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NZ755699B2 - Neuroactive steroid formulations and methods of treating CNS disorders - Google Patents
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NZ755699B2 - Neuroactive steroid formulations and methods of treating CNS disorders - Google Patents

Neuroactive steroid formulations and methods of treating CNS disorders Download PDF

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Publication number
NZ755699B2
NZ755699B2 NZ755699A NZ75569913A NZ755699B2 NZ 755699 B2 NZ755699 B2 NZ 755699B2 NZ 755699 A NZ755699 A NZ 755699A NZ 75569913 A NZ75569913 A NZ 75569913A NZ 755699 B2 NZ755699 B2 NZ 755699B2
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NZ
New Zealand
Prior art keywords
cyclodextrin
allopregnanolone
captisol
butyl ether
sulfo butyl
Prior art date
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NZ755699A
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NZ755699A (en
Inventor
Kiran Reddy
Original Assignee
Sage Therapeutics Inc
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Publication date
Application filed by Sage Therapeutics Inc filed Critical Sage Therapeutics Inc
Priority to NZ773177A priority Critical patent/NZ773177A/en
Priority claimed from NZ74140613A external-priority patent/NZ741406A/en
Publication of NZ755699A publication Critical patent/NZ755699A/en
Publication of NZ755699B2 publication Critical patent/NZ755699B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Use of allopregnanolone in a cylodextrin carrier in the manufacture of a medicament for treating traumatic brain injury in an individual in need thereof for treatment of a central nervous system injury and for treating a CNS disorder in a subject. Further, a pharmaceutical dosage unit comprising a complex of an alloprenanolone and a cylodextrin. omplex of an alloprenanolone and a cylodextrin.

Description

NEUROACTIVE STEROID FORMULATIONS AND METHODS OF TREATING CNS DISORDERS Cross-Reference to Related Applications This ation is a divisional application of New Zealand Patent Application No. 741406 filed on 6 April 2018, which is a divisional application of New Zealand Patent Application No. 724345 filed on 14 ber 2016, which is a divisional application of New Zealand Patent Application No. 627781 filed on 23 January 2013, and is related to International Patent ation No. , filed on 23 y 2013, and claims priority from United States Patent Application No. 61/589,740, filed on 23 January 2012, each of which is incorporated herein by reference in its entirety.
Field of the Invention The present invention generally relates to neuroactive steroid formulations, particularly allopregnanolone, for the ent of CNS es and/or diseases.
Background of the Invention Central nervous system (CNS) related disorders include disorders which affect either or both the brain or spinal cord. CNS related disorders can include, e.g., a traumatic injury, e.g., a traumatic brain injury. A tic injury to the CNS is characterized by a physical impact to the central nervous system, e.g., a traumatic brain injury. Status epilepticus (SE) is another example of a CNS related disorder, e.g., generalized status epilepticus, early status ticus, established status ticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, e.g., complex l status epilepticus.
Summary of the Invention The disclosure features, inter alia, compositions sing 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®. The disclosure also features, inter alia, methods of treating a subject having a CNS disorder, e.g., a traumatic brain injury, status epilepticus, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus, the methods comprising administering to the subject a composition described herein, e.g., a neuroactive steroid, e.g., allopregnanolone, and optionally a cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®..
In one aspect, the disclosure features a composition, the composition comprising a neuroactive d, e.g., allopregnanolone, and cyclodextrin, e. g., a neuroactive steroid, e.g., allopregnanolone, and optionally a cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e. g., a odextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex. a B- cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e. g., a B-cyclodextrin, e. g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex.
In some embodiments, the neuroactive d is a progestin derivative, e.g., allopregnanolone. In an embodiment, the neuroactive steroid is allopregnanolone.
In some embodiments, the cyclodextrin is a B-cyclodextrin. In an embodiment, the cyclodextrin is a sulfo butyl ether B-cyclodextrin. In an ment, the cyclodextrin is CAPTISOL®. In some embodiments, the cyclodextrin is a B-cyclodextrin disclosed in US. Patent Nos. 5,874,418; 6,046,177; or 7,635,733, which are herein incorporated by reference.
In some embodiments, the neuroactive steroid is a progestin derivative, e.g., allopregnanolone, and the cyclodextrin is a B—cyclodextrin. In an embodiment, the ctive steroid is allopregnanolone and the cyclodextrin is CAPTISOL®.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., OL®, complex is formulated for parenteral administration. In an ment, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., OL®, complex is formulated as an aqueous composition comprising the neuroactive steroid at a concentration between 0.25—30mg/mL, 0.5—30mg/mL; 1— 30mg/mL; 5-30mg/mL, 10—30mg/mL; 15—30mg/mL, 0.25—20mg/mL; 0.5— 20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL, 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; l- 5mg/mL; /mL; /mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2- 7mg/mL; mL; 5—15mg/mL; 7—12mg/mL; 7—10mg/mL; 8-9mg/mL; 3- 5mg/mL; or 3-4mg/mL. In some embodiments, the neuroactive steroid, e.g., egnanolone, and extrin, e.g., a B—cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive d at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, lOmg/mL, lSmg/mL, 20mg/mL, L, or 30 mg/mL. In an embodiment, the ctive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the ctive steroid at a concentration of 1.5mg/mL. In an embodiment, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid at a concentration of 5mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the ctive steroid at a concentration of 15mg/mL.
In some ments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an s composition comprising the cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B- cyclodextrin, e.g., CAPTISOL®, at a concentration between 25—400mg/mL; 25— 300mg/mL; 25-200mg/mL; 25—100mg/mL; g/mL; 50—400mg/mL; 50— 300mg/mL; 60-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; 30-100mg/mL; 300-400mg/mL; 30- 100mg/mL; 45-75mg/mL; 50-70mg/mL; 55-65mg/mL; or 50-60mg/mL. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e. g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., OL®, complex is formulated as an aqueous composition comprising the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 25mg/mL; L; 35mg/mL; L; L; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; L; 90mg/mL, 95mg/mL; 100mg/mL; mL; 200mg/mL; 250mg/mL; 300mg/mL; 350mg/mL; or 400mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 60mg/ml. In some embodiments, the ctive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising between 25—40%, —30%, 25-20%, 25-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30%, 6- %, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3- %, 45-75%, 5-7%, 55-65% of the extrin, e.g., OL®. In some embodiments, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as 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%, %, 15%, 20%, 25%, 30%, 35% or 40% of the cyclodextrin, e.g., CAPTISOL®. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an s composition comprising 6% of the extrin. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a [3- cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising 15% of the cyclodextrin. In an embodiment, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising 30% of the cyclodextrin.
In some ments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the ctive steroid, e.g., allopregnanolone, at a tration between 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, 10—30mg/mL; 15—30mg/mL, 0.25-20mg/mL; 0.5—20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1- 20mg/mL, 5-20mg/mL, 10-20mg/mL, 0.25—15mg/mL, mg/mL; 0.5- 10mg/mL; 1-15mg/mL, 1-10mg/mL; 1—5mg/mL; 5-15mg/mL; 5-10mg/mL; 10- 15mg/mL; 1-10mg/mL; 2—8mg/mL; mL; 3—5mg/mL; 5-15mg/mL; 7- 12mg/mL; 7-10mg/mL; 8—9mg/mL; 3—5mg/mL; or 3—4mg/mL; and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, at a concentration between 25-400mg/mL; 25-300mg/mL; 25- 200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 50-300mg/mL; 60- 400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 0mg/mL; 30—100mg/mL; 300—400mg/mL; 30-100mg/mL; g/mL; g/mL; 55—65mg/mL; or 50—60mg/mL. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, 0.5- 30mg/mL; l—30mg/mL; 5—30mg/mL, 10—30mg/mL; 15—30mg/mL, 0.25— L; 0.5—20mg/mL; /mL, 0.5—20mg/mL; 1—20mg/mL, 5—20mg/InL, —20mg/mL, 0.25-15mg/mL, 0.5—15mg/mL; 0.5—10mg/mL; /mL, 1— 10mg/mL; 1-5mg/mL; 5-15mg/mL; 5-10mg/mL; 10-15mg/mL; 1-10mg/mL; 2- ; 2-7mg/mL; 3-5mg/mL; 5-15mg/mL; 7-12mg/mL; 7-10mg/mL; 8- 9mg/mL; 3-5mg/mL; or 3-4mg/mL; and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, at a concentration of 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; L; L; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; 90mg/mL, 95mg/mL; lOOmg/mL; lSOmg/mL; 200mg/mL; 250mg/mL; 300mg/mL; mL; or 400mg/mL.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, lO—30mg/mL; 15—30mg/mL, 0.25-20mg/mL; mg/mL; l-20mg/mL, 0.5-20mg/mL; l- 20mg/mL, 5-20mg/mL, g/mL, 0.25—15mg/mL, 0.5-15mg/mL; 0.5- lOmg/mL; l-lSmg/mL, l-lOmg/mL; l—Smg/mL; /mL; 5-lOmg/mL; 10- lSmg/mL; l-lOmg/mL; mL; 2—7mg/mL; 3—5mg/mL; 5-15mg/mL; 7- 12mg/mL; 7-lOmg/mL; mL; 3—5mg/mL; or 3—4mg/mL; and n 2.5- 40%, 25—30%, 25-20%, 25—10%, 5—40%, 5—30%, 5—20%, 5—10%, 640%, 6— %, 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25- %, 3-10%, 45-75%, 5-7%, 55-65% of the cyclodextrin, e.g., CAPTISOL®.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous ition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration between 0.25- 30mg/mL, 0.5—30mg/mL; 1—30mg/mL; 5—30mg/mL, 10—30mg/mL; 15- 30mg/mL, 0.25-20mg/mL; 0.5—20mg/mL; 1—20mg/mL, 0.5-20mg/mL; 1- 20mg/mL, 5-20mg/mL, 10-20mg/mL, 0.25—15mg/mL, 0.5-15mg/mL; 0.5- 10mg/mL; 1-15mg/mL, 1-10mg/mL; 1—5mg/mL; 5—15mg/mL; 5-10mg/mL; 10- 15mg/mL; /mL; 2—8mg/mL; 2—7mg/mL; 3—5mg/mL; 5—15mg/mL; 7— 12mg/mL; 7-10mg/mL; 8—9mg/mL; 3—5mg/mL; or 3—4mg/mL; and 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, %, 25%, 30%, 35% or 40% of the cyclodextrin, e.g., CAPTISOL®.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and the cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B- cyclodextrin, e. g., CAPTISOL®, at a concentration between 25-400mg/mL; 25- 300mg/mL; 25—200mg/mL; 25—100mg/mL; g/mL; 50—400mg/mL; 50— 300mg/mL; mg/mL; 60—300mg/mL; 0mg/mL; 150—300mg/mL; 200—300mg/mL; 200—400mg/mL; mg/mL; 300—400mg/mL; 30— 100mg/mL; 45-75mg/mL; 50—70mg/mL; g/mL; or 50-60mg/mL. In some embodiments, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; mL; 4.5mg/mL; 5.0mg/mL, mL, mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, L, 20mg/mL, 25mg.mL, or 30 mg/mL; and the cyclodextrin, e.g., CAPTISOL® at a concentration of 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; 90mg/mL, 95mg/mL; mL; 150mg/mL; 200mg/mL; 250mg/mL; 300mg/mL; 350mg/mL; or 400mg/mL.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive d, e.g., allopregnanolone, at a concentration of /mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/rnL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/rnL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, L, 20mg/rnL, 25mg.mL, or 30 mg/mL; and between 25-40%, 25—30%, 25—20%, 25—10%, 5—40%, 5—30%, 5— %, 5—10%, 6—40%, 6—30%, 6—20%, 6—10%, 10—40%, 10—30%, 10—20%, 20— 40%, 20—30%, , 25—30%, 3—10%, 45—75%, 5—7%, 55—65% of the cyclodextrin, e.g., CAPTISOL®. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, x is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/mL, mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; mL; mL, .5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and 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% of the cyclodextrin, e.g., CAPTISOL®.
In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration of 1.5mg/mL, and the cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%. In an embodiment, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 10mg/mL, and the cyclodextrin, e. g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%. In an embodiment, the neuroactive d, e. g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 15mg/mL, and the cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%.
In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a tration of 1.5mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., OL®, at a concentration of 15%. In an embodiment, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., OL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of lOmg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a tration of 15%. In an ment, the ctive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 15mg/mL, and the cyclodextrin, e. g., a B—cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, at a concentration of 15%.
In an embodiment, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 1.5mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, at a concentration of 30%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a [3- cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e. g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration of lOmg/mL, and the cyclodextrin, e. g., a odextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 30%. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 15mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, at a concentration of 30%.
In some embodiments, the allopregnanolone and CAPTISOL® x is formulated as an aqueous composition with a pH between 3-10, 4-9, 4-8, 4-7, 4—6, 4—5, 5—9, 5—8, 5—7, 5—6, 4535, or 55—75 In some embodiments, the egnanolone and CAPTISOL® complex is formulated as an s composition with apH 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 egnanolone and OL® complex is formulated as an s composition with a pH about 6.
In one aspect, the disclosure features a composition, the composition sing a neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex, wherein the composition comprises less than 100ppm of a ate, and the cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, has an absorption of less than 0.2 AU. due to a drug—degrading agent, as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution comprising 300 mg of the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e. g., CAPTISOL®, per mL of solution in a cell having a lcm path length.
In some embodiments, the cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether odextrin, e. g., CAPTISOL®, has an absorption of less than 0.2 AU. due to a color forming agent, as ined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution comprising 500 mg of the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cell having a lcm path length.
In some ments, the cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, further comprises: less than 20 ppm of a sulfoalkylating agent; less than 0.5% wt. of an underivatized cyclodextrin; less than 1% wt. of an alkali metal halide salt; and less than 0.25% wt. of a hydrolyzed sulfoalkylating agent.
In some embodiments, the cyclodextrin, e.g., a B—cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e. g., CAPTISOL®, has an tion of less than 0.2 AU. due to a egrading agent, as determined by UV/vis ophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution comprising 500 mg of the cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cell having a 1 cm path .
In some ments, the cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g, CAPTISOL®, further comprises: less than 50 ppm of a phosphate; less than 10 ppm of a sulfoalkylating agent; less than 0.2% wt. of an underivatized cyclodextrin; less than 0.5% wt. of an alkali metal halide salt; and less than 0.1% wt. of a yzed lkylating agent; and wherein the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, has an absorption of less than 0.2 A.U. due to the color—forming agent, as determined by U/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution comprising 500 mg of the extrin, e.g., a B- cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cell having a 1 cm path length.
In some embodiments, the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e. g., CAPTISOL®, further comprises: less than 10 ppm of a phosphate; less than 2 ppm of a sulfoalkylating agent; less than 0.1% wt. of an underivatized cyclodextrin; less than 0.2% wt. of an alkali metal halide salt; and less than 0.08% wt. of a hydrolyzed sulfoalkylating agent; and wherein the cyclodextrin, e. g., a odextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, has an tion of less than 0.1 A.U. due to the color—forming agent, as determined by UV/vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution comprising 500 mg of the cyclodextrin, e.g., a [3- cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cell having a 1 cm path length.
In some embodiments, the cyclodextrin, e.g., a odextrin, e. g., a sulfo butyl ether odextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e. g., CAPTISOL®, further comprises: less than 5 ppm of a phosphate; less than 0.1% wt. of an alkali metal halide salt; and less than 0.05% wt. of a hydrolyzed sulfoalkylating agent.
In some embodiments, the neuroactive steroid is a progestin derivative, e.g., egnanolone. In an embodiment, the ctive steroid is allopregnanolone.
In some embodiments, the cyclodextrin is a B-cyclodextrin. In an embodiment, the cyclodextrin is a sulfo butyl ether B-cyclodextrin. In an embodiment, the cyclodextrin is CAPTISOL®. In some embodiments, the cyclodextrin is a B-cyclodextrin sed in US. Patent Nos. 418; 6,046,177; and 7,635,733, Which are herein incorporated by reference.
In some embodiments, the neuroactive steroid is a progestin derivative, e.g., allopregnanolone, and the cyclodextrin is a B-cyclodextrin. In an embodiment, the neuroactive steroid is allopregnanolone and the cyclodextrin is CAPTISOL®.
In some embodiments, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., OL®, complex is formulated for parenteral administration. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition. In some ments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an s composition comprising the neuroactive steroid at a concentration between 0.25—30mg/mL, 0.5—30mg/mL; 1— 30mg/mL; 5—30mg/mL, 10—30mg/mL; 15—30mg/mL, 0.25-20mg/mL; 0.5— 20mg/mL; l-20mg/mL, 0.5-20mg/mL; l—20mg/mL, 5-20mg/mL, g/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5—10mg/mL; l-lSmg/mL, l-lOmg/mL; l- Smg/mL; 5-15mg/mL; 5-lOmg/mL; lO—lSmg/mL; l-lOmg/mL; 2-8mg/mL; 2- 7mg/mL; 3-5mg/mL; 5-15mg/mL; 7—12mg/mL; 7—10mg/mL; 8-9mg/mL; 3- 5mg/mL; or 3—4mg/mL. In some embodiments, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, lOmg/mL, lSmg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL. In an ment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid at a concentration of 1.5mg/mL. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B- extrin, e. g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the ctive steroid at a tration of 5mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising the neuroactive steroid at a concentration of lSmg/mL.
In some ments, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., OL®, complex is formulated as an s composition comprising the cyclodextrin, e.g., a B—cyclodextrin, e. g., a sulfo butyl ether [3— cyclodextrin, e. g., CAPTISOL®, at a concentration between 25—400mg/mL; 25— 300mg/mL; 25—200mg/mL; 25—100mg/mL; 25—50mg/mL; 50—400mg/mL; 50— 300mg/mL; 60—400mg/mL; 60—300mg/mL; 150-400mg/mL; 150—300mg/mL; 200—300mg/mL; 200—400mg/mL; mg/mL; 300—400mg/mL; 30— 100mg/mL; 45-75mg/mL; 50—70mg/mL; 55—65mg/mL; or 50-60mg/mL. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 25mg/mL; 30mg/mL; 35mg/mL; L; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL; 300mg/mL; 350mg/mL; or 400mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising the extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 60mg/ml. In some embodiments, the neuroactive steroid, e. g., allopregnanolone, and extrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., OL®, x is formulated as an aqueous ition comprising between 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— %, 6—10%, 10—40%, 10—30%, 10—20%, , 20—30%, 25—40%, , 3— %, 45—75%, 5-7%, 55-65% of the extrin, e.g., CAPTISOL®. In some embodiments, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as 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%, %, 15%, 20%, 25%, 30%, 35% or 40% of the cyclodextrin, e.g., CAPTISOL®. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising 6% of the cyclodextrin. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous ition comprising 15% of the cyclodextrin. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is ated as an s composition comprising 30% of the cyclodextrin.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, mg/mL; /mL; 5-30mg/mL, lO—30mg/mL; l5—30mg/mL, 0.25-20mg/mL; mg/mL; /mL, 0.5-20mg/mL; l- 20mg/mL, 5-20mg/mL, lO-20mg/mL, 0.25—15mg/mL, 0.5-l5mg/mL; 0.5- lOmg/mL; l-l5mg/mL, l-lOmg/mL; l—5mg/mL; 5-l5mg/mL; 5-lOmg/mL; 10- l5mg/mL; l-lOmg/mL; 2—8mg/mL; 2—7mg/mL; 3-5mg/mL; /mL; 7- 12mg/mL; 7-lOmg/mL; 8-9mg/mL; 3—5mg/mL; or 3-4mg/mL; and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration between 25-400mg/mL; 25-300mg/mL; 25- 200mg/mL; 25—100mg/mL; 25—50mg/mL; 50-400mg/mL; 50—300mg/mL; 60— 400mg/mL; 60—300mg/mL; 150—400mg/mL; 150—300mg/mL; 0mg/mL; 0mg/mL; 30—100mg/mL; 300—400mg/mL; 30—100mg/mL; 45-75mg/mL; 50—70mg/mL; 55—65mg/mL; or 50—60mg/mL. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B— cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an s composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, 0.5- 30mg/mL; 1—30mg/mL; 5—30mg/mL, 10—30mg/mL; 15-30mg/mL, 0.25— 20mg/mL; 0.5-20mg/mL; l—20mg/mL, 0.5—20mg/mL; l-20mg/mL, 5-20mg/mL, lO-20mg/mL, 0.25-15mg/mL, 0.5—15mg/mL; 0.5—10mg/mL; l-l5mg/mL, l- lOmg/mL; l-5mg/mL; 5-15mg/mL; 5—10mg/mL; lO-lSmg/mL; l-lOmg/mL; 2- 8mg/mL; 2-7mg/mL; 3-5mg/mL; 5—15mg/mL; 7-12mg/mL; 7-lOmg/mL; 8- 9mg/mL; 3-5mg/mL; or 3-4mg/mL; and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a tration of 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ":‘5mg/mL; 80mg/mL; 85mg/mL; 90mg/mL, L; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL; 300mg/mL; 350mg/mL; or mL.
In some ments, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, 0.5—30mg/mL; 1—30mg/mL; 5-30mg/mL, lO—30mg/mL; l5—30mg/mL, 0mg/mL; 0.5—20mg/mL; 1—20mg/mL, 0.5-20mg/mL; l- 20mg/mL, 5-20mg/mL, lO-ZOmg/mL, 0.25—15mg/mL, 0.5-l5mg/mL; 0.5- lOmg/mL; l-l5mg/mL, l-lOmg/mL; l—5mg/mL; 5-l5mg/mL; 5-lOmg/mL; 10- l5mg/mL; l-lOmg/mL; 2—8mg/mL; 2—7mg/mL; 3-5mg/mL; 5-l5mg/mL; 7- lng/mL; 7-lOmg/mL; 8-9mg/mL; 3—5mg/mL; or 3-4mg/mL; and between 2.5- 40%, , , 25—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— %, 3—lO%, 45—75%, 5—7%, 55—65% of the cyclodextrin, e.g., CAPTISOL®.
In some embodiments, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, x is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25— 30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, 10-30mg/mL; 15- 30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1- L, 5-20mg/mL, 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5- 10mg/mL; 1—15mg/mL, l—lOmg/mL; 1—5mg/mL; 5—15mg/mL; /mL; 10- 15mg/mL; l-lOmg/mL; mL; 2—7mg/mL; 3—5mg/mL; 5-l5mg/mL; 7- lng/mL; 7-10mg/mL; mL; 3—5mg/mL; or 3-4mg/mL; and 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, %, 25%, 30%, 35% or 40% of the cyclodextrin, e.g., CAPTISOL®.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, x is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/mL, 0.5mg/mL; mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and the cyclodextrin, e.g., a B—cyclodextrin, e. g., a sulfo butyl ether [3- cyclodextrin, e. g., CAPTISOL®, at a concentration between 25-400mg/mL; 25- 300mg/mL; 25—200mg/mL; 25—100mg/mL; 25—50mg/mL; 50—400mg/mL; 50— 300mg/mL; 60—400mg/mL; 60—300mg/mL; 150—400mg/mL; 150—300mg/mL; 200—300mg/mL; 200—400mg/mL; 30—100mg/mL; 300—400mg/mL; 30— 100mg/mL; 45-75mg/mL; 50-70mg/mL; 55—65mg/mL; or 50-60mg/mL. In some embodiments, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, lOmg/mL, lSmg/mL, L, 25mg.mL, or 30 mg/mL; and the cyclodextrin, e. g., CAPTISOL® at a concentration of 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; L; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL; 300mg/mL; 350mg/mL; or 400mg/mL.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and between 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5- %, 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%, 45-15%, 5-7%, 55-65% of the extrin, e.g., CAPTISOL®. In some embodiments, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., egnanolone, at a concentration of /mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mL, .5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and 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% of the cyclodextrin, e.g., CAPTISOL®.
In an embodiment, the neuroactive steroid, e. g., egnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 1.5mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a odextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an s composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of L, and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising the neuroactive steroid, e.g., egnanolone, at a concentration of 15mg/mL, and the cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%.
In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e. g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous ition comprising the neuroactive steroid, e. g., allopregnanolone, at a tration of 1.5mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a tration of 15%. In an embodiment, the neuroactive d, e. g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, complex is formulated as an aqueous composition sing the neuroactive steroid, e. g., allopregnanolone, at a concentration of 10mg/mL, and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 15%. In an embodiment, the ctive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 15mg/mL, and the cyclodextrin, e. g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 15%.
In an embodiment, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration of 1.5mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 30%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, x is formulated as an aqueous composition sing the neuroactive steroid, e.g., allopregnanolone, at a tration of 10mg/mL, and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., OL®, at a concentration of 30%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, x is formulated as an aqueous composition comprising the neuroactive d, e.g., allopregnanolone, at a concentration of 15mg/mL, and the cyclodextrin, e. g., a B-cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, at a concentration of 30%.
In some embodiments, the allopregnanolone and OL® complex is formulated as an aqueous composition with a pH between 3-10, 4-9, 4-8, 4-7, 4—6, 4—5, 5—9, 5—8, 5—7, 5—6, 45-75, or 55—75 In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition with apH 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 formulated as an aqueous composition with a pH about 6.
In one aspect, the disclosure features a method of treating a subject having a CNS disorder, e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status ticus, established status epilepticus, refractory status epilepticus, refractory status epilepticus; non- convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; periodic lateralized epileptiform discharges; a seizure, e. g., acute repetitive seizures, cluster seizures, the method comprising administering to the subject a neuroactive steroid.
In some embodiments, the neuroactive steroid is a progestin derivative, e.g., allopregnanolone. In an ment, the neuroactive d is allopregnanolone.
In some embodiments, the CNS disorder is a traumatic brain injury. In some embodiments, the CNS disorder is status epilepticus, convulsive status ticus, e. g., early status ticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e. g., generalized status epilepticus, complex l status epilepticus; generalized periodic epileptiform discharges; periodic lateralized epileptiform discharges. In some embodiments, the CNS disorder is a traumatic brain injury. In some embodiments, the CNS disorder is a seizure, e.g., acute repetitive seizures, cluster seizures.
In an embodiment, the disclosure features a method of treating a subject having status epilepticus, e. g., refractory sive status epilepticus, non- convulsive status epilepticus, the method comprising administering to the subject allopregnanolone. In an embodiment, the disclosure features a method of ng a subject having a traumatic brain injury the method comprising administering to the subject allopregnanolone.
In one aspect, the disclosure features a method of treating a subject having a CNS disorder, e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non— convulsive status epilepticus, e.g., lized status epilepticus, complex partial status epilepticus; lized periodic epileptiform discharges; periodic lateralized epileptiform discharges; a seizure, e.g., acute repetitive seizures, cluster seizures, the method comprising administering to the subject a ctive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B— extrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex.
In some embodiments, the neuroactive steroid is a progestin derivative, e.g., allopregnanolone. In an embodiment, the neuroactive steroid is allopregnanolone.
In some embodiments, the cyclodextrin is a B—cyclodextrin. In an embodiment, the extrin is a sulfo butyl ether B-cyclodextrin. In an embodiment, the cyclodextrin is CAPTISOL®.
In some embodiments, the neuroactive steroid is a progestin derivative, e.g., allopregnanolone, and the extrin is a B—cyclodextrin. In an embodiment, the neuroactive d is allopregnanolone and the cyclodextrin is CAPTISOL®.
In some embodiments, the CNS disorder is a traumatic brain injury. In some embodiments, the CNS disorder is status epilepticus, convulsive status epilepticus, e.g., early status epilepticus, established status ticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized ic epileptiform discharges; periodic lateralized epileptiform discharges. In some embodiments, the CNS disorder is a traumatic brain injury. In some embodiments, the CNS disorder is a seizure, e. g., acute repetitive seizures, cluster es.
In an embodiment, the disclosure features a method of ng a subject haVing a traumatic brain injury, the method sing administering to the subject an allopregnanolone and CAPTISOL® complex. In an embodiment, the disclosure features a method of treating a subject having status epilepticus, convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non- convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus, the method sing stering to the t an allopregnanolone and CAPTISOL® complex. In an embodiment, the disclosure features a method of treating a subject having a a e, e.g., acute tive seizures, cluster es, the method comprising administering to the subject an allopregnanolone and CAPTISOL® complex.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated for parenteral administration. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous ition. In some ments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the ctive steroid at a concentration between 0mg/mL, 0.5-30mg/mL; l— 30mg/mL; 5—30mg/mL, 10—30mg/mL; 15—30mg/mL, 0.25-20mg/mL; 0.5— 20mg/mL; l-20mg/mL, 0.5-20mg/mL; 1—20mg/mL, 5-20mg/mL, lO-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5—10mg/mL; 1-15mg/mL, l-lOmg/mL; l- 5mg/mL; /mL; /mL; lO—lSmg/mL; l-lOmg/mL; 2-8mg/mL; 2- ; 3-5mg/mL; 5-15mg/mL; 7—12mg/mL; 7-10mg/mL; 8-9mg/mL; 3- 5mg/mL; or 3-4mg/mL. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an s composition comprising the neuroactive d at a concentration of 0.25mg/mL, 0.5mg/mL; mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, L, 25mg.mL, or 30 mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid at a concentration of 1.5mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, x is formulated as an aqueous composition comprising the neuroactive d at a concentration of 5mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid at a concentration of 15mg/mL.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether B- cyclodextrin, e. g., CAPTISOL®, at a concentration between 25-400mg/mL; 25- 300mg/mL; 25—200mg/mL; 25—100mg/mL; 25—50mg/mL; 50—400mg/mL; 50— 300mg/mL; 60—400mg/mL; 60—300mg/mL; 0mg/mL; l50—300mg/mL; 200—300mg/mL; 200—400mg/mL; 30—100mg/mL; 300—400mg/mL; 30— lOOmg/mL; 45-75mg/mL; 50-70mg/mL; 55-65mg/mL; or 50—60mg/mL. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 25mg/mL; 30mg/mL; L; L; 45mg/mL; 50mg/mL; 55mg/mL; L; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; L, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL; 300mg/mL; mL; or 400mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the cyclodextrin, e. g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 60mg/ml. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, complex is formulated as an aqueous ition comprising between 25-40%, —30%, 25—20%, , 5—40%, 5—30%, 5—20%, 5—10%, 6—40%, 6—30%, 6— %, 6—10%, 10—40%, 10—30%, 10—20%, 20—40%, , 25—40%, 25—30%, 3— %, 45-75%, 5-7%, 55—65% of the cyclodextrin, e.g., CAPTISOL®. In some embodiments, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as 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%, %, 15%, 20%, 25%, 30%, 35% or 40% of the cyclodextrin, e.g., CAPTISOL®. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., OL®, complex is formulated as an aqueous composition sing 6% of the cyclodextrin. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, complex is formulated as an aqueous composition comprising 15% of the cyclodextrin. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising 30% of the cyclodextrin.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., OL®, complex is ated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, 10-30mg/mL; —30mg/mL, 0.25—20mg/mL; 0.5—20mg/mL; 1—20mg/mL, 0.5-20mg/mL; 1- L, 5-20mg/mL, 10—20mg/mL, 0.25—15mg/mL, mg/mL; 0.5- 10mg/mL; 1-15mg/mL, 1—10mg/mL; 1—5mg/mL; 5—15mg/mL; 5-10mg/mL; 10- lSmg/mL; l-lOmg/mL; 2-8mg/mL; 2—7mg/mL; 3-5mg/mL; 5-15mg/mL; 7- ; 7-lOmg/mL; 8-9mg/mL; 3—5mg/mL; or 3-4mg/mL; and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, at a tration between 25—400mg/mL; mg/mL; 25- 200mg/mL; 25—100mg/mL; 25—50mg/mL; 50—400mg/mL; 50—300mg/mL; 60— mL; 60-300mg/mL; 150—400mg/mL; 150—300mg/mL; 200—300mg/mL; 200-400mg/mL; 30-100mg/mL; 300-400mg/mL; 30-100mg/mL; 45-75mg/mL; 50-70mg/mL; 55-65mg/mL; or 50-60mg/mL. In some ments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a [3- cyclodextrin, e. g., a sulfo butyl ether odextrin, e. g., CAPTISOL®, complex is ated as an aqueous ition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration n 0.25-30mg/mL, 0.5- L; l—30mg/mL; 5—30mg/mL, 10—30mg/mL; 15—30mg/mL, 0.25— 20mg/mL; 0.5-20mg/mL; l-20mg/mL, 0.5—20mg/mL; l-20mg/mL, 5-20mg/mL, lO-20mg/mL, 0.25-15mg/mL, 0.5—15mg/mL; 0.5-10mg/mL; l-lSmg/mL, l- lOmg/mL; l-Smg/mL; 5-15mg/mL; 5—10mg/mL; lO-lSmg/mL; l-lOmg/mL; 2- 8mg/mL; 2-7mg/mL; 3-5mg/mL; 5—15mg/mL; 7-12mg/mL; /mL; 8- 9mg/mL; 3-5mg/mL; or 3-4mg/mL; and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; L; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; L, 95mg/mL; lOOmg/mL; lSOmg/mL; 200mg/mL; 250mg/mL; 300mg/mL; 350mg/mL; or 400mg/mL.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, lO-30mg/mL; —30mg/mL, 0.25—20mg/mL; 0.5—20mg/mL; 1—20mg/mL, 0.5-20mg/mL; l- 20mg/mL, 5-20mg/mL, lO—ZOmg/mL, 0.25—15mg/mL, 0.5-15mg/mL; 0.5— lOmg/mL; l-lSmg/mL, l—lOmg/mL; 1—5mg/mL; /mL; 5-10mg/mL; 10- 15mg/mL; 1-10mg/mL; 2-8mg/mL; 2—7mg/mL; mL; 5-15mg/mL; 7- 12mg/mL; 7-10mg/mL; 8-9mg/mL; 3—5mg/mL; or 3-4mg/mL; and between 2.5- 40%, 25—30%, 25—20%, 25—10%, 5—40%, 5—30%, 5—20%, 5—10%, 6—40%, 6— %, 6—20%, 6—10%, 10-40%, 10—30%, 10—20%, 20—40%, 20—30%, 25—40%, 25— %, 3—10%, , 53%, 55—65% of the cyclodextrin, e.g., CAPTISOL®.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25- 30mg/mL, 0.5—30mg/mL; 1—30mg/mL; 5—30mg/mL, 10-30mg/mL; 15- 30mg/mL, 0.25-20mg/mL; 0.5—20mg/mL; 1—20mg/mL, 0.5-20mg/mL; 1- 20mg/mL, 5-20mg/mL, 10—20mg/mL, 5mg/mL, 0.5-15mg/mL; 0.5- L; 1-15mg/mL, 1-10mg/mL; 1—5mg/mL; 5-15mg/mL; 5-10mg/mL; 10- 15mg/mL; 1-10mg/mL; mL; 2—7mg/mL; 3-5mg/mL; 5-15mg/mL; 7- 12mg/mL; 7-10mg/mL; 8-9mg/mL; 3—5mg/mL; or 3-4mg/mL; and 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, %, 25%, 30%, 35% or 40% of the cyclodextrin, e.g., OL®.
In some embodiments, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; mL; mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, L, 25mg.mL, or 30 mg/mL; and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether [3- cyclodextrin, e.g., CAPTISOL®, at a concentration between 25-400mg/mL; 25- 300mg/mL; mg/mL; 25—100mg/mL; 25—50mg/mL; 50—400mg/mL; 50— 300mg/mL; 60—400mg/mL; 60—300mg/mL; 150—400mg/mL; 150—300mg/mL; 200—300mg/mL; 200—400mg/mL; 30—100mg/mL; 300-400mg/mL; 30— lOOmg/mL; 45-75mg/mL; 50—70mg/mL; 55-65mg/mL; or 50-60mg/mL. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an s ition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/rnL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and the cyclodextrin, e. g., CAPTISOL® at a concentration of 25mg/mL; 30mg/mL; 35mg/mL; L; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; 90mg/mL, 95mg/mL; lOOmg/mL; lSOmg/mL; 200mg/mL; 250mg/mL; 300mg/mL; 350mg/mL; or 400mg/mL.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/mL, 0.5mg/mL; l.0mg/mL; 1.5mg/mL; 2.0mg/mL; mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, mL, 9.0mg/mL, mL, lOmg/mL, lSmg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and n 25-40%, 25—30%, 25—20%, 25—10%, 5—40%, 5—30%, 5— %, 5—10%, 6—40%, 6—30%, 6—20%, 6—10%, 10—40%, , 10—20%, 20— 40%, , , 25—30%, 3—10%, 45—75%, 5—7%, 55—65% of the cyclodextrin, e.g., CAPTISOL®. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, x is ated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/mL, mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, .5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, ?.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, L, 20mg/mL, 25mg.mL, or 30 mg/mL; and 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% of the cyclodextrin, e.g., CAPTISOL®.
In an ment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration of 1.5mg/mL, and the cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an s composition comprising the neuroactive steroid, e.g., allopregnanolone, at a tration of L, and the cyclodextrin, e.g., a odextrin, e. g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%. In an embodiment, the ctive steroid, e.g., allopregnanolone, and extrin, e.g., a odextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 15mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%.
In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration of 1.5mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 15%. In an ment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B— cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, complex is formulated as an aqueous composition sing the neuroactive steroid, e.g., allopregnanolone, at a concentration of lOmg/mL, and the extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 15%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a tration of 15mg/mL, and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 15%.
In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration of 1.5mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 30%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, complex is ated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of lOmg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., OL®, at a concentration of 30%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, x is formulated as an aqueous ition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of L, and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., OL®, at a concentration of 30%.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition with a pH between 3-10, 4-9, 4-8, 4-7, 4—6, 4—5, 5—9, 5—8, 5—7, 5—6, 45—75, or 55—75 In some ments, the egnanolone and CAPTISOL® complex is formulated as an aqueous composition with apH 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 ated as an aqueous composition with a pH about 6.
In some embodiments, the allopregnanolone and OL® complex is ated as an aqueous composition and is administered intravenously. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is stered intramuscularly.
In some embodiments, the egnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered for l, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an s composition and is administered between 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 ated as an aqueous composition and is administered for 5 consecutive days. In some embodiments, the duration of administration is l, 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 formulated as an aqueous composition and is 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 formulated as an aqueous composition and is administered at a load, e.g., bolus, dose for l, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a maintenance, e.g., infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In an ment, the allopregnanolone and OL® complex is formulated as an aqueous composition and is administered at a load, e.g., bolus, dose of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, L, 25mg.mL, or 30 mg/mL neuroactive d, e.g., allopregnanolone, for 1 day and then administered at a maintenance, e.g., infusion, dose for 3 consecutive days of 0.25mg/mL, mL; mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL neuroactive steroid, e.g., egnanolone. In some ments, a nance, e.g., infusion, dose described herein, is lower than a load, e.g., bolus, dose described herein. In some embodiments, the maintenance, e.g., infusion, dose is less than 0.25mg/mL, mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; .0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, lSmg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL.
In some ments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a nance, e.g., infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or consecutive days and then administered at a taper 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 as an aqueous composition and is administered at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a maintenance, e. g., infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then stered at a first taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours.
In some embodiments, the egnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a maintenance, e.g., infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or consecutive days and then administered at a first taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then administered at a second taper dose for 1, 2, 3, 4, , 6, 7, 8, 9, or 10 hours. In some embodiments, the allopregnanolone and CAPTISOL® x is formulated as an aqueous composition and is administered at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a maintenance, e.g., infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a first taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then administered at a second taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then administered at a third taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours.
In some embodiments the first, second, or third taper dose is less than the maintenance, e.g., infusion, dose. In some ments, the second taper or third taper dose is less than the first taper dose. In some embodiments, the third taper dose is less than the second taper dose. In some ments, the first taper 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, e.g., infusion, dose. In some embodiments, the first taper dose is between 95-50%, 75—50%, 85—50%, 90-50%, , or 75—100% of the maintenance, e.g., infusion, dose. In an embodiment, the first taper dose is 75% of the maintenance, e.g., infusion, dose.
In some embodiments, the second taper dose is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, %, or 5% of the maintenance, e.g., infusion, dose. In some embodiments, the second taper dose is between 95—30%, 75—30%, 85—30%, 60—30%, 70—30%, 50— %, or 50-40% of the nance, e.g., infusion, dose. In an embodiment, the second taper dose is 50% of the maintenance, e.g., infusion, dose.
In some embodiments, the third taper dose is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, %, or 5% of the nance, e.g., infusion, dose. In some embodiments, the third taper dose is between 50—5%, 40—5%, 30—5%, 25—5%, 25—10%, 25—20%, or -40% of the maintenance, e.g., infusion, dose. In an ment, the second taper dose is 50% of the maintenance, e.g., infusion, dose. In an embodiment, the third taper dose is 25% of the maintenance, e.g., infusion, dose.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered at a dose necessary to achieve a predetermined burst suppression pattern, e.g., inter-burst intervals of between 2-30 seconds; as measured by a method of neurophysiological monitoring, e. g., EEG, CFM. In some ments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is stered at a dose necessary to achieve a predetermined burst suppression pattern, e.g., inter-burst intervals of between 2-30 s, 5-30 seconds, 10-30 s, 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 a method of neurophysiological monitoring, e.g., EEG, CFM.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is stered within 48 hours, 24 hours, 20 hours, 18 hours, 16 hours, 10 hours, 8 hours, 5 hours, 3 hours, 1 hour, or 0.5 hour after a traumatic brain injury. In an embodiment, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered within 10 hours after a traumatic brain injury.
In an embodiment, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered Within 8 hours after a traumatic brain injury.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered Within 10 hours, 8 hours, 5 hours, 3 hours, 1 hour, or 0.5 hour after a seizure, e.g., a status epileptic seizure, e.g., a tory status epileptic seizure has started. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous ition and is administered within 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 s after a seizure, e. g., a status epileptic e, e. g., a refractory status epileptic seizure has started. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered after a seizure, e.g., a status epileptic seizure, e. g., a refractory status epileptic seizure has lasted 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 s or 60 s.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered prior to the onset of a seizure, e.g., a status tic seizure, e.g., a refractory status epileptic seizure.
In one aspect, the disclosure features a method of treating a t having a CNS disorder, e.g., a traumatic brain , status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non— convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; lized periodic epileptiform discharges; periodic lateralized epileptiform discharges; a seizure, e.g., acute tive seizures, cluster seizures, the method sing administering to the subject a neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B— cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex wherein the ition comprises less than 100ppm of a phosphate, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., a B- cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, has an absorption of less than 0.2 AU. due to a drug—degrading agent, as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution comprising 300 mg of the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cell having a lcm path length.
In some embodiments, the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e. g., CAPTISOL®, has an absorption of less than 0.2 AU. due to a color forming agent, as determined by UV/vis ophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution sing 500 mg of the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cell having a lcm path length.
In some embodiments, the cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether odextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e. g., CAPTISOL®, further comprises: less than 20 ppm of a sulfoalkylating agent; less than 0.5% wt. of an underivatized cyclodextrin; less than 1% wt. of an alkali metal halide salt; and less than 0.25% wt. of a hydrolyzed sulfoalkylating agent.
In some embodiments, the cyclodextrin, e.g., a B—cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, has an tion of less than 0.2 AU. due to a drug-degrading agent, as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous on comprising 500 mg of the cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cell having a 1 cm path length.
In some embodiments, the cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g, CAPTISOL®, comprises: less than 50 ppm of a phosphate; less than 10 ppm of a sulfoalkylating agent; less than 0.2% wt. of an underivatized cyclodextrin; less than 0.5% wt. of an alkali metal halide salt; and less than 0.1% wt. of a hydrolyzed sulfoalkylating agent; and wherein the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, has an absorption of less than 0.2 A.U. due to the color—forming agent, as ined by U/vis ophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution comprising 500 mg of the cyclodextrin, e.g., a B- cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cell having a 1 cm path length.
In some embodiments, the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether B-cyclodextrin, e. g., CAPTISOL®, comprises: less than 10 ppm of a ate; less than 2 ppm of a sulfoalkylating agent; less than 0.1% wt. of an underivatized cyclodextrin; less than 0.2% wt. of an alkali metal halide salt; and less than 0.08% wt. of a hydrolyzed sulfoalkylating agent; and wherein the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e. g., CAPTISOL®, has an absorption of less than 0.1 A.U. due to the color—forming agent, as determined by UV/vis spectrophotometry at a ngth of 320 nm to 350 nm for an aqueous on comprising 500 mg of the cyclodextrin, e.g., a [3- cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, per mL of solution in a cell having a 1 cm path length.
In some embodiments, the cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e. g., CAPTISOL®, ses: less than 5 ppm of a phosphate; less than 0.1% wt. of an alkali metal halide salt; and less than 0.05% wt. of a hydrolyzed sulfoalkylating agent.
In some embodiments, the CNS er is a traumatic brain injury. In some embodiments, the CNS disorder is status epilepticus, convulsive status epilepticus, e. g., early status epilepticus, established status epilepticus, refractory status epilepticus, super—refractory status epilepticus; non-convulsive status epilepticus, e.g., lized status ticus, complex partial status epilepticus; generalized periodic epileptiform discharges; periodic lateralized epileptiform discharges. In some embodiments, the CNS er is a traumatic brain injury. In some embodiments, the CNS disorder is a seizure, e. g., acute repetitive seizures, cluster es.
In an embodiment, the disclosure features a method of treating a subject having a traumatic brain injury, the method comprising administering to the subject an allopregnanolone and CAPTISOL® complex. In an embodiment, the disclosure features a method of treating a subject having status epilepticus, convulsive status epilepticus, e.g., early status epilepticus, ished status epilepticus, refractory status epilepticus, super—refractory status epilepticus; non- convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; periodic lateralized epileptiform rges, the method comprising administering to the subject an allopregnanolone and OL® complex. In an embodiment, the disclosure features a method of treating a subject having a a seizure, e. g., acute tive seizures, cluster seizures, the method comprising stering to the subject an allopregnanolone and CAPTISOL® complex.
In some embodiments, the neuroactive steroid is a progestin derivative, e.g., allopregnanolone. In an embodiment, the neuroactive steroid is allopregnanolone.
In some embodiments, the cyclodextrin is a B—cyclodextrin. In an embodiment, the cyclodextrin is a sulfo butyl ether B—cyclodextrin. In an embodiment, the cyclodextrin is CAPTISOL®. In some embodiments, the cyclodextrin is a B-cyclodextrin disclosed in US. Patent Nos. 5,874,418; 6,046,177; and 7,635,733, which are herein incorporated by reference.
In some embodiments, the neuroactive steroid is a progestin derivative, e.g., allopregnanolone, and the cyclodextrin is a B—cyclodextrin. In an embodiment, the neuroactive steroid is allopregnanolone and the cyclodextrin is CAPTISOL®.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated for parenteral administration. In an ment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous ition. In some embodiments, the ctive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition sing the neuroactive steroid at a concentration n 0.25—30mg/mL, 0.5-30mg/mL; 1— 30mg/mL; 5—30mg/mL, 10—30mg/mL; 15—30mg/mL, 0.25—20mg/mL; 0.5— 20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL, 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; /mL, 1-10mg/mL; 1- 5mg/mL; 5-15mg/mL; 5-10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2- ; 3—5mg/mL; 5—15mg/mL; 7—12mg/mL; /mL; 8-9mg/mL; 3- 5mg/mL; or 3-4mg/mL. In some embodiments, the ctive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition sing the neuroactive steroid at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, L, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL. In an ment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid at a concentration of mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid at a concentration of 5mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid at a concentration of lSmg/mL.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., OL®, complex is formulated as an aqueous composition comprising the cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B- cyclodextrin, e.g., CAPTISOL®, at a concentration between 25-400mg/mL; 25- 300mg/mL; mg/mL; 25—100mg/mL; 25—50mg/mL; 50—400mg/mL; 50— 300mg/mL; 60-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; mg/mL; 300-400mg/mL; 30- 100mg/mL; 45-75mg/mL; g/mL; 55-65mg/mL; or 50-60mg/mL. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e. g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; 90mg/mL, 95mg/mL; lOOmg/mL; 150mg/mL; 200mg/mL; mL; 300mg/mL; 350mg/mL; or 400mg/mL. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the cyclodextrin, e.g., a odextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of l. In some ments, the ctive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising between , —30%, 25—20%, 25—10%, 5—40%, 5—30%, 5—20%, 5—10%, 6—40%, 6—30%, 6— 20%, 6—10%, , 10—30%, 10—20%, 20—40%, 20—30%, 25—40%, 25—30%, 3— %, 45-75%, 5-7%, 55-65% of the cyclodextrin, e.g., CAPTISOL®. In some embodiments, the ctive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as 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%, %, 15%, 20%, 25%, 30%, 35% or 40% of the cyclodextrin, e.g., CAPTISOL®. In an embodiment, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising 6% of the cyclodextrin. In an ment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising 15% of the cyclodextrin. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., OL®, complex is formulated as an aqueous composition comprising 30% of the cyclodextrin.
In some ments, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is ated as an s ition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, lO-30mg/mL; -30mg/mL, 0mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; l- 20mg/mL, 5-20mg/mL, 10—20mg/mL, 0.25—15mg/mL, 0.5-15mg/mL; 0.5- lOmg/mL; /mL, /mL; l—Smg/mL; 5—15mg/mL; 5-10mg/mL; 10- lSmg/mL; l-lOmg/mL; 2—8mg/mL; mL; 3—5mg/mL; 5-15mg/mL; 7- lng/mL; 7-10mg/mL; 8-9mg/mL; 3—5mg/mL; or 3-4mg/mL; and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration between 25—400mg/mL; 25-300mg/mL; 25- 200mg/mL; 25—100mg/mL; 25—50mg/mL; 50—400mg/mL; 50—300mg/mL; 60— 400mg/mL; 60—300mg/mL; 150—400mg/mL; 150—300mg/mL; 0mg/mL; 200—400mg/mL; 30—100mg/mL; 300—400mg/mL; 30—100mg/mL; 45-75mg/mL; 50—70mg/mL; 55—65mg/mL; or 50—60mg/mL. In some embodiments, the neuroactive steroid, e.g., egnanolone, and cyclodextrin, e.g., a B- cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, 0.5- 30mg/mL; l—30mg/mL; 5—30mg/mL, 10—30mg/mL; 15—30mg/mL, 0.25— 20mg/mL; 0.5-20mg/mL; 1—20mg/mL, 0.5—20mg/mL; 1—20mg/mL, 5—20mg/mL, -20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1- 10mg/mL; 1-5mg/mL; 5-15mg/mL; 5-10mg/mL; 10-15mg/mL; 1-10mg/mL; 2- 8mg/mL; 2-7mg/mL; 3-5mg/mL; 5-15mg/mL; 7-12mg/mL; 7-10mg/mL; 8- 9mg/mL; 3—5mg/mL; or 3—4mg/mL; and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, at a tration of 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; 90mg/mL, 95mg/mL; lOOmg/mL; lSOmg/mL; 200mg/mL; 250mg/mL; 300mg/mL; 350mg/mL; or mL.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration between 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; /mL, lO-30mg/mL; -30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; l- 20mg/mL, 5-20mg/mL, 10—20mg/mL, 0.25—15mg/mL, 0.5-15mg/mL; 0.5- lOmg/mL; l-lSmg/mL, l—lOmg/mL; l—5mg/mL; 5—15mg/mL; 5-10mg/mL; 10- 15mg/mL; l-lOmg/mL; 2-8mg/mL; 2—7mg/mL; 3—5mg/mL; 5-15mg/mL; 7- l2mg/mL; 7-10mg/mL; 8-9mg/mL; 3—5mg/mL; or 3-4mg/mL; and between 2.5- 40%, 25—30%, , 25—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— %, 3—10%, 45—75%, 5—7%, 55—65% of the extrin, e.g., CAPTISOL®.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e. g., a odextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., egnanolone, at a concentration between 0.25- 30mg/mL, 0.5—30mg/mL; /mL; 5—30mg/mL, 10—30mg/mL; 15- 30mg/mL, 0mg/mL; 0.5—20mg/mL; l—20mg/mL, 0.5-20mg/mL; l- 20mg/mL, 5-20mg/mL, lO—20mg/mL, 0.25—15mg/mL, 0.5-15mg/mL; 0.5- lOmg/mL; l-lSmg/mL, l—lOmg/mL; mL; 5—15mg/mL; 5-10mg/mL; 10- L; l—lOmg/mL; 2—8mg/mL; 2—7mg/mL; 3—5mg/mL; 5—15mg/InL; 7— L; 7-10mg/mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, %, 25%, 30%, 35% or 40% of the cyclodextrin, e.g., CAPTISOL®.
In some embodiments, the ctive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous ition comprising the neuroactive steroid, e.g., egnanolone, at a concentration of /mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, lOmg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and the cyclodextrin, e.g., a B-cyclodextrin, e. g., a sulfo butyl ether [3- cyclodextrin, e.g., CAPTISOL®, at a concentration between 25-400mg/mL; 25- 300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 50- 300mg/mL; 60—400mg/mL; 60—300mg/mL; 150—400mg/mL; l50—300mg/mL; 200—300mg/mL; 200—400mg/mL; 30—100mg/mL; 300-400mg/mL; 30— lOOmg/mL; 45-75mg/mL; 50—70mg/mL; g/mL; or 50-60mg/mL. In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, mL, 6.5mg/mL, mL, mL, 8.0mg/mL, mL, 9.0mg/mL, mL, L, 15mg/mL, 20mg/mL, L, or 30 mg/mL; and the cyclodextrin, e.g., CAPTISOL® at a concentration of 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; 75mg/mL; 80mg/mL; 85mg/mL; 90mg/mL, 95mg/mL; lOOmg/mL; l50mg/mL; 200mg/mL; 250mg/mL; mL; 350mg/mL; or 400mg/mL.
In some embodiments, the neuroactive steroid, e.g., allopregnanolone, and extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and n 2.5-40%, 2.5—30%, %, 2.5—10%, 5—40%, 5—30%, 5— %, 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%, 45—75%, 5—7%, 55-65% of the cyclodextrin, e.g., CAPTISOL®. In some ments, the neuroactive d, e.g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of /mL, 0.5mg/mL; mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, .5mg/mL, mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL; and 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% of the cyclodextrin, e.g., CAPTISOL®.
In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, at a concentration of 6%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is ated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 10mg/mL, and the cyclodextrin, e. g., a B-cyclodextrin, e. g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%. In an embodiment, the neuroactive steroid, e. g., allopregnanolone, and cyclodextrin, e.g., a B—cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e.g., CAPTISOL®, complex is formulated as an s composition comprising the ctive steroid, e.g., allopregnanolone, at a tration of 15mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 6%.
In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous ition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 1.5mg/mL, and the extrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 15%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B— cyclodextrin, e. g., a sulfo butyl ether odextrin, e. g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e. g., allopregnanolone, at a concentration of lOmg/mL, and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, at a tration of 15%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e. g., a odextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous ition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 15mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 15%.
In an embodiment, the ctive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., allopregnanolone, at a concentration of 1.5mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, at a concentration of 30%. In an embodiment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B— cyclodextrin, e. g., a sulfo butyl ether B—cyclodextrin, e. g., OL®, complex is formulated as an aqueous composition comprising the neuroactive d, e. g., allopregnanolone, at a concentration of 10mg/mL, and the cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether odextrin, e.g., CAPTISOL®, at a concentration of 30%. In an ment, the neuroactive steroid, e.g., allopregnanolone, and cyclodextrin, e.g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, complex is formulated as an aqueous composition comprising the neuroactive steroid, e.g., egnanolone, at a concentration of 15mg/mL, and the cyclodextrin, e. g., a B-cyclodextrin, e.g., a sulfo butyl ether B-cyclodextrin, e.g., CAPTISOL®, at a concentration of 30%.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an s composition with a pH between 3-10, 4-9, 4-8, 4-7, 4—6, 4—5, 5—9, 5—8, 5—7, 5—6, 45—75, or 55—75 In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition With apH 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 formulated as an aqueous composition with a pH about 6.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered intravenously. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered intramuscularly.
In some embodiments, the allopregnanolone and OL® complex is formulated as an aqueous composition and is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In some embodiments, the allopregnanolone and CAPTISOL® x is ated as an aqueous composition and is administered between 1-10, 1-5, 5-10, 1-6, 2-6, 3-6, 4-5, or 1-9 utive days. In an embodiment, the allopregnanolone and CAPTISOL® x is formulated as an aqueous composition and is 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 on of administration is 5 days.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is 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 formulated as an s composition and is administered at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a maintenance, e. g., infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In an embodiment, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is stered at a load, e. g., bolus, dose of 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, lOmg/mL, 15mg/mL, 20mg/mL, L, or 30 mg/mL neuroactive steroid, e.g., allopregnanolone, for 1 day and then administered at a maintenance, e.g., infusion, dose for 3 consecutive days of /mL, mL; mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, mL, 9.5mg/mL, lOmg/mL, 15mg/mL, 20mg/mL, L, or 30 mg/mL neuroactive steroid, e.g., allopregnanolone. In some embodiments, a maintenance, e.g., infusion, dose described herein, is lower than a load, e.g., bolus, dose described herein. In some embodiments, the maintenance, e.g., infusion, dose is less than 0.25mg/mL, mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; .0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30 mg/mL.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a maintenance, e.g., infusion, dose for l, 2, 3, 4, 5, 6, 7, 8, 9, or consecutive days and then administered at a taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In some ments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a nance, e. g., infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a first taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 utive days and then administered at a maintenance, e.g., infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or consecutive days and then stered at a first taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then administered at a second taper dose for 1, 2, 3, 4, , 6, 7, 8, 9, or 10 hours. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is stered at a load, e.g., bolus, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a maintenance, e.g., infusion, dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days and then administered at a first taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then administered at a second taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours and then administered at a third taper dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours.
In some ments the first, second, or third taper dose is less than the maintenance, e.g., infusion, dose. In some embodiments, the second taper or third taper dose is less than the first taper dose. In some embodiments, the third taper dose is less than the second taper dose. In some embodiments, the first taper 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, e.g., infusion, dose. In some embodiments, the first taper dose is between , 75—50%, 85—50%, 90—50%, 80—50%, or 75—100% of the maintenance, e.g., infusion, dose. In an embodiment, the first taper dose is 75% of the maintenance, e.g., on, dose.
In some embodiments, the second taper dose is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, %, or 5% of the maintenance, e.g., infusion, dose. In some embodiments, the second taper dose is between 95-30%, , 85-30%, 60-30%, 70-30%, 50- %, or 50-40% of the maintenance, e.g., infusion, dose. In an embodiment, the second taper dose is 50% of the maintenance, e.g., infusion, dose.
In some embodiments, the third taper dose is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, %, or 5% of the maintenance, e.g., on, dose. In some embodiments, the third taper dose is between 50—5%, 40—5%, 30—5%, 25—5%, , 25—20%, or 25-40% of the maintenance, e.g., infusion, dose. In an embodiment, the second taper dose is 50% of the maintenance, e.g., infusion, dose. In an embodiment, the third taper dose is 25% of the nance, e.g., infusion, dose.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered at a dose necessary to achieve a predetermined burst suppression pattern, e.g., inter-burst intervals of between 2-30 seconds; as measured by a method of neurophysiological monitoring, e.g., EEG, CFM. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered at a dose necessary to achieve a predetermined burst suppression pattern, e.g., inter-burst intervals of between 2-30 seconds, 5-30 seconds, 10-30 seconds, 15-30 seconds, 1-30 s, 0-30 seconds, 2-20 seconds, 2-10 s, 5-20 seconds, 10-20 seconds, 15-25 seconds, 5-15 seconds or 5-10 seconds; as measured by a method of neurophysiological monitoring, e.g., EEG, CFM.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered within 48 hours, 24 hours, 20 hours, 18 hours, 16 hours, 10 hours, 8 hours, 5 hours, 3 hours, 1 hour, or 0.5 hour after a traumatic brain . In an embodiment, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered within 10 hours after a traumatic brain .
In an embodiment, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered within 8 hours after a traumatic brain injury.
In some embodiments, the allopregnanolone and OL® complex is formulated as an s composition and is administered within 10 hours, 8 hours, 5 hours, 3 hours, 1 hour, or 0.5 hour after a seizure, e.g., a status epileptic e, e. g., a refractory status epileptic seizure has started. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is administered within 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes after a seizure, e. g., a status tic seizure, e. g., a refractory status epileptic seizure has started. In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is stered after a seizure, e. g., a status epileptic seizure, e.g., a refractory status epileptic seizure has lasted 5 minutes, minutes, 15 minutes, 20 minutes, 30 minutes or 60 minutes.
In some embodiments, the allopregnanolone and CAPTISOL® complex is formulated as an aqueous composition and is stered prior to the onset of a seizure, e.g., a status epileptic seizure, e.g., a refractory status epileptic seizure.
Brief Description of the Drawings is a bar graph depicting the t seizure infmrI KO mice intraperitoneally administered 3, 10, 30 mg/kg allopregnanolone in 30% B- Cyclodextrin. is a bar graph depicting the percent al infmr] KO mice intraperitoneally administered 3, 10, 30 mg/kg allopregnanolone in 30% B- Cyclodextrin. is a graph depicting the e rank in PZT treated /J mice intraperitoneally administered 3, 10, 30 mg/kg allopregnanolone in 15% B— Cyclodextrin. is graph depicting the latency to death period in PZT treated C57BL6/J mice intraperitoneally administered 3, 10, 30 mg/kg allopregnanolone in 15% B-Cyclodextrin. is a graph depicting the plasma concentration profile of a patient intravenously administered 1.5 mg/ml allopregnanolone in 6% hydroxypropyl—B— cyclodextrin in 0.9% sodium de for 5 days. depicts the plasma exposure profiles of allopregnanolone measured by LC/MS-MS after single intramuscular (10mg/kg) or intravenous (5mg/kg) allopregnanolone dose in 30% CAPTISOL® in SD rats. depicts the brain exposure profiles of allopregnanolone measured by LC/MS- MS after single intramuscular (10mg/kg) or intravenous (5mg/kg) allopregnanolone dose in 30% CAPTISOL® in SD rats. depicts the latency to fall period (seconds) in a penetrating ballistic brain injury rodent model of tic brain injury in both the low and high dose groups progesterone in 6% CAPTISOL®. depicts the mean motor score in a penetrating tic brain injury rodent model of traumatic brain injury in both the low and high dose groups progesterone in 6% CAPTISOL®.
Detailed Description of the ion As used herein "allopregnanolone" also encompasses pharmaceutically acceptable, pharmacologically active tives including individual enantiomers (dextrogyral and levrogyral enantiomers) and their pharmaceutically able salts, mixtures of enantiomers and their pharmaceutically acceptable salts, and active metabolites and their pharmaceutically able salts, unless otherwise noted. It is understood that in some cases dosages of enantiomers, derivatives, and metabolites may need to be ed based on ve activity of the racemic mixture of allopregnanolone.
As used herein, "pharmaceutically able salts" refer to tives of the disclosed compounds wherein the parent compound is modified by making the acid-addition or base-addition salts thereof. Example of pharmaceutically acceptable salts include but are not limited to mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non—toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non—toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, c, lactic, malic, tartaric, , ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, ic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane onic, oxalic, and isethionic salts. d release dosage form: A delayed release dosage form is one that releases a drug (or drugs) at a time other than promptly after administration.
Extended release dosage form: An extended release dosage form is one that allows at least a d reduction in dosing frequency as compared to the drug presented as a conventional dosage form (e.g. as a solution or prompt drug- releasing, conventional solid dosage form).
Modified release dosage form: A ed release dosage form is one for which the drug release characteristics of time, course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms.
Delayed release and extended e dosage forms and their combinations are types of modified release dosage forms.
Matrix-forming materials: Matrix forming materials are als which form strong, viscous gels upon hydration and provide control of drug diffusion and release. In hydrophilic matrix systems, matrix forming als are uniformly incorporated throughout the tablet. Upon contact with water, the outer tablet layer is partially ed, forming a gel layer. The rate of diffusion of the drug(s) out of the gel layer and the rate of n of the gel layer ine overall tablet dissolution and drug delivery rates. Examples of matrix forming materials include cellulose ethers that are water-soluble such as methylcellulose, ethyl cellulose and hydroxypropyl methylcellulose.
"Alkyl", as used herein, refers to the radical of saturated or unsaturated aliphatic , including straight—chain alkyl, alkenyl, or alkynyl groups, branched-chain alkyl, alkenyl, or alkynyl groups, cycloalkyl, cycloalkenyl, or cycloalkynyl (alicyclic) groups, alkyl substituted cycloalkyl, cycloalkenyl, or cycloalkynyl groups, and cycloalkyl tuted alkyl, alkenyl, or alkynyl groups. Unless otherwise indicated, a straight chain or branched chain alkyl has or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), more preferably 20 or fewer carbon atoms, more preferably 12 or fewer carbon atoms, and most preferably 8 or fewer carbon atoms. In certain ments, alkyl groups contain between 1 and 6, more preferably between 1 and 4 carbon atoms. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 s in the ring ure. The ranges provided above are inclusive of all values between the minimum value and the maximum value.
The alkyl groups may also be substituted with one or more groups including, but not limited to, halogen, hydroxy, amino, thio, ether, ester, carboxy, oxo, and aldehyde groups. The alkyl groups may also contain one or more heteroatoms within the carbon backbone. Preferably the heteroatoms incorporated into the carbon backbone are oxygen, nitrogen, sulfur, and combinations thereof. In certain embodiments, the alkyl group contains between one and four heteroatoms.
"Alkenyl" and "Alkynyl", as used herein, refer to rated aliphatic groups containing or comprising one or more double or triple bonds analogous in length (e.g., C2—C30) and possible substitution to the alkyl groups described above.
"Heterocycle" or "heterocyclic", as used , refers to a cyclic radical attached Via a ring carbon or nitrogen of a monocyclic or bicyclic ring containing or comprising 3-10 ring atoms, and preferably from 5-6 ring atoms, consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, 0, (C14) alkyl, phenyl or benzyl, and optionally containing or comprising one or more double or triple bonds, and optionally substituted With one or more substituents. The term ocycle" also encompasses substituted and unsubstituted heteroaryl rings. Examples of heterocyclic ring include, but are not limited to, benzimidazolyl, uranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, olyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H—1 ithiazinyl, ofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, olyl, lH—indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4—oxadiazolyl, 1,2,5—oxadiazolyl, 1,3,4- oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, dinyl, piperidonyl, 4-piperidony1, piperonyl, inyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, oxazole, pyridoimidazole, pyridothiazole, pyridinyl, l, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H—pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H—quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5—thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl.
"Halogen", as used herein, refers to fluorine, chlorine, bromine, or iodine.
The term "substituted" as used herein, refers to all permissible substituents of the compounds described herein. In the broadest sense, the permissible tuents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, ns, hydroxyl groups, or any other organic groupings containing or comprising any number of carbon atoms, preferably 1—14 carbon atoms, and optionally include one or more atoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents e alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted aryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, tuted phenoxy, aroxy, substituted aroxy, hio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, tuted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, tuted phosphonyl, polyaryl, substituted polyaryl, C3-C20 cyclic, tuted C3-C20 , cyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups.
Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that "substitution" or "substituted" includes the implicit proviso that such substitution is in accordance With ted valence of the tuted atom and the substituent, and that the substitution results in a stable compound, 1'. e. a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
A eutically effective treatment is one that results in alleviation of one or more symptoms of the injury, such as improved morphological recovery (i.e., enhanced tissue ity) and/or behavioral recovery. The ement can be characterized as an increase in either the rate and/or the extent of behavioral and/or anatomical ry following the tic CNS injury.
Neurodegeneration is the ssive loss of neurons in the central nervous system. As used herein, "neuroprotection" is the arrest and/or reverse progression of neurodegeneration following a traumatic l nervous system injury. Multiple physiological events lead to the neurodegeneration of the CNS tissues following a traumatic CNS injury. These events include, for example, cerebral edema, ction of vascular integrity, increase in the immune and inflammatory se, demyelinization, and lipid peroxidation. The formulation may be useful in reducing and/or preventing the physiological events leading to neurodegeneration, including reducing or eliminating neuronal cell death, edema, ischemia, and enhancing tissue viability following a traumatic injury to the central nervous system.
Modified Release Neuroactive steroid Formulations A. Neuroactive Steroids Neuroactive steroids (or neurosteroids) are natural, synthetic, or semi- synthetic steroids that rapidly alter neuronal excitability through ction with neurotransmitter-gated ion channels. Neuroactive steroids effect binding to membrane-bound receptors such as those for inhibitory and (or) excitatory neurotransmitters including GABAA, NMDA, and sigma receptors.
The steroids that may be classified into functional groups according to chemical structure and logical activity and include estrogenic hormones, progestational hormones, and androgenic es. Of particular interest are progestational hormones, referred to herein as "progestins" or "progestogens", and their tives and bioactive metabolites. Members of this broad family include steroid hormones disclosed in Remington's Pharmaceutical Sciences, Gennaro et al., Mack Publishing Co. (18th ed. 1990), 990-993. As with all other classes of steroids, isomerism is of fundamental importance with the sex hormones. As used , a variety of progestins (i.e., progesterone) and their derivatives, including both synthetic and natural products, can be used, as well as progestin metabolites such as progesterone.
The term "progesterone" as used herein refers to a member of the progestin family and includes a 21 carbon steroid hormone. Progesterone is also known as D4-pregnene—3,20—dione; A4—pregnene—3,20-dione; or pregnene- 3,20-dione. As used herein a "synthetic progestin" is a molecule whose structure is related to that of progesterone, is synthetically derived, and retains the biologically activity of progesterone (i.e., treats a traumatic CNS injury).
Representative synthetic progestins include, but are not limited to, substitutions at the 17-position of the progesterone ring to introduce a hydroxyl, acetyl, hydroxyl acetyl, aliphatic, nitro, or heterocyclic group, modifications to e 170L-OH esters (i. e., 17 u—hydroxyprogesterone te), as well as cations that introduce 6-methyl, 6—ene, and 6-chloro substituents onto progesterone (i.e., medroxyprogesterone acetate, megestrol acetate, and chlomadinone acetate), and which retains the ically activity of progesterone (i.e., treats a traumatic CNS injury). Such progestin derivatives e 5-dehydroprogesterone, 6—dehydro—retroprogesterone (dydrogesterone), allopregnanolone (allopregnan—30t, or 3B—ol—20—one), diol diacetate, hydroxyprogesterone caproate (pregn-4—ene—3,20—dione, 17—(1—oxohexy)oxy); levonorgestrel, norethindrone, norethindrone acetate (19-norpregnenyn- 3-one, 17-(acetyloxy)-,(17(x)-); norethynodrel, norgestrel, pregnenolone, and megestrol acetate.
Useful progestins also can e allopregnone-3a or 38, 20a or 2013— diol (see Merck Index 258—261); egnane,—38,21-diol-11,20-dione; allopregnane-3 [3,170L-diol—20—one; 3,20—allopregnanedione, allopregnane, 38,11B,170L,20B,21-pentol; allopregnane—3B,170i,20[3,21-tetrol; allopregnane-30L or 38,118,170L,21-tetrol-2O-one, allopregnane—3B,170L or ZOB-triol; egnane— 3B,170L,21-triol-11,20-dione; allopregnane—3B,11B,21-triol-20—one; allopregnane— 3B,170L,21-triolone; allopregnane—3a or 3B—ol—20—one; pregnanediol; 3,20- pregnanedione; pregnan-30r—ol—20—one; 4—pregnene—20,21—diol—3,1 1—dione; 4— pregnene-l 1 B,17a,20[3,21—tetr01—3—0ne; 4—pregnene—17a,2OB,21—triol—3,1 1—dione; 4-pregnene-17a,20[3,21-triolone, and nolone methyl ether. Further progestin derivatives e esters with non-toxic organic acids such as acetic acid, benzoic acid, maleic acid, malic acid, caproic acid, and citric acid and inorganic salts such as hydrochloride, sulfate, nitrate, bicarbonate and carbonate salts. Other suitable progestins include alphaxalone, alphadolone, hydroxydione, and minaxolone.
Additional suitable ctive steroids are disclosed in United States Patent ation Publication Nos. US 2011/0092473 and US 2010/031763 8, and US. Patent No. 5,232,917, which are incorporated herein by reference for the neuroactive steroids described therein.
In certain embodiments, the ctive steroid is defined by a I Formula I wherein, R1 is hydrogen or an alkyl group, alkenyl group, or alkynyl group; R2 is hydrogen, or an amino, thio, sulfinyl, sulfonyl, halogen, trifluoromethyl, nitro, alkoxy, alkyl, alkenyl, or alkynyl group; Rga is a yl group and R31, is hydrogen, or Rga and R31, taken together represent a keto group; R4 is hydrogen when the bonds between C4 and C5 and C5 and C6 are single bonds, or is absent when a double bond is present between C4 and C5 of the steroid ring system or C5 and C6 of the steroid ring system; R5 is hydrogen, or an alkyl, alkoxy, amino, nitro, hydroxyl, halogen, trifluoromethyl, cyano, alkenyl, or l group; R6 is hydrogen, or an alkyl, alkoxy, amino, nitro, hydroxyl, halogen, trifluoromethyl, cyano, l, or alkynyl group; R7a is hydrogen, or an acetyl, hydroxyl acetyl, acyl, alkyl, alkoxy, amino, nitro, halogen, trifluoromethyl, cyano, alkenyl, yclic, or alkynyl group; R7}, is hydrogen, or an acetyl, hydroxyl acetyl, acyl, alkyl, alkoxy, amino, nitro, halogen, trifluoromethyl, cyano, l, hetercyclic, or alkynyl group; R8 is hydrogen, or an acetyl, hydroxyl , acyl, alkyl, alkoxy, amino, nitro, halogen, trifluoromethyl, cyano, alkenyl, hetercyclic, or alkynyl group; or R7b and Rg, er with the carbon atoms to which they are attached form a C3-C7 carbocyclic or heterocyclic ring, optionally substituted with one or more substituents selected from is hydrogen, or an acetyl, hydroxyl , acyl, alkyl, alkoxy, amino, nitro, halogen, trifluoromethyl, cyano, alkenyl, hetercyclic, epoxy, or alkynyl group; R9 is hydrogen, or an amino, thio, sulfinyl, nitro, yl, halogen, alkoxy, alkyl, l, keto, or alkynyl group; R10 is R5 is hydrogen, or an alkyl, alkoxy, amino, nitro, hydroxyl, halogen, trifluoromethyl, cyano, alkenyl, or alkynyl group, preferably hydrogen; R11 is absent or is hydrogen, or an alkyl, alkoxy, amino, nitro, yl, halogen, trifluoromethyl, cyano, alkenyl, or alkynyl group, preferably hydrogen if R11 is present; and wherein the dotted lines indicate that a single or double bond may be present.
In particular embodiments, the steroids are one or more of a series sedative-hypnotic 3 alpha—hydroxy ring A—reduced pregnane steroids that include the major metabolites of progesterone and deoxycorticosterone, 3 alpha- hydroxy-5 alpha-pregnan-20—one (allopregnanolone) and 3 alpha,2l-dihydroxy— alpha-pregnanone (allotetrahydroDOC), respectively. These 3 alpha- hydroxysteroids do not interact with classical intracellular d receptors but bind stereoselectively and with high affinity to receptors for the major inhibitory neurotransmitter in the brain, gamma—amino—butyric acid (GABA).
In n embodiments, the neuroactive steroids are progesterone, allopregnanolone or other progesterone analogs. In a particular embodiment, the neuroactive steroid is egnanolone or a derivative thereof. Exemplary derivatives include, but are not limited to, (20R)—17beta-(l-hydroxy—2,3— butadienyl)-5alpha-androstane—3alpha—01 (HBAO). Additional derivatives are described in WC 2012/127176.
The lipophilic nature of allopregnanolone can make it different to ate for in viva administration. As discussed above, allopregnanolone can be formulated With a host, such as a cyclodextrin to improve the solubility.
Alternatively, or additionally, allopregnanolone can be ed in an attempt to improve the solubility. For e, polar groups can be introduced onto position 160. With the goal of sing water solubility, brain accessibility, and potency of neuroactive steroids as described in Kasal et al., J. Med. Chem, 52(7), 2119—215 (2009).
As used herein active steroid" also encompasses ceutically acceptable, pharmacologically active derivatives of neuroactive steroids including both indiVidual enantiomers of neuroactive steroids (dextrogyral and levrogyral enantiomers) and their pharmaceutically acceptable salts, mixtures of neuroactive steroid enantiomers and their pharmaceutically acceptable salts, and active metabolites of ctive steroid and their pharmaceutically acceptable salts, unless ise noted. It is understood that in some cases dosages of enantiomers, derivatives, and metabolites may need to be adjusted based on relative activity of the racemic mixture of neuroactive steroid.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making the acid-addition or base—addition salts thereof. Example of pharmaceutically acceptable salts include but are not limited to l or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non—toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non—toxic inorganic or c acids. Such conventional xic salts include those derived from inorganic acids such as hydrochloric, hydrobromjc, sulfuric, sulfamic, oric, and nitric acids; and the salts prepared from c acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, , hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and onic salts.
The 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 free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a e of the two; generally, non—aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704.
The phrase "pharmaceutically acceptable" is employed herein to refer to those nds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, tion, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
Neuroprotective ds lly contain one or more chiral centers, and thus exist as one or more stereoisomers. Such stereoisomers can be prepared and/or ed as a single enantiomer, a e of diastereomers, or a racemic mixture.
As used herein, the term "stereoisomers" refers to compounds made up of the same atoms having the same bond order but having different three- dimensional arrangements of atoms which are not hangeable. The three— dimensional structures are called configurations. As used herein, the term "enantiomers" refers to two stereoisomers which are non-superimposable mirror images of one another. As used herein, the term "optical isomer" is equivalent to the term "enantiomer". As used herein the term "diastereomer" refers to two stereoisomers which are not mirror images but also not superimposable. 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 ent groups are attached. Choice of the appropriate chiral , eluent, and conditions necessary to effect separation of the pair of enantiomers is well known to one of ordinary skill in the art using standard techniques (see e. g. Jacques, J. et al., "Enantiomers, Racemates, and tions", John Wiley and Sons, Inc. 1981).
B. Dosage and Pharmacokinetics The compositions including the therapeutically effective concentration of progesterone, allopregnanolone, or a synthetic progestin may be administered using any acceptable method known in the art. For example, the ceutical composition including progesterone, allopregnanolone, or a synthetic progestin can be administered by any method, including intramuscular (1M) injection, subcutaneous (SC) injection, intrathecal administration, or via the pulmonary, nasal or mucosal routes of administration. The formulation is designed to mimic the intra-CNS levels achieved with terone, egnanolone, or a synthetic progestin administered by infusion over a period of about 1 to about 120 hours, more preferably over a period of about 24 to about 72 hours, over a period of about 48 to about 96 hours, or over a period of about 24 to about 120 hours.
In one embodiment, progesterone, allopregnanolone, or a tic progestin is administered in a dose equivalent to parenteral administration of about 0.1 ng to about 100 g per kg of body weight, about 10 ng to about 50 g per kg of body weight, about 100 ng to about 1 g per kg of body weight, from about lug to about 100 mg per kg of body weight, from about 1 ug to about 50 mg per kg of body weight, from about 1 mg to about 500 mg per kg of body weight; and from about 1 mg to about 50 mg per kg of body weight. Alternatively, the amount of progesterone, allopregnanolone, or a tic progestin administered to achieve a therapeutic effective dose is about 0.1 ng, 1 ng, 10 ng, 100 ng, 1 pg, 10 ug, 100 ug, 1 mg, 1.5mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 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 greater.
Although the progesterone, allopregnanolone, or a synthetic progestin may be stered once or several times a day, and the duration of the ent may be once per day for a period of about 1, 2, 3, 4, 5, 6, 7 days or more, it is more preferably to administer either a single dose in the form of an individual dosage unit or several smaller dosage units or by le administration of subdivided dosages at certain intervals. For instance, a dosage unit can be administered from about 0 hours to about 1 hr, about 1 hr to about 24 hr, about 1 to about 72 hours, about 1 to about 120 hours, or about 24 hours to at least about 120 hours post injury. atively, the dosage unit can be administered from about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, , 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 40, 48, 72, 96, 120 hours or longer post injury. Subsequent dosage units can be administered any time ing the initial administration such that a therapeutic effect is achieved. For instance, additional dosage units can be administered to protect the subject from the secondary wave of edema that may occur over the first several days post-injury.
The therapy with the progesterone, allopregnanolone, or a synthetic progestin can instead include a level progesterone, allopregnanolone, or a synthetic progestin dosing regimen wherein the progesterone, allopregnanolone, or a synthetic tin is administered during two or more time periods, preferably having a combined duration of about 12 hours to about 7 days, including, 1, 2, 3, 4, or 5 days or about 15, 15, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, or 144 hours or about 1 to 24 hours, about 12 to 36 hours, about 24 to 48 hours, about 36 to 60 hours, about 48 to 72 hours, about 60 to 96 hours, about 72 to 108 hours, about 96 to 120 hours, or about 108 to 136 hours. In one embodiment, the two-level progesterone, allopregnanolone, or a synthetic tin dosing regimen has a combined on of about 1 day to about 5 days; in other embodiments, the two-level progesterone, allopregnanolone, or a tic progestin dosing regimen has a combined duration of about 1 day to about 3 days.
In one embodiment, the total hourly dose of progesterone, allopregnanolone, or a synthetic progestin that is to be administered during the first and second time periods of the two—level progesterone, allopregnanolone, or a synthetic progestin dosing regimen is chosen such that a higher total dose of progesterone, allopregnanolone, or a synthetic progestin per hour is given during the first time period and a lower dose of progesterone, egnanolone, or a synthetic progestin per hour is given during the second time period. The duration of the individual first and second time s of the two-level progesterone, allopregnanolone, or a synthetic progestin dosing regimen can vary, depending upon the health of the individual and y of the tic injury. Generally, the subject is administered higher total dose of progesterone, allopregnanolone, or a synthetic progestin per hour for at least 1, 2, 3, 4, 5, 6, 12 or 24 hours out of the 1 day to 5 day two—level progesterone, allopregnanolone, or a synthetic progestin dosing regimen. The length of the second time period can be adjusted accordingly, and range for example, from about 12 hrs, 24 hrs, 36 hrs, 48 hrs, 60 hrs, 72 hrs, 84 hrs, 96 hrs, 108 hrs, 120 hrs or about 12 to about 36 hrs, about 24 to about 36 hrs, about 24 to about 48 hrs, about 36 hrs to about 60 hours, about 48 hrs to about 72 hrs, about 60 hrs to about 84 hours, about 72 hrs to about 96 hrs, or about 108 hrs to about 120 hrs. Thus, for example, Where the two—level progesterone, allopregnanolone, or a synthetic progestin dosing regimen has a combined on of 3 days, the higher total doses of progesterone, allopregnanolone, or a synthetic progestin could be administered for the first hour, and the lower total hourly dose of progesterone, allopregnanolone, or a synthetic progestin could be administered for hours 2 to Area under the curve (AUC) refers to the area under the curve that tracks the serum concentration (nmol/L) of progesterone, allopregnanolone, or a synthetic progestin over a give time following the IV administration of the reference progesterone, egnanolone, or a synthetic progestin standard. By "reference progesterone, allopregnanolone, or a synthetic tin standard" is intended the ation of progesterone, allopregnanolone, or a synthetic progestin that serves as the basis for determination of the total hourly progesterone, allopregnanolone, or a synthetic progestin dose to be administered to a human subject With a traumatic central nervous system injury to e the desired positive effect, i.e., a positive therapeutic response that is improved With respect to that observed Without administration of progesterone, allopregnanolone, or a synthetic progestin. In an embodiment, the dose of progesterone, allopregnanolone, or a synthetic progestin to be stered provides a final serum level of progesterone, allopregnanolone, or a tic tin of about 100 ng/ml to about 1000 ng/ml, about 1100 ng/ml to about 1450 ng/ml, 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, about 600 ng/ml to about 750 ng/ml, about 7‘00 ng/ml to about 850 ng/ml, about 800 ng/ml to about 950 ng/ml, about 900 ng/ml to about 1050 ng/ml, about 1000 ng/ml to about 1150 ng/ml, about 100 ng/ml to about 1250 ng/ml, about 1200 ng/ml to about 1350 ng/ml, about 1300 ng/ml to about 1500 ng/m. In specific embodiments, the serum level of progesterone, allopregnanolone, or a synthetic progestin 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 other embodiments, the constant progesterone, allopregnanolone, or a synthetic progestin therapy or the two—level progesterone, allopregnanolone, or a synthetic progestin therapy includes a final time period in which the administration of progesterone, allopregnanolone, or a synthetic progestin is tapered. By ed administration" is meant an administration protocol which reduces the dose of administration to the t and thereby produces a gradual reduction and eventual elimination of progesterone, allopregnanolone, or a synthetic tin, either over a fixed period of time or a time determined empirically by a physician‘s assessment based on regular monitoring of a eutic response of a subject to a traumatic CNS injury. The period of the tapered progesterone, allopregnanolone, or a synthetic tin administration can be about 12, 24, 36, 48 hours or longer. Alternatively, the period of the tapered progesterone, allopregnanolone, or a synthetic progestin administration can range from about 1 to 12 hours, about 12 to about 48 hours, or about 24 to about 36 hours.
The drug taper employed could be a "linear" taper. For example, a "10%" linear taper from 500 mg would go 500, 450, 400, 350, 300, 250, 200, 150, 100, 50. Alternatively, an exponential taper could be employed which, if the m ed above is used as an example, the exponential taper would be, e.g., 500, 450, 405, 365, 329, 296, 266,239, etc. Accordingly, about a 5%, 10%, %,30%, or 40% linear or exponential taper could be employed in the methods of the invention. In addition, a linear or exponential taper 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% could be employed.
Where a subject undergoing y exhibits a partial se, or a relapse following completion of the first cycle of the therapy, subsequent s of progesterone, allopregnanolone, or a synthetic progestin therapy may be needed to achieve a partial or complete therapeutic response. Thus, subsequent to a period of time off from a first treatment period, which may have included a constant progesterone, allopregnanolone, or a synthetic progestin dosing regimen or a vel progesterone, allopregnanolone, or a tic progestin dosing regimen, a subject may receive one or more additional treatment periods including either constant or two-level progesterone, allopregnanolone, or a synthetic progestin dosing regimens. Such a period of time off between treatment periods is referred to herein as a time period of tinuance. It is recognized that the length of the time period of tinuance is dependent upon the degree of subject response (i.e., complete versus partial) ed with any prior treatment periods of the progesterone, allopregnanolone, or a synthetic progestin therapy.
These multiple treatment sessions are referred to herein as maintenance cycles, where each maintenance cycle includes a completed nt or two- level progesterone, allopregnanolone, or a synthetic progestin dosing regimen.
By "completed two-level terone, allopregnanolone, or a synthetic progestin dosing regimen" is intended the subject has been administered both the first period and the second period of progesterone, allopregnanolone, or a synthetic progestin dosing. The necessity for multiple maintenance cycles can be assessed by monitoring the physiological and behavioral improvement of the patient. The duration between maintenance cycles can be about 1 hr, 15 hr, 1 day, 2 day, 3 day, 4 day, 5 day, 6 day or other such time periods falling within the range of about 1 day to about 14 days.
As used herein, "about" means imately plus or minus ten percent.
C. Formulations Formulations of neuroactive ds contain one or more neuroactive steroids in combination with one or more pharmaceutically acceptable ents. In some cases, formulations contain just one neuroactive steroid. In other cases, the formulations include a mixture of two or more neuroactive steroids. The neuroactive steroids can be incorporated in the formulations described below as neutral compounds, ceutically acceptable salts, and/or prodrugs or metabolites.
Pharmaceutical formulations can be designed for immediate release, sustained release, d release and/or burst e of one or more neuroactive steroids in a therapeutically effective amount. In an ment, the formulation provides an initial burst release of a "loading dosage", followed by a ned release to maintain the therapeutically effective dosage. This can be accomplished using a delayed and/or extended release formulation. 1. Solubilization ofNeuroactive Steroids Many neuroactive steroids s limited aqueous solubility. In order to provide formulations capable of delivering therapeutically effective dosages, a variety of methods can be employed to enhance the solubility and bioavailability of neuroactive steroids. See, for example, "Water-Insoluble Drug Formulation", 2nd n, edited by Rong Liu (CRC Press, Boca Raton, FL, 2008). Using the techniques bed 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 formulations described in sections 2 and 3 a. Inclusion Complexes The solubility of neuroactive steroids can be improved by inclusion complexation (i.e., host-guest formulations). Inclusion complexes are formed when a nonpolar molecule (i. e., the guest, such as a drug with poor aqueous stability) or portion of a molecule inserts into a nonpolar cavity of another molecule or group of molecules (i.e., the host). If the host le or molecules t water good solubility, the solubility of the host-guest complex will be greater than the solubility of the guest alone.
Inclusion complexes containing or comprising one or more neuroactive steroids can be formed using any suitable host le or molecules. For example, the water solubility of neuroactive steroids can be increased by inclusion complexation with extrins. Steroid-cyclodextrin complexes are known in the art. See, for example, US. Patent No. 7,569,557 to Backensfeld, et al., and US. Patent Application Publication No. US 058262 to Zoppetti, et al.
Dextrans are e polysaccharides produced by bacteria and yeasts.
They are characterized by a inance (>95%) of (‘1. (1-6) backbone linkages and varying proportions of oa( 1—2), (1(1— 3) and (1(1-4) linkages typically at branch points 1, 2. Dextrins are partially hydrolyzed glucose homopolymers composed exclusively of 0t(1—4) backbone linkages.
Cyclodextrins are cyclic oligosaccharides containing or comprising six (oz-cyclodextrin), seven (B-cyclodextrin), eight (y-cyclodextrin), or more 0,-(1,4)- linked glucose residues. The hydroxyl groups of the cyclodextrins are ed to the outside of the ring while the glucosidic oxygen and two rings of the non- exchangeable hydrogen atoms are directed towards the interior of the cavity. As a result, cyclodextrins possess a hydrophobic inner cavity combined with a hilic exterior which s water solubility. Upon combination with a hydrophobic drug, such as a neuroactive steroid, the neuroactive steroid (i.e., the guest) inserts into the hydrophobic interior of the cyclodextrin (i.e., the host).
The uest complex retains water solubility as a consequence of the hydrophobic exterior of the cyclodextrin ring. ctive steroid-cyclodextrin complexes can, as solubility permits, be incorporated into any of the parenteral and non-parenteral formulations described below. If desired, the s solubility of solid ctive steroid- extrin complexes can be further enhanced by isolating the neuoractive steroid-cyclodextrin complex as a solid via lyophilization and/or via micronizing the solid neuoractive steroid—cyclodextrin complex.
This cyclic orientation provides a ted cone structure that is hydrophilic on the exterior and lipophilic on the interior. Cyclodextrin complexes are formed when a guest molecule is partially or fully contained in the interior of the cavity. The parent (1—, [3—, and y—cyclodextrins (particularly B) have limited aqueous solubility and show toxicity when given parenterally.
Therefore, the parent cyclodextrin structure can be ally modified to te a parenterally safe ivative. The cations are typically made at one or more of the 2, 3, or 6 position hydroxyls.
Neuroactive steroid-cyclodextrin complexes are preferably formed from a cyclodextrin selected from the group consisting of odextrin, B— cyclodextrin, y-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 functionalized with a pendant group.
Suitable pendant groups include, but are not limited to, sulfinyl, sulfonyl, phosphate, acyl, and C1-C12 alkyl groups optionally substituted with one or more (e.g., l, 2, 3, or 4) hydroxy, carboxy, carbonyl, acyl, oxy, oxo; or a combination thereof. s of modifying these alcohol residues are known in the art, and many extrin derivatives are commercially available, including sulfo butyl ether odextrins available under the trade name CAPTISOL® from Ligand Pharmaceuticals (La Jolla, CA).
Examples of suitable cyclodextrins for use in neuroactive steroid, e.g., allopregnanolone formulations, can e cyclodextrins disclosed in US.
Patent Nos. 5,874,418; 6,046,177; and 733, which are herein orated by reference. Other examples of suitable cyclodextrins for use in neuroactive steroid formulations non-exclusively include a—cyclodextrin; B—cyclodextrin; y— cyclodextrin; methyl or-cyclodextrin; methyl B-cyclodextrin; methyl 7- cyclodextrin; ethyl odextrin; butyl (x-cyclodextrin; butyl B-cyclodextrin; butyl y-cyclodextrin; pentyl y-cyclodextrin; hydroxyethyl B-cyclodextrin; hydroxyethyl y—cyclodextrin; 2—hydroxypropyl (ii—cyclodextrin; 2-hydroxypropyl B—cyclodextrin; 2—hydroxypropyl y—cyclodextrin; 2—hydroxybutyl B—cyclodextrin; acetyl (ii-cyclodextrin; acetyl B—cyclodextrin; acetyl y-cyclodextrin; propionyl B- cyclodextrin; butyryl B-cyclodextrin; succinyl a-cyclodextrin; yl B- cyclodextrin; yl y-cyclodextrin; benzoyl B-cyclodextrin; palmityl B- extrin; toluenesulfonyl B—cyclodextrin; acetyl methyl B-cyclodextrin; acetyl butyl B-cyclodextrin; glucosyl a—cyclodextrin; glucosyl B-cyclodextrin; glucosyl y—cyclodextrin; maltosyl a—cyclodextrin; maltosyl B—cyclodextrin; maltosyl y-cyclodextrin; a—cyclodextrin carboxymethylether; B—cyclodextrin ymethylether; y—cyclodextrin carboxymethylether; carboxymethylethyl [3- cyclodextrin; phosphate ester os-cyclodextrin; phosphate ester B-cyclodextrin; phosphate ester odextrin; 3-trimethylammoniumhydroxypropyl [3- cyclodextrin; sulfobutyl ether B—cyclodextrin; carboxymethyl u-cyclodextrin; carboxymethyl B-cyclodextrin; carboxymethyl y—cyclodextrin, and combinations thereof.
Preferred cyclodextrins include, but are not limited to, alkyl cyclodextrins, hydroxy alkyl cyclodextrins, such as hydroxy propyl B- cyclodextrin, carboxy alkyl cyclodextrins and sulfoalkyl ether cyclodextrins, such as sulfo butyl ether B-cyclodextrin.
In particular embodiments, the cyclodextrin is a alpha, beta, or gamma cyclodextrin having a plurality of charges (e.g., negative or positive) on the surface. In more particular embodiments, the cyclodextrin is a B-cyclodextrin containing or comprising a plurality of functional groups that are negatively charged at physiological pH. es of such functional groups include, but are not limited to, carboxylic acid (carboxylate) groups, sulfonate (RSOg'), phosphonate groups, phosphinate groups, and amino acids that are negatively charged at physiological pH. The d functional groups can be bound directly to the cyclodextrins or can be linked by a space, such as an ne chain. The number of carbon atoms in the alkylene chain can be varied, but is generally between about 1 and 10 carbons, ably 1-6 s, more preferably 1-4 carbons. Highly ed cyclodextrins are described in US.
Patent No. 6,316,613.
In one ment, the cyclodextrins is a B-cyclodextrin functionalized with a plurality of sulfobutyl ether groups. Such a cyclodextrins is sold under the tradename CAPTISOL®.
CAPTISOL® is a polyanionic beta—cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group, or sulfobutylether (SBE). CAPTISOL® is not a single chemical species, but comprised of a multitude of polymeric structures of varying degrees of substitution and positional/regional isomers dictated and controlled to a uniform pattern by a ed manufacturing process consistently practiced and ed to control ties.
CAPTISOL® contains six to seven sulfobutyl ether groups per cyclodextrin molecule. Because of the very low pKa of the ic acid groups, CAPTISOL® carries multiple negative charges at physiologically compatible pH values. The four-carbon butyl chain coupled with repulsion of the end group negative charges allows for an sion" of the cyclodextrin cavity. This often s in stronger binding to drug candidates than can be achieved using other ed cyclodextrins. It also provides a potential for ionic charge interactions between the cyclodextrin and a positively d drug molecule. In addition, these derivatives impart ional solubility and parenteral safety to the molecule. Relative to beta-cyclodextrin, CAPTISOL® provides higher interaction characteristics and superior water solubility in excess of 100 100 ml, a 50-fold improvement.
In other embodiments, the extrins has plurality of 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 ine- derivatised B-cyclodextrin (BCD).
Preferably, the cyclodextrin is present in an amount of from about 0.1% to about 40% W/W of the overall formulation, preferably from about 5% to about 40% W/W, more preferably about 10% to about 40% W/W, most preferably about % to about 35% w/w. In certain embodiments, the concentration of the cyclodextrins is from about 15% to about 35% w/w, preferably from about 20% to about 35% w/w, more preferably about 30% to about 35% w/w. In one embodiment, the formulation contains about 1 to about 2, ably about 1.5 mg neuroactive d (e.g., allopregnanolone) per ml of cyclodextin, e. g., CAPTISOL®. b. [an Exchange Resins Ion exchange resins (IER) are high molecular weight water insoluble rs containing or comprising fixed positively or negatively charged functional groups in their matrix, which have an affinity for oppositely charged counter ions. IER are solid insoluble high molecular weight poly olytes that can exchange with nding medium reversibly and stochiometrically.
IER are Styrene (Di Vinyl Benzene) copolymer containing or comprising - Acidic groups: Carboxylic or sulphonic for Cation E.R.
- Basic groups: Quaternary Ammonium for Anion E.R Based on the nature of the ionic species being interchanged, the IE process is known as either cation exchange (CE) or anion exchange (AE).The IE process is itive in nature. In practice, drug in an ionic form (usually on) is mixed with the appropriate IER form a complex, known as ‘resinate’.
The performance of resinates are governed by several factors, such as: 1. The pH and temperature of the drug solution; 2. The molecular weight and charge intensity of the drug and IER; 3. Geometry; 4. Mixing speed; . Ionic strength of the drug solution; 6. Degree of cross linking and le size of the IER; 7. The nature of solvent; and 8. Contact time between the drug species and the IER.
In general, IER consist of spherical beads of approximately 0.5—1.2 mm in diameter. The most common type is an opaque yellow in color, although other colors are also reported. The constitution of each cal particle of IER is similar to that of a homogeneous gel. The shrinkage or expansion of the spherical volume that takes place is based on the ionic nment in which the IER is present.
A major drawback of controlled or ned release systems is dose dumping, resulting in increased risk of toxicity. Ion exchange resins offers better drug retaining properties and prevention of dose dumping. The polymeric (physical) and ionic (chemical) properties of ion exchange resin will release the drugs more uniformly than that of simple matrices se of physical properties only). Drug loaded onto the strong IER resinates provides simplest form of controlled or sustained release delivery system. Resinates can be filled directly in a capsule, suspended in liquids, suspended in matrices or compressed into s. Drug will be slowly released by ion exchange phenomenon and absorbed.
Microencapsulation of tes provides better control over the drug release for oral or depo release. The absorption of the drug from coated resinates is a consequence of the entry of the counter ions into the coated resinates and release of drug ions from drug resin complex by the ion exchange process and diffusion of drug ions through the membrane into the dissolution medium. Designed release rate at the d level can be obtained by zation of g thickness. Microencapsulation of resinates can be achieved by air suspension coating er s), interfacial polymerization, solvent evaporation or pan coating.
Modification of the coating of resinates for example, by pretreatment with polyethylene glycol 400, can be used to maintain the ry and improve coating process. The pretreated resinates are then coated with ethyl cellulose or any other water insoluble polymer. The polyethylene glycol helps in controlling the swelling rate of matrix in water, while an outer ethyl cellulose coating modifies the ion pattern of ions in and out of system. A major drawback of controlled or sustained release systems is dose dumping, resulting in increased risk of toxicity. Ion exchange resins offers better drug retaining properties and prevention of dose dumping. The polymeric (physical) and ionic cal) ties of ion exchange resin release the drugs more uniformly than that of simple es.
Drug loaded onto the strong IER resinates provides simplest form of controlled or sustained release delivery system. Resinates can be filled directly in a e, suspended in liquids, suspended in matrices or compressed into tablets. Drug will be slowly released by ion exchange phenomenon and absorbed.
There are a few ion exchange resins suitable for intravenous administration of drug. For example, a, et al., in Jpn J. Antibiot. 1985 Sep;38(9):2496-502, describes a clinical study on unmodified intravenous dried ion-exchange resin treated human normal immunoglobulin, SM-4300 that showed efficacy with no obvious antipyretic effect, c effect or healing impairment. c. Lipid Carriers To facilitate the administration of neuroactive ds possessing poor s solubility, a variety of lipid carriers may be used.
Lipid Emulsions Neuroactive steroids can be combined suspended or dissolved using a lipid emulsion. Lipid emulsions are known in the art. See, for example, U.S.
Patent No. 6361792 to Long, et. al.; U.S. Patent No. 7,550,155 to Zhang, et al., and U.S. Patent ation Publication No. US 2006/0067952. Lipid emulsions formulations typically include one or more neuroactive steroids, an oil component, an emulsifier, and water.
The oil component can be a monoglyceride, a diglyceride, a triglyceride, or ations thereof. In some cases, the oil component includes an ester formed between one or more fatty acids and an alcohol other than glycerol. The oil component can be, for example, a vegetable oil such as almond oil, borage oil, black currant seed oil, corn oil, safflower oil, soybean oil, sesame oil, cottonseed oil, peanut oil, olive oil, rapeseed oil, t oil, palm oil, canola oil, or combinations thereof. Vegetable oils are typically long-chain triglycerides formed from C14—C22 fatty acids. The oil ent can also include medium chain triglycerides formed from C8-C12 fatty acids, such as Miglyol 812, Crodamol® GTCC—PN, or Neobees M-5 oil.
The emulsifier serves to stabilize the lipid emulsion by preventing separation of the on into individual oil and aqueous phases. Suitable emulsifiers include, but are not limited to, propylene glycol mono— and di—fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, yethylene-polyoxypropylene co-polymers and block co- polymers, salts of fatty alcohol sulphates, sorbitan fatty acid esters, esters of hylene—glycol ol ethers, oil and wax based emulsifiers, glycerol monostearate, glycerine sorbitan fatty acid esters and phospholipids. In some cases the fier is a phospholipid.
In some cases, the emulsifier is a vitamin E derivative. Suitable vitamin E derivatives include, but are not limited to, (X—tOCOphCl‘yl oxalate, (it-tocopheryl malonate, (it-tocopheryl succinate, u—tocopheryl glutarate, u-tocopheryl adipate, (it-tocopheryl pimelate, (it-tocopheryl suberate, (x-tocopheryl azelate, and D-OL- tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS).
Exemplary phospholipids include lecithin (a , phosphatidyl chlorine, mixture of choline ester of phosphorylated diacylglyceride), phosphatidylethanolamine, atidylglycerol, phosphatidic acid with about 4 to about 22 carbon atoms, and more generally from about 10 to about 18 carbon atoms and varying degrees of saturation. Preferably, the phospholipid is of natural . lly ing phospholipids include soy lecithin, egg lecithin, hydrogenated soy lecithin, hydrogenated egg lecithin, sphingosine, gangliosides, and phytosphingosine, and combinations thereof.
Suitable lipid emulsions generally contain between about 1% and 40% w/v oil ent and between about 0.1% and 7.5% w/v fier. le commercially available lipid emulsions include lipid emulsions containing or comprising soybean oil, such as Intralipid® 10%, Intralipid® 20%, and Intralipid® 30%, as well as lipid emulsions containing or comprising a mixture of soybean and safflower oils, such as Liposyn® ll 10% and Liposyn® II 20%.
Lipid emulsions can optionally contain one or more additional components. For example, lipid formulations can contain one or more non- aqueous le co-solvents, such as an alcohol or glycol. In some preferred formulations, glycerol and/or propylene glycol is present as a co-solvent.
Many lipid ons are capable of supporting bacterial growth.
Accordingly, in some cases, one or more components may be added to the lipid emulsion formulation to t or retard bacterial growth, for example disodium edatate, citric acid, metabisulfate, benzyl alcohol, one or more parabens, chlorobutanol, phenol, sorbic acid, or thimerosal. onally, lipid emulsions can contain one or more agents used to modify or stabilize the pH of the solution, including phosphate buffers, acetate buffers, and citrate buffers.
In one embodiment, the formulation is an oil-in-water emulsion containing or comprising a eutically ive amount of one or more neuroactive steroids dissolved in a solution containing or comprising between about 1% w/v and about 25% w/v soybean oil, between about 0.5% and about 7.5% w/v egg yolk phospholipid, and between about 0.5% w/v and about 5% w/v of a miscible co-solvent.
In another embodiment, the formulation is an oil-in-water emulsion containing or sing a therapeutically ive amount of one or more neuroactive steroids dissolved in a solution containing or comprising between about 1% w/v and about 15% w/v soybean oil, between about 1% w/v and about % w/v er oil, between about 0.5% and about 7.5% w/v egg phosphatides, and between 0.5% w/v and about 5% w/v of a miscible co- solvent.
Lipid emulsions can be stered as described above, or incorporated into the parenteral formulations described below.
Liposomes One or more neuroactive steroids can be incorporated into liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. See, for example, "Remington— The science and practice of cy", 20th Edition, Jennaro et. al., (Phila, Lippencott, Williams, and Wilkens, 2000).
Liposomes are lly derived from phospholipids or other lipid substances. Liposomes are formed by mono— or multi—lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
The sed compositions in liposome form can contain, in addition to one or more neuroactive steroids, stabilizers, preservatives, excipients, and other suitable excipients.
Examples of le lipids are the phospholipids and the phosphatidylcholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, e.g., Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York p. 33 et seq., 1976. The liposomes can be cationic liposomes (e.g., based on DOTMA, DOPE, DC cholesterol) or anionic liposomes. Liposomes can further comprise proteins to facilitate targeting a particular cell, if desired. Administration of a composition comprising a compound and a ic liposome can be administered to the blood afferent to a target organ or inhaled into the respiratory tract to target cells of the respiratory tract.
One or more neuroactive steroids can formulated using commercially available liposome preparations such as CTIN®, CTAMIE® (GlBCO-BRL, lnc., rsburg, Md.), SUPERFECT® n, Inc. Hilden, Germany) and TRANSFECTAM® (Promega Biotec, Inc., Madison, Wis.), as well as other liposomes developed according to procedures standard in the art.
Liposomes where the diffusion of the compound or delivery of the compound from the liposome is designed for a ic rate or dosage can also be used.
One or more ctive steroids can also be formulated using noisomes.
Noisomes are multilamellar or unilamellar vesicles involving non-ionic surfactants. An aqueous solution of solute is enclosed by a bilayer resulting from the organization of surfactant olecules. Similar to liposomes, noisomes are used in targeted delivery of, for e, anticancer drugs, including methotrexate, doxorubicin, and immunoadjuvants. They are lly understood to be different from transferosomes, vesicles prepared from amphiphilic ydrate and amino group containing or comprising polymers, e.g., chitosan.
One or more neuroactive steroids can also be deliverd using nanoerythrosomes. Nanoerythrosomes are nano—vesicles made of red blood cells via dialysis through filters of defined pore size. These vesicles can be loaded with one or more neuroactive steroids.
Lipid Nanoemulsions Lipid nanoemulsions can also be used. Lipid nanoemulsions are known in the art. See, for example, U.S. Patent Application Publication No. US 2007/0207173 to Chen, et al, and U.S. Patent Application ation No. US 2001/0045050 to umi, et a1. Lipid nanoemulsions can be prepared by microemulsification of any of the lipid emulsions described above using for example, a high pressure homogenizer, or via a phase inversion temperature method (PIT).
In preferred lipid nanoemulsions ning or comprising neuroactive steroids, vitamin E succinate and/or Vitamin E TPGS are included as emulsifiers.
The lipid nanoemulsion can further be lyophilized if desired. See, for example, U.S. Patent Publication No. US 2011/0015266.
Lipid anoemulsions can be administered as described above, or incorporated into the parenteral or non—parenteral ations described below.
The pre-concentrate includes an oil phase which has at least one fatty acid oil. Fatty acid oils of the present invention include at least one polyunsaturated fatty acid. The term "polyunsaturated fatty acid" e those fatty acids having at least 50 weight percent or more of polyunsaturated fatty acids. Polyunsaturated fat can be found in grain products, fish and sea food (herring, , mackerel, halibut), soybeans, and fish oil. Polyunsaturated fatty acids include omega—3 fatty acids and omega—6 fatty acids. Polyunsaturated fatty acids include linolic acid and linolenic acid. Preferable polyunsaturated fatty acids include eicosapentaenoic acid, salts of pentaenoic ocosahexaenoic acid, salts of docosahexaenoic acid, triglycerides of eicosapentaenoic acid, tryglycerides of docosahexaenoic acid, ethyl esters of eicosapentaenoic acid, or ethyl esters of docosahexaenoic acid.
Polyunsaturated fatty acids include omega—3 fatty acid oils and medium chain triglycerides (MCT). A medium chain triglyceride contains about 6 to 14 carbon atoms, preferably about 8 to 12 carbon atoms are suitable for use in the oil phase. Preferable medium chain ide includes, for example, caprylic/capric triglyceride such as "Migriol 810", "Migriol 812" (both trade names, manufactured by Huls Co., Ltd., available from Mitsuba Trading Co., Ltd), a glyceryl tricaprylate (tricaprylin) such as "Panasate 800" (trade name, manufactured by NOF Corporation, Japan).
The pre-concentrate includes an emulsifier component. The emulsifier component has one or more surfactants. Surfactants include any molecule having both a polar head group, which energetically prefers solvation by water, and a hydrophobic tail that is not well ed by water. The ratio of the oil phase to the emulsifier component is important for the toxicity of the ulsion prepared from the pre—concentrate. Surfactants suitable for use with the ncentrate and emulsion include a variety of anionic and nonionic tants, as well as other emulsifying compounds that are capable of promoting the formation of oil—in—water emulsions; so long as they are on the GRAS (Generally Recognized as Safe) list and are approved for human consumption such as lecithin, solutol HS—lS (polyoxyethylene esters of 12- hydroxystearic acid), polysorbate 80 or Cremophore EL (polyethoxylated castor oil). See McCutcheon‘s Volume 1: Emulsifiers and Detergents North American Edition, 1996 (incorporated herein by reference). 2. Formulationsfor Parenteral Administration The compounds described herein can be formulated for parenteral administration. "Parenteral administration", as used herein, refers to enous or intraarterial stration. le Size Reduction The lity of one or more neuractive ds can be improved by sing drug particle size. By decreasing particle size, the surface area to volume ratio of the drug les is increased, resulting in increased solvation of the drug particle.
Particle size reduction can be achieved using a variety of micronization techniques including, but not limited to, grinding, g (e.g., air—attrition milling (jet milling), ball milling), coacervation, high pressure nization, spray drying, and/or supercritical fluid crystallization. In some instances, particles are sized by mechanical impact (e.g., by hammer mills, ball mill and/or pin mills). In some instances, particles are sized via fluid energy (e.g., by spiral jet mills, loop jet mills, and/or fluidized bed jet mills). After micronization, the drug particles can be further processed. For example, the ized drug particles may be coated to further influence solubility and/or drug release. ing on the micronization process and active agent involved, the micronized drug particles can be crystalline or amorphous. Using micronization techniques, drug particles ranging from 10 nm to 100 microns can be formed.
The average particle size and distribution of the drug particles can be controlled through the selection of micronization technique as well as by variation of process conditions. ingly, formulations of drug particles can be prepared which contain nanoparticles of drug, microparticles of drug, and combinations thereof. Appropriate micronization techniques can be ed to produce populations of drug particles with monodisperse or polydisperse particle size distributions. Methods of producing monodisperse drug particles are known in the art. atively, populations of drug particles can be separated following micronization to obtain drug particle populations with the desired size range and distribution.
In addition to improving solubility, micronization can also be used to control drug e profiles. As different sized drug particles will dissolve at different rates and over different periods of time, micronization can be used to e controlled release, sustained release, pulsatile e, and delayed release formulations. For example, populations of micronized drug particles with different average particle sizes and/or different particle size distributions can be mixed. The resulting mixtures will exhibit a drug release profile which is the combination of the drug release profile of component populations of drug les. In some embodiments, micronized drug particles containing or sing different neuroactive steroids can be mixed to effect combination therapy.
Micronized drug particles can be incorporated into any of the parenteral and non-parenteral formulations described below as a sion or dispersion in a solid or fluid carrier. Micronized drug particles can also be used to form solutions for parenteral or renteral administration. ized drug particles can also be provided, for example, in a kit used to prepare solutions or suspensions for injection.
Aqueous Compositions eral formulations can be prepared as aqueous itions using techniques is known in the art. Typically, such compositions can be prepared as inj ectable formulations, for example, solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the on of a reconstitution medium prior to injection; emulsions, such as water-in-oil (w/o) emulsions, oil-in-water (o/w) emulsions, and microemulsions thereof, liposomes, or emulsomes.
The carrier can be a solvent or dispersion medium containing or comprising, 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.
The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the nance of the required particle size in the case of dispersion and/or by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
Solutions and sions of the active compounds as the free acid or base or pharmacologically acceptable salts thereof can be ed in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, surfactants, dispersants, emulsifiers, pH modifying agents, and combination thereof.
Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not d to, those ning or comprising carboxylate, sulfonate and sulfate ions.
Examples of anionic surfactants include sodium, potassium, um of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene ate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)- sulfosuccinate; and alkyl sulfates such as sodium lauryl e. Cationic surfactants include, but are not d to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, onium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryloleate, sorbitan acylate, e acylate, PEG-150 laurate, PEG- 400 monolaurate, yethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. es of amphoteric surfactants include sodium N-dodecyl- ne, sodium N—lauryl- -iminodipropionate, myristoamphoacetate, lauryl e and lauryl sulfobetaine.
The formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, butanol, phenol, sorbic acid, and thimerosal. The formulation may also contain an antioxidant to prevent degradation of the active agent(s).
The formulation is typically buffered to a pH of 3-8 for parenteral administration upon reconstitution. Suitable buffers include, but are not limited to, ate buffers, acetate buffers, and citrate buffers.
Water soluble polymers are often used in formulations for parenteral stration. Suitable water—soluble polymers include, but are not limited to, polyVinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.
Sterile able solutions can be prepared by incorporating the active nds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by ed sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
The powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are well known in the art. a. Controlled releaseformulations The parenteral formulations described herein can be formulated for lled release including immediate release, delayed release, extended release, pulsatile release, and combinations thereof.
Nano- and microparticles For parenteral administration, the compounds, and optionally one or more additional active , can be incorporated into articles, nanoparticles, or combinations thereof that provide lled release. In ments wherein the formulations contains two or more drugs, the drugs can be formulated for the same type of controlled release (e. g., delayed, extended, immediate, or pulsatile) or the drugs can be independently formulated for different types of release (e.g., immediate and delayed, ate and extended, delayed and extended, delayed and pulsatile, etc).
For example, the compounds and/or one or more additional active agents can be incorporated into polymeric microparticles which provide controlled release of the drug(s). Release of the drug(s) is controlled by diffusion of the drug(s) out of the microparticles and/or degradation of the polymeric particles by hydrolysis and/or enzymatic degradation. Suitable polymers e ethylcellulose and other natural or tic cellulose derivatives.
Polymers which are slowly e and form a gel in an aqueous environment, such as hydroxypropyl methylcellulose or polyethylene oxide may also be suitable as materials for drug containing or comprising articles.
Other polymers include, but are not limited to, polyanhydrides, poly(ester anhydrides), polyhydroxy acids, such as polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly—3—hydroxybutyrate (PHB) and mers thereof, polyhydroxybutyrate (P4HB) and copolymers thereof, polycaprolactone and copolymers thereof, and combinations thereof.
Alternatively, the ) can be incorporated into microparticles prepared from materials which are insoluble in aqueous solution or slowly soluble in aqueous solution, but are capable of degrading within the GI tract by means including enzymatic degradation, surfactant action of bile acids, and/or mechanical n. As used herein, the term "slowly soluble in water" refers to als that are not dissolved in water within a period of 30 minutes.
Preferred examples include fats, fatty substances, waxes, ke substances and mixtures thereof. Suitable fats and fatty substances include fatty alcohols (such as lauryl, myristyl stearyl, cetyl or cetostearyl l), fatty acids and derivatives, including, but not limited to, fatty acid esters, fatty acid glycerides (mono—, di— and tri-glycerides), 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 materials include natural or tic waxes, hydrocarbons, and normal waxes. Specific examples of waxes include beeswax, glycowax, castor wax, carnauba wax, ins and candelilla wax. As used herein, a wax- like material is defined as any material which is normally solid at room temperature and has a melting point of from about 30 to 300°C.
In some cases, it may be desirable to alter the rate of water penetration into the microparticles. To this end, ontrolling (wicking) agents may be formulated along with the fats or waxes listed above. Examples of rate— lling materials include certain starch derivatives (e.g., waxy maltodextrin and drum dried corn starch), cellulose derivatives (e.g., hydroxypropylmethyl- cellulose, hydroxypropylcellulose, methylcellulose, and carboxymethyl- cellulose), alginic acid, lactose and talc. Additionally, a pharmaceutically acceptable surfactant (for example, lecithin) may be added to tate the ation of such articles.
Proteins which are water insoluble, such as zein, can also be used as materials for the formation of drug containing or comprising microparticles.
Additionally, proteins, polysaccharides and combinations thereof which are water soluble can be formulated with drug into articles and subsequently cross-linked to form an ble network. For example, cyclodextrins can be complexed with individual drug molecules and subsequently cross-linked.
Encapsulation or incorporation of drug into carrier materials to produce drug containing or comprising microparticles can be achieved through known pharmaceutical formulation techniques. In the case of formulation in fats, waxes or wax-like materials, the carrier material is typically heated above its melting temperature and the drug is added to form a mixture comprising drug particles suspended in the r al, drug dissolved in the carrier material, or a mixture thereof. Microparticles can be subsequently formulated through several methods ing, but not limited to, the processes of congealing, extrusion, spray chilling or aqueous dispersion. In a preferred process, wax is heated above its melting temperature, drug is added, and the molten wax-drug mixture is congealed under constant stirring as the mixture cools. Alternatively, the molten ug mixture can be extruded and spheronized to form pellets or beads. Detailed descriptions of these ses can be found in "Remington— The science and practice of pharmacy", 20th Edition, Jennaro et. al., (Phila, Lippencott, ms, and Wilkens, 2000).
For some carrier materials it may be desirable to use a solvent evaporation technique to produce drug ning or sing microparticles.
In this case drug and carrier al are co—dissolved in a mutual t and microparticles can uently be produced by several techniques including, but not limited to, forming an emulsion in water or other appropriate media, spray drying or by evaporating off the solvent from the bulk solution and milling the resulting material.
In some embodiments, drug in a particulate form is homogeneously dispersed in a insoluble or slowly water soluble material. To minimize the size of the drug particles within the composition, the drug powder itself may be milled to generate fine particles prior to formulation. The process of jet milling, known in the pharmaceutical art, can be used for this purpose. In some embodiments drug in a particulate form is homogeneously dispersed in a wax or wax like substance by heating the wax or wax like nce above its melting point and adding the drug particles while stirring the mixture. In this case a pharmaceutically acceptable surfactant may be added to the mixture to facilitate the dispersion of the drug particles.
The les can also be coated with one or more modified release coatings. Solid esters of fatty acids, which are hydrolyzed by lipases, can be spray coated onto microparticles or drug particles. Zein is an example of a naturally water-insoluble protein. It can be coated onto drug containing or comprising microparticles or drug particles by spray coating or by wet granulation techniques. In addition to naturally water—insoluble als, some substrates of digestive enzymes can be treated with cross-linking procedures, resulting in the formation of non-soluble networks. Many methods of cross- linking proteins, initiated by both chemical and physical means, have been reported. One of the most common methods to obtain cross-linking is the use of chemical cross—linking agents. Examples of chemical linking agents include aldehydes (gluteraldehyde and dehyde), epoxy compounds, carbodiimides, and genipin. In addition to these cross-linking agents, oxidized and native sugars have been used to cross—link gelatin (Cortesi, R., et al., Biomalerials 19 (1998) 1641—1649). linking can also be accomplished using enzymatic means; for example, transglutaminase has been approved as a GRAS substance for cross—linking seafood products. Finally, cross—linking can be initiated by physical means such as thermal treatment, UV irradiation and gamma irradiation.
To e a coating layer of cross-linked protein surrounding drug ning or comprising microparticles or drug particles, a water soluble protein can be spray coated onto the microparticles and subsequently cross— linked by the one of the methods described above. Alternatively, drug containing or comprising articles can be microencapsulated within protein by coacervation-phase tion (for example, by the addition of salts) and uently cross-linked. Some suitable proteins for this purpose include gelatin, albumin, casein, and gluten.
Polysaccharides can also be linked to form a insoluble network. For many polysaccharides, this can be accomplished by reaction with calcium salts or alent cations which cross—link the main polymer chains. Pectin, alginate, dextran, amylose and guar gum are subject to cross-linking in the presence of multivalent cations. Complexes between oppositely charged polysaccharides can also be formed; pectin and chitosan, for example, can be xed via electrostatic interactions. 3. Formulations for Non-Parenteral Administration Neuroactive steroids can be formulated for non—parenteral administration. Non-parenteral formulations may be useful for oral, subcutaneous, intra-peritoneal, intramuscular, transdermal, nasal, pulmonary, or mucosal delivery. a. Depot Formulations Neuroactive steroids, including terone and progesterone analogues such as decanoate salts or esters of progesterone, can be formulated for depot injection. In a depot injection, the active agent is formulated with one or more pharmaceutically acceptable carriers that provide for the l release of active agent over a period of hours or days after injection. The depot formulation can be administered by any suitable means; however, the depot formulation is typically administered via aneous or intramuscular injection.
A variety of carriers may be incorporated into the depot ation to provide for the controlled release of the active agent. In some cases, depot formulations contain one or more biodegradable polymeric or oligomeric carriers. Suitable polymeric carriers e, but are not limited to poly(lactic acid) (PLA), poly(lactic—co—glycolic acid) (PLGA), poly(lactic acid)— polyethyleneglycol (FLA—PEG) block copolymers, polyanhydrides, poly(ester anhydrides), ppolyglycolide (PGA), poly—3—hydroxybutyrate (PHB) and copolymers thereof, polyhydroxybutyrate (P4HB), polycaprolactone, cellulose, hydroxypropyl methylcellulose, ethylcellulose, as well as blends, derivatives, copolymers, and combinations thereof.
In depot formulations containing or comprising a polymeric or oligomeric carrier, the carrier and active agent can be ated as a solution, an emulsion, or suspension. One or more neuroactive steroids, and optionally one or more additional active agents, can also be orated into polymeric or oligomeric microparticles, nanoparticles, or combinations thereof.
In some cases, the formulation is fluid and designed to solidify or gel (i.e., forming a hydrogel or organogel) upon injection. This can result from a change in solubility of the composition upon injection, or for example, by injecting a lymer mixed with an initiator and/or crosslinking agent. The r matrix, polymer solution, or polymeric les entrap the active agent at the injection site. As the polymeric r is gradually degraded, the active agent is ed, either by diffusion of the agent out of the matrix and/or ation of the matrix as it is absorbed. The release rate of the active agent from the injection site can be controlled by varying, for example, the chemical composition, molecular weight, crosslink density, and concentration of the polymeric carrier. Examples of such systems include those described in US.
Pat. Nos. 4,938,763, 5,480,656 and 6,113,943.
Depot formulations can also be ed by using other rate-controlling excipients, including hydrophobic materials, including able oils (e.g., peanut oil, corn oil, sesame oil, cottonseed oil, etc.) and phospholipids, ion— exchange , and sparingly soluble carriers.
The depot ation can r contain a solvent or dispersion medium containing or comprising, for example, water, l, 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 ations thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants. In many cases, it Will be preferable to include isotonic agents, for example, sugars or sodium chloride.
Solutions and sions of the neuroactive compounds as the free acid or base or pharmacologically acceptable salts f can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, surfactants, dispersants, fiers, pH modifying agents, and combination thereof.
Suitable surfactants may be anionic, cationic, amphoteric or ic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing or comprising carboxylate, sulfonate and sulfate ions.
Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium uccinates, such as sodium bis-(2-ethylthioxyl)- uccinate; 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 dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol earate, propylene glycol ate, glyceryl monostearate, glyceryl stearate, polyglyceryloleate, sorbitan acylate, sucrose e, PEG-150 laurate, PEG- 400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, yl opropanolamide, and polyoxyethylene hydrogenated tallow amide. es of amphoteric surfactants include sodium N-dodecyl-B-alanine, sodium N—lauryl—B—iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
The formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and osal. The formulation may also contain an antioxidant to prevent degradation of the active agent(s).
The formulation is typically buffered to a pH of 3-8 for parenteral administration upon reconstitution. Suitable buffers include, but are not limited to, phosphate s, acetate buffers, and citrate buffers.
Water soluble polymers are often used in ations for parenteral stration. Suitable water—soluble polymers include, but are not d to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.
Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile e which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ient from a previously sterile-filtered solution thereof.
The powders can be prepared in such a manner that the particles are porous in nature, which can increase ution of the particles. Methods for making porous particles are well known in the art. b. Gels Formulations may be in the form of an organogel (assuming the neuroactive steroid is relatively water insoluble) or a hydrogel. Numerous gel formulations are known. See, for example, U.S. Patent No. 737 by Hsu, et al. Hydrogels, especially those further including nanoparticles microparticles for sustained, immediate and/or delayed release, can also be used. See, for example, US. Patent No. 6,589,549 to Shih, et al.
US. patent application No. 20100295113 by Hoffman, et al., describes a composite hydrogel including a blend of an s solution of an c polysaccharide or a derivative f, such as or a derivative thereof and an aqueous solution of methylcellulose or another water soluble cellulose derivative f, having dispersed polymeric particles, such as polymeric micro particles and nanoparticles, and wherein the stability of the hydrogel is enhanced relative to the stability of the hydrogel alone. The polymeric les may contain at least one therapeutic agent, in which case each therapeutic agent exhibits a linear sustained release rate that can be tuned or altered by selecting the appropriate polymer formulation of the micro particles and/or nanoparticles.
The composite may be inj ectable, and in the absence of a therapeutic agent may be used as a bulking agent for tructive and ic surgery or may act as a platform for subsequent ry of therapeutic agents.
See also, Salem, Int J Nanomedicine. 2010 Nov 10;5:943-54, describing a sustained release form of natural progesterone to be given as IM injection. A progesterone spension (PNS) was first developed and then dispersed in a thermosensitive gel matrix. The selected nanoparticles showed an average particle size of 267 nm and a zeta potential ching-41 mV. The in vitro release profile of PNS from Pluronic F127 plus methyl cellulose gel followed zero order kinetics and correlated linearly with the weight percentage of gel dissolved, demonstrating that the overall rate of e of PNS is controlled by dissolution of the pluronic F127/methyl cellulose (MC) gel.
Gels can also be administered in combination with oral or subcutaneously administered drug. See, for example, Tomic, et al., Gynecol Endocrinol. 2011 Apr 19. c. Oral Formulations Formulations are prepared using a pharmaceutically acceptable "carrier" composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The "carrier" is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. The term "carrier" includes but is not limited to diluents, binders, lubricants, disintegrators, fillers, matrix—forming compositions and coating compositions. er" also includes all components of the coating composition which may include plasticizers, pigments, colorants, izing agents, and glidants.
The delayed release dosage formulations may be prepared as described in references such as "Pharmaceutical dosage form tablets", eds. an et. al.
(New York, Marcel Dekker, Inc., 1989), "Remington — The science and ce of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6th Edition, Ansel et.al., , PA: Williams and Wilkins, 1995) which provides information on carriers, materials, equipment and processes for preparing tablets and capsules and delayed release dosage forms of s, capsules, and granules. es of suitable coating materials include, but are not d to, cellulose polymers such as cellulose acetate ate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; nyl acetate phthalate, c acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name it® (Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides.
Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, nts, glidants, ization , pore s and surfactants.
Optional pharmaceutically acceptable excipients present in the drug- containing or comprising tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also termed "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and es. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium e, lactose, sucrose, mannitol, ol, cellulose, rystalline ose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pre-gelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powder sugar.
Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, latinized starch, n, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene , waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl rylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyVinylpyrrolidone. Some of the als which are suitable as binders can also be used as matrix-forming materials such as hydroxypropyl methyl cellulose, ethyl cellulose, and microcrystalline cellulose.
Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, m stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, latinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross—linked PVP lasdone® XL from GAF Chemical Corp).
Stabilizers are used to inhibit or retard drug decomposition reactions which e, by way of example, oxidative reactions.
Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable c surfactants include, but are not limited to, those containing or comprising carboxylate, sulfonate and sulfate ions. Examples of anionic tants include sodium, potassium, ammonium salts of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium 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 nds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ne glycol monostearate, propylene glycol myristate, yl monostearate, glyceryl stearate, yceryloleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG- 400 monolaurate, polyoxyethylene monolaurate, rbates, polyoxyethylene octylphenylether, 00 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
Examples of amphoteric tants include sodium cyl-beta-alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
If desired, the s, beads, granules or les may also contain minor amount of ic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives.
The delayed-release portion is designed to prevent drug e after a defined period of time. Although oral is not a preferred route of administration, in the case of an orally delivered formulation, this would be in the upper part of the gastrointestinal (GI) tract. Delayed release in an oral formulation can be achieved using enteric coatings. The enteric coated formulation remains intact or substantially intact in the stomach but dissolves and releases the contents of the dosage form once it reaches the small intestine. Other types of coatings can be used to provide delayed release following injection subcutaneously, intra- tissue or intramuscularly at a site near or at the area to be treated.
Extended release dosage forms The extended release formulations are generally prepared as diffusion or osmotic s, for example, as described in "Remington — The e and practice of pharmacy" (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000). A ion system typically consists of two types of devices, a reservoir and a matrix, and is well known and described in the art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form. The three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic es include, but are not d to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.
Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl— cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and Carbopol® 934, polyethylene oxides and mixtures thereof. Fatty compounds include, but are not limited to, various waxes such as ba wax and glyceryl tristearate and pe substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.
In certain preferred embodiments, the plastic material is a pharmaceutically acceptable acrylic r, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethyl rylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acry1ic acid), poly(methacry1ic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
In n preferred embodiments, the acrylic polymer is included of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
In one preferred embodiment, the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the ame Eudragit®. In further preferred embodiments, the acrylic polymer includes a mixture of two c resin lacquers cially available from Rohm Pharma under the tradenames Eudragit® RL30D and Eudragit® RS30D, tively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining l (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RSSOD. The mean molecular weight is about 0. Edragit® 8-100 and Eudragit® L-100 are also preferred. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these . Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids.
The polymers described above such as Eudragit® RL/RS may be mixed together in any desired ratio in order to ultimately obtain a sustained—release formulation having a desirable dissolution e. Desirable sustained-release multiparticulate systems may be obtained, for instance, from 100% it® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL and 90% Eudragit® RS. One skilled in the art will ize that other acrylic polymers may also be used, such as, for example, Eudragit® L.
Alternatively, extended release formulations can be prepared using osmotic systems or by applying a semi—permeable g to the dosage form.
In the latter case, the desired drug release profile can be achieved by combining low ble and high permeable g materials in suitable proportion.
The devices with different drug release mechanisms described above can be combined in a final dosage form including single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing or comprising s, beads, or granules.
An immediate e portion can be added to the extended release system by means of either ng an immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing or comprising extended and ate release beads.
Extended release tablets containing or comprising hydrophilic polymers are prepared by techniques ly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations y incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient. The usual ts include inert powdered substances such as starches, powdered ose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, , calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also . Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders. A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and m stearate, c acid and enated vegetable oils.
Extended e tablets containing or comprising wax materials are generally prepared using methods known in the art such as a direct blend , a congealing method, and an aqueous dispersion method. In the congealing method, the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed.
Delayed release dosage forms Delayed release formulations are created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral nment of the small intestine.
The delayed release dosage units can be prepared, for e, by coating a drug or a drug-containing or comprising composition with a selected coating material. The drug-containing or sing composition may be, e. g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing or comprising beads, particles or es, for incorporation into either a tablet or capsule.
Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically able polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. le coating als for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate ate, cellulose e trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename it® (Rohm Pharma; Westerstadt, Germany), including Eudragit® L30D—55 and L100—55 (soluble at pH 5.5 and above), Eudragit® L-100 (soluble at pH 6.0 and above), Eudragit® S le at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragits® NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl rs and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene—vinyl acetate copolymer; enzymatically degradable polymers such as azo rs, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different coating materials may also be used. Multi—layer coatings using different polymers may also be applied.
The preferred coating weights for particular coating materials may be readily determined by those skilled in the art by ting individual release profiles for tablets, beads and granules prepared with different quantities of various coating als. It is the combination of materials, method and form of application that produce the desired release teristics, which one can determine only from the clinical studies.
The coating composition may include conventional additives, such as cizers, ts, colorants, izing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating, and will generally ent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer.
Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl ate, l sebacate, triethyl citrate, yl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film ion and , and will generally ent approximately 25 wt. % to 100 wt. % of the polymer weight in the g solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium e may also be used. Small quantities of an anti—foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating ition.
Methods ofmanufacturing As will be appreciated by those skilled in the art and as described in the pertinent texts and literature, a number of methods are available for preparing drug-containing or comprising tablets, beads, granules or particles that provide a variety of drug release profiles. Such methods e, but are not limited to, the following: coating a drug or ontaining or sing composition with an appropriate g material, typically although not necessarily, incorporating a polymeric material, increasing drug particle size, placing the drug within a matrix, and forming complexes of the drug with a suitable complexing agent.
The delayed release dosage units may be coated with the delayed release polymer coating using conventional techniques, e.g., using a conventional g pan, an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert), or the like. For detailed information concerning materials, equipment and processes for preparing tablets and delayed release dosage forms, see Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al.
(New York: Marcel Dekker, Inc., 1989), and Ansel et al., ceutical Dosage Forms and Drug Delivery Systems, 6.sup.th Ed. (Media, PA: Williams & Wilkins, 1995).
Alternatively, a delayed release tablet may be formulated by dispersing the drug within a matrix of a suitable material such as a hydrophilic r or a fatty compound. The hydrophilic polymers may be included of polymers or copolymers of cellulose, cellulose ester, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, and vinyl or enzymatically degradable polymers or copolymers as bed above. These hydrophilic polymers are particularly useful for providing a delayed release matrix. Fatty compounds for use as a matrix material include, but are not limited to, waxes (e.g. carnauba wax) and glycerol tristearate. Once the active ingredient is mixed with the matrix material, the mixture can be compressed into tablets.
A red method for preparing extended e tablets is compressing a drug-containing or comprising blend, e.g., blend of granules, prepared using a direct blend, wet-granulation, or dry-granulation process. Extended e s may also be molded rather than compressed, starting with a moist material containing or comprising a suitable water—soluble lubricant. However, tablets are preferably manufactured using compression rather than molding. A preferred method for forming an extended release drug-containing or comprising blend is to mix drug particles directly with one or more excipients such as ts (or fillers), binders, egrants, lubricants, glidants, and colorants. As an alternative to direct blending, a drug—containing or comprising blend may be prepared by using anulation or dry—granulation processes. Beads containing or comprising the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion.
For example, a l method for preparing drug-containing or comprising beads involves dispersing or dissolving the active agent in a coating suspension or solution ning or comprising pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, plasticizers or the like. The admixture is used to coat a bead core such as a sugar sphere (or so-called "non—pareil") having a size of approximately 60 to 20 mesh.
An ative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable ents, such as microcrystalline cellulose, e, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form the immediate release beads. d. Implants Neuroactive steroid can also be administered by insertion of an implant such as the silastic tube used for delivery of ceptive hormones. See, for example, Levonorgestrel and Norplant, both of which delivery long term release of hormone for ception, following mal tation. The effective dosage is increased by sing the size of the hole by which drug exits the reservoir to the individual to be treated. e. Transdermal Patches Neuroactive steroid can also be administered by a transdermal patch, similar to those used for contraception, although in a significantly higher dosage. See, for example, the Transdermal atch (estradiol/norethindrone) and the TestogenTM TDS® -enhanced testosterone.
Dosage can be increased by increasing the release mechanisms and/or increasing the concentration in the patch.
D. Combinations with Other Active Compounds Neuroactive steroid can be administered adjunctively With other active compounds such as analgesics, anti—inflammatory drugs, antipyretics, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti asthma drugs, cardiovascular drugs, corticosteroids, nergics, electrolytes, parasympathomimetics, stimulants, anorectics and anti-narcoleptics.
All publications cited are incorporated by nce. 111. Administration of Neuroactive steroid Formulations A composition described herein, can be administered to a subject in need thereof, to treat a er, e.g., a CNS related disorder, e.g., a traumatic brain injury; e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nvulsive status epilepticus, e. g., generalized status epilepticus, complex partial status epilepticus; a e, e. g., acute repatitve seizures, cluster seizures. Although preferred patients are human, typically any mammal including domestic s such as dogs, cats and horses, may also be treated.
Traumatic brain injury The amount of the active ingredients to be administered is chosen based on the amount which provides the desired dose to the patient in need of such treatment to alleviate symptoms or treat a condition. Behavioral assays can be used to determine the rate and extent of behavior recovery in response to the treatment. Improved patient motor skills, spatial learning performance, ive function, sensory tion, speech and/or a decrease in the propensity to seizure may also be used to measure the neuroprotective effect. Such functional/behavioral tests used to assess sensorimortor and reflex function are described in, for example, Bederson et a1. (1986) Stroke 17:472-476, DeRyck et a1. (1992) Brain Res. 573244—60, Markgraf et a1. (1992) Brain Res. 8-246, Alexis et a1. (1995) Stroke 26:2336—2346. Enhancement of neuronal survival may also be measured using the Scandinavian Stroke Scale (SSS) or the Barthl Index.
The treatment of a traumatic brain injury can be monitored by employing a variety of neurological measurements. For example, a partial therapeutic responses can be red by determining if, for example, there is an improvement in the subjects a) maximum daily Glasgow Coma Score; b) duration of coma; 3) daily intracranial pressure-therapeutic intensity levels; 4) extent of cerebral edema/mass effect measured on serial CT scans; and, 5) duration of ventilator support. A brief description of each of these assays is provided below.
The Glasgow Coma Score (index GCS) is a reflection of the depth of impaired consciousness and is best ed ing initial resuscitation nation, ation and t of blood pressure) but prior to use of sedating drugs, neuromuscular blocking agents, or endotracheal intubation.
The duration of coma is defined as the number of hours from the time of injury that the subject is unable to purposefully respond to commands or mechanical stimulation. For non—intubated subjects, this equates to a GCS score of >8. For intubated patients, this correlates with a GCS motor score of q.5. Duration of coma has been found to be predictive of functional outcome (Uhler et al. (1994) Neurosurgery 34(1): 122-8; Jiang et al. (1996) Brain Res : 101-7; and Gonzalez—Vidal et al. (1998) Arch Med Res 29(2): 117-24). Time spent in a coma induced pharmacologically for reasons other than brain injury should be subtracted in the final analysis.
The intracranial pressure (ICP) of patients with severe TBI is often monitored with an intracranial pressure device. Monitoring ICP can provide a measure of al edema. r, inherent variability and analysis complexities due to therapeutic interventions intended on ng the ICP mire using ICP ements. To adjust for these interventions a therapeutic intensity scale was developed. This scale, known as the Therapeutic Intensity Level (TIL), measures treatment aggressiveness for elevated ICPs (Allolio et a1. (1995) European Journal of Endocrinology 133(6): 696-700; Adashi et a1. (1996) Reproductive endocrinology, surgery, and technology elphia: Lippincott-Raven; and, Beers et al. eds. (1999) The Merck manual of diagnosis and y. 17th ed., Merck Sharp & Dohme Research Laboratories, Rahway, N.J.).
The extent of cerebral edema and mass effect can be determined by CT scans. For example, the volume of focal lesions can be measured. Mass lesions, either high-density or density abnormalities, will be ted by measuring the area of the abnormality as a region of interest, multiplying the area by the slice thickness, and summing these volumes for contiguous slices showing the same lesion. Each lesion will be measured three times, and the mean volume will be entered. This technique has been shown to be reliable (Garcia-Estrada et a1. (1993) Brain Res 628(1—2): 271—8).
Intracerebral lesions can be further characterized by location (frontal, temporal, parietal, occipital, basal ganglia, or any combination). When an edematous zone is present, its volume (the hypodense perimeter) can be measured and analyzed separately. Midline shift will be measured using the septum pellucidum as the midline structure. The cle-brain ratio (VBR) will be calculated to quantify the degree of cerebral atrophy. Levin et a1. ) Archives of Neurology 38(10):623—9) found that the VBR had satisfactory ility across different examiners, and was related both to the severity of acute injury and neurobehavioral sequelae (Hoffman et al. (1994) J Neurotrauma 11(4): 417—31).
The duration of ventilator support will be defined as the number of hours the patient receives positive pressure mechanical ventilation (Uhler et a1. (1994) urgery 34(1): 122-8; Jiang et al. (1996) Brain Res 735(1): 101—7; and Gonzalez-Vidal et al. (1998) Arch Med Res 29(2): 117-24). Time spent under ventilator support for s other than brain injury will be subtracted in the final analysis.
In on to the neurological measurements discussed above, a partial therapeutic response can also be assayed through various functional and sychological outcomes. Several standardized measures of neuropsychological and functional performance are known. For instance subjects may display an improvement in the Glasgow Outcome Scale (GOS)/Glasgow Outcome Scale Extender (GOSE) and/or in the Disability Rating Scale (DRS). The Glasgow Outcome Score is one of the most widely used measures of brain injury recovery in the world (Garcia-Estrada et al. (1999) Int J Dev ci 17(2): p. 145-51). Patients are classified into one of five ries: death, persistent vegetative state, severe disability, moderate disability, and good recovery. It is easy to administer and score, and has a high degree of reliability and validity.
The Disability Rating Scale (DRS) offers more precision than the GOS for measuring outcomes of moderate brain injury (Goodman et al. (1996) J Neurochem 66(5): 1836-44). The DRS consists of an eight—item rating of arousal and awareness, daily living activities, physical dependence, and employability (Vedder et al. ( 1999) J hem 72(6):2531-8). Inter-rater reliability for the entire DRS is high (0.97 to 0.98).
The Functional Independence Measure (FIM) can be used to assess physical and cognitive disability. It contains 18 items in the following domains: self—care, sphincter control, ty, locomotion, communication, and social cognition (Baulieu (1997) Mult Scler 3(2): 105—12). The FIM has demonstrated reliability and ty as an outcome measure following moderate and severe TBI (Jung-Testas et a1. (1994) J Steroid Biochem Mol Biol 48(1): 145-54).
The Sickness Impact Profile is one method for measuring self-perceived health status (Schumacher et al. (1995) Ciba Found Symp 191: p.90—1 12 and Koenig et a1. (1995) Science 268(5216):1500—3). It consists of 136 ons divided into 12 categories: sleep and rest, , work, home management, tion and pastimes, ambulation, mobility, body care and movement, social interaction, alertness, behavior, emotional behavior, and communication. It has been widely used across a variety of diseases and injuries, including head injury (Thomas et a1. (1999) Spine 24:2134—8). Baseline SIP scores will reflect pre- injury health status, while —up scores will examine post-injury functioning.
Ischemia Global ischemia, as used herein in reference to the CNS, refers to a condition which results from a general diminution of blood flow to the entire brain, forebrain, or spinal cord, which causes the delayed death of neurons, ularly those in metabolically active loci, throughout these tissues.
Focal ischemia, as used herein in nce to the CNS, refers to a condition that results from the blockage of a single artery that es blood to the brain or spinal cord, resulting in the death of all cellular elements (pan- necrosis) in the territory supplied by that artery.
Epilepsy Epilepsy is a brain disorder characterized by repeated seizures overtime.
Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, le nyoclonic epilepsy, epilepsy with grand— mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., al lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of ood.
Status epilepticus (SE) Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status ticus is characterized by the presence of convulsive status epileptic seizures, and can e early status epilepticus, established status ticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which t despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status tic seizures which persist despite treatment With a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status ticus is characterized by status epileptic seizures Which persist despite treatment With a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.
Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non—convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, al absence non-convulsive status epilepticus, or typical absence non—convulsive status ticus.
Compositions described herein can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status ticus, established status epilepticus, refractory status epilepticus, super- tory status epilepticus; non-convulsive status epilepticus, e. g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lized epileptiform discharges; prior to the onset of a seizure.
Seizures Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e. g., refractory convulsive status epilepticus, non—convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic—clonic seizures; simple partial seizures; x partial seizures; arily lized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile es; emotional seizures; focal seizures; gelastic seizures; generalized onset es; infantile spasms; Jacksonian seizures; massive ral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.
The present invention will be further understood by reference to the following non-limiting examples.
Example 1. Stability studies of formulations comprising egnanolone and CAPTISOL® Materials and Methods Formulations of allopregnanolone (1.5 mg/ml) and CAPTISOL® (6%) were evaluated for stability after storage at different temperatures and relative humidities over a 12 week period. The ations were stored in an IntraVia flexible bag layer polyolefin c, (PL 2408), non-latex, non-PVC, non- DEHP] or a vial (Type 1 glass vial with a 20 mm stopper, ec, 0 Westar). The samples were prepared from a stock solution of 250 ml of 6 mg/ml allopreganolone in CAPTISOL®. The formulations were evaluated based on clarity/color, assay (potency), ties (known, unknown, and total), osmolality, pH, bacterial xins, and particulate matter.
Results The studies demonstrated that the formulation was stable under all conditions that were tested for twelve weeks: refrigerated 2-5°C; refrigerated °C/50% RH; refrigerated 40°C/75% RH; refrigerated 60°C; refrigerated 2-5°C; erated 25°C/60% RH; refrigerated 40°C/75% RH; and refrigerated 60°C.
Example 2. Allopregnanolone rescue of AGS SE in Fmr] Knockout Mice.
Allopregnanolone reversed the sensitization to audiogenic seizure (AGS) — a form of status epilepticus (SE) — in Fmr] KO mice at 3, 10, 30 mg/kg dosed intraperitoneal (IP) in 30% b-Cyclodextrin, as indicated by the significant decrease in Percent Seizure (), and increase Percent Survival () relative to vehicle treated control. Plasma levels of six animals in each Allopregnanolone treatment group were collected randomly at completion of study and analyzed by LC—MS/MS. Bioanalytical measures are ted in ng/mL (). Data are presented as mean +/— SEM. >"P<0.05 indicate a statistically significant difference relative to vehicle control by Fisher’s PLSD.
MPEP 30mg/kg was used as a positive control in the study.
Example 3. Allopregnanolone prevention of status ticus in PZT-Seizure model.
Allopregnanolone at 3, 10, 30 mg/kg dosed intraperitoneal (IP) in 15% B-Cyclodextrin prevented status epilepticus in PTZ (pentylenetetrazol) (85 mg/kg lP)-treated /J mice, as indicated by the significant decrease in Seizure rank (), and se y to Death () relative to vehicle-treated control. Plasma levels of three animals in each Allopregnanolone treatment group were collected randomly at completion of study and analyzed by LC-MS/MS. Bioanalytical measures are indicated in ng/mL (). Data are ted as mean +/- SEM. *P<0.05 te a statistically significant difference relative to vehicle control by ’s PLSD. Valproate 400 mg/kg was used as a positive control in the study.
Example 4. Plasma concentration of egnanolone in refractory status epilepticus.
The plasma concentration profile over time of allopregnanolone in male patient diagnosed with refractory status ticus was evaluated as shown in The patient was dosed Allopregnanolone 1.5 mg/ml in 6%hydroxypropyl-B-cyclodextrin in 0.9% sodium chloride intravenously for 5 days. Infusion rate 86 ug/kg/h. Dosing schedule included 5.6 mg/h of egnanolone at 3.8 mL/h. Plasma concentrations was analyzed 2 hours prior to start of infusion then 52, 76, 100, 124, and 148 hours.
Example 5. Allopregnanolone in viva plasma concentration post intramuscular and intravenous administration.
The plasma and brain exposure profiles of Allopregnanolone were measured by LC/MS-MS after single intramuscular (IM) (10mg/kg) or intravenous (IV) (5mg/kg) dose in 30% CAPTISOL® in SD rats. Analysis shows that egnanolone dosed IM (10mg/kg) has an unexpectedly ntially greater exposure in plasma 16%, 0.5-2 hr) and brain (506%, 1 hr) relative to IV (5mg/kg) dose as indicated in Table 1 and 2. N=2/ time point. Error bars, SEM ( and 4B).
Example 6. Progesterone in 6% CAPTISOL® rescue of injury in TBI rodent model.
Progesterone in 6% CAPTISOL® rescued motor impairment in a penetrating ballistic brain injury rodent model of traumatic brain injury in both the low and high dose groups ( and ). Progesterone was administered Via a bolus loading dose followed by a 5 day continuous infusion where progesterone was d over the last 24 hours every 8 hrs by 25%. The low dose group received 2.5 mg/kg/hr for a 1 hr bolus infusion followed by a maintenance dose of 1.25 mg/kg/hr over 5 days with the last 24 hours being a taper. The high dose group received 5.0 mg/kg/hr for a 1 hr bolus on followed by a maintenance dose of 2.50 mg/kg/hr over 5 days with the last 24 hours being a taper.
It is understood that the disclosed ion is not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the ology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope which will be limited only by the appended claims.
Although any methods and materials r or equivalent to those described herein can be used in the practice or testing, the preferred methods, devices, and materials are as described. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.
In a first embodiment there is provided the use of an aqueous ceutical composition in the manufacture of a ment for treating a CNS-related disorder, comprising allopregnanolone at a concentration n 1 to 5 mg/mL, sulfo butyl ether βcyclodextrin at a concentration of between 150 and 400 mg/mL, and a buffer, wherein the pH of the medicament is from 5 to 9, and wherein the medicament is formulated for parenteral stration.
In a second embodiment there is provided the use of an aqueous pharmaceutical ition in the manufacture of a medicament for treating a CNS-related disorder, comprising allopregnanolone at a concentration between 5 to 10 mg/mL, sulfo butyl ether βcyclodextrin at a concentration of between 300 and 400 mg/mL, and a buffer, wherein the pH of the medicament is from 5 to 9, and wherein the medicament is formulated for parenteral administration.
In a third embodiment there is provided the use of a medicament as defined in the first or second embodiment, and substantially as hereinbefore described, with reference to the anying examples.

Claims (22)

What we claim is:
1. Use of an aqueous pharmaceutical composition in the manufacture of a medicament for treating a CNS-related disorder, comprising allopregnanolone at a concentration between 1 to 5 mg/mL, sulfo butyl ether β-cyclodextrin at a concentration of between 150 and 400 mg/mL, and a buffer, wherein the pH of the medicament is from 5 to 9, and wherein the medicament is formulated for parenteral administration.
2. The use of claim 1, comprising egnanolone at a concentration between 3 to 5 mg/mL.
3. The use of claim 1 or claim 2, comprising sulfo butyl ether β-cyclodextrin at a concentration of between 200 and 400 mg/mL.
4. The use of any one of claims 1-3, comprising allopregnanolone at a tration of 5 mg/mL and sulfo butyl ether β-cyclodextrin at a concentration of 250 mg/mL.
5. The use of any one of claims 1-4, wherein the medicament is formulated for intravenous or subcutaneous administration.
6. The use of any one of claims 1-5, wherein the ment is formulated for intravenous administration.
7. The use of any one of claims 1-5, wherein the medicament is formulated for subcutaneous administration.
8. The use of any one of claims 1-7, wherein the medicament further comprises an antioxidant.
9. The use of any one of claims 1-8, wherein the buffer is ed from a phosphate buffer, acetate buffer, or citrate buffer.
10. The use of claim 9, n the buffer is a citrate buffer.
11. The use of any one of claims 1-10, wherein the pH of the medicament is about 6.
12. Use of an aqueous pharmaceutical composition in the cture of a ment for treating a CNS-related disorder, comprising allopregnanolone at a concentration between 5 to 10 mg/mL, sulfo butyl ether β-cyclodextrin at a concentration of between 300 and 400 mg/mL, and a buffer, wherein the pH of the medicament is from 5 to 9, and wherein the medicament is formulated for parenteral administration.
13. The use of claim 12, wherein the medicament is formulated for intravenous or subcutaneous administration.
14. The use of claim 13, wherein the medicament is ated for intravenous administration.
15. The use of claim 13, n the ment is formulated for subcutaneous administration.
16. The use of any one of claims 12-15, wherein the medicament further comprises an antioxidant.
17. The use of any one of claims 12-16, wherein the buffer is selected from a phosphate buffer, acetate buffer, or citrate buffer.
18. The use of claim 17, wherein the buffer is a citrate buffer.
19. The use of any one of claims 12-18, wherein the pH of the medicament is about 6.
20. The use of any one of claims 1-19, wherein the CNS-related disorder is a traumatic brain injury (TBI).
21. The use of any one of claims 1-20, wherein the medicament is contained within a glass vial.
22. The use as claimed in any one of claims 1-21, wherein said pharmaceutical composition is substantially as hereinbefore described, with nce to example 1.
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