Methods and compositions for treating epileptic disorders

Abstract

The present application relates to methods and compositions for treating epileptic disorders. The use of allosteric modulators and / or gaboxadol for treating an epileptic disorder in a subject in need thereof.

Description

[0001] This application is a divisional application of the application filed on August 10, 2017, with application number 201780057575.9 and invention title "Method and Composition for Treating Epilepsy Disorders". Cross-references to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 62 / 373,589, filed August 11, 2016, and U.S. Provisional Application No. 62 / 490,293, filed April 26, 2017, which are incorporated herein by reference in their entirety. Technical Field

[0003] Methods of using allosteric modulators and / or gaboxadol or their pharmaceutically acceptable salts to treat epileptic disorders in subjects with appropriate need. background

[0004] Allosteric modulators such as neurosteroids (e.g., ganaxolone, allopregnanolone), benzodiazepines (e.g., diazepam), and potassium channel openers (e.g., ritigabine) have been used to treat epilepsy. However, treatment with these agents is generally limited to patients who do not respond to conventional drugs. For example, allopregnanolone is currently being developed for the treatment of highly refractory status epilepticus. Additionally, diazepam is currently marketed... ® It is used in emergency situations to terminate cluster seizures in people who are taking other medications to treat epilepsy.

[0005] Gaboroxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol) (THIP) is described in EP Patent No. 0000338, EP Patent No. 0840601, and U.S. Patent Nos. 4,278,676, 4,362,731, 4,353,910, and WO 2005 / 094820. Gaboroxadol is a selective GABA... A Receptor agonists, having a receptor for GABA containing the δ subunit AReceptor preference. In the early 1980s, gabosadol was the subject of a series of experimental studies testing its efficacy as an analgesic and anti-anxiety medication, as well as its effectiveness in treating tardive dyskinesia, Huntington's disease, Alzheimer's disease, and spastic states. In the 1990s, gabosadol entered late-stage development for the treatment of insomnia, but a three-month efficacy study failed to demonstrate a significant effect on sleep onset and sleep maintenance. Furthermore, patients with a history of drug abuse who received gabosadol experienced a sharp increase in adverse psychological events. Due to these negative results, the development of gabosadol was terminated.

[0006] Parenteral dosage forms are intended for administration as injections or infusions. Common injection types are intravenous (inside a vein), subcutaneous (under the skin), and intramuscular (inside a muscle). Infusion is usually administered via the intravenous route. Parenteral preparations typically contain excipients to enhance or maintain the solubility (solvent) and / or stability of the active ingredient (buffers, antioxidants, chelating agents, cryoprotectants, and lyoprotectants). Excipients are also important in parenteral preparations to ensure safety (antimicrobial preservatives), minimize post-injection pain and irritation (tension agents), and control or prolong drug delivery (polymers). However, excipients can also have negative effects, such as loss of drug solubility, activity, and / or stability.

[0007] There remains a need in the art for safe and effective methods and pharmaceutical compositions for the treatment of epilepsy. Therefore, this disclosure provides pharmaceutical compositions and methods for use in applications involving epileptic disorders such as status epilepticus. Overview

[0008] A method is provided for treating epileptic disorders by administering a pharmaceutical composition comprising an allosteric modulator to a patient in need, wherein the epileptic disorders include epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absence seizures, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Ohtahara syndrome, Rasmussen syndrome, West syndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute repetitive seizures, benign Rolandicepilepsy, status epilepticus, refractory status epilepticus, extremely refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, increased seizure activity, or breakthrough seizures. Seizures (increased seizure activity, also known as continuous or clustered seizures) and type 1 sodium channel protein α subunit (Scn1α)-related disorders. Allosteric modulators include one or more of neurosteroids, benzodiazepines, and potassium channel openers. In embodiments, a method of treating epileptic disorders is provided, the method comprising administering to a patient with appropriate need a pharmaceutical composition comprising an allosteric modulator in combination with gabosadol or a pharmaceutically acceptable salt thereof.

[0009] This document provides a parenteral formulation of gapository or a pharmaceutically acceptable salt thereof. A method for treating epileptic disorders, including status epilepticus, with a parenteral formulation of gapository or a pharmaceutically acceptable salt thereof is provided. In an embodiment, a parenteral formulation comprising gapository or a pharmaceutically acceptable salt thereof is administered, alone or in combination with an allosteric modifier, to a patient in need of treating an epileptic disorder.

[0010] In the embodiments, a method is provided for treating epileptic disorders by administering to a patient with appropriate need a pharmaceutical composition comprising, alone or in combination with, a pharmaceutically acceptable salt of gabosadol or a gabosadol thereof, an allosteric modulator, including status epilepticus, benign Rolandoscopic epilepsy (BRE), refractory childhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome, and Lennox-Gastaut syndrome (LGS). In the embodiments, a method is provided for treating epileptic disorders by administering to a patient with appropriate need a pharmaceutical composition comprising, alone or in combination with, a pharmaceutically acceptable salt of gabosadol or a gabosadol thereof, an allosteric modulator, including status epilepticus, benign Rolandoscopic epilepsy (BRE), refractory childhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome, and Lennox-Gastaut syndrome (LGS).

[0011] The implementation plan provides a method for treating epileptic disorders characterized as type 1 sodium channel protein α subunit (Scn1a)-related disorders. Scn1a-related disorders include generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, intractable infantile partial seizures (myoclonic-astatic epilepsy), myoclonic-astatic epilepsy, severe myoclonic-pilepsy in infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-associated encephalopathy and seizures. In the embodiments, methods are provided for treating type 1 sodium channel protein α subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising an allosteric modulator to a patient in need. In the embodiments, methods are provided for treating type 1 sodium channel protein α subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising an allosteric modulator in combination with gaboroxatol or a pharmaceutically acceptable salt thereof to a patient in need. In the embodiments, methods are provided for treating type 1 sodium channel protein α subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising gaboroxatol or a pharmaceutically acceptable salt thereof in combination with an allosteric modulator to a patient in need. In the embodiments, methods are provided for treating type 1 sodium channel protein α subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising gaboroxatol or a pharmaceutically acceptable salt thereof in combination with an allosteric modulator to a patient in need. In the embodiments, methods are provided for treating type 1 sodium channel protein α subunit (Scn1a)-related disorders by administering a parenteral formulation comprising gaboroxatol or a pharmaceutically acceptable salt thereof to a patient in need. In the implementation plan, a method is provided for treating type 1 sodium channel protein α subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising an allosteric modulator in combination with a parenteral formulation comprising gabosadol or a pharmaceutically acceptable salt thereof to a patient in need.

[0012] In one implementation scheme, a combination of allosteric modulators, such as neurosteroids, benzodiazepines, or potassium channel openers, may be administered to patients in need. In another implementation scheme, a combination of one or more allosteric modulators and gaboroxadol or a pharmaceutically acceptable salt thereof may be administered to patients in need. Brief description of the attached diagram

[0013] Figure 1 The theoretical and measured solubility of Gabosado at different pH values ​​are shown.

[0014] Figure 2 This is a schematic diagram depicting the timeline used to evaluate the ability of allogestrinone, ganexone, and gabosadol to block benzodiazepine tolerance in rats in the context of status epilepticus.

[0015] Figure 3 It is a bar chart depicting the percentage protection against allogeneic ketone, ganexone, or gabosadol against dose.

[0016] Figure 4 It is a bar chart depicting dose-based 24-hour survival results for allogestrinone, ganexone, or gabosadol.

[0017] Figure 5 It is a bar chart showing the number of observed seizures in response to the dosage of allogestrinone, ganexone, or gabosadol.

[0018] Figure 6A It is a bar chart showing the weight change 24 hours after status epilepticus as a function of the percentage of loss versus the dose.

[0019] Figure 6B This is a bar chart showing the 24-hour weight loss for the 0.5 mg / kg dose group.

[0020] Figure 7 This is a schematic diagram depicting the timeline of prospective evaluation studies on the ability of allogeneic ketone, ganexone, and gabosadole to synergistically block benzodiazepine tolerance in status epilepticus in rats. Detailed description

[0021] This article describes methods for treating epileptic disorders, including epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absence seizures, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Otahara syndrome, Rasmussen syndrome, infantile spasms (or West syndrome), Lennox-Gastaut syndrome (LGS), Rett syndrome, Dravet syndrome, Doose syndrome, CDKL5 disorders, refractory childhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), essential tremor, acute recurrent seizures, benign Rolandotype epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, increased seizure activity, or sudden onset of seizures (increased seizure activity; also known as continuous or clustered seizures). The compositions and methods described herein can be used to treat epileptic disorders characterized as type 1 sodium channel protein α subunit (Scn1A)-related disorders. For example, Scn1A-related disorders include generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory infantile partial seizures, myoclonic-agnosia epilepsy, severe myoclonic epilepsy in infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome, infantile spasms, and vaccine-associated encephalopathy and seizures. The compositions and methods described herein involve allosteric modifiers and / or gaboroxadol or pharmaceutically acceptable salts thereof.

[0022] In some embodiments, a method of treating epileptic disorders may include administering a pharmaceutical composition comprising an allosteric modifier to a patient in need. In some embodiments, a method of treating epileptic disorders may include administering a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need. In some embodiments, a method of treating epileptic disorders may include administering gaboxadol or a pharmaceutically acceptable salt thereof in combination with an allosteric modifier to a patient in need. In some embodiments, a method of treating epileptic disorders may include administering a parenteral pharmaceutical preparation comprising an allosteric modifier to a patient in need. In some embodiments, a method of treating epileptic disorders may include administering a parenteral pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need. In some embodiments, a method of treating epileptic disorders may include administering a parenteral pharmaceutical composition comprising an allosteric modifier and gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need.

[0023] Many pharmaceutical products are administered at fixed doses at regular intervals to achieve therapeutic efficacy. The duration of action is reflected by the product's plasma half-life. Because efficacy often depends on sufficient exposure in the central nervous system, administration of CNS drugs with short half-lives may require frequent maintenance dosing. Advantageously, this document discloses methods for treating epileptic disorders by administering an allosteric modulator. For example, in an embodiment, a method for treating epileptic disorders is provided, the method comprising administering to a patient with appropriate need a pharmaceutical composition comprising about 0.05 mg to about 2000 mg of an allosteric modulator, wherein the composition provides an improvement lasting longer than 6 hours after administration to the patient. Advantageously, this document discloses methods for treating epileptic disorders by administering gaboroxadol or a pharmaceutically acceptable salt thereof. For example, in an embodiment, a method for treating epileptic disorders is provided, the method comprising administering to a patient with appropriate need a pharmaceutical composition comprising about 0.05 mg to about 75 mg of gaboroxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides an improvement lasting longer than 6 hours after administration to the patient.

[0024] In one embodiment, a method of treating epileptic disorders includes administering to a patient in need a pharmaceutical composition comprising about 0.05 mg to about 50 mg of gaboroxadol or a pharmaceutically acceptable salt thereof. In another embodiment, a method of treating epileptic disorders includes administering to a patient in need a pharmaceutical composition comprising about 0.1 mg to about 30 mg of gaboroxadol or a pharmaceutically acceptable salt thereof.

[0025] For example, the dosage may include amounts of gabosadol or its pharmaceutically acceptable salts in the range of approximately, for example, 0.05 mg to 50 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.1 mg to 30 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, wherein the amounts are 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg. The doses of 9 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25 mg and 30 mg are specific dosage examples.

[0026] Typically, gabosadol or a pharmaceutically acceptable salt thereof is administered once or twice daily to patients in need. The methods and compositions described herein may provide reduced dosing frequency and reduced adverse events and / or increased efficacy. In the implementation scheme, the dosage is approximately, for example, 0.05-30 mg / day, 0.1-20 mg / day, or 0.2-15 mg / day, or 0.5-10 mg / day, or 0.75-5 mg / day, for example, 0.1 mg / day, 0.2 mg / day, 0.5 mg / day, 0.75 mg / day, 1 mg / day, 1.5 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 21 mg / day, 22 mg / day, 23 mg / day, 24 mg / day, 25 mg / day, 26 mg / day, etc. mg / day, 27 mg / day, 28 mg / day, 29 mg / day, or 30 mg / day. In the implementation plan, gapoxetine or a pharmaceutically acceptable salt thereof, or a derivative or analog thereof, is administered in infants at a dose of 0.2 mg to 1 mg once daily or in adults at a dose of 1 mg to 20 mg once daily.

[0027] In the embodiments, the pharmaceutical composition comprises 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg of Gaboroxadol or a pharmaceutically acceptable salt thereof.

[0028] In the embodiments, the pharmaceutical composition comprises 5 mg to 20 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg of Gabosadol or a pharmaceutically acceptable salt thereof.

[0029] In one embodiment, the pharmaceutical composition comprises 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg of gaboroxadol or a pharmaceutically acceptable salt thereof, or multiples thereof. In another embodiment, the pharmaceutical composition comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of gaboroxadol or a pharmaceutically acceptable salt thereof.

[0030] In the implementation plan, the total amount of gaboxador or its pharmaceutically acceptable salts and / or gaboxador administered to the subject over a 24-hour period is from 1 mg to 50 mg. In the implementation plan, the total amount of gaboxador or its pharmaceutically acceptable salts and / or gaboxador administered to the subject over a 24-hour period is from 1 mg to 20 mg. In the implementation plan, the total amount of gaboxador or its pharmaceutically acceptable salts and / or gaboxador administered to the subject over a 24-hour period is 5 mg, 10 mg, 15 mg, or 20 mg. In the implementation plan, the total amount of gaboxador or its pharmaceutically acceptable salts administered to the subject over a 24-hour period is from 1 mg to 50 mg. In the implementation plan, the subject may start with a low dose and increase the dose. In this way, it can be determined whether the drug is well tolerated in the subject. The dose for children may be lower than the dose for adults. In the implementation plan, the dose of gaboxador for children may be from 0.1 mg / kg to 1 mg / kg.

[0031] Allosteric modulators may include neurosteroids such as ganexone or allogestrinone, benzodiazepines such as midazolam, clonazepam, clonazepam, diazepam, lorazepam, flurazepam, etc., or potassium channel openers such as retigabine or flupirtine.

[0032] In the implementation scheme, a method is provided for treating epileptic disorders by administering ganexone to a patient with appropriate need. In the implementation scheme, a method is provided for treating epileptic disorders by administering allogestrinone to a patient with appropriate need. In the implementation scheme, a method is provided for treating epileptic disorders by administering a compound of formula I: Formula I.

[0033] In the implementation scheme, the allosteric modifier or a pharmaceutically acceptable salt thereof is administered at least once daily at a dose ranging from about 0.001 mg / kg to about 30 mg / kg of the patient’s body weight, for example, from about 0.01 mg / kg to 20 mg / kg. For example, the dosage may include an amount of allosteric modifier or its pharmaceutically acceptable salt in the range of about, for example, 1 mg to 30 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.1 mg to 10 mg, or 0.2 mg to 10 mg, wherein 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, etc. The doses of 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, and 30 mg are specific dosage examples. For example, the dosage may include, for example, 50 mg to 75 mg, 75 mg to 100 mg, 100 mg to 125 mg, 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, 275 mg to 300 mg, 300 mg to 325 mg, 325 mg to 350 mg, 350 mg to 375 mg, 375 mg to 400 mg, 400 mg to 425 mg, 425 mg to 450 mg, 450 mg to 475 mg, 475 mg to 500 mg, 500 mg to 525 mg, 525 mg to 550 mg, 550 mg to 575 mg, 575 mg to 600 mg, 600 mg to 625 mg, 625 mg to 650 mg. mg, 650 mg to 675 mg, 675 mg to 700 mg, 700 mg to 725 mg, 725 mg to 750 mg, 750mg to 775 mg, 775 mg to 800 mg, 800 mg to 825 mg, 825 mg to 850 mg, 850 mg to 875 mg, 875 mg to 900 mg, 900 mg to 925 mg, 925 mg to 950 mg, 950 mg to 975 mg, 975 mg to 1000 mg, 1000 mg to 1025 mg, 1025 mg to 1050 mg, 1050 mg to 1075 mg, 1075 mg to 1100 mg, 1100 mg to 1125 mg, 1125 mg to 1150 mg, 1150 mg to 1175 mg, 1175 mg to 1200 mg, 1200 mg to 1225 mg, 1225 mg to 1250 mg, 1250 mg to 1275 mg, 1275 mg to 1300 mg, 13 ... mg to 1325 mg, 1325 mg to 1350 mg, 1350 mg to 1375 mg, 1375 mg to 1400 mg, 1400 mg to 1425 mg, 1425 mg to 1450 mg, 1450 mg to 1475 mg, 1475 mg to 1500 mg, 1500 mg to 1525 mg, 1525 mg to 1550 mg, 1550 mg to 1575 mg, 1575 mg to 1600 mg, 1600 mg to 1625 mg, 1625 mg to 1650 mg, 1650 mg to 1675 mg, 1675 mg to 1700 mg, 1700 mg to 1725 mg, 1725 mg to 1750 mg, 1750 mg to 1775 mg, 1775 mg to 1800 mg, 1800 mg to 1825 mg An amount of allosteric modifier or its pharmaceutically acceptable salt in the range of 1825 mg to 1850 mg, 1850 mg to 1875 mg, 1875 mg to 1900 mg, 1900 mg to 1925 mg, 1925 mg to 1950 mg, 1950 mg to 1975 mg or 1975 mg to 2000 mg.

[0034] Typically, allosteric modifiers or their pharmaceutically acceptable salts are administered to patients as needed, once daily, twice daily, three times daily, or four times daily. In some embodiments, the allosteric modifier may be administered once weekly. The methods and compositions described herein can provide reduced dosing frequency and reduced adverse events and / or increased efficacy. In some embodiments, the dose of the allosteric modifier may be about, for example, 0.1-20 mg / day, or 0.2-15 mg / day, or 0.5-10 mg / day, or 0.75-5 mg / day, for example, 0.2 mg / day, 0.5 mg / day, 0.75 mg / day, 1 mg / day, 1.5 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, or 10 mg / day. In the implementation plan, patients may be administered the following amounts of allosteric modulators: for example, 10 mg / day to 25 mg / day, 25 mg / day to 50 mg / day, 50 mg / day to 75 mg / day, 75 mg / day to 100 mg / day, 100 mg / day to 125 mg / day, 125 mg / day to 150 mg / day, 150 mg / day to 175 mg / day, 175 mg / day to 200 mg / day, 200 mg / day to 225 mg / day, 225 mg / day to 250 mg / day, 250 mg / day to 275 mg / day, 275 mg / day to 300 mg / day, 300 mg / day to 325 mg / day, 325 mg / day to 350 mg / day, 350 mg / day to 375 mg / day, 375 mg / day to 400 mg / day, 400 mg / day to 425 mg / day. mg / day, 425 mg / day to 450 mg / day, 450 mg / day to 475 mg / day, 475 mg / day to 500 mg / day, 500 mg / day to 525 mg / day, 525 mg / day to 550 mg / day, 550 mg / day to 575 mg / day, 575 mg / day to 600 mg / day, 600 mg / day to 625 mg / day, 625 mg / day to 650 mg / day, 650 mg / day to 675 mg / day, 675 mg / day to 700 mg / day, 700 mg / day to 725 mg / day, 725 mg / day to 750 mg / day, 750 mg / day to 775 mg / day, 775 mg / day to 800 mg / day, 800 mg / day to 825 mg / day, 825 mg / day to 850 mg / day, 850 mg / day mg / day to 875 mg / day, 875 mg / day to 900 mg / day, 900 mg / day to 925 mg / day, 925 mg / day to 950 mg / daymg / day, 950 mg / day to 975 mg / day, 975 mg / day to 1000 mg / day, 1000 mg / day to 1025 mg / day, 1025 mg / day to 1050 mg / day, 1050 mg / day to 1075 mg / day, 1075 mg / day to 1100 mg / day, 1100 mg / day to 1125 mg / day, 1125 mg / day to 1150 mg / day, 1150 mg / day to 1175 mg / day, 1175 mg / day to 1200 mg / day, 1200 mg / day to 1225 mg / day, 1225 mg / day to 1250 mg / day, 1250 mg / day to 1275 mg / day, 1275 mg / day to 1300 mg / day, 1300 mg / day to 1325 mg / day, 1325 mg / day mg / day to 1350 mg / day, 1350 mg / day to 1375 mg / day, 1375 mg / day to 1400 mg / day, 1400 mg / day to 1425 mg / day, 1425 mg / day to 1450 mg / day, 1450 mg / day to 1475 mg / day, 1475 mg / day to 1500 mg / day, 1500 mg / day to 1525 mg / day, 1525 mg / day to 1550 mg / day, 1550 mg / day to 1575 mg / day, 1575 mg / day to 1600 mg / day, 1600 mg / day to 1625 mg / day, 1625 mg / day to 1650 mg / day, 1650 mg / day to 1675 mg / day, 1675 mg / day to 1700 mg / day, 1700 mg / day The dosage ranges from 1725 mg / day to 1750 mg / day, 1750 mg / day to 1775 mg / day, 1775 mg / day to 1800 mg / day, 1800 mg / day to 1825 mg / day, 1825 mg / day to 1850 mg / day, 1850 mg / day to 1875 mg / day, 1875 mg / day to 1900 mg / day, 1900 mg / day to 1925 mg / day, 1925 mg / day to 1950 mg / day, 1950 mg / day to 1975 mg / day, or 1975 mg / day to 2000 mg / day. In the embodiments, the allosteric modifier or its derivatives or analogs are administered in infants at a dose of 0.2 mg to 1 mg once daily or in adults at a dose of 1-20 mg once daily.

[0035] In the implementation scheme, a method of treating epileptic disorders such as status epilepticus includes administering ganedrone or a pharmaceutically acceptable salt thereof to a patient with appropriate need. Ganedrone or a pharmaceutically acceptable salt thereof may be administered at doses ranging from 10 mg / kg to 40 mg / kg, for example, 11 mg / kg to 39 mg / kg, 12 mg / kg to 38 mg / kg, 13 mg / kg to 37 mg / kg, 14 mg / kg to 36 mg / kg, 15 mg / kg to 35 mg / kg, 16 mg / kg to 34 mg / kg, 17 mg / kg to 33 mg / kg, 18 mg / kg to 32 mg / kg, 19 mg / kg to 31 mg / kg, 20 mg / kg to 30 mg / kg, 21 mg / kg to 29 mg / kg, 22 mg / kg to 28 mg / kg, 23 mg / kg to 27 mg / kg, or 24 mg / kg to 26 mg / kg. In the implementation scheme, the dosage of ganedrone can be, for example, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg. 1375 mg mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg or 2000 mg.

[0036] Ganexolone or a pharmaceutically acceptable salt thereof may be administered, for example, once daily, twice daily, three times daily, or four times daily. In one embodiment, Ganexolone or a pharmaceutically acceptable salt thereof may be administered once weekly. In another embodiment, Ganexolone or a pharmaceutically acceptable salt thereof may be administered parenterally as soon as possible after a seizure. In yet another embodiment, Ganexolone or a pharmaceutically acceptable salt thereof may be administered parenterally in escalating doses as soon as possible after a seizure.

[0037] In the implementation plan, methods for treating epileptic disorders such as status epilepticus include administering allogestrinone or a pharmaceutically acceptable salt thereof to patients in need. Allogestrinone or its pharmaceutically acceptable salts may be available in, for example, in the range of 0.01 mg / kg to 20 mg / kg, 0.02 mg / kg to 19 mg / kg, 0.03 mg / kg to 18 mg / kg, 0.04 mg / kg to 17 mg / kg, 0.05 mg / kg to 16 mg / kg, 0.06 mg / kg to 15 mg / kg, 0.07 mg / kg to 14 mg / kg, 0.08 mg / kg to 14 mg / kg, 0.09 mg / kg to 13 mg / kg, 0.1 mg / kg to 12 mg / kg, 0.2 mg / kg to 11 mg / kg, 0.3 mg / kg to 10 mg / kg, 0.4 mg / kg to 9 mg / kg, 0.5 mg / kg to 8 mg / kg, 0.6 mg / kg to 7 mg / kg, 0.7 mg / kg to 6 mg / kg, 0.8 mg / kg to 5 mg / kg, 0.9 mg / kg to 10 ...9 mg / kg to 10 mg / kg, 0.9 mg / kg to 10 mg / kg, 0.9 mg / kg to 10 mg / kg, 0.9 mg / kg to 10 mg / kg, 0.9 mg / kg to 10 mg / kg, 0.9 mg / kg to 10 mg / kg, 0.9 mg / kg to The dosage of allogeneolone may be, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.

[0038] Eugesterone or a pharmaceutically acceptable salt thereof may be administered, for example, once daily, twice daily, three times daily, or four times daily. In one embodiment, eugesterone or a pharmaceutically acceptable salt thereof may be administered once weekly. In another embodiment, eugesterone or a pharmaceutically acceptable salt thereof may be administered parenterally as soon as possible after a seizure. In yet another embodiment, eugesterone or a pharmaceutically acceptable salt thereof may be administered parenterally in escalating doses as soon as possible after a seizure.

[0039] Methods are provided for treating epileptic disorders by administering to a subject with an effective amount, alone or in combination with an allosteric modulator or a pharmaceutically acceptable salt, derivative or analogue, or a combination thereof, of gabosadol or a pharmaceutically acceptable salt thereof.

[0040] An effective dose, or therapeutically effective dose, may be sufficient to treat, suppress, or reduce one or more symptoms of an epileptic disorder, such as reducing the frequency or severity of seizures, reducing behavioral abnormalities (or otherwise improving behavior); or to provide the desired pharmacological and / or physiological effects, such as reducing, suppressing, or reversing one or more possible pathophysiological mechanisms causing neurological dysfunction, increasing dopamine levels or signal transduction, or a combination thereof. The precise dose will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, clinical symptoms, etc.). In the implementation plan, subjects may start with a low dose and increase the dose incrementally. In this way, it can be determined whether the drug is well tolerated in the subject. Children's doses may be lower than adult doses.

[0041] In implementation schemes, the methods described herein effectively reduce, delay, or prevent one or more other clinical symptoms of epileptic disorders, such as acute recurrent seizures. For example, the effects of gapository or its pharmaceutically acceptable salts and / or allosteric modifiers or their pharmaceutically acceptable salts, derivatives, or analogs on specific symptoms, pharmacological, or physiological parameters can be compared to the condition of untreated subjects or subjects before treatment. In implementation schemes, the symptoms, pharmacological, and / or physiological parameters of subjects are measured before treatment and also once or more after treatment begins. In implementation schemes, controls are reference levels or averages determined based on measurements of symptoms, pharmacological, or physiological parameters in one or more subjects (e.g., healthy subjects) who do not have the disease or condition to be treated. In examples, the effects of this treatment are compared to those of conventional treatments known in the art.

[0042] In the embodiments, compositions and treatment methods with low doses of gabosadol and / or allosteric modulators are provided, enabling patients to receive one or more beneficial effects associated with epileptic disorders, such as reduced seizure activity, reduced fatigue, improved mood, increased concentration, increased behavioral control, and / or increased cognitive abilities. Dosing regimens are provided herein that allow for effective treatment of epileptic disorders with potentially limited or minimal adverse side effects (e.g., seizures and / or sleep disruption). Therefore, the methods described herein can provide treatment for epileptic disorders in a way that may be considered surprising and unexpected. For example, methods for treating epileptic disorders in patients with corresponding needs are provided herein that do not cause sleep disruption. In the embodiments, the methods described herein can provide effective treatment for epileptic disorders without interrupting slow-wave sleep. In the embodiments, methods for treating epileptic disorders without causing insomnia or difficulty falling asleep are provided.

[0043] In implementations, the methods described herein can be used to treat epileptic disorders, including acute recurrent seizures, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), and Dravet syndrome. In implementations, the methods include treating acute recurrent seizures.

[0044] In the implementation plan, the methods described herein can be used to treat epileptic disorders, including benign Rolando epilepsy (BRE), refractory childhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome), generalized epilepsy with febrile seizures plus (GEFS+), and Lennox-Gastaut syndrome (LGS).

[0045] In the implementation plan, the methods described herein can be used to treat type 1 sodium channel protein α subunit (Scn1A)-related disorders. Examples of Scn1A-related disorders include generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory infantile partial seizures, myoclonic-aortic epilepsy, severe myoclonic epilepsy in infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, vaccine-associated encephalopathy, and seizures.

[0046] The methods described herein are for subjects experiencing refractory seizures, status epilepticus, akinetic seizures, myoclonic seizures, absence seizures, or severe myoclonic epilepsy of infancy (SMEI). In the implementation plan, these conditions are characterized by refractory seizures. Refractory seizures (also known as “uncontrolled” or “treatment-resistant” seizures) are seizures that cannot be controlled by conventional treatment. For example, a subject may have refractory seizures or another disorder characterized by refractory seizures, or a disorder characterized by status epilepticus. Status epilepticus is a condition in which seizures occur one after another without recovery of consciousness between them. Therefore, in the implementation plan, the disclosed methods are used to treat subjects who are otherwise resistant to one or more conventional therapies.

[0047] The methods described herein can be particularly useful for treating children and infants, and for treating disorders that develop during infancy or childhood. In implementation, the subjects of the disclosed methods are newborns, infants, toddlers, preschool children, school-aged children, pre-pubescent children, or adolescents. In implementation, the subjects are 18 years of age or younger, 12 years of age or younger, 10 years of age or younger, 8 years of age or younger, 6 years of age or younger, 4 years of age or younger, 2 years of age or younger, or 1 year of age or younger. In implementation, the subjects are adults over 18 years of age.

[0048] In the implementation scheme, the epileptic disorder is characterized by seizures associated with epilepsy. In the implementation scheme, the seizures are non-epileptic seizures (NES) or dissociative seizures, distinct from epilepsy. Non-epileptic seizures include organic non-epileptic seizures and psychogenic seizures.

[0049] Epilepsy is a neurological disorder that occurs when the activity of nerve cells in the brain is disrupted, resulting in seizures or periods of abnormal behavior, sensation, and sometimes loss of consciousness. A subject may be diagnosed with epilepsy when they experience two seizures without a clear cause. Epilepsy can occur in both adults and children and may be associated with specific syndromes. Therefore, in this implementation plan, the subject is diagnosed with a childhood epilepsy syndrome such as benign Rolando epilepsy (BRE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome, or Lennox-Gastaut syndrome (LGS).

[0050] In the implementation plan, subjects did not experience diagnosable seizures but exhibited subclinical discharges, which are defined as a high rate of seizure-like activity when the subject's brain waves were measured using electroencephalography (EEG). Epilepsy syndromes associated with these seizure-like discharges include Landau-Kleffner syndrome, Dravet syndrome, and persistent spike-wave activity during slow-wave sleep.

[0051] In the implementation scheme, the epileptic disorders treated by the methods and compositions described herein include Scn1A-related seizure disorders. Scn1A-related seizure disorders range from mild outcomes of simple febrile seizures (FS) and generalized tonic-clonic seizures with febrile seizures plus (GEFS+) to severe outcomes of Dravet syndrome and refractory childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). Specific Scn1A-related seizure disorders include, but are not limited to, generalized tonic-clonic seizures with febrile seizures plus, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory infantile partial seizures, myoclonic-agnostic epilepsy, severe myoclonic epilepsy in infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-associated encephalopathy.

[0052] In the implementation scheme, the subjects have intellectual developmental disability (IDD), such as autism spectrum disorder (ASD). In the implementation scheme, the subjects of the disclosed methods have epilepsy and IDD or ASD disorders. Common IDD and ASD with seizures and epilepsy include, but are not limited to, Fragile X syndrome (FXS), Rett syndrome (RTT), Angelman syndrome, Prader-Willi syndrome, Velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, neuroligin mutations, and "interneuronopathy" caused by X-linked aristoless-related homeobox (X-linked) (ARX) and Nueropilin 2 (NRP2) gene mutations.

[0053] This document also provides methods and compositions for treating epileptic disorders by co-administering an allosteric modifier and gaboxado, its derivatives, or pharmaceutically acceptable salts thereof to patients in need. In embodiments, the methods and compositions described herein include dosage forms comprising gaboxado or a pharmaceutically acceptable salt thereof and an allosteric modifier. In embodiments, the methods and compositions described herein may include dosage forms comprising gaboxado or a pharmaceutically acceptable salt thereof, and dosage forms comprising only an allosteric modifier or a pharmaceutically acceptable salt thereof.

[0054] Gabosadol or its pharmaceutically acceptable salts may be provided as acid addition salts, zwitterionic hydrates, anhydrous zwitterionic salts, hydrochlorides or hydrobromic acids, or as zwitterionic monohydrates. Acid addition salts include, but are not limited to, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, or theophylline acetic acid, as well as 8-halotheophylline, such as 8-bromotheophylline. In other suitable embodiments, inorganic acid addition salts may be used, including but not limited to, addition salts of hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, or nitric acid.

[0055] In the embodiments, gaboxador is provided as gaboxador monohydrate. Those skilled in the art will readily understand that the amount of the active ingredient in the pharmaceutical composition will depend on the form of gaboxador provided. For example, a pharmaceutical composition containing 5.0 mg, 10.0 mg, or 15.0 mg of gaboxador corresponds to 5.6 mg, 11.3 mg, or 16.9 mg of gaboxador monohydrate, respectively.

[0056] In the embodiments, gabosadol is crystalline, such as crystalline hydrochloride, crystalline hydrobromide, or crystalline zwitterionic monohydrate. In the embodiments, gabosadol is provided in the form of a crystalline monohydrate.

[0057] It has been previously demonstrated that deuteration of certain drug classes improves pharmacokinetic (PK), pharmacodynamic (PD), and toxicity profiles. Therefore, the use of deuterium-enriched gaboxadol is envisioned and falls within the scope of the methods and compositions described herein. According to synthetic procedures known in the art, deuterium can be incorporated at any position to replace hydrogen. For example, deuterium can be incorporated into various positions with exchangeable protons, such as amine N--H, via proton-deuterium equilibrium exchange. Therefore, deuterium can be selectively or non-selectively incorporated using methods known in the art to provide deuterium-enriched gaboxadol. See Journal of Labeled Compounds and Radiopharmaceuticals 19(5)689-702 (1982).

[0058] The pharmaceutical compositions described herein may be provided with immediate release, delayed release, extended release, or modified release profiles. In embodiments, pharmaceutical compositions with different drug release profiles may be combined to produce a two- or three-stage release profile. For example, pharmaceutical compositions may be provided with immediate and extended release profiles. In embodiments, pharmaceutical compositions may be provided with extended and delayed release profiles. Such compositions may be provided as pulsatile formulations, multilayer tablets, or capsules, including tablets, beads, granules, etc. The compositions may be prepared using pharmaceutically acceptable “carriers” made from materials considered safe and effective. A “carrier” includes all components present in a pharmaceutical formulation other than one or more active ingredients. The term “carrier” includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions.

[0059] In some implementations, the pharmaceutical composition described herein is administered once daily, twice daily, three times daily, four times daily, or every other day. In some implementations, the pharmaceutical composition described herein is administered to the patient at night. In some implementations, the pharmaceutical composition described herein is administered to the patient once at night and once in the morning. In some implementations, the pharmaceutical composition described herein is administered as soon as possible after the onset of a seizure. In some implementations, the pharmaceutical composition described herein is administered continuously.

[0060] In one implementation scheme, the total amount of allosteric modulator and / or gaboxado administered to the subject over a 24-hour period is 1 mg to 50 mg. In another implementation scheme, the total amount of allosteric modulator and / or gaboxado administered to the subject over a 24-hour period is 1 mg to 20 mg. In yet another implementation scheme, the total amount of allosteric modulator and / or gaboxado administered to the subject over a 24-hour period is 5 mg, 10 mg, or 15 mg. In yet another implementation scheme, the total amount of allosteric modulator and / or gaboxado or its pharmaceutically acceptable salts administered to the subject over a 24-hour period is 1 mg to 50 mg. In this implementation scheme, the subject may start with a low dose and increase the dose. In this way, it can be determined whether the drug is well tolerated in the subject. The dose for children may be lower than the dose for adults.

[0061] In embodiments, this document provides a method for treating epileptic disorders, the method comprising administering to a patient with appropriate need a pharmaceutical composition comprising an allosteric modulator and / or gaboroxadol, wherein the composition provides improvement in at least one symptom of the epileptic disorder. In embodiments, a method is provided for treating epileptic disorders by administering to a subject with appropriate need an effective amount of an allosteric modulator and / or gaboroxadol, or a combination thereof. An effective amount or therapeutically effective amount may be sufficient to treat, suppress, or reduce one or more symptoms of the epileptic disorder, such as a dose that reduces the frequency or severity of seizures, reduces behavioral abnormalities (or otherwise improves behavior); or a dose that provides the desired pharmacological and / or physiological effects, such as a dose that reduces, suppresses, or reverses one or more underlying pathophysiological mechanisms causing neurological dysfunction, increases dopamine levels or signal transduction, or a combination thereof. The precise dose will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, clinical symptoms, etc.).

[0062] In the implementation scheme, the methods described herein effectively reduce, delay, or prevent one or more other clinical symptoms of epileptic disorders, such as epilepsy or Dravet syndrome. For example, the effect of a composition comprising an allosteric modulator and / or gaposadol on a specific symptom, pharmacological, or physiological indicator can be compared to the condition of an untreated subject or a subject before treatment. In the implementation scheme, symptoms, pharmacological, and / or physiological indicators in subjects are measured before treatment and also once or more after treatment begins. In the implementation scheme, the control is a reference level or average based on measurements of symptoms, pharmacological, or physiological indicators in one or more subjects (e.g., healthy subjects) who do not have the disease or condition to be treated. In the implementation scheme, the effect of this treatment is compared to that of conventional treatments known in the art.

[0063] In embodiments, this document provides a method for treating epileptic disorders, such as status epilepticus, the method comprising administering to a patient with corresponding need a pharmaceutical composition comprising an allosteric modulator and / or gaboroxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in at least one symptom of the epileptic disorder. In embodiments, the provided method can also surprisingly and unexpectedly reduce or prevent seizures or symptoms thereof in a subject with corresponding need. In embodiments, the provided method can reduce or prevent one or more different types of seizures. In embodiments, the provided method can also surprisingly and unexpectedly reduce or prevent seizures or symptoms thereof in a subject with corresponding need. In embodiments, the provided method can reduce or prevent one or more different types of seizures. Generally, seizures may include convulsions, repetitive movements, abnormal sensations, and combinations thereof. Seizures can be classified as focal seizures (also known as partial seizures) and generalized seizures. Focal seizures affect only one side of the brain, while generalized seizures affect both sides of the brain. Specific types of focal seizures include simple focal seizures, complex focal seizures, and secondary generalized seizures. Simple focal seizures can be confined to or concentrated in a specific lobe (e.g., temporal, frontal, parietal, or occipital). Complex focal seizures, compared to simple focal seizures, typically affect a larger portion of a hemisphere, but usually originate in the temporal or frontal lobe. When a focal seizure spreads from one side (hemisphere) of the brain to both sides, the seizure is called a secondary generalized seizure. Specific types of generalized seizures include absence seizures (also known as petit mal seizures), tonic seizures, atonic seizures, myoclonic seizures, tonic-clonic seizures (also known as grand mal seizures), and clonic seizures.

[0064] In the implementation, the methods described herein can reduce the frequency of seizures, reduce the severity of seizures, change the type of seizures (e.g., from a more severe type to a less severe type) or a combination thereof in subjects after treatment, compared to no treatment (e.g., before treatment) or treatment using optional conventional treatments.

[0065] In embodiments, this document provides a method for treating epileptic disorders, wherein, after administration of a pharmaceutical composition to a patient, the patient is provided with improvement in at least one symptom lasting longer than 4 hours. In embodiments, this disclosure provides improvement in at least one symptom lasting longer than 6 hours after administration of a pharmaceutical composition to a patient. In embodiments, this disclosure provides improvement in at least one symptom lasting longer than, for example, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of a pharmaceutical composition to a patient. In embodiments, this disclosure provides improvement in at least one symptom lasting at least, for example, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of a pharmaceutical composition to a patient. In embodiments, this disclosure provides improvement in at least one symptom lasting 12 hours after administration of a pharmaceutical composition to a patient.

[0066] In its implementation, this document provides a method for treating epileptic disorders, the method comprising administering the pharmaceutical composition of this document to a patient with a corresponding need, wherein the composition provides the patient with functional improvement the following day.

[0067] In the embodiments, this document provides a method for treating epileptic disorders, wherein, about 4 hours after administration of the pharmaceutical composition, the amount of the active substance, such as an allosteric modifier and / or gaboroxadol, in the patient is less than about 75% of the administered dose. In the embodiments, this document provides a method wherein, about, for example, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition, the amount of the allosteric modifier and / or gaboroxadol or a pharmaceutically acceptable salt thereof in the patient is less than about 75%.

[0068] In the embodiments, this document provides a method for treating epileptic disorders, wherein, about 4 hours after administration of the pharmaceutical composition, the amount of active substance, such as an allosteric modifier and / or gaboroxadol, in the patient is less than about 80% of the administered dose. In the embodiments, this document provides a method wherein, about, for example, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition, the amount of active substance, such as an allosteric modifier and / or gaboroxadol, in the patient is less than about 80% of the administered dose.

[0069] In the embodiments, this document provides a method for treating epileptic disorders, wherein, about 4 hours after administration of the pharmaceutical composition, the amount of the active substance, such as an allosteric modulator and / or gaboroxadol, in the patient is between about 65% and about 85% of the administered dose. In the embodiments, about, for example, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition, the amount of the active substance, such as an allosteric modulator and / or gaboroxadol, in the patient is between about 65% and about 85% of the administered dose.

[0070] In the implementation scheme, this document provides a method for treating epileptic disorders, the method comprising administering to a patient with appropriate need a pharmaceutical composition comprising an active substance, such as an allosteric modulator and / or gabosadol, wherein the composition provides a C concentration of less than about 500 ng / ml. max The composition provides an improvement in the in vivo plasma profile. In the embodiments, the composition provides an improvement lasting longer than 6 hours after administration to a patient.

[0071] In embodiments, the composition provides a C0 having a concentration of less than, for example, 450 ng / ml, 400 ng / ml, 350 ng / ml, or 300 ng / ml. max The composition provides the patient with improved function the following day, based on their in vivo plasma profile. In embodiments, the composition provides a C-value of less than, for example, about 250 ng / ml, 200 ng / ml, 150 ng / ml, or 100 ng / ml. max The composition provides patients with improved function the following day by analyzing their plasma profile.

[0072] In the implementation scheme, this document provides a method for treating epileptic disorders, the method comprising administering a pharmaceutical composition to a patient in need, wherein the composition provides an AUC of less than about 900 ng•hr / ml. 0-∞ A constant in vivo plasma profile. In one embodiment, the composition provides the patient with improved function the following day. In another embodiment, the composition provides an AUC of less than, for example, about, 850 ng•hr / ml, 800 ng•hr / ml, 750 ng•hr / ml, or 700 ng•hr / ml. 0-∞ The composition provides the patient with improved function the following day, based on the patient's plasma profile. In one embodiment, the composition provides improvement in one or more symptoms lasting for more than 6 hours after administration.

[0073] In the implementation scheme, this document provides a method for treating epileptic disorders, the method comprising administering to a patient with appropriate need a pharmaceutical composition comprising an active substance, such as an allosteric modifier and / or gabosadol, wherein the composition provides an AUC having less than, for example, about, 650 ng•hr / ml, 600 ng•hr / ml, 550 ng•hr / ml, 500 ng•hr / ml or 450 ng•hr / ml. 0-∞ The composition provides an in vivo plasma profile. In an embodiment, the composition provides an AUC of less than, for example, 400 ng·hr / ml, 350 ng·hr / ml, 300 ng·hr / ml, 250 ng·hr / ml, or 200 ng·hr / ml. 0-∞ The composition provides an in vivo plasma profile. In embodiments, the composition provides an AUC of less than, for example, 150 ng·hr / ml, 100 ng·hr / ml, 75 ng·hr / ml, or 50 ng·hr / ml. 0-∞ The composition provides the patient with improved function the following day after administration of the composition to the patient, provided the administration continues for more than, for example, 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours.

[0074] In embodiments, this document provides a method for treating epileptic disorders, the method comprising administering to a patient in need a first pharmaceutical composition comprising gaboxador or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising gaboxador or a pharmaceutically acceptable salt thereof. In some embodiments, the second pharmaceutical composition provides an average AUC that is at least about 20% smaller than that of the first pharmaceutical composition. 0-∞ The plasma profile in the body.

[0075] In the embodiments, this document provides a method for treating epileptic disorders, the method comprising administering to a patient with appropriate need a first pharmaceutical composition comprising an allosteric modulator and a second pharmaceutical composition comprising gaposidoxur or a pharmaceutically acceptable salt thereof. In the embodiments, the second pharmaceutical composition provides an average AUC that is at least about 20% smaller than that of the first pharmaceutical composition. 0-∞ The plasma profile in the body.

[0076] In one embodiment, the first drug composition and / or the second drug composition are administered once daily, twice daily, three times daily, or four times daily, or every other day. In another embodiment, the first or second drug composition is delivered to the patient at night. In another embodiment, the second drug composition comprises at least one-third the amount of the allosteric modifier in the first drug composition. In yet another embodiment, the second drug composition comprises at least half the amount of the allosteric modifier provided in the first drug composition.

[0077] In the implementation scheme, the first pharmaceutical composition and / or the second pharmaceutical composition are administered to the patient once in the evening and once in the morning. In the implementation scheme, the total amount of the allosteric modifier administered to the subject over a 24-hour period is from 1 mg to 2500 mg. In the implementation scheme, the total amount of the allosteric modifier administered to the subject over a 24-hour period is from 1 mg / kg to 35 mg / kg. In the implementation scheme, the total amount of gaboxador or a pharmaceutically acceptable salt thereof administered to the subject over a 24-hour period is from 1 mg to 75 mg. In the implementation scheme, the total amount of the active substance, such as gaboxador or a pharmaceutically acceptable salt thereof, administered to the subject over a 24-hour period is less than about 75 mg, 50 mg, 25 mg, 20 mg, 10 mg, or 5 mg. In the implementation scheme, the total amount of the active substance, such as gaboxador or a pharmaceutically acceptable salt thereof, administered to the subject over a 24-hour period is less than 15 mg. In the implementation scheme, the total amount of the active substance, such as allosteric modifiers and / or gaboroxadol, administered to the subject over a 24-hour period is less than about 2500 mg, 2250 mg, 2000 mg, 1750 mg, 1500 mg, 1250 mg, 1000 mg, 750 mg, 500 mg, 250 mg, 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg, 25 mg, 20 mg, 10 mg, or 5 mg. In the implementation scheme, the total amount of the active substance, such as allosteric modifiers and / or gaboroxadol, administered to the subject over a 24-hour period is less than 15 mg.

[0078] In embodiments, the first and / or second pharmaceutical compositions may be provided with an immediate release, delayed release, extended release, or modified release profile. The first and second pharmaceutical compositions may be provided simultaneously or separated by time intervals such as 6 hours, 12 hours, etc. In embodiments, the first and second pharmaceutical compositions may be provided with different drug release profiles to produce a two-stage release profile. For example, the first pharmaceutical composition may be provided with an immediate release profile, while the second pharmaceutical composition may be provided with an extended release profile. In embodiments, one or both of the first and second pharmaceutical compositions may be provided with an extended release or delayed release profile. Such compositions may be provided as pulsatile formulations, multilayer tablets, or capsules, including tablets, beads, granules, etc. In some embodiments, the first pharmaceutical composition is an immediate release composition. In embodiments, the second pharmaceutical composition is an immediate release composition. In embodiments, the first and second pharmaceutical compositions are provided as separate immediate release compositions, such as tablets or capsules. In embodiments, the first and second pharmaceutical compositions are provided 12 hours apart.

[0079] In the embodiments, the compositions described herein are suitable for parenteral administration, including, for example, intramuscular (IM), intravenous (IV), subcutaneous (SC), intraperitoneal (IP), or intrathecal (IT). The parenteral compositions must be sterile for administration by injection, infusion, or implantation into the body and may be packaged in single-dose or multi-dose containers.

[0080] In one embodiment, the liquid pharmaceutical composition for parenteral administration to a subject comprises an active substance, such as an allosteric modifier and / or gaboroxadol, at a concentration of about 0.005 μg / ml to about 500 μg / ml. In another embodiment, the composition comprises an active substance, such as an allosteric modifier and / or gaboroxadol, at concentrations of, for example, about 0.005 μg / ml to about 250 μg / ml, about 0.005 μg / ml to about 200 μg / ml, about 0.005 μg / ml to about 150 μg / ml, about 0.005 μg / ml to about 100 μg / ml, or about 0.005 μg / ml to about 50 μg / ml.

[0081] In one embodiment, the pharmaceutical composition comprises an active substance, such as an allosteric modifier and / or gaboroxatol, at concentrations of, for example, from about 0.05 μg / ml to about 50 μg / ml, from about 0.1 μg / ml to about 50 μg / ml, from about 0.05 μg / ml to about 25 μg / ml, from about 0.05 μg / ml to about 10 μg / ml, from about 0.05 μg / ml to about 5 μg / ml, or from about 0.05 μg / ml to about 1 μg / ml. In another embodiment, the pharmaceutical composition comprises an active substance, such as an allosteric modifier and / or gaboroxatol, at concentrations of, for example, from about 0.05 μg / ml to about 15 μg / ml, from about 0.5 μg / ml to about 10 μg / ml, from about 0.5 μg / ml to about 7 μg / ml, from about 1 μg / ml to about 10 μg / ml, from about 5 μg / ml to about 10 μg / ml, or from about 5 μg / ml to about 15 μg / ml. In embodiments, the pharmaceutical composition for parenteral administration is formulated to a total volume of approximately, for example, 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In embodiments, the composition is contained in a bag, glass vial, plastic vial, or bottle.

[0082] In embodiments, the composition for parenteral administration comprises about 0.05 mg to about 100 mg of an active substance, such as an allosteric modifier and / or gaboxard. In embodiments, the pharmaceutical composition comprises about, for example, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg of an active substance, such as an allosteric modifier and / or gaboxard.

[0083] In one embodiment, the pharmaceutical composition comprises about, for example, 5 mg to 20 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg of an active substance, such as an allosteric modifier and / or gaboxard. In another embodiment, the pharmaceutical composition comprises about, for example, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg of an active substance, such as an allosteric modifier and / or gaboxard, or multiples of such doses. The composition may be contained in a bag, glass vial, plastic vial, or bottle.

[0084] In one embodiment, the pharmaceutical composition for parenteral administration to a subject comprises an active substance, such as an allosteric modifier and / or gaboroxadol, at a concentration of about 0.005 mg / ml to about 500 mg / ml. In another embodiment, the composition comprises an active substance, such as an allosteric modifier and / or gaboroxadol, at concentrations of, for example, about 0.05 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 25 mg / ml, about 0.05 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 5 mg / ml, or about 0.05 mg / ml to about 1 mg / ml. In embodiments, the composition comprises an active substance, such as an allosteric modifier and / or gaposadol, at concentrations of, for example, from about 0.05 mg / ml to about 15 mg / ml, from about 0.5 mg / ml to about 10 mg / ml, from about 0.25 mg / ml to about 5 mg / ml, from about 0.5 mg / ml to about 7 mg / ml, from about 1 mg / ml to about 10 mg / ml, from about 5 mg / ml to about 10 mg / ml, or from about 5 mg / ml to about 15 mg / ml. In embodiments, the pharmaceutical composition for parenteral administration is formulated to a total volume of about, for example, 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In embodiments, the composition is packaged and stored in a bag, glass vial, plastic vial, or bottle.

[0085] In embodiments, the pharmaceutical compositions herein comprise an active substance, such as an allosteric modifier and / or gaboroxadol, wherein the active substance is present at a molar concentration of less than about 1.0 M. In embodiments, the active substance, such as the allosteric modifier and / or gaboroxadol, is present at a molar concentration greater than, for example, about 0.0001 M, about 0.001 M, about 0.01 M, about 0.1 M, about 0.2 M, greater than about 0.5 M, greater than about 1.0 M, greater than about 1.2 M, greater than about 1.5 M, greater than about 1.75 M, greater than about 2.0 M, or greater than about 2.5 M. In embodiments, the active substance, such as the allosteric modifier and / or gaboroxadol, is present at a molar concentration, for example, between about 0.00001 M to about 0.1 M, about 0.01 M to about 0.1 M, about 0.1 M to about 1.0 M, about 1.0 M to about 5.0 M, or about 5.0 M to about 10.0 M. In the embodiments, the active substance, such as an allosteric modifier and / or gabosador, is present at a molar concentration of less than, for example, about 0.01 M, about 0.1 M, about 1.0 M, about 5.0 M or about 10.0 M.

[0086] In the embodiments, when measured, for example, in water at 25°C, the solubility of the active substance in the composition, such as the allosteric modifier and / or gabosadol, is greater than, for example, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 40 mg / ml, about 50 mg / ml, about 75 mg / ml, about 100 mg / ml, or about 150 mg / ml.

[0087] In the embodiments, when measured, for example, in water at 25°C, the solubility of the active substance in the composition, such as the allosteric modifier and / or gabosadoc, is, for example, between about 1 mg / ml and about 50 mg / ml, about 5 mg / ml and about 50 mg / ml, about 10 mg / ml and about 50 mg / ml, about 20 mg / ml and about 50 mg / ml, about 20 mg / ml and about 30 mg / ml, or about 10 mg / ml and about 45 mg / ml.

[0088] In the embodiments, pharmaceutical compositions for parenteral administration are provided, wherein the pharmaceutical composition remains stable for at least six months. In the embodiments, the active substance of the pharmaceutical composition herein, such as an allosteric modifier and / or gaboxador, exhibits a reduction of no more than about 5% after 3 or 6 months. In the embodiments, the amount of degradation of gaboxador or its pharmaceutically acceptable salts is no more than about, for example, 2.5%, 1%, 0.5%, or 0.1%. In the embodiments, the degradation is less than about, for example, 5%, 2.5%, 1%, 0.5%, 0.25%, or 0.1% over at least six months.

[0089] In the embodiments, pharmaceutical compositions for parenteral administration are provided, wherein the pharmaceutical composition remains soluble. In the embodiments, stable, soluble, site-compatible, and / or ready-to-use pharmaceutical compositions are provided. In the embodiments, the pharmaceutical compositions herein are ready for direct administration to patients with appropriate needs.

[0090] The parenteral compositions provided herein may contain one or more excipients, such as solvents, solubility enhancers, suspending agents, buffers, isotonic agents, stabilizers, or antimicrobial preservatives. When used, the excipients in the parenteral compositions do not adversely affect the stability, bioavailability, safety, and / or efficacy of the allosteric modifiers and / or gaborsard or pharmaceutically acceptable salts used in the composition. Therefore, parenteral compositions are provided in which there is no incompatibility between any components of the dosage form.

[0091] In the embodiments, the parenteral composition of the allosteric modifier and / or gapository or a pharmaceutically acceptable salt thereof comprises a stable amount of at least one excipient. For example, the excipient may be selected from the group consisting of buffers, solubilizers, tensioning agents, antioxidants, chelating agents, antibacterial agents, and preservatives. Those skilled in the art will understand that excipients may have more than one function and be classified into one or more defined groups.

[0092] In one embodiment, the pharmaceutical composition comprises an allosteric modifier and / or gaboroxadol or a pharmaceutically acceptable salt thereof and excipients, wherein the excipients are present in a weight percentage (w / v) of less than, for example, 10%, 5%, 2.5%, 1%, or 0.5%. In another embodiment, the excipients are present in a weight percentage of, for example, between 1.0% and 10%, 10% and 25%, 15% and 35%, 0.5% and 5%, 0.001% and 1%, 0.01% and 1%, 0.1% and 1%, or 0.5% and 1%. In yet another embodiment, the excipients are present in a weight percentage of, for example, between 0.001% and 1%, 0.01% and 1%, 1.0% and 5%, 10% and 15%, or 1% and 15%.

[0093] In embodiments, a pharmaceutical composition comprising gabosadol or a pharmaceutically acceptable salt thereof and an excipient is provided, wherein the excipient is present in, for example, a molar ratio of excipient to gabosadol or a pharmaceutically acceptable salt of about 0.01:1 to about 0.45:1, about 0.1:1 to about 0.15:1, about 0.01:1 to about 0.1:1, and about 0.001:1 to about 0.01:1. In embodiments, the excipient is present in a molar ratio of excipient to gabosadol or a pharmaceutically acceptable salt of about 0.0001:1 to about 0.1:1.

[0094] In the embodiments, a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient is provided, wherein the excipient includes a stable amount of a buffer. The buffer can be used to maintain the pH of the pharmaceutical composition, wherein gaboxadol or a pharmaceutically acceptable salt thereof remains soluble, stable, and / or physiologically compatible. For example, in the embodiments, the parenteral composition comprises a buffer, wherein the composition remains stable without significant degradation of gaboxadol. In the embodiments, it is desirable to incorporate a buffer to control pH to enhance stability without significantly catalyzing or degrading gaboxadol or its salts, and / or significantly causing pain to the patient after infusion.

[0095] In the embodiments, the buffer can be a citrate, phosphate, acetate, tartrate, carbonate, glutamate, lactate, succinate, bicarbonate buffer, or a combination thereof. For example, sodium citrate, anhydrous trisodium citrate, trisodium citrate dihydrate, dehydrated sodium citrate, triethanolamine (TRIS), trisodium citrate dihydrate (i.e., dehydrated trisodium citrate), acetic acid, citric acid, glutamate, and phosphoric acid can be used as buffers. In the embodiments, the buffer can be an amino acid, alkali metal, or alkaline earth metal buffer. For example, the buffer can be sodium acetate or hydrogen phosphate.

[0096] In embodiments, an active substance, such as an allosteric modifier and / or gapository, is provided in a parenteral composition, wherein the pH of the composition is between about 4.0 and about 8.0. In embodiments, the pH of the composition is, for example, between about 5.0 and about 8.0, about 6.0 and about 8.0, or about 6.5 and about 8.0. In embodiments, the pH of the composition is, for example, between about 6.5 and about 7.5, about 7.0 and about 7.8, about 7.2 and about 7.8, or about 7.3 and about 7.6. In embodiments, the pH of the aqueous solution is, for example, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.

[0097] In embodiments, a pharmaceutical composition comprises an active substance, such as an allosteric modifier and / or gaposadol or a pharmaceutically acceptable salt thereof, and excipients, wherein the excipients include a solubilizer. For example, solubilizers according to the invention may include, for example, sodium hydroxide, L-lysine, L-arginine, sodium carbonate, potassium carbonate, sodium phosphate, and / or potassium phosphate. The amount of solubilizer in the composition will be sufficient such that the solution remains soluble at all concentrations, i.e., without turbidity and / or the formation of precipitates.

[0098] In embodiments, this document provides pharmaceutical compositions of active substances, such as allosteric modifiers and / or gaposidoxime or pharmaceutically acceptable salts thereof, and excipients, wherein the excipients include a particulate formation inhibitor. A particulate formation inhibitor is a compound having the desired property of inhibiting the formation of particles in a parenteral composition. The particulate formation inhibitors of the present invention include ethylenediaminetetraacetic acid (EDTA) and its salts, such as calcium disodium EDTA (preferably as a hydrate); diammonium EDTA (preferably as a hydrate); dipotassium EDTA (preferably as a dihydrate); disodium EDTA (preferably as a dihydrate, and, if desired, as an anhydrous form); tetrasodium EDTA (preferably as a hydrate); tripotassium EDTA (preferably as a dihydrate); trisodium EDTA (preferably as a hydrate); and disodium EDTA USP (preferably as a dihydrate). In embodiments, the pharmaceutical compositions described herein have an effective amount of the particulate formation inhibitor. In the embodiments, excipients may include, for example, amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins such as serum albumin, collagen and gelatin; salts such as EDTA or EGTA, and sodium chloride, liposomes, polyvinylpyrrolidone, sugars such as dextran, mannitol, sorbitol and glycerol, propylene glycol and polyethylene glycol (e.g. PEG-4000, PEG-6000), glycerol, glycine and / or lipids.

[0099] In embodiments, this document provides pharmaceutical compositions of active substances, such as allosteric modifiers and / or gapository or pharmaceutically acceptable salts thereof, and excipients, wherein the excipients include solubilizers. For example, solubilizers may include, but are not limited to, acids, such as carboxylic acids and amino acids. In other embodiments, the solubilizer may be a saturated carboxylic acid, an unsaturated carboxylic acid, a fatty acid, a keto acid, an aromatic carboxylic acid, a dicarboxylic acid, a tricarboxylic acid, an α-hydroxy acid, an amino acid, or a combination thereof.

[0100] In the embodiments, this document provides pharmaceutical compositions of active substances, such as allosteric modifiers and / or gaposadol or pharmaceutically acceptable salts thereof, and excipients, wherein the excipients include solubilizers such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, caprylic acid, nonanoic acid, decanoic acid, lauric acid, stearic acid, acrylic acid, docosahexaenoic acid, eicosapentaenoic acid, pyruvic acid, benzoic acid, salicylic acid, aldonic acid, oxalic acid, malonic acid, malic acid, succinic acid, glutaric acid, adipic acid, citric acid, lactic acid, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and combinations thereof.

[0101] In this embodiment, the solubilizer is selected from acetic acid, its salts and combinations thereof (e.g., acetic acid / sodium acetate), citric acid, its salts and combinations thereof (e.g., citric acid / sodium citrate), DL-arginine, L-arginine, and histidine. In this embodiment, the solubilizer is DL-arginine. In this embodiment, the solubilizer is L-arginine. In this embodiment, the solubilizer is acetic acid / sodium acetate. In this embodiment, the solubilizer is citric acid / sodium citrate.

[0102] In embodiments, this document provides pharmaceutical compositions of active substances, such as allosteric modifiers and / or gaposadol or pharmaceutically acceptable salts thereof, and excipients, wherein the excipients make the composition isotonic. The isotonic pharmaceutical compositions of this document can be achieved by adding appropriate amounts of sodium chloride, glucose, levulose, dextran, mannitol, or potassium chloride, or calcium chloride, or calcium gluconoglucoheptonate, or mixtures thereof. For example, the excipients may include one or more tension agents, such as, for example, sodium chloride, potassium chloride, glycerol, mannitol, and / or dextran. Tension agents can be used to minimize tissue damage and irritation, reduce hemolysis of blood cells, and / or prevent electrolyte imbalance. For example, parenteral compositions may be aqueous solutions containing sodium chloride, wherein the composition is isotonic. In embodiments, the isotonic agent is sodium chloride. In embodiments, the concentration of the isotonic agent is between about 0.01 and about 2.0% by weight. In embodiments, the pharmaceutical composition may contain up to about 10% isotonic agent. In embodiments, the pharmaceutical composition may contain up to about, for example, 0.25%, 0.5%, 1%, or 2.5% isotonic agent. In embodiments, the amount of isotonic agent in the pharmaceutical composition is, for example, between about 0.01% to 1%, 0.1% to 1%, 0.25% to 1%, or 0.5% to 1%.

[0103] In the embodiments, this document provides pharmaceutical compositions of active substances, such as allosteric modifiers and / or gaposadol or pharmaceutically acceptable salts thereof, and excipients, wherein the excipients include free radical antagonists. In the embodiments, the free radical antagonist is ascorbic acid, ascorbic acid derivatives, organic compounds having at least one thiol group, alkyl polyhydroxylated compounds, and cycloalkyl polyhydroxylated compounds, and combinations thereof.

[0104] In the embodiments, this document provides pharmaceutical compositions of active substances, such as allosteric modifiers and / or gaposadol or pharmaceutically acceptable salts thereof, and excipients, wherein the excipients include free radical scavengers selected from thiolacetic acid, thiohydroxyacetic acid, dithiothreitol, reduced glutathione, thiourea, α-thioglycerol, cysteine, acetylcysteine, mercaptoethane sulfonic acid, and combinations thereof.

[0105] In the embodiments, this document provides pharmaceutical compositions having an active substance, such as an allosteric modifier and / or gaposadol or a pharmaceutically acceptable salt thereof, and excipients, wherein the excipients include riboflavin, dithiothreitol, sodium thiosulfate, thiourea, ascorbic acid, methylene blue, sodium metabisulfite, sodium bisulfite, propyl gallate, acetylcysteine, phenol, acetone sodium bisulfate, ascorbic acid, ascorbic acid ester, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine, nordihydroguiaretic acid (NDGA), monothioglycerol, sodium bisulfite, sodium metabisulfite, tocopherol, and / or glutathione.

[0106] In embodiments, this document provides pharmaceutical compositions of active substances, such as allosteric modifiers and / or gaposadol or pharmaceutically acceptable salts thereof, and excipients, wherein the excipients include preservatives. In embodiments, the preservative is selected from benzalkonium chloride, benzyl alcohol, chlorobutanol, chlorocresol, m-cresol, phenol, phenylmercuric nitrate, phenylmercuric acetate, methylparaben, propylparaben, butylparaben, and thimerosal. In other embodiments, the preservative is selected from the group consisting of phenol, m-cresol, benzyl alcohol, parabens (e.g., methylparaben, propylparaben, butylparaben), benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric salts (e.g., acetates, borates, or nitrates), and combinations thereof.

[0107] In embodiments, the compositions herein comprise a co-solvent. For example, in some cases, the solubility of gaposidoxur can be much lower than the therapeutic dose, and therefore a co-solvent system can be used. A co-solvent is a mixture of solvents that can be used to achieve sufficiently high solubility and increase stability. For example, a co-solvent can be a water-miscible organic solvent, such as ethanol, propylene, ethylene glycol, Capmul PG, propylene glycol, glycerol, polyethylene glycol, sorbitol, dimethylacetamide, and / or dimethyl sulfoxide (DMSO). In embodiments, the co-solvent can constitute up to about 75% of the pharmaceutical composition. In other embodiments, the amount of co-solvent used constitutes up to about, for example, 1%, 5%, 10%, 15%, 25%, 40%, or 50% of the pharmaceutical composition.

[0108] The dosage form can be prepared, for example, by aseptically mixing an allosteric modifier and / or gaborsard or a pharmaceutically acceptable salt thereof with one or more excipients (e.g., buffers, solubilizers, tensioning agents, antioxidants, chelating agents, antimicrobial agents, and / or preservatives) in a mixer until a homogeneous blend is obtained. A suitable amount of the aseptic blend can then be filled into pre-sterilized vials. The predetermined amount of the aseptic blend can then be mixed with a solvent, such as water, saline, about 5%–10% sugar (e.g., glucose, dextrose) solution, or combinations thereof, prior to administration. Alternatively, the solution can be frozen and thawed before further processing.

[0109] The excipients can be used in solid or solution form. When used in solid form, the excipients and allosteric modifiers and / or gaboroxadol or pharmaceutically acceptable salts thereof can be mixed together as described above, and then a solvent is added prior to parenteral administration. When used in solution form, the allosteric modifiers and / or gaboroxadol or pharmaceutically acceptable salts thereof can be mixed with a solution of the excipients prior to parenteral administration.

[0110] Parenteral solutions containing allosteric modifiers and / or gaboroxadol or pharmaceutically acceptable salts thereof can be prepared by mixing the desired amount of allosteric modifiers and / or gaboroxadol or pharmaceutically acceptable salts thereof into a parenteral fluid such as D5W, distilled water, saline, or PEG and adjusting the pH of the solution to between 6.8 and 8. The allosteric modifiers and / or gaboroxadol or pharmaceutically acceptable salts thereof may be purified prior to use. This process can be carried out at room temperature, or the solution may be appropriately warmed to increase concentration. Other solvents such as PEG 400, PEG 600, polypropylene glycol, or other glycols may be used to enhance solubility. The resulting solution, after cooling to room temperature, can be sterilized by known methods such as ultrafiltration using, for example, a 0.45-micron filter, or by ethylene oxide treatment or heating, and can be packaged into ampoules, vials, or pre-filled syringes suitable for dispensing sterile parenteral preparations.

[0111] When administered, the parenteral composition described herein provides, in human patients, a time to peak plasma concentration (Tc) of gapository of approximately 1 hour or more (e.g., approximately 1.5 hours or more). max In the implementation plan, Gaposad's T in human patients max The range is, for example, between about 1 hour and about 5 hours, about 1 hour and about 4 hours, about 1 hour and about 3 hours, and about 1 hour and about 2 hours. In the implementation plan, T values ​​of gaposadol were observed in human patients. max More than approximately 1.5. In the implementation plan, T values ​​of Gaposadol were observed in human patients. max Less than approximately 3 hours. The time to maximum plasma concentration is measured after the infusion is complete.

[0112] In the embodiments described herein, dosage forms comprise from about 1 mg to about 500 mg of gabosadol, wherein parenteral administration of the dosage form (e.g., intramuscular, intravenous, subcutaneous, intraperitoneal, or intrathecal) provides a mean AUC of more than about 25 ng•hr / ml. 0-∞ The in vivo plasma profile of Gaboroxadol. In the implementation scheme, a single dose of the dosage form provides an average AUC comprising, for example, 50 ng·hr / ml, 75 ng·hr / ml, 150 ng·hr / ml, 250 ng·hr / ml, 500 ng·hr / ml, 1000 ng·hr / ml, or 1500 ng·hr / ml. 0-∞ The value of Gabosado's plasma spectrum.

[0113] In the implementation scheme, the dosage form comprises about 1 mg to about 500 mg of gabosadol, wherein administration of the dosage form provides an average C concentration of less than about 10,000 ng / ml. maxThe in vivo plasma profile of Gaborasad. In embodiments, a single dose of the composition provides an average C10 concentration of less than, for example, 5000 ng / ml, 2500 ng / ml, 1000 ng / ml, 500 ng / ml, 250 ng / ml, or 100 ng / ml. max The plasma spectrum of Gabosado.

[0114] In the implementation scheme, the pharmaceutical composition for parenteral administration comprises gaboroxadol or a pharmaceutically acceptable salt thereof, wherein the parenteral administration exhibits the following pharmacokinetic profile after administration of the parenteral composition: at a Tg of approximately 1 minute to approximately 120 minutes... max ; followed by at least 50% of a duration lasting from approximately 90 minutes to approximately 360 minutes. max The plasma drug concentration. In the implementation plan, after parenteral administration of gaboroxadol, the plasma drug concentration is at least 50% C. max The duration can be, for example, about 10 minutes to about 60 minutes, about 15 minutes to about 90 minutes, about 30 minutes to about 120 minutes, about 60 minutes to about 180 minutes, or about 90 minutes to about 180 minutes.

[0115] In the embodiments, the stable pharmaceutical composition is provided in a unit dosage form suitable for parenteral administration in vials or ampoules, the stable pharmaceutical composition having a therapeutically effective amount of the allosteric modifier and / or gaboroxadol or a pharmaceutically acceptable salt thereof dissolved in sterile water to form a solution, wherein the composition is substantially free of any excipients, organic solvents, buffers, acids, bases, or salts other than the allosteric modifier and / or gaboroxadol or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition remains sufficiently soluble and can be administered directly. In the embodiments, the pharmaceutical composition can be stored for at least 6 months in the absence of an inert atmosphere.

[0116] In this embodiment, a stable pharmaceutical composition in a unit dosage form in vials or ampoules, suitable for parenteral administration, is provided. The stable pharmaceutical composition contains a therapeutically effective amount of an allosteric modifier and / or gaboroxadol or a pharmaceutically acceptable salt thereof dissolved in sterile water to form a solution. The composition is free of excipients, organic solvents, buffers, acids, bases, and salts, except for the allosteric modifier and / or gaboroxadol or a pharmaceutically acceptable salt thereof. In this embodiment, the pharmaceutical composition remains sufficiently soluble and can be administered directly. In this embodiment, the pharmaceutical composition can be stored for at least 6 months in the absence of an inert atmosphere.

[0117] In one embodiment, the stable pharmaceutical composition suitable for parenteral administration contains an allosteric modifier and / or gaposadol or a pharmaceutically acceptable salt thereof in an aqueous solution having an osmolarity between 225 mOsm / kg and 350 mOsm / kg and a pH in the range of 7.0 and 8.0. In another embodiment, the aqueous solution has an osmolarity between 270 and 310. In yet another embodiment, the aqueous solution has a pH in the range of 7.2 and 7.8.

[0118] In its implementation, this document provides a method for treating epileptic disorders, the method comprising administering to a patient with appropriate need a first pharmaceutical composition and a second pharmaceutical composition comprising gabosadol or a pharmaceutically acceptable salt thereof and / or an allosteric modulator, wherein the second pharmaceutical composition provides an average AUC that is at least about, for example, 25%, 30%, 35%, 40%, 45%, or 50% smaller than that of the first pharmaceutical composition. 0-∞ A stable in vivo plasma profile. In the embodiments, the composition provides the patient with improved function the following day. For example, after administration of the first pharmaceutical composition and / or the second pharmaceutical composition, the composition may provide improvement in one or more symptoms lasting for more than about, for example, 6 hours, 8 hours, 10 hours, or 12 hours.

[0119] In the embodiments, the parenteral composition may be administered as needed, such as once daily, twice daily, three times daily, four times daily, or more times daily, or continuously as needed by the patient. In the embodiments, the parenteral composition may be administered immediately at the onset of a seizure or as soon as possible thereafter. In the embodiments, the parenteral composition may be administered as soon as possible when warning signs of a seizure are present, such as auras, unusual smells, or abnormal sensations.

[0120] In the implementation scheme, this document provides a method for treating epileptic disorders, the method comprising administering a first drug dose containing a subtherapeutic dose of an allosteric modulator to a patient in need, wherein the composition provides an improvement lasting for more than 6 hours after administration.

[0121] In the implementation scheme, this document provides a method for treating epileptic disorders, the method comprising administering to a patient in need a first drug dose comprising a subtherapeutic dose of gabosadol or a pharmaceutically acceptable salt thereof, wherein the composition provides an improvement lasting for more than 6 hours after administration.

[0122] In the implementation scheme, this document provides a method for treating epileptic disorders, the method comprising administering to a patient with appropriate need a first pharmaceutical composition comprising an allosteric modulator and a second pharmaceutical composition comprising gabosadol or a pharmaceutically acceptable salt thereof, wherein the second pharmaceutical composition provides an average AUC of less than about 900 ng•hr / ml. 0-∞ The in vivo plasma profile. In an embodiment, the second pharmaceutical composition provides an AUC of less than about, for example, 800 ng•hr / ml, 750 ng•hr / ml, 700 ng•hr / ml, 650 ng•hr / ml, or 600 ng•hr / ml. 0-∞ The in vivo plasma profile. In an embodiment, the second pharmaceutical composition provides an AUC of less than about, for example, 550 ng•hr / ml, 500 ng•hr / ml, 450 ng•hr / ml, 400 ng•hr / ml, or 350 ng•hr / ml. 0-∞ The in vivo plasma profile. In an embodiment, the second pharmaceutical composition provides an AUC of less than about, for example, 300 ng·hr / ml, 250 ng·hr / ml, 200 ng·hr / ml, 150 ng·hr / ml, or 100 ng·hr / ml. 0-∞ The in vivo plasma profile. In one embodiment, a first pharmaceutical composition and a second pharmaceutical composition are administered, wherein the compositions provide the patient with improved function the following day. In another embodiment, the first pharmaceutical composition provides improvement in one or more symptoms lasting for more than, for example, 6 hours, 8 hours, or 12 hours after administration of the first pharmaceutical composition.

[0123] In the implementation scheme, this document provides a method for treating epileptic disorders, the method comprising administering to a patient with appropriate need a first pharmaceutical composition comprising an allosteric modulator and a second pharmaceutical composition comprising gaposidoxur or a pharmaceutically acceptable salt thereof, wherein the first composition provides a Cg concentration greater than that provided by administration of the second pharmaceutical composition. max Mostly more than 50% of C max The in vivo plasma profile. As used herein, C is provided by administration of the second pharmaceutical composition. max The plasma spectrum contribution of the first pharmaceutical composition may or may not be included. In one embodiment, administration of the second pharmaceutical composition does not include the plasma spectrum contribution of the first pharmaceutical composition. In another embodiment, the first composition provides a C-value greater than that provided by administration of the second pharmaceutical composition. max Mostly, for example, 60%, 70%, 80% or 90% of C max The plasma profile in the body.

[0124] In the implementation scheme, the T of the first pharmaceutical composition maxIt is less than 3 hours. In the implementation plan, the T of the first pharmaceutical composition max It is less than 2.5 hours. In the implementation plan, the T of the first pharmaceutical composition... max It is less than 2 hours. In the implementation plan, the T of the first pharmaceutical composition max It is less than 1.5 hours. In the implementation plan, the T of the first pharmaceutical composition... max It is less than 1 hour.

[0125] In one embodiment, the first pharmaceutical composition provides a dissolution rate of at least about 80% within the first 20 minutes of administration to a patient with the corresponding need. In another embodiment, the first pharmaceutical composition provides a dissolution rate of at least about, for example, 85%, 90%, or 95% within the first 20 minutes of administration to a patient with the corresponding need. In yet another embodiment, the first pharmaceutical composition provides a dissolution rate of at least 80% within the first 10 minutes of administration to a patient with the corresponding need.

[0126] In embodiments, the first and / or second pharmaceutical compositions are subtherapeutic doses. A subtherapeutic dose is an amount of an active substance, such as an allosteric modifier and / or gaboroxadol or a pharmaceutically acceptable salt thereof, less than the amount required for therapeutic effect. In embodiments, a subtherapeutic dose is an amount of an allosteric modifier or a pharmaceutically acceptable salt thereof that, alone, cannot provide improvement in at least one symptom of epileptic disorder but is sufficient to maintain such improvement. In embodiments, a subtherapeutic dose is an amount of gaboroxadol or a pharmaceutically acceptable salt thereof that, alone, cannot provide improvement in at least one symptom of epileptic disorder but is sufficient to maintain such improvement. In embodiments, the method comprises administering a first pharmaceutical composition and a second pharmaceutical composition, the first pharmaceutical composition providing improvement in at least one symptom of epileptic disorder, and the second pharmaceutical composition maintaining that improvement. In embodiments, after administration of the first pharmaceutical composition, the second pharmaceutical composition may provide a synergistic effect to improve at least one symptom of epileptic disorder. In embodiments, the second pharmaceutical composition may provide a synergistic effect to improve at least one symptom of epileptic disorder.

[0127] In the embodiments, this document provides a method for treating epileptic disorders, the method comprising administering to a patient in need a pharmaceutical composition comprising a first pharmaceutical dose and a second pharmaceutical composition, wherein the first pharmaceutical dose provides an improvement lasting for more than 6 hours after administration, and the second pharmaceutical composition comprises a subtherapeutic dose of gapoxetine or a pharmaceutically acceptable salt thereof.

[0128] The first and second drug compositions may be administered simultaneously or at intervals to achieve immediate, intermediate, or long-term improvement in at least one symptom. In one embodiment, the first and second drug compositions may be administered 6 hours apart. In another embodiment, the first and second drug compositions may be administered 12 hours apart. In yet another embodiment, the first and second drug compositions may be administered within, for example, 15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 18 hours, 24 hours, etc. In another embodiment, the first and second drug compositions may be administered together. In yet another embodiment, the first and second drug compositions may be administered at least, for example, 15 minutes, 30 minutes, 1 hour, 2 hours, 12 hours, 18 hours, 24 hours, etc. In one embodiment, improvement in at least one symptom of epileptic disorder lasting more than 8 hours after administration to a patient is provided. In another embodiment, improvement lasting more than about, for example, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration to a patient is provided.

[0129] In the implementation scheme, administration of the first pharmaceutical composition and the second pharmaceutical composition may provide a synergistic effect to improve at least one symptom of epileptic disorder.

[0130] In the implementation scheme, the first pharmaceutical composition and / or the second pharmaceutical composition contain any of the aforementioned amounts of an active substance, such as an allosteric modifier and / or gaposadol and its pharmaceutically acceptable salts.

[0131] In the embodiments, the first pharmaceutical composition and / or the second pharmaceutical composition comprise 5 mg to 15 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg of an active substance, such as an allosteric modifier and / or gabosadol.

[0132] In embodiments, the first pharmaceutical composition and / or the second pharmaceutical composition comprises 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg of an active substance, such as an allosteric modifier and / or gabosadoc, or multiples thereof. In embodiments, the first pharmaceutical composition comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of an allosteric modifier. In embodiments, the second pharmaceutical composition comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of an allosteric modifier.

[0133] In embodiments, methods of treating epileptic disorders include administering an allosteric modulator and / or gaposadol or a pharmaceutically acceptable salt thereof in combination with one or more other active compounds. Combination therapy may include administering the active agents together in the same mixture or as separate mixtures. In embodiments, the pharmaceutical composition comprises two, three, or more active agents. In embodiments, the combination produces a more than additive effect in the treatment of the disease or disorder. Therefore, a combination therapy of agents is provided for epileptic disorders, where the combined agents may provide a synergistic effect enhancing efficacy.

[0134] In the implementation plan, gaposadol or a pharmaceutically acceptable salt thereof is administered in combination with conventional therapies for seizures, epilepsy, or one of the other disorders disclosed herein. Common conventional therapies for seizures and epilepsy include antiepileptic and non-antiepileptic drug treatments, such as low-carbohydrate diets (e.g., ketogenic diets, such as the classic diet, medium-chain triglyceride (MCT) diet, modified Atkins diet (MAD), and low glycemic index therapy (LGIT)), intravenous immunoglobulins, steroids, exclusion diets, valgus nerve stimulation, corticetomy, and multiple subpial transections.

[0135] Common antiepileptic and anticonvulsant active compounds that can be used in combination with allosteric modifiers and / or gabosadol or their pharmaceutically acceptable salts include, but are not limited to, acetazolamide, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, valproate, stearyl alcohol, thiabendazole, topiramate, vigabatrin, and zonisamide.

[0136] The disclosed compounds, such as gaboroxadol or a pharmaceutically acceptable salt thereof, or allosteric modifiers, their pharmaceutically acceptable salts, derivatives, and / or analogs, can be used alone as a monotherapy, as the sole active agent. In embodiments, methods of treating epileptic disorders using allosteric modifiers or their pharmaceutically acceptable salts are provided. In embodiments, methods of treating epileptic disorders include administering an allosteric modifier, its pharmaceutically acceptable salt, derivative, and / or analog in combination with one or more other active agents, such as an allosteric modifier or gaboroxadol. Combination therapy may include administering the active agent, such as an allosteric modifier or gaboroxadol, together in the same mixture or as a separate mixture. In embodiments, the pharmaceutical composition comprises two, three, or more active agents. In embodiments, the combination produces an effect greater than an additive effect in the treatment of the disease or disorder. Therefore, combination therapy of agents for epileptic disorders is provided, whereby the combined agents may provide a synergistic effect enhancing efficacy.

[0137] In the implementation plan, gapoxetine or a pharmaceutically acceptable salt thereof, or an allosteric modulator, a pharmaceutically acceptable salt thereof, derivatives and / or analogs thereof, or both, are administered in combination with conventional therapies for seizures, epilepsy, or one of the other disorders disclosed herein. For example, common conventional therapies for seizures and epilepsy include antiepileptic and non-antiepileptic drug treatments, such as low-carbohydrate diets (e.g., ketogenic diets, such as the classic diet, medium-chain triglyceride (MCT) diet, modified Atkins diet (MAD), and low glycemic index treatment (LGIT)), intravenous immunoglobulins, steroids, exclusion diets, abducens nerve stimulation, corticetomy, and multiple subpial transections.

[0138] Common antiepileptic and anticonvulsant active compounds that can be used in combination with allosteric modulators include, but are not limited to, acetazolamide, carbamazepine, clonazan, clonazepam, escritazapine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitroxamethasone, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufedipine, valproate, stearyl alcohol, thiabendazole, topiramate, vigabatrin, and zonisamide.

[0139] In the implementation plan, co-treatment with an allosteric modulator, a pharmaceutically acceptable salt thereof, or a derivative thereof, and gabosadol or a pharmaceutically acceptable salt thereof effectively reduces the frequency or severity of seizures in subjects compared to administration of either compound alone. In the implementation plan, co-treatment produces more results than additive results compared to the compounds administered alone.

[0140] In the implementation plan, subjects can start with a low dose and gradually increase the dose. This allows for the determination of whether the drug is well tolerated in the subjects. Children may receive a lower dose than adults.

[0141] In implementation schemes, such as combination therapy, the dose of gabosadol for children may be from 0.1 mg / kg to 1 mg / kg, and the dose of the allosteric modifier may be from 0.01 mg / kg to 0.1 mg / kg. In implementation schemes, the weight / weight ratio of gabosadol to the allosteric modifier may be 10:1. However, based on the dosage ratio of the active pharmaceutical ingredient (API) in milligrams, the range of gabosadol to allosteric modifier may be from 0.1:1 to 100:1, respectively.

[0142] An effective treatment for the epileptic disorder (e.g., acute recurrent seizures) described in this paper can be established by demonstrating a reduction in seizure frequency (e.g., more than 50%) compared to baseline after a certain period of time. For example, after a 1-month baseline period, patients may be randomized to gaboroxadol or an allosteric modulator or placebo as an adjunct to standard therapy (such as valproate and clobazian) during a 2-month double-blind period. The primary outcome measure may include the percentage of responders to gaboroxadol or an allosteric modulator and to placebo, defined as having experienced at least a 50% reduction in the frequency of clonic (or tonic-clonic) seizures compared to baseline during the second month of the double-blind period. Patients experiencing status epilepticus during the double-blind period may be considered non-responders. Secondary outcomes may include the absolute count of clonic (or tonic-clonic) seizures during the second month of the double-blind period (normalized to 30 days by dividing the original count by the exact number of days observed and multiplying by 30) and the percentage change from baseline.

[0143] The efficacy of gabosadol and / or allosteric modulators for the treatment of publicly known epileptic disorders (e.g., those associated with Dravet syndrome or Lennox-Gastaut syndrome) can be established in other controlled studies. For example, a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period, followed by a 3-week titration period and a 12-week maintenance period can be used in patients aged 2–54 years with a current or previously diagnosed diagnosis of Dravet syndrome or LGS. Multiple target maintenance doses of gabosadol and / or allosteric modulators can be tested based on patient weight and specific dosing regimens. The primary efficacy measure may include the percentage reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic) (also known as drop attacks) from the 4-week baseline period to the 12-week maintenance period. Therefore, efficacy can be measured as the percentage reduction in weekly seizure frequency (e.g., atonic, tonic, or myoclonic) from baseline, for example, 0 to <20, 20 to <40, 40 to <60, 60 to <80, 80 to <100.

[0144] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0145] As used herein, the terms “about” or “approximately” mean within an acceptable range of error for a particular value, as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to practice in the art, “about” may mean within three or more standard deviations. Alternatively, “about” may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and still more preferably up to 1%, of a given value. Alternatively, particularly, with respect to biological systems or processes, the term may mean within orders of magnitude of the value, preferably within five times the value, and more preferably within twice the value.

[0146] As used herein, the term "treating" or "treatment" means the relief, reduction, or delay of the onset of clinical symptoms of a disease or condition in a subject who may be susceptible to or have a disease or condition but has not yet experienced or displayed clinical or subclinical symptoms of the disease or condition. In some embodiments, "treating" or "treatment" may refer to the prevention of the onset of clinical symptoms of a disease or condition in a subject who may be susceptible to or have a disease or condition but has not yet experienced or displayed clinical or subclinical symptoms of the disease or condition. "Treating" or "treatment" may also refer to the suppression of a disease or condition, for example, preventing or reducing its development or at least one of its clinical or subclinical symptoms. "Treating" or "treatment" also refers to the relief of a disease or condition, for example, causing the remission of a disease or condition or at least one of its clinical or subclinical symptoms. The benefit to the treated subject may be statistically significant, mathematically significant, or at least perceptible to the subject and / or physician. Nevertheless, prophylactic and therapeutic treatments are two separate implementations of the disclosure herein.

[0147] "Effective dose" or "therapeutic effective dose" means a dose that is sufficient to alleviate one or more symptoms of the disorder, disease, or condition being treated, or otherwise to provide the desired pharmacological and / or physiological effect.

[0148] "Improvement" refers to the treatment of symptoms or conditions related to epileptic disorders as measured relative to at least one symptom or condition of a metabolic disease.

[0149] "Improvement of function the next day" or "wherein improvement of function the next day" refers to improvement after waking from overnight sleep, wherein the beneficial effect of administration of one or more of gabosadol alone or a pharmaceutically acceptable salt thereof, or of gabosadol alone, or in combination with an allosteric modifier, is applicable to at least one symptom or condition associated with epileptic disorder, and is subjectively perceptible to the patient or objectively perceptible to an observer within a certain period of time after waking, such as immediately, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc.

[0150] The terms “composition,” “pharmaceutical composition,” “formulation,” and “pharmaceutical formulation” are used interchangeably in this document. “Composition,” “pharmaceutical composition,” “formulation,” and “pharmaceutical formulation” include dosage forms. Dosage forms may include unit doses.

[0151] "Pharmaceutical acceptable" means a molecular entity or composition that is "generally considered safe," for example, that is physiologically tolerable and does not typically produce allergic reactions or similar adverse reactions (such as stomach upset) when administered to humans. In the implementation plan, this term refers to a molecular entity or composition approved by a federal or state regulatory agency as a GRAS (Generally Recognized As Safe) list (having undergone premarket review and approved by the FDA under Sections 204(s) and 409 of the Federal Food, Drug, and Cosmetic Act) or a similar list (United States Pharmacopeia or another recognized pharmacopoeia for use in animals and more particularly in humans).

[0152] As used herein, the terms “prevention” or “preventing” mean applying a composition to a subject or system at risk of or prone to having one or more symptoms caused by a disease or disorder, in order to promote the cessation of a specific symptom of the disease or disorder, the reduction and prevention of one or more symptoms of the disease or disorder, the reduction of the severity of the disease or disorder, the complete elimination of the disease or disorder, or the stabilization or delay of the development or progression of the disease or disorder.

[0153] As used herein, "prodrug" refers to a pharmacological substance (drug) administered to a subject in an inactive (or significantly less active) form. After administration, the prodrug is metabolized in the body (in vivo) into a compound having the desired pharmacological activity.

[0154] The terms “analog,” “analogue,” and “derivative” are used interchangeably herein and refer to compounds that have the same core as the parent compound but may differ from the parent compound in terms of bond order, the absence or presence of one or more atoms and / or atomic groups, and their combinations thereof. A derivative may, for example, differ from the parent compound in terms of one or more substituents present on the core, which may include one or more atoms, functional groups, or substructures. Generally, it is conceivable that derivatives are formed from the parent compound, at least theoretically, through chemical and / or physical processes.

[0155] As used herein, a “stereoisomer” is an isomer of molecules that have the same molecular formula and bonded atomic sequence (composition), but whose atoms have different three-dimensional orientations in space. Examples of stereoisomers include enantiomers and diastereomers. As used herein, an enantiomer is one of two mirror images of an optically active or chiral molecule. A diastereomer (or diastereoisomer) is a stereoisomer that is not an enantiomer (a mirror image of another molecule that does not overlap). A chiral molecule contains a chiral center, also called a stereocenter or stereogenic center, which is any point in the molecule, but not necessarily an atom, that carries a group that causes the exchange of any two groups to result in a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus, or sulfur atom, but other atoms are also possible in both organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is attributed to a tetrahedral stereocenter (e.g., tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry typically have fewer stereoisomers than the maximum possible number. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Optionally, a mixture of enantiomers can be enantiomer-enriched, such that one enantiomer is present in an amount greater than 50%. Enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. “Chirality” also includes axial and planar chirality.

[0156] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound as defined herein, wherein the parent compound is modified by preparing its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, or nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and hydroxyethanesulfonates. Pharmaceutically acceptable salts of compounds can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods. For example, Gabosado can be formulated for administration to patients using pharmaceutically acceptable salts (including acid addition salts, zwitterionic hydrates, zwitterionic anhydrous salts, hydrochlorides, or hydrobromic acids) or as zwitterionic monohydrates. Acid addition salts include, but are not limited to, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citralic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, or theophylline acetic acid addition salts, as well as 8-halotheophyllines, such as 8-bromotheophylline. In other suitable embodiments, inorganic acid addition salts may be used, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, or nitrate addition salts.

[0157] "Excipient" is a substance other than the active pharmaceutical ingredient (e.g., gaposadol) in a pharmaceutical composition that has been appropriately evaluated for safety and is included in a drug delivery system to assist in the processing of the drug delivery system during its manufacture; protect; support; enhance stability, bioavailability, or patient acceptability; assist in product identification; or any other property that enhances the overall safety and effectiveness of the drug delivery system during storage or use.

[0158] "Stabilizer" or "stabilizing amount" refers to the amount of one or more excipients contained in a parenteral composition that provides sufficient stability without adversely affecting the bioavailability, safety, and / or efficacy of the allosteric modifier and / or gaborsard or its pharmaceutically acceptable salts used in the composition.

[0159] "Stable" means that after a specified period of time, such as 3 months or 6 months, gaposadol or its pharmaceutically acceptable salts are essentially not degraded.

[0160] "Soluble" means that the solution of the allosteric modifier and / or gabosadol or its pharmaceutically acceptable salt does not become cloudy and / or there is essentially no precipitate in the solution.

[0161] "Sufficiently soluble" means that the particle content is low enough and the material is sterile enough for parenteral administration. For example, the number of particles in the liquid composition should be, for instance, less than 6,000 10 μm particles per 10 ml volume of solvent, preferably less than 10,000, less than 5,000, less than 3,000, less than 1,000, or less than 400 10 μm particles. In some instances, the number of particles in the liquid composition should be less than 1,000, less than 600, or less than 200 25 μm particles per 10 ml volume.

[0162] The term "site-compatible" in this document means that the composition is tolerated at the injection or infusion site, thus minimizing side effects such as local skin irritation or venous irritation, including inflammatory reactions at the infusion site. The parenteral compositions described herein may have fewer side effects, such as skin irritation or phlebitis, than conventional products.

[0163] As used herein, "purified" means a substance that has been isolated under conditions that reduce or eliminate the presence of irrelevant substances (i.e., contaminants, including the natural material from which the substance is obtained). As used herein, the term "substantially free" is operable in the context of analytical testing of the substance. Preferably, purified material that is substantially free of contaminants is at least 95% pure; more preferably at least 97% pure, and still more preferably at least 99% pure. Purity can be evaluated, for example, by chromatography or any other method known in the art. In embodiments, purified means that the level of contaminants is below the level acceptable to regulatory authorities for safe administration to humans or non-human animals.

[0164] When the composition mentioned herein is referred to as “ready-to-use,” it should mean a prepared article in reconstructed form, having a standardized concentration and quality, prefilled in a single-use container such as a glass vial, infusion bag, or syringe, ready for direct administration to a patient.

[0165] When referring to the compositions herein as “direct administration,” it means immediate administration, i.e., without further dilution, premixing with other substances, or otherwise altering the composition or its formulation. Such compositions are typically expelled directly from the infusion device and administered via a vascular access inlet or through a central line.

[0166] "Dosage" is intended to include formulations expressed in the terms μg / kg / day, μg / kg / hour, mg / kg / day, or mg / kg / hour. Dosage is the amount of an ingredient administered according to a specific dosage regimen. "Dose" is the amount of a dose administered to a mammal per unit volume or mass, for example, expressed as an absolute unit dose in mg or μg of the dose. Dose depends on the concentration of the dose in the formulation, such as moles / L (M), mass / volume (m / v), or mass / mass (m / m). These two terms are closely related because a specific dosage arises from a dosage regimen of one or more doses of the formulation. The specific meaning in any case will be apparent from the context.

[0167] The terms “patient” and “subject” are used interchangeably in this document and include, but are not limited to, primates such as humans, canines, pigs, ungulates, rodents, poultry, and avian.

[0168] The terms "co-administered with," "in combination with," "administered in combination with," "acombination of," "administered along with," or "co-therapy" are used interchangeably and refer to the administration of two or more agents during treatment. Agents may be administered together at the same time or individually at intervals. Agents may be administered in a single dosage form or in individual dosage forms.

[0169] "PK" refers to pharmacokinetic profile. max Defined as the highest estimated plasma drug concentration (ng / ml) during the experiment. T max Defined as when C max The estimated time (min). AUC 0-∞ The total area under the plasma drug concentration-time curve from drug administration to drug excretion (ng / L) hr / ml or μg (hr / ml). The area under the curve is determined by the clearance rate. The clearance rate is defined as the volume of blood or plasma (ml / min) in which the drug content is completely removed per unit time. Example

[0170] The embodiments provided herein are included only to increase the disclosure of this document and should not be considered as limiting in any way.

[0171] Example 1 Gapoxadiol plasma concentration spectrum The following examples provide plasma concentration profiles and dose proportionality of gabosadole monohydrate after a single oral dose ranging from 2.5 mg to 20 mg. Absolute bioavailability of gabosadole monohydrate capsules ranging from 2.5 mg to 20 mg was also evaluated.

[0172] This study included a separate group of 10 healthy adult subjects (at least 4 subjects per sex) who participated in a 6-cycle, double-blind, randomized, crossover study designed to evaluate the dose-proportioning relationship and absolute bioavailability of gapository across five single oral doses spanning a dose range of 2.5 mg to 20 mg. During treatment cycles 1 through 5, the order in which subjects received the five single oral doses of gapository (2.5 mg; 5 mg; 10 mg; 15 mg; and 20 mg) was randomized. Each subject was expected to complete all 6 treatment cycles, with at least 4 days of washout between each cycle.

[0173] Each oral administration during the treatment period consists of two test drug capsules taken concurrently with each scheduled dosing. The treatments for oral administration of the study drug are named as follows: Treatment A – one 2.5 mg gapository capsule and one matched placebo capsule; Treatment B – one 5 mg gapository capsule and one matched placebo capsule; Treatment C – one 10 mg gapository capsule and one matched placebo capsule; Treatment D – one 15 mg gapository capsule and one matched placebo capsule; and Treatment E – 20 mg gapository (two 10 mg gapository capsules). Subjects receive their study drug with 240 mL of water at approximately 8:00 AM after an overnight fast. Free access to water is permitted except for one hour before and after administration of the study drug. No food is permitted for four hours after administration.

[0174] For each subject in each treatment, plasma and urine samples were collected within 16 hours after administration to determine pharmacokinetic parameters (e.g., AUC, C10, etc., as appropriate). max T maxApparent t 1 / 2 Cumulative urinary excretion, renal clearance, clearance rate, and steady-state distribution volume. AUC and C of gabosadole. max Efficacy adjustments were made to facilitate comparison of pharmacokinetic data across studies. Table 1 provides the individual efficacy-adjusted pharmacokinetic parameters for adding borsadol after a single oral dose (2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg).

[0175] Table 1. Pharmacokinetic parameters of gaboxard after oral and intravenous administration

[0176] Example 2 Evaluation of the residual effect produced by gaposadol administration This study was a double-blind, double-dummy, randomized, single-dose, three-cycle crossover study with active agent and placebo controls, followed by an open-label, single-dose, single-cycle study in healthy older male and female participants. Participants were randomly assigned to each of three treatments (treatments A, B, and C), which were administered in a crossover manner over the first three treatment cycles. For treatment A, participants received a single dose of 10 mg gaboxard; for treatment B, participants received a single dose of 30 mg flurazepam; and for treatment C, participants received a single dose of placebo. Doses were administered orally at bedtime on day 1. Participants remained at home during each treatment cycle from early evening of administration until approximately 36 hours after administration (morning of day 3). Participants who participated in treatment cycles 1–3 participated in a fourth treatment cycle. In this cycle, for the gaboxard pharmacokinetics, a single dose of 10 mg gaboxard was administered orally on an open-label basis on the morning of day 1 (treatment D). There was a minimum 14-day washout period between doses in consecutive treatment cycles. Study participants included healthy, older men and women aged 65 to 80 years with a Mini Mental Status of 24 and a weight of at least 55 kg. All participants received 10 mg gaboxard monohydrate capsules and 30 mg flurazepam (provided as 2 × 15 mg capsules), with a placebo-matched combination of gaboxard and flurazepam.

[0177] The primary endpoints evaluated included pharmacodynamics (measurements of psychomotor performance, memory, attention, and daytime sleepiness after pm dosing), gabosaccharide pharmacokinetics, and safety. For the primary endpoints of Choice Reaction Time and Critical Flicker Fusion, gabosaccharide (single 10 mg dose) showed no residual effect 9 hours after dosing, while the active reference, flurazepam (30 mg single dose), showed a significant effect on the same tests. Furthermore, gabosaccharide showed no signs of residual effect on other measurements used in the study (Multiple Sleep Latency Test (MSLT); Digit Substitution Test (DSST); tracking, memory tests, body rocking, and the Leeds Sleep Assessment Questionnaire).

[0178] Example 3 Evaluation of the ability of allogestrinone, ganexone, and gaboxard to block benzodiazepine tolerance in status epilepticus Evaluate the acute anticonvulsant efficacy of allegenone, ganexone, and gabosadol when administered in escalating doses 30 minutes after the onset of status epilepticus (typically the time point for benzodiazepine tolerance). Compare results obtained with these agents to those obtained from side-by-side studies in animals treated with the same drug.

[0179] Male Sprague Dawley rats (n=10 treatments / groups, 100–125 g; Charles River Laboratories) were systemically treated with lithium chloride (127 mg / kg; intraperitoneal (ip)) 24 hours prior to administration of the chemoconvulsant pilocarpine. The following day, the rats received pilocarpine hydrochloride (50 mg / kg; ip) and were carefully monitored for the presence or absence of convulsive seizure activity. Pilocarpine administration induced convulsive seizures within 5–20 min, and any rat that did not exhibit convulsive seizure activity within 45 min of pilocarpine administration was excluded from further study. On the day of study, the incidence of convulsive seizures was evaluated 30 minutes after the first observed seizure. The ability of each study compound (allogestrinone (ALLO), ganexone (GNX), or gapoxetine (GBD)) or mediator (VEH) (40% hydroxypropyl β-cyclodextrin) administered via incremental doses per ip after 120 min to prevent convulsive status epilepticus in a Li-Pilo model of status epilepticus. Throughout the study, the researchers conducting behavioral observations were unaware of the treatment conditions (i.e., allogestrinone, ganexone, or gapoxetine). All rats were observed and their seizure severity was scored 120 min after drug administration, and any accompanying behavioral effects were also recorded by researchers unaware of the treatment conditions. At the end of the behavioral observation period, all surviving rats were administered 3 ml of lactated Ringer's solution to replace any SE-induced fluid loss.

[0180] The dosage of each study compound (allogestrinone, ganexone, or gaboxard) was varied in groups of 10 rats until at least two points were established between the limits of 100% protection (absence of convulsive seizures 10 min after drug administration) and 0% protection. The drug dosage required to produce the desired endpoint in 50% of animals (ED50 or TD50) and at a 95% confidence interval was calculated by a computer program based on the Probit method (Finney DJ. Probit Analysis. Cambridge University Press. 1971). Such dose-response evaluation typically requires up to five treatment groups for each study compound, with a total of up to 50 rats per compound. Therefore, up to 150 rats can be used for the quantification of these study compounds (allogestrinone, ganexone, or gaboxard), and there is also a mediator treatment group (n = 10), making the total number of rodents in Study 1 160. All animals in the study were retained for 24 hours after the completion of the study for evaluation of weight changes. The dosage of allogestrinone, ganexone, or gapoxetine is 0.5 mg / kg, 2 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / kg.

[0181] Pharmacokinetic Sample Collection: Brain and plasma were collected from each dose's satellite cohort of rats for evaluation (n = 3 rats / dose / compound; up to 45 rats in total). Plasma was collected from trunk blood after centrifugation at 10,000 × g for 10 min at 4 °C. The anticoagulant was lithium heparin. Brain was rapidly frozen on dry ice. All samples were stored at -20 °C. The test procedure timeline is as follows: Figure 2 As shown in the image.

[0182] Dose-response curves were constructed and expressed as an ED50 (95% confidence interval), calculated for administration of each study compound (allogestrinone, ganexone, or gabosadol) 30 minutes after the first observed seizure. In cases where data did not allow for ED50 calculation due to lack of efficacy, the highest dose tested was recorded. For all treatment conditions, measurements of additional effects, such as motor injury, post-SE weight change, or survival 24 hours after SE, were also recorded during the study period.

[0183] Table 2. Overall Survival Rate and Protection Outcomes

[0184] Figure 3It is a bar chart showing the percentage of protection against allogeneic ketone, ganexone, or gabosadol versus dosage. Figure 4 It is a bar chart showing the dose-based 24-hour survival results for allogestrinone, ganexone, or gabosadone. Figure 5 It is a bar chart showing the observed number of epileptic seizures against the dose. Figure 6A It is a bar chart showing the change in body weight 24 hours after status epilepticus as a function of the percentage of loss versus the dose. Figure 6B This is a bar chart showing the 24-hour weight loss in the 0.5 mg / kg dose group. Dose-response assessment of treatment during benzodiazepine-resistant status epilepticus showed a dose-dependent efficacy of ganedrone (ip) – a significant improvement in protection at 20 mg / kg (p<0.02). Potential for an inverted U-shaped response curve of gaboxard at 0.5 mg / kg, p = 0.071. A significant improvement in 24-hour survival was shown in rats treated with gaboxard (10 mg / kg).

[0185] Example 4 A prospective study to characterize the ability of allogestrinone, ganexone, and gabosadol to block benzodiazepine tolerance-induced status epilepticus. Initial dose-response studies of allogeneolone (ALLO), ganexone (GNX), and gaboroxadol (GBD) administered intraperitoneally (ip) demonstrated their potential efficacy against benzodiazepine-resistant status epilepticus (Example 3). This study will evaluate the potential for synergistic activity of gaboroxadol with allogeneolone, ganexone, or benzodiazepines, and lorazepam (LZP) against benzodiazepine-resistant status epilepticus in a Li-Pilo rat model. Specifically, a low dose (e.g., 0.5 mg / kg) of gaboroxadol will be administered in combination with a fixed dose of allogeneolone, ganexone, or lorazepam. The doses of allogeneolone and ganexone will be those previously found to confer anticonvulsant effects in Example 3 (Table 2). The dose of lorazepam will be 2 mg / kg (Walton and Treiman, 1990). Neurology 40: 990-994 (1990). The activity of each compound will also be evaluated individually. A mediator treatment group will be included. At 30 min after a status epileptic seizure, a single ip dose (Table 3) of each dose or dose combination will be administered to rats (n = 13 / group). The presence or absence of further seizure activity in the rats will be observed.

[0186] Table 3. Study compounds and combinations to be evaluated (n=13 rats / treatment group, of which n=3 rats were sacrificed for PK analysis).

[0187]

[0188] Twenty-four hours prior to administration of the chemoconvulsant pilocarpine, male Sprague Dawley rats (n=13 treatments or treatment / group; from Charles River Laboratories, 100–125 g upon arrival) were systemically treated with lithium chloride (127 mg / kg; ip). The following day, the rats received pilocarpine hydrochloride (50 mg / kg; (ip)) and were carefully monitored for the presence or absence of convulsive seizure activity. Pilocarpine administration induced psychotic seizures within 5–20 min, and any rat that did not exhibit convulsive seizure activity within 45 min of pilocarpine administration was excluded from further study. On the day of study, the ability of each study compound (allogestrinone, ganexone, or gapoxetine) or mediator (VEH) administered 30 min after the first observed convulsive seizure (as outlined in Table 3) to prevent status epilepticus in the Li-Pilo model was evaluated. Throughout the study, the researchers conducting behavioral observations were unaware of the treatment conditions (i.e., allogestrinone, ganexone, or gaboxard, lorazepam, or VEH). All rats were observed and their seizure severity was scored 120 min after drug administration, and any accompanying behavioral effects were also recorded by researchers unaware of the treatment conditions. At the end of the behavioral observation period, all surviving rats were administered 3 ml of lactated Ringer's solution to replace any fluid loss induced by status epilepticus.

[0189] For a total of 130 rats, the dose of each study compound will be administered to the rats (n=13 / compound dose; Table 3). The expected non-response rate for rats pretreated with Li-Cl but not developing convulsive status epilepticus within a 45-minute timeframe is 15%. Therefore, up to 150 rats will be used for this study, including potential non-responders. All animals in this study will be retained for 24 hours after the study to evaluate weight changes and overall behavioral performance at that time (e.g., lethargy / activity). Behavioral performance will be evaluated by a researcher unaware of the treatment status.

[0190] Pharmacokinetic Sample Collection: Brain and plasma will be collected from rat groups for each dose for evaluation (n = 3 rats / dose / compound). Plasma will be separated from trunk blood after centrifugation at 10,000 × g for 10 min at 4 °C. The anticoagulant will be lithium heparin. Brain will be rapidly frozen on dry ice. The test procedure timeline is as follows: Figure 7 As shown.

[0191] Those skilled in the art will recognize, or be able to determine, many equivalents of the specific embodiments described herein using no more than conventional experiments. Such equivalents are intended to be included in the claims.

[0192] This application provides the following: Project 1. A method for treating epileptic disorders, the method comprising administering a pharmaceutical composition containing an allosteric modulator to a patient in need.

[0193] Project 2. According to the method described in Project 1, the epileptic disorder is selected from the group consisting of epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absence, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Otahara syndrome, Rasmussen syndrome, West syndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute recurrent epileptic seizures, benign Rolando epilepsy, status epilepticus, refractory status epilepticus, extremely refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, increased epileptic seizure activity, or sudden epileptic seizures.

[0194] Project 3. According to the method described in Project 1, the epileptic disorder is status epilepticus.

[0195] Project 4. According to the method described in Project 1, the epileptic disorder is acute recurrent epileptic seizures.

[0196] Project 5. According to the method described in Project 1, the epileptic disorder is Lennox-Gastaut syndrome.

[0197] Project 6. The method according to Project 1, wherein the composition provides a reduction in the frequency of seizures, the severity of seizures, or a combination thereof in patients diagnosed with epileptic disorders.

[0198] Project 7. According to the method described in Project 1, wherein the allosteric modulator is selected from the group consisting of neurosteroids, benzodiazepines and potassium channel openers.

[0199] Item 8. The method according to Item 1, wherein the allosteric modifier is ganexone.

[0200] Project 9. According to the method described in Project 1, the allosteric modifier is allogenein ketone.

[0201] Item 10. According to the method of Item 1, the allosteric modifier is a benzodiazepine.

[0202] Item 11. The method according to Item 10, wherein the benzodiazepines are selected from the group consisting of midazolam, clonazepam, clonazepam, diazepam, lorazepam, flurazepam and lorazepam.

[0203] Project 12. According to the method described in Project 1, wherein the allosteric modifier is a potassium channel opener.

[0204] Item 13. The method according to Item 12, wherein the potassium channel opener is retigabine or flupirtine.

[0205] Item 14. The method according to Item 1, wherein the patient is also administered gabosadol or a pharmaceutically acceptable salt thereof.

[0206] Item 15. The method according to Item 1, wherein the allosteric modifier is applied once daily, twice daily, three times daily, or every other day.

[0207] Project 16. The method according to Project 1, the method further comprising administering a compound selected from the group consisting of acetazolamide, carbamazepine, escricazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitroxazone, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, rufenamide, sodium valproate, stearyl alcohol, thiabendazole, topiramate, azithromycin, and zonisamide.

[0208] Item 17. The method according to Item 1, wherein the pharmaceutical composition is a parenteral preparation.

[0209] Item 18. A method for treating epileptic disorders, the method comprising administering to a patient in need a pharmaceutical composition comprising gabosadol or a pharmaceutically acceptable salt thereof.

[0210] Project 19. According to the method described in Project 18, the epileptic disorder is selected from the group consisting of epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absence, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Otahara syndrome, Rasmussen syndrome, West syndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute recurrent epileptic seizures, benign Rolando epilepsy, status epilepticus, refractory status epilepticus, extremely refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, increased epileptic seizure activity, or sudden epileptic seizures.

[0211] Item 20. The method according to Item 18, wherein the epileptic disorder is status epilepticus.

[0212] Item 21. According to the method described in Item 18, the epileptic disorder is acute recurrent epileptic seizures.

[0213] Item 22. The method described in Item 18, wherein the epileptic disorder is Lennox-Gastaut syndrome.

[0214] Item 23. The method according to Item 18, wherein the composition provides a reduction in the frequency of seizures, the severity of seizures, or a combination thereof in a patient diagnosed with epileptic disorders.

[0215] Item 24. The method according to Item 18, wherein the patient is also administered an allosteric modulator.

[0216] Item 25. The method according to Item 24, wherein the allosteric modulator is selected from the group consisting of neurosteroids, benzodiazepines and potassium channel openers.

[0217] Item 26. The method according to Item 24, wherein the allosteric modifier is ganexone.

[0218] Item 27. The method according to Item 24, wherein the allosteric modifier is allogenein ketone.

[0219] Item 28. The method according to Item 24, wherein the allosteric modifier is a benzodiazepine.

[0220] Item 29. The method according to Item 28, wherein the benzodiazepine is selected from the group consisting of midazolam, clonazepam, clonazepam, diazepam, lorazepam, flurazepam and lorazepam.

[0221] Item 30. The method according to Item 24, wherein the allosteric modifier is a potassium channel opener.

[0222] Item 31. The method according to Item 30, wherein the potassium channel opener is retigabine or flupirtine.

[0223] Item 32. The method according to Item 18, wherein the gabosadol or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, three times daily, or every other day.

[0224] Item 33. The method according to Item 32, wherein the gabosadol or a pharmaceutically acceptable salt thereof is administered immediately after the onset of a seizure.

[0225] Item 34. The method according to Item 32, wherein the gaposadol or a pharmaceutically acceptable salt thereof is administered after the onset of warning signs of a seizure.

[0226] Item 35. The method according to Item 18, the method further comprising administering a compound selected from the group consisting of acetazolamide, carbamazepine, escricazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitroxazone, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, rufenamide, sodium valproate, stearyl alcohol, thiabendazole, topiramate, azithromycin, and zonisamide.

[0227] Item 36. The method according to Item 18, wherein the pharmaceutical composition is a parenteral preparation.

[0228] Item 37. A pharmaceutical composition for parenteral administration, said pharmaceutical composition comprising about 0.005 μg / ml to about 500 μg / ml of Gaboroxadol or a pharmaceutically acceptable salt thereof.

[0229] Item 38. A pharmaceutical composition for parenteral administration, said pharmaceutical composition comprising about 0.05 mg to about 100 mg of gaposadol or a pharmaceutically acceptable salt thereof.

[0230] Item 39. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the gaposadol or a pharmaceutically acceptable salt thereof is present at a molar concentration of less than about 10.0 M.

[0231] Item 40. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the solubility of borsadol or a salt thereof in the composition is between about 1 mg / ml and about 50 mg / ml.

[0232] Item 41. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the pharmaceutical composition exhibits a time to peak plasma concentration (Tc) of gapository of about 1 hour or more after administration of the parenteral dosage form. max ).

[0233] Item 42. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the parenteral administration of said composition provides a dose comprising more than about 25 ng Average AUC per hr / ml 0-∞ The plasma spectrum of Gabosado.

[0234] Item 43. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the parenteral administration of said composition provides an average Cg of less than about 10,000 ng / ml. max The plasma spectrum of Gabosado.

[0235] Item 44. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the parenteral administration exhibits a pharmacokinetic profile including the following after administration of the parenteral composition: T0 at approximately 1 minute to approximately 120 minutes. max ; followed by at least 50% of a duration lasting from approximately 90 minutes to approximately 360 minutes. max Plasma drug concentration.

[0236] Item 45. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is contained in a bag, glass vial, plastic vial or bottle.

[0237] Item 46. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is aqueous.

[0238] Item 47. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is ready for use.

[0239] Item 48. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is sufficiently soluble.

[0240] Item 49. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises an excipient selected from the group consisting of buffers, solubilizers, tensioning agents, antioxidants, chelating agents, antimicrobial agents and preservatives.

[0241] Item 50. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises an excipient present in a weight percentage (w / v) of less than about 10%.

[0242] Item 51. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises an excipient present in a weight percentage (w / v) of about 0.01% to about 10%.

[0243] Item 52. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the excipient is present in a molar ratio of the excipient to gabosadol or a pharmaceutically acceptable salt thereof of about 0.1:1 to about 0.25:1.

[0244] Item 53. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition comprises an excipient comprising a stable amount of a buffer.

[0245] Item 54. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is at a pH of about 4 to about 8.

[0246] Item 55. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is at a pH of about 6 to about 8.

[0247] Item 56. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is an aqueous solution and the pH of said aqueous solution is from about 6.8 to about 7.8.

[0248] Item 57. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises sodium chloride at a concentration between about 0.01 and about 2.0 weight percent.

[0249] Item 58. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises sodium chloride at a concentration of about 0.9% by weight.

[0250] Item 59. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is formulated to a total volume selected from the group consisting of 20 ml, 50 ml and 100 ml.

[0251] Item 60. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is prepared for subcutaneous, intramuscular, transdermal or intravenous administration.

[0252] Item 61. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition comprises an excipient that is a stable amount of solubilizer.

[0253] Item 62. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition does not show detectable chemical degradation after one month at 40°C.

[0254] Item 63. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition may be stored under ambient conditions and remain clear and colorless for at least about 12 weeks.

Claims

1. Use of ganedrone or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical formulation for the treatment of CDKL5 disorders, wherein the total amount of ganedrone administered daily is up to 1,800 mg.

2. The use according to claim 1, wherein the pharmaceutical preparation is for oral administration.

3. The use according to claim 1 or claim 2, wherein the amount of ganedrone administered is 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 450 mg or 600 mg per dose.

4. The use according to claim 3, wherein ganedrone is administered three times daily.

5. The use according to claim 1, wherein ganesodium has a solubility of about 50 mg / mL in the pharmaceutical preparation.

6. Use of ganedrone or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical formulation for the treatment of CDKL5 disorders, wherein ganedrone is administered at least once daily and up to 20 mg / kg.

7. The use according to claim 6, wherein the pharmaceutical preparation is for oral administration.

8. The use according to claim 7, wherein the pharmaceutical preparation is to be administered three times daily, at a dose of up to 20 mg / kg of ganexone.

9. The use according to claim 6, wherein ganesodium has a solubility of about 50 mg / mL in the pharmaceutical formulation.

10. Use of ganedrone or a pharmaceutically acceptable salt thereof in the preparation of an orally available, immediately released form of a drug for the treatment of seizures associated with CDKL5 disorder.

11. The use according to claim 10, wherein the oral immediate-release form of the drug provides a reduction in the frequency of seizures, a reduction in the severity of seizures, or a combination thereof.

12. The use according to claim 10, wherein the oral immediate-release form of the drug is an oral capsule.

13. The use according to claim 12, wherein the oral capsule comprises 50 mg to 75 mg of ganedrone, 75 mg to 100 mg of ganedrone, 100 mg to 125 mg of ganedrone, 125 mg to 150 mg of ganedrone, 150 mg to 175 mg of ganedrone, 175 mg to 200 mg of ganedrone, 200 mg to 225 mg of ganedrone, 225 mg to 250 mg of ganedrone, 275 mg to 300 mg of ganedrone, 300 mg to 325 mg of ganedrone, 425 mg to 450 mg of ganedrone, 450 mg to 475 mg of ganedrone, 575 mg to 600 mg of ganedrone, 600 mg to 625 mg of ganedrone, 650 mg to 675 mg of ganedrone, 675 mg to 700 mg of ganedrone, 875 mg to 900 mg of ganedrone. mg of Ganexorone or 900 mg to 925 mg of Ganexorone.

14. The use according to claim 12, wherein the oral capsule comprises 25 mg of ganexone, 50 mg of ganexone, 75 mg of ganexone, 100 mg of ganexone, 150 mg of ganexone, 200 mg of ganexone, 225 mg of ganexone, 300 mg of ganexone, 450 mg of ganexone, 600 mg of ganexone, 675 mg of ganexone, or 900 mg of ganexone.

15. The use according to claim 12, claim 13 or claim 14, wherein the oral capsule is for administration twice daily.

16. The use according to claim 10, wherein the oral immediate-release form is for administration in three doses daily.

17. Use of ganedrone or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical formulation for the treatment of epileptic disorders.

18. The use according to claim 17, wherein the epileptic disorder is a CDKL5 disorder.

19. The use according to claim 18, wherein the pharmaceutical preparation is for oral administration.

20. The use according to claim 19, wherein the pharmaceutical preparation is an oral capsule or an oral tablet.

21. The use according to claim 19, wherein the pharmaceutical preparation is for administration in three doses daily, each dose being up to 600 mg of ganexone.

22. Use of ganexone or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical formulation for the treatment of status epilepticus, wherein the pharmaceutical formulation is intended for parenteral administration.

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