RU2824132C2 - Methods of treatment of epilepsy or status epilepticus - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: invention is intended for the preparation of a composition containing allopregnanolone. A method of preparing a formulation containing allopregnanolone includes providing a high shear mixing step for an aqueous formulation containing 5 mg/mL of allopregnanolone and 25% sulfobutyl ether β-cyclodextrin.

EFFECT: use of the invention makes it possible to prepare an allopregnanolone composition that can be used to treat epilepsy or status epilepticus.

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Description

STATEMENT OF PRIORITY

This application claims priority to U.S. Provisional Patent Application No. 61/691,545, filed August 21, 2012, and U.S. Provisional Patent Application No. 61/789,491, filed March 15, 2013, the contents of which are incorporated herein by reference in their entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention generally relates to methods of treating epilepsy or status epilepticus by administering a neuroactive steroid.

ESSENCE OF THE INVENTION

Methods are described for treating epilepsy or status epilepticus, such as convulsive status epilepticus, such as incipient status epilepticus, advanced status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; periodic lateralized epileptiform discharges; convulsive seizure, such as acute recurrent seizures, cluster seizures, the method comprising administering to the individual a neuroactive steroid. In one aspect, the invention relates to a method of treating an individual having epilepsy or status epilepticus by administering to the individual a neuroactive steroid and a benzodiazepine in combination. In some embodiments, the method further comprises administering at least one of a neuroactive steroid or a benzodiazepine parenterally (e.g., intranasally, buccally, intravenously, or intramuscularly, such as intravenously or intramuscularly). In some embodiments, both the neuroactive steroid and the benzodiazepine are administered parenterally.

In some embodiments, the neuroactive steroid and the benzodiazepine are administered together (e.g., administered simultaneously). In some embodiments, the neuroactive steroid and the benzodiazepine are administered sequentially. In some embodiments, the neuroactive steroid and the benzodiazepine are administered in a single dosage form.

When the substances described herein (e.g., a neuroactive steroid and a benzodiazepine) are administered in combination, both substances should be present in doses of about 1 to 100%, and more preferably about 5 to 95%, of the dose normally administered without the combination regimen. The substances may be administered separately, as part of a multiple-dose regimen. Alternatively, the substances may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition.

In some embodiments, the neuroactive steroid is a progestin derivative, such as allopregnanolone. In an embodiment, the neuroactive steroid is allopregnanolone.

In some embodiments, a neuroactive steroid, such as allopregnanolone, is formulated for parenteral administration (e.g., intranasally, buccally, intravenously, or intramuscularly, such as intravenously or intramuscularly).

In some embodiments, a neuroactive steroid, e.g., allopregnanolone, is administered in a composition comprising a complex of a cyclodextrin, e.g., a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®.

In some embodiments, the cyclodextrin is β-cyclodextrin. In an embodiment, the cyclodextrin is sulfobutyl ether β-cyclodextrin. In an embodiment, the cyclodextrin is CAPTISOL®. In some embodiments, the cyclodextrin is β-cyclodextrin described in U.S. Patent Nos. 5,874,418; No. 6,046,177; or No. 7,635,733, which are incorporated herein by reference.

In some embodiments, the neuroactive steroid is a progestin derivative, such as allopregnanolone, and the cyclodextrin is β-cyclodextrin. In an embodiment, the neuroactive steroid is allopregnanolone and the cyclodextrin is ^CAPTISOL® .

In some embodiments, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as a β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as ^CAPTISOL® , is included in a formulation for parenteral administration. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as a β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as ^CAPTISOL® , is included in an aqueous composition. In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., ^CAPTISOL® , is formulated in an aqueous composition comprising the neuroactive steroid at a concentration of 0.25-30 mg/mL, 0.5-30 mg/mL; 1-30 mg/mL; 5-30 mg/mL; 10-30 mg/mL; 15-30 mg/mL; 0.25-20 mg/mL; 0.5-20 mg/mL; 1-20 mg/mL; 0.5-20 mg/mL; l-20 mg/ml, 5-20 mg/ml, 10-20 mg/ml, 0.25-15 mg/ml, 0.5-15 mg/ml; 0.5-10 mg/ml; l-15 mg/ml, 1-10 mg/ml; l-5 mg/ml; 5-15 mg/ml; 5-10 mg/ml; 10-15 mg/ml; 1-10 mg/ml; 2-8 mg/ml; 2-7 mg/ml; 3-5 mg/ml; 5-15 mg/ml; 7-12 mg/ml; 7-10 mg/ml; 8-9 mg/ml; 3-5 mg/ml; or 3-4 mg/ml. In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising the neuroactive steroid at a concentration of 0.25 mg/mL; 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL; 3.0 mg/mL; 3.5 mg/mL; 4.0 mg/mL; 4.5 mg/mL; 5.0 mg/ml, 5.5 mg/ml, 6.0 mg/ml, 6.5 mg/ml, 7.0 mg/ml, 7.5 mg/ml, 8.0 mg/ml, 8.5 mg/ml, 9.0 mg/ml, 9.5 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml or 30 mg/ml. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as a β-cyclodextrin, such as a sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition containing the neuroactive steroid at a concentration of 1.5 mg/ml. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising the neuroactive steroid at a concentration of 5 mg/mL. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising the neuroactive steroid at a concentration of 15 mg/mL.

In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, at a concentration in the range of 25-400 mg/mL; 25-300 mg/mL; 25-200 mg/mL; 25-100 mg/mL; 25-50 mg/mL; 50-400 mg/mL; 50-300 mg/mL; 60-400 mg/mL; 60-300 mg/mL; 150-400 mg/ml; 150-300 mg/ml; 200-300 mg/ml; 200-400 mg/ml; 30-100 mg/ml; 300-400 mg/ml; 30-100 mg/ml; 45-75 mg/ml; 50-70 mg/ml; 55-65 mg/ml or 50-60 mg/ml. In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, at a concentration of 25 mg/mL; 30 mg/mL; 35 mg/mL; 40 mg/mL; 45 mg/mL; 50 mg/mL; 55 mg/mL; 60 mg/mL; 65 mg/mL; 70 mg/mL; 75 mg/mL; 80 mg/mL; 85 mg/mL; 90 mg/mL, 95 mg/mL; 100 mg/mL; 150 mg/mL; 200 mg/mL; 250 mg/mL; 300 mg/mL; 350 mg/mL; or 400 mg/mL. In an embodiment, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, at a concentration of 60 mg/mL. In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., ^CAPTISOL® , is formulated in an aqueous composition comprising 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30%, 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10%, 4.5-7.5%, 5-7%, 5.5-6.5% cyclodextrin, e.g., ^CAPTISOL® . In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., ^CAPTISOL® , is formulated in an aqueous composition comprising 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% cyclodextrin, e.g., ^CAPTISOL® . In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising 6% cyclodextrin. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as ^CAPTISOL® , is included in an aqueous composition comprising 15% cyclodextrin. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as a β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition containing 30% cyclodextrin.

In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition having a pH in the range of 3-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-9, 5-8, 5-7, 5-6, 4.5-7.5, or 5.5-7.5. In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition having a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. In an embodiment, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition having a pH of about 6.

In an embodiment, a composition comprising a complex of a neuroactive steroid, e.g. allopregnanolone, and a cyclodextrin, e.g. β-cyclodextrin, e.g. sulfobutyl ether β-cyclodextrin, e.g. β-cyclodextrin, e.g. sulfobutyl ether β-cyclodextrin, e.g. CAPTISOL®, comprises less than 100 ppm phosphate, and the cyclodextrin, e.g. β-cyclodextrin, e.g. sulfobutyl ether β-cyclodextrin, e.g. β-cyclodextrin, e.g. sulfobutyl ether β-cyclodextrin, e.g. CAPTISOL® has an absorption value of less than 0.2 op.u. due to the presence of a drug-destroying reagent, as determined by optical spectrometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, per ml of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, a cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfobutyl ether of β-cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfobutyl ether of β-cyclodextrin, e.g., CAPTISOL®, has an absorbance value of less than 0.2 op. u. due to the presence of a color-forming reagent, as determined by optical spectrometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfobutyl ether of β-cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfobutyl ether of β-cyclodextrin, e.g., CAPTISOL®, per ml of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, further comprises: less than 20 ppm sulfoalkylating agent; less than 0.5 wt.% non-derivatized cyclodextrin; less than 1 wt.% alkali metal halide; and less than 0.25 wt.% hydrolyzed sulfoalkylating agent.

In some embodiments, a cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfobutyl ether of β-cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfobutyl ether of β-cyclodextrin, e.g., CAPTISOL®, has an absorbance value of less than 0.2 opioid units due to the presence of a drug degrading reagent, as determined by optical spectrometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfobutyl ether of β-cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfobutyl ether of β-cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, further comprises: less than 50 ppm phosphate; less than 10 ppm sulfoalkylating agent; less than 0.2 wt.% non-derivatized cyclodextrin; less than 0.5 wt.% alkali metal halide; and less than 0.1 wt.% hydrolyzed sulfoalkylating agent; and wherein the cyclodextrin, for example β-cyclodextrin, for example sulfobutyl ether of β-cyclodextrin, for example β-cyclodextrin, for example sulfobutyl ether of β-cyclodextrin, for example CAPTISOL®, has an absorption value of less than 0.2 op. units due to the presence of a color-forming reagent, which was determined using optical spectrometry at a wavelength of from 320 nm to 350 nm for an aqueous solution containing 500 mg of cyclodextrin, for example β-cyclodextrin, for example sulfobutyl ether of β-cyclodextrin, for example β-cyclodextrin, for example sulfobutyl ether of β-cyclodextrin, for example CAPTISOL®, per ml of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, further comprises: less than 10 ppm phosphate; less than 2 ppm sulfoalkylating agent; less than 0.1 wt.% non-derivatized cyclodextrin; less than 0.2 wt.% alkali metal halide; and less than 0.08 wt.% hydrolyzed sulfoalkylating agent; and wherein the cyclodextrin, for example β-cyclodextrin, for example sulfobutyl ether of β-cyclodextrin, for example β-cyclodextrin, for example sulfobutyl ether of β-cyclodextrin, for example CAPTISOL®, has an absorption value of less than 0.1 op.u. due to the presence of a color-forming reagent, which was determined using optical spectrometry at a wavelength of from 320 nm to 350 nm for an aqueous solution containing 500 mg of cyclodextrin, for example β-cyclodextrin, for example sulfobutyl ether of β-cyclodextrin, for example β-cyclodextrin, for example sulfobutyl ether of β-cyclodextrin, for example CAPTISOL®, per ml of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, further comprises: less than 5 ppm phosphate; less than 0.1 wt.% alkali metal halide; and less than 0.05 wt.% hydrolyzed sulfoalkylating agent.

In some embodiments, a complex of a neuroactive steroid (e.g., allopregnanolone) and CAPTISOL® is included in an aqueous composition and administered within 10 hours, 8 hours, 5 hours, 3 hours, 1 hour, or 0.5 hours after a seizure, such as a seizure in status epilepticus, such as after a seizure in refractory status epilepticus has begun. In some embodiments, a complex of allopregnanolone and CAPTISOL® is included in an aqueous composition and administered within 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes after a seizure, such as a seizure in status epilepticus, such as after a seizure in refractory status epilepticus has begun. In some embodiments, a complex of a neuroactive steroid (e.g., allopregnanolone) and CAPTISOL® is included in an aqueous composition and administered after a seizure, e.g., a seizure in status epilepticus, e.g., after a seizure in refractory status epilepticus has lasted for 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, or 60 minutes.

In some embodiments, a complex of a neuroactive steroid (e.g., allopregnanolone) and CAPTISOL® is included in an aqueous composition and administered prior to the onset of a seizure, e.g., a seizure in status epilepticus, e.g., a seizure in refractory status epilepticus.

In some embodiments, the benzodiazepine is clonazepam, lorazepam, midazolam, or diazepam.

In some embodiments, the benzodiazepine is formulated for oral administration. In some embodiments, the benzodiazepine is formulated for parenteral administration (e.g., intranasally, buccally, intravenously, or intramuscularly, such as intravenously or intramuscularly).

In some embodiments, both the neuroactive steroid and the benzodiazepine are formulated for parenteral administration (e.g., intranasally, buccally, intravenously, or intramuscularly, such as intravenously or intramuscularly).

In some embodiments, a neuroactive steroid, such as allopregnanolone, and a benzodiazepine, when used in combination, are administered in an amount sufficient to achieve “burst-suppression” (e.g., a predetermined “burst-suppression” pattern, e.g., with interburst intervals of 2-30 seconds; as measured by neurophysiological monitoring, e.g., EEG, CDR). In some embodiments, a neuroactive steroid such as allopregnanolone and a benzodiazepine, when used in combination, are administered at a dose sufficient to achieve a predetermined burst-suppression pattern, such as interburst intervals of 2-30 seconds, 5-30 seconds, 10-30 seconds, 15-30 seconds, 1-30 seconds, 0-30 seconds, 2-20 seconds, 2-10 seconds, 5-20 seconds, 10-20 seconds, 15-25 seconds, 5-15 seconds, or 5-10 seconds; as measured by neurophysiological monitoring, such as EEG, CDR.

In one aspect, the invention relates to a method of treating an individual (e.g., a human individual) having a seizure disorder, e.g., status epilepticus (SE), e.g., refractory status epilepticus (RSE) or super-refractory status epilepticus (SRSE), comprising administering to said individual (e.g., a human individual), an effective amount of allopregnanolone, wherein simultaneously with said administration, said individual (e.g., a human individual) is under general anesthesia, thereby treating said individual (e.g., a human individual).

In one aspect, the invention relates to a method of treating an individual (e.g., a human individual) having a seizure disorder, e.g., status epilepticus (SE), e.g., refractory status epilepticus (RSE) or super-refractory status epilepticus (SRSE), comprising administering a first dose, e.g., a loading dose, of allopregnanolone, e.g., to a patient under general anesthesia; administering a second dose, e.g., a maintenance dose of allopregnanolone, which is lower than said first dose; and administering a third dose, e.g., a tapering dose of allopregnanolone, said doses of allopregnanolone being sufficient to treat said individual (e.g., a human individual).

In some embodiments, the individual (e.g., a human individual) is not under general anesthesia during at least a portion of the second dose. In some embodiments, the individual (e.g., a human individual) is not under general anesthesia during at least a portion of the third dose. In some embodiments, the individual (e.g., a human individual) is under general anesthesia during the administration of the first dose and during the administration of a portion of the second dose, such as for at least or up to 6, 12, 24, or 47 hours of the administration of the second dose.

In some embodiments, the second dose is administered over a period of time that is at least 60, 65, 70, 80, 90, 100, 110, 120 times longer than the period of time during which said first dose is administered. In some embodiments, the second dose is administered over a period of time that is no more than 80, 90, 100, 110, 120, 130, or 140 times longer than the period of time during which said first dose is administered.

In some embodiments, the second dose is administered over a period of time that is at least 2, 3, 4, 5, 6 times longer than the period of time during which said third dose is administered. In some embodiments, the second dose is administered over a period of time that is no more than 5, 6, 7, 8, 9, or 10 times longer than the period of time during which said third dose is administered.

In some embodiments, the rate of administration, such as the amount of allopregnanolone delivered/unit time in the second dose, such as measured in mcg/kg/hour, is at least 2, 3, 4, 5, or 6 times lower than the rate of administration of the first dose.

In some embodiments, one, two, or all of the specified doses are administered by injection, such as by intravenous administration.

In some embodiments, the subject (e.g., a human subject) does not respond to a first-line therapy, such as a benzodiazepine (e.g., midazolam), such as evidenced by a failure to induce a burst-suppression pattern in the EEG, failure to control a seizure, continued paroxysmal activity on the EEG after 24 hours or more of first-line therapy, or failure to discontinue first-line therapy without recurrence of paroxysmal activity as evidenced by the EEG.

In some embodiments, the subject (e.g., a human subject) does not respond to a second-line therapy, such as phenytoin, fosphenytoin, valproate, phenobarbital, or levetiracetam, such as evidenced by a failure to induce a burst-suppression pattern in an EEG, failure to control a seizure, continued paroxysmal activity on an EEG recording after 24 hours or more using a first-line therapy, or failure to discontinue the first-line therapy without recurrence of paroxysmal activity as evidenced by an EEG.

In some embodiments, the method further comprises administering an anesthetic in an amount sufficient to place said individual (e.g., a human individual) under general anesthesia. In some embodiments, said anesthetic is selected from a benzodiazepine (e.g., midazolam), propofol, and pentobarbital.

In some embodiments, the method further comprises a "weaning off" period during which said individual (e.g., a human individual) is brought out of said general anesthesia. In some embodiments, said "weaning off" period begins at the time of administration of said second dose. In some embodiments, said "weaning off" period ends at the time of administration of said second dose. In some embodiments, said "weaning off" period begins within 12, 24, 36, 48, 60, or 72 hours after the start or completion of administration of the first dose of allopregnanolone. In some embodiments, said "weaning off" period begins 48 hours after the start or completion of administration of the first dose of allopregnanolone. In some embodiments, the duration of said "weaning off" period is from 18 to 30 hours, 20 to 28 hours, or from 22 to 26 hours. In some embodiments, the duration of said "weaning off" period is 24 hours.

In some embodiments, the administration of allopregnanolone, such as a first or loading dose, is started at a preselected time period, wherein said period begins with: administration of said anesthetic; or induction of general anesthesia. In some embodiments, said preselected time period is no more than 48, 24, 12, 6, 5, 4, 3, 2, or 1 hour. In some embodiments, said preselected time period is no more than 120, 60, 30, 15, or 5 minutes.

In some embodiments, the administration of said second dose is initiated while the subject (e.g., a human subject) is under general anesthesia. In some embodiments, the amount of allopregnanolone delivered per hour in said second dose is the same as or less than the amount delivered per hour in said first dose.

In some embodiments, the administration of the first dose of allopregnanolone is started at a preselected time period, wherein said period begins with: administration of said anesthetic or induction of general anesthesia. In some embodiments, said preselected period is at least 6, 12, 24, 48 or 60 hours. In some embodiments, said preselected period is no more than 24, 48 or 60 hours. In some embodiments, said preselected period is from 2 to 120, from 2 to 60, from 4 to 120, from 4 to 60, from 4 to 48, from 4 to 36, or from 4 to 24 hours. In some embodiments, said preselected period is no more than 48, 24, 12, 6, 5, 4, 3, 2 or 1 hour. In some embodiments, the specified pre-selected period is no more than 120, 60, 30, 15, or 5 minutes.

In some embodiments, administration of said first dose is commenced after the individual (e.g., a human individual) has failed to respond to a prior therapy. In some embodiments, the failure to respond is evidenced by one or more of, failure to induce a burst-suppression EEG pattern, failure to control a seizure, continued paroxysmal activity on the EEG after 24 hours or more using a first-line therapy, or failure to discontinue the first-line therapy without recurrence of paroxysmal activity as evidenced by the EEG. In some embodiments, said prior therapy includes the use of a first-line agent, such as a benzodiazepine (e.g., midazolam). In some embodiments, said prior therapy includes the use of a second-line agent, such as phenytoin, fosphenytoin, valproate, phenobarbital, or levetiracetam.

In some embodiments, said first dose is a loading dose, such as a bolus dose. In some embodiments, said first dose creates a plasma concentration of 50 to 500 nM, 100 to 400 nM, or 200 to 300 nM. In some embodiments, said first dose creates a plasma concentration of 500 to 1000 nM, 600 to 900 nM, or 700 to 800 nM. In some embodiments, said first dose creates a plasma concentration of 1000 to 1500 nM, 1100 to 1400 nM, or 1200 to 1300 nM. In some embodiments, said first dose creates a plasma concentration of 1500 to 2000 nM, 1600 to 1900 nM, or 1700 to 1800 nM. In some embodiments, said first dose creates a plasma concentration of 2000 to 2500 nM, 2100 to 2400 nM, or 2200 to 2300 nM. In some embodiments, said first dose creates a plasma concentration of 300 to 800 nM, 400 to 700 nM, or 500 to 600 nM. In some embodiments, said first dose creates a plasma concentration of 800 to 1300 nM, 900 to 1200 nM, or 1000 to 1100 nM. In some embodiments, said first dose creates a plasma concentration of 1300 to 1800 nM, 1400 to 1700 nM, or 1500 to 1600 nM. In some embodiments, said first dose creates a plasma concentration of 1800 to 2300 nM, 1900 to 2200 nM, or 2000 to 2100 nM. In some embodiments, said first dose creates a plasma concentration of 2300 to 2600 nM, 2400 to 2500 nM. In some embodiments, said first dose produces a plasma concentration of 300 to 400 nM, 400 to 500 nM, 600 to 700 nM, 800 to 900 nM, 1100 to 1200 nM, 1300 to 1400 nM, 1400 to 1500 nM, 1600 to 1700 nM, 1800 to 1900 nM, 1900 to 2000 nM, 2100 to 2200 nM, 2300 to 2400 nM. In some embodiments, said first dose creates a plasma concentration of 500 to 2500 nM, 500 to 1500 nM, 500 to 1000 nM, 500 to 800, or 500 to 600 nM. In some embodiments, said first dose creates a plasma concentration of 50 to 250 nM, 100 to 200 nM, or 140 to 160 nM. In some embodiments, said first dose creates a plasma concentration of 150+/-30 nM, 150+/-20 nM, 150+/-10 nM, or 150 nM.

In some embodiments, the plasma concentration after administration of said first dose is measured at a predetermined time, such as 10, 15, 20, 30, 45, 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours, 2, 3, 4 days after the start of administration of said first dose.

In some embodiments, said first dose is administered over a period of time that is no more than 6, 5, 4, 3, 2, or 1 hour. In some embodiments, said first dose is administered over a period of time that is at least 10, 20, 30, 40, 50, 60, 70, 80, or 90 minutes. In some embodiments, said first dose is administered over a period of time that is between 30 and 120 minutes, between 45 and 100 minutes, or between 50 and 70 minutes. In some embodiments, said first dose is administered over a period of time that is 60+/-15 minutes, 60+/-10 minutes, 60+/-5 minutes, or 60 minutes.

In some embodiments, said first dose is administered at a rate of 200-3500 mcg/kg/hour. In some embodiments, said first dose is administered at a rate of 200-350 mcg/kg/hour, 250-300 mcg/kg/hour, 280-290 mcg/kg/hour, 286 mcg/kg/hour, 287 mcg/kg/hour, or 288 mcg/kg/hour, such as over one hour.

In some embodiments, said second dose is a maintenance dose. In some embodiments, said second dose is started at a preselected time period, wherein said time period begins with the administration of said anesthetic. In some embodiments, said second dose is started at a preselected time period, wherein said time period begins with the induction of general anesthesia. In some embodiments, said second dose is started at a preselected time period, wherein said time period begins with the start of the first dose. In some embodiments, said second dose is started at a preselected time period, wherein said time period begins with the end of the first dose. In some embodiments, said second dose is started at a preselected time period, wherein said time period begins with the achievement of a predetermined level of allopregnanolone, for example, in plasma. In some embodiments, said time period begins with the end of the first dose. In some embodiments, said preselected period of time begins with the start or end of the first dose administration and is no more than 240, 180, 120, 60, 30, 15, or 5 minutes. In some embodiments, said preselected period of time begins with the start or end of the first dose administration and is no more than 90, 80, 70, or 60 minutes. In some embodiments, the second dose administration begins no later than 90, 80, 70, 60, or 30 minutes after the start or end of the first dose administration. In some embodiments, the second dose administration begins 50 to 70, 55 to 65, or 60 minutes after the start or end of the first dose administration. In some embodiments, the second dose administration begins no later than 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, 1 minute after the end of the first dose administration. In some embodiments, administration of the second dose begins at the end of administration of the first dose.

In some embodiments, the administration of the first dose and the initiation of the administration of the second dose are performed using the same delivery device, such as using the same cannula or reservoir.

In some embodiments, said second dose is administered over a period of time that is between 48 and 192 hours, between 60 and 144 hours, between 60 and 120 hours, between 80 and 110 hours, and between 90 and 100 hours. In some embodiments, said second dose is administered for 95+/-5 hours. In some embodiments, said second dose is administered for 95 hours.

In some embodiments, said second dose creates a plasma concentration of 50 to 500 nM, 100 to 400 nM, or 200 to 300 nM. In some embodiments, said second dose creates a plasma concentration of 500 to 1000 nM, 600 to 900 nM, or 700 to 800 nM. In some embodiments, said second dose creates a plasma concentration of 1000 to 1500 nM, 1100 to 1400 nM, or 1200 to 1300 nM. In some embodiments, said second dose creates a plasma concentration of 1500 to 2000 nM, 1600 to 1900 nM, or 1700 to 1800 nM. In some embodiments, said second dose creates a plasma concentration of 2000 to 2500 nM, 2100 to 2400 nM, or 2200 to 2300 nM. In some embodiments, said second dose creates a plasma concentration of 300 to 800 nM, 400 to 700 nM, or 500 to 600 nM. In some embodiments, said second dose creates a plasma concentration of 800 to 1300 nM, 900 to 1200 nM, or 1000 to 1100 nM. In some embodiments, said first dose creates a plasma concentration of 1300 to 1800 nM, 1400 to 1700 nM, or 1500 to 1600 nM. In some embodiments, said second dose creates a plasma concentration of 1800 to 2300 nM, 1900 to 2200 nM, or 2000 to 2100 nM. In some embodiments, said second dose creates a plasma concentration of 2300 to 2600 nM, 2400 to 2500 nM. In some embodiments, said second dose produces a plasma concentration of 300 to 400 nM, 400 to 500 nM, 600 to 700 nM, 800 to 900 nM, 1100 to 1200 nM, 1300 to 1400 nM, 1400 to 1500 nM, 1600 to 1700 nM, 1800 to 1900 nM, 1900 to 2000 nM, 2100 to 2200 nM, 2300 to 2400 nM. In some embodiments, said second dose creates a plasma concentration of 500 to 2500 nM, 500 to 1500 nM, 500 to 1000 nM, 500 to 800 nM, or 500 to 600 nM. In some embodiments, said second dose creates a plasma concentration of 50 to 250 nM, 100 to 200 nM, or 140 to 160 nM. In some embodiments, said second dose creates a plasma concentration of 150+/-30 nM, 150+/-20 nM, 150+/-10 nM, or 150 nM.

In some embodiments, the plasma concentration after administration of said second dose is measured at a pre-selected time, such as 10, 15, 20, 30, 45, 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours, 2, 3, 4 days after the start of administration of said second dose.

In some embodiments, said second dose creates a plasma concentration of 150 nM, for example, which is measured at a pre-selected time, for example, 10, 15, 20, 30, 45, 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours, 2, 3, 4 days after the start of administration of said second dose.

In some embodiments, said second dose is administered at a constant infusion rate, such as the amount of allopregnanolone administered/unit of time, throughout the administration of the second dose. In some embodiments, the infusion rate, such as the amount of allopregnanolone administered/unit of time, varies during the administration of the second dose. In some embodiments, said second dose is administered at an infusion rate, such as the amount of allopregnanolone/unit of time of 25-1500 mcg/kg/hour. In some embodiments, said second dose is administered at an infusion rate, such as the amount of allopregnanolone/unit of time of 25-150 mcg/kg/hour, 50-100 mcg/kg/hour, 75-100 mcg/kg/hour, 85 mcg/kg/hour, 86 mcg/kg/hour, or 87 mcg/kg/hour.

In some embodiments, said gradually decreasing dose comprises a steadily decreasing amount of allopregnanolone. In some embodiments, administering said gradually decreasing dose comprises administering a steadily decreasing amount of allopregnanolone/unit time. In some embodiments, administering said gradually decreasing dose comprises administering doses in multiple steps, wherein the dose of each subsequent step is lower than the dose of the step preceding it. In some embodiments, administering said gradually decreasing dose comprises administering doses in multiple steps, wherein the dose of each subsequent step delivers a lesser amount of allopregnanolone/unit time than the dose of the step preceding it.

In some embodiments, the method comprises administering a first, a second, and a third step dose. In some embodiments, said first step dose is between 60 and 90% of the second/maintenance dose; said second step dose is between 40 and 70% of the second/maintenance dose; and said third step dose is between 10 and 40% of the second/maintenance dose. In some embodiments, the amount of allopregnanolone delivered/unit time in said first step dose is between 60 and 90% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; the amount of allopregnanolone delivered/unit time in said second step dose is between 40 and 70% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; and the amount of allopregnanolone delivered/unit time in said third step dose is from 10 to 40% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose. In some embodiments, said first step dose is from 70 to 80% of the second/maintenance dose; said second step dose is from 40 to 60% of the second/maintenance dose; and said third step dose is from 20 to 30% of the second/maintenance dose. In some embodiments, the amount of allopregnanolone delivered/unit time in said first step dose is from 70 to 80% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; the amount of allopregnanolone delivered/unit time in said second step dose is from 40 to 60% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; and the amount of allopregnanolone delivered/unit time in said third step dose is from 20 to 30% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose. In some embodiments, said first step dose is 75% of the second/maintenance dose; said second step dose is 50% of the second/maintenance dose; and said third step dose is 25% of the second/maintenance dose. In some embodiments, the amount of allopregnanolone delivered/unit time in said first step dose is 75% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose. In some embodiments, the amount of allopregnanolone delivered/unit time in said second step dose is 50% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose. In some embodiments, the amount of allopregnanolone delivered/unit time in said third step dose is 25% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose.

In some embodiments, after completion of said third step dose administration, allopregnanolone is not administered to the individual (e.g., a human individual) for at least 10, 20, 30, 40, 50, or 60 days, or until the patient experiences a subsequent episode of SRSE.

In some embodiments, said first step dose is administered in an amount of allopregnanolone/unit time of 25-1000 mcg/kg/hour. In some embodiments, said first step dose is administered in an amount of allopregnanolone/unit time of 25-100 mcg/kg/hour, 50-75 mcg/kg/hour, 60-70 mcg/kg/hour, 63 mcg/kg/hour, 64 mcg/kg/hour, or 65 mcg/kg/hour. In some embodiments, said second step dose is administered in an amount of allopregnanolone/unit time of 10-700 mcg/kg/hour. In some embodiments, said second step dose is administered in an allopregnanolone/time unit amount of 10-70 mcg/kg/hour, 25-55 mcg/kg/hour, 40-50 mcg/kg/hour, 42 mcg/kg/hour, 43 mcg/kg/hour, or 44 mcg/kg/hour. In some embodiments, said third step dose is administered in an allopregnanolone/time unit amount of 5-500 mcg/kg/hour. In some embodiments, said third step dose is administered in an amount of allopregnanolone/unit time of 5-50 mcg/kg/hour, 10-35 mcg/kg/hour, 15-25 mcg/kg/hour, 20 mcg/kg/hour, 21 mcg/kg/hour, or 22 mcg/kg/hour.

In some embodiments, the third/tapering dose is started no later than 90, 80, 70, 60, or 30 minutes after the start of the second dose or the end of the second dose. In some embodiments, the third/tapering dose is started at the end of the second dose.

In some embodiments, the second dose is administered and the third/tapered dose is initiated using the same delivery device, such as the same cannula.

In some embodiments, the time between the end of administration of said first step dose and the start of administration of said second step dose is less than 120, 60, 30, 15, or 5 minutes.

In some embodiments, the time between the end of administration of said second step dose and the start of administration of said third step dose is less than 120, 60, 30, 15, or 5 minutes.

In some embodiments, said third dose is administered over a period of time that is from 10 to 100 hours, from 12 to 96 hours, from 12 to 48 hours, from 16 to 32 hours, or from 20 to 30 hours.

In some embodiments, said third dose is administered within 24 hours.

In some embodiments, allopregnanolone is present in a composition comprising a cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®. In some embodiments, allopregnanolone is present at a concentration of 0.1 to 10 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 1.25 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 2.5 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 3.75 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 5 mg/mL allopregnanolone.

In some embodiments, the cyclodextrin is present in the composition at a concentration of 1-30%, 2-18%, 10-15% by weight of cyclodextrin per volume of the composition. In some embodiments, the cyclodextrin is present in the composition at a concentration of 1, 2.5, 5, 10, 12, 13, 15, 30% by weight of cyclodextrin per volume of the composition. In some embodiments, the cyclodextrin is present in the composition at a concentration of 12% by weight of cyclodextrin per volume of the composition.

In some embodiments, the cyclodextrin is present in the composition at a concentration of 1-30%, 2-18%, 10-15% by weight of cyclodextrin per volume of the composition, and allopregnanolone is present at a concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL allopregnanolone. In some embodiments, the cyclodextrin is present in the composition at a concentration of 1, 2.5, 5, 10, 12, 13, 15, 30% by weight of the cyclodextrin per volume of the composition, and the allopregnanolone is present at a concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL allopregnanolone.

In some embodiments, the cyclodextrin is present in the composition at a concentration of 12% by weight of cyclodextrin per volume of the composition, and the allopregnanolone is present at a concentration of 5 mg/mL allopregnanolone. In some embodiments, the cyclodextrin is present in the composition at a concentration of 12% by weight of cyclodextrin per volume of the composition, and the allopregnanolone is present at a concentration of 3.75 mg/mL allopregnanolone. In some embodiments, the cyclodextrin is present in the composition at a concentration of 12% by weight of cyclodextrin per volume of the composition, and the allopregnanolone is used at a concentration of 2.5 mg/mL allopregnanolone. In some embodiments, the cyclodextrin is present in the composition at a concentration of 12% by weight of cyclodextrin per volume of the composition, and the allopregnanolone is present at a concentration of 1.25 mg/mL allopregnanolone.

In some embodiments, the method further comprises assessing the condition of the individual (e.g., a human individual), wherein the assessing comprises performing a continuous ECG recording. In some embodiments, the method further comprises assessing the condition of the individual (e.g., a human individual), wherein the assessing comprises performing an EEG. In some embodiments, the method further comprises assessing the condition of the individual (e.g., a human individual) in the form of a blood chemistry test (e.g., one or more of albumin, AST, ALT, bicarbonate, bilirubin, urea, calcium, chloride, creatine kinase, lipase, creatinine, magnesium, potassium, sodium, total protein, or glucose). In some embodiments, the method further comprises assessing the condition of the individual (e.g., a human individual) in the form of a complete blood count (e.g., one or more of the following: red blood cell count, hemoglobin, hematocrit, MCV, MCH, MCHC, platelet count, white blood cell count, including neutrophil, eosinophil, basophil, lymphocyte, or monocyte count). In some embodiments, the method further comprises assessing the condition of the individual (e.g., a human individual) in the form of serum allopregnanolone, progesterone, and 5α-dihydrotestosterone levels. In some embodiments, the method comprises comparing the observed value with a reference value.

In some embodiments, an assessment is made of the state of said individual (e.g., a human individual) with respect to a parameter described herein during said “weaning” period.

In one aspect, the invention relates to a method of treating an individual (e.g., a human individual) having SE, RSE, or SRSE, the method comprising: administering a first/loading, e.g., bolus dose concurrently with general anesthesia, wherein administration of said first dose: begins 2-120 hours after induction of general anesthesia; continues for 30-90 minutes; and causes an allopregnanolone plasma concentration of 100-2000 nM allopregnanolone; administering a second/maintenance dose, wherein administration of said second dose begins no later than 1-60 minutes after completion of administration of the second dose; continues for 1-6 days; and causes an allopregnanolone plasma concentration of 100-2000 nM allopregnanolone; administering a third tapering dose, wherein administration of said third tapering dose begins no later than 1-60 minutes after completion of administration of the third dose; continues for 10-100 hours; and results in a plasma allopregnanolone level of 0-1500 nM allopregnanolone; wherein the total administrations are provided in an amount sufficient to treat the specified individual (e.g., a human individual).

In some embodiments, the method includes administering a first/loading, such as bolus, dose simultaneously with general anesthesia, wherein the administration of said first dose: begins 2-120 hours after induction of general anesthesia; continues for 60+/-15 minutes; administering a second/maintenance dose, wherein the administration of said second dose begins no later than 30 minutes after completion of administration of the second dose; continues for 70 to 110 hours; administering a third gradually decreasing dose, wherein the administration of said third gradually decreasing dose begins no later than 1-60 minutes after completion of administration of the third dose; continues for 10-30 hours.

In some embodiments, the method includes administering a first/loading, such as bolus, dose simultaneously with general anesthesia, wherein the administration of said first dose: begins 2-120 hours after induction of general anesthesia; continues for 60+/-15 minutes; administering a second/maintenance dose, wherein the administration of said second dose begins no later than 30 minutes after completion of the administration of the second dose; continues for 70 to 110 hours; and administering a third gradually decreasing dose, wherein the administration of said third gradually decreasing dose begins no later than 1-60 minutes after completion of the administration of the third dose; continues for 24+/-2 hours, and said third, gradually decreasing dose includes a dose of the first, second, and third steps.

In some embodiments, the method comprises administering a first/loading, e.g., bolus dose simultaneously with general anesthesia, wherein the administration of said first dose continues for 60+/-15 minutes; administering a second/maintenance dose, wherein the administration of said second dose begins no later than 30 minutes after the end of the administration of the second dose; continues for 85 to 105 hours; administering a third tapering dose, wherein the administration of said third tapering dose begins no later than 1-60 minutes after the end of the administration of the third dose; continues for 10-30 hours; and the amount of allopregnanolone delivered/unit time in said first dose is from 70 to 80% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; the amount of allopregnanolone delivered/unit time in said second step dose is from 40 to 60% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; and the amount of allopregnanolone delivered/unit time in said third step dose is from 20 to 30% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose.

In some embodiments, the method comprises administering a first/loading, e.g., bolus dose simultaneously with general anesthesia, wherein the administration of said first dose continues for 60+/-5 minutes; administering a second/maintenance dose, wherein the administration of said second dose begins no later than 30 minutes after the end of the administration of the second dose; continues for 96+/-4 hours; administering a third tapering dose, wherein the administration of said third tapering dose begins no later than 1-60 minutes after the end of the administration of the third dose; continues for 24+/-2 hours; and the amount of allopregnanolone delivered/unit time in said first step dose is 75% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; the amount of allopregnanolone delivered/unit time in said second step dose is 50% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; and the amount of allopregnanolone delivered/unit time at the specified third step dose is 25% of the amount of allopregnanolone delivered/unit time at the specified second/maintenance dose.

In some embodiments, the method further comprises administering a composition selected from benzodiazepines (e.g., midazolam), propofol, barbiturates, and ketamine, in an amount sufficient to place said individual (e.g., a human individual) into a state of general anesthesia.

In one aspect, the invention relates to a kit comprising one or more of: an allopregnanolone preparation, such as multiple allopregnanolone preparations at concentrations suitable for use in a first, second and third dose; and instructions for use for treating an individual (e.g., a human individual) having a seizure disorder, such as status epilepticus (SE), such as super-refractory status epilepticus (SRSE).

In some embodiments, the kit further comprises a suitable diluent (e.g., water, saline, cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®).

In some embodiments, allopregnanolone is present at a concentration of 0.1-10 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 0.5-7.5 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 1-6 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 5 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 3.75 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 2.5 mg/mL allopregnanolone. In some embodiments, allopregnanolone is present at a concentration of 1.25 mg/mL allopregnanolone.

In one aspect, the invention relates to a method for preparing a series of dosages, the method comprising combining a diluent and allopregnanolone in dosage form proportions suitable for use as a first, second and one or more step doses for said third dose.

In one aspect, the invention relates to a method of controlling the amount of diluents and/or allopregnanolone flowing into or out of a delivery device, such as a catheter, reservoir, the method comprising changing, such as decreasing, the flow rate of allopregnanolone flowing into the delivery device to sequentially release two or more of the first dose, the second dose and one or more stepped doses of the third dose.

In one aspect, the invention relates to a method of treating an individual having a seizure, epilepsy, or status epilepticus by administering to the individual a combination of a neuroactive steroid and a benzodiazepine or an anesthetic/sedative. In some embodiments, the method further comprises administering at least one of said neuroactive steroid and the benzodiazepine or an anesthetic/sedative parenterally (e.g., intranasally, buccally, intravenously, or intramuscularly, such as intravenously or intramuscularly). In some embodiments, both the neuroactive steroid and the benzodiazepine or anesthetic/sedative are administered parenterally.

In some embodiments, the neuroactive steroid and the benzodiazepine or anesthetic/sedative are administered together (e.g., administered simultaneously, administered concurrently). In some embodiments, the neuroactive steroid and the benzodiazepine or anesthetic/sedative are administered sequentially. In some embodiments, the neuroactive steroid and the benzodiazepine or anesthetic/sedative are administered in a single dosage form.

When the substances described herein (e.g., a neuroactive steroid and a benzodiazepine or an anesthetic/sedative) are administered in combination, both substances should be present at dosage levels of from about 1 to 100%, and more preferably from about 5 to 95%, of the dose normally administered in the absence of a combination regimen. The substances may be administered separately, as part of a multiple-dose regimen. Alternatively, the substances may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition.

In some embodiments, the neuroactive steroid is a progestin derivative, such as allopregnanolone. In an embodiment, the neuroactive steroid is allopregnanolone.

In some embodiments, a neuroactive steroid, such as allopregnanolone, is formulated for parenteral administration (e.g., intranasally, buccally, intravenously, or intramuscularly, such as intravenously or intramuscularly).

In some embodiments, a neuroactive steroid, such as allopregnanolone, is administered in a composition comprising a cyclodextrin complex, such as a β-cyclodextrin, such as a sulfobutyl ether β-cyclodextrin, such as CAPTISOL®.

In some embodiments, the cyclodextrin is β-cyclodextrin. In an embodiment, the cyclodextrin is sulfobutyl ether β-cyclodextrin. In an embodiment, the cyclodextrin is CAPTISOL®. In some embodiments, the cyclodextrin is β-cyclodextrin described in U.S. Patent Nos. 5,874,418; 6,046,177; or 7,635,733, which are incorporated herein by reference.

In some embodiments, the neuroactive steroid is a progestin derivative, such as allopregnanolone, and the cyclodextrin is β-cyclodextrin. In some embodiments, the neuroactive steroid is a progestin derivative, such as allopregnanolone, and the cyclodextrin is sulfobutyl ether β-cyclodextrin. In an embodiment, the neuroactive steroid is allopregnanolone and the cyclodextrin is ^CAPTISOL® .

In some embodiments, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in a formulation for parenteral administration. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition. In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising the neuroactive steroid at a concentration in the range of 0.25-30 mg/mL, 0.5-30 mg/mL; 1-30 mg/mL; 5-30 mg/mL; 10-30 mg/mL; 15-30 mg/mL; 0.25-20 mg/mL; 0.5-20 mg/mL; 1-20 mg/mL; 0.5-20 mg/mL; 1-20 mg/ml, 5-20 mg/ml, 10-20 mg/ml, 0.25-15 mg/ml, 0.5-15 mg/ml; 0.5-10 mg/ml; 0.5-7 mg/ml; l-15 mg/ml, 1-10 mg/ml; 1-7 mg/ml; l-5 mg/ml; 5-15 mg/ml; 5-10 mg/ml; 10-15 mg/ml; 1-10 mg/ml; 2-8 mg/ml; 2-7 mg/ml; 3-5 mg/ml; 5-15 mg/ml; 3-7 mg/ml; 4-6 mg/ml; 7-12 mg/ml; 7-10 mg/ml; 8-9 mg/ml; 3-5 mg/mL; or 3-4 mg/mL. In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising the neuroactive steroid at a concentration of 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL; 3.0 mg/mL; 3.5 mg/mL; 4.0 mg/mL; 4.5 mg/mL; 5.0 mg/ml, 5.5 mg/ml, 6.0 mg/ml, 6.5 mg/ml, 7.0 mg/ml, 7.5 mg/ml, 8.0 mg/ml, 8.5 mg/ml, 9.0 mg/ml, 9.5 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml or 30 mg/ml. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as a β-cyclodextrin, such as a sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition containing the neuroactive steroid at a concentration of 1.5 mg/ml. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising the neuroactive steroid at a concentration of 2.5 mg/mL. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising the neuroactive steroid at a concentration of 3.5 mg/mL. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as ^CAPTISOL®, is included in an aqueous composition comprising the neuroactive steroid at a concentration of 5 mg/mL. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as ^CAPTISOL® , is included in an aqueous composition comprising the neuroactive steroid at a concentration of 6 mg/mL. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as a β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as ^CAPTISOL® , is included in an aqueous composition containing the neuroactive steroid at a concentration of 15 mg/ml.

In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising the neuroactive steroid at a concentration in the range of 0.1-50 μM; 0.1-40 μM; 0.1-30 μM; 0.1-20 μM; 0.1-15 μM; 0.5-50 μM; 0.5-40 μM; 0.5-30 μM; 0.5-20 μM; 0.5-15 μM; 1-50 μM; 1-40 μM; 1-30 μM; 1-20 μM; 1-15 μM; 2-50 μM; 2-40 μM; 2-30 μM; 2-20 μM; 2-15 μM; 0.5-15 μM; 1-15 μM; 2-15 μM; 3-15 μM; 1-20 μM. In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising the neuroactive steroid at a concentration of 0.1 μM; 0.5-1 μM; 2 μM; 4 μM; 5 μM; 7 μM; 10 μM; 15 μM; 20 μM; 25 μM; 40 μM; 50 μM. In an embodiment, a complex of a neuroactive steroid, for example, allopregnanolone and a cyclodextrin, for example, β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, for example, ^CAPTISOL® , is included in an aqueous composition containing the neuroactive steroid at a concentration of 1 μM. In an embodiment, a complex of a neuroactive steroid, for example, allopregnanolone and a cyclodextrin, for example, β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, for example, CAPTISOL®, is included in an aqueous composition containing the neuroactive steroid at a concentration of 2 μM. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as a β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as ^CAPTISOL® , is included in an aqueous composition containing the neuroactive steroid at a concentration of 5 μM.

In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., ^CAPTISOL® , at a concentration in the range of 25-400 mg/mL; 25-300 mg/mL; 25-200 mg/mL; 25-100 mg/mL; 25-50 mg/mL; 50-400 mg/mL; 50-300 mg/mL; 60-400 mg/mL; 60-300 mg/mL; 150-400 mg/ml; 150-300 mg/ml; 200-300 mg/ml; 200-400 mg/ml; 30-100 mg/ml; 30-300 mg/ml; 30-400 mg/ml; 45-75 mg/ml; 50-70 mg/ml; 55-65 mg/ml; or 50-60 mg/ml. In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., ^CAPTISOL® , is formulated in an aqueous composition comprising a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, at a concentration of 25 mg/mL; 30 mg/mL; 35 mg/mL; 40 mg/mL; 45 mg/mL; 50 mg/mL; 55 mg/mL; 60 mg/mL; 65 mg/mL; 70 mg/mL; 75 mg/mL; 80 mg/mL; 85 mg/mL; 90 mg/mL, 95 mg/mL; 100 mg/mL; 150 mg/mL; 200 mg/mL; 250 mg/mL; 300 mg/mL; 350 mg/mL; or 400 mg/mL. In an embodiment, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising a cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., ^CAPTISOL® , at a concentration of 60 mg/mL.

In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, is formulated in an aqueous composition comprising 2.5-40%, 2.5-30%, 2.5-20%, 2.5-15%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-15%, 5-10%, 6-40%, 6-30%, 6-20%, 6-10%, 6-20%, 6-30%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10%, 3-15%, 4.5-7.5%, 4-13%, 5-7%, 5-13%, 5.5-6.5%, 7-13% by weight of cyclodextrin, such as CAPTISOL® by weight of solution.

In some embodiments, a complex of a neuroactive steroid, e.g., allopregnanolone, and a cyclodextrin, e.g., a β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., ^CAPTISOL® , is formulated in an aqueous composition comprising 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 12%, 15%, 20%, 25%, 30%, 35%, or 40% by weight of a cyclodextrin, e.g., ^CAPTISOL®, per weight of solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising 6% by weight of a cyclodextrin, such as ^CAPTISOL® , per weight of solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising 12% by weight of a cyclodextrin, such as CAPTISOL®, per weight of solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising 15% by weight of a cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising 30% by weight of a cyclodextrin, such as CAPTISOL®, per weight of the solution.

In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 1.5 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 6% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 10 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 6% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 15 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as ^CAPTISOL® , at a concentration of 6% by weight of the cyclodextrin, such as ^CAPTISOL® , per weight of the solution.

In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 1.25 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 12% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as ^CAPTISOL® , is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 1.5 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 12% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 2.5 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 12% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 3.75 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 12% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 5 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 12% by weight of the cyclodextrin, such as ^CAPTISOL® , per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 10 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 12% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 15 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 12% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution.

In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 1.5 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 15% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 10 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 15% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 15 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 15% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution.

In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 1.5 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 30% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as a β-cyclodextrin, such as a sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 10 mg/mL and a cyclodextrin, such as a β-cyclodextrin, such as a sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 30% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution. In an embodiment, a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, is included in an aqueous composition comprising a neuroactive steroid, such as allopregnanolone, at a concentration of 15 mg/mL, and a cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, at a concentration of 30% by weight of the cyclodextrin, such as CAPTISOL®, per weight of the solution.

In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition having a pH in the range of 3-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-9, 5-8, 5-7, 5-6, 4.5-7.5, or 5.5-7.5. In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition having a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. In an embodiment, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition having a pH of about 6.

In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition and administered intravenously. In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition and administered intramuscularly.

In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition and administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition and administered for 1-10, 1-5, 5-10, 1-6, 2-6, 3-6, 4-5, or 1-9 consecutive days. In an embodiment, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition and administered for 5 consecutive days. In some embodiments, the duration of administration is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the duration of administration is 3-7, 4-6, 4-5, or 5-6 days. In some embodiments, the duration of administration is 5 days.

In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition and administered at the same dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In some embodiments, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition and administered at a loading dose, such as a bolus dose, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a maintenance dose, such as a dose administered by infusion, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In an embodiment, the allopregnanolone and CAPTISOL® complex is included in an aqueous composition and administered in a loading, e.g., bolus dose of 0.25 mg/ml, 0.5 mg/ml; 1.0 mg/ml; 1.5 mg/ml; 2.0 mg/ml; 2.5 mg/ml; 3.0 mg/ml; 3.5 mg/ml; 4.0 mg/ml; 4.5 mg/ml; 5.0 mg/ml, 5.5 mg/ml, 6.0 mg/ml, 6.5 mg/ml, 7.0 mg/ml, 7.5 mg/ml, 8.0 mg/ml, 8.5 mg/ml, 9.0 mg/ml, 9.5 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, or 30 mg/ml of a neuroactive steroid, e.g., allopregnanolone, for 1 day and then administered as a maintenance dose, e.g., a dose administered by infusion, for 1, 2, 3, 4, 5, or 6 consecutive days 0.25 mg/ml, 0.5 mg/ml; 1.0 mg/ml; 1.5 mg/ml; 2.0 mg/ml; 2.5 mg/mL; 3.0 mg/mL; 3.5 mg/mL; 4.0 mg/mL; 4.5 mg/mL; 5.0 mg/mL, 5.5 mg/mL, 6.0 mg/mL, 6.5 mg/mL, 7.0 mg/mL, 7.5 mg/mL, 8.0 mg/mL, 8.5 mg/mL, 9.0 mg/mL, 9.5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, or 30 mg/mL of a neuroactive steroid, e.g., allopregnanolone. In some embodiments, the maintenance dose, e.g., the infusion dose, described herein, is lower than the loading dose, e.g., the bolus dose, described herein. In some embodiments, the maintenance dose, e.g., a dose administered by infusion, described herein, is the same as the loading dose, e.g., a bolus dose, described herein. In some embodiments, the maintenance dose, e.g., a dose administered by infusion, is less than 0.25 mg/mL; 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL; 3.0 mg/mL; 3.5 mg/mL; 4.0 mg/mL; 4.5 mg/mL; 5.0 mg/ml, 5.5 mg/ml, 6.0 mg/ml, 6.5 mg/ml, 7.0 mg/ml, 7.5 mg/ml, 8.0 mg/ml, 8.5 mg/ml, 9.0 mg/ml, 9.5 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, or 30 mg/ml.

In some embodiments, the allopregnanolone and ^CAPTISOL® complex is formulated into an aqueous composition and administered in a loading dose, such as a bolus dose, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered in a maintenance dose, such as an infusion dose, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, and then administered in a tapering dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In some embodiments, the allopregnanolone and ^CAPTISOL® complex is formulated into an aqueous composition and administered in a loading dose, such as a bolus dose, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered in a maintenance dose, such as an infusion dose, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, and then administered in a first step dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours.

In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated into an aqueous composition and administered in a loading dose, such as a bolus dose, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered in a maintenance dose, such as a dose administered by infusion, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered in a first step dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then administered in a second step dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated in an aqueous composition and administered in a loading dose, such as a bolus dose, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered in a maintenance dose, such as a dose administered by infusion, for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered in a first treatment step dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then administered in a second treatment step dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then administered in a third treatment step dose for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours.

In some embodiments, the first, second, or third step dose is less than the maintenance dose, such as the dose administered by infusion. In some embodiments, the second, tapering dose, or third step dose is less than the first step dose. In some embodiments, the third step dose is less than the second step dose. In some embodiments, the first step dose is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the maintenance dose, such as the dose administered by infusion. In some embodiments, the first step dose is 95-50%, 75-50%, 85-50%, 90-50%, 80-50%, or 75-100% of the maintenance dose, such as the dose administered by infusion. In an embodiment, the first step dose is 75% of the maintenance dose, such as the dose administered by infusion.

In some embodiments, the second step dose is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the maintenance dose, such as the dose administered by infusion. In some embodiments, the second step dose is 95-30%, 75-30%, 85-30%, 60-30%, 70-30%, 50-30%, or 50-40% of the maintenance dose, such as the dose administered by infusion. In an embodiment, the second step dose is 50% of the maintenance dose, such as the dose administered by infusion.

In some embodiments, the third step dose is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the maintenance dose, such as the dose administered by infusion. In some embodiments, the third step dose is 50-5%, 40-5%, 30-5%, 25-5%, 25-10%, 25-20%, or 25-40% of the maintenance dose, such as the dose administered by infusion. In an embodiment, the second step dose is 50% of the maintenance dose, such as the dose administered by infusion. In an embodiment, the third step dose is 25% of the maintenance dose, such as the dose administered by infusion.

In an embodiment, a composition comprising a complex of a neuroactive steroid, such as allopregnanolone, and a cyclodextrin, such as a β-cyclodextrin, such as a sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, comprises less than 100 ppm phosphate and the cyclodextrin, such as a β-cyclodextrin, such as a sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, has an absorption value of less than 0.2 op.u. due to the presence of a drug-destroying reagent, as determined by optical spectrometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, per ml of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, has an absorbance value of less than 0.2 op. units due to the presence of a color-forming reagent, as determined by optical spectrometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, per ml of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, further comprises: less than 20 ppm sulfoalkylating agent; less than 0.5 wt.% non-derivatized cyclodextrin; less than 1 wt.% alkali metal halide; and less than 0.25 wt.% hydrolyzed sulfoalkylating agent.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, has an absorbance value of less than 0.2 opioid units due to the presence of a drug-degrading reagent, as determined by optical spectrometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, further comprises: less than 50 ppm phosphate; less than 10 ppm sulfoalkylating agent; less than 0.2 wt. % non-derivatized cyclodextrin; less than 0.5 wt. % alkali metal halide; and less than 0.1 wt. % hydrolyzed sulfoalkylating agent; and wherein the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, has an absorbance value of less than 0.2 op. due to the presence of a colour-forming reagent, as determined by optical spectrometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 ml of cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, per ml of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, further comprises: less than 10 ppm phosphate; less than 2 ppm sulfoalkylating agent; less than 0.1 wt.% non-derivatized cyclodextrin; less than 0.2 wt.% alkali metal halide; and less than 0.08 wt.% hydrolyzed sulfoalkylating agent; and wherein the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, has an absorbance value of less than 0.1 op. due to the presence of a colour-forming reagent, as determined by optical spectrometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of cyclodextrin, such as β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, such as CAPTISOL®, per ml of solution in a cuvette with an optical path length of 1 cm.

In some embodiments, the cyclodextrin, e.g., β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, e.g., CAPTISOL®, further comprises: less than 5 ppm phosphate; less than 0.1 wt.% alkali metal halide; and less than 0.05 wt.% hydrolyzed sulfoalkylating agent.

In some embodiments, a complex of a neuroactive steroid (e.g., allopregnanolone) and CAPTISOL® is prepared as an aqueous composition and administered within 48 hours, 24 hours, 10 hours, 8 hours, 5 hours, 3 hours, 1 hour, or 0.5 hours after the onset of a seizure, e.g., a status epilepticus seizure, e.g., a refractory status epilepticus seizure. In some embodiments, a complex of allopregnanolone and CAPTISOL® is prepared as an aqueous composition and administered within 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes after the onset of a seizure, e.g., a status epilepticus seizure, e.g., a refractory status epilepticus seizure. In some embodiments, the complex of a neuroactive steroid (e.g., allopregnanolone) and CAPTISOL® is prepared as an aqueous composition and administered after a seizure, e.g., a seizure in status epilepticus, e.g., a seizure in refractory status epilepticus, has lasted 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, or 60 minutes.

In some embodiments, the complex of a neuroactive steroid (e.g., allopregnanolone) and CAPTISOL® is prepared as an aqueous composition and administered prior to the onset of a seizure, e.g., a status epilepticus seizure, e.g., a refractory status epilepticus seizure.

In some embodiments, the benzodiazepine is clonazepam, lorazepam, midazolam, or diazepam.

In some embodiments, the benzodiazepine is formulated for oral administration. In some embodiments, the benzodiazepine is formulated for parenteral administration (e.g., intranasally, buccally, intravenously, or intramuscularly, such as intravenously or intramuscularly).

In some embodiments, the anesthetic/sedative is propofol or a barbiturate such as pentobarbital.

In some embodiments, both the neuroactive steroid and the benzodiazepine or anesthetic/sedative are formulated for parenteral administration (e.g., intranasally, buccally, intravenously, or intramuscularly, such as intravenously or intramuscularly).

In some embodiments, a neuroactive steroid, such as an allopregnanolone and a benzodiazepine or an anesthetic/sedative, when used in combination, is administered in an amount sufficient to achieve “burst-suppression” (e.g., a predetermined “burst-suppression” pattern, e.g., with interburst intervals of 2-30 seconds; as measured by neurophysiological monitoring, e.g., EEG, CDI). In some embodiments, a neuroactive steroid such as allopregnanolone and a benzodiazepine or anesthetic/sedative, when used in combination, are administered in an amount sufficient to achieve a predetermined burst-suppression pattern, such as with interburst intervals of 2-30 seconds, 5-30 seconds, 10-30 seconds, 15-30 seconds, 1-30 seconds, 0-30 seconds, 2-20 seconds, 2-10 seconds, 5-20 seconds, 10-20 seconds, 15-25 seconds, 5-15 seconds, or 5-10 seconds; which is measured by neurophysiological monitoring, such as EEG, CDI.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1. Physical properties of ALLO compositions with captisol.

Fig. 2. Plasma allopregnanolone levels from a study in a patient with SE. The plasma allopregnanolone concentration-time profile was obtained in one male patient. The patient received allopregnanolone (ALLO) 1.5 mg/mL in 6% hydroxypropyl-β-cyclodextrin in 0.9% sodium chloride intravenously for 5 days (120 hours). The infusion rate was 86 mcg/kg/hour. The patient received 5.6 mg/hour of allopregnanolone at 3.8 mL/hour. Plasma concentrations were measured 2 hours before the start of the infusion and then at 52, 76, 100, 124, and 148 hours after the start of the infusion.

DETAILED DESCRIPTION OF THE INVENTION

In this context, "administration in combination" or combined administration of two substances (e.g., a neuroactive steroid and a benzodiazepine or an anaesthetic/sedative) means that two or more substances are administered to an individual at the same time or within a time interval such that the patient experiences an overlapping effect of each substance. Preferably, the substances are administered within 15, 10, 5 or 1 minute of each other. Preferably, the substances are administered close enough to each other that a combined effect is achieved. The substances may be administered simultaneously, such as in a combined single dose (delivering both substances simultaneously). Alternatively, the substances may be administered at a predetermined time interval, such as an interval of minutes, hours, days or weeks. Typically, the substances are simultaneously bioavailable, such as detectable in the individual. In an embodiment, the substances (e.g., a neuroactive steroid and a benzodiazepine or an anesthetic/sedative) are administered substantially simultaneously, such as two single doses administered at the same time, or a combined single dose of the two substances. In another embodiment, the substances are delivered in separate single doses. The substances can be administered in any order or as one or more preparations that include two or more substances. In an embodiment, at least one administration of one of the substances, such as the first substance, is carried out within minutes, one, two, three, or four hours, or even one or two days before the administration of the other substance, such as the second substance. In some cases, the use of combinations allows for synergistic effects to be achieved, such as those that are greater than additive effects, such as those that are at least 20, 50, 70, or 100% greater than additive effects.

In this context, "simultaneous" administration of a treatment method with a selected condition, such as a condition under general anaesthesia, or at the same time as a second treatment method is administered, or is presented at a pre-selected level, such as a therapeutic level, means that the administration of the treatment method overlaps or occurs at the same time as, for example, the administration of the second treatment method.

In this context, the amount of a compound used to treat a disorder, or a "therapeutically effective amount," refers to the amount of the compound that is effective, upon single or multiple dose administration to an individual, in treating a cell, or in treating, reducing symptoms, eliminating symptoms, or improving the condition of an individual having a disorder after its administration, than would be expected in the absence of such treatment.

In this context, "general anesthesia" or "GA" is an induced state where an individual is given medications, such as for amnesia, analgesia, muscle paralysis, and sedation. For example, GA is a drug that induces deep sleep so that patients do not feel pain during surgery. A patient under general anesthesia can be thought of as being in a state of reversible and controlled loss of consciousness. GA medications can be administered intravenously or by inhalation.

In this context, the term "individual" includes humans and animals. Typical human individuals include a human patient with a disorder, such as a disorder described herein, or a healthy individual. The term "animals" includes all vertebrates, such as non-mammals (e.g., chickens, amphibians, reptiles) and mammals, such as primates, domestic and/or farm animals, such as sheep, dogs, cats, cows, pigs, etc.

Medicines

Neuroactive steroids

Neuroactive steroids (or neurosteroids) are natural, synthetic, or semisynthetic steroids that rapidly alter neuronal excitability by interacting with neurotransmitter-gated ion channels. Neuroactive steroids act by binding to membrane-bound receptors such as inhibitory and/or excitatory neurotransmitter receptors, including GABA _A , NMDA, and sigma receptors.

Steroids can be classified into functional groups according to chemical structure and physiological activity, and include estrogenic hormones, progestogenic hormones, and androgenic hormones. Of particular interest are the progestogenic hormones, referred to herein as "progestins" or "progestogens," and their derivatives and biologically active metabolites. Members of this large family include the steroid hormones described in Remington's Pharmaceutical Sciences, Gennaro et al., Mack Publishing Co. (18th ed. 1990), 990-993. As with all other classes of steroids, stereoisomerism is of fundamental importance for the sex hormones. In this context, various progestins (e.g., progesterone) and their derivatives, including both synthetic and natural products, may be used, as well as progestin metabolites such as progesterone.

The term "progesterone" in this context refers to a member of the progestin family of steroid hormones consisting of 21 carbon atoms. Progesterone is also known as D4-pregnene-3,20-dione; Δ4-pregnene-3,20-dione; or pregn-4-ene-3,20-dione. In this context, a "synthetic progestin" is a molecule whose structure is related to that of progesterone, is produced synthetically, and retains the biological activity of progesterone.

Typical synthetic progestins include, but are not limited to, substitutions at position 17 of the progesterone ring to introduce hydroxyl, acetyl, hydroxyl acetyl, aliphatic, nitro, or heterocyclic groups, modifications to produce 17α-OH esters (e.g., 17α-hydroxyprogesterone caproate), and modifications that introduce 6-methyl, 6-ene, and 6-chloro substituents into progesterone (e.g., medroxyprogesterone acetate, megestrol acetate, and chlormadinone acetate), and which retain the biological activity of progesterone. Such progestin derivatives include 5-dehydroprogesterone, 6-dehydro-retroprogesterone (dydroprogesterone), allopregnanolone (allopregnan-3α, or 3β-ol-20-one), ethynodiol diacetate, hydroxyprogesterone caproate (pregn-4-ene-3,20-dione, 17-(1-oxohexy)oxy); levonorgestrel, norethindrone, norethindrone acetate (19-norpregn-4-ene-20-yn-3-one, 17-(acetyloxy)-, (17α)-); noretynodrel, norgestrol pregnenolone, and megestrol acetate.

Useful progestins may also include allopregnone-3α or 3β, 20α, or 20β-diol (see Merck Index 258-261); allopregnan-3β,21-diol-ll,20-dione; allopregnan-3β,17α-diol-20-one; 3,20-allopregnanedione, allopregnan, 3β,11β,17α,20β,21-pentol; allopregnan-3β,17α,20β,21-tetrol; allopregnan-3α or 3β,l1β,17α,21-tetrol-20-one, allopregnan-3β,17α, or 20β-triol; allopregnan-3β,17α,21-triol-11,20-dione; allopregnan-3β,l1β,21-triol-20-one; allopregnan-3β,17α,21-triol-20-one; allopregnan-3α or 3β-ol-20-one; pregnanediol; 3,20-pregnanedione; pregnane-3α-ol-20-one; 4-pregnene-20,21-diol-3,ll-dione; 4-pregnene-llβ,17a,20β,21-tetrol-3-one; 4-pregnene-17a,20β,21-triol-3,ll-dione; 4-pregnen-17a,20β,21-triol-3-one, and pregnenolone methyl ester. Other progestin derivatives include esters with nontoxic organic acids such as acetic acid, benzoic acid, maleic acid, malic acid, caproic acid, and citric acid and inorganic salts such as the hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Other suitable progestins include alfaxalone, alphadolone, hydroxydione, and minaxolone.

Additional suitable neuroactive steroids are described in published U.S. Patent Application Nos. US 2011/0092473 and US 2010/0317638, and U.S. Patent No. 5,232,917, which are incorporated by reference into the specification for the neuroactive steroids described herein.

In specific embodiments, the steroids are one or more steroids from the series of sedative-hypnotic pregnane steroids with a reduced 3 alpha-hydroxy ring A, which include the major metabolites of progesterone and deoxycorticosterone, 3 alpha-hydroxy-5-alpha-pregnan-20-one (allopregnanolone) and 3 alpha-21-dihydroxy-5-alpha-pregnan-20-one (allotetrahydroDOC), respectively. These 3 alpha-hydroxy steroids do not interact with classical intracellular steroid receptors, but bind stereoselectively and with high affinity to receptors for the major inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA).

In certain embodiments, the neuroactive steroids are progesterone, allopregnanolone, or other progesterone analogs. In a particular embodiment, the neuroactive steroid is allopregnanolone or a derivative thereof. Exemplary derivatives include, but are not limited to, (20R)-17beta-(1-hydroxy-2,3-butadienyl)-5alpha-androstan-3alpha-ol (HBAO). Additional derivatives are described in WO 2012/127176.

In this context, "allopregnanolone" also encompasses pharmaceutically acceptable, pharmacologically active derivatives, including individual enantiomers (dextrorotatory and levorotatory enantiomers) and their pharmaceutically acceptable salts, mixtures of enantiomers and their pharmaceutically acceptable salts, and active metabolites and their pharmaceutically acceptable salts, unless otherwise specified. It should be understood that in some cases it may be necessary to adjust the doses of enantiomers, derivatives, and metabolites based on the relative potency of the racemic mixture of allopregnanolone.

The lipophilic nature of allopregnanolone may pose challenges when formulating for in vivo use. As discussed above, allopregnanolone can be formulated with a host such as cyclodextrin to enhance solubility. Alternatively or additionally, allopregnanolone can be modified to improve solubility. For example, polar groups can be introduced at the 16α position to enhance aqueous solubility, brain availability, and potency of neuroactive steroids, as described in Kasal et al., J. Med. Chem., 52(7), 2119–215 (2009).

In some embodiments, the compounds described herein (e.g., allopregnanolone) are administered to an individual under general anesthesia.

Anesthetics and sedatives

An anesthetic (e.g., general anesthetic) or sedative is a drug that produces, causes, and maintains reversible loss of consciousness. A sedative is a substance that produces sedation by decreasing irritability or agitation in an individual. Intravenous injection of anesthetics is generally preferred over inhalation, intramuscular, or subcutaneous injection because it is faster, usually less painful, and more reliable. Typical anesthetics include propofol, etomidate, barbiturates (e.g., pentobarbital, methohexital, thiopentone/thiopental), benzodiazepines (e.g., those described herein, such as midazolam), and ketamine.

In some embodiments, the individual who has been administered the anesthetic or anaesthetic is under general anesthesia.

Benzodiazepines

A benzodiazepine is a compound whose chemical structure is based on a benzene ring bonded to a diazepine ring. The first benzodiazepine, chlordiazepoxide, was discovered in 1955.

Benzodiazepines can enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABA _A receptor, and as a result may have sedative, hypnotic (sleep-inducing), tranquilizer (anti-anxiety), anticonvulsant, or muscle relaxant properties. Benzodiazepines are classified as short-acting, intermediate-acting, or long-acting. Typical benzodiazepines include alprazolam, bretazenil, bromazepam, brotizolam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, etizolam, ethyl loflazepate, flunitrazepam, flurazepam, flunitrazepam, halazepam, ketazolam, lorpazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, temazepam, tatrazepam, and triazolam.

A commonly used anesthetic is midazolam. In some embodiments, the benzodiazepine is midazolam.

Barbiturates

Barbiturates are drugs that are used as CNS depressants and are used, for example, to induce a mild sedative effect, general anesthesia; and are used as an anxiolytic, hypnotic, anticonvulsant, and analgesic. Side effects of barbiturates include the possibility of developing dependence, such as physical and psychological dependence.

Barbiturates can be classified as, for example, ultra-short-acting, short/intermediate-acting, and long-acting. Typical barbiturates include pentobarbital, allobarbital, amobarbital, aprobarbital, barbital, and brallobarbital.

Propofol

Propofol (2,6-diisopropylphenol) is an intravenous drug that induces loss of consciousness and can be used with other general anesthetics. The main advantages are favorable conditions for surgery and rapid recovery of consciousness, but there are disadvantages, which include a relatively high incidence of apnea and decreased blood pressure.

In this context, "neuroactive steroid" also includes pharmaceutically acceptable, pharmacologically active derivatives of the substances indicated (e.g., neuroactive steroids, including individual enantiomers of neuroactive steroids (dextrorotatory and levorotatory enantiomers)) and their pharmaceutically acceptable salts, mixtures of enantiomers and their pharmaceutically acceptable salts, and active metabolites and their pharmaceutically acceptable salts, unless otherwise indicated. It should be understood that in some cases it may be necessary to adjust the doses of enantiomers, derivatives and metabolites based on the relative potency of the racemic mixture.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by forming base addition salts or acid addition salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids and basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, naphthalenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isethionic acids.

Pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the compounds in the free acid or base forms with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of water and solvent; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704.

The phrase "pharmaceutically acceptable" is used in the description to mean compounds, substances, compositions and/or dosage forms that are suitable, from a medical point of view, for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications commensurate with a reasonable benefit/risk ratio.

The compounds described herein, such as neuroactive steroids, typically contain one or more chiral centers and thus exist as one or more stereoisomers. Such stereoisomers may be prepared and/or isolated as a single enantiomer, a mixture of diastereomers, or a racemic mixture.

In this context, the term "stereoisomers" refers to compounds that have the same atoms, having the same bond order, but have different three-dimensional arrangements of the atoms that are not interchangeable. The three-dimensional structures are called configurations. In this context, the term "enantiomers" refers to two stereoisomers that are not mirror images of each other. In this context, the term "optical isomer" is synonymous with the term "enantiomer". In this context, the term "diastereomer" refers to two stereoisomers that are not mirror images, but are not superposable. The terms "racemate," "racemic mixture," or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. The appropriate chiral column, eluent, and conditions necessary to effect the separation of a pair of enantiomers using standard techniques are well known to those skilled in the art (see, e.g., Jacques, J. et al., "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc. 1981).

Dosage and pharmacokinetics

The compositions described herein comprise a therapeutically effective amount of a neuroactive steroid, such as allopregnanolone, and a therapeutically effective amount of a benzodiazepine or anesthetic/sedative. In some embodiments, the neuroactive steroid and the benzodiazepine or anesthetic/sedative are formulated in a single composition or dose. In some embodiments, the neuroactive steroid and the benzodiazepine or anesthetic/sedative are administered separately. In some embodiments, the neuroactive steroid and the benzodiazepine or anesthetic/sedative are administered sequentially. In some embodiments, the neuroactive steroid and the benzodiazepine or anesthetic/sedative are administered separately and sequentially. In general, at least one of the neuroactive steroid and the benzodiazepine or anesthetic/sedative is administered parenterally (e.g., intranasally, bucally, intravenously, or intramuscularly, such as by intramuscular (IM) injection or intravenously). In some embodiments, both the neuroactive steroid and the benzodiazepine or anesthetic/sedative are administered parenterally (e.g., intranasally, bucally, intravenously, or intramuscularly).

In one embodiment, the neuroactive steroid and/or benzodiazepine or anesthetic/sedative is administered at a dose equivalent to parenteral administration of about 0.1 ng to 100 g per kg body weight, about 10 ng to 50 g per kg body weight, about 100 ng to 1 g per kg body weight, about 1 μg to 100 mg per kg body weight, about 10 μg to 10 mg per kg body weight, about 100 μg to 5 mg per kg body weight, about 250 μg to 3 mg per kg body weight, about 500 μg to 2 mg per kg body weight, about 1 μg to 50 mg per kg body weight, about 1 μg to 500 μg per kg body weight; and about 1 μg to 50 μg per kg body weight. Alternatively, the amount of neuroactive steroid and/or benzodiazepine or anesthetic/sedative administered to achieve a therapeutically effective dose is approximately 0.1 ng, 1 ng, 10 ng, 100 ng, 1 mcg, 10 mcg, 100 mcg, 1 mg, 1.5 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, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 500 mg per kg of body weight or more.

In one embodiment, the neuroactive steroid is administered as an intravenous bolus infusion at a dose equivalent to parenteral administration of about 0.1 ng to 100 g per kg body weight, about 10 ng to 50 g per kg body weight, about 100 ng to 1 g per kg body weight, about 1 μg to 100 mg per kg body weight, about 1 μg to 50 mg per kg body weight, about 10 μg to 5 mg per kg body weight, about 100 μg to 500 μg per kg body weight, about 100 μg to 400 μg per kg body weight, about 150 μg to 350 μg per kg body weight, about 250 μg to 300 μg per kg body weight. In one embodiment, the neuroactive steroid is administered as an intravenous bolus infusion at a dose equivalent to parenteral administration of about 100 to 400 mcg/kg. In some embodiments, the neuroactive steroid is administered as an intravenous bolus infusion in an amount of about 150 to 350 mcg/kg. In some embodiments, the neuroactive steroid is administered as an intravenous bolus infusion in an amount of about 250 to 300 mcg/kg. In specific embodiments, the neuroactive steroid is administered as an intravenous bolus infusion at a dose equivalent to 100 mcg/kg, 125 mcg/kg, 150 mcg/kg, 175 mcg/kg, 200 mcg/kg, 225 mcg/kg, 250 mcg/kg, 260 mcg/kg, 270 mcg/kg, 280 mcg/kg, 290 mcg/kg, 300 mcg/kg, 325 mcg/kg, or 350 mcg/kg.

In one embodiment, the neuroactive steroid is administered as an intravenous bolus infusion at a dose equivalent to parenteral administration of about 0.1 nmol/L to 100 μmol/L per kg body weight, about 1 nmol/L to 10 μmol/L per kg body weight, about 10 nmol/L to 10 μmol/L per kg body weight, about 100 nmol/L to 10 μmol/L per kg body weight, about 300 nmol/L to 5 μmol/L per kg body weight, about 500 nmol/L to 5 μmol/L per kg body weight; about 750 nmol/L to 1 μmol/L per kg body weight. Alternatively, the amount of neuroactive steroid administered to achieve a therapeutically effective dose is approximately 0.1 ng, 1 ng, 10 ng, 100 ng, 1 mcg, 10 mcg, 100 mcg, 1 mg, 1.5 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, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 500 mg per kg of body weight or more.

In some embodiments, the neuroactive steroid and/or benzodiazepine or anesthetic/sedative can be administered once or several times per day. The duration of treatment can be, for example, once per day for a period of about 1, 2, 3, 4, 5, 6, 7 days or more. In some embodiments, either a single dose is administered in the form of an individual dosage unit, or several smaller dosage units, or by multiple administration of divided doses at a certain interval. For example, a dosage unit can be administered from about 0 hours to 1 hour, from about 1 hour to 24 hours, from about 1 hour to 72 hours, from about 1 hour to 120 hours, or from about 24 hours to at least about 120 hours after injury. Alternatively, the dosage unit may be administered approximately 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 40, 48, 72, 96, 120 hours or more after injury. Subsequent dosage units may be administered at any time after the initial administration, thereby achieving a therapeutic effect. For example, additional dosage units may be administered to protect the subject from a second wave of cerebral edema that may occur during the first few days after injury.

The area under the curve (AUC) refers to the area under the curve that represents the serum concentration (nmol/L) of a neuroactive steroid and/or benzodiazepine or anesthetic/sedative over a given time after IV administration of a reference neuroactive steroid or benzodiazepine or anesthetic/sedative standard. By "reference neuroactive steroid" or "benzodiazepine standard" or "anesthetic/sedative standard" is meant a formulation of a neuroactive steroid or benzodiazepine or anesthetic/sedative that serves as the basis for determining the total dose per hour of neuroactive steroid and/or benzodiazepine or anesthetic/sedative that is administered to a human subject with epilepsy or status epilepticus to achieve the desired beneficial effect, i.e. a positive therapeutic response that is improved over the response observed without the administration of a neuroactive steroid and/or benzodiazepine or anesthetic/sedative. In an embodiment, the dose of the neuroactive steroid and/or benzodiazepine or anesthetic/sedative that is administered provides a final serum level of the neuroactive steroid and/or benzodiazepine or anesthetic/sedative of about 100 ng/mL to about 1000 ng/mL, about 1100 ng/mL to about 1450 ng/mL, about 100 ng/mL to about 250 ng/mL, about 200 ng/mL to about 350 ng/mL, about 300 ng/mL to about 450 ng/mL, about 350 ng/mL to about 450 ng/mL, about 400 ng/mL to about 550 ng/mL, about 500 ng/mL to about 650 ng/mL, from about 600 ng/ml to 750 ng/ml, from about 700 ng/ml to 850 ng/ml, from about 800 ng/ml to 950 ng/ml, from about 900 ng/ml to 1050 ng/ml, from about 1000 ng/ml to 1150 ng/ml, from about 100 ng/ml to 1250 ng/ml, from about 1200 ng/ml to 1350 ng/ml, from about 1300 ng/ml to 1500 ng/ml. In specific embodiments, the serum level of the neuroactive steroid and/or benzodiazepine or anesthetic/sedative is about 100 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 360 ng/mL, 370 ng/mL, 380 ng/mL, 390 ng/mL, 400 ng/mL, 410 ng/mL, 420 ng/mL, 430 ng/mL, 440 ng/mL, 450 ng/mL, 500 ng/mL, 750 ng/mL, 900 ng/mL, 1200 ng/mL, 1400 ng/mL, or 1600 ng/mL.

In an embodiment, the dose of neuroactive steroid that is administered provides a final serum level of neuroactive steroid of about 100 nmol/L to 5000 nmol/L, about 100 nmol/L to 2500 nmol/L, about 100 nmol/L to 1000 nmol/L, about 100 nmol/L to 500 nmol/L, about 100 nmol/L to 250 nmol/L, about 100 nmol/L to 200 nmol/L, about 125 nmol/L to 175 nmol/L, or about 140 nmol/L to 160 nmol/L. In specific embodiments, the serum level of the neuroactive steroid and/or benzodiazepine or anesthetic/sedative is about 100 nmol/L, 125 nmol/L, 150 nmol/L, 175 nmol/L, 200 nmol/L, 250 nmol/L, 300 nmol/L, 350 nmol/L, 500 nmol/L, 750 nmol/L, 1000 nmol/L, 1500 nmol/L, 2000 nmol/L, 2500 nmol/L, or 5000 nmol/L.

In some embodiments, administration of the neuroactive steroid and the benzodiazepine or anesthetic/sedative includes a period of time during which the benzodiazepine therapy or anesthetic/sedative is gradually tapered.

As used herein, "weaning" or "weaning dose" refers to a protocol of administration in which the dose administered to a patient is reduced and thereby a gradual reduction and subsequent discontinuation of the benzodiazepine or anesthetic/sedative is effected, either over a predetermined period of time or over a period of time determined empirically by a physician based on ongoing monitoring of the individual's therapeutic response. The "weaning" period of the benzodiazepine or anesthetic/sedative may be about 12, 24, 36, 48 hours, or longer. Alternatively, the "weaning" period of the benzodiazepine or anesthetic/sedative may vary from about 1 to 12 hours, from about 12 to 48 hours, or from about 24 to 36 hours. In some embodiments, the "weaning" period of the benzodiazepine or anesthetic/sedative is about 24 hours.

The weaning used can be a "linear weaning". For example, a "10% linear weaning" from a 500 mg dose would be 500, 450, 400, 350, 300, 250, 200, 150, 100, 50 mg. Alternatively, an "exponential weaning" can be used, where if the program above is used as an example, the "exponential weaning" would be, for example, 500, 450, 405, 365, 329, 296, 266, 239 mg, etc. Thus, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% linear or exponential weaning can be used in the methods of the invention. In addition, linear or exponential weaning of about 1% to 5%, about 6% to 10%, about 11% to 15%, about 16% to 20%, about 21% to 25%, about 26% to 30%, about 31% to 35%, about 36% to 40% can be used.

In other embodiments, the administration of the neuroactive steroid and the benzodiazepine or anesthetic/sedative includes a terminal period of time during which the administration of the neuroactive steroid is gradually tapered.

In this context, "tapering", "tapering dose", and "decreasing taper" refer to an administration protocol in which the dose administered to a patient is reduced, thereby gradually reducing and then discontinuing the neuroactive steroid, either over a predetermined period of time or over a period of time determined empirically by a physician based on ongoing monitoring of the individual's therapeutic response. The period of tapering the neuroactive steroid may be about 12, 24, 36, 48 hours, or longer. Alternatively, the period of tapering the neuroactive steroid may vary from about 1 to 12 hours, from about 12 to 48 hours, or from about 24 to 36 hours. In some embodiments, the period of tapering the neuroactive steroid is about 24 hours.

The tapering of the drug dose used may be a "linear" tapering. For example, a "10%" linear tapering of 500 mg would be 500, 450, 400, 350, 300, 250, 200, 150, 100, 50 mg. Alternatively, an exponential tapering may be used, wherein, if the program presented above is used as an example, the exponential tapering of the dose would be, for example, 500, 450, 405, 365, 329, 296, 266, 239, etc. Thus, approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% linear or exponential tapering of the dose may be used in the methods of the invention. In addition, a linear or exponential dose reduction may be used, from about 1% to 5%, from about 6% to 10%, from about 11% to 15%, from about 16% to 20%, from about 21% to 25%, from about 26% to 30%, from about 31% to 35%, from about 36% to 40%. In some embodiments, the dose reduction is about a 25% linear reduction.

If an individual receiving therapy experiences a partial response, or no response, after completion of the first cycle of therapy, subsequent courses of treatment with the neuroactive steroid may be required to achieve a partial or complete therapeutic response. Thus, following the rest period from the first treatment period, which may have included a continuous dosing regimen of the neuroactive steroid or a two-stage dosing regimen of the neuroactive steroid and/or a benzodiazepine or anesthetic/sedative, the individual may receive one or more additional treatment periods comprising either a continuous or two-stage dosing regimen of the neuroactive steroid and/or a benzodiazepine or anesthetic/sedative. Such a rest period between treatment periods is referred to herein as a rest period. It should be understood that the length of the treatment rest period will depend on the degree of the individual's response (i.e., complete or partial response) achieved in any of the preceding treatment periods with the neuroactive steroid.

In some embodiments, the neuroactive steroid is administered as an intravenous infusion over about 5 minutes to about 1 week; about 30 minutes to about 24 hours; about 1 hour to about 12 hours; about 2 hours to about 12 hours; about 4 hours to about 12 hours; about 6 hours to about 12 hours; about 6 hours to about 10 hours; about 5 minutes to about 1 hour; about 5 minutes to 30 minutes; about 12 hours to 1 week; about 24 hours to 1 week; about 2 days to 5 days; or about 3 days to 5 days. In one embodiment, the neuroactive steroid is administered as an intravenous infusion over about 5, 10, 15, 30, 45, or 60 minutes or more; approximately 1, 2, 4, 6, 8, 10, 12, 16, or 24 hours or more; approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more.

These multiple treatment sessions are referred to herein as maintenance cycles, where each maintenance cycle includes a completed continuous or bi-level dosing regimen of a neuroactive steroid or benzodiazepine. The phrase "completed bi-level dosing regimen of progesterone, allopregnanolone, or synthetic progestin" means that the patient has been administered both a first and a second period dose of a neuroactive steroid or benzodiazepine. The need for multiple maintenance cycles can be assessed by monitoring the patient's physiological or behavioral improvement. The length of time between maintenance cycles can be approximately 1 hour, 15 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or other periods of time ranging from approximately 1 day to 14 days.

In some embodiments, the maintenance cycle is about 2 days. In some embodiments, the maintenance cycle is about 3 days. In some embodiments, the maintenance cycle is about 4 days. In some embodiments, the maintenance cycle is about 5 days.

In some embodiments, the maintenance treatment cycle is started about 30 minutes to 24 hours, about 30 minutes to 12 hours, about 30 minutes to 8 hours, about 30 minutes to 4 hours, about 30 minutes to 2 hours, about 30 minutes to 1 hour after the initial bolus infusion is administered. In some embodiments, the maintenance treatment cycle is started 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, or more after the initial bolus infusion is administered.

In one embodiment, in the maintenance treatment cycle, the neuroactive steroid is administered as an intravenous infusion in an amount of neuroactive steroid/unit time of about 20 to 5000 mcg/kg/hour. In some embodiments, in the maintenance treatment cycle, the neuroactive steroid is administered as an intravenous infusion in an amount of neuroactive steroid/unit time of about 20 to 2500 mcg/kg/hour. In some embodiments, in the maintenance treatment cycle, the neuroactive steroid is administered as an intravenous infusion in an amount of neuroactive steroid/unit time of about 20 to 500 mcg/kg/hour. In some embodiments, the neuroactive steroid is administered as an intravenous infusion at a rate of about 20 to 250 mcg/kg/hour. In some embodiments, the neuroactive steroid is administered as an intravenous infusion in an amount of neuroactive steroid/unit time of about 20 to 200 mcg/kg/hour. In some embodiments, the neuroactive steroid is administered as an intravenous infusion in an amount of neuroactive steroid/unit time of about 20 to 150 mcg/kg/hour. In some embodiments, the neuroactive steroid is administered as an intravenous infusion in an amount of neuroactive steroid/unit time of about 50 to 100 mcg/kg/hour. In some embodiments, the neuroactive steroid is administered as an intravenous infusion in an amount of neuroactive steroid/unit time of about 70 to 100 mcg/kg/hour. In specific embodiments, the neuroactive steroid is administered as an intravenous infusion in an amount of neuroactive steroid/unit time of about 25 mcg/kg/hour, 50 mcg/kg/hour, 75 mcg/kg/hour, 80 mcg/kg/hour, 85 mcg/kg/hour, 86 mcg/kg/hour, 87 mcg/kg/hour, 88 mcg/kg/hour, 89 mcg/kg/hour, 90 mcg/kg/hour, 100 mcg/kg/hour, 125 mcg/kg/hour, 150 mcg/kg/hour, or 200 mcg/kg/hour.

In one embodiment, the neuroactive steroid is administered as an intravenous infusion at a dose equivalent to parenteral administration of about 0.1 ng to 100 g per kg body weight, about 10 ng to 50 g per kg body weight, about 100 ng to 1 g per kg body weight, about 1 μg to 100 mg per kg body weight, about 1 μg to 50 mg per kg body weight, about 10 μg to 5 mg per kg body weight; and about 100 μg to 1000 μg per kg body weight. In one embodiment, the neuroactive steroid is administered as an intravenous infusion at a dose equivalent to parenteral administration of about 0.1 nmol/L to 100 μmol/L per kg body weight, about 1 nmol/L to 10 μmol/L per kg body weight, about 10 nmol/L to 10 μmol/L per kg body weight, about 100 nmol/L to 10 μmol/L per kg body weight, about 300 nmol/L to 5 μmol/L per kg body weight, about 500 nmol/L to 5 μmol/L per kg body weight, and about 750 nmol/L to 5 μmol/L per kg body weight. Alternatively, the amount of neuroactive steroid administered to achieve a therapeutically effective dose is approximately 0.1 ng, 1 ng, 10 ng, 100 ng, 1 mcg, 10 mcg, 100 mcg, 1 mg, 1.5 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, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 500 mg per kg of body weight or more.

In this context, "approximately" means approximately plus or minus ten percent.

Compositions

The compositions described herein comprise a neuroactive steroid and/or a benzodiazepine or an anesthetic/sedative in combination with one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises both a neuroactive steroid and a benzodiazepine or an anesthetic/sedative.

Matrix-forming substances

Matrix formers are substances that form strong, viscous gels upon hydration and allow controlled diffusion and release of the drug. In hydrophilic matrix systems, the matrix formers are uniformly incorporated throughout the tablet. Upon contact with water, the outer layer of the tablet partially hydrates to form a gel layer. The rate of diffusion of the drug(s) from the gel layer and the rate of erosion of the gel layer determine the overall rate of tablet diffusion and drug delivery. Examples of matrix formers include cellulose ethers that are soluble in water, such as methylcellulose, ethylcellulose, and hydroxypropyl methylcellulose.

Solubilization of neuroactive steroids

Many neuroactive steroids have limited solubility in water. In order to provide formulations that deliver therapeutically effective doses, various methods can be used to enhance the solubility and bioavailability of neuroactive steroids. See, for example, "Water-Insoluble Drug Formulation", 2nd Edition, edited by Rong Liu (CRC Press, Boca Raton, FL, 2008). Using the techniques described below, a solubilized formulation of one or more neuroactive steroids can be prepared. These solubilized formulations can be further incorporated into the parenteral and non-parenteral compositions described in Sections 2 and 3.

Inclusion complexes

The solubility of neuroactive steroids can be improved by forming inclusion complexes (e.g., host-guest compounds). Inclusion complexes are formed when a non-polar molecule (i.e., the guest, such as a drug with low stability in water) or part of a molecule is placed into a non-polar pocket of another molecule or group of molecules (i.e., the host). If the host molecule or molecules have good solubility in water, the solubility of the host-guest complex will be greater than the solubility of the guest alone.

Inclusion complexes comprising or including one or more neuroactive steroids can be formed using any suitable host molecule or molecules. For example, the aqueous solubility of neuroactive steroids can be increased by forming inclusion complexes with cyclodextrins. Steroid-cyclodextrin complexes are known in the art. See, for example, U.S. Patent No. 7,569,557 to Backensfeld, et al., and U.S. Patent Application Publication No. US 2006/0058262 to Zoppetti, et al.

Dextrans are soluble polysaccharides obtained from bacteria and yeast. They are characterized by a predominance (>95) of α(1-6) linkages in the backbone and the presence of α(1-2), α(1-3), and α(1-4) linkages in varying proportions, usually at branch points 1, 2. Dextrins are partially hydrolyzed homopolymers of glucose consisting exclusively of (1-4) linear linkages.

Cyclodextrins are cyclic oligosaccharides containing or incorporating six (α-cyclodextrin), seven (β-cyclodextrin), eight (γ-cyclodextrin), or more α-(1,4)-linked glucose residues. The hydroxyl groups of cyclodextrins are oriented toward the outside of the ring, while the glycosidic oxygen and two rings of essential hydrogen atoms are directed toward the cavity of the pocket. As a result, cyclodextrins have an internal hydrophobic cavity combined with a hydrophilic outer region that provides aqueous solubility. Upon combination with a hydrophobic drug such as a neuroactive steroid, the neuroactive steroid (i.e., the “guest”) is introduced into the internal hydrophobic portion of the cyclodextrin (i.e., the “host”). The host-guest complex maintains aqueous solubility due to the hydrophilic outer region of the cyclodextrin ring.

The neuroactive steroid-cyclodextrin complexes may be incorporated, so far as solubility permits, into any of the parenteral or non-parenteral preparations described below. If desired, the aqueous solubility of the solid neuroactive steroid-cyclodextrin complexes may be further increased by isolating the neuroactive steroid-cyclodextrin complex as a solid by lyophilization and/or by micronization of the solid neuroactive steroid-cyclodextrin complex.

This cyclic orientation results in a truncated cone structure that is hydrophilic on the outside and lipophilic on the inside. Cyclodextrin complexes are formed when the guest molecule is partially or completely contained within the internal cavity. The parent α-, β-, and γ-cyclodextrins (especially β) have limited solubility in water and exhibit toxicity when administered parenterally. Thus, the structure of the parent cyclodextrin can be chemically modified to produce a CD derivative that is safe for parenteral administration. Modifications are typically made with one or more hydroxyls at the 2-, 3-, or 6-position.

The neuroactive steroid-cyclodextrin complexes are preferably formed from a cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and derivatives thereof. The cyclodextrin may be chemically modified such that some or all of the primary or secondary hydroxyl groups of the macrocycle, or both, are replaced by a pendent group. Suitable pendent groups include, but are not limited to, sulfinyl, sulfonyl, phosphate, acyl, and C ₁ -C ₁₂ alkyl groups optionally substituted with one or more (e.g., 1, 2, 3, or 4) hydroxy, carboxy, carbonyl, acyl, oxy, oxo groups; or a combination thereof. Methods for modifying these alcohol moieties are known in the art, and many cyclodextrin derivatives are commercially available, including sulfobutyl ether β-cyclodextrins available under the trade name CAPTISOL® from Ligand Pharmaceuticals (La Jolla, CA).

Examples of cyclodextrins suitable for use in compositions of a neuroactive steroid, for example, allopregnanolone, may include the cyclodextrins described in U.S. Patents 5,874,418; 6,046,177; and 7,635,733, which are incorporated herein by reference. Other examples of suitable cyclodextrins for use in preparations of a neuroactive steroid include, without limitation, α-cyclodextrin; β-cyclodextrin; γ-cyclodextrin; methyl-α-cyclodextrin; methyl-β-cyclodextrin; methyl-γ-cyclodextrin; ethyl-β-cyclodextrin; butyl-α-cyclodextrin; butyl-β-cyclodextrin; butyl-γ-cyclodextrin; pentyl-γ-cyclodextrin; hydroxyethyl-β-cyclodextrin; hydroxyethyl-γ-cyclodextrin; 2-hydroxypropyl-α-cyclodextrin; 2-hydroxypropyl-β-cyclodextrin; 2-hydroxypropyl-γ-cyclodextrin; 2-hydroxybutyl-β-cyclodextrin; acetyl-α-cyclodextrin; acetyl-β-cyclodextrin; acetyl-γ-cyclodextrin; propionyl-β-cyclodextrin; butyryl-β-cyclodextrin; succinyl-α-cyclodextrin; succinyl-β-cyclodextrin; succinyl-γ-cyclodextrin; benzoyl-β-cyclodextrin; palmityl-β-cyclodextrin; toluenesulfonyl-β-cyclodextrin; acetimethyl-β-cyclodextrin; acetylbutyl-β-cyclodextrin; glycosyl-α-cyclodextrin; glycosyl-β-cyclodextrin; glycosyl-γ-cyclodextrin; maltosyl-α-cyclodextrin; maltosyl-β-cyclodextrin; maltosyl-γ-cyclodextrin; carboxymethyl ether of α-cyclodextrin; carboxymethyl ether of β-cyclodextrin; carboxymethyl ether of γ-cyclodextrin; carboxymethyl ether of α-cyclodextrin; carboxymethyl ether of β-cyclodextrin; carboxymethyl ether of γ-cyclodextrin; carboxymethyl ethyl β-cyclodextrin; phosphate ester of α-cyclodextrin; phosphate ester of β-cyclodextrin; phosphate ester of γ-cyclodextrin; 3-trimethylammonium-2-hydroxypropyl-β-cyclodextrin; sulfobutyl ether β-cyclodextrin; carboxymethyl-α-cyclodextrin; carboxymethyl-β-cyclodextrin; carboxymethyl-γ-cyclodextrin, and combinations thereof.

Preferred cyclodextrins include, but are not limited to, alkyl cyclodextrins, hydroxyalkyl cyclodextrins such as hydroxypropyl-β-cyclodextrin, carboxyalkyl cyclodextrins, and sulfoalkyl ether cyclodextrins such as sulfobutyl ether β-cyclodextrin.

In particular embodiments, the cyclodextrin is an alpha, beta, or gamma cyclodextrin having multiple charges (e.g., positive or negative) on the surface. In more particular embodiments, the cyclodextrin is a β-cyclodextrin comprising or including multiple functional groups that are negatively charged at physiological pH. Examples of such functional groups include, but are not limited to, carboxylic acid groups (carboxylate), sulfonate (RSO ₃ ^- ), phosphonate groups, phosphinate groups, and amino acids that are negatively charged at physiological pH. The charged functional groups can be bonded directly to the cyclodextrins or can be attached via a spacer such as an alkylene chain. The number of carbon atoms in the alkylene chain can vary, but is typically from about 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Highly sulfated cyclodextrins are described in U.S. Patent No. 6,316,613.

In one embodiment, the cyclodextrins are β-cyclodextrin functionalized with multiple sulfobutyl ether groups. Such cyclodextrin is sold under the trade name CAPTISOL®.

CAPTISOL® is a polyanionic derivative of beta-cyclodextrin with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether or sulfobutyl ether (SBE) spacer group.

CAPTISOL® is not a single chemical substance but comprises a large number of polymeric structures of varying degrees of substitution and isomers with positional/regional differences, prescribed and controlled for a single sample by a proprietary manufacturing process, consistently applied in practice and improved to control impurities.

CAPTISOL® contains six to seven sulfobutyl ether groups per cyclodextrin molecule.

Due to the very low pKa value of the sulfonic acid groups, CAPTISOL® has multiple negative charges at physiological pH values. The chain of four butyl carbons, combined with the repulsion of the negative charges of the end groups, creates the opportunity to "pull out" the cyclodextrin cavity. This results in stronger binding to drug candidates than can be achieved with other modified cyclodextrins. It also creates the possibility of ionic interactions between the cyclodextrin and the positively charged drug molecule. In addition, these derivatives provide the molecule with improved solubility and safety during parenteral administration. Compared to beta-cyclodextrin, CAPTISOL® provides higher interaction characteristics and excellent aqueous solubility of over 100 grams/100 ml, a 50-fold increase.

In other embodiments, the cyclodextrins have multiple functional groups that are negatively charged at physiological pH. Suitable positively charged groups include, but are not limited to, quaternary ammonium groups. Exemplary cyclodextrins include, but are not limited to, mono-6(A)-butylammonium-6(A)-deoxy-beta-cyclodextrin tosylate (BuAM-beta-CD) and amine- and guanidine-derivatized β-cyclodextrin (PCD).

Preferably, the cyclodextrin is present in an amount of from about 0.1% to about 40% w/w of the total composition, preferably from about 5% to about 40% w/w, more preferably from about 10% to about 40% w/w, more preferably from about 10% to about 35% w/w. In certain embodiments, the concentration of cyclodextrins is from about 15% to about 35% w/w, preferably from about 20% to about 35% w/w, more preferably from about 30% to about 35% w/w. In one embodiment, the composition comprises from about 1 to 2, preferably about 1.5 mg of a neuroactive steroid (e.g., allopregnanolone) per ml of cyclodextrin, e.g., CAPTISOL®.

Ion exchange resins

Ion exchange resins (IERs) are high molecular weight, water-insoluble polymers containing or incorporating fixed positively or negatively charged functional groups in the matrix that have an affinity for oppositely charged counterions. IERs are solid, insoluble, high molecular weight polyelectrolytes that can exchange ions with the environment reversibly and stoichiometrically. IERs are a styrene (divinylbenzene) copolymer containing or incorporating

- acid groups: carboxylic or sulfonic acids carboxyl or sulfonic in the case of cationic E.R.

- main groups: quaternary ammonium in case of anionic E.R.

Based on the nature of the ionic species involved in the exchange, the IE process is called either cation exchange (CE) or anion exchange (AE). The IE process is competitive in nature. In practice, the drug in ionic form (usually a solution) is mixed with the corresponding IER to form a complex called a “resinate”.

The activity of resinates is determined by several factors, such as:

1. pH and temperature of the drug solution;

2. Molecular weight and charge density of the drug and IER;

3. Geometry;

4. Stirring speed;

5. Ionic strength of the drug solution;

6. Degree of crosslinking and particle size IER;

7. Nature of the solvent; and; and

8. Contact time between drug particles and IER.

Typically, IER consists of spherical beads with a diameter of approximately 0.5-1.2 mm. The most common type is opaque yellow beads, although beads of other colors have been described. The structure of each spherical IER particle is similar to that of the particles that make up a homogeneous gel. The compression or expansion of the spherical volume that occurs corresponds to the ionic environment in which the IER is located.

The main disadvantage of controlled or sustained release systems is dose dumping, which increases the risk of toxic effects. Ion exchange resins have improved drug retention and dose dumping prevention properties. The polymeric (physical) and ionic (chemical) properties of the ion exchange resin provide a more uniform drug release than simple matrices (since they have only physical properties). Drug encapsulated in strong IER resinates is the simplest form of controlled or sustained release delivery system. Resinates can be directly encapsulated, suspended in liquid, suspended in matrices, or pressed into tablets. The drug will be slowly released by the ion exchange effect and absorbed.

Microencapsulation of resinates provides better control of drug release during oral administration or release from a depot. Drug absorption from coated resinates is a consequence of the entry of counterions into the coated resinates and the release of drug ions from the drug-resin complex as a result of the ion exchange process and the diffusion of drug ions through the membrane into the dissolution medium. The intended release rate at the required level can be obtained by optimizing the coating thickness. Microencapsulation of resinates can be achieved by air-suspension coating (Wurster process), interfacial polymerization, evaporation of the volatile solvent, or pan coating.

Modification of the coating process of resinate formulations, such as pre-treatment with polyethylene glycol 400, can be used to maintain geometry and improve the coating process. The pre-treated resinates are then coated with ethyl cellulose or any other water-insoluble polymer. Polyethylene glycol helps to control the swelling rate of the matrix in water, while the outer ethyl cellulose coating changes the diffusion pattern of ions into or out of the system. The major drawback of controlled or sustained release systems is dose dumping, which increases the risk of toxic effects. Ion exchange resins have improved drug retention and dose dumping prevention properties. The polymeric (physical) and ionic (chemical) properties of the ion exchange resin provide a more uniform drug release than that from simple matrices (since they have only physical properties).

Drug encapsulated in strong IER resinates is the simplest form of controlled or sustained release delivery system. Resinates can be directly encapsulated, suspended in liquid, suspended in matrices or compressed into tablets. The drug will be slowly released by ion exchange and absorbed.

There are several ion exchange resins suitable for intravenous drug delivery. For example, Shimada, et al., in Jpn J. Antibiot. 1985 Sep;38(9):2496-502, describe a clinical study of an unmodified dry intravenous ion exchange resin coated with normal human immunoglobulin, SM-4300, which demonstrated the drug's efficacy without antipyretic action, opsonic effect, or impairment of healing.

Lipid carriers

To facilitate the administration of neuroactive steroids that have poor water solubility, various lipid carriers can be used.

Lipid emulsions

The neuroactive steroids may be combined, suspended, or dissolved using a lipid emulsion. Lipid emulsions are known in the art. See, for example, U.S. Patent No. 6,361,792 to Long, et al.; U.S. Patent No. 7,550,155 to Zhang, et al., and U.S. Patent Application Publication No. US 2006/0067952. Lipid emulsion formulations typically include one or more neuroactive steroids, an oil component, an emulsifier, and water.

The oil component may be a monoglyceride, a diglyceride, a triglyceride, or a combination thereof. In some cases, the oil component comprises an ester formed from one or more fatty acids and an alcohol other than glycerol. The oil component may be, for example, vegetable oils such as almond oil, borage oil, blackcurrant seed oil, corn oil, safflower oil, soybean oil, sesame oil, cottonseed oil, peanut oil, olive oil, rapeseed oil, coconut oil, palm oil, canola oil, or a combination thereof. Vegetable oils are typically long-chain triglycerides derived from C ₁₄ -C ₂₂ fatty acids. The oil component may also include medium chain triglycerides formed from _C8 - _C12 fatty acids, such as Miglyol 812 oil, Crodamol® GTCC-PN, or Neobees M-5.

The emulsifier serves to stabilize the lipid emulsion by preventing the emulsion from separating into separate oil and water phases. Suitable emulsifiers include, but are not limited to, mono- and di-esters of fatty acids and propylene glycol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene copolymers and block copolymers, salts of fatty alcohol sulfates of sorbitan fatty acid esters, polyethylene glycol esters of glycerol esters, oil and wax emulsifiers, glycerol monostearate, glycerol sorbitan fatty acid esters, and phospholipids. In some cases, the emulsifier is a phospholipid.

In some cases, the emulsifier is a vitamin E derivative. Suitable vitamin E derivatives include, but are not limited to, α-tocopheryl oxalate, α-tocopheryl malonate, α-tocopheryl succinate, α-tocopheryl glutarate, α-tocopheryl adipate, α-tocopheryl pimelate, α-tocopheryl suberate, α-tocopheryl azelaine, and D-α-tocopheryl polyethyleneglycol 1000 succinate (vitamin E TPGS).

Typical phospholipids include phosphatidylcholine, lecithin (a mixture of choline ester and phosphorylated diacylglyceride), phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid containing from about 4 to 22 carbon atoms, and more often from about 10 to 18 carbon atoms and varying degrees of saturation. Preferably, the phospholipid is a naturally occurring phospholipid. Naturally occurring phospholipids include soy lecithin, egg lecithin, hydrogenated soy lecithin, hydrogenated egg lecithin, sphingosine, gangliosides and phytosphingosine, and combinations thereof.

Suitable lipid emulsions typically comprise from about 1% to 40% w/v of an oil component and from about 0.1% to 7.5% w/v of an emulsifier. Suitable commercially available lipid emulsions include lipid emulsions containing or consisting of soybean oil, such as Intralipid® 10%, Intralipid® 20%, and Intralipid® 30%, and lipid emulsions containing or consisting of a mixture of soybean oil and safflower oil, such as Liposyn® II 10% and Liposyn® II 20%.

The lipid emulsions may in some cases contain one or more additional components. For example, the lipid compositions may contain one or more non-aqueous compatible cosolvents, such as an alcohol or a glycol. In some preferred compositions, glycerol and/or propylene glycol are present as a cosolvent.

Many lipid emulsions are capable of supporting bacterial growth. Accordingly, in some cases, one or more components may be added to the lipid emulsion composition to prevent or retard bacterial growth, such as disodium edetate, citric acid, metabisulfate, benzyl alcohol, one or more parabens, chlorobutanol, phenol, sorbic acid, or thimerosal.

In addition, lipid emulsions may contain one or more substances used to alter or stabilize the pH of the solution, including phosphate buffers, acetate buffers, and citrate buffers.

In one embodiment, the composition is an oil-in-water emulsion comprising or consisting of a therapeutically effective amount of one or more neuroactive steroids dissolved in a solution comprising or consisting of about 1% w/v to 25% w/v soybean oil, about 0.5% w/v to 7.5% w/v egg yolk phospholipid, and about 0.5% w/v to 5% w/v compatible cosolvent.

In another embodiment, the composition is an oil-in-water emulsion comprising or consisting of a therapeutically effective amount of one or more neuroactive steroids dissolved in a solution comprising or consisting of about 1% w/v to 15% w/v soybean oil, about 1% w/v to 15% w/v safflower oil, about 0.5% w/v to 7.5% w/v egg yolk phospholipid, and about 0.5% w/v to 5% w/v compatible cosolvent.

Lipid emulsions may be used as described above or may be incorporated into parenteral preparations described below.

Liposomes

One or more neuroactive steroids may be incorporated into liposomes. As is known in the art, liposomes are typically prepared from phospholipids or other lipid substances. See, for example, "Remington: The science and practice of pharmacy", 20th Edition, Jennaro et. al., (Phila, Lippencott, Williams, and Wilkens, 2000).

Liposomes are obtained from mono- or multilayer hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The described compositions in the form of liposomes can contain, in addition to one or more neuroactive steroids, stabilizers, preservatives, fillers and other suitable auxiliary substances.

Examples of suitable lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for creating liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York p. 33 et seq., 1976. The liposomes may be cationic liposomes (e.g., based on DOTMA, DOPE, DC-cholesterol) or anionic liposomes. If desired, the liposomes may further contain proteins to provide an effect on a specific cell. A composition containing a compound and a cationic liposome may be injected into the blood flowing to a target organ or inhaled into the respiratory tract to affect cells of the respiratory tract.

One or more neuroactive steroids may be formulated using commercially available liposome preparations such as LIPOFECTIN®, LIPOFECTAMIE® (GIBCO-BRL, Inc., Gaithersburg, Md.), SUPERFECT® (Qiagen, Inc. Hilden, Germany), and TRANSFECTAM® (Promega Biotec, Inc., Madison, Wis.), as well as other liposomes prepared according to methods generally accepted in the art. Liposomes may also be used in cases where diffusion of the compound or delivery of the compound from the liposome is calculated at a certain rate or dose.

One or more neuroactive steroids may be formulated using niosomes. Niosomes are multilayer or unilamellar particles prepared using nonionic surfactants. An aqueous solution of the solute is surrounded by a bilayer resulting from the organization of the surfactant macromolecules. Similar to liposomes, niosomes are used for targeted delivery of, for example, anticancer drugs including methotrexate, doxorubicin, and immunoadjuvants. In general, they are considered to be distinct from transferosomes, particles prepared from an amphiphilic carbohydrate and an amine group containing or incorporating polymers such as chitosan.

One or more neuroactive steroids can also be delivered using nanoerythrosomes.

Nanoerythrosomes are nanoparticles obtained from red blood cells by dialysis through filters of defined pore size. These particles may contain one or more neuroactive steroids.

Lipid nanoemulsions

Lipid nanoemulsions may also be used. Lipid nanoemulsions are known in the art. See, for example, U.S. Patent Application Publication No. US 2007/0207173, Chen, et al., and U.S. Patent Application Publication No. US 2001/0045050, Elbayoumi, et al. Lipid nanoemulsions may be prepared by microemulsifying any of the lipid emulsions described above using, for example, a high-pressure homogenizer or by a phase inversion temperature (PIT) method.

Preferred lipid nanoemulsions containing or including neuroactive steroids include vitamin E succinate and/or vitamin E TPGS as emulsifiers.

If necessary, the lipid nanoemulsion can be further lyophilized. See, for example, US Patent Publication No. US 2011/0015266.

The lipid nanoemulsions may be used as described above or incorporated into parenteral or non-parenteral compositions described below.

The preconcentrate comprises an oil phase that comprises at least one fatty acid-containing oil. The fatty acid-containing oils of the present invention comprise at least one polyunsaturated fatty acid. The term "polyunsaturated fatty acids" refers to fatty acids that contain at least 50 percent by weight or more polyunsaturated fatty acids. Polyunsaturated fat is found in cereals, fish and seafood (herring, salmon, mackerel, halibut), soybeans, and fish oil. Polyunsaturated fatty acids include omega-3 fatty acids and omega-6 fatty acids. Polyunsaturated fatty acids include linoleic acid and linolenic acid.

Preferred polyunsaturated fatty acids include eicosapentaenoic acid, eicosapentaenoic acid salts, docosahexaenoic acid, docosahexaenoic acid salts, eicosapentaenoic acid triglycerides, docosahexaenoic acid triglycerides, eicosapentaenoic acid ethyl esters, or docosahexaenoic acid ethyl esters.

Polyunsaturated fatty acids include oils containing omega-3 fatty acids and medium-chain triglycerides (MCT). The medium-chain triglyceride has about 6 to 14 carbon atoms, preferably about 8 to 12 carbon atoms. A preferred medium-chain triglyceride includes, for example, caprylic/capric acid triglyceride such as "Migriol 810", "Migriol 812" (both trade names, manufactured by Huls Co., Ltd., available from Mitsuba Trading Co., Ltd.), glycerol tricaprylate (tricaprylin) such as "Panasate 800" (trade name, manufactured by NOF Corporation, Japan).

The preconcentrate includes an emulsifier component. The emulsifier component has one or more surfactants. Surfactants include any molecule having a polar head that energetically prefers solvation by water and a hydrophobic tail that is not solvated by water. The ratio of the oil phase to the emulsifier component is important for the toxicity of the nanoemulsion formed from the preconcentrate. Surfactants suitable for use with the preconcentrate and emulsion include a variety of anionic and nonionic surfactants, as well as other emulsifying compounds that are capable of causing the formation of oil-in-water emulsions; provided that they are GRAS (generally recognized as safe) and approved for human consumption, such as lecithin, Solutol HS-15 (polyoxyethylene esters of 12-hydroxystearic acid), polysorbate 80, or Cremophor EL (polyethoxylated castor oil). See McCutcheon's Volume 1: Emulsifiers and Detergents North American Edition, 1996 (incorporated herein by reference).

Preparations for parenteral administration

The compounds (e.g., allopregnanolone) described herein can be formulated for parenteral administration. Preferred doses, dosage forms, or routes of administration are those for parenteral administration, such as intranasal, buccal, intravenous, intramuscular, subcutaneous, intraperitoneal, mucosal, sublingual, intraocular, and topical administration (e.g., intravenous or intramuscular). In another embodiment, the informational material can include instructions for using a compound described herein in a suitable individual, such as a human, such as a human already having or at increased risk for developing a disorder described herein. In some preferred embodiments, at least one of a neuroactive steroid and a benzodiazepine or an anesthetic/sedative is formulated for parenteral administration. In some embodiments, both the neuroactive steroid and the benzodiazepine or anesthetic/sedative are included in the parenteral formulation.

Preparations for parenteral administration can be prepared as aqueous compositions using methods known in the art. Typically, such compositions can be prepared as injectables, such as solutions or suspensions; solid forms suitable for use in preparing solutions or suspensions by adding a solvent before injection; emulsions, such as water-in-oil (w/o) emulsions, oil-in-water (o/w) emulsions, and microemulsions, liposomes or emulsions thereof.

In some embodiments, parenteral formulations are prepared as an injectable formulation, such as for intravenous administration. In some embodiments, the parenteral formulation comprises a compound (e.g., a neurosteroid as described herein, such as allopregnanolone), and a cyclodextrin, such as a β-cyclodextrin, such as a sulfobutyl ether β-cyclodextrin, such as CAPTISOL®). In some embodiments, the parenteral formulation comprises allopregnanolone and a sulfobutyl ether β-cyclodextrin, such as CAPTISOL®.

The carrier can be a solvent or dispersion medium containing or consisting of, for example, water (e.g., water for injection, USP), ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof.

Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion and/or by using surfactants. In many cases, it is preferable to include isotonic substances, such as sugars or sodium chloride.

Solutions and dispersions of the active compounds as a free acid or base, or their pharmacologically acceptable salts, can be prepared in water or another solvent or dispersion medium, suitably mixed with one or more pharmaceutically acceptable excipients, including, but not limited to, surfactants, dispersants, emulsifiers, pH modifying agents, and combinations thereof.

Suitable surfactants may be anionic, cationic, amphoteric, or nonionic surfactants. Suitable anionic surfactants include, but are not limited to, surfactants that contain or include carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include long-chain sodium, potassium, ammonium, and alkyl aryl sulfonates such as sodium dodecylbenzenesulfonate; sodium dialkyl sulfosuccinates such as sodium dodecylbenzenesulfonate; sodium dialkyl sulfosuccinates such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethyl benzyl ammonium chloride, polyoxyethylene, and an amine derived from coconut fatty acids. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acetate, sucrose acetate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene derivatives of hydrogenated tallow fatty acid amides. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

The preparation may contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The composition may also contain an antioxidant to prevent degradation of the active substance (c).

Typically, the preparation is adjusted to a pH of 3-8 for parenteral administration after dilution. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers.

Water-soluble polymers are often used in parenteral formulations. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethyleneglycol.

Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount into an appropriate solvent or dispersion medium with one or more of the excipients enumerated above, if necessary, followed by filter sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from among those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization, which yield a powder of the active ingredient plus any additional desired ingredient from a solution previously sterilized by filtration. Powders can be prepared such that the particles are porous in nature, which can enhance dissolution of the particles. Methods for preparing porous particles are well known in the art.

In some embodiments, at least one of the neuroactive steroid or benzodiazepine or anesthetic/sedative is formulated for intranasal, buccal, intramuscular or intravenous administration (e.g., intramuscular or intravenous administration). In some embodiments, both the neuroactive steroid and the benzodiazepine or anesthetic/sedative are formulated for intranasal, buccal, intramuscular or intravenous administration (e.g., intramuscular or intravenous administration).

The parenteral formulations described herein may be formulated for controlled release, including immediate release, delayed release, extended release, pulsatile release, and combinations thereof.

Nano- and microcapsules

For parenteral administration, the compounds and, optionally, one or more additional active substances can be incorporated into microparticles, nanoparticles, or combinations thereof that provide controlled release. In embodiments where the compositions contain two or more drugs, the drugs can be formulated for the same type of controlled release (e.g., delayed, extended, immediate, or pulsatile release) or the drugs can be independently formulated for different types of release (e.g., immediate and delayed, immediate and extended, delayed and extended, delayed and pulsatile release, etc.).

For example, the compounds and/or one or more additional active reagents can be incorporated into polymeric microparticles that provide controlled release of the drug(s). The release of the drug(s) is controlled by diffusion of the drug(s) from the microparticles and/or degradation of the polymer particles by hydrolysis and/or enzymatic degradation. Suitable polymers include ethylcellulose and other natural or synthetic cellulose derivatives.

Polymers that dissolve slowly and form a gel in an aqueous medium, such as hydroxypropyl methylcellulose or polyethylene oxide, can also be used as materials for a drug comprising or including microparticles. Other polymers include, but are not limited to, polyanhydrides, poly(ester anhydride), polyhydroxy acids such as polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly-3-hydroxybutyrate (PHB) and their copolymers, poly-4-hydroxybutyrate (P4HB) and its copolymers, polycaprolactone and its copolymers, and combinations thereof.

Alternatively, the drug(s) may be incorporated into microparticles that are made of materials that are insoluble in aqueous solution or slightly soluble in aqueous solution but can be destroyed in the gastrointestinal tract by means including enzymatic degradation, surfactant action of bile acids, and/or mechanical erosion. As used herein, the term "slightly water soluble" refers to materials that do not dissolve in water within 30 minutes. Preferred examples include fats, fatty substances, waxes, waxy substances, and mixtures thereof. Suitable fats and fatty substances include fatty alcohols (such as lauryl, myristyl, cetyl stearyl, or cetostearyl alcohol), fatty acids and derivatives including, but not limited to, fatty acid esters, fatty acid glycerides (mono-, di-, and triglycerides), and hydrogenated fats. Specific examples include, but are not limited to, hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated oils available under the trade name Sterotex®, stearic acid, cocoa butter, and stearyl alcohol. Suitable waxes and wax-like substances include natural or synthetic waxes, hydrocarbons, and conventional waxes. Specific examples of waxes include beeswax, Glycowax®, hydrogenated castor oil, carnauba wax, paraffins, and candelilla wax. As used herein, a wax-like substance is defined as any substance that is generally solid at room temperature and has a melting point of approximately 30 to 300°C.

In some cases, it may be desirable to modify the rate of water penetration into the microparticles. For this purpose, rate-regulating (wicking) agents may be included in the formulation along with the fatty substances or waxes listed above. Examples of rate-regulating agents include certain starch derivatives (e.g., maltodextrin derived from waxy maize starch and drum-dried maize starch), cellulose derivatives (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and carboxymethylcellulose), alginic acid, lactose, and talc. In addition, a pharmaceutically acceptable surfactant (e.g., lecithin) may be added to facilitate the disintegration of such microparticles.

Proteins that are insoluble in water, such as zein, can also be used as suitable substances for creating a drug containing or including microparticles. In addition, proteins, polysaccharides and combinations thereof that are soluble in water can be combined with the drug in the microparticles and then cross-linked to form an insoluble lattice. For example, cyclodextrins can be complexed with individual drug molecules and then cross-linked.

Encapsulation or inclusion of a drug in carrier materials to form drug-containing or drug-containing microparticles can be achieved using known drug-forming methods. In the case of formulations with fatty substances, waxes or waxy substances, the carrier material is typically heated above its melting point and the drug is added to form a mixture containing drug particles suspended in the carrier material, the drug dissolved in the carrier material or a mixture thereof. The microparticles can then be formed by several methods, including but not limited to solidification, extrusion, spray cooling or aqueous dispersion methods. In a preferred method, the wax is heated above its melting point, the drug is added and the molten wax-drug mixture is cooled with constant stirring while the mixture cools. Alternatively, the molten wax-drug mixture can be extruded and spheronized to form pellets or beads. A detailed description of these methods can be found in "Remington: The science and practice of pharmacy", 20th Edition, Jennaro et. al., (Phila, Lippencott, Williams, and Wilkens, 2000).

For some carrier materials, it may be desirable to use a solvent evaporation method to form microcapsules containing or including the drug. In such a case, the drug and carrier material are dissolved together in a common solvent, and the microcapsules may then be prepared by several methods, including, but not limited to, forming an emulsion in water or other suitable media, spray drying, or evaporating the solvent from the bulk solution and grinding the resulting material.

In some embodiments, the particulate drug is uniformly dispersed in a water-insoluble or poorly water-soluble substance. In order to reduce the particle size of the drug in the composition to a minimum, the drug powder can be milled to obtain fine particles before inclusion in the composition. For this purpose, a jet milling method can be used. In some embodiments, the particulate drug is uniformly dispersed in a wax or waxy substance by heating the wax or waxy substance above its melting point and adding the drug particles while stirring the mixture. In such a case, a pharmaceutically acceptable surfactant can be added to the mixture to facilitate dispersion of the drug particles.

The particles may also be coated with one or more release-modifying coatings. Solid fatty acid esters that are hydrolyzed by lipases may be spray-coated onto the microparticles or drug particles. Zein is an example of a naturally occurring water-insoluble protein. It may be coated onto drug-containing or drug-incorporating microparticles or drug particles by spray coating or wet granulation. In addition to naturally occurring water-insoluble substances, certain digestive enzyme substrates may be subjected to cross-linking procedures that result in the formation of an insoluble network. Many methods for cross-linking proteins initiated by physical and chemical means have been described. One of the most common methods for obtaining cross-linking is the use of chemical cross-linking agents. Examples of chemical cross-linking agents include aldehydes (glutaraldehyde and formaldehyde), epoxy compounds, carbodiimides, and genipin. In addition to the above crosslinking agents, oxidized and purified sugars are used to crosslink gelatin (Cortesi, R., et al., Biomaterials 19 (1998) 1641-1649). Crosslinking can also be accomplished using enzymatic means; for example, transglutaminase has been approved as a GRAS substance for crosslinking seafood. Finally, crosslinking can be initiated by physical means such as heat treatment, UV irradiation, and gamma irradiation.

To form a cross-linked protein coating layer that surrounds drug-containing or drug-incorporating microparticles or drug particles, a water-soluble protein may be sprayed onto the microparticles and then cross-linked by one of the methods described above. Alternatively, drug-containing or drug-incorporating microparticles may be microencapsulated in protein by coacervation - phase separation (e.g., by adding salts) and subsequent cross-linking. Some proteins suitable in this regard include gelatin, albumin, casein, and gluten.

Polysaccharides can also be cross-linked to form a water-insoluble network. For many polysaccharides, cross-linking can be accomplished by reaction with calcium salts or multivalent cations, which cross-link the polymer backbones. Pectin, alginate, dextran, amylose, and guar gum can be cross-linked in the presence of multivalent cations. Complexes of oppositely charged polysaccharides can also be created; pectin and chitosan, for example, can form complexes through electrostatic interactions.

In some embodiments, at least one of the neuroactive steroid and/or the benzodiazepine or the anesthetic/sedative is formulated for intranasal, buccal, intramuscular, or intravenous administration (e.g., intramuscular or intravenous administration). In some embodiments, both the neuroactive steroid and the benzodiazepine or the anesthetic/sedative are formulated for intranasal, buccal, intramuscular, or intravenous administration (e.g., intramuscular or intravenous administration).

The compounds described herein may be formulated as a depot injection. In a depot injection, the active substance is formulated with one or more pharmaceutically acceptable carriers that provide gradual release of the active agent over a period of several hours or days following injection. The depot preparation may be administered by any suitable route; however, the depot preparation is typically administered by subcutaneous or intramuscular injection.

Various carriers may be included in the depot preparation to provide controlled release of the active substance. In some cases, the depot preparations comprise one or more biodegradable polymeric or oligomeric carriers. Suitable polymeric carriers include, but are not limited to, poly(lactic acid) (PLA), poly(lactic acid)-co-(glycolic acid) (PLGA), block copolymers of poly(lactic acid) and polyethylene glycol (PLA-PEG), polyanhydrides, poly(ester anhydride), polyglycolide (PGA), poly-3-hydroxybutyrate (PHB) and copolymers thereof, poly-4-hydroxybutyrate (P4HB), polycaprolactone, cellulose, hydroxypropyl methylcellulose, ethylcellulose, as well as mixtures, derivatives, copolymers and combinations thereof.

In depot preparations containing or including a polymeric or oligomeric carrier, the carrier and the active substance may be included in the composition as a solution, emulsion, or suspension. One or more neuroactive steroids, and optionally one or more additional active substances, may also be included in polymeric or oligomeric microparticles, nanoparticles, or combinations thereof.

In some cases, the preparation is a liquid and is designed to solidify or gel (i.e., form a hydrogel or organogel) after injection. Solidification or gelation may occur as a result of a change in the solubility of the composition after injection, or, for example, by injecting a prepolymer mixed with an initiator and/or crosslinking agent. The polymer matrix, polymer solution, or polymer particles entrap the active agent at the injection site. As the polymer carrier gradually degrades, the active agent is released by diffusion of the agent out of the matrix and/or by degradation of the matrix as it is absorbed. The rate of release of the active agent from the injection site can be controlled by changing, for example, the chemical composition, molecular weight, crosslinking density, and concentration of the polymer carrier. Examples of such systems include those described in U.S. Pat. Nos. 4,938,763, 5,480,656, and 6,113,943.

Depot preparations can also be prepared by using other release rate regulating excipients, including hydrophobic substances, including suitable oils (e.g. peanut oil, corn oil, sesame oil, cottonseed oil, etc.) and phospholipids, ion exchange resins, and sparingly soluble carriers.

The depot preparation may further comprise a solvent or dispersion medium comprising or including, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and/or by using surfactants. In many cases, it is preferable to include isotonic substances, such as sugars or sodium chloride.

Solutions and dispersions of a neuroactive steroid or benzodiazepine or an anesthetic/sedative in the form of a free acid or base or pharmacologically acceptable salts thereof can be prepared in water or other solvent or dispersion medium suitably mixed with one or more pharmaceutically acceptable excipients, including but not limited to surfactants, dispersants, emulsifiers, pH modifiers and combinations thereof.

Suitable surfactants may be anionic, cationic, amphoteric, or nonionic surfactants. Suitable anionic surfactants include, but are not limited to, surfactants that contain or include carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include long-chain sodium, potassium, ammonium, and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; sodium dialkyl sulfosuccinates such as sodium dodecylbenzene sulfonate; sodium dialkyl sulfosuccinates such as sodium bis(2-ethylthioxyl)sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethyl benzyl ammonium chloride, polyoxyethylene, and an amine derived from coconut fatty acids. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acetate, sucrose acetate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amides. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

The preparation may contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The composition may also contain an antioxidant to prevent degradation of the active substance (c).

Typically, the preparation is adjusted to a pH of 3-8 for parenteral administration after dilution. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers.

Water-soluble polymers are often used in parenteral formulations. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethyleneglycol.

Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount into an appropriate solvent or dispersion medium with one or more of the excipients enumerated above, if necessary, followed by filter sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from among those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization, which yield a powder of the active ingredient plus any additional desired ingredient from a solution previously sterilized by filtration. Powders can be prepared such that the particles are porous in nature, which can enhance dissolution of the particles. Methods for preparing porous particles are well known in the art.

In some embodiments, at least one of the neuroactive steroid and/or the benzodiazepine or the anesthetic/sedative is formulated for intranasal, buccal, intramuscular, or intravenous administration (e.g., intramuscular or intravenous administration). In some embodiments, both the neuroactive steroid and the benzodiazepine or the anesthetic/sedative are formulated for intranasal, buccal, intramuscular, or intravenous administration (e.g., intramuscular or intravenous administration).

Combinations of active compounds

The composition described herein can be administered additionally with other active compounds such as anesthetics or sedatives, for example, a benzodiazepine, for example midazolam, propofol, pentobarbital, and ketamine.

Methods of use

The composition described herein can be administered to an individual in need thereof for the treatment of a disorder described herein. Examples of disorders include epilepsy, such as convulsive status epilepticus, such as incipient status epilepticus, advanced status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; seizure, such as acute recurrent seizures, seizure clusters.

In some embodiments, a composition described herein (e.g., a composition comprising allopregnanolone) is administered to an individual under general anesthesia.

Seizures and seizure-related disorders

Seizures described herein may include epileptic seizures; acute recurrent seizures; seizure clusters; persistent seizures; continuous seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, such as refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; seizures associated with emotion; focal seizures; gelastic seizures; primarily generalized seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonic seizures; multifocal seizures; seizures with onset in the neonatal period; nocturnal seizures; seizures in occipito-lobar epilepsy; posttraumatic seizures; mild seizures; benign epileptic seizures of childhood; visual reflex seizures; or seizures due to drug withdrawal.

Publications cited in this document and the materials for which they are cited are expressly incorporated by reference.

Status epilepticus (SE)

Status epilepticus (SE) encompasses a group of disorders involving persistent or recurrent seizures. Standard of care in the United States of America (US) typically involves initial treatment of status epilepticus with a benzodiazepine as first-line treatment for 'initial' SE. A recent study found that 26.6% of patients did not respond to first-line treatment with intramuscular (IM) midazolam and 36.6% of patients did not respond to intravenous (IV) lorazepam (Silbergleit et al, 2012).

If patients continue to have seizures after a benzodiazepine, they are treated with a second-line antiepileptic drug for "advanced" SE, which in the United States is usually IV fosphenytoin or IV phenytoin. If patients continue to have seizures after first- and second-line drugs, they are considered to have entered the "refractory" SE (RSE) stage.

The accepted treatment for patients with RSE is general anesthesia (GA) induced by a drug such as midazolam, propofol, pentobarbital, or ketamine. There is no approved drug for the treatment of RSE, and clinical data on the comparative efficacy of commonly used drugs are insufficient (Shorvon, 2011). The goal of treatment with these drugs for GA is to induce a burst-suppression electroencephalographic state in an attempt to block the excitotoxic brain damage that appears to result from the continuous seizure activity in the brain. Burst-suppression is an electroencephalographic pattern consisting of alternating periods of high-amplitude slow waves (burst) and periods of flat electroencephalogram (EEG) (suppression); the pattern is associated with comatose states of various etiologies and with the anesthetic state (Amzica & Kroeger, 2011). The goal of treatment is that after recovery from general anesthesia, the patient will have no clinical or electroencephalographic evidence of paroxysmal activity. EEG and EEG terminology are described in Hirsch et al., J. Clin. Neurophysiol. 2013; 30: 1–27, which is incorporated by reference in its entirety.

Patients who experience super-refractory SE (SRSE) or super-refractory generalized SE are a subset of patients with RSE who experience ongoing or recurrent seizures for 24 hours or more after initiation of anesthetic therapy; this state is often seen as a return of paroxysmal activity when the patient's anesthetic therapy is discontinued. It has been estimated that ~15% of patients admitted to hospital with SE develop a super-refractory state (Shorvon & Ferlisi, 2011).

SE may include, for example, convulsive status epilepticus, such as incipient status epilepticus, advanced status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of status epilepticus seizures, and may include incipient status epilepticus, advanced status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Incipient status epilepticus is treated with first-line drugs. Advanced status epilepticus is characterized by status epilepticus seizures that continue despite treatment with first-line drugs, and second-line drugs are administered. Refractory status epilepticus is characterized by status epilepticus seizures that continue despite treatment with first-line and second-line drugs, and usually general anesthesia. Super-refractory status epilepticus is characterized by status epilepticus seizures that continue despite treatment with first-line and second-line drugs, and general anesthesia for 24 hours or more.

Nonconvulsive status epilepticus may include, for example, focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, atypical nonconvulsive status epilepticus; generalized nonconvulsive status epilepticus, such as late-onset nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

The compositions described herein can also be administered as a prophylactic agent to an individual having a CNS disorder, such as traumatic brain injury, status epilepticus, such as convulsive status epilepticus, such as incipient status epilepticus, advanced status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of an epileptic seizure.

Epilepsy

Epilepsy is a disorder of the brain characterized by recurrent seizures. Types of epilepsy may include, but are not limited to, generalized epilepsy such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with generalized tonic-clonic seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy such as temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

EXAMPLES

Example 1. ALLO composition in captisol

Four prototypes of allopregnanolone in Captisol were created: 5 mg/ml, 7.5 mg/ml, 9 mg/ml, and 10 mg/ml allopregnanolone in 25% Captisol.

All compositions were mixed in a high shear mixer for 1 hour, then placed on a magnetic stirrer platform for mixing for 24 hours.

5 mg/mL - the solution appeared clear and colorless after approximately 30 min of high shear mixing. The solution was clear, colorless, and free of particles visible to the naked eye.

7.5 mg/mL - the solution appeared clear and colorless during high shear stirring. After the solution had been stirred for 1 hour on a high shear stirrer, it was placed on a dark background and a fine suspension visible to the naked eye was observed. After stirring on a magnetic stirrer overnight, the suspension was still visible.

9 mg/mL - the solution was turbid even after 1 hour of high shear mixing. Turbidity was still noticeable after 19 hours of mixing.

10 mg/mL - the solution was turbid even after 1 hour of high shear mixing. Turbidity was still noticeable after 16 hours of mixing.

Turbidity appears as a "gradient" of ALLO concentration.

Table 1 Description of physical properties of ALLO compositions with captisol Compositions Physical properties 5.0 mg/ml ALLO, 25% captisol transparent solution 7.5 mg/ml ALLO, 25% captisol very slight turbidity 9.0 mg/ml ALLO, 25% captisol slightly cloudy solution 10.0 mg/ml ALLO, 25% captisol cloudy solution

Example 2. Study of the effect of ALLO injection in the treatment of super-refractory status epilepticus

A physician at Massachusetts General Hospital, Boston, treated a patient with SRSE with allopregnanolone in a hydroxypropyl-beta-cyclodextrin formulation. The patient was a 23-year-old, previously healthy male college graduate who began allopregnanolone on day 92 of SRSE. Before allopregnanolone treatment, the patient had undergone extensive testing, including a brain biopsy, to determine the cause of SE; the testing was inconclusive, and the cause of the paroxysmal activity was not identified.

During his hospital treatment, the patient had previously received propofol, midazolam, lacosamide, phenytoin, phenobarbital, ketamine, clonazepam, levetiracetam, valproate, pentobarbital, topiramate, steroids, pyridoxine, coq-10, lidocaine, electroconvulsive therapy (ECT), bromides, therapeutic hypothermia, ketogenic diet, and acupuncture. Although a surge-suppression pattern was achieved with the anesthetics, all attempts to discontinue them resulted in the patient relapsing into generalized paroxysmal seizures; including an attempt to discontinue the drug 1 week before starting allopregnanolone.

At the time of initiation of allopregnanolone, the patient was still in a pentobarbital-induced coma and was also receiving lacosamide, phenobarbital, clonazepam, and levetiracetam. The patient was initially given allopregnanolone at a constant infusion rate of 86 mcg/kg/h for 5 days, after which the allopregnanolone dose was rapidly tapered and discontinued over a 24-hour period. Plasma samples were obtained at 5 hours, 29 hours, 53 hours, 77 hours, 101 hours, 125 hours, 149 hours, and 173 hours after initiation of dosing, and the corresponding results are shown in Fig. 2. Plasma drug levels increased and reached the target value of 150 nmol/L by day 2. Pentobarbital was tapered and discontinued over the first 36 hours of allopregnanolone therapy. At 36 hours, when the patient was completely weaned off pentobarbital and receiving allopregnanolone, the EEG began to normalize. The EEG continued to improve, and by 72 hours the patient was awake and following simple commands. The patient continued to improve, and he was verbally cooperative, made jokes, and was transferred to a rehabilitation center in April 2013. The patient had no adverse events attributable to allopregnanolone.

Claims (3)

1. A method for preparing a composition containing allopregnanolone, said method comprising providing a high shear mixing step of an aqueous composition containing 5 mg/ml allopregnanolone and 25% sulfobutyl ether β-cyclodextrin. 2. The method of claim 1, wherein the high shear mixing step is performed for a period of time necessary for the aqueous composition to become clear. 3. The method according to item 2, wherein the time period is at least 30 minutes.

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