Neuroactive steroid formulations and methods of treating cns disorders

Abstract

Formulations of comprising a neuroactive steroid, e.g., allopregnanolone; and optionally a cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfo butyl ether β-cyclodextrin, e.g., a β-cyclodextrin, e.g., a sulfo butyl ether β-cyclodextrin, e.g., CAPTISOL®; and methods of use in treating CNS disorders.

1 . A method of treating a traumatic brain injury comprising administering an effective amount of a dosage formulation of allopregnanolone in a cyclodextrin carrier to an individual in need thereof for treatment of a central nervous system injury. 
     
     
         2 . The method of  claim 1 , wherein the allopregnanolone is administered in a therapeutically effective two-level dosing regimen of allopregnanolone, including a first time period, wherein a first hourly dose of allopregnanolone is administered to the subject, followed by a second time period, wherein a lower hourly infusion dose of allopregnanolone is administered. 
     
     
         3 . The method of  claim 2 , wherein the allopregnanolone is administered a loading dose administered over 1 hour followed by a maintenance infusion for the next 95 hours, and then tapered off by reducing the dose. 
     
     
         4 . The method of  claim 1 , wherein the allopregnanolone is administered over a period of five days. 
     
     
         5 . The method of  claim 1 , wherein the concentration of the allopregnanolone is between about 0.25 mg/mL and about 15 mg/mL. 
     
     
         6 . The method of  claim 1 , wherein the concentration of the allopregnanolone is about 1.5 mg/mL. 
     
     
         7 . The method of  claim 1 , wherein the dosage of allopregnanolone administered by infusion produces a steady-state serum allopregnanolone concentration between about 150 nM and 2500 nM. 
     
     
         8 . The method of  claim 1 , wherein the allopregnanolone (3α,5α-tetrahydroprogesterone), is formulated with 6% pharmaceutical grade sulfobutylether-β-cyclodextrin (SBEβCD). 
     
     
         9 . The method of  claim 1 , wherein the allopregnanolone (3α,5α-tetrahydroprogesterone), is formulated with 15% pharmaceutical grade sulfobutylether-β-cyclodextrin (SBEβCD). 
     
     
         10 . The method of  claim 1 , wherein the allopregnanolone (3α,5α-tetrahydroprogesterone), is formulated with 30% pharmaceutical grade sulfobutylether-β-cyclodextrin (SBEβCD). 
     
     
         11 . A pharmaceutical dosage unit comprising complex of an allopregnanolone and a cyclodextrin. 
     
     
         12 . The dosage unit of  claim 11 , wherein the allopregnanolone is selected from the group consisting of allopregnanolone and salts and enantomeric forms thereof. 
     
     
         13 . The dosage unit of  claim 11 , wherein the cyclodextrin is selected from the group consisting of cyclic oligosaccharides containing or comprising six (α-cyclodextrin), seven (β-cyclodextrin), eight (γ-cyclodextrin), or more α-(1,4)-linked glucose residues, and chemically modified cyclodextrins. 
     
     
         14 . The dosage unit of  claim 11 , wherein the cyclodextrin is selected from the group consisting of 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; acetyl methyl β-cyclodextrin; acetyl butyl β-cyclodextrin; glucosyl α-cyclodextrin; glucosyl β-cyclodextrin; glucosyl γ-cyclodextrin; maltosyl α-cyclodextrin; maltosyl β-cyclodextrin; maltosyl γ-cyclodextrin; α-cyclodextrin carboxymethylether; β-cyclodextrin carboxymethylether; γ-cyclodextrin carboxymethylether; carboxymethylethyl β-cyclodextrin; phosphate ester α-cyclodextrin; phosphate ester β-cyclodextrin; phosphate ester γ-cyclodextrin; 3-trimethylammonium-2-hydroxypropyl β-cyclodextrin; sulfobutyl ether β-cyclodextrin; carboxymethyl α-cyclodextrin; carboxymethyl β-cyclodextrin; carboxymethyl γ-cyclodextrin, alkyl cyclodextrins, hydroxy alkyl cyclodextrins, carboxy alkyl cyclodextrins and sulfoalkyl ether cyclodextrins, and combinations thereof. 
     
     
         15 . The pharmaceutical dosage unit of  claim 11  comprising a complex of 3α,5α-tetrahydroprogesterone with sulfobutylether-βcyclodextrin (SBEβCD). 
     
     
         16 . The pharmaceutical dosage unit of  claim 15  comprising 3α,5α-tetrahydroprogesterone formulated in sterile 0.9% sodium chloride containing or comprising 6% pharmaceutical grade sulfobutylether-βcyclodextrin (SBEβCD). 
     
     
         17 . The pharmaceutical dosage unit of  claim 15  comprising 3α,5α-tetrahydroprogesterone formulated in sterile 0.9% sodium chloride comprising 15% pharmaceutical grade sulfobutylether-βcyclodextrin (SBEβCD). 
     
     
         18 . The pharmaceutical dosage unit of  claim 15  comprising 3α,5α-tetrahydroprogesterone formulated in sterile 0.9% sodium chloride comprising 30% pharmaceutical grade sulfobutylether-βcyclodextrin (SBEβCD). 
     
     
         19 . A method of treating a CNS disorder comprising administering to a subject, an effective amount of a dosage formulation of allopregnanolone in a cyclodextrin carrier. 
     
     
         20 . The method of  claim 19 , wherein the allopregnanolone is administered in a therapeutically effective two-level dosing regimen of allopregnanolone, including a first time period, wherein a first hourly dose of allopregnanolone is administered to the subject, followed by a second time period, wherein a lower hourly infusion dose of allopregnanolone is administered. 
     
     
         21 . The method of  claim 20 , wherein the allopregnanolone is administered a loading dose administered over 1 hour followed by a maintenance infusion for the next 95 hours, and then tapered off by reducing the dose. 
     
     
         22 . The method of  claim 19 , wherein the allopregnanolone is administered over a period of five days. 
     
     
         23 . The method of  claim 19 , wherein the concentration of the allopregnanolone is between about 0.25 mg/mL and about 15 mg/mL. 
     
     
         24 . The method of  claim 19 , wherein the concentration of the allopregnanolone is between about 1.5 mg/mL. 
     
     
         25 . The method of  claim 19 , wherein the dosage of allopregnanolone administered by infusion produces a steady-state serum allopregnanolone concentration between about 150 nM and 2500 nM. 
     
     
         26 . The method of  claim 19 , wherein the allopregnanolone (3α,5α-tetrahydroprogesterone), is formulated with 6% pharmaceutical grade sulfobutylether-β-cyclodextrin (SBEβCD). 
     
     
         27 . The method of  claim 19 , wherein the allopregnanolone (3α,5α-tetrahydroprogesterone), is formulated with 15% pharmaceutical grade sulfobutylether-β-cyclodextrin (SBEβCD). 
     
     
         28 . The method of  claim 19 , wherein the allopregnanolone (3α,5α-tetrahydroprogesterone), is formulated with 30% pharmaceutical grade sulfobutylether-β-cyclodextrin (SBEβCD). 
     
     
         29 . The method of  claim 19 , wherein the CNS disorder is status epilepticus. 
     
     
         30 . The method of  claim 29 , wherein the status epilepticus disorder is refractory status epilepticus. 
     
     
         31 . The method of  claim 19 , wherein the status epilepticus disorder is non-convulsive status epilepticus. 
     
     
         32 . The method of  claim 19 , wherein the CNS disorder is a traumatic brain injury. 
     
     
         33 . The method of  claim 19 , wherein the CNS disorder is a seizure. 
     
     
         34 . The method of  claim 19 , wherein the seizure is an acute repetitive seizure or a cluster seizure. 
     
     
         35 . A method of treating a CNS disorder comprising administering to a subject, an effective amount of a dosage formulation of allopregnanolone, wherein the CNS disorder is a seizure or status epilepticus. 
     
     
         36 . The method of  claim 35 , wherein the disorder is status epilepticus. 
     
     
         37 . The method of  claim 35 , wherein the status epilepticus disorder is refractory status epilepticus. 
     
     
         38 . The method of  claim 35 , wherein the status epilepticus disorder is non-convulsive status epilepticus. 
     
     
         39 . The method of  claim 35 , wherein the allopregnanolone is administered in a therapeutically effective two-level dosing regimen of allopregnanolone, including a first time period, wherein a first hourly dose of allopregnanolone is administered to the subject, followed by a second time period, wherein a lower hourly infusion dose of allopregnanolone is administered. 
     
     
         40 . The method of  claim 39 , wherein the allopregnanolone is administered a loading dose administered over 1 hour followed by a maintenance infusion for the next 95 hours, and then tapered off by reducing the dose. 
     
     
         41 . The method of  claim 35 , wherein the allopregnanolone is administered over a period of five days. 
     
     
         42 . The method of  claim 35 , wherein the concentration of the allopregnanolone is between about 0.25 mg/mL and about 15 mg/mL. 
     
     
         43 . The method of  claim 35 , wherein the concentration of the allopregnanolone is between about 1.5 mg/mL. 
     
     
         44 . The method of  claim 35 , wherein the dosage of allopregnanolone administered by infusion produces a steady-state serum allopregnanolone concentration between about 150 nM and 2500 nM. 
     
     
         45 . The method of  claim 35 , wherein the allopregnanolone (3α,5α-tetrahydroprogesterone), is formulated with 6% pharmaceutical grade sulfobutylether-β-cyclodextrin (SBEβCD). 
     
     
         46 . The method of  claim 35 , wherein the allopregnanolone (3α,5α-tetrahydroprogesterone), is formulated with 15% pharmaceutical grade sulfobutylether-β-cyclodextrin (SBEβCD). 
     
     
         47 . The method of  claim 35 , wherein the allopregnanolone (3α,5α-tetrahydroprogesterone), is formulated with 30% pharmaceutical grade sulfobutylether-β-cyclodextrin (SBEβCD).