Compositions comprising enzyme-cleavable prodrugs and controlled release nafamostat and methods of use thereof

A composition comprising:

• an active agent prodrug selected from the group consisting of:
• 1) a compound of formula KC-(IIIa):
• wherein:
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)—NR5—(C(R1)(R2))n—NR3R4;
• R5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• or R1 and R2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R2 or R3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n is an integer from 2 to 4;
• R3 is hydrogen or (1-4C) alkyl;
• R4 is
• each R6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• each W is independently —NR8—, —O— or —S—;
• each R8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R6 and R8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• p is an integer from one to 100;
• and
• R7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• or a salt, hydrate or solvate;
• 2) a compound of formula PC-(I)
• or a pharmaceutically acceptable salt thereof, wherein:
• 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;
• and
• 3) a compound of formula AM-(I):
• wherein
• R1 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
• and
• R2 is an acyl, substituted acyl, or an N-acyl derivative of a peptide;
• or a salt, hydrate or solvate thereof;
• and
• an oral composition comprising nafamostat or a pharmaceutically acceptable salt thereof, wherein the composition comprises:
• an immediate release composition comprising nafamostat or pharmaceutically acceptable salt thereof, and
• a controlled release composition comprising nafamostat or a pharmaceutically acceptable salt thereof.