Pharmaceutical formulation of 3-alpha-ethynyl-3-beta-hydroxyandrostan-17-one oxime
Inventors
Alhadeff, Paul • Doverskog, Magnus • Johansson, Maja • Meijer, Thomas • Schipper, Nicolaas
Assignees
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Publication Number
US-11123351-B2
Publication Date
2021-09-21
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 hepatic encephalopathy by the use of a pharmaceutical formulation as claimed.
Core Innovation
The document describes a formulation strategy for 3α-ethynyl-3β-hydroxyandrostan-17-one oxime as a lipid-based pharmaceutical formulation to address poor aqueous solubility. The formulation comprises the compound and a vehicle comprising propylene glycol monoester, optionally with propylene glycol diester, with the monoester defined as a specified mixture of fatty acids within defined amount ranges. The amount of the compound is constrained to 0.1–10% by weight of the total composition, and the formulation is presented as a capsule dosage form.
The vehicle is defined by selecting fatty acids for the propylene glycol monoester and, optionally, a propylene glycol diester. The fatty acids include caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid, each with specified amount limits. The vehicle comprises 45–100% of a monoester of propylene glycol and optionally up to 51% of a diester of propylene glycol, subject to the fatty acid composition constraints.
The document further states that the formulation provides improved bioavailability and drug exposure for orally administered Compound I while being achievable without additional surfactants. The solubility of Compound I in the vehicle can be high, and the document includes solubility evaluation across multiple lipid carriers and presentation as capsule formulations. In addition to formulation description, the document reports Phase I pharmacokinetic findings and related antagonist challenge study outcomes supporting oral dosing performance and pharmacodynamic relevance.
Claims Coverage
The document provides one independent claim that defines the formulation composition, centered on 3α-ethynyl-3β-hydroxyandrostan-17-one oxime in a specifically constrained propylene glycol monoester, optionally with propylene glycol diester, vehicle with defined fatty-acid amount ranges and a defined active concentration. The claim set further includes dependent refinements that narrow concentration ranges, constrain vehicle fraction, specify particular diester selections, and limit presentation to capsules, plus a dependent therapeutic use claim context for hepatic encephalopathy.
Propylene glycol monoester vehicle formulation for 3α-ethynyl-3β-hydroxyandrostan-17-one oxime
A pharmaceutical formulation comprising 3α-ethynyl-3β-hydroxyandrostan-17-one oxime and a vehicle comprising 45–100% of a monoester of propylene glycol, optionally up to 51% of a diester of propylene glycol, wherein the monoester and/or diester comprises fatty acids selected from caprylic acid, capric acid, caproic acid, lauric acid, palmitic acid, myristic acid, stearic acid, oleic acid, and linoleic acid in respective specified amount ranges, and wherein the amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is from 0.1–10% by weight of the total weight of the composition.
Narrowed active concentration range
A formulation according to the independent claim where the amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is constrained to a narrower range within 0.1–5% by weight or 0.1–4% by weight of the total formulation.
Vehicle fraction constrained
A formulation according to the independent claim where the vehicle comprises 90–99.9% by weight of the total weight of the formulation.
Optional diester specification by defined propylene glycol diesters
A formulation according to the independent claim where the propylene glycol diester is selected from defined propylene glycol diesters.
Capsule presentation
A formulation according to the independent claim provided in a capsule.
Treatment use in hepatic encephalopathy
A method for treating hepatic encephalopathy by administering the pharmaceutical formulation according to the independent claim to a patient in need of such treatment.
Overall, claim coverage centers on delivering 3α-ethynyl-3β-hydroxyandrostan-17-one oxime in a propylene glycol monoester vehicle with defined fatty-acid amount ranges, optionally with a propylene glycol diester, and with a specified 0.1–10% by-weight active concentration; dependent claims narrow the active and vehicle ranges, specify diester selections, restrict the dosage form to capsules, and add a therapeutic method for hepatic encephalopathy.
Stated Advantages
Improved bioavailability/drug exposure for Compound I when formulated in the specified vehicle.
High solubility of Compound I in the specified vehicle.
Surfactant-free formulation, i.e., improved exposure can be achieved without needing additional surfactants.
Documented Applications
Treatment of hepatic encephalopathy by administering the pharmaceutical formulation to a patient who needs such treatment.
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