INTRAVENOUS GANAXOLONE FORMULATIONS AND METHODS OF USE IN TREATING STATUS EPILEPTICUS AND OTHER SEIZURE DISORDERS
The disclosure provides an injectable ganaxolone formulation comprising ganaxolone, sulfobutyl ether-β-cyclodextrin; and water. The injectable ganaxolone formulation optionally includes a surfactant and a pH modifier. The ganaxolone and sulfobutyl ether-β-cyclodextrin may be in an inclusion complex. The disclosure also provides a lyophilized powder of the ganaxolone/sulfobutyl ether-β-cyclodextrin formulation that may be reconstituted in water for injection. The disclosure provides a method of treating a patient having a seizure disorder, stroke, or traumatic brain injury, comprising administering an effective amount of the injectable ganaxolone formulation comprising ganaxolone, sulfobutyl ether-β-cyclodextrin; and water. The disclosure also provides combination methods in which the injectable ganaxolone/sulfobutyl ether-β-cyclodextrin formulation is administered in combination with at least one additional active agent.
1 . An aqueous injectable ganaxolone formulation comprising
a) ganaxolone and sulfobutyl ether-β-cyclodextrin in an inclusion complex; and
b) water.
2 . The formulation of claim 1 , wherein the complex comprising ganaxolone and sulfobutyl ether-β-cyclodextrin comprises a 1:1 ganaxolone:sulfobutyl ether-β-cyclodextrin complex.
3 . The formulation of claim 1 or 2 , wherein the ganaxolone concentration is about 0.1 mg/mL to about 15 mg/mL.
4 . The formulation of any one of claims 1 - 3 , additionally comprising a 0.5% to 1.5% concentration of sodium chloride in the formulation.
5 . The formulation of any one of claims 1 - 4 , wherein the w/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is about 52:1 or greater.
6 . The formulation of any one of claims 1 - 4 , wherein the w/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is within the range from about 52:1 to about 80:1.
7 . The formulation of claim 6 , wherein the w/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is about 55:1.
8 . The formulation of any one of claims 1 - 7 , comprising 5 mg/mL to 800 mg/ml sulfobutyl ether-β-cyclodextrin.
9 . The formulation of any one of claim 1 - 8 , comprising a surfactant.
10 . The formulation of claim 9 , wherein the surfactant is a sorbitan ester, a polyoxyethylene sorbitan fatty acid ester, a poloxamer, a cholesterol salt, or a bile salt.
10 . formulation of claim 10 , wherein the formulation is about 0.5 to about 15 weight percent surfactant.
12 . The formulation of claim 11 , wherein the surfactant is polysorbate 80.
13 . The formulation of any one of claims 1 - 12 , having a pH in the range of approximately 2.5-11.0.
14 . The formulation of any one of claims 1 - 13 , additionally comprising a buffer.
15 . The formulation of claim 14 , having a pH of about 6.8 to about 7.6.
16 . The formulation of claim 14 or 15 , wherein the buffer is a phosphate buffer.
17 . The formulation of claim 16 , wherein the buffer is phosphate buffered saline.
18 . The formulation of claim 16 , wherein the buffer is a combination of a monobasic phosphate buffer and a dibasic phosphate buffer, wherein the concentration of each phosphate buffer is 2 mM to 50 mM.
19 . The formulation of claim 1 , wherein
the concentration of ganaxolone is 2 mg/ml to 8 mg/ml,
the w/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is within the range from about 52:1 to about 90:1;
the formulation contains a buffer and has a pH of 6.7 to 7.3; and
the formulation contains from 0.5 to 15 weight percent surfactant.
20 . The formulation of claim 1 , wherein
the concentration of ganaxolone is 1 mg/ml to 5 mg/ml;
the weight percent of sulfobutyl ether-β-cyclodextrin 25% to 35%; and
the formulation contains from 5% to 15% (weight percent) of at least one of the following: a surfactant, ethanol, glycerin or propylene glycol.
21 . The formulation of any one of claims 1 to 19 , additionally comprising a preservative.
22 . The formulation of claim 20 , wherein the preservative is benzyl alcohol, chlorbutanol, 2-ethoxyethanol, parabens (including methyl, ethyl propyl, butyl, and combinations), benzoic acid, sorbic acid, chlorhexidene, phenol, 3-cresol, thimerosal, or a phenylmercurate salt.
23 . The formulation of claim 22 , wherein the inclusion complex provides at least 2.0 mg/mL ganaxolone, when the amount of ganaxolone provided by the complex is measured at a sulfobutyl ether-β-cyclodextrin concentration of about 30% w/v in water.
24 . A lyophilized ganaxolone formulation comprising ganaxolone and sulfobutyl ether-β-cyclodextrin, wherein the ganaxolone formulation is 1.0% to 1.5% ganaxolone.
25 . A lyophilized ganaxolone formulation comprising the ganaxolone formulation of any one of claims 1 to 23 .
26 . The lyophilized ganaxolone formulation of claim 25 , additionally comprising one or more of a surfactant, a buffer, and a preservative.
27 . The lyophilized ganaxolone formulation of any one of claims 24 to 26 , wherein the lyophilized ganaxolone formulation can be reconstituted in water to provide a clear solution.
28 . The lyophilized ganaxolone formulation of claim 27 , additionally comprising a bulking agent.
29 . The lyophilized ganaxolone formulation of claim 28 , wherein the bulking agent is mannitol, lactose, sucrose, trehalose, sorbitol, glucose, rafinose, glycine, histidine, polyethylene glycol (PEG), or polyvinyl pyrrolidone (PVP).
30 . A method of treating a patient having a seizure disorder, stroke, or traumatic brain injury, the method comprising administering a therapeutically effective amount of the ganaxolone formulation of any one of claims 1 to 29 .
31 . The method of claim 30 , wherein the seizure disorder is status epilepticus, refractory status epilepticus, super refractory status epilepticus, or PCDH19 female pediatric epilepsy.
32 . The method of claim 30 or 31 wherein the amount of ganaxolone administered is from about 1 mg/kg to about 200 mg/kg.
33 . The method of any one of claims 30 to 32 wherein the ganaxolone formulation is administered intramuscularly or intravenously.
34 . The method of any one of claims 30 to 33 comprising administering a single bolus dose of the ganaxolone formulation to the patient.
35 . The method of claim 34 wherein the bolus dose provides a sufficient amount of ganaxolone to provide a plasma C max of ganaxolone of about 100 ng/mL to about 1000 ng/mL in the patient.
36 . The method of claim 34 , wherein the bolus dose provides a sufficient amount of ganaxolone to provide a plasma C max of ganaxolone of about 600 ng/mL to about 900 ng/mL in the patient.
37 . The method of any one of claims 34 to 36 , wherein the bolus dose in administered in less than 10 minutes and Cmax occurs within 1 hour of completion of administration.
38 . The method of claim 34 , wherein the single bolus dose comprises from about 1 mg/kg to about 20 mg/kg ganaxolone.
39 . The method of any one of claims 30 to 33 comprising administering multiple bolus doses of the ganaxolone formulation to the patient.
40 . The method of claim 39 wherein the multiple bolus doses are given over 1 to 10 days at intervals of 1 to 24 hours.
41 . The method of claim 39 wherein each bolus dose provides a sufficient amount of ganaxolone to produce a plasma C max of ganaxolone of about 100 ng/mL to about 1000 ng/mL in the patient.
42 . The method of claim 41 , wherein the interval between bolus doses is from about 10 to about 24 hours and once an initial C max is reached the plasma concentration of ganaxolone is not below 100 ng/mL at any time between bolus doses.
43 . The method of claim 41 , wherein the interval between bolus doses is from about 20 to about 24 hours and once an initial C max is reached the concentration of ganaxolone in the patient's plasma does not fall below 25% of the initial C max at any time between bolus doses.
44 . The method of any one of claims 39 to 43 wherein each bolus dose comprises about 1 mg/kg to about 20 mg/kg ganaxolone.
45 . The method of any one of claims 30 to 32 comprising administering an intravenous infusion of the ganaxolone formulation to the patient, with or without an initial bolus dose.
46 . The method of claim 45 comprising administering the intravenous infusion for 1 to 10 consecutive days at a rate of 1 to 10 mg/kg/hr without an initial bolus dose.
47 . The method of claim 45 comprising administering an initial bolus dose of from about 1 mg/kg to about 20 mg/kg ganaxolone, followed within 24 hours by administration of an intravenous infusion of the ganaxolone formulation for 1 to 10 consecutive days at a rate of 1 to 10 mg/kg/hr.
48 . The method of claim 47 , wherein the initial bolus dose provides a sufficient amount of ganaxolone to provide an initial plasma C max of ganaxolone of about 100 ng/mL to about 1000 ng/mL in the patient and the concentration of ganaxolone in the patient's plasma does not fall below 25% of the initial C max until after the infusion is concluded.
49 . The method of claim 47 , wherein the initial bolus dose provides a sufficient amount of ganaxolone to provide an initial plasma C max of ganaxolone of about 100 ng/mL to about 1000 ng/mL in the patient, the patient is then administered an intravenous infusion of the ganaxolone formulation at a constant dose sufficient to provide a concentration of ganaxolone in the patient's plasma of at least 40% of C max , followed by an intravenous infusion of ganaxolone formulation at a gradually reducing dose so that the concentration of ganaxolone in the patient's plasma is less than 20% of C max when the intravenous infusion is concluded.
50 . The method any one of claims 30 to 49 wherein the ganaxolone formulation is a first active agent and is administered concurrently or sequentially with at least one additional active agent.
51 . The method of claim 50 wherein the at least one additional active agent is an anticonvulsant or anesthetic/sedative.
52 . The method of claim 51 wherein the at least one additional active agent is an anticonvulsant chosen from a GABAA A receptor modulator, a sodium channel blocker, a GAT-1 GABA transporter modulator, a GABA transaminase modulator, a voltage-gated calcium channel blocker, and a peroxisome proliferator-activated alpha modulator.
53 . The method of claim 51 wherein the at least one additional active agent is an anesthetic/sedative chosen from an inhalational anesthetics (including desflurane, enflurane, ethyl chloride, halothane, isoflurane, methoxyflurane, sevoflurane, and trichloroethylene), an intravenous, non-barbiturate anesthetics (including atracurium, cisatracurium, etodimidate, ketamine, propofol, and rocuronium), a barbiturate anesthetic (including amobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, thiamylal, and thiopental), and a benzodiazepine anesthetic (including diazepam, flunitrazepam, lorazepam, and midazolam).
54 . The method of claim 51 , wherein the additional active agent is an anesthetic/sedative and the patient is given a sufficient dosage of the anesthetic/sedative to induce coma.
55 . The method of claim 54 , wherein the additional active agent is a barbiturate.
56 . The method of claim 54 , wherein the additional active agent is pentobarbital or thiopental.
57 . The method of claim 54 , wherein the additional active agent is propofol.
58 . The method of claim 50 , wherein a first additional active agent is an anticonvulsant and a second additional active agent is an anesthetic/sedative.
59 . The method of claim 58 , wherein the anticonvulsant is carbamazepine, tiagabine, levetiracetam, lamotrigine, pregabalin, gabapentin, or phenytoin and the anesthetic/sedative is pentobarbital, thiopental, or propofol.