Oral allopregnanolone compositions and methods of use
Inventors
Ogle, Jonathan • BRUNO, Benjamin J. • Papangkorn, Kongnara • Akapo, Samuel • Frank, Joel • Chidambaram, Nachiappan • Patel, Mahesh V.
Assignees
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Publication Number
US-12186327-B2
Publication Date
2025-01-07
Expiration Date
Abstract
Disclosed is a method and an oral composition for treating CNS disorders. An embodiment of the invention comprises orally administering an allopregnanolone containing composition to a subject having a CNS disorder. Exemplary CNS disorders include sleep disorders, mood disorders, dysthymic disorders, bipolar disorders, anxiety disorders, stress disorders, compulsive disorders, schizophrenia spectrum disorders, convulsive disorders, memory disorders, cognition disorders, movement disorders, personality disorders, autism spectrum disorders, substance abuse disorders, dementia, pain, traumatic brain injury (TBI), vascular disease, withdrawal syndrome, and tinnitus. The composition and methods disclosed herein exhibit effective oral absorption/bioavailability.
Core Innovation
The invention relates to orally administering encapsulated or solid dosage form oral pharmaceutical compositions comprising allopregnanolone to a human subject for treating a CNS disorder. The composition includes at least about 3% w/w of allopregnanolone, at least one hydrophilic additive, and at least one lipophilic additive, and the approach emphasizes effective oral absorption and bioavailability, including under food effects.
The hydrophilic additive is a hydrophilic surfactant with an HLB value of at least about 10, and the lipophilic additive is a lipophilic surfactant with an HLB value less than about 10. Treatment success is defined through serum and exposure outcomes after oral administration, including at least one of a Cmax of at least 10 ng/ml of allopregnanolone, an effective dose of at least 10 mg of allopregnanolone, and, after at least two days of administration, a serum concentration level in a defined range and exposure comparability to an intravenous administration reference within specified percentage windows.
In some embodiments, administration of the composition results in substantial improvement, reduction, or elimination in at least one CNS disorder of the subject. The disclosures also describe multiple discrete dose administrations over several days, with dosing frequency categories including qd, bid, tid, qid, greater than qid, and intermittent dose.
Claims Coverage
The independent claims identified in the provided claim set center on oral administration of an encapsulated or solid allopregnanolone composition containing both hydrophilic and lipophilic additives, with defined allopregnanolone exposure and/or dose targets, including comparability to intravenous administration and timing based on at least two days of administration. Four inventive features are identified across the independent claims.
Oral encapsulated or solid allopregnanolone composition with hydrophilic and lipophilic additives
Orally administering to the human subject an encapsulated or solid dosage form oral pharmaceutical composition comprising at least about 3% w/w of allopregnanolone, at least one hydrophilic additive, and at least one lipophilic additive.
Cmax and effective dose targets after oral administration
Wherein the administration results in at least one of: a Cmax of at least 10 ng/ml of allopregnanolone in the subject, and an effective dose of at least 10 mg of allopregnanolone in the subject.
Substantial improvement, reduction, or elimination of CNS disorder
Wherein the administration results in a substantial improvement, reduction, or elimination in at least one CNS disorder of the subject.
Serum concentration range and IV comparability for oral allopregnanolone after at least two days
In response to at least two days of administration of the composition, the administration results in at least one of: a serum concentration level of allopregnanolone in the range of about 0.47 ng/ml to about 134.5 ng/ml; an effective dose of allopregnanolone of at least 1311 mg; a comparable Cmax within +50%/-50% of an intravenous administration reference; and a comparable AUC0-t within +25%/-20% of an intravenous administration reference.
Overall, the independent claims require orally administering encapsulated or solid allopregnanolone oral pharmaceutical compositions containing at least about 3% w/w allopregnanolone plus both hydrophilic and lipophilic additives, and achieving defined allopregnanolone exposure and/or effective dose outcomes. Additional independent-claim-level constraints include at least two days of administration and, in some cases, defined serum concentration levels and comparability of Cmax and AUC to an intravenous reference.
Stated Advantages
Achieves a Cmax of at least 10 ng/ml of allopregnanolone after oral administration.
Delivers an effective dose of at least 10 mg of allopregnanolone.
Produces substantial improvement, reduction, or elimination in at least one CNS disorder.
Provides serum concentration and exposure comparability to intravenous administration using specified ranges and windows.
Produces treatment performance that can be defined without regard to fed/fasting state.
Documented Applications
Treating a CNS disorder in a human subject, wherein the CNS disorder comprises at least one of: sleep disorder, mood disorder, PND, PPD, postpartum psychosis, essential tremors, treatment resistant depression, perinatal depression, dysthymic disorder, bipolar disorder, GAD, social anxiety disorder, stress, PTSD, OCD, schizophrenia, schizoaffective disorder, epilepsy, SE, seizures, ADHD, dementia, Huntington's disease, Parkinson's disease, anti-social personality disorder, autism, synaptopathy, Rett syndrome, Fragile X syndrome, Angelman syndrome, neuropathic pain, an injury related pain syndrome, acute pain, chronic pain, TBI, stroke, ischemia, a vascular malformation, a substance abuse disorder, a withdrawal syndrome, and tinnitus.
Treating a CNS disorder in a human subject by orally administering the defined encapsulated or solid dosage form oral pharmaceutical composition with outcomes defined by Cmax/effective dose and, for at least two days of administration, by serum concentration level and comparability versus intravenous administration.
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