Oral formulations of kappa opioid receptor agonists
Inventors
Wilson, Bryan R. • O'Connor, Stephen J.
Assignees
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Publication Number
US-11033629-B2
Publication Date
2021-06-15
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 using particles embedded with an oligomeric saccharide matrix. The particles comprise about 18% to about 23% (w/w) kappa opioid receptor agonist and about 60% to about 77% (w/w) trehalose, and the kappa opioid receptor agonist is D-Phe-D-Phe-D-Arg-D-Lys-ω(4-aminopiperidine-4-carboxylic acid).HCl (CR845.HCl). The particles are suspended in a liquid suspension in an oral dosage form.
The liquid suspension comprises about 0.01% to about 5% (w/w) of the kappa opioid receptor agonist and about 60% to about 100% (w/w) of an absorption enhancer. The absorption enhancer comprises medium chain fatty acid triglyceride components and capric acid/caprylic acid fatty-acid components, including caprylic acid and capric acid in defined weight-percentage ranges, or alternative defined mixtures of capric acid with a medium chain fatty acid triglyceride. In related embodiments, the absorption enhancer further optionally comprises sodium caprate and/or EDTA.
The formulations further specify quantitative composition constraints for the particle phase and for the absorption enhancer phase, including trehalose embedded particles and defined medium-chain triglyceride and capric acid/sodium caprate content. The document also describes stability/purity retention for CR845.HCl at specified storage conditions and time periods, and it describes oral dosage form refinements including spray dried particles and enterically coated capsules.
Claims Coverage
The provided claim set contains four independent claims and each independent claim is directed to oral delivery formulations with trehalose-containing particles suspended in a liquid suspension and constrained by multiple quantitative inventive features. Across the independent claims, the inventive features focus on trehalose particle composition with a specified kappa opioid receptor agonist, suspension in a liquid containing a specified proportion of the agonist and an absorption enhancer, and defined compositions of the medium-chain fatty acid triglyceride/capric acid absorption enhancer, optionally with sodium caprate and EDTA.
Trehalose embedded particles of CR845.HCl
Particles comprising about 18% to about 23% (w/w) kappa opioid receptor agonist and about 60% to about 77% (w/w) trehalose, wherein the kappa opioid receptor agonist is D-Phe-D-Phe-D-Arg-D-Lys-ω(4-aminopiperidine-4-carboxylic acid).HCl (CR845.HCl).
Liquid suspension with defined CR845.HCl and absorption enhancer
The particles are suspended in a liquid suspension comprising about 0.01% to about 5% (w/w) of the kappa opioid receptor agonist and about 60% to about 100% (w/w) of an absorption enhancer.
Absorption enhancer defined by medium chain fatty acids and triglyceride ranges
The absorption enhancer comprises a medium chain fatty acid triglyceride comprising 55% to 60% (w/w) caprylic acid and 40% to 45% (w/w) capric acid; or a mixture consisting of 10% capric acid and 90% of a medium chain fatty acid triglyceride comprising 55% to 60% (w/w) caprylic acid and 40% to 45% (w/w) capric acid.
Absorption enhancer with medium chain triglycerides, optional sodium caprate and EDTA
The absorption enhancer comprises a medium chain fatty acid triglyceride comprising 55% to 60% (w/w) caprylic acid and 40% to 45% (w/w) capric acid and optionally further comprising about 13% to about 22% sodium caprate and/or about 5% to 9% EDTA; or a mixture consisting of 10% capric acid and 90% of a medium chain fatty acid triglyceride comprising 55% to 60% (w/w) caprylic acid and 40% to 45% (w/w) capric acid, and optionally further comprising about 13% to about 22% sodium caprate and/or about 5% to 9% EDTA.
Specific kappa opioid receptor agonist identity
The kappa opioid receptor agonist is D-Phe-D-Phe-D-Leu-D-Lys-ω(4-aminopiperidine-4-carboxylic acid)]-OH, (CR845.HCl).
The independent claims cover trehalose-containing particles with specific kappa opioid receptor agonist identity and defined particle composition, suspended in a liquid suspension with defined agonist and absorption enhancer proportions. The claims further constrain the absorption enhancer to specified medium-chain triglyceride/capric acid compositions, optionally with sodium caprate and/or EDTA, and identify the agonist as CR845.HCl in the specified peptide form.
Stated Advantages
Stability/purity retention for CR845.HCl at specified storage conditions and time periods is described, including retention of at least about 98% purity for 4 months at 40°C and 75% relative humidity and retention of at least about 98% purity for at least a year when stored at 25°C.
Oral delivery formulations are described, including enteric capsule formulations, with nonclinical bioavailability and pharmacokinetic plasma profiles.
Stable particle size and minimal loss of content/purity under specified storage conditions are described for trehalose-embedded CR845.HCl in specified absorption enhancers.
Documented Applications
Treatment and prophylaxis of kappa-opioid-associated conditions including pain.
Treatment and prophylaxis of kappa-opioid-associated conditions including pruritus.
Treatment and prophylaxis of kappa-opioid-associated conditions including inflammation.
Treatment and prophylaxis of kappa-opioid-associated conditions including edema.
Treatment and prophylaxis of kappa-opioid-associated conditions including hyponatremia.
Treatment and prophylaxis of kappa-opioid-associated conditions including glaucoma.
Oral delivery using enteric coated capsules and/or capsules in nonclinical bioavailability and pharmacokinetic evaluations.
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