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 - 59 . (canceled)
60 . A method of treating status epilepticus comprising administering to a human subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ganaxolone; wherein the pharmaceutical composition is administered as an intravenous bolus and a continuous intravenous infusion.
61 . The method of claim 60 , wherein the subject has refractory status epilepticus.
62 . The method of claim 60 , wherein the subject has super refractory status epilepticus.
63 . The method of claim 60 , wherein status epilepticus is suppressed for at least 5 hours.
64 . The method of claim 60 , wherein status epilepticus is suppressed about 15 minutes after administration of the intravenous ganaxolone formulation.
65 . The method of claim 60 , wherein the subject is monitored by electroencephalogram (EEG).
66 . The method of claim 60 , wherein seizure activity in the subject is monitored by EEG.
67 . The method of claim 60 , wherein the intravenous ganaxolone formulation is administered with at least one or more additional active agents.
68 . The method of claim 69 , wherein the additional active agent is an anticonvulsant agent.
69 . The method of claim 60 , wherein the intravenous bolus produces a ganaxolone plasma C max of about 600 ng/ml to about 900 ng/ml in the subject and the continuous infusion maintains the ganaxolone plasma concentration of at least about 25% of ganaxolone plasma C max in the subject for the duration of the infusion.
70 . The method of claim 60 , wherein the pharmaceutical composition is an aqueous solution.
71 . The method of claim 60 , wherein the pharmaceutical composition is not a suspension.
72 . The method of claim 60 , wherein the pharmaceutical composition further comprises a cyclodextrin.
73 . The method of claim 60 , wherein the concentration of ganaxolone in the pharmaceutical composition is about 1 mg/ml to about 5 mg/ml.
74 . The method of claim 75 , wherein the cyclodextrin comprises a sulfobutyl ether-β-cyclodextrin and the w/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is about 52:1 to about 70:1.
75 . The method of claim 77 , wherein the cyclodextrin comprises a sulfobutyl ether-β-cyclodextrin and the w/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is about 60:1.
76 . The method of claim 77 , wherein the cyclodextrin comprises a sulfobutyl ether-β-cyclodextrin and the w/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is about 70:1.
77 . An aqueous injectable ganaxolone formulation comprising:
a) ganaxolone in an amount of about 1 mg/ml;
b) sulfobutyl ether-β-cyclodextrin; and
d) a buffer selected from
i) a phosphate; or
ii) a citrate buffer;
wherein the ganaxolone and sulfobutyl ether-β-cyclodextrin form an inclusion complex, the w/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is about 52:1 to about 70:1, and the aqueous injectable formulation has a pH of about 6.01-7.10.
78 . The aqueous injectable ganaxolone formulation of claim 60 , wherein the inclusion complex comprises a ratio of one ganaxolone molecule to one sulfobutyl ether-β-cyclodextrin molecule.
79 . The aqueous injectable ganaxolone formulation of claim 60 , wherein the w/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is about 60:1.
80 . The aqueous injectable ganaxolone formulation of claim 60 , wherein the formulation is formulated for intravenous administration.