Compositions and methods for treating CNS disorders
Inventors
Patel, Mahesh V. • Chidambaram, Nachiappan • Kim, Kilyoung • Papangkorn, Kongnara • BRUNO, Benjamin J. • Vangara, Kiran Kumar • Ogle, Jonathan • Akapo, Samuel • Frank, Joel
Assignees
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Publication Number
US-12208103-B1
Publication Date
2025-01-28
Expiration Date
Abstract
The present disclosure is drawn to compositions and methods for treating CNS disorders. In one embodiment, an oral pharmaceutical composition can comprise a therapeutically effective amount of pregn-4-ene-3,20-dione; and a pharmaceutically acceptable carrier that provides formation of either 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or both in an amount sufficient to treat a CNS disorder when orally administered to a subject. In another embodiment, a method of treating a CNS disorder can comprise orally administering to a subject, a therapeutically effective amount of pregn-4-ene-3,20-dione that provides an amount of GABA receptor binding pregn-4-ene-3,20-dione metabolites that is sufficient to treat the CNS disorder. In another embodiment, a method of treating a CNS disorder can comprise orally administering to the subject, a therapeutically effective amount of pregn-4-ene-3,20-dione that provides an amount of 3α-OH-5α-pregnan-20-one, or 3α-OH-5β-pregnan-20-one, or both that is sufficient to treat the CNS disorder.
Core Innovation
The invention discloses treating depression by orally administering an oral dosage form pharmaceutical composition comprising or prepared from a neuroactive steroid comprising 3α-OH-5α-pregnan-20-one. The administration provides pharmacokinetic exposure targets based on serum Cmax-based ranges and at least one serum Cmax threshold for 3α-OH-5α-pregnan-20-one, and in some embodiments a sum of Cmax for 3α-OH-5α-pregnan-20-one and 3α-OH-5β-pregnan-20-one normalized by dose.
The oral dosage form is administered as a plurality of doses given at a frequency of at least four hours apart. The disclosed compositions are NAS-containing oral dosage forms prepared from a NAS and a pharmaceutically acceptable carrier, where the carrier promotes conversion via 5-alpha-reductase to GABA_A receptor allosteric metabolites, including 3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one.
The document also describes NAS physical forms such as substantially non-crystalline and/or substantially solubilized or partially solubilized and partially crystalline forms, and oral and drinkable formulation examples using lipid/surfactant/excipient carrier systems. It presents in vitro dissolution release comparisons versus micronized forms and clinical PK comparisons showing enhanced metabolite generation at lower or equivalent doses.
Claims Coverage
The independent claims include oral treatment of depression using 3α-OH-5α-pregnan-20-one-containing NAS with specified dose ranges, pharmacokinetic exposure targets, and multiple doses spaced at least four hours apart. Across the claims, the inventive coverage centers on serum Cmax and/or Cavg, a combined metabolite Cmax metric, a Cmax threshold greater than about 10 ng/ml, and use of a pharmaceutically acceptable carrier in some claims.
Depression treatment with 3α-OH-5α-pregnan-20-one serum Cmax and dosing frequency
Orally administering to treat depression an oral dosage form composition comprising or prepared from a neuroactive steroid comprising 3α-OH-5α-pregnan-20-one in an amount of from about 10 mg to about 400 mg, wherein administration provides at least one of a Cmax of 3α-OH-5α-pregnan-20-one/dose within specified ranges, a sum of Cmax of 3α-OH-5α-pregnan-20-one and 3α-OH-5β-pregnan-20-one normalized by dose, and a Cmax of 3α-OH-5α-pregnan-20-one of greater than about 10 ng/ml; wherein administration comprises a plurality of doses administered at a frequency of at least four hours apart.
Depression treatment with serum Cmax and/or Cavg achieved by multi-dose oral regimen
Orally administering to a subject an oral dosage form pharmaceutical composition comprising or prepared from a neuroactive steroid and a pharmaceutically acceptable carrier, wherein said neuroactive steroid comprises 3α-OH-5α-pregnan-20-one in an amount of from about 10 mg to about 400 mg, and wherein administration provides in said subject at least one of a serum level Cmax of 3α-OH-5α-pregnan-20-one and a serum level Cavg of 3α-OH-5α-pregnan-20-one; wherein administration comprises a plurality of doses administered at a frequency of at least four hours apart.
Daily depression treatment with Cmax threshold greater than 10 ng/ml
Orally administering to a subject a daily dose of from about 10 mg to about 400 mg of a composition comprising or prepared from a neuroactive steroid comprising 3α-OH-5α-pregnan-20-one, wherein administration provides a serum level Cmax of 3α-OH-5α-pregnan-20-one of greater than about 10 ng/ml, and wherein administration comprises a plurality of doses of said composition administered at a frequency of at least four hours apart.
The claims center on oral treatment of depression using NAS containing 3α-OH-5α-pregnan-20-one, with exposure defined by serum Cmax and, in one claim, serum Cavg, together with multiple dosing intervals of at least four hours apart. The claims also reference a pharmaceutically acceptable carrier, specified dose ranges, and combined metabolite exposure metrics.
Stated Advantages
Improves in vivo conversion toward PAM neurosteroid metabolites 3α-OH-5α-pregnan-20-one and/or 3α-OH-5β-pregnan-20-one by using pharmaceutically acceptable carriers that control conversion.
Provides higher, faster, and more reliable metabolite levels versus purpose-inadequate carriers and micronized drug.
Provides treatment-onset and depression efficacy outcomes assessed by HAM-D and other depression scales, including reductions and remission criteria.
Documented Applications
Treating depression in a subject, including clinical depression, perinatal depression, and postpartum depression (PPD).
Postpartum depression using HAM-D, saccadic eye velocity (SEV), and mood rating scale (MRS).
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