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Publication Number
US-9095627-B2
Publication Date
2015-08-04
Expiration Date
Abstract
The embodiments provide prodrug compounds of Formulae I-XV. The present disclosure also provides compositions, and their methods of use, where the compositions comprise a prodrug compound of Formulae I-XV that provides controlled release of an opioid. Such compositions can optionally provide a trypsin inhibitor that interacts with the enzyme that mediates the controlled release of an opioid from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
Core Innovation
The invention relates to compositions and methods for treating or preventing pain in a patient in need thereof by administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula III or formula VI. The compounds are defined by variable structural features including X, where X is hydromorphone, morphine or oxymorphone, and by substituent and ring parameters constrained to specified selections and numeric ranges. The compounds may be provided as a salt, hydrate or solvate thereof.
A further aspect provides an opioid prodrug in which an opioid is covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, such that cleavage of the GI enzyme-cleavable moiety by a GI enzyme mediates release of the opioid. The method comprises administering an effective amount of a composition that includes the opioid prodrug of formula III or formula VI, together with a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically-controlled release of the opioid from the opioid prodrug following ingestion of the composition. The structural definitions further characterize the opioid prodrug within the claimed framework.
The document also describes phenolic, amide-modified, and related GI-enzyme-cleavable opioid prodrug architectures, with general structural formulae for phenolic opioid prodrugs, amide-modified opioid prodrugs, and an expanded scope across ketone, phenolic, and amide-containing opioids. Representative compound examples include KC-48 through KC-55, TP-5, and opioid substrates such as hydromorphone, morphine, oxymorphone, tapentadol, alfentanil, carfentanil, fentanyl, loperamide, remifentanil, and sufentanil.
Claims Coverage
Two independent claims are present. The claim set centers on administering a pharmaceutical composition containing structurally defined compounds of formula III or formula VI for treating or preventing pain, and on an opioid prodrug with GI enzyme-controlled release together with a GI enzyme inhibitor. Across the claims, the inventive features include defined opioid-associated structures, constrained substituent and ring parameters, and optional salt, hydrate, or solvate forms.
Pain treatment using formula III or formula VI compounds
A method of treating or preventing pain in a patient in need thereof by administering an effective amount of a composition comprising a pharmaceutically acceptable excipient and a compound of formula III or a compound of formula VI, wherein X is hydromorphone, morphine or oxymorphone and the variables are constrained by the recited selections for the A ring, Y, c, R1, R2, a, R3, R5, R6, b, and R7, including the conditional ring-size rules and optional salt, hydrate or solvate forms.
GI enzyme-cleavable opioid prodrug with GI enzyme inhibitor
A method of treating or preventing pain in a patient in need thereof by administering an effective amount of a composition comprising an opioid prodrug in which an opioid is 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 opioid; wherein the opioid prodrug is of formula III or formula VI with X selected from hydromorphone, morphine or oxymorphone and with the recited substituent and ring parameter constraints; and wherein the composition includes a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically-controlled release of the opioid from the opioid prodrug following ingestion of the composition.
Claim coverage centers on pain treatment via administering compositions containing compounds defined by formula III or formula VI with extensive structural parameter constraints. The narrower independent claim adds a GI enzyme-cleavable opioid prodrug mechanism and requires co-administration of a GI enzyme inhibitor interacting with the mediating GI enzyme.
Stated Advantages
Treating or preventing pain in a patient in need thereof.
Documented Applications
Treating or preventing pain in a patient in need thereof using a composition comprising a pharmaceutically acceptable excipient and a compound of formula III or formula VI.
Treating or preventing pain using an opioid prodrug in which cleavage of a GI enzyme-cleavable moiety mediates release of the opioid, together with a GI enzyme inhibitor that interacts with the GI enzyme after ingestion.
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