Compositions Comprising Enzyme-Cleavable Phenol-Modified Opioid Prodrugs and Inhibitors Thereof
AssigneeSignature Therapeutics, Inc.
InventorsThomas E. Jenkins, Craig O. Husfeld, 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 phenol-modified 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 phenol-modified opioid prodrug so as to modify enzymatic cleavage of the phenol-modified opioid prodrug.
Claims36
A composition comprising:
- a phenol-modified opioid prodrug comprising a phenolic opioid covalently bound to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of the phenolic opioid;
- and
- a trypsin inhibitor that interacts with the trypsin that mediates enzymatically-controlled release of the phenolic opioid from the phenol-modified opioid prodrug following ingestion of the composition.
(canceled)
A method of making a dose unit, the method comprising:
- combining in a dose unit:
- a phenol-modified opioid prodrug comprising a phenolic opioid covalently bound to a promoiety cleavable by trypsin, wherein cleavage of the promoiety by the trypsin mediates release of the phenolic opioid from the phenol-modified opioid prodrug;
- and
- a trypsin inhibitor that interacts with the trypsin that mediates enzymatically-controlled release of the phenolic opioid from the phenol-modified opioid prodrug;
- wherein the phenol-modified opioid prodrug and trypsin inhibitor are present in the dose unit in an amount effective to attenuate release of the phenolic opioid from the phenol-modified opioid prodrug such that ingestion of multiples of dose units by a patient does not provide a proportional release of phenolic opioid.
A method for identifying a phenol-modified opioid prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:
- combining a phenol-modified opioid prodrug, a trypsin inhibitor, and trypsin in a reaction mixture, wherein the phenol-modified opioid prodrug comprises a phenolic opioid covalently bound to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of the phenolic opioid;
- and
- detecting phenol-modified opioid prodrug conversion,
- wherein a decrease in phenol-modified opioid prodrug conversion in the presence of the trypsin inhibitor as compared to phenol-modified opioid prodrug conversion in the absence of the trypsin inhibitor indicates the phenol-modified opioid prodrug and trypsin inhibitor are suitable for formulation in a dose unit.
A method for identifying a phenol-modified opioid prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:
- administering to an animal a phenol-modified opioid prodrug and a trypsin inhibitor, wherein the phenol-modified opioid prodrug comprises a phenolic opioid covalently bound to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of the phenolic opioid;
- and
- detecting phenol-modified opioid prodrug conversion, wherein a decrease in phenolic opioid conversion in the presence of the trypsin inhibitor as compared to phenolic opioid conversion in the absence of the trypsin inhibitor indicates the phenol-modified opioid prodrug and trypsin inhibitor are suitable for formulation in a dose unit.
A method for identifying a phenol-modified opioid prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:
- administering to an animal tissue a phenol-modified opioid prodrug and a trypsin inhibitor, wherein the phenol-modified opioid prodrug comprises a phenolic opioid covalently bound to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of the phenolic opioid;
- and
- detecting phenol-modified opioid prodrug conversion, wherein a decrease in phenol-modified opioid prodrug conversion in the presence of the trypsin inhibitor as compared to phenol-modified opioid prodrug conversion in the absence of the trypsin inhibitor indicates the phenol-modified opioid prodrug and trypsin inhibitor are suitable for formulation in a dose unit.
[2-(2-Malonyl-5-guanidino-pentanoylamino)-ethyl]-ethyl-carbamic acid hydromorphone ester (Compound PC-6), or acceptable salt, solvate, or hydrate thereof.
Dependencies are inferred from the claim text.