Compositions Comprising Enzyme-Cleavable Prodrugs of Active Agents and Inhibitors Thereof
AssigneeSignature Therapeutics, Inc.
InventorsThomas E. Jenkins, Craig O. Husfeld, Julie D. Seroogy, Jonathan W. Wray
Life of this patent
Estimating the term…
Abstract
The present disclosure provides pharmaceutical compositions, and their methods of use, where the pharmaceutical compositions comprise a prodrug that provides enzymatically-controlled release of a drug and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the drug from the prodrug so as to attenuate enzymatic cleavage of the prodrug. The disclosure provides pharmaceutical compositions which comprise an enzyme inhibitor and a prodrug that contains an enzyme-cleavable moiety that, when cleaved, facilitates release of the drug.
Claims65
A composition comprising:
- a prodrug comprising a drug covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by a GI enzyme mediates release of the drug;
- and
- a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically-controlled release of the drug from the prodrug following ingestion of the composition.
A method of making a dose unit, the method comprising:
- combining in a dose unit:
- a prodrug comprising a drug covalently bound to a promoiety cleavable by a GI enzyme, wherein cleavage of the promoiety by the enzyme mediates release of the drug from the prodrug;
- and
- a GI enzyme inhibitor that interacts with the enzyme that mediates enzymatically-controlled release of the drug from the prodrug;
- wherein the prodrug and GI enzyme inhibitor are present in the dose unit in an amount effective to attenuate release of the drug from the prodrug such that ingestion of multiples of dose units by a patient does not provide a proportional release of drug.
A method for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
- combining a prodrug, a GI enzyme inhibitor, and GI enzyme in a reaction mixture, wherein the prodrug comprises a drug covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the enzyme mediates release of the drug;
- and
- detecting prodrug conversion,
- wherein a decrease in prodrug conversion in the presence of the GI enzyme inhibitor as compared to prodrug conversion in the absence of the GI enzyme inhibitor indicates the prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.
A method for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
- administering to an animal a prodrug and a GI enzyme inhibitor, wherein the prodrug comprises a drug covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the enzyme mediates release of the drug;
- and
- detecting prodrug conversion, wherein a decrease in drug conversion in the presence of the GI enzyme inhibitor as compared to drug conversion in the absence of the GI enzyme inhibitor indicates the prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.
A method for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
- administering to an animal tissue a prodrug and a GI enzyme inhibitor, wherein the prodrug comprises a drug covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the enzyme mediates release of the drug;
- and
- detecting prodrug conversion, wherein a decrease in prodrug conversion in the presence of the GI enzyme inhibitor as compared to prodrug conversion in the absence of the GI enzyme inhibitor indicates the prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.
Dependencies are inferred from the claim text.