Oral formulations of kappa opioid receptor agonists
Inventors
Wilson, Bryan R. • O'Connor, Stephen J.
Assignees
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Publication Number
US-11684674-B2
Publication Date
2023-06-27
Expiration Date
Abstract
The invention provides formulations for oral delivery of a therapeutic agent wherein the formulation comprises a kappa opioid receptor agonist and an absorption enhancer, the absorption enhancer includes a medium chain fatty acid or a salt of a medium chain fatty acid; and a medium chain fatty acid glyceride. The kappa opioid receptor agonist may be embedded in an oligosaccharide, such as trehalose. Also provided are capsules containing the oral formulations of the kappa opioid receptor agonists and the absorption enhancer of the invention and methods use of these formulations for the prophylaxis and treatment of variety of kappa opioid receptor-associated diseases and conditions such as pain, pruritus and inflammation; the method comprising administering to the mammal the formulation comprising the kappa opioid receptor agonist and an absorption enhancer.
Core Innovation
The invention relates to oral delivery formulations for a kappa opioid receptor agonist, including CR845.HCl, defined as D-Phe-D-Phe-D-Leu-D-Lys[ω(4-aminopyperidine-4carboxylic acid)].HCl. The formulations include trehalose and a glyceride of one or more medium chain fatty acids selected from caproic acid, caprylic acid and capric acid, and may optionally include chelators such as EDTA and salts such as sodium caprate.
In the formulation system, CR845.HCl is embedded in trehalose to form stabilized particles. The disclosed delivery formats include pharmaceutical compositions for oral delivery, including enteric-coated and intrinsically enteric capsule forms.
The disclosure further characterizes performance of different CR845.HCl forms and excipient selections, including bioavailability, dissolution profiles, and stability observations under stress and long-term storage conditions.
Claims Coverage
The independent claims cover two principal formulation concepts with measurable performance requirements: one oral formulation with a bioavailability threshold and one oral formulation with a long-term stability threshold. The claims center on CR845.HCl, trehalose, and a glyceride of one or more medium chain fatty acids.
Bioavailability-qualified CR845.HCl oral formulation with trehalose and medium-chain fatty-acid glyceride
A formulation of CR845.HCl with trehalose and a glyceride of one or more medium chain fatty acids selected from caproic acid, caprylic acid and capric acid, wherein the CR845.HCl exhibits a bioavailability of greater than 10%.
Trehalose-embedded CR845.HCl oral formulation with long-term stability
A formulation for oral delivery of a kappa opioid receptor agonist, comprising CR845.HCl and a glyceride of one or more medium chain fatty acids selected from caproic, caprylic and capric acids, wherein the CR845.HCl is embedded in trehalose and exhibits a stability of greater than about 96% stored for at least a year at 25°C.
Overall, the claim coverage centers on oral formulations that combine CR845.HCl with trehalose and selected medium-chain fatty-acid glycerides, while requiring either a bioavailability threshold or a defined long-term stability threshold. Dependent claims further specify component variants, stability thresholds under set conditions, and enteric capsule delivery formats.
Stated Advantages
CR845.HCl exhibits a bioavailability of greater than 10% in the specified formulation.
The formulation exhibits a stability of greater than about 96% stored for at least a year at 25°C.
The formulation exhibits a stability of greater than about 96% stored for 3 months at 40°C and 75% relative humidity.
Oral delivery is supported in enterically coated capsules or capsules having intrinsically enteric properties.
Documented Applications
Oral delivery of a kappa opioid receptor agonist, including CR845.HCl, for kappa opioid receptor-associated conditions including pain, pruritus, inflammation, glaucoma, edema, ileus, tussis, and hyponatremia.
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