Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof
Inventors
Jenkins, Thomas E. • Husfeld, Craig O. • Seroogy, Julie D. • Wray, Jonathan W.
Assignees
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Publication Number
US-9585963-B2
Publication Date
2017-03-07
Expiration Date
Abstract
Pharmaceutical compositions and their methods of use are provided, where the pharmaceutical compositions comprise an opioid prodrug that provides enzymatically-controlled release of an opioid, and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the opioid from the opioid prodrug so as to attenuate enzymatic cleavage of the opioid prodrug.
Core Innovation
The invention relates to a method to treat a patient by administering a pharmaceutical composition comprising an opioid prodrug and a GI enzyme inhibitor. The opioid prodrug comprises a ketone-containing opioid covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, and the GI enzyme inhibitor interacts with the GI enzyme that mediates enzymatically-controlled release of the opioid from the opioid prodrug following ingestion of the composition.
The prodrug structures are defined through multiple compound families, including KC-(Ia), KC-(Ib), KC-(II), KC-(IIIa), KC-(IIIb), KC-(IV), KC-(Va), KC-(Vb), KC-(VI), KC-(VII), KC-(VIII), and KC-(IX), together with salts, solvates, and hydrates thereof. These families use extensive substituent variables, integer and range parameters, and covalent bond replacement at the enolic group of the ketone to define the promoiety architecture.
The promoiety concept includes GI enzyme-cleavable moieties and specific variants such as trypsin-cleavable moieties. The disclosed compositions and methods are framed around GI enzyme-mediated, enzymatically-controlled release after ingestion, modulated by the GI enzyme inhibitor that interacts with the GI enzyme.
Claims Coverage
The consolidated content includes one independent claim directed to a method for treating a patient by administering a pharmaceutical composition containing an opioid prodrug with a GI enzyme-cleavable moiety and a GI enzyme inhibitor. The claim covers multiple alternative ketone-containing opioid prodrug families, including KC-(Ia) through KC-(IX), with structural definitions for the promoiety and covalent linkage.
GI enzyme inhibitor and GI enzyme-cleavable opioid prodrug
Administering a pharmaceutical composition comprising an opioid prodrug comprising a ketone-containing opioid covalently bound to a promoiety comprising a GI enzyme-cleavable moiety and a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically-controlled release of the opioid from the opioid prodrug following ingestion.
Ketone-containing opioid covalently bound prodrug compound families
The opioid prodrug comprises a compound of formula KC-(Ia), KC-(Ib), KC-(II), KC-(IIIa), KC-(IIIb), KC-(IV), KC-(Va), KC-(Vb), KC-(VI), KC-(VII), KC-(VIII), or KC-(IX), or salts, solvates or hydrates thereof, with the ketone-containing opioid residue covalently bound to the promoiety framework.
Trypsin-cleavable and GI enzyme-cleavable moiety variants
Within the prodrug families, specific embodiments define R4 as a trypsin-cleavable moiety or a GI enzyme-cleavable moiety, alongside other variable substituent and integer/range parameters.
The claim coverage centers on a method of treating a patient by administering a pharmaceutical composition containing a ketone-containing opioid prodrug with a promoiety comprising a GI enzyme-cleavable moiety and a GI enzyme inhibitor that interacts with the GI enzyme mediating enzymatically-controlled opioid release, implemented through multiple KC compound families and salt, solvate, or hydrate variants.
Stated Advantages
Reduced side effects.
Reduced overdose/misuse/abuse risk.
Improved compliance/clinician control.
Enzymatically-controlled release of the opioid from the opioid prodrug following ingestion of the composition.
Attenuation of enzymatic cleavage via a GI enzyme inhibitor that interacts with the GI enzyme that mediates release after ingestion.
Suppresses and delays oxycodone plasma appearance compared with oxycodone.
Trypsin inhibitors reduce trypsin-mediated prodrug conversion.
Documented Applications
Treating a patient by administering a pharmaceutical composition containing an opioid prodrug and a GI enzyme inhibitor for enzymatically-controlled release following ingestion.
Treatment of a patient by administering a pharmaceutical composition comprising an opioid prodrug designed for enzymatically-controlled release after ingestion.
Pharmacokinetic evaluation in rats comparing Compound KC-2 versus oxycodone, including plasma Cmax and plasma Tmax after PO and IV administration.
In vitro stability evaluation involving enzyme exposure and assessment of trypsin-mediated prodrug conversion, including the effect of trypsin inhibitors on conversion.
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