and somatic hallucinations.

[0027] Preferably, in the psychosis symptoms, the disorganized thoughts (language) include one or more of the following: disorganized thoughts and disorganized conversations.

[0028] Preferably, in the psychosis symptoms, the agitation includes one or more of the following: increased aimless motor activity, marked restlessness, aggression, and emotional instability.

[0029] Preferably, in the psychosis symptoms, the severely disorganized or abnormal motor behavior (including catatonia) includes one or more of the following: marked confusion or abnormal motor behavior and catatonia.

[0030] More preferably, in the severely disorganized or abnormal motor behavior (including catatonia), the catatonia includes one or more of the following: negativity, mutism, stupor, and pathological agitation.

[0031] Preferably, in the psychosis symptoms, the irritability includes one or more of the following: irritability, impatience, anger, sadness, anger, excitement, aggression, and temper tantrums.

[0032] Furthermore, the present invention provides a pharmaceutical composition or pharmaceutical preparation comprising gliclazide or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of psychosis symptoms.

[0033] Furthermore, in addition to glyclazide or a pharmaceutically acceptable salt thereof, the pharmaceutical composition or pharmaceutical preparation may further optionally contain one or more other pharmaceutically active ingredients and / or one or more pharmaceutically acceptable additives.

[0034] <The Third Phase> The present invention provides a method for preventing and / or treating psychosis symptoms, comprising the step of administering a prophylactic and / or therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0035] Furthermore, in the above method, the psychosis symptoms are associated with schizophrenia and one or more other disorders for which antipsychotic drugs may be used.

[0036] Furthermore, in the above method, the psychotic symptoms are one or more of the following: delusions, hallucinations, disorganized thoughts (language), agitation, severely disorganized or abnormal motor behavior (including catatonia), and irritability.

[0037] Furthermore, in the above method, the psychotic symptoms are one or more of the following: delusions, hallucinations, and agitation.

[0038] Preferably, in the psychosis symptoms, the delusion includes one or more of the following: persecutory delusions, delusions of reference, somatic delusions, grandiose delusions, loving delusions, nihilistic delusions, and jealous delusions.

[0039] Preferably, in the psychosis symptoms, the hallucinations include one or more of the following: auditory hallucinations, visual hallucinations, gustatory hallucinations, olfactory hallucinations, tactile hallucinations, and somatic hallucinations.

[0040] Preferably, in the psychosis symptoms described above, the disorganized thoughts (language) include one or more types of disorganized thoughts and disorganized conversations.

[0041] Preferably, in the psychosis symptoms described above, the agitation includes one or more of the following: increased aimless motor activity, marked restlessness, aggression, and emotional instability.

[0042] Preferably, in the psychosis symptoms, the severely disorganized or abnormal motor behavior (including catatonia) includes one or more of the following: marked confusion or abnormal motor behavior and catatonia.

[0043] More preferably, in the severely disorganized or abnormal motor behavior (including catatonia), the catatonia includes one or more of the following: negativity, mutism, stupor, and pathological agitation.

[0044] Preferably, in the psychosis symptoms, the irritability includes one or more of the following: irritability, impatience, anger, sadness, anger, excitement, aggression, and temper tantrums.

[0045] Furthermore, the present invention provides a method for preventing and / or treating psychosis symptoms, comprising the step of administering a pharmaceutical composition or drug formulation containing a preventive and / or therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof to an individual in need.

[0046] Furthermore, in the above method, in addition to glyclazide or a pharmaceutically acceptable salt thereof, the pharmaceutical composition or pharmaceutical preparation optionally further comprises one or more other pharmaceutically active ingredients and / or optionally one or more pharmaceutically acceptable additives.

[0047] <Fourth Phase> The present invention provides a pharmaceutical composition or drug formulation for preventing and / or treating psychotic symptoms, comprising gliclazide or a pharmaceutically acceptable salt thereof.

[0048] Furthermore, the aforementioned psychosis symptoms are associated with schizophrenia and one or more other disorders for which antipsychotic drugs may be used.

[0049] Furthermore, the psychotic symptoms include one or more of the following: delusions, hallucinations, disorganized thoughts (language), agitation, severely disorganized or abnormal motor behavior (including catatonia), and irritability.

[0050] Furthermore, the aforementioned psychotic symptoms include one or more of the following: delusions, hallucinations, and agitation.

[0051] Preferably, in the psychosis symptoms, the delusion includes one or more of the following: persecutory delusions, delusions of reference, somatic delusions, grandiose delusions, loving delusions, nihilistic delusions, and jealous delusions.

[0052] Preferably, in the psychosis symptoms, the hallucinations include one or more of the following: auditory hallucinations, visual hallucinations, gustatory hallucinations, olfactory hallucinations, tactile hallucinations, and somatic hallucinations.

[0053] Preferably, in the psychosis symptoms, the disorganized thoughts (language) include one or more of the following: disorganized thoughts and disorganized conversations.

[0054] Preferably, in the psychosis symptoms, the agitation includes one or more of the following: increased aimless motor activity, marked restlessness, aggression, and emotional instability.

[0055] Preferably, in the psychosis symptoms, the severely disorganized or abnormal motor behavior (including catatonia) includes one or more of the following: marked confusion or abnormal motor behavior and catatonia.

[0056] More preferably, in the severely disorganized or abnormal motor behavior (including catatonia), the catatonia includes one or more of the following: negativity, mutism, stupor, and pathological agitation.

[0057] Preferably, in the psychosis symptoms, the irritability includes one or more of the following: irritability, impatience, anger, sadness, anger, excitement, aggression, and temper tantrums.

[0058] Furthermore, in addition to glyclazide or a pharmaceutically acceptable salt thereof, the pharmaceutical composition or pharmaceutical preparation may further optionally contain one or more other pharmaceutically active ingredients and / or one or more pharmaceutically acceptable additives. [Effects of the Invention]

[0059] The gliclazide or its derivatives in this invention are useful for the prevention and / or treatment of psychotic symptoms such as hallucinations, delusions, and agitation. [Brief explanation of the drawing]

[0060] [Figure 1] Figure 1 shows the inhibitory effect of gliclazide on the increase in spontaneous motility in mice induced by MK-801. [Figure 2] Figure 2 shows the ameliorative effect of gliclazide on MK-801-induced prepulse suppression impairment. [Modes for carrying out the invention]

[0061] Definition of Terms The following describes exemplary embodiments of the present invention in detail. The term "exemplary" as used in this invention means "used as an example, embodiment, or description," unless otherwise specified, and an embodiment described as "exemplary" is not necessarily construed as preferable to other embodiments. Furthermore, some specific details are provided in the following specific embodiments to better illustrate the present invention. Those skilled in the art should understand that the present invention can be effectively implemented even without these specific details.

[0062] Unless otherwise specified, the numerical values ​​or numerical ranges in this invention should be understood to include unavoidable systematic errors in industrial production, and the numerical range expressed as "numerical value A to numerical value B" represents a range that includes the limit values ​​numerical values ​​A and B.

[0063] Unless otherwise specified, all units used in this invention are International Standard Units.

[0064] As used in this invention, the terms "may" or "may" mean, unless otherwise specified, that a particular process may or may not be performed in a subsequent step or process. Similarly, the terms "may," "either," "optionally," or "optionally" mean that the events or circumstances described below may occur, but are not necessarily required, and this description includes both cases in which such events or circumstances occur and cases in which they do not.

[0065] The terms "several specific / preferred embodiments," "other specific / preferred embodiments," and "embodiments" used herein, unless otherwise specified, mean that certain elements (e.g., features, structures, and / or properties) related to the described embodiment are included in at least one embodiment described herein and may or may not be present in other embodiments. Furthermore, those skilled in the art should understand that such elements may be combined in any suitable manner in various embodiments.

[0066] The term "glyclazide or a pharmaceutically acceptable salt thereof" as used in this invention is not limited to specific isomers (stereoisomers, tautomers, etc.) unless otherwise specified. Furthermore, the term "glyclazide or a pharmaceutically acceptable salt thereof" as used in this invention may be replaced with isotopically labeled products.

[0067] Furthermore, the term "gliclazide or a pharmaceutically acceptable salt thereof" as used in this invention may also refer to its active metabolite or prodrug.

[0068] Furthermore, the term "glyclazide or a pharmaceutically acceptable salt thereof" as used in this invention may also refer to solvates. This invention also encompasses such various solvates.

[0069] As used in this invention, the terms “pharmaceutically acceptable salt” or “medicinal salt” mean, unless otherwise specified, a salt that, within the bounds of sound medical judgment, is suitable for use in contact with mammalian (especially human) tissue without excessive toxicity, irritation, or allergic reactions, and that has a reasonable benefit-risk ratio. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds (e.g., amides, ureids, etc.) are well known in the art. Such salts may be prepared in situ during the final isolation and purification of the compounds of this invention, or they may be prepared separately by reacting a free base or free acid with a suitable reagent. Examples of pharmaceutically acceptable base addition salts of the present invention include, but are not limited to, alkali metal salts (e.g., lithium salt, sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., magnesium salt, calcium salt, barium salt, etc.), transition metal salts (e.g., zinc salt, iron salt, etc.), ammonium salts of glyclazide or its derivatives, and salts of these with organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, methylamine, ethylenediamine, pyridine, methylpyridine, quinoline, etc.) or basic amino acids (e.g., lysine, arginine, histidine, etc.). Examples of pharmaceutically acceptable acid addition salts in the present invention include, but are not limited to, salts formed by glyclazide or its derivatives with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.), or acidic amino acids (e.g., glutamic acid, aspartic acid, etc.).

[0070] As used in this invention, the terms “solvide” or “solvate” mean, unless otherwise specified, a physical bond between the compound of the invention and one or more solvent molecules (whether organic or inorganic). This physical bond includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be isolated. The solvent molecules in the solvate may exist in regular and / or irregular arrangements. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. “Solvate” includes the solution phase and the isolateable solvate. Exemplary examples of solvates include, but are not limited to, hydrates, ethanol dihydrates, methanol dihydrates, and isopropanol dihydrates. Furthermore, solvation methods are well known to those skilled in the art.

[0071] As used in this invention, the term "stereoisomer" includes geometric isomers, configuration isomers, conformational isomers, etc., unless otherwise specified. Here, "geometric isomer" (especially "cis / trans isomer") refers to isomers containing a carbon-carbon or carbon-nitrogen double bond in an E or Z configuration. Here, "E" indicates that the higher-order substituent is on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and "Z" indicates that the higher-order substituent is on the same side of the carbon-carbon or carbon-nitrogen double bond, and their order can be determined by the Kahn-Ingold-Prelogue order rule. The compounds of this invention may also exist as mixtures of "E" isomers and "Z" isomers.

[0072] As used in this invention, the term "tautomer" means isomers having different energies and being convertible to each other via low barriers, unless otherwise specified. If tautomerism is possible (for example, in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called proton transfer tautomers) include tautomers that are converted to each other via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and amide-imino alcohol isomerization. Valence tautomers include tautomers that are converted to each other by rearrangement of bonding electrons.

[0073] Furthermore, the structural formulas described in the present invention include all isomers (geometric isomers, conformational isomers, tautomers, etc.). Therefore, any single stereochemical isomer of the compounds of the present invention, or a mixture of its geometric isomers, conformational isomers and / or tautomers, is included within the scope of the present invention.

[0074] As used herein, the term "isotope derivative" means that, unless otherwise specified, the compounds of the present invention can exist in a form labeled with an isotope or an isotopically enriched form, and contain one or more atoms different from the atomic weight or mass number of the atom with the highest natural abundance. The isotopes may be radioactive isotopes or non-radioactive isotopes. Isotopes commonly used as isotope labels include hydrogen isotopes: 2 H and 3 H, carbon isotopes: 13 C and 14 C, chlorine isotopes: 35 Cl and 37 Cl, fluorine isotopes: 18 F, iodine isotopes: 123 I and 125 I, nitrogen isotopes: 13 N and 15 N, oxygen isotopes: 15 O, 17 O and 18 O, and sulfur isotopes: 35 S, etc., but are not limited thereto. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, 2 H and 13 C are widely used because they are easy to label and detect.

[0075] As used in this invention, the terms "active metabolite" or "active metabolite product" refer to molecules with a certain level of physiological activity that are produced by the metabolism of a pharmaceutical product, unless otherwise specified. Some drug molecules can continue to affect the body even after being metabolized in a subject's body. These effects are usually equivalent to or weaker than those of the original drug molecule, but can still be considerable. In addition, some drugs are initially inactive but are designed to produce active components only after being metabolized in the body. Such drugs are called prodrugs. Drugs are designed in this way because prodrugs are more stable during manufacturing and storage, or because they are better absorbed in the body and have superior pharmacokinetic properties.

[0076] As used in this invention, the term “prodrug” means a drug that is converted to a parent drug in the body unless otherwise specified. Prodrugs are generally useful and can improve certain undesirable physical or biological properties. Physical properties are usually related to solubility (excessive or insufficient solubility in lipids or water) or stability, while biological properties of concern may include excessively rapid metabolism or low bioavailability, which may themselves be related to physicochemical properties. For example, a prodrug can be utilized in the body orally, whereas a parent drug cannot be utilized orally. The solubility of a prodrug in a pharmaceutical composition is also improved compared to the parent drug. Exemplary examples of prodrugs include, but are not limited to, any compound of this invention that is administered as an imide or hydrazine ("prodrug") to promote cell membrane permeability and is hydrolyzed into an active substance upon entering the cell.

[0077] Furthermore, the technical scope of the present invention also includes stereoisomers, tautomers, isotope-labeled compounds, active metabolites, or prodrugs of glyclazide, as well as pharmaceutical compositions or drug formulations containing stereoisomers, tautomers, isotope-labeled compounds, active metabolites, or prodrugs of glyclazide.

[0078] Furthermore, pharmaceutical compositions or drug formulations comprising stereoisomers, tautomers, isotope-labeled compounds, active metabolites, or prodrugs of glyclazide, as well as pharmaceutically acceptable salts of stereoisomers, tautomers, isotope-labeled compounds, active metabolites, or prodrugs of glyclazide, are also included in the technical scope of the present invention.

[0079] Furthermore, the technical scope of the present invention also includes glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites, or solvates of prodrugs, as well as pharmaceutical compositions or drug formulations containing glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites, or solvates of prodrugs.

[0080] Furthermore, pharmaceutical compositions or drug formulations comprising glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites, or solvates of pharmaceutically acceptable salts of prodrugs are also included in the technical scope of the present invention.

[0081] As used in this invention, the terms “active pharmaceutical ingredient” (API), “pharmaceutical active entity,” or “pharmaceutical active molecule” mean, unless otherwise specified, any substance or mixture of substances used to prepare a pharmaceutical, which may exert pharmacological activity or other direct related effects in the prevention, diagnosis, treatment, or relief of disease, or may affect the physical function or structure of a subject. Furthermore, in this invention, pharmaceuticals manufactured using an active pharmaceutical ingredient (e.g., gliclazide or its derivatives) are useful and may, for example, be pharmaceuticals that alleviate side effects (e.g., extrapyramidal symptoms).

[0082] As used in the present invention, the term "pharmaceutical composition" means, unless otherwise specified, a composition comprising a specific pharmacovigilant active ingredient and optionally one or more other pharmacovigilant active ingredients and / or optionally one or more pharmaceutically acceptable additives, wherein the components in the composition may be physically mixed or separated. Unless otherwise specified, the term "pharmaceutically acceptable additive" has meanings familiar to those skilled in the art and includes, but is not limited to, diluents (or fillers), lubricants, binders, disintegrants, stabilizers, surfactants, flavoring agents, odoring agents, solvents, co-solvents, pH adjusters, osmotic pressure adjusters, etc.

[0083] The pharmaceutical composition of the present invention is administered to individuals requiring it by either oral or parenteral administration.

[0084] Furthermore, by appropriately changing the effective amount, dosage form, and / or various pharmaceutical additives of the compound of the present invention, the pharmaceutical composition can be made into a pharmaceutical formulation suitable for children, the elderly, critically ill patients, or surgical patients.

[0085] As used in this invention, the term "pharmaceutical preparation" means, unless otherwise specified, a specific finished pharmaceutical product prepared in accordance with a certain dosage form, comprising one type of pharmacovigilant active ingredient and optionally one or more other pharmacovigilant active ingredients and / or optionally one or more pharmaceutically acceptable additives. Unless otherwise specified, the term "dosage form" has meanings familiar to those skilled in the art and includes, but is not limited to, tablets, capsules, granules, lozenges, suppositories, ointments, creams, injections, suspensions, compounded medicines, tinctures, topical medicines, lotions, inhalants, aerosols, and the like.

[0086] As used in this invention, the term "treatment" means eliminating, alleviating, or improving a disease or condition and / or symptoms associated therewith, unless otherwise specified. Treatment of a disease or condition does not necessarily require the complete elimination of the associated disease, condition, or symptoms. The term "treatment" may refer to administering a therapeutically effective amount of a medicinal active ingredient to an individual in need of such treatment. Treatment may be symptomatic, such as symptom suppression. Treatment may be short-term, medium-term, or long-term, such as maintenance therapy.

[0087] As used in this invention, the term “prevention” means, unless otherwise specified, avoiding the onset of a disease or illness and / or associated symptoms in an individual, or preventing an individual from contracting a disease or illness and / or associated symptoms, and further includes delaying the onset of a disease and / or associated symptoms in an individual, and reducing the risk of an individual contracting a disease and / or associated symptoms. Furthermore, the term “prevention” further includes “preventive treatment,” which means reducing the probability of further progression or recurrence of a disease or symptom in an individual who is at risk or prone to such progression or recurrence, without further progression of the disease or symptom or a recurrence of a previously controlled disease or symptom.

[0088] As used in this invention, the term "effective dose" means the amount of drug that can perform a role consistent with the preventive and / or therapeutic purpose, or achieve the corresponding effect, unless otherwise specified. For example, the "effective dose" and dosage can be determined considering the patient's age, weight, sex, type and severity of the disease, route of administration, etc. In the case of gliclazide or its derivatives in this invention, the daily dose can be, for example, about 1 mg to about 3000 mg, or about 1 mg to about 2000 mg, or about 100 mg to about 2000 mg, and the single dose can be, for example, about 1 mg to about 3000 mg, or about 1 mg to about 2000 mg, or about 100 mg to about 2000 mg.

[0089] The term "psychosis symptoms" as used in this invention, unless otherwise specified, is based on the Diagnostic and Statistical Manual of Mental Disorders (5th Edition) (abbreviated as DSM-V or DSM-5), and includes delusions, hallucinations, disorganized thinking (language), agitation, severely disorganized or abnormal motor behavior (including catatonia), and irritability, but does not include cognitive impairment.

[0090] As used herein, the term “delusion” refers, unless otherwise specified, to a fixed belief that remains unchanged despite conflicting evidence, or a false belief held in the absence of evidence or proof. Delusions can encompass a variety of themes, including persecutory delusions, delusions of reference, somatic delusions, and grandiose delusions. Specifically, persecutory delusions (e.g., the belief that one is being harmed or humiliated by another person, organization, or group) are the most common. Delusions of reference (e.g., the belief that a particular gesture, statement, or environmental factor is directed at oneself) are also common. Grandiose delusions (e.g., the belief that one possesses extraordinary power, wealth, or fame) and pederasty delusions (e.g., the false belief that another person is in love with oneself) are also seen. Nihilistic delusions include the belief that a major disaster is about to occur. Somatic delusions are beliefs about health or organ function. Delusions of jealousy, also known as Othello syndrome, are pathological beliefs that one's spouse or lover is unfaithful. Patients typically don't take any measures to obtain evidence of infidelity (such as hiring a private detective or installing a video camera at home to secretly film their partner), but rather collect trivial evidence (such as dirty clothes or stained sheets) and make erroneous inferences to prove their delusions are true. The delusions are bizarre, clearly untrue, incomprehensible to individuals from the same cultural background, and not based on everyday experiences.

[0091] As used in this invention, the term "hallucinations" refers, unless otherwise specified, to sensory experiences that occur in the absence of actual external stimuli. These experiences are clear and vivid, possess all the elements of normal sensation, and are not subject to voluntary control. Hallucinations can occur in any sensory mode (e.g., auditory, visual, gustatory, olfactory, tactile, or somatic hallucinations), but auditory hallucinations (also called auditory hallucinations) are the most common in schizophrenia and related disorders. Auditory hallucinations are usually experienced as voices distinct from the person's own thoughts, regardless of whether the voices are familiar or not. Since hallucinations must occur while awake, hallucinations that occur just before falling asleep (before going to sleep) or just before waking up (before waking up) are considered normal experiences.

[0092] As used in this invention, the term “disorganized thinking / speech” refers to a state of confusion in an individual’s thinking or speech, unless otherwise specified. Generally, disorganized thinking (formal thought disorder) refers to illogical, irrelevant, or loosely related thoughts inferred from an individual’s speech. An individual may jump from one topic to another (thought digression or loose association). Answers to questions may be irrelevant or completely irrelevant (contact thinking digression). An individual’s speech may be so severely confused that it is completely incomprehensible, and its linguistic construction may be illogical, similar to sensory aphasia (incoherence or “word salad”). Mild language confusion is common, so the symptom needs to be somewhat severe to affect effective communication. Assessing the severity of symptoms can be very difficult when the evaluator and subject have different cultural backgrounds. Mild thinking or language disorders may appear in the pre-symptomatic and residual stages of schizophrenia.

[0093] As used in this invention, the term "agitation" refers, unless otherwise specified, to a behavioral syndrome characterized by increased aimless motor activity, marked restlessness, aggression, and emotional instability.

[0094] As used in this invention, the term “grossly disorganized or abnormal motor behavior (including catatonia)” is divided into the following two aspects unless otherwise specified: (1) Grossly disorganized or abnormal motor behavior can manifest as a variety of behaviors, ranging from childlike “silliness” to unpredictable agitation. Individuals may have difficulty with any goal-oriented behavior, which can interfere with daily life. (2) Catatonia is a state of significantly reduced responsiveness to the environment and includes resistance to instructions (rejection), maintenance of rigid and bizarre postures, and complete absence of verbal and motor responses (mutism and stupor). It also includes aimless and excessive motor behavior (catatonia) without any apparent trigger. Other features include stereotypic movements, staring, grimacing, mutism, and echolalia. While catatonia has historically been associated with schizophrenia, catatonic symptoms are not unique to schizophrenia and can also be present in other mental disorders (e.g., bipolar disorder or depression with catatonic symptoms) or physical illnesses (catatonia caused by other physical illnesses).

[0095] As used in this invention, the term "irritability" refers to intense but short-lived emotional disorders, including, but not limited to, irritability, impatience, anger, sadness, anger, agitation, aggression, and temper tantrums, unless otherwise specified.

[0096] As used in this invention, the term "schizophrenia" adopts the definition of "schizophrenia spectrum and other psychotic disorders" as defined in the Diagnostic and Statistical Manual of Mental Disorders (5th Edition) (abbreviated as DSM-V or DSM-5), unless otherwise specified. This definition includes schizophrenia, other psychotic disorders and ataxic (personality) disorders, which can be identified by one or more of five abnormalities: delusions, hallucinations, disorganized thinking (language), severely disorganized or abnormal motor behavior (including catatonia), and negative symptoms.

[0097] As used in this invention, the term "other diseases for which antipsychotic drugs may be used" includes, but is not limited to, bipolar disorder and related disorders, autism spectrum disorder, depressive disorder, substance-related disorders and addiction disorders, and dementia, unless otherwise specified.

[0098] As used in this invention, the term "bipolar and related disorders" refers, unless otherwise specified, to a type of mood disorder characterized by both manic or hypomanic episodes and depressive episodes, generally exhibiting an episodic course in which mania and depression occur repeatedly, alternately, or in a mixed state. The symptoms of each episode often persist for a certain period, negatively impacting the patient's daily life and social functioning. This includes, but is not limited to, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar and related disorders, bipolar and related disorders due to other medical conditions, other specific bipolar and related disorders, and unspecified bipolar and related disorders.

[0099] As used in this invention, the terms “autism spectrum disorder” or “autism spectrum disorder” refer, unless otherwise specified, to persistent deficits in social communication and social interaction in a variety of contexts, including deficits in social interaction, deficits in the use of nonverbal communication in social interaction, and deficits in the development, maintenance, and understanding of interpersonal skills. In addition to deficits in social communication, a diagnosis of autism spectrum disorder must be made possible by the presence of restricted, repetitive patterns of behavior, interests, or activities. Symptoms can change with development and may be masked by compensatory mechanisms, so while the diagnostic criteria may be met based on past information, current clinical symptoms should cause a significant impairment.

[0100] As used in this invention, the term "depressive disorder" refers, unless otherwise specified, to a type of mood disorder characterized primarily by a depressed mood, and includes, but is not limited to, destructive mood disorder, major depressive disorder (including major depressive episodes), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to other medical conditions, and other specific or unspecified depressive disorders.

[0101] As used in this invention, the terms “substance-related disorders and addictive disorders” refer to a group of physiological, behavioral, and cognitive symptoms, including, but not limited to, substance-related disorders (including, but not limited to, alcohol-related disorders, caffeine-related disorders, cannabis-related disorders, hallucinogenic drug-related disorders, inhalant-related disorders, opioid-related disorders, sedative, hypnotic or anxiolytic-related disorders, psychostimulant-related disorders, tobacco-related disorders, and other (or unknown) substance-related disorders) and non-substance-related disorders (including gambling disorders).

[0102] As used in this invention, the term "dementia" refers, unless otherwise specified, to a syndrome characterized by acquired cognitive impairment that results in a significant decline in a patient's daily living abilities, learning abilities, work abilities, and social interaction abilities. Cognitive impairment in patients includes impairments in memory, learning, orientation, comprehension, judgment, calculation, language, visuospatial function, and problem-solving abilities. In the DSM-5, dementia is described as a "neurocognitive disorder." Dementia is divided into degenerative and non-degenerative dementias. The former primarily includes Alzheimer's disease (AD), Lewy body dementia (DLB), Parkinson's disease (PDD), and frontotemporal dementia (FTLD).

[0103] Medical uses of gliclazide First, the present invention provides novel applications for glyclazide or its derivatives in the pharmaceutical field.

[0104] Specifically, the present invention provides the use of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or pharmaceutically acceptable salts of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or solvates of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs in the manufacture of pharmaceuticals for the prevention and / or treatment of psychosis symptoms.

[0105] In some embodiments, the psychotic symptoms described above may be associated with schizophrenia and one or more other disorders for which antipsychotic drugs may be used.

[0106] In some specific embodiments, the psychosis symptoms described above may be associated with, or only with, schizophrenia.

[0107] In some specific embodiments, the psychotic symptoms described above may be associated with, or only with, other conditions for which antipsychotic drugs may be used.

[0108] In some specific embodiments, the psychosis symptoms described above may be associated with at least bipolar disorder and related disorders, or may be associated only with bipolar disorder and related disorders.

[0109] In some specific embodiments, the psychosis symptoms described above may be associated with at least autism spectrum disorder, or may be associated solely with autism spectrum disorder.

[0110] In some specific embodiments, the psychosis symptoms described above may be associated with, or only with, a group of depressive disorders.

[0111] In some specific embodiments, the psychosis symptoms described above may be associated with at least substance-related disorders and addictive disorders, or may be associated with substance-related disorders and addictive disorders alone.

[0112] In some specific embodiments, the psychosis symptoms described above may be associated with, or only with, dementia (such as Alzheimer's disease or Parkinson's disease).

[0113] In some embodiments, the psychotic symptoms described above may include a variety of specific symptoms, such as delusions, hallucinations, disorganized thoughts (language), agitation, severely disorganized or abnormal motor behavior (including catatonia), and one or more types of irritability.

[0114] In some specific embodiments, the psychotic symptoms described above may include delusions, or they may consist solely of delusions.

[0115] In some more specific embodiments, the above-mentioned delusions may include a variety of specific symptoms, such as one or more of the following: persecutory delusions, delusions of reference, somatic delusions, grandiose delusions, loving delusions, nihilistic delusions, and jealousy delusions.

[0116] In some more specific embodiments, the above-mentioned delusion may include paranoid delusions, or it may consist solely of paranoid delusions.

[0117] In some more specific embodiments, the above delusion may include delusions of reference, or it may consist solely of delusions of reference.

[0118] In some more specific embodiments, the above-mentioned delusion may include somatic delusions, or it may consist solely of somatic delusions.

[0119] In some more specific embodiments, the delusion may include or consist solely of grandiose delusions.

[0120] In some more specific embodiments, the above delusion may include a pederasty delusion, or it may consist solely of a pederasty delusion.

[0121] In some more specific embodiments, the above-mentioned delusion may include nihilistic delusions, or it may consist solely of nihilistic delusions.

[0122] In some more specific embodiments, the above delusion may include or consist solely of a delusion of jealousy.

[0123] In some specific embodiments, the psychotic symptoms described above may include hallucinations, or they may consist solely of hallucinations.

[0124] In some more specific embodiments, the hallucinations described above may include a variety of specific symptoms, such as one or more of the following: auditory hallucinations, visual hallucinations, gustatory hallucinations, olfactory hallucinations, tactile hallucinations, and somatic hallucinations.

[0125] In some more specific embodiments, the hallucinations described above may include auditory hallucinations, or they may consist solely of auditory hallucinations.

[0126] In some more specific embodiments, the hallucination may include or consist solely of visual hallucinations.

[0127] In some more specific embodiments, the hallucination may include a taste hallucination, or it may consist solely of a taste hallucination.

[0128] In some more specific embodiments, the hallucination may include or may consist solely of olfactory hallucinations.

[0129] In some more specific embodiments, the hallucination may include tactile hallucinations, or it may consist solely of tactile hallucinations.

[0130] In some more specific embodiments, the hallucination may include or consist solely of somatic hallucinations.

[0131] In some specific embodiments, the psychotic symptoms described above may include distorted thoughts (language), or they may consist solely of distorted thoughts (language).

[0132] In some more specific embodiments, the deconstructed thoughts (language) may include a variety of specific symptoms, such as one or more of the following: disorganized thoughts and disorganized conversations.

[0133] In some more specific embodiments, the deconstructed thoughts (language) may include disorganized thoughts, or may consist solely of disorganized thoughts.

[0134] In some more specific embodiments, the deconstructed thoughts (language) may include or consist solely of disjointed conversation.

[0135] In some specific embodiments, the psychotic symptoms described above may include agitation, or may consist solely of agitation.

[0136] In some specific embodiments, the agitation may include a variety of specific symptoms, such as increased aimless motor activity, marked restlessness, aggression, and emotional instability, one or more of these.

[0137] In some more specific embodiments, the above-mentioned exertion may include, or may consist solely of, an increase in aimless physical activity.

[0138] In some more specific embodiments, the agitation may include, or may consist solely of, extreme restlessness.

[0139] In some more specific embodiments, the above aggression may include or consist solely of aggression.

[0140] In some more specific embodiments, the agitation may include, or may consist solely of, emotional instability.

[0141] In some specific embodiments, the psychotic symptoms described above may include severe disarray or abnormal motor behavior (including catatonia), or may consist solely of severe disarray or abnormal motor behavior (including catatonia).

[0142] In some more specific embodiments, the severely disorganized or abnormal motor behavior (including catatonia) described above may include a variety of specific symptoms, such as markedly confused or abnormal motor behavior and one or more types of catatonia.

[0143] In some more specific embodiments, the severely disorganized or abnormal motor behavior (including catatonia) described above may include marked confusion or abnormal motor behavior, or may consist solely of marked confusion or abnormal motor behavior.

[0144] In some more specific embodiments, the severely disorganized or abnormal motor behaviors described above (including catatonia) may include catatonia or may consist solely of catatonia.

[0145] In some specific embodiments, the catatonia may include a variety of specific symptoms, such as one or more of the following: negativity, mutism, stupor, and catatonic agitation.

[0146] In some specific embodiments, the catatonia described above may include or consist solely of rejection.

[0147] Furthermore, in some specific embodiments, the catatonia described above may include mutism, or it may consist solely of mutism.

[0148] In some specific embodiments, the catatonia may include stupor, or it may consist solely of stupor.

[0149] Furthermore, in some specific embodiments, the catatonia described above may include pathological excitement, or may consist solely of pathological excitement.

[0150] In some specific embodiments, the psychosis symptoms described above may include irritability, or may consist solely of irritability.

[0151] In some more specific embodiments, the above-mentioned irritability may include or consist solely of irritability.

[0152] In some more specific embodiments, the above-mentioned irritability may include or consist solely of restlessness.

[0153] In some more specific embodiments, the above-mentioned irritability may include anger, or may consist solely of anger.

[0154] In some more specific embodiments, the above-mentioned irritability may include sadness, or may consist solely of sadness.

[0155] In some more specific embodiments, the above-mentioned irritability may include irritability, or it may consist solely of irritability.

[0156] In some more specific embodiments, the above-mentioned irritability may include or consist solely of excitation.

[0157] In some more specific embodiments, the above irritability may include aggression, or may consist solely of aggression.

[0158] In some more specific embodiments, the above-mentioned irritability may include or may consist solely of tantrums.

[0159] Gliclazide or its derivatives exist not only in the form of monomer compounds or mixtures of monomer compounds, but can also be further manufactured into pharmaceutical compositions or drug formulations (particularly pharmaceutical compositions or drug formulations for the prevention and / or treatment of psychotic symptoms). Accordingly, the present invention also provides for the use of pharmaceutical compositions or drug formulations containing glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or pharmaceutically acceptable salts of glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or solvates of glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs in the manufacture of pharmaceuticals for the prevention and / or treatment of psychotic symptoms.

[0160] In some specific embodiments, the pharmaceutical composition or pharmaceutical preparation may further optionally contain one or more other pharmaceutically active ingredients and / or one or more pharmaceutically acceptable additives.

[0161] In some more specific embodiments, the pharmaceutical composition or pharmaceutical preparation may optionally further contain one or more other active pharmaceutical ingredients (or may optionally contain only one or more other active pharmaceutical ingredients).

[0162] In some more specific embodiments, the pharmaceutical composition or pharmaceutical preparation may further contain one or more pharmaceutically acceptable additives (or may contain only one or more pharmaceutically acceptable additives).

[0163] In some specific embodiments, the pharmaceutical composition or pharmaceutical preparation may further optionally contain one or more other active pharmaceutical ingredients and one or more pharmaceutically acceptable additives (or may contain only one or more other active pharmaceutical ingredients and one or more pharmaceutically acceptable additives).

[0164] In some specific embodiments, the glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or pharmaceutically acceptable salts of the glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or solvates of the glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, is the sole active pharmaceutical ingredient in the pharmaceutical product.

[0165] Furthermore, the present invention provides novel pharmaceutical applications for glyclazide or its derivatives.

[0166] Specifically, the present invention provides gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs used for the prevention and / or treatment of psychosis symptoms, or pharmaceutically acceptable salts of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or solvates of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs.

[0167] In some specific embodiments, the psychosis symptoms have the same meaning as the psychosis symptoms described in the novel applications in the pharmaceutical field mentioned above.

[0168] Gliclazide or its derivatives may exist not only in the form of monomer compounds or mixtures of monomer compounds, but may also be manufactured into pharmaceutical compositions or drug formulations containing them. Accordingly, the present invention also provides pharmaceutical compositions or drug formulations containing glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or pharmacogally acceptable salts of glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or solvates of glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, for use in the prevention and / or treatment of psychosis symptoms.

[0169] In some specific embodiments, the pharmaceutical composition or drug formulation has the same meaning as the pharmaceutical composition or drug formulation described in the novel applications in the pharmaceutical field described above.

[0170] In some specific embodiments, glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or pharmaceutically acceptable salts of glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or solvates of glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, are used alone or as the sole active pharmaceutical ingredient.

[0171] Finally, the present invention provides novel applications for gliclazide or its derivatives in the field of disease prevention and treatment methods.

[0172] Specifically, the present invention provides a method for preventing and / or treating psychosis symptoms, comprising the step of administering a prophylactic and / or therapeutically effective amount of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or pharmaceutically acceptable salts of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or solvates of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs to an individual in need thereof.

[0173] In some specific embodiments, the individuals requiring it may include vertebrates (e.g., fish, amphibians, reptiles, birds, mammals, etc.) or may consist solely of vertebrates.

[0174] In some more specific embodiments, the individuals requiring it may include mammals (e.g., marsupials, insectivores, carnivores, chiropterans, primates, odd-toed ungulates, artiodactyls, etc.) or may be mammals only.

[0175] In some more specific embodiments, the individuals requiring it may include primates (e.g., Lorisidae, Lemuridae, Aye-ayeidae, Tarsiidae, Cebidae, Marmosets, Cercopithecidae, Gibbonidae, Hominidae, etc.) or may consist only of primates.

[0176] In some specific embodiments, the individuals requiring it may include or be exclusively hominins (e.g., orangutans, gorillas, chimpanzees, and humans).

[0177] In some specific embodiments, the individuals requiring it may include or may consist solely of animals of the genus Homo (e.g., Homo sapiens).

[0178] In some specific embodiments, the psychosis symptoms have the same meaning as the psychosis symptoms described in the novel applications in the pharmaceutical field mentioned above.

[0179] Gliclazide or its derivatives may exist not only in the form of monomer compounds or mixtures of monomer compounds, but may also be further manufactured into pharmaceutical compositions or drug formulations containing them. Accordingly, the present invention also provides a method for preventing and / or treating psychotic symptoms, comprising the step of administering a pharmaceutical composition or drug formulation containing glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or pharmaceutically acceptable salts of glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or solvates of glyclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs to an individual in need thereof.

[0180] In some specific embodiments, the pharmaceutical composition or drug formulation has the same meaning as the pharmaceutical composition or drug formulation described in the novel applications in the pharmaceutical field described above.

[0181] In some specific embodiments, gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or pharmaceutically acceptable salts of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, or solvates of gliclazide or its stereoisomers, tautomers, isotope-labeled compounds, active metabolites or prodrugs, are administered to the individual requiring them as the sole active pharmaceutical ingredient.

[0182] The present invention will be further described below with reference to specific examples. In the following examples, experimental methods for which specific conditions are not explicitly stated shall follow normal conditions or conditions recommended by the manufacturer. Furthermore, all methods and materials similar or equivalent to those described can be applied to the methods of the present invention.

[0183] Effectiveness evaluation based on the MK-801 mouse model 1. Using the MK-801 model, a common nonclinical evaluation system for assessing the improvement of psychosis symptoms, we evaluated the inhibitory effect of gliclazide on the increase in spontaneous motility in mice induced by MK-801.

[0184] 1.1 Experimental Materials 1.1.1 Animals C57BL / 6J mouse, 7 weeks old, male. Before the experiment, the mice were allowed to acclimate to the environment for one week. After that, each mouse underwent a health check, which included evaluation of their fur, limbs, and mouthparts, as well as examinations for any abnormalities in posture or movement.

[0185] 1.1.2 Pharmaceuticals Methylcellulose; MK-801 (also known as Dizocilpine); Glyclazide.

[0186] 1.2 Experimental Procedure 1.2.1 Preparation of pharmaceuticals 1.2.1.1 Preparation of MK-801 solution Measure an appropriate amount of MK801 into a clean test tube, add an appropriate amount of physiological saline, and sonicate and vortex the solution until it becomes clear. This solution has a concentration of 0.2-0.3 mg / mL and should be stored at -20°C for later use. Transfer an appropriate amount of the MK801 solution to another clean test tube, dilute it with an appropriate amount of physiological saline to obtain an MK801 solution with a concentration of 0.02-0.03 mg / mL. When administering (e.g., intraperitoneal injection), the dose should be 10 mL / kg.

[0187] 1.2.1.2 Preparation of glyclazide solution A suitable amount of gliclazide is weighed into a clean test tube, a suitable amount of 0.5% w / v methylcellulose aqueous solution is added, and the solution is sonicated and vortexed until it becomes clear. This process is repeated three times in parallel to prepare gliclazide solutions with concentrations of 8 mg / mL, 16 mg / mL, and 32 mg / mL, respectively. When administering (by oral administration or gastric tube administration, etc.), the dose is 10 mL / kg, which corresponds to 80 mg / kg, 160 mg / kg, and 320 mg / kg for the low-dose, medium-dose, and high-dose groups of gliclazide, respectively.

[0188] 1.2.2 Administration and Efficacy Monitoring As an induction, mice were intraperitoneally injected with MK-801 solution (dosage: 0.2-0.3 mg / kg body weight), and the increase in spontaneous motility of the mice was measured (this parameter can be used as a behavioral indicator of psychosis symptoms).

[0189] Sixty minutes before MK-801 administration, mice in the negative control group and the low-dose, medium-dose, and high-dose gliclazide groups (8 mice per group) were orally administered gliclazide solutions at doses of 0, 80, 160, and 320 mg / kg body weight, respectively. Then, within 10 minutes from 10 to 20 minutes after MK-801 administration, the increase in spontaneous motility in each group of mice was measured.

[0190] 1.3 Experimental Results Figure 1 ( *** The experimental results shown, using the Kruskal-Wallis test and subsequent Conover test (representing p<0.001 compared to the negative control group), indicate that gliclazide can significantly suppress the increase in spontaneous motility in mice induced by MK-801.

[0191] 2. The ameliorative effect of gliclazide on prepulse suppression disorders. Currently, psychotic symptoms associated with schizophrenia are known to be related to cognitive function. In this invention, we investigated the effect of gliclazide on sensorimotor gating disorders in the MK-801 mouse model.

[0192] 2.1 Experimental Materials 2.1.1 Animals This is the same as item 1.1.1. 2.1.2 Pharmaceuticals This is the same as item 1.1.2.

[0193] 2.2 Experimental Procedure 2.2.1 Preparation of pharmaceuticals 2.2.1.1 Preparation of MK-801 solution This is the same as item 1.2.1.1. 2.2.1.2 Preparation of glyclazide solution This is the same as item 1.2.1.2.

[0194] 2.2.2 Administration and Efficacy Monitoring Sixty minutes prior to MK-801 administration, mice in the sham surgery group, negative control group, low-dose group, medium-dose group, and high-dose group (8 mice in the sham surgery group, and 10 mice each in the other four groups) were orally administered gliclazide solutions at doses of 0, 0, 80, 160, and 320 mg / kg body weight, respectively. Subsequently, the mice in the negative control group, low-dose group, medium-dose group, and high-dose group were intraperitoneally administered MK-801 solution (at a dose of 0.2-0.3 mg / kg body weight), while the mice in the sham surgery group were intraperitoneally administered the same volume of physiological saline. Twenty minutes after administration, the sensorimotor gating function of the mice was measured using a pre-pulse inhibition of the acoustic startle reflex evaluation system.

[0195] 2.2.3 Data Analysis Pre-pulse inhibition (PPI) is calculated using the following formula. (Startle response when a prepulse sound stimulus is given) / (Startle response when no prepulse sound stimulus is given) × 100%.

[0196] 2.3 Experimental Results Figure 2 ( *The experimental results shown (where p<0.05 is relative to the negative control group) indicate that gliclazide can improve prepulse inhibition impairment induced by MK-801, and that this improvement is dose-dependent within a certain range. Furthermore, the improvement effect in the high-dose (320 mg / kg) gliclazide group was more pronounced compared to the negative control group, and the results were almost equivalent to those of the sham surgery group.

[0197] While exemplary embodiments of the present invention have been described above, this is not exhaustive, and the present invention is not limited to the specific embodiments disclosed. It will be obvious to those skilled in the art that many modifications and changes can be made without departing from the scope and spirit of the specific embodiments described, and all of these fall within the scope of the present invention.

Claims

1. The use of gliclazide or a pharmaceutically acceptable salt thereof in the manufacture of pharmaceuticals for the prevention and / or treatment of psychotic symptoms.

2. The use according to claim 1, characterized in that the psychosis symptoms are associated with schizophrenia and one or more other disorders for which antipsychotic drugs may be used.

3. The use according to claim 1 or 2, characterized in that the psychosis symptoms are one or more of the following: delusions, hallucinations, disorganized thoughts (language), agitation, severely disorganized or abnormal motor behavior (including catatonia), and irritability.

4. The use according to claim 3, characterized in that the psychotic symptoms are one or more of the following: delusion, hallucination, and agitation.

5. The use according to any one of claims 1 to 4, characterized in that the glyclazide or a pharmaceutically acceptable salt thereof is the sole active pharmaceutical ingredient in the pharmaceutical.

6. Use of a pharmaceutical composition or pharmaceutical preparation comprising gliclazide or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the prevention and / or treatment of psychosis symptoms, wherein the pharmaceutical composition or pharmaceutical preparation further comprises optionally one or more other pharmaceutically active ingredients and / or optionally one or more pharmaceutically acceptable additives.

7. The use according to claim 6, characterized in that the psychosis symptoms are associated with schizophrenia and one or more other disorders for which antipsychotic drugs may be used.

8. The use according to claim 6 or 7, characterized in that the psychotic symptoms are one or more of the following: delusions, hallucinations, disorganized thinking (language), agitation, severely disorganized or abnormal motor behavior (including catatonia), and irritability.

9. The use according to claim 8, characterized in that the psychotic symptoms are one or more of the following: delusion, hallucination, and agitation.

10. The use according to any one of claims 6 to 9, characterized in that the glyclazide or a pharmaceutically acceptable salt thereof is the sole active pharmaceutical ingredient in the pharmaceutical.

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