Pharmaceutical compositions with attenuated release of phenolic opioids
Inventors
Jenkins, Thomas E. • Seroogy, Julie D. • Wray, Jonathan W.
Assignees
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Publication Number
US-9534014-B2
Publication Date
2017-01-03
Expiration Date
Abstract
Pharmaceutical compositions and their methods of use are provided, where the pharmaceutical compositions comprise a phenolic opioid prodrug that provides enzymatically-controlled release of a phenolic opioid, and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the phenolic opioid from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
Core Innovation
The invention relates to pharmaceutical compositions comprising a trypsin inhibitor together with a compound of general formula (II) or a pharmaceutically acceptable salt thereof. In the compound of general formula (II), a phenolic opioid residue is covalently linked through the phenolic hydroxyl group position to a —C(O)—NR1(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5) framework.
The phenolic opioid residue is selected from buprenorphine, hydromorphone, morphine, oxymorphone, naloxone, naltrexone, and other listed phenolic opioids. The hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to the —C(O)—NR1(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5) segment.
Substituent definitions are provided for R1, R2, R3, n, R4, and R5. R1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl, and substituted aryl; n is an integer from 2 to 4; R4 corresponds in configuration to that in an L-amino acid; and R5 represents hydrogen, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
Claims Coverage
The independent claim centers on one pharmaceutical composition combining a trypsin inhibitor with a compound of general formula (II). The claim defines the phenolic opioid residue and constrains R1, R2, R3, n, R4, and R5, resulting in a structurally bounded composition claim with two inventive features.
Trypsin inhibitor plus phenolic opioid prodrug framework
A pharmaceutical composition comprising a trypsin inhibitor and a compound of general formula (II) or a pharmaceutically acceptable salt thereof, where the phenolic hydroxyl hydrogen of a phenolic opioid is replaced by a covalent bond to the —C(O)—NR1(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5) framework.
Defined substituent selection for the general formula (II) framework
R1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; each R2 and R3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl, or R2 and R3 together form a cycloalkyl or substituted cycloalkyl group; n is an integer from 2 to 4; R4 corresponds in configuration to that in an L-amino acid; and R5 is hydrogen, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
The claims cover a pharmaceutical composition that pairs a trypsin inhibitor with a structurally defined phenolic opioid compound of general formula (II), together with explicit substituent constraints on the framework.
Stated Advantages
Attenuation of trypsin-mediated release is described in the disclosed combination.
Attenuation of enzymatic cleavage and reduced overexposure of released phenolic opioids are described in the disclosed combination.
Reduced hydromorphone release is indicated by the document summary.
Documented Applications
Pharmaceutical use for attenuating release of phenolic opioids, exemplified by reduced hydromorphone release.
Use of trypsin inhibitors together with the phenolic opioid prodrug framework in a pharmaceutical composition to attenuate enzymatically controlled release of phenolic opioids.
Treatment of pain using the described pharmaceutical compositions comprising phenolic opioid prodrugs together with trypsin inhibitors.
Thwarting drug abuse via trypsin-mediated release inhibition.
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