Methods and compositions for treating epileptic disorders

Abstract

The present application relates to methods and compositions for treating epileptic disorders. The present invention relates to the use of allosteric modulators and / or gboxadol for the treatment of epileptic disorders in a subject in need thereof.

Description

[0001] This application is a divisional application of an application filed on August 10, 2017, with application number 201780057575.9 and invention name “Methods and compositions for treating epileptic disorders”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 373,589, filed on August 11, 2016, and U.S. Provisional Application No. 62 / 490,293, filed on April 26, 2017, which are incorporated herein by reference in their respective entireties. Technical Field

[0004] A method of using an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof for treating an epileptic disorder in a subject in need thereof. background

[0006] Allosteric modulators such as neurosteroids (e.g., ganaxolone, allopregnanolone), benzodiazapines (e.g., diazepam), and potassium channel openers (e.g., ritigabine) have been used to treat epilepsy. However, treatment with these agents is generally limited to patients who do not respond to traditional drugs. For example, allopregnanolone is currently being developed for use in the treatment of ultra-refractory status epilepticus. In addition, diazepam is currently marketed as For use in emergency situations to stop cluster seizures in people who are taking other medicines to treat epilepsy.

[0007] Gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) (THIP) is described in EP Patent No. 0000338, EP Patent No. 0840601, and in U.S. Pat. Nos. 4,278,676, 4,362,731, 4,353,910, and WO 2005 / 094820. Gaboxadol is a selective GABA A GABA receptor agonists with a δ subunit AThe drug was first approved for use in the treatment of insomnia in the 1990s, but failed to show a significant effect on sleep onset and sleep maintenance in a three-month efficacy study. In addition, patients with a history of drug abuse who received gaboxadol experienced a sharp increase in psychiatric adverse events. Due to these negative results, the development of gaboxadol was terminated.

[0008] Parenteral dosage forms are intended to be used as injections or infusions. Common injection types are intravenous (intravenous), subcutaneous (under the skin) and intramuscular (intramuscular). Infusion is usually given by intravenous route. Parenteral preparations usually include excipients to enhance or maintain active ingredient solubility (solubilizers) and / or stability (buffers, antioxidants, chelating agents, cryoprotectants (cryoprotectant) and lyophilization protectants (lyoprotectant). Excipients are also important in parenteral preparations to ensure safety (antimicrobial preservatives), minimize pain and stimulation after injection (tonicity agents) and control or extend drug delivery (polymers). However, excipients may also have negative effects, such as loss of drug solubility, activity and / or stability.

[0009] There remains a need in the art for safe and effective methods and pharmaceutical compositions that provide epileptic treatments. Accordingly, the present disclosure provides pharmaceutical compositions and methods that can be used in applications of epileptic disorders such as status epilepticus.

[0010] Overview

[0011] Methods for treating epileptic disorders including epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Ohtahara syndrome, Rasmussen syndrome, West syndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, super refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, increased seizure activity, or breakthrough seizures are provided by administering a pharmaceutical composition comprising an allosteric modulator to a patient in need thereof. seizures) (increased seizure activity, also called continuous or clustered seizures) and type 1 sodium channel protein alpha subunit (Scn1α)-related disorders. Allosteric modulators include one or more of neurosteroids, benzodiazepines, and potassium channel openers. In an embodiment, a method for treating epileptic disorders is provided, the method 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.

[0012] Provided herein are parenteral formulations of gaboxadol or a pharmaceutically acceptable salt thereof. Methods of treating epileptic disorders including status epilepticus with parenteral formulations of gaboxadol or a pharmaceutically acceptable salt thereof are provided. In an embodiment, a parenteral formulation comprising gaboxadol or a pharmaceutically acceptable salt thereof, alone or in combination with an allosteric modulator, is administered to a patient in need thereof to treat an epileptic disorder.

[0013] In an embodiment, a method is provided for treating an epileptic disorder including status epilepticus, benign rolando epilepsy (BRE), refractory childhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasm (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, alone or in combination with gaboxadol or a pharmaceutically acceptable salt thereof. In an embodiment, a method is provided for treating an epileptic disorder including status epilepticus, benign rolando epilepsy (BRE), refractory childhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasm (or West syndrome), Dravet syndrome, and Lennox-Gastaut syndrome (LGS) by administering to a patient in need thereof a pharmaceutical composition comprising gaboxadol, alone or in combination with an allosteric modulator thereof.

[0014] In an embodiment, a method for treating an epileptic disorder characterized as a sodium channel protein type 1 alpha subunit (Scn1a)-related disorder is provided. Scn1a-related disorders include generalized epilepsy with febrile seizures plus, intractable childhood epilepsy with generalized tonic-clonic seizures, intractable infantile partial seizures, myoclonic-astatic epilepsy, myoclonic-astatic epilepsy, severe myoclonicepilepsy in infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and epileptic seizures. In embodiments, methods are provided for treating type 1 sodium channel protein alpha subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising an allosteric modulator to a patient in need thereof. In embodiments, methods are provided for treating type 1 sodium channel protein alpha subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising an allosteric modulator in combination with gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods are provided for treating type 1 sodium channel protein alpha subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods are provided for treating type 1 sodium channel protein alpha subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof in combination with an allosteric modulator to a patient in need thereof. In embodiments, methods are provided for treating type 1 sodium channel protein alpha subunit (Scn1a)-related disorders by administering a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof in combination with an allosteric modulator to a patient in need thereof. In embodiments, methods are provided for treating type 1 sodium channel protein alpha subunit (Scn1a)-related disorders by administering a parenteral formulation comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In an embodiment, methods are provided for treating sodium channel protein type 1 alpha subunit (Scn1a)-related disorders 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.

[0015] In an embodiment, a combination of allosteric modulators, such as neurosteroids, benzodiazepines, or potassium channel openers, may be administered to a patient in need thereof. In an embodiment, a combination of one or more allosteric modulators and gaboxadol or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Theoretical and measured solubility of gaboxadol at different pH values ​​are shown.

[0018] Figure 2 is a schematic diagram depicting the timeline used to evaluate the ability of allopregnanolone, ganaxolone, and gaboxadol to block status epilepticus in rats induced by benzodiazepine tolerance.

[0019] Figure 3 is a bar graph depicting percent protection versus dose for allopregnanolone, ganaxolone, or gaboxadol.

[0020] Figure 4 is a bar graph depicting the 24-hour survival results based on dose for allopregnanolone, ganaxolone, or gaboxadol.

[0021] Figure 5 is a bar graph showing the number of observed seizures versus the dose of allopregnanolone, ganaxolone, or gaboxadol.

[0022] Fig. 6A is a bar graph showing body weight change 24 hours after status epilepticus as a function of percent loss versus dose.

[0023] Figure 6B is a bar graph showing 24 hour body weight loss for the 0.5 mg / kg dose group.

[0024] Figure 7 is a schematic diagram depicting the timeline of a prospective evaluation study of the ability of allopregnanolone, ganaxolone, and gaboxadol to synergistically block status epilepticus in benzodiazepine-tolerant rats. Detailed Description

[0026] Described herein are methods for treating epileptic disorders, including epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Ohtawara syndrome, Rasmussen syndrome, infantile spasms (or West syndrome), Lennox-Gastaut syndrome (LGS), Rett syndrome, Dravet syndrome, Doose syndrome, CDKL5 disorder, refractory childhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), essential tremor, acute recurrent seizures, benign Rolando epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 infantile epilepsy, increased seizure activity, or paroxysmal seizures (increased seizure activity; also known as continuous or clustered seizures). The compositions and methods described herein can be used to treat epileptic disorders characterized as type 1 sodium channel protein alpha subunit (Scn1A)-related disorders. For example, Scn1A-associated disorders include generalized epilepsy with febrile seizures plus, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory infantile 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 relate to allosteric modulators and / or gaboxadol or a pharmaceutically acceptable salt thereof.

[0027] In embodiments, methods for treating epileptic disorders may include administering a pharmaceutical composition comprising an allosteric modulator to a patient in need thereof. In embodiments, methods for treating epileptic disorders may include administering a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods for treating epileptic disorders may include administering gaboxadol or a pharmaceutically acceptable salt thereof in combination with an allosteric modulator to a patient in need thereof. In embodiments, methods for treating epileptic disorders may include administering a parenteral pharmaceutical preparation comprising an allosteric modulator to a patient in need thereof. In embodiments, methods for treating epileptic disorders may include administering a parenteral pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods for treating epileptic disorders may include administering a parenteral pharmaceutical composition comprising an allosteric modulator and gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0028] Many drug products are administered in fixed doses at regular intervals to achieve therapeutic efficacy. The duration of action is reflected by the plasma half-life of the product. Since efficacy generally depends on sufficient exposure in the central nervous system, the administration of CNS drugs with a short half-life may require frequent maintenance dosing. Advantageously, disclosed herein is a method for treating epileptic disorders by administering an allosteric modulator. For example, in an embodiment, a method for treating epileptic disorders is provided, the method comprising administering a pharmaceutical composition comprising about 0.05 mg to about 2000 mg of an allosteric modulator to a patient with corresponding needs, wherein the composition provides an improvement of more than 6 hours after administration to the patient. Advantageously, disclosed herein is a method for treating epileptic disorders by administering gaboxadol or a pharmaceutically acceptable salt thereof. For example, in an embodiment, a method for treating epileptic disorders is provided, the method comprising administering a pharmaceutical composition comprising about 0.05 mg to about 75 mg of gaboxadol or a pharmaceutically acceptable salt thereof to a patient with corresponding needs, wherein the composition provides an improvement of more than 6 hours after administration to the patient.

[0029] In an embodiment, a method of 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 an embodiment, a method of 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.

[0030] For example, a dosage may include an amount of gaboxadol or a pharmaceutically acceptable salt thereof in the range of about, for example, 0.05 mg to 50 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.1 mg to 30 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, wherein 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg , 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25 mg and 30 mg are specific dosage examples.

[0031] Typically, a dose of gaboxadol or a pharmaceutically acceptable salt thereof is administered once or twice daily to a patient in need thereof. The methods and compositions described herein can provide reduced dosing frequency and reduced adverse events and / or increased efficacy. In an embodiment, the dose is about, for example, 0.05-30 mg / day, 0.1-20 mg / day, or 0.2-15 mg / day, or 0.5-10 mg / day, or 0.75-5 mg / day, for example, 0.1 mg / day, 0.2 mg / day, 0.5 mg / day, 0.75 mg / day, 1 mg / day, 1.5 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 21 mg / day, 22 mg / day, 23 mg / day, 24 mg / day, 25 mg / day, 26 mg / day, 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, 5 In some embodiments, gaboxadol or a pharmaceutically acceptable salt thereof, or a derivative or analog thereof is administered at a dose of 0.2 mg to 1 mg once a day in infants or 1 mg to 20 mg once a day in adults.

[0032] In an 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 mg to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg gaboxadol or a pharmaceutically acceptable salt thereof.

[0033] In an 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.

[0034] In an embodiment, the pharmaceutical composition comprises 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg of gaboxadol or a pharmaceutically acceptable salt thereof or an amount multiple of these doses. In an embodiment, the pharmaceutical composition comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg of gaboxadol or a pharmaceutically acceptable salt thereof.

[0035] In an embodiment, the total amount of gaboxadol or its pharmaceutically acceptable salt and / or gaboxadol administered to a subject within a 24-hour period is 1 mg to 50 mg. In an embodiment, the total amount of gaboxadol or its pharmaceutically acceptable salt and / or gaboxadol administered to a subject within a 24-hour period is 1 mg to 20 mg. In an embodiment, the total amount of gaboxadol or its pharmaceutically acceptable salt and / or gaboxadol administered to a subject within a 24-hour period is 5 mg, 10 mg, 15 mg or 20 mg. In an embodiment, the total amount of gaboxadol or its pharmaceutically acceptable salt administered to a subject within a 24-hour period is 1 mg to 50 mg. In an embodiment, a subject can start with a low dose and increase the dose. In this way, it can be determined whether the drug is well tolerated in a subject. The dose for children can be lower than that for adults. In an embodiment, the dose of gaboxadol for children can be 0.1 mg / kg to 1 mg / kg.

[0036] 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.

[0037] In an embodiment, a method for treating an epileptic disorder by administering ganaxolone to a patient in need thereof is provided. In an embodiment, a method for treating an epileptic disorder by administering allopregnanolone to a patient in need thereof is provided. In an embodiment, a method for treating an epileptic disorder by administering a compound of Formula I is provided:

[0038]

[0039] In an embodiment, the allosteric modulator or a pharmaceutically acceptable salt thereof is administered at least once a day in a range of about 0.001 mg / kg to about 30 mg / kg of the body weight of a patient in need thereof, for example, about 0.01 mg / kg to 20 mg / kg. For example, a dosage can include an amount of an allosteric modulator or a pharmaceutically acceptable salt thereof in a range of about, for example, 1 mg to 30 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.1 mg to 10 mg, or 0.2 mg to 10 mg, wherein 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 1.8 mg, 2.0 mg, 3.5 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 11.0 mg, 12.5 mg, 13.0 mg, 14.0 mg, 15.0 mg, 16.0 mg, 17.0 mg, 18.0 mg, 19.0 mg, 20.0 mg, 21.0 mg, 22.0 mg, 23.0 mg, 24.0 mg, 25.0 mg, 26.0 mg, 27.0 mg, 28.0 mg, 29.0 mg, 30.0 mg, Doses of 100 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg and 30 mg are specific dosage examples. For example, dosages may include about, for example, 50 mg to 75 mg, 75 mg to 100 mg, 100 mg to 125 mg, 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, 275 mg to 300 mg, 300 mg to 325 mg, 325 mg to 350 mg, 350 mg to 375 mg, 375 mg to 400 mg, 400 mg to 425 mg, 425 mg to 450 mg, 450 mg to 475 mg, 475 mg to 500 mg, 500 mg to 525mg, 525mg to 550mg, 550mg to 575mg, 575mg to 600mg, 600mg to 625mg, 625mg to 650mg, 650mg to 675mg, 675mg to 700mg, 700mg to 725mg, 725mg to 750mg, 750mg to 775mg, 775mg to 800mg, 800mg to 825mg, 825mg to 850mg, 850mg to 875mg, 875mg to 900mg, 900mg to 925mg, 925mg to 950mg, 950mg to 975mg, 975mg to 1000mg,1000mg to 1025mg, 1025mg to 1050mg, 1050mg to 1075mg, 1075mg to 1100mg, 1100mg to 1125mg, 1125mg to 1150mg, 1150mg to 1175mg, 1175mg to 1200mg, 1200mg to 1225mg, 1225mg to 1250mg, 1250mg g to 1275mg, 1275mg to 1300mg, 1300mg to 1325mg, 1325mg to 1350mg, 1350mg to 1375mg, 1375mg to 1400mg, 1400mg to 1425mg, 1425mg to 1450mg, 1450mg to 1475mg, 1475mg to 1500mg, 1500mg to 1525 or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention relates to an amount of an allosteric modulator or a pharmaceutically acceptable salt thereof in the range of 1500 mg to 2000 mg, 1525 mg to 1550 mg, 1550 mg to 1575 mg, 1575 mg to 1600 mg, 1600 mg to 1625 mg, 1625 mg to 1650 mg, 1650 mg to 1675 mg, 1675 mg to 1700 mg, 1700 mg to 1725 mg, 1725 mg to 1750 mg, 1750 mg to 1775 mg, 1775 mg to 1800 mg, 1800 mg to 1825 mg, 1825 mg to 1850 mg, 1850 mg to 1875 mg, 1875 mg to 1900 mg, 1900 mg to 1925 mg, 1925 mg to 1950 mg, 1950 mg to 1975 mg, or 1975 mg to 2000 mg. ,

[0040] Typically, the dosage of an allosteric modulator or its pharmaceutically acceptable salt is administered once a day, twice a day, three times a day, or four times a day to a patient with corresponding needs. In embodiments, an allosteric modulator can be administered once a week. Methods and compositions described herein can provide reduced dosing frequency and reduced adverse events and / or increased efficacy. In embodiments, the dosage of an allosteric modulator can be about, for example, 0.1-20 mg / days, or 0.2-15 mg / days, or 0.5-10 mg / days, or 0.75-5 mg / days, for example, 0.2 mg / days, 0.5 mg / days, 0.75 mg / days, 1 mg / days, 1.5 mg / days, 2 mg / days, 3 mg / days, 4 mg / days, 5 mg / days, 6 mg / days, 7 mg / days, 8 mg / days, 9 mg / days, or 10 mg / days. In embodiments, a patient may be administered an allosteric modulator in an amount of, for example, 10 mg / day to 25 mg / day, 25 mg / day to 50 mg / day, 50 mg / day to 75 mg / day, 75 mg / day to 100 mg / day, 100 mg / day to 125 mg / day, 125 mg / day to 150 mg / day, 150 mg / day to 175 mg / day, 175 mg / day to 200 mg / day, 200 mg / day to 225 mg / day, 225 mg / day to 250 mg / day. day, 250mg / day to 275mg / day, 275mg / day to 300mg / day, 300mg / day to 325mg / day, 325mg / day to 350mg / day, 350mg / day to 375mg / day, 375mg / day to 400mg / day, 400mg / day to 425mg / day, 425mg / day to 450mg / day, 450mg / day to 475mg / day, 475mg / day to 500mg / day, 500mg / day to 525mg / day, 5 25mg / day to 550mg / day, 550mg / day to 575mg / day, 575mg / day to 600mg / day, 600mg / day to 625mg / day, 625mg / day to 650mg / day, 650mg / day to 675mg / day, 675mg / day to 700mg / day, 700mg / day to 725mg / day, 725mg / day to 750mg / day, 750mg / day to 775mg / day, 775mg / day to 800mg / day, 800mg / day g / day to 825mg / day, 825mg / day to 850mg / day, 850mg / day to 875mg / day, 875mg / day to 900mg / day, 900mg / day to 925mg / day, 925mg / day to 950mg / day, 950mg / day to 975mg / day, 975mg / day to 1000mg / day, 1000mg / day to 1025mg / day, 1025mg / day to 1050mg / day, 1050mg / day to 1075mg / day,1075mg / day to 1100mg / day, 1100mg / day to 1125mg / day, 1125mg / day to 1150mg / day, 1150mg / day to 1175mg / day, 1175mg / day to 1200mg / day, 1200mg / day to 1225mg / day, 1225mg / day to 1250mg / day, 1250mg / day to 1275mg / day, 1275mg / day to 1300mg / day, 1300mg / day mg / day to 1325mg / day, 1325mg / day to 1350mg / day, 1350mg / day to 1375mg / day, 1375mg / day to 1400mg / day, 1400mg / day to 1425mg / day, 1425mg / day to 1450mg / day, 1450mg / day to 1475mg / day, 1475mg / day to 1500mg / day, 1500mg / day to 1525mg / day, 1525mg / day to 1550mg / day, 1550mg / day to 1575mg / day, 1575mg / day to 1600mg / day, 1600mg / day to 1625mg / day, 1625mg / day to 1650mg / day, 1650mg / day to 1675mg / day, 1675mg / day to 1700mg / day, 1700mg / day to 1725mg / day, 1725mg / day to 1750mg / day, 1750mg / day to 1775 In some embodiments, the allosteric modulator or derivative or analog thereof is administered at a dose of 0.2 mg to 1 mg once a day in infants or 1-20 mg once a day in adults.

[0041] In an embodiment, a method of 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 may 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 embodiments, the dosage of ganaxolone can be, for example, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg. g, 975mg, 1000mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, 1500mg, 1525mg, 1550mg, 1575mg , 1600mg, 1625mg, 1650mg, 1675mg, 1700mg, 1725mg, 1750mg, 1775mg, 1800mg, 1825mg, 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg or 2000mg.

[0042] Ganaxolone or a pharmaceutically acceptable salt thereof may be administered, for example, once a day, twice a day, three times a day, or four times a day. In embodiments, ganaxolone or a pharmaceutically acceptable salt thereof may be administered once a week. In embodiments, ganaxolone or a pharmaceutically acceptable salt thereof may be administered parenterally as soon as possible after the onset of the seizure. In embodiments, ganaxolone or a pharmaceutically acceptable salt thereof may be administered parenterally in ascending doses as soon as possible after the onset of the seizure.

[0043] In an embodiment, a method of treating an epileptic disorder such as 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 in a range 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 16 mg / kg, 0.10 mg / kg to 17 mg / kg, 0.11 mg / kg to 18 mg / kg, 0.12 mg / kg to 19 mg / kg, 0.13 mg / kg to 19 mg / kg, 0.14 mg / kg to 19 mg / kg, 0.15 mg / kg to 19 mg / kg, 0.16 mg / kg to 19 mg / kg, 0.17 mg / kg to 19 mg / kg, 0.18 mg / kg to 19 mg / kg, 0.19 mg / kg to 19 mg / kg, 0.20 mg / kg to 19 mg / kg, 0.21 mg / kg to 19 mg / kg, 0.22 mg / kg to 19 mg / kg, 0.23 mg / kg to 19 mg / kg, 0.24 mg / kg to 19 mg / kg, 0.25 mg / kg to 19 mg / kg, 0.26 mg / kg to 19 mg / kg, 0.27 mg / kg to 19 mg / kg, 0.28 mg / kg to 19 mg In some embodiments, the dosage of allopregnanolone can 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.

[0044] Allopregnanolone or a pharmaceutically acceptable salt thereof may be administered, for example, once a day, twice a day, three times a day, or four times a day. In an embodiment, allopregnanolone or a pharmaceutically acceptable salt thereof may be administered once a week. In an embodiment, allopregnanolone or a pharmaceutically acceptable salt thereof may be administered parenterally as soon as possible after the onset of an epileptic seizure. In an embodiment, allopregnanolone or a pharmaceutically acceptable salt thereof may be administered parenterally in increasing doses as soon as possible after the onset of an epileptic seizure.

[0045] Methods of treating epileptic disorders by administering to a subject in need thereof an effective amount of gaboxadol or a pharmaceutically acceptable salt thereof, alone or in combination with an allosteric modulator or a pharmaceutically acceptable salt, derivative or analog thereof, or a combination thereof are provided. Methods of treating epileptic disorders by administering to a subject in need thereof an effective amount of an allosteric modulator or a pharmaceutically acceptable salt, derivative or analog thereof, alone (or in combination with gaboxadol or a pharmaceutically acceptable salt thereof, or a combination thereof) are provided.

[0046] An effective amount or therapeutically effective amount can be enough to treat, suppress or alleviate one or more symptoms of epileptic disorder, such as reducing the frequency or severity of epileptic seizures, reducing abnormal behavior (or otherwise improving behavior); or provide a desired pharmacological and / or physiological effect, for example, reducing, suppressing or reversing one or more possible pathophysiological mechanisms causing abnormal neurological function, increasing dopamine levels or signal transduction or a combination thereof. The exact dosage will vary according to a variety of factors, such as subject dependent variables (e.g., age, immune system health status, clinical symptoms, etc.). In embodiments, the subject can start with a low dose and increase the dose. In this way, it can be determined whether the drug is well tolerated in the subject. The dosage of children can be lower than that of adults.

[0047] In embodiments, the methods described herein are effective to reduce, delay or prevent one or more other clinical symptoms of epileptic disorders, such as acute recurrent epileptic seizures. For example, the effects of gaboxadol or its pharmaceutically acceptable salt and / or allosteric modulator or its pharmaceutically acceptable salt, derivative or analog on specific symptoms, pharmacological or physiological indicators can be compared with the condition of untreated subjects or subjects before treatment. In embodiments, the symptoms, pharmacological and / or physiological indicators of the subject are measured before treatment, and once or more times are measured after the start of treatment as well. In embodiments, the control is a reference level or mean value determined based on measuring symptoms, pharmacological or physiological indicators in one or more subjects (e.g., healthy subjects) who do not suffer from the disease to be treated or the condition. In an embodiment, the treatment is compared with the effect of conventional treatment known in the art.

[0048] In an embodiment, compositions and treatment methods with low doses of gaboxadol and / or allosteric modulators are provided so as to provide patients with one or more beneficial effects associated with epileptic disorders, such as reduced seizure activity, reduced fatigue, increased mood, increased concentration, increased behavioral control, and / or increased cognitive abilities. A dosing regimen is provided herein that allows effective treatment of epileptic disorders, and adverse side effects (e.g., convulsions and / or sleep disruptions) may be limited or substantially rare. Therefore, the methods described herein can provide treatment for epileptic disorders, which can be considered surprising and unexpected. For example, a method for treating an epileptic disorder in a patient in need thereof is provided herein, and the method may not cause sleep disruption. In an embodiment, the methods described herein can provide effective treatment for epileptic disorders without interrupting slow wave sleep. In an embodiment, a method for treating an epileptic disorder without causing insomnia or difficulty falling asleep is provided.

[0049] In embodiments, the methods described herein can be used to treat epileptic disorders, including acute repetitive epileptic seizures, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), and Dravet syndrome. In embodiments, the methods include treating acute repetitive epileptic seizures.

[0050] In embodiments, the methods described herein can be used to treat epileptic disorders, including benign Rolando epilepsy (BRE), intractable 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).

[0051] In embodiments, the methods described herein can be used to treat sodium channel protein type 1 alpha subunit (Scn1A)-related disorders. For example, Scn1A-related disorders include generalized epilepsy with febrile seizures plus, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory infantile partial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsy of infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and epileptic seizures.

[0052] Methods described herein are for subjects experiencing refractory epileptic seizures, status epilepticus, akinetic seizures, myoclonic seizures, absence seizures, or severe myoclonic epilepsy of infancy (SMEI). In embodiments, the characteristics of these conditions are refractory epilepsy. Refractory epileptic seizures (also referred to as "uncontrolled" or "refractory" epileptic seizures) are seizures that cannot be controlled by conventional treatments. For example, a subject may suffer from refractory epileptic seizures or another disorder characterized by refractory epileptic seizures, or a disorder characterized by status epilepticus. Status epilepticus is a condition in which epileptic seizures occur one after another without recovery of consciousness between them. Therefore, in embodiments, the disclosed methods are used to treat subjects who are otherwise tolerant to one or more conventional therapies.

[0053] The methods described herein can be particularly useful for treating children and infants, and for treating disorders that develop during infancy or childhood. In embodiments, the subject of the disclosed methods is a neonate, infant, toddler, preschooler, school-age child, tween, or teenager. In embodiments, the 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 embodiments, the subject is an adult over 18 years old.

[0054] In embodiments, the epileptic disorder is characterized by seizures associated with epilepsy. In embodiments, the seizures are non-epileptic seizures (NES) or dissociative seizures, which are distinct from epilepsy. Non-epileptic seizures include organic non-epileptic seizures and psychogenic seizures.

[0055] Epilepsy is a neurological disorder that occurs when the activity of nerve cells in the brain is damaged, causing epileptic seizures or abnormal behavior, sensations, and sometimes loss of consciousness. When there are two epileptic seizures without obvious reasons, the subject can be referred to as suffering from epilepsy. Epilepsy can occur in both adults and children, and may be associated with a specific syndrome. Therefore, in embodiments, the subject suffers from childhood epilepsy syndrome, such as benign Rolando epilepsy (BRE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome or Lennox-Gastaut syndrome (LGS).

[0056] In embodiments, the subject does not experience a diagnosable epileptic seizure, but exhibits subclinical discharges, which refer to a high rate of seizure-like activity when the subject's brain waves are measured with an electroencephalogram. Epilepsy syndromes associated with these seizure-like discharges include Landau-Kleffner syndrome, Dravet syndrome, and sustained spike-wave activity during slow-wave sleep.

[0057] In embodiments, epileptic disorders treated by the methods and compositions described herein include Scn1A-related seizure disorders. Scn1A-related seizure disorders include mild outcomes such as simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) to severe outcomes such as Dravet syndrome and refractory childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). Specific Scn1A-related seizure disorders include, but are not limited to, generalized epilepsy with febrile seizures plus, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory infantile 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.

[0058] In embodiments, the subject suffers from intellectual developmental disorder (IDD), such as autism spectrum disorder (ASD). In embodiments, the subject of the disclosed method suffers from epilepsy and IDD or ASD disorder. Common IDD and ASD with seizures and epilepsy include but are not limited to fragile X syndrome (FXS), Rett syndrome (RTT), Angelman syndrome, Prader-Willi syndrome, velocardiofacial syndrome (Velocardiofacial syndrome), Smith-Lemli-Opitz syndrome, neuroligin mutations and "interneuron disease" caused by mutations in X-linked aristales-related homeobox (ARX) and Nueropilin 2 (NRP2) genes.

[0059] Also provided herein are methods and compositions for treating epileptic disorders by co-administering an allosteric modulator and gaboxadol, a derivative thereof, or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, the methods and compositions described herein include dosage forms comprising gaboxadol or a pharmaceutically acceptable salt thereof and an allosteric modulator. In embodiments, the methods and compositions described herein may include a 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.

[0060] Gaboxadol or its pharmaceutically acceptable salt can be provided in the form of acid addition salt, zwitter ion hydrate, zwitter ion anhydrate, hydrochloride or hydrobromide, or zwitter ion monohydrate. Acid addition salts include but are not limited to maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid or theophylline acetic acid, and 8-halotheophylline, such as 8-bromo-theophylline. In other suitable embodiments, inorganic acid addition salts can be used, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid or nitric acid.

[0061] In an embodiment, gaboxadol is provided as gaboxadol monohydrate. One skilled in the art will readily appreciate that the amount of active ingredient in the pharmaceutical composition will depend on the form in which gaboxadol is provided. For example, a pharmaceutical composition comprising 5.0 mg, 10.0 mg, or 15.0 mg of gaboxadol corresponds to 5.6 mg, 11.3 mg, or 16.9 mg of gaboxadol monohydrate.

[0062] In an embodiment, gaboxadol is crystalline, such as a crystalline hydrochloride salt, a crystalline hydrobromide salt, or a crystalline zwitter ion monohydrate. In an embodiment, gaboxadol is provided in the form of a crystalline monohydrate.

[0063] It has been previously demonstrated that deuteration of drugs of some drug classes improves pharmacokinetics (PK), pharmacodynamics (PD) and toxicity profiles. Therefore, the use of deuterium-enriched gaboxadol is contemplated and is within the scope of the methods and compositions described herein. According to synthetic procedures known in the art, deuterium can be incorporated into any position to replace hydrogen by synthesis. For example, deuterium can be incorporated into a variety of positions with exchangeable protons, such as amine N--H, by proton-deuterium equilibrium exchange. Therefore, deuterium can be selectively or non-selectively incorporated by methods known in the art to provide deuterium-enriched gaboxadol (gaboxadol). See Journal of Labeled Compounds and Radiopharmaceuticals 19 (5) 689-702 (1982).

[0064] The pharmaceutical composition herein can be provided with immediate release, delayed release, extended release or modified release profile. In an embodiment, pharmaceutical compositions with different drug release profiles can be combined to produce a two-stage or three-stage release profile. For example, the pharmaceutical composition can be provided with an immediate release and an extended release profile. In an embodiment, the pharmaceutical composition can be provided with an extended release and a delayed release profile. Such compositions can be provided as pulsatile formulations, multilayer tablets or capsules, including tablets, beads, particles, etc. The composition can be prepared using a pharmaceutically acceptable "carrier" made of materials that are considered to be safe and effective. "Carrier" includes all components present in the pharmaceutical preparation except one active ingredient or more active ingredients (the active ingredient or ingredients). The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers and coating compositions.

[0065] In embodiments, the pharmaceutical compositions described herein are administered once a day, twice a day, three times a day, four times a day, or every other day. In embodiments, the pharmaceutical compositions described herein are provided to the patient in the evening. In embodiments, the pharmaceutical compositions described herein are provided to the patient once in the evening and once in the morning. In embodiments, the pharmaceutical compositions herein are provided as soon as possible after the onset of an epileptic seizure. In embodiments, the pharmaceutical compositions herein are provided continuously.

[0066] In an embodiment, the total amount of allosteric modulator and / or gaboxadol administered to a subject within a 24-hour period is 1 mg to 50 mg. In an embodiment, the total amount of allosteric modulator and / or gaboxadol administered to a subject within a 24-hour period is 1 mg to 20 mg. In an embodiment, the total amount of allosteric modulator and / or gaboxadol administered to a subject within a 24-hour period is 5 mg, 10 mg or 15 mg. In an embodiment, the total amount of allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof administered to a subject within a 24-hour period is 1 mg to 50 mg. In an embodiment, a subject can start with a low dose and increase the dose. In this way, it can be determined whether the drug is well tolerated in a subject. The dosage for children can be lower than that for adults.

[0067] In an embodiment, provided herein is a method for treating an epileptic disorder, the method 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 an epileptic disorder. In an embodiment, provided is a method for treating an epileptic disorder 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 therapeutically effective amount may be a dose sufficient to treat, inhibit or alleviate one or more symptoms of an epileptic disorder, such as reducing the frequency or severity of epileptic seizures, reducing abnormal behavior (or otherwise improving behavior); or providing a desired pharmacological and / or physiological effect, for example, reducing, inhibiting or reversing one or more potential pathophysiological mechanisms causing abnormal neurological function, increasing dopamine levels or signaling, or a dose of a combination thereof. The exact dose will vary according to a variety of factors, such as subject-dependent variables (e.g., age, immune system health, clinical symptoms, etc.).

[0068] In embodiments, the methods described herein are effective to reduce, delay or prevent one or more other clinical symptoms of epileptic disorders, such as epilepsy or Dravet syndrome. For example, the effects of a composition comprising an allosteric modulator and / or gaboxadol on specific symptoms, pharmacological or physiological indicators can be compared with the condition of an untreated subject or a subject before treatment. In embodiments, symptoms, pharmacological and / or physiological indicators are measured in a subject before treatment, and are also measured once or more times after the start of treatment. In embodiments, a control is a reference level or mean value determined based on measuring symptoms, pharmacological or physiological indicators in one or more subjects (e.g., healthy subjects) who do not suffer from the disease or condition to be treated. In embodiments, the treatment is compared with the effect of conventional treatments known in the art.

[0069] In embodiments, provided herein is a method for treating an epileptic disorder, such as status epilepticus, 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 an epileptic disorder. In embodiments, the provided method may also surprisingly and unexpectedly reduce or prevent epileptic seizures or symptoms thereof in a subject in need thereof. In embodiments, the provided method may reduce or prevent one or more different types of epileptic seizures. In embodiments, the provided method may also surprisingly and unexpectedly reduce or prevent epileptic seizures or symptoms thereof in a subject in need thereof. In embodiments, the provided method may reduce or prevent one or more different types of epileptic seizures. Typically, epileptic seizures may include convulsions, repetitive movements, abnormal sensations, and combinations thereof. Epileptic seizures may be classified as focal epileptic seizures (also referred to as partial epileptic seizures) and generalized epileptic seizures. Focal epileptic seizures affect only one side of the brain, while generalized epileptic seizures affect both sides of the brain. Specific types of focal epileptic seizures include simple focal epileptic seizures, complex focal epileptic seizures, and secondary generalized epileptic seizures. Simple focal epileptic seizures can be limited or concentrated in specific lobes (such as temporal lobe, frontal lobe, parietal lobe or occipital lobe).Compared to simple focal epileptic seizures, complex focal epileptic seizures usually affect a larger part of a hemisphere, but usually originate from the temporal lobe or frontal lobe.When focal epileptic seizures spread to both sides from one side (hemisphere) of the brain, epileptic seizures are referred to as secondary generalized epileptic seizures.Specific types of generalized epileptic seizures include absence (also referred to as petit mal seizures), tonic epileptic seizures, atonic epileptic seizures, myoclonic epileptic seizures, tonic-clonic epileptic seizures (also referred to as grand mal seizures) and clonic epileptic seizures.

[0070] In embodiments, the methods described herein can reduce the frequency of seizures, reduce the severity of seizures, change the type of seizure (e.g., from a more severe type to a less severe type), or a combination thereof in a subject following treatment, compared to the absence of treatment (e.g., before treatment), or compared to treatment with an alternative conventional treatment.

[0071] In embodiments, provided herein is a method for treating an epileptic disorder, wherein after administering a pharmaceutical composition to a patient, the patient is provided with an improvement in at least one symptom that lasts more than 4 hours. In embodiments, provided herein is an improvement in at least one symptom that lasts more than 6 hours after administering a pharmaceutical composition to a patient. In embodiments, provided herein is an improvement in at least one symptom that lasts more than, for example, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administering a pharmaceutical composition to a patient. In embodiments, provided herein is an improvement in at least one symptom that lasts at least, for example, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administering a pharmaceutical composition to a patient. In embodiments, provided herein is an improvement in at least one symptom that lasts 12 hours after administering a pharmaceutical composition to a patient.

[0072] In an embodiment, provided herein is a method of treating an epileptic disorder, the method comprising administering a pharmaceutical composition herein to a patient in need thereof, wherein the composition provides improvement in next day function to the patient.

[0073] In embodiments, provided herein are methods of treating epileptic disorders, wherein about 4 hours after administration of the pharmaceutical composition, the amount of active agent, e.g., allosteric modulator and / or gaboxadol, in the patient is less than about 75% of the administered dose. In embodiments, provided herein are methods, wherein about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition, the amount of allosteric modulator and / or gaboxadol, or a pharmaceutically acceptable salt thereof, in the patient is less than about 75%.

[0074] In embodiments, provided herein are methods of treating epileptic disorders, wherein about 4 hours after administration of the pharmaceutical composition, the amount of active agent, e.g., allosteric modulator and / or gaboxadol, in the patient is less than about 80% of the administered dose. In embodiments, provided herein are methods, wherein about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition, the amount of active agent, e.g., allosteric modulator and / or gaboxadol, in the patient is less than about 80% of the administered dose.

[0075] In embodiments, provided herein are methods of treating epileptic disorders, wherein about 4 hours after administration of the pharmaceutical composition, the amount of active agent, e.g., allosteric modulator and / or gaboxadol, in the patient is between about 65% and about 85% of the administered dose. In embodiments, about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition, the amount of active agent, e.g., allosteric modulator and / or gaboxadol, in the patient is between about 65% and about 85% of the administered dose.

[0076] In embodiments, provided herein are methods of treating epileptic disorders 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 provides a C of less than about 500 ng / ml. max In embodiments, the composition provides improvements that persist for more than 6 hours after administration to a patient.

[0077] In embodiments, the composition provides a C of less than about, e.g., 450 ng / ml, 400 ng / ml, 350 ng / ml, or 300 ng / ml. max In an embodiment, the composition provides a plasma profile of less than about, for example, 250 ng / ml, 200 ng / ml, 150 ng / ml, or 100 ng / ml. max in vivo plasma profile of a composition comprising a composition comprising: ...

[0078] In an embodiment, provided herein is a method of treating an epileptic disorder, the method comprising administering a pharmaceutical composition to a patient in need thereof, wherein the composition provides an AUC of less than about 900 ng·hr / ml. 0-∞ In embodiments, the composition provides an improvement in next-day function to the patient. In embodiments, the composition provides an AUC of less than about, e.g., 850 ng·hr / ml, 800 ng·hr / ml, 750 ng·hr / ml, or 700 ng·hr / ml. 0-∞ In vivo plasma profile of, and wherein the composition provides improvement in next-day function to the patient. In embodiments, the composition provides improvement in one or more symptoms that lasts for more than 6 hours after administration.

[0079] In embodiments, provided herein are methods of treating epileptic disorders, the methods 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 provides an AUC of less than about, e.g., 650 ng·hr / ml, 600 ng·hr / ml, 550 ng·hr / ml, 500 ng·hr / ml, or 450 ng·hr / ml. 0-∞ In an embodiment, the composition provides an AUC of less than about, for example, 400 ng·hr / ml, 350 ng·hr / ml, 300 ng·hr / ml, 250 ng·hr / ml, or 200 ng·hr / ml. 0-∞ In an embodiment, the composition provides an AUC of less than about, for example, 150 ng·hr / ml, 100 ng·hr / ml, 75 ng·hr / ml, or 50 ng·hr / ml. 0-∞ In embodiments, after administration of the composition to a patient, the composition provides an improvement in next-day function to the patient after administration for more than, for example, 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours.

[0080] In embodiments, provided herein are methods of treating epileptic disorders, the methods 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 provides an average AUC of at least about 20% less than that of the first pharmaceutical composition. 0-∞ In vivo plasma profile.

[0081] In embodiments, provided herein are methods of treating epileptic disorders 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 embodiments, the second pharmaceutical composition provides an average AUC of at least about 20% less than that of the first pharmaceutical composition. 0-∞ In vivo plasma profile.

[0082] In embodiments, the first pharmaceutical composition and / or the second pharmaceutical composition is administered once a day, twice a day, three times a day, or four times a day, or is administered every other day. In embodiments, the first pharmaceutical composition or the second pharmaceutical composition is provided to the patient at night. In embodiments, the second pharmaceutical composition comprises gaboxadol in an amount that is at least one-third of the amount of the allosteric modulator in the first pharmaceutical composition. In embodiments, the second pharmaceutical composition comprises gaboxadol in an amount that is at least half of the amount of the allosteric modulator provided in the first pharmaceutical composition.

[0083] In an embodiment, the first pharmaceutical composition and / or the second pharmaceutical composition is provided to the patient once in the evening and once in the morning. In an embodiment, the total amount of the allosteric modulator administered to the subject within a 24-hour period is 1 mg to 2500 mg. In an embodiment, the total amount of the allosteric modulator administered to the subject within a 24-hour period is 1 mg / kg to 35 mg / kg. In an embodiment, the total amount of gaboxadol or a pharmaceutically acceptable salt thereof administered to the subject within a 24-hour period is 1 mg to 75 mg. In an embodiment, the total amount of active substance administered to the subject within a 24-hour period, for example, gaboxadol or a pharmaceutically acceptable salt thereof is less than about 75 mg, 50 mg, 25 mg, 20 mg, 10 mg or 5 mg. In an embodiment, the total amount of active substance administered to the subject within a 24-hour period, for example, gaboxadol or a pharmaceutically acceptable salt thereof is less than 15 mg. In embodiments, the total amount of active agent, e.g., allosteric modulator 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 embodiments, the total amount of active agent, e.g., allosteric modulator and / or gaboxadol, administered to a subject in a 24 hour period is less than 15 mg.

[0084] In an embodiment, the first pharmaceutical composition and / or the second pharmaceutical composition can be provided with an immediate release, delayed release, extended release or modified release profile. The first pharmaceutical composition and the second pharmaceutical composition can be provided simultaneously or at intervals of, for example, 6 hours, 12 hours, etc. In an embodiment, the first pharmaceutical composition and the second pharmaceutical composition can be provided with different drug release profiles to produce a two-stage release profile. For example, the first pharmaceutical composition can be provided with an immediate release profile, and the second pharmaceutical composition can be provided with an extended release profile. In an embodiment, one or both of the first pharmaceutical composition and the second pharmaceutical composition can be provided with an extended release or delayed release profile. Such compositions can be provided as pulsatile preparations, multilayer tablets or capsules, including tablets, beads, particles, etc. In some embodiments, the first pharmaceutical composition is an immediate release composition. In an embodiment, the second pharmaceutical composition is an immediate release composition. In an embodiment, the first pharmaceutical composition and the second pharmaceutical composition are provided with separate immediate release compositions, for example, tablets or capsules. In an embodiment, the first pharmaceutical composition and the second pharmaceutical composition are provided 12 hours apart.

[0085] In embodiments, 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 so as to be administered by injection, infusion or implantation into the body, and can be packaged in single-dose or multi-dose containers.

[0086] In an embodiment, a liquid 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 μg / ml to about 500 μg / ml. In an embodiment, the composition comprises an active substance, e.g., an allosteric modulator and / or gaboxadol, at a concentration of, e.g., 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.

[0087] In an embodiment, the pharmaceutical composition comprises an active substance, such as an allosteric modulator and / or gaboxadol, at a concentration of, for example, 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 an embodiment, the pharmaceutical composition comprises 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 an embodiment, the pharmaceutical composition for parenteral administration is formulated to a total volume of about, e.g., 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In an embodiment, the composition is contained in a bag, a glass vial, a plastic vial, or a bottle.

[0088] In an embodiment, the composition for parenteral administration comprises from about 0.05 mg to about 100 mg of active substance, e.g., an allosteric modulator and / or gaboxadol. In an embodiment, the pharmaceutical composition comprises about, e.g., 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg of active substance, e.g., an allosteric modulator and / or gaboxadol.

[0089] In an embodiment, the pharmaceutical composition comprises about, for example, 5 mg to 20 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg of active substance, for example, an allosteric modulator and / or gaboxadol. In an embodiment, the pharmaceutical composition comprises about, for example, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg of active substance, for example, an allosteric modulator and / or gaboxadol or an amount multiple of such a dose. The composition may be contained in a bag, a glass vial, a plastic vial, or a bottle.

[0090] In an embodiment, a 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 an embodiment, a composition comprises an active substance, e.g., an allosteric modulator and / or gaboxadol, at a concentration of, e.g., about 0.05 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 25 mg / ml, about 0.05 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 5 mg / ml, or about 0.05 mg / ml to about 1 mg / ml. In embodiments, the composition comprises an active substance, e.g., an allosteric modulator and / or gaboxadol, at a concentration of, e.g., 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 embodiments, the pharmaceutical composition for parenteral administration is formulated into a total volume of about, e.g., 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In embodiments, the composition is packaged and stored in a bag, glass vial, plastic vial, or bottle.

[0091] In embodiments, 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 embodiments, the active agent, e.g., an allosteric modulator and / or gaboxadol is present at a molar concentration of greater than, e.g., about 0.0001 M, about 0.001 M, about 0.01 M, about 0.1 M, about 0.2 M, greater than about 0.5, greater than about 1.0 M, greater than about 1.2 M, greater than about 1.5 M, greater than about 1.75 M, greater than about 2.0 M, or greater than about 2.5 M. In embodiments, the active agent, e.g., an allosteric modulator and / or gaboxadol is present at a molar concentration of, e.g., between about 0.00001 M and about 0.1 M, about 0.01 and about 0.1 M, about 0.1 M and about 1.0 M, about 1.0 M and about 5.0 M, or about 5.0 M and about 10.0 M. In embodiments, the active agent, e.g., allosteric modulator and / or gaboxadol, is present at a molar concentration of less than, e.g., about 0.01M, about 0.1M, about 1.0M, about 5.0M, or about 10.0M.

[0092] In embodiments, the solubility of the active agent, e.g., allosteric modulator and / or gaboxadol, in the composition is greater than, e.g., 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, about 150 mg / ml, when measured, e.g., in water at 25°C.

[0093] In embodiments, the solubility of the active agent, e.g., allosteric modulator and / or gaboxadol, in the composition is, e.g., between 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, e.g., in water at 25°C.

[0094] In an embodiment, a pharmaceutical composition for parenteral administration is provided, wherein the pharmaceutical composition is stable for at least six months. In an embodiment, the active substance of the pharmaceutical composition herein, e.g., an allosteric modulator and / or gaboxadol, exhibits a reduction of no more than about 5%, e.g., after 3 or 6 months. In an embodiment, the amount of gaboxadol or a pharmaceutically acceptable salt thereof degrades is no more than about, e.g., 2.5%, 1%, 0.5%, or 0.1%. In an embodiment, the degradation is less than about, e.g., 5%, 2.5%, 1%, 0.5%, 0.25%, 0.1%, for at least six months.

[0095] In an embodiment, a pharmaceutical composition for parenteral administration is provided, wherein the pharmaceutical composition remains soluble. In an embodiment, a stable, soluble, local site compatible and / or ready-to-use pharmaceutical composition is provided. In an embodiment, the pharmaceutical composition herein is ready-to-use for direct administration to a patient in need thereof.

[0096] The parenteral compositions provided herein may include one or more excipients, such as solvents, solubility enhancers, suspending agents, buffers, isotonic agents, stabilizers, or antimicrobial preservatives. When used, the excipients of the parenteral compositions will not adversely affect the stability, bioavailability, safety, and / or efficacy of the allosteric modulators and / or gaboxadol or pharmaceutically acceptable salts used in the compositions. Therefore, parenteral compositions are provided wherein there is no incompatibility between any of the components of the dosage form.

[0097] In an embodiment, the parenteral composition of the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof comprises a stabilizing amount of at least one excipient. For example, the excipient may be selected from the group consisting of a buffer, a solubilizer, a tonicity agent, an antioxidant, a chelating agent, an antibacterial agent, and a preservative. It will be appreciated by those skilled in the art that an excipient may have more than one function and be classified into one or more defined groups.

[0098] In an embodiment, the pharmaceutical composition comprises an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient is present at a weight percentage (w / v) of less than about, for example, 10%, 5%, 2.5%, 1%, or 0.5%. In an embodiment, the excipient is present at a weight percentage of about, for example, 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%, 0.01% to 1%, 0.1% to 1%, or 0.5% to 1%. In an embodiment, the excipient is present at a weight percentage of about, for example, 0.001% to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15%, or 1% to 15%.

[0099] In an embodiment, a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient is provided, wherein the excipient is present in a molar ratio of excipient to gaboxadol or a pharmaceutically acceptable salt 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, and about 0.001:1 to about 0.01:1. In an embodiment, the excipient is present in a molar ratio of excipient to gaboxadol or a pharmaceutically acceptable salt of about 0.0001:1 to about 0.1:1.

[0100] In an embodiment, a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and an excipient is provided, wherein the excipient comprises a stabilizing amount of a buffer. The buffer can be used to maintain the pH of the pharmaceutical composition, wherein gaboxadol or a pharmaceutically acceptable salt thereof remains soluble, stable and / or physiologically compatible. For example, in an embodiment, a parenteral composition comprises a buffer, wherein the composition remains stable without significant degradation of gaboxadol. In an embodiment, it is desirable to add a buffer for controlling pH to enhance stability without significantly catalyzing or degrading gaboxadol or a salt thereof, and / or causing significant pain to a patient after infusion.

[0101] In embodiments, the buffer can be citrate, phosphate, acetate, tartrate, carbonate, glutamate, lactate, succinate, bicarbonate buffer and combinations thereof. For example, sodium citrate, anhydrous trisodium citrate, trisodium citrate dihydrate, sodium citrate dehydrate, triethanolamine (TRIS), trisodium citrate dihydrate (i.e. trisodium citrate dehydrate), acetic acid, citric acid, glutamic acid, phosphoric acid can be used as buffer. In embodiments, the buffer can be an amino acid, an alkali metal or an alkaline earth metal buffer. For example, the buffer can be sodium acetate or hydrogen phosphate.

[0102] In an embodiment, an active substance, e.g., an allosteric modulator and / or a parenteral composition of gaboxadol is provided, wherein the pH of the composition is between about 4.0 and about 8.0. In an embodiment, the pH of the composition is, e.g., between about 5.0 and about 8.0, about 6.0 and about 8.0, about 6.5 and about 8.0. In an embodiment, the pH of the composition is, e.g., between about 6.5 and about 7.5, about 7.0 and about 7.8, about 7.2 and about 7.8, or about 7.3 and about 7.6. In an embodiment, the pH of the aqueous solution is, e.g., 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.

[0103] In an embodiment, 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. For example, a solubilizing agent according to the present invention may comprise, for example, sodium hydroxide, L-lysine, L-arginine, sodium carbonate, potassium carbonate, sodium phosphate and / or potassium phosphate. The amount of solubilizing agent in the composition will be sufficient so that the solution remains soluble at all concentrations, i.e., does not become turbid and / or form a precipitate.

[0104] In an embodiment, provided herein is 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 includes a particulate formation inhibitor. A particulate formation inhibitor refers to a compound having the desired property of inhibiting the formation of particles in a parenteral composition. The particulate formation inhibitors of the present invention include ethylenediaminetetraacetic acid (EDTA) and its salts, such as EDTA calcium disodium salt (preferably as a hydrate); EDTA diammonium salt (preferably as a hydrate); EDTA dipotassium salt (preferably as a dihydrate); EDTA disodium salt (preferably as a dihydrate, and if desired, as an anhydrous form); EDTA tetrasodium salt (preferably as a hydrate); EDTA tripotassium salt (preferably as a dihydrate); EDTA trisodium salt (preferably as a hydrate) and EDTA disodium salt USP (preferably as a dihydrate). In an embodiment, the pharmaceutical composition described herein has an effective amount of a particulate formation inhibitor. In embodiments, excipients may include, for example, amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins such as serum albumin, collagen, and gelatin; salts such as EDTA or EGTA, and sodium chloride, liposomes, polyvinylpyrrolidone, sugars such as dextran, mannitol, sorbitol and glycerol, propylene glycol and polyethylene glycol (e.g., PEG-4000, PEG-6000), glycerol, glycine, and / or lipids.

[0105] In an embodiment, provided herein is 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. For example, the solubilizing agent may include, but is not limited to, acids such as carboxylic acids, amino acids. In other embodiments, the solubilizing agent may be a saturated carboxylic acid, an unsaturated carboxylic acid, a fatty acid, a keto acid, an aromatic carboxylic acid, a dicarboxylic acid, a tricarboxylic acid, an alpha-hydroxy acid, an amino acid, and combinations thereof.

[0106] In an embodiment, provided herein are pharmaceutical compositions of an active agent, e.g., an allosteric modulator and / or gaboxadol, or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises a solubilizing agent such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, nonanoic 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, proline, serine, threonine, tryptophan, tyrosine, valine, and combinations thereof.

[0107] In embodiments, the solubilizing agent is selected from acetic acid, salts thereof and combinations thereof (e.g., acetic acid / sodium acetate), citric acid, salts thereof and combinations thereof (e.g., citric acid / sodium citrate), DL-arginine, L-arginine, and histidine. In embodiments, the solubilizing agent is DL-arginine. In embodiments, the solubilizing agent is L-arginine. In embodiments, the solubilizing agent is acetic acid / sodium acetate. In embodiments, the solubilizing agent is citric acid / sodium citrate.

[0108] In embodiments, provided herein is an active substance, for example, an allosteric modulator and / or a pharmaceutical composition of gaboxadol or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient makes the composition isotonic. The isotonic pharmaceutical composition herein can be achieved by adding an appropriate amount of sodium chloride, glucose, laevulose, dextrose, mannitol, or potassium chloride, or calcium chloride, or calcium gluconoglucoheptonate, or a mixture thereof. For example, an excipient may include one or more tonicity agents, such as, for example, sodium chloride, potassium chloride, glycerol, mannitol, and / or dextrose. Tonicity agents may be used to minimize tissue damage and stimulation, reduce hemolysis of blood cells, and / or prevent electrolyte imbalance. For example, a parenteral composition may be an aqueous solution comprising sodium chloride, wherein the composition is isotonic. In embodiments, an isotonic agent is sodium chloride. In embodiments, the concentration of an isotonic agent is between about 0.01 and about 2.0 weight percent. In embodiments, a pharmaceutical composition may include up to about 10% of an isotonic agent. In embodiments, the pharmaceutical composition may contain up to about, e.g., 0.25%, 0.5%, 1%, 2.5% of an isotonic agent. In embodiments, the amount of isotonic agent in the pharmaceutical composition is between about, e.g., 0.01% to 1%, 0.1% to 1%, 0.25% to 1%, or 0.5% to 1%.

[0109] In an embodiment, provided herein is 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 antagonist. In an embodiment, the free radical antagonist is ascorbic acid, an ascorbic acid derivative, an organic compound having at least one thiol group, an alkyl polyhydroxylated compound, and a cycloalkyl polyhydroxylated compound, and combinations thereof.

[0110] In an embodiment, provided herein is 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 thioglycolic acid, thiolacetic acid, dithiothreitol, reduced glutathione, thiourea, α-thioglycerol, cysteine, acetylcysteine, mercaptoethane sulfonic acid, and combinations thereof.

[0111] In an embodiment, provided herein are pharmaceutical compositions having an active agent, e.g., an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient comprises riboflavin, dithiothreitol, sodium thiosulfate, thiourea, ascorbic acid, methylene blue, sodium metabisulfite, sodium bisulfite, propyl gallate, acetylcysteine, phenol, acetone sodium bisulfate, ascorbic acid, ascorbyl esters, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine, nordihydroguaiaretic acid (NDGA), monothioglycerol, sodium bisulfite, sodium metabisulfate, tocopherol and / or glutathione.

[0112] In embodiments, provided herein are pharmaceutical compositions of active substances, e.g., allosteric modulators and / or gaboxadol or pharmaceutically acceptable salts thereof, and excipients, wherein the excipients include preservatives. In embodiments, the preservatives are selected from benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, chlorocresol, metacresol, phenol, phenylmercuric nitrate, phenylmercuric acetate, methylparaben, propylparaben, butylparaben, 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.

[0113] In embodiments, the compositions herein include co-solvents. For example, in some cases, the solubility of gaboxadol can be much lower than the therapeutic dose, and therefore a co-solvent system can be used. A co-solvent is a mixture of solvents that can be used to achieve sufficiently high solubility and can increase stability. For example, a co-solvent can be an organic solvent miscible with water, such as ethanol, propylene, ethylene glycol, Capmul PG, propylene glycol, glycerol, polyethylene glycol, sorbitol, dimethylacetamide and / or dimethyl sulfoxide (DMSO). In embodiments, a co-solvent can account for up to about 75% of a pharmaceutical composition. In other embodiments, the amount of the co-solvent used constitutes up to about, for example 1%, 5%, 10%, 15%, 25%, 40%, 50% of a pharmaceutical composition.

[0114] The dosage form can be, for example, prepared by mixing the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof and one or more excipients (e.g., buffers, solubilizers, tonicity agents, antioxidants, chelating agents, antimicrobial agents and / or preservatives) in a blender under aseptic conditions until a uniform blend is obtained. Pre-sterilized vials can then be filled with an appropriate amount of the sterile blend. A predetermined amount of the sterile blend can then be mixed with a solvent, such as water, saline, about 5%-10% sugar (e.g., glucose, dextrose) solution, and combinations thereof, prior to administration. In addition, the solution can be frozen and thawed before further processing.

[0115] The excipient may be used in solid or solution form. When used in solid form, the excipient and allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof may be mixed together as described above, and then a solvent may be added prior to parenteral administration. When used in solution form, the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof may be mixed with a solution of the excipient prior to parenteral administration.

[0116] The parenteral solution comprising allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt can be prepared by mixing the required amount of allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt in parenteral fluid such as D5W, distilled water, saline or PEG and adjusting the pH of the solution between 6.8-8, and the allosteric modulator and / or gaboxadol or its pharmaceutically acceptable salt can be purified before use. The process can be carried out at room temperature, or in order to increase the concentration, the solution can be appropriately warmed. Other solvents such as PEG 400, PEG 600, polypropylene glycol or other glycols can be used to enhance solubility. After being cooled to room temperature, the resulting solution can be sterilized by known methods, such as ultrafiltration or ethylene oxide treatment or heating using, for example, a 0.45 micron filter, and can be packaged into ampoules, vials or pre-filled syringes suitable for dispensing sterile parenteral preparations.

[0117] When administered, the parenteral compositions herein provide a maximum plasma concentration time (Tmax) of gaboxadol in a human patient of about 1 hour or more (e.g., about 1.5 hours or more). max In an embodiment, the T of gaboxadol in a human patient is max The range is, for example, between about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours. In embodiments, the T of gaboxadol in human patients is observed to be max In embodiments, the T of gaboxadol in human patients is observed to be greater than about 1.5. max Less than about 3 hours. After the infusion is complete, the time to maximum plasma concentration is measured.

[0118] In embodiments herein, the dosage form comprises from about 1 mg to about 500 mg of gaboxadol, wherein parenteral administration (e.g., intramuscularly, intravenously, subcutaneously, intraperitoneally, or intrathecally) of the dosage form provides a mean AUC comprising more than about 25 ng·hr / ml 0-∞ In an embodiment, a single dose administration of a dosage form provides a mean AUC comprising more than about, for example, 50 ng·hr / ml, 75 ng·hr / ml, 150 ng·hr / ml, 250 ng·hr / ml, 500 ng·hr / ml, 1000 ng·hr / ml, or 1500 ng·hr / ml. 0-∞ In vivo plasma profile of gaboxadol.

[0119] In an embodiment, the dosage form comprises about 1 mg to about 500 mg of gaboxadol, wherein administration of the dosage form provides a mean C of less than about 10,000 ng / ml. max In embodiments, a single dose of the composition provides a mean C of less than about, e.g., 5000 ng / ml, 2500 ng / ml, 1000 ng / ml, 500 ng / ml, 250 ng / ml, or 100 ng / ml. max In vivo plasma profile of gaboxadol.

[0120] In an embodiment, the pharmaceutical composition for parenteral administration comprises gaboxadol or a pharmaceutically acceptable salt thereof, wherein the parenteral administration exhibits the following pharmacokinetic profile after administration of the parenteral composition: at a T of about 1 minute to about 120 minutes max ; followed by at least 50% of the duration of about 90 minutes to about 360 minutes C max In an embodiment, after parenteral administration of gaboxadol, the plasma drug concentration is at least 50% C max, for a duration of, for example, about 10 minutes to about 60 minutes, about 15 minutes to about 90 minutes, about 30 minutes to about 120 minutes, about 60 minutes to about 180 minutes, about 90 minutes to about 180 minutes.

[0121] In an embodiment, a stable pharmaceutical composition is provided in a unit dosage form in a vial or ampoule suitable for parenteral administration, the stable pharmaceutical composition having a therapeutically effective amount of an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof dissolved in sterile water to form a solution, wherein the composition is substantially free of any excipients, organic solvents, buffers, acids, bases, salts other than the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition remains sufficiently soluble and can be administered directly. In an embodiment, the pharmaceutical composition can be stored for at least 6 months in the absence of an inert atmosphere.

[0122] In an embodiment, provided herein is a stable pharmaceutical composition in a unit dosage form in a vial or ampoule suitable for parenteral administration, the stable pharmaceutical composition having a therapeutically effective amount of an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof dissolved in sterile water to form a solution, wherein the composition does not contain any excipients, organic solvents, buffers, acids, bases, salts except for the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition remains sufficiently soluble and can be directly administered. In an embodiment, the pharmaceutical composition can be stored for at least 6 months in the absence of an inert atmosphere.

[0123] In an 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 osmolarity between 225 mOsm / kg and 350 mOsm / kg and a pH in the range of between 7.0 and 8.0. In an embodiment, the aqueous solution has an osmolarity between 270 and 310. In an embodiment, the aqueous solution has a pH in the range of between 7.2 and 7.8.

[0124] In embodiments, provided herein are methods of treating epileptic disorders comprising administering to a patient in need thereof a first pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof and / or an allosteric modulator and a second pharmaceutical composition, wherein the second pharmaceutical composition provides an average AUC of at least about, e.g., 25%, 30%, 35%, 40%, 45%, or 50% less than that of the first pharmaceutical composition. 0-∞In embodiments, the composition provides an improvement in next-day function to the patient. For example, after administration of the first pharmaceutical composition and / or the second pharmaceutical composition, the composition can provide an improvement in one or more symptoms that lasts for more than about, for example, 6 hours, 8 hours, 10 hours, or 12 hours.

[0125] In an embodiment, the parenteral composition can be administered as needed, e.g., once a day, twice a day, three times a day, or four times a day, or more times a day, or continuously as needed by the patient. In an embodiment, the parenteral composition can be administered immediately at the onset of an epileptic seizure or as soon as possible thereafter. In an embodiment, the parenteral composition can be administered as soon as possible when warning signs of an epileptic seizure are present, such as a sense of odor (auras), a sense of unusual smells (unusual smells), abnormal sensations, etc.

[0126] In an embodiment, provided herein are methods of treating an epileptic disorder comprising administering to a patient in need thereof a first drug dose comprising a subtherapeutic dose of an allosteric modulator, wherein the composition provides an improvement that persists for more than 6 hours after administration.

[0127] In an embodiment, provided herein are methods of treating an epileptic disorder comprising administering to a patient in need thereof a first drug dose comprising a subtherapeutic dose of gaboxadol or a pharmaceutically acceptable salt thereof, wherein the composition provides an improvement that persists for more than 6 hours after administration.

[0128] In an embodiment, provided herein is 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 provides an average AUC of less than about 900 ng·hr / ml. 0-∞ In an embodiment, the second pharmaceutical composition provides an AUC of less than about, for example, 800 ng·hr / ml, 750 ng·hr / ml, 700 ng·hr / ml, 650 ng·hr / ml, or 600 ng·hr / ml. 0-∞ In an embodiment, the second pharmaceutical composition provides an AUC of less than about, for example, 550 ng·hr / ml, 500 ng·hr / ml, 450 ng·hr / ml, 400 ng·hr / ml, or 350 ng·hr / ml. 0-∞ In an embodiment, the second pharmaceutical composition provides an AUC of less than about, for example, 300 ng·hr / ml, 250 ng·hr / ml, 200 ng·hr / ml, 150 ng·hr / ml, or 100 ng·hr / ml.0-∞ In an embodiment, a first pharmaceutical composition and a second pharmaceutical composition are administered, wherein the compositions provide an improvement in next-day function to the patient. In an embodiment, the first pharmaceutical composition provides an improvement in one or more symptoms that lasts for more than, for example, 6 hours, 8 hours, or 12 hours after administration of the first pharmaceutical composition.

[0129] In an embodiment, provided herein is 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 having a greater than provided by administration of the second pharmaceutical composition. max Mostly more than about 50% C max As used herein, the C provided by administering the second pharmaceutical composition max The plasma profile contribution of the first pharmaceutical composition may or may not be included. In embodiments, administration of the second pharmaceutical composition does not include the plasma profile contribution of the first pharmaceutical composition. In embodiments, the first composition provides a plasma profile having a C greater than that provided by administration of the second pharmaceutical composition. max Most of the C max In vivo plasma profile.

[0130] In an embodiment, the T of the first pharmaceutical composition max is less than 3 hours. In an embodiment, the T of the first pharmaceutical composition max is less than 2.5 hours. In an embodiment, the T of the first pharmaceutical composition max is less than 2 hours. In an embodiment, the T of the first pharmaceutical composition max is less than 1.5 hours. In an embodiment, the T of the first pharmaceutical composition max Is less than 1 hour.

[0131] In embodiments, the first pharmaceutical composition provides a dissolution rate of at least about 80% within the first 20 minutes of administration to a patient in need thereof. In embodiments, the first pharmaceutical composition provides a dissolution rate of at least about, e.g., 85%, 90%, or 95% within the first 20 minutes of administration to a patient in need thereof. In embodiments, the first pharmaceutical composition provides a dissolution rate of at least 80% within the first 10 minutes of administration to a patient in need thereof.

[0132] In an embodiment, the first pharmaceutical composition and / or the 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 an 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 an improvement. In an 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 an improvement. In an embodiment, the method provides for administering a first pharmaceutical composition and a second pharmaceutical composition, the first pharmaceutical composition providing an improvement in at least one symptom of an epileptic disorder, and the second pharmaceutical composition maintaining the improvement. In an embodiment, after administering the first pharmaceutical composition, the second pharmaceutical composition may provide a synergistic effect to improve at least one symptom of an epileptic disorder. In an embodiment, the second pharmaceutical composition may provide a synergistic effect to improve at least one symptom of an epileptic disorder.

[0133] In an embodiment, provided herein is a method of treating an epileptic disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising a first drug dose in which the composition provides an improvement that lasts for more than 6 hours after administration and a second pharmaceutical composition comprising a subtherapeutic dose of gaboxadol or a pharmaceutically acceptable salt thereof.

[0134] The administration of the first pharmaceutical composition and the second pharmaceutical composition can be simultaneous or separated by a certain time interval to achieve immediate, medium-term or long-term improvement of at least one symptom. In an embodiment, the first pharmaceutical composition and the second pharmaceutical composition can be administered 6 hours apart. In an embodiment, the first pharmaceutical composition and the second pharmaceutical composition can be administered 12 hours apart. In an embodiment, the first pharmaceutical composition and the second pharmaceutical composition can be administered within, for example, 15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 18 hours, 24 hours, etc. In an embodiment, the first pharmaceutical composition and the second pharmaceutical composition can be administered together. In an embodiment, the first pharmaceutical composition and the second pharmaceutical composition can be administered at least, for example, 15 minutes, 30 minutes, 1 hour, 2 hours, 12 hours, 18 hours, 24 hours, etc. In an embodiment, an improvement of at least one symptom of epileptic disorder that lasts more than 8 hours after being administered to a patient is provided. In an embodiment, an improvement that lasts more than about, for example, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours or 24 hours after being administered to a patient is provided.

[0135] In embodiments, administration of the first pharmaceutical composition and the second pharmaceutical composition may provide a synergistic effect to improve at least one symptom of an epileptic disorder.

[0136] In an embodiment, the first pharmaceutical composition and / or the second pharmaceutical composition comprises any of the aforementioned amounts of an active substance, such as an allosteric modulator and / or gaboxadol and pharmaceutically acceptable salts thereof.

[0137] In an embodiment, the first pharmaceutical composition and / or the 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 active substance, e.g., an allosteric modulator and / or gaboxadol.

[0138] In an embodiment, the first pharmaceutical composition and / or the second pharmaceutical composition comprises 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg of active substance, such as an allosteric modulator and / or gaboxadol, or an amount multiple of such a dose. In an embodiment, the first pharmaceutical composition comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of an allosteric modulator. In an embodiment, the second pharmaceutical composition comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of an allosteric modulator.

[0139] In an embodiment, a method for treating an epileptic disorder comprises administering an allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof in combination with one or more other active compounds. Combination therapy may include administering the active agents together in the same mixture or in separate mixtures. In an embodiment, the pharmaceutical composition comprises two, three or more active agents. In an embodiment, the combination produces a more than additive effect on the treatment of the disease or disorder. Thus, a combination of agents is provided for treating an epileptic disorder, and the combined agents may provide a synergistic effect that enhances efficacy.

[0140] In an embodiment, gaboxadol or a pharmaceutically acceptable salt thereof is administered in combination with a conventional therapy for seizures, epilepsy, or one of the other disorders disclosed herein. For example, common conventional therapies for seizures and epilepsy include anti-epileptic drugs and non-anti-epileptic 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 therapy (LGIT)), intravenous immunoglobulin, steroids, elimination diets, valgus nerve stimulation, corticetomy, and multiple subpial transections.

[0141] Common anti-epileptic and anticonvulsant active compounds that can be used in combination with an 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, valproate, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide.

[0142] 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 alone as a monotherapy as the sole active agent. In an embodiment, a method for treating epileptic disorders using an allosteric modulator or a pharmaceutically acceptable salt thereof is provided. In an embodiment, the method for treating epileptic disorders comprises 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 may include administering an active agent, such as an allosteric modulator or gaboxadol together in the same mixture or in a separate mixture. In an embodiment, the pharmaceutical composition comprises two, three or more active agents. In an embodiment, the combination produces an effect that is more than an additive effect on the treatment of a disease or disorder. Therefore, a combination of agents is provided to treat epileptic disorders, and the agents combined can provide a synergistic effect that enhances efficacy.

[0143] In an embodiment, gaboxadol or a pharmaceutically acceptable salt thereof, or an allosteric modulator, a pharmaceutically acceptable salt, derivative and / or analog thereof, or both, is administered in combination with a conventional therapy for seizures, epilepsy, or one of the other disorders disclosed herein. For example, common conventional therapies for seizures and epilepsy include anti-epileptic drugs and non-anti-epileptic drug treatments, such as low carbohydrate diets (e.g., ketogenic diets, such as classic diets, medium chain triglyceride (MCT) diets, modified Atkins diets (MADs), and low glycemic index therapy (LGIT)), intravenous immunoglobulins, steroids, elimination diets, abducens nerve stimulation, corticetomy, and multiple subpial transections.

[0144] Common anti-epileptic and anticonvulsant active compounds that can be used in combination with 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, valproate, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide.

[0145] In embodiments, co-therapy of an allosteric modulator, a pharmaceutically acceptable salt thereof, or a derivative thereof and gaboxadol or a pharmaceutically acceptable salt thereof is effective to reduce the frequency or severity of epileptic seizures in a subject compared to administration of either compound alone. In embodiments, the co-therapy produces a more than additive result compared to the compounds administered alone.

[0146] In an embodiment, the subject can be started at a low dose and the dose can be increased. In this way, it can be determined whether the drug is well tolerated in the subject. The dose for children can be lower than the dose for adults.

[0147] In embodiments, such as combination therapy, the dose of gaboxadol for children 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 embodiments, the weight / weight ratio of gaboxadol to the allosteric modulator may be 10 to 1. However, based on the dosing ratio of mg of active pharmaceutical ingredient (API), the range of gaboxadol to allosteric modulator may be 0.1 to 1 to 100 to 1, respectively.

[0148] By showing a reduction in the frequency of epileptic seizures compared to baseline after a certain period of time (e.g., more than 50%), an effective treatment for epileptic disorders (e.g., acute recurrent seizures) herein can be established. For example, after a baseline period of 1 month, patients can be randomly assigned to gaboxadol or an allosteric modulator or a placebo as an add-on therapy to standard therapy (such as valproate and clobazam) during a 2-month double-blind period. The primary outcome measurement value may include the percentage of responders to gaboxadol or an allosteric modulator and to a placebo, which is defined as having experienced at least a 50% reduction in the frequency of clonic (or tonic-clonic) seizures during the second month of the double-blind period compared to baseline. Patients who develop status epilepticus during the double-blind period may be considered non-responders. Secondary outcomes may include the absolute counts of clonic (or tonic-clonic) seizures during the second month of the double-blind period (normalized to 30 days, the raw counts divided by the exact number of observation days and multiplied by 30) and the percentage of change from baseline.

[0149] The effectiveness of gaboxadol and / or allosteric modulators for treating disclosed epileptic disorders (e.g., associated with Dravet syndrome or Lennox-Gastaut syndrome) can be established in other controlled studies. For example, a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period, followed by a 3-week titration period and a 12-week maintenance period can be used for patients aged 2-54 years who are currently or previously diagnosed with Dravet syndrome or LGS. Multiple target maintenance doses of gaboxadol and / or allosteric modulators can be tested based on patient weight and specific dosing regimens. The primary efficacy measure can include a percentage reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic) (also known as drop attacks) from a 4-week baseline period to a 12-week maintenance period. Thus, efficacy can be measured as the percent reduction from baseline in weekly seizure (e.g., atonic, atonic, or myoclonic) frequency, e.g., 0 to <20, 20 to <40, 40 to <60, 60 to <80, 80 to <100.

[0150] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0151] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to the practice in the art, "about" can mean within 3 or more standard deviations. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and still more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude of a value, preferably within 5-fold of a value, and more preferably within 2-fold of a value.

[0152] As used herein, the term "treating" or "treatment" refers to relieving, alleviating or delaying the appearance of clinical symptoms of a disease or condition in a subject who may suffer from or be susceptible to a disease or condition but has not yet experienced or displayed clinical or subclinical symptoms of the disease or condition. In certain embodiments, "treating" or "treatment" may refer to preventing the appearance of clinical symptoms of a disease or condition in a subject who may suffer from or be susceptible to a disease or condition but has not yet experienced or displayed clinical or subclinical symptoms of the disease or condition. "Treatment" or "treatment" may also refer to inhibiting a disease or condition, for example, preventing or reducing its development or at least one clinical or subclinical symptom thereof. "Treatment" or "treatment" also refers to relieving a disease or condition, for example, causing the regression of a disease or condition or at least one clinical or subclinical symptom thereof. The benefit to the subject being treated may be statistically significant, mathematically significant or at least perceptible to the subject or and / or physician. Nevertheless, prophylactic (preventive) and therapeutic treatments are two separate embodiments of the disclosure herein.

[0153] "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 to otherwise provide the desired pharmacological and / or physiological effect.

[0154] "Improvement" 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 disease.

[0155] "Improvement in next-day function" or "wherein there is an improvement in next-day function" refers to an improvement after waking from an overnight sleep period, wherein the beneficial effect of the administration of one or more of gaboxadol, alone or a pharmaceutically acceptable salt thereof, or an allosteric modulator, alone or in combination with an allosteric modulator, is applicable to at least one symptom or condition associated with an epileptic disorder and is discernible subjectively by the patient or objectively by an observer within a certain 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.

[0156] "Composition", "pharmaceutical composition", "formulation", "pharmaceutical formulation" are used interchangeably herein. "Composition", "pharmaceutical composition", "formulation", "pharmaceutical formulation" include dosage forms. Dosage forms may include unit doses.

[0157] "Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally recognized as safe," e.g., are physiologically tolerated and do not typically produce allergic or similar adverse reactions (such as stomach upset, etc.) when administered to humans. In embodiments, the term refers to molecular entities and compositions that are approved by a federal or state regulatory agency as being on the GRAS list (subject to premarketing review and approved by the FDA under Sections 204(s) and 409 of the Federal Food, Drug, and Cosmetic Act) or a similar list (U.S. Pharmacopeia or another generally recognized pharmacopoeia for use in animals, and more particularly in humans).

[0158] As used herein, the terms "prevention" or "preventing" mean administering a composition to a subject or system at risk of or prone to one or more symptoms caused by a disease or disorder to promote cessation of specific symptoms of the disease or disorder, reduction and prevention of one or more symptoms of the disease or disorder, reduction in the severity of the disease or disorder, complete elimination of the disease or disorder, stabilization or delay in the development or progression of the disease or disorder.

[0159] As used herein, "prodrug" refers to a pharmacological substance (drug) that is administered to a subject in an inactive (or significantly less active) form. After administration, the prodrug is metabolized in the body (in vivo) to a compound with the desired pharmacological activity.

[0160] "Analog," "analogue," and "derivative" are used interchangeably herein and refer to compounds that have the same nucleus as a parent compound but may differ from the parent compound in terms of bond order, the absence or presence of one or more atoms and / or groups of atoms, and combinations thereof. A derivative may differ from the parent compound, for example, in one or more substituents present on the nucleus, which may include one or more atoms, functional groups, or substructures. In general, it is contemplated that derivatives are formed, at least in theory, from the parent compound by chemical and / or physical processes.

[0161] As used herein, "stereoisomer" refers to isomeric molecules with the same molecular formula and bonded atomic order (composition), but their atoms have different three-dimensional orientations in space. Examples of stereoisomers include enantiomers and diastereomers. As used herein, enantiomers refer to one of two mirror-image forms of optically active or chiral molecules. Diastereomers (diastereomers) (or diastereoisomers) are stereoisomers that are not enantiomers (mirrors that cannot overlap each other). Chiral molecules contain chiral centers, also known as stereocenters (stereocenters) or stereogenic centers (stereogenic center), any point in the molecule, but not necessarily an atom, which carries a group that causes the exchange of any two groups to cause stereoisomers. In organic compounds, chiral centers are typically carbon, phosphorus or sulfur atoms, but it is also possible that other atoms in organic and inorganic compounds are stereocenters. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is attributed to tetrahedral stereocenters (e.g., tetrahedral carbons), it is assumed that the total number of possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry generally have a number of stereoisomers less than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. "Chirality" also includes axial and planar chirality.

[0162] The term "pharmaceutically acceptable salt" as used herein refers to a derivative of a compound as defined herein, wherein the parent compound is modified by preparing its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed by non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid or nitric acid; and salts prepared from the following organic acids: such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and hydroxyethanesulfonate. The pharmaceutically acceptable salt of the compound can be synthesized by conventional chemical methods from the parent compound comprising an alkaline or acidic part. For example, gaboxadol can be prepared for administration to a patient using a pharmaceutically acceptable salt (including acid addition salts, zwitter ion hydrates, zwitter ion anhydrates, hydrochlorides or hydrobromides) or in the form of zwitter ion monohydrates. Acid addition salts include, but are not limited to, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid or theophylline acetic acid addition salts and 8-halotheophylline, such as 8-bromo-theophylline. In other suitable embodiments, inorganic acid addition salts may be used, including, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, or nitric acid addition salts.

[0163] An "excipient" is a substance, other than the active drug substance (e.g., gaboxadol) of a pharmaceutical composition, that has been appropriately evaluated for safety and is included in a drug delivery system to aid in processing of the drug delivery system during its manufacture; to protect; to support; to enhance stability, bioavailability, or patient acceptability; to aid in product identification; or to enhance any other attribute of the overall safety and effectiveness of the drug delivery system during storage or use.

[0164] "Stabilizer" or "stabilizing amount" refers to an amount of one or more excipients included in a parenteral composition that provides adequate 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.

[0165] "Stable" means that there is substantially no degradation of gaboxadol or a pharmaceutically acceptable salt thereof after a specified period of time, for example, after 3 months or 6 months.

[0166] By "soluble" is meant that the solution of the allosteric modulator and / or gaboxadol or a pharmaceutically acceptable salt thereof does not become cloudy and / or that substantially no precipitate is present in the solution.

[0167] "Sufficiently soluble" means that the particle content is low enough and the material is sterile enough so that it can be used for parenteral administration. For example, the number of particles in the liquid composition should be, for example, less than 6,000 10 μm particles per 10 ml volume of solvent, preferably less than 10,000, less than 5,000, less than 3,000, less than 1,000, or less than 400 10 μm particles. In some examples, the number of particles in the liquid composition should be less than 1000, less than 600, or less than 200 25 μm particles per 10 ml volume.

[0168] "Topical site compatible" herein shall mean that the composition is tolerated at the injection or infusion site, thus minimizing side effects, such as local skin irritation or venous irritation, including inflammatory reactions at the infusion site. The parenteral compositions herein may have fewer side effects, such as skin irritation or phlebitis, than conventional products.

[0169] As used herein, "purified" refers to a substance that has been separated under conditions that reduce or eliminate the presence of irrelevant substances (i.e., contaminants, including natural materials from which the substance is obtained). As used herein, the term "substantially free" is used operatively in the context of analytical testing of the substance. Preferably, the purified material that is substantially free of contaminants is at least 95% pure; more preferably at least 97% pure, and still more preferably at least 99% pure. Purity can be evaluated, for example, by chromatography or any other method known in the art. In an embodiment, purified means that the level of contaminants is below the acceptable level for safe administration to humans or non-human animals by regulatory authorities.

[0170] Reference to a composition herein as "ready-to-use" shall mean a preparation in a reconstituted form, with standardized concentration and quality, prefilled in a single-use container such as a glass vial, infusion bag or syringe, ready for direct administration to a patient.

[0171] Reference to "direct administration" of a composition herein shall mean immediate administration, i.e., without further dilution, premixing with other substances, or otherwise altering the composition or formulation of the composition. Such compositions are typically discharged directly from an infusion set and administered through a vascular access port or through a central line.

[0172] "Dosage" is intended to include formulations expressed in terms of μg / kg / day, μg / kg / hour, mg / kg / day, or mg / kg / hour. Dosage is the amount of a component administered according to a specific dosage regimen. "Dose" is the amount of a dose administered to a mammal per unit volume or mass, for example, an absolute unit dose expressed in mg or μg of a dose. The dose depends on the concentration of the dose in the formulation, for example, moles / L (M), mass / volume (m / v), or mass / mass (m / m). The two terms are closely related because a specific dosage results from a dose or doses of a formulation's administration regimen. The specific meaning in any case will be apparent from the context.

[0173] "Patient" and "subject" are used interchangeably herein and include, but are not limited to, primates such as humans, canines, swine, ungulates, rodents, poultry, and avian.

[0174] "Co-administered with," "in combination with," "administered in combination with," "acombination of," "administered along with," or "co-therapy" are used interchangeably and mean the administration of two or more agents during a therapy. 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.

[0175] "PK" refers to pharmacokinetic profile. max T is defined as the highest estimated plasma drug concentration (ng / ml) during the experimental period. max is defined as when C max Estimated time (min). AUC 0-∞It is the total area under the plasma drug concentration-time curve from the time the drug is administered until it is excreted (ng·hr / ml or μg·hr / ml). The area under the curve is determined by the clearance rate. The clearance rate is defined as the volume of blood or plasma that completely clears its drug content per unit time (ml / min). Example

[0176] The examples provided herein are included merely to increase the disclosure herein and should not be considered limiting in any respect.

[0177] Example 1

[0178] Gaboxadol plasma concentration profile

[0179] The following examples provide plasma concentration profiles and dose proportionality of gaboxadol monohydrate following single oral doses ranging from 2.5 mg to 20 mg.The absolute bioavailability of gaboxadol monohydrate capsules ranging from 2.5 mg to 20 mg was also evaluated.

[0180] The study included a separate group of 10 healthy adult subjects (at least 4 subjects of each sex) who participated in a 6-period, double-blind, randomized, crossover study designed to evaluate the dose proportionality and absolute bioavailability of 5 single oral doses of gaboxadol across a dose range of 2.5 mg to 20 mg. The order in which the subjects received 5 single oral doses of gaboxadol (2.5 mg; 5 mg; 10 mg; 15 mg; and 20 mg) was randomized during treatment cycles 1 to 5. Each subject was expected to complete all 6 treatment cycles with at least 4 days of washout between each treatment cycle.

[0181] Each oral administration during the treatment cycle consisted of 2 capsules of the test drug taken simultaneously at each scheduled administration. The treatments for oral administration of the study drug were named 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). Subjects received their study drug at approximately 8:00 AM in the morning with 240 mL of water after an overnight fast. Water was allowed ad libitum except within 1 hour before and after study drug administration. No food was allowed for 4 hours after dosing.

[0182] For each subject in each treatment, plasma and urine samples were collected within 16 hours after dosing to determine pharmacokinetic parameters (e.g., AUC, C max 、T max , apparent t 1 / 2 , cumulative urinary excretion, renal clearance, clearance, and steady-state volume of distribution). The AUC and C max Efficacy adjustments were made to facilitate comparison of pharmacokinetic data across studies. Table 1 provides the individual efficacy-adjusted pharmacokinetic parameters of gaboxadol following single oral doses (2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg).

[0183] Table 1. Pharmacokinetic parameters of gaboxadol following oral and IV administration

[0184]

[0185] Example 2

[0186] Evaluation of residual effect caused by gaboxadol administration

[0187] The study was a double-blind, double-dummy, randomized, active-controlled and placebo-controlled, single-dose, 3-period crossover study followed by an open-label, single-dose, single-period study in healthy elderly male and female subjects. Subjects were randomly assigned to each of the 3 treatments (Treatments A, B, and C), which were administered in a crossover manner during the first 3 treatment cycles. 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 lived in the residence during each treatment cycle from the early evening of dosing until ~36 hours after dosing (morning of Day 3). Subjects who participated in Treatment Cycles 1-3 participated in the fourth treatment cycle. In this cycle, for the PK of gaboxadol, a single dose of gaboxadol 10 mg (Treatment D) was administered orally in an open-label manner in the morning of Day 1. There was a washout of at least 14 days between doses of consecutive treatment cycles. Study participants included healthy, elderly male and female subjects between the ages of 65 and 80 years, with a Mini Mental Status of 24 and a body weight of 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 placebo provided for both gaboxadol and flurazepam.

[0188] The primary endpoints evaluated included pharmacodynamics (measures of psychomotor performance, memory, attention, and daytime sleepiness after pm dosing), gaboxadol pharmacokinetics, and safety. For the primary endpoints Choice Reaction Time and Critical Flicker Fusion, gaboxadol (single dose of 10 mg) showed no residual effect 9 hours after dosing, whereas the active reference, flurazepam (single dose of 30 mg), showed a significant effect for the same tests. In addition, gaboxadol did not show any signs of residual effect for the other measures used in the study (Multiple Sleep Latency Test (MSLT); Digit Symbol Substitution Test (DSST), Tracking, Memory Test, Body Sway, and Leeds Sleep Assessment Questionnaire).

[0189] Example 3

[0190] Evaluation of the ability of allopregnanolone, ganaxolone, and gaboxadol to block benzodiazepine-resistant status epilepticus

[0191] Allopregnanolone, ganaxolone, and gaboxadol were evaluated for their acute anticonvulsant efficacy when administered in ascending doses 30 min after the onset of convulsive status epilepticus, a time point at which benzodiazepines are usually tolerated. The results obtained with these agents were compared with those obtained from side-by-side studies in animals treated with vehicle.

[0192] Male Sprague Dawley rats (n=10 treatments / group, 100-125 g; Charles River Laboratories) were treated systemically with lithium chloride (127 mg / kg; intraperitoneal (ip)) 24 hours prior to administration of the chemoconvulsant pilocarpine. On the following day, rats received pilocarpine hydrochloride (50 mg / kg; ip) and were carefully monitored for the presence or absence of convulsive seizure activity. Administration of pilocarpine induced behavioral seizures within 5-20 min, and any rat that did not exhibit convulsive seizure activity within 45 min of pilocarpine administration was excluded from further study. On the day of the study, each study compound (allopregnanolone (ALLO), ganaxolone (GAB)), administered ip at increasing doses 30 min after the first observed convulsive seizure, was evaluated. The ability of allopregnanolone (GNX) or gaboxadol (GBD) or vehicle (VEH) (40% hydroxypropyl β-cyclodextrin) to prevent convulsive status epilepticus in the Li-Pilo model of status epilepticus. Throughout the study, the experimenter performing the behavioral observations was blinded to the treatment condition (i.e., allopregnanolone, ganaxolone, or gaboxadol). All rats were observed and scored for seizure severity 120 min after drug administration and any accompanying behavioral effects were also recorded by the experimenter who was blinded to the treatment condition. At the end of the behavioral observation period, all surviving rats were administered a 3 ml injection of lactated Ringer's solution to replace any SE-induced fluid loss.

[0193] The dose of each study compound (allopregnenolone, ganaxolone or gaboxadol) was varied in groups of 10 rats until at least two points were established between the limits of 100% protection (no more convulsive seizures 10 min after drug administration) and 0% protection. The drug dose required to produce the desired endpoint in 50% of the animals (ED50 or TD50) and the 95% confidence interval were calculated by a computer program based on the Probit method (Finney DJ. Probit Analysis. Cambridge University Press. 1971). Such dose-response evaluations typically require up to 5 treatment groups per study compound, totaling up to 50 rats per compound. Thus, up to 150 rats can be used for the quantification of these study compounds (allopregnenolone, ganaxolone or gaboxadol), and there is also a vehicle-treated group (n=10), making the total number of rodents in Study 1 160. All animals in the study were retained for 24 hours after completion of the study for evaluation of body weight changes. Allopregnanolone, ganaxolone or gaboxadol was administered at a dose of 0.5 mg / kg, 2 mg / kg, 5 mg / kg, 10 mg / kg or 20 mg / kg.

[0194] Pharmacokinetic Sample Collection: Brain and plasma can be collected from satellite cohorts of rats for evaluation at each dose (n=3 rats / dose / compound; up to 45 rats total). Plasma is collected from trunk blood after centrifugation at 10,000×g for 10 min at 4°C. The anticoagulant is lithium heparin. Brains are snap frozen on dry ice. All samples are stored at -20°C. Test procedure timeline as follows Figure 2 as shown in .

[0195] Dose-response curves were constructed and presented as ED50 (95% confidence interval) calculated for each study compound (allopregnanolone, ganaxolone, or gaboxadol) administered 30 min after the first observed convulsive seizure. In cases where the data did not allow calculation of an ED50 (95% confidence interval) due to lack of efficacy, the highest dose tested was recorded. For all treatment conditions, additional effects measures such as motor impairment, change in body weight after SE, or survival 24 h after SE were also recorded during the study. Table 2. Overall survival and protection outcomes

[0196]

[0197] *Significant difference from VEH, p<0.05

[0198] # Rats in the PK group died spontaneously during SE at 110 min after the onset of SE, but samples were collected.

[0199] Figure 3 is a bar graph showing percent protection versus dose for allopregnanolone, ganaxolone, or gaboxadol. Figure 4 is a bar graph showing the 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. Fig. 6A is a bar graph showing body weight change 24 hours after status epilepticus as a function of percent loss versus dose. Figure 6B is a bar graph showing 24 hour body weight loss for the 0.5 mg / kg dose group. Dose-response evaluation of treatment during benzodiazepine-resistant status epilepticus demonstrated dose-dependent efficacy of ganaxolone (ip) - significant improvement in protection at 20 mg / kg (p<0.02). Potential for an inverted U-shaped response curve for gaboxadol - at 0.5 mg / kg, p=0.071. Significant improvement in 24 hour survival for gaboxadol treated rats (10 mg / kg) is shown.

[0200] Example 4

[0201] A prospective study to characterize the ability of allopregnanolone, ganaxolone, and gaboxadol to block benzodiazepine-resistant status epilepticus

[0202] Initial dose-response studies of allopregnanolone (ALLO), ganaxolone (GNX), and gaboxadol (GBD) administered intraperitoneally (ip) showed potential for efficacy in benzodiazepine-resistant status epilepticus (Example 3). This study will evaluate the potential for synergistic activity of gaboxadol with allopregnanolone, ganaxolone, or the benzodiazepine, lorazepam (LZP) in benzodiazepine-resistant status epilepticus in the Li-Pilo rat model. In particular, low doses (e.g., 0.5 mg / kg) of gaboxadol will be administered in combination with fixed doses of allopregnanolone, ganaxolone, or lorazepam. The doses of allopregnanolone and ganaxolone will be those doses previously found to confer anticonvulsant effects in Example 3 (Table 2). The dose of lorazepam will be 2 mg / kg (Walton and Treiman, 1990, Neurology 40:990-994 1990). The activity of each compound will also be evaluated individually. A vehicle-treated group will be included. A single ip dose of each dose or dose combination (Table 3) will be administered to rats (n=13 / group) 30 min after the onset of status epilepticus. The rats will be observed for the presence or absence of further convulsive activity.

[0203] Table 3. Study compounds and combinations to be evaluated (n=13 rats / treatment group, of which n=3 rats were sacrificed for PK analysis).

[0204]

[0205] Male Sprague Dawley rats (n=13 treatments or treatments / group; from Charles River Laboratories, 100-125 g on arrival) were treated systemically with lithium chloride (127 mg / kg; ip) 24 hours prior to administration of the chemical convulsant pilocarpine. On the second day, the rats received pilocarpine hydrochloride (50 mg / kg; (ip)) and were carefully monitored for the presence or absence of convulsive seizure activity. Administration of pilocarpine induced behavioral seizures within 5-20 min, and any rat that did not exhibit convulsive seizure activity within 45 min of pilocarpine administration was excluded from further study. On the day of the study, the ability of each study compound (allopregnanolone, ganaxolone, or gaboxadol) or vehicle (VEH) administered 30 min after the first observed convulsive seizure (as summarized in Table 3) to prevent convulsive status epilepticus in the Li-Pilo model of status epilepticus was evaluated. Throughout the study, the experimenter performing the behavioral observations was blinded to the treatment condition (i.e., allopregnanolone, ganaxolone or gaboxadol, lorazepam or VEH). All rats were observed and scored for seizure severity 120 min after drug administration and any accompanying behavioral effects were also recorded by the experimenter blinded to the treatment condition. At the end of the behavioral observation period, all surviving rats were administered a 3 ml injection of lactated Ringer's solution to replace any status epilepticus-induced fluid losses.

[0206] For a total of 130 rats, each dose of the study compound will be administered to rats (n=13 / compound dose; Table 3). For rats pretreated with Li-Cl, but not developing convulsive status epilepticus within a 45-minute period, the expected non-response rate is 15%. Therefore, up to 150 rats will be used for this study, including potential non-responders. All animals in this study will be retained for 24 hours after the completion of the study for evaluation of body weight change and overall behavioral performance (e.g., lethargic / active) at that time. Behavioral performance will be evaluated by a researcher who is blinded to treatment status.

[0207] Pharmacokinetic Sample Collection: Brain and plasma will be collected from the rat cohort for each dose for evaluation (n=3 rats / dose / compound). Plasma will be separated from trunk blood after centrifugation at 10,000×g for 10 min at 4°C. The anticoagulant will be lithium heparin. Brain will be snap frozen on dry ice. Test procedure timeline as follows Figure 7 shown.

[0208] 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. Such equivalents are intended to be encompassed by the claims.

[0209] This application provides the following:

[0210] Item 1. A method for treating epileptic disorders, the method comprising administering a pharmaceutical composition comprising an allosteric modulator to a patient in need thereof.

[0211] Item 2. A method according to Item 1, wherein the epileptic disorder is selected from the group consisting of epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Ohtawara syndrome, Rasmussen syndrome, West syndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute recurrent epileptic seizures, benign Rolando epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, increased seizure activity or paroxysmal seizures.

[0212] Item 3. A method according to Item 1, wherein the epileptic disorder is status epilepticus.

[0213] Item 4. A method according to Item 1, wherein the epileptic disorder is acute recurrent epileptic seizures.

[0214] Item 5. A method according to Item 1, wherein the epileptic disorder is Lennox-Gastaut syndrome.

[0215] Item 6. The method of Item 1, wherein the composition provides a reduction in seizure frequency, seizure severity, or a combination thereof in a patient diagnosed with an epileptic disorder.

[0216] Item 7. The method according to Item 1, wherein the allosteric modulator is selected from the group consisting of neurosteroids, benzodiazepines and potassium channel openers.

[0217] Item 8. The method according to Item 1, wherein the allosteric modulator is ganaxolone.

[0218] Item 9. A method according to Item 1, wherein the allosteric modulator is allopregnanolone.

[0219] Item 10. A method according to Item 1, wherein the allosteric modulator is a benzodiazepine.

[0220] Item 11. The method according to Item 10, wherein the benzodiazepine is selected from the group consisting of midazolam, clobazam, clonazepam, diazepam, lorazepam, flurazepam and lorazepam.

[0221] Item 12. A method according to Item 1, wherein the allosteric modulator is a potassium channel opener.

[0222] Item 13. The method according to Item 12, wherein the potassium channel opener is retigabine or flupirtine.

[0223] Item 14. The method according to Item 1, wherein the patient is also administered gaboxadol or a pharmaceutically acceptable salt thereof.

[0224] Item 15. The method according to Item 1, wherein the allosteric modulator is administered once a day, twice a day, three times a day, or every other day.

[0225] Item 16. The method according to Item 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, tadalafil and zonisamide.

[0226] Item 17. The method according to Item 1, wherein the pharmaceutical composition is a parenteral preparation.

[0227] Item 18. A method for treating epileptic disorders, the method comprising administering a pharmaceutical composition comprising gaboxadol or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0228] Item 19. A method according to Item 18, wherein the epileptic disorder is selected from the group consisting of epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Ohtawara syndrome, Rasmussen syndrome, West syndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute recurrent epileptic seizures, benign Rolando epilepsy, status epilepticus, refractory status epilepticus, super refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, increased seizure activity or paroxysmal seizures.

[0229] Item 20. A method according to Item 18, wherein the epileptic disorder is status epilepticus.

[0230] Item 21. A method according to Item 18, wherein the epileptic disorder is acute recurrent epileptic seizures.

[0231] Item 22. A method according to Item 18, wherein the epileptic disorder is Lennox-Gastaut syndrome.

[0232] Item 23. A method according to Item 18, wherein the composition provides a reduction in seizure frequency, seizure severity, or a combination thereof in a patient diagnosed with an epileptic disorder.

[0233] Item 24. A method according to Item 18, wherein the patient is also administered an allosteric modulator.

[0234] Item 25. The method according to Item 24, wherein the allosteric modulator is selected from the group consisting of neurosteroids, benzodiazepines and potassium channel openers.

[0235] Item 26. The method of Item 24, wherein the allosteric modulator is ganaxolone.

[0236] Item 27. A method according to Item 24, wherein the allosteric modulator is allopregnanolone.

[0237] Item 28. A method according to Item 24, wherein the allosteric modulator is a benzodiazepine.

[0238] Item 29. The method according to Item 28, wherein the benzodiazepine is selected from the group consisting of midazolam, clobazam, clonazepam, diazepam, lorazepam, flurazepam and lorazepam.

[0239] Item 30. A method according to Item 24, wherein the allosteric modulator is a potassium channel opener.

[0240] Item 31. The method according to Item 30, wherein the potassium channel opener is retigabine or flupirtine.

[0241] Item 32. The method according to Item 18, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, or every other day.

[0242] Item 33. The method according to Item 32, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is administered immediately after the onset of an epileptic seizure.

[0243] Item 34. The method according to Item 32, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is administered after the onset of warning signs of an epileptic seizure.

[0244] Item 35. The method according to Item 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, tadalafil and zonisamide.

[0245] Item 36. The method according to Item 18, wherein the pharmaceutical composition is a parenteral preparation.

[0246] Item 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.

[0247] Item 38. A pharmaceutical composition for parenteral administration, comprising about 0.05 mg to about 100 mg of gaboxadol or a pharmaceutically acceptable salt thereof.

[0248] Item 39. The pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the gaboxadol or a pharmaceutically acceptable salt thereof is present in a molar concentration of less than about 10.0M.

[0249] Item 40. The pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the solubility of gaboxadol or its salt in the composition is between about 1 mg / ml and about 50 mg / ml.

[0250] Item 41. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the pharmaceutical composition exhibits a maximum plasma concentration time (Tmax) of gaboxadol of about 1 hour or more after administration of the parenteral dosage form. max ).

[0251] Item 42. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein parenteral administration of the composition provides an average AUC of more than about 25 ng·hr / ml 0-∞ In vivo plasma profile of gaboxadol.

[0252] Item 43. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein parenteral administration of the composition provides an average C of less than about 10000 ng / ml. max In vivo plasma profile of gaboxadol.

[0253] Item 44. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein parenteral administration exhibits a pharmacokinetic profile comprising the following after administration of the parenteral composition: T max ; followed by at least 50% of the duration of about 90 minutes to about 360 minutes C max plasma drug concentration.

[0254] Item 45. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is contained in a bag, a glass vial, a plastic vial or a bottle.

[0255] Item 46. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is aqueous.

[0256] Item 47. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is ready for use.

[0257] Item 48. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is sufficiently soluble.

[0258] Item 49. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises an excipient selected from the group consisting of a buffer, a solubilizer, a tonicity agent, an antioxidant, a chelating agent, an antimicrobial agent and a preservative.

[0259] Item 50. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises an excipient, wherein the excipient is present in a weight percentage (w / v) of less than about 10%.

[0260] Item 51. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises an excipient, wherein the excipient is present in a weight percentage (w / v) between about 0.01% and about 10%.

[0261] Item 52. The pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the excipient is present in a molar ratio of excipient to gaboxadol or a pharmaceutically acceptable salt thereof of about 0.1:1 to about 0.25:1.

[0262] Item 53. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition comprises an excipient including a stabilizing amount of a buffer.

[0263] Item 54. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is at a pH of about 4 to about 8.

[0264] Item 55. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is at a pH of about 6 to about 8.

[0265] Item 56. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is an aqueous solution, and the pH of the aqueous solution is from about 6.8 to about 7.8.

[0266] Item 57. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises sodium chloride at a concentration between about 0.01 and about 2.0 weight percent.

[0267] Item 58. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition further comprises sodium chloride at a concentration of about 0.9 weight percent.

[0268] Item 59. The pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is formulated into a total volume selected from the group consisting of 20 ml, 50 ml and 100 ml.

[0269] Item 60. The pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition is prepared for subcutaneous, intramuscular, transdermal or intravenous administration.

[0270] Item 61. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition comprises an excipient which is a stabilizing amount of a solubilizer.

[0271] Item 62. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition shows no detectable chemical degradation after one month at 40°C.

[0272] Item 63. A pharmaceutical composition for parenteral administration according to Item 37 or 38, wherein the composition can be stored under ambient conditions and remain clear and colorless for at least about 12 weeks.

Claims

1. Use of ganaxolone or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating CDKL5 disorder in a patient in need thereof.

2. The use according to claim 1, wherein the pharmaceutical composition comprises 200 mg to 600 mg of ganaxolone or a pharmaceutically acceptable salt thereof.

3. The use according to claim 1, wherein the pharmaceutical composition is a composition for intravenous administration, wherein intravenous administration of the pharmaceutical composition provides a plasma concentration of ganaxolone of less than 900 ng·hr / ml.

4. The use according to any one of claims 1 to 3, wherein When the pharmaceutical composition is used, 1 mg to 2500 mg of ganaxolone is administered to a human patient over a 24 hour period to treat a CDKL5 disorder.

5. The use according to any one of claims 1 to 4, wherein The total amount of ganaxolone administered in a 24 hour period was less than 2000 mg.

6. The use according to any one of claims 1 to 4, wherein The total amount of ganaxolone administered in a 24 hour period was less than 1500 mg.

7. The use of claim 1, wherein the ganaxolone or a pharmaceutically acceptable salt thereof is administered as an intravenous infusion to maintain a plasma concentration of ganaxolone of less than 650 ng·hr / ml.

8. The use according to any one of claims 1 to 7, wherein the total amount of ganaxolone administered is 700 mg / day.

9. The use according to any one of claims 1 to 7, wherein the total amount of ganaxolone administered is 650 mg / day.

10. The use according to any one of claims 1 to 7, wherein the total amount of ganaxolone administered is 500 mg / day.

11. The use according to any one of claims 1 to 7, wherein the patient is a human patient.

12. The use according to claim 1, wherein the pharmaceutical composition is a suspension for oral administration.

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