# US 9,040,032 B2 · Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof

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- Number: US 9,040,032 B2
- Document ID: US9040032B2
- Status: Granted
- Kind: B2
- Application number: 13/686,725
- Filed: 2012-11-27
- Published: 2013-08-15
- Granted: 2015-05-26
- Earliest claimed: 2010-04-21
- Assignees: Signature Therapeutics, Inc.
- Applicants: Signature Therapeutics, Inc.
- Inventors: Thomas E. Jenkins; Craig O. Husfeld; Julie D. Seroogy; Jonathan W. Wray
- Web page: https://patentgrep.com/patent/US9040032B2

## CPC

- A61K 47/555: {pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells}
- A61K 9/51: Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)}
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- C07D 489/02: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
- C07D 489/08: Oxygen atom
- C12Q 1/37: involving peptidase or proteinase
- G01N 33/5088: {of vertebrates}
- G01N 33/9486: {Analgesics, e.g. opiates, aspirine}
- G01N 2333/976: Trypsin; Chymotrypsin
- G01N 2500/00: Screening for compounds of potential therapeutic value
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Pharmaceutical compositions and their methods of use are provided, where the pharmaceutical compositions comprise an opioid prodrug that provides enzymatically-controlled release of an opioid, and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the opioid from the opioid prodrug so as to attenuate enzymatic cleavage of the opioid prodrug.

## Claims

### Claim 1

A composition comprising:
an opioid prodrug comprising a ketone-containing opioid covalently bound to a promoiety comprising a GI enzyme-cleavable moiety wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to the GI enzyme-cleavable moiety, and wherein cleavage of the GI enzyme-cleavable moiety by a GI enzyme mediates release of the opioid; and
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 2 (depends on 1)

A composition comprising:
a container suitable for containing a composition for administration to a patient; and
a dose unit comprising the composition of claim 1 disposed within the container.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the composition is a dose unit having a total weight of from 1 microgram to 2 grams.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the composition has a combined weight of opioid prodrug and GI enzyme inhibitor of from 0.1% to 99% per gram of the composition.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(Ia):
wherein:
Ra is hydrogen or hydroxyl;
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 R1 or R2 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 thereof.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(Ib):
wherein:
Ra is hydrogen or hydroxyl;
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 or substituted cycloalkyl group, or two R1 or R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl 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 thereof.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(II):
wherein:
Ra is hydrogen or hydroxyl;
R5 is selected from (1-6C)alkyl, (1-6C) substituted alkyl, —(CH2)q(C6H4)—COOH, —(CH2)q(C6H4)—COOCH3, and —(CH2)q(C6H4)—COOCH2CH3, where q is an integer from one to 10;
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 or substituted cycloalkyl group, or two R1 or R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
n is 2 or 3;
R3 is hydrogen;
R4 is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or a residue of an N-acyl derivative of any of said amino acids; or a residue of a peptide composed of at least two L-amino acid residues selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or a residue of an N-acyl derivative thereof.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is 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 thereof.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(IIIb):
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 or substituted cycloalkyl group, or two R1 or R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl 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 thereof.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(IV):
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 (1-6C)alkyl, (1-6C) substituted alkyl, —(CH2)q(C6H4)—COOH, —(CH2)q(C6H4)—COOCH3, and —(CH2)q(C6H4)—COOCH2CH3, where q is an integer from one to 10;
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 or substituted cycloalkyl group, or two R1 or R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
n is 2 or 3;
R3 is hydrogen;
R4 is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or a residue of an N-acyl derivative of any of said amino acids; or a residue of a peptide composed of at least two L-amino acid residues selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or a residue of an N-acyl derivative thereof;
or a salt, hydrate or solvate thereof.

### Claim 11 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(Va):
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 R1 or R2 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;
R4 is a trypsin-cleavable moiety;
or a salt, hydrate or solvate thereof.

### Claim 12 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(Vb):
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 R1 or R2 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;
R4 is a GI enzyme-cleavable moiety;
or a salt, hydrate or solvate thereof.

### Claim 13 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(VI):
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)—Y—(C(R1)(R2))n—NR3R4;
Y is —NR5—, —O— or —S—;
n is an integer from 1 to 4;
each R1, R2, R3 and R5 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R1 and R2 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group;
R4 is
each R6 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R6 and R7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
R7 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
p is an integer from 1 to 10;
each W is independently —NR8—, —O— or —S—; and
each R8 is independently hydrogen, alkyl, substituted alkyl, aryl or 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.

### Claim 14 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(VII):
or salts, solvates or hydrates thereof 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 —(CR12R13)—Y—Z—R11;
R12 and R13 are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
Y is aryl, heteroaryl or arylaryl optionally substituted with one or more —F, —Cl, —Br, —I, —R14, —O−, —OR14, —SR14, —S−, —NR14R15, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, —S(O)2O−, —S(O)2OH, —S(O)2R14, —OS(O2)O−, —OS(O)2R14, —P(O)(O−)2, —P(O)(OR14)(O−), —OP(O)(OR14)(OR15), —C(O)R14, —C(S)R14, —C(O)OR14, —C(O)NR14R15, —C(O)O−, —C(S)OR14, —NR16C(O)NR14R15, —NR16C(S)NR14R15, —NR17C(NR16)NR15R14 or —C(NR16)NR15R14;
R14, R15, R16 and R17 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R14 and R15 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
Z is N(R18)—, —O— or —S—;
R18 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or
each W is independently —NR20—, —O— or —S—;
each R19 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R19 and R20 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
each R20 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R20 and R21 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
R21 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
n is an integer from 0 to 5;
R11 is
each U is independently —NR23—, —O— or —S—;
each R22 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R22 and R23 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
each R23 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or optionally, R23 and R24 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
R24 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and
o is an integer from 1 to 100;
provided that Z is oriented para or ortho to X—(CR12R13)— and that both R18 and R11 are not hydrogen.

### Claim 15 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(VIII):
or salts, solvates or hydrates thereof 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 —(CR12R13)—Y—Z—R11;
R12 and R13 are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
Rk26 are each independently selected from the group consisting of one or more of —F, —Cl, —Br, —I, —R14, —O−, —OR14, —SR14, —S−, —NR14R15, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N 3, —S(O)2O−, —S(O)2OH, —S(O)2R14, —OS(O)2R14, —P(O)(O−)2, —P(O)(OR14)(O−), —OP(O)(OR14)(OR15), —C(O)R14, —C(S)R14, —C(O)OR14, —C(O)NR14R15, —C(O)O−, —C(S)OR14, —NR16C(O)N R14R15, —NR16C(S)NR14R15, —NR17C(NR16)NR15R14 and —C(NR16)NR15R14, and k is 0, 1, 2, 3, or 4;
R14, R15, R16 and R17 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R4 and R5 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
R18 is hydrogen or methyl;
R22 is a side chain of an amino acid or a derivative of a side chain of an amino acid;
each U is independently —NR23—, —O— or —S—;
each R23 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R23 and R24 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and
R24 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and
o is an integer from 1 to 100.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the opioid prodrug is a compound of formula KC-(IX):
X—C(R31a)(R32a))—Ar—Z—C(O)—Y—(C(R31)(R32))n—N—(R33)(R34)A- (KC-(IX))
or a salt, hydrate or solvate thereof 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(R31a)(R32a)—Ar—Z—C(O)—Y—(C(R31)(R32))n—N—(R33)(R34);
R31a and R32a are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
Ar is aryl, heteroaryl or arylaryl optionally substituted with one or more —F, —Cl, —Br, —I, —R34a, —O−, —OR34a, —SR34a, —S—, —NR34aR35a, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, —S(O)2O′, —S(O)2OH, —S(O)2R34a, —OS(O2)O″, —OS(O)2R34a, —P(0)(0″)2, —P(O)(OR34a)(O″), —OP(O)(OR34a)(OR35a), —C(0)R34a, —C(S)R34a, —C(O)OR34a, —C(O)NR34aR35a, —C(O)O; —C(S)OR34a, —NR36aC(O)NR34aR35a, —NR36aC(S)NR34aR35a, —NR37aC(NR36a)NR35aR34a or —C(NR36a)NR35aR34a, or tethered to a polymer;
R34a, R35a, R36a and R37a are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R34 and R35 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
Z is O, S or NH;
Y is —NR35—, —O— or —S—;
n is an integer from 1 to 10;
each R31, R32, R33 and R35 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R31 and R32 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R31 or R32 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
each R36 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R36 and R37 together with
the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
R37 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
p is an integer from 1 to 5;
each W is independently —NR38—, —O— or —S—;
each R38 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R36 and R38 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and
A′ represents an anion.

### Claim 17 (depends on 1)

A method to treat a patient comprising administering a pharmaceutical composition or dose unit comprising the composition of claim 1 to a patient in need thereof.

### Claim 18 (depends on 5)

The composition of claim 5, wherein R3 is hydrogen.

### Claim 19 (depends on 6)

The composition of claim 6, wherein R3 is hydrogen.

### Claim 20 (depends on 8)

The composition of claim 8, wherein R3 is hydrogen.

### Claim 21 (depends on 9)

The composition of claim 9, wherein R3 is hydrogen.

### Claim 22 (depends on 11)

The composition of claim 11, wherein X is hydrocodone or oxycodone.

### Claim 23 (depends on 11)

The composition of claim 11, wherein R5 is alkyl or substituted alkyl.

### Claim 24 (depends on 23)

The composition of claim 23, wherein R5 is ethyl or methyl.

### Claim 25 (depends on 23)

The composition of claim 23, wherein R5 is methyl.

### Claim 26 (depends on 11)

The composition of claim 11, wherein each R1 and R2 is independently selected from hydrogen, alkyl, substituted alkyl and aminoacyl.

### Claim 27 (depends on 26)

The composition of claim 26, wherein R1 and R2 are hydrogen.

### Claim 28 (depends on 26)

The composition of claim 26, wherein R1 and R2 which are on the same carbon are alkyl.

### Claim 29 (depends on 26)

The composition of claim 26, wherein R1 and R2 which are on the same carbon are methyl.

### Claim 30 (depends on 26)

The composition of claim 26, wherein the alkyl is methyl.

### Claim 31 (depends on 26)

The composition of claim 26, wherein the aminoacyl is —C(O)NR10aR10b, wherein each R10a and R10b is independently selected from hydrogen, alkyl, substituted alkyl, and acyl.

### Claim 32 (depends on 31)

The composition of claim 31, wherein R10a and R10b are methyl.

### Claim 33 (depends on 11)

The composition of claim 11, wherein each R4 is
p is 1 or 2;
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;
each W is —NR8—;
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; and
R7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl.

### Claim 34 (depends on 33)

The composition of claim 33, wherein p is 1 and wherein R6 is a side chain of an amino acid residue selected from lysine, arginine, homolysine, homoarginine, ornithine, arginine mimics, arginine homologues, arginine truncates, arginine with varying oxidation, lysine mimics, lysine homologues, lysine truncates, and lysine with varying oxidation states.

### Claim 35 (depends on 33)

The composition of claim 33, wherein p is 1 and wherein R6 is a side chain of an amino acid residue selected from L-lysine and L-arginine.

### Claim 36 (depends on 33)

The composition of claim 33, wherein p is 2, and wherein a first R6 is a side chain of an amino acid residue selected from lysine, arginine, homolysine, homoarginine, ornithine, arginine mimics, arginine homologues, arginine truncates, arginine with varying oxidation, lysine mimics, lysine homologues, lysine truncates, and lysine with varying oxidation states and a second R6 is a side chain of an amino acid residue selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or a residue of an N-acyl derivative thereof.

### Claim 37 (depends on 33)

The composition of claim 33, wherein each R6 is independently a side chain of an amino acid residue selected from glycine, L-lysine or L-arginine.

### Claim 38 (depends on 33)

The composition of claim 33, wherein a first R6 is a side chain of an amino acid residue selected from L-lysine or L-arginine and a second R6 is a side chain of glycine.

### Claim 39 (depends on 33)

The composition of claim 33, wherein each R8 is hydrogen.

### Claim 40 (depends on 33)

The composition of claim 33, wherein R7 is selected from hydrogen and acyl.

### Claim 41 (depends on 40)

The composition of claim 40, wherein R7 is selected from hydrogen, acetyl, benzoyl, malonyl, piperonyl and succinyl.

### Claim 42 (depends on 41)

The composition of claim 41, wherein R7 is acetyl or malonyl.

### Claim 43 (depends on 11)

The composition of claim 11, wherein the opioid prodrug is a compound selected from the group consisting of:

### Claim 44 (depends on 11)

The composition of claim 11, wherein:
X is hydrocodone;
R5 is methyl;
n is 2;
each R1 is independently selected from hydrogen and —C(O)NR10aR10b), wherein R10a and R10b are methyl;
each R2 is hydrogen;
R3 is hydrogen;
R4 is
wherein p is 2;
each R6 is independently hydrogen or —CH2CH2CH2NH(C═NH)NH2;
each W is —NR8—;
each R8 is hydrogen; and
R7 is malonyl or acetyl;
or a salt, hydrate or solvate thereof.

### Claim 45 (depends on 11)

The composition of claim 11, wherein:
X is hydrocodone;
R5 is methyl;
n is 2;
each R1 is independently selected from hydrogen and methyl;
each R2 is independently selected from hydrogen and methyl;
R3 is hydrogen;
R4 is
wherein p is 2;
each R6 is independently hydrogen or —CH2CH2CH2NH(C═NH)NH2;
each W is —NR8—;
each R8 is hydrogen; and
R7 is acetyl;
or a salt, hydrate or solvate thereof.

### Claim 46 (depends on 11)

The composition of claim 11, wherein:
X is oxycodone;
R5 is methyl;
n is 2;
each R1 is independently selected from hydrogen and —C(O)NR10aR10b, wherein R10a and R10b are —CH2C(O)OH;
each R2 is hydrogen;
R3 is hydrogen;
R4 is
wherein p is 2;
each R6 is independently hydrogen or —CH2CH2CH2NH(C═NH)NH2;
each W is —NR8—;
each R8 is hydrogen; and
R7 is acetyl;
or a salt, hydrate or solvate thereof.

### Claim 47 (depends on 11)

The composition of claim 11, wherein:
X is oxycodone;
R5 is methyl;
n is 3;
each R1 is independently selected from hydrogen and dimethyl;
each R2 is independently selected from hydrogen and dimethyl;
R3 is hydrogen;
R4 is
wherein p is 2;
each R6 is independently hydrogen or —CH2CH2CH2NH(C═NH)NH2;
each W is —NR8—;
each R8 is hydrogen; and
R7 is malonyl;
or a salt, hydrate or solvate thereof.

### Claim 48 (depends on 11)

The composition of claim 11, wherein:
X is oxycodone;
R5 is methyl;
n is 2;
each R1 is independently selected from hydrogen and —C(O)NR10aR10b, wherein R10a and R10b are methyl;
each R2 is hydrogen;
R3 is hydrogen;
R4 is
wherein p is 2;
each R6 is independently hydrogen or —CH2CH2CH2NH(C═NH)NH2;
each W is —NR8—;
each R8 is hydrogen; and
R7 is malonyl or acetyl;
or a salt, hydrate or solvate thereof.

### Claim 49 (depends on 39)

The composition of claim 39, wherein:
X is oxycodone;
R5 is methyl;
n is 2;
each R1 is independently selected from hydrogen and methyl;
each R2 is independently selected from hydrogen and methyl;
R3 is hydrogen;
R4 is
wherein p is 2;
each R6 is independently hydrogen or —CH2CH2CH2NH(C═NH)NH2;
each W is —NR8—;
each R8 is hydrogen; and
R7 is acetyl;
or a salt, hydrate or solvate thereof.

### Claim 50 (depends on 11)

The composition of claim 11, wherein:
X is hydrocodone;
R5 is methyl;
n is 2;
each R1 is independently selected from hydrogen and —C(O)NR10aR10b, wherein R10a and R10b are —CH2C(O)OH;
each R2 is hydrogen;
R3 is hydrogen;
R4 is
wherein p is 2;
each R6 is independently hydrogen or —CH2CH2CH2NH(C═NH)NH2;
each W is —NR8—;
each R8 is hydrogen; and
R7 is acetyl;
or a salt, hydrate or solvate thereof.

### Claim 51 (depends on 11)

The composition of claim 11, wherein:
X is hydrocodone;
R5 is methyl;
n is 3;
each R1 is independently selected from hydrogen and dimethyl;
each R2 is independently selected from hydrogen and dimethyl;
R3 is hydrogen;
R4 is
wherein p is 2;
each R6 is independently hydrogen or —CH2CH2CH2NH(C═NH)NH2;
each W is —NR8—;
each R8 is hydrogen; and
R7 is malonyl;
or a salt, hydrate or solvate thereof.