Methods and compositions for treatment of epileptic disorders

Abstract

To provide a pharmaceutical composition usable in applications of epileptic disorders, for example status epilepticus.SOLUTION: The present invention provides a pharmaceutical composition comprising ganaxolone or a pharmaceutically acceptable salt thereof for treating CDKL5 disorder, the composition being intravenously administered to a subject in need of treatment.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and priority to 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, each of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention relates to methods of using allosteric modulators and / or gaboxadol or a pharmaceutically acceptable salt thereof for the treatment of an epileptic disorder in a subject in need thereof. [Background technology]

[0003] Allosteric modulators, such as neurosteroids (e.g., ganaxolone, allopregnanolone), benzodiazepines (e.g., diazepam), and potassium channel openers (e.g., retigabine), are used in the treatment of epilepsy. However, treatment with these agents is often limited to patients who do not respond to conventional medications. For example, allopregnanolone is currently in development for the treatment of extremely treatment-resistant status epilepticus. Diazepam is also currently marketed (Diastat®) for use in emergency situations to terminate cluster seizures in people taking other medications to treat epilepsy.

[0004] Gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) (THIP) is described in European Patent No. 0000338, European Patent No. 0840601, U.S. Patent No. 4,278,676, U.S. Patent No. 4,362,731, U.S. Patent No. 4,353,910, and International Publication No. WO 2005 / 094820. Gaboxadol inhibits the action of GABA. A Selective GABA receptors preferring δ-subunit containing receptors AIt is a receptor agonist. In the early 1980s, gaboxadol was the subject of a series of pilot studies testing its efficacy as an analgesic and anxiolytic, as well as a treatment for tardive dyskinesia, Huntington's disease, Alzheimer's disease, and spasticity. In the 1990s, gaboxadol moved into late-stage development for the treatment of insomnia, but a 3-month efficacy trial failed to demonstrate significant effects on sleep onset and sleep maintenance. Additionally, patients with a history of substance abuse who received gaboxadol experienced a sharp increase in psychiatric adverse events. Due to these negative results, development of gaboxadol was discontinued.

[0005] Parenteral dosage forms are intended for administration as an injection or infusion. Common types of injections are intravenous (into a vein), subcutaneous (under the skin), and intramuscular (into a muscle). Infusions are typically administered via the intravenous route. Parenteral formulations often contain additives to improve or maintain the solubility (solubilizers) and / or stability (buffers, antioxidants, chelating agents, cryo- and lyoprotectants) of the active ingredient. Additives are also important in parenteral formulations to ensure safety (antimicrobial preservatives), minimize pain and irritation upon injection (tonicity agents), and control or prolong drug delivery (polymers). However, additives can also have negative effects, such as loss of drug solubility, activity, and / or stability.

[0006] There remains a need in the art for safe and effective methods and pharmaceutical compositions that provide treatment for epilepsy. Accordingly, the present disclosure provides pharmaceutical compositions and methods that can be used in the treatment of epileptic disorders, such as status epilepticus. Summary of the Invention

[0007] Methods are provided for treating epileptic disorders, including epilepsy, epilepsy with generalized tonic-clonic seizures, myoclonic absence epilepsy, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Ohtahara syndrome, Rasmussen syndrome, West syndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, CDKL5 disorders, childhood absence epilepsy, essential tremor, Dravet syndrome, Douzé syndrome, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, treatment-resistant status epilepticus, very treatment-resistant status epilepticus (SRSE), PCDH19 childhood epilepsy, increased seizure activity or seizure recurrence (also referred to as increased seizure activity, trains, or clusters), and sodium channel alpha subunit type 1 protein (Scn1a)-related disorders, by administering to a patient in need thereof a pharmaceutical composition comprising an allosteric modulator. Allosteric modulators include one or more of neurosteroids, benzodiazepines, and potassium channel openers. In one embodiment, provided is a method for treating an epileptic disorder, comprising administering to a patient in need thereof a pharmaceutical composition comprising an allosteric modulator in combination with gaboxadol or a pharmaceutically acceptable salt thereof.

[0008] Provided herein is a parenteral formulation of gaboxadol or a pharmaceutically acceptable salt thereof. Provided is a method for treating epileptic disorders, including status epilepticus, with a parenteral formulation of gaboxadol or a pharmaceutically acceptable salt thereof. In one embodiment, a parenteral formulation comprising gaboxadol or a pharmaceutically acceptable salt thereof is administered alone or in combination with an allosteric modulator to a patient in need thereof to treat an epileptic disorder.

[0009] In one embodiment, methods are provided for the treatment of epileptic disorders, including status epilepticus, benign rolandic 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), by administering to a patient in need thereof a pharmaceutical composition comprising an allosteric modulator either alone or in combination with gaboxadol or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method for the treatment of epileptic disorders, including status epilepticus, benign rolandic 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), by administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, either alone or in combination with an allosteric modulator.

[0010] In one embodiment, a method is provided for treating epileptic disorders characterized as sodium channel alpha subunit type 1 protein (Scn1a)-associated disorders. Scn1a-associated disorders include generalized epilepsy with febrile seizures plus, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory childhood partial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsy of infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile convulsions, and vaccine-associated encephalopathy and seizures. In one embodiment, a method is provided for treating sodium channel alpha subunit type 1 protein (Scn1a)-associated disorders by administering to a patient in need thereof a pharmaceutical composition comprising an allosteric modulator. In one embodiment, a method is provided for treating sodium channel alpha subunit type 1 protein (Scn1a)-associated disorders by administering to a patient in need thereof a pharmaceutical composition comprising an allosteric modulator in combination with gaboxadol or a pharmaceutically acceptable salt thereof. In one embodiment, a method is provided for treating a sodium channel alpha subunit type 1 protein (Scn1a)-related disorder by administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof. In one embodiment, a method is provided for treating a sodium channel alpha subunit type 1 protein (Scn1a)-related disorder by administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof in combination with an allosteric modulator. In one embodiment, a method is provided for treating a sodium channel alpha subunit type 1 protein (Scn1a)-related disorder by administering to a patient in need thereof a parenteral formulation comprising gaboxadol or a pharmaceutically acceptable salt thereof. In one embodiment, a method is provided for treating a sodium channel alpha subunit type 1 protein (Scn1a)-related disorder by administering to a patient in need thereof a pharmaceutical composition comprising an allosteric modulator in combination with a parenteral formulation comprising gaboxadol or a pharmaceutically acceptable salt thereof.

[0011] In one embodiment, a combination of allosteric modulators, such as neurosteroids, benzodiazepines or potassium channel openers, can be administered to a patient in need thereof.In one embodiment, a combination of one or more allosteric modulators and gaboxadol or its pharmaceutically acceptable salts can be administered to a patient in need thereof. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows both the theoretical and measured solubility of gaboxadol at various pH values. [Figure 2] FIG. 2 is a schematic diagram showing the timeline for studies evaluating the ability of allopregnanolone, ganaxolone, and gaboxadol to block benzodiazepine-resistant status epilepticus in rats. [Figure 3] FIG. 3 is a bar graph showing percent protection versus dose for allopregnanolone, ganaxalone, or gaboxadol. [Figure 4] FIG. 4 is a bar graph showing 24-hour survival results based on dose for allopregnanolone, ganaxolone, or gaboxadol. [Figure 5] FIG. 5 is a bar graph showing the number of observed seizures versus the dose of allopregnanolone, ganaxolone, or gaboxadol. [Figure 6A] FIG. 6A is a bar graph showing the change in body weight 24 hours after status epilepticus as a function of percent reduction versus dose. [Figure 6B] FIG. 6B is a bar graph showing 24-hour weight loss for the 0.5 mg / kg dose group. [Figure 7] FIG. 7 is a schematic showing the timeline for a prospective evaluation study of the ability of allopregnanolone, ganaxolone, and gaboxadol to synergistically block benzodiazepine-resistant status epilepticus in rats. DETAILED DESCRIPTION OF THE INVENTION

[0013]

[0003] Described herein are methods of treating epileptic disorders, including epilepsy, epilepsy with generalized tonic-clonic seizures, myoclonic absence epilepsy, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Ohtahara syndrome, Rasmussen syndrome, infantile spasms (or West syndrome), Lennox-Gastaut syndrome (LGS), Rett syndrome, Dravet syndrome, Douzé syndrome, CDKL5 disorders, refractory childhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, treatment-resistant status epilepticus, very treatment-resistant status epilepticus (SRSE), PCDH19 childhood epilepsy, increased seizure activity or seizure recurrence (increased seizure activity; also referred to as series or cluster seizures). The compositions and methods described herein can be used to treat epileptic disorders characterized as sodium channel alpha subunit type 1 protein (Scn1A)-associated disorders. For example, Scn1A-associated disorders include generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory childhood partial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsy of infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome, infantile spasms, and vaccine-associated encephalopathy and seizures. The compositions and methods described herein comprise an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof.

[0014] In one embodiment, a method for treating an epileptic disorder may comprise administering to a patient in need thereof a pharmaceutical composition comprising an allosteric modulator. In one embodiment, a method for treating an epileptic disorder may comprise administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof. In one embodiment, a method for treating an epileptic disorder may comprise administering to a patient in need thereof gaboxadol or a pharmaceutically acceptable salt thereof in combination with an allosteric modulator. In one embodiment, a method for treating an epileptic disorder may comprise administering to a patient in need thereof a parenteral pharmaceutical formulation comprising an allosteric modulator. In one embodiment, a method for treating an epileptic disorder may comprise administering to a patient in need thereof a parenteral pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof. In one embodiment, a method for treating an epileptic disorder may comprise administering to a patient in need thereof a parenteral pharmaceutical composition comprising an allosteric modulator and gaboxadol or a pharmaceutically acceptable salt thereof.

[0015] Many pharmaceuticals are administered as fixed doses at regular intervals to achieve a therapeutic effect. The duration of action is reflected by the plasma half-life of the pharmaceutical. Because efficacy often depends on sufficient exposure within the central nervous system, administration of CNS drugs with short half-lives may require frequent maintenance administration. Advantageously, a method for treating an epileptic disorder by administering an allosteric modulator is described herein. For example, in one embodiment, a method for treating an epileptic disorder is provided, comprising administering to a patient in need thereof a pharmaceutical composition comprising about 0.05 mg to about 2000 mg of an allosteric modulator, wherein the composition provides improvement for more than 6 hours after administration to the patient. Advantageously, a method for treating an epileptic disorder by administering gaboxadol or a pharmaceutically acceptable salt thereof is described herein. For example, in one embodiment, there is provided a method of treating an epileptic disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising about 0.05 mg to about 75 mg of gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement for more than 6 hours after administration to the patient.

[0016] In one embodiment, the method for treating an epileptic disorder comprises administering to a patient in need thereof a pharmaceutical composition comprising about 0.05 mg to about 50 mg of gaboxadol or a pharmaceutically acceptable salt thereof. In one embodiment, the method for treating an epileptic disorder comprises administering to a patient in need thereof a pharmaceutical composition comprising about 0.1 mg to about 30 mg of gaboxadol or a pharmaceutically acceptable salt thereof.

[0017] For example, a dose may include an amount of gaboxadol or a pharmaceutically acceptable salt thereof in the range of, for example, about 0.05 mg to about 50 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 15 mg, about 0.1 mg to about 30 mg, about 0.15 mg to about 12.5 mg, or about 0.2 mg to about 10 mg, and may be, for example, 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 Doses of 1 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25 mg and 30 mg are exemplary dosages.

[0018] Typically, a dose of gaboxadol or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once or twice daily. The methods and compositions described herein may provide for reduced administration frequency and reduced adverse events and / or increased efficacy. In one embodiment, the dosage is, for example, about 0.05 to 30 mg / day, about 0.1 to 20 mg / day, or about 0.2 to 15 mg / day, or about 0.5 to 10 mg / day, or about 0.75 to 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, 27 mg / day, 28 mg / day, 29 mg / day, 30 mg / day, 31 mg / day, 32 mg / day, 33 mg / day, 34 mg / day, 35 mg / day, 36 mg / day, 37 mg / day, 38 mg / day, 39 mg / day, 40 mg / day, 41 mg / day, 42 mg / day, 43 mg / day, 44 mg / day, 45 mg / day, 46 mg / day, 47 mg / day, 48 mg / day, 49 mg / day, 50 mg / day, 51 mg / day, 52 mg / day, 53 mg / day, 54 mg / day, 55 mg / day, 56 mg / day, 57 mg mg / day, 27 mg / day, 28 mg / day, 29 mg / day or 30 mg / day. In one embodiment, gaboxadol or a pharmaceutically acceptable salt thereof, or a derivative or analog thereof is administered once daily at a dosage of 0.2 mg to 1 mg in infants or 1 to 20 mg in adults.

[0019] In one embodiment, 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 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 gaboxadol or a pharmaceutically acceptable salt thereof.

[0020] In one embodiment, 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 gaboxadol or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment, the pharmaceutical composition contains 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, 20 mg of gaboxadol or a pharmaceutically acceptable salt thereof, or a multiple of said dosage amounts. In one embodiment, the pharmaceutical composition contains 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of gaboxadol or a pharmaceutically acceptable salt thereof.

[0022] In one embodiment, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof and / or gaboxadol administered to a subject in a 24-hour period is 1 mg to 50 mg. In one embodiment, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof and / or gaboxadol administered to a subject in a 24-hour period is 1 mg to 20 mg. In one embodiment, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof and / or gaboxadol administered to a subject in a 24-hour period is 5 mg, 10 mg, 15 mg, or 20 mg. In one embodiment, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof and / or gaboxadol administered to a subject in a 24-hour period is 1 mg to 50 mg. In one embodiment, a subject can be started at a low dose and the dose gradually increased. In this manner, it can be determined whether the drug is well tolerated in the subject. The dose for children can be lower than that for adults. In one embodiment, the dose of gaboxadol for children can be 0.1 mg / kg to 1 mg / kg.

[0023] Allosteric modulators may include neurosteroids such as ganaxolone or allopregnanolone, benzodiazepines such as midazolam, clobazam, clonazepam, diazepam, lorazepam, flurazepam, lorazepam, etc., or potassium channel openers such as retigabine or flupirtine.

[0024] In one embodiment, there is provided a method for treating an epileptic disorder by administering ganaxolone to a patient in need thereof. In one embodiment, there is provided a method for treating an epileptic disorder by administering allopregnanolone to a patient in need thereof. In one embodiment, there is provided a compound of Formula I: [ka] The present invention provides a method for treating epileptic disorders by administering a compound of the formula:

[0025] In one embodiment, the allosteric modulator or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 0.001 mg / kg to about 30 mg / kg, for example, about 0.01 mg / kg to 20 mg / kg, of the patient's body weight in need thereof at least once daily. For example, a dose may include an amount of an allosteric modulator or a pharmaceutically acceptable salt thereof in the range of, for example, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 15 mg, about 0.15 mg to about 12.5 mg, or about 0.1 mg to about 10 mg, or about 0.2 mg to about 10 mg, and may include, for example, 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 Doses of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 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 exemplary dosages. For example, the dosage may be, for example, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, about 200 mg to about 225 mg, about 225 mg to about 250 mg, about 250 mg to about 275 mg, about 275 mg to about 300 mg, about 300 mg to about 325 mg, about 325 mg to about 350 mg, about 350 mg to about 375 mg, about 375 mg to about 400 mg, about 400 mg to about 425 mg, about 425 mg to about 450 mg, about 450 mg to about 475 mg, about 475 mg to about 500 mg, about 500 mg to about 525 mg, about 525 mg to about 550 mg, mg, about 550mg~575 mg, 575 mg~600 mg, 600 mg~625 mg, 625 mg~650 mg, 650 mg~675 mg, 675 mg~700 mg, 700 mg~725 mg, 725 mg~750 mg, 750 mg~775 mg, 775 mg~800 800 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 mg ~ approx. 1050 mg, approx. 1050 mg ~ approx. 1075 mg, approx. 1075 mg ~ approx. 1100 mg, approx. 1100 mg ~ approx. 1125 mg, approx. 1125 mg ~ approx. 1150 mg, approx. mg ~ approx. 1275 mg, approx. 1275 mg ~ approx. 1300 mg, approx. 1300 mg ~ approx. 1325 mg, approx. 1325 mg ~ approx. 1350 mg, approx. mg ~ approx. 1475 mg, approx. 1475 mg ~ approx. 1500 mg, about 1500 mg to about 1525 mg, about 1525 mg to about 1550 mg, about 1550 mg to about 1575 mg, about 1575 mg to about 1600 mg, about 1625 mg to about 1650 mg, about 1650 mg to about 1675 mg, about 1675 mg to about 1700 mg, approx. 1700 mg ~ approx. 1725 mg, approx. 1725 mg ~ approx. 1750 mg, approx. 1750 mg ~ approx. 1775 mg, approx. 1775 mg ~ approx. 1800 mg, approx. 1800 mg ~ approx. mg, about 1900 mg to about 1925 mg, about 1925 mg to about 1950 mg, about 1950 mg to about 1975 mg, or about 1975The composition may contain an amount of the allosteric modulator or a pharmaceutically acceptable salt thereof ranging from about 1000 mg to about 2000 mg of the allosteric modulator.

[0026] Typically, the dose of the allosteric modulator or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once daily, twice daily, three times daily, or four times daily. In one embodiment, the allosteric modulator may be administered once weekly. The methods and compositions described herein may provide reduced administration frequency and reduced adverse events and / or increased efficacy. In one embodiment, the dose of the allosteric modulator may be, for example, about 0.1 to 20 mg / day, about 0.2 to 15 mg / day, about 0.5 to 10 mg / day, or about 0.75 to 5 mg / day, such as 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 one embodiment, the patient may receive, for example, 10 mg to 25 mg / day, 25 mg to 50 mg / day, 50 mg to 75 mg / day, 75 mg to 100 mg / day, 100 mg to 125 mg / day, 125 mg to 150 mg / day, 150 mg to 175 mg / day, 175 mg to 200 mg / day, 200 mg to 225 mg / day, 225 mg to 250 mg / day, 250 mg to 275 mg / day, 275 mg to 300 mg / day, 300 mg to 325 mg / day, 325 mg to 350 mg / day, 350 mg to 375 mg / day, 375 mg to 400 mg / day, 400 mg to 425 mg / day, 425 mg to 450 mg / day, 450 mg to 475 mg / day, 475 mg to 500 mg / day, 500 mg to 600 mg / day, 600 mg to 700 mg / day, 600 mg to 750 mg / day, 600 mg to 800 mg / day, 600 mg to 85 ... mg~525 mg / day, 525 mg~550 mg / day, 550 mg~575 mg / day, 575 mg~600 mg / day, 600 mg~625 mg / day, 625 mg~650 mg / day, 650 mg~675 mg / day, 675 mg~700 mg / day, 700 mg~725 mg / day, 725 mg~750 mg / day, 750 mg~775 mg / day, 775 mg~800 mg / day, 800 mg~825 mg / day, 825 mg~850 mg / day, 850 mg~875 mg / day, 875 mg~900 mg / day, 900 mg~925 mg / day, 925 mg~950 mg / day, 950mg~975 mg / day, 975 mg~1000 mg / day, 1000 mg~1025 mg / day, 1025 mg~1050 mg / day, 1050 mg~1075 mg / day, 1075 mg~1100 mg / day, 1100 mg~1125 mg / day, 1125 mg~1150 mg / day, 1150 mg~1175 mg / day, 1175 mg~1200 mg / day, 1200 mg~1225 mg / day, 1225 mg~1250 mg / day, 1250 mg~1275 mg / day, 1275 mg~1300 mg / day, 1300 mg~1325 mg / day, 1325 mg~1350 mg / day, 1350 mg~1375 mg / day, 1375 mg~1400 mg / day, 1400 mg~1425 mg / day, 1425 mg~1450 mg / day, 1450 mg~1475 mg / day, 1475 mg~1500 mg / day, 1500 mg~1525 mg / day, 1525 mg~1550 mg / day, 1550 mg~1575 mg / day, 1575 mg~1600 mg / day, 1600 mg~1625 mg / day, 1625 mg~1650 mg / day, 1650 mg~1675 mg / day, 1675 mg~1700 mg / day, 1700 mg~1725 mg / day, 1725 mg~1750 mg / day, 1750 mg~1775 mg / day, 1775 mg~1800 mg / day, 1800 mg~1825 mg / day, 1825 The allosteric modulator may be administered in an amount of 1850 mg to 1875 mg / day, 1875 mg to 1900 mg / day, 1900 mg to 1925 mg / day, 1925 mg to 1950 mg / day, 1950 mg to 1975 mg / day, or 1975 mg to 2000 mg / day. In one embodiment, the allosteric modulator, or a derivative or analog thereof, is administered once daily at a dosage of 0.2 mg to 1 mg in infants or 1 to 20 mg in adults.

[0027] In one embodiment, a method for treating an epileptic disorder, such as status epilepticus, comprises administering ganaxolone or a pharmaceutically acceptable salt thereof to a patient in need thereof. Ganaxolone or a pharmaceutically acceptable salt thereof can be administered at a dose ranging from 10 mg / kg to 40 mg / kg, e.g., 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 one embodiment, the dosage of ganaxolone is, 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, 1400 mg, 1425 mg, 1450 mg, 1460 mg, 1470 mg, 1480 mg, 1490 mg, 1500 mg, 1510 mg, 1520 mg, 1530 mg, 1540 mg, 1550 mg, 1560 mg, 1570 mg, 1580 mg, 1590 mg, 1600 mg, 1610 mg, 1625 mg, 1630 mg, 1640 mg, 1650 mg, 1660 mg, 1670 mg, 1680 mg, 1680 mg, 1690 mg, 1700 mg, 1710 mg, 1725 mg, 1 The amount of the compound can be 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg or 2000 mg.

[0028] Ganaxolone or its pharmaceutically acceptable salt can be administered, for example, once a day, twice a day, three times a day, or four times a day.In one embodiment, ganaxolone or its pharmaceutically acceptable salt can be administered once a week.In one embodiment, ganaxolone or its pharmaceutically acceptable salt can be administered parenterally as soon as possible after the onset of an attack.In one embodiment, ganaxolone or its pharmaceutically acceptable salt can be administered parenterally at increasing doses as soon as possible after the onset of an attack.

[0029] In one embodiment, the method of treating an epileptic disorder, eg, status epilepticus, comprises administering allopregnanolone or a pharmaceutically acceptable salt thereof to a patient in need thereof. Allopregnanolone or a pharmaceutically acceptable salt thereof may be administered in an amount of, for example, 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 12 ... In one embodiment, the dosage of allopregnanolone 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.

[0030] Allopregnanolone or a pharmaceutically acceptable salt thereof can be administered, for example, once a day, twice a day, three times a day, or four times a day. In one embodiment, allopregnanolone or a pharmaceutically acceptable salt thereof can be administered once a week. In one embodiment, allopregnanolone or a pharmaceutically acceptable salt thereof can be administered parenterally as soon as possible after the onset of an attack. In one embodiment, allopregnanolone or a pharmaceutically acceptable salt thereof can be administered parenterally in increasing doses as soon as possible after the onset of an attack.

[0031] A method for treating an epileptic disorder is provided by administering to a patient in need thereof an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof, either alone or in combination with an allosteric modulator or a pharmaceutically acceptable salt, derivative or analogue or combination.A method for treating an epileptic disorder is provided by administering to a patient in need thereof an effective amount of an allosteric modulator or a pharmaceutically acceptable salt, derivative or analogue or combination, either alone or in combination with gaboxadol or a pharmaceutically acceptable salt thereof.

[0032] An effective amount or a therapeutically effective amount can be a dosage that is sufficient to treat, suppress or alleviate one or more symptoms of epileptic disorders, for example, to reduce the frequency or severity of seizures, reduce behavioral abnormalities (or otherwise improve behavior); or to provide a desired pharmacological and / or physiological effect, for example, to alleviate, suppress or reverse one or more underlying pathophysiological mechanisms underlying neurological dysfunction, increase dopamine levels or signal transduction, or a combination thereof.The exact dosage will vary depending on various factors, such as subject-dependent variables (for example, age, immune system health, clinical symptoms, etc.).In one embodiment, a subject can be started at a low dosage, and the dosage will be gradually increased.In this way, it can be determined whether the drug is well tolerated in the subject.The dosage for children can be lower than that for adults.

[0033] In one embodiment, the methods described herein are effective for alleviating, delaying or preventing one or more other clinical symptoms of epileptic disorders, such as acute recurrent seizures.For example, the effect of gaboxadol or its pharmaceutically acceptable salt and / or allosteric modulator or its pharmaceutically acceptable salt, derivative or analog on certain symptoms, pharmacological or physiological indicators can be compared with the condition of untreated subjects or subjects before treatment.In one embodiment, symptoms, pharmacological and / or physiological indicators are measured in subjects before treatment and again one or more times after treatment begins.In one embodiment, the control is a reference level or average determined based on the measurement of symptoms, pharmacological or physiological indicators in one or more subjects (e.g., healthy subjects) that do not have the disease or condition to be treated.In one embodiment, the effect of treatment is compared with conventional treatments known in the art.

[0034] In one embodiment, compositions and methods are provided with low doses of gaboxadol and / or allosteric modulators, so as to provide patients with 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 performance.Dosage regimens are provided that allow for effective treatment of epileptic disorders, potentially with limited or substantially no negative side effects, such as convulsions and / or sleep disorders.Therefore, the methods described herein may provide treatments for epileptic disorders that may be considered surprising and unexpected.For example, methods are provided for treating epileptic disorders in patients in need thereof that do not cause sleep disorders.In one embodiment, the methods described herein may provide effective treatments for epileptic disorders that do not disrupt slow-wave sleep.In one embodiment, methods are provided for treating epileptic disorders that do not cause insomnia or sleep-onset disorders.

[0035] In one embodiment, the methods described herein can be used to treat epileptic disorders, including acute repetitive seizures, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), and Dravet syndrome. In one embodiment, the methods include treatment of acute repetitive seizures.

[0036] In one embodiment, the methods described herein may be used to treat epileptic disorders, including benign rolandic 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).

[0037] In one embodiment, the methods described herein can be used to treat sodium channel alpha subunit type 1 protein (Scn1A)-related disorders, including generalized epilepsy with febrile seizures plus, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory childhood partial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsy of infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-associated encephalopathy and seizures.

[0038] The methods described herein may also be effective in subjects experiencing refractory seizures, status epilepticus, akinetic seizures, myoclonic seizures, absence seizures, or severe myoclonic epilepsy of infancy (SMEI). In one embodiment, the disorder is characterized by refractory seizures. Intractable seizures (also referred to as "uncontrolled" or "refractory" seizures) are seizures that cannot be controlled with conventional treatments. For example, the subject may have refractory epilepsy, 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 the other without recovery of consciousness between seizures. Thus, in one embodiment, the disclosed methods are used to treat a subject who is otherwise resistant to one or more conventional therapies.

[0039] The method described herein can be particularly useful for treating children and infants, and treating the disorders that appear in infants or childhood.In one embodiment, the subject of the disclosed method is newborn, infant, toddler, preschooler, school-age child, tween or teenager.In one embodiment, subject is 18 years old or younger, 12 years old or younger, 10 years old or younger, 8 years old or younger, 6 years old or younger, 4 years old or younger, 2 years old or younger, 1 year old or younger.In one embodiment, subject is an adult who is over 18 years old.

[0040] In one embodiment, epileptic disorder is characterized by seizures related to epilepsy.In one embodiment, seizures are non-epileptic seizures (NES) or dissociative seizures that are distinct from epilepsy.Non-epileptic seizures include organic non-epileptic seizures and psychogenic seizures.

[0041] Epilepsy is a neurological disorder that occurs when neuronal activity in the brain is disrupted, resulting in seizures or periods of abnormal behavior, sensation, and sometimes loss of consciousness. A subject is said to have epilepsy when they have two seizures without an obvious cause. Epilepsy can occur in both adults and children and can be associated with specific syndromes. Thus, in one embodiment, the subject has a childhood epilepsy syndrome, such as benign rolandic epilepsy (BRE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome, or Lennox-Gastaut syndrome (LGS).

[0042] In one embodiment, the subject does not experience diagnosable seizures but exhibits subclinical electrical discharges, which refer to a high rate of seizure-like activity when measured by electroencephalography. Epileptic syndromes associated with these seizure-like discharges include Landau-Kleffner syndrome, Dravet syndrome, and slow-wave sleep-phase continuous spike-and-wave activity.

[0043] In one embodiment, the epileptic disorder treated by the methods and compositions described herein includes Scn1A-associated seizure disorders. Scn1A-associated seizure disorders range from the mildest, simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+), to the most severe, Dravet syndrome and refractory childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). Specific Scn1A-associated seizure disorders include, but are not limited to, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory childhood partial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsy of infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-associated encephalopathy.

[0044] In one embodiment, the subject has intellectual disability (IDD), such as autism spectrum disorder (ASD). In one embodiment, the subject of the disclosed method has epilepsy and an IDD or ASD disorder. Common IDD and ASD disorders associated with seizures and epilepsy include, but are not limited to, fragile X syndrome (FXS), Rett syndrome (RTT), Angelman syndrome, Prader-Willi syndrome, tectocardiofacial syndrome, Smith-Lemli-Opitz syndrome, neuroligin mutations, and "interferonopathies" caused by Alias-related homeobox, X-linked (ARX) and neuropilin 2 (NRP2) gene mutations.

[0045] Also provided are methods and compositions for treating epileptic disorders by co-administering an allosteric modulator and gaboxadol, its derivative or a pharmaceutically acceptable salt thereof to a patient in need thereof. In one embodiment, the methods and compositions described herein comprise a dosage form comprising gaboxadol or a pharmaceutically acceptable salt thereof and an allosteric modulator. In one embodiment, the methods and compositions described herein may comprise one dosage form comprising gaboxadol or a pharmaceutically acceptable salt thereof, and a separate dosage form comprising an allosteric modulator or a pharmaceutically acceptable salt thereof.

[0046] Gaboxadol or its pharmaceutically acceptable salts may be provided as an acid addition salt, zwitterion hydrate, zwitterion anhydrate, hydrochloride or hydrobromide salt, or in the form of a zwitterion monohydrate. Acid addition salts include, but are not limited to, addition salts of 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 acetate, and 8-halotheophylline, e.g., 8-bromo-theophylline. 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, sulfamic acid, phosphoric acid, or nitric acid.

[0047] In one embodiment, gaboxadol is provided as gaboxadol monohydrate.Those skilled in the art will readily understand that the amount of active ingredient in a pharmaceutical composition depends on the form of gaboxadol provided.For example, a pharmaceutical composition containing 5.0, 10.0 or 15.0 mg of gaboxadol corresponds to 5.6, 11.3 or 16.9 mg of gaboxadol monohydrate.

[0048] In one embodiment, gaboxadol is a crystal, such as a hydrochloride crystal, a hydrobromide crystal, or a zwitterion monohydrate crystal. In one embodiment, gaboxadol is provided as a monohydrate crystal.

[0049] Deuteration of pharmaceuticals has previously been shown to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles for several classes of drugs. Therefore, the use of deuterium-enriched gaboxadol is contemplated and is within the scope of the methods and compositions described herein. Deuterium can be synthetically incorporated into any position in place of hydrogen according to synthetic procedures known in the art. For example, deuterium can be incorporated into various positions with exchangeable protons, such as amine N--H, by proton-deuterium equilibrium exchange. Thus, deuterium can be selectively or non-selectively incorporated according to methods known in the art to provide deuterium-enriched gaboxadol. See Journal of Labeled Compounds and Radiopharmaceuticals 19(5) 689-702 (1982).

[0050] The pharmaceutical compositions herein may provide immediate-release, delayed-release, sustained-release, or modified-release profiles. In one embodiment, pharmaceutical compositions with different drug release profiles may be combined to produce a two-phase or three-phase release profile. For example, a pharmaceutical composition may provide immediate-release and sustained-release profiles. In one embodiment, a pharmaceutical composition may provide sustained-release and sustained-release profiles. The compositions may be provided as pulsatile formulations, multi-layer tablets, or capsules containing tablets, beads, granules, etc. The compositions may be prepared using a pharmaceutically acceptable "carrier" made of materials considered safe and effective. "Carrier" includes all ingredients 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, excipients, and coating compositions.

[0051] In one embodiment, the pharmaceutical compositions described herein are administered once, twice, three times or four times a day, or every other day.In one embodiment, the pharmaceutical compositions described herein are provided to patients in the evening.In one embodiment, the pharmaceutical compositions described herein are provided to patients once in the evening and once in the morning.In one embodiment, the pharmaceutical compositions herein are provided as soon as possible after the onset of attack.In one embodiment, the pharmaceutical compositions herein are provided continuously.

[0052] In one embodiment, the total amount of the allosteric modulator and / or gaboxadol administered to a subject in a 24-hour period is 1 mg to 50 mg. In one embodiment, the total amount of the allosteric modulator and / or gaboxadol administered to a subject in a 24-hour period is 1 mg to 20 mg. In one embodiment, the total amount of the allosteric modulator and / or gaboxadol administered to a subject in a 24-hour period is 5 mg, 10 mg, or 15 mg. In one embodiment, the total amount of the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof administered to a subject in a 24-hour period is 1 mg to 50 mg. In one embodiment, a subject may be started at a low dose and the dose gradually increased. In this manner, it may be determined whether the drug is well tolerated by the subject. The dose for children may be lower than that for adults.

[0053] In one embodiment, a method for treating epileptic disorders is provided, comprising administering a pharmaceutical composition comprising an allosteric modulator and / or gaboxadol to a patient in need thereof, wherein the composition provides an improvement in at least one symptom of the epileptic disorder. In one embodiment, a method for treating epileptic disorders is provided by administering an effective amount of an allosteric modulator and / or gaboxadol or a combination thereof to a subject in need thereof. An effective amount or a therapeutically effective amount can be a dosage sufficient to treat, suppress or alleviate one or more symptoms of an epileptic disorder, for example, to reduce the frequency or severity of seizures, reduce behavioral abnormalities (or otherwise improve behavior); or to provide a desired pharmacological and / or physiological effect, for example, to alleviate, suppress or reverse one or more underlying pathophysiological mechanisms underlying neurological dysfunction, increase dopamine levels or signal transduction, or a combination thereof. The exact dosage will vary depending on various factors, such as subject-dependent variables (for example, age, immune system health, clinical symptoms, etc.).

[0054] In one embodiment, the methods described herein are effective for alleviating, delaying or preventing one or more other clinical symptoms of epileptic disorders, such as epilepsy or Dravet syndrome.For example, the effect of a composition comprising allosteric modulator and / or gaboxadol on certain symptoms, pharmacological or physiological indicators can be compared with the condition of an untreated subject or a subject before treatment.In one embodiment, symptoms, pharmacological and / or physiological indicators are measured in a subject before treatment and again one or more times after treatment begins.In one embodiment, the control is a reference level or average determined based on the measurement of symptoms, pharmacological or physiological indicators in one or more subjects (e.g., healthy subjects) that do not have the disease or condition to be treated.In one embodiment, the effect of treatment is compared with conventional treatments known in the art.

[0055] In one embodiment, a method for treating an epileptic disorder, such as status epilepticus, is provided, comprising administering to a patient in need thereof a pharmaceutical composition comprising an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides an improvement in at least one symptom of the epileptic disorder. In one embodiment, the provided method can also surprisingly and unexpectedly reduce or prevent seizures or symptoms in a subject in need thereof. In one embodiment, the provided method can reduce or prevent one or more different types of seizures. In one embodiment, the provided method can also surprisingly and unexpectedly reduce or prevent seizures or symptoms in a subject in need thereof. In one embodiment, the provided method can reduce or prevent one or more different types of seizures. Generally, seizures can include convulsions, repetitive movements, abnormal sensations, and combinations thereof. Seizures can be classified as focal seizures (also called 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 secondarily generalized seizures. Simple focal seizures may be limited to or concentrated in a particular lobe (e.g., the temporal, frontal, parietal, or occipital lobe). Complex focal seizures generally affect a larger portion of one hemisphere than simple focal seizures, but generally begin in the temporal or frontal lobe. When focal seizures spread from one side (hemisphere) to both sides of the brain, the seizures are called secondarily generalized seizures. Specific types of generalized seizures include absence (also called petit mal), tonic, atonic, myoclonic, tonic-clonic (also called grand mal), and clonic seizures.

[0056] In one embodiment, the methods described herein may reduce the frequency of seizures, reduce the severity of seizures, change the type of seizures (e.g., from a more severe type to a milder type), or a combination thereof, in a subject after treatment compared to no treatment (e.g., before treatment) or treatment with another conventional treatment.

[0057] In one embodiment, a method for treating epileptic disorders is provided, which provides a patient with an improvement in at least one symptom for more than 4 hours after administering the pharmaceutical composition to the patient.In one embodiment, the present disclosure provides an improvement in at least one symptom for more than 6 hours after administering the pharmaceutical composition to the patient.In one embodiment, the present disclosure provides an improvement in at least one symptom for, for example, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administering the pharmaceutical composition to the patient.In one embodiment, the present disclosure provides an improvement in at least one symptom for, for example, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administering the pharmaceutical composition to the patient.In one embodiment, the present disclosure provides an improvement in at least one symptom for, for example, 12 hours after administering the pharmaceutical composition to the patient.

[0058] In one embodiment, a method for treating an epileptic disorder comprising administering the composition to a patient in need thereof. wherein the composition provides improved next day function to the patient.

[0059] In one embodiment, a method for treating an epileptic disorder is provided, wherein the amount of an active substance, such as an allosteric modulator and / or gaboxadol, in a patient about 4 hours after administration of the pharmaceutical composition is less than about 75% of the administered amount.In one embodiment, a method is provided, wherein the amount of an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof in a patient about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 15 hours, or about 20 hours after administration of the pharmaceutical composition is less than about 75%.

[0060] In one embodiment, a method for treating an epileptic disorder is provided, wherein the amount of an active substance, such as an allosteric modulator and / or gaboxadol, in a patient about 4 hours after administration of the pharmaceutical composition is less than about 80% of the administered amount. In one embodiment, a method is provided, wherein the amount of an active substance, such as an allosteric modulator and / or gaboxadol, in a patient about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 15 hours, or about 20 hours after administration of the pharmaceutical composition is less than about 80% of the administered amount.

[0061] In one embodiment, a method is provided for treating an epileptic disorder, wherein the amount of an active agent, e.g., an allosteric modulator and / or gaboxadol, is about 65% to about 85% of the administered dose in a patient about 4 hours after administration of the pharmaceutical composition. In one embodiment, a method is provided wherein the amount of an active agent, e.g., an allosteric modulator and / or gaboxadol, is about 65% to about 85% of the administered dose in a patient, e.g., about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 15 hours, or about 20 hours after administration of the pharmaceutical composition.

[0062] In one embodiment, there is provided a method of treating an epileptic disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising an active agent, e.g., an allosteric modulator and / or gaboxadol, wherein the composition has a C of less than about 500 ng / ml. max In one embodiment, the composition provides an improvement greater than 6 hours after administration to the patient.

[0063] In one embodiment, the composition has a C of less than, e.g., about 450 ng / ml, about 400 ng / ml, about 350 ng / ml, or about 300 ng / ml. max In one embodiment, the composition provides an in vivo plasma profile having a C of less than about 250 ng / ml, about 200 ng / ml, about 150 ng / ml, or about 100 ng / ml, wherein the composition provides improved next-day function in the patient. maxwherein the composition provides an improvement in the patient's next day function.

[0064] In one embodiment, there is provided a method of treating an epileptic disorder comprising administering a pharmaceutical composition to a patient in need thereof, wherein the composition has an AUC of less than about 900 ng·hr / ml. 0-∞ In one embodiment, the composition provides a consistent in vivo plasma profile having an AUC of less than about 850 ng·hr / ml, about 800 ng·hr / ml, about 750 ng·hr / ml, or about 700 ng·hr / ml. In one embodiment, the composition provides an improvement in a patient's next day function. In one embodiment, the composition provides an AUC of less than about 850 ng·hr / ml, about 800 ng·hr / ml, about 750 ng·hr / ml, or about 700 ng·hr / ml. 0-∞ wherein the composition provides an improvement in the patient's next day function. In one embodiment, the composition provides an improvement in one or more symptoms for more than 6 hours after administration.

[0065] In one embodiment, there is provided a method of treating an epileptic disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising an active agent, e.g., an allosteric modulator and / or gaboxadol, wherein the composition has an AUC of less than about 650 ng·hr / ml, about 600 ng·hr / ml, about 550 ng·hr / ml, about 500 ng·hr / ml, or about 450 ng·hr / ml. 0-∞ In one embodiment, the composition has an AUC of less than about 400 ng·hr / ml, about 350 ng·hr / ml, about 300 ng·hr / ml, about 250 ng·hr / ml, or about 200 ng·hr / ml. 0-∞ In one embodiment, the composition provides an in vivo plasma profile having an AUC of less than, e.g., about 150 ng·hr / ml, about 100 ng·hr / ml, about 75 ng·hr / ml, or about 50 ng·hr / ml. 0-∞In one embodiment, the composition provides an improvement in the patient's next day function after administration, e.g., more than 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours after administration of the composition to the patient.

[0066] In one embodiment, a method for treating an epileptic disorder is provided, comprising administering to a patient in need thereof a first pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and a second pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof. In some embodiments, the second pharmaceutical composition has a mean AUC 0-∞ and providing an in vivo plasma profile having:

[0067] In one embodiment, a method for treating an epileptic disorder is provided, comprising administering to a patient in need thereof a first pharmaceutical composition comprising an allosteric modulator and a second pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof. In one embodiment, the second pharmaceutical composition has a mean AUC 0-∞ and providing an in vivo plasma profile having:

[0068] In one embodiment, the first and / or second pharmaceutical composition is administered once, twice, three or four times a day, or every other day. In one embodiment, the first or second pharmaceutical composition is provided to the patient in the evening. In one embodiment, the second pharmaceutical composition contains an amount of gaboxadol that is at least one-third of the amount of the allosteric modulator in the first pharmaceutical composition. In one embodiment, the second pharmaceutical composition contains an amount of gaboxadol that is at least half of the amount of the allosteric modulator provided in the first pharmaceutical composition.

[0069] In one embodiment, the first and / or second pharmaceutical compositions are provided to a patient once in the evening and once in the morning. In one embodiment, the total amount of the allosteric modulator administered to a subject in a 24-hour period is 1 mg to 2500 mg. In one embodiment, the total amount of the allosteric modulator administered to a subject in a 24-hour period is 1 mg / kg to 35 mg / kg. In one embodiment, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof administered to a subject in a 24-hour period is 1 mg to 75 mg. In one embodiment, the total amount of an active agent, e.g., gaboxadol or a pharmaceutically acceptable salt thereof, administered to a subject in a 24-hour period is less than about 75 mg, 50 mg, 25 mg, 20 mg, 10 mg, or 5 mg. In one embodiment, the total amount of an active agent, e.g., gaboxadol or a pharmaceutically acceptable salt thereof, administered to a subject in a 24-hour period is less than 15 mg. In one embodiment, the total amount of active agents, such as allosteric modulators and / or gaboxadol, administered to a subject in 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 one embodiment, the total amount of active agents, such as allosteric modulators and / or gaboxadol, administered to a subject in a 24-hour period is less than 15 mg.

[0070] In one embodiment, the first and / or second pharmaceutical composition can provide an immediate-release, delayed-release, sustained-release, or modified-release profile. The first and second pharmaceutical compositions can be provided simultaneously or separated by a period of time, such as 6 hours, 12 hours, etc. In one embodiment, the first and second pharmaceutical compositions can be combined to produce a two-phase release profile. For example, the first pharmaceutical composition can provide an immediate-release profile, and the second pharmaceutical composition can provide an extended-release profile. In one embodiment, one or both of the first and second pharmaceutical compositions can provide an extended-release or delayed-release profile. The compositions can be provided as a pulsatile formulation, multi-layered tablet, or capsule containing tablets, beads, granules, etc. In some embodiments, the first pharmaceutical composition is an immediate-release composition. In one embodiment, the second pharmaceutical composition is an immediate-release composition. In one embodiment, the first and second pharmaceutical compositions are provided as separate immediate-release compositions, such as tablets or capsules. In one embodiment, the first and second pharmaceutical compositions are provided 12 hours apart.

[0071] In one embodiment, the compositions described herein are suitable for parenteral administration, including, for example, intramuscular (im), intravenous (iv), subcutaneous (sc), intraperitoneal (ip) or intrathecal (it). Parenteral compositions must be sterile for administration by injection, infusion or implantation into the body and can be packaged in either single-dose or multi-dose containers.

[0072] In one embodiment, a liquid pharmaceutical composition for parenteral administration to a subject comprises an active agent, e.g., an allosteric modulator and / or gaboxadol, at a concentration of about 0.005 μg / ml to about 500 μg / ml. In one embodiment, the composition comprises an active agent, e.g., an allosteric modulator and / or gaboxadol, at a concentration 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.

[0073] In one embodiment, the composition comprises an active agent, e.g., an allosteric modulator and / or gaboxadol, at a concentration of, e.g., about 0.05 μg / ml to about 50 μg / ml, about 0.1 μg / ml to about 50 μg / ml, about 0.05 μg / ml to about 25 μg / ml, about 0.05 μg / ml to about 10 μg / ml, about 0.05 μg / ml to about 5 μg / ml, or about 0.05 μg / ml to about 1 μg / ml. In one embodiment, the composition contains an active substance, such as an allosteric modulator and / or gaboxadol, at a concentration of, for example, about 0.05 μg / ml to about 15 μg / ml, about 0.5 μg / ml to about 10 μg / ml, about 0.5 μg / ml to about 7 μg / ml, about 1 μg / ml to about 10 μg / ml, about 5 μg / ml to about 10 μg / ml, or about 5 μg / ml to about 15 μg / ml. In one embodiment, the pharmaceutical composition for parenteral administration is formulated to have a total volume of, for example, about 10 ml, about 20 ml, about 25 ml, about 50 ml, about 100 ml, about 200 ml, about 250 ml, or about 500 ml. In one embodiment, the composition is contained in a bag, glass vial, plastic vial, or bottle.

[0074] In one embodiment, the composition for parenteral administration comprises from about 0.05 mg to about 100 mg of an active agent, eg, an allosteric modulator and / or gaboxadol. In one embodiment, the pharmaceutical composition contains, for example, about 0.1 mg to about 25 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 15 mg, about 0.5 mg to about 25 mg, about 0.5 mg to about 20 mg, about 0.5 to about 15 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1.5 mg to about 25 mg, about 1.5 mg to about 20 mg, about 1.5 mg to about 15 mg, about 2 mg to about 25 mg, about 2 mg to about 20 mg, about 2 mg to about 15 mg, about 2.5 mg to about 25 mg, about 2.5 mg to about 20 mg, about 2.5 mg to about 15 mg, about 3 mg to about 25 mg, about 3 mg to about 20 mg, or about 3 mg to about 15 mg of an active substance, such as an allosteric modulator and / or gaboxadol.

[0075] In one embodiment, the pharmaceutical composition contains, for example, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 4 mg to about 6 mg, about 6 mg to about 8 mg, about 8 mg to about 10 mg, about 10 mg to about 12 mg, about 12 mg to about 14 mg, about 14 mg to about 16 mg, about 16 mg to about 18 mg, or about 18 mg to about 20 mg of an active substance, such as an allosteric modulator and / or gaboxadol. In one embodiment, the pharmaceutical composition contains, for example, about 0.1 mg, about 0.25 mg, about 0.5 mg, about 1 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 7 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg of an active substance, such as an allosteric modulator and / or gaboxadol, or a multiple of said dosage amounts. The composition may be contained in a bag, glass vial, plastic vial or bottle.

[0076] In one embodiment, the pharmaceutical composition for parenteral administration to a subject comprises an active substance, e.g., an allosteric modulator and / or gaboxadol, at a concentration of about 0.005 mg / ml to about 500 mg / ml. In one embodiment, the composition comprises an active substance, e.g., an allosteric modulator and / or gaboxadol, at a concentration 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 one embodiment, the composition contains an active substance, such as an allosteric modulator and / or gaboxadol, at a concentration of, for example, about 0.05 mg / ml to about 15 mg / ml, about 0.5 mg / ml to about 10 mg / ml, about 0.25 mg / ml to about 5 mg / ml, about 0.5 mg / ml to about 7 mg / ml, about 1 mg / ml to about 10 mg / ml, about 5 mg / ml to about 10 mg / ml, or about 5 mg / ml to about 15 mg / ml. In one embodiment, the pharmaceutical composition for parenteral administration is formulated to have a total volume of, for example, about 10 ml, about 20 ml, about 25 ml, about 50 ml, about 100 ml, about 200 ml, about 250 ml, or about 500 ml. In one embodiment, the composition is packaged and stored in a bag, glass vial, plastic vial, or bottle.

[0077] In one embodiment, the pharmaceutical compositions herein comprise an active agent, e.g., an allosteric modulator and / or gaboxadol, wherein the active agent is present at a molar concentration of less than about 1.0 M. In one embodiment, the active agent, e.g., an allosteric modulator and / or gaboxadol, is present at a molar concentration of, e.g., about 0.0001 M, about 0.001 M, about 0.01 M, about 0.1 M, greater than 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 one embodiment, the active agent, e.g., the allosteric modulator and / or gaboxadol, is present in a molar concentration of, e.g., about 0.00001 M to about 0.1 M, about 0.01 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 one embodiment, the active agent, e.g., the allosteric modulator and / or gaboxadol, is present in a molar concentration of, e.g., about 0.01 M, about 0.1 M, about 1.0 M, about 5.0 M, or less than about 10.0 M.

[0078] In one embodiment, the solubility of the active agent, e.g., the allosteric modulator and / or gaboxadol, in the composition is, e.g., greater than 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, e.g., when measured in water at 25°C.

[0079] In one embodiment, the solubility of the active agent in the composition, e.g., the allosteric modulator and / or gaboxadol, is, for example, about 1 mg / mL to about 50 mg / mL, about 5 mg / mL to about 50 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 30 mg / mL, or about 10 mg / mL to about 45 mg / mL, when measured in water, e.g., at 25°C.

[0080] In one embodiment, the pharmaceutical composition for parenteral administration is provided, and the pharmaceutical composition is stable for at least 6 months.In one embodiment, the pharmaceutical composition herein shows only about 5% decrease in active substance, for example, allosteric modulator and / or gaboxadol, for example, in 3 months or 6 months.In one embodiment, the degradation amount of gaboxadol or its pharmaceutically acceptable salt is only, for example, about 2.5%, about 1%, about 0.5% or 0.1%.In one embodiment, the degradation is, for example, less than about 5%, about 2.5%, about 1%, about 0.5%, about 0.25%, about 0.1% for at least 6 months.

[0081] In one embodiment, the pharmaceutical composition for parenteral administration is provided, and the pharmaceutical composition remains soluble.In one embodiment, the pharmaceutical composition is provided, which is stable, soluble, topically compatible and / or ready-to-use.In one embodiment, the pharmaceutical composition herein is ready-to-use for direct administration to a patient in need.

[0082] The parenteral composition provided herein can contain one or more additives, such as solvents, solubility enhancers, suspending agents, buffers, isotonicity agents, stabilizers, or antimicrobial preservatives.When used, the additives of the parenteral composition do not adversely affect the stability, bioavailability, safety, and / or efficacy of the allosteric modulator and / or gaboxadol or pharmaceutically acceptable salt used in the composition.Therefore, a parenteral composition is provided that is free from incompatibility between any of the components of the dosage form.

[0083] In one embodiment, the parenteral composition of allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt comprises a stabilizing amount of at least one additive.For example, the additive can be selected from the group consisting of buffering agents, solubilizing agents, isotonicity agents, antioxidants, chelating agents, antibacterial agents and preservatives.Those skilled in the art will understand that an additive can have more than one function and can be classified into one or more specific groups.

[0084] In one embodiment, the pharmaceutical composition comprises an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof and an additive, wherein the additive is present in a weight percent (w / v) of, for example, about 10%, about 5%, about 2.5%, about 1%, or less than about 0.5%. In one embodiment, the additive is present in a weight percent of, for example, about 1.0% to about 10%, about 10% to about 25%, about 15% to about 35%, about 0.5% to about 5%, about 0.001% to about 1%, about 0.01% to about 1%, about 0.1% to about 1%, or about 0.5% to about 1%. In one embodiment, the additive is present in a weight percent of, for example, about 0.001% to about 1%, about 0.01% to about 1%, about 1.0% to about 5%, about 10% to about 15%, or about 1% to about 15%.

[0085] In one embodiment, there is provided a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient is present in a molar ratio of the excipient to gaboxadol or a pharmaceutically acceptable salt thereof of, for example, 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, or about 0.001:1 to about 0.01:1. In one embodiment, the excipient is present in a molar ratio of the excipient to gaboxadol or a pharmaceutically acceptable salt thereof of about 0.0001:1 to about 0.1:1 or about 0.001:1 to about 0.001:1.

[0086] In one embodiment, a pharmaceutical composition is provided comprising gaboxadol or a pharmaceutically acceptable salt thereof and an additive, wherein the additive comprises a stabilizing amount of a buffering agent. The buffering agent can be used to maintain the pH of the pharmaceutical composition so that gaboxadol or its pharmaceutically acceptable salt remains soluble, stable, and / or physiologically compatible. For example, in one embodiment, the parenteral composition comprises a composition that remains stable without significant degradation of gaboxadol. In one embodiment, the addition of a buffering agent is desired to control the pH to improve stability without significantly catalyzing or decomposing gaboxadol or its salt and / or causing pain to patients during infusion.

[0087] In one embodiment, the buffering agent can be citric acid, phosphoric acid, acetic acid, tartaric acid, carbonic acid, glutamic acid, lactic acid, succinic acid, bicarbonate buffer solution, and combinations thereof.For example, sodium citrate, anhydrous trisodium citrate, trisodium citrate dihydrate, sodium citrate dehydrate, triethanolamine (TRIS), trisodium citrate pentahydrate dihydrate (i.e., trisodium citrate dehydrate), acetic acid, citric acid, glutamic acid, phosphoric acid can be used as buffering agent.In one embodiment, the buffering agent can be amino acid, alkali metal or alkaline earth metal buffer solution.For example, the buffering agent can be sodium acetate or hydrogen phosphate.

[0088] In one embodiment, a parenteral composition of an active substance, such as an allosteric modulator and / or gaboxadol, is provided, wherein the pH of the composition is about 4.0 to about 8.0. In one embodiment, the pH of the composition is, for example, about 5.0 to about 8.0, about 6.0 to about 8.0, or about 6.5 to about 8.0. In one embodiment, the pH of the composition is, for example, about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In one embodiment, 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.

[0089] In one embodiment, the present invention provides a pharmaceutical composition of an active substance, such as an allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt, and an additive, wherein the additive comprises a solubilizer.For example, the solubilizer according to the present invention can comprise, 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 is sufficient so that the solution remains soluble at all concentrations, i.e., does not become cloudy and / or does not form precipitates.

[0090] In one embodiment, a pharmaceutical composition is provided that contains an active substance, such as an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof, and an additive, wherein the additive comprises a particle formation inhibitor.Particle formation inhibitor refers to a compound that has the desired property of inhibiting particle formation in parenteral compositions.Particle formation inhibitors of the present invention include ethylenediaminetetraacetic acid (EDTA) and its salts, such as calcium disodium ethylenediaminetetraacetic acid (preferably as a hydrate); diammonium ethylenediaminetetraacetic acid (preferably as a hydrate); dipotassium ethylenediaminetetraacetic acid (preferably as a dihydrate); disodium ethylenediaminetetraacetic acid (preferably as a dihydrate, optionally in anhydrous form); tetrasodium ethylenediaminetetraacetic acid (preferably as a hydrate); tripotassium ethylenediaminetetraacetic acid (preferably as a dihydrate); trisodium ethylenediaminetetraacetic acid (preferably as a hydrate) and disodium ethylenediaminetetraacetic acid, USP (preferably as a dihydrate).In one embodiment, the pharmaceutical composition described herein contains an effective amount of particle formation inhibitor. In one embodiment, the additives may include, for example, amino acids, urea, alcohol, 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 glycols (e.g., PEG-4000, PEG-6000), glycerol, glycine, and / or lipids.

[0091] In one embodiment, provide a pharmaceutical composition of an active substance, for example, an allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt, and an additive, wherein the additive comprises a solubilizing agent.For example, the solubilizing agent can include, but is not limited to, acids, such as carboxylic acids, amino acids.In another example, the solubilizing agent can be saturated carboxylic acids, unsaturated carboxylic acids, fatty acids, keto acids, aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, alpha-hydroxy acids, amino acids, and combinations thereof.

[0092] In one embodiment, there is provided a pharmaceutical composition of an active substance, e.g., an allosteric modulator and / or gaboxadol, or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises a solubilizing agent, e.g., formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, stearic acid, acrylic acid, docosahexaenoic acid, eicosapentaenoic acid, pyruvic acid, benzoic acid, salicylic acid, aldaric 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, praline, serine, threonine, tryptophan, tyrosine, valine, and combinations thereof.

[0093] In one embodiment, the solubilizing agent 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 one embodiment, the solubilizing agent is DL-arginine. In one embodiment, the solubilizing agent is L-arginine. In one embodiment, the solubilizing agent is acetic acid / sodium acetate. In one embodiment, the solubilizing agent is citric acid / sodium citrate.

[0094] In one embodiment, a pharmaceutical composition is provided comprising an active substance, such as an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof, and an additive, wherein the additive renders the composition isotonic. The isotonic pharmaceutical composition herein can be achieved by adding an appropriate amount of sodium chloride, glucose, fructose, dextrose, mannitol, potassium chloride, calcium chloride, calcium gluconoglucoheptonate, or a mixture thereof. For example, the additive can include one or more isotonicity agents, such as sodium chloride, potassium chloride, glycerin, mannitol, and / or dextrose. The isotonicity agent can be used to minimize tissue damage and irritation, reduce hemolysis of blood cells, and / or prevent electrolyte imbalance. For example, the parenteral composition can be an aqueous solution containing sodium chloride, which renders the composition isotonic. In one embodiment, the isotonicity agent is sodium chloride. In one embodiment, the concentration of the isotonicity agent is about 0.01 to about 2.0% by weight. In one embodiment, the pharmaceutical composition can contain up to about 10% isotonicity agent. In one embodiment, the pharmaceutical composition may contain, for example, about 0.25%, about 0.5%, about 1%, or up to about 2.5% of a tonicity agent. In one embodiment, the amount of the tonicity agent in the pharmaceutical is, for example, about 0.01% to about 1%, about 0.1% to about 1%, about 0.25% to about 1%, or about 0.5% to about 1%.

[0095] In one embodiment, provide a pharmaceutical composition of active substance, for example, allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt and additive, wherein the additive comprises free radical antagonist.In one embodiment, the free radical antagonist is ascorbic acid, ascorbic acid derivative, organic compound having at least one thiol, polyhydroxylated alkyl and polyhydroxylated cycloalkyl compound, and combinations thereof.

[0096] In one embodiment, there is provided a pharmaceutical composition of an active substance, e.g., an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises a free radical scavenger selected from thiolyglycolic acid, thiolacetic acid, dithiothreitol, reduced glutathione, thiourea, α-thioglycerol, cysteine, acetylcysteine, mercaptoethanesulfonic acid, and combinations thereof.

[0097] In one embodiment, there is provided a pharmaceutical composition of an active substance, e.g., an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises dithiothreitol, sodium thiosulfate, thiourea, ascorbic acid, methylene blue, sodium metabisulfite, sodium bisulfite, propyl gallate acetylcysteine, phenol, acetone sodium bisulfate, ascorbic acid, ascorbic acid esters, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), cysteine, nordihydroguaiaretic acid (NDGA), monothioglycerol, sodium sulfite, sodium metabisulfite, tocopherol, and / or glutathione.

[0098] In one embodiment, a pharmaceutical composition is provided comprising an active substance, such as an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof, and an additive, wherein the additive comprises a preservative. In one embodiment, the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, chlorocresol, metacresol, phenol, phenylmercuric nitrate, phenylmercuric acetate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, and thimerosal. In other embodiments, the preservative is selected from the group consisting of phenol, metacresol, benzyl alcohol, parabens (e.g., methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric salts (e.g., acetate, borate, or nitrate), and combinations thereof.

[0099] In one embodiment, the composition herein comprises a cosolvent. For example, in some cases, the solubility of gaboxadol may be well below the therapeutic dose, so a cosolvent system may be used. A cosolvent is a mixture of solvents that can be used to achieve sufficiently high solubility and increase stability. For example, the cosolvent may be a water-miscible organic solvent, such as ethanol, propylene glycol, Capmul PG, propylene glycol, glycerin, polyethylene glycol, sorbitol, dimethylacetamide, and / or dimethyl sulfoxide (DMSO). In one embodiment, the cosolvent may comprise up to about 75% of the pharmaceutical composition. In other embodiments, the amount of cosolvent used may comprise, for example, about 1%, about 5%, about 10%, about 15%, about 25%, about 40%, or up to about 50% of the pharmaceutical composition.

[0100] Dosage forms can be prepared, for example, by mixing the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof with one or more additives (e.g., buffers, solubilizers, isotonicity agents, antioxidants, chelating agents, antimicrobial agents, and / or preservatives) in a mixer under sterile conditions until a homogeneous mixture is obtained. An appropriate amount of the sterile mixture can then be filled into a pre-sterilized vial. A given amount of the sterile mixture can then be mixed with a solvent, such as water, saline, about 5-10% sugar (e.g., glucose, dextrose) solution, or a combination thereof, prior to administration. The solution can also be frozen and thawed before further processing.

[0101] The additive can be used in solid or solution form.When used in solid form, the additive and the allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt can be mixed together as described above, and a solvent can be added before parenteral administration.When used in liquid form, the allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt can be mixed with the solution of the additive before parenteral administration.

[0102] Parenteral solutions containing an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof can be prepared by mixing the required amount of the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof (which may be purified before use) in a parenteral liquid, such as D5W, distilled water, saline, or PEG, and adjusting the pH of the solution to 6.8-8. The process can be carried out at room temperature, or the solution can be warmed appropriately to increase the concentration. Other solvents, such as PEG 400, 600, polypropylene glycol, or other glycols, can be used to improve solubility. After cooling to room temperature, the resulting solution can be sterilized by known methods, such as ultrafiltration, e.g., using a 0.45 μm filter, or by ethylene oxide treatment or heating, and packaged in ampoules, vials, or prefilled syringes suitable for administering the sterile parenteral formulation.

[0103] When administered, the parenteral compositions herein provide a time to peak plasma concentration (Tp) of gaboxadol of about 1 hour or more (e.g., about 1.5 hours or more) in a human patient. max In one embodiment, the T of gaboxadol in a human patient is max is, for example, in the range of about 1 to about 5 hours, about 1 to about 4 hours, about 1 to about 3 hours, or about 1 to about 2 hours. In one embodiment, the T of gaboxadol in a human patient is greater than about 1.5. max In one embodiment, a T of gaboxadol in a human patient of less than about 3 hours is observed. max Once the infusion is complete, the time to peak plasma concentration is measured.

[0104] In one embodiment, the dosage forms herein contain about 1 mg to about 500 mg of gaboxadol, wherein parenteral administration (e.g., intramuscular, intravenous, subcutaneous, intraperitoneal, or intrathecal) of the dosage form results in a mean AUC of greater than about 25 ng·hr / ml. 0-∞ In one embodiment, a single dose administration of the dosage form provides an in vivo plasma profile of gaboxadol comprising, for example, a mean AUC greater than 50 ng·hr / ml, about 75 ng·hr / ml, about 150 ng·hr / ml, about 250 ng·hr / ml, about 500 ng·hr / ml, about 1000 ng·hr / ml or about 1500 ng·hr / ml. 0-∞ 1 provides an in vivo plasma profile of gaboxadol, including:

[0105] In one embodiment, the dosage form comprises about 1 mg to about 500 mg of gaboxadol, wherein administration of the dosage form results in a mean C of less than about 10,000 ng / ml. max In one embodiment, a single dose administration of the composition provides an in vivo plasma profile of gaboxadol comprising, for example, a mean C of less than about 5000 ng / ml, about 2500 ng / ml, about 1000 ng / ml, about 500 ng / ml, about 250 ng / ml, or about 100 ng / ml. max 1 provides the in vivo plasma profile of gaboxadol.

[0106] In one embodiment, the pharmaceutical composition for parenteral administration comprises gaboxadol or a pharmaceutically acceptable salt thereof, wherein the parenteral administration is administered at a T of about 1 to about 120 minutes after administration of the parenteral composition. max ; followed by at least 50% C for approximately 90 to 360 minutes max In one embodiment, parenteral administration of gaboxadol is continued for, for example, about 10 to about 60 minutes, about 15 to about 90 minutes, about 30 to about 120 minutes, about 60 to about 180 minutes, or about 90 to about 180 minutes, followed by at least 50% C max plasma drug concentrations of

[0107] In one embodiment, provide a stable pharmaceutical composition in a unit dosage form in a vial or ampoule suitable for parenteral administration, wherein a therapeutically effective amount of an allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt is dissolved in sterile water to form a solution, and the composition is substantially free of any additives, organic solvents, buffers, acids, bases, salts other than the allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt.In one embodiment, the pharmaceutical composition remains sufficiently soluble and can be administered directly.In one embodiment, the pharmaceutical composition can be stored for at least 6 months in the absence of an inert atmosphere.

[0108] In one embodiment, provide a stable pharmaceutical composition in a unit dosage form in a vial or ampoule suitable for parenteral administration, wherein a therapeutically effective amount of an allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt is dissolved in sterile water to form a solution, and the composition does not have any additives, organic solvents, buffers, acids, bases, salts other than the allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt.In one embodiment, the pharmaceutical composition remains sufficiently soluble and can be administered directly.In one embodiment, the pharmaceutical composition can be stored for at least 6 months in the absence of an inert atmosphere.

[0109] In one embodiment, a stable pharmaceutical composition suitable for parenteral administration comprises an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof in an aqueous solution having an osmolality of 225-350 mOsm / kg and a pH in the range of 7.0-8.0. In one embodiment, the aqueous solution has an osmolality of 270-310. In one embodiment, the aqueous solution has a pH in the range of 7.2-7.8.

[0110] In one embodiment, there is provided a method of treating an epileptic disorder comprising administering to a patient in need thereof a first medicament and a second pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and / or an allosteric modulator, wherein the second pharmaceutical composition has a mean AUC 0-∞ The present invention provides a method for providing a stable in vivo plasma profile having ...

[0111] In one embodiment, parenteral composition can be administered as needed, for example, once, twice, three times or four times or more per day, or continuously according to the patient's needs.In one embodiment, parenteral composition can be administered immediately after the onset of attack or as soon as possible thereafter.In one embodiment, parenteral composition can be administered as soon as the patient shows warning signs of attack, such as smell, unusual smell, normal feelings, etc.

[0112] In one embodiment, a method of treating an epileptic disorder is provided comprising administering to a patient in need thereof a first pharmaceutical dose comprising a sub-therapeutic dose of an allosteric modulator, wherein the composition provides improvement for greater than 6 hours after administration.

[0113] In one embodiment, there is provided a method of treating an epileptic disorder comprising administering to a patient in need thereof a first pharmaceutical dose comprising a sub-therapeutic dose of gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement for more than 6 hours after administration.

[0114] In one embodiment, there is provided a method of treating an epileptic disorder comprising administering to a patient in need thereof a first pharmaceutical composition comprising an allosteric modulator and a second pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein the second pharmaceutical composition has a mean AUC 0-∞ In one embodiment, the second pharmaceutical composition has an AUC of less than about 800 ng·hr / ml, about 750 ng·hr / ml, about 700 ng·hr / ml, about 650 ng·hr / ml, or about 600 ng·hr / ml. 0-∞ In one embodiment, the second pharmaceutical composition provides an in vivo plasma profile having an AUC of less than, e.g., about 550 ng·hr / ml, about 500 ng·hr / ml, about 450 ng·hr / ml, about 400 ng·hr / ml, or about 350 ng·hr / ml. 0-∞ In one embodiment, the second pharmaceutical composition provides an in vivo plasma profile having an AUC of less than about 300 ng·hr / ml, about 250 ng·hr / ml, about 200 ng·hr / ml, about 150 ng·hr / ml, or about 100 ng·hr / ml, e.g., 0-∞ In one embodiment, the first and second pharmaceutical compositions are administered to provide an improvement in the patient's next-day function. In one embodiment, the first pharmaceutical composition provides an improvement in one or more symptoms, for example, more than 6 hours, 8 hours, or 12 hours after administration of the first pharmaceutical composition.

[0115] In one embodiment, there is provided a method of treating an epileptic disorder comprising administering to a patient in need thereof a first pharmaceutical composition comprising an allosteric modulator and a second pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof, wherein the first composition provides a C provided by administration of the second pharmaceutical composition. max C, which is approximately 50% larger than max As used herein, the C provided by administration of the second pharmaceutical composition is max may or may not include the plasma profile contribution of the first pharmaceutical composition. In one embodiment, administration of the second pharmaceutical composition does not include the plasma profile contribution of the first pharmaceutical composition. In one embodiment, the first composition provides a C provided by administration of the second pharmaceutical composition. max For example, about 60%, about 70%, about 80%, or about 90% greater than C max and providing an in vivo plasma profile having:

[0116] In one embodiment, the T of the first pharmaceutical composition max In one embodiment, the T of the first pharmaceutical composition is less than 3 hours. max In one embodiment, the T of the first pharmaceutical composition is less than 2.5 hours. max In one embodiment, the T of the first pharmaceutical composition is less than 2 hours. max In one embodiment, the T of the first pharmaceutical composition is less than 1.5 hours. max is less than an hour.

[0117] In one embodiment, the first pharmaceutical composition provides at least about 80% dissolution within the first 20 minutes of administration to a patient in need thereof.In one embodiment, the first pharmaceutical composition provides at least, for example, about 85%, about 90% or about 95% dissolution within the first 20 minutes of administration to a patient in need thereof.In one embodiment, the first pharmaceutical composition provides at least 80% dissolution within the first 10 minutes of administration to a patient in need thereof.

[0118] In one embodiment, the first and / or second pharmaceutical composition is a subtherapeutic dose. A subtherapeutic dose is an amount of an active substance, such as an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof, that is less than the amount required for therapeutic effect. In one embodiment, a subtherapeutic dose is an amount of an allosteric modulator or a pharmaceutically acceptable salt thereof that alone cannot provide an improvement in at least one symptom of an epileptic disorder, but is sufficient to maintain such improvement. In one embodiment, a subtherapeutic dose is an amount of gaboxadol or a pharmaceutically acceptable salt thereof that alone cannot provide an improvement in at least one symptom of an epileptic disorder, but is sufficient to maintain such improvement. In one embodiment, the method provides for administering a first pharmaceutical composition that provides an improvement in at least one symptom of an epileptic disorder, and a second composition that maintains the improvement. In one embodiment, after administering the first pharmaceutical composition, the second pharmaceutical composition can provide a synergistic effect of improving at least one symptom of an epileptic disorder. In one embodiment, the second pharmaceutical composition may provide a synergistic effect that improves at least one symptom of an epileptic disorder.

[0119] In one embodiment, there is provided a method of treating an epileptic disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising a first pharmaceutical dose, wherein the composition provides improvement for more than 6 hours after administration, and a second pharmaceutical composition comprising a sub-therapeutic dose of gaboxadol or a pharmaceutically acceptable salt thereof.

[0120] The administration of the first and second pharmaceutical compositions can be simultaneous or at a certain time apart to achieve immediate, intermediate or long-term improvement of at least one symptom. In one embodiment, the first and second pharmaceutical compositions can be administered 6 hours apart. In one embodiment, the first and second pharmaceutical compositions can be administered 12 hours apart. In one embodiment, the first and second pharmaceutical compositions can be administered, for example, within 15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 18 hours, 24 hours, etc. In one embodiment, the first and second pharmaceutical compositions can be administered at least 15 minutes, 30 minutes, 1 hour, 2 hours, 12 hours, 18 hours, 24 hours, etc. In one embodiment, the improvement of at least one symptom of an epileptic disorder is provided for more than 8 hours after administration to a patient. In one embodiment, the improvement is provided for more than about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 20 hours, or about 24 hours after administration to a patient.

[0121] In one embodiment, the administration of the first and second pharmaceutical compositions may provide a synergistic effect that improves at least one symptom of an epileptic disorder.

[0122] In one embodiment, the first and / or second pharmaceutical composition comprises the above-mentioned amounts of an active substance, such as an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof.

[0123] In one embodiment, the first and / or second pharmaceutical composition comprises 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 modulator and / or gaboxadol.

[0124] In one embodiment, the first and / or second pharmaceutical composition contains 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, 20 mg of an active substance, such as an allosteric modulator and / or gaboxadol, or a multiple of said dosage amounts. In one embodiment, the first pharmaceutical composition contains 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of an allosteric modulator. In one embodiment, the second pharmaceutical composition contains 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of an allosteric modulator.

[0125] In one embodiment, the method for treating epileptic disorders comprises administering an allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt in combination with one or more other active compounds.Combined therapy can comprise administering active agents together in the same mixture or in separate mixtures.In one embodiment, the pharmaceutical composition comprises two, three or more active agents.In one embodiment, the combination produces a greater than additive effect in the treatment of disease or disorder.Therefore, the treatment of epileptic disorders provided by the combination of drugs can provide a synergistic effect that improves efficacy.

[0126] In one embodiment, gaboxadol or its pharmaceutically acceptable salt is administered in combination with conventional therapy for seizures, epilepsy, or one of the other disorders described herein.For example, the common conventional therapy for seizures and epilepsy includes antiepileptic drugs and non-antiepileptic drug treatments, such as low-carbohydrate diets (e.g., ketogenic diets, such as classic diets, medium-chain triglyceride (MCT) diets, modified Atkins diets (MAD), and low glycemic index treatments (LGIT)), intravenous immunoglobulin, steroids, elimination diets, valgus nerve stimulation, corticotomy, and subpial corticotomy.

[0127] Common antiepileptic and anticonvulsant active compounds that may be used in combination with the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof include, but are not limited to, acetazolamide, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

[0128] The disclosed compounds, such as gaboxadol or a pharmaceutically acceptable salt thereof, or an allosteric modulator, a pharmaceutically acceptable salt thereof, a derivative, and / or an analog thereof, can be used independently as the sole active agent in monotherapy. In one embodiment, a method for treating an epileptic disorder using an allosteric modulator or a pharmaceutically acceptable salt thereof is provided. In one embodiment, the method for treating an epileptic disorder includes administering an allosteric modulator, a pharmaceutically acceptable salt thereof, a derivative, and / or an analog thereof in combination with one or more other active agents, such as an allosteric modulator or gaboxadol. Combination therapy can include administering active agents, such as an allosteric modulator or gaboxadol, together in the same mixture or in separate mixtures. In one embodiment, the pharmaceutical composition includes two, three, or more active agents. In one embodiment, the combination produces a more than additive effect in the treatment of a disease or disorder. Thus, the treatment of an epileptic disorder provided by a combination of drugs can provide a synergistic effect that improves efficacy.

[0129] In one embodiment, gaboxadol or its pharmaceutically acceptable salt, or the allosteric modulator, its pharmaceutically acceptable salt, derivative and / or analog, or both are administered in combination with conventional therapy for seizures, epilepsy, or one of the other disorders described herein.For example, common conventional therapy for seizures and epilepsy includes 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 immunoglobulin, steroids, elimination diets, valgus nerve stimulation, corticotomy, and subpial corticotomy.

[0130] Common antiepileptic and anticonvulsant active compounds that may be used in combination with the allosteric modulators include, but are not limited to, acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

[0131] In one embodiment, co-treatment of an allosteric modulator, a pharmaceutically acceptable salt thereof, or a derivative thereof, and gaboxadol or a pharmaceutically acceptable salt thereof is more effective in reducing seizure frequency or severity in a subject than administration of either compound alone, hi one embodiment, the co-treatment provides more than additive results compared to the compounds administered individually.

[0132] In one embodiment, a subject may be started on a low dose and the dose gradually increased. In this way, it can be determined whether the drug is well tolerated in the subject. Doses for children may be lower than those for adults.

[0133] In one embodiment, e.g., in combination therapy, the pediatric dose of gaboxadol may be 0.1 mg / kg to 1 mg / kg and the dose of the allosteric modulator may be 0.01 mg / kg to 0.1 mg / kg. In one embodiment, the weight / weight ratio of gaboxadol to allosteric modulator may be 10 to 1. However, the dosage ratio based on milligrams of active pharmaceutical ingredient (API) may range from 0.1 to 1 to 100 to 1 of gaboxadol to allosteric modulator, respectively.

[0134] Effective treatment of epileptic disorders (e.g., acute recurrent seizures) herein can be established by demonstrating a reduction (e.g., more than 50%) in seizure frequency after a certain period compared to baseline.For example, after a one-month baseline period, patients can be randomly assigned to gaboxadol, an allosteric modulator, or a placebo as add-on therapy to standard therapy, such as valproic acid and clobazam, during a two-month double-blind period.The primary outcome measurement can include the percentage of responders to gaboxadol, an allosteric modulator, and a placebo, defined as experiencing at least a 50% reduction in clonic (or tonic-clonic) seizure frequency during the second month of the double-blind period compared to baseline.Patients who show status epilepticus during the double-blind period can be considered non-responders. Secondary outcomes may include the absolute number of clonic (or tonic-clonic) seizures during the second month of the double-blind period (normalized to 30 days by dividing the raw number by the exact number of observation days and multiplying by 30) and the percentage change from baseline.

[0135] The efficacy of gaboxadol and / or allosteric modulators for the treatment of disclosed epileptic disorders, such as those associated with Dravet syndrome or Lennox-Gastaut syndrome, may be established in other controlled trials. For example, a randomized, double-blind, placebo-controlled trial consisting of a 4-week baseline period followed by a 3-week titration period and a 12-week maintenance period may be used in patients aged 2 to 54 years who are currently or previously diagnosed with Dravet syndrome or LGS. Multiple target maintenance doses of gaboxadol and / or allosteric modulators may be tested according to patient weight and specific dosing regimens. The primary efficacy measure may include a percentage reduction in the weekly frequency of astatic seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 12-week maintenance period. Thus, efficacy can be measured as a percentage reduction in weekly seizure (e.g., atonic, tonic, or myoclonic) frequency from baseline, e.g., 0 to <20, 20 to <40, 40 to <60, 60 to <80, 80 to <100.

[0136] 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 the disclosure herein belongs.

[0137] As used herein, the term "about" or "approximately" refers to within an acceptable error range of a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more standard deviations, as is customary in the art. Alternatively, "about" can mean within 20%, preferably 10%, more preferably 5%, and even more preferably 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within one order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value.

[0138] As used herein, the term "treating" or "treatment" refers to alleviating or delaying the appearance of clinical symptoms of disease or pathology in a subject who is suffering from or may be suffering from a disease or pathology, but has not yet experienced or exhibited the clinical or subclinical symptoms of the disease or pathology.In certain embodiments, "treating" or "treatment" can refer to preventing the appearance of clinical symptoms of disease or pathology in a subject who is suffering from or may be suffering from a disease or pathology, but has not yet experienced or exhibited the clinical or subclinical symptoms of the disease or pathology."Treatment" or "treatment" can also refer to suppressing a disease or pathology, for example, preventing or reducing epilepsy or at least one of its clinical or subclinical symptoms."Treatment" or "treatment" can also refer to alleviating a disease or pathology, for example, causing the regression of a disease or pathology or at least one of its clinical or subclinical symptoms. The benefit to a 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 embodiments of the present disclosure.

[0139] An "effective amount" or "therapeutically effective amount" means a dosage sufficient to alleviate one or more symptoms of the disorder, disease or condition being treated or otherwise provide the desired pharmacological and / or physiological effect.

[0140] "Amelioration" refers to treatment of a symptom or condition associated with an epileptic disorder as measured relative to at least one symptom or condition of a metabolic disorder.

[0141] "Improved next day function" or "has improved next day function" refers to a beneficial effect of one or more administrations of gaboxadol or a pharmaceutically acceptable salt thereof alone, or an allosteric modulator alone, or a combination of gaboxadol and an allosteric modulator, which applies to at least one symptom or condition associated with an epileptic disorder for a period of time after waking, e.g., immediately, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc., that is discernible subjectively by the patient or objectively by an observer, following waking from a night's sleep.

[0142] The terms "composition," "pharmaceutical composition," "formulation," and "pharmaceutical formulation" are used interchangeably herein. A "composition," "pharmaceutical composition," "formulation," and "pharmaceutical formulation" encompasses a dosage form. A dosage form can comprise a unit dosage.

[0143] "Pharmaceutically acceptable" refers to molecules and compositions that are "generally regarded as safe," e.g., physiologically tolerated and typically do not produce allergic or similar adverse reactions, such as stomach upset, when administered to humans. In one embodiment, the term refers to molecules and compositions approved by a federal or state regulatory agency with respect to the GRAS list or similar list under Sections 204(s) and 409 of the Federal Food, Drug, and Cosmetic Act, the United States Pharmacopoeia, or another pharmacopoeia generally recognized as for use in animals, more specifically in humans, that are subject to premarket review and approval by the FDA.

[0144] As used herein, the term "prevention" or "preventing" means administering a composition to a subject or system at risk of or predisposed to one or more symptoms caused by a disease or disorder to facilitate the cessation of a particular symptom of a disease or disorder, the reduction or prevention of one or more symptoms of a disease or disorder, the lessening of the severity of a disease or disorder, the complete elimination of a disease or disorder, or the stabilization or slowing of the progression of epilepsy or a disease or disorder.

[0145] As used herein, a "prodrug" refers to a pharmacological substance (drug) that is administered to a subject in an inactive (or significantly less active) form. Upon administration, the prodrug is metabolized in the body (in vivo) to a compound possessing the desired pharmacological activity.

[0146] "Analog," "analogue," and "derivative" are used interchangeably herein to refer to a compound that has the same nucleus as the parent compound, but may differ from the parent compound in the bond order, the presence or absence of one or more atoms and / or groups of atoms, and combinations thereof. A derivative may differ from the parent compound in the inclusion of one or more atoms, functional groups, or substructures, for example, in one or more substitutions present in the nucleus. In general, a derivative may be envisioned, at least theoretically, to be formed from the parent compound by chemical and / or physical processes.

[0147] As used herein, "stereoisomer" refers to isomeric molecules that have the same molecular formula and bonded atom sequence (configuration), but differ in the three-dimensional orientation of their atoms in space. Examples of stereoisomers include enantiomers and diastereomers. As used herein, an enantiomer refers to one of two mirror images of an optically active or chiral molecule. A diastereomer (or diastereoisomer) is a stereoisomer (a non-superimposable mirror image of each other) that is not an enantiomer. A chiral molecule contains a chiral center (also called a stereogenic center or stereogenic center), which is any point, but not necessarily an atom, in the molecule bearing groups such that the interchange of any two groups results in a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus, or sulfur atom, although other atoms can be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, resulting in many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbons), the total number of hypothetical possible stereoisomers does not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry often have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers may be enantiomerically enriched, such that one enantiomer is present in an amount greater than 50%. Enantiomers and / or diastereomers may be resolved or separated using techniques known in the art. "Chirality" also includes axial and planar chirality.

[0148] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of compounds defined herein, in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, 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, sulfamic 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, pamoic 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 isethionate. Pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. For example, gaboxadol can be formulated for administration to a patient using pharmaceutically acceptable salts, including acid addition salts, zwitterion hydrates, zwitterion anhydrates, hydrochlorides or hydrobromides, or in the form of a zwitterion monohydrate. Acid addition salts include, but are not limited to, addition salts of 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 acetate, and 8-halotheophylline, e.g., 8-bromo-theophylline. 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, sulfamic acid, phosphoric acid, or nitric acid.

[0149] An "excipient" is a substance, other than the active drug substance of a pharmaceutical composition, e.g., gaboxadol, that has been appropriately evaluated for safety and that is included in a drug delivery system to aid in the processing of the drug delivery system during manufacturing; to protect; to support; to improve the stability, bioavailability or patient tolerability; to aid in product identification; or to improve other attributes of the overall safety and effectiveness of the drug delivery system during storage or use.

[0150] "Stabilizer" or "stabilizing amount" refers to the amount of one or more additives included in a parenteral composition that provides sufficient stability but does not adversely affect the bioavailability, safety, and / or efficacy of the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof used in the composition.

[0151] "Stable" means that there is substantially no degradation of gaboxadol or a pharmaceutically acceptable salt thereof after a particular period of time, for example, after 3 or 6 months.

[0152] By "soluble" is meant that a solution of the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof is not cloudy and / or there is substantially no precipitate in the solution.

[0153] " Sufficiently soluble " means that the particle content is low enough and the substance is sufficiently sterile so that it is useful for parenteral administration.For example, the particle number in the liquid composition should be, for example, less than 6,000 10 μm particles in 10 ml of solvent volume, and 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 examples, the particle number in the liquid composition should be less than 1,000, less than 600 or less than 200 25 μm particles in 10 ml of volume.

[0154] "Topically compatible" herein means that the composition is tolerated at the site of injection or infusion, thereby minimizing side effects, such as local skin or venous irritation (including inflammatory reactions at the infusion site). The parenteral compositions herein may have fewer side effects, such as skin irritation or phlebitis, than conventional products.

[0155] As used herein, "purified" refers to a material that has been isolated under conditions that reduce or eliminate the presence of unrelated substances, i.e., contaminants (including the material from which it was obtained). As used herein, the term "substantially free" is used operationally in the context of analytical testing of a material. Preferably, a material produced that is substantially free of contaminants is at least 95% pure; more preferably, at least 97% pure, and even more preferably, at least 99% pure. Purity can be assessed, for example, by chromatography or other methods known in the art. In one embodiment, purified means that the level of contaminants is below that acceptable to regulatory authorities for safe administration to humans or non-human animals.

[0156] "Ready-to-use" herein with respect to compositions means a formulation that is in a reconstituted form, has a standardized concentration and quality, and is pre-filled into a single-use container, such as a glass vial, an infusion bag, or a syringe, ready for direct administration to a patient.

[0157] "Direct administration" herein with respect to compositions means immediate administration, i.e., administration without further dilution, premixing with other substances, or other alteration of the composition or its formulation. Such compositions are typically released directly from an infusion device and administered via a vascular access port or central line.

[0158] "Dosage" is intended to encompass formulations expressed in terms of μg / kg / day, μg / kg / hour, mg / kg / day, or mg / kg / hour. A dose is the amount of an ingredient administered according to a particular administration regimen. A "dose" is the amount of a drug administered to a mammal in a unit volume or amount, e.g., an absolute unit dose expressed in mg or μg of drug. The dosage depends on the concentration of the drug in the formulation, e.g., in moles per liter (M), amount per volume (m / v), or amount per volume (m / m). The two terms are closely related, such that a particular dose results from a regimen of administration of one or more doses of a formulation. The specific meaning in either case is clear from the context.

[0159] "Patient" and "subject" are used interchangeably herein and include, but are not limited to, primates, such as humans, dogs, pigs, ungulates, rodents, poultry and birds.

[0160] "Co-administered with," "in combination with," "administered in combination with," "combination of," "administered together with," or "co-treatment" may be used interchangeably and mean that two or more agents are administered during the course of treatment. The agents may be administered together at the same time or separately at intervals. The agents may be administered in a single dosage form or in separate dosage forms.

[0161] "PK" refers to pharmacokinetic profile. max is defined as the highest plasma drug concentration (ng / ml) estimated during the experiment. max is C max AUC is defined as the time point (minutes) at which the 0-∞ is the total area under the plasma drug concentration-time curve from drug administration to drug elimination (ng·h / ml or μg·h / ml). The area under the curve is governed by clearance, which is defined as the volume of blood or plasma completely cleared of drug content per unit time (ml / min). [Example]

[0162] The examples provided herein are included merely to enhance the disclosure and should not be construed as limiting in any way.

[0163] Example 1 Gaboxadol plasma concentration profile The following example provides the plasma concentration profile and dose proportionality of gaboxadol monohydrate after single oral administration in the range of 2.5 to 20 mg. The absolute bioavailability of gaboxadol monohydrate capsule tablets in the range of 2.5 to 20 mg is also evaluated.

[0164] This study consisted of 10 healthy adults (at least four of each sex) participating in a six-period, double-blind, randomized, crossover trial designed to evaluate the dose proportionality and absolute bioavailability of five single oral doses of gaboxadol across a dose range of 2.5 to 20 mg. The order in which subjects received the five single oral doses of gaboxadol (2.5, 5, 10, 15, and 20 mg) was randomized within treatment periods 1 to 5. Each subject was expected to complete all six treatment periods, with at least four days of washout between each treatment period.

[0165] Each oral dose within the treatment period consisted of two capsules of study medication taken simultaneously at each scheduled dose. Treatment designations for orally administered study medication were as follows: Treatment A - one 2.5 mg gaboxadol capsule and one matching placebo capsule; Treatment B - one 5 mg gaboxadol capsule and one matching placebo capsule; Treatment C - one 10 mg gaboxadol capsule and one matching placebo capsule; Treatment D - one 15 mg gaboxadol capsule and one matching placebo capsule; and Treatment E - 20 mg gaboxadol (two 10 mg gaboxadol capsules). After an overnight fast, subjects received their study medication with 240 mL of water at approximately 8:00 AM in the morning. Water was permitted ad libitum, except within one hour before and after study medication administration. Food was not permitted for four hours after administration.

[0166] For each subject in each treatment, plasma and urine specimens were collected for 16 hours post-dose for determination of pharmacokinetic parameters (e.g., AUC, Cmax, Tmax, apparent t1 / 2, cumulative urinary excretion, renal clearance, clearance, and steady-state volume of distribution, as appropriate). The AUC and Cmax of gaboxadol were potency-adjusted to facilitate comparison of pharmacokinetic data across study groups. Table 1 provides the individual potency-adjusted pharmacokinetic parameters of gaboxadol after single oral doses (2.5, 5, 10, 15, and 20 mg). [Table 1]

[0167] Example 2 Assessment of residual effects of gaboxadol administration This study was a double-blind, double-dummy, randomized, active- and placebo-controlled, single-dose, three-period crossover study followed by an open-label, single-period study in healthy elderly male and female subjects. Subjects were randomized to each of three treatments (Treatments A, B, and C) and administered in a crossover fashion for the first three treatment periods. For Treatment A, subjects received a single dose of gaboxadol 10 mg; for Treatment B, subjects received a single dose of flurazepam 30 mg; and for Treatment C, subjects received a single dose of placebo. Doses were administered orally at bedtime on Day 1. Subjects remained at home from early the evening of dosing during each treatment period until approximately 36 hours after dosing (the morning of Day 3). Subjects who participated in Treatment Periods 1 through 3 participated in the fourth treatment period. During this period, a single dose of 10 mg gaboxadol (Treatment D) was administered orally in an open-label fashion on the morning of Day 1 for gaboxadol PK assessment. There was a minimum of 14 days of washout between doses of consecutive treatment periods. Study participants included healthy elderly male and female subjects aged 65-80 years, with a Mini-Mental State Score of 24 and weighing at least 55 kg. All subjects received 10 mg gaboxadol monohydrate capsules and 30 mg flurazepam (provided as 2 x 15 mg capsules), with matching placebos provided for both gaboxadol and flurazepam.

[0168] Primary endpoints evaluated included measures of psychomotor performance, memory, attention, and daytime sleepiness after an afternoon dose, gaboxadol pharmacokinetics, and safety. Gaboxadol (a single 10 mg dose) showed no residual effects 9 hours after administration on the primary endpoints of choice reaction time and critical flicker fusion, whereas the active control, flurazepam (a single 30 mg dose), showed significant effects in the same tests. Gaboxadol also showed no signs of residual effects on other measures administered in the study (Multiple Sleep Latency Test (MSLT); Digit symbol substitution test (DSST), tracking, memory tests, body sway, and the Leeds Sleep Assessment Questionnaire).

[0169] Example 3 Evaluation of the ability of allopregnanolone, ganaxolone, and gaboxadol to block benzodiazepine-resistant status epilepticus Allopregnanolone, ganaxolone, and gaboxadol will be evaluated for acute anticonvulsant efficacy when administered in increasing doses 30 minutes after the onset of convulsive status epilepticus (a time point typically refractory to benzodiazepines). Results obtained with these agents will be compared to those obtained from parallel studies in vehicle-treated animals.

[0170] Male Sprague Dawley rats (n = 10 treatments / group, 100-125 g; Charles River Laboratories) are treated systemically with lithium chloride (127 mg / kg; intraperitoneally (i.p.)) 24 hours prior to administration of the chemical convulsion inducer pilocarpine. The following day, rats are administered pilocarpine hydrochloride (50 mg / kg; i.p.) and closely monitored for the presence or absence of convulsive seizure activity. Pilocarpine administration induces behavioral seizures within 5-20 minutes, and rats that do not demonstrate convulsive seizure activity within 45 minutes of pilocarpine administration are excluded from further testing. On the test day, each test compound (allopregnanolone (ALLO), ganaxolone (GNX), or gaboxadol (GBD)) or vehicle (VEH) (40% hydroxypropyl β-cyclodextrin) is administered to rats in the Li-Pilo model of status epilepticus. The ability of drugs to terminate SE-induced convulsive status epilepticus is assessed with increasing doses administered i.p. 30 min after the first observed convulsive seizure. Throughout the study, the experimenter conducting behavioral observations is blinded to treatment condition (i.e., allopregnanolone, ganaxolone, or gaboxadol). All rats are observed and scored for seizure severity for 120 min after drug administration, and any accompanying behavioral changes are also recorded by an experimenter blinded to treatment condition. At the end of the behavioral observation period, a 3 mL injection of lactated Ringer's solution is administered to all surviving rats to compensate for SE-induced fluid loss.

[0171] The dose of each test compound (allopregnanolone, ganaxolone, or gaboxadol) is varied in groups of 10 rats until at least two points are established between 100% protection (no further convulsive seizures 10 minutes after drug administration) and 0% protection. The drug dose required to produce the desired endpoint (ED50 or TD50) and 95% confidence interval in 50% of animals is calculated using a computer program based on the Probit method (Finney DJ. Probit Analysis. Cambridge University Press. 1971). This dose-response assessment typically requires up to five treatment groups per test compound, for a total of up to 50 rats per compound. Therefore, up to 150 rats can be used to quantify the test compound (allopregnanolone, ganaxolone, or gaboxadol), and there is also one vehicle-treated group (n=10), so the total number of rodents in Test 1 is 160. All animals in the study are kept for 24 hours after completion of the study for evaluation of weight change. The doses administered for allopregnanolone, ganaxolone, or gaboxadol are 0.5 mg / kg, 2 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / kg.

[0172] Pharmacokinetic Sampling: Brain and plasma may be collected for evaluation from satellite cohorts of rats for each dose (n=3 rats / dose / compound; maximum 45 rats total). Plasma is collected from trunk blood after centrifugation at 10,000 x g for 10 minutes at 4°C. The anticoagulant is lithium heparin. Brains are flash frozen on dry ice. All samples are stored at -20°C. The study procedure timeline is shown in Figure 2.

[0173] Dose-response curves were generated and expressed as the calculated ED50 (95% confidence interval) for each test compound (allopregnanolone, ganaxolone, or gaboxadol) administered 30 minutes after the first observed convulsive seizure. If the data do not allow for calculation of an ED50 (95% confidence interval) due to lack of efficacy, the highest dose tested is shown. Additional measures of efficacy, such as motor impairment, weight change after SE, and 24-hour survival from SE, are also recorded throughout the study for all treatment conditions. [Table 2]

[0174] Figure 3 is a bar graph showing percent protection versus dose for allopregnanolone, ganaxolone, or gaboxadol. Figure 4 is a bar graph showing 24-hour survival results based on dose for allopregnanolone, ganaxolone, or gaboxadol. Figure 5 is a bar graph showing the number of observed seizures versus dose. Figure 6A is a bar graph showing percent weight loss 24 hours after status epilepticus as a function of dose versus dose. Figure 6B is a bar graph showing 24-hour weight loss for the 0.5 mg / kg dose group. Dose-response evaluation of treatment during benzodiazepine-resistant status epilepticus suggests dose-dependent efficacy of ganaxolone (ip)—significant (p<0.02) improvement in protection at 20 mg / kg. Possible inverted U response profile for gaboxadol (ip) - p=0.071 at 0.5 mg / kg. A significant improvement in 24 hour survival rate is shown for gaboxadol treated rats (10 mg / kg).

[0175] Example 4 A prospective study to characterize the ability of allopregnanolone, ganaxolone, and gaboxadol to block benzodiazepine-resistant status epilepticus An initial dose-response study of intraperitoneally (ip) administered allopregnanolone (ALLO), ganaxolone (GNX), and gaboxadol (GBD) suggests potential efficacy for benzodiazepine-resistant status epilepticus (Example 3). This study evaluates the potential synergistic effects of allopregnanolone, ganaxolone, or the benzodiazepine lorazepam (LZP) with gaboxadol for benzodiazepine-resistant status epilepticus in the rat Li-Pilo model. Specifically, a low dose (e.g., 0.5 mg / kg) of gaboxadol is administered in combination with a fixed dose of either allopregnanolone, ganaxolone, or lorazepam. The doses of allopregnanolone and ganaxolone were those previously found to produce anticonvulsant effects in Example 3 (Table 2). The dose of lorazepam is 2 mg / kg (Walton and Treiman. 1990. Neurology 40: 990-994 1990). The activity of each compound is also evaluated alone. A vehicle-treated group is included. 30 minutes after the onset of status epilepticus, rats are administered a single ip dose of each dose or dose combination (Table 3) (n=13 / group). The rats are monitored for further seizure activity. [Table 3]

[0176] Male Sprague Dawley rats (n = 13 treatments / group; 100-125 g upon arrival from Charles River Laboratories) are treated systemically with lithium chloride (127 mg / kg; i.p.) 24 hours prior to administration of the chemical convulsion inducer pilocarpine. The following day, rats are administered pilocarpine hydrochloride (50 mg / kg; i.p.) and closely monitored for the presence or absence of convulsive seizure activity. Pilocarpine administration induces behavioral seizures within 5-20 minutes, and rats that do not demonstrate convulsive seizure activity within 45 minutes of pilocarpine administration are excluded from further testing. On the test day, the ability of each test compound (allopregnanolone, ganaxolone, or gaboxadol) or vehicle (VEH) to terminate convulsive status epilepticus in the Li-Pilo model of status epilepticus is assessed 30 minutes after administration of the first observed convulsive seizure, as outlined in Table 3. Throughout the study, the experimenter conducting behavioral observations is blinded to the treatment condition (e.g., allopregnanolone, ganaxolone, or gaboxadol, lorazepam, or VEH). All rats are observed and scored for seizure severity for 120 minutes after drug administration, and any accompanying behavioral changes are also recorded by an experimenter blinded to the treatment condition. At the end of the behavioral observation period, a 3 mL injection of lactated Ringer's solution is administered to all surviving rats to compensate for status epilepticus-induced fluid loss.

[0177] Each test compound dose is administered to rats (n=13 / compound dose; Table 3) for a total of 130 rats. A 15% non-responder rate (those who do not develop convulsive status epilepticus within 45 minutes) is predicted for rats pretreated with Li-Cl. Therefore, a maximum of 150 rats will be used in this study, including potential non-responders. All animals in the study will be kept for 24 hours after completion of the study for evaluation of weight change and overall behavioral status at that time (e.g., lethargy / activity). Behavior will be assessed by an experimenter blinded to treatment conditions.

[0178] Pharmacokinetic Sampling: Brain and plasma are collected for evaluation from a cohort of rats for each dose (n=3 rats / dose / compound). Plasma is isolated from trunk blood after centrifugation at 10,000×g for 10 minutes at 4° C. The anticoagulant is lithium heparin. Brains are flash-frozen on dry ice. The study procedure timeline is shown in Figure 7.

[0179] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein which equivalents are intended to be encompassed by the claims.

Claims

1. A method of treating an epileptic disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising an allosteric modulator.

2. 2. The method of claim 1, wherein the epileptic disorder is selected from the group consisting of epilepsy, epilepsy with generalized tonic-clonic seizures, myoclonic absence epilepsy, 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, Douzé syndrome, acute recurrent seizures, benign rolandic epilepsy, status epilepticus, treatment-resistant status epilepticus, very treatment-resistant status epilepticus (SRSE), PCDH19 childhood epilepsy, increased seizure activity, or seizure recurrence.

3. 10. The method of claim 1, wherein the epileptic disorder is status epilepticus.

4. 10. The method of claim 1, wherein the epileptic disorder is acute recurrent seizures.

5. 10. The method of claim 1, wherein the epileptic disorder is Lennox-Gastaut syndrome.

6. 10. The method of claim 1, wherein the composition provides a reduction in seizure frequency, seizure severity, or a combination thereof, in a patient diagnosed with an epileptic disorder.

7. 2. The method of claim 1, wherein the allosteric modulator is selected from the group consisting of neurosteroids, benzodiazepines, and potassium channel openers.

8. 10. The method of claim 1, wherein the allosteric modulator is ganaxolone.

9. 2. The method of claim 1, wherein the allosteric modulator is allopregnanolone.

10. 10. The method of claim 1, wherein the allosteric modulator is a benzodiazepine.

11. 11. The method of claim 10, wherein the benzodiazepine is selected from the group consisting of midazolam, clobazam, clonazepam, diazepam, lorazepam, flurazepam and lorazepam.

12. The method of claim 1, wherein the allosteric modulator is a potassium channel opener.

13. 13. The method of claim 12, wherein the potassium channel opener is retigabine or flupirtine.

14. 10. The method of claim 1, wherein the patient is further administered gaboxadol or a pharmaceutically acceptable salt thereof.

15. 10. The method of claim 1, wherein the allosteric modulator is administered once, twice, or three times daily, or every other day.

16. 10. The method of claim 1, further comprising administering a compound selected from the group consisting of acetazolamide, carbamazepine, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

17. 10. The method of claim 1, wherein the pharmaceutical composition is a parenteral formulation.

18. 1. A method of treating an epileptic disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof.

19. 19. The method of claim 18, wherein the epileptic disorder is selected from the group consisting of epilepsy, epilepsy with generalized tonic-clonic seizures, myoclonic absence epilepsy, 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, Douzé syndrome, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, treatment-resistant status epilepticus, very treatment-resistant status epilepticus (SRSE), PCDH19 childhood epilepsy, increased seizure activity, or seizure recurrence.

20. 19. The method of claim 18, wherein the epileptic disorder is status epilepticus.

21. 19. The method of claim 18, wherein the epileptic disorder is acute recurrent seizures.

22. 19. The method of claim 18, wherein the epileptic disorder is Lennox-Gastaut syndrome.

23. 20. The method of claim 18, wherein the composition provides a reduction in seizure frequency, seizure severity, or a combination thereof, in a patient diagnosed with an epileptic disorder.

24. 20. The method of claim 18, wherein the patient is further administered an allosteric modulator.

25. 25. The method of claim 24, wherein the allosteric modulator is selected from the group consisting of neurosteroids, benzodiazepines, and potassium channel openers.

26. 25. The method of claim 24, wherein the allosteric modulator is ganaxolone.

27. 25. The method of claim 24, wherein the allosteric modulator is allopregnanolone.

28. 25. The method of claim 24, wherein the allosteric modulator is a benzodiazepine.

29. 29. The method of claim 28, wherein the benzodiazepine is selected from the group consisting of midazolam, clobazam, clonazepam, diazepam, lorazepam, flurazepam and lorazepam.

30. 25. The method of claim 24, wherein the allosteric modulator is a potassium channel opener.

31. 31. The method of claim 30, wherein the potassium channel opener is retigabine or flupirtine.

32. 19. The method of claim 18, wherein gaboxadol or a pharmaceutically acceptable salt thereof is administered once, twice, or three times a day, or every other day.

33. 33. The method of claim 32, wherein gaboxadol or a pharmaceutically acceptable salt thereof is administered immediately after the onset of a seizure.

34. 33. The method of claim 32, wherein gaboxadol or a pharmaceutically acceptable salt thereof is administered after the onset of a seizure warning sign.

35. 19. The method of claim 18, further comprising administering a compound selected from the group consisting of acetazolamide, carbamazepine, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

36. 19. The method of claim 18, wherein the pharmaceutical composition is a parenteral formulation.

37. A pharmaceutical composition for parenteral administration comprising about 0.005 μg / ml to about 500 μg / ml of gaboxadol or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition for parenteral administration comprising about 0.05 mg to about 100 mg of gaboxadol or a pharmaceutically acceptable salt thereof.

39. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein gaboxadol or a pharmaceutically acceptable salt thereof is present in a molar concentration of less than about 10.0 M.

40. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the solubility of gaboxadol or a salt thereof in the composition is from about 1 mg / mL to about 50 mg / mL.

41. The pharmaceutical composition has a time to peak plasma concentration (T) of gaboxadol of about 1 hour or more after administration of the parenteral dosage form. max 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein

42. Parenteral administration of the composition provides a mean AUC of greater than about 25 ng·hr / ml 0-∞ 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, which provides an in vivo plasma profile of gaboxadol comprising:

43. Parenteral administration of the composition provides a mean C of less than about 10,000 ng / ml max 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, which provides an in vivo plasma profile of gaboxadol comprising:

44. The parenteral administration may provide a T max followed by at least 50% C for about 90 to about 360 minutes max 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition exhibits a pharmacokinetic profile comprising a plasma drug concentration of

45. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition is contained in a bag, a glass vial, a plastic vial or a bottle.

46. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition is aqueous.

47. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition is ready to use.

48. 39. A pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition is sufficiently soluble.

49. 39. The pharmaceutical composition for parenteral administration of claim 37 or 38, wherein the composition further comprises an additive selected from the group consisting of a buffering agent, a solubilizing agent, an isotonicity agent, an antioxidant, a chelating agent, an antibacterial agent, and a preservative.

50. 39. The pharmaceutical composition for parenteral administration of claim 37 or 38, wherein the composition further comprises an additive present in a weight percent (w / v) of less than about 10%.

51. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition further comprises an additive present in a weight percent (w / v) of about 0.01% to about 10%.

52. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the additive is present in a molar ratio of additive to gaboxadol or a pharmaceutically acceptable salt thereof of about 0.1:1 to about 0.25:

1.

53. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition comprises an excipient comprising a stabilizing amount of a buffering agent.

54. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition has a pH of about 4 to about 8.

55. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition has a pH of about 6 to about 8.

56. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition is an aqueous solution, and the pH of the aqueous solution is from about 6.8 to about 7.

8.

57. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition further comprises sodium chloride at a concentration of about 0.01 to about 2.0% by weight.

58. 39. The pharmaceutical composition for parenteral administration of claim 37 or 38, wherein the composition further comprises sodium chloride at a concentration of about 0.9% by weight.

59. 39. The pharmaceutical composition for parenteral administration of claim 37 or 38, wherein the composition is formulated in a total volume selected from the group consisting of 20 ml, 50 ml and 100 ml.

60. 39. A pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition is prepared for subcutaneous, intramuscular, transdermal or intravenous administration.

61. 39. A pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition comprises a stabilizing amount of an additive which is a solubilizing agent.

62. 39. The pharmaceutical composition for parenteral administration according to claim 37 or 38, wherein the composition shows no detectable chemical degradation after one month at 40°C.

63. 39. The pharmaceutical composition for parenteral administration of claim 37 or 38, wherein the composition can be stored at ambient conditions and remains clear and colorless for at least about 12 weeks.

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