Compositions Comprising Enzyme-Cleavable Phenol-Modified Opioid Prodrugs and Inhibitors Thereof
Pharmaceutical compositions and their methods of use are provided, where the pharmaceutical compositions comprise a phenol-modified opioid prodrug that provides enzymatically-controlled release of a phenolic opioid, and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the phenolic opioid from the phenol-modified opioid prodrug so as to modify enzymatic cleavage of the phenol-modified opioid prodrug.
1 . A composition comprising:
a phenol-modified opioid prodrug comprising a phenolic opioid covalently bound to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of the phenolic opioid; and
a trypsin inhibitor that interacts with the trypsin that mediates enzymatically-controlled release of the phenolic opioid from the phenol-modified opioid prodrug following ingestion of the composition.
2 . A dose unit comprising the composition of claim 1 , wherein
the phenol-modified opioid prodrug and trypsin inhibitor are present in the dose unit in an amount effective to provide for a pre-selected pharmacokinetic (PK) profile following ingestion.
3 . The dose unit of claim 2 , wherein the pre-selected PK profile comprises at least one PK parameter value that is less than the PK parameter value of phenolic opioid released following ingestion of an equivalent dosage of phenol-modified opioid prodrug in the absence of inhibitor.
4 . The dose unit of claim 3 , wherein the PK parameter value is selected from a phenolic opioid Cmaxvalue, a phenolic opioid exposure value, and a (1/phenolic opioid Tmax) value.
5 . The dose unit of claim 2 , wherein the dose unit provides for a pre-selected PK profile following ingestion of at least two dose units.
6 . The dose unit of claim 5 , wherein the pre-selected PK profile is modified relative to the PK profile following ingestion of an equivalent dosage of phenol-modified opioid prodrug in the absence of inhibitor.
7 . The dose unit of claim 5 , wherein the dose unit provides that ingestion of an increasing number of the dose units provides for a linear PK profile.
8 . The dose unit of claim 5 , wherein the dose unit provides that ingestion of an increasing number of the dose units provides for a nonlinear PK profile.
9 . The dose unit of claim 5 , wherein the PK parameter value is selected from a phenolic opioid Cmaxvalue, a (1/phenolic opioid Tmax) value, and a phenolic opioid exposure value.
10 . 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.
11 . The composition of claim 1 , wherein the composition is a dose unit having a total weight of from 1 microgram to 2 grams.
12 . The composition of claim 1 , wherein the composition has a combined weight of phenol-modified opioid prodrug and trypsin inhibitor of from 0.1% to 99% per gram of the composition.
13 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(I)
X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 ) (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)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );
R 1 represents a (1-4C)alkyl group;
R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;
n represents 2 or 3;
R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and
R 5 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.
14 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(IIa):
X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 ) (PC-(IIa))
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)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );
R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 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 represents an integer from 2 to 4;
R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and
R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
15 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(IIb):
X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 ) (PC-(IIb))
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)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );
R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
n represents an integer from 2 to 4;
R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and
R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
16 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(III):
X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 ) (PC-(III))
or 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)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );
R 1 represents a (1-4C)alkyl group;
R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;
n represents 2 or 3;
R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and
R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
17 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(IV):
or pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or hydroxyl;
R b is oxo (═O) or hydroxyl;
the dashed line is a double bond or single bond;
R 1 represents a (1-4C)alkyl group;
R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;
n represents 2 or 3;
R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and
R 5 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.
18 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(Va):
or pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or hydroxyl;
R b is oxo (═O) or hydroxyl;
the dashed line is a double bond or single bond;
R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 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 represents an integer from 2 to 4;
R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and
R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
19 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(Vb):
or pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or hydroxyl;
R b is oxo (═O) or hydroxyl;
the dashed line is a double bond or single bond;
R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
n represents an integer from 2 to 4;
R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and
R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
20 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(VI):
or pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or hydroxyl;
R b is oxo (═O) or hydroxyl;
the dashed line is a double bond or single bond;
R 1 represents a (1-4C)alkyl group;
R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;
n represents 2 or 3;
R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and
R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
21 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(VII):
X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6 (PC-(VII))
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)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6 ;
R 1 represents a (1-4C)alkyl group;
R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;
n represents 2 or 3; and
R 6 is a trypsin-cleavable moiety.
22 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(VIII):
X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6 (PC-(VIII))
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)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6 ;
R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 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 represents an integer from 2 to 4; and
R 6 is a trypsin-cleavable moiety.
23 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(IX):
or pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or hydroxyl;
R b is oxo (═O) or hydroxyl;
the dashed line is a double bond or single bond;
R 1 represents a (1-4C)alkyl group;
R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group;
n represents 2 or 3; and
R 6 is a trypsin-cleavable moiety.
24 . The composition of claim 1 , wherein the phenol-modified opioid prodrug is a compound of formula PC-(X):
or pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or hydroxyl;
R b is oxo (═O) or hydroxyl;
the dashed line is a double bond or single bond;
R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 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 represents an integer from 2 to 4; and
R 6 is a trypsin-cleavable moiety.
25 . 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.
26 . A method of making a dose unit, the method comprising:
combining in a dose unit:
a phenol-modified opioid prodrug comprising a phenolic opioid covalently bound to a promoiety cleavable by trypsin, wherein cleavage of the promoiety by the trypsin mediates release of the phenolic opioid from the phenol-modified opioid prodrug; and
a trypsin inhibitor that interacts with the trypsin that mediates enzymatically-controlled release of the phenolic opioid from the phenol-modified opioid prodrug;
wherein the phenol-modified opioid prodrug and trypsin inhibitor are present in the dose unit in an amount effective to attenuate release of the phenolic opioid from the phenol-modified opioid prodrug such that ingestion of multiples of dose units by a patient does not provide a proportional release of phenolic opioid.
27 . A method of claim 26 , wherein said release of phenolic opioid is decreased compared to release of phenolic opioid by an equivalent dosage of prodrug in the absence of inhibitor.
28 . A method for identifying a phenol-modified opioid prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:
combining a phenol-modified opioid prodrug, a trypsin inhibitor, and trypsin in a reaction mixture, wherein the phenol-modified opioid prodrug comprises a phenolic opioid covalently bound to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of the phenolic opioid; and
detecting phenol-modified opioid prodrug conversion,
wherein a decrease in phenol-modified opioid prodrug conversion in the presence of the trypsin inhibitor as compared to phenol-modified opioid prodrug conversion in the absence of the trypsin inhibitor indicates the phenol-modified opioid prodrug and trypsin inhibitor are suitable for formulation in a dose unit.
29 . A method for identifying a phenol-modified opioid prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:
administering to an animal a phenol-modified opioid prodrug and a trypsin inhibitor, wherein the phenol-modified opioid prodrug comprises a phenolic opioid covalently bound to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of the phenolic opioid; and
detecting phenol-modified opioid prodrug conversion, wherein a decrease in phenolic opioid conversion in the presence of the trypsin inhibitor as compared to phenolic opioid conversion in the absence of the trypsin inhibitor indicates the phenol-modified opioid prodrug and trypsin inhibitor are suitable for formulation in a dose unit.
30 . The method of claim 29 , wherein said administering comprises administering to the animal increasing doses of inhibitor co-dosed with a selected fixed dose of phenol-modified opioid prodrug.
31 . The method of claim 29 , wherein said detecting facilitates identification of a dose of inhibitor and a dose of phenol-modified opioid prodrug that provides for a pre-selected pharmacokinetic (PK) profile.
32 . The method of claim 29 , wherein said method comprises an in vivo assay.
33 . The method of claim 29 , wherein said method comprises an ex vivo assay.
34 . A method for identifying a phenol-modified opioid prodrug and a trypsin inhibitor suitable for formulation in a dose unit, the method comprising:
administering to an animal tissue a phenol-modified opioid prodrug and a trypsin inhibitor, wherein the phenol-modified opioid prodrug comprises a phenolic opioid covalently bound to a promoiety comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety by trypsin mediates release of the phenolic opioid; and
detecting phenol-modified opioid prodrug conversion, wherein a decrease in phenol-modified opioid prodrug conversion in the presence of the trypsin inhibitor as compared to phenol-modified opioid prodrug conversion in the absence of the trypsin inhibitor indicates the phenol-modified opioid prodrug and trypsin inhibitor are suitable for formulation in a dose unit.