Compositions comprising enzyme-cleavable oxycodone prodrug
AssigneeSignature Therapeutics, Inc.
InventorsThomas E. Jenkins, Craig O. Husfeld
Life of this patent
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Abstract
The embodiments provide Compound KC-8, N-1-[3-(oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, or acceptable salts, solvates, and hydrates thereof. The present disclosure also provides compositions, and their methods of use, where the compositions comprise a prodrug, Compound KC-8, that provides controlled release of oxycodone. Such compositions can optionally provide a trypsin inhibitor that interacts with the enzyme that mediates the controlled release of oxycodone from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
Claims31
N-1-[3-(Oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, Compound KC-8, shown below:
- or acceptable salts, solvate, or hydrate thereof.
A composition comprising N-1-[3-(oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, Compound KC-8, shown below:
- or acceptable salts, solvate, or hydrate thereof.
A composition comprising a trypsin inhibitor and N-1-[3-(oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, Compound KC-8, shown below:
- or acceptable salts, solvate, or hydrate thereof.
A composition comprising:
- a prodrug comprising oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-8:
- (N-1-[3-(Oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, Compound KC-8, shown below:
- or acceptable salts, solvate, and hydrate thereof;
- and
- a trypsin inhibitor that interacts with the trypsin that mediates enzymatically-controlled release of oxycodone 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 oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-8;
- and
- a trypsin inhibitor that interacts with the trypsin that mediates enzymatically-controlled release of oxycodone from the prodrug;
- wherein the prodrug and trypsin inhibitor are present in the dose unit in an amount effective to attenuate release of oxycodone from the prodrug such that ingestion of multiples of dose units by a patient does not provide a proportional release of oxycodone.
A method for identifying a prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:
- combining a prodrug, a trypsin inhibitor, and trypsin in a reaction mixture, wherein the prodrug comprises oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-8;
- and
- detecting prodrug conversion,
- wherein a decrease in prodrug conversion in the presence of the trypsin inhibitor as compared to prodrug conversion in the absence of the trypsin inhibitor indicates the prodrug and trypsin inhibitor are suitable for formulation in a dose unit.
A method for identifying a prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:
- administering to an animal a prodrug and a trypsin inhibitor, wherein the prodrug comprises oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-8;
- and
- detecting prodrug conversion, wherein a decrease in oxycodone conversion in the presence of the trypsin inhibitor as compared to oxycodone conversion in the absence of the trypsin inhibitor indicates the prodrug and trypsin inhibitor are suitable for formulation in a dose unit.
A method for identifying a prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:
- administering to an animal tissue a prodrug and a trypsin inhibitor, wherein the prodrug comprises oxycodone covalently bound through the enolic oxygen to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of oxycodone, wherein the prodrug is Compound KC-8;
- and
- detecting prodrug conversion, wherein a decrease in prodrug conversion in the presence of the trypsin inhibitor as compared to prodrug conversion in the absence of the trypsin inhibitor indicates the prodrug and trypsin inhibitor are suitable for formulation in a dose unit.
Dependencies are inferred from the claim text.