Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof
Inventors
Jenkins, Thomas E. • Husfeld, Craig O. • Seroogy, Julie D. • Wray, Jonathan W.
Assignees
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Publication Number
US-9493477-B2
Publication Date
2016-11-15
Expiration Date
Abstract
A method of providing a patient with controlled release of ketone-containing opioid using a prodrug capable, upon enzymatic activation and intramolecular cyclization, of releasing the ketone-containing opioid is disclosed. The disclosure also provides such prodrug compounds and pharmaceutical compositions comprising such compounds. Such pharmaceutical compositions can optionally include an enzyme inhibitor that interacts with the enzyme(s) to mediate the enzymatically-controlled release of the ketone-containing opioid from the prodrug so as to modify enzymatic cleavage of the prodrug. Also included are methods to use such compounds and pharmaceutical compositions.
Core Innovation
The invention relates to ketone-containing opioid prodrugs in which the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to a C(O)NR5(C(R1)(R2))nNR3R4 framework. The ketone-containing opioid residue is labeled X, and the structural formulas KC-(IIIa), KC-(IIIb), and KC-(V) define variable substituent groups and integer parameters for n. The compounds are optionally provided as a salt, hydrate, or solvate.
Within the ketone-containing opioid family, R5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl, and substituted aryl, while each R1 and each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl. Alternatively, R1 and R2 together with the carbon to which they are attached form cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl groups, and n is 2 to 4. The disclosure further defines R4 as a residue derived from an L-amino acid or peptide residue, or as a trypsin-cleavable moiety.
The disclosed ketone-containing opioid prodrug compounds include oxycodone and hydrocodone variants and related peptide or substituted variants. The material also describes trypsin/GI protease inhibition as a co-formulation strategy to control prodrug conversion or release, and identifies trypsin inhibitors including SBTI, Bowman-Birk inhibitor, and camostat.
Claims Coverage
The identified independent claim coverage centers on ketone-containing opioid prodrug compounds with a covalent C(O)NR5(C(R1)(R2))nNR3R4 scaffold, and a related KC-(V) framework that specifies R4 as a trypsin-cleavable moiety. Across the independent claims, the core inventive features are the ketone-containing opioid enolic covalent framework, the broad substituent definitions for R5, R1, and R2, and the defined integer parameter n, with the KC-(V) claim further introducing trypsin-cleavable R4.
Ketone-containing opioid covalent framework with defined R5, R1, R2 and n
A compound of formula KC-(IIIa) or KC-(IIIb) wherein X is a residue of a ketone-containing opioid and the enolic hydrogen of the ketone is replaced by a covalent bond to C(O)NR5(C(R1)(R2))nNR3R4, with R5 selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl, and substituted aryl; each R1 and each R2 independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; the stated cycloalkyl and aryl combinations; n is 2 to 4; R3 is hydrogen; and the compound is a salt, hydrate or solvate thereof.
Ketone-containing opioid with trypsin-cleavable moiety R4
A compound of formula KC-(V) wherein X is a residue of a ketone-containing opioid and the enolic hydrogen of the ketone is replaced by a covalent bond to C(O)NR5(C(R1)(R2))nNR3R4, with R5 selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl, and substituted aryl; each R1 and each R2 independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; n is 2 to 4; R3 is hydrogen; and R4 is a trypsin-cleavable moiety, or a salt, hydrate or solvate.
Across the independent claims, the invention is directed to ketone-containing opioid-derived compounds where an enolic hydrogen is replaced by a covalent C(O)NR5(C(R1)(R2))nNR3R4 motif. The KC-(V) claim further narrows the framework by specifying that R4 is a trypsin-cleavable moiety.
Stated Advantages
Attenuate or modulate prodrug cleavage or release to modify pharmacokinetic parameters.
Lower Cmax, exposure, or alter 1/Cmax or 1/Tmax metrics.
Reduce drug abuse potential by reducing the user's ability to release the ketone-modified opioid from the ketone-modified opioid prodrug in the presence of trypsin.
Reduce side effects and improve compliance.
Reduce risk of unintended overdose and deter misuse or abuse.
Provide multiple dose units producing non-proportional release.
Documented Applications
Treating or preventing pain by administering an effective amount of a compound of formula KC-(V) or the claimed formula to a patient who needs it.
Reducing drug abuse potential of a ketone-modified opioid prodrug composition by combining a compound of formula KC-(V) with a trypsin inhibitor.
Identifying a suitable prodrug/inhibitor pair by assessing conversion or prodrug cleavage in the presence and absence of a trypsin inhibitor.
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