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Publication Number
US-11617758-B2
Publication Date
2023-04-04
Expiration Date
Abstract
A SEDDS or SMEDDS or SNEDDS formulation for drug delivery of a lipophilic therapeutic agent, providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of the therapeutic agent by formulation with a lipophilic surfactant, a hydrophilic surfactant, one or more solubilizers and, optionally, digestible oils, resulting in higher bioavailability of the therapeutic agent administered to a subject in need of such therapeutic agent. Also described are pharmaceutical compositions containing the formulations and methods of making and methods of using the formulations and pharmaceutical compositions. Formulations of the disclosure can be constituted to minimize the synthesis of dihydrotestosterone when the therapeutic agent includes testosterone or testosterone esters.
Core Innovation
The invention provides a pharmaceutical composition that comprises solubilized testosterone undecanoate and is formulated as a self-emulsifying oral formulation. The formulation includes hydrogenated castor oil ethoxylate, a defined lipophilic surfactant selected from particular fatty acids or lipophilic surfactant components, phytosterol esters, and optional dl-alpha-tocopherol.
The composition is described for lipophilic drug delivery, with emphasis on improving solubility and stability of testosterone undecanoate. The disclosed approach also targets enhanced lymphatic absorption and reduced food effect associated with oral administration, in the context of self-emulsifying drug delivery systems such as SEDDS, SMEDDS, and SNEDDS.
In the testosterone therapy context, the invention addresses the balance between testosterone and dihydrotestosterone by maintaining near-physiological DHT/T ratios. Supporting evaluation includes beagle dog pharmacokinetics, and the description reports improved pharmacokinetic exposure and dissolution behavior that supports the intended oral delivery performance.
Claims Coverage
The independent claim set shown contains one independent claim. The main inventive features cover a self-emulsifying oral formulation with specified weight ranges for solubilized testosterone undecanoate, hydrogenated castor oil ethoxylate, a defined lipophilic surfactant selection, and phytosterol esters, with optional dl-alpha-tocopherol, and a method of treating male hypogonadism by administering the composition.
Self-emulsifying oral formulation with solubilized testosterone undecanoate and defined surfactant/sterol composition
A pharmaceutical composition comprising from 10 to 25% by weight of solubilized testosterone undecanoate, from 10 to 37.5% by weight of hydrogenated castor oil ethoxylate, from 10 to 60% by weight of lipophilic surfactant selected from the group consisting of octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, propylene glycol monolaurate, glycerol/glyceryl monolinoleate, glyceryl mono-and dicaprylocaprate, or a combination thereof, from 5 to 37.5% by weight of one or more phytosterol esters, and 0-10% by weight of dl-alpha-tocopherol, wherein the composition is a self-emulsifying oral formulation.
Treatment of male hypogonadism by administering the composition
A method of treating male hypogonadism comprising administering to a male subject in need thereof the pharmaceutical composition.
Overall coverage centers on a self-emulsifying oral formulation composed of solubilized testosterone undecanoate, hydrogenated castor oil ethoxylate, a defined lipophilic surfactant selection, and phytosterol esters, with dl-alpha-tocopherol in an optional range, and further includes treating male hypogonadism via administration of the composition.
Stated Advantages
Unexpectedly increases solubility of testosterone and testosterone undecanoate in lipid-based formulations including SEDDS, SMEDDS, and SNEDDS.
Provides mutual solubility enhancement when saturated with phytosterols and vice versa.
Improves in vivo absorption and exposure of oral testosterone formulations.
Helps maintain or improve DHT/T control in vivo.
Reduces oxidative degradation of unsaturated lipid formulations with phytosterols, as indicated by stability iodine value.
Enhanced lymphatic absorption.
Reduced food effect.
Near-physiological DHT/T ratios.
Documented Applications
Oral administration of testosterone formulations for improving exposure and controlling DHT/T.
Treatment of male hypogonadism by administering the pharmaceutical composition to a male subject in need thereof.
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