Pharmaceutical formulation of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime
Inventors
Alhadeff, Paul • Doverskog, Magnus • Johansson, Maja • Meijer, Thomas • Schipper, Nicolaas
Assignees
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Publication Number
US-10603326-B2
Publication Date
2020-03-31
Expiration Date
Abstract
The present invention is directed to a novel pharmaceutical formulation comprising 3α-ethynyl-3β-hydroxyandrostan-17-one oxime in an amount of 0.1-10% by weight of the total weight of the composition; and a vehicle comprising (a) 45-100% of a monoester; (b) optionally up to 51% of a diester; and (c) optionally up to about 10% of a triester. Also claimed is a method for the treatment of medical conditions such as hypersomnia and hepathic encephalopathy by the use of a pharmaceutical formulation as claimed.
Core Innovation
The disclosure relates to a lipid-based pharmaceutical formulation comprising 3α-ethynyl-3β-hydroxyandrostan-17-one oxime (Compound I). The formulation includes a vehicle based on monoglyceride, optionally diglyceride, and optionally triglyceride, with quantitative ranges for the proportions of monoglyceride, diglyceride, and triglyceride in the vehicle fraction and compositional ranges of fatty acids selected from caprylic acid (C8), capric acid (C10), caproic acid (C6), lauric acid (C12), palmitic acid (C16), myristic acid (C14), stearic acid (C18), oleic acid (C18:1), and linoleic acid (C18:2).
A central problem addressed is poor aqueous solubility of the compound. The formulation is designed to improve bioavailability and drug exposure by using a fatty-acid ester vehicle while avoiding the need for added surfactants or excipients, as argued in the disclosure. The oxime is present in an amount of 0.1–10% by weight of the total composition.
The disclosure reports human Phase I pharmacokinetic and neuropharmacology outcomes, including linear dose-proportional pharmacokinetics and brain penetration, along with antagonism of allopregnanolone at the GABA-A receptor. The reported neuropharmacology includes mitigation of sedation and changes in saccadic eye velocity, and medical uses described include hepatic encephalopathy and hypersomnolence.
Claims Coverage
The partial content provides one independent claim. This claim covers the pharmaceutical formulation itself, centered on combining 3α-ethynyl-3β-hydroxyandrostan-17-one oxime with a specifically defined fatty-acid glyceride vehicle and an oxime loading range of 0.1–10% by weight, with dependent claims refining vehicle composition, dosage form, and treatment indication and co-therapy concepts.
Oxime-containing pharmaceutical formulation with defined glyceride vehicle proportions
A pharmaceutical formulation consisting of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime and a vehicle, wherein the vehicle comprises 45–100% of a monoglyceride, optionally up to 51% of a diglyceride, and optionally up to about 10% of a triglyceride.
Fatty-acid composition ranges for the glyceride components
The monoglyceride, diglyceride (if any) and/or triglyceride (if any) comprises a fatty acid selected from caprylic acid (C8) in an amount of 50–90%, capric acid (C10) in an amount of 10–50%, caproic acid (C6) in an amount of up to 3%, lauric acid (C12) in an amount of up to 100%, palmitic acid (C16) in an amount of up to 12%, myristic acid (C14) in an amount of up to 3%, stearic acid (C18) in an amount of up to 6%, oleic acid (C18:1) in an amount of up to 100%, and linoleic acid (C18:2) in an amount of up to 35%.
Oxime loading of 0.1–10% by weight
The amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is from 0.1–10% by weight of the total weight of the composition.
Across the provided independent claim, protection is directed to a formulation where the oxime is loaded at 0.1–10% by weight into a vehicle defined by monoglyceride/diglyceride/triglyceride proportion ranges and by fatty-acid composition ranges of the glyceride components.
Stated Advantages
Improved bioavailability and drug exposure.
Solubility enhancements in specific fatty ester vehicles.
Does not require added surfactants or excipients.
Pharmacokinetics are linear and dose-proportional.
Brain penetration is reported.
Antagonism of allopregnanolone at the GABA-A receptor is reported.
Mitigation of sedation and changes in saccadic eye velocity are reported.
Documented Applications
Treatment of hepatic encephalopathy.
Treatment of hypersomnolence/hypersomnia.
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