Pharmaceutical compositions with attenuated release of phenolic opioids
AssigneeSignature Therapeutics, Inc.
InventorsThomas E. Jenkins, Julie D. Seroogy, Jonathan W. Wray
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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.
Claims54
A pharmaceutical composition, which comprises a trypsin inhibitor and a compound of general formula (I)
- X—C(O)—NR1—(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5) (I)
- or a pharmaceutically acceptable salt thereof, in which:
- X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR1—(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5);
- R1 represents a (1-4C)alkyl group;
- R2 and R3 each independently represents a hydrogen atom or a (1-4C)alkyl group;
- n represents 2 or 3;
- R4 represents —CH2CH2CH2NH(C═NH)NH2 or —CH2CH2CH2CH2NH2, the configuration of the carbon atom to which R4 is attached corresponding with that in an L-amino acid;
- and
- R5 represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
A pharmaceutical composition, which comprises a trypsin inhibitor and a compound of general formula (II):
- X—C(O)—NR1—(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5) (II)
- or a pharmaceutically acceptable salt thereof, in which:
- X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR1—(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5);
- R1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
- each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
- each R3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
- or R2 and R3 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R2 or R3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
- n represents an integer from 2 to 4;
- R4 represents —CH2CH2CH2NH(C═NH)NH2 or —CH2CH2CH2CH2NH2, the configuration of the carbon atom to which R4 is attached corresponding with that in an L-amino acid;
- and
- R5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
A pharmaceutical composition comprising:
- a phenolic opioid prodrug comprising a trypsin-labile moiety that provides enzymatically-controlled release of a phenolic opioid, and
- a trypsin inhibitor that mediates the enzymatically-controlled release of the phenolic opioid from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
A method for reducing drug abuse potential of a composition containing a phenolic opioid prodrug, the method comprising:
- combining a phenolic opioid prodrug comprising a trypsin-labile moiety that provides enzymatically-controlled release of a phenolic opioid with a trypsin inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the phenolic opioid from the prodrug,
- wherein the trypsin inhibitor reduces the ability of a user to release a phenolic opioid from the phenolic opioid prodrug by addition of the enzyme.
Dependencies are inferred from the claim text.